Page 753 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 40 The Gonadal Hormones & Inhibitors 739

Danazol has also been used in the treatment of fibrocystic Pharmacologic Effects
disease of the breast and hematologic or allergic disorders, includ-
ing hemophilia, Christmas disease, idiopathic thrombocytopenic A. Mechanisms of Action
purpura, and angioneurotic edema. Clomiphene is a partial agonist at estrogen receptors. The
The major adverse effects are weight gain, edema, decreased estrogenic agonist effects are best demonstrated in animals with
breast size, acne and oily skin, increased hair growth, deepening marked gonadal deficiency. Clomiphene has also been shown to
of the voice, headache, hot flushes, changes in libido, and muscle effectively inhibit the action of stronger estrogens. In humans
cramps. Although mild adverse effects are very common, it is it leads to an increase in the secretion of gonadotropins and
seldom necessary to discontinue the drug because of them. Occa- estrogens by inhibiting estradiol’s negative feedback effect on the
sionally, because of its inherent glucocorticoid activity, danazol release of gonadotropins (Figure 40–5).
may cause adrenal suppression.
Danazol should be used with great caution in patients with B. Effects
hepatic dysfunction, since it has been reported to produce mild The pharmacologic importance of clomiphene rests on its ability
to moderate hepatocellular damage in some patients, as evidenced to stimulate ovulation in women with oligomenorrhea or amen-
by enzyme changes. It is also contraindicated during pregnancy orrhea and ovulatory dysfunction. The majority of patients suffer
and breast-feeding, as it may produce urogenital abnormalities in from polycystic ovary syndrome, a common disorder affecting
the offspring. about 7% of women of reproductive age. The syndrome is char-
acterized by gonadotropin-dependent ovarian hyperandrogenism
associated with anovulation and infertility. The disorder is fre-
OTHER INHIBITORS quently accompanied by adrenal hyperandrogenism. Clomiphene
probably blocks the feedback inhibitory influence of estrogens on
Anastrozole, a selective nonsteroidal inhibitor of aromatase (the the hypothalamus, causing a surge of gonadotropins, which leads
enzyme required for estrogen synthesis, Figures 40–2 and 40–5), to ovulation.
is effective in some women whose breast tumors have become
resistant to tamoxifen (see Chapter 54). Letrozole is similar. Clinical Use
Exemestane, a steroid molecule, is an irreversible inhibitor of
aromatase. Like anastrozole and letrozole, it is approved for use in Clomiphene is used in the treatment of disorders of ovulation in
women with advanced breast cancer (see Chapter 54). patients who wish to become pregnant. Usually, a single ovulation
Several other aromatase inhibitors are undergoing clinical trials is induced by a single course of therapy, and the patient must be
in patients with breast cancer. Fadrozole is an oral nonsteroidal treated repeatedly until pregnancy is achieved, since normal cyclic
(triazole) inhibitor of aromatase activity. These compounds appear to ovulatory function does not usually resume. The compound is of
be as effective as tamoxifen. In addition to their use in breast cancer, no value in patients with ovarian or pituitary failure.
aromatase inhibitors have been successfully employed as adjuncts to When clomiphene is administered in a dosage of 100 mg/d for
androgen antagonists in the treatment of precocious puberty and as 5 days, a rise in plasma LH and FSH is observed after several days.
primary treatment in the excessive aromatase syndrome. In patients who ovulate, the initial rise is followed by a second rise
Fulvestrant is a pure estrogen receptor antagonist that has of gonadotropin levels just prior to ovulation.
been somewhat more effective than those with partial agonist
effects in some patients who have become resistant to tamoxifen. Adverse Effects
Fulvestrant is approved for use in breast cancer patients who have The most common adverse effects in patients treated with this
become resistant to tamoxifen. ICI 164,384 is a newer antagonist; drug are hot flushes, which resemble those experienced by meno-
it inhibits dimerization of the occupied estrogen receptor and pausal patients. They tend to be mild, and disappear when the
interferes with its binding to DNA. drug is discontinued. There have been occasional reports of eye
GnRH and its analogs (nafarelin, buserelin, etc) have become symptoms due to intensification and prolongation of afterimages.
important in both stimulating and inhibiting ovarian function. These are generally of short duration. Headache, constipation,
They are discussed in Chapter 37. allergic skin reactions, and reversible hair loss have been reported
occasionally.
OVULATION-INDUCING AGENTS The effective use of clomiphene is associated with some stimu-
lation of the ovaries and usually with ovarian enlargement. The
CLOMIPHENE degree of enlargement tends to be greater and its incidence higher
in patients who have enlarged ovaries at the beginning of therapy.
Clomiphene citrate, a partial estrogen agonist, is closely related A variety of other symptoms such as nausea and vomiting,
to the estrogen chlorotrianisene (Figure 40–3). This compound increased nervous tension, depression, fatigue, breast soreness,
is well absorbed when taken orally. It has a half-life of 5–7 days weight gain, urinary frequency, and heavy menses have also been
and is excreted primarily in the urine. It exhibits significant pro- reported. However, these appear to result from the hormonal
tein binding and enterohepatic circulation and is distributed to changes associated with an ovulatory menstrual cycle rather than
adipose tissues. from the medication. The incidence of multiple pregnancy is