Clinical manifestations

Presentation and course

A congenital deficiency in gonadotropin secretion is responsible for hypogonadism in isolated hypogonadotropic hypogonadism. This deficiency ranges from mild to severe. In mild isolated hypogonadotropic hypogonadism, some secondary sexual characteristics (eg, pubic hair) are often present due to adrenally sourced androgens, and especially mild forms of isolated hypogonadotropic hypogonadism can have preserved fertility (71; 76; 65). Spontaneous reversal of hypogonadism has been documented in some of these patients with mild isolated hypogonadotropic hypogonadism (23); in others, reversal may occur after hormonal therapy (69). In more severe forms, levels of luteinizing and follicle-stimulating hormones are low, sexual maturation is absent, and the patient is infertile. Diagnosing isolated hypogonadotropic hypogonadism is difficult before puberty and is traditionally done later when delayed sexual maturation becomes evident. However, abnormalities of male genitalia (ie, micropenis and cryptorchidism) can be detected in as many as 20% to 60% of male neonates with isolated hypogonadotropic hypogonadism (73).

In Kallmann syndrome, deficient olfaction accompanies isolated hypogonadotropic hypogonadism, either partially (hyposmia) or completely (anosmia), as determined by standardized quantitative testing or patient self-report (quantitative testing is far more accurate as up to 60% of “normosmic” patients by self-report have olfactory impairment when subjected to standardized testing) (45). Approximately two thirds of patients with isolated hypogonadotropic hypogonadism are classified as having Kallmann syndrome, with roughly one third each having anosmia or hyposmia (45). As mentioned earlier, many genetic etiologies can present as either isolated hypogonadotropic hypogonadism or Kallmann syndrome (eg, AXL, CHD7, DUSP6, FGF8, FGF17, FGFR1, FLRT3, HS6ST1, NSMF, PROKR2/PROK2, SPRY4, WDR11), whereas others present exclusively as Kallmann syndrome (ANOS1(KAL1), CCDC141, FEZF1, IL17RD, SEMA3A, SOX10) or exclusively as normosmic isolated hypogonadotropic hypogonadism (GNRH1, GNRHR, KISS1, KISS1R, SRA1, TACR3) (06). The severity of hypogonadism and loss of smell are not necessarily correlated in Kallmann syndrome: complete anosmia may be associated with partial gonadotropin deficiency (92; 23), and hyposmic patients with Kallmann syndrome can have some olfaction despite complete lack of secondary sex characteristics. Even in highly penetrant, genetically characterized forms of Kallmann syndrome, such as that due to ANOS1 variants, there can be variable degrees of olfactory impairment (52).

Despite the depressed production of gonadotropins in isolated hypogonadotropic hypogonadism, structural abnormalities of the pituitary gland or stalk have not been conclusively demonstrated or associated with specific genetic etiologies of isolated hypogonadotropic hypogonadism. Rather, early work and experts in reproductive endocrinology typically describe the pituitary gland as normal in patients with isolated hypogonadotropic hypogonadism (91; 06). A partially empty sella or small pituitary gland has been described in isolated case reports or in a minority of patients with isolated hypogonadotropic hypogonadism in some series (18; 79; 13). However, an actual statistical enrichment of this finding has not been demonstrated, and the precise radiographic criteria used in these studies are unclear. Additionally, it should be noted that a partially empty sella or small pituitary gland does not necessarily indicate depressed function (eg, incompetence of the diaphragma sella can be asymptomatic). Regardless of the true prevalence of pituitary hypoplasia in isolated hypogonadotropic hypogonadism, it should be acknowledged that some isolated hypogonadotropic hypogonadism genes have been implicated in morphologic abnormalities resembling septo-optic dysplasia, which does commonly have depressed pituitary volume (see below) and that pan-hypopituitarism has been described in a patient with a deficient pituitary stalk, ectopic posterior pituitary gland, and variants in both PROKR2 and WDR11 (55).

On the other hand, congenital structural abnormalities of the olfactory apparatus are common in Kallmann syndrome. Specifically, MRI abnormalities in the olfactory apparatus are reported in almost all anosmic patients and the vast majority of hyposmic patients (42; 45; 20; 79). The olfactory anomalies demonstrate a hierarchy of abnormality in that olfactory sulcus hypoplasia is typically only encountered in patients who also have olfactory bulb hypoplasia (79), and olfactory anomalies are asymmetric in as many as a half of the patients with Kallmann syndrome (95; 13). Because of the high penetrance of anosmia in ANOS1-related Kallmann syndrome, patients with this form of Kallmann syndrome almost always have olfactory anomalies (74; 45). Nonetheless, normal olfactory apparatus findings on imaging can be seen in as many as a third of hyposmic patients (45) and very rarely in anosmic patients also (20; 94). Perhaps even more perplexing, mild olfactory abnormalities (eg, unilateral bulb hypoplasia) have been reported in normosmic patients with isolated hypogonadotropic hypogonadism though the reported prevalence covers a wide range, from rare to a third of normosmic patients (91; 45; 20; 94).

Morphologic abnormalities and functional impairment can be seen outside of the hypothalamic-pituitary axis and olfactory apparatus in isolated hypogonadotropic hypogonadism and Kallmann syndrome. Of specific interest to neurologists, synkinesia (mirror movements) has been described in as many as 40% of patients with ANOS1-related Kallmann syndrome and a much smaller percentage of patients with FGFR1-related Kallmann syndrome (84). Structural abnormalities proposed to underlie the mirror movements include abnormal decussation of the corticospinal tracts and subtle alterations in gray matter distribution visible only after quantitative analysis (42; 50; 87). Additional neurologic symptoms reported in isolated hypogonadotropic hypogonadism include hearing loss in SOX10, IL17RD, and CHD7 (17; 56; 63), nystagmus in ANOS1 (84), focal dystonia of the lower limbs in a genetically uncharacterized patient (34), microphthalmia in a group of genetically uncharacterized patients with isolated hypogonadotropic hypogonadism (40; 44; 20), and intellectual disability in CHD7 (93; 46). Color blindness was a feature of Kallmann’s original patients, but a reliable association of this finding is difficult to locate in modern literature, especially in genetically ascertained cohorts (08).

On MRI, several structural abnormalities of the brain have been described in association with isolated hypogonadotropic hypogonadism. Dandy-Walker malformation or variant has been diagnosed in two unrelated teenage males (85; 03). Partial agenesis of the corpus callosum, white matter abnormalities resembling multiple sclerosis, and acoustic schwannoma have been reported in an older cohort of patients with Kallmann syndrome, though the degree to which these findings differ from the general population is unclear (49). Multiple papers have suggested an overlapping spectrum of neuroimaging findings in isolated hypogonadotropic hypogonadism, septo-optic dysplasia, and holoprosencephaly that blur classic genotype-phenotype relationships. This work includes cases of holoprosencephaly attributed to isolated hypogonadotropic hypogonadism genes, such as FGFR1, and mouse knock-out models of WDR11 (35; 28) as well as cases of isolated hypogonadotropic hypogonadism with variants in holoprosencephaly genes (86). Variants in septo-optic dysplasia genes, such as HESX1, have also been identified in isolated hypogonadotropic hypogonadism subjects (57; 15). Lastly, brain malformations associated with septo-optic dysplasia and midline anomalies more broadly (eg, schizencephaly, septal deficiency, optic nerve hypoplasia, callosal dysgenesis) have been found in individuals with variants in FGFR1 and PROKR2 (68; 54) though many of these variants are listed as “uncertain significance” or even benign in gnomAD (41). The validity of these associations awaits additional subjects and a better understanding of isolated hypogonadotropic hypogonadism genetics, especially instances of oligogenic inheritance.

Outside the nervous system, congenital anomalies reported in isolated hypogonadotropic hypogonadism include renal agenesis in ANOS1 (67) and cleft lip or palate and dental anomalies in FGF8 and FGFR1 (01; 64; 84; 05; 83; 90). In the case of CHD7, isolated hypogonadotropic hypogonadism can occur as part of the CHD7 disease spectrum (93; 46) with the suggestion that missense variants are more likely to produce isolated hypogonadotropic hypogonadism than CHARGE syndrome (51). Deficient nasal cartilage has been described in FGFR1-related isolated hypogonadotropic hypogonadism as well as in genetically unsolved cases (84; 20). Additional abnormalities described in isolated hypogonadotropic hypogonadism include thoracic cage anomalies (pectus excacatum), highly arched feet (pes cavus), and ichthyosis (43; 16; 20; 22). The sporadic appearance of femur-fibula-ulna dysostosis has been observed in one female patient with Kallmann syndrome (27). Although final height is typically normal in patients with isolated hypogonadotropic hypogonadism, arm span is typically increased due to delayed closure of epiphyses from the hypogonadism (66; 89).

Prognosis and complications

The effects of hypogonadism, namely delayed sexual maturation and infertility, are treatable (see treatment section below). However, there are several known comorbidities in isolated hypogonadotropic hypogonadism in addition to anosmia, some of which are treatment-related. Known comorbidities include increased fat mass and body mass index as well as osteopenia and insufficiency fractures (80; 44; 36; 04). The onset of testosterone therapy can also induce painful, low-flow priapism, which, in one case, required placement of a cavernous spongiosal shunt for relief (77). Finally, specific genetic causes of isolated hypogonadotropic hypogonadism are associated with nonendocrine co-morbidities, such as hearing loss, cleft lip or palate, hypodontia, and renal agenesis (06).

Biological basis

Etiology and pathogenesis

Although genetic testing still explains only half of the cases of isolated hypogonadotropic hypogonadism (48), the more than 25 genes implicated thus far fall into two general categories: (1) defects specific to gonadotropin-releasing hormone (GnRH) secretion or action and (2) defects in GnRH secreting neuron migration or specification (11; 06; 25). Alterations of genes in the first category cause isolated deficiency of gonadotropin-releasing hormone and, thus, normosmic isolated hypogonadotropic hypogonadism (eg, GNRH1 and GNRHR, GnRH and its cognate receptor). Alterations in the second category cause broader forebrain neuron deficiencies, resulting in either Kallmann syndrome only (eg, ANOS1, SOX10) or both Kallmann syndrome and normosmic isolated hypogonadotropic hypogonadism (eg, PROK2, PROKR2, WDR11).

The genetics of isolated hypogonadotropic hypogonadism are extremely complex, and the details are beyond the scope of this review (06). However, several points are worth emphasizing. First, even the most frequent genetic causes of isolated hypogonadotropic hypogonadism or Kallmann syndrome (eg, ANOS1, GNRHR, FGFR1) are individually rare, accounting for 5% to 10% of large populations of patients with isolated hypogonadotropic hypogonadism ascertained by specialty clinics, and the vast majority of genes explain no more than a few percent of isolated hypogonadotropic hypogonadism or Kallmann syndrome cases (06; 61). Second, ANOS1 is the only known isolated hypogonadotropic hypogonadism or Kallmann syndrome gene with X-linked inheritance, and ANOS1-related Kallmann syndrome is almost exclusively seen in males with near complete penetrance (48). Despite the theoretical possibility of breakthrough symptoms in ANOS1 females due to X-linked inactivation, ascertained populations of patients with Kallmann syndrome and isolated hypogonadotropic hypogonadism have demonstrated either no females (25) or the extremely rare hyposmic ANOS1 female (45). Third, the penetrance of autosomal recessive forms is fairly high, typically manifesting exclusively as normosmic isolated hypogonadotropic hypogonadism (eg, GNRHR, GNRH1, TAC3, TACR3) or Kallmann syndrome (eg, FEZF1). However, penetrance for heterozygous forms of isolated hypogonadotropic hypogonadism is more unpredictable with a range of endocrine and olfactory impairment (06). Fourth, virtually all known isolated hypogonadotropic hypogonadism genes have been found to demonstrate oligenic inheritance (48; 06). For example, PROKR2-related Kallmann syndrome has been seen in conjunction with variants in multiple other isolated hypogonadotropic hypogonadism genes, including ANOS1 (32), SEMA3A (29), WDR11 (55), and PROK2 (16).

Epidemiology

Isolated hypogonadotropic hypogonadism is estimated to occur in anywhere from 1:10,000 to 1:86,000 individuals (33), and Kallman syndrome has been estimated to occur in a minimum of 1:30,000 males and 1:125,000 females (44). Isolated hypogonadotropic hypogonadism affects males far more frequently than females, with male-to-female ratios in the range of 2.6 to 4 males for every female patient (06; 25). In one analysis of female versus male patients with isolated hypogonadotropic hypogonadism, males were found more likely to have renal anomalies (driven by ANOS1 variants) but also more likely to have midline defects; age at diagnosis and Tanner stage at presentation showed no difference by sex (25). As noted earlier, normosmic, hyposmic, and anosmic subpopulations of isolated hypogonadotropic hypogonadism occur in a ratio of 1:1:1 (45).

Prevention

Familial isolated hypogonadotropic hypogonadism can be potentially avoided by preimplantation diagnosis (47), but this intervention requires knowledge of a causative mutation. Estimates for the frequency of de novo mutations in isolated hypogonadotropic hypogonadism-related genes are lacking. However, over 10% of FGFR1-linked isolated hypogonadotropic hypogonadism cases are de novo (48), and 70% of ANOS1-related isolated hypogonadotropic hypogonadism is simplex (presumed de novo) (06). Even if there is an apparently de novo variant in one child, subsequent children will still have a higher risk of isolated hypogonadotropic hypogonadism than the general population due to possible parental germline mosaicism (75; 48).

Differential diagnosis

Confusing conditions

Although this review has focused on congenital hypogonadotropic hypogonadism, hypogonadotropic hypogonadism can also be caused by acquired conditions, including sellar or pituitary tumors (eg, prolactinoma), systemic conditions (eg, sarcoidosis, hemochromatosis), and trauma (07). Hypergonadotropic hypogonadism (also called primary hypogonadism) is readily distinguishable from isolated hypogonadotropic hypogonadism due to the appropriate elevation of gonadotropins in response to decreased sex hormone secretion by the gonads (81). Common causes for hypergonadotropic hypogonadism include genetic disorders (eg, Klinefelter syndrome) and acquired conditions more common to older patients (eg, trauma, chemotherapy, radiation).

Associated or underlying disorders

Hypogonadotropic hypogonadism can be seen in the setting of multisystem disorders, which are often omitted from discussions of isolated hypogonadotropic hypogonadism or can manifest as isolated hypogonadotropic hypogonadism as well as a broader disorder. For example, the so-called “4H” syndrome caused by pathogenic variants in POLR3A/POLR3B presents as a hypomyelinating leukodystrophy with hypodontia in addition to hypogonadotropic hypogonadism (09); POLR3B variants have also been reported as a cause of isolated hypogonadotropic hypogonadism (70). Similarly, CHD7-related disorders comprise a spectrum that includes Kallmann syndrome (93) and more complex presentations such as CHARGE syndrome (88). There are also more complex genetic conditions, such as RAB18 deficiency, where hypogonadotropic hypogonadism is just a part of a complex reproducible phenotype (30).

There is evidence of a spectrum of morphologic abnormalities that include septo-optic dysplasia, Kallmann syndrome, and holoprosencephaly. In this regard, it is important to recall that septo-optic dysplasia is ultimately a clinicoradiologic syndrome and need not necessarily have a deficiency of the septum pellucidum (78). With this in mind, it is perhaps unsurprising that a single gene, such as HESX1, can present as septo-optic dysplasia, combined pituitary hormone deficiency, or isolated hypogonadotropic hypogonadism (19; 82; 57; 24).

Isolated anatomic features of isolated hypogonadotropic hypogonadism or Kallmann syndrome can be seen in several genetic conditions that do not have hypogonadotropic hypogonadism. Micropenis can be observed in a variety of other syndromes (60). Absent olfactory bulbs and tracts are observed in a number of malformation complexes, including holoprosencephaly, or may be isolated. Some affected patients have abnormal karyotypes or Mendelian disorders (12; 02).

Diagnostic workup

Physical diagnosis and imaging. Because secondary sexual characteristics do not manifest until adolescence, isolated hypogonadotropic hypogonadism is generally difficult to detect earlier in life. However, one exception is the detection of micropenis and cryptorchidism, which occur in 15% and 29%, respectively, of male patients with isolated hypogonadotropic hypogonadism and are even more frequent in patients with Kallmann syndrome who have a more pronounced reproductive phenotype (65). Because of physiologic “mini-puberty” seen during neonatal life, males with isolated hypogonadotropic hypogonadism can be confirmed as having deficient sex hormone and gonadotropin during this period, opening a window for treatment with testosterone, gonadotropins, or pulsatile GnRH (14). In older patients, the key examination finding is delayed development of secondary sexual characteristics, usually defined as 2.5 standard deviations later than the population mean for sex. A working definition of delayed puberty is testicular volume less than 4 mL for a 14-year-old boy or lack of breast development by 13 years of age in a girl (59; 11). Pubic hair specifically is not a reliable indicator of hypogonadism because of adrenally sourced androgens. Differentiating isolated hypogonadotropic hypogonadism from constitutional delay in puberty may be difficult until late into adolescence in the absence of positive family history, co-occurring symptoms (eg, anosmia, renal agenesis), or positive genetic testing because constitutional delay and isolated hypogonadotropic hypogonadism have overlapping hormonal profiles (06). Although self-report of anosmia is generally accurate, a standardized testing instrument is far more accurate in detecting and quantifying the severity of olfactory impairment and should be implemented when isolated hypogonadotropic hypogonadism is raised as a diagnostic possibility (45).

Imaging can be a useful adjunct in the diagnosis of isolated hypogonadotropic hypogonadism. Specifically, olfactory apparatus hypoplasia is readily detected by brain MRI and can support the diagnosis of isolated hypogonadotropic hypogonadism or Kallmann syndrome more specifically. Additionally, brain MRI can be used to exclude other disorders that may potentially mimic isolated hypogonadotropic hypogonadism, such as brain tumors, mild forms of holoprosencephaly, and other findings suggestive of a syndromic diagnosis (eg, hypomyelination in “4H syndrome”). CT provides a better depiction of hypodontia but is unlikely to provide definitive information about the olfactory apparatus or the hypothalamus or pituitary gland. Renal ultrasound is another useful tool that may help build evidence of a genetic cause of isolated hypogonadotropic hypogonadism (eg, ANOS1-related renal agenesis) (39). Finally, it is worth noting that bone ages will typically be delayed in patients with isolated hypogonadotropic hypogonadism, though this is a nonspecific finding with myriad alternative medical explanations (59).

History. A careful history should be elicited with emphasis on pubertal signs and clues to syndromic causes of isolated hypogonadotropic hypogonadism (eg, impaired olfaction). Potential alternative explanations for hypogonadism should also be explored, including chronic medical illness, history of cancer, associated therapies, medications, and trauma (53; 81). Family history is also important for detecting inherited causes of isolated hypogonadotropic hypogonadism and also for differentiating isolated hypogonadotropic hypogonadism from constitutional delay in puberty (59).

Other morphological tests. Due to their invasive nature, biopsies are not a standard procedure in the workup and management of isolated hypogonadotropic hypogonadism. However, testicular biopsy has shown no evidence of sexual maturation in the complete form of isolated hypogonadotropic hypogonadism; interstitial fibrosis and decreased (type B) Sertoli and Leydig cell populations have been described (62). Conversely, some germinal cell maturation can be detected in milder isolated hypogonadotropic hypogonadism cases (58). Laparoscopy has also been employed to visualize hypoplastic internal female genitalia and to biopsy immature ovaries (27).

Endocrine studies. In the complete form of Kallmann syndrome, serum levels of testosterone, estrogen, follicle-stimulating hormone, and luteinizing hormone are low. However, these hormones and other serum markers do not reliably distinguish isolated hypogonadotropic hypogonadism from constitutional pubertal delay with any reliability (59; 07; 11).

Biochemical tests. In addition to endocrine studies, laboratory tests can also be performed to exclude alternative causes of hypogonadism (eg, hemochromatosis) (11).

Genetics. The genetics of isolated hypogonadotropic hypogonadism is complex due to there being more than 25 genes implicated thus far, a variety of inheritance patterns (X-linked recessive, autosomal dominant, autosomal recessive), evidence of oligenic inheritance for some genes, and incomplete penetrance.

Management

Management of isolated hypogonadotropic hypogonadism is directed at restoring normal sex hormone function through exogenous supplementation and enabling fertility for those patients desiring it. As mentioned earlier, preadolescent diagnosis of isolated hypogonadotropic hypogonadism is usually restricted to male neonates who normally experience “mini-puberty,” which facilitates diagnosis of gonadotropin deficiency. In these patients, testosterone or exogenous gonadotropin can be administered to increase penis size and to increase testicular volumes (14). For most patients, the diagnosis of isolated hypogonadotropic hypogonadism is made in adolescence, at which time exogenous sex steroids (ie, testosterone for males, estrogen later followed by cyclic progestin use for females) provide the most straightforward means of inducing secondary sexual characteristics (11). However, sex steroids alone are inadequate to induce gametogenesis and fertility, something that requires gonadotropin injection or pulsatile GnRH administration to simulate physiologic stimulation of the pituitary (06). Monitoring for complications of hormone replacement therapy (eg, erythrocytosis, hyperlipidemia from exogenous testosterone) and effects of hypogonadism (eg, osteopenia) may lead to a need for additional medical treatment (07; 11). Although sex steroids are generally required for the remainder of an isolated hypogonadotropic hypogonadism patient’s life, reversal of isolated hypogonadotropic hypogonadism (ie, acceleration in testicular growth and function) following cessation of testosterone therapy has been reported in up to 10% of men with isolated hypogonadotropic hypogonadism (69).

Outcomes

Overall differences in life expectancy have not been reported for isolated hypogonadotropic hypogonadism.

Special considerations

Pregnancy

Once fertilization is achieved by induction of ovulation or assisted reproductive technologies (eg, in vitro fertilization, intracytoplasmic sperm injection), pregnancies in women with isolated hypogonadotropic hypogonadism have a similar rate of live births as patients with other causes of infertility. Spontaneous abortion rate and multiparity have been reported as 4% and 30%, respectively, for pulsatile GnRH induction (37) and 8% and 13%, respectively, for pregnancies achieved with assisted reproductive technologies (26).

Anesthesia

Regarding anesthesia, there are no considerations specific to isolated hypogonadotropic hypogonadism.