A variety of other symptoms such as nausea and vomiting, increased nervous tension, depression, fatigue, breast soreness, weight gain, urinary frequency, and heavy menses have also been reported. However, these appear to result from the hormonal changes associated with an ovulatory menstrual cycle rather than from the medication. The incidence of multiple pregnancy is approximately 10%. Clomiphene has not been shown to have an adverse effect when inadvertently given to women who are already pregnant.
Special precautions should be observed in patients with enlarged ovaries. These women are thought to be more sensitive to this drug and should receive small doses. Any patient who complains of abdominal symptoms should be examined carefully. Maximum ovarian enlargement occurs after the 5-day course has been completed, and many patients can be shown to have a palpable increase in ovarian size by the seventh to tenth days. Treatment with clomiphene for more than a year may be associated with an increased risk of low-grade ovarian cancer; however, the evidence for this effect is not conclusive.
Special precautions must also be taken in patients who have visual symptoms associated with clomiphene therapy, since these symptoms may make activities such as driving more hazardous.
In addition to clomiphene, a variety of other hormonal and non-hormonal agents are used in treating anovulatory disorders. They are discussed in Chapter 37.
■ THE TESTIS (ANDROGENS & ANABOLIC STEROIDS, ANTIANDROGENS, & MALE CONTRACEPTION)
The testis, like the ovary, has both gametogenic and endocrine functions. The onset of gametogenic function of the testes is controlled largely by the secretion of FSH by the pituitary. High concentrations of testosterone locally are also required for continuing sperm production in the seminiferous tubules. The Sertoli cells in the seminiferous tubules may be the source of the estradiol produced in the testes via aromatization of locally produced testosterone. With LH stimulation, testosterone is produced by the interstitial or Leydig cells found in the spaces between the seminiferous tubules.
The Sertoli cells in the testis synthesize and secrete a variety of active proteins, including müllerian duct inhibitory factor, inhibin, and activin. As in the ovary, inhibin and activin appear to be the product of three genes that produce a common α subunit and two β subunits, A and B. Activin is composed of the two β subunits (βAβB). There are two inhibins (A and B), which contain the α subunit and one of the β subunits. Activin stimulates pituitary FSH release and is structurally similar to transforming growth factor-β, which also increases FSH. The inhibins in conjunction with testosterone and dihydrotestosterone are responsible for the feedback inhibition of pituitary FSH secretion.
In humans, the most important androgen secreted by the testis is testosterone. The pathways of synthesis of testosterone in the testes are similar to those previously described for the adrenal gland and ovary (Figures 39–1 and 40–2).
In men, approximately 8 mg of testosterone is produced daily. About 95% is produced by the Leydig cells and only 5% by the adrenals. The testis also secretes small amounts of another potent androgen, dihydrotestosterone, as well as androstenedione and dehydroepiandrosterone, which are weak androgens. Pregnenolone and progesterone and their 17-hydroxylated derivatives are also released in small amounts. Plasma levels of testosterone in males are about 0.6 mcg/dL after puberty and appear to decline after age 50. Testosterone is also present in the plasma of women in concentrations of approximately 0.03 mcg/dL and is derived in approximately equal parts from the ovaries and adrenals and by the peripheral conversion of other hormones.