Page 754 - Basic _ Clinical Pharmacology ( PDFDrive )

740 SECTION VII Endocrine Drugs

approximately 10%. Clomiphene has not been shown to have an ANDROGENS & ANABOLIC
adverse effect when inadvertently given to women who are already
pregnant. STEROIDS
In humans, the most important androgen secreted by the testis is
Contraindications & Cautions testosterone. The pathways of synthesis of testosterone in the tes-
tes are similar to those previously described for the adrenal gland
Special precautions should be observed in patients with enlarged and ovary (Figures 39–1 and 40–2).
ovaries. These women are thought to be more sensitive to this In men, approximately 8 mg of testosterone is produced daily.
drug and should receive small doses. Any patient who complains About 95% is produced by the Leydig cells and only 5% by the
of abdominal symptoms should be examined carefully. Maxi- adrenals. The testis also secretes small amounts of another potent
mum ovarian enlargement occurs after the 5-day course has been androgen, dihydrotestosterone, as well as androstenedione and
completed, and many patients can be shown to have a palpable dehydroepiandrosterone, which are weak androgens. Pregneno-
increase in ovarian size by the seventh to tenth days. Treatment lone and progesterone and their 17-hydroxylated derivatives are
with clomiphene for more than a year may be associated with an also released in small amounts. Plasma levels of testosterone in
increased risk of low-grade ovarian cancer; however, the evidence males are about 0.6 mcg/dL after puberty and appear to decline
for this effect is not conclusive. after age 50. Testosterone is also present in the plasma of women
Special precautions must also be taken in patients who have
visual symptoms associated with clomiphene therapy, since these in concentrations of approximately 0.03 mcg/dL and is derived in
approximately equal parts from the ovaries and adrenals and by
symptoms may make activities such as driving more hazardous.
the peripheral conversion of other hormones.
About 65% of circulating testosterone is bound to sex hor-
OTHER DRUGS USED IN mone-binding globulin. SHBG is increased in plasma by estrogen,
OVULATORY DISORDERS by thyroid hormone, and in patients with cirrhosis of the liver. It
is decreased by androgen and growth hormone and is lower in
In addition to clomiphene, a variety of other hormonal and non- obese individuals. Most of the remaining testosterone is bound to
hormonal agents are used in treating anovulatory disorders. They albumin. Approximately 2% remains free and available to enter
are discussed in Chapter 37. cells and bind to intracellular receptors.

Metabolism
■ THE TESTIS (ANDROGENS In many target tissues, testosterone is converted to dihydrotestos-
& ANABOLIC STEROIDS, terone by 5α-reductase. In these tissues, dihydrotestosterone is the
ANTIANDROGENS, & MALE major active androgen. The conversion of testosterone to estradiol
by P450 aromatase also occurs in some tissues, including adipose
CONTRACEPTION) tissue, liver, and the hypothalamus, where it may be of importance
in regulating gonadal function.
The testis, like the ovary, has both gametogenic and endocrine The major pathway for the degradation of testosterone in
functions. The onset of gametogenic function of the testes is humans occurs in the liver, with the reduction of the double bond
4
controlled largely by the secretion of FSH by the pituitary. High and ketone in the A ring, as is seen in other steroids with a Δ -
concentrations of testosterone locally are also required for con- ketone configuration in the A ring. This leads to the production of
tinuing sperm production in the seminiferous tubules. The Sertoli inactive substances such as androsterone and etiocholanolone that
cells in the seminiferous tubules may be the source of the estra- are then conjugated and excreted in the urine.
diol produced in the testes via aromatization of locally produced Androstenedione, dehydroepiandrosterone (DHEA), and
testosterone. With LH stimulation, testosterone is produced by dehydroepiandrosterone sulfate (DHEAS) are also produced in
the interstitial or Leydig cells found in the spaces between the significant amounts in humans, although largely in the adrenal
seminiferous tubules. gland rather than in the testes. They contribute slightly to the
The Sertoli cells in the testis synthesize and secrete a variety normal maturation process supporting other androgen-dependent
of active proteins, including müllerian duct inhibitory factor, pubertal changes in the human, primarily development of pubic
inhibin, and activin. As in the ovary, inhibin and activin appear to and axillary hair and bone maturation. As noted in Chapter 39,
be the product of three genes that produce a common α subunit some studies suggest that DHEA and DHEAS may have other
and two β subunits, A and B. Activin is composed of the two β central nervous system and metabolic effects and may prolong
β ). There are two inhibins (A and B), which con- life in rabbits. In men they may improve the sense of well-
subunits (β A B
tain the α subunit and one of the β subunits. Activin stimulates being and inhibit atherosclerosis. In a placebo-controlled clini-
pituitary FSH release and is structurally similar to transforming cal trial in patients with systemic lupus erythematosus, DHEA
growth factor-β, which also increases FSH. The inhibins in con- demonstrated some beneficial effects (see Adrenal Androgens,
junction with testosterone and dihydrotestosterone are responsible Chapter 39). Adrenal androgens are to a large extent metabo-
for the feedback inhibition of pituitary FSH secretion. lized in the same fashion as testosterone. Both steroids—but