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 reproductive technology (e.g., in vitro fertilization). Of the drugs used for ovarian stimulation, six are used to promote follicular matura-tion, two are used to stimulate ovulamatura-tion, and two are used to prevent premature stimulation of ovulation by endogenous hormones (Table 63.1).
Clomiphene
Therapeutic Use. Clomiphene [Clomid, 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 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 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—goserelin, leuprolide, and nafarelin—are also effective, but can’t be used long term, owing to side effects, especially osteoporosis and hot flashes.
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, hyperten-sion, 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—thus the name of the condition. However, the presence of cysts is not required for a positive diagnosis. 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, to reverse hyperandrogenism (eliminating acne and hirsutism), and to decrease the long-term risk for diabetes, cancer, and heart disease. Treatment options include the following:
• Weight loss can reduce insulin and androgen levels, improve insulin sensitivity, restore menstruation and ovulation, and increase pregnancy rates.
• Clomiphene [Clomid, 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.
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.
Preparations, Dosage, and Administration. Clomiphene [Clomid, 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.
Hazardous Drugs and Special Administration Requirements. In 2016 the National Institute for Occupational Safety and Health (NIOSH) expanded the list of drugs identified as hazardous. (See https://www.cdc.gov/
niosh/docs/2016-161/pdfs/2016-161.pdf.) Clomiphene is included on that list.
NIOSH requires special handling of drugs identified as hazardous. The Safety Alert box that follows lists all the hazardous drugs in this chapter. See Chapter 3, Table 3.1, for administration and handling guidelines.
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 ovula-tion. In properly selected patients, the ovulation rate is about 90%. Because of its mechanism of action, 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 before 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.
Monitoring. Effects on the ovary can be monitored with serial ultrasound examinations. 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 flashes (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,
Generic Name Brand Name Mechanism of Action
DRUGS THAT PROMOTE FOLLICULAR MATURATION
Clomiphene Clomid, 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, Gonal-f RFF Follitropin beta Follistim AQ, Puregon
Urofollitropin Bravelle
Lutropin alfa Generic only Lutropin alfa is a recombinant form of LH used in combination with follitropin alfa [Gonal-f, Gonal-f RFF] to promote follicular maturation. Treatment is followed by hCG to induce ovulation.
DRUGS THAT STIMULATE OVULATION Human chorionic
gonadotropin (hCG) Novarel, Pregnyl 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
TABLE 63.1 ■ Drugs for Controlled Ovarian Stimulation
CHAPTER 63 Drug Therapy for Infertility
ovarian failure. Among properly selected patients, the rate of ovulation approaches 100%. It should be noted that menotropins is very expensive.
Ovulatory Women. Menotropins can be used to induce the development of multiple follicles in ovulatory women participating in an in vitro fertilization program.
Men. Menotropins has been used off-label to promote spermatogenesis in males with primary or secondary hypogo-nadotropic hypogonadism.
Adverse Effects. The most serious adverse response is ovarian hyperstimulation syndrome, a condition characterized by sudden enlargement of the ovaries. Mild to moderate ovarian enlargement is common, occurring in about 20% of patients.
This condition is benign and resolves spontaneously after discontinuing drug use. Of greater concern is ovarian enlarge-ment that occurs rapidly and that may be accompanied by ascites, pleural effusion, and considerable pain. If this manifesta-tion of ovarian stimulamanifesta-tion occurs, menotropins should be withdrawn and the patient hospitalized. Treatment is usually supportive (bed rest, analgesics, fluid and electrolyte replace-ment). Paracentesis can be used to remove some excess ascitic fluid. If rupture of ovarian cysts occurs, surgery may be required to stop bleeding. Enlargement of the ovaries is most likely during the first 2 weeks of treatment. To ensure early detection, the patient should be examined at least every other day while taking menotropins and for 2 weeks after stopping. Ovarian stimulation can be minimized by keeping the dosage as low as possible.
Pregnancies facilitated by menotropins often result in multiple births: 15% of pregnancies result in twins, and 5%
of pregnancies result in three or more babies.
Monitoring Therapy. Ovarian responses to menotropins must be monitored to determine timing of hCG administration and to minimize the risk for ovarian enlargement. Responses can be monitored by ultrasonography of the developing follicles and by measuring serum estrogen. When ultrasonography indicates that follicles have enlarged to 16 to 20 mm and when serum estrogen is 200 pg/mL per maturing follicle, then menotropins administration should cease and hCG should be injected.
Preparations, Dosage, and Administration. Menotropins [Repronex , Menopur] is supplied as a powder or pellet to be reconstituted immediately before use. Ampules of menotropins contain 75 international units (IU) of FSH activity plus 75 IU of LH activity. Repronex is admin-istered subQ or IM; Menopur is adminadmin-istered subQ.
Menotropins is used sequentially with hCG: After follicular maturation has been induced with menotropins, hCG is injected to promote ovulation.
For the initial cycle, the contents of 1 menotropins ampule are injected daily for 9 to 12 days. When estrogen measurements indicate follicular maturation has occurred, menotropins is discontinued; hCG (5000 to 10,000 USP units) is injected 24 hours after the last menotropins dose. Ovulation occurs 2 to 3 days after injecting hCG. Accordingly, patients should be instructed to have intercourse on the evening before hCG injection and on the following 2 to 3 days. If there is evidence of ovulation but conception does not take place, treatment should be repeated for two more courses using the same menotropins dosage. If treatment remains ineffective, two additional courses may be tried, using twice as much menotropins as previously. If there is still no conception, further treatment is unlikely to help.
Follitropins
Description. Three follitropins are available: urofollitropin [Bravelle], follitropin alfa [Gonal-f, Gonal-f RFF], and follitropin beta [Follistim AQ, Puregon ]. All three are preparations of FSH. Urofollitropin is a highly purified preparation of FSH extracted from the urine of postmenopausal women.
Follitropin alfa and follitropin beta are produced by recombinant DNA technol-ogy. A long-acting preparation—corifollitropin alfa [Elonva]—is available in Europe, but not in the United States or Canada.
Menotropins
Menotropins [Repronex , Menopur]—also known as human menopausal gonadotropin, or hMG—consists of equal amounts of LH and FSH activity. Commercial menotropins is prepared by extraction from the urine of postmenopausal women.
Therapeutic Actions and Uses
Anovulatory Women. Menotropins, in conjunction with hCG, is used to promote follicular maturation and ovulation in anovulatory patients. Menotropins acts directly on the ovaries to cause maturation of follicles. Once follicles have ripened, hCG is given to induce ovulation.
Menotropins is employed when gonadotropin secretion by the pituitary is insufficient to provide adequate ovarian stimula-tion. Candidates must have ovaries capable of responding to FSH and LH; menotropins is of no help in women with primary
Infertility Drugs
Life Stage Patient Care Concerns
Children Drugs for infertility are inappropriate for prepubertal children. In males, hCG may be prescribed for prepubertal cryptorchidism;
however, this may cause precocious puberty.
Pregnant
women Infertility drugs are not indicated for women who are already pregnant. Clomiphene, cetrorelix, ganirelix, follitropins, human chorionic gonadotropin, choriogonadotropin alfa, and menotropins are Pregnancy Risk Category X.a Animal and/or human developmental abnormalities and abortions have occurred. Bromocriptine and cabergoline are Pregnancy Risk Category B.a
Breast-feeding
women Bromocriptine, cabergoline, and clomiphene may decrease milk production. Breast-feeding is contraindicated when taking lutropin alfa, follitropins, and cetrorelix. Manufacturers recommend caution when taking clomiphene and hCG. While FDA labeling does not contraindicate breast-feeding by women taking menotropins and ganirelix, the manufacturer does not recommend it. As with all drugs, benefits should be weighed against risks.
Older adults Infertility drugs are not typically recommended for older patients; however, there are no age-related contraindications.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
aAs of 2020, the FDA will no longer use Pregnancy Risk Categories.
Please refer to Chapter 9 for more information.
Safety Alert
HAZARDOUS DRUGS REQUIRING SPECIAL HANDLING
Cabergoline Cetrorelix Clomiphene Ganirelix
Human chorionic gonadotropin Menotropins
dose. When used in conjunction with menotropins or a follitropin, hCG is injected 1 day after the last menotropins or follitropin dose.
Choriogonadotropin Alfa
Choriogonadotropin alfa [Ovidrel] is a form of hCG produced by recombinant DNA technology. The drug’s physicochemical, immunologic, and biologic activities are equivalent to those of naturally occurring hCG, produced by extraction from the urine of pregnant women. However, unlike urine-derived hCG, which must be injected IM, choriogonadotropin alfa is injected subQ.
As a result, administration is more comfortable. (IM injections can be painful.) Choriogonadotropin alfa has two indications. First, like natural hCG, the drug is given to trigger ovulation in women who are infertile owing to anovulation.
Second, the drug is used to promote late follicular maturation and early luteinization in women undergoing assisted reproductive technology (e.g., in vitro fertilization). For both indications, follicular maturation must first be induced with a follicle-stimulating agent (e.g., menotropins). Choriogonadotropin alfa (250 mcg) is then given as a single subQ injection 1 day after the last dose of the follicle-stimulating agent. Major adverse effects are the same as those of natural hCG: ovarian hyperstimulation syndrome, rupture of ovarian cysts, and multiple births.
Gonadotropin-Releasing Hormone Antagonists
GnRH antagonists are used to prevent a premature surge of endogenous LH in women undergoing controlled ovarian stimulation (with menotropins or follitropin [FSH]). As discussed earlier, after follicles have matured under the influence of exogenous menotropins or FSH, the patient is given an injection of hCG (LH) to cause ovulation. However, in some women, the natural midcycle LH surge occurs early, causing ovulation before the eggs have fully matured.
As a result, the chances of successful conception and implantation are reduced.
The GnRH antagonists prevent premature LH release and thereby eliminate the chance of premature ovulation.
Two GnRH antagonists are available: ganirelix (generic only) and cetrorelix [Cetrotide]. Both drugs block GnRH receptors and thereby prevent GnRH from promoting the production and release of LH from the pituitary. Various dosing schedules are employed. One option for either drug is to give 250 mcg subQ daily, beginning in the early follicular phase and continuing until the day of hCG administration. Injections are made by the patient into the upper thigh or the region around the navel.