Several other aromatase inhibitors are undergoing clinical trials in patients with breast cancer. Fadrozole is an oral nonsteroidal (triazole) inhibitor of aromatase activity. These compounds appear to be as effective as tamoxifen. In addition to their use in breast cancer, aromatase inhibitors have been successfully employed as adjuncts to androgen antagonists in the treatment of precocious puberty and as primary treatment in the excessive aromatase syndrome.
Fulvestrant is a pure estrogen receptor antagonist that has been somewhat more effective than those with partial agonist effects in some patients who have become resistant to tamoxifen. Fulvestrant is approved for use in breast cancer patients who have become resistant to tamoxifen. ICI 164,384 is a newer antagonist; it inhibits dimerization of the occupied estrogen receptor and interferes with its binding to DNA.
GnRH and its analogs (nafarelin, buserelin, etc) have become important in both stimulating and inhibiting ovarian function. They are discussed in Chapter 37.
Clomiphene citrate, a partial estrogen agonist, is closely related to the estrogen chlorotrianisene (Figure 40–3). This compound is well absorbed when taken orally. It has a half-life of 5–7 days and is excreted primarily in the urine. It exhibits significant protein binding and enterohepatic circulation and is distributed to adipose tissues.
A. Mechanisms of Action
Clomiphene is a partial agonist at estrogen receptors. The estrogenic agonist effects are best demonstrated in animals with marked gonadal deficiency. Clomiphene has also been shown to effectively inhibit the action of stronger estrogens. In humans it leads to an increase in the secretion of gonadotropins and estrogens by inhibiting estradiol’s negative feedback effect on the release of gonadotropins (Figure 40–5).
B. Effects
The pharmacologic importance of clomiphene rests on its ability to stimulate ovulation in women with oligomenorrhea or amenorrhea and ovulatory dysfunction. The majority of patients suffer from polycystic ovary syndrome, a common disorder affecting about 7% of women of reproductive age. The syndrome is characterized by gonadotropin-dependent ovarian hyperandrogenism associated with anovulation and infertility. The disorder is frequently accompanied by adrenal hyperandrogenism. Clomiphene probably blocks the feedback inhibitory influence of estrogens on the hypothalamus, causing a surge of gonadotropins, which leads to ovulation.
Clomiphene is used in the treatment of disorders of ovulation in patients who wish to become pregnant. Usually, a single ovulation is induced by a single course of therapy, and the patient must be treated repeatedly until pregnancy is achieved, since normal cyclic ovulatory function does not usually resume. The compound is of no value in patients with ovarian or pituitary failure.
When clomiphene is administered in a dosage of 100 mg/d for 5 days, a rise in plasma LH and FSH is observed after several days. In patients who ovulate, the initial rise is followed by a second rise of gonadotropin levels just prior to ovulation.
The most common adverse effects in patients treated with this drug are hot flushes, which resemble those experienced by menopausal patients. They tend to be mild, and disappear when the drug is discontinued. There have been occasional reports of eye symptoms due to intensification and prolongation of afterimages. These are generally of short duration. Headache, constipation, allergic skin reactions, and reversible hair loss have been reported occasionally.
The effective use of clomiphene is associated with some stimulation of the ovaries and usually with ovarian enlargement. The degree of enlargement tends to be greater and its incidence higher in patients who have enlarged ovaries at the beginning of therapy.