Infertility (subfertility) is defined as a decrease in the ability to reproduce. This contrasts with sterility, which is the complete absence of reproductive ability. About 10% of couples attempting to have children experience infertility. Failure to conceive may be due to reproductive dysfunction of the male partner, the female partner, or both. When medical treatment is implemented, approximately one-half of infertile couples achieve pregnancy. To date, drug therapy of female infertility has been considerably more successful than drug therapy of male infertility.

In treating infertility, the chances of success are greatly enhanced by accurate diagnosis. A thorough history of both partners is essential, including information on frequency and timing of coitus and use of drugs that might lower fertility. Routine evaluation should include a semen analysis, determination of fallopian tube patency, and assessment of ovulation. If the patient reports regular menstrual cycles, ovulation is presumed, and hence there is no need to determine estrogen and progesterone levels.

In this chapter, we discuss infertility in two stages. First, we discuss the underlying causes of reproductive dysfunction. Second, we discuss the fertility-promoting drugs. As preparation to study these agents, you should review Chapter 61 for information on the menstrual cycle and information on the biosynthesis and physiologic and pharmacologic effects of estrogens and progestins. Pay special attention to the roles of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH).

Infertility: causes and treatment strategies

Female infertility

Female infertility can result from dysfunction in all phases of the reproductive process. The most critical phases are follicular maturation, ovulation, transport of the ovum through the fallopian tubes, fertilization of the ovum, nidation (implantation), and growth and development of the conceptus. These events can take place only if the ovaries, uterus, hypothalamus, and pituitary are functioning properly. If the activity of any of these structures is disturbed, fertility can be impaired. Causes of female infertility that respond to drug therapy are discussed below.

Anovulation and failure of follicular maturation

In the absence of adequate hormonal stimulation, ovarian follicles will not ripen and ovulation will not take place. Frequently, these causes of infertility can be corrected with drugs. The agents used to promote follicular maturation and/or ovulation are clomiphene, menotropins, follitropins (eg, urofollitropin), and human chorionic gonadotropin (hCG). Clomiphene induces follicular maturation and ovulation by promoting release of FSH and LH from the pituitary; in some cases, induction of ovulation requires co-treatment with hCG. Menotropins and follitropins are used in conjunction with hCG: Menotropins and follitropins act directly on the ovary to promote follicular development; after follicles have matured, hCG is given to induce ovulation. Because hCG acts on mature follicles to cause ovulation, the drug is used only after follicular maturation has been induced with another agent (menotropins, a follitropin, or clomiphene). The pharmacology of clomiphene, menotropins, follitropins, and hCG is discussed below.

Unfavorable cervical mucus

In the periovulatory period, the cervical glands normally secrete large volumes of thin, watery mucus. These secretions, which are produced under the influence of estrogen, facilitate passage of sperm through the cervical canal. If the cervical mucus is scant or of inappropriate consistency (thick, sticky), sperm will be unable to pass through to the uterus. Production of unfavorable mucus may occur spontaneously or as a side effect of clomiphene (see below).

Cervical mucus can be restored to its proper volume and consistency by administering estrogen. Two regimens have been employed. In one, ethinyl estradiol is given beginning early in the menstrual cycle (on day 6, 7, or 8) and continued through day 12 or 13; dosages range from 20 to 80 mcg/day. In the other regimen, conjugated estrogens are administered from day 5 through day 15 of the cycle; dosages range from 2.5 to 5 mg/day. When used to counteract the effects of clomiphene on the cervical mucus, estrogens are administered for 10 days beginning 1 day after the last clomiphene dose.

Hyperprolactinemia

Elevation of prolactin levels may be caused by a pituitary adenoma or by disturbed regulation of the healthy pituitary. Amenorrhea, galactorrhea, and infertility may all occur in association with excessive prolactin. The mechanism by which hyperprolactinemia impairs fertility is unknown. Hyperprolactinemia can be treated with cabergoline, bromocriptine, and other dopamine agonists.

Endometriosis

Endometriosis is a condition in which endometrial tissue has become implanted outside the uterus, usually on the ovaries, pelvic peritoneum, or rectovaginal septum. These endometrial implants respond to hormonal stimulation in much the same way as the normally situated endometrium. Endometriosis affects about 5.5 million women in the United States and Canada, and is a common cause of infertility. When pregnancies do occur, the rate of spontaneous abortion is high (about 50%).

The mechanism by which endometriosis reduces fertility is not always clear. In some cases, infertility results from ovarian or tubal adhesions that impede transport of the ovum. However, when endometriosis is mild, a visible cause of infertility may be absent.

Endometriosis can be treated with surgery, drugs, or both. Surgery reduces symptoms of endometriosis and increases fertility. In contrast, although drugs can reduce discomfort, they do not enhance fertility. First-line agents for pain relief are nonsteroidal anti-inflammatory drugs (NSAIDs) and combination oral contraceptives. Gonadotropin-releasing hormone agonists—leuprolide and nafarelin—are also effective, but can’t be used long term owing to side effects, especially osteoporosis and hot flushes.

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a combined endocrine-metabolic disorder characterized by androgen excess and insulin resistance. Symptoms include irregular periods, anovulation, infertility, acne, and hirsutism. About 50% of patients are obese. PCOS increases the risk for diabetes, hyperlipidemia, hypertension, and cancer of the ovaries and endometrium. The syndrome was first described in a woman whose ovaries were enlarged and covered with multiple fluid-filled cysts. However, the presence of cysts is not required for a positive diagnosis. Hence the disease name can be misleading. PCOS is the most common endocrine disorder in young women, affecting 5% to 7% of women of reproductive age.

PCOS can be treated with lifestyle changes and drugs. The goal is to restore regular menstruation and ovulation, reverse hyperandrogenism (and thereby eliminate acne and hirsutism), and decrease the long-term risk of diabetes, cancer, and heart disease. Treatment options include the following:

• Weight loss, through exercise and diet, can reduce insulin and androgen levels, improve insulin sensitivity, restore menstruation and ovulation, and increase pregnancy rates.

• Clomiphene [Clomid, Milophene, Serophene] is considered a first-line drug for inducing ovulation. It may be used alone or in combination with metformin.

• Metformin [Glucophage, others], a drug for type 2 diabetes, increases insulin sensitivity and decreases insulin levels, which, through an indirect mechanism, lowers androgen levels. The net result is improved glucose tolerance, improved ovulation, and increased pregnancy rates.

• Pioglitazone [Actos], another drug for type 2 diabetes, acts like metformin, causing an increase in insulin sensitivity, and a decrease in insulin levels and androgen levels. However, pioglitazone can harm the fetus, and hence should not be used by women trying to become pregnant.

• Oral contraceptives can restore regular periods and reduce acne and hirsutism, but obviously won’t improve fertility.

• Spironolactone has antiandrogenic actions, and can thereby decrease hirsutism and acne. The drug can harm the fetus, and hence must not be used during pregnancy.

Male infertility

For about 50% of infertile couples, failure to conceive is due entirely to reproductive dysfunction in the male. The most common cause is decreased density or motility of sperm, or semen of abnormal volume or quality. The most obvious cause is erectile dysfunction (ED). In most cases, infertility in males is not associated with an identifiable endocrine disorder. Unfortunately, with the exception of ED, male infertility is generally unresponsive to drugs.

Hypogonadotropic hypogonadism

A few males may be incapable of spermatogenesis owing to insufficient gonadotropin secretion. In these rare cases, drugs may help. If the gonadotropin deficiency is only partial, sperm counts can be increased using hCG (alone or in combination with menotropins). If the deficiency is severe, treatment with androgens is required (see Chapter 65). If therapy with hCG and menotropins is intended, the patient should be informed that treatment will be both prolonged (3 to 4 years) and expensive.

Erectile dysfunction

Inability to achieve erection is the most conspicuous cause of male infertility. Sildenafil [Viagra] and other drugs for ED are discussed in Chapter 66.

Idiopathic male infertility

Idiopathic infertility is defined as infertility for which no cause can be identified. About 25% to 40% of male infertility is idiopathic. Since the cause is unknown, specific drug therapy is impossible. Accordingly, treatment is empiric (trial and error). Several drugs, including androgens, clomiphene, and hCG, have been administered in hopes of improving idiopathic infertility in males. However, success is rare.

Drugs used to treat female infertility

Drugs for controlled ovarian stimulation

The term controlled ovarian stimulation refers to the use of drugs to facilitate follicular maturation and ovulation. Following ovulation, fertilization can be accomplished either naturally (through sexual intercourse) or through assisted reproduction technology (eg, in vitro fertilization). Of the drugs discussed below, six are used to promote follicular maturation, two are used to stimulate ovulation, and two are used to prevent premature stimulation of ovulation by endogenous hormones (Table 63–1).

TABLE 63–1 

Drugs for Controlled Ovarian Stimulation

Generic Name	Trade Name	Mechanism of Action
Drugs That Promote Follicular Maturation
Clomiphene	Clomid, Milophene, Serophene	Clomiphene blocks estrogen receptors in the hypothalamus and pituitary, and thereby causes a compensatory increase in the release of LH and FSH, which then act on the ovary to promote follicular maturation (and possibly ovulation).
Menotropins	Repronex, Menopur	Menotropins is a 50:50 mixture of FSH and LH that acts on the ovary to promote follicular maturation. Treatment is followed by hCG to induce ovulation.
Follitropins		Follitropins are preparations of FSH that act on the ovary to promote follicular maturation. Treatment is followed by hCG to induce ovulation.
Follitropin alfa	Gonal-F
Follitropin beta	Follistim AQ, Puregon
Urofollitropin	Bravelle
Lutropin alfa	Luveris	Lutropin alfa is a recombinant form of LH used in combination with follitropin alfa [Gonal-F] to promote follicular maturation. Treatment is followed by hCG to induce ovulation.
Drugs That Stimulate Ovulation
Human chorionic gonadotropin (hCG)	Choron 10, Gonic, Novarel, Pregnyl, Profasi	hCG is similar in structure and identical in action to LH. The drug acts on the ovary to induce ovulation.
Choriogonadotropin alfa	Ovidrel	Choriogonadotropin is a recombinant form of hCG that acts on the ovary to induce ovulation.
Drugs That Prevent Premature Ovulation
Ganirelix	Generic only	These drugs are GnRH antagonists that block endogenous release of LH, and thereby prevent possible premature ovulation in women receiving drugs to promote follicular maturation.
Cetrorelix	Cetrotide

Clomiphene

Therapeutic use.

Clomiphene [Clomid, Milophene, Serophene] is used to promote follicular maturation and ovulation in selected infertile women.

Mechanism of fertility promotion.

Clomiphene blocks receptors for estrogen. Receptor blockade in the hypothalamus and pituitary makes it appear to these structures that estrogen levels are low. In response, the pituitary increases secretion of gonadotropins (LH and FSH), and these hormones then stimulate the ovary, promoting follicular maturation and ovulation. In properly selected patients, the ovulation rate is about 90%. Because of its mechanism, clomiphene can induce ovulation only if the pituitary is capable of producing LH and FSH, and only if the ovaries are capable of responding. Success is impossible in women with primary pituitary or ovarian failure. Accordingly, pituitary and ovarian function should be verified prior to clomiphene therapy. If treatment produces follicular maturation but ovulation fails to occur, it may be possible to induce ovulation by adding hCG to the regimen (see below).

Monitoring.

Effects on the ovary can be monitored with serial ultrasound exams. When treatment is successful, the scans will show progressive follicular enlargement, followed by conversion of the follicle to a corpus luteum after ovulation occurs.

Adverse effects.

Common side effects include hot flushes (similar to the vasomotor responses of menopause), nausea, abdominal discomfort, bloating, and breast engorgement. Some patients experience visual disturbances (blurred vision, visual flashes), which usually reverse following drug withdrawal. Multiple births (usually twins) occur in 8% to 10% of clomiphene-facilitated pregnancies. Patients should be told of this possibility.

Very rarely, clomiphene can cause ovarian hyperstimulation. Symptoms include low abdominal pain, pressure, weight gain, and swelling. Hyperstimulation can be minimized by avoiding unnecessarily large doses. If undue ovarian enlargement occurs, clomiphene use should cease. The ovaries will then regress to normal size.

Some actions of clomiphene may interfere with conception. Luteal-phase defect may be induced, but can be corrected by giving progesterone. Because it has antiestrogenic actions, clomiphene may force the production of scant and viscous cervical mucus; estrogen therapy can render cervical secretions more hospitable to sperm.

Clomiphene should be avoided during pregnancy. Although no human fetal defects have been reported, clomiphene has produced developmental abnormalities in animals.

Preparations, dosage, and administration.

Clomiphene [Clomid, Milophene, Serophene] is supplied in 50-mg oral tablets. The initial course of treatment consists of 50 mg once daily for 5 days. If cyclic menstrual bleeding has been occurring, therapy should begin on the fifth day after the onset of menses. If menstruation has been absent, dosing can start any time (assuming pregnancy has been ruled out). If the first course of treatment fails to induce ovulation, a second 5-day course (using 100 mg/day) may be tried. The second course may begin as early as 30 days after the previous one. Doses may be increased in subsequent courses. However, doses above 100 mg/day are rarely needed. Once a dose that induces ovulation has been established, that dose should be used for a maximum of three cycles. If pregnancy has not occurred, further treatment is unlikely to succeed. When ovulation does occur, it is usually within 5 to 10 days after the last clomiphene dose; patients should be instructed to have coitus at least every other day during this interval.

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