Hypogonadism Clinical Presentation

For both males and females with hypogonadism, determining whether evidence of a genital abnormality is present at birth or determining the timing and extent of puberty is important. In addition, because Kallmann syndrome (hypogonadotropic hypogonadism and anosmia [ie, lack of a sense of smell]) is a common cause of hypogonadotropic hypogonadism, inquiring about the sense of smell is important.

• Males

  • Specific issues include the presence of developmental anomalies associated with the genital system (eg, hypospadias, micropenis, cryptorchidism). Guidelines for micropenis have been established.^[4]
  • For postpubertal males, inquire about the rate of beard growth, libido and sexual function, muscle strength, and energy levels.
  • Investigate possible causes of acquired testicular failure (eg, mumps orchitis, trauma, radiation exposure of the head or testes, chemotherapy). Drugs that may interrupt testicular function include agents that interfere with testosterone synthesis, such as spironolactone, cyproterone, marijuana, heroin, and methadone.
• Females

  • Ask about specific signs associated with Turner syndrome, such as lymphedema, cardiac or renal congenital anomalies, and short growth pattern.
  • Determine the age of menarche. Menstrual history is important in postpubertal females.

Physical findings may include the following:

• Males

  • Evaluation of the testes is the most important feature of the physical examination. Determine whether both testes are palpable, their position in the scrotum, and their consistency. Testes size can be quantitated by comparison with testicular models (orchidometer), or their length and width may be measured. Before puberty, testes usually are 1-3 cm³ in volume (approximately 2 cm in length). During puberty, testes grow up to 25 cm³ in size.
  • Examining the genitalia for hypospadias is the next important step. Check the scrotum to see if it is completely fused. Finally, evaluate the extent of virilization.
  • Puberty should be staged using the Tanner criteria for genitalia, pubic hair, and axillary hair.
  • Look for signs of Klinefelter syndrome, such as tall stature (especially if legs are disproportionately long), gynecomastia, small or soft testes, and a eunuchoid body habitus.
• Females

  • Examination of the genitalia is important.
  • Determine the extent of androgenization, which may be adrenal or ovarian in origin and is demonstrated in pubic and axillary hair.
  • Determine the extent of estrogenization, as evidenced by breast development and maturation of the vaginal mucosa.
  • Look for signs of Turner syndrome, such as short stature, webbing of the neck (eg, pterygium colli), a highly arched palate, short fourth metacarpals, widely spaced nipples, or multiple pigmented nevi.

The following causes of hypogonadism are noted:

• Hypogonadotropic hypogonadism (See the image below.)Types of idiopathic hypogonadotropic hypogonadism.

  • CNS disorders
  • Tumors
    • Craniopharyngioma
    • Germinoma
    • Other germ cell tumors
    • Hypothalamic and optic glioma
    • Astrocytoma
    • Pituitary tumor
  • Miscellaneous causes
    • Langerhans histiocytosis
    • Postinfectious lesions of the CNS
    • Vascular abnormalities of the CNS
    • Radiation therapy
    • Congenital malformations (especially associated with craniofacial anomalies)
    • Head trauma
  • Genetic causes (see Genetics of hypogonadotropic hypogonadism)
    • Kallmann syndrome (mutation in the KAL [anosmin] gene, as well as FGFR1, PROK2, and PROKR2), with hyposmia or anosmia or without anosmia
    • Mutations in GNRH1, KISS1R, GNRHR, TAC3, TACR3
    • Congenital adrenal hypoplasia (mutation in the DAX1 gene)
    • Mutations in the PROP1 and HESX1 genes
    • Mutations in the gene coding for the gonadotropin-releasing hormone (GnRH) receptor
    • Isolated luteinizing hormone (LH) deficiency
    • Isolated follicle-stimulating hormone (FSH) deficiency
  • Idiopathic and genetic forms of multiple hormone deficiencies
    • Chronic systemic disease and malnutrition
    • Exercise-induced amenorrhea
    • Miscellaneous disorders, including Prader-Willi syndrome, Laurence-Moon syndrome, Bardet-Biedl syndrome,^[5] functional gonadotropin deficiency (psychogenic amenorrhea, hypothyroidism, diabetes mellitus, Cushing syndrome), hyperprolactinemia, marijuana use, and Gaucher disease
• Hypergonadotropic hypogonadism in males

  • Klinefelter syndrome
  • Inactivating mutations
    • LH beta subunit
    • FSH beta subunit
    • LH receptor
    • FSH receptor
  • Other causes of primary testicular failure
    • Chemotherapy
    • Radiation therapy
    • Testicular biosynthetic defects
    • Sertoli-cell-only syndrome
    • LH resistance
    • Anorchism and cryptorchidism
• Hypergonadotropic hypogonadism in females

  • Turner syndrome
  • Inactivating mutations
    • LH beta subunit
    • FSH beta subunit
    • LH receptor
    • FSH receptor
  • XX and XY gonadal dysgenesis
    • Familial and sporadic XX gonadal dysgenesis and its variants
    • Familial and sporadic XY gonadal dysgenesis and its variants
  • Other causes of primary ovarian failure
    • Premature menopause
    • Radiation therapy
    • Chemotherapy
    • Autoimmune oophoritis
    • Resistant ovary
    • Galactosemia
    • Glycoprotein syndrome type 1
    • FSH-receptor gene mutations
    • LH/human chorionic gonadotropin (hCG) resistance
    • Polycystic ovarian disease
    • Noonan syndrome
  • Genetics of hypogonadotropic hypogonadism: To date, numerous genes have been identified as causes of hypogonadotropic hypogonadism. The genes include the following:
  • KAL is located on the X chromosome, just below the pseudoautosomal region. An abnormality in this gene results in Kallmann syndrome, which is characterized by anosmia and hypogonadotropic hypogonadism. FGFR1, FGF8, PROK2, and PROKR2 have also been associated with Kallmann syndrome. The relationship with Kallmann syndrome is thought to be due to the relation of these genes to the development and migration of gonadotropin-releasing hormone (GnRH) neurons.
  • The DAX1 gene is associated with X-linked adrenal hypoplasia congenita (hypogonadotropic hypogonadism and adrenal insufficiency).
  • GNRHR is the gene associated with the GnRH (LHRH) receptor.
  • GNRH1, KISS1R, and GNRHR genes have been associated with normosmic (sense of smell is not disrupted) hypogonadotropic hypogonadism.
  • TAC3 and TACR3 mutations have also been associated with normosmic hypogonadotropic hypogonadism, although their exact functions are unclear.
  • CHD7 mutation, which has been associated with CHARGE syndrome, has also been found in patients with both normosmic and anosmic hypogonadotropic hypogonadism.
  • PC1 is the gene for prohormone convertase 1. Abnormality of this gene causes hypogonadotropic hypogonadism and defects in prohormone processing.
  • In addition, mutations in the PROP1 gene have resulted in absence of several pituitary hormones, including growth hormone, thyroid-stimulating hormone, prolactin, and gonadotropins. PROP1 encodes a protein expressed in the embryonic pituitary, which is necessary for function of POU1F1 (formerly PIT1), which codes for a pituitary transcription factor.
  • In addition, mutation of the gene HESX1 has been associated with septooptic dysplasia, which may include poor development of the pituitary.