Hypogonadism Clinical Presentation

Updated: Aug 03, 2022
  • Author: Maria G Vogiatzi, MD; Chief Editor: George T Griffing, MD  more...
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Males and females

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

For prepubertal males or females with delayed puberty (ie, lack of sexual characteristics by age 13 years in females or ages 13-14 years in males; also, the presence of primary amenorrhea at age 16 years), inquire about a family history of constitutional delay of growth and development. Constitutional delay in pubertal development is the most frequent clinical scenario.

Inquire about chronic illness (including frequent headaches), intentional or unintentional weight loss, and strenuous exercise. 


Specific issues include the presence of developmental anomalies associated with the genital system (eg, hypospadias, micropenis, cryptorchidism). Guidelines for micropenis have been established. [2]

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, frequent transfusions). Drugs that may interrupt testicular function include agents that interfere with testosterone synthesis, such as spironolactone and cyproterone. Agents such as cortisol, marijuana, heroin, and methadone may interfere with gonadotropin secretion.


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.

For postpubertal females, inquire about the presence of galactorrhea or symptoms suggestive of androgen excess, such as acne or hirsutism.



Males and females

The presence of congenital anomalies and dysmorphic features may suggest a specific syndrome. For example, the existence of dysmorphology associated with obesity and developmental delays may suggest syndromes such as Prader-Willi and Laurence-Moon. The presence of nystagmus in an individual with suspected panhypopituitarism raises the suspicion for septo-optic dysplasia.


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. (Hypospadias is usually not related to an endocrine abnormality, but it may be seen in disorders associated with a testosterone biosynthesis defect, partial androgen insensitivity syndrome, or a defect in testicular determination.) Finally, evaluate the extent of virilization.

The presence of microphallus suggests Kallmann syndrome or panhypopituitarism.

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 the legs are disproportionately long), gynecomastia, small or soft testes, and a eunuchoid body habitus.


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.



Hypogonadism can occur in association with miscellaneous congenital disorders, including Prader-Willi syndrome, Laurence-Moon syndrome, Bardet-Biedl syndrome, [1]  and Gaucher disease. Leptin deficiency (also associated with morbid obesity) and iron overload from chronic transfusions or hemochromatosis are other sources of hypogonadism.

The following causes of hypogonadism are noted.

Hypogonadotropic hypogonadism

See the image below.

Types of idiopathic hypogonadotropic hypogonadism. Types of idiopathic hypogonadotropic hypogonadism.

Causes of hypogonadotropic hypogonadism include the following:

  • Central nervous system (CNS) disorders
    • Tumors
    • Miscellaneous causes involving the pituitary/hypothalamic area
      • Langerhans histiocytosis
      • Postinfectious lesions of the CNS
      • Vascular abnormalities of the CNS
      • Radiation therapy
      • Congenital malformations (especially associated with craniofacial anomalies)
      • Head trauma
      • CNS surgery
  • Genetic causes
    • Kallmann syndrome (mutation in the KAL [anosmin-1] 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
  • Miscellaneous congenital disorders
    • Congenital deficiencies of multiple pituitary hormones - septo-optic dysplasia
    • Miscellaneous congenital disorders, including Prader-Willi syndrome, Laurence-Moon syndrome, Bardet-Biedl syndrome, [1]  and Gaucher disease; leptin deficiency (also associated with morbid obesity) and iron overload from chronic transfusions or hemochromatosis are also associated with hypogonadism.
  • Miscellaneous acquired disorders
    • Chronic systemic disease and malnutrition
    • Exercise-induced hypogonadism
    • Psychogenic hypogonadism
    • Hyperprolactinemia
    • Cushing syndrome
    • HIV infection/AIDS
    • Morbid obesity
    • Type II diabetes mellitus 
    • Medications - Chronic glucocorticoid therapy, chronic opioids, psychotropic medications resulting in hyperprolactinemia, anabolic steroids
    • Older men with testosterone deficiency

Hypergonadotropic hypogonadism in males

Causes include the following:

  • Klinefelter syndrome
  • Inactivating mutations
    • LH beta subunit
    • FSH beta subunit
    • LH receptor
    • FSH receptor
  • Other causes of primary testicular failure
    • Chemotherapy
    • Radiation therapy
    • Gonadectomy
    • Anorchism and cryptorchidism
    • Testicular biosynthetic defects (17β-hydroxylase dehydrogenase deficiency, 5α-reductase deficiency, 17-hydroxylase deficiency)
    • Defects in testicular determination (gonadal dysgenesis)
    • Other rare disorders of sex development (DSDs) (ovotesticular DSD, XX males)
    • Sertoli-cell-only syndrome
    • LH resistance

Hypergonadotropic hypogonadism in females

Causes include the following:

  • 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.