Neuropharmacology & Neurotherapeutics
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May. 14, 2026
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Sex hormones and the nervous system …
- Updated 12.01.2025
- Released 10.22.2010
- Expires For CME 12.01.2028
Sex hormones and the nervous system
Introduction
Overview
Estrogens, progestins, and androgens represent the three major classes of endogenous sex steroids. Prototypical hormones in each class are estradiol, progesterone, and testosterone, respectively. The prototypical hormones in each class include 17beta-estradiol, progesterone, and testosterone. Estetrol is a natural estrogen with important antioxidative activity.
Many neurologic conditions are triggered by hormonal imbalance changes associated with the menstrual cycle, pregnancy, menopause, and use of oral contraceptives. Besides their effects on reproduction, estrogens exert neuroprotective effects against development or progression of brain diseases. Thus, estrogens improve the negative aspects of aging and some age-associated diseases in affecting the nervous system, including hypertension. Advances in laboratory testing have increased the visibility of hormone-binding sites within the nervous system.
A more thorough understanding of the sex hormone-related neural function and dysfunction may permit rational hormonal and antihormonal therapies for many of the conditions.
The role of sex hormones in catamenial migraine, catamenial epilepsy, and cerebrovascular disease are the main subtopics discussed in this review of sex hormones and the nervous system.
Key points
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• Plasma sex hormones are secreted from ovaries, testes, and adrenal glands but may also be derived from enzyme-mediated conversions of prohormones in extraglandular tissues. | |
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• Sex hormones influence a broad spectrum of normal and abnormal neurologic functions. | |
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• The immune, endocrine, and nervous systems communicate with each other through a myriad of various molecules, including cytokines, hormones, and neurotransmitters. | |
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• Relationships between endogenous and exogenous sex hormones influence the development and progression of many neurologic conditions including migraine, stroke, and certain movement disorders like chorea, are well established. | |
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• The effects of sex steroids on neurologic function in health and disease constitute a rapidly developing area of basic and clinical neuroscience. | |
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• Fluctuating sex hormone levels also influence the expression of certain neuropsychiatric states and neuroendocrine disorders. |
Historical note and nomenclature
Steroids. A “steroid” is a biologically active four-ring organic compound with a specific chemical configuration. The steroid core structure is composed of 17 carbon atoms, bonded in four fused rings: three six-member cyclohexane rings (rings A-C) and one five-member cyclopentane ring (ring D).
Steroids vary by the functional groups attached to this 4-ring core and by the oxidation state of the rings. Steroids serve as important fluidity-altering components of cell membranes and as signaling molecules.
Steroid hormone. A “steroid hormone” is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: (1) corticosteroids (including mineralocorticoids), made in the adrenal cortex; and (2) sex steroids, primarily made in the gonads or placenta. So-called female sex hormones are progestogens and estrogens whereas male sex hormones are androgens. Despite the designations of “male” and “female” for classes of sex hormones, both sexes make some of each class, although the amounts differ across the sexes.
The biosynthesis of steroid hormones derives from cholesterol, a molecule with four linked rings and 27 carbons.
Cholesterol is first converted to a series of progestogens with 21 carbons (following the action of cholesterol side-chain cleavage enzyme). Progestogens can be converted by hydroxylation (at carbon 21) to mineralocorticoids or glucocorticoids (both with 21 carbons) or by an elimination reaction to androgens (with 19 carbons). Androgens can in turn be converted to estrogens (with 18 carbons) by the action of an aromatase enzyme that is located in estrogen-producing cells in the adrenal glands, ovaries, placenta, testicles, adipose (fat) tissue, and brain. The aromatase enzyme converts ring A to a monocyclic aromatic six-carbon ring.
Progestogen. “Progestogen” (also known as progestagen or gestagen) is a generic term for a class of steroid hormones that bind to and activate the progesterone receptor. Progestogens are named for their function in maintaining pregnancy (ie, progestational agents). All endogenous progestogens share a basic 21-carbon skeleton called a pregnane skeleton (C21) with ketone or hydroxyl groups at the C3 and C20 positions. Progesterone is the primary progestogen in the body, and it is produced primarily by the corpus luteum of the ovary and by the placenta. Progesterone levels in the blood vary significantly during the menstrual cycle.
“Progestins” are synthetic progestogens that are structural analogues of progesterone (259); examples include the 17α-hydroxyprogesterone derivative medroxyprogesterone acetate and the 19-nortestosterone derivative norethisterone. A progestogen is specifically added to estrogen regimens of postmenopausal hormone therapy when the uterus is still present because unopposed estrogen therapy promotes endometrial thickening and can increase the risk of uterine cancer whereas progestogen administration reduces this risk.
In women, progesterone helps regulate the menstrual cycle, maintain pregnancies, and prepare the mammary glands for lactation and breastfeeding following parturition.
The corpus luteum--a temporary endocrine gland that forms from the empty ovarian follicle after ovulation—becomes the main source of progesterone immediately after fertilization and implantation. After conception, the placenta forms and begins to secrete progesterone to supplement, and ultimately surpass, the progesterone already secreted by the corpus luteum. The high level of progesterone during pregnancy prevents other eggs from maturing and it also promotes changes in breast tissue to prepare for lactation. If fertilization does not occur, the corpus luteum breaks down, causing less progesterone to be produced; with progesterone levels dropping below those needed to maintain the uterine lining, it breaks away, resulting in menstrual bleeding.
Men also need progesterone to produce testosterone (progesterone is a metabolic intermediate in the biosynthesis of testosterone). In men progesterone also is necessary for spermiogenesis and sperm capacitation (ie, the physiological changes spermatozoa must undergo in order to have the ability to penetrate and fertilize an egg). In men, progesterone is produced by the adrenals and the testes.
Androgen. “Androgen” is a generic term for a class of natural or synthetic steroid hormones that regulate the development and maintenance of the male sexual phenotype by binding to androgen receptors. The androgen receptor (also known as NR3C4 or nuclear receptor subfamily 3, group C, member 4) binds to androgenic hormones in the cytoplasm and then translocates into the nucleus. The androgen receptor serves mainly as a DNA-binding transcription factor that regulates gene expression.
Androgens are present in both males and females, and they increase in boys and girls during puberty. The principal androgens are testosterone, dihydrotestosterone (DHT), and androstenedione.
Testosterone is the primary male sex hormone. Testosterone plays a key role in the development of male reproductive tissues (ie, testes and prostate) and secondary sexual characteristics (eg, increased muscle and bone mass and growth of body hair). Insufficient levels of testosterone in men may lead to frailty and bone loss.
Testosterone is an anabolic steroid, containing keto and hydroxyl groups at the 3 and 17 positions, respectively. In men the vast majority of testosterone (greater than 95%) is produced by the Leydig cells in the testes, with adrenal gland production accounting for most of the remainder; in women, testosterone is synthesized in far smaller total quantities by the adrenal glands, thecal cells of the ovaries, and, during pregnancy, by the placenta. Men have testosterone levels about seven to eight times greater than those in women. Testosterone is supplied to target tissues via the blood, where much of it is transported bound to a specific plasma protein, sex hormone-binding globulin. In target tissues, testosterone binds to and activates the androgen receptor. Testosterone is converted in the liver to inactive metabolites.
In males, androgens regulate the embryological development of the primary male sex organs and the pubertal development of male secondary sex characteristics. In particular, dihydrotestosterone causes differentiation of the penis, scrotum, and prostate in utero whereas in adulthood dihydrotestosterone contributes to balding, prostate growth, and sebaceous gland activity. In females, androgens are responsible for pubic and body hair growth and contribute to libido and sexual arousal.
Androgens are also used as medications, for example, in androgen replacement therapy (also known as testosterone replacement therapy) in cisgender men to counteract the effects of male hypogonadism, in hormone therapy in transgender men (female-to-male), and in anabolic-androgenic steroids (a category that includes both natural androgens as well as synthetic androgens) to stimulate muscle growth and appetite, induce male puberty, and treat chronic wasting conditions such as cancer and AIDS. Anabolic-androgenic steroids are also frequently used as performance-enhancing drugs in sports; such ergogenic use of anabolic-androgenic steroids (“doping”) is controversial because of the associated adverse health effects and the unfair advantage this provides in physical competitions. Consequently, use of anabolic-androgenic steroids is banned by most major sporting bodies.
Estrogen. “Estrogen” is a generic term for a class of steroid hormones that are important for sexual and reproductive development in women. The word “estrogen” (or “oestrogen”) was derived in the 1920s from the words "estros" (or "oestros," a periodic state of sexual activity in female mammals) and “genos” (ie, generating).
There are three primary estrogens in the human body, varying by the number of hydroxyl groups, from 1 to 4: estrone (E1), estradiol (E2), estriol (E3), and estetrol (E4).
Estradiol is the most potent of these and is also the most prevalent in non-pregnant females during their reproductive years.
In contrast, levels of estriol in nonpregnant women are almost undetectable, but during pregnancy estriol is synthesized in very high quantities by the placenta and is then the most produced estrogen in the body.
Estetrol is produced only during pregnancy by the human fetal liver; estetrol has important antioxidative activity and in animal models of neonatal hypoxic-ischemic encephalopathy was shown to enhance cell proliferation in primary hippocampal neuronal cell cultures in vitro and to decrease early gray matter loss and promote neuro- and angiogenesis in vivo (275).
In postmenopausal women estrone becomes the primary form of estrogen in the body.
Estradiol levels in the blood vary significantly during the menstrual cycle.
Circulating estrogens are bound to albumin or sex hormone-binding globulin. Like all steroid hormones, estrogens readily diffuse across the cell membrane; once inside the cell, they bind to and activate estrogen receptors in the cell nucleus of target tissues. The estrogen receptor is a dimeric nuclear protein. Like the androgen receptor, the estrogen receptor serves mainly as a DNA-binding transcription factor that regulates gene expression. The estrogen-receptor complex binds to specific DNA sequences called a “hormone response element” to activate the transcription of target genes. The estrogen receptor is expressed in specific tissues, including the ovary, uterus, and breast. Estrogens also bind to and activate rapid-signaling membrane estrogen receptors.
Estrogens are metabolized primarily in the liver via hydroxylation by cytochrome P450 enzymes and via conjugation by estrogen sulfotransferases (sulfation) and UDP-glucuronyltransferases (glucuronidation). In addition, estradiol (E2) is dehydrogenated by 17β-hydroxysteroid dehydrogenase into the much less potent estrogen estrone (E1). Estrogens are excreted primarily by the kidneys as conjugates via the urine.
Estrogens are frequently used as medications, for instance in postmenopausal hormone therapy and hormonal birth control.
In women, estrogens are responsible for the pubertal development of female secondary sexual characteristics including breast development, widening of the hips, and female fat distribution. In addition, estrogens are responsible for maturation and maintenance of the vagina and uterus and for maturation of ovarian follicles. In men, estrogens help regulate the maturation of sperm and may be necessary for a healthy libido.
The hypothalamic-pituitary-gonadal axis. The hypothalamic-pituitary-gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. This is a hierarchical system with multilevel negative feedback. Communication within the axis is accomplished by an array of hormones.
Gonadotropin-releasing hormone. Gonadotropin-releasing hormone (GnRH), as the name suggests, is a releasing hormone responsible for the release of gonadotropins (ie, glycoprotein polypeptide hormones). Gonadotropin-releasing hormone initiates activation of the reproductive axis by causing the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. In women, luteinizing hormone and follicle-stimulating hormone act on the ovaries to release estrogen and progesterone, whereas in men luteinizing hormone and follicle-stimulating hormone act on the testes to release testosterone.
The testosterone produced by the testes actually provides negative feedback to both the hypothalamus and pituitary gland, although some of the direct effect of testosterone at the pituitary level in men is mediated by estradiol (E2), presumably from conversion of testosterone (23).
Kisspeptin is a ligand for G protein-coupled receptor 54 (GPR54; aka Kiss1R) (193). Binding of kisspeptin to its cognate in gonadotropin-releasing hormone neurons within the arcuate nucleus of the hypothalamus stimulates release of the peptide hormone gonadotropin-releasing hormone (226). Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone at puberty (253). The activity of kisspeptin neurons is modulated by sex steroids and other regulatory factors (12).
Luteinizing hormone. Luteinizing hormone is a heterodimeric glycoprotein that is synthesized and secreted by gonadotropic cells in the anterior pituitary gland. In females, an acute rise of luteinizing hormone ("LH surge") triggers ovulation and development of the corpus luteum. In males, where luteinizing hormone had also been called interstitial cell-stimulating hormone, it stimulates Leydig cell production of testosterone. Luteinizing hormone levels in the blood vary significantly during the menstrual cycle.
Leutenizing hormone levels in the blood during the menstrual cycle
Leutenizing hormone levels vary considerably throughout the menstrual cycle, peaking just before ovulation. (Source: Häggström M. Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone d...
Follicle-stimulating hormone. Like luteinizing hormone, follicle-stimulating hormone is a heterodimeric glycoprotein that is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland. Follicle-stimulating hormone regulates pubertal maturation and the reproductive processes of the body. Follicle-stimulating hormone levels in the blood vary significantly during the menstrual cycle.
Follicle-stimulating hormone levels in the blood during the menstrual cycle
Follicle-stimulating hormone levels vary considerably throughout the menstrual cycle, peaking at ovulation. (Source: Häggström M. Reference ranges for estradiol, progesterone, luteinizing hormone and follicle-stimulating hormone d...
In both females and males, follicle-stimulating hormone stimulates the maturation of primordial germ cells.
In females, follicle-stimulating hormone initiates follicular growth, specifically affecting granulosa cells (or follicular cell), somatic cells that are closely associated with the developing oocyte in the ovary. With the concomitant rise in inhibin B, follicle-stimulating hormone levels then decline in the late follicular phase, allowing only the most advanced follicle to proceed to ovulation. At the end of the luteal phase, there is a slight rise in follicle-stimulating hormone that helps initiate the next ovulatory cycle. In contrast, in males, follicle-stimulating hormone activation of Sertoli cells sustains spermatogenesis and stimulates inhibin B secretion. Follicle-stimulating hormone induces Sertoli cells to secrete androgen-binding proteins, regulated by inhibin's negative feedback mechanism on the anterior pituitary.
The menstrual cycle. The menstrual cycle is a cyclic series of anatomical and physiological changes a woman's body goes through in preparation for a possible pregnancy. The first day of menstruation is considered day 1 and the preceding day is considered day −1; note that by convention there is no day 0. Cycle length varies from 24 to 38 days. Cycle length also changes between menarche (ie, when periods first start during puberty) and menopause (ie, when periods stop permanently).
The menstrual cycle can be considered as comprised of two linked cycles in different organs: one happening in the ovaries and the other in the uterus. Each cycle has several phases.
Table 1. Phases of the Linked Ovarian and Uterine Subcycles of the Menstrual Cycle
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Cycle |
Preovulation |
Ovulation |
Postovulation | |
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Ovarian |
Follicular phase |
Luteal phase | ||
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Uterine |
Menstruation (a “period”) |
Proliferative phase |
Secretory phase |
The ovarian cycle begins with the development of a dominant follicle (under the influence of follicle-stimulating hormone), which produces estrogen as it grows. This follicular phase generally lasts from 10 to 22 days. Estrogen peaks just before ovulation, precipitating a spike in luteinizing hormone, which in turn triggers ovulation. At ovulation, the dominant follicle releases an oocyte from the ovary into the fallopian tube; this generally occurs about midway through the cycle, or about 13 to 15 days before the next period. In the ensuing luteal phase, the dominant follicle (now sans oocyte) transforms into a corpus luteum, a transitory endocrine organ that begins to produce progesterone and estrogen. If fertilization does not occur, the corpus luteum starts to degenerate between 9 and 11 days after ovulation, causing progesterone and estrogen levels to fall. Consequently, in the absence of fertilization, progesterone levels peak about halfway through this phase. The luteal phase typically lasts about 14 days but can range from 9 and 16 days.
The simultaneously occurring uterine cycle begins with menstruation with shedding of endometrium and blood through the cervix and vagina (typically 5 or 6 days but can be up to 8 days). Menstruation is triggered by the dropping progesterone and estrogen levels in the final phase of the ovarian cycle. Menstruation is followed by estrogen-induced proliferative phase with reproliferation of the uterine lining in preparation for possible pregnancy. After ovulation the uterus enters a secretory phase, when the endometrium begins secreting prostaglandins. Levels of prostaglandins F2α (PGF2α) and E2 (PGE2) rise during this phase. If pregnancy does not occur, progesterone and estrogen levels fall causing the endometrium to break down, while the prostaglandins cause uterine muscle to contract and uterine blood vessels to constrict, helping to induce menstruation. If pregnancy does occur, prostaglandin production is inhibited to allow fetal development to proceed, and the placenta begins producing hormones.
Pregnancy and puerperium. During the first stage of pregnancy, the trophoblast releases human chorionic gonadotropin, which enables the corpus luteum to continue producing estrogen and progesterone until the placenta develops. The placenta subsequently produces most of estrogen and progesterone necessary to sustain the pregnancy. Maternal serum levels of estradiol and progesterone begin to rise during the 6th to 8th week of pregnancy and gradually increase to their highest levels during the third trimester. By the third trimester, serum estradiol levels are 30 to 40 times higher and progesterone levels are 20 times higher than their peak levels during the menstrual cycle. Hormone levels drop sharply to the pre-pregnancy state during the puerperium (ie, from delivery to 6 weeks postpartum).
Menopause. Menopause marks the end of a woman’s reproductive years, when menstrual periods have stopped and when the ovaries no longer produce high levels of sex hormones. A corollary is that during menopause sex hormone levels no longer oscillate.
Estrogen-binding neurons are located in the preoptic area, medial basal hypothalamus, medial amygdala, and circumventricular organs. In addition, estrogen-binding neurons also reside, to a minimal extent, in the basal forebrain, the hippocampus, in several thalamic nuclei, sensory regions of the brainstem and spinal cord, and the neonatal neocortex (76; 68). The presence of estradiol receptors in hippocampus and hypothalamus suggests the possibility of direct effects of estradiol on brain cells. Successful neuroprotection produced by estradiol in hypertensive rats encourages treatment with non-feminizing estrogens and estrogen receptor modulators for age-associated diseases (71). Increase in sympathetic nerve activity is one of the crucial components involved in the development of hypertension in both men and women. Brain regions important for the regulation of sympathetic nerve activity have also been implicated in mechanisms underlying risk factors for hypertension such as obesity, stress, and inflammation. Further understandings of the mechanisms by which estrogen acts at these sites will be important areas to focus on for newer medications treating hypertension (115).
Sex hormones have both organizational and activational effects. Organizational effects refer to differentiation of neural circuitry from exposure to sex steroids during brain development in an irreversible fashion. Activational effects refer to reversible neurophysiological change by gonadal hormones on the mature nervous system.
During the neonatal and peripubertal periods, estrogens and aromatizable androgens induce trophic changes in the rodent hypothalamus, whereas in later life, estrogens accelerate aging-related changes in the endocrine hypothalamus that may contribute to the onset of reproductive senescence. These interactions are essential for regulation of the brain-pituitary-gonadal axis and for the establishment of normal patterns of sexual, cognitive, and autonomic behaviors at various phases (menstrual cycle, pregnancy, and menopause) (268; 97).
The neuroprotective and therapeutic effects of estetrol have been reviewed before and after hypoxic-ischemic encephalopathy (275). Estetrol has been shown to enhance cell proliferation in primary hippocampal neuronal cell cultures in vitro and promotes neuro- and angiogenesis in vivo.
Clinical manifestations
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• There is a well-established relationship between migraine and hormonal fluctuations in women. | |
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• The peak prevalence of migraine occurs in women of reproductive age. | |
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• Hormonal replacement with estrogen can exacerbate migraine and so can oral contraceptives. | |
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• The frequency or severity of migraine attacks often diminishes with gestation, particularly in patients whose headaches are linked to the menstrual cycle. | |
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• Migraine generally improves during pregnancy, particularly for women with migraine without aura. | |
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• After childbirth, the recurrence rate of migraine attacks increases, especially during the first month, and some women may have a particularly intense migraine shortly after delivery because of the precipitous decrease in estradiol levels. | |
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• Premenstrual migraines regularly occur during or after the time when the female hormones estrogen and progesterone drop to their lowest levels. | |
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• Menstrual-related migraine should be suspected in females whose migraine occurs predominantly between 2 days before and 3 days after the start of menstruation in at least two of three consecutive menstrual cycles. | |
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• Epilepsy may worsen around the time of ovulation or premenstrually (catamenial epilepsy) and during pregnancy. | |
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• Catamenial epilepsy is the subset of epilepsy that includes women whose seizures are exacerbated by their menstrual cycle. In such women, seizures correlate positively with mean estrogen/progesterone ratios and negatively with plasma progesterone levels. | |
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• The use of hormone replacement therapy after menopause produces an increase in seizure frequency and severity in women with a history of catamenial epilepsy. |
Sex hormones play an important role in a number of various neurologic disorders and diseases including headaches, cerebrovascular disease, seizures, movement disorders, brain malignancies, multiple sclerosis and other neuroimmunologic disorders, dementia, neuropsychiatric disorders, sleep disorders, catamenial sciatica, myotonic dystrophy, growth-hormone insufficiency, acromegaly, and porphyria.
Migraine. There is a well-established relationship between migraine and hormonal fluctuations in women.
The peak prevalence of migraine occurs in women of reproductive age (43). Not only are women much more likely to have migraine than men, but women have a higher burden of migraine-related symptoms and disability than men (43; 02) and the frequency and character of the headaches often change at periods of altered sex hormone levels, including menarche, menses, pregnancy, and menopause.
Hormonal replacement with estrogen can exacerbate migraine and so can oral contraceptives. Women often can precipitate new-onset migraine, exacerbate existing migraine, or exacerbation of, or change the character of migraine when taking oral contraceptives (247).
The frequency or severity of migraine attacks often diminishes with gestation, particularly in patients whose headaches are linked to the menstrual cycle (57). Migraine generally improves during pregnancy, particularly for women with migraine without aura (295; 187; 235; 190; 102; 124; 90; 09). The relative hormonal stability in pregnancy has been assumed to be the basis for the improvement in headache. Migraine may also first occur during pregnancy (217); migraine developing during pregnancy may indicate an underlying structural or functional disorder (295). After childbirth, the recurrence rate of migraine attacks increases, especially during the first month (236; 145; 124; 09), and some women may have a particularly intense migraine shortly after delivery because of the precipitous decrease in estradiol levels (233; 90). Compared to pregnancy, there is a postpartum increase in the mean intensity and duration of headaches, as well as in the mean number of analgesics used (235; 145). Some (235; 124; 09), but not all (145) studies report that breastfeeding exerts a protective effect against the reappearance of migraine.
Menstrual migraine (menstrually associated migraine, menstrually related migraine, menstruation-related migraine, catamenial migraine). Migraine often has a temporal relationship with menstruation. Premenstrual migraines regularly occur during or after the time when the female hormones estrogen and progesterone drop to their lowest levels.
In The International Classification of Headache Disorders 3rd edition (ICHD-3) of the International Headache Society includes criteria for “A1.1.1 Pure menstrual migraine,” “A1.1.2 Menstruation-related migraine,” “A1.2.0.1 Pure menstrual migraine with aura,” and “A1.2.0.2 Menstruation-related migraine with aura,” but in an appendix because of uncertainty over whether they should be regarded as separate entities (116). Note that for the purposes of ICHD-3, menstruation is endometrial bleeding resulting either from the normal menstrual cycle or from the withdrawal of exogenous progestogens, as in the use of combined oral contraceptives or cyclical hormone replacement therapy. Menstruation-related migraine without aura (A1.1.2) is characterized by attacks, in a menstruating woman, fulfilling criteria for migraine without aura and occurring on days −2 to +3 of menstruation in at least two of three menstrual cycles, and additionally at other times of the cycle. Pure menstrual migraine without aura (A1.1.1) is similar to menstruation-related migraine without aura (A1.1.2), but headaches occur only perimenstrually and at no other times of the cycle. A parallel arrangement applies for pure menstrual migraine with aura (A1.2.0.1) and menstruation-related migraine with aura (A1.2.0.2). There is no consensus on whether menstrual migraine attacks should be defined as starting instead of occurring on day 1 ± 2 of menstruation (283; 54).
Modifications of the ICHD-3 criteria have been proposed (54). For pure menstrual migraine, (1) attacks in menstruating women fulfil the ICHD-3 diagnostic criteria for 1.1 migraine without aura and/or 1.2 migraine with aura; (2) attacks occur exclusively during menstruation (during at least three menstruations) beginning on day 1 ± 2 (ie, days −1 to +3) of menstruation and at no other times of the cycle. If after a menstrual migraine attack, the patient is headache free for at least 24 hours, either spontaneously or as a result of treatment, and migraine reoccurs within the −1- to +3-day menstrual interval, the attacks are regarded as separate menstrual migraine attacks. For menstruation-related migraine, (1) attacks in menstruating women fulfil the ICHD-3 diagnostic criteria for 1.1 migraine without aura and/or 1.2 migraine with aura; (2) at least half of all migraine attacks (during at least three menstruations) begin on day 1 ± 2 (ie, days −1 to +3) of menstruation. If after a menstrual migraine attack, the patient is headache free for at least 24 hours, either spontaneously or as a result of treatment, and migraine reoccurs within the −1- to +3-day menstrual interval, the attacks are regarded as separate menstrual attacks.
Self-reported menstrual migraine diagnosis has poor accuracy (283). Two thirds of female migraineurs suffer from menstrual migraine (independent of self-reports), but pure menstrual migraine is rare (283). Prospective headache diaries are required for the diagnosis of menstrual migraine (283).
Menstrual-related migraine should be suspected in females whose migraine occurs predominantly between 2 days before and 3 days after the start of menstruation in at least two of three consecutive menstrual cycles. In women with both menstrual and nonmenstrual migraines, menstrual migraines are generally not associated with aura, are of longer duration, are more likely to be severe, are more likely to have nausea and vomiting, are associated with more functional disability, and are usually more resistant to treatment compared with attacks at other times of the month (250; 166; 40; 159; 90; 54). Compared to non-menstrual migraine, menstrual migraine is associated with a higher frequency of migraine-accompanying symptoms, more frequent and more severe migraine attacks, lower frequency of nonmigraine headache, an overall greater response to treatment with triptans, better improvement of migraine attacks during late pregnancy, and faster reappearance of migraine attacks postpartum (54).
Menstruation-related migraine before pregnancy is associated with lack of headache improvement in the first and third trimesters of pregnancy whereas second-trimester hyperemesis and a pathological pregnancy course are associated with lack of headache improvement in the second trimester (235).
Headaches from pseudotumor cerebri can be secondary to estrogenic attenuation of the blood-brain barrier, and this might explain the female predilection for this disorder (310).
Cluster headache. In contrast to migraine, cluster headache mostly affects men (although a progressive decrease in the male-to-female ratio has occurred over time) (10). When considering the gender-specific features of cluster headache, women with cluster headache more often have clinical features (eg, nausea and osmophobia) that overlap with those of migraine (10). In addition, among women with cluster headache, the onset of disease often corresponded with changes in the levels of sexual hormones (menarche, postpartum, menopause) (10).
Epilepsy. Seizure disorders and antiepileptic therapy can significantly interfere with normal reproductive processes in women, and conversely changes in hormone levels associated with pregnancy can alter anticonvulsant levels and seizure control (215; 122; 286; 13).
Epilepsy may worsen around the time of ovulation or premenstrually (catamenial epilepsy) and during pregnancy (186; 111; 14; 13). The course of epilepsy and its management, therefore, is greatly influenced by specific phases of the reproductive cycle.
Pregnant epileptic women experience higher rates of maternal and fetal complications, including vaginal hemorrhage, prematurity, low birth weight, and perinatal mortality (280). Oral contraceptive failure and teratogenicity has been associated with the use of older enzyme-inducing anticonvulsants like phenytoin, phenobarbital, primidone, ethosuximide, and carbamazepine (312; 137; 285), but not with valproate or with newer antiepileptic medications such as lamotrigine, gabapentin, and vigabatrin (312; 42). Topiramate and felbamate may also affect contraceptive efficacy (231).
Catamenial epilepsy. Catamenial epilepsy is epilepsy with perimenstrual exacerbation, a phenomenon that occurs in about 40% of women with epilepsy. In such women, seizures correlate positively with mean estrogen/progesterone ratios and negatively with plasma progesterone levels (21).
Catamenial epilepsy is an epileptic condition in which there is clustering of seizures in relation to the menstrual cycle. Catamenial epilepsy is attributable to the neuroactive properties of steroid sex hormones combined with the cyclic variation in serum levels of these hormones (120). The frequency of catamenial epilepsy depends heavily on how the condition is defined (80; 120). In any case, patient claims about frequency of seizures in relation to menstruation are not always accurate (80).
Various classifications of catamenial epilepsy have been proposed (80), but the most widely used classification categorizes catamenial epilepsy into three patterns as either perimenstrual (C1), periovulatory (C2), or luteal (C3), based on the serum estradiol to progesterone ratio, and a 24- to 34-day menstrual cycle in which menses begins on day 1 and ovulation occurs 14 days prior to menstruation (120). For this classification, the menstrual cycle was divided into four phases with an adjustment for variable cycle length: menstrual phase (M) = -3 to +3, follicular phase (F) = 4 to 9, ovulatory phase (O) = 10 to -13, and luteal phase (L) = -12 to -4. Onset of menstruation was considered as day 1 and ovulation was considered to occur on day -14, with the negative number indicating 14 days before the onset of menstruation. The latter designation was used because ovulation generally occurs 14 days before onset of menstruation regardless of cycle interval. Using the system of Herzog and colleagues about one third of women with intractable partial epilepsy in their childbearing years have catamenial epilepsy (120).
The perimenstrual (catamenial pattern 1, C1) category of catamenial epilepsy is defined as a 2-fold or greater increase in average daily seizure occurrence during the menstrual (M) phase of the menstrual cycle (ie, occurring in normal cycles from 3 days before to 3 days after the onset of menstruation) compared with the follicular (F) and luteal (L) phases during normal ovulatory cycles (120). The designation of C1 as day -3 to 3 includes at least 3 days beyond the duration of progesterone withdrawal. Perimenstrual exacerbation of seizures has been attributed to withdrawal of the protective effects of progesterone (21) and more specifically to withdrawal of the progesterone-derived GABAergic neurosteroids due to the decline in progesterone level at the time of menstruation (219). Although the menstrual phase is characterized by marked decreases in both progesterone and estrogen levels, the estradiol to progesterone ratio is highest during the days before menstruation (C1) and ovulation (C2). Moreover, patients with the C1 pattern of catamenial epilepsy have lower progesterone levels than healthy controls during the menstruation phase of the menstrual cycle (85). Extrasynaptic δGABAA receptors, which are sensitive to neurosteroids and provide increased seizure protection, are upregulated during the perimenstrual period (219).
The periovulatory (catamenial pattern 2, C2) category of catamenial epilepsy is associated with a 2-fold or greater increase in average daily seizure occurrence during the ovulatory (O) phase (ie, occurring from days 10 to -13) compared with the follicular (F) and luteal (L) phases during normal ovulatory cycles (120). C2 extends beyond the preovulatory surge of estradiol and ovulatory onset of greater progesterone secretion. Periovulatory exacerbation of seizures has been attributed to the excitatory effects of estrogens. The ovulatory phase of the menstrual cycle is characterized by a surge of estrogen before ovulation, whereas an associated progesterone surge does not occur until ovulation actually occurs. This “estrogen effect,” without a corresponding progesterone surge of protection, intensifies seizure events.
The luteal (catamenial pattern 3, C3) category of catamenial epilepsy is associated with a 2-fold or greater increase in average daily seizure occurrence during the ovulatory (O), luteal (L), and menstrual (M) phases (ie, the entire second half of the cycle) than during the follicular (F) phase in inadequate luteal phase cycles (ie, abnormal or inadequate luteal phase cycles, days 10 to 3) (120). C3, like C1, involves the early days of menstruation, a period that extends beyond the withdrawal of progesterone premenstrually. Anovulatory females do not typically have a midcycle surge of progesterone, but still experience a surge in estrogen; these women have abnormally low progesterone levels during the ovulatory, luteal, and menstruation phases, regardless of whether ovulation occurs. Patients with C3 pattern of catamenial epilepsy have overall lower progesterone levels than healthy controls during the luteal phase of the menstrual cycle (85).
One caveat of this scheme is that neuroactive sex hormones may produce changes in the structure and biological activity of neuronal excitatory and inhibitory receptors that outlast the brief duration of the hormone-receptor interaction (120).
During menopause, there are marked changes in the production of gonadal hormones. Most of the sex hormones diminish initially around menopause, becoming irregular, and often showing wide and unpredictable fluctuations, and consequently variable effects on the frequency of seizures in those with a history of catamenial epilepsy (228). As menopause progresses, there is cessation of estrogen (estradiol) production by the ovaries and a marked decrease in risk of seizures during menopause if there was a catamenial relationship (228).
The use of hormone replacement therapy after menopause produces an increase in seizure frequency and severity in women with a history of catamenial epilepsy (112). Such women need closer anticonvulsant medication monitoring to maintain or reduce seizure occurrence (112). For menopausal women with a history of catamenial epilepsy and needing symptomatic relief (eg, when “hot flushes” are disruptive), estrogen-only preparations are relatively contraindicated but the combination of a single estrogenic compound (eg, 17-β-estradiol) and natural progesterone can be considered (112).
These anticonvulsants induce the hepatic cytochrome P450 microsomal enzyme system, which, in turn, accelerates catabolism of endogenous and exogenous sex hormones. Oral contraceptive failure does not occur with valproic acid, which may actually inhibit cytochrome P450 enzymes, causing elevations in plasma steroid concentrations. Valproic acid, however, may cause hyperandrogenism and polycystic ovaries (122; 210).
Of the newer antiepileptic medications, lamotrigine, gabapentin, and vigabatrin do not induce the hepatic P450 microsomal enzyme system, and oral contraceptive failure has not been reported with concomitant use of these drugs (312; 42). Topiramate and felbamate may affect contraceptive efficacy by affecting sex hormone pharmacokinetics (231). During pregnancy, serum levels of phenytoin, phenobarbital, and valproic acid may decrease by 30% to 40% of pregestational levels, with a lesser decline in carbamazepine. Primidone levels are reportedly stable during pregnancy, but the concentration of primidone-derived phenobarbital is reduced (153; 113).
Cerebrovascular disease. Altered levels of sex hormones are associated with cerebral venous thrombosis, ischemic stroke, and subarachnoid hemorrhage (51; 44; 79; 245). Sex hormones can induce a hypercoagulable state, which may contribute to the development of cerebral venous thrombosis complicating pregnancy and the puerperium (88). Estrogen increases plasma levels of fibrinogen and clotting factors VII, VIII, IX, X, and XII. Ischemic stroke in users of oral contraceptives may occur in the carotid and vertebrobasilar distributions. Increased prevalence of mitral valve prolapse among users of oral contraceptives with ischemic stroke has been reported (84; 229).
Sex hormones have not been proven to play a role in mediating ischemic stroke among elderly men or women, though some of the data are conflicting. In a prospective study of incident cardiovascular disease among 552 community-dwelling elderly men (65 years and older), endogenous levels of testosterone, estradiol, and sex hormone-binding globulin were not associated with increased risk of coronary, cerebrovascular, or peripheral arterial events (61). In a nested case-control study of postmenopausal women from the Nurses' Health Study, among 419 postmenopausal women with confirmed incident ischemic stroke and 419 matched controls, testosterone and sex hormone-binding globulin levels were not associated with ischemic stroke among either current or never/past users of exogenous hormone therapy (125). In contrast, in a subset of 13,192 postmenopausal women free of prevalent stroke, as part of the Women's Health Initiative prospective cohort study conducted at 40 sites across the United States from 1993 to 1998, there was a statistically significant inverse association between serum sex hormone-binding globulin levels and ischemic stroke risk, with hazard ratios of 1.6 to 1.9 in different multivariate models (160); including potential mediators attenuated but did not eliminate these associations.
Several large randomized controlled studies indicate that hormone replacement therapy does not protect against stroke or coronary artery disease in women with established vascular disease and may actually worsen outcomes in this high-risk population (251; 33; 274).
Sex hormones alter the function and morphology of platelets and fibrin networks, and changes in platelet and fibrin network morphology offer one of the earliest confirmations of inflammation. Sex hormone levels, inflammatory processes, and thrombotic mechanisms are profoundly interconnected in predicting the outcome of cerebral ischemia (278).
Cigarette smoking and age greater than 35 years old significantly increase the risk of subarachnoid hemorrhage in users of oral contraceptives (204; 260). Female sex hormones may predispose to bleeding from both aneurysms and arteriovenous malformations, although the pathophysiological mechanisms underlying these phenomena remain controversial (77).
In a cross-sectional study of 6157 subjects, serum testosterone levels were negatively correlated with stroke in males, whereas the serum cortisol/testosterone ratio was positively correlated with stroke in both males and females (301).
Movement disorders. Both gestational chorea (chorea gravidarum) and oral contraceptive-related chorea are closely associated with prior rheumatic fever (77). Contraceptive-related chorea has also been reported in patients with a history of congenital cyanotic heart disease and Henoch-Schonlein purpura (224). In most cases, dyskinesias resolve completely by the end of pregnancy or after discontinuation of the contraceptive medication.
There are anecdotal reports in the early clinical literature of motor deterioration in idiopathic and neuroleptic-induced parkinsonism after exposure to exogenous estrogens. Although premenopausal women are reportedly more susceptible to drug-induced parkinsonism than men of similar age (31), postmenopausal estrogen therapy had no significant dopaminergic effect (265; 151).
Gonadal dysfunction, reduced androgen levels, and an abnormal hypothalamic-pituitary-gonadal axis have been reported in Huntington disease (243). In addition, a potential relationship between the gonadal dysfunction and abnormal hippocampal plasticity in Huntington disease may help explain the putative role of the HTT gene in the regulation of steroidogenesis in both the gonads and the brain (243).
Kisspeptin is an important regulator of reproduction, and the neurons are localized in the arcuate nucleus. The activity of kisspeptin neurons is modulated by sex steroids and other regulatory factors (12).
Wilson disease can produce chorea, seizures, and psychosis from the toxic effects of excessive copper deposition in neural tissues (191). An increase in serum ceruloplasmin levels can occur during pregnancy and after treatment with exogenous estrogens. In normal individuals, serum ceruloplasmin and copper levels increase during pregnancy and after administration of estrogen or estrogen-progestogen contraceptives (307). Although ceruloplasmin levels are characteristically low in Wilson disease, exposure to hormonal contraceptives may elevate falsely normal ceruloplasmin levels into the normal range, leading to a delay in diagnosing Wilson disease (240).
Intracranial malignancies. Meningiomas are more common in obese women and in patients with hormone-dependent breast carcinoma (242; 130). They occur more frequently in women than in men and rarely prior to pubertal period (241; 206; 130). Meningiomas undergo a relatively rapid expansion during pregnancy, followed by spontaneous regression during the postpartum period (240; 110). Similarly, there are anecdotal reports of the enlargement of astrocytomas during pregnancy, followed by spontaneous regression in the puerperium (194). In addition, acoustic neuromas (20) and pituitary adenomas (83) may show responsiveness to sex hormones.
Neuroimmunologic disorders. Multiple sclerosis is more prevalent among women than men. Menarche may be a time of increased disease activity in girls with multiple sclerosis (41; 144). Age at menarche is inversely associated with risk of incident multiple sclerosis, which is largely mediated by the strong association between age at puberty and obesity (114). Among women with multiple sclerosis, cognitive functions and physical performance deteriorate during the premenstrual period (108). In addition, the relapse rate of multiple sclerosis declines by almost 70% in the third trimester of pregnancy, an effect more robust than that from treatment with interferon-beta, glatiramer acetate, or intravenous immunoglobulin (126; 58). In contrast, multiple sclerosis exacerbations are more common during the first 3 postpartum months (292). Mothers who breastfeed longer may be at lower subsequent risk of developing multiple sclerosis (149).
In a systematic review, there was no difference in the rates of relapse before and after menopause and evidence of a potential causal effect of estrogen depletion on disability was deemed inconclusive (135). The effect of hormone replacement therapy on the natural course of the disease remains to be defined.
Dementia. In a meta-analysis of 12 observational studies, Massoud and colleagues revealed that postmenopausal estrogen replacement therapy appears to be associated with a significantly decreased risk of developing Alzheimer disease (184). In addition, it has also been shown that postmenopausal estrogen replacement therapy protects against the development of dementia in women with Parkinson disease (225).
Neuropsychiatric disorders. Depression and other major affective disorders may also develop in association with the menstrual cycle, the puerperium, and menopause (222). Sex hormones have been shown to produce stress effects, which ultimately impact emotional learning and memory (192).
Psychotic disorders characterized by extreme agitation, hallucinations, paranoid delusions, incoherent speech, and mood lability may arise during the postpartum period or may recur consistently during the late luteal phase of the menstrual cycle (290).
Sex hormones produce stress effects that ultimately impact emotional learning and memory (192).
Sleep disorders. Changes in the balance of estrogen and progestin may also impact sleep-related issues as evidenced by their replacement. For example, female sex hormones may help improve sleep in hypogonadal women by shortening mean sleep latencies, prolonging the duration of rapid eye movement sleep periods, and reducing nocturnal movement arousals (244; 207; 132).
Progestins have also been shown to improve hypoventilation in a patient with central sleep apnea (195). Removal of a benign testosterone-producing ovarian tumor resolved obstructive sleep apnea in one case (74) whereas progestin administration improved hypoventilation in a patient with central sleep apnea (195). In addition, testosterone administration has been shown to increase the hypocapnic apnea threshold in premenopausal women (306; 60).
Choi and colleagues demonstrated that testosterone can decrease and cortisol can increase pain induced by electrical stimulation, suggesting that acute clinical pain may be relieved by controlling stress and managing consequent stress-related testosterone and cortisol (59). In their review, Bale and Epperson discussed potential underlying mechanisms driving sex differences across the lifespan in stress responses and their relevance to disease (25).
Neuromuscular disorders. Catamenial sciatica, a radiculopathy related to endometriosis, causes pain in the nerve or nerve root distribution, which usually begins 2 to 3 days before the onset of menses (234). Pain may continue for a variable duration after cessation of flow. In addition to pain, patients may have numbness, weakness, and loss of ankle reflexes. Endometriotic sciatica is less likely to respond to bed rest, and the imaging findings are usually unimpressive (56).
Sex differences in pain sensitivity have been well recognized; however, pathophysiology is incompletely understood. A study by Veldhuijzen and colleagues evaluated how pain-related neural processing varies across the menstrual cycle with fluctuating sex hormone levels (281). It revealed no significant cycle phase differences for pain intensity stimuli applied during functional magnetic resonance imaging scans.
Estrogens may influence the natural history of Bell palsy, recurrent brachial plexopathy, and carpal tunnel syndrome (293). Myotonic dystrophy patients may have dysfunction of testicular peritubular myoid cells and corpus cavernosum smooth muscle, contributing to hypergonadotropic hypogonadism and impotence in men (185).
Kennedy disease, or spinal and bulbar muscular atrophy, is an X-linked neuromuscular disease caused by an abnormal CAG trinucleotide repeat expansion in the androgen receptor gene. Although cases continue to be misdiagnosed as amyotrophic lateral sclerosis, several features distinguished this disorder from other motor neuron disorders: (1) clinical onset in middle life; (2) X-linked recessive inheritance; (3) proximal spinal and bulbar muscular weakness and atrophy; (4) generalized fasciculations, especially prominent about the lips and chin; (5) absence of pyramidal tract (upper motor neuron), cerebellar, or sensory involvement; (6) a slowly progressive course with an apparently normal life span; and (7) gynecomastia.
Disorders of growth hormone. A reduction in desire and arousability, both in men and women, together with an impairment of erectile function in men, have been described both in patients with growth hormone deficiency and acromegaly. However, it remains unclear whether they are directly dependent on the hormone defect or excess, or whether they are consequence of the hypogonadism or any other clinical complications affecting sexual function (95).
Porphyria. Women with acute intermittent porphyria frequently have cyclic symptoms, particularly during the luteal phase of their menstrual cycles (01). Similarly, most females affected by catamenial attacks have premenstrual attacks (ie, in the luteal phase of the menstrual cycle) (16). Some patients experience disabling attacks with almost every menstrual cycle (16). Furthermore, estradiol, some other steroids, and controlled ovarian hyperstimulation for in vitro fertilization may precipitate porphyric crises (198).
Neurologic manifestations in porphyria, when present, include seizures, behavioral symptoms, and sensorimotor and autonomic neuropathies. Estradiol and other steroids with a 5-beta configuration induce the enzyme δ-aminolevulinic acid synthase and may precipitate porphyric crises. Oral contraceptives increase urinary excretion of this enzyme in normal individuals, and, therefore, asymptomatic relatives of patients with porphyria need to be made aware of the potential consequences (240).
Clinical vignette
A 24-year-old woman presented with a recurring history of left buttock pain with radiation to the posterior thigh, calf, and sole of the foot. Symptoms were present during her menstrual cycle and for at least 3 to 4 days afterwards. The patient had no symptoms during the rest of her cycle. Neurologic examination during the symptoms revealed no weakness; muscle stretch reflexes were reduced at the left ankle, and sensory examination was essentially unremarkable. Laboratory testing revealed EMG findings were consistent with an S1 radiculopathy, and MRI showed ectopic endometrium surrounding the S1 vertebral body encroaching on the S1 nerve root. Laparoscopic surgery removed the foci of endometriosis. The patient was symptom-free in the 3-month follow-up period after her surgery.
Pathogenesis and pathophysiology
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• During the neonatal and peripubertal periods, estrogens and aromatizable androgens induce trophic changes in the hypothalamus, whereas in later life, estrogens accelerate aging-related changes in the endocrine hypothalamus that may contribute to the onset of reproductive senescence; these interactions are essential for regulation of the brain-pituitary-gonadal axis and for the establishment of normal patterns of sexual, cognitive, and autonomic behaviors at various phases (eg, menstrual cycle, pregnancy, and menopause). | |
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• The pathogenesis of menstrual migraine is not fully understood, but investigators have suspected that it may be related to estrogen or prostaglandin withdrawal. | |
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• Estrogen priming lowers the seizure threshold in the hippocampus in animal models, and, similarly, it was recognized that administration of estrogen-based hormonal therapies can increase seizure frequency in some women with epilepsy. | |
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• Progesterone has a neuroprotective effect on hippocampal neurons in seizure models induced by kainic acid; progesterone’s anticonvulsant and neuroprotective effects are apparently due to the steroid's actions on GABAA-benzodiazepine receptor complexes rather than intracellular progesterone receptors. |
Sex hormones. Estrogen-binding neurons are located in the preoptic area, medial basal hypothalamus, medial amygdala, and circumventricular organs. Estrogen-binding neurons also reside, to a minimal extent, in the basal forebrain, the hippocampus, several thalamic nuclei, sensory regions of the brainstem and spinal cord, and the neonatal neocortex (76; 68). Estradiol receptors in hippocampus and hypothalamus imply that estradiol directly affects brain cells.
During the neonatal and peripubertal periods, estrogens and aromatizable androgens induce trophic changes in the hypothalamus, whereas in later life, estrogens accelerate aging-related changes in the endocrine hypothalamus that may contribute to the onset of reproductive senescence. These interactions are essential for regulation of the brain-pituitary-gonadal axis and for the establishment of normal patterns of sexual, cognitive, and autonomic behaviors at various phases (menstrual cycle, pregnancy, and menopause) (268; 97).
Sex hormones have both organizational and activational effects. Organizational effects refer to differentiation of neural circuitry from exposure to sex steroids during brain development in an irreversible fashion. Activational effects refer to reversible neurophysiological change by gonadal hormones on the mature nervous system.
Sex steroid regulation of the balance of neuroexcitatory and neuroinhibitory activities may have a role in modulating clinical susceptibility to different neurologic conditions such as migraine, catamenial epilepsy, premenstrual dysphoric disorder, and premenstrual syndrome (92).
Progesterone acts on neurons directly by activating progesterone receptors (through enhanced expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors) and through metabolic conversion to “neurosteroids” (134).
Premenstrual syndrome. Neuropsychiatric symptoms of premenstrual syndrome include headache, fatigue, depression, irritability, or changes in dietary habits. Symptoms typically begin toward the end of the luteal phase of the menstrual cycle and usually, but not invariably, resolve with the onset of menses.
Over 90% of menstruating women report some premenstrual symptoms such as headaches and moodiness. Proposed causes include an increased luteal phase estrogen-to-/progesterone ratio, hypothyroidism, hyperprolactinemia, and disordered renin-angiotensin-aldosterone axis (223; 222). Estradiol augments N-methyl-D-aspartate-mediated glutamate receptor activity, whereas progesterone enhances gamma-aminobutyric acid-mediated chloride conductance, but it is unclear whether premenstrual dysphoric disorder can be explained by these mechanisms.
Menstrual migraine. The late luteal phase decline in plasma estradiol appears to play an important role in the precipitation of catamenial migraine (179; 289). Associations have been reported between estrogen “withdrawal” in the late luteal/peri-menstrual period (ie, shortly before and during menses) and attacks of migraine without aura, and between high estrogen states and attacks of migraine with aura (179; 246; 166; 163; 162; 289). Other potential contributing factors include: (1) release of prostaglandins (ie, from shedding endometrium) that sensitize peripheral nociceptors; (2) decline in serum magnesium levels; (3) decreases in inhibitory neurotransmitters (eg, serotonin, GABA) that modulate neuronal firing rates within second-order neurons of the trigeminal system (182); (4) modulation calcitonin gene-related peptide in the trigeminovascular system; and (5) modulation of cortical spreading depression susceptibility.
The pathogenesis of menstrual migraine is not fully understood, but investigators have suspected that it may be related to estrogen or prostaglandin withdrawal (181; 169; 211; 279). However, existing studies are limited by methodologic inconsistencies, small sample sizes, and variable case definitions (211).
Unfortunately, studies have identified no clear hormonal difference in reproductive-age women with menstrually related migraine versus those with nonmenstrually related migraine (87). Attempts at preventing menstrually related migraine with oral estrogen supplements or estradiol implants did not result in overall clinical improvement and in fact some women experienced more headaches than before the treatment (257; 258). Furthermore, administration of progesterone against a background of prolonged exposure to high estrogen levels did not provoke migraine, nor did its subsequent withdrawal result in migraine (258). More recently, investigators have concluded that “estrogen and progesterone can be preventative or provocative for migraine headache under different circumstances, depending on their absolute serum levels, constancy of exposure, and types of estrogen/progesterone derivatives” (182), but this vague statement seems to reflect continued uncertainty over the specific hormonal relationship that is producing the cyclic pattern of menstrually related migraine.
One study reported that women with menstrual and menstrually related migraine headaches have a significantly higher number of migraine attacks during the late luteal/early follicular phase of falling estrogen (ie, perimenstrually) and lower number of attacks during rising phases of estrogen (169). Although the authors concluded that the findings “confirm a relationship between migraine and changing levels of estrogen, supporting the hypothesis of perimenstrual but not postovulatory estrogen ‘withdrawal’ migraine,” the finding is suspect because the women were in fact selected for having the specific pattern of headaches that they were then found to have.
Improvement of migraine without aura after menopause is generally attributed to the absence of variations in sex hormone levels, not necessarily the lower levels of circulating sex hormones (164).
Catamenial epilepsy. It has been known for 50 years that estrogen priming lowers the seizure threshold in the hippocampus in animal models (271), and similarly it was soon recognized that administration of estrogen-based hormonal therapies can increase seizure frequency in some women with epilepsy. It is now recognized that estrogens have epileptogenic properties whereas progestins have anticonvulsant properties (196; 65; 286). Estrogen both augments glutamatergic neurotransmission and suppresses GABAergic neurotransmission, favoring epileptogenesis, whereas progesterone has the opposite effect (196; 65). Cyclical changes in the circulating levels of estrogens and progesterone play a central role in the development of catamenial epilepsy (286; 221).
Synaptic functioning and neuronal excitability in the hippocampus are subject to both long-term and short-term excitatory modulation by sex steroids (298; 299). In particular, intracellular estrogen receptors are present in the hippocampus allowing estrogen to have long-term genomic effects with influence synaptic transmission (299). Estrogen and progesterone also have rapid nongenomic effects on CA1 neurons relevant to synaptic transmission over periods of seconds to minutes (299). A progesterone metabolite (ie, 3α-hydroxy-5α-dihydroprogesterone) binds to the GABAA receptor to potentiate the GABA-activated chloride current in CA1 neurons (175) and estradiol directly increases NMDA-mediated receptors of glutamate activity at the neuronal membrane, facilitating excitation and inducing repetitive firing of hippocampal pyramidal neurons in CA1 (273; 255; 254; 299). Dendritic spine density on CA1 hippocampal pyramidal cells also fluctuates during the menstrual cycle as a function of estradiol levels, using a mechanism that requires activation of NMDA receptors (300; 119). In addition, estriol also inhibits GABA and promotes kindling and epileptiform discharges (03); although estriol is only produced in significant quantities during pregnancy (via placental aromatization of fetal androgen), it can be synthesized in smaller quantities in nonpregnant individuals (in the liver by hydroxylation of estrone).
Progesterone has a neuroprotective effect on hippocampal neurons in seizure models induced by kainic acid (94); progesterone’s anticonvulsant and neuroprotective effects are apparently due to the steroid's actions on GABAA-benzodiazepine receptor complexes rather than intracellular progesterone receptors (94).
Seizures during pregnancy. Increased seizure activity during pregnancy may result from two different effects: a dominant estrogenic effect early in pregnancy that directly affects the central nervous system to lower the seizure threshold, and a decrease of at least 50% in plasma levels of anticonvulsant drugs late in pregnancy (215). In general, plasma anticonvulsant levels fall during pregnancy and rise during the puerperium (140). During pregnancy, serum levels of phenytoin, phenobarbital, and valproic acid may decrease by 30% to 40% of pregestational levels, with a lesser decline in carbamazepine. Primidone levels are reportedly stable during pregnancy, but the concentration of primidone-derived phenobarbital is reduced (153; 113). Several factors contribute to the fall in plasma anticonvulsant levels fall during pregnancy, including reduced absorption, increased volume of distribution, reduced protein binding, increased clearance, and noncompliance (140).
Cerebrovascular disease. Several different mechanisms may be involved in the interaction or association of sex hormones with cerebrovascular disease incidence. Sex hormone levels, inflammatory processes, and thrombotic mechanisms are profoundly interconnected in predicting the outcome of cerebral ischemia (278).
Sex hormones can induce a hypercoagulable state, which may contribute to the development of cerebral venous thrombosis complicating pregnancy and the puerperium (88). Estrogen increases plasma levels of fibrinogen and clotting factors VII, VIII, IX, X, and XII.
Estrogens can alter cerebrovascular tone either by acting directly on vascular smooth muscle or by altering central prostaglandin, serotonin, opioid, or prolactin metabolism (240; 34). Many of the detrimental effects of aging on ischemic stroke outcome in females can be replicated by ovariectomy, suggesting that hormones such as estrogen play a neuroprotective role (178). Animal models have also demonstrated evidence of estradiol-mediated protection in hypertensive encephalopathy (71).
Premenopausal women are less likely to develop hypertension than age-matched men, but after age 60 the incidence of hypertension increases in women and surpasses that seen in older men (115). A decline in estrogen levels with age may be involved in the increase in hypertension in older women (115). Brain regions important for the regulation of sympathetic nerve activity (eg, the subfornical organ, the paraventricular nucleus, and the rostral ventral lateral medulla) also express specific subtypes of estrogen receptors (115).
Polymorphisms in the estrogen receptor β gene (ESR2) are associated with an increased risk of first-ever stroke in Chinese women, and among Chinese women with a specific polymorphism the use of combined oral contraceptives significantly increased the risk of hemorrhagic stroke—a multiplicative gene-environment interaction (302).
The prevalence of mitral valve prolapse is increased among users of oral contraceptives with ischemic stroke (84; 229).
Female sex hormones may predispose to bleeding from both aneurysms and arteriovenous malformations, although the pathophysiological mechanisms underlying these phenomena remain controversial (77).
In oral contraceptive users, cigarette smoking and age greater than 35 years significantly increase the risk of subarachnoid hemorrhage (204; 260).
Movement disorders. Oral contraceptives may unmask latent chorea by augmenting dopaminergic neurotransmission in basal ganglia previously damaged by rheumatic or hypoxic encephalopathy (240).
Intracranial malignancies. Sex steroid receptors have also been reported in malignant lymphomas, metastatic breast cancers, hemangioblastomas, and anaplastic ependymomas, suggesting that the natural history of these neoplasms may be influenced by sex hormones and their antagonists (150; 208; 142; 252).
The greater prevalence of meningioma in obese individuals may be related to higher circulating estrogen levels derived from the aromatization of androstenedione to estrone in adipocytes (143). Although estrogens promote the growth of meningiomas, the presence of progestin receptors may well indicate a more favorable prognosis because progesterone receptor-negative meningiomas have been associated with a greater tendency for brain invasiveness, higher mitotic indices, and necrosis (272).
Astroglial tumors predominantly express estrogen receptor beta, and expression levels reportedly decline with increasing histological grade of malignancy (29; 36).
Oligodendrogliomas have also been reported to contain sex steroid receptors and could theoretically be subject to hormonal manipulations (287; 209).
Neuroimmunologic disorders. Over 50% of patients with multiple sclerosis experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in more than 30% of these patients. Although postmortem pathology studies and in vivo magnetic resonance imaging demonstrate that the hippocampus is targeted in multiple sclerosis, the neuropathology underlying hippocampal dysfunction remains unknown (308). Prolactin does not fall in the sex hormone group. However, given its extraordinary neuroprotective and remyelinating properties, it is now being considered as a disease-promoting factor in multiple sclerosis (62).
Reduction in the exacerbation of multiple sclerosis during pregnancy has been thought to be from gestational immunosuppression of estradiol, progesterone, human chorionic gonadotropin, human placental lactogen, cortisol, alpha-fetoprotein, and interleukin-10 (126; 58). However, not all studies found a substantial beneficial effect of pregnancy on either the risk of clinically definite multiple sclerosis or disability accrual (311).
In animal studies, pregnancy significantly delays the onset of experimental allergic encephalomyelitis (a model for multiple sclerosis) after inoculation with spinal cord homogenate or myelin basic protein (138; 89; 26).
Dementia. Two thirds of patients with Alzheimer disease are women. Gonadal steroids are thought to contribute to the gender disparity in Alzheimer disease. The “estrogen hypothesis” posits that sex hormones (especially 17β-estradiol) exert a neuroprotective effect by shielding females’ brains from disease development whereas postmenopausal estrogen dysfunction may exacerbate or precipitate the pathophysiological changes underlying Alzheimer disease in women (213). Indeed, the onset of menopause is associated with the emergence of Alzheimer disease-related brain changes in women in contrast to men of the same age (213). In particular, estrogens reduce the deposition of fibrillar beta-amyloid and modulate apolipoprotein E expression, thus, ultimately suppressing neuritic plaque formation (237; 118).
In older women (aged greater than 70 years), postmenopausal hormone therapy users exhibited faster regional tau accumulation relative to non-users, localized to the entorhinal cortex and the inferior temporal and fusiform gyri (63); this presumably may produce an indirect effect of postmenopausal hormone therapy on cognitive decline through its effect to increase regional tau accumulation. In contrast, in younger women (aged less than 70 years), the association of postmenopausal hormone therapy with tau accumulation was negligible.
Neuropsychiatric symptoms. Estrogen may facilitate drug abuse in women by interacting with reward- and stress-related systems (19). Females are more vulnerable than males to key phases of the addiction process including initiation, drug bingeing, and relapse (19). In addition, phases of the menstrual cycle when estrogen levels are high are associated with enhanced positive subjective measures following cocaine and amphetamine administration. Similarly, in animal studies, the administration of estrogen increases drug taking and facilitates the acquisition, escalation, and reinstatement of cocaine-seeking behavior.
Psychotic disorders characterized by extreme agitation, hallucinations, paranoid delusions, incoherent speech, and mood lability may arise during the postpartum period or may recur consistently during the late luteal phase of the cycle (290).
Sleep disorders. Estrogen and progestin may help improve sleep in hypogonadal women by shortening mean sleep latencies, prolonging the duration of rapid eye movement sleep periods and reducing nocturnal movement arousals (244; 207; 132). Progestins have also been shown to improve hypoventilation in a patient with central sleep apnea (195).
Neuromuscular disorders. Catamenial sciatica or low back pain is seen, with ectopic endometrial tissue destroying lumbar vertebrae or even invasion of the lumbosacral plexus in the retroperitoneal space and implantation within the sciatic nerve sheath. On occasions where evidence of endometriosis is minimally seen, surgical exploration of the sciatic nerve may be required for diagnosis (24; 56).
Patients with myotonic dystrophy may have dysfunction of testicular peritubular myoid cells and corpus cavernosum smooth muscle, contributing to hypergonadotropic hypogonadism and impotence in men (185).
Abnormally high estrone levels have been reported in male patients with motor neuron disorders like amyotrophic lateral sclerosis, bulbospinal muscular atrophy (Kennedy disease), Kugelberg-Welander disease, and Duchenne muscular dystrophy (277). Testosterone, luteinizing hormone, and follicle-stimulating hormone levels were all essentially normal, except for low follicle-stimulating hormone levels in Duchenne muscular dystrophy patients. Because these patients were not overweight and did not have liver or glandular abnormalities, the elevated serum estrone levels presumably resulted from increased peripheral androgen-to-estrogen conversion.
Kennedy disease, or spinal and bulbar muscular atrophy, is an X-linked neuromuscular disease caused by an abnormal CAG trinucleotide repeat expansion in the androgen receptor gene. During protein synthesis, the CAG repeats are translated into a series of uninterrupted glutamine residues, forming what is known as a polyglutamine tract ("polyQ"). Such polyglutamine tracts are subject to increased aggregation and deposition of misfolded proteins. Therefore, spinal and bulbar muscular atrophy belongs to a family of “polyQ diseases,” a group of fatal neurodegenerative disorders caused by protein-mediated, toxic, gain-of-function mechanisms that include dentato-rubro-pallido-luysian atrophy (DRPLA), Huntington disease, and various inherited spinocerebellar ataxias (ie, types 1- 3, 6, 7, and 17).
Disorders of growth hormone. Reductions in sexual desire and arousability are reported in male and female patients with disorders of growth hormone (either growth hormone deficiency or acromegaly), together with an impairment of erectile function in men with these disorders, and it remains unclear whether these problems are directly dependent on the growth hormone defect or excess or whether they are consequence of the hypogonadism or any other clinical complications affecting sexual function (95).
Porphyria. The principal acute porphyrias include acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Each of these is due to a separate genetic defect in the pathway of heme synthesis.
In hepatocytes, a critically low level of intracellular heme triggers overproduction of the precursor molecules, δ-aminolevulinic acid and porphobilinogen. Raised concentrations of δ-aminolevulinic and porphobilinogen are associated with inherited deficiency of hydroxmeythyl bilane synthase in acute intermittent porphyria and with allosteric inhibition of hydroxmeythyl bilane synthase by accumulating coproporphyrinogen and or protoporphyrinogen in variegate porphyria and hereditary coproporphyria (189).
Although the pathogenesis of attacks is not completely understood, δ-aminolevulinic acid may be the toxic agent that acts on nerves because other disorders associated with excess production of δ-aminolevulinic acid but not porphobilinogen (eg, lead poisoning and hereditary tyrosinemia) have similar clinical presentations to acute intermittent porphyria (35; 262). This is not the full explanation, though, because plasma and urinary δ-aminolevulinic acid levels correlate poorly with porphyria symptoms (262).
Most attacks of acute intermittent porphyria are precipitated by hormonal factors (262), and cyclic symptoms and catamenial porphyric crises have been reported in patients with acute intermittent porphyria due to a triggering effect of menstrual cycle hormones (309; 16; 106; 17; 01; 131). Women with acute intermittent porphyria frequently have cyclic symptoms (136; 01), particularly during the luteal phase of their menstrual cycles (01). Similarly, most females affected by catamenial attacks have premenstrual attacks (ie, in the luteal phase of the menstrual cycle) (16). In a population-based study in Finland, nearly one third of the women had symptoms of porphyria associated with the menstrual cycle but these seldom proceeded to an acute attack (136). Nevertheless, some patients experience disabling attacks with almost every menstrual cycle (16).
Administration of oral contraceptives, progestins, or androgens can interrupt ovulation and have been beneficial in preventing perimenstrual attacks in some patients (203; 106) but they also precipitated attacks of porphyria in others, including some with previously latent disease (152; 296; 309; 202; 147; 17; 37). In a population-based study in northern Sweden, more than half of the women with acute intermittent porphyria had used oral hormonal contraceptives and about 25% of oral contraceptive users with manifest acute intermittent porphyria reported attacks associated with such drugs (17). In addition, danazol, a synthetic steroid with weak androgenic properties, was used in an attempt to prevent cyclical attacks but instead exacerbated the disease (147). Withdrawal of oral contraceptives has also been anecdotally reported to trigger attacks (98).
Some preliminary studies demonstrated an increase in porphobilinogen but not coproporphyrin or uroporphyrin with oral contraceptive agents (δ-aminolevulinic was not measured) (133), whereas later studies with low-dose oral contraceptives found that they did not affect measured porphyrin precursors (including δ-aminolevulinic) or urinary porphyrin excretion (106).
The frequent exacerbations in women with porphyria treated with oral contraceptives, progestins, or androgens prompted consideration of novel alternatives such as agonistic analogues of gonadotropin-releasing hormone (Gn-RH; eg, “D-His“). Gonadotropin-releasing hormone analogues can suppress ovulation and cyclical increases in ovarian steroids without inducing δ-aminolevulinic acid synthase 1; this inhibits porphyrin precursor excretion (though not to normal levels) enough to suppress cyclic attacks in acute intermittent porphyria and hereditary coproporphyria (16; 303; 127). The optimal duration of gonadotropin-releasing hormone analogue administration is unknown.
In the dominantly transmitted acute porphyrias, a functional gene is inherited from the unaffected parent, so residual enzyme activity is typically 50% or normal, which is generally sufficient for heme homeostasis (22). Nevertheless, upregulation of δ-aminolevulinic acid synthase may cause accumulation and release of porphyrins and their precursors from the liver (262); this can occur cyclically due to normal hormonal oscillations in the menstrual cycle or with administration of various medications such as oral contraceptives and testosterone.
Benign intracranial hypertension. Benign intracranial hypertension (pseudotumor cerebri) can be secondary to estrogen-mediated effects on the blood-brain barrier, which may explain the female predilection for this disorder (310).
Traumatic brain injury. Sex steroid regulation of the balance of neuroexcitatory and neuroinhibitory activities may have a role in modulating clinical susceptibility to different neurologic conditions such as migraine, catamenial epilepsy, premenstrual dysphoric disorder, and premenstrual syndrome (92).
Although estrogens have been shown to enhance cerebral endothelial cell permeability and posttraumatic brain edema, progesterone suppresses posttraumatic cerebral edema and intracranial hypertension through the inhibition of cerebrospinal fluid production by the choroid plexus and reduction in blood-brain barrier permeability (156; 310; 227; 86; 100).
Progesterone is a potent neurosteroid that can protect damaged cells in the central and peripheral nervous systems and has rapid actions that go well beyond its effects on the classical intranuclear progesterone receptor. Progesterone holds promise as a treatment for traumatic brain injury. Its multiple neuroprotective mechanisms of action may work synergistically to prevent the death of neurons and glia, leading to reduced morbidity and mortality following traumatic brain injury (27; 261).
Pain. Pain-related neural processing varies across the menstrual cycle with fluctuating sex hormone levels (281). In addition, testosterone can decrease pain induced by electrical stimulation whereas cortisol can increase pain (59).
Stress response. Sex differences in stress responses can be found at all stages of life and are largely driven by gonadal hormone changes that occur over dynamic periods of development and maturation (25).
Epidemiology
|
• No gender difference in migraine prevalence is apparent before puberty, but during the reproductive years, migraine is three times more common in women than men. | |
|
• In women, migraine attack frequency and severity vary with reproductive status. | |
|
• Among women migraineurs, both in the general population and presenting to specialist clinics, at least half identify menstruation as a trigger for attacks, and between one fifth and one third of the subgroup of women with migraine without aura experience migraine attacks associated with menstruation. | |
|
• Compared with all other phases of the menstrual cycle, incidence of migraine without aura is greatest during a 5-day perimenstrual period (ie, occurring on days -2 to +3 of menstruation). | |
|
• Compared with migraine at other times of the cycle, menstrual attacks last longer (some more than 72 hours) and are more severe, more likely to relapse, less responsive to pharmacologic treatment, and associated with greater menstrual distress and work-related disability. |
Premenstrual syndrome. Premenstrual syndrome occurs in approximately 30% of women during their reproductive years.
Migraine. There are significant gender-related differences in the epidemiology and natural history of migraines such that they need to be separately analyzed for men and women (93). No gender difference in migraine prevalence is apparent before puberty, but during the reproductive years, migraine is three times more common in women than men (246; 40; 34). In women migraine attack frequency and severity vary with reproductive status (166; 163; 40).
Migraines are three times as common in adult women as in men; however, no gender difference in the prevalence of migraine is apparent before puberty (246; 34). Almost two thirds of women with migraine experience perimenstrual exacerbations of their headaches (catamenial migraine). Headaches attenuated by pregnancy may relapse at the time of parturition due to a sudden fall in sex hormone levels (236).
Menstrual migraine (catamenial migraine). Among women migraineurs, both in the general population and presenting to specialist clinics, at least half identify menstruation as a trigger for attacks (87; 69; 168; 105; 81; 64; 06; 166; 40; 162), and between one fifth and one third of the subgroup of women with migraine without aura experience migraine attacks associated with menstruation (230). The peak incidence of migraine during the menstrual cycle occurs on the days directly before and after the first day of menstruation, whereas the lowest risk for headache is around the expected time of ovulation (129; 264; 81; 166; 162). For most women with menstrual migraine, migraine also occurs at other times of the month (ie, “menstrually related” migraine); fewer than 10% to 20% of women report migraine exclusively with menstruation and at no other time of the month (ie, “pure” menstrual migraine) (168; 105; 66; 81; 166; 162; 288; 232).
Compared with all other phases of the menstrual cycle, incidence of migraine without aura is greatest during a 5-day perimenstrual period (ie, occurring on days −2 to +3 of menstruation) (129; 264; 81; 166; 232).
In a longitudinal E-diary study among 526 premenopausal women with migraine, prevalence of menstrual migraine did not differ significantly between women with migraine without aura and migraine with aura (59% vs. 53%, respectively) (284). The increased risk of migraine attacks without aura during the perimenstrual window did not differ significantly for women with migraine without aura and those with migraine with aura. The perimenstrual window was not associated with an increased risk of attacks with migraine aura. Women with migraine with aura more often reported increased migraine frequency during pregnancy and breastfeeding compared to women with migraine without aura.
Compared with migraine at other times of the cycle, menstrual attacks last longer (some more than 72 hours), are more severe, more likely to relapse, less responsive to pharmacologic treatment, and associated with greater menstrual distress and work-related disability (30; 264; 64; 06; 103; 166; 166; 166; 78; 139; 162; 174; 205; 232). Among women with menstrually-related migraine, menstrual headaches are associated with a higher pain score than other attacks (166; 162; 232). In a study using diary data from 155 women, migraine was most likely to occur perimenstrually and was more likely to be severe at this time: indeed, compared with all other times of the cycle, migraine was 1.7 times more likely to occur during the two days before menstruation and 2.1 times more likely to be severe and 2.5 times more likely to occur during the first three days of menstruation and 3.4 times more likely to be severe (166).
Catamenial epilepsy. Epilepsy may worsen around the time of ovulation or premenstrually (catamenial epilepsy) and during pregnancy (186; 111). The course of epilepsy and its management, therefore, is greatly influenced by specific phases of the reproductive cycle.
The occurrence and distribution of patterns of catamenial epilepsy were studied in a prospective, observational study of a heterogenous cohort of women with epilepsy on no hormonal therapies (291). The authors measured progesterone concentrations for one to three cycles in women who recorded one or more menstrual cycles with one or more seizures. Catamenial patterns were defined as 2-fold or greater than average daily seizure frequency around menstruation (C1), ovulation (C2), and for anovulatory cycles, from midcycle through menstruation (C3). Twelve of 23 (52%) eligible women met criteria for catamenial epilepsy: of those with catamenial epilepsy, five demonstrated only a C1 pattern, two only a C2 pattern, and five a combined C1/C2 pattern.
Cerebrovascular disease. Hypertension, migraine, and age greater than 35 years old were associated, but independent, risk factors for cerebral infarction in patients taking oral contraceptives (50; 117). Although less often implicated than estrogens, progestins may contribute to the danger of cerebral infarction by promoting hypertension, hypercoagulability, and adverse serum lipoprotein levels (266; 276).
Movement disorders. Epidemiological studies have suggested that early menopause may be a risk factor for the development of Parkinson disease (32; 212; 154; 239).
Patients with chorea gravidarum are at increased risk of later developing oral contraceptive-related dyskinesias (96; 214). There is recurrence of chorea in almost one of five women with subsequent pregnancies (99).
Neuroimmunology. The higher prevalence of multiple sclerosis in females, along with the observed modulation of disease activity during pregnancy and the postpartum period, has suggested a hormonal influence in multiple sclerosis (62). In animals, pregnancy significantly delays the onset of experimental allergic encephalomyelitis (a model for multiple sclerosis) after inoculation with spinal cord homogenate or myelin basic protein (138; 89; 26).
In animals, pregnancy significantly delays the onset of experimental allergic encephalomyelitis (a model for multiple sclerosis) after inoculation with spinal cord homogenate or myelin basic protein (138; 89; 26).
Porphyria. In a population-based study in northern Sweden, more than half of the women with acute intermittent porphyria had used oral hormonal contraceptives and about 25% of oral contraceptive users with manifest acute intermittent porphyria reported attacks associated with such drugs (17).
Prevention
Prevention relies on control of the underlying sex hormonal dysfunction.
Prognosis and complications
The prognosis of any neurologic event occurring in the setting of sex hormonal dysfunction depends on the specific clinical situation and etiology of the process in question.
Management
|
• Combined hormonal contraceptives have been considered contraindicated for women who have migraine with aura, particularly because the high estrogen-dose formulations of these drugs used in the 1960s and 1970s clearly increased the risk of ischemic stroke in this group of women. | |
|
• Systematic reviews have found an additive increase in stroke risk with combined hormonal contraceptive use in women with migraine with aura, with some studies suggesting a 2- to 4-fold increased risk of stroke among women with migraine who use combined hormonal contraceptives compared with nonuse. | |
|
• Combined hormonal contraceptives should not be routinely employed in females who have migraine with aura. | |
|
• Combined oral contraceptives can initiate or aggravate migraine without aura in some women, though the headaches generally improve after several months of combined oral contraceptives use. | |
|
• With persistent migraine without aura while on sustained use of combined oral contraceptives, attacks are more likely to occur during the pill-free week, a condition referred to as oral contraceptive-induced menstrual migraine. | |
|
• Combined oral contraceptives are useful for women with menstrual migraine who require contraception, although attacks tend to occur during the pill-free interval; if these are contraindicated (as is at least relatively the case in migraine with aura), depot progestogen is an alternative as it also inhibits ovulation and can improve migraine, provided amenorrhea is achieved. | |
|
• Oral contraceptive failure is associated with the use of older enzyme-inducing anticonvulsants but not with newer nonenzyme-inducing antiepileptic medications. | |
|
• Several different approaches have been proposed for treatment of catamenial epilepsy, including: (1) premenstrual or periovulatory supplementation of anticonvulsant doses; (2) addition of an adjunctive antiepileptic drug; (3) cyclic administration of acetazolamide, a mild diuretic with weak antiepileptic activity; and (4) progesterone supplementation. |
Menopausal hormone therapy. As reported initially in 2013, ischemic stroke risk was increased during menopausal hormone replacement therapy in the Women's Health Initiative but there was no significant effect after the cessation of therapy (177) and no difference in mortality at long-term follow-up (176).
In 2016, an observational cohort study of combined oral contraceptive therapy in 5 million French women found that for the same type of progestogen, an estrogen (ethinylestradiol) dose of 20 μg versus 30 to 40 μg was associated with lower risks of ischemic stroke, myocardial infarction, and pulmonary embolism (294).
In 2017, a pooled analysis of data from population-based cohort studies found that menopausal hormone therapy is not associated with increased risks of incident ischemic or hemorrhagic stroke when initiated early in relation to menopause onset, regardless of the route of administration, type of hormone therapy, active ingredient, or duration of use (51). Instead, initiation of menopausal hormone therapy within five years following menopause onset, as compared to never use, is associated with a decreased risk of ischemic and hemorrhagic stroke (51). However, late initiation of single hormone therapy with conjugated equine estrogen is associated with elevated risks of ischemic and hemorrhagic stroke, and late initiation of combined hormone therapy is associated with an elevated risk of hemorrhagic stroke (51).
Another large cohort of Danish women suggested that the specific route of administration was important, finding that although oral estrogen increased risk of stroke, absorption through the skin had no impact and vaginal estrogen actually had a decreased risk (157). When given by nonoral routes, there was no association between hormone replacement therapy and stroke and instead hormone replacement therapy may have been preventative (157).
In several large randomized controlled studies, menopausal hormone therapy did not protect against either stroke or coronary artery disease among women with established vascular disease and instead it may have worsened outcomes in this high-risk population (251; 33; 274).
For hormone replacement therapy in menopausal women with migraine, nonoral routes of estrogen delivery provide stable levels and are more likely to improve migraine than oral estrogens, which produce variable day-to-day levels (197; 161; 162). Optimal doses of continuous estrogens can control both migraine and menopausal symptoms but too high a dose of estrogen, particularly if coupled with surges of endogenous estrogen, can trigger migraine auras (161). Using only the lowest doses of transdermal estrogen necessary to control vasomotor symptoms will minimize the risk of unwanted side effects (161; 165). Note that in contrast to contraceptive doses of ethinylestradiol, the presence of migraine aura does not contraindicate use of physiological doses of natural estrogen (165). Additional progestogen, necessary for women without a prior hysterectomy to minimize risks of endometrial cancer, can exacerbate migraine (161).
In an observational study of 95 postmenopausal female participants from the prospective Nurses’ Health Study with a diagnosis of definite or probable multiple sclerosis, systemic hormone therapy use (61 of 95 women) was associated with better physical quality of life (38).
Combined hormonal contraceptives. Combined hormonal contraceptives have been considered contraindicated for women who have migraine with aura, particularly because the high-estrogen-dose formulations of these drugs used in the 1960s and 1970s clearly increased the risk of ischemic stroke in this group of women (47). Systematic reviews have found an additive increase in stroke risk with combined hormonal contraceptive use in women with migraine with aura, with some studies suggesting a 2- to 4-fold increased risk of stroke among women with migraine who use combined hormonal contraceptives compared with nonuse (270; 245).
Combined hormonal contraceptives should not be routinely employed in females who have migraine with aura (297; 52; 67; 245). If migraine with aura develops in a woman on combined oral contraceptives, these should generally be discontinued, and other methods of contraception should be used instead. This issue, though, is controversial. Some have considered migraine with aura to be an “absolute contraindication” to the use of combined oral contraceptives, and guidelines from the U.S. Centers for Disease Control and Prevention still consider combined oral contraceptives to have “unacceptable health risks (method not to be used)” (67) whereas other authorities advocate a risk/benefit assessment that does not preclude their use in this situation (47) or indicate only that “oral contraceptives should be used with caution as this may add to the risk of stroke in this population” (249). Based on the lower estrogen doses used in modern formulations, one group concluded that the risk of stroke among women taking low-dose oral combined hormonal contraceptives is “tenuous at best and perhaps nonexistent” (55). A systematic review noted a lack of good quality studies assessing risk of stroke associated with low dose estrogen use in women with migraine; the authors recommended that, “Since the absolute risk of stroke is low even in the presence of these risk factors, use of [combined hormonal contraceptives] in women who have migraine with aura should be based on an individualized assessment of harms and benefits” (245).
Some literature reviews and syntheses have concluded that stroke risk is not significantly increased in women who have migraine with aura with current hormonal contraceptive preparations that contain less than 30 μg of ethinyl estradiol; moreover, ultra-low-dose formulations containing less than 20 μg of ethinyl estradiol may help prevent menstrual migraine and reduce the frequency of aura (47). Other reviews have concluded that: (1) women using combined oral contraceptives have a higher risk of stroke, even with a lower estrogen dosage and different types of progestogen, regardless of the duration of use; and (2) use of combined oral contraceptives associated with migraine, smoking, hypertension, hypercholesterolemia, obesity, and a sedentary lifestyle further increases the risk of stroke (155). These disparities will only be resolved with better quality studies assessing risk of stroke associated with low-dose estrogen use in women with migraine. Progestogen-only contraceptives are considered safe (155).
Combined oral contraceptives can initiate or aggravate migraine without aura in some women, though the headaches generally improve after several months of combined oral contraceptives use (07; 08). With persistent migraine without aura while on sustained use of combined oral contraceptives, attacks are more likely to occur during the pill-free week, a condition referred to as oral contraceptive-induced menstrual migraine (07; 08).
In females taking combined oral contraceptive pills, if migraine without aura occurs during the pill-free interval in a cycle, options include: (1) using alternative contraception methods; (2) changing to a more estrogen-dominant pill; (3) adding low-dose estrogen supplementation after 21 days of combined oral contraceptives during the 7-day pill-free interval (45; 07; 08); (4) using extended-cycle combined oral contraceptive regimens (ie, greater than 28 days of active combined hormones) (267; 07; 46; 82; 08; 90); and (5) using a progestogen-only pill (07; 08). One extended-cycle combined oral contraceptive regimen requires taking the pill continuously for 9 weeks rather than 3 (ie, so-called "tricycling"), followed by the usual 7-day pill-free interval, producing five rather than 13 withdrawal bleeds per year (07; 08). Even longer extended regimens have been tried: compared to the standard 21/7-day oral contraception regimen, a 168-day extended regimen of combined oral contraceptive containing 3 mg of drosperinone and 30 mcg of ethinyl estradiol led to a decrease in headache severity along with improvement in work productivity and involvement in activities (267). A progestogen-only pill is a safe option even for women suffering from migraine with aura (in whom combined oral contraceptives are contraindicated) and its use can reduce the frequency of migraine attacks and the duration of aura symptoms (07; 08).
Combined oral contraceptives are useful for women with menstrual migraine who require contraception, although attacks tend to occur during the pill-free interval (161). If these are contraindicated (as is at least relatively the case in migraine with aura), depot progestogen is an alternative as it also inhibits ovulation and can improve migraine, provided amenorrhea is achieved (161). Oral progestogen-only contraception is not used in the management of menstrual migraine because it does not inhibit ovulation and is often associated with a disrupted menstrual cycle (161).
Oral contraceptive failure is associated with the use of older enzyme-inducing anticonvulsants, but not with newer nonenzyme-inducing antiepileptic medications (312; 42). Older enzyme-inducing anticonvulsants, like phenytoin, phenobarbital, primidone, ethosuximide, and carbamazepine induce the hepatic cytochrome P450 microsomal enzyme system, which, in turn, accelerates catabolism of endogenous and exogenous sex hormones (312; 137; 285). Oral contraceptive failure does not occur with valproic acid, which may instead inhibit cytochrome P450 enzymes, causing elevations in plasma steroid concentrations; valproic acid, however, may cause hyperandrogenism and polycystic ovaries (122; 210). Of the newer antiepileptic medications, lamotrigine, gabapentin, and vigabatrin do not induce the hepatic P450 microsomal enzyme system, and oral contraceptive failure has not been reported with these drugs (312; 263; 42). Topiramate and felbamate may affect contraceptive efficacy by affecting sex hormone pharmacokinetics (231).
Specific neurologic disorders. Several specific neurologic disorders may be amenable to hormonal therapies or require modifications in management during periods of significant changes in sex hormone levels.
Migraine. There are different ways of approaching a patient with migraine at various phases of life. The initial approach to the management of gestational or nongestational migraine should be nonpharmacological. This approach is critical during the first trimester when risks of teratogenicity and embryotoxicity are at the peak. Among the nonpharmacological migraine prophylaxis, only relaxation techniques, biofeedback in particular, and acupuncture have accumulated sufficient evidence in support of their efficacy and safety (04).
Pharmacotherapy for migraines can be abortive or prophylactic (57). The prophylactic properties of magnesium, riboflavin, and coenzyme Q10 are probably low, but their lack of severe adverse effects compared to other used medications makes them good treatment options. Some vitamins and dietary supplements have also been proposed (04). Serotonin 5-HT1D receptor agonists are effective for both noncatamenial and menstrual migraine (39). Lasmiditan, a high affinity and selective 5-HT1F receptor agonist, was effective in the treatment of perimenstrual migraine attacks in a randomized, double-blind, placebo-controlled clinical trial (172); lasmiditan treatment was associated with freedom from migraine-related head pain at two hours, early onset of efficacy, and sustained efficacy. Bromocriptine therapy (2.5 mg three times daily) has also been shown to reduce menstrual migraine in most patients (120; 180). Anti-CGRP (calcitonin gene-related peptide) monoclonal antibodies or CGRP receptor antagonists have good efficacy and safety in the treatment of menstrual migraine (128). Refractory cases of severe catamenial migraine may benefit from late luteal phase therapy with prostaglandin inhibitors (eg, naproxen, 250 to 500 mg orally twice daily) and mild diuretics (75). Danazol (200 mg twice daily for 25 days) has been utilized for premenstrual migraine associated with endometriosis (49). The triptans are currently rated by the United States Food and Drug Administration (FDA) as Category C agents. Soldin and colleagues have looked into the effects of the seven types of triptans currently available on the U.S. market (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) on pregnancy (256). Information on the use of sumatriptan during pregnancy is relatively more abundant, given that it has been on the market longer than the other triptans. There are no data to suggest teratogenicity for any of the triptans, although preterm birth rates appear to be elevated.
There are limited data that support the use of hormone contraceptive use in menstrually related migraines (53).
During pregnancy, the choices are complicated by safety concerns for the developing fetus (see Table 2).
Table 2. Safety and Effectiveness of Preventive Migraine Treatments in Pregnancy
|
Medication |
Safety |
Effectiveness |
|
Propranolol |
+++ |
+++ |
|
Memantine |
+++ |
++ |
|
Coenzyme Q10 |
+++ |
+ |
|
Magnesium |
+++ |
+ |
|
Onabotulinum toxin A |
++ |
+++ |
|
Amitriptyline/nortriptyline |
++ |
+++ |
|
Venlafaxine |
++ |
++ |
|
Gabapentin |
++ |
+ |
|
Riboflavin |
++ |
+ |
|
Verapamil |
++ |
+ |
|
Calcitonin gene-related peptide targeting agents |
+ |
+++ |
|
Topiramate |
+ |
+++ |
|
Candesartan |
+ |
++ |
|
Lisinopril |
+ |
++ |
|
Feverfew (Tanacetum parthenium) |
+ |
+ |
|
Valproic acid |
- |
+++ |
|
| ||
Menstrual migraine (catamenial migraine). The low frequency and constricted time period of attacks in most patients with menstrual migraine supports an initial symptomatic approach with specific drugs.
Acute treatment. For acute treatments, rizatriptan has the best overall evidence (159), but sumatriptan, rizatriptan, NSAIDs (eg, naproxen, mefenamic acid), and ergot derivatives are among other options (104; 39; 269). A network meta-analysis to compare the relative efficacy of treatments for menstrual migraine found that sumatriptan 100 mg is the most effective for acute treatment (305).
Preventative therapies. Preventative therapies may be considered in those who either have failed abortive medications or have attacks lasting longer than 2 days (181), but this should only be pursued once the association between migraine and menstruation has been confirmed with prospective records kept for a minimum of three cycles (161). They can be administered during only the perimenstrual time period or continuously throughout the menstrual cycle. Short-term prophylactic therapies are generally preferred because menstrual migraines generally last for only 1 to 4 days, but continuous prophylactic therapies may be considered in those with attacks that are refractory to short-term therapies. Prophylaxis for menstrual migraine should be tried for a minimum of three cycles before it is considered ineffective.
Short-term intermittent prophylactic (also called “mini-prophylaxis” or “mini-prevention”) options include perimenstrual prophylaxis with triptans, NSAIDs (eg, naproxen or mefenamic acid), magnesium, estrogen (percutaneous or transdermal), or dihydroergotamine (104; 06; 107; 269; 159). For females with predictable menstrual-related migraine that does not respond adequately to standard acute treatment, preventive treatment can be considered with triptans on the days migraine is expected (199; 52; 249; 159); frovatriptan (2.5 QD or BID), naratriptan (1 mg BID), and zolmiptriptan (2.5 mgs BID and 2.5 mgs TID) are effective preventative agents when administered for 4 to 5 days during the perimenstrual time period, though frovatriptan appears to be the triptan of choice based on overall efficacy in this patient group (249; 305). Naproxen sodium (eg, 550 mgs BID given 6 days before to 7 days after menses) is also effective for prevention of menstrual migraine (75).
Monoclonal antibodies (eg, galcanezumab, erenumab, or fremanezumab) designed to attach to and block calcitonin gene-related peptide (CGRP) are also effective for migraine prevention in women with menstrually related migraine (282; 173). For erenumab and fremanezumab, the reduction in migraine days under treatment was similar during the menstrual window and the remainder of the menstrual cycle (282).
Hormonal preventive therapies. Various options are available for hormonal treatment of menstrual migraine. Each of these has potential advantages and disadvantages (279), although evidence of prevention using hormonal treatments is poor (53; 28; 70).
Some recommend estrogen supplements for menstrual migraine prevention (eg, 1.5 mg of transdermal estradiol gel applied for 7 days, beginning 10 days after ovulation and continued through the second day of menstrual bleeding; or transdermal estradiol patches, 0.1 mg, started three days before the onset of menses and continued for 7 days) even though evidence from controlled trials is limited and inconsistent with some small trials reporting benefit (69; 73; 170), whereas others did not (11). Although perimenstrual percutaneous estradiol showed benefit during treatment in some trials, this was offset by deferred estrogen withdrawal, often triggering postdosing migraine shortly after the gel was stopped (69; 170). To minimize the issues of estrogen withdrawal, estrogen can be “added back” during the hormone-free interval: so, if withdrawal bleeding is scheduled, adequate estrogen supplementation (ie, estrogen add-back therapy) can be given with estradiol-17b during the pill-free week to limit the decrease to an equivalent of 10 mg of ethinyl estradiol or less, a level that can prevent estrogen-withdrawal headaches or menstrually related migraine (90). If the patient is menstruating regularly, additional progestogen for endometrial protection is not required. Other options include extended-cycle dosing of an ultralow-dose contraceptive ring and gonadotropic-releasing hormone antagonists (90).
A continuous preventative therapy is generally utilized for patients with irregular menses and those who have not had success with short-term-prevention approaches. One long-duration oral-contraceptive approach involves taking combined oral contraceptives containing both ethinyl estrogen and progestin continuously for 9 weeks rather than 3 (ie, so-called "tricycling"), followed by the usual 7-day pill-free interval, producing five rather than 13 withdrawal bleeds per year (146). Alternative nonhormonal therapies include standard prophylactic agents such beta-blockers, calcium channel blockers, tricyclic antidepressants, and anticonvulsants.
Note that many antiepileptic medications used in migraine prevention can affect the efficacy of oral contraceptives and hormonal treatments, so caution is warranted (159). Many antiepileptic medications can cause enzyme induction affecting oral contraceptives and other hormonal treatments. Topiramate at doses below 200 mg/day has the least effect on oral contraceptives.
Catamenial epilepsy. Several different approaches have been proposed for treatment of catamenial epilepsy including: (1) premenstrual or periovulatory supplementation of anticonvulsant doses; (2) addition of an adjunctive antiepileptic drug; (3) cyclic administration of acetazolamide, a mild diuretic with weak antiepileptic activity; and (4) progesterone supplementation (121; 304; 286). The current consensus in catamenial epilepsy focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns that estrogen manipulation may cause seizure provocation (28). Although data from uncontrolled studies suggest that hormone therapy with progesterone may be useful in the treatment of catamenial epilepsy, the efficacy of progesterone for this indication has not been demonstrated in controlled trials (200). Variations in concentrations of antiepileptic drugs across the menstrual cycle may contribute to increased seizure susceptibility.
Movement disorders. Chorea gravidarum carries a good prognosis. The condition is usually self-limited, and premature delivery is rarely required. Women with a history of oral contraceptive-induced or gestational chorea should probably minimize further exposure to any estrogen-containing medications. In severe cases, use of neuroleptics may afford symptomatic relief (96; 214). In patients with Wilson disease, normalization of serum ceruloplasmin levels by estrogen administration is of no significant benefit and may produce deterioration in some patients (307).
In patients with Wilson disease, normalization of serum ceruloplasmin levels by estrogen administration is of no significant benefit and may produce deterioration in some patients (307).
Neuroimmunologic disorders. Although not FDA approved, intravenous steroids have been used as standard of care for multiple sclerosis attacks in pregnancy. Prophylactic therapy (eg, interferon-beta) should be discontinued three months before planned conception and should not be used during pregnancy or when breastfeeding (126; 201). Intravenous immune globulin immediately postpartum seems to have a beneficial effect on multiple sclerosis relapse rate in the first 6 months after delivery (109).
Most women diagnosed with multiple sclerosis can have children without incurring an increased risk of relapses (148). Women with suboptimal disease control before pregnancy may benefit from highly effective disease-modifying therapies that are compatible with pregnancy and lactation (148). Women with multiple sclerosis should be encouraged to breastfeed exclusively because exclusive breastfeeding and a longer duration of breastfeeding are associated with significantly lower relapse rates (149; 148), although not all studies found a substantial beneficial effect of pregnancy or breastfeeding on either the risk of clinically definite multiple sclerosis or disability accrual (311). Rituximab, natalizumab, and other monoclonal antibody disease-modifying therapies, along with Interferon-beta and glatiramer acetate, are thought to be compatible with lactation (148).
Dementia. The third Canadian Consensus Conference for the Diagnosis and Treatment of Dementia (2006) recommended against the use of estrogen-progestin replacement therapy for reducing the risk of dementia in postmenopausal women. It also concluded that there is insufficient evidence for or against the prescription of androgen replacement for cognitive dysfunction in elderly men.
In a cohort of postmenopausal women at risk for dementia, high and low insulin resistance groups revealed a significant metabolic decline of the medial prefrontal gyrus, irrespective of the randomized hormone therapy group (216).
Neuropsychiatric disorders. Psychotic disorders may be refractory to conventional therapies (neuroleptics, lithium, electroconvulsive therapy) but respond well to particular hormonal interventions, including the use of oral contraceptives and danazol (91; 72; 18).
Numerous hormonal and nonhormonal therapies, including oral contraceptives, bromocriptine, gonadotropin-releasing hormone agonists, diuretics, prostaglandin inhibitors, vitamin B6, and lithium, are prescribed for the management of premenstrual syndrome and premenstrual dysphoric disorder (222).
Although oral contraceptives may precipitate depression in susceptible individuals, estrogen replacement may help with postmenopausal depression (101; 188).
Neuropsychiatric disorders. Psychotic disorders that are refractory to conventional therapies (neuroleptics, lithium, electroconvulsive therapy) may respond well to specific hormonal interventions including the use of oral contraceptives and danazol (91; 72; 18).
Although oral contraceptives may precipitate depression in susceptible individuals, estrogen replacement may help with postmenopausal depression (101; 188).
Neuromuscular disorders. Symptoms of catamenial sciatica may show dramatic improvement with standard therapy for endometriosis, including danazol, progestins, and in refractory cases, bilateral oophorectomy (24; 158; 238).
In an anecdotal report, high-dose testosterone therapy yielded considerable symptomatic improvement in a patient with bulbospinal muscular atrophy (141).
Catamenial sciatica (endometriosis). Symptoms of catamenial sciatica may show dramatic improvement with standard therapy for endometriosis, including danazol, progestins, and in refractory cases, bilateral oophorectomy (24; 158; 238). In an anecdotal report, high-dose testosterone therapy yielded considerable symptomatic improvement in a patient with bulbospinal muscular atrophy (141).
Sleep disorders. One case reported that removal of a benign testosterone-producing ovarian tumor resolved obstructive sleep apnea (74). In addition, testosterone administration has been shown to increase hypocapnic apnea threshold in premenopausal women (306; 60).
Porphyria. In addition to standard treatment involving removal of precipitating factors and intravenous administration of hemin for acute attacks (15), gonadotropin-releasing hormone analogues have been utilized in the management of catamenial acute intermittent porphyria and hereditary coproporphyria (if cyclic attacks are frequent) (303; 05).
Media
References
- 01
- Ahangari A, Bäckström T, Innala E, Andersson C, Turkmen S. Acute intermittent porphyria symptoms during the menstrual cycle. Intern Med J 2015;45(7):725-31. PMID 25871503
- 02
- Ahmad SR, Rosendale N. Sex and gender considerations in episodic migraine. Curr Pain Headache Rep 2022;26(7):505-16. PMID 35679008
- 03
- Ahmad A, Vohora D. Proconvulsant effects of estriol, the third estrogen, in the mouse PTZ-kindling model. Neurol Sci 2014;35(10):1561-6. PMID 24748480
- 04
- Airola G, Allais G, Castagnoli Gabellari I, Rolando S, Mana O, Benedetto C. Non-pharmacological management of migraine during pregnancy. Neurol Sci 2010;31 Suppl 1:S63-5. PMID 20464586
- 05
- Akira S, Mine K, Kuwabara Y, Takeshita T. Efficacy of long-term, low-dose gonadotropin-releasing hormone agonist therapy (draw-back therapy) for adenomyosis. Med Sci Monit 2009;15(1):CR1-4. PMID 19114964
- 06
- Allais G, Benedetto C. Update on menstrual migraine: from clinical aspects to therapeutical strategies. Neurol Sci 2004;25 Suppl 3:S229-31. PMID 15549543
- 07
- Allais G, Castagnoli Gabellari I, De Lorenzo C, Mana O, Benedetto C. Oral contraceptives in migraine therapy. Neurol Sci 2011;32 Suppl 1:S135-9. PMID 21533729
- 08
- Allais G, Chiarle G, Bergandi F, Benedetto C. The use of progestogen-only pill in migraine patients. Expert Rev Neurother 2016;16(1):71-82. PMID 26630354
- 09
- Allais G, Chiarle G, Sinigaglia S, Mana O, Benedetto C. Migraine during pregnancy and in the puerperium. Neurol Sci 2019;40(Suppl 1):81-91. PMID 30880362
- 10
- Allena M, De Icco R, Sances G, et al. Gender differences in the clinical presentation of cluster headache: a role for sexual hormones? Front Neurol 2019;10:1220. PMID 31824403
- 11
- Almén-Christensson A, Hammar M, Lindh-Åstrand L, Landtblom AM, Brynhildsen J. Prevention of menstrual migraine with perimenstrual transdermal 17-β-estradiol: a randomized, placebo-controlled, double-blind crossover study. Fertil Steril 2011;96(2):498-500.e1. PMID 21704313
- 12
- Alreja M. Electrophysiology of kisspeptin neurons. Adv Exp Med Biol 2013;784:349-62. PMID 23550014
- 13
- Alshakhouri M, Sharpe C, Bergin P, Sumner RL. Female sex steroids and epilepsy: Part 2. A practical and human focus on catamenial epilepsy. Epilepsia 2024b;65(3):569-82. PMID 37925609
- 14
- Alshakhouri M, Sharpe C, Bergin P, Sumner RL. Female sex steroids and epilepsy: Part 1. A review of reciprocal changes in reproductive systems, cycles, and seizures. Epilepsia 2024a;65(3):556-68. PMID 38036939
- 15
- Anderson KE. Acute hepatic porphyrias: current diagnosis & management. Mol Genet Metab 2019;128(3):219-27. PMID 31311713
- 16
- Anderson KE, Spitz IM, Bardin CW, Kappas A. A gonadotropin releasing hormone analogue prevents cyclical attacks of porphyria. Arch Intern Med 1990;150(7):1469-74. PMID 2196028
- 17
- Andersson C, Innala E, Bäckström T. Acute intermittent porphyria in women: clinical expression, use and experience of exogenous sex hormones. A population-based study in northern Sweden. J Intern Med 2003;254(2):176-83. PMID 12859699
- 18
- Andreou C, Syngelakis M, Karavatos A. Metformine for psychosis associated with the menstrual cycle in a patient with polycystic ovary syndrome. Arch Womens Ment Health 2008;11(5-6):387-8. PMID 18827957
- 19
- Anker JJ, Carroll ME. Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones. Curr Top Behav Neurosci 2011;8:73-96. PMID 21769724
- 20
- Aronson NI, Kaplow S, Goldstein PJ. Brain tumors during pregnancy. In: Goldstein P, ed. Neurological Disorders of Pregnancy. Mt Kisco, NY: Futura, 1986:41.
- 21
- Bäckström T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle. Acta Neurol Scand 1976;54(4):321-47. PMID 973554
- 22
- Badminton MN, Elder GH. Molecular mechanisms of dominant expression in porphyria. J Inherit Metab Dis 2005;28(3):277-86. PMID 15868463
- 23
- Bagatell CJ, Dahl KD, Bremner WJ. The direct pituitary effect of testosterone to inhibit gonadotropin secretion in men is partially mediated by aromatization to estradiol. J Androl 1994;15(1):15-21. PMID 8188534
- 24
- Baker GS, Parsons WR, Welch JS. Endometriosis within the sheath of the sciatic nerve: Report of two patients with progressive paralysis. J Neurosurg 1966;25(6):652-5. PMID 5951227
- 25
- Bale TL, Epperson CN. Sex differences and stress across the lifespan. Nat Neurosci 2015;18(10):1413-20. PMID 26404716
- 26
- Barac-Latas V, Muhvic D, Radosevic-Stabic B. The influence of pregnancy on development and course of chronic relapsing experimental autoimmune encephalomyelitis in rats: implications for multiple sclerosis. Coll Antropol 2010;34 Suppl 1:267-71. PMID 20402331
- 27
- Barha CK, Ishrat T, Epp JR, Galea LA, Stein DG. Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury. Exp Neurol 2011;231(1):72-81. PMID 21684276
- 28
- Barone JC, Butler MP, Ross A, Patterson A, Wagner-Schuman M, Eisenlohr-Moul TA. A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy. Front Neuroendocrinol 2023;71:101098. PMID 37619655
- 29
- Batistatou A, Stefanou D, Goussia A, Arkoumani E, Papavassiliou AG, Agnantis NJ. Estrogen receptor beta (ERbeta) is expressed in brain astrocytic tumors and declines with dedifferentiation of the neoplasm. J Cancer Res Clin Oncol 2004;130(7):405-10. PMID 15141349
- 30
- Beckham JC, Krug LM, Penzien DB, et al. The relationship of ovarian steroids, headache activity and menstrual distress: a pilot study with female migraineurs. Headache 1992;32(6):292-7. PMID 1399550
- 31
- Bedard P, Langelier P, Villeneuve A. Oestrogens and extrapyramidal system. Lancet 1977;2(8052-8053):1367. PMID 74783
- 32
- Benedetti MD, Maraganore DM, Bower JH, et al. Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: an exploratory case-control study. Mov Disord 2001;16(5):830-7. PMID 11746612
- 33
- Billeci AM, Paciaroni M, Caso V, Agnelli G. Hormone replacement therapy and stroke. Curr Vasc Pharmacol 2008;6(2):112-23. PMID 18393913
- 34
- Bingel U. [Migraine and hormones: what can we be certain of.] [Article in German] Schmerz 2008;22 Suppl 1:31-6. PMID 18256855
- 35
- Bissell DM, Lai JC, Meister RK, Blanc PD. Role of delta-aminolevulinic acid in the symptoms of acute porphyria. Am J Med 2015;128(3):313-7. PMID 25446301
- 36
- Bogush TA, Dudko EA, Beme AA, Bogush EA, Polotskii BE, Tiuliandin SA, Davydov MI. [Estrogen receptor expression in tumors different from breast cancer.] [Article in Russian] Antibiot Khimioter 2009;54(7-8):41-9. PMID 20201403
- 37
- Bonkovsky HL, Maddukuri VC, Yazici C, et al. Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium. Am J Med 2014;127(12):1233-41. PMID 25016127
- 38
- Bove R, White CC, Fitzgerald KC, et al. Hormone therapy use and physical quality of life in postmenopausal women with multiple sclerosis. Neurology 2016;87(14):1457-63. PMID 27605175
- 39
- Boyle CA. Management of menstrual migraine. Neurology 1999;53(4 Suppl 1):S14-8. PMID 10487508
- 40
- Brandes JL. The influence of estrogen on migraine: a systematic review. JAMA 2006;295(15):1824-30. PMID 16622144
- 41
- Brenton JN. Menarche and relapses in multiple sclerosis: associations between a physiologic developmental milestone and disease activity. Neurology 2025;104(4):e213321. PMID 39899792
- 42
- Burakgazi E, Harden C, Kelly JJ. Contraception for women with epilepsy. Rev Neurol Dis 2009;6(2):E62-7. PMID 19587632
- 43
- Burch R. Epidemiology and treatment of menstrual migraine and migraine during pregnancy and lactation: a narrative review. Headache 2020;60(1):200-16. PMID 31579938
- 44
- Cai H, Ye X, Zheng W, Ma L, Hu X, Jin X. Pitfalls in the diagnosis and initial management of acute cerebral venous thrombosis. Rev Cardiovasc Med 2018;19(4):129-33. PMID 31064164
- 45
- Calhoun AH. A novel specific prophylaxis for menstrual-associated migraine. South Med J 2004;97(9):819-22. PMID 15455962
- 46
- Calhoun AH. Menstrual migraine: update on pathophysiology and approach to therapy and management. Curr Treat Options Neurol 2012;14(1):1-14. PMID 22072055
- 47
- Calhoun AH. Hormonal contraceptives and migraine with aura: is there still a risk? Headache 2017;57(2):184-93. PMID 27774589
- 48
- Calhoun AH, Batur P. Combined hormonal contraceptives and migraine: an update on the evidence. Cleve Clin J Med 2017;84(8):631-8. PMID 28806162
- 49
- Calton GJ, Burnett JW. Danazol and migraine. N Engl J Med 1984;310(11):721-2. PMID 6700650
- 50
- Carr BR, Ory H. Estrogen and progestin components of oral contraceptives: relationship to vascular disease. Contraception 1997;55(5):267-72. PMID 9220222
- 51
- Carrasquilla GD, Frumento P, Berglund A, et al. Postmenopausal hormone therapy and risk of stroke: a pooled analysis of data from population-based cohort studies. PLoS Med 2017;14(11):e1002445. PMID 29149179
- 52
- Carville S, Padhi S, Reason T, Underwood M, Guideline Development Group. Diagnosis and management of headaches in young people and adults: summary of NICE guidance. BMJ 2012;345:e5765. PMID 22993393
- 53
- Chai NC, Peterlin BL, Calhoun AH. Migraine and estrogen. Curr Opin Neurol 2014;27(3):315-24. PMID 24792340
- 54
- Chalmer MA, Kogelman LJA, Ullum H, et al. Population-based characterization of menstrual migraine and proposed diagnostic criteria. JAMA Netw Open 2023;6(5):e2313235. PMID 37184838
- 55
- Chan WS, Ray J, Wai EK, et al. Risk of stroke in women exposed to low-dose oral contraceptives: a critical evaluation of the evidence. Arch Intern Med 2004;164(7):741-7. PMID 15078643
- 56
- Chawla J. Pregnancy related neuropathies. In: Biller J, ed. The Interface of Neurology & Internal Medicine. Lippincott Williams & Wilkins, 2007.
- 57
- Chawla J. Migraine Headache (in Neurology reference). eMedicine from WebMD. Available at:http://emedicine.medscape.com/article/1142556-overview. Accessed September 2014.
- 58
- Chofflon M, Lalive PH. [Multiple sclerosis and pregnancy.] [Article in French] Rev Med Suisse 2009;5(201):936, 938-40. PMID 19476055
- 59
- Choi JC, Chung MI, Lee YD. Modulation of pain sensation by stress-related testosterone and cortisol. Anaesthesia 2012;67(10):1146-51. PMID 22804789
- 60
- Chowdhuri S, Shanidze I, Pierchala L, Belen D, Mateika JH, Badr MS. Effect of episodic hypoxia on the susceptibility to hypocapnic central apnea during NREM sleep. J Appl Physiol 2010;108(2):369-77. PMID 19940101
- 61
- Collet TH, Ewing SK, Ensrud KE, et al. Endogenous testosterone levels and the risk of incident cardiovascular events in elderly men: the MrOS prospective study. J Endocr Soc 2020;4(5):bvaa038. PMID 32337470
- 62
- Costanza M, Pedotti R. Prolactin: friend or foe in central nervous system autoimmune inflammation? Int J Mol Sci 2016;17(12). PMID 27918427
- 63
- Coughlan GT, Rubinstein Z, Klinger H, et al. Associations between hormone therapy use and tau accumulation in brain regions vulnerable to Alzheimer's disease. Sci Adv 2025;11(10):eadt1288. PMID 40043125
- 64
- Couturier EG, Bomhof MA, Neven AK, van Duijn NP. Menstrual migraine in a representative Dutch population sample: prevalence, disability and treatment. Cephalalgia 2003;23(4):302-8. PMID 12716349
- 65
- Crawford PM. Managing epilepsy in women of childbearing age. Drug Saf 2009;32(4):293-307. PMID 19388721
- 66
- Cupini LM, Matteis M, Troisi E, Calabresi P, Bernardi G, Silvestrini M. Sex-hormone-related events in migrainous females. A clinical comparative study between migraine with aura and migraine without aura. Cephalalgia 1995;15(2):140-4. PMID 7641250
- 67
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep 2016;65(3):1-103. PMID 27467196
- 68
- Cushman T, Kim N, Hoyt R, Traish AM. Estradiol restores diabetes-induced reductions in sex steroid receptor expression and distribution in the vagina of db/db mouse model. J Steroid Biochem Mol Biol 2009;114(3-5):186-94. PMID 19429450
- 69
- de Lignières B, Vincens M, Mauvais-Jarvis P, Mas JL, Touboul PJ, Bousser MG. Prevention of menstrual migraine by percutaneous oestradiol. Br Med J (Clin Res Ed) 1986;293(6561):1540. PMID 3099950
- 70
- de Matteis E, Ornello R, Sacco S. Menstrually associated migraine. Handb Clin Neurol 2024;199:331-51. PMID 38307655
- 71
- de Nicola AF, Brocca ME, Pietranera L, Garcia-Sequra LM. Neuroprotection and sex steroid hormones: evidence of estradiol-mediated protection in hypertensive encephalopathy. Mini Rev Med Chem 2012;12(11):1081-9. PMID 22827218
- 72
- Dennerstein L, Judd F, Davies B. Psychosis and the menstrual cycle. Med J Aust 1983;1(11):524-6. PMID 6682476
- 73
- Dennerstein L, Morse C, Burrows G, Oats J, Brown J, Smith M. Menstrual migraine: a double-blind trial of percutaneous estradiol. Gynecol Endocrinol 1988;2(2):113-20. PMID 3055819
- 74
- Dexter DD, Dovre EJ. Obstructive sleep apnea due to endogenous testosterone production in a woman. Mayo Clin Proc 1998;73(3):246-8. PMID 9511783
- 75
- Diamond S. Menstrual migraine and non-steroidal anti-inflammatory agents. Headache 1984;24(1):52. PMID 6706556
- 76
- Donahue JE, Stopa EG, Chorsky RL, et al. Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain. Brain Res 2000;856(1-2):142-51. PMID 10677621
- 77
- Donaldson J. Neurology of Pregnancy. Philadelphia: WB Saunders, 1978.
- 78
- Dowson AJ, Kilminster SG, Salt R, Clark M, Bundy MJ. Disability associated with headaches occurring inside and outside the menstrual period in those with migraine: a general practice study. Headache 2005;45(4):274-82. PMID 15836563
- 79
- Dulicek P, Ivanova E, Kostal M, et al. Analysis of risk factors of stroke and venous thromboembolism in females with oral contraceptives use. Clin Appl Thromb Hemost 2018;24(5):797-802. PMID 28884608
- 80
- Duncan S, Read CL, Brodie MJ. How common is catamenial epilepsy? Epilepsia 1993;34(5):827-31. PMID 8404732
- 81
- Dzoljic E, Sipetic S, Vlajinac H, et al. Prevalence of menstrually related migraine and nonmigraine primary headache in female students of Belgrade University. Headache 2002;42(3):185-93. PMID 11903541
- 82
- Edelman A, Micks E, Gallo MF, Jensen JT, Grimes DA. Continuous or extended cycle vs. cyclic use of combined hormonal contraceptives for contraception. Cochrane Database Syst Rev 2014;(7):CD004695. PMID 25072731
- 83
- Eftekhari N, Mohammadalizadeh S. Pregnancy rate following bromocriptine treatment in infertile women with galactorrhea. Gynecol Endocrinol 2009;25(2):122-4. PMID 19253108
- 84
- Elam MB, Viar MJ, Ratts TE, Chesney CM. Mitral valve prolapse in women with oral contraceptive-related cerebrovascular insufficiency. Associated persistent hypercoagulable state. Arch Intern Med 1986;146(1):73-7. PMID 2935107
- 85
- El-Khayat HA, Soliman NA, Tomoum HY, Omran MA, El-Wakad AS, Shatla RH. Reproductive hormonal changes and catamenial pattern in adolescent females with epilepsy. Epilepsia 2008;49(9):1619-26. PMID 18435756
- 86
- Emerson CS, Headrick JP, Vink R. Estrogen improves biochemical and neurologic outcome following traumatic brain injury in male rats, but not in females. Brain Res 1993;608(1):95-100. PMID 8495351
- 87
- Epstein MT, Hockaday JM, Hockaday TD. Migraine and reproductive hormones through the menstrual cycle. Lancet 1975;1(7906):543-8. PMID 47017
- 88
- Estanol B, Rodriguez A, Conte G, Aleman JM, Loyo M, Pizzuto J. Intracranial venous thrombosis in young women. Stroke 1979;10(6):680-4. PMID 524408
- 89
- Evron S, Brenner T, Abramsky O. Suppressive effect of pregnancy on the development of experimental allergic encephalomyelitis in rabbits. Am J Reprod Immunol 1984;5(3):109-13. PMID 6204544
- 90
- Faubion SS, Batur P, Calhoun AH. Migraine throughout the female reproductive life cycle. Mayo Clin Proc 2018;93(5):639-45. PMID 29728203
- 91
- Felthous AR, Robinson DB, Conroy RW. Prevention of recurrent menstrual psychosis by an oral contraceptive. Am J Psychiatry 1980;137(2):245-6. PMID 6101529
- 92
- Finocchi C, Ferrari M. Female reproductive steroids and neuronal excitability. Neurol Sci 2011;32(Suppl 1):S31-5. PMID 21533709
- 93
- Finocchi C, Strada L. Sex-related differences in migraine. Neurol Sci 2014;35 Suppl 1:207-13. PMID 24867868
- 94
- Frye CA. The neurosteroid 3 alpha, 5 apha-THP has antiseizure and possible neuroprotective effects in an animal model of epilepsy. Brain Res 1995;696(1-2):113-20. PMID 8574658
- 95
- Galdiero M, Pivonello R, Grasso LF, Cozzolino A, Colao A. Growth hormone, prolactin, and sexuality. J Endocrinol Invest 2012;35(8):782-94. PMID 23014134
- 96
- Gamboa ET, Isaacs G, Harter DH. Chorea associated with oral contraceptive therapy. Arch Neurol 1971;25(2):112-4. PMID 5571013
- 97
- Garcia-Falgueras A, Swaab DF. Sexual hormones and the brain: an essential alliance for sexual identity and sexual orientation. Endocr Dev 2010;17:22-35. PMID 19955753
- 98
- Gerlis LS. Acute intermittent porphyria on withdrawal of oral contraceptives. J Int Med Res 1978;6(4):255-6. PMID 689289
- 99
- Ghanem Q. Recurrent chorea gravidarum in four pregnancies. Can J Neurol Sci 1985;12(2):136-8. PMID 4040415
- 100
- Gilmer LK, Roberts KN, Scheff SW. Efficacy of progesterone following a moderate unilateral cortical contusion injury. J Neurotrauma 2008;25(6):593-602. PMID 18476780
- 101
- Glick ID, Quitkin FM, Bennett SE. The influence of estrogens, progestins, and oral contraceptives on depression. In: Halbreich U, ed. Hormones and Depression. New York: Raven Press, 1987:339.
- 102
- Goadsby PJ, Goldberg J, Silberstein SD. Migraine in pregnancy. BMJ 2008;336(7659):1502-4. PMID 18583683
- 103
- Granella F, Sances G, Allais G, et al. Characteristics of menstrual and nonmenstrual attacks in women with menstrually related migraine referred to headache centres. Cephalalgia 2004;24(9):707-16. PMID 15315526
- 104
- Granella F, Sances G, Messa G, de Marinis M, Manzoni GC. Treatment of menstrual migraine. Cephalalgia 1997;17 Suppl 20:35-8. PMID 9496777
- 105
- Granella F, Sances G, Zanferrari C, Costa A, Martignoni E, Manzoni GC. Migraine without aura and reproductive life events: a clinical epidemiological study in 1300 women. Headache 1993;33(7):385-9. PMID 8376100
- 106
- Gross U, Honcamp M, Daume E, Frank M, Düsterberg B, Doss MO. Hormonal oral contraceptives, urinary porphyrin excretion and porphyrias. Horm Metab Res 1995;27(8):379-83. PMID 7590628
- 107
- Guidotti M, Mauri M, Barrilà C, Guidotti F, Belloni C. Frovatriptan vs.transdermal oestrogens or naproxen sodium for the prophylaxis of menstrual migraine. J Headache Pain 2007;8(5):283-8. PMID 17955167
- 108
- Guven Yorgun Y, Ozakbas S. Effect of hormonal changes on the neurological status in the menstrual cycle of patient with multiple sclerosis. Clin Neurol Neurosurg 2019;186:105499. PMID 31541863
- 109
- Haas J, Hommes OR. A dose comparison study of IVIG in postpartum relapsing-remitting multiple sclerosis. Mult Scler 2007;13(7):900-8. PMID 17881400
- 110
- Haddad G, Haddad F, Worseley K, et al. Brain tumours and pregnancy. Can J Neurol Sci 1991;18:231.
- 111
- Hamed SA. Neuroendocrine hormonal conditions in epilepsy: relationship to reproductive and sexual functions. Neurologist 2008;14(3):157-69. PMID 18469673
- 112
- Harden CL. Hormone replacement therapy: will it affect seizure control and AED levels? Seizure 2008;17(2):176-80. PMID 18187348
- 113
- Harden CL, Meador KJ, Pennell PB, et al. Practice parameter update: management issues for women with epilepsy--focus on pregnancy (an evidence-based review): teratogenesis and perinatal outcomes: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society. Neurology 2009;73(2):133-41. PMID 19398681
- 114
- Harroud A, Morris JA, Forgetta V, et al. Effect of age at puberty on risk of multiple sclerosis: A mendelian randomization study. Neurology 2019;92(16):e1803-10. PMID 30894442
- 115
- Hay M. Sex, the brain and hypertension: brain oestrogen receptors and high blood pressure risk factors. Clin Sci (Lond) 2016;130(1):9-18. PMID 26621877
- 116
- Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38(1):1-211. PMID 29368949
- 117
- Heinemann LA, Dinger JC, Assmann A, Minh TD. Use of oral contraceptives containing gestodene and risk of venous thromboembolism: outlook 10 years after the third-generation "pill scare." Contraception 2010;81(5):401-7. PMID 20399946
- 118
- Henderson VW, Brinton RD. Menopause and mitochondria: windows into estrogen effects on Alzheimer's disease risk and therapy. Prog Brain Res 2010;182:77-96. PMID 20541661
- 119
- Herzog AG. Catamenial epilepsy: definition, prevalence pathophysiology and treatment. Seizure 2008;17(2):151-9. PMID 18164632
- 120
- Herzog AG. Continuous bromocriptine therapy in menstrual migraine. Neurology 1997;48(1):101. PMID 9008502
- 121
- Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology 1999;52(9):1917-8. PMID 10371551
- 122
- Herzog AG. Menstrual disorders in women with epilepsy. Neurology 2006;66(6 Suppl 3):S23-8. PMID 16567738
- 123
- Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia 1997;38(10):1082-8. PMID 9579954
- 124
- Hoshiyama E, Tatsumoto M, Iwanami H, et al. Postpartum migraines: a long-term prospective study. Intern Med 2012;51(22):3119-23. PMID 23154716
- 125
- Hu J, Lin JH, Jiménez MC, Manson JE, Hankinson SE, Rexrode KM. Plasma estradiol and testosterone levels and ischemic stroke in postmenopausal women. Stroke 2020;51(4):1297-300. PMID 32078496
- 126
- Hutchinson M. Pregnancy and multiple sclerosis. MS Management 1999;6:3.
- 127
- Innala E, Bäckström T, Bixo M, Andersson C. Evaluation of gonadotropin-releasing hormone agonist treatment for prevention of menstrual-related attacks in acute porphyria. Acta Obstet Gynecol Scand 2010;89(1):95-100. PMID 20021268
- 128
- Jiang Y, Huang ZL. Recent advances in targeting calcitonin gene-related peptide for the treatment of menstrual migraine: A narrative review. Medicine (Baltimore) 2022;101(24):e29361. PMID 35713436
- 129
- Johannes CB, Linet MS, Stewart WF, Celentano DD, Lipton RB, Szklo M. Relationship of headache to phase of the menstrual cycle among young women: a daily diary study. Neurology 1995;45(6):1076-82. PMID 7783866
- 130
- Johnson MD, Vito F, O'Connell MJ. Mesothelin expression in the leptomeninges and meningiomas. J Histochem Cytochem 2008;56(6):579-85. PMID 18347077
- 131
- Júnior VRS, Lemos VMV, Feitosa IML, et al. Effect of menstrual cycle on acute intermittent porphyria. Child Neurol Open 2017;4:2329048X17736170. PMID 29094055
- 132
- Kalleinen N, Polo O, Himanen SL, Joutsen A, Polo-Kantola P. The effect of estrogen plus progestin treatment on sleep: a randomized, placebo-controlled, double-blind trial in premenopausal and late postmenopausal women. Climacteric 2008;11(3):233-43. PMID 18568788
- 133
- Kansky A, Gregorc J, Pavlic M. Oral contraceptives and their influence on porphyrin concentrations in erythrocytes and urine. Dermatologica 1978;157(3):181-5. PMID 680302
- 134
- Kapur J, Joshi S. Progesterone modulates neuronal excitability bidirectionally. Neurosci Lett 2021;744:135619. PMID 33421486
- 135
- Karageorgiou V, Lambrinoudaki I, Goulis DG. Menopause in women with multiple sclerosis: a systematic review. Maturitas 2020;135:68-73. PMID 32252967
- 136
- Kauppinen R, Mustajoki P. Prognosis of acute porphyria: occurrence of acute attacks, precipitating factors, and associated diseases. Medicine (Baltimore) 1992;71(1):1-13. PMID 1549056
- 137
- Kearney BP, Mathias A. Lack of effect of tenofovir disoproxil fumarate on pharmacokinetics of hormonal contraceptives. Pharmacotherapy 2009;29(8):924-9. PMID 19637945
- 138
- Keith AB. Effect of pregnancy on experimental allergic encephalomyelitis in guinea pigs and rats. J Neurol Sci 1978;38(3):317-26. PMID 569689
- 139
- Kibler JL, Rhudy JL, Penzien DB, et al. Hormones, menstrual distress, and migraine across the phases of the menstrual cycle. Headache 2005;45(9):1181-9. PMID 16178948
- 140
- Kilpatrick CJ, Moulds RF. Anticonvulsants in pregnancy. Med J Aust 1991;154(3):199-202. PMID 1988794
- 141
- Kinirons P, Rouleau GA. Administration of testosterone results in reversible deterioration in Kennedy's disease. J Neurol Neurosurg Psychiatry 2008;79(1):106-7. PMID 17056629
- 142
- Kirby M, Zsarnovszky A, Belcher SM. Estrogen receptor expression in a human primitive neuroectodermal tumor cell line from the cerebral cortex: estrogen stimulates rapid ERK1/2 activation and receptor-dependent cell migration. Biochem Biophys Res Commun 2004;319(3):753-8. PMID 15184047
- 143
- Kirschner M, Schneider G, Ertel NH, Worton E. Obesity, androgens, estrogens and cancer risk. Cancer Res 1982;42(8Suppl):3281s-3285s. PMID 7083187
- 144
- Krysko KM, Waltz M, Chitnis T, et al. Study of the association between menarche and disease course in pediatric multiple sclerosis. Neurology 2025;104(4):e210213. PMID 39899789
- 145
- Kvisvik EV, Stovner LJ, Helde G, Bovim G, Linde M. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain 2011;12(4):443-51. PMID 21442333
- 146
- LaGuardia KD, Fisher AC, Bainbridge JD, LoCoco JM, Friedman AJ. Suppression of estrogen-withdrawal headache with extended transdermal contraception. Fertil Steril 2005;83(6):1875-7. PMID 15950671
- 147
- Lamon JM, Frykholm BC, Herrera W, Tschudy DP. Danazol administration to females with menses-associated exacerbations of acute intermittent porphyria. J Clin Endocrinol Metab 1979;48(1):123-6. PMID 422693
- 148
- Langer-Gould A, Smith JB, Albers KB, et al. Pregnancy-related relapses and breastfeeding in a contemporary multiple sclerosis cohort. Neurology 2020;94(18):e1939-49. PMID 32284359
- 149
- Langer-Gould A, Smith JB, Hellwig K, et al. Breastfeeding, ovulatory years, and risk of multiple sclerosis. Neurology 2017;89(6):563-9. PMID 28701499
- 150
- Lee LS, Chi CW, Chang TJ, Chou MD, Liu HC, Liu TY. Steroid hormone receptors in meningiomas of Chinese patients. Neurosurgery 1989;25(4):541-5. PMID 2797392
- 151
- Leentjens AF, Koester J, Fruh B, Shephard DT, Barone P, Houben JJ. The effect of pramipexole on mood and motivational symptoms in Parkinson's disease: a meta-analysis of placebo-controlled studies. Clin Ther 2009;31(1):89-98. PMID 19243709
- 152
- Levit EJ, Nodine JH, Perloff WH. Progesterone-induced porphyria. Am J Med 1957;22:831-3. PMID 13410972
- 153
- Levy RH, Yerby MS. Effects of pregnancy on antiepileptic drug utilization. Epilepsia 1985;26 Suppl 1:S52-7. PMID 3922750
- 154
- Li XL, Cheng WD, Li J, et al. Does estrogen receptor gene polymorphism play a role in Parkinson's disease. Biomed Pharmacother 2009;63(8):599-602. PMID 18980828
- 155
- Lima ACS, Martins LCG, Lopes MVO, et al. Influence of hormonal contraceptives and the occurrence of stroke: integrative review. Rev Bras Enferm 2017;70(3):647-55. PMID 28562816
- 156
- Lindvall-Axelsson M, Owman C. Actions of sex steroids and corticosteroids on rabbit choroid plexus as shown by changes in transport capacity and rate of cerebrospinal fluid formation. Neurol Res 1990;12(3):181-6. PMID 1979849
- 157
- Løkkegaard E, Nielsen LH, Keiding N. Risk of stroke with various types of menopausal hormone therapies: a national cohort study. Stroke 2017;48(8):2266-2269. PMID 28626058
- 158
- Lombardo L, Mateos JH, Barroeta FF. Subarachnoid hemorrhage due to endometriosis of the spinal canal. Neurology 1968;18(5):423-6. PMID 5691170
- 159
- Maasumi K, Tepper SJ, Kriegler JS. Menstrual migraine and treatment options: review. Headache 2017;57(2):194-208. PMID 27910087
- 160
- Madsen TE, Luo X, Huang M, et al. Circulating SHBG (sex hormone-binding globulin) and risk of ischemic stroke: findings from the WHI. Stroke 2020;51(4):1257-64. PMID 32078494
- 161
- MacGregor A. Migraine associated with menstruation. Funct Neurol 2000;15 Suppl 3:143-53. PMID 11200785
- 162
- MacGregor EA. Estrogen replacement and migraine. Maturitas 2009;63(1):51-5. PMID 19375252
- 163
- MacGregor EA. Female sex hormones and migraine. Rev Neurol (Paris) 2005;161(6-7):677-8. PMID 16141956
- 164
- MacGregor EA. Menstrual migraine: therapeutic approaches. Ther Adv Neurol Disord 2009a;2(5):327-36. PMID 21180623
- 165
- MacGregor EA. Migraine, menopause and hormone replacement therapy. Post Reprod Health 2018;24(1):11-8. PMID 28994639
- 166
- MacGregor EA. Oestrogen and attacks of migraine with and without aura. Lancet Neurol 2004;3(6):354-61. PMID 15157850
- 167
- MacGregor EA, Brandes J, Eikermann A, Giammarco R. Impact of migraine on patients and their families: the Migraine And Zolmitriptan Evaluation (MAZE) survey--Phase III. Curr Med Res Opin 2004;20(7):1143-50. PMID 15265259
- 168
- MacGregor EA, Chia H, Vohrah RC, Wilkinson M. Migraine and menstruation: a pilot study. Cephalalgia 1990;10(6):305-10. PMID 2289231
- 169
- MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A. Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen. Neurology 2006b;67(12):2154-8. PMID 16971700
- 170
- MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A. Prevention of menstrual attacks of migraine: a double-blind placebo-controlled crossover study. Neurology 2006a;67(12):2159-63. PMID 17190936
- 171
- MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology 2004;63(2):351-3. PMID 15277635
- 172
- MacGregor EA, Komori M, Krege JH, Baygani S, Vincent M, Pavlovic J, Igarashi H. Efficacy of lasmiditan for the acute treatment of perimenstrual migraine. Cephalalgia 2022;42(14):1467-75. PMID 35979677
- 173
- MacGregor EA, Okonkwo R, Detke HC, Polavieja P, Fernandes MS, Pavlovic JM. Effect of galcanezumab in women with episodic migraine meeting criteria for menstrually related migraine: a post hoc analysis of EVOLVE-1 and EVOLVE-2. Headache 2024;64(2):179-87. PMID 38017629
- 174
- MacGregor EA, Victor TW, Hu X, et al. Characteristics of menstrual vs nonmenstrual migraine: a post hoc, within-woman analysis of the usual-care phase of a nonrandomized menstrual migraine clinical trial. Headache 2010;50(4):528-38. PMID 20236340
- 175
- Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science 1986;232(4753):1004-7. PMID 2422758
- 176
- Manson JE, Aragaki AK, Rossouw JE, et al. Menopausal hormone therapy and long-term all-cause and cause-specific mortality: The Women's Health Initiative randomized trials. JAMA 2017;318(10):927-38. PMID 28898378
- 177
- Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 2013;310(13):1353-68. PMID 24084921
- 178
- Manwani B, McCullough LD. Sexual dimorphism in ischemic stroke: lessons from the laboratory. Womens Health (Lond Engl) 2011;7(3):319-39. PMID 21612353
- 179
- Marcus DA. Interrelationships of neurochemicals, estrogen, and recurring headache. Pain 1995;62(2):129-39. PMID 8545137
- 180
- Marcus DA, Bernstein CD, Sullivan EA, Rudy TE. Perimenstrual eletriptan prevents menstrual migraine: an open-label study. Headache 2010;50(4):551-62. PMID 20236337
- 181
- Martin VT. Menstrual migraine: a review of prophylactic therapies. Curr Pain Headache Rep 2004;8(3):229-37. PMID 15115643
- 182
- Martin VT, Behbehani M. Ovarian hormones and migraine headache: understanding mechanisms and pathogenesis--part 2. Headache 2006;46(3):365-86. PMID 16618254
- 183
- Martin VT, Lipton RB. Epidemiology and biology of menstrual migraine. Headache 2008;48 Suppl 3:S124-30. PMID 19076658
- 184
- Massoud F, Yaffe K, Sano M. Estrogen. In: Qizilbash N, Schneider LS, Chui H, eds. Evidence-based Dementia Practice. Oxford: Blackwell, 2002:523.
- 185
- Mastrogiacomo I, Bonanni G, Menegazzo E, et al. Clinical and hormonal aspects of male hypogonadism in myotonic dystrophy. Ital J Neurol Sci 1996;17(1):59-65. PMID 8742989
- 186
- Mattson RH, Cramer JA. Epilepsy, sex hormones, and antiepileptic drugs. Epilepsia 1985;26 Suppl 1:S40-51. PMID 3158512
- 187
- Mattsson P. Hormonal factors in migraine: a population-based study of women aged 40 to 74 years. Headache 2003;43(1):27-35. PMID 12864755
- 188
- McEwen BS. Gonadal and adrenal steroids and the brain: implications for depression. In: Halbreich U, ed. Hormones and Depression. New York: Raven Press, 1987:239.
- 189
- Meissner P, Adams P, Kirsch R. Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen. A possible mechanism for the acute attack of variegate porphyria. J Clin Invest 1993;91(4):1436-44. PMID 7682572
- 190
- Melhado EM, Maciel JA Jr, Guerreiro CA. Headache during gestation: evaluation of 1101 women. Can J Neurol Sci 2007;34(2):187-92. PMID 17598596
- 191
- Menkes J. Disorders of metal metabolism. In: Rowland LP, ed. Merritt's Textbook of Neurology. 8th edition. Philadelphia: Lea & Febiger, 1989:538.
- 192
- Merz CJ, Wolf OT. Sex differences in stress effects on emotional learning. J Neurosci Res 2017;95(1-2):93-105. PMID 27870431
- 193
- Messager S, Chatzidaki EE, Ma D, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A 2005;102(5):1761-6. PMID 15665093
- 194
- Michelsen JJ, New PF. Brain tumour and pregnancy. J Neurol Neurosurg Psychiatry 1969;32(4):305-7. PMID 4980021
- 195
- Milerad J, Lagercrantz H, Lofgren O. Alveolar hypoventilation treated with medroxyprogesterone. Arch Dis Child 1985;60(2):150-5. PMID 3156565
- 196
- Morrell MJ. Epilepsy in women: the science of why it is special. Neurology 1999;53(4 Suppl 1):S42-8. PMID 10487515
- 197
- Nappi RE, Cagnacci A, Granella F, Piccinini F, Polatti F, Facchinetti F. Course of primary headaches during hormone replacement therapy. Maturitas 2001;38(2):157-63. PMID 11306204
- 198
- New GH, Hsu PY, Wu MH. Acute intermittent porphyria exacerbation following in vitro fertilization treatment. Taiwan J Obstet Gynecol 2016;55(2):281-4. PMID 27125415
- 199
- Newman LC, Lipton RB, Lay CL, Solomon S. A pilot study of oral sumatriptan as intermittent prophylaxis of menstruation-related migraine. Neurology 1998;51(1):307-9. PMID 9674831
- 200
- Nucera B, Rinaldi F, Dono F, et al. Progesterone and its derivatives for the treatment of catamenial epilepsy: a systematic review. Seizure 2023;109:52-9. PMID 37229848
- 201
- Orvieto R, Achiron R, Rotstein Z, Noy S, Bar-Hava I, Achiron A. Pregnancy and multiple sclerosis: a 2-year experience. Eur J Obstet Gynecol Reprod Biol 1999;82(2):191-4. PMID 10206414
- 202
- Paxton JW, Moore MR, Beattie AD, Goldberg A. 17-Oxosteroid conjugates in plasma and urine of patients with acute intermittent porphyria. Clin Sci Mol Med 1974;46:207-22. PMID 4817273
- 203
- Perlroth MG, Marver HS, Tschudy DP. Oral contraceptive agents and the management of acute intermittent porphyria. JAMA 1965;194(10):1037-42. PMID 5897774
- 204
- Petitti DB, Sidney S, Bernstein A, Wolf S, Quesenberry C, Ziel HK. Stroke in users of low-dose oral contraceptives. N Engl J Med 1996;335(1):8-15. PMID 8637557
- 205
- Pinkerman B, Holroyd K. Menstrual and nonmenstrual migraines differ in women with menstrually-related migraine. Cephalalgia 2010;30(10):1187-94. PMID 20855364
- 206
- Poisson M. Sex steroid receptors in human meningiomas. Clin Neuropharmacol 1984;7(4):320-4. PMID 6391661
- 207
- Polo-Kantola P, Erkkola R, Irjala K, Pullinen S, Virtanen I, Polo O. Effect of short-term transdermal estrogen replacement therapy on sleep: a randomized, double-blind crossover trial in postmenopausal women. Fertil Steril 1999;71(5):873-80. PMID 10231049
- 208
- Pors H, von Eyben FE, Sorensen OS, Larsen M. Longterm remission of multiple brain metastases with tamoxifen. J Neurooncol 1991;10(2):173-7. PMID 1716670
- 209
- Preusser M, Budka H, Rössler K, Hainfellner JA. OLIG2 is a useful immunohistochemical marker in differential diagnosis of clear cell primary CNS neoplasms. Histopathology 2007;50(3):365-70. PMID 17257132
- 210
- Quigg M, Smithson SD, Fowler KM, Sursal T, Herzog AG; NIH Progesterone Trial Study Group. Laterality and location influence catamenial seizure expression in women with partial epilepsy. Neurology 2009;73(3):223-7. PMID 19620611
- 211
- Raffaelli B, Do TP, Chaudhry BA, Ashina M, Amin FM, Ashina H. Menstrual migraine is caused by estrogen withdrawal: revisiting the evidence. J Headache Pain 2023;24(1):131. PMID 37730536
- 212
- Ragonese P, D'Amelio M, Salemi G, et al. Risk of Parkinson disease in women: effect of reproductive characters. Neurology 2004;62(11):2010-4. PMID 15184606
- 213
- Rahman A, Jackson H, Hristov H, et al. Sex and gender driven modifiers of Alzheimer's: the role for estrogenic control across age, race, medical, and lifestyle risks. Front Aging Neurosci 2019;11:315. PMID 31803046
- 214
- Ramanan PV, Premkumar S, Ramnath B. Youngest patient with Sydenham's chorea: a case report. J Indian Med Assoc 2009;107(4):246, 253. PMID 19810372
- 215
- Ramsay RE. Effect of hormones on seizure activity during pregnancy. J Clin Neurophysiol 1987;4(1):23-5. PMID 3584436
- 216
- Rasgon NL, Kenna HA, Wroolie TE, Williams KE, DeMuth BN, Silverman DH. Insulin resistance and medial prefrontal gyrus metabolism in women receiving hormone therapy. Psychiatry Res 2014;223(1):28-36. PMID 24819305
- 217
- Rasmussen BK, Olesen J. Migraine with aura and migraine without aura: an epidemiological study. Cephalalgia 1992;12(4):221-8;discussion 186. PMID 1525797
- 218
- Rayhill M. Headache in pregnancy and lactation. Continuum (Minneap Minn) 2022;28(1):72-92. PMID 35133312
- 219
- Reddy DS. Catamenial epilepsy: discovery of an extrasynaptic molecular mechanism for targeted therapy. Front Cell Neurosci 2016;10:101. PMID 27147973
- 220
- Reddy DS, Thompson W, Calderara G. Molecular mechanisms of sex differences in epilepsy and seizure susceptibility in chemical, genetic and acquired epileptogenesis. Neurosci Lett 2021a;750:135753. PMID 33610673
- 221
- Reddy N, Desai MN, Schoenbrunner A, Schneeberger S, Janis JE. The complex relationship between estrogen and migraines: a scoping review. Syst Rev 2021b;10(1):72. PMID 33691790
- 222
- Reed SC, Levin FR, Evans SM. Changes in mood, cognitive performance and appetite in the late luteal and follicular phases of the menstrual cycle in women with and without PMDD (premenstrual dysphoric disorder). Horm Behav 2008;54(1):185-93. PMID 18413151
- 223
- Reid RL, Yen SS. Premenstrual syndrome. Am J Obstet Gynecol 1981;139(1):85-104. PMID 7006400
- 224
- Riddoch D, Jefferson M, Bickerstaff ER. Chorea and the oral contraceptives. Br Med J 1971;4(5781):217-8. PMID 5115575
- 225
- Robottom BJ, Weiner WJ. Dementia in Parkinson's disease. Int Rev Neurobiol 2009;84:229-44. PMID 19501721
- 226
- Rønnekleiv OK, Kelly MJ. Kisspeptin excitation of GnRH neurons. Adv Exp Med Biol 2013;784:113-31. PMID 23550004
- 227
- Roof RL, Duvdevani R, Stein DG. Progesterone treatment attenuates brain edema following contusion injury in male and female rats. Restor Neurol Neurosci 1992;4:425. PMID 21551677
- 228
- Røste LS, Taubøll E, Svalheim S, Gjerstad L. Does menopause affect the epilepsy? Seizure 2008;17(2):172-5. PMID 18164217
- 229
- Roy S. Effects of smoking on prostacyclin formation and platelet aggregation in users of oral contraceptives. Am J Obstet Gynecol 1999;180(6 Pt 2):S364-8. PMID 10368522
- 230
- Russell MB. Genetics of menstrual migraine: the epidemiological evidence. Curr Pain Headache Rep 2010;14(5):385-8. PMID 20697844
- 231
- Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther 1995;58(5):523-31. PMID 7586946
- 232
- Sacco S, Ricci S, Degan D, Carolei A. Migraine in women: the role of hormones and their impact on vascular diseases. J Headache Pain 2012;13(3):177-89. PMID 22367631
- 233
- Sacco S, Ripa P. Migraine in pregnancy. J Headache Pain 2015; 16(suppl 1):A24. PMID 28132364
- 234
- Salazar-Grueso E, Roos R. Sciatic endometriosis: a treatable sensorimotor mononeuropathy. Neurology 1986;36(10):1360-3. PMID 3762945
- 235
- Sances G, Granella F, Nappi RE, et al. Course of migraine during pregnancy and postpartum: a prospective study. Cephalalgia 2003;23(3):197-205. PMID 12662187
- 236
- Saper JR. Migraine. II. Treatment. JAMA 1978;239(23):2480-4. PMID 650834
- 237
- Sapolsky RM. Is this relevant to the human. In: Sapolsky RM, ed. Stress, the Aging Brain, and the Mechanisms of Neuron Death. Cambridge: MIT Press, 1992:305.
- 238
- Sather MD, Gibson MD, Treves JS. Spinal subarachnoid hematoma resulting from lumbar myelography. AJNR Am J Neuroradiol 2007;28(2):220-1. PMID 17296983
- 239
- Savica R, Grossardt BR, Carlin JM, et al. Anemia or low hemoglobin levels preceding Parkinson disease: a case-control study. Neurology 2009;73(17):1381-7. PMID 19858460
- 240
- Schipper HM. Neurology of sex steroids and oral contraceptives. Neurol Clin 1986;4(4):721-51. PMID 3025581
- 241
- Schoenberg BS. Nervous system. In: Schottenfeld D, Fraumeni JF, eds. Cancer Epidemiology and Prevention. Philadelphia: WB Saunders, 1982:968.
- 242
- Schoenberg BS, Christine BW, Whisnant JP. Nervous system neoplasms and primary malignancies of other sites. The unique association between meningiomas and breast cancer. Neurology 1975;25(8):705-12. PMID 1171403
- 243
- Selvaraj K, Manickam N, Kumaran E, et al. Deterioration of neuroregenerative plasticity in association with testicular atrophy and dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis in Huntington's disease: a putative role of the huntingtin gene in steroidogenesis. J Steroid Biochem Mol Biol 2020;197:105526. PMID 31715317
- 244
- Shaver J, Giblin E, Lentz M, Lee K. Sleep patterns and stability in perimenopausal women. Sleep 1988;11(6):556-61. PMID 3148991
- 245
- Sheikh HU, Pavlovic J, Loder E, Burch R. Risk of stroke associated with use of estrogen containing contraceptives in women with migraine: a systematic review. Headache 2018;58(1):5-21. PMID 29139115
- 246
- Silberstein SD. Menstrual migraine. J Womens Health Gend Based Med 1999;8(7):919-31. PMID 10534294
- 247
- Silberstein SD, Merriam GR. Sex hormones and headache. J Pain Symptom Manage 1993;8(2):98-114. PMID 8492007
- 248
- Silberstein S, Merriam G. Sex hormones and headache 1999 (menstrual migraine). Neurology 1999;53(4 Suppl 1):S3-13. PMID 10487507
- 249
- Silberstein S, Patel S. Menstrual migraine: an updated review on hormonal causes, prophylaxis and treatment. Expert Opin Pharmacother 2014;15(14):2063-70. PMID 25100506
- 250
- Silberstein SD, Massiou H, Le Jeunne C, Johnson-Pratt L, McCarroll KA, Lines CR. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol 2000;96(2):237-42. PMID 10908770
- 251
- Simon JA, Hsia J, Cauley JA, et al. Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-progestin Replacement Study (HERS). Circulation 2001;103(5):638-42. PMID 11156873
- 252
- Sirianni R, Chimento A, Ruggiero C, De Luca A. The novel estrogen receptor, G protein-coupled receptor 30, mediates the proliferative effects induced by 17beta-estradiol on mouse spermatogonial GC-1 cell line. Endocrinology 2008;149(10):5043-51. PMID 18566133
- 253
- Skorupskaite K, George JT, Anderson RA. The kisspeptin-GnRH pathway in human reproductive health and disease. Hum Reprod Update 2014;20(4):485-500. PMID 24615662
- 254
- Smith SS, Waterhouse BD, Woodward DJ. Locally applied estrogens potentiate glutamate-evoked excitation of cerebellar Purkinje cells. Brain Res 1988;475(2):272-82. PMID 2905623
- 255
- Smith SS, Waterhouse BD, Woodward DJ. Sex steroid effects on extrahypothalamic CNS. I. Estrogen augments neuronal responsiveness to iontophoretically applied glutamate in the cerebellum. Brain Res 1987;422(1):40-51. PMID 2890417
- 256
- Soldin OP, Dahlin J, O'Mara DM. Triptans in pregnancy. Ther Drug Monit 2008;30(1):5-9. PMID 18223456
- 257
- Somerville BW. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology 1975a;25(3):239-44. PMID 1167630
- 258
- Somerville BW. Estrogen-withdrawal migraine. II. Attempted prophylaxis by continuous estradiol administration. Neurology 1975b;25(3):245-50. PMID 1167631
- 259
- Spark MJ. Progesterone or progestogen or progestin; which is it? BMJ 2009;339:b4380.
- 260
- Speroff L.Transdermal hormone therapy and the risk of stroke and venous thrombosis. Climacteric. 2010;13(5):429-32. PMID 20670199
- 261
- Stein DG. Is progesterone a worthy candidate as a novel therapy for traumatic brain injury. Dialogues Clin Neurosci 2011;13(3):352-9. PMID 22033509
- 262
- Stein PE, Badminton MN, Rees DC. Update review of the acute porphyrias. Br J Haematol 2017;176(4):527-38. PMID 27982422
- 263
- Steinhoff BJ. Pregnancy, epilepsy, and anticonvulsants. Dialogues Clin Neurosci 2008;10(1):63-75. PMID 18472485
- 264
- Stewart WF, Lipton RB, Chee E, Sawyer J, Silberstein SD. Menstrual cycle and headache in a population sample of migraineurs. Neurology 2000;55(10):1517-23. PMID 11094107
- 265
- Strijks E, Kremer JA, Horstink MW. Effects of female sex steroids on Parkinson's disease in postmenopausal women. Clin Neuropharmacol 1999;22(2):93-7. PMID 10202604
- 266
- Stubblefield PG. The effects on hemostasis of oral contraceptives containing desogestrel. Am J Obstet Gynecol 1993;168(3 Pt 2):1047-52. PMID 8447359
- 267
- Sulak P, Willis S, Kuehl T, Coffee A, Clark J. Headaches and oral contraceptives: impact of eliminating the standard 7-day placebo interval. Headache 2007;47(1):27-37. PMID 17355491
- 268
- Swaab DF, Zhou JN, Fodor M, et al. Gender and sexual orientation-related differences in the human hypothalamus. Frontier Endocrinol 1996;20:135.
- 269
- Taylor FR. Clinical aspects of perimenstrual headaches. Curr Pain Headache Rep 2009;13(1):75-81. PMID 19126376
- 270
- Tepper NK, Whiteman MK, Zapata LB, Marchbanks PA, Curtis KM. Safety of hormonal contraceptives among women with migraine: a systematic review. Contraception 2016;94(6):630-40. PMID 27153744
- 271
- Terasawa E, Timiras PS. Electrical activity during the estrous cycle of the rat: cyclic changes in limbic structures. Endocrinology 1968;83(2):207-16. PMID 4874282
- 272
- Terzi A, Saglam EA, Barak A, Soylemezoglu F. The significance of immunohistochemical expression of Ki-67, p53, p21, and p16 in meningiomas tissue arrays. Pathol Res Pract 2008;204(5):305-14. PMID 18374497
- 273
- Teyler TJ, Vardaris RM, Lewis D, Rawitch AB. Gonadal steroids: effects on excitability of hippocampal pyramidal cells. Science 1980;209(4460):1017-8. PMID 7190730
- 274
- Toh S, Hernández-Díaz S, Logan R, Rossouw JE, Hernán MA. Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: does the increased risk ever disappear. A randomized trial. Ann Intern Med 2010;152(4):211-7. PMID 20157135
- 275
- Tskitishvili E, Nisolle M, Munaut C, et al. Estetrol attenuates neonatal hypoxic-ischemic brain injury. Exp Neurol 2014;261:298-307. PMID 25079370
- 276
- Uchikova E, Pehlivanov B. Effect of two low-dose gestodene containing monophasic oral contraceptives on hemostasis in Bulgarian women. Expert Opin Pharmacother 2008;9(11):1839-44. PMID 18627323
- 277
- Usuki F, Nakazato O, Osame M, Igata A. Hyperestrogenemia in neuromuscular diseases. J Neurol Sci 1989;89(2-3):189-97. PMID 2926448
- 278
- Van der Spuy WJ, Pretorius E. Interrelation between inflammation, thrombosis, and neuroprotection in cerebral ischemia. Rev Neurosci 2012;23(3):269-78. PMID 22752784
- 279
- van Lohuizen R, Paungarttner J, Lampl C, MaassenVanDenBrink A, Al-Hassany L. Considerations for hormonal therapy in migraine patients: a critical review of current practice. Expert Rev Neurother 2023;24(1):1-21. PMID 38112066
- 280
- Veiby G, Daltveit AK, Engelsen BA, Gilhus NE. Pregnancy, delivery, and outcome for the child in maternal epilepsy. Epilepsia 2009;50(9):2130-9. PMID 19490036
- 281
- Veldhuijzen DS, Keaser ML, Traub DS, Zhuo J, Gullapalli RP, Greenspan JD. The role of circulating sex hormones in menstrual cycle-dependent modulation of pain-related brain activation. Pain 2013;154(4):548-59. PMID 23528204
- 282
- Verhagen IE, de Vries Lentsch S, van der Arend BWH, le Cessie S, MaassenVanDenBrink A, Terwindt GM. Both perimenstrual and nonperimenstrual migraine days respond to anti-calcitonin gene-related peptide (receptor) antibodies. Eur J Neurol 2023a;30(7):2117-21. PMID 36941533
- 283
- Verhagen IE, Spaink HA, van der Arend BW, et al. Validation of diagnostic ICHD-3 criteria for menstrual migraine. Cephalalgia 2022;42(11-12):1184-93. PMID 35514214
- 284
- Verhagen IE, van der Arend BW, van Casteren DS, et al. Migraine with and without aura in relation to the menstrual cycle and other hormonal milestones: a prospective cohort study. Cephalalgia 2023b;43(6):3331024231164322. PMID 37259230
- 285
- Verrotti A, D'Egidio C, Coppola G, Parisi P, Chiarelli F. Epilepsy, sex hormones and antiepileptic drugs in female patients. Expert Rev Neurother 2009;9(12):1803-14. PMID 19951139
- 286
- Verrotti A, Laus M, Coppola G, Parisi P, Mohn A, Chiarelli F. Catamenial epilepsy: hormonal aspects. Gynecol Endocrinol 2010;26(11):783-90. PMID 20518639
- 287
- Verzat C, Courriere P, Hollande E. Heterotransplantation of a human oligoastrocytoma into nude mice: difference in tumour growth between males and females. Neuropathol Appl Neurobiol 1992;18(1):37-51. PMID 1579199
- 288
- Vetvik KG, MacGregor EA, Lundqvist C, Russell MB. Self-reported menstrual migraine in the general population. J Headache Pain 2010;11(2):87-92. PMID 20186561
- 289
- Vetvik KG, Russell MB. [Menstrual migraine.] [Article in Norwegian] Tidsskr Nor Laegeforen 2008;128(22):2575-8. PMID 19023354
- 290
- Vinogradov S, Csernansky JG. Postpartum psychosis with abnormal movements: dopamine supersensitivity unmasked by withdrawal of endogenous estrogens. J Clin Psychiatry 1990;51(9):365-6. PMID 2211549
- 291
- Voinescu PE, Kelly M, French JA, et al. Catamenial epilepsy occurrence and patterns in a mixed population of women with epilepsy. Epilepsia 2023;64(9):e194-9. PMID 37452790
- 292
- Vukusic S, Ionescu I, El-Etr M, et al. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: rationale, objectives and state of advancement. J Neurol Sci 2009;286(1-2):114-8. PMID 19758607
- 293
- Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. Effect of estrogen plus progestin on stroke in postmenopausal women. the Women's Health Initiative: a randomized trial. JAMA 2003;289(20):2673-84. PMID 12771114
- 294
- Weill A, Dalichampt M, Raguideau F, et al. Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study. BMJ 2016;353:i2002. PMID 27164970
- 295
- Welch KM. Migraine and pregnancy. Adv Neurol 1994;64:77-81. PMID 8291477
- 296
- Welland FH, Hellman ES, Collins A, Hunter GWJ, Tschudy DP. Factors affecting the excretion of porphyrin precursors by patients with acute intermittent porphyria, II: the effect of ethinyl estradiol. Metabolism 1964;13:251-258. PMID 14127692
- 297
- WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. Lancet 1996;348(9026):498-505. PMID 8757151
- 298
- Wong M, Moss RL. Electrophysiological evidence for a rapid membrane action of the gonadal steroid, 17 beta-estradiol, on CA1 pyramidal neurons of the rat hippocampus. Brain Res 1991;543(1):148-52. PMID 2054668
- 299
- Wong M, Moss RL. Long-term and short-term electrophysiological effects of estrogen on the synaptic properties of hippocampal CA1 neurons. J Neurosci 1992;12(8):3217-25. PMID 1353794
- 300
- Woolley CS, McEwen BS. Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. J Neurosci 1994;14(12):7680-7. PMID 7996203
- 301
- Wu B, Lu J, Wei D, Wang C, Mao Z, Liu P. The association of cortisol, testosterone, and cortisol/testosterone ratio with stroke: A cross-sectional study. J Stroke Cerebrovasc Dis 2024;33(9):107821. PMID 38878843
- 302
- Xu Z, Li Y, Huang X, et al. ESR2 genetic variants and combined oral contraceptive use associated with the risk of stroke. Arch Med Res 2017;48(2):203-11. PMID 28625324
- 303
- Yamamori I, Asai M, Tanaka E, Muramoto A, Hasegawa H. Prevention of premenstrual exacerbation of hereditary coproporphyria by gonadotropin-releasing hormone analogue. Intern Med 1999;38(4):365-8. PMID 10361911
- 304
- Zahn C. Catamenial epilepsy: clinical aspects. Neurology 1999;53(4 Suppl 1):S34-7. PMID 10487512
- 305
- Zhang H, Qi JZ, Zhang ZH. Comparative efficacy of different treatments for menstrual migraine: a systematic review and network meta-analysis. J Headache Pain 2023;24(1):81. PMID 37400775
- 306
- Zhou XS, Rowley JA, Demirovic F, Diamond MP, Badr MS. Effect of testosterone on the apneic threshold in women during NREM sleep. J Appl Physiol 2003;94(1):101-7. PMID 12391093
- 307
- Ziaei S, Janghorban R, Shariatdoust S, Faghihzadeh S. The effects of iron supplementation on serum copper and zinc levels in pregnant women with high-normal hemoglobin. Int J Gynaecol Obstet 2008;100(2):133-5. PMID 17963760
- 308
- Ziehn MO, Avedisian AA, Dervin SM, Umeda EA, O’Dell TJ, Voskuhl RR. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci 2012;32(36):12312-24. PMID 22956822
- 309
- Zimmerman TS, McMillin JM, Watson CJ. Onset of manifestations of hepatic porphyria in relation to the influence of female sex hormones. Arch Intern Med 1966;118(3):229-40. PMID 5947302
- 310
- Ziylan YZ, Lefauconnier JM, Bernard G, Bourre JM. Blood-brain barrier permeability: regional alterations after acute and chronic administration of ethinyl estradiol. Neurosci Lett 1990;118(2):181-4. PMID 2274267
- 311
- Zuluaga MI, Otero-Romero S, Rovira A, et al. Menarche, pregnancies, and breastfeeding do not modify long-term prognosis in multiple sclerosis. Neurology 2019;92(13):e1507-16. PMID 30824557
- 312
- Zupanc ML. Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy. Neurology 2006;66(6 Suppl 3):S37-45. PMID 16567741
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health has no relevant financial relationships to disclose.
See Profile
Former Authors
- Jasvinder Chawla MD MBA
Patient Profile
- Age range of presentation
-
- 0 month to 65+ years
- Heredity
-
- Heredity may be a factor
- Population groups selectively affected
-
- None selectively affected
- Occupation groups selectively affected
-
- None selectively affected
ICD & OMIM codes
- ICD-10
-
- Lack or loss of sexual desire: F52.0
- Failure of genital response: F52.2
- Other sexual dysfunction, not caused by organic disorder or disease: F52.8
- Unspecified sexual dysfunction, not caused by organic disorder or disease: F52.9
- Spinal stenosis: M48.0
- Idiopathic peripheral autonomic neuropathy: G90.0
- ICD-11
-
- Hypoactive sexual desire dysfunction: HA00
- Sexual dysfunctions, unspecified: HA0Z
- Sexual arousal dysfunctions, unspecified: HA01.Z
- Spinal stenosis: FA82
- Other specified autonomic neuropathies: 8D88.Y
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