Goodman and Gilman Manual of Pharmacology and Therapeutics
Special Systems Pharmacology
Contraception and Pharmacotherapy of Obstetrical and Gynecological Disorders
Drugs to control fertility and treat disorders of the female reproductive organs collectively are among the most frequently prescribed agents in clinical practice. This chapter discusses a number of common clinical issues and their drug therapies that are central to women’s health. The focus is on reproductive disorders and aspects of therapy rather than comprehensive coverage of the drugs themselves, which are described in more detail elsewhere (e.g., see Chapter 33 for prostaglandins; Chapter 38 for the gonadotropins, gonadotropin-releasing hormone [GnRH] agonists and antagonists, and oxytocin; Chapter 40 for estrogens and progestins; Section VII for antibiotics).
Contraception can be administered as planned prophylaxis or postcoitally for emergency contraception (i.e., high-dose estrogen-containing oral contraceptive pills, high-dose progestin pills, a progesterone antagonist, intrauterine devices). A progesterone antagonist also can be used to terminate an established pregnancy.
COMBINATION ORAL CONTRACEPTIVES. Pills containing an estrogen and progestin are the most widely used (Table 66–1); they act primarily by suppressing the luteinizing hormone (LH) surge and thereby preventing ovulation. A wide variety of preparations are available for oral, transdermal, and vaginal administration (see Table 66–2 in the 12th edition of the parent text for a list of branded formulations, many of which are available as generics). Almost all contain ethinyl estradiol as the estrogen and a 17α-alkyl-19-nortestosterone derivative as the progestin, and are administered for the first 21-24 days of a 28-day cycle.
One-Year Failure Rate with Various Forms of Contraception
Sexually Transmitted Gynecological Infections and Recommended Therapie
MECHANISMS OF ACTION. Estrogen sensitizes the hypothalamus and pituitary gonadotropes to the feedback inhibitory effects of the progestin and minimizes breakthrough bleeding. The progestin exerts negative feedback, which suppresses the LH surge and thereby prevents ovulation, and protects against uterine cancer by opposing the proliferative effects of the estrogen on the uterine endometrium.
FORMULATIONS. Newer formulations offer effective contraception with improved activity profiles. They contain lower amounts of hormones to minimize adverse effects; some incorporate progestins with less androgenic activity (e.g., gestodene, desogestrel) or that antagonize the mineralocorticoid receptor and thereby reduce the tendency toward edema (e.g., drospirenone). Traditionally, combination oral contraceptives were packaged with 21 pills containing active hormone and 7 placebo tablets; each active pill contained a constant amount of the estrogen and progestin (i.e., a monophasic formulation). In an effort to maximize the antiovulatory effects and prevent breakthrough bleeding while minimizing total exposure to the hormones, some formulations provide active pills with 2 (biphasic) or 3 (triphasic) different amounts of 1 or both hormones to be used sequentially during each cycle.
“Extended-cycle” contraceptives extend the number of active pills per cycle and thus decrease the duration of menstrual bleeding. Two products contain 24 active pills with only 4 placebo tablets (e.g., YAZ[which contains drospirenone as the progestin] and LOESTRIN 24). Two products are packaged as 91-day packets, with 84 estrogen/progestin tablets and 7 placebo tablets (SEASONALE) or 7 tablets containing a lower dose of ethinyl estradiol alone (SEASONIQUE). Finally, LYBREL is provided in 28-day packets that contain only hormone pills and no placebo. All of these extended-cycle formulations appear to be comparable to the traditional products as contraceptives; aside from an increased frequency of breakthrough bleeding initially, no unexpected adverse effects have been observed.
A weekly transdermal contraceptive patch (ORTHO EVRA) releases ethinyl estradiol (20 μg/day) and norelgestromin (which is metabolized to norgestimate; 150 μg/day). In response to pharmacokinetic data suggesting that this patch provides higher estrogen exposure (AUC) than the low-dose oral contraceptive pills, the FDA added a black box advisory that notes this pharmacokinetic difference and warns of a potential increased risk of venous thromboembolism. Local reactions to the patch occur in ~5-15% of users and may be decreased by pre-application of a topical glucocorticoid. A vaginal ring (NUVARING)also is available that releases ethinyl estradiol (15 μg daily) and etonogestrel (an active metabolite of desogestrel; 120 μg daily). Each ring is used for 3 weeks, followed by a 1-week interval without the ring.
The combination estrogen/progestin formulations provide highly effective (~99%) contraception and also have a number of noncontraceptive benefits, including protection against certain cancers (e.g., ovarian, endometrial, colorectal), decreased iron-deficiency anemia secondary to menstrual blood loss, and decreased risk of fractures due to osteoporosis. Combination oral contraceptives also are widely used for conditions such as endometriosis, dysmenorrhea, menorrhagia, irregular menstrual cycles, premenstrual dysphoric disorder, acne, and hirsutism.
ADVERSE EFFECTS. Serious adverse effects of the combination estrogen/progestin contraceptive agents are relatively rare. Thromboembolic disease, largely due to the estrogenic component, is the most common serious side effect. Estrogen concentration, the patient’s age, smoking, and inherited thrombophilias all influence the risk of developing thromboembolic disease. The impact of combination oral contraceptives on breast cancer has been highly debated; although a meta-analysis of epidemiological studies concluded that the combination oral contraceptives did increase the risk of breast cancer, studies conducted with the lower doses of hormones in current formulations suggest that the risk of breast cancer is not increased.
Other adverse effects include hypertension, edema, gallbladder disease, and elevations in serum triglycerides (see Chapter 40). With pills containing drospirenone, which antagonizes the mineralocorticoid receptor, serum K+ should be monitored in women at risk for hyperkalemia (e.g., those on K+-sparing diuretics or drugs that inhibit the renin–angiotensin system). The combination oral contraceptives are contraindicated in women with a history of thromboembolic disease, cerebrovascular disease, migraine headaches with aura, estrogen-dependent cancer, impaired hepatic function or active liver disease, undiagnosed uterine bleeding, and suspected pregnancy. Patients with a history of gestational diabetes should be monitored closely, and drug cessation should be strongly considered in anticipation of events associated with an increased risk of venous thromboembolism (e.g., elective surgery).
PROGESTIN-ONLY CONTRACEPTIVES. Progestin-only minipills contain derivatives of 17α-alkyl-19-nortestosterone but no estrogen. Although they do inhibit ovulation to some degree, their efficacy also reflects changes in the cervical mucus that inhibit fertilization and endometrial changes that inhibit implantation. They are slightly less effective than the combination estrogen/progestin formulations. Their major adverse effect is breakthrough bleeding.
Progestins also are used for long-acting contraception. A depot formulation of medroxyprogesterone (DEPO-PROVERA) injected subcutaneously or intramuscularly provides effective contraception for 3 months. Its use has been associated with decreased bone mineral density. Subdermal implants of progestin-impregnated rods provide effective contraception over several years. The only implant system currently approved in the U.S. is IMPLANON, which incorporates 3-ketodesogestrel, an active metabolite of desogestrel, into an inert matrix. An intrauterine device that releases levonorgestrel (MIRENA) provides highly effective contraception for up to 5 years. It acts predominantly to inhibit gamete function and survival via local changes in the cervical mucus.
Postcoital (or emergency) contraception is indicated for use in cases of mechanical failure of barrier devices or in circumstances of unprotected intercourse. It is not intended as a regular method of contraception. The mechanisms of action of the postcoital contraceptives are not fully understood.
PLAN-B one-step, which contains 2 tablets of the progestin levonorgestrel (0.75 mg each), is marketed specifically for postcoital contraception and may be obtained in the U.S. without a prescription by women >18 years of age. Treatment is most effective if the first dose is taken within 72 h of intercourse, followed by a second dose 12 h later; a single dose of 1.5 mg within 72 h of intercourse appears to be equally effective. Other options for postcoital contraception include mifepristone (MIFEPREX), which is not FDA-approved for this indication but is highly effective in oral doses ranging from 10-50 mg when taken within 5 days after unprotected intercourse, and copper intrauterine devices when inserted within 4 days of unprotected intercourse. Mifepristone also has abortifacient activity when used in a different treatment regimen. The selective progesterone receptor modulator ulipristal (ELLA, ELLAONE) was recently approved as an emergency contraceptive, effective up to 120 h after unprotected intercourse; see Chapter 40 for details.
If contraception is not used or fails, either mifepristone (RU-486, MIFEPREX) or methotrexate (50 mg/m2 intramuscularly or orally) can be used to terminate an unwanted pregnancy in settings outside surgical centers. A prostaglandin then is administered to stimulate uterine contractions and expel the detached conceptus; in the U.S., prostaglandins used include dinoprostone (PGE2; PROSTIN E2) administered vaginally or the PGE1 analog misoprostol (CYTOTEC) given orally or vaginally, both of which are used off label for this purpose. Prostaglandins used in other countries include the PGE2 analog sulprostone (NALADOR) and the PGE1 analog gemeprost (CERVAGEM).
MIFEPRISTONE. Mifepristone is a 17α-alkyl-19-nortestosterone derivative that acts as a competitive antagonist at the progesterone receptor. Its actions are associated with focal hemorrhage and breakdown of the stromal extracellular matrix that ultimately leads to the breakdown of the uterine endometrium. In addition, mifepristone increases the sensitivity of the uterus to the uterotonic effects of prostaglandins. Mifepristone is metabolized through a series of reactions initiated by hepatic CYP3A4. Women receiving chronic glucocorticoid therapy should not be given mifepristone because of its anti-glucocorticoid activity, and the drug should be used cautiously in women who are anemic or receiving anticoagulants.
As approved by the FDA, mifepristone (600 mg) is taken for pregnancy termination within 49 days after the start of a woman’s last menstrual period. The synthetic PGE1 analog misoprostol (400 μg) is administered orally 48 h later; vaginal administration is at least as effective but is not FDA-approved. Complete abortion using this procedure exceeds 90%; when termination of pregnancy fails or is incomplete, surgical intervention is required. Repeated doses of misoprostol alone (e.g., 800 μg vaginally or sublingually every 3 h or every 12 h for 3 doses) also have been effective in settings where mifepristone is unavailable. Vaginal bleeding follows pregnancy termination and typically lasts from 1-2 weeks but rarely (in 0.1% of patients) is severe enough to require blood transfusion. A high percentage of women also experience abdominal pain and uterine cramps, nausea and vomiting, and diarrhea secondary to the prostaglandin. Because mifepristone carries a risk of serious, and sometimes fatal, infection and bleeding following its use for medical abortion, a black box warning has been added to the product labeling. Women receiving mifepristone should be informed of these risks and cautioned to seek immediate medical attention if symptoms or signs of these conditions occur. Fulminant septic shock associated with Clostridium sordellii infections may result and is attributable to the combined effects of uterine infection and inhibition of glucocorticoid action by mifepristone.
METHOTREXATE. Methotrexate is a potent abortifacient, probably as a result of the ability of the placenta to concentrate FH2Glun (dihydrofolate polyglutamate) and its analogs (see Chapter 61).
DRUG THERAPY IN GYNECOLOGY
INDUCTION OF SEXUAL MATURATION
A number of clinical disorders, including Turner syndrome and other forms of gonadal dysgenesis, are associated with impaired production of ovarian steroids in phenotypic females. Such patients typically fail to develop secondary sexual characteristics at the normal time of puberty (sexual infantilism) or fail to have menses (primary amenorrhea). In these cases, steroid hormones are administered to induce development of the secondary sex characteristics; however, treatment is initiated only after the diagnosis is ascertained and underlying disorders that might respond to more specific therapy (e.g., prolactinomas) are excluded (see Chapter 38).
Types of estrogens used and the treatment regimens may vary by country or individual preference. Examples include conjugated estrogens, 0.3-1.25 mg; micronized 17β-estradiol, 0.5-2.0 mg; ethinyl estradiol, 5-20 μg; and transdermal 17β-estradiol, 25-50 μg. To achieve optimal breast development, treatment typically is initiated with a low dose of estrogen (e.g., conjugated estrogens at a starting dosage of 0.3 mg/day or ethinyl estradiol at 5 μg/day) starting in patients between ages 10 and 12 years or immediately if the diagnosis is made after this age. After 3-6 months, the dosage is increased (e.g., 0.9-1.25 mg/day of conjugated estrogens or 20 μg/day of ethinyl estradiol). Once this is achieved, a progestin (e.g., medroxyprogesterone, 10 mg/day, or micronized progesterone, 200-400 μg/day) for 12 days each cycle is added to the regimen to optimize breast development and permit cyclical menses, thereby avoiding endometrial hyperplasia and its consequent risk of uterine cancer. Once menses are established, many clinicians will switch to a standard low-dose oral contraceptive pill or even may use an extended-cycle formulation.
Short stature, a universal feature of non-mosaic Turner syndrome, usually is treated with human growth hormone, often together with an androgen such as oxandrolone (see Chapter 41). Initiating treatment with human growth hormone and androgen and delaying the onset of estrogen therapy generally produces a better growth response (see Chapter 38).
Menopause refers to the permanent cessation of menstrual periods (i.e., for >12 months) resulting from the loss of ovarian follicular activity; it usually occurs when women are between 45 and 60 years of age.
The decline in estradiol levels produces a variety of symptoms and signs, including vasomotor disturbances (hot flashes or flushes), sweating, irritability, sleep disturbances, and atrophy of estrogen-dependent tissue. In addition, postmenopausal women are at increased risk for osteoporosis, bone fractures, and coronary heart disease and experience increased memory loss and other cognitive difficulties.
ESTROGEN THERAPY. The observed estrogen deficiency associated with menopause, as well as a number of studies showing positive effects of estrogen replacement therapy on these parameters, led to widespread use of hormone replacement therapy in peri- and postmenopausal women.
The initial publication of data from the Women’s Health Initiative (WHI), a large, randomized, placebo-controlled trial, dramatically altered therapeutic approaches to menopause. As expected, treatment of postmenopausal women with 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone (in women with a uterus) or with 0.625 mg of conjugated estrogen alone (in women lacking a uterus) improved bone mineral density and decreased the risk of fractures and colorectal cancer. In addition, estrogen therapy in both the estrogen plus progestin and the estrogen-alone groups was associated with an increased incidence of deep venous thrombosis and stroke; and the incidence of breast cancer and coronary heart disease also increased in women receiving both estrogen and progestin. In women >65 years of age, hormone therapy did not improve cognitive function or protect against dementia. Based on these findings, it was recommended that hormone replacement therapy not be used to decrease the risk of coronary heart disease, cognitive impairment, or dementia. Subsequent subgroup analyses of the WHI data suggest that cardiovascular risk was not increased when hormone therapy was initiated within 10 years of menopause and that the risks of estrogen therapy may be minimal in women who are perimenopausal or recently menopausal.
Available routes of estrogen administration for hormone replacement therapy include oral, transdermal (patch, gel, and spray), and vaginal (cream, ring, and tablets) (see Table 66–3 of the 12th edition of the parent text). In women who have undergone hysterectomy, estrogen alone is used. For women with an intact uterus, a progestin also is administered to oppose the proliferative effect of the estrogen on the uterine endometrium.
FDA Use-in-Pregnancy Ratings
Other therapies for vasomotor symptoms include phytoestrogens (e.g., soy products), herbal extracts (e.g., black cohosh), selective serotonin reuptake inhibitors (e.g., fluoxetine, controlled-release paroxetine, sertraline), clonidine, and gabapentin. However, hormone replacement remains the most effective therapy for vasomotor symptoms in menopausal women. Current recommendations advise using estrogen replacement at the lowest possible effective dose and for the shortest duration to treat moderate to severe vasomotor symptoms and vaginal dryness. For vaginal dryness alone, topical preparations are preferred.
Endometriosis is an estrogen-dependent disorder that results from endometrial tissue ectopically located outside of the uterine cavity. It predominantly affects women during their reproductive years, with a prevalence of 0.5-5% in fertile women and 25-40% in infertile women. Diagnosis typically is made at laparoscopy, either prompted by unexplained pelvic pain (dysmenorrhea or dyspareunia) or infertility. The infertility is thought to reflect involvement of the fallopian tubes with the underlying process and, possibly, impaired oocyte maturation.
Because the proliferation of ectopic endometrial tissue is responsive to ovarian steroid hormones, many symptomatic approaches to therapy aim to produce a relatively hypoestrogenic state. Combination oral contraceptives have been standard first-line treatment for symptoms of endometriosis, and ample evidence from observational trials supports their benefit. The predominant mechanism of action is believed to be suppression of gonadotropin secretion, with subsequent inhibition of estrogen biosynthesis. Progestins (e.g., medroxyprogesterone, dienogest) also have been used to promote decidualization of the ectopic endometrial tissue. The levonorgestrel intrauterine system, which is approved for contraception, also has been used off label for this indication, as well as for menorrhagia.
Stable GnRH agonists can suppress gonadotropin secretion and thus effect medical castration. Drugs that carry an indication for endometriosis include leuprolide (LUPRON), goserelin (ZOLADEX), and nafarelin (SYNAREL); other GnRH agonists also may be used off label for this purpose (see Chapter 38). Due to significant decreases in bone density and symptoms of estrogen withdrawal, “add-back” therapy with either a low-dose synthetic estrogen (e.g., conjugated equine estrogens, 0.625-1.25 mg) or a high-dose progestin (e.g., norethindrone, 5 mg) has been used when the duration of therapy has exceeded 6 months. Danazol (DANOCRINE), a synthetic androgen that inhibits gonadotropin production via feedback inhibition of the pituitary-ovarian axis, also is FDA-approved for endometriosis therapy; it rarely is used now because of its significant adverse effects, including hirsutism and elevation of hepatic transaminases. In Europe and elsewhere, the antiprogestin gestrinone has been employed.
Hirsutism, or increased hair growth in the male distribution, affects ~10% of women of reproductive age. It can be a relatively benign, idiopathic process or part of a more severe disorder of androgen excess that includes overt virilization (voice deepening, increased muscle mass, male pattern balding, clitoromegaly) and often results from ovarian or adrenal tumors. Specific etiologies associated with hirsutism include congenital adrenal hyperplasia, polycystic ovary syndrome (PCOS), and Cushing syndrome. After excluding serious pathology such as a steroid-producing malignancy, the treatment largely becomes empirical.
Pharmacotherapy is directed at decreasing androgen production and action. Initial therapy often involves treatment with combination oral contraceptive pills, which suppress gonadotropin secretion and thus the production of ovarian androgens. The estrogen also increases the concentration of sex hormone–binding globulin, thereby diminishing the free concentration of testosterone. The full effect of this suppression may take up to 6-9 months. GnRH agonists downregulate gonadotropin secretion and also may be used to suppress ovarian steroid production.
In patients who fail to respond to ovarian suppression, efforts to block androgen action may be effective. Spironolactone (ALDACTONE), a mineralocorticoid-receptor antagonist, and flutamide (EULEXIN; seeChapter 41) inhibit the androgen receptor. In Europe and elsewhere, cyproterone (50-100 mg/day) is used as an androgen-receptor blocker, often in conjunction with a combination oral contraceptive. Male offspring of women who become pregnant while taking any of these androgen inhibitors are at risk of impaired virilization secondary to impaired synthesis or action of dihydrotestosterone (Pregnancy Risk Category X, see Table 66–3). The antifungal ketoconazole (NIZORAL), which inhibits CYP steroid hydroxylases (see Chapters 42 and 57), also can block androgen biosynthesis but may cause liver toxicity. Topical eflornithine (VANIQA), an ornithine decarboxylase inhibitor, has been used with some success to decrease the rate of facial hair growth.
Non-pharmacological approaches include bleaching, depilatory treatments (e.g., shaving, treatment with hair-removing chemicals), or methods that remove the entire hair follicle (e.g., plucking, electrolysis, laser ablation).
INFECTIONS OF THE FEMALE REPRODUCTIVE TRACT
A variety of pathogens can cause infections of the female reproductive tract that range from vaginitis to pelvic inflammatory disease; Table 66–2 shows current recommendations for pharmacotherapy of selected sexually transmitted gynecological infections as issued by the Centers for Disease Control and Prevention.
The individual drugs used for systemic or topical therapy are described in more detail in Section VII. Infections have been implicated as important factors in preterm labor, as discussed further in “Prevention or Arrest of Preterm Labor.”
Infertility (i.e., the failure to conceive after 1 year of unprotected sex) affects 10-15% of couples in developed nations and is increasing in incidence as more women choose to delay childbearing until later in life. The major impediment to pregnancy in an infertile couple can be attributed primarily to the woman in approximately one-third, to the man in approximately one-third, and to both in approximately one-third. The likelihood of a successful pharmacological induction of fertility in these couples depends greatly on the reason for the infertility.
Defined abnormalities in the male partner that lead to impaired fertility (e.g., hypogonadism, Y chromosome microdeletions, Klinefelter syndrome) typically are detected by analysis of a semen sample; most often, male infertility is idiopathic. The medical therapy for some of these conditions is discussed in Chapters 38 and 41.
Anovulation accounts for ~50% of female infertility and is a major focus of pharmacological interventions used to achieve conception. Thus, whether a woman is ovulating is a key question. In infertile women who ovulate, analysis of the patency of the fallopian tubes and the structure of the uterus is an important part of the diagnostic evaluation. A number of approaches have been used to stimulate ovulation in anovulatory women. Often, a stepwise approach is taken, initially using simpler and less expensive treatments, followed by more complex and expensive regimens if initial therapy is unsuccessful. In obese patients with PCOS, the inclusion of lifestyle modifications directed at weight loss is warranted based on the association of obesity with anovulation, pregnancy loss, and complicated pregnancies (e.g., gestational diabetes, pre-eclampsia). Definitive evidence that weight loss improves fertility is not currently available.
CLOMIPHENE. Clomiphene citrate (CLOMID, SEROPHENE) is a potent anti-estrogen that primarily is used for treatment of anovulation in the setting of an intact hypothalamic—pituitary axis and adequate estrogen production (e.g., PCOS). By inhibiting the negative feedback effects of estrogen at hypothalamic and pituitary levels, clomiphene increases follicle-stimulating hormone (FSH) levels—typically by t50%—and thereby enhances follicular maturation (see Chapter 40). A typical regimen is 50 mg/day orally for 5 consecutive days starting between days 2 and 5 of the cycle. If this regimen fails to induce ovulation, the dose of clomiphene is increased, first to the FDA-approved maximum of 100 mg/day and possibly as high as 150 or 200 mg/day. Although clomiphene is effective in inducing ovulation in perhaps 75% of women, successful pregnancy ensues in only 40-50% of those who ovulate.
Untoward effects of clomiphene include the ovarian hyperstimulation syndrome (OHSS) and increased incidences of multifetal gestations (twins in ~5-10% and more than 2 babies in ~0.3% of pregnancies), ovarian cysts, hot flashes, headaches, and blurred vision. A few studies have suggested that prolonged use (e.g., >12 cycles) may increase the risk of ovarian and endometrial cancer; thus, the recommended maximum number of cycles is 6. Clomiphene should not be administered to pregnant women (FDA Category X).
Tamoxifen may be as effective as clomiphene for ovulation induction but is not FDA-approved for this indication.
GONADOTROPINS. The preparations of gonadotropins available for clinical use are detailed in Chapter 38. Gonadotropins are indicated for ovulation induction in anovulatory women withhypogonadotropic hypogonadism secondary to hypothalamic or pituitary dysfunction, and also are used to induce ovulation in women with PCOS who do not respond to clomiphene. Figure 66–1 shows a typical regimen for ovulation induction. Gonadotropin-induced ovulation results in multiple births in up to 10-20% of cases due to the pharmacologically induced development of more than 1 pre-ovulatory follicle and the release of more than 1 ovum.
Figure 66–1 Idealized regimens using exogenous gonadotropins for fertility induction. A. Step-up regimen for ovulation induction. After menses, daily injections of gonadotropin (75 IU) are started. Follicle maturation is assessed by serial measurement of plasma estradiol and follicle size, as discussed in the text. If an inadequate response is seen, the dose of gonadotropin is increased to 112 or 150 IU/day. When 1 or 2 follicles have achieved a size of ≥17 mm in diameter, final follicle maturation and ovulation are induced by injection of human chorionic gonadotropin (hCG). Fertilization then is achieved at 36 h after hCG injection by intercourse or intrauterine insemination (IUI). If more than 2 mature follicles are seen, the cycle is terminated and barrier contraception is used to avoid triplets or higher degrees of multifetal gestation. B. Long protocol for ovarian hyperstimulation using gonadotropin-releasing hormone (GnRH) agonist to inhibit premature ovulation, followed by in vitro fertilization (IVF). After the GnRH agonist has inhibited endogenous secretion of gonadotropins, therapy with exogenous gonadotropins is initiated. Follicle maturation is assessed by serial measurements of plasma estradiol and follicle size by ultrasonography. When 3 or more follicles are ≥17 mm in diameter, then ovulation is induced by injection of hCG. At 32-36 h after the hCG injection, the eggs are retrieved and used for IVF. Exogenous progesterone is provided to promote a receptive endometrium, followed by embryo transfer at 3-5 days after fertilization. C. Protocol for ovarian hyperstimulation in an IVF protocol using a GnRH antagonist. The cycle duration is shorter because the GnRH antagonist does not induce a transient flare of gonadotropin secretion that might disrupt the timing of the cycle, but many other elements of the cycle are analogous to those in B. IU, intrauterine.
Gonadotropin induction also is used for ovarian stimulation in conjunction with in vitro fertilization (IVF; see Figure 66–1). In this setting, larger doses of FSH (typically 225-300 IU/day) are administered to induce the maturation of multiple (ideally at least 5 and up to 20) oocytes that can be retrieved for IVF and intrauterine transfer. To prevent the LH surge and subsequent premature luteinization of the ovarian follicles, gonadotropins typically are administered in conjunction with a GnRH agonist.
GnRH antagonists also can be used to inhibit endogenous LH secretion. Because they do not transiently increase gonadotropin secretion, they can be initiated later in the cycle in a “short protocol.” Current regimens include daily injection in a dose of 0.25 mg (ganirelix [ANTAGON] or cetrorelix [CETROTIDE]) starting on the fifth or sixth day of gonadotropin stimulation or a single dose of 3 mg of cetrorelix administered on day 8 or 9 of the late follicular phase. Using either the long or short protocols, hCG (at typical doses of 5000-10,000 IU of urine-derived product or 250 μg of recombinant hCG) is given to induce final oocyte development, and the mature eggs are retrieved from the pre-ovulatory follicles at 32-36 h thereafter. The retrieved ova are fertilized in vitro with sperm (IVF) or by intracytoplasmic sperm injection; 1 or 2 embryos then are transferred to the uterus 3-5 days after fertilization.
Repeated injections of hCG, while sustaining the corpus luteum, may increase the risk of OHSS. Thus, standard IVF regimens typically provide exogenous progesterone replacement to support the fetus until the placenta acquires the biosynthetic capacity to take over this function; regimens include progesterone in oil (50-100 mg/day intramuscularly) or micronized progesterone (180-300 mg twice daily vaginally). Vaginal preparations containing 100 mg (ENDOMETRIN) or 90 mg (PROCHIEVE, CRINONE) of micronized progesterone are approved for administration 2 or 3 times daily as part of IVF and other fertility technologies.
Aside from the attendant complications of multifetal gestation, the major side effect of gonadotropin treatment is OHSS. Symptoms and signs include abdominal pain and/or distention, nausea and vomiting, diarrhea, dyspnea, oliguria, and marked ovarian enlargement on ultrasonography. OHSS can lead to hypovolemia, electrolyte abnormalities, acute respiratory distress syndrome, thromboembolic events, and hepatic dysfunction. In ovulation induction, incipient OHSS should be suspected if routine laboratory investigation reveals the presence of more than 4 to 6 follicles >17 mm or a serum estradiol level of >1500 pg/mL; in this setting, hCG should be withheld and barrier contraception used. In an effort to avoid overt hyperstimulation, the FSH can be withheld for a day or 2 (“coasting”) if the plasma level of estradiol is near the top of this range. In either case, ovulation induction with recombinant LH, which has a considerably shorter t1/2 than hCG, or with a GnRH agonist may diminish the incidence of OHSS. The potential deleterious effects of gonadotropins are debated. There is no evidence that the gonadotropins themselves or components of the IVF process increase the rate of congenital abnormalities in babies born from stimulated oocytes.
INSULIN SENSITIZERS. PCOS affects 4-7% of women of reproductive age and is the most frequent cause of anovulatory infertility. Inasmuch as PCOS patients often exhibit hyperinsulinemia and insulin resistance, insulin sensitizers such as metformin have been evaluated for their effects on ovulation and fertility (see Chapter 43). Although several small trials suggested that metformin increased ovulation in PCOS patients relative to placebo; metformin was less effective than clomiphene in inducing ovulation, promoting conception, or improving live birth rates.
Preliminary results suggested that the use of rosiglitazone (AVANDIA), pioglitazone (ACTOS), and other members of the thiazolidinedione family may increase ovulation in PCOS patients; however, there is considerable reluctance to use these drugs in this setting given their association with an increased risk of congestive heart failure and myocardial ischemia.
AROMATASE INHIBITORS. Aromatase are under evaluation as potential drugs for infertility. By inhibiting estrogen biosynthesis, these drugs decrease estrogen negative feedback and thus increase FSH levels and stimulate follicle development. The aromatase inhibitor anastrozole (ARIMIDEX) has been used off label for ovulation induction. Some data suggest that anastrozole is less effective than clomiphene in inducing follicle maturation but more likely to lead to pregnancy.
DRUG THERAPY IN OBSTETRICS
GENERAL PRINCIPLES OF DRUG THERAPY OF PREGNANT WOMEN
The processes of evaluating potential adverse effects of various drugs as described in Chapter 1, often do not provide sufficient information regarding safety in pregnant women or children. Individuals at the extremes of the age spectrum are particularly vulnerable to the toxic effects of drugs (see Chapter 4). In pregnant women, the placenta provides a barrier for the transfer of certain drugs from the mother to the fetus; however, many compounds can freely cross the placental barrier and access the fetal circulation.
The teratogenic effects of thalidomide on limb formation, alcohol on development of the CNS and cognition, and diethylstilbestrol (DES) on genital development in males and females are stark reminders of the dangers of fetal exposure to drugs.
PRECAUTIONS AND RECOMMENDATIONS. Based on the relative paucity of human data on the teratogenic effects of drugs and the limited reliability of animal models, a fundamental tenet in treating pregnant women is to minimize, whenever possible, the exposure of mother and fetus to drugs. Of equal importance, substances of abuse (e.g., cigarettes, alcohol, illegal drugs) should be avoided and, whenever possible, eliminated before conception. In addition, all pregnant women should take a multivitamin containing 400 μg of folic acid daily to diminish the incidence of neural tube defects.
The greatest concern is during the period of organogenesis in the first trimester, when a number of the most vulnerable tissues are formed. Cancer chemotherapy drugs cannot be given with reasonable safety during the first trimester, but most cytotoxics may be administered without teratogenic effects and with maintenance of pregnancy in the third trimester (see Chapters 61-63). Drugs that are used to promote fertility are a special case, since they, by nature of their use, will be present in the mother at the time of conception.
USE-IN-PREGNANCY LISTING OF DRUGS. The FDA assigns different levels of risk to drugs for use in pregnant women, as listed in Table 66–3.
Certain drugs are so toxic to the developing fetus that they must never be administered to a pregnant woman (Category X); in some cases (e.g., thalidomide, retinoids), the potential for fetal harm is so great that multiple forms of effective contraception must be in place before the drug is initiated. For other drugs, the risk of adverse effects on the fetus may range from Category A (drugs that have not been proven to have adverse effects on the fetus despite adequate investigation) to Category D (drugs with risks that sometimes may be justified based on the severity of the underlying condition; see “Pregnancy-Induced Hypertension/Pre-eclampsia” and “Tocolytic Therapy for Established Preterm Labor”). Unfortunately, the FDA listings may be overly simplistic or outdated for a given drug; for example, oral contraceptives are listed as Category X, even though considerable data now indicate that birth defects are not increased in women taking oral contraceptives at the time of conception.
Nursing mothers constitute a second special situation with respect to potential adverse effects of drugs. Some drugs may interfere with milk production and/or secretion (e.g., estrogen-containing oral contraceptives) and thus should be avoided if possible in mothers who wish to breast-feed. Other drugs may be secreted into breast milk and expose the baby to potentially toxic levels during the vulnerable perinatal period.
Hypertension affects up to 10% of pregnant women in the U.S.
Hypertension that precedes pregnancy or manifests before 20 weeks of gestation is believed to overlap considerably in pathogenesis with essential hypertension. These patients appear to be at increased risk for gestational diabetes and need careful monitoring. In contrast, pregnancy-induced hypertension, or pre-eclampsia, generally presents after 20 weeks of gestation as a new-onset hypertension with proteinuria (>300 mg of urinary protein/24 h); pre-eclampsia is thought to involve placenta-derived factors that affect vascular integrity and endothelial function in the mother, thus causing peripheral edema, renal and hepatic dysfunction, and in severe cases, seizures. Chronic hypertension is an established risk factor for pre-eclampsia. The consensus panel recommended initiation of drug therapy in women with a diastolic blood pressure >105 mm Hg or a systolic blood pressure >160 mm Hg. If severe pre-eclampsia ensues, with marked hypertension and evidence of end-organ damage, then termination of the pregnancy by delivery of the baby is the treatment of choice, provided that the fetus is sufficiently mature to survive outside the uterus. If the baby is very preterm, then hospitalization and pharmacotherapy may be employed in an effort to permit further fetal maturation in utero.
Several drugs commonly used for hypertension in non-pregnant patients (e.g., angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists) should not be used in pregnant women due to unequivocal evidence of adverse fetal effects. Many experts will convert the patient to the centrally acting α adrenergic agonist α-methyldopa (ALDOMET; 250 mg twice daily) (FDA Category B), which rarely is used for hypertension in non-pregnant patients. Other drugs with reasonable evidence of safety (Category C) also may be used, including the combination α-selective, β-nonselective adrenergic antagonist labetalol (TRANDATE; 100 mg twice daily) and the Ca2+ channel blocker nifedipine (PROCARDIA XL, ADALAT CC; 30 mg once daily).
If severe pre-eclampsia or impending labor requires hospitalization, blood pressure can be controlled acutely with hydralazine (5 or 10 mg intravenously or intramuscularly, with repeated dosing at 20-min intervals depending on blood pressure response) or labetalol (20 mg intravenously, with dose escalation to 40 mg at 10 min if blood pressure control is inadequate). In addition to receiving drugs for blood pressure control, women with severe pre-eclampsia or who have CNS manifestations (e.g., headache, visual disturbance, or altered mental status) are treated as inpatients with magnesium sulfate, based on its documented efficacy in seizure prevention and lack of adverse effects on the mother or baby. Such treatment also should be considered for postpartum women with CNS manifestations: ~20% of episodes of eclampsia occur in women more than 48 h post-delivery.
PREVENTION OR ARREST OF PRETERM LABOR
Preterm birth, defined as delivery before 37 weeks of gestation, occurs in >10% of pregnancies in the U.S., is increasing in frequency, and is associated with significant complications, such as neonatal respiratory distress syndrome, pulmonary hypertension, and intracranial hemorrhage. Risk factors for preterm labor include multifetal gestation, premature rupture of the membranes, intrauterine infection, and placental insufficiency. The more premature the baby, the greater the risk of complications, prompting efforts to prevent or interrupt preterm labor.
The therapeutic objective in preterm labor is to delay delivery so that the mother can be transported to a regional facility specializing in the care of premature babies and supportive agents can be administered, such as glucocorticoids to stimulate fetal lung maturation (see Chapter 42) and antibiotics (e.g., erythromycin, ampicillin) to diminish the frequency of neonatal infection with group B β-hemolytic Streptococcus. Due to concerns over deleterious effects of antibiotic therapy, antibiotics must not be administered indiscriminately to all women thought to have preterm labor, but rather be reserved for those with premature rupture of the membranes and evidence of infection.
PREVENTION OF PRETERM LABOR: Progesterone Therapy. Progesterone levels diminish considerably in association with labor, whereas administration of progesterone inhibits the secretion of pro-inflammatory cytokines and delays cervical ripening. Although progesterone and its derivatives have long been advocated to diminish the onset of preterm labor, results from clinical trials have been controversial and the role of progesterone prophylaxis during pregnancy remains to be established.
TOCOLYTIC THERAPY FOR ESTABLISHED PRETERM LABOR. Inhibition of uterine contractions of preterm labor, or tocolysis, has been a focus of therapy. Although tocolytic agents delay delivery in ~80% of women, they neither prevent premature births nor improve adverse fetal outcomes such as respiratory distress syndrome. Specific tocolytic agents include β adrenergic receptor agonists, MgSO4, Ca2+ channel blockers, COX inhibitors, oxytocin-receptor antagonists, and NO donors (Figure 66–2).
Figure 66–2 Sites of action of tocolytic drugs in the uterine myometrium. The elevation of cellular Ca2+ promotes contraction via the Ca2+/calmodulin-dependent activation of myosin light chain kinase (MLCK). Relaxation is promoted by the elevation of cyclic nucleotides (cAMP and cGMP) and their activation of protein kinases, which cause phosphorylation/inactivation of MLCK. Pharmacological manipulations to reduce myometrial contraction include:
• Inhibiting Ca2+ entry (Ca2+ channel blockers, Mg2SO4)
• Reducing mobilization of intracellular Ca2+ by antagonizing GPCR-mediated activation of the Gq-PLC-IP3-Ca2+ pathway (with antagonists of the FP and OXT receptors) or reducing production of the FP agonist, PGF2α (with COX inhibitors)
• Enhancing relaxation by elevating cellular cyclic AMP (with β2 adrenergic agonists that ac-tivate Gs-AC) and cyclic GMP (with NO donors that stimulate soluble guanylyl cyclase)
AC, adenylyl cyclase; COX, cyclooxygenase; FP, the PGF2α receptor; OXT, the oxytocin receptor; PLC, phospholipase C; sGC, soluble guanylyl cyclase.
Based on the role of prostaglandins in uterine contraction, COX inhibitors (e.g., indomethacin) have been used to inhibit preterm labor. Because they also can inhibit platelet function and induce closure in utero of the ductus arteriosus, these inhibitors should not be employed in term pregnancies (or in pregnancies beyond 32 weeks of gestation). Atosiban (TRACTOCILE), a nonapeptide analog of oxytocin, competitively inhibits the interaction of oxytocin with its membrane receptor on uterine cells and thereby decreases the frequency of uterine contractions. Atosiban is widely used in Europe, but is not FDA-approved in the U.S. Despite numerous clinical trials, the superiority of any one therapy has not been established, and none of the drugs has been shown definitively to improve fetal outcome. Ca2+ channel blockers and atosiban (not available in the U.S.) appear to provide the best balance of successfully delayed delivery with lesser risks to the mother and baby.
INITIATION OF LABOR
Labor induction is indicated when the perceived risk of continued pregnancy to the mother or fetus exceeds the risks of delivery or pharmacological induction. Such circumstances include premature rupture of the membranes, isoimmunization, fetal growth restriction, uteroplacental insufficiency (as in diabetes, pre-eclampsia, or eclampsia), and gestation beyond 42 weeks.
PROSTAGLANDINS AND CERVICAL RIPENING. Prostaglandins play key roles in parturition (see Chapter 33). Thus, PGE1, PGE2, and PGF2a are used to facilitate labor by promoting ripening and dilation of the cervix. They can be administered either orally or via local administration (either vaginally or intracervically). The ability of certain prostaglandins to stimulate uterine contractions also makes them valuable agents in the therapy of postpartum hemorrhage.
Available preparations include dinoprostone (PGE2), used to facilitate cervical ripening. Dinoprostone is formulated as a gel for intracervical administration via syringe in a dose of 0.5 mg (PREPIDIL) or as a vaginal insert (pessary) in a dose of 10 mg (CERVIDIL); the latter is designed to release active PGE2 at a rate of 0.3 mg/hr for up to 12 h. Dinoprostone should not be used in women with a history of asthma, glaucoma, or myocardial infarction. The major adverse effect is uterine hyperstimulation.
Misoprostol (CYTOTEC), a synthetic derivative of PGE1, is used off label either orally or vaginally to induce cervical ripening; typical doses are 100 μg (orally) or 25 μg (vaginally); an advantage of misoprostol in this setting is its considerably lower cost. Adverse effects include uterine hyperstimulation and, rarely, uterine rupture. Misoprostol should be discontinued for at least 3 h before initiating oxytocin therapy.
OXYTOCIN. The structure and physiology of oxytocin are discussed in Chapter 38. The obstetrical uses of oxytocin include the induction of labor, the augmentation of labor that is not progressing, and the prophylaxis and/or treatment of postpartum hemorrhage. Although widely used, oxytocin recently was added to a list of drugs “bearing a heightened risk of harm.”
Labor Induction. Oxytocin (PITOCIN, SYNTOCINON) is the drug of choice for labor induction. It is administered by intravenous infusion of a diluted solution preferably via an infusion pump. Current protocols start with an oxytocin dose of 6 mIU/min, that is increased as needed, up to 40 mIU/min. Uterine hyperstimulation should be avoided. Because the t1/2 of intravenous oxytocin is relatively short (12-15 min), the hyperstimulatory effects of oxytocin will dissipate fairly rapidly after the infusion is discontinued. Oxytocin at higher doses activates the vasopressin V2 receptor and has antidiuretic effects. Vasodilating actions of oxytocin also have been noted that may provoke hypotension and reflex tachycardia. Deep anesthesia may exaggerate the hypotensive effect of oxytocin by preventing the reflex tachycardia.
Augmentation of Dysfunctional Labor. Oxytocin also is used when spontaneous labor is not progressing at an acceptable rate. To augment hypotonic contractions, an infusion rate of 10 mIU/min typically is sufficient. As with labor induction, potential complications of uterine overstimulation include trauma of the mother or fetus due to forced passage through an incompletely dilated cervix, uterine rupture, and compromised fetal oxygenation due to decreased uterine perfusion.
PREVENTION/TREATMENT OF POSTPARTUM HEMORRHAGE
Oxytocin (10 IU intramuscularly) is given immediately after delivery to help maintain uterine contractions and tone. Alternatively, oxytocin (20 IU) is diluted in 1 L of intravenous solution and infused at a rate of 10 mL/min until the uterus is contracted. The infusion rate then is reduced to 1-2 mL/min until the mother is ready for transfer to the postpartum unit. Ergot alkaloids markedly increase the motor activity of the uterus to prevent or treat postpartum hemorrhage in normotensive women. The preferred ergot alkaloids are ergonovine (ERGOTRATE) or methylergonovine (METHERGINE). They are administered intramuscularly or intravenously, exhibit rapid onsets of action (2-3 min intramuscularly, <1 min intravenously), and their effects persist for 45 min to 3 h depending on the route of administration. Adverse effects include nausea and vomiting, elevated blood pressure, and decreased pain threshold requiring analgesia. The PGE1 analog misoprostol (600 μg administered orally or sublingually) may be used off label to stimulate uterine contractions and prevent or treat postpartum hemorrhage.