LH and FSH
response to GnRH
Results summary and further testing recommendations.
1. Testosterone low, LH and FSH elevated — primary hypogonadism: order karyotype.
2. Testosterone low, LH and FSH normal or low—secondary hypogonadism, obtain PRL and CTscan of head to screen for mass lesion; remaining pituitary hormones must be tested for deficiency.
3. Testosterone and LH normal, FSH high — abnormal seminiferous tubule compartment; order semen analysis.
4. Testosterone, LH and FSH high — androgen resistance syndrome.
Table 4 Clinical presentation of peripubertal and postpubertal hypogonadism Peripheral hypogonadism
* Small testes, phallus, and prostate (prepubertal testes are between 3 and 4 mL in volume and less than 3 cm long by 2 cm wide; peripubertal testes are between 4 and 15 mL in volume and 3-4 cm long by 2-3 cm wide)
* Lack of male-pattern hair growth
* Scant pubic and axillary hair, if adrenal androgens are also deficient
* Disproportionately long arms and legs (from delayed epiphyseal closure, eunuchoidism; with the crown-to-pubis ratio < 1 and an arm span more than 6 cm greater than height)
* No pubertal growth spurt
* No increase in libido or potency
* Reduced male musculature
* Persistently high-pitched voice Postpubertal hypogonadism
* Progressive decrease in muscle mass
* Loss of libido
* Infertility with oligospermia or azoospermia
* Hot flashes (with acute onset of hypogonadism)
* Adult testes are usually 15-30 mL and 4.5-5.5 cm long by 2.8-3.3 cm wide
* Mild depression
* Reduced energy
A well-characterized disorder relates to congenital 5-a-reductase deficiency. In genetically affected males, congenital 5-a-reductase deficiency due to mutation of the type 2 enzyme protein12 causes genital ambiguity and undermasculinization. At puberty these males become virilized, including phallic growth and, occasionally, masculine gender reorientation, but the prostatic development remains rudimentary. This disorder establishes the dependence of the urogenital sinus-derivative tissues on strong expression of 5-a-reductase as a local amplification mechanism. Azasteroid 5-a-reductase inhibitors13 were developed that inhibit type 2, 5-a-reductase (finasteride; 4-azaandrost-1-ene-17-carboxamine, N-(1,1-dimethyl)-3-oxo-, (5a, 17b)) and both type 1 and 2,5-a-reductases (dutasteride; (5a, 17b)-N-(2,5-bis(trifluoromethyl)phenyl)-3-oxo-4-azaandrost-1-ene-17-carboxamide). These agents block more than 95% of testosterone entering the prostate from being converted to DHT and have been used clinically to treat benign and malignant prostate growth and to reverse male-pattern hair loss in males. They must be used with great caution in females because of the potential sexual differentiation disorders that may occur in male fetuses.
Estrogen resistance has also been characterized in males. The biological importance of estradiol in male physiology is important, as illustrated by developmental defects in bone and other tissues of a man14 and mouse line15 with genetic mutations inactivating the estrogen receptor ERa. Inactivating genetic mutations of ERb has little effect on male mouse phenotype,16 but mutations in humans have yet to be reported. Males with aromatase deficiency not only have the same phenotype as in estrogen resistance but estrogen therapy produces significant bone maturation. These observations suggest that, at least in bone, estradiol is critical in males, but androgen action also contributes substantially to bone health. Bone mass in males is greater than in females, although circulating estradiol levels are lower in males than in premenopausal normal female. Animals and humans with androgen resistance but responsiveness to estrogen have normal bone mass, and androgens incapable of conversion to estrogen also increase bone mass in females. Further studies are thus needed to clarify the contributions of androgens and estrogens in bone physiology.
6.22.4 Current Treatment
Testosterone is synthesized by Leydig cells (interstitial) of the testes by an enzymatic sequence of steps beginning with cholesterol, which can be synthesized de novo, supplied from intracellular cholesterol ester stores or from circulating low-density lipoproteins.1'2 LH mainly drives testicular testosterone secretion through its regulation of the rate-limiting conversion of cholesterol to pregnenolone. In males, testosterone is secreted transiently during the first trimester of intrauterine life and again during neonatal life and then continually after puberty to sustain virilization. After 30-40 years of age, circulating total and free testosterone levels decline gradually as gonadotrophin and sex hormone-binding globulin (SHBG) levels increase - the so-called 'andropause.' Andropause is attributed to impaired hypothalamic regulation of testicular function, Leydig cell attrition, and dysfunction.
Endogenous adrenal androgens contribute negligibly to direct virilization of males,1,2 but in individuals with congenital adrenal hyperplasia they may be converted in sufficient amounts to testosterone to cause virilization. In children and females, adrenal androgens make a proportionately larger contribution to the much lower circulating testosterone concentrations, which are ~5-10% of values in males.
Testosterone circulates in blood avidly bound to SHBG.1,2 Endogenous sex steroids and parenteral administration of testosterone that maintains physiological hormone concentrations (transdermal, injections, depot implants), have minimal effects on altering blood SHBG concentrations. Circulating SHBG levels may be elevated by acute or chronic liver disease, estrogens, thyroxine, and androgen deficiency. In contrast, obesity, glucocorticoids, androgens, protein-losing states, and genetic SHBG deficiency markedly lower SHBG. Under physiological conditions, 60-70% of circulating testosterone is SHBG-bound, with the remainder bound to albumin at lower affinity, and 1-2% remaining nonprotein-bound or free. The free (nonprotein-bound) fraction is the most biologically active while the albumin-bound plus the free testosterone is considered the bioavailable fraction of circulating testosterone. Free testosterone levels can be estimated by tracer equilibrium dialysis or ultrafiltration methods or calculated by a variety of nomograms based on immunoassays or mass spectrometry total testosterone and SHBG. The direct analog assay17 and the free testosterone index are clearly invalid.
Testosterone is inactivated in the liver, kidney, gut, muscle, and adipose tissue but predominantly by hepatic oxidases, and in the liver predominantly by the cytochrome P450 3A family and by hepatic conjugation to glucuronides (phase II metabolism), which are excreted by the kidney.1,2
Testosterone undergoes metabolism to DHT predominantly in the skin and prostate and to estradiol. Approximately 4% of circulating testosterone is metabolized to the more potent androgen, DHT^^18 which has a three- to 10-fold greater molar potency than testosterone in binding to androgen receptors. Testosterone is converted to DHT by the enzyme 5-a-reductase that originates from two distinct genes (I and II). Type 1 5-a-reductase (EC 22.214.171.124) is expressed in liver, kidney, skin, and brain, and type 2, 5-a-reductase (EC 126.96.36.199) is characteristically robustly expressed in the prostate but also at lower levels in skin (hair follicles) and liver.
About 0.2% of testosterone is also converted by the enzyme aromatase (EC 188.8.131.52) to estradiol, which activates ERs. In normal males, about 80% of circulating estradiol is derived from extratesticular aromatization. The metabolic clearance rate of testosterone is reduced by the elevation of circulating SHBG levels, aging, liver dysfunction, and reduced hepatic blood flow. Rapid hepatic metabolic inactivation of testosterone reduces oral bioavailability1,2 and duration of action of parenterally administered testosterone. Body mass index also correlates positively with the clearance of testosterone from the circulation. In androgen replacement, these limitations must be considered for parenteral depot testosterone formulations (e.g., injectable testosterone esters, testosterone implants, or transdermal testosterone) and oral delivery systems that involve portal bypass (buccal, sublingual, gut, lymphatic, or synthetic androgens).
Sex steroids initiate their biological actions by binding to their respective receptors located in most tissues and cause activation of the receptor and the biological response.18 Local metabolism of testosterone can modulate and amplify the biological response by converting testosterone to DHTor estradiol.18 The magnitude of the direct effects on the androgen receptor relative to indirect effects via active metabolites varies between androgens and target tissues. In the prostate, the magnification of testosterone to DHT is profound.
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