Testosterone

5a— reductase

Dihydrotestosterone

Androgen Receptor

External Genitalia: -differentiation during gestation -maturation during puberty -adulthood prostatic diseases

Hair Follicles: -increased growth during puberty

CYP19 (aromatase)

Androgen Receptor

Internal Genitalia: - Wolffian development during gestation

Skeletal Muscle -Increase mass and strength during puberty

Erythropoiesis ? Bone

Estradiol

Estrogen Receptor

Bone: -epiphyseal closure increased density ? Libido

FIGURE 58-4 Direct effects of testosterone and indirect effects mediated by dihydrotestosterone or estradiol.

mechanism by which androgens have different actions in diverse tissues is the higher affinity with which dihydrotestosterone binds to and activates the AR compared to testosterone. Another mechanism involves tissue-specific coactivators and corepressors.

Mutations in the AR cause resistance to the actions of testosterone and dihydrotestosterone. Male sexual differentiation and pubertal development therefore are incomplete. Other AR mutations occur in patients who have spinal and bulbar muscular atrophy, known as Kennedy's disease. These patients have an expansion of the CAG repeat, which codes for glutamine, at the amino terminus of the AR; they exhibit very mild androgen resistance—manifest principally by gynecomastia—but progressively severe motor neuron atrophy, the basis of which is poorly understood.

Metastatic prostate cancer often regresses initially in response to androgen-deprivation treatment but then becomes unresponsive to continued deprivation. The AR not only continues to be expressed in androgen-independent prostate cancer, but its signaling remains active in the absence of testosterone. This ligand-independent signaling may result from mutations in the AR gene or from changes in AR coregulatory proteins.

effects that occur via the estrogen receptor Certain effects of testosterone are mediated after its conversion to estradiol by CYP19 (Figures 58-3 and 58-4). In the rare males deficient in CYP19 or the estrogen receptor, the epiphyses do not fuse, long-bone growth continues indefinitely, and the bones are osteoporotic. Estradiol administration corrects the bone abnormalities in patients with CYP19 deficiency, but not if there is an estrogen-receptor defect. Because men have larger bones than women, and bone cells express the AR, testosterone also may have a direct effect on bone via the AR. Administration of estradiol to a man with CYP19 deficiency increased his libido, suggesting that the effect of testosterone on male libido may be mediated by conversion to estradiol.

EFFECTS OF ANDROGENS AT DIFFERENT STAGES OF LIFE In Utero

The fetal testes, stimulated by hCG, begin to secrete testosterone at about the eighth week of gestation, and the high local concentration of testosterone around the testes induces the nearby wolf-fian ducts to differentiate into the male internal genitalia: the epididymis, vas deferens, and seminal vesicles. Farther away, in the anlage of the external genitalia, testosterone is converted to dihydrotestosterone, which causes the development of the male external genitalia—the penis and scrotum—and the prostate. The increase in testosterone at the end of gestation (Figure 58-2) may result in further phallic growth.

Puberty

Puberty in boys begins at a mean age of 12 years when pulsatile GnRH stimulates the secretion of FSH and LH from the gonadotropes. The first sign of puberty is a gonadotropin-induced increase in testes size. The increase in testosterone production by Leydig cells, along with the effects of FSH on the Sertoli cells, stimulates the development of the seminiferous tubules, eventually producing mature sperm. Increased secretion of testosterone into the systemic circulation affects many tissues simultaneously; most changes occur gradually over the course of several years. The phallus enlarges in length and width, the scrotum becomes rugated, and the prostate begins secreting the fluid it contributes to the semen. The skin becomes coarser and oilier due to increased sebum production, which contributes to the development of acne. Sexual hair begins to grow, initially pubic and axillary hair (driven also by adrenal androgens), and then other body hair and facial hair. Muscle mass and strength increase, and subcutaneous fat decreases. Epi-physeal bone growth accelerates, resulting in the pubertal growth spurt, but epiphyseal maturation leads eventually to a slowing and then cessation of growth. Bones also become thicker. The increase in the mass of muscle and bone results in a pronounced increase in body weight. Ery-thropoiesis increases, resulting in higher hematocrit in men than boys or women. The larynx thickens, resulting in a lower voice. Libido develops.

Adulthood

The serum testosterone concentration and the characteristics of the adult male are largely maintained during early adulthood and midlife. One change during this time is the gradual development of male pattern baldness. Two conditions that can develop are of much greater medical significance: benign prostatic hyperplasia and prostate cancer, Prostatic hyperplasia occurs to a variable degree in almost all men, sometimes obstructing urine outflow by compressing the urethra as it passes through the prostate, and is mediated by the conversion of testosterone to dihydrotestosterone by 5a-reductase II within prostatic cells. Although there is no proven causal role, prostate cancer is dependent on testosterone, at least to some degree and at some time in its course. This dependency is the basis for treating metastatic prostate cancer by lowering the serum testosterone concentration or by blocking its action.

Senescence

As men age, the serum testosterone concentration gradually declines, and the SHBG concentration gradually increases; by age 80, the total testosterone concentration is approximately 80% and the free testosterone is approximately 40% of that present at age 20. This decline in serum testosterone may contribute to several other changes that occur with increasing age in men, including decreased energy, libido, muscle mass and strength, and bone mineral density. A causal role is suggested by the occurrence of similar changes in men who develop hypogonadism at a younger age.

Consequences of Androgen Deficiency

During Fetal Development Testosterone deficiency in a male fetus during the first trimester causes incomplete sexual differentiation. Complete deficiency of testosterone secretion results in entirely female external genitalia; less severe testosterone deficiency impairs virilization of the external genitalia proportionate to the degree of deficiency. Testosterone deficiency at this stage of development also leads to failure of the wolffian ducts to differentiate into the vas deferens and seminal vesicles, but the Mullerian ducts do not form the female internal genitalia as long as the testes secrete Mullerian-inhibiting substance. Similar changes occur if the action of testosterone is diminished because of an abnormality of the AR or of 5a-reductase. Abnormalities of the AR can have quite varied effects. The most severe form results in complete absence of androgen action and a female phenotype; moderately severe forms result in partial virilization of the external genitalia; and the mildest forms permit normal virilization in utero and result only in impaired spermatogenesis in adulthood. Abnormal 5a-reductase results in incomplete virilization of the external genitalia in utero but normal development of the male internal genitalia, which requires only testosterone.

Testosterone deficiency during the third trimester impairs phallus growth, a condition called microphallus, and causes cryptorchidism—the failure of the testes to descend into the scrotum. These conditions occur commonly in boys whose LH secretion is impaired (see Chapter 55).

Before Completion of Puberty Postnatal defects in testosterone synthesis acquired before the anticipated age of puberty result in failure to initiate or complete puberty. All of the pubertal changes described above, including those of the external genitalia, sexual hair, muscle mass, voice, and behavior, are impaired to a degree proportionate to the abnormality of testosterone secretion. If growth hormone secretion remains intact when testosterone secretion is subnormal, the epiphy-ses do not close, and the long bones continue to lengthen. The result is longer arms and legs relative to the trunk. Another consequence of subnormal testosterone secretion during the age of expected puberty is enlargement of glandular breast tissue (gynecomastia).

After Completion of Puberty Regression of the pubertal effects of testosterone depends on both the degree and the duration of testosterone deficiency. When the deficiency is severe, libido and energy decrease within a week or two, but other testosterone-dependent characteristics decline more slowly. A clinically detectable decrease in muscle mass does not occur for several years. A pronounced decrease in hematocrit and hemoglobin will occur within several months. A decrease in bone mineral density probably is detectable within 2 years by dual-energy x-ray absorptiometry, but an increase in fracture incidence would not be likely to occur for many years. A loss of sexual hair takes many years.

In Women Loss of androgen secretion in women results in a decrease in sexual hair, but not for many years. Some experts have proposed that the loss of androgens, especially the severe loss of both ovarian and adrenal androgens that occurs in panhypopituitarism, is associated with decreased libido, energy, muscle mass and strength, and bone mineral density. Testosterone preparations that yield physiological serum testosterone concentrations in women currently are being developed and tested in clinical trials.

Therapeutic Androgen Preparations

Androgen therapy is complicated by the fact that orally ingested testosterone undergoes rapid hepatic metabolism, and hypogonadal men generally cannot ingest testosterone in sufficient amounts

Testosterone

(histerone, others)

Testosterone

(histerone, others)

Testosterone Esters

Testosterone enanthate

(delatestryl, others)

Testosterone enanthate

(delatestryl, others)

Testosterone cypionate

(depo-testosterone, others)

Testosterone cypionate

(depo-testosterone, others)

Testosterone undecanoate

(andriol)

Testosterone undecanoate

(andriol)

17a-Alkylated Androgens o

Methyltestosterone

(oretin methyl, others)

oh st--chs

Methyltestosterone

(oretin methyl, others)

Oxandrolone

(oxandrin)

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