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  • Updated 01.19.2024
  • Released 05.19.1999
  • Expires For CME 01.19.2027

Isolated hypogonadotropic hypogonadism



Isolated hypogonadotropic hypogonadism (IHH) refers to failed sexual development and reproductive function due to a congenital deficiency of gonadotropins. By definition, it excludes panhypopituitarism, causes of impaired function at the level of the gonads (hypergonadotropic hypogonadism or primary hypogonadism), and acquired causes of hypothalamic-pituitary dysfunction (eg, CNS tumor, brain injury). When coupled with impaired olfaction, isolated hypogonadotropic hypogonadism is known as Kallmann syndrome, but genetically defined causes of isolated hypogonadotropic hypogonadism commonly present with both normosmic and anosmic phenotypes, diminishing the usefulness of this distinction. Additionally, the genetics of isolated hypogonadotropic hypogonadism are extremely complex, reflecting a mixture of classic Mendelian inheritance patterns (X-linked, autosomal recessive, autosomal dominant), variable degrees of penetrance, and instances of oligogenic inheritance, with more than 25 genetically defined forms currently recognized. In this article, the author reviews the clinical manifestations, pathogenesis, genetics, epidemiology, diagnosis, and management of isolated hypogonadotropic hypogonadism.

Key points

• Isolated hypogonadotropic hypogonadism refers to congenital deficiency of gonadotropins.

• When occurring in combination with impaired olfactory function, isolated hypogonadotropic hypogonadism is known as Kallmann syndrome, which is defined as a subset of isolated hypogonadotropic hypogonadism for the purposes of this review.

• The diagnosis may be suggested by the observation of micropenis or cryptorchidism in infancy or delayed onset of puberty in older patients. Because of the clinical overlap between constitutional delay in puberty and isolated hypogonadotropic hypogonadism, diagnosis can be challenging.

• Affected individuals have variably deficient gonadal function and additional comorbidities related to the specific genetic etiology.

• More than 25 genetic causes of isolated hypogonadotropic hypogonadism have been described. Although many genetic etiologies of isolated hypogonadotropic hypogonadism have classic Mendelian inheritance and full penetrance, several genetic etiologies have complex inheritance patterns that are not yet fully understood.

Historical note and terminology

Hypogonadism manifests as a failure of the major functions of gonads, namely the production of sex steroids and gametogenesis. The understanding of this condition has evolved with the basic science understanding of the hypothalamic-pituitary axis and the ability to probe it through diagnostic testing (06). Defects at the level of the gonads (eg, gonadotropin receptor deficiency, sex chromosome aneuploidy) characteristically demonstrate elevated gonadotropins (ie, follicle-stimulating hormone and luteinizing hormone), hypergonadotropic hypogonadism, whereas central deficiencies (eg, pituitary or hypothalamic defects) manifest as hypogonadotropic hypogonadism. Once imaging and laboratory investigations exclude those individuals with lesional or systemic causes of hypogonadotropic hypogonadism (eg, hemochromatosis, CNS tumor), a population of “idiopathic” or “isolated” hypogonadotropic hypogonadism patients can be defined (henceforth termed isolated hypogonadotropic hypogonadism or isolated hypogonadotropic hypogonadism). In practice, most of these patients demonstrate an inability to synthesize gonadotropin-releasing hormone (GnRH); therefore, some authors prefer the term isolated GnRH deficiency.

When isolated hypogonadotropic hypogonadism occurs in combination with anosmia or hyposmia, it is termed Kallmann syndrome. The condition was described by Kallmann and colleagues in 1944, although it was apparently recognized by other investigators as early as 1856 (38; 21; 10; 31). Given the unique X-linked inheritance and highly penetrant presentation for ANOS1-related Kallmann syndrome, the genetic elucidation of Kallmann syndrome provided the first genetic and mechanistic explanation for isolated hypogonadotropic hypogonadism (72). However, subsequent investigations have demonstrated that many genetic causes of isolated hypogonadotropic hypogonadism can present with both anosmic and normosmic forms (06). As a result, it is necessary to consider genetic causes of normosmic isolated hypogonadotropic hypogonadism and anosmic or hyposmic isolated hypogonadotropic hypogonadism (Kallmann syndrome) together when evaluating a patient for isolated hypogonadotropic hypogonadism.

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