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.
Dopamine Agonists for
CHAPTER 63 Drug Therapy for Infertility
result, leuprolide causes continuous activation of pituitary GnRH receptors, which has the paradoxical effect of suppressing FSH and LH release, depriving the ovary of the stimulation needed for hormone production. By decreasing production of ovarian hormones, the drug reduces the area of endometriosis and improves symptoms. It must be stressed that leuprolide does not produce cure. Within 6 months after the drug is withdrawn, symptoms return in up to 50% of women who had previously been rendered symptom free.
Adverse Effects. Most undesired effects are secondary to estrogen deficiency. Common responses include hot flashes, vaginal dryness, decreased libido, mood changes, and headache. Nasal irritation also occurs (with administration by nasal spray). Leuprolide is teratogenic and must not be used during pregnancy.
The adverse effect of greatest concern is bone loss. After 3 to 6 months of treatment, bone mass and mineral content may decrease. To minimize the risk for osteoporosis, the manufacturer recommends that treatment last no more than 6 months.
Preparations, Dosage, and Administration. For treatment of endometriosis, a depot formulation is used. Dosing consists of either 3.75 mg IM once a month or 11.25 mg IM every 3 months. As noted, treatment should stop after 6 months; however, if it is necessary to continue for an additional 6 months, norethindrone should be added to the medication regimen.
Nafarelin. Like leuprolide, nafarelin [Synarel] is a GnRH analog that can reduce symptoms of endometriosis, but it does not improve fertility.
Nafarelin has the same mechanism as leuprolide (suppression of LH and FSH release) as well as the same adverse effects (hot flashes, vaginal dryness, amenorrhea, headache, depression, osteoporosis). Nafarelin is supplied as a nasal spray. (The drug cannot be given orally owing to rapid degradation by GI enzymes.) The initial dosage is 200 mcg (1 spray) in the morning and evening. Doses should alternate between nostrils. Treatment should begin between days 2 and 4 of the menstrual cycle.
Goserelin
Therapeutic Uses. Goserelin [Zoladex] has several uses. In addition to reducing the pain and size of endometrial growths associated with endometriosis, it can be used to thin the endometrium in management of dysfunctional uterine bleeding. It is also approved for treatment of prostate cancer and breast cancer.
Goserelin shares the same mechanism of action and adverse effects as leuprolide and nafarelin.
Preparations, Dosage, and Administration. For management of endometriosis, 3.6 mg of goserelin is administered subQ every 28 days for 6 months. Goserelin is available as implants for management of prostate cancer;
these are not used for management of endometriosis.
Danazol
Therapeutic Use. Danazol [Cyclomen] can improve symptoms of endometriosis, but it does not increase fertility. Treatment leads to complete regression of endometrial implants in the majority of patients. However, implants will eventually recur after treatment stops. In addition to the therapy of endometriosis, danazol has been used to treat angioneurotic edema and fibrocystic breast disease. Since the introduction of GnRH agonists, the use of danazol for endometriosis has sharply declined. Today, the drug is given only when GnRH agonists are contraindicated.
Mechanism of Action. Danazol acts by multiple mechanisms to induce regression of endometrial implants. First, the drug inhibits several of the enzymes needed to synthesize ovarian hormones, and thereby deprives the implant of the hormonal environment it needs for maintenance. Second, danazol suppresses secretion of pituitary gonadotropins (FSH and LH), and thereby further decreases the availability of ovarian hormones. Lastly, danazol may act directly on the implant to block ovarian hormone receptors. All of these actions result in atrophy of ectopic endometrial tissue. The normal endometrium atrophies as well.
Adverse Effects and Interactions. Danazol is weakly androgenic and may induce virilization. Potential manifestations include acne, deepening of the voice, and growth of facial hair. These effects usually reverse after treatment stops. Danazol may also cause edema, and therefore should be used with caution in patients with cardiac and renal disorders. Thrombotic events, including fatal strokes, have been reported. Liver impairment may also occur, and hence liver function should be assessed at baseline and periodically thereafter. Danazol may intensify the anticoagulant effects of warfarin. Lastly, the drug can masculinize the female fetus, and hence is contraindicated during pregnancy.
Preparations, Dosage, and Administration. Danazol is supplied in capsules (50, 100, and 200 mg) for oral use. A dosage of 200 to 300 mg twice daily is usually effective. To ensure that danazol is not taken during pregnancy, therapy should be initiated at the time of menstruation. The usual course of treatment is 3 to 9 months.
dosing, but absolute bioavailability is unknown. Cabergoline undergoes extensive hepatic metabolism followed by excretion in the urine and feces. It has a long elimination half-life of about 65 hours. In patients with severe hepatic impairment, cabergoline levels may rise.
Adverse Effects. The most common adverse effects are nausea, headache, and dizziness. Orthostatic hypotension may occur, but is rare at recommended doses. Adverse effects can be minimized by initiating treatment at low doses. Like other ergot derivatives, cabergoline may pose a risk for valvular heart damage.
Preparations, Dosage, and Administration. Cabergoline is supplied in 0.5-mg tablets. The initial dosage is 0.25 mg twice a week, administered with or without food. Dosage may be increased in 0.25-mg increments to a maximum of 1 mg twice a week. At least 4 weeks should separate each rise in dosage. After prolactin has been maintained at a normal level for at least 6 months, treatment can stop.
Bromocriptine
Actions and Therapeutic Uses. Like cabergoline, bromocriptine [Parlodel] activates dopamine receptors in the pituitary and can thereby reduce prolactin secretion. As a result, it can correct amenorrhea, galactorrhea, and infertility. If hyperprolactinemia is caused by a pituitary adenoma, bromocriptine can induce regression of the tumor (in addition to reducing prolactin secretion).
Continuous treatment can suppress tumor growth for years. Bromocriptine is also used in Parkinson disease (see Chapter 21).
Adverse Effects. When bromocriptine is used for infertility, adverse effects are frequent but usually mild. Nausea occurs in about half of patients.
Headache, dizziness, fatigue, and abdominal cramps are also common.
Orthostatic hypotension may occur, but is rare at the doses employed. Tera-togenic effects have not been reported. Adverse effects can be minimized by taking bromocriptine with meals and initiating treatment at low doses. Like cabergoline and other ergot derivatives, bromocriptine may pose a risk for valvular heart injury.
Preparations, Dosage, and Administration. Bromocriptine mesylate is supplied in 2.5-mg tablets and 5-mg capsules. Dosing is begun at 1.25 to 2.5 mg once a day and then gradually increased by 2.5 mg every 2 to 7 days until an optimal response is achieved. The typical dosage range is 2.5 to 15 mg a day. All doses should be administered with food. Normalization of the menstrual cycle may occur rapidly (within a few days); however, some women may require up to 2 months of treatment. As soon as pregnancy is achieved, use of bromocriptine should cease. As a rule, administration should not resume until after delivery. If treatment is not reinstated, hypersecretion of prolactin is almost certain to recur within a year.
Drugs for Endometriosis
As noted previously, the first-line drugs for pain of endometriosis are NSAIDs (e.g., ibuprofen) and combination oral contraceptives, usually taken cyclically.
The NSAIDs are discussed in Chapter 71. The oral contraceptives are discussed in Chapter 62. The drugs discussed in the sections that follow—GnRH agonists and danazol—cause regression of endometrial implants. Both are considered second- or third-line treatments.
GnRH Agonists
Leuprolide, nafarelin, and goserelin are synthetic analogs of GnRH. These drugs are used to relieve pain of endometriosis. However, although they can reduce symptoms, they do not increase fertility. Although women are unlikely to become pregnant while taking these drugs, precautions to avoid pregnancy are still advised.
Leuprolide
Therapeutic Uses. Leuprolide [Lupron Depot, Eligard] is a GnRH analog with several approved uses. In addition to endometriosis, the drug is indicated for uterine fibroids, central precocious puberty, and advanced prostate cancer (see Chapter 103). Discussion here is limited to treatment of endometriosis.
Mechanism of Action. Like the normal endometrium, ectopic endometrial implants are dependent on ovarian hormones. Leuprolide suppresses endo-metriosis by indirectly suppressing ovarian hormone production. Initial doses actually increase hormone production because leuprolide, like endogenous GnRH, acts on the pituitary to promote release of FSH and LH, which in turn act on the ovary to stimulate hormone production. However, in contrast to endogenous GnRH, which has a short half-life and is released in a pulsatile fashion, leuprolide has a long half-life and blood levels remain steady. As a
■ Infertility (subfertility) is a decrease in reproductive ability;
sterility is a complete absence of reproductive ability.
■ Infertility in a couple may result from infertility in one or both partners.
■ Clomiphene is used to promote follicular maturation and ovulation.
■ Clomiphene acts by blocking estrogen receptors in the hypothalamus and pituitary, causing a compensatory increase in the release of LH and FSH, which then act on the ovary to promote follicular maturation and ovulation.
■ Menotropins is a 50 : 50 mixture of LH and FSH.
■ Menotropins is used sequentially with hCG: Menotropins is given to promote follicular maturation, and then hCG is given to promote ovulation.
■ The most serious adverse effect of menotropins is ovarian hyperstimulation syndrome, characterized by sudden enlargement of the ovaries.
■ hCG is given to stimulate ovulation (after another agent, such as menotropins, has been given to promote follicular maturation).
■ Like menotropins, hCG can cause ovarian hyperstimulation syndrome.
■ Cabergoline is a dopamine agonist used to suppress exces-sive prolactin release.
■ Three GnRH agonists—leuprolide, nafarelin, and goserelin—can promote regression of endometrial implants, but these drugs will not increase fertility.
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Summary of Major Nursing Implications
aCLOMIPHENE
The implications here apply only to the use of clomiphene for promoting maturation of ovarian follicles and ovulation.
Preadministration Assessment Therapeutic Goal
Promotion of follicular maturation and ovulation in carefully selected patients.
Baseline Data
Take a complete health and gynecologic history, and assess for tubal patency. Ovarian and pituitary function must be confirmed. Pregnancy must be ruled out.
Identifying High-Risk Patients
Clomiphene is contraindicated during pregnancy and in women with liver disease or abnormal uterine bleeding of undetermined origin.
Implementation: Administration Route
Oral.
Administration
If cyclic menstrual bleeding has been occurring, begin therapy 5 days after the onset of menses. If menstruation has been absent, begin any time.
The initial course consists of 50 mg once daily for 5 days.
If ovulation fails to occur, additional courses may be tried, each beginning no sooner than 30 days after the previous course.
Implementation: Measures to Enhance Therapeutic Effects
Timing of Coitus
Advise the couple to have coitus at least every other day during the 5- to 10-day period that follows the last clomiphene dose.
Adjunctive Use of hCG
If ovulation fails to occur under the influence of clomiphene alone, injecting hCG 7 to 9 days after the last clomiphene dose may bring success.
Ongoing Evaluation and Interventions Evaluating Therapeutic Effects
Monitor treatment with serial ultrasound examinations of the ovary. Success is indicated by progressive follicular enlarge-ment followed by conversion of the follicle to a corpus luteum.
Minimizing Adverse Effects
Ovarian Enlargement. Instruct the patient to notify the prescriber if pelvic pain occurs (an indication of ovarian enlargement). If ovarian enlargement is diagnosed, clomiphene should be withdrawn, after which ovarian size usually regresses spontaneously.
Reduced Fertility. Clomiphene may cause luteal-phase defect, which can be corrected with progesterone. Alteration of cervical mucus may occur; estrogens can be used to restore the volume and fluidity of cervical secretions.
Multiple Births. Inform the couple that multiple births (usually twins) are not uncommon in clomiphene-facilitated pregnancies.
Visual Disturbances. Forewarn the patient about possible visual disturbances (blurred vision, visual flashes), and instruct her to notify the prescriber if these occur. Visual aberrations usually cease following drug withdrawal.
Other Adverse Effects. Common side effects include hot flashes (similar to the vasomotor responses of menopause), nausea, abdominal discomfort, bloating, and breast engorge-ment. Inform the patient about these effects, and instruct her to notify the prescriber if they are especially disturbing.
MENOTROPINS
The implications here refer only to the use of menotropins (together with hCG) for induction of follicular maturation and ovulation. (Menotropins is also used to treat infertility in men.)
CHAPTER 63 Drug Therapy for Infertility
Preadministration Assessment Therapeutic Goal
Induction of follicular maturation and ovulation (in conjunction with hCG) in carefully selected patients.
Baseline Data
A thorough gynecologic and endocrinologic evaluation should precede treatment. Ovarian function must be verified. Obtain a baseline value for serum estrogen.
Identifying High-Risk Patients
Menotropins is contraindicated in the presence of pregnancy, primary ovarian failure, thyroid dysfunction, adrenal dysfunc-tion, ovarian cysts, and ovarian enlargement (other than that caused by polycystic ovary syndrome).
Implementation: Administration Route
Intramuscular.
Administration
Reconstitute powdered menotropins with sterile saline immediately before injection.
Menotropins is employed sequentially with hCG.
Administer menotropins for 9 to 12 days (to promote follicular maturation). Twenty-four hours after the last dose, inject hCG.
Ovulation follows in 2 to 3 days.
Ultrasonography and serum estrogen level are used to assess follicular maturation. Upon follicular maturation, menotropins is discontinued and hCG is injected.
Implementation: Measures to Enhance Therapeutic Effects
Timing of Coitus
Advise the couple to have intercourse on the evening before hCG injection and on the following 2 to 3 days (i.e., during the probable period of ovulation).
Ongoing Evaluation and Interventions Minimizing Adverse Effects
Ovarian Hyperstimulation Syndrome. Rapid ovarian enlargement can occur, sometimes associated with pain, ascites, pleural effusion, and shortness of breath. If ovarian enlargement is excessive, discontinue menotropins and hospitalize the patient. Treatment is supportive (bed rest, analgesics, fluid and electrolyte replacement). Paracentesis can be used to remove excess ascitic fluid. If ovarian cysts rupture, surgery may be required to stop bleeding. To ensure early detection of ovarian enlargement, the patient should be examined at least every other day during menotropins use, and for 2 weeks after dosing stops.
Other Adverse Effects. Inform the couple that multiple births are relatively common in menotropins-facilitated pregnancies.
HUMAN CHORIONIC GONADOTROPIN
The implications here apply only to the use of hCG in the treatment of infertility in women.
Preadministration Assessment Therapeutic Goal
Induction of ovulation in women who are infertile because of anovulation. Pretreatment with menotropins, urofollitropin, or clomiphene is required.
Implementation: Administration Route
Intramuscular.
Administration
hCG must be used in conjunction with menotropins, a fol-litropin, or clomiphene. When used with menotropins or a follitropin, hCG is injected 1 day after the last menotropins dose. When used with clomiphene, hCG is administered 7 to 9 days after the last clomiphene dose.
Ongoing Evaluation and Interventions Minimizing Adverse Effects
Ovarian Hyperstimulation Syndrome. See Minimizing Adverse Effects for menotropins.
CABERGOLINE
Preadministration Assessment Therapeutic Goal
Treatment of female infertility occurring secondary to hyperprolactinemia.
Identifying High-Risk Patients
Cabergoline should be used with caution in patients with severe hepatic insufficiency.
Implementation: Administration Route
Oral.
Administration
Instruct patients to take cabergoline twice a week, with or without food.
Treatment can stop after prolactin levels have been maintained in the normal range (below 20 pg/mL) for at least 6 months.
Ongoing Evaluation and Interventions Minimizing Adverse Effects
Nausea, Headache, and Dizziness. Initiating treatment at low doses may help minimize these effects.
Summary of Major Nursing Implications
a—cont’d
aPatient education information is highlighted as blue text.