Hypogonadism 

Updated: Apr 03, 2019
Author: Maria G Vogiatzi, MD; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

Hypogonadism refers to a condition in which little or no hormone is produced by the testes or ovaries. The condition can be hypergonadotropic (primary, resulting when the gonads fail) or hypogonadotropic. The latter can result from failure of the hypothalamic luteinizing-hormone releasing hormone [LHRH] pulse generator or from the inability of the pituitary to respond with secretion of luteinizing hormone [LH] and follicle-stimulating hormone [FSH]. (See the image below.) Morbidity for men and women with hypogonadism includes infertility and an increased risk of osteoporosis; there is no increase in mortality.

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

Causes of hypogonadism

Hypogonadotropic hypogonadism can result from the following:

  • Central nervous system (CNS) disorders - Including tumors and miscellaneous causes involving the pituitary/hypothalamic area
  • Genetic causes - Eg, Kallmann syndrome
  • Congenital disorders - Eg, Prader-Willi syndrome, Laurence-Moon syndrome, Bardet-Biedl syndrome, [1]  and Gaucher disease
  • Acquired disorders - Eg, exercise-induced hypogonadism, psychogenic hypogonadism, hyperprolactinemia, Cushing syndrome, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), morbid obesity, type II diabetes mellitus

Causes of hypergonadotropic hypogonadism (primary hypogonadism) in males include the following:

  • Klinefelter syndrome
  • Inactivating mutation
  • 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

Causes of hypergonadotropic hypogonadism (primary hypogonadism) in females include the following:

  • Turner syndrome
  • Inactivating mutations
  • XX and XY gonadal dysgenesis
  • 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

Signs and symptoms of hypogonadism

History

Considerations in the evaluation of males with hypogonadism include the following:

  • Developmental anomalies associated with the genital system (eg, hypospadias, micropenis, and cryptorchidism)[2]

  • For postpubertal males, the rate of beard growth, libido and sexual function, muscle strength, and energy levels

  • Possible causes of acquired testicular failure (eg, mumps orchitis, trauma, radiation exposure of the head or testes, and chemotherapy)

  • Drugs that may interrupt testicular function - Including agents that interfere with testosterone synthesis, such as spironolactone and cyproterone. Agents such as cortisol, marijuana, heroin, and methadone may interfere with gonadotropin secretion.

Considerations in the evaluation of females with hypogonadism include the following:

  • Signs associated with Turner syndrome (eg, lymphedema, cardiac or renal congenital anomalies, and short growth pattern)

  • Age of menarche

Physical examination

Considerations in the physical examination of males with hypogonadism include the following:

  • Evaluation of the testes: This 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

  • Examination of the genitalia for hypospadias

  • Examination of the scrotum to see if it is completely fused

  • Evaluation of the extent of virilization

  • Staging of puberty: Use the Tanner criteria for genitalia, pubic hair, and axillary hair

  • Examination for signs of Klinefelter syndrome (eg, tall stature, especially if the legs are disproportionately long, gynecomastia, small or soft testes, and a eunuchoid body habitus)

Considerations in the physical examination of females with hypogonadism include the following:

  • Examination of the genitalia is important

  • Determination of the extent of androgenization: May be adrenal or ovarian in origin and is demonstrated in pubic and axillary hair

  • Determination of the extent of estrogenization: As evidenced by breast development and maturation of the vaginal mucosa

  • Examination for signs of Turner syndrome (eg, short stature, webbing of the neck [such as pterygium colli], a highly arched palate, short fourth metacarpals, widely spaced nipples, or multiple pigmented nevi)

See Clinical Presentation for more detail.

Diagnosis of hypogonadism

The following studies may be indicated in males with hypogonadism:

  • Follicle-stimulating hormone (FSH) levels

  • Luteinizing hormone (LH) levels

  • Prolactin levels

  • Testosterone levels

  • Thyroid function

  • Seminal fluid examination

  • Karyotyping

  • Testicular biopsy

For males after puberty, the Guidelines of the Endocrine Society[3] require that the diagnosis of hypogonadism be based on symptoms and signs of hypogonadism plus the presence of a low testosterone level measured on at least 2 occasions.

The following studies may be indicated in females with hypogonadism:

  • FSH levels

  • LH levels

  • Prolactin levels

  • Estradiol levels

  • Antiovarian antibody levels: If gonadotropin levels are elevated

  • Thyroid function

  • Karyotyping

Additional tests in the evaluation of patients with hypogonadism include the following:

  • Adrenocorticotropic hormone (ACTH) stimulation testing: In patients in whom a form of congenital adrenal hyperplasia is suspected, adrenal steroid synthesis is best evaluated by performing a cosyntropin (ACTH 1-24) stimulation test

  • Luteinizing-hormone releasing hormone (LHRH) stimulation testing: To distinguish between true hypogonadotropic hypogonadism and constitutional delay in growth and maturation

  • Testicular tissue testing: If the testes are not palpable and if it is not certain whether any testicular tissue is present, administering human chorionic gonadotropin (hCG) and measuring testosterone response may be helpful

See Workup for more detail.

Management

Hormonal replacement

The simplest and most successful treatment for males and females with either hypergonadotropic or hypogonadotropic hypogonadism is replacement of sex steroids, but the therapy does not confer fertility or, in men, stimulate testicular growth.

When fertility is desired, an alternative therapy for men with hypogonadotropic hypogonadism is administration of pulsatile LHRH or injections of hCG and FSH. (In patients with hypergonadotropic hypogonadism [primary hypogonadism], fertility is not possible.)

In a 6-year European study of men being treated for hypogonadism, long-term transdermal testosterone treatment did not increase prostate-specific antigen (PSA) levels or influence prostate cancer risk.[4, 5]

Investigators used data from a 5-year, open-label extension of a 1-year trial of a transdermal testosterone patch (Testopatch) in men with hypogonadism. Study subjects wore two 60 cm2 patches, each of which delivered 2.4 mg of testosterone per day. More than 90% of patients had PSA concentrations below 2 ng/mL during the 6-year study, and no prostate cancer was found in patients over the course of the trial.

See Treatment and Medication for more detail.

Background

Hypogonadism manifests differently in males and in females before and after the onset of puberty.[6] If onset is in prepubertal males and testosterone replacement is not instituted, the individual has features of eunuchoidism, which include sparse body hair, poor development of skeletal muscles, and delay in epiphyseal closure, resulting in long arms and legs. When hypogonadism occurs in postpubertal males, lack of energy and decreased sexual function are the usual concerns. In females with hypogonadism before puberty, failure to progress through puberty or primary amenorrhea is the most common presenting feature. When hypogonadism occurs in postpubertal females, secondary amenorrhea is the usual concern.

Pathophysiology

The gonads (ovaries or testes) function as part of the hypothalamic-pituitary-gonadal axis. A hypothalamic pulse generator resides in the arcuate nucleus, which releases luteinizing hormone (LH)-releasing hormone (LHRH), which is also termed gonadotropin-releasing hormone (GnRH), into the hypothalamic-pituitary portal system. Data suggest that a gene named KISS is important in the development of the LHRH-secreting cells.[7, 8]

In response to these pulses of LHRH, the anterior pituitary secretes follicle-stimulating hormone (FSH) and LH, which, in turn, stimulate gonadal activity. The increase in gonadal hormones results in lowered FSH and LH secretion at the pituitary level, completing the feedback loop. In the testes, LH stimulates Leydig cells to secrete testosterone, whereas FSH is necessary for tubular growth. In the ovaries, LH acts on theca and interstitial cells to produce progestins and androgens, and FSH acts on granulosa cells to stimulate aromatization of these precursor steroids to estrogen.

Hypogonadism may occur if the hypothalamic-pituitary-gonadal axis is interrupted at any level. Hypergonadotropic hypogonadism (primary hypogonadism) results if the gonad does not produce the amount of sex steroid sufficient to suppress secretion of LH and FSH at normal levels. Hypogonadotropic hypogonadism may result from failure of the hypothalamic LHRH pulse generator or from inability of the pituitary to respond with secretion of LH and FSH. Hypogonadotropic hypogonadism is most commonly observed as one aspect of multiple pituitary hormone deficiencies resulting from malformations (eg, septooptic dysplasia, other midline defects) or lesions of the pituitary that are acquired postnatally. In 1944, Kallmann and colleagues first described familial isolated gonadotropin deficiency. Recently, many other genetic causes for hypogonadotropic hypogonadism have been identified.

Normosmic hypogonadotropic hypogonadism, in which the sense of smell is not disrupted, has been associated with mutations in GNRH1, KISS1R, and GNRHR genes. Although their exact functions are unclear, the genes TAC3 and TACR3 have also been associated with normosmic hypogonadotropic hypogonadism. Kallmann syndrome (anosmic hypogonadotropic hypogonadism) has been associated with mutations in KAL1, FGFR1, FGF8, PROK2, and PROKR2 genes. The relationship with Kallmann syndrome is thought to be because these genes are all related to the development and migration of GnRH neurons. Mutations of an additional gene, CHD7, which has been associated with CHARGE syndrome, has also been found in patients with normosmic or anosmic hypogonadotropic hypogonadism.

Frequency

In women with hypergonadotropic hypogonadism (ie, gonadal failure), the most common cause of hypogonadism is Turner syndrome, which has an incidence of 1 case per 2,500-10,000 live births. In men with hypergonadotropic hypogonadism, the most common cause is Klinefelter syndrome, which has an incidence of 1 case per 500-1000 live births. Hypogonadotropic hypogonadism is rarer.

A study by Livingston et al found that among men whose testosterone levels were checked in primary health-care exams, potential hypogonadism was found in a significant minority. The investigators reported a total testosterone level of under 10 nmol/L in 1924 out of 8788 men (21.9%) in whom testosterone results were determined.[9]

Epidemiology

No racial predilection has been described.

Hypergonadotropic hypogonadism is more common in males than in females because the incidence of Klinefelter syndrome (the most common cause of primary hypogonadism in males) is higher than the incidence of Turner syndrome (the most common cause of hypogonadism in females). Incidence of hypogonadotropic hypogonadism is equal in males and females.

Hypogonadism may occur at any age; however, consequences differ according to the age at onset. If hypogonadism occurs prenatally (even if incomplete), sexual ambiguity may result. If hypogonadism occurs before puberty, puberty does not progress. If hypogonadism occurs after puberty, infertility and sexual dysfunction result.

Prognosis

No increase in mortality is observed in patients with hypogonadism. Morbidity for men and women includes infertility and an increased risk of osteoporosis. In women, an increased risk of severe osteoporosis is noted. In men, hypogonadism causes decreased muscle strength and sexual dysfunction.

Men and women with hypogonadism can lead a normal life with hormone replacement.

Approximately 10-20% of females with Turner syndrome have some spontaneous puberty. Spontaneous estrogenization occurs more commonly in women with mosaic karyotypes and those karyotypes with an abnormal second X chromosome, such as 46,XXiq or 46,XXip. Reports exist of women with mosaic Turner syndrome becoming pregnant without in vitro fertilization.

Patient Education

For patient education resources, see the Men's Health Center and Women's Health Center, as well as Impotence/Erectile Dysfunction and Amenorrhea.

 

Presentation

History

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. 

Males

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.

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.

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

Physical

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.

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. (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.

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.

Causes

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.
 

DDx

Diagnostic Considerations

For adolescents with delayed puberty, the differential diagnosis is mainly between constitutional delay of puberty and hypogonadism. Constitutional delay is by far more common than hypogonadism and is frequently associated with a positive family history.

If hypogonadism is suspected, measurement of serum LH and FSH concentrations can be used to distinguish between hypogonadotropic and hypergonadotropic hypogonadism and guide further evaluation and management. Serum LH and FSH levels are elevated in cases of hypergonadotropic hypogonadism.

Hypergonadotropic hypogonadism indicates a primary gonadal defect (congenital or acquired), while hypogonadotropic hypogonadism suggests a hypothalamic/pituitary process (congenital or acquired). The differential diagnosis between hypogonadotropic hypogonadism and constitutional delay can be challenging because low LH values can be seen in both.

A history of anosmia and/or the presence of microphallus raise concerns for the presence of hypogonadotropic hypogonadism.

Turner syndrome should be considered in short females with absent sexual development. However, a small number of patients experience spontaneous puberty (approximately 10%) and can later present with primary or secondary amenorrhea.

Arrested puberty in the presence of gynecomastia in a male raises concern for gonadal failure. Klinefelter syndrome needs to be ruled out in such cases.

Differential Diagnoses

 

Workup

Approach Considerations

Careful history taking, including of family and medication history, along with a physical examination, can guide the differential diagnosis and appropriate workup in hypogonadism. In postpubertal males, measurement of morning serum testosterone concentrations can establish the diagnosis of hypogonadism.

LH and FSH can be used to distinguish between hypogonadotropic and hypergonadotropic hypogonadism and guide further evaluation and management in both males and females. Hypergonadotropic hypogonadism indicates a primary gonadal defect (congenital or acquired), while hypogonadotropic hypogonadism suggests a hypothalamic/pituitary process (congenital or acquired).

Further hormonal testing (ie, measurement of serum prolactin or thyroid function tests) can be ordered based on presentation and history. Obtaining a karyotype can be considered in certain cases.

In the absence of specific symptoms or signs to direct the workup, evaluation for chronic illness includes a complete white blood count, a sedimentation rate, a comprehensive metabolic panel, a celiac screening, thyroid function tests, and a urinalysis.

Laboratory Studies

Males

For males after puberty, the guidelines of the Endocrine Society[3] require that the diagnosis of hypogonadism be based on symptoms and signs of hypogonadism plus the presence of a low testosterone level measured on at least two occasions. Because of the diurnal variation in testosterone levels, a morning sample is recommended.

For postpubertal males with total testosterone concentrations near the lower limit of the normal range, measurement of free or bioavailable testosterone using a reliable assay is suggested if there is suspicion of sex hormone binding globulin (SHBG) changes.[3]

Obesity decreases serum SHBG concentrations to a degree that is proportionate to the severity of the obesity, thereby decreasing total testosterone values without usually affecting free testosterone. However, morbid obesity (BMI >40 kg/m2) may be associated with a low free testosterone concentration because of hypothalamic hypogonadism. Decreased SHBG concentrations are also seen in insulin resistance, type II diabetes mellitus, hypothyroidism, glucocorticoid use, and nephrotic syndrome. Increased SHBG concentrations can occur with aging, hyperthyroidism, liver disease, and anticonvulsant use.  

Examination of seminal fluid, karyotyping, and testicular biopsy may be helpful.

Females

Karyotyping may be helpful. In females with normal karyotype and elevated gonadotropin levels, measure antiovarian antibody levels to rule out autoimmune disease.

In postpubertal females with signs of acne, hirsutism, and/or amenorrhea or irregular menses, measurement of total and free testosterone and 17-hydroxyprogesterone concentrations is indicated.

Imaging Studies

Magnetic resonance imaging (MRI) of the brain should be considered in cases of anosmia and suspected hypogonadotropic hypogonadism. Absence of the olfactory bulbs is associated with Kallmann syndrome.

Moreover, brain MRI should be ordered in cases of hypogonadotropic hypogonadism that are either isolated or occurring in combination with pituitary defects.

MRI of the pelvis is usually performed in DSD cases, such as androgen insensitivity or ovotesticular DSD, to help delineate the anatomy of internal genitalia. Uterine aplasia in a pubertal girl with normal gonadal function and amenorrhea can be seen in Mayer-Rokitansky-Küster-Hauser syndrome.

Pelvic ultrasonography may be helpful in females.

Bone age may be helpful in the evaluation of adolescents with delayed puberty and provides insight into their growth potential.

Other Tests

Adrenocorticotropic hormone (ACTH) stimulation testing: In patients in whom a form of congenital adrenal hyperplasia is suspected, adrenal steroid synthesis is best evaluated by performing a cosyntropin (ACTH 1-24) stimulation test. Baseline serum adrenocortical hormone levels are measured, then 0.25 mg of cosyntropin is intravenously injected, and serum hormone levels are remeasured after 60 minutes. Precursor product ratios are compared with those in age-matched control subjects to determine whether a steroidogenic defect is involved in sex hormone synthesis.

Luteinizing-hormone releasing hormone (LHRH) stimulation testing: To distinguish between true hypogonadotropic hypogonadism and constitutional delay in growth and maturation, performing a stimulation test with LHRH may be helpful.

  • LHRH is intravenously injected, and LH and FSH levels are determined at 15-minute intervals following LHRH administration.

  • A shortened version of the study has been used, in which LHRH is subcutaneously injected, and the specimen for LH and FSH levels is taken at 30-40 minutes.

  • Obtaining LHRH for testing over the past several years has been difficult. Some centers have substituted testing LH response to aqueous leuprolide.

Testicular tissue testing: If testes are not palpable and whether any testicular tissue is present is unclear, administering human chorionic gonadotropin (hCG) and measuring testosterone response may be helpful.

Procedures

In prepubertal males with delayed puberty, priming with testosterone (usually testosterone enanthate 50 mg IM monthly for a total of 3 months) may lead to puberty initiation and help in the differential diagnosis of hypogonadotropic hypogonadism.

In postpubertal females with amenorrhea, withdrawal bleeding after a 5-10 day course of progestin (such as medroxyprogesterone 10mg hs) indicates adequate estrogen secretion and implies intact gonadal function.

Occasionally, testicular biopsy findings are helpful, particularly if azoospermia or oligospermia is present.

 

Treatment

Approach Considerations

Patients with hypogonadism are typically treated with sex steroid replacement. The goals of treatment are:

  • To promote the development of and maintain secondary sexual characteristics and normal sexual function
  • To build and sustain normal bone and muscle mass
  • To assist in the proper psychosocial adjustment of adolescents with hypogonadism

Fertility options can be explored in consultation with a reproductive endocrinologist or urologist. Pulsatile LHRH or gonadotropin therapy can induce fertility in individuals with hypogonadotropic hypogonadism.

Medical Care

In prepubertal patients with hypogonadism, treatment is directed at initiating pubertal development at the appropriate age. Age of therapy initiation takes into account the patient's psychosocial needs, current growth, and growth potential. Treatment entails hormonal replacement therapy with sex steroids, ie, estrogen for females and testosterone for males.

Introduction of sex steroids in such cases starts with the use of small, escalating doses over a period of a couple of years. In females, introduction of puberty can begin with administration of small doses of estrogen given either orally or transdermally. One traditional regimen uses conjugated estrogen starting at doses as low as 0.15 mg daily and titrating upwards in 6-12 month intervals to typically 0.625 mg daily, at which point menses can be induced with the introduction of a progestin. Alternatively, transdermal 17β-estradiol (0.08 to 0.12 mcg estradiol/kg) can be used.

In boys, introduction of puberty is achieved with the use of testosterone, administered intramuscularly or transdermally (in the form of a patch or gel). A typical regimen involves testosterone enanthate injections 50 mg monthly, titrating up to 200-250 mg every 2 weeks, which is a typical adult replacement dose. Adult testosterone dose can be adjusted to maintain serum testosterone concentrations in the normal adult range.

Therapy with sex steroid replacement ensures development of secondary sexual characteristics and maintenance of normal sexual function. In patients with hypergonadotropic hypogonadism, fertility is not possible. However, patients with hypogonadotropic hypogonadism have fertility potential, although therapy with sex steroids does not confer fertility or stimulate testicular growth in men. An alternative for men with hypogonadotropic hypogonadism has been treatment with pulsatile LHRH or hCG, either of which can stimulate testicular growth and spermatogenesis.

Because such treatment is more complex than testosterone replacement, and because treatment with testosterone does not interfere with later therapy to induce fertility, most male patients with hypogonadotropic hypogonadism prefer to initiate and maintain virilization with testosterone. At a time when fertility is desired, it may be induced with either pulsatile LHRH or (more commonly) with a schedule of injections of hCG and FSH. Similarly, fertility can be achieved in females with pulsatile LHRH or exogenous gonadotropin. Such therapy results in ovulation in 95% of women.

A phase III, multicenter, open-label, single-arm trial by Nieschlag et al indicated that corifollitropin-alfa therapy combined with hCG treatment can significantly increase testicular volume and induce spermatogenesis in adult males with hypogonadotropic hypogonadism whose azoospermia could not be cured by hCG treatment alone. Patients in the study who remained azoospermic, though with normalized testosterone levels, after 16 weeks of hCG treatment underwent 52 weeks of twice-weekly hCG therapy along with every-other-week corifollitropin-alfa treatment (150 μg). Mean testicular volume in these patients rose from 8.6 mL to 17.8 mL, while spermatogenesis was induced in more than 75% of subjects.[10]

The use of oral testosterone preparations, such as 17α-alkylated androgens (eg, methyltestosterone), is discouraged because of liver toxicity. However, oral testosterone undecanoate is available in some countries and is now approved in the United States. Intramuscular testosterone is available as testosterone enanthate or cypionate. Transdermal testosterone can be administered either in the form of a patch or gel. A nasal testosterone replacement therapy has been approved by the US Food and Drug Administration (FDA) for adult males with conditions such as primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired) resulting from a deficiency or absence of endogenous testosterone.[11] The recommended dosage is 33 mg/day in three divided doses. The drug has not been approved for males younger than 18 years.

For older men with testosterone deficiency, a review by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) found that the evidence concerning the risk of serious cardiovascular side effects from the use of testosterone in men with hypogonadism was inconsistent.[12, 13] The PRAC determined that the benefits of testosterone outweigh its risks but stressed that testosterone-containing medicines should be used only when lack of testosterone has been confirmed by signs and symptoms, as well as by laboratory tests. However, a literature review by Albert and Morley indicated that testosterone supplementation in males aged 65 years or older may increase the risk of cardiovascular events, particularly during the first year of treatment, although intramuscular testosterone seemed to carry less risk than other forms.[14]

On the other hand, a study by Traish et al suggested that long-term testosterone therapy in men with hypogonadism significantly reduces cardiovascular disease–related mortality. Patients in the study’s testosterone-treated group (n=360) underwent therapy for up to 10 years, with median follow-up being 7 years. The investigators found no cardiovascular event–related deaths in the treated patients, compared with 19 such deaths in the group that received no testosterone therapy (n=296). According to the study, mortality in the testosterone-treated patients was reduced by an estimated 66-92%.[15]

A literature review by Corona et al indicated that testosterone replacement therapy is safe for age- or comorbidity-related (functional) male hypogonadism, not just for the organic variety. The investigators reported that the safety of testosterone replacement therapy in functional cases, with regard to cardiovascular and venous thromboembolism risk, as well as prostate concerns, is high enough to allow for the treatment.[16]

The latest Endocrine Society clinical practice guidelines suggest testosterone therapy for men receiving high doses of glucocorticoids who also have low testosterone levels, to promote bone health. The guidelines also suggest such therapy in human immunodeficiency virus (HIV)–infected men with low testosterone levels, to maintain lean bone mass and muscle strength.

Surgical Care

Because of the significant risk of gonadoblastoma and carcinoma, gonadal tissue should be removed in females with karyotypes containing a Y chromosome. This situation is observed in females with XY gonadal dysgenesis or in patients with Turner syndrome who have a karyotype that contains a Y chromosome (usually in 1 of 2 or more mosaic karyotypes). Males with nonfunctioning testicular tissue should undergo orchiectomy and replacement with prostheses.

Consultations

Consultation with a reproductive endocrinologist or urologist is required for patients with hypogonadotropic hypogonadism who would like to become fertile. Administration of pulsatile LHRH or gonadotropins in females results in ovulation in 95% of the cases. In males, pulsatile LHRH therapy or hCG alone or in combination with gonadotropins can induce spermatogenesis and results in normal adult male testosterone levels.

Patients with hypergonadotropic hypogonadism are traditionally considered infertile. However, men with Klinefelter syndrome may benefit from a consultation with a reproductive urologist and testicular sperm extraction (TESE) followed by in vitro fertilization. This technique has allowed men with Klinefelter syndrome to father children. For boys with Klinefelter syndrome who have reached puberty, cryopreservation of semen samples containing very low numbers of spermatozoa is possible and should be offered before testosterone supplementation, since supplementation may suppress spermatogenesis.

Complications

In men, complications of untreated hypogonadism include loss of libido, failure to achieve physical strength, the social implications of failing to go through puberty with peers (if hypogonadism occurs before puberty), and osteoporosis. In addition, if hypogonadism occurs before epiphyseal closure, the result is usually tall stature with a eunuchoid body habitus. Males with hypergonadotropic hypogonadism are typically infertile, although procedures such as TESE have resulted in fertility in Klinefelter syndrome. Men who have hypogonadism due to hypothalamic or pituitary dysfunction can potentially become fertile with administration of gonadotropins.

A retrospective study by Baillargeon et al indicated that males with untreated hypogonadism are at increased risk for the development of any rheumatic autoimmune disease, as well as for rheumatoid arthritis and lupus.[17]

In women with hypogonadism, complications include the social implication of failing to go through puberty with peers (if hypogonadism occurs before puberty). An additional concern for untreated women is osteoporosis, which can be avoided with estrogen replacement. Women who have hypogonadism because of hypothalamic or pituitary dysfunction can potentially become fertile with administration of gonadotropins. Women with primary hypogonadism are infertile; however, with in vitro fertilization using a donor ovum, these women can carry an infant to term.

Osteoporosis has an earlier onset in individuals with hypogonadism; hence, bone mineral density should be compared with age-matched normative standards, and followed longitudinally. Prescribe treatment using appropriate therapeutic interventions.

Long-Term Monitoring

Patients with hypogonadism require lifelong treatment, with the exception of persons with congenital hypogonadotropic hypogonadism (spontaneous recovery having been described in 10-20% of these individuals). Patients with hypogonadism receiving hormone replacement therapy are typically evaluated every 6-12 months. Monitoring may include measurement of testosterone concentrations in males, evaluation of bone mass by dual radiographic absorptiometry, and assessment of cardiovascular risk factors.

Polycythemia can be a complication of testosterone replacement. For older adult men with testosterone deficiency, the Endocrine Society clinical guidelines recommend monitoring hematocrit values to avoid polycythemia. Also in these individuals, prostate examination and prostate-specific antigen (PSA) measurements should be performed before testosterone therapy and periodically after treatment is instituted.[3] Referral to a urologist can be considered based on individual assessment for prostate cancer.

 

Medication

Medication Summary

Treatment of patients with hypergonadotropic hypogonadism involves replacement of sex steroids in both males and females.

For treatment of patients with hypogonadotropic hypogonadism, the usual approach is replacement of sex steroids that initiate development and maintain secondary sex characteristics.

Sex steroid replacement does not result in increased testicular size in males or fertility in either males or females. Gonadotropin or GnRH replacement is offered to the patient when fertility is desired.

Many oral contraceptives can provide estrogen and progesterone in a combination that meets the replacement needs of the patient. Selection of a specific oral contraceptive agent needs to be individualized. All of the contraindications, cautions, and drug interactions for estrogens and progesterones apply, as listed in the tables below.

Testosterone agents

Class Summary

These agents are used for sex steroid replacement in males. All testosterone preparations are regulated as Schedule III controlled substances according to the Anabolic Steroids Control Act.

Testosterone (Aveed, Depo-Testosterone, Jatenzo, Testopel, Xyosted)

Testosterone is available as various salts (eg, enanthate, cypionate, undecanoate). It is also available in a variety of dosage forms. Depo-Testosterone and Aveed are administered IM, Jatenzo is an oral capsule, and Xyosted is injected SC. Testopel is an implant that is placed under the skin SC. Testosterone promotes and maintains secondary sex characteristics in androgen-deficient males.

Testosterone transdermal (Androderm, AndroGel, Axiron, Fortesta, Testim)

Androgenic anabolic steroid indicated for testosterone replacement. Several preparations are available as topical gels or transdermal patches. Patches are changed daily. Testosterone is a schedule III controlled substance.

Estrogen agents

Class Summary

These agents are used for sex steroid replacement in females.

Estradiol (Alora, Climara, Esclim, Estrace, FemPatch, Vivelle)

Transdermal: May initiate puberty in girls. Initially, a 0.05-mg patch may be applied 1-2 times/wk. After 6-12 mo, dose may be increased and cycled. After first 6 mo, adding progestogen is often helpful. A very low starting dose of estrogen is desired in young girls with bone ages at or below 12-13 y. Starting at higher doses may cause rapid epiphyseal maturation. If necessary, patches with a matrix-release mechanism (eg, Climara, Vivelle) may be cut to deliver a smaller dose. In the case of the Vivelle dot, half of the dot may be covered in order to lower the amount of estrogen absorbed.

PO: A small unopposed dose (0.02 mg) is administered daily for 3-6 mo, then the dose is increased and cycled. After the first 6 mo, adding progestogen is often helpful.

Conjugated estrogen (Premarin)

May initiate puberty in girls. A small unopposed dose is administered for 3-6 mo, then the dose is increased. After the first 6 mo, adding progestogen is often helpful.

Progesterone agents

Class Summary

These agents are added during the last 12-14 days of the menstrual cycle.

Norethindrone acetate (Aygestin)

Transforms proliferative into secretory endometrium.

Medroxyprogesterone (Provera, Amen, Cycrin)

Transforms proliferative into secretory endometrium.

 

Questions & Answers

Overview

What is hypogonadism, and what is the morbidity?

What are the causes of hypogonadism?

What is the focus of the evaluation for hypogonadism in males?

What is the focus of evaluation for hypogonadism in females?

What is included in the physical exam of hypogonadism in males?

What is included in the physical exam of hypogonadism in females?

Which lab studies are performed in the evaluation of hypogonadism in males?

Which lab studies are performed in the evaluation of hypogonadism in females?

Which tests may be clinically indicated for the evaluation of hypogonadism?

What is the primary treatment for hypogonadism?

What are the treatment options for men with hypogonadism when fertility is desired?

What is the risk for prostate cancer from transdermal testosterone treatment for hypogonadism?

How is hypogonadism manifested differently in males and females?

What is the physiology of hypogonadism?

What is the difference in the pathophysiology of hypergonadotropic hypogonadism and hypogonadotropic hypogonadism?

What is the role of genetics in the pathophysiology of hypogonadism?

What is the incidence of hypogonadism?

What is the prevalence of hypogonadism in men?

What are the racial predilections of hypogonadism?

How does the prevalence of hypogonadism vary by sex?

How does the prevalence of hypogonadism vary by age?

What is the morbidity of hypogonadism?

What is the prognosis of hypogonadism?

How are females with Turner syndrome affected by hypogonadism?

Where are patient education resources for hypogonadism found?

Presentation

What is the focus of history for suspected hypogonadism?

What pubertal history is characteristic of hypogonadism?

What general patient history information is needed for the evaluation of hypogonadism?

What are the male-specific signs of hypogonadism?

What should be the focus of postpubertal history in the evaluation of hypogonadism in men?

Which causes of acquired testicular failure should be considered in the evaluation of hypogonadism?

What are female-specific signs of hypogonadism?

What does the presence of congenital anomalies and dysmorphic features indicate in the evaluation for hypogonadism?

Which physical findings of the testes are characteristic of hypogonadism in males?

Which physical findings of the genitalia are characteristic of hypogonadism in males?

Which etiologies are suggested by the presence of microphallus in hypogonadism?

How is puberty staged in the evaluation of hypogonadism?

Which findings suggest a diagnosis of Klinefelter syndrome in the evaluation of hypogonadism?

What is included in an exam of female genitalia in suspected hypogonadism?

How is the extent of estrogenization determined in the evaluation of hypogonadism in females?

What are signs of Turner syndrome in females with hypogonadism?

What are common causes of hypogonadism?

What are the CNS causes of hypogonadotropic hypogonadism?

What are the genetic causes of hypogonadotropic hypogonadism?

What are congenital disorders associated with hypogonadotropic hypogonadism?

What are acquired disorders associated with hypogonadotropic hypogonadism?

What are the causes of hypergonadotropic hypogonadism in males?

What are the causes of hypergonadotropic hypogonadism in females?

What is the role of genetics in the etiology of hypogonadotropic hypogonadism?

DDX

How is hypogonadism differentiated from constitutional delay of puberty?

How are hypogonadotropic and hypergonadotropic hypogonadism differentiated?

What makes differentiating between hypogonadotropic hypogonadism and constitutional delay challenging?

What is the significance of anosmia and/or microphallus in the diagnosis of hypogonadism?

What are the diagnostic considerations for Turner syndrome in females with hypogonadism?

What are the diagnostic considerations for Klinefelter syndrome in males with hypogonadism?

What are the differential diagnoses for Hypogonadism?

Workup

What is the general approach to the evaluation of hypogonadism?

Which test is performed to distinguish between hypogonadotropic and hypergonadotropic hypogonadism?

What is the role of hormone testing in the evaluation of hypogonadism?

What should be including in the initial evaluation of hypogonadism in the absence of specific symptoms or signs?

How is hypogonadism diagnosed in males after puberty?

What is the role of testosterone testing in the diagnosis of hypogonadism in males?

How does obesity affect lab study results in men with hypogonadism?

Which tests may be helpful in the evaluation of men with hypogonadism?

What is the role of karyotyping in the workup of females with hypogonadism?

Which lab studies should be performed in the evaluation of hypogonadism in females?

What is the role of brain MRI in the workup of hypogonadism?

What is the role of pelvis imaging in the workup of hypogonadism?

What is the role of bone age in the evaluation of adolescents with hypogonadism?

What is the role of adrenocorticotropic hormone (ACTH) stimulation testing in the workup of hypogonadism?

What is the role of luteinizing-hormone releasing hormone (LHRH) stimulation testing in the workup of hypogonadism?

What is the role of testicular tissue testing in the workup of hypogonadism?

What is the role of testosterone priming in the management of hypogonadism?

What is the role of progestin in the evaluation of females with hypogonadism?

What is the role of testicular biopsy in the workup of hypogonadism?

Treatment

What are the goals of sex steroid replacement in the treatment of hypogonadism?

What are the options for fertility inducement in the treatment of hypogonadism?

What is the efficacy of sex steroid replacement in the treatment of hypogonadism?

What is the focus of treatment for hypogonadism in prepubertal patients?

How are sex steroids used in the treatment of hypogonadism in females?

How is testosterone used in the treatment of hypogonadism in males?

How are male patients treated for hypogonadism when fertility is desired?

What is the efficacy of combined corifollitropin-alfa and hCG in the treatment of hypogonadism?

How is testosterone administered in the treatment of hypogonadism?

What are the treatment options for older men with testosterone deficiency and hypogonadism?

How safe is testosterone replacement therapy for the treatment of male hypogonadism?

What are the benefits of testosterone therapy for men with hypogonadism?

What is the role of surgery in the treatment of hypogonadism?

Which specialist consultations are beneficial for patients with hypogonadism seeking fertility?

Which specialist consultations are beneficial for patients with Klinefelter syndrome and hypogonadism?

What are the complications of hypogonadism in males?

What are the complications of hypogonadism in females?

How is the risk for osteoporosis managed in hypogonadism?

What is included in long-term monitoring of patients with hypogonadism?

How is the risk for polycythemia managed in hypogonadism?

Medications

Which medications are used in the treatment of hypergonadotropic hypogonadism?

Which medications are used in the treatment of hypogonadotropic hypogonadism?

What are the limitations of sex steroid replacement in the treatment of hypogonadism?

What is the role of oral contraceptives in the treatment of hypogonadism?

Which medications in the drug class Progesterone agents are used in the treatment of Hypogonadism?

Which medications in the drug class Estrogen agents are used in the treatment of Hypogonadism?

Which medications in the drug class Testosterone agents are used in the treatment of Hypogonadism?