No. 34. Management of Infertility Caused by Ovulatory Dysfunction

ACOGPRACTICEBULLETIN

CLINICAL MANAGEMENT GUIDELINES FOROBSTETRICIAN–GYNECOLOGISTS

NUMBER 34, FEBRUARY 2002

This Practice Bulletin wasdeveloped by the ACOG Com-mittee on Practice Bulletins—Gynecology with the assistanceof Robert Barbieri, MD. Theinformation is designed to aidpractitioners in making deci-sions about appropriate obstet-ric and gynecologic care. Theseguidelines should not be con-strued as dictating an exclusivecourse of treatment or proce-dure. Variations in practice maybe warranted based on theneeds of the individual patient,resources, and limitationsunique to the institution or typeof practice.

Management ofInfertility Caused byOvulatory DysfunctionApproximately 20% of infertile women have ovulatory disorders (1, 2). In infer-tile women with ovulatory disorders, the cause of anovulation will guide theselection of an appropriate treatment plan. Advances in reproductiveendocrinology allow the generalist obstetrician–gynecologist to provide treat-ment that results in successful ovulatory stimulation and pregnancy in mostwomen with ovulatory disorders.

BackgroundEtiologyOvulatory dysfunction is likely to be present in women with polymenorrhea oroligomenorrhea and is almost always present in women with amenorrhea(except in patients with uterine disease, such as uterine synechiae orAsherman’s syndrome). Regular menstrual cycles, with a cycle length between22 and 35 days, and the presence of premenstrual bloating, dysmenorrhea, andbreast tenderness suggest the presence of ovulatory cycles.

Laboratory methods for determining ovulation include the basal body tem-perature chart, urine testing for the luteinizing hormone (LH) surge, properlytimed measurement of serum progesterone, and endometrial biopsy. Serialpelvic ultrasonography also may be able to identify the growth and rupture ofa follicle, suggesting that ovulation has occurred. Basal body temperaturecharts are inexpensive but may be a burden to the patient to complete and onlydocument ovulation retrospectively. The pulsatile ovarian secretion of proges-terone in the luteal phase may decrease the sensitivity of a single measurementof progesterone, but a serum progesterone level higher than 3 ng/mL is highlyspecific for detecting ovulation. (These tests also can detect ovulation ininduced cycles.)

VOL. 99, NO.2, FEBRUARY 2002 ACOG Practice Bulletin No. 34 Management of Infertility 347Caused by Ovulatory Dysfunction

If anovulation or clinically significant oligo-ovula-tion has been documented, a complete physical exam-ination and selected laboratory testing are important toidentify the etiology of the ovulatory dysfunction.The most common causes of ovulatory dysfunction are1) polycystic ovary syndrome (PCOS) (approximately70% of cases of ovulatory dysfunction) (3), 2) hypothal-amic amenorrhea, also known as hypogonadotropichypogonadism (approximately 10% of cases), 3) hyper-prolactinemia (approximately 10% of cases), and 4) pre-mature ovarian failure, also known as hypergonadotropichypoestrogenic anovulation (approximately 10% ofcases) (4).

During the physical examination, the practitionershould note the presence of galactorrhea, thyromegaly orother evidence of hypothyroidism or hyperthyroidism,acanthosis nigricans, hirsutism, acne, or signs of viriliza-tion. In addition, the patient’s body mass index (BMI)should be calculated. A BMI less than 20 may indicatehypothalamic ovulatory dysfunction (low gonadotropin-releasing hormone [GnRH] secretion, low LH andfollicle-stimulating hormone [FSH] secretion, lowendogenous estrogen secretion) (5). The combination ofamenorrhea and galactorrhea strongly correlates withhyperprolactinemia. The presence of acanthosis nigricanssuggests the patient has a marked degree of insulinresistance.

In general, clinicians should first recommend theleast resource-intensive ovulation induction regimensthat are appropriate for each cause of ovulatory dysfunc-tion. For example, for women with hypogonadotropichypogonadism and a BMI less than 20, weight gain maybe associated with the resumption of normal menses.

Polycystic Ovary SyndromePolycystic ovary syndrome is defined as the presence ofoligomenorrhea or amenorrhea and hyperandrogenism inthe absence of other hyperandrogenic disorders, such asandrogen-secreting tumors or nonclassical adrenal hyper-plasia. Clinical evidence of hyperandrogenism includeshirsutism and acne. Laboratory evidence of hyperandro-genism includes an elevated total, bioavailable, or freetestosterone concentration. Elevated serum dehy-droepiandrosterone sulfate (DHEAS) or androstenedionelevels also are evidence of hyperandrogenism. The mor-phologic characteristics of “polycystic ovaries” asdemonstrated on pelvic ultrasonography are not essentialfor the diagnosis of PCOS but support the diagnosis. Inwomen of reproductive age, the prevalence of PCOS isapproximately 5%, making it one of the most commonreproductive disorders (3). Among women with ovula-tory dysfunction, about 70% have PCOS (3).

In women with PCOS, many therapies are availableto treat anovulatory infertility, including weight loss,clomiphene, clomiphene plus metformin, clomipheneplus glucocorticoid, gonadotropin injections, ovarian sur-gery, and in vitro fertilization-embryo transfer (IVF-ET).Using the principle of progressing from the leastresource-intensive treatments to the most resource-inten-sive treatments, one potential strategy for organizing thecare of women with PCOS is presented in the box.

Hypothalamic AnovulationHypothalamic anovulation (hypogonadotropic hypogo-nadism) usually is associated with low levels of GnRHsecretion, low or normal levels of LH and FSH secretion,and low levels of endogenous estrogen secretion.Diseases associated with hypothalamic anovulationinclude anorexia nervosa, Kallmann’s syndrome, andhypothalamic tumors and cysts. Factors associated withhypogonadotropic hypogonadism include a low BMI(<20); high-intensity exercise; certain dietary patterns,including high-fiber, low-fat diets; and excessive stress.One approach to treating this condition is to reverse thelifestyle factors that contribute to the anovulation. Forexample, in one study of 26 underweight women whopracticed strict dieting and were infertile, the subjectswere counseled by a dietitian and given physician-direct-ed advice to increase their BMI (5). After the interven-tion, the women gained a mean 3.7 kg, and 73% of thewomen became pregnant. Decreasing the intensity of

A Step-by-Step Approach to Ovulation Inductionin Women with PCOS

The least resource-intensive interventions are recom-mended in the early steps in the protocol, while themost resource-intensive interventions are reserved forlater treatment.

Step 1. If the BMI is higher than 30, recommend weight loss of at least 10% of body weight.

Step 2. Prescribe clomiphene to induce ovulation.Step 3. If DHEAS is higher than 2 µg/mL, consider

combining clomiphene with a glucocorticoid toinduce ovulation.

Step 4. If clomiphene does not result in ovulation, consider a combination of metformin plus clomiphene.

Step 5. Initiate low-dose FSH injections.Step 6. Initiate low-dose FSH injections plus metformin.Step 7. Consider laparoscopic ovarian surgery or in vitro

fertilization.

348 ACOG Practice Bulletin No. 34 Management of Infertility OBSTETRICS & GYNECOLOGYCaused by Ovulatory Dysfunction

pituitary gland secretion of FSH increases. An elevatedrandom FSH level in amenorrheic or severely oligomen-orrheic women or an elevated day-3 FSH level in womenwith menses is highly sensitive and specific for identify-ing women with a depleted ovarian follicular pool (16).If initial attempts at ovulation induction do not result ina pregnancy in women older than 37 years, consultationwith an infertility specialist may be advisable to developa plan for when assisted reproductive procedures, suchas IVF-ET or oocyte donation should be pursued.

Treatments proposed to induce ovulation in womenwith premature ovarian failure include 1) oral contracep-tive suppression of gonadotropins followed by discontin-uation of the oral contraceptive to allow a rebound ingonadotropin secretion and ovarian function, 2) GnRH-agonist suppression of gonadotropin secretion followedby high-dose gonadotropin injections, and 3) glucocorti-coid suppression of the immune system. None of thesetreatments has demonstrated efficacy in randomizedclinical trials for inducing ovulation in women with pre-mature ovarian failure (17). Women with infertility, ovu-latory dysfunction, and an elevated FSH level should bereferred to a physician with specialized expertise intreating infertility.

Luteal Phase Deficiency

Luteal phase deficiency is a theoretical disorder in whichovulation occurs, but there is insufficient progesteroneproduction by the corpus luteum to allow for successfulimplantation. Luteal phase deficiency is thought to causerecurrent pregnancy loss, especially in the first trimester,and is believed to be responsible for a subset of cases ofinfertility. Studies that have attempted to establish lutealphase deficiency as a cause of infertility have not includ-ed control groups of fertile women. However, womenwho have regular menstrual cycles may have luteal phaseabnormalities in as many as 31% of their cycles (18).Methods to diagnose and treat luteal phase deficiencies,therefore, are largely speculative. Because current infer-tility treatment often includes empiric treatment forunexplained infertility, most women who have lutealphase deficiencies and are infertile will receive treatmentthat includes controlled ovarian hyperstimulation.Therefore, a therapy specific to luteal phase deficiency isnot being aggressively pursued.

Treatment Options

Clomiphene CitrateThe precise mechanism of action of clomiphene citrate isnot completely understood. The administration ofclomiphene to anovulatory women with endogenous

exercise and stress also may help improve the rate ofovulation in some of these women. However, no well-designed clinical trials testing these recommendationshave been reported.

In the past, one option for ovulation induction forhypogonadotropic hypogonadism was the parenteraladministration of GnRH in pulses using a portable pro-grammable pump. It was associated with monofollicularovulation and a high rate of singleton pregnancy but thepump is not commercially available in the United States(6, 7).

HyperprolactinemiaThe most common causes of hyperprolactinemia are aprolactin-secreting pituitary gland tumor and the use ofpsychiatric medications. The presence of hyperpro-lactinemia should be confirmed if there is any questionabout the timing of the blood test or the quality of theassay; blood should be drawn after the patient has fastedand preferably not after a breast examination or breaststimulation (8). All women with hyperprolactinemiashould be tested for hypothyroidism (a thyroid-stimulat-ing hormone screening or additional thyroid hormonetesting as clinically indicated) and pregnancy (9). Animaging study (magnetic resonance imaging or comput-ed tomography) of the central nervous system and thepituitary gland should be obtained in all women withhyperprolactinemia unless there is an obvious cause,such as hypothyroidism, that makes a pituitary glandtumor unlikely (10). If the imaging study reveals amacroadenoma of the pituitary gland (tumor diameter≥10 mm), the patient should be referred to a physicianwith expertise in endocrinology or pituitary gland dis-ease for consultation. Induction of ovulation in womenwith large pituitary gland tumors is associated with ahigh risk of neurosurgical complications during preg-nancy (11–13). In addition, women with large pituitarygland tumors may have undiagnosed adrenal insufficien-cy, a condition that poses significant health risks. Forwomen with microadenomas (tumor diameter <10 mm)that secrete prolactin, the risk of pituitary insufficiencyand neurosurgical complications during pregnancy isvery low (<1%) (11–13). Observational studies indicatethat during 4– 6 years of observation, 95% of microade-nomas do not increase in size (14, 15).

Age-Related Ovulation Dysfunction andPremature Ovarian FailureAs the ovarian follicular pool depletes with age, theremaining follicles appear to be less capable of fertiliza-tion and establishing a successful pregnancy. Inhibin Bproduction by the small follicles decreases with age, theinhibin suppression of FSH secretion decreases, and


estrogen secretion often is followed by an increase inboth hypothalamic GnRH secretion and pituitary LH andFSH secretion, which causes follicle growth, triggeringthe LH surge and ovulation.

Clomiphene treatment is most effective in womenwith normal FSH levels and adequate endogenous pro-duction of estrogen and is least effective in women withhypothalamic amenorrhea or in women with an elevatedbasal FSH concentration (19). In women with PCOS, thepresence of obesity, elevated testosterone concentration,and severe insulin resistance decreases the efficacy ofclomiphene citrate (20). Most women with hypogo-nadotropic hypogonadism do not ovulate in response totreatment with clomiphene.

Most clomiphene-induced pregnancies occur withinthe first three menstrual cycles, and the vast majority occurwithin 6 months. There is no benefit to increasing thedosage once ovulation has occurred or to continuingbeyond 6 months of treatment (21). Clomiphene admin-istration in anovulatory women differs from superovula-tion, or controlled ovarian hyperstimulation, which isfrequently attempted in couples with unexplained infertil-ity. With clomiphene, monofolliculogenesis is the goal,and adjunctive treatments, such as intensive follicle mon-itoring and intrauterine insemination, do not have adefined role. With superovulation, women are alreadyovulatory; clomiphene, if administered, is typically givenwith human chorionic gonadotropin (hCG) to ensure ovu-lation, and intrauterine insemination also is appropriate.

Gonadotropin InjectionGonadotropins can be administered using human urinarymenopausal gonadotropins, which contain both LH andFSH, or by using recombinant FSH. Both types ofgonadotropins are effective in treating anovulation inwomen with PCOS. The use of gonadotropin injectionsto induce ovulation in women with PCOS is resourceintensive and is associated with a high risk of adverseoutcomes, such as ovarian hyperstimulation and high-order multiple pregnancy.

Gonadotropin injections are effective in the treat-ment of hypothalamic anovulation. Women with hypo-thalamic anovulation who have a baseline serum LHlevel lower than 0.5 IU/L should be treated with bothFSH and LH because they have a deficiency in bothgonadotropins. Women with hypothalamic amenorrheaand a baseline LH level higher than 0.5 IU/L can be suc-cessfully treated with FSH alone (22). In most circum-stances, the use of FSH injections to induce ovulationshould be performed by physicians with advanced train-ing in treating infertility.

MetforminMetformin is an oral biguanide antihyperglycemic agentapproved for the treatment of adult-onset diabetes melli-tus. It is a category-B drug used by some clinicians totreat diabetes mellitus in pregnant women. Metformindecreases blood glucose levels by inhibiting hepatic glu-cose production and by enhancing peripheral glucoseuptake. Metformin increases insulin sensitivity at thepostreceptor level and stimulates insulin-mediated glu-cose disposal. Unlike sulfonylureas, metformin does notcause hypoglycemia because it does not increase insulinsecretion. Unlike phenformin, metformin does not blockmitochondrial metabolism of lactate unless the patienthas renal failure (renal failure will cause lactate to accu-mulate to very high concentrations) or severe hypoxia(mitochondrial dysfunction). Metformin is not approvedby the U.S. Food and Drug Administration (FDA) forovulation induction.

Dopamine AgonistsDopamine-agonist drugs (bromocriptine, pergolide,cabergoline) are the treatment of choice for ovulationinduction in women with hyperprolactinemia (23).Dopamine-agonist drugs directly suppress prolactin pro-duction by the tumor and cause an increase in endoge-nous GnRH secretion, which stimulates pituitary glandsecretion of LH and FSH and consequently induces folli-cle development and ovulation. In addition, dopamineagonists decrease the size of prolactin-secreting pituitarygland tumors.

With dopamine-agonist therapy, a near-maximaldecrease in serum prolactin levels should be achievedafter 4 weeks of treatment. Serum prolactin levels shouldbe measured approximately 1 month after initiating ther-apy and about 1 month after a change in the dosage ordrug. Normalization of prolactin levels is the therapeuticgoal, as well as assuring that the tumor is responding tothe dopamine agonists. If the serum prolactin concentra-tion is normal and no side effects have occurred, the ini-tial dosage should be continued. If the serum prolactinlevel has not decreased to normal and no side effects arepresent, the dosage should be gradually increased. Themaximal dosage of bromocriptine is 5 mg twice daily;pergolide, 0.25 mg once daily. Cabergoline is the newestof these agents; it can be administered less frequently andmay induce nausea less often. However, as a result ofFDA approval, its use in pregnancy is extremely limited.Women who do not tolerate the side effects of bromocrip-tine may need to be referred to a practitioner with addi-tional expertise in the field to discuss in detail the risksand benefits of newer therapies that have not been testedas thoroughly.


If the serum prolactin level does not decrease to nor-mal, switching to a different dopamine agonist may beeffective. If the patient cannot tolerate the dopamine ago-nist initially prescribed, a different dopamine agonistmay be associated with fewer side effects. If the patientexperiences side effects with all dopamine agonists, vagi-nal administration can be tried. If the patient cannottolerate any of the dopamine agonists, transsphenoidalsurgery may be effective in removing the tumor, return-ing prolactin secretion to normal, and causing theresumption of ovulatory menses.

Following correction of hyperprolactinemia, about80% of women will ovulate, and cumulative pregnancyrates of 80% are commonly observed (24). Treatmentusually is discontinued once pregnancy is diagnosed.However, in women with a macroprolactinoma, therapyshould be continued throughout pregnancy to decreasethe risk of tumor growth and neurosurgical complica-tions, such as compression of the optic nerve.

In the small percentage of women with hyperpro-lactinemia who do not respond to dopamine-agonisttherapy, standard ovulation induction therapy with clomi-phene citrate may be considered. In rare cases, gonado-tropin therapy may be considered.

Clinical Considerations andRecommendations

How is the diagnosis of ovulatory dysfunctionestablished?

If the patient is amenorrheic, the minimal laboratoryevaluation should include measurement of serum levelsof FSH, thyroid-stimulating hormone, and prolactin. Ifthe patient has evidence of hyperandrogenism (eg, hir-sutism, acne, signs of virilization), measurement oftestosterone and DHEAS may have clinical value if ovu-lation induction is planned. Clinical evaluation may beused to determine if testing for Cushing’s syndrome orAddison’s disease should be performed. If the patient hasa BMI higher than 30, testing for diabetes mellitus maybe indicated before inducing ovulation (25). To decreasethe risk of congenital malformations, diabetes mellitusshould be treated before inducing pregnancy. In womenwith irregular menses, attempting to obtain a luteal-phaseprogesterone measurement may be cumbersome andunnecessary if menses are relatively infrequent.Documenting ovulation by basal body temperature eval-uation or LH surge testing may be helpful. Women withregular menses can be assessed for ovulatory status byany of the techniques described previously.

Before using ovulation-inducing medications, it isuseful to consider evaluating the couple for male factorinfertility by performing a semen analysis. Routinely per-forming hysterosalpingography is unnecessary. However,if the woman has a history of sexually transmitted dis-eases, pelvic inflammatory disease, appendicitis withrupture, in utero exposure to diethylstilbestrol, or previ-ous pelvic surgery, hysterosalpingography should be con-sidered to establish tubal patency. Laparoscopy is notroutinely necessary before ovulation induction. The ageof the woman strongly influences the pregnancy rate withovulation induction (see Fig. 1). In older women, thismay lead to a greater sense of urgency and a rapid pro-gression to more intensive treatments, with their greaterassociated risks (26, 27).

Does weight loss improve fertility in obesewomen?

In women with a high BMI, abnormal hypothalamicGnRH secretion, pituitary gland LH and FSH secretion,insulin resistance, and anovulation are common (28).Women with a BMI greater than 30 and oligo-ovulationoften have PCOS.

Epidemiologic studies have demonstrated that aBMI greater than 27 is associated with an increased riskof ovulatory infertility. For example, in one study of 597

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Figure 1. Cumulative pregnancy rates for hypogonadotropicanovulatory women treated with gonadotropins. (FromLunenfeld B, Insler V. Human gonadotropins. In: Wallach EE,Zacur HA, eds. Reproductive medicine and surgery. St. Louis:Mosby-Year Book, 1995:617)

cumulative pregnancy rate in women younger than 35 years

cumulative pregnancy rate in women older than 35 years


women with ovulatory infertility and 1,695 controls, thewomen with a BMI higher than 27 had a relative risk ofovulatory infertility of 3.1 (95% confidence interval,2.2– 4.4) when compared with the control group with aBMI of 20–24.9 (29).

Many studies (most without a control group) havedemonstrated that in women who have PCOS and areobese, weight loss often is associated with a decrease inserum testosterone concentration, resumption of ovulation,and, for infertile women, pregnancy. For example, in onestudy, 18 obese women with PCOS were treated with ahypocaloric diet (30). Before the diet, the mean weight ofthe women was 77 kg; after the diet, it was 57 kg. The plas-ma testosterone concentration was 0.75 ng/mL before thediet and 0.39 ng/mL after (P <0.001). Many of the womenresumed ovulation after weight loss. Another study evalu-ated the effects of weight loss on 20 obese women withPCOS (31). Before the diet, the women had a mean BMIof 32, amenorrhea for more than 3 months, and increasedplasma concentrations of androstenedione, testosterone, orDHEAS. Following a hypocaloric diet of 1,000–1,500kcal per day, weight loss ranged from 4.8 kg to 15.2 kg.After weight loss, significant reductions in the concentra-tion of LH (45% decrease), fasting insulin (40% decrease),and testosterone (35% decrease) were observed. Afterweight loss, most of the women ovulated, and many of theinfertile women became pregnant.

In a small trial that examined the effect of weightloss on reproductive function in 12 obese women withPCOS, the women were randomized to either a weightreduction program or a “waiting list” observation controlgroup (32). The six women randomized to the weightreduction program had a mean weight decrease of 16 kg,a significant decrease in circulating testosterone concen-tration, and a decrease in fasting insulin; four of the sixwomen resumed ovulating. The women randomized tothe observational control group had no weight changeduring the study. All of the women in the control groupwho were anovulatory before the study (five) remainedanovulatory during the study.

Weight reduction is best achieved by a combinationof diet and exercise. However, exercise at levels greaterthan 60 minutes per day has been associated with anincrease in ovulatory infertility (33).

How is clomiphene citrate administered?

The FDA has approved clomiphene dosages of 50 mg or100 mg daily for a maximum of 5 days per cycle. Afterspontaneous menses or the induction of menses with aprogestin withdrawal, clomiphene is started on cycle day3, 4, or 5 at 50 mg daily for 5 days. Starting clomipheneon cycle day 3 or 5 does not appear to influence the preg-

nancy rate (34). It is important to give clomiphene onlyafter menstrual bleeding to help ensure that the patient isnot pregnant. In properly selected women, approximate-ly 50% will ovulate using the 50-mg daily dosage, andanother 25% will ovulate if the dosage is increased to100 mg daily (35). If lower dosages are not successful ininducing ovulation, many clinicians will prescribe150 mg daily for 5 days; a few have used dosages as highas 250 mg daily for 5 days. However, the pregnancy ratesassociated with the use of clomiphene at dosages higherthan 150 mg daily for 5 days are very low (21). In gen-eral, if the 150-mg dosage is not successful, alternativeapproaches to ovulation induction should be considered.Of those women who ovulate while taking clomiphene,between 40% and 80% will become pregnant. In onestudy of 3,022 women taking clomiphene, the pregnancyrate per ovulatory cycle was 20% (36). The pregnancyrate decreases substantially after six cycles of clomi-phene therapy (37).

Patients taking clomiphene should be monitored forovulation, pregnancy, and ovarian enlargement, as clini-cally indicated. Ovulation can be determined by measur-ing serum progesterone levels (about 14 days after thelast dose of clomiphene), basal body temperature chart-ing, or properly timed endometrial biopsy. Detection ofan LH surge in the urine suggests a preovulatory folliclehas triggered the surge. Intense cycle monitoring withfrequent measurement of serum estradiol levels and pel-vic ultrasonography is generally not necessary with theuse of clomiphene but is required for gonadotropin ther-apy. Clomiphene treatment can be associated with lutealphase defects and the suboptimal production of cervicalmucus. Some clinicians recommend an endometrial biop-sy in a test cycle of clomiphene treatment to assesswhether clomiphene-induced ovulation is associated withluteal phase defect (38). A few authorities recommend apostcoital test be performed during the first clomiphenecycle to assess cervical mucus quality and quantity.However, little evidence exists to support either practice.

Of clomiphene-induced pregnancies, 7% are twingestations and 0.3% are triplet gestations (39). The rateof spontaneous abortion after clomiphene-induced preg-nancy is approximately 15%. The incidence of birthdefects is similar to that seen in spontaneous pregnancy(40). The most common symptoms experienced bywomen taking clomiphene include vasomotor symptoms(20%), adnexal tenderness (5%), nausea (3%), headache(1%), and, rarely, blurring of vision or scotomata (21,41). Many clinicians permanently discontinue clomi-phene treatment in women with clomiphene-inducedvisual changes. The main contraindications to the use ofclomiphene are pregnancy, hypersensitivity to the med-ication, and ovarian cysts.

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In women who do not ovulate using clomi-phene alone, can the chances of ovulation beimproved by adding glucocorticoids?

Women with PCOS and a serum DHEAS concentrationhigher than the middle of the normal range (>2 µg/mL)appear to have decreased ovulation and pregnancy rateswhen they are treated with clomiphene. Some studiessuggest treatment with clomiphene plus a glucocorticoidimproves pregnancy rates in these women. One studyrandomized 64 anovulatory infertile women to receiveeither clomiphene, 50 mg daily on cycle days 5–9, orclomiphene plus 0.5 mg dexamethasone daily (42). Ifovulation did not occur, the dosage of clomiphene wasincreased by 50-mg increments up to 150 mg daily for5 days each cycle. The investigators observed signifi-cantly higher rates of ovulation and conception inwomen treated with clomiphene plus dexamethasonethan with clomiphene alone. The impact of combinedtherapy was especially marked in the women with aDHEAS concentration higher than 2 µg/mL. Of thewomen with a DHEAS concentration higher than2 µg/mL, 12 were randomized to receive clomiphenealone, and 13 were randomized to receive clomipheneplus dexamethasone. Among the 12 women receivingclomiphene alone, six (50%) ovulated and four (33%)became pregnant. Among the 13 women who receivedclomiphene plus dexamethasone, 13 (100%) ovulatedand 11 (85%) became pregnant.

In women who do not ovulate using clomi-phene alone, can the chances of ovulation beimproved by adding an hCG injection?

The combination of clomiphene plus a single dose ofhCG may increase the efficacy of clomiphene inductionof ovulation when women fail to ovulate with standarddosages of clomiphene (43). After the last dose ofclomiphene, pelvic ultrasonography can be used to mon-itor follicle size. When the mean diameter of the leadfollicle reaches 18 mm, a single dose of hCG can beadministered. Ovulation occurs approximately 36–44hours after the injection. There are no randomized con-trolled clinical trials that document the efficacy of thisapproach.

It has been proposed that a regimen of 2 months oforal contraceptives before ovulation induction withclomiphene followed by an hCG injection when follicleripening has occurred may improve the rate of ovulationand pregnancy. No randomized clinical trial supports thisapproach. However, a clinical trial without controlsreported oral contraceptive treatment followed byclomiphene therapy (100 mg daily for 5 days) plus an

hCG injection was an inexpensive and potentially effec-tive approach to treating women with PCOS who hadfailed to ovulate and become pregnant with standardclomiphene therapy (44). In that study, 38 infertilewomen with PCOS who had failed to ovulate when treat-ed with clomiphene (150 mg daily for 5 days) and whohad a DHEAS concentration lower than 2 µg/mL tookoral contraceptives (ethinyl estradiol 0.03 mg, and deso-gestrel 0.15 mg daily) for 2 months followed byclomiphene. Instead of the usual 7-day pill-free intervalbetween cycles, the investigators prescribed a regimenwith a 3-day pill-free interval. On cycle days 5–9 aftercompletion of the second month of oral contraceptives,clomiphene (100 mg daily for 5 days) was prescribed.Transvaginal ultrasonography was initiated on cycle day12 and repeated every 1–2 days until hCG was adminis-tered. When the mean diameter of the lead folliclereached 20 mm, hCG (10,000 units) was administered.The 38 women completed 95 treatment cycles. Sixty-nine of the 95 cycles were ovulatory (73%), and 29 ofthe 38 women (76%) ovulated. Twenty-two pregnanciesoccurred. Most of the pregnancies (82%) occurred in oneof the first three treatment cycles.

In women who do not respond to clomi-phene, does ovarian diathermy increase thechances of ovulation more than FSH?

A number of surgical techniques have been describedthat may increase the rate of ovulation in women withPCOS. To date, no randomized, controlled clinical trialhas demonstrated the efficacy of surgery in this setting,but case series totaling more than 1,000 subjects havebeen published. Although ovarian wedge resection wasthe initial surgical procedure reported to increase ovula-tion in women with PCOS, this procedure has beenreplaced by laparoscopic techniques that use electrosur-gical or laser energy. Overall, the case series report ovu-lation rates of 80% and pregnancy rates of 50% (45). Forwomen with PCOS, ovulation induction with FSH also isassociated with pregnancy rates of 50% (46). Injectionswith FSH for ovulation induction are associated with ahigh rate of multiple gestations (approximately 20%),and it is not known if ovarian diathermy affects ovarianreserve. Thus, treatment should be individualized.

In women with hyperprolactinemia, whichmedical treatments stimulate the resumptionof ovulation?

Bromocriptine has been used for more than 25 years toinduce ovulation in women with hyperprolactinemia. Inone study of 280 women with hyperprolactinemia,

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bromocriptine normalized the circulating prolactin levelin 82% of the women (47). The main side effects associ-ated with bromocriptine are nausea, vomiting, and ortho-static hypotension. To minimize these potential sideeffects, it is recommended that bromocriptine be initiat-ed at a dosage of 1.25 mg at bedtime. After 1 week, thedosage can be increased to 1.25 mg twice daily. Thedosage can then be increased to 2.5 mg twice daily, astandard dosage that successfully decreases serumprolactin levels in most women with hyperprolac-tinemia (47).

Pergolide, an ergot dopamine agonist, is approvedby the FDA for the treatment of Parkinson’s disease butis not approved for the treatment of hyperprolactinemia.Unlike bromocriptine, pergolide can be given once perday. Pergolide is the least expensive of the dopamineagonists.

In women with PCOS, what is the role ofgonadotropins in inducing ovulation?

In one randomized clinical trial, low-dose FSH treatmentappeared to improve outcomes and decrease adverseevents when compared with standard-dose FSH treat-ment in women with PCOS (48). In this study, 50 infer-tile women with PCOS who had failed to conceive withclomiphene therapy were randomized to receive eitherconventional FSH treatment (75 IU daily, increasing by75 IU every 5–6 days until follicular ripening occurred)or low-dose FSH treatment (75 IU daily for 14 days oftreatment, increasing by 37.5 IU every 7 days thereafteruntil follicular ripening was complete). Compared withstandard FSH treatment, women who received long-term, low-dose FSH treatment had more cycles with thedevelopment of a single dominant follicle (74% versus27%), fewer high-order multiple gestations, and a high-er pregnancy rate (40% versus 24%).

When should metformin be added for thetreatment of ovulatory infertility?

Insulin sensitizers can be used alone or in combinationwith clomiphene to induce ovulation in infertile womenwith oligo-ovulation, hyperandrogenism, and insulinresistance (49). To date, no large-scale clinical trials havebeen published that demonstrate the impact of met-formin on live birth rates in women with PCOS andinsulin resistance. A few small clinical trials have beenpublished demonstrating that in women with PCOS thecombination of clomiphene plus metformin is associatedwith higher rates of ovulation and pregnancy thanclomiphene plus a placebo (50, 51). In one study, womenwith PCOS who did not ovulate when treated withclomiphene (150 mg daily for 5 days) were randomized

to receive either metformin (1,500 mg daily) or placebofor 7 weeks (51). During the initial 7-week treatmentperiod, one of the 12 women in the metformin groupovulated, and none of the 15 women in the placebogroup ovulated. After this initial treatment period, all ofthe women received clomiphene citrate, beginning at adosage of 50 mg daily for 5 days, with dosage escalationif ovulation did not occur. Nine of the 12 women in themetformin-plus-clomiphene group ovulated, comparedwith four of the 15 women in the placebo-plus-clomiphene group (P <0 .02). Of the women whocompleted the clinical trial, six (of 11) in the metformin-plus-clomiphene group became pregnant, and one (of14) in the placebo-plus-clomiphene group became preg-nant (P <0.02). Of the six pregnancies in the metformin-plus-clomiphene group, two resulted in spontaneousabortion and four resulted in live singleton births. Theone pregnancy in the placebo-plus-clomiphene groupresulted in a live singleton birth.

A commonly used dosage of metformin is 500 mgthree times daily. The most common side effects ofmetformin are gastrointestinal disturbances, includingdiarrhea, nausea, vomiting, and abdominal bloating. Tominimize gastrointestinal side effects, many cliniciansrecommend starting metformin at 500 mg daily for 1week, increasing to 500 mg twice daily for 1 week, andthen increasing to 500 mg three times daily. Once the fulldosage is achieved, some clinicians switch to a dosingregimen of 850 mg twice daily to improve patient com-pliance. Progesterone measurements can be periodicallyobtained to determine whether ovulation has occurred, orthe patient can keep a basal body temperature chart. Ifovulation has not occurred after 4–8 weeks of met-formin therapy, clomiphene (50 mg daily for 5 days) canbe administered after progestin-induced menstrual with-drawal bleeding. If the patient becomes pregnant, themetformin therapy can be discontinued. Ovulation, if itis going to occur, can be expected to occur within 6–8weeks.

In rare cases, metformin therapy has caused fatallactic acidosis. In most of these cases, renal insuffi-ciency or severe hypoxia (congestive heart failure, septicshock) was present. Before treatment with metformin isinitiated, it is recommended that serum creatinine levelsbe demonstrated to be lower than 1.4 mg/dL. Womenwith liver dysfunction should not take metformin. Also,metformin should be discontinued 48 hours before—andnot restarted for 72 hours after—any radiologic testinvolving intravenous contrast or before surgery.

Metformin appears to improve the ovulatoryresponse in women with PCOS treated with FSH injec-tions. A trial randomized 20 infertile women with PCOSand insulin resistance who had failed to ovulate when

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treated with clomiphene (150 mg daily for 5 days) toreceive either FSH injections alone or FSH injections plusmetformin (500 mg three times daily) (52). The meanBMI of the subjects was approximately 27. Comparedwith the women who received FSH alone, the womenwho received both FSH and metformin had fewer domi-nant follicles (2.4 versus 4.5, P <0.01), a lower peak estra-diol concentration (450 pg/mL versus 720 pg/mL,P <0.001), and a lower cycle cancellation rate (0% versus32%, P < 0.03). The investigators concluded a combina-tion of FSH plus metformin is associated with an orderlyfollicular response that probably decreases the risk forovarian hyperstimulation and multiple pregnancy.

Is a postcoital test useful in a patient takingclomiphene citrate?

The postcoital test has low reproducibility and low inter-observer reliability and has not been proved to helpguide treatment recommendations (53–55). In addition,there is little consensus on what constitutes an abnormalpostcoital test result. Given these limitations, there is lit-tle scientific rationale for performing a postcoital test.However, clinical experience suggests that clomiphene,acting as an antiestrogen in the cervix, can cause cervi-cal mucus production that is abnormal in quantity andquality. Therefore, some clinicians recommend perform-ing a postcoital test to assess the impact of clomipheneon cervical mucus production.

Can the risk of multiple gestation be mini-mized?

Multiple gestation is a growing problem. Public aware-ness is increasing about the hazards associated withmultiple births, as well as the long-term costs and con-sequences (56). Monofolliculogenesis is the goal of ther-apy in infertile patients.

To decrease the risk of multiple gestation, treat-ments associated with low rates of multiple gestationshould be used. For example, in women with PCOS,ovulation induction with weight loss, clomiphene,clomiphene plus metformin, clomiphene plus glucocor-ticoid, and ovarian surgery are associated with low ratesof triplet pregnancy. Gonadotropin injections and in vitrofertilization are associated with higher rates of multiplegestation (48). When using gonadotropin injections, theuse of low-dose regimens appears to be associated withlower rates of multiple gestation than the use of standarddose regimens. In addition, the risk of multiple gestationwith FSH injections can probably be decreased by with-holding hCG and prescribing a barrier contraceptivewhenever more than three follicles greater than 15 mm indiameter are detected with pelvic ultrasonography.

Is the risk of ovarian cancer increased withthe use of induction agents, such asclomiphene or gonadotropin injections?

The risk of ovarian cancer is increased in women who arenulligravid (voluntarily and involuntarily) and womenwith a strong family history of ovarian cancer. The risk ofovarian cancer is decreased by pregnancy, use of oral con-traceptives for more than 6 months, surgical tubal ligation,and hysterectomy. Preliminary studies reported ovulation-inducing medications may be associated with a smallincrease in the risk of ovarian tumors (borderline tumorsand cancer) and that the risk may increase with the extend-ed use of ovulation-inducing agents for many months (57,58). In one of these studies, the strongest risk occurredamong 13 nulligravid women who had used infertilitydrugs and had never become pregnant. In this subset, theassociation was statistically significant, but the confidenceinterval was wide, suggesting a great deal of variation, andthe sample size was small (n=13). Some practitionersbelieve infertility (involuntary childlessness) is a morepowerful risk factor for ovarian tumors than treatmentwith an ovulation-inducing medication. However, giventhe low pregnancy rates observed after six cycles of ovu-lation induction with an induction agent (such asclomiphene) and the potential (although low) risk that 12or more cycles of clomiphene may be associated with anincreased risk of ovarian tumors, it is reasonable to limitclomiphene treatment to fewer than 12 cycles. There areno evidence-based guidelines about the appropriate dura-tion of gonadotropin administration; however, given thepossibility that such agents can cause harm, it seemsappropriate to use them sparingly and only with clear-cutindications.

Summary ofRecommendations

The following recommendations are based on lim-ited or inconsistent scientific evidence (Level B):

In obese women with PCOS, weight loss should beconsidered because it is associated with a decreasein circulating testosterone concentration, anincrease in the frequency of ovulation, and in somewomen, pregnancy.

In obese women with PCOS who did not ovulatewhen treated with clomiphene, the combination ofclomiphene plus metformin may be consideredbecause the rate of ovulation is greater than it is withclomiphene alone.

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In women with PCOS and a serum DHEAS levelhigher than 2 µg/mL, the combination of clomi-phene plus glucocorticoid may be consideredbecause the rate of ovulation is greater than it is withclomiphene alone.

In women with hypothalamic amenorrhea and aBMI lower than 20, weight gain should be consid-ered because it may be associated with the resump-tion of ovulation and pregnancy.

In women with PCOS receiving gonadotropin injec-tions for ovulation induction, low-dose FSH may beconsidered because it is associated with a higherrate of cycles with the development of a single dom-inant follicle and fewer high-order multiple gesta-tions.

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3. Knochenhauer ES, Key TJ, Kashar-Miller M, WaggonerW, Boots LR, Azziz R. Prevalence of the polycystic ovarysyndrome in unselected black and white women of thesoutheastern United States: a prospective study. J ClinEndocrinol Metab 1998;83:3078–3082 (Level II-3)

4. Reindollar RH, Novak M, Tho SP, McDonough PG.Adult-onset amenorrhea: a study of 262 patients. Am JObstet Gynecol 1986;155:531–543 (Level III)

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8. Reichlin S. Neuroendocrinology. In: Wilson JD, FosterDW, Kronenberg HM, Larsen PR, eds. Williams text-book of endocrinology. Philadelphia: WB Saunders,1998: 165– 248 (Level III)

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18. Davis OK, Berkeley AS, Naus GJ, Cholst IN, FreedmanKS. The incidence of luteal phase defect in normal, fertilewomen, determined by serial endometrial biopsy. FertilSteril 1989;51:582–586 (Level III)

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20. Murakawa H, Hasegawa I, Kurabayashi T, Tanaka K.Polycystic ovary syndrome. Insulin resistance and ovula-tory responses to clomiphene citrate. J Reprod Med1999;44:23–27 (Level II-2)

21. Derman SG, Adashi EY. Induction of ovulation. ComprTher 1995;21:583–589 (Level III)

22. Sills ES, Levy DP, Moomjy M, McGee M, Rosenwaks Z.A prospective, randomized comparison of ovulationinduction using highly purified follicle-stimulating hor-mone alone and with recombinant human luteinizing hor-mone in in-vitro fertilization. Hum Reprod 1999;14:2230–2235 (Level I)

23. Verhelst J, Abs R, Maiter D, van den Bruel A, vandewegheM, Velkeniers B. Cabergoline in the treatment of hyper-prolactinemia: a study in 455 patients. J Clin EndocrinolMetab 1999;84:2518–2522 (Level II-3)

24. Weil C. The safety of bromocriptine in hyperprolacti-naemic female infertility: a literature review. Curr MedRes Opin 1986;10:172–195 (Level III)

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25. Legro RS, Kunselman AR, Dodson WC, Dunaif A.Prevalence and predictors of risk for type 2 diabetes mel-litus and impaired glucose tolerance in polycystic ovarysyndrome: a prospective, controlled study in 254 affectedwomen. J Clin Endocrinol Metab 1999;84:165–169(Level II-2)

26. Gleicher N, Campbell DP, Chan CL, Karande V, Rao R,Balin M, et al. The desire for multiple births in coupleswith infertility problems contradicts present practice pat-terns. Hum Reprod 1995;10:1079–1085 (Level III)

27. Paulson RJ, Ory SJ, Giudice LC, Schlaff WD, SantoroNF, Coddington C 3rd. Multiple pregnancies: what actionshould we take? [comment] Fertil Steril 2001;75:14–15;discussion 16–17 (Level III)

28. Yen SS. Chronic anovulation due to CNS-hypothalamic-pituitary dysfunction. In: Yen SS, Jaffe RB, Barbieri RL,eds. Reproductive endocrinology: physiology, pathophys-iology, and clinical management. 4th ed. Philadelphia:WB Saunders, 1999:516–561 (Level III)

29. Grodstein F, Goldman MB, Cramer DW. Body mass indexand ovulatory infertility. Epidemiology 1994;5:247–250(Level II-2)

30. Bates GW, Whitworth NS. Effect of body weight reduc-tion on plasma androgens in obese, infertile women. FertilSteril 1982;38:406–409 (Level II-2)

31. Pasquali R, Antenucci D, Casimirri F, Venturoli S,Paradisi R, Fabbri R, et al. Clinical and hormonal charac-teristics of obese amenorrheic hyperandrogenic womenbefore and after weight loss. J Clin Endocrinol Metab1989;68:173–179 (Level III)

32. Guzick DS, Wing R, Smith D, Berga SL, Winters SJ.Endocrine consequences of weight loss in obese, hyper-androgenic, anovulatory women. Fertil Steril 1994;61:598–604 (Level II-2)

33. Green BB, Daling JR, Weiss NS, Liff JM, Koepsell T.Exercise as a risk factor for infertility with ovulatory dys-function. Am J Public Health 1986;76:1432–1436(Level II-2)

34. Wu CH, Winkel CA. The effect of therapy initiation dayon clomiphene citrate therapy. Fertil Steril 1989;52:564–568 (Level II-3)

35. Gysler M, March CM, Mishell DR Jr, Bailey EJ. Adecade’s experience with an individualized clomiphenetreatment regimen including its effect on the postcoitaltest. Fertil Steril 1982;37:161–167 (Level II-3)

36. Macgregor AH, Johnson JE, Bunde CA. Further clinicalexperience with clomiphene citrate. Fertil Steril 1968;19:616–622 (Level II-3)

37. Hammond MG. Monitoring techniques for improvedpregnancy rates during clomiphene ovulation induction.Fertil Steril 1984;42:499–509 (Level III)

38. Keenan JA, Herbert CM, Bush JR, Wentz AC. Diagnosisand management of out-of-phase endometrial biopsiesamong patients receiving clomiphene citrate for ovulationinduction. Fertil Steril 1989;51:964–967 (Level II-2)

39. Dickey RP, Holtkamp DE. Development, pharmacologyand clinical experience with clomiphene citrate. HumReprod Update 1996;2:483–506 (Level III)

40. Kurachi K, Aono T, Minagawa J, Miyuake A. Congenitalmalformations of newborn infants after clomiphene inducedovulation. Fertil Steril 1983;40:187–189 (Level II-2)

41. Clomid. In: Physicians’ desk reference. 55th ed. Montvale,New Jersey: Medical Economics Company, 2001:700–702 (Level III)

42. Daly DC, Walters CA, Soto-Albors CE, Tohan N, RiddickDH. A randomized study of dexamethasone in ovulationinduction with clomiphene citrate. Fertil Steril 1984;41:844–848 (Level I)

43. Swyer GI, Radwanska E, Mcgarrigle HH. Plasma oestra-diol and progesterone estimation for the monitoring ofinduction of ovulation with clomiphene and chorionicgonadotrophin. Br J Obstet Gynaecol 1975;82:794–804(Level II-2)

44. Branigan EF, Estes MA. Treatment of chronic anovulationresistant to clomiphene citrate (CC) by using oral contra-ceptive ovarian suppression followed by repeat CC treat-ment. Fertil Steril 1999;71:544–546 (Level III)

45. Donesky BW, Adashi EY. Surgically induced ovulation inthe polycystic ovary syndrome: wedge resection revistedin the age of laparoscopy. Fertil Steril 1995;63:439–463(Level III)

46. Lunenfeld B, Insler V. Human gonadotropins. In: WallachEE, Zacur HA, eds. Reproductive medicine and surgery.St. Louis: Mosby-Year Book, 1995:611–638 (Level III)

47. Vance ML, Evans WS, Thorner MO. Drugs five yearslater. Bromocriptine. Ann Intern Med 1984;100:78–91(Level III)

48. Homburg R, Levy T, Ben-Rafael Z. A comparative studyof conventional regimen with chronic low-dose adminis-tration of follicle-stimulating hormone for anovulationassociated with polycystic ovary syndrome. Fertil Steril1995;63:729–733 (Level II-2)

49. Barbieri RL. Induction of ovulation in infertile womenwith hyperandrogenism and insulin resistance. Am JObstet Gynecol 2000;183:1412–1418 (Level III)

50. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R.Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. NEngl J Med 1998;38:1876–1880 (Level II-2)

51. Vandermolen DT, Ratts VS, Evans WS, Stovall DW,Kauma SW, Nestler JE. Metformin increases the ovulato-ry rate and pregnancy rate from clomiphene citrate inpatients with polycystic ovary syndrome who are resistantto clomiphene citrate alone. Fertil Steril 2001;75: 310–315(Level I)

52. De Leo V, la Marca A, Ditto A, Morgante G, Cianci A.Effects of metformin on gonadotropin-induced ovulationin women with polycystic ovary syndrome. Fertil Steril1999;72:282–285 (Level I)

53. Glatstein IZ, Best CL, Palumbo A, Sleeper LA, FriedmanAJ, Hornstein MD. The reproducibility of the postcoitaltest: a prospective study. Obstet Gynecol 1995;85:396–400 (Level III)

54. Griffith CS, Grimes DA. The validity of the postcoitaltest. Am J Obstet Gynecol 1990;162:615–620 (Level III)


55. Oei SG, Helmerhorst FM, Bloemenkamp KW, HollantsFA, Meerpoel DE, Keirse MJ. Effectiveness of the post-coital test: randomised controlled trial. BMJ 1998;317:502–505 (Level I)

56. Callahan TL, Hall JE, Ettner SL, Christiansen CL, GreenMF, Crowley WF Jr. The economic impact of multiple-gestation pregnancies and the contribution of assisted-reproduction techniques to their incidence. N Engl J Med1994;331:244–249 (Level III)

57. Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG.Ovarian tumors in a cohort of infertile women. N Engl JMed 1994;331:771–776 (Level II-2)

58. Whittemore AS, Harris R, Itnyre J. Characteristics relat-ing to ovarian cancer risk: collaborative analysis of 12 UScase-control studies. II. Invasive epithelial ovarian cancersin white women. Collaborative Ovarian Cancer Group.Am J Epidemiol 1992;136:1184–1203 (Level II-2)

The MEDLINE database, the Cochrane Library, andACOG’s own internal resources and documents were usedto conduct a literature search to locate relevant articles pub-lished between January 1985 and June 2001. The searchwas restricted to articles published in the English language.Priority was given to articles reporting results of originalresearch, although review articles and commentaries alsowere consulted. Abstracts of research presented at sympo-sia and scientific conferences were not considered adequatefor inclusion in this document. Guidelines published by or-ganizations or institutions such as the National Institutes ofHealth and the American College of Obstetricians and Gy-necologists were reviewed, and additional studies werelocated by reviewing bibliographies of identified articles.When reliable research was not available, expert opinionsfrom obstetrician–gynecologists were used.

Studies were reviewed and evaluated for quality accordingto the method outlined by the U.S. Preventive Services TaskForce:

I Evidence obtained from at least one properly de-signed randomized controlled trial.

II-1 Evidence obtained from well-designed controlledtrials without randomization.

II-2 Evidence obtained from well-designed cohort orcase–control analytic studies, preferably from morethan one center or research group.

II-3 Evidence obtained from multiple time series with orwithout the intervention. Dramatic results in uncon-trolled experiments could also be regarded as thistype of evidence.

III Opinions of respected authorities, based on clinicalexperience, descriptive studies, or reports of expertcommittees.

Based on the highest level of evidence found in the data,recommendations are provided and graded according to thefollowing categories:

Level A—Recommendations are based on good and consis-tent scientific evidence.

Level B—Recommendations are based on limited or incon-sistent scientific evidence.

Level C—Recommendations are based primarily on con-sensus and expert opinion.

Copyright © February 2002 by the American College of Obste-tricians and Gynecologists. All rights reserved. No part of thispublication may be reproduced, stored in a retrieval system, ortransmitted, in any form or by any means, electronic, mechan-ical, photocopying, recording, or otherwise, without priorwritten permission from the publisher.

Requests for authorization to make photocopies should bedirected to Copyright Clearance Center, 222 Rosewood Drive,Danvers, MA 01923, (978) 750-8400.

The American College of Obstetricians and Gynecologists409 12th Street, SW, PO Box 96920Washington, DC 20090-6920

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Management of infertility caused by ovulatory dysfunction. ACOGPractice Bulletin No. 34. American College of Obstetricians andGynecologists. Obstet Gynecol 2002;99:347–358


General

255 Psychosocial Risk Factors: Perinatal Screening and Intervention (November 1999, Obstet Gynecol Vol. 94, No. 5)

258 Breastfeeding: Maternal and Infant Aspects (July 2000, Obstet Gynecol Vol. 96, No. 1)

Obstetrics1 Premature Rupture of Membranes (June 1998, Obstet Gynecol Vol. 91, No. 6)

4 Prevention of Rh D Alloimmunization (May 1999, Obstet Gynecol Vol. 93, No. 5)

5 Vaginal Birth After Previous Cesarean Delivery (July 1999, Obstet GynecolVol. 94, No. 1)

6 Thrombocytopenia in Pregnancy (September 1999, Obstet Gynecol Vol. 94, No. 3)

8 Management of Herpes in Pregnancy (October 1999, Obstet Gynecol Vol. 94, No. 4)

9 Antepartum Fetal Surveillance (October 1999, Obstet Gynecol Vol. 94, No. 4)

10 Induction of Labor (November 1999, Obstet Gynecol Vol. 94, No. 5)

12 Intrauterine Growth Restriction (January 2000, Obstet Gynecol Vol. 95, No. 1)

13 External Cephalic Version (February 2000, Obstet Gynecol Vol. 95, No. 2)

17 Operative Vaginal Delivery (June 2000, Obstet Gynecol Vol. 95, No. 6)

19 Thromboembolism in Pregnancy (August 2000, Obstet Gynecol Vol. 96, No. 2)

20 Perinatal Viral and Parasitic Infections (September 2000, Obstet Gynecol Vol.96, No. 3)

22 Fetal Macrosomia (November 2000, Obstet Gynecol Vol. 96, No. 5)

24 Management of Recurrent Early Pregnancy Loss (February 2001, Obstet GynecolVol. 97, No. 2)

27 Prenatal Diagnosis of Fetal Chromosomal Abnormalities (May 2001, ObstetGynecol Vol. 97, No. 5)

29 Chronic Hypertension in Pregnancy (Obstet Gynecol 2001;98:177–185)

*30 Gestational Diabetes (Obstet Gynecol 2001;98:525–538)

*31 Assessment of Risk Factors for Preterm Birth (Obstet Gynecol 2001;98:709–716)

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Educational and Practice Bulletins provide obstetricians and gynecologists withcurrent information on established techniques and clinical management guide-lines. ACOG continuously surveys the field for advances to be incorporated inthese series and monitors existing bulletins to ensure they are current. Individualbulletins are withdrawn from and added to these series on a continuing basis. Also listed are current Practice Patterns, which provide evidence-based guidelines.A list of withdrawn and replaced titles appears at the end.

LIST OF TITLES — FEBRUARY 2002▼

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ACOGEDUCATIONAL and

PRACTICE BULLETINS

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VOL. 99, NO. 2, FEBRUARY 2002 ACOG Educational and Practice Bulletins List of Titles 359

16 Surgical Alternatives to Hysterectomy in theManagement of Leiomyomas (May 2000, ObstetGynecol Vol. 95, No. 5)

18 The Use of Hormonal Contraception in Women withCoexisting Medical Conditions (July 2000, ObstetGynecol Vol. 96, No. 1)

21 Prevention of Deep Vein Thrombosis and PulmonaryEmbolism (October 2000, Obstet Gynecol Vol. 96, No. 4)

23 Antibiotic Prophylaxis for Gynecologic Procedures(January 2001, Obstet Gynecol Vol. 97, No. 1)

25 Emergency Oral Contraception (March 2001, ObstetGynecol Vol. 97, No. 3)

26 Medical Management of Abortion (April 2001, ObstetGynecol Vol. 97, No. 4)

28 Use of Botanicals for Management of MenopausalSymptoms (June 2001, Obstet Gynecol Vol. 97, No. 6)

*34 Management of Infertility Caused by OvulatoryDysfunction (Obstet Gynecol 2002;99:347–358)

210 Health Maintenance for Perimenopausal Women (August1995)

222 Sterilization (April 1996)

Reproductive Endocrinology and Fertility

246 Osteoporosis (April 1998, Obstet Gynecol Vol. 91, No. 4)

247 Hormone Replacement Therapy (May 1998, Obstet Gynecol Vol. 91, No. 5)

Practice Patterns5 Routine Ultrasound in Low-Risk Pregnancy

(August 1997)

6 Management of Postterm Pregnancy (October 1997)

7 Shoulder Dystocia (October 1997)

Obstetrics (continued)

*32 Thyroid Disease in Pregnancy (Obstet Gynecol2001;98:879–888)

*33 Diagnosis and Management of Preeclampsia and Eclampsia (Obstet Gynecol 2002;99:159–167)

207 Fetal Heart Rate Patterns: Monitoring, Interpretation andManagement (July 1995)

218 Dystocia and the Augmentation of Labor (December 1995)

227 Management of Isoimmunization in Pregnancy (August1996)

230 Assessment of Fetal Lung Maturity (November 1996)

244 Antiphospholipid Syndrome (February 1998)

236 Teratology (April 1997)

248 Viral Hepatitis in Pregnancy (July 1998, Obstet GynecolVol. 92, No. 1)

251 Obstetric Aspects of Trauma Management (September1998, Obstet Gynecol Vol. 92, No. 3)

253 Special Problems of Multiple Gestation (November1998, Obstet Gynecol Vol. 92, No. 5)

260 Smoking Cessation During Pregnancy (September2000, Obstet Gynecol Vol. 96, No. 3)

Gynecology

3 Medical Management of Tubal Pregnancy (December1998, Obstet Gynecol Vol. 92, No. 6)

7 Prophylactic Oophorectomy (September 1999, ObstetGynecol Vol. 94, No. 3)

11 Medical Management of Endometriosis (December1999, Obstet Gynecol Vol. 94, No. 6)

14 Management of Anovulatory Bleeding (March 2000,Obstet Gynecol Vol. 95, No. 3)

15 Premenstrual Syndrome (April 2000, Obstet GynecolVol. 95, No. 4)

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*Title issued since publication of last listingPractice Bulletin

For ordering information, contact the ACOG Distribution Center at 800-762-2264, or order online at sales.acog.com.

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360 ACOG Educational and Practice Bulletins List of Titles OBSTETRICS & GYNECOLOGY

The following Educational and Technical Bulletins will be replaced by Ethics in Obstetrics and Gynecology:136 Ethical Decision-Making in Obstetrics and Gynecology

The following Educational and Technical Bulletins will be replaced by Adolescent Health:249 Confidentiality in Adolescent Health Care 254 Primary and Preventive Health Care for Female Adolescents 256 Oral Contraceptives for Adolescents: Benefits and Safety

The following Educational and Technical Bulletins will be replaced by Special Issues in Women’s Health:194 Substance Abuse201 Pediatric Gynecologic Disorders240 Smoking and Women’s Health242 Sexual Assault252 Adolescent Victims of Sexual Assault 257 Domestic Violence259 Adult Manifestations of Childhood Sexual Abuse

The following Educational and Technical Bulletins have been withdrawn from circulation:109 Methods of Midtrimester Abortion125 Infertility128 Amenorrhea156 Nonmalignant Conditions of the Breast160 Immunization During Pregnancy162 Carcinoma of the Endometrium163 Fetal and Neonatal Neurologic Injury164 The Intrauterine Device171 Rubella and Pregnancy173 Women and Exercise 175 Invasive Hemodynamic Monitoring in Obstetrics and Gynecology176 Diagnosis and Management of Fetal Death178 Management of Gestational Trophoblastic Disease181 Thyroid Disease in Pregnancy (replaced by Practice Bulletin No. 32)182 Depression in Women183 Cervical Cytology: Evaluation and Management of Abnormalities186 Vulvar Cancer187 Ultrasonography in Pregnancy189 Exercise During Pregnancy and the Postpartum Period191 Hysteroscopy193 Genital Human Papillomavirus Infections195 Substance Abuse in Pregnancy197 Managing the Anovulatory State: Medical Induction of Ovulation198 Hormonal Contraception199 Blood Component Therapy200 Diabetes and Pregnancy (replaced by Practice Bulletin No. 30)202 Hyperandrogenic Chronic Anovulation203 Evaluation and Treatment of Hirsute Women204 Septic Shock205 Preconceptional Care206 Preterm Labor (replaced by Practice Bulletin No. 31)208 Genetic Technologies211 Sexual Dysfunction213 Urinary Incontinence214 Pelvic Organ Prolapse215 Gynecologic Ultrasonography216 Umbilical Artery Blood Acid–Base Analysis223 Chronic Pelvic Pain224 Pulmonary Disease in Pregnancy225 Obstetric Analgesia and Anesthesia226 Vaginitis229 Nutrition and Women 231 Seizure Disorders in Pregnancy235 Hemorrhagic Shock238 Lower Urinary Tract Operative Injuries239 Operative Laparoscopy 241 Vulvar Nonneoplastic Epithelial Disorders243 Postpartum Hemorrhage245 Antimicrobial Therapy for Obstetric Patients 250 Ovarian Cancer

VOL. 99, NO. 2, FEBRUARY 2002 ACOG Educational and Practice Bulletins List of Titles 361

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ISBN 0-915473-70-4 The American College of Obstetricians and Gynecologists

Women’s Health Care Physicians

List of TitlesFebruary 2002

Committee Opinions are intended to provide timely information on controversial issues, ethical concerns, and emerg-ing approaches to clinical management. They represent the considered views of the sponsoring committee based oninterpretation of published data in peer-reviewed journals. Committee Opinions are reviewed periodically for contin-ued relevance or needed update. Note: Because individual Committee Opinions are withdrawn from and added to theseries on a continuing basis, the titles listed in this index may not be identical to those contained in complete sets.A list of withdrawn and replaced titles appears at the end.

ACOG Committee Opinions

Publication ReaffirmedNumber Title Date Date

Committee on Coding and Nomenclature205 Tubal Ligation with Cesarean Delivery (Obstet Gynecol Vol. 92, No. 2) August 1998249 Coding Responsibility (Obstet Gynecol Vol. 97, No. 1) January 2001250 Inappropriate Reimbursement Practices by Third-Party Payers

(Obstet Gynecol Vol. 97, No. 1) January 2001

Committee on Genetics (to be published as a separate volume)

161 Fragile X Syndrome October 1995 2000162 Screening for Tay–Sachs Disease November 1995 2000183 Routine Storage of Umbilical Cord Blood for Potential Future

Transplantation (Joint with Committee on Obstetric Practice) April 1997 2000189 Advanced Paternal Age: Risks to the Fetus October 1997 2000192 Genetic Screening of Gamete Donors October 1997 2001212 Screening for Canavan Disease (Obstet Gynecol Vol. 92, No. 5) November 1998 2000223 First-Trimester Screening for Fetal Anomalies with Nuchal Translucency

(Obstet Gynecol Vol. 94, No. 4) October 1999 2001230 Maternal Phenylketonuria (Obstet Gynecol Vol. 95, No. 1) January 2000238 Genetic Screening for Hemoglobinopathies (Obstet Gynecol Vol. 96, No. 1) July 2000239 Breast–Ovarian Cancer Screening (Obstet Gynecol Vol. 96, No. 2) August 2000257 Genetic Evaluation of Stillbirths and Neonatal Deaths

(Obstet Gynecol Vol. 97, No. 5) May 2001

Committee on Gynecologic Practice152 Recommendations on Frequency of Pap Test Screening March 1995 1998164 Incidental Appendectomy December 1995 2000186 Role of the Obstetrician–Gynecologist in the Diagnosis

and Treatment of Breast Disease September 1997 2000191 Length of Hospital Stay for Gynecologic Procedures October 1997 2000195 Role of Loop Electrosurgical Excision Procedure in the Evaluation

of Abnormal Pap Test Results November 1997 2000203 Hepatitis Virus Infections in Obstetrician–Gynecologists

(Obstet Gynecol Vol. 92, No. 1) July 1998 2001224 Tamoxifen and the Prevention of Breast Cancer in High-Risk Women

(Obstet Gynecol Vol. 94, No. 4) October 1999 2001226 Hormone Replacement Therapy in Women with Previously Treated

Breast Cancer (Obstet Gynecol Vol. 94, No. 5) November 1999 2001232 Tamoxifen and Endometrial Cancer (Obstet Gynecol Vol. 95, No. 4) April 2000 2001235 Hormone Replacement Therapy in Women Treated

for Endometrial Cancer (Obstet Gynecol Vol. 95, No. 5) May 2000 2001240 Statement on Surgical Assistants (Obstet Gynecol Vol. 96, No. 2)

(Joint with Committee on Obstetric Practice) August 2000242 Concurrent Chemoradiation in the Treatment of Cervical Cancer

(Obstet Gynecol Vol. 96, No. 4) October 2000243 Performance and Interpretation of Imaging Studies

by Obstetrician–Gynecologists (Obstet Gynecol Vol. 96, No. 5) November 2000

VOL. 99, NO.2, FEBRUARY 2002 ACOG Committee Opinions List of Titles 363

Committee on Gynecologic Practice (continued)244 Androgen Treatment of Decreased Libido

(Obstet Gynecol Vol. 96, No. 5) November 2000245 Mifepristone for Medical Pregnancy Termination

(Obstet Gynecol Vol. 96, No. 6) December 2000246 Primary and Preventive Care: Periodic Assessments

(Obstet Gynecol Vol. 96, No. 6) December 2000247 Routine Cancer Screening (Obstet Gynecol Vol. 96, No. 6) December 2000253 Nongynecologic Procedures (Obstet Gynecol Vol. 97, No. 3) March 2001

*262 Risk of Breast Cancer with Estrogen–Progestin Replacement Therapy(Obstet Gynecol 2001;98:1181–1183) December 2001

*263 Von Willebrand’s Disease in Gynecologic Practice(Obstet Gynecol 2001;98:1185–1186) December 2001

Committee on Obstetric Practice125 Placental Pathology July 1993 2000138 Utility of Umbilical Cord Blood Acid–Base Assessment April 1994 2000158 Guidelines for Diagnostic Imaging During Pregnancy September 1995 2000163 Perinatal Care at the Threshold of Viability

(Joint with AAP Committee on Fetus and Newborn) November 1995 1997173 Prevention of Early-Onset Group B Streptococcal Disease in Newborns June 1996 1999174 Use and Abuse of the Apgar Score (Joint with AAP Committee

on Fetus and Newborn) July 1996 1999180 New Ultrasound Output Display Standard November 1996 2000183 Routine Storage of Umbilical Cord Blood for Potential

Future Transplantation (Joint with Committee on Genetics) April 1997 2000197 Inappropriate Use of the Terms Fetal Distress and Birth Asphyxia February 1998 2001210 Antenatal Corticosteroid Therapy for Fetal Maturation

(Obstet Gynecol Vol. 92, No. 4) October 1998228 Induction of Labor with Misoprostol (Obstet Gynecol Vol. 94, No. 5) November 1999 2001231 Pain Relief During Labor (Joint with American Society

of Anesthesiologists) (Obstet Gynecol Vol. 95, No. 2) February 2000 2001234 Scheduled Cesarean Delivery and the Prevention of Vertical Transmission

of HIV Infection (Obstet Gynecol Vol. 95, No. 5) May 2000 2001240 Statement on Surgical Assistants (Joint with Committee

on Gynecologic Practice) (Obstet Gynecol Vol. 96, No. 2) August 2000248 Response to Searle’s Drug Warning on Misoprostol

(Obstet Gynecol Vol. 96, No. 6) December 2000252 Fetal Surgery for Open Neural Tube Defects

(Obstet Gynecol Vol. 97, No. 3) March 2001256 Optimal Goals for Anesthesia Care in Obstetrics (Joint with American Society

of Anesthesiologists) (Obstet Gynecol Vol. 97, No. 5) May 2001*258 Fetal Pulse Oximetry (Obstet Gynecol 2001;98:523–524) September 2001*260 Circumcision (Obstet Gynecol 2001;98:707–708) October 2001*264 Air Travel During Pregnancy (Obstet Gynecol 2001;98:1187–1188) December 2001*265 Mode of Term Singleton Breech Delivery

(Obstet Gynecol 2001;98:1189–1190) December 2001*266 Placenta Accreta (Obstet Gynecol 2002;99:169–170) January 2002*267 Exercise During Pregnancy and the Postpartum Period

(Obstet Gynecol 2002;99:171–173) January 2002*268 Management of Asymptomatic Pregnant or Lactating Women

Exposed to Anthrax (Obstet Gynecol 2002;99:366–368) February 2002*269 Analgesia and Cesarean Delivery Rates (Obstet Gynecol 2002;99:369–370) February 2002

Committee on Primary Care 227 Complementary and Alternative Medicine

(Obstet Gynecol Vol. 94, No. 5) November 1999 2001

Committee on Professional Liability236 Coping with the Stress of Malpractice Litigation

(Obstet Gynecol Vol. 95, No. 6) June 2000237 Informed Refusal (Obstet Gynecol Vol. 95, No. 6) June 2000

Publication ReaffirmedNumber Title Date Date

For ordering information, contact the ACOG Distribution Center at 800-762-2264, or order online at sales.acog.com.

*Title issued since publication of last index.

364 ACOG Committee Opinions List of Titles OBSTETRICS & GYNECOLOGY

The following Committee Opinions will be replaced by Ethics in Obstetrics and Gynecology:

46 Endorsement of Institutional Ethics Committees108 Ethical Dimensions of Informed Consent136 Preembryo Research: History, Scientific Background, and Ethical Considerations144 Sexual Misconduct in the Practice of Obstetrics and Gynecology: Ethical Considerations156 End-of-Life Decision Making: Understanding the Goals of Care159 Ethical Guidance for Patient Testing170 Physician Responsibility Under Managed Care: Patient Advocacy in a Changing Health Care Environment177 Sex Selection181 Ethical Issues in Obstetric–Gynecologic Education194 Obstetrician–Gynecologists’ Ethical Responsibilities, Concerns, and Risks Pertaining to Adoption204 Institutional Responsibility to Provide Legal Representation214 Patient Choice and the Maternal–Fetal Relationship215 Nonselective Embryo Reduction: Ethical Guidance for the Obstetrician–Gynecologist216 Sterilization of Women, Including Those with Mental Disabilities217 Ethical Issues Related to Expert Testimony by Obstetricians and Gynecologists225 Responsibilities of Physicians Regarding Surrogate Motherhood233 Ethical Dimensions of Seeking and Giving Consultation254 Commercial Enterprises in Medical Practice: Selling and Promoting Products255 Human Immunodeficiency Virus: Ethical Guidelines for Obstetricians and Gynecologists 259 Guidelines for Relationships with Industry 261 Medical Futility

The following Committee Opinions will be replaced by Adolescent Health:139 Adolescents’ Right to Refuse Long-Term Contraceptives154 Condom Availability for Adolescents190 Prevention of Adolescent Suicide

The following Committee Opinions will be replaced by Special Issues in Women’s Health:200 Mandatory Reporting of Domestic Violence201 Cultural Competency in Health Care202 Access to Health Care for Women with Physical Disabilities

The following Committee Opinions have been withdrawn from circulation:87 Deception

101 Current Status of Cystic Fibrosis Carrier Screening104 Anesthesia for Emergency Deliveries105 Postpartum Tubal Sterilization 121 Obstetric Management of Patients with Spinal Cord Injury129 Commercial Ventures in Medicine: Concerns About the Patenting of Procedures133 Colposcopy Training and Practice149 Financial Influences on Mode of Delivery151 Female Genital Mutilation153 Absence of Endocervical Cells on a Pap Test167 Perinatal and Infant Mortality Statistics171 Cost Containment in Medical Care 172 Home Uterine Activity Monitoring (replaced by Practice Bulletin No. 31)175 Scope of Services for Uncomplicated Obstetric Care179 Rate of Vaginal Births After Cesarean Delivery184 Hepatitis B Immunization for Adolescents187 Fetal Fibronectin Preterm Labor Risk Test (replaced by Practice Bulletin No. 31)196 Vitamin A Supplementation During Pregnancy207 Liability Implications of Recording Procedures or Treatments213 Ethical Considerations in Research Involving Pregnant Women221 Telecommunication in Medicine 222 Quality of Laboratory and Imaging Services: Physician Responsibility in the Age of Managed Care 241 Screening for Hypothyroidism (replaced by Practice Bulletin No. 32)251 SalEst as a Predictor of Risk for Preterm Labor (replaced by Practice Bulletin No. 31)

Current Committee Opinions

125 138 152 158 161 162 163 164 173 174 180 183 186189 191 192 195 197 203 205 210 212 223 224 226 227228 230 231 232 234 235 236 237 238 239 240 242 243244 245 246 247 248 249 250 252 253 256 257 258 260262 263 264 265 266 267 268 269

VOL. 99, NO.2, FEBRUARY 2002 ACOG Committee Opinions List of Titles 365

Documents

No. 34. Management of Infertility Caused by Ovulatory Dysfunction