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(See also Male Reproductive Endocrinology: Male Hypogonadism.)
Male
hypogonadism is decreased production of testosterone, sperm, or
both or, rarely, decreased response to testosterone, resulting in delayed
puberty, reproductive insufficiency, or both. Diagnosis is by measurement
of serum testosterone, luteinizing hormone, and follicle-stimulating
hormone and by stimulation tests with human chorionic gonadotropin
or gonadotropin-releasing hormone. Treatment depends on the cause.
Classification
There are 3 types of hypogonadism: primary, secondary, and a type caused by defective androgen action, primarily due to defective androgen receptor activity.
Primary
In primary (hypergonadotropic) hypogonadism, damage to the Leydig cells impairs testosterone production, damages the seminiferous tubules, or does both; oligospermia or azoospermia and elevated gonadotropins result. The most common cause is Klinefelter's syndrome; other causes are gonadal dysgenesis (rare), cryptorchidism, bilateral anorchia, Leydig cell aplasia, Noonan's syndrome, and myotonic dystrophy. Rare causes include orchitis due to mumps, which is becoming even rarer as immunization rates increase; testicular torsion; and trauma.
Klinefelter's
syndrome is seminiferous tubule dysgenesis associated with the 47, XXY karyotype, in which an extra X chromosome is acquired through maternal or, to a lesser extent, paternal meiotic nondisjunction (see also Chromosomal Anomalies: Klinefelter's Syndrome (47,XXY)). The syndrome is usually identified at puberty, when inadequate sexual development is noted, or later, when infertility is investigated. Diagnosis is based on elevated gonadotropin levels and low to low-normal testosterone levels.
Gonadal
dysgenesis occurs in hermaphroditism, which is rare.
In cryptorchidism, one or both testes are undescended (see Congenital Renal and Genitourinary Anomalies: Cryptorchidism). Etiology is usually unknown. Sperm counts may be slightly low if one testis is undescended but are almost always very low if both are undescended.
In bilateral
anorchia (vanishing testes syndrome), the testes were presumably present but were resorbed before or after birth. External genitals and wolffian structures are normal, but müllerian duct structures are lacking. Thus, testicular tissue must have been present during the first 12 wk of embryogenesis because testicular differentiation occurred and testosterone and müllerian-inhibiting factor were produced.
Leydig
cell aplasia occurs when congenital absence of Leydig cells causes male pseudohermaphroditism with ambiguous external genitals. Although wolffian ducts develop to some extent, testosterone production is insufficient to induce normal male differentiation of the external genitals. Müllerian ducts are absent because of normal production of müllerian-inhibiting hormone by Sertoli cells. Gonadotropin levels are high with low testosterone levels.
Noonan's
syndrome may occur sporadically or as an autosomal dominant disorder. Phenotypic abnormalities include hyperelasticity of the skin, hypertelorism, ptosis, low-set ears, short stature, shortened 4th metacarpals, high-arched palate, and primarily right-sided cardiovascular abnormalities (eg, pulmonic valve stenosis, atrial septal defect). Testes are often small or cryptorchid. Testosterone levels may be low with high gonadotropin levels.
Defective
androgen synthesis is caused by enzyme defects that impair androgen synthesis, which may occur in any of the pathways leading from cholesterol to dihydrotestosterone. These congenital problems may occur in congenital adrenal hyperplasia when the same enzyme defect occurs in the adrenal glands and the testes, resulting in defective androgen activity and ambiguous external genitals (ie, male pseudohermaphroditism) of varying degrees.
Secondary
Causes of secondary hypogonadism include panhypopituitarism, hypothalamic pituitary tumors, isolated gonadotropin deficiency, Kallmann syndrome, Laurence-Moon syndrome, constitutional delay of puberty, isolated luteinizing hormone deficiency, Prader-Willi syndrome, and functional and acquired disorders of the CNS (eg, trauma, infection). Several acute disorders and chronic systemic disorders (eg, chronic renal insufficiency, anorexia nervosa) may lead to hypogonadotropic hypogonadism, which resolves after recovery from the underlying disorder. Relative hypogonadism is becoming more common among long-term survivors of childhood cancers treated with craniospinal irradiation. Chemotherapy with alkylating drugs may lead to testicular damage and relative hypogonadism.
Panhypopituitarism may occur congenitally or anatomically (eg, in septo-optic dysplasia or Dandy-Walker malformation), causing deficiency of hypothalamic-releasing factors or pituitary hormones. Acquired hypopituitarism may result from tumors, neoplasia, their treatment, vascular disorders, infiltrative disorders (eg, sarcoidosis, Langerhans' cell histiocytosis), infections (eg, encephalitis, meningitis), or trauma. Hypopituitarism in childhood may cause delayed growth, hypothyroidism, diabetes insipidus, hypoadrenalism, and lack of sexual development when puberty is expected. Hormone deficiencies, whether originating in the anterior or posterior pituitary, may be varied and multiple.
Kallmann
syndrome is characterized by anosmia due to aplasia or hypoplasia of the olfactory lobes and by hypogonadism due to deficiency of hypothalamic gonadotropin-releasing hormone (GnRH). It occurs when fetal GnRH neurosecretory neurons do not migrate from the olfactory placode to the hypothalamus. The genetic defect is known; inheritance is usually X-linked. Other manifestations include microphallus, cryptorchidism, midline defects, and unilateral kidney agenesis.
Laurence-Moon
syndrome is characterized by obesity, intellectual disability, retinitis pigmentosa, and polydactyly.
Constitutional
delay of puberty is absence of pubertal development in boys ≥ 14 yr. Many have a family history of delayed sexual development in a parent or sibling. Most affected boys have some evidence of sexual maturation by age 18 yr or have a skeletal age of at least 12 yr (the average age at which testicular enlargement is first noted). Typically, stature is usually short during childhood, adolescence, or both but ultimately reaches normal range. Growth velocity is nearly normal, and growth pattern parallels the lower percentile curves of the growth chart; the pubertal growth spurt is delayed. When skeletal age is plotted on the growth curve, it essentially equals the percentile curve of the genetic target. Diagnosis is by exclusion of growth hormone deficiency, hypothyroidism, and hypogonadism (whether primary or due to gonadotropin deficiency).
Isolated
luteinizing hormone (LH) deficiency (fertile eunuch syndrome) is monotropic loss of LH secretion in boys; follicle-stimulating hormone (FSH) levels are normal. At puberty, growth of the testes is normal because most testicular volume consists of seminiferous tubules, which respond to FSH. Spermatogenesis may occur as tubular development proceeds. However, absence of LH results in Leydig cell atrophy and testosterone deficiency. Therefore, patients do not develop normal secondary sexual characteristics, but they continue to grow, reaching eunuchoidal proportions because the epiphyses do not close.
Prader-Willi
syndrome is characterized by diminished fetal activity, muscular hypotonia, and failure to thrive during early childhood, obesity from early childhood, intellectual disability, and hypogonadotropic hypogonadism. The syndrome is caused by deletion or disruption of a gene or genes on the proximal long arm of paternal chromosome 15 or by uniparental disomy of maternal chromosome 15. Failure to thrive due to hypotonia and feeding difficulties during infancy usually resolves after age 6 to 12 mo. From 12 to 18 mo onward, uncontrollable hyperphagia causes excessive weight gain and psychologic problems; plethoric obesity becomes the most striking feature. Rapid weight gain continues into adulthood; stature remains short. Features include emotional lability, poor gross motor skills, facial abnormalities (eg, a narrow bitemporal dimension, almond-shaped eyes, a mouth with thin upper lips and down-turned corners), and skeletal abnormalities (eg, scoliosis, kyphosis, osteopenia). Hands and feet are small. Other features include cryptorchidism and a hypoplastic penis and scrotum.
Symptoms and Signs
Clinical presentation depends on whether, when, and how testosterone and sperm production are affected. (For presentation in adulthood, see Male Reproductive Endocrinology: Symptoms and Signs.)
If androgen deficiency or defects in androgen activity occur during the 1st trimester (< 12 wk gestation), differentiation of internal wolffian ducts and external genitals is inadequate. Presentation may range from ambiguous external genitals (ie, male pseudohermaphroditism) to normal-appearing female external genitals. Androgen deficiency during the 2nd and 3rd trimesters may cause a microphallus and partially or completely undescended testes.
Androgen deficiency that develops early in childhood has few consequences, but if it occurs when puberty is expected, secondary sexual development is impaired. Such patients have poor muscle development, a high-pitched voice, inadequate phallic and testicular growth, a small scrotum, sparse pubic and axillary hair, and absent body hair. They may develop gynecomastia and grow to eunuchoidal body proportions (arm span exceeds height by 5 cm; pubic to floor length exceeds crown to pubic length by > 5 cm) because fusion of the epiphyses is delayed and long bone growth continues.
Diagnosis
Diagnosis is often suspected based on developmental abnormalities or delayed puberty but requires confirmation by testing, including measurement of testosterone, LH, and FSH. LH and FSH levels are more sensitive than testosterone levels, especially for detecting primary hypogonadism.
LH and FSH levels also help determine whether hypogonadism is primary or secondary:
In boys with short stature, delayed pubertal development, low testosterone and low FSH and LH levels may indicate constitutional delay. Elevated serum FSH levels with normal serum testosterone and LH levels typically indicate impaired spermatogenesis but not impaired testosterone production. In primary hypogonadism, it is important to determine the karyotype to investigate for Klinefelter's syndrome.
Measurement of testosterone, FSH, and LH for diagnosis of hypogonadism requires an understanding of how the levels vary. Before puberty, serum testosterone levels are < 20 ng/dL (< 0.7 nmol/L) and in adulthood, levels are > 300 to 1200 mg/dL. Serum testosterone secretion is primarily circadian. In the 2nd half of puberty, levels are higher at night than during the latter part of the day. A single sample obtained in the morning can establish that circulating testosterone levels are normal. Because 98% of testosterone is bound to carrier proteins in serum (testosterone-binding globulin), alterations in these protein levels alter total testosterone levels. Measurement of total serum testosterone (protein bound and free) is usually the most accurate indicator of testosterone secretion.
For LH and FSH levels, 3 blood samples should be taken at 20-min intervals. This approach maximizes the likelihood of detecting LH pulsations, which occur at 90- to 120-min intervals. Serum LH and FSH levels are usually < 5 mIU/mL before puberty and fluctuate between 5 and 20 mIU/mL during the 2nd half of puberty and into adulthood.
The human chorionic gonadotropin (hCG) stimulation test is done to assess the presence and secretory ability of testicular tissue; hCG 100 IU/kg is given to children. hCG stimulates Leydig cells, as does LH, with which it shares a structural subunit, and stimulates testicular production of testosterone. Testosterone levels should double after 3 to 4 days.
The GnRH stimulation test is done in boys to distinguish between hypothalamic dysfunction and pituitary dysfunction as the cause of hypogonadotropic hypogonadism. GnRH 2.5 μg/kg or leuprolide acetate 500 μg is rapidly injected IV. The injection directly stimulates the pituitary to secrete LH and FSH, which are measured every 20 to 30 min for 2 h. Throughout childhood and into early puberty, response to GnRH is predominantly an increase in FSH with little or no increase in LH. During puberty, LH and FSH respond more or less equally (by doubling or tripling). An inadequate to absent increase in FSH and LH may indicate hypopituitarism.
Treatment
Cryptorchidism is corrected early to obviate concerns about cancer developing in later adulthood and to prevent testicular torsion (see Congenital Renal and Genitourinary Anomalies: Cryptorchidism).
For secondary hypogonadism, any underlying pituitary or hypothalamic disorder is treated. Overall, the goal is to provide androgen replacement starting with a low dose and progressively increasing the dose over 18 to 24 mo.
Adolescents with androgen deficiency should be given long-acting injectable testosterone enanthate or cypionate 50 mg q 2 to 4 wk; the dose is increased up to 200 mg over 18 to 24 mo. A transdermal patch or gel may be used instead.
Treatment of Kallmann syndrome with hCG can correct cryptorchidism and establish fertility. Pulsatile GnRH therapy given subcutaneously by a portable pump leads to endogenous sex hormone secretion, progressive virilization, and even fertility.
In isolated LH deficiency, testosterone, via conversion to estrogen by aromatase, induces normal epiphyseal closure.
Last full review/revision May 2009 by Nicholas Jospe, MD
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