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30Induction of Ovulation

Induction of Ovulation With Clomiphene Citrate Selection of Patients for Clomiphene Treatment Clomiphene and Unexplained Infertility

How to Use Clomiphene Results With Clomiphene Complications With ClomipheneWhat to Do With Clomiphene Failures Treatment of Hyperinsulinemia The Addition of Dexamethasone to Clomiphene

Extended Clomiphene Treatment Pretreatment Suppression The Addition of Bromocriptine to Clomiphene Ovarian Surgical ProceduresInduction of Ovulation With Human Gonadotropins Selection of Patients for Gonadotropin Treatment How to Use Gonadotropin Therapy Results With ClomipheneThe Hyperstimulation SyndromeWhat to Do With Gonadotropin Failures? Can Failure to Respond Be Predicted?GnRH Agonist and Gonadotropin Combined Treatment



GnRH AntagonistsAdding Growth HormoneInduction of Ovulation With Gonadotropin-Releasing Hormone (GnRH)Ovarian Surgical ProceduresSuperovulation and IUI for Unexplained Infertility

Fertility Drugs and the Risk of Ovarian Cancer Chapter References

In previous editions of this book, we began this chapter with a statement in celebration of one of the greatest achievements of reproductive endocrinology, the ability to induceovulation and attain pregnancy in women who in the past had little basis or hope for reversal of their ovulatory dysfunction. As we approach a half century of ovulationinduction for infertility, this elation remains justified. A variety of logical strategies, oftenempirically defined, designed to respond to specific indications do yield excellent results.In many clinical circumstances accurate data confirm the theoretical expectation thattreatment can result in pregnancy rates equivalent to those in the normal population.

As the field has matured, however, the initial exuberance has been tempered by therealities of objective review. Results of treatment, despite restriction to a singleindication, are not uniform. Complications occur, and escalation to more costly andhazardous treatments is a common occurrence. Perhaps most concerning is the vexingly persistent disparity between rates of successful ovulation (high) and pregnancy (relativelylow). This paradox presents two challenges.

1.The informed consent dialogue with the infertile couple does not conclude with the initialoutline of strategic options. Helping the couple deal with the frustration of repeated partial success but persistent ultimate failure requires special time, sensitivity, andcompassion.

2.The disparity between ovulation and pregnancy rates is an emphatic reminder for theclinician of the imprecision of the diagnosis, “ovulatory dysfunction and/or failure,” theinadequacy of the available tests to determine if induction of ovulation has actuallyoccurred, and the existence of more basic inherent defects in the reproductive process notdisclosed by our current thorough work up or simply not discovered.These considerations are all the more reason for the clinician to understand thoroughlythe various indications and the many options available for induction of ovulation. Thischapter will review the principles which guide the use of clomiphene, human menopausalgonadotropins, purified follicle-stimulating hormone (FSH), recombinant FSH, bromocriptine, and gonadotropin-releasing hormone (GnRH), and consider the resultsand complications of the medical induction of ovulation. In addition, laparoscopicovarian surgical procedures (modified wedge resection) and the impact of GnRH agonisttherapy will be reviewed.Despite the specificity of the therapy and the promise of successful results, it isincumbent upon the practitioner to perform the appropriate medical evaluation to ensurethat a contraindication to therapy is not overlooked. The reader is referred to Chapter 12



and Chapter 13 for a consideration of anovulation and hirsutism, and Chapter 11 for theevaluation of amenorrhea and galactorrhea.For reference purposes, we provide the following definitions of ovulatory deficienciesaccording to the World Health Organization.Group I: Hypothalamic-Pituitary Failure

This classfication includes patients diagnosed as hypothalamic amenorrhea, and includesstress-related amenorrhea, anorexia nervosa and its variants, Kallmann's syndrome, andisolated gonadotropin deficiency. These patients display hypogonadotropichypogonadism with low gonadotropin and estrogen levels, normal prolactinconcentrations, and a failure to bleed after the administration of a progestational agent(the progestational challenge).Group II: Hypothalamic-Pituitary DysfunctionThis classification includes normogonadotropic, normoestrogenic, anovulatory,oligoamenorrheic women. The classic anovulatory polycystic ovary syndrome is in thiscategory.Group III: Ovarian Failure

Patients in this classification are hypergonadotropic hypogonadal individuals with lowestrogen levels. All variants of ovarian failure and ovarian resistance are in this category.For the purposes of this chapter, as well as the expression of our clinical philosophy,hyperprolactinemic ovulatory dysfunction is treated as a specific treatment entity.Induction of Ovulation With Clomiphene CitrateClomiphene citrate was first synthesized in 1956, introduced for clinical trials in 1960,and approved for clinical use in the United States in 1967.1, 2 Clomiphene citrate is anorally active nonsteroidal agent distantly related to diethylstilbestrol. Clomiphene is aracemic mixture of its 2 stereochemical isomers, originally described as the cis and transisomers. This designation is now recognized to have been inaccurate, and the isomershave been relabeled as zuclomiphene and enclomiphene citrate.3 Clomiphene is availablein 50 mg tablets, which contain 38% of the more active zuclomiphene form.The similarity of clomiphene's structure to an estrogenic substance is the clue to itsmechanism of action. Clomiphene exerts only a very weak biologic estrogenic effect. Thestructural similarity to estrogen is sufficient to achieve uptake and binding by estrogenreceptors; however, there are several important different characteristics.4, 5 Perhaps mostimportantly, clomiphene occupies the nuclear receptor for long periods of time, for weeksrather than hours. Clomiphene modifies hypothalamic activity by affecting theconcentration of the intracellular estrogen receptors. Specifically, the concentration of estrogen receptors is reduced by inhibition of the process of receptor replenishment.When exposed to clomiphene, the hypothalamic-pituitary axis is blind to the endogenousestrogen level in the circulation. Because receptor capacity is reduced and the trueestrogen signal falsely lowered, negative feedback is diminished and the neuroendocrinemechanism for GnRH secretion is activated. When clomiphene is administered tonormally cycling women, FSH and luteinizing hormone (LH) pulse frequency (but notamplitude) is increased, suggesting an increase in GnRH pulse frequency.6 Anovulatorywomen, however, respond in a different fashion. Clomiphene stimulates an increase ingonadotropin pulse amplitude, presumably because GnRH pulses are already operating atmaximal frequency in anovulatory women with polycystic ovaries.7 Nevertheless, theexperimental data indicate that the primary site of action is the hypothalamus.



During clomiphene administration, circulating levels of FSH and LH rise. Thesubsequent ovulation that occurs after clomiphene therapy is a manifestation of thehormone and morphologic changes produced by the growing follicles. Clomiphene

therapy does not directly stimulate ovulation, but it retrieves and magnifies the sequenceof events that are the physiologic features of a normal cycle. The effectiveness of thedrug, however, may not be restricted to its ability to cause an appropriate GnRHdischarge.In animal models, clomiphene exerts an estrogenic effect on the pituitary and directlystimulates gonadotropin release, independent of its action on GnRH.5 In the presence of estrogen, clomiphene influences pituitary response to GnRH in women, preferentially promoting FSH secretion.8 In addition, clomiphene exerts a direct ovarian effect. In theabsence of estrogen, clomiphene is an estrogen agonist, directly enhancing FSHstimulation of LH receptors in granulosa cells.9 In an important contrast, in the uterus,cervix, and vagina, clomiphene acts primarily as an antiestrogen. Thus vaginal

cornification is attenuated, and the effect of estrogen on cervical mucus and endometriumis antagonized, potentially important actions affecting implantation, sperm transport, andearly embryonic development.10 However, no significant effects on luteal phaseendometrial morphology could be detected when clomiphene was administered to normalwomen.11 Nor could a detrimental impact on cervical mucus be documented in either anovulatory or normal women.12 In addition, the administration of clomiphene failed toaffect endometrial concentrations of estrogen and progesterone receptors in normalovulatory women.13 These latter observations indicate that the potential antiestrogenic,adverse effects of clomiphene do not appear when clomiphene is used clinically.Clomiphene has no progestational, corticotropic, androgenic, or antiandrogenic effects.Clomiphene does not interfere with adrenal or thyroid function. Although the pharmacologic effect of the drug is brief, only 51% of the oral dose is excreted after 5days, and radioactivity from labeled clomiphene appears in the feces up to 6 weeks after administration. Significant plasma concentrations of the active zu isomer can be detectedup to 1 month after treatment with a single dose of 50 mg.14This long half-life of clomiphene presents theoretical concern. The presence of clomiphene at the time of ovulation and during the luteal phase could have unwantedeffects. In vitro, clomiphene inhibits progesterone production by luteal granulosa cells ina fashion that suggests that clomiphene in the presence of estrogen, by virtue of itsantiestrogenic action, interferes with the induction of LH receptors.15 Because thisinhibition is reversed by human chorionic gonadotropin (HCG), pregnancy and theappearance of HCG may prevent this unwelcome effect.In rats and rabbits, a dose-dependent increase in the incidence of fetal malformations isseen when clomiphene is given during the period of organogenesis. Clomiphene has beenfound to cause disruptions of the organization of the uterine mesenchyme and tubalepithelium in human fetal reproductive tissue transplanted to athymic nude mice.16Extremely high doses inhibit fetal development. In these experiments, exposure took place at later periods of gestation than those associated with clomiphene exposure whenthe drug is taken for the induction of ovulation. Although clomiphene therapy should bewithheld if there is any possibility of pregnancy, there is no good evidence that



clomiphene is teratogenic in humans.17, 18, 19 Furthermore, infant survival and performance after delivery are normal.Selection of Patients for Clomiphene TreatmentAbsent or infrequent ovulation is the chief indication for clomiphene therapy. It is theclinician's responsibility to rule out disorders of pituitary, adrenal, and thyroid origin

requiring specific treatment before initiating clomiphene therapy. A complete history and physical examination are mandatory, but only a minimum of laboratory procedures isnecessary. Liver function evaluation should precede clomiphene therapy if history and physical examination findings suggest liver disease. The vast majority of patients arehealthy women suffering only from infertility secondary to oligoovulation or anovulation.If periods are infrequent, it is not absolutely necessary to document infrequent or absentovulation by basal body temperature records or endometrial biopsy. An endometrial biopsy is a wise precaution in a patient who has been anovulatory for a long period of time because of the tendency for these patients to develop hyperplasia and evencarcinoma of the endometrium. It is also wise to precede therapy with an evaluation of the semen, to avoid an unnecessary waste of time and effort in the presence of

azoospermia. A dedicated effort must be made to detect galactorrhea, and the prolactinlevel must be measured. Galactorrhea or hyperprolactinemia dictate a differenttherapeutic approach: dopamine agonist treatment. The remainder of the infertilityworkup in a patient with no previous medical or surgical problems is deferred until after atrial of clomiphene therapy. Because approximately 75% of pregnancies occur during thefirst 3 treatment cycles, the infertility workup is pursued only after the patient hasresponded with 3 months of ovulatory cycles and has not become pregnant.20 This isappropriate because clomiphene is simple, safe, and cost-effective.Cases of ovarian failure are unresponsive to any form of ovulation induction. Therefore,the presence of ovarian tissue capable of responding to gonadotropins must bedocumented. This is only a problem in the patient with amenorrhea, since the presence of menstrual bleeding confirms the function (although perhaps limited) of the hypothalamic- pituitary-ovarian axis. The patient with amenorrhea who fails to produce a withdrawal bleed after a course of a progestational agent (medroxyprogesterone acetate, 10 mg dailyfor 5 days) must be further evaluated (Chapter 11). A case has been made by others for the usefulness of an ovarian biopsy, perhaps via the laparoscope, to establish the presenceof competent ovarian tissue. It is our practice, however, to rely on the immunoassay of gonadotropin levels and the response to a progestin, thus avoiding unnecessary surgicaland anesthetic risks, to accurately rule out hypergonadotropic hypogonadism (ovarianfailure). Attempts at medical induction of ovulation in these patients would be a waste of time and money.The patients most likely to respond to clomiphene display some evidence of pituitary-ovarian activity as expressed in the biologic presence of estrogen (spontaneous or withdrawal menstrual bleeding). These are anovulatory women who have gonadotropinand estrogen production, but do not cycle, or women with inadequate luteal phases.If the mechanism of an inadequate corpus luteum is inadequate FSH stimulation duringthe follicular phase, it makes sense to treat this condition with clomiphene, and a goodresponse has been observed by ourselves and others.21 Two randomized trials comparingclomiphene to progesterone treatment for inadequate luteal phases demonstrated equal pregnancy rates with each treatment.22, 23 Clomiphene does not prolong the luteal phase



(as progesterone supplementation does). This is an important advantage, avoiding theanxiety and heightened monthly emotional response of infertile couples.The patient who is deficient in gonadotropin secretion and, as a result, is hypoestrogenic,cannot be expected to respond to further lowering of the estrogen signal and thus shouldnot respond to clomiphene. However, this principle is not completely applicable to

clinical practice. An occasional patient who is, by all criteria, hypoestrogenic willrespond. Therefore, any otherwise medically uncomplicated patient with infertilitysecondary to lack of ovulation is a candidate for clomiphene therapy unless galactorrheaor hyperprolactinemia is present. Hypoestrogenic women respond so rarely, however,that it is appropriate to omit treatment with clomiphene and move to other more productive options.In addition to anovulation, treatment with clomiphene is indicated to improve the timingand frequency of ovulation and to enhance the possibilities of conception in the patientwho ovulates only occasionally. Clomiphene can also be used to regulate the timing of ovulation in women undergoing insemination.There is one special group in whom clomiphene is indicated in women who ovulate

regularly and spontaneously. Certain religious requirements, such as those in OrthodoxJudaism, interfere with the normal reproductive process. In the devout Orthodox Jewishcouple, intercourse is prohibited in the presence of menstrual flow and for 7 daysfollowing its conclusion. In some women menstrual flow is prolonged or the follicular phase is shortened, so that coitus cannot take place until after ovulation. In the usualmode of treatment, medication is begun on day 5 of the cycle. Ovulation can be delayedto a more appropriate time by starting clomiphene later, usually on day 7 or 8 of thecycle. Ovulation can be expected in the interval 5–10 days after the last day of medication. This manipulation has its limitations. Administration too late in the cycle, beyond day 9, may have no effect.The question is often asked whether the indications for clomiphene therapy should beextended to include the initiation of cyclicity in the oligoamenorrheic patient who doesnot seek fertility. In our opinion, this is an inappropriate use of clomiphene for severalreasons: 1) the effectiveness of clomiphene is restricted to the cycle in which it is usedand it should not be expected to induce cyclicity following the conclusion of treatment, 2)the use of clomiphene may aggravate the clinical problems of acne and hirsutism duringthe treatment cycle by increasing LH stimulation of ovarian steroid production, and 3) theinability to induce cyclicity can be so discouraging to the patient that her acceptance of the drug will be impaired at some future date when it is legitimately offered as a fertilityagent for the induction of ovulation.Clomiphene and Unexplained InfertilityClomiphene is used for the treatment of unexplained infertility; i.e., women who have prolonged (more than 3 years) infertility but who ovulate spontaneously and repeatedly by all available measures and do not have other abnormalities. While the spontaneous pregnancy rate is high in these patients (cumulative rates approach 50%), patient pressureand physician enthusiasm have led to superovulation induction in these couples. Therationale is appealingly clear. With more than one ovulation, surely there is an increased probability of successful fertilization, and such therapy would reverse (if present)episodic, unpredictable, recurrent, occult ovulatory dysfunction. Despite the highspontaneous pregnancy rate, clomiphene does have value in the empiric treatment of



unexplained infertility, particularly prior to undertaking the more expensive and morecomplicated assisted reproductive technologies. In some studies, but not all, treatmentwith clomiphene has been associated with higher pregnancy rates. Superovulation for unexplained infertility is discussed in greater detail at the end of this chapter.How to Use Clomiphene

A program of clomiphene therapy is begun on the 5th day of a cycle following either spontaneous or induced bleeding. It has not been established that a progestin withdrawal bleed is necessary before starting clomiphene treatment; we often omit this step if we arecertain that the patient is not pregnant. The initial dose is 50 mg daily for 5 days. There isno advantage to beginning with a higher dose for the following two reasons: 1) in arandom distribution of our patients begun with initial doses of either 50 mg or 100 mgdaily, the pregnancy rate was identical; and 2) the highest incidence of side effects in our experience occurs at the 50 mg dose, and beginning with 100 mg, patients may developmore serious reactions. About 50% of patients conceive at the 50 mg dose, and another 20% at 100 mg.20, 24 An occasional patient will be exceptionally sensitive toclomiphene and can achieve pregnancy at the reduced dose of 25 mg.

Beginning clomiphene on the 5th day is a method arrived at empirically; however, wecan now offer a rational explanation based on ovarian physiology. The clomiphene-induced increase in gonadotropins during days 5–9 occurs at a time when the dominantfollicle is being selected. Beginning clomiphene earlier can be expected to stimulatemultiple follicular maturation resulting in a greater incidence of multiple gestation.Indeed, clomiphene is administered earlier in in vitro fertilization programs in order toobtain more than one oocyte. However, in standard ovulation induction protocols, nodifferences have been observed in the rates of ovulation, pregnancy, or spontaneousmiscarriage whether clomiphene was started on day 2, 3, 4, or 5.25If ovulation is not achieved in the very first cycle of treatment, dosage is increased to 100mg. Thereafter, if ovulation and a normal luteal phase are not achieved in any cycle,dosage is increased in a staircase fashion by 50 mg increments to a maximum of 200–250mg daily for 5 days. The highest dose is pursued for 3–4 months before considering the patient to be a clomiphene failure. The quantity of drug and the number of cycles go beyond those recommended by manufacturers. However, in our experience thoserecommendations are inappropriately limiting. We have achieved a 15% pregnancy rateat the 150 mg and 200 mg dose levels.20There is a significant correlation between body weight and the dose of clomiphenerequired for ovulation.26, 27 and 28 One must adhere to the usual regimen, however, because the weight cannot be used to predict prospectively the correct ovulatory dose. Inother words, some obese women ovulate at the same low dose that achieves ovulation inthin women. Clomiphene is not stored in adipose tissue, and the increased dose oftennecessary in obese women is more likely due to a more intense anovulatory state withhigher androgen levels producing a more resistant hypothalamic-pituitary-ovarian axis.Increasing the dose of clomiphene will eventually achieve the same level of success inoverweight women as can be attained in lean women.29, 30At the present time there is no clinical or laboratory parameter that can predict the dose of clomiphene necessary to achieve ovulation. Androgen and estrogen levels do not showany correlation with the dose of clomiphene that proves successful.31



Following the 5-day course of clomiphene, the ovulatory surge of gonadotropins canoccur anywhere from 5 to 12 days after the last day of clomiphene administration, butmost commonly on cycle day 16 or 17 when clomiphene is administered on days 5–9.32Once ovulation is established, the subsequent treatment cycles are uniformly consistent.The patient is advised to have intercourse every other day for 1 week beginning 5 days

after the last day of medication. In view of the role prostaglandins play in the physicalexpulsion of an oocyte, it is prudent to advise patients involved in programs of ovulationinduction to avoid the use of agents that inhibit prostaglandin synthesis.

After the first treatment cycle the patient is evaluated for side effects, residual ovarianenlargement, and basal body temperature changes. We have found it unnecessary to perform a pelvic examination every month because significant ovarian enlargement isencountered infrequently, and it is usually symptomatic. It is more economical, for both patient and clinician, to mail the temperature chart to the office and several days later plan by telephone for the following month. Cysts within a reasonable size range (3–5 cm)

do not require a rest from treatment; they do not respond to further stimulation, and theydo not impact upon subsequent response.We recommend basal body temperature charting to follow the response. If an inadequateluteal phase is evident, (temperature elevation less than 11 days duration) the amount of clomiphene is increased to the next dose level. If the patient is already at the maximallevel, consider the available options for dealing with clomiphene failure (detailed below).Biphasic changes are taken as an indication of ovulation and success. Maintenance of thetemperature elevation beyond the expected time of menses is the earliest practicalindication of pregnancy.When the temperature chart is inconclusive or when the patient is not pregnant despite a period of apparently normal ovulations, an endometrial biopsy is indicated to documentthe adequacy of the luteal phase. One should also consider ultrasonographic monitoringfor treatment failures, looking for follicles which do not reach mature size or theluteinized unruptured follicle syndrome (although it is by no means certain that luteinizedunruptured follicles are a factor in infertility). For most patients, adding ultrasonographyand urinary LH testing to basal body temperature charting does not improve pregnancyrates.33The additional use of HCG is limited to those cases in which there is a failure to ovulateat the maximal dose level or, when at that level, a short luteal phase is demonstrated. Therationale is to improve on the midcycle LH surge; therefore, 10,000 IU of HCG can begiven as a single intramuscular dose on the 7th day after clomiphene when follicular maturation is at its peak. Because premature HCG administration may interfere withnormal ovulation by down-regulating LH receptors, more accurate timing of HCGadministration may be desirable. This requires either measurement of the blood estradiollevel or estimation of follicular size (18–20 mm diameter) by sonography. When HCG isadministered, intercourse is advised for that night and for the next 2 days. In our experience as well as in others reported in the literature, the addition of HCG has not hada significant impact on the pregnancy rate.34Care should be taken to review with the patient the pathophysiology of her condition, the principles of treatment, the prolonged course of therapy that may be necessary, and



possible complications. Repeated failures accumulate frustration and despair in thecouple, making each successive cycle of treatment more difficult. The anxiety and stressmay hinder coital performance, and it is not uncommon for a couple to have difficulty performing scheduled intercourse.Results With Clomiphene

In properly selected patients, 80% can be expected to ovulate, and approximately 40% become pregnant.20, 24 The percent of pregnancies per induced ovulatory cycle is about20–25%. The multiple pregnancy rate is approximately 10%, almost entirely twins.35There have been rare cases of quintuplet and sextuplet births. In our own experience, withstandardization of therapy, the incidence of twins has decreased.The miscarriage rate is not increased.19, 36 Most importantly, the incidence of congenitalmalformations is not increased, and infant survival and performance after delivery are nodifferent from normal.18, 19 and 37The discrepancy between ovulation rates and pregnancy rates is mainly due to 2 factors,the presence of other causes of infertility and a lack of persistence. In those patients withno other cause of

infertility, the cumulative 6-month conception rate approaches a normal rate of 60– 75%.24, 31, 35 The pregnancy rate per ovulatory cycle equals the normal rate. The pregnancy rate in 70 of our patients who received therapy sufficient to ovulate in at least3 cycles was 55.7%, the same pregnancy rate after 3 months of exposure in the general population.20 With additional treatment cycles, the pregnancy rate decreases, althoughthe ovulatory rate remains high. Approximately 15% of patients treated with the higher doses of 150–250 mg will become pregnant.20 Therefore there may be no need toattribute negative effects of clomiphene on oocyte, endometrium, the corpus luteum, andan early embryo.If all factors are corrected, and conception has not occurred in 6 months, prognosis is poor.In one large series, only 7.8% of those who had one or more infertility factors in additionto anovulation became pregnant.24Complications With ClomipheneSide effects do not appear to be dose related, occurring more frequently at the 50 mgdose. Patients requiring the high doses are probably less sensitive to the drug. The mostcommon problems are vasomotor flushes (10%), abdominal distension, bloating, pain, or soreness (5.5%), breast discomfort (2%), nausea and vomiting (2.2%), visual symptoms(1.5%), headache (1.3%), and dryness or loss of hair (0.3%). Patients who are extremelysensitive to the side effects of clomiphene can be successfully treated with half a tablet(25 mg) daily for 5 days, and even with half a tablet daily for 3 days.A common antiestrogenic effect is an increase in the basal body temperature during the 5-day period of clomiphene administration. This is sometimes incorrectly interpreted asevidence of an early ovulation.Visual symptoms include blurring vision, scotoma (visual spots or flashes), or abnormal perception. The cause of these symptoms is unknown, but in almost all cases, the visualsymptoms have disappeared upon discontinuation of the medication. Usually thesesymptoms disappear within a few days but may take 1 or 2 weeks. There is one report of 3 women who had a persistence of visual side effects (shimmering, afterimages, and photophobia) after discontinuing treatment.38 It is likely that this problem is increased



with increasing dosage and duration of exposure. Persistence of treatment in the presenceof this reaction is not recommended.Significant ovarian enlargement is associated with longer periods of treatment and isinfrequent (5%) with the usual 5-day course. Maximal enlargement of the ovary usuallyoccurs several days after discontinuing the clomiphene (in response to the increase in

gonadotropins). If the patient is symptomatic, pelvic examination, intercourse, and undue physical exercise should be avoided because the enlarged ovaries are very fragile.Ovarian enlargement dissipates rapidly and only rarely is a subsequent treatment cycledelayed.Because of multiple ovulations in some patients, it is possible that the risk of ectopic pregnancy is increased. However, evidence in the literature indicates that this increase atmost is only slight.2, 19What to Do With Clomiphene FailuresPatients most likely to not respond to clomiphene are those who are mosthyperandrogenic and overweight (and probably insulin resistant).39 There are severaloptions available for the 10–20% of women who fail to become pregnant with

clomiphene up to the highest dose. Knowledge gained from experience with in vitrofertilization provides us with several explanations for failure to respond to clomiphene.31These include the effects of excessive LH in the follicular phase, the dysfunctional effectsof an untimely LH surge, excess local concentrations of androgens, andhyperinsulinemia. These mechanisms may yield impaired folliculogenesis, increasedatresia, poor oocyte quality, precocious or impaired oocyte maturation, low fertilizationrates, variable implantation rates, and deficient corpus luteum function. Strategies havedeveloped to mitigate or avoid many of these detrimental effects: the treatment of hyperinsulinemia, the supplemental use of dexamethasone (to reduce androgen burden),GnRH agonists (to eliminate endogenous LH intrusion), pulsatile GnRH therapy (to preserve physiologic interactive feedback mechanisms), and, finally, the use of humangonadotropins. We are also seeing the return of modified ovarian wedge resection bylaparoscopic multiple ovarian tissue destruction with cautery or laser techniques.First, make sure galactorrhea has not been overlooked and a prolactin level has beenobtained. The good results with dopamine agonist treatment make it essential that thiscause of anovulation be detected. It is worth performing a postcoital test to assess thequality of the cervical mucus. Despite the antiestrogen action of clomiphene theincidence of poor cervical mucus on the postcoital test is only 15%.24 In the past,estrogen (0.625 to 2.5 mg conjugated estrogens daily) was administered from day 10 today 16 (for 1 week starting the day after the last day of clomiphene administration) in aneffort to improve mucus production. Although high doses of estrogen do not interferewith the gonadotropin response, ovulation, or the pregnancy rate, there is reason to believe that estrogen treatment is ineffective.40, 41 Another alternative, the one we prefer, is to proceed with intrauterine inseminations of prepared sperm, bypassing thecervix.After 6 months of clomiphene therapy, and in the absence of any other infertility factors,we proceed to one of the available options.Treatment of HyperinsulinemiaAnovulatory women with polycystic ovaries and hyperinsulinemia are more resistant toclomiphene treatment. The best therapy for these women who are obese is weight loss.



Both the hyperinsulinemia and the hyperandrogenism can be reduced with weight loss,which is at least more than 5% of the initial weight.42, 43, 44, 45, 46 and 47 Thesemetabolic improvements are associated with an impressive rate of resumption of ovulation and pregnancy.48, 49 In one study, 60 of 67 anovulatory women, who lost from4 to 15 kg, resumed ovulation.50 A goal for weight loss that correlates with a good

chance of achieving pregnancy, a reduction in insulin levels, and a decrease in freetestosterone levels is a body mass index of less than 27 (see the nomogram for calculating body mass index in Chapter 19). It should be emphasized, that only a relatively small percentage of weight (5–10%) need be lost to have a beneficial impact upon insulinresistance and cardiovascular hemodynamic function.51It is reasonable to assume that all overweight, anovulatory women with polycysticovaries are hyperinsulinemic. Nevertheless we recommend the measurement of the ratioof fasting glucose to fasting insulin in order to provide evidence that lends credence andimportance to counseling efforts. A ratio of less than 4.5 is consistent with insulin resistance.52All anovulatory women who are hyperandrogenic should be assessed for insulin

resistance and glucose tolerance with measurements of:

1.The fasting glucose:insulin ratio, followed by

2.The 2-hour glucose level after a 75 g glucose load:

normal — less than 140 mg/dL impaired — 140–199 mg/dL noninsulin-dependent diabetes mellitus — 200 mg/dL and higher

The best application of drugs, such as metformin and troglitazone, remains to bedetermined by data from appropriate clinical trials. Metformin improves insulinsensitivity, but the primary effect is a significant reduction in gluconeogenesis, thusdecreasing hepatic glucose production. Metformin treatment (500 mg tid) reduceshyperinsulinemia, basal and stimulated LH levels, and free testosterone concentrations inoverweight women with polycystic ovaries.53, 54 and 55 A significant number of theseanovulatory women treated with metformin ovulate and achieve pregnancy.56, 57 In agroup of obese women with polycystic ovaries, 90% of the women treated withmetformin and 50 mg clomiphene ovulated compared with 8% in the group treated with



placebo and clomiphene.58 However, there has been controversy, suggesting that theimprovement was the result of the weight loss that often accompanies the use of metformin.59 In a study designed to control the effect of body weight, the administrationof metformin was without effect on insulin resistance in extremely overweight womenwith polycystic ovaries.60 In another well-designed study, metformin again had no effect

on insulin resistance when body weights remained unchanged, and in this study baselineweights and hyperinsulinemia were only modestly increased.61 In lean, anovulatorywomen with hyperinsulinemia, metformin treatment reduced hyperandrogenemiaalthough there was no change in body weight; however, a decrease in the waist to hipratio accompanied a reduction in the hyperinsulinemia.62 This study indicates that bothobese and nonobese patients with hyperinsulinemia respond to metformin treatment. Thereasons for the differences among the studies is not apparent. Perhaps only certain patients will respond to metformin, and, thus, patient selection could influence thereported results. Lactic acidosis is a rare complication in patients treated with metformin;however, virtually all cases have occurred in patients with complicated medical problems, such as sepsis, renal insufficiency, and congestive heart failure. Patients who

become ill should discontinue metformin treatment, and metformin should not beadministered to women who have abnormal renal chemistries.The thiazolidinediones markedly improve insulin sensitivity and insulin secretion(improved peripheral glucose utilization and b-cell function) without weight changes.Troglitazone (400 mg daily) decreases hyperinsulinemia, and improvements in metabolicabnormalities (decreased androgens, increased SHBG, decreased PAI-1 consistent withimproved fibrinolytic capacity, and decreased LH), and a return to ovulation in veryobese women have been reported with this agent.63, 64 Although changes areuncommon, liver function must be monitored during troglitazone treatment. The pharmaceutical company's package information should be consulted for the currentlyrecommended monitoring regimen of serum alanine aminotransferase levels.There is little doubt that these drugs can produce significant and beneficial improvementsin this condition, although metformin may be effective only when weight loss occurs.However, is short-term use better than our standard methods of the induction of ovulation, and are these drugs safe during pregnancy and lactation? How effective arethese agents in women who are of normal or only slightly elevated body weight?Appropriate clinical trials are required to answer these questions. In the meantime,clinicians have offered treatment with these agents to patients who have failed to respondto clomiphene. If an ovulatory response does not occur within 3 months, clomiphenetreatment, beginning again at the lowest dose, is resumed in addition to the drug therapyfor hyperinsulinemia.The Addition of Dexamethasone to ClomiphenePatients with hirsutism and high circulating androgen concentrations are more resistant toclomiphene.65, 66, and 67 Dexamethasone, 0.5 mg at bedtime to blunt the nighttime peak of ACTH, is added to decrease the adrenal contribution to circulating androgens and,thus, diminish the androgen level in the microenvironment of the ovarian follicles. Higher ovulation and conception rates are achieved with this treatment when the circulating levelof dehydroepiandrosterone sulfate (DHAS) is greater than the upper limit of normal. Thedexamethasone is maintained daily until pregnancy is apparent. The dose of clomipheneis returned to the starting point of 50 mg and increased in incremental fashion as needed.



One report indicated that even non-responders to clomiphene with normal DHAS levelsachieved ovulation and pregnancy with the addition of a 10-day course of dexamethasone begun concurrently with clomiphene.68Extended Clomiphene TreatmentSeveral approaches have been reported for extending clomiphene treatment. We have

very little experience with extended clomiphene treatment. In one approach, 250 mg of clomiphene was given for 8 days, followed by 10,000 IU HCG 6 days later. Three pregnancies were achieved out of 25 treatment cycles.69 In another series, theclomiphene dose was increased every 5 days, with some patients receiving up to 25 daysof consecutive treatment, the last 5 days at 250 mg daily.70 Eight of 21 patientsconceived and, in those patients who responded, measurement of gonadotropin revealedsustained elevations in FSH. This latter approach requires estrogen monitoring withdiscontinuation of the clomiphene when an increase in estrogen is detected. No patientovulated after more than 21 days of treatment. Extending a dose of 100 mg clomiphene to10 days has been reported to achieve pregnancies in women previously resistant to a 5-day regimen.71 A simple approach is to extend the duration of clomiphene treatment

until a follicle of 18 mm diameter (on ultrasound) is obtained, then administer HCG.Pretreatment SuppressionThe anovulatory state is a dysfunctional condition. It is reasonable to expect suppressionof the contributing factors to be followed by a reassertion of the harmony operating in anormal menstrual cycle, at least for a short time. Clinicians have long advocated (without benefit of careful study) a period of suppression (at least 6 months) with an oralcontraceptive, followed immediately by resumption of clomiphene administration. Thesame principle applies to the use of a GnRH agonist. Spontaneous resumption of ovulation has been reported to follow suppression for 6 months with a combination of aGnRH agonist and an oral contraceptive.72 Pretreatment suppression has an addedattraction. There is reason to believe that women with elevated LH and testosterone levelsnot only have more difficulty achieving pregnancy, but also experience a higher spontaneous miscarriage rate.73, 74 and 75 However, an excellent, randomized trial,testing pituitary suppression in women with polycystic ovaries, elevated LH levels, andrecurrent miscarriages, obtained equal and good live birth rates with gonadotropintreatment in both the GnRH agonist-suppressed group and the non-suppressed group.76The Addition of Bromocriptine to ClomipheneAlthough the use of bromocriptine to induce ovulation is indicated in the presence of galactorrhea or hyperprolactinemia, its use in the clomiphene failure patient with anormal prolactin and no galactorrhea is controversial. Anovulatory patients with normallevels of prolactin do respond to bromocriptine, but the effectiveness of this treatment hasnot been established by controlled studies. Nevertheless, the clinical response isoccasionally impressive.Bromocriptine. Elevated prolactin levels interfere with the normal function of themenstrual cycle by suppressing the pulsatile secretion of GnRH. This is manifestedclinically by a spectrum, ranging from a subtle inadequate luteal phase to totalsuppression and hypoestrogenic amenorrhea. Regardless of the prolactin level, weinterpret the presence of galactorrhea to indicate excessive prolactin stimulation. Wescreen all patients with galactorrhea or any ovulatory disorder with an assessment of the prolactin level. After a consideration of the problems of amenorrhea, galactorrhea, and



the pituitary adenoma (as discussed in Chapter 11), bromocriptine emerges as the drug of choice for the induction of ovulation in these patients.Ovulatory dysfunction in the presence of galactorrhea responds well to bromocriptine,even if the prolactin level is normal.77 Either biologic activity is not being detected bythe immunoassay or a random blood sample fails to reveal subtle elevations in prolactin.

Bromocriptine is examined in detail in Chapter 11, but it would be helpful to review pertinent details here. Bromocriptine is a dopamine agonist that directly inhibits pituitarysecretion of prolactin. Suppression of prolactin levels restores CNS-pituitarygonadotropin function and also appears to increase ovarian responsiveness. The increasein ovarian responsiveness is seen in patients with normal prolactin levels and nogalactorrhea. This is the apparent mechanism for an increase in sensitivity to clomiphenewhen bromocriptine is added to the therapeutic regimen. In women with persistentanovulation and polycystic ovaries, LH secretion is decreased by bromocriptinetreatment, thus providing a rationale for why it might enhance the ovulatory response inthese patients.78The gastrointestinal and cardiovascular systems react to the dopaminergic action of

bromocriptine, and, therefore, the side effects are mainly nausea, diarrhea, dizziness,headache, and fatigue. Side effects can be minimized by slowly building tolerance towardthe usual dose, 2.5 mg bid. We start treatment with an initial dose of 2.5 mg at bedtime. If intolerance occurs, the tablet can be cut in half, and a slower program, developed by the patient, can be followed to work up to the standard dose. Usually, the second dose isadded after 1 week, at breakfast or at lunch. In some patients, elevated prolactin levelscan be reduced to normal levels with very small doses of bromocriptine, as little as 0.625or 1.25 mg.79 Patients extremely sensitive to the side effects of bromocriptine can betreated by administering the drug intravaginally. Usually one 2.5 mg tablet daily will beeffective; if the prolactin level is elevated, the dose can be titrated to bring the prolactinlevel into the normal range.The usual regimen is to administer bromocriptine daily until it is apparent the patient is pregnant, as usually determined by the basal body temperature chart. Although there has been no evidence of any harmful effects on the fetus, some patients and clinicians prefer to avoid bromocriptine in the luteal phase and, therefore, during early pregnancy. Thedrug is stopped when a temperature rise occurs and resumed when menses begin.Ovulatory menses and pregnancy are achieved in 80% of patients with galactorrhea andhyperprolactinemia. Response is rapid, and, therefore, if there is no indication of ovulation (a rise in the basal body temperature) within 2 months, clomiphene is added tothe regimen. The starting dose of clomiphene is 50 mg daily for 5 days, given andincreased in the usual fashion.Cabergoline is also an ergot-derived dopamine agonist.80 Patients resistant to both bromocriptine and quinagolide have been reported to respond to cabergoline.81Cabergoline can be administered orally at doses of 0.5 to 3.0 mg only once weekly,although it can be given twice weekly if necessary, with minimal dopamine agonist sideeffects (headache being the most common complaint).82, 83, 84 and 85 The low rate of sideeffects and the once weekly dosage make cabergoline an attractive choice for initialtreatment, replacing bromocriptine. The only reservation (a small one) is a more limitedexperience documenting fetal safety for patients being treated for infertility.86



Cabergoline can also be administered vaginally for the rare patient who cannot tolerate itorally.87Bromocriptine for Euprolactinemic Women. Clinical experience suggests that successfulinduction of ovulation and achievement of pregnancy with bromocriptine can occur in theabsence of galactorrhea and with a normal prolactin level in women who have failed to

respond to clomiphene.88 Some anovulatory women with normal prolactin levels whoovulated in response to bromocriptine have been found to have elevated nocturnal peaksof prolactin.89 The mechanism of action may be an increase in follicular responsivenesseither due to suppression of prolactin or suppression of LH (a known action of dopamine). A decrease in LH may alter local follicular steroidogenesis in such a way tocreate a more favorable microenvironment. The method of administration is the same asabove. If, after 2 months of treatment, there is no response, clomiphene is reinitiated,working up again from the starting dose of 50 mg daily. A carefully designed study hasdemonstrated that bromocriptine has nothing to offer for ovulatory women withunexplained infertility.90 On the other hand, bromocriptine or bromocriptine plusclomiphene treatment of ovulatory women with galactorrhea (and normal prolactin

levels) yielded higher pregnancy rates when compared to a control group.91 Once againthe importance of detecting galactorrhea is emphasized.Ovarian Surgical ProceduresThe clomiphene-resistant patient can be treated by an ovarian surgical procedure. Thissubject is discussed near the end of this chapter.Induction of Ovulation With Human GonadotropinsFor over 30 years, the only preparation used for gonadotropin treatment consisted of human menopausal gonadotropins, a preparation of gonadotropins extracted from theurine of postmenopausal women. The commercial preparation is still available, witheither 75 units of FSH and 75 units of LH per ampule, or in an ampule with twice theamount, 150 units of each gonadotropin. Gonadotropins are inactive orally and, therefore,must be given parenterally; the heavy protein content of the urinary preparation requiresintramuscular injections.A more purified urinary preparation of FSH became available by removing most of theLH in the urinary product. This product still requires intramuscular injection. A morehighly purified form is available that can be administered subcutaneously.Recombinant FSH is now produced in Chinese hamster ovary cells transfected with thehuman FSH subunit genes.92 Recombinant FSH is homogeneous and free of contamination by proteins (characteristic of menopausal gonadotropins from urinaryextracts); this allows simpler subcutaneous administration.Because of its structural and biologic similarity to LH, HCG, readily available fromhuman pregnancy urine and placental tissue, is used to simulate the midcycle LHovulatory surge.Recombinant HCG and recombinant LH are now available. These preparations will allow patient self-administration by subcutaneous injections. It is unlikely that the results will be different; however, it is possible that the risk of ovarian hyperstimulation will bereduced.

PREPARATION



TRADE NAMESHuman menopausal gonadotropinsPergonal, Humegon, Menogon, RepronexPurified urinary FSHMetrodin, Normegon, Orgafol

Highly purified urinary FSHFertinex or Metrodin HPRecombinant FSHPuregon, Gonal-F, FollistimHuman chorionic gonadotropinPregnyl, Profasi, A.P.L.Recombinant HCGOvidrelRecombinant LHLHadi

Selection of Patients for Gonadotropin Treatment Not only because of its expense but because of its greater complication rate, patientsshould not receive gonadotropin therapy without a very careful evaluation. An absoluterequirement is the demonstration of ovarian competence. Abnormally high serumgonadotropins with a failure to demonstrate withdrawal bleeding indicate ovarian failureand preclude induction of ovulation except in those special cases of ovarian failurediscussed in Chapter 11. Successful induction of ovulation and pregnancy has beenreported in women with apparent ovarian failure, treated with a combination of estrogen(to suppress FSH to normal levels) and gonadotropins. Our own experience with thisapproach has been disappointing, and the chance of achieving pregnancy must be verylow.

A thorough infertility investigation must be performed. In addition to the demonstrationof ovarian competence, tubal and uterine pathology should be ruled out, anovulationdocumented, and semen analysis obtained. Nongynecologic endocrine problems must betreated. Hypogonadotropic function (low serum gonadotropins), including galactorrheasyndromes, requires evaluation for an intracranial lesion, with appropriate imaging andmeasurement of prolactin levels. It is imperative to take all steps necessary to excludetreatable pathology to which anovulation is secondary.In our practice we sometimes, but not often, offer a course of clomiphene, not only because of the cost and complications associated with gonadotropin therapy, but also because some apparently hypogonadotropic patients will unpredictably respond toclomiphene. Because some patients cannot tolerate dopamine agonist treatment, it isimportant to know that hyperprolactinemia has no adverse effect on response togonadotropins.93How to Use Gonadotropin TherapyInstruction and counseling of the couple are essential. A thorough understanding of theneed for daily treatment and frequent observation is necessary prior to initiating therapy.As part of this instruction, the partner can be taught to administer injections. Dailyrecording of the basal body temperature and body weight is important for proper



management. The couple should be told about the need for scheduled intercourse, the possibility that more than one course of treatment may be necessary, and the expense of the treatment. Above all, the patient must be prepared for the anguish that accompaniesfailure. Because this is a pressure-packed situation, unexpected impotence is occasionallyencountered on the days of scheduled intercourse.

Although there is evidence indicating that recombinant FSH yields better results with invitro fertilization, there is no clear-cut indication that better results are obtained with anyof the gonadotropin preparations when used for ovulation induction.94 Optimal resultsare dependent on the experience and judgement of the clinician, not on the preparationused. There is no doubt that some LH is necessary for normal ovarian steroidogenesis(see Chapter 6), and very low day 3 LH levels (less than 3 IU/L) have been reported to predict poor response to gonadotropin stimulation.95 In this circumstance, perhaps a preparation containing some LH would be a better choice; for example, in patients withamenorrhea due to weight loss and anorexia.A variable dosage method is used to achieve follicular growth and maturation. Folliclestimulation is achieved by 7–14 days of continuous gonadotropin, beginning with one

ampule daily. Response is judged by the degree of estrogen produced by the growingfollicles. The patient is monitored periodically with the measurement of the circulatingestradiol level and vaginal ultrasound assessment of the number and size of follicles. The patient is seen on the 7th day of treatment, and a decision is made to continue or increasethe dose (step up method). After the 7th day, the patient is seen anywhere from daily toevery one or two days. Another approach, the step down method, starts with a higher dose (2–3 ampules) and reduces the dose to one ampule after the initial response,theoretically approximating the changes in FSH in a normal ovulatory cycle.Patients with polycystic ovaries are handled more gingerly because they are moresensitive to gonadotropin stimulation, and, therefore, at greater risk for multiple pregnancy and the ovarian hyperstimulation syndrome. The increased sensitivity to FSHis apparently due to the availability of a larger cohort of small follicles ready to respondto FSH (recruitable follicles).96 In these patients, monitoring begins on the 4th or 5th dayof treatment. Excessive stimulation can be avoided in women with polycystic ovaries byusing lower doses of gonadotropin extended over a longer duration of treatment.97, 98 Inaddition, good results are inversely correlated with the degree of insulin resistance,99 andconsideration should be given to treatment that improves insulin sensitivity (seeelsewhere in this chapter and Chapter 12).It cannot be emphasized too strongly that dosage administration and the judicious use of estrogen measurements depend upon the experience of the clinician administeringgonadotropin therapy. When estradiol and ultrasound monitoring indicate that the patientis ready to receive the ovulatory stimulus, 10,000 units of HCG are given as a single doseintramuscularly. Neither manipulation of HCG dosage nor time of administration has been successful in changing the rates of multiple gestation and hyperstimulation. The patient is advised to have intercourse the day of the HCG injection and for the next 2days. In view of the fragility of hyperstimulated ovaries, further intercourse as well asstrenuous physical exercise should be avoided.Pregnancy is usually achieved with the administration of gonadotropins for 7–12 days.The best results are obtained when the treatment period covers 10–15 days; when lessthan 10 days, the spontaneous miscarriage rate is increased.100 In general there is a direct



relationship between dose and body weight; however, the same empiric approach isneeded even in obese patients.101 In some individuals, presumably with extremelyhyposensitive ovaries, adequate follicular stimulation requires doses up to 4, 6, and moreampules/day. In this group of amenorrheic women massive doses of gonadotropins arenecessary, and with proper monitoring, pregnancy can be achieved safely.

The range between the dose that does not induce ovulation and the dose that results inhyperstimulation is narrow. The situation is made even more difficult because the ovariesmay react differently to essentially similar doses from month to month. Close supervisionand experience in the use of gonadotropin therapy are necessary to avoid difficulties.There is no reason to avoid consecutive cycles of ovarian stimulation; indeed, anincreased cycle fecundity has been observed in consecutive treatment cycles whencompared to alternating stimulation and nontreatment.102, 103Estrogen MonitoringThe use of estrogen measurements is necessary to choose the correct moment for administering the ovulatory dose of HCG in order to prevent hyperstimulation. On day 7of the therapeutic cycle, blood is assayed for estradiol. Depending on the findings, the

dosage of gonadotropin is individualized for the duration of the cycle. With experience,the clinician can avoid daily estrogen measurements, although sometimes this isnecessary.What should the blood estradiol level be? Because the blood estradiol is determined on asingle sample of blood, the timing of the sampling with relationship to the previousinjection of gonadotropin becomes a significant variable. When gonadotropin injectionsare given between 5 and 8 PM and blood samples are obtained first thing in the morning,an estradiol window of 1000–1500 pg/mL is optimal.104 The risk of hyperstimulation issignificant from 1500 to 2000 pg/mL and, as a general rule, over 2000 pg/mL, HCGshould not be given, and the ovarian follicles should be allowed to regress. Carefulcorrelation of estrogen levels with the ultrasonographic picture allows a more aggressiveapproach. Haning has calculated that an upper limit for estradiol of 3800 pg/mL for anovulatory women (with polycystic ovaries) and 2400 for women with hypothalamicamenorrhea gives a risk of severe hyperstimulation of 5% in pregnant cycles and 1% innonconception cycles.105Attempting to reproduce the normal midcycle levels of estradiol does not achieve amaximal pregnancy rate, and higher levels are required. The relative safety of thisapproach was seen in our series, where only 2 of 24 patients with estradiol levels over 1000 pg/mL developed hyperstimulation and it was moderate in both cases.104 When a patient nears ovulation, timing of the HCG administration can be predicted fairlyaccurately by plotting the estradiol values on semilogarithmic paper. The rate of increasein estradiol is the same in spontaneous and induced cycles, and does not differ in cyclesthat result in multiple gestation.106 The level which is reached at the time of HCGadministration is more critical than the slope of increase. Once a linear rise of estradiol isestablished, there is no need to increase the dose.Ultrasound MonitoringUltrasound assessment of the growth and development of the ovarian follicle indicatesthe degree of follicular maturity and capability.107 During normal cycles, the growingcohort of follicles can be first identified by ultrasonography on days 5 to 7 as smallsonolucent cysts. The dominant follicle will become apparent by days 8–10. The maximal



mean diameter, indicating ovum maturity, of the preovulatory dominant follicle variesfrom 20 to 24 mm (range 14–28 mm) in normal, spontaneous cycles. Individual womentend to produce the same maximal diameter on repeated cycles. Pregnancies have not been observed with follicles less than 17 mm diameter in normal cycles.107 Subordinatefollicles rarely exceed 14 mm in diameter. In 5–11% of cycles, two dominant follicles

develop.During the 5 days preceding ovum expulsion, the dominant follicle exhibits a linear growth pattern of approximately 2 to 3 mm per day, followed by rapid exponentialgrowth during the last 24 hours prior to ovulation. Ultrasonographic surveillance of ovaries reveals that mittelschmerz is associated notwith follicular rupture but with the rapid expansion of the dominant follicle, thus the pain precedes follicular rupture.Ovulation is associated with complete emptying of the follicular contents in 1 to 45minutes. Fluid can be detected frequently, but not always, in the cul-de-sac. The follicleeither disappears or more commonly appears as a smaller, irregular cyst whichdiminishes in size over the next 4–5 days.

In response to clomiphene treatment, follicles pursue a linear but generally acceleratedrate of growth compared to spontaneous cycles.108 The maximal diameter of clomiphene-induced preovulatory follicles is similar to that seen with spontaneous cycles,20–24 mm, but ovulation can be successfully induced with HCG administration when thediameter reaches 18–20 mm (by the time of ovulation, the follicle will have grownanother 2–3 mm). With gonadotropin therapy, the maximal follicular diameter (15–18mm) is smaller than that seen during spontaneous and clomiphene-induced cycles. Whenfollicles reach this size, ovulation will occur approximately 36 hours after HCG isadministered.Ultrasound monitoring does not eliminate the risks of multiple gestation andhyperstimulation. It is claimed that a higher pregnancy rate can be achieved whenultrasound is combined with estrogen monitoring.109 The guiding principle has been toadminister HCG when mature follicles correlate with an estrogen level of 200–400 pg per mature follicle (greater than 13 mm diameter). This principle only applies when there areseveral leading follicles, not when many intermediate (9–16 mm) and small (<9 mm)follicles are present. As a general rule, hyperstimulation is associated with the presenceof more follicles. We believe that HCG should not be administered if there are more than3–5 follicles 13 mm or greater in diameter (offering some protection against multiplegestation and hyperstimulation). Mild hyperstimulation has been associated with anincreased number of intermediate size follicles, and severe hyperstimulation with anincrease in small follicles.110, 111 A large number (11 or more) of smaller follicles alsoshould preclude HCG administration.Measurement of Endometrial Thickness. Ultrasonographic studies in cycles of in vitrofertilization have revealed that successful implantation is correlated with endometrialthickness on the day of HCG administration.112 This same correlation has been observedin patients in non-IVF patients receiving gonadotropins for ovulation induction.113Consistent with the antiestrogenic action of clomiphene, endometrial thickness is reducedin women treated with clomiphene (and reversed with estrogen). In a program utilizingclomiphene and timed administration of HCG for the purposes of intrauterineinseminations, no pregnancies occurred when the endometrial thickness measured less



than 6 mm.114 The chance of pregnancy is greatest, no matter what program of ovarianstimulation is being used, if endometrial thickness is 9–10 mm or more.115, 116The Effect of Persistent Ovarian Cysts. In contrast to results with IVF or GIFT, the presence of a baseline ovarian cyst greater than 10 mm in diameter is associated withdecreased fecundity in ovulation induction with gonadotropins.117 With large cysts,

treatment should be either delayed, or cyst suppression with a GnRH agonist or oralcontaceptives should be considered, although it has never been proven that suchtreatment is effective. With this exception, there is no advantage in avoiding multiplesuccessive treatment cycles (such as alternating treatment and nontreatment cycles).102,103Clomiphene-Gonadotropin CombinationThe combination of clomiphene and gonadotropin was explored in order to minimize theamount and the cost of gonadotropin alone. As long as treatment is monitored withestrogen levels, the side effects and complications should not be dissimilar to those withgonadotropin alone. It has not been demonstrated that patients unresponsive togonadotropin alone would respond to the sequence method, and there is no logical reason

to assume that this would be true.The usual method of treatment is to administer clomiphene 100 mg for 5–7 days, then toimmediately proceed with gonadotropin beginning with 2 ampules per day. Estrogenlevels are monitored as usual. This method may decrease the amount of gonadotropinrequired by approximately 50%; however, the same risks of multiple pregnancy andhyperstimulation can be expected. This reduced requirement for gonadotropin is foundonly in those patients who demonstrate a positive withdrawal bleeding following progestin medication or who have spontaneous menses.118Pulsatile Administration of GonadotropinGonadotropin can be administered in pulsatile fashion, either subcutaneously or intravenously, using an appropriate pump system.119, 120 The aim is to reproduce the pulsatile pattern of gonadotropin secretion during the normal menstrual cycle. The doseadministered intravenously is 6–9 units per pulse every 90 minutes, with adjustmentsupward according to response. The usual monitoring with estradiol levels andultrasonography is necessary. It is not certain whether this complicated method is better beyond a decrease in dose and possibly a response in patients unresponsive to thetraditional intramuscular regimen.Results With Gonadotropin TreatmentThe most significant aspect of this method of treatment is that it does achieve pregnancyin otherwise untreatable situations. A cumulative conception rate of 90% after 6treatment cycles can be achieved in women with hypothalamic amenorrhea (this rateexceeds that observed in spontaneously ovulating women), with a 23% rate of spontaneous miscarriage.121, 122 Women with normogonadotropic anovulation achieveonly a slightly lower cumulative conception rate with relatively, but slightly, higher ratesof miscarriage; however, with appropriate and careful gonadotropin treatment, these ratesequal those in the normal population123. A slightly higher rate of spontaneousmiscarriage reflects the combination of better detection of early pregnancy loss, advancedmaternal age, and the increased incidence of multiple pregnancies. As with clomiphene,there is a normal incidence of congenital malformations, and the children have a normal postnatal development.18 The risk of ectopic pregnancy is increased with ovulation



induction, a consequence of multiple oocytes and high hormone levels.124 These patientsshould be closely monitored in the early weeks of their pregnancies.Women with polycystic ovaries and moderate obesity require larger doses of gonadotropin and ovulate at a lesser rate compared to leaner women with polycysticovaries.125 A comparable pregnancy rate (40%) is achieved. However, spontaneous

miscarriage is more frequent, which is consistent with the observation that spontaneousmiscarriage is more frequent in obese women.HCG disappears from the blood with an initial component having a half-life of about 6hours and a second, slower, component with a half-life of about 24 hours. It is thisrelatively slow half-life that enables a single injection of 10,000 IU to maintain thecorpus luteum until pregnancy takes over. The HCG concentration after the ovulationinjection should be less than 50–100 IU/L by day 14 after the injection. A b-subunit assayof HCG at this time or one of the urine assays performed 2–4 weeks after the HCGinjection are reliable tests for pregnancy. Additional HCG (during the luteal phase) doesnot improve pregnancy rates.126 Luteal supplementation is required only with concurrenttreatment with a GnRH agonist.

The rate of serious hyperstimulation is 1–2%. Prior to the present era of more carefulmonitoring, the multiple pregnancy rate was reported as approximately 30% (triplets or more, 5%). Currently, the multiple pregnancy rate can be as low as 10% with carefulmonitoring and good medical judgment; however, rates as high as 40% are reported.109A striking increase in multiple births in many countries, especially triplets andquadruplets, can be directly attributed to ovulation stimulation for the treatment of infertility.127, 128 and 129The multiple pregnancies are secondary to multiple ovulations, and, therefore, thesiblings are not identical. The rate of spontaneous occurrence of twins is only about 1%and that of triplets 0.010–0.017% of the pregnant population. Dizygotic twinning variesamong different populations and is inherited through the mother. The monozygotictwinning rate is about 0.3–0.4%, fairly constant, and uninfluenced by heredity.Surprisingly, induction of ovulation increases the frequency of monozygotic twinning 3-fold.130 It is not known whether the multiple pregnancy rate with gonadotropin issignificantly affected by a maternal history of twinning.Maternal complications and fetal loss caused by prematurity in the multiple pregnancieshave been serious problems. In addition, the miscarriage rate with gonadotropin issomewhat higher (25%) than normal, probably a combination of the effect of age,multiple pregnancies, and recognition of early miscarriages.131After at least one gonadotropin-induced pregnancy, the subsequent spontaneous pregnancy rate reaches 30% after 5 years.132 Most of the pregnancies occur within 3years of the gonadotropin-induced pregnancy, and the more endogenous hypothalamic- pituitary-ovarian function a patient has, the more likely a spontaneous pregnancy willoccur.133 This is consistent with a return to normal function in some women after suppression of a dysfunctional state. With time, it is logical to expect the originaldysfunctional state to reestablish itself.Multifetal Pregnancy Reduction. Induced abortion in the case of triplets or more is anoption, but it would be surprising if patient and clinician would choose this solution. Onthe other hand, selective reduction of embryos in multiple pregnancy can beaccomplished.134 Under ultrasound guidance, a gestational sac can be aspirated or a



cardiotoxic drug (potassium chloride) can be injected into, or adjacent to, the fetal heart.The transvaginal procedure is best performed between the 8th and 9th weeks of gestationand the transabdominal procedure between the 11th and 12th weeks. A later procedure isworthwhile because the spontaneous disappearance of one or more gestational sacs inmultiple gestations can occur, an incidence of approximately 5% after fetal heartbeats

have been identified.135 Selection of which gestational sac to terminate is based solelyon technical considerations, such as accessibility. The subsequent risk of losing one or more of the remaining fetuses is 4–9%, and of losing the pregnancy, 10% by experiencedclinicians and higher with less experience. Reduction of a monochorionic pregnancy isnot advisable because of shared vasculature and the high risk of losing all fetuses. Themoral and ethical aspects of fetal reduction are significant, but in view of the potential problems associated with a multiple birth, it is a reasonable alternative for some.The Hyperstimulation SyndromeOvarian hyperstimulation can be life-threatening. In mild cases the syndrome includesovarian enlargement, abdominal distension, and weight gain. In severe cases, a criticalcondition develops with ascites, pleural effusion, electrolyte imbalance, and hypovolemia

with hypotension and oliguria.136, 137 and 138 The ovaries are tremendously enlargedwith multiple follicular cysts, stromal edema, and many corpora lutea. Because of thisenlargement, torsion of the adnexa is a relatively common complication of thissyndrome.139The incidence of clinically important hyperstimulation is striking. Although it might beexpected that the mild type would be relatively common, the moderate to severe formappears at an impressive rate (1–2%). Two-thirds of cases occur early in a conceptioncycle, the remainder in nonconception cycles. For purposes of one of the methods of assisted reproduction, the ovaries are stimulated at an even greater rate than for conventional ovulation induction; however, the incidence of hyperstimulation is nogreater, or even lower.140, 141 For this reason, it has been suggested that follicular aspiration offers partial protection against the hyperstimulation syndrome. Some reportshave indicated a higher incidence of hyperstimulation in in vitro fertilization protocolsusing the combination of gonadotropin and a GnRH agonist.140 Because support duringthe luteal phase is required when GnRH agonist treatment is used, the additional HCGadministered is responsible for greater stimulation. The use of progesterone for lutealsupport is probably safer, and therefore, when estradiol levels are high (greater than 2500 pg/mL) and when the follicle number is greater than 15, progesterone supplementation isrecommended instead of HCG.Anovulatory women with polycystic ovaries are at greatest risk for the hyperstimulationsyndrome. The use of a GnRH agonist in combined therapy does not eliminate this risk.These patients should be treated slowly with careful titration of dose as described earlier.The basic disturbance in hyperstimulation is a shift of fluid from the intravascular spaceinto the abdominal cavity, creating a massive third space. The resulting hypovolemialeads to circulatory and excretory problems. The genesis of the ascites is unclear. Thevery high level of estrogen secretion by the ovaries may be the primary factor, inducingincreased local capillary permeability and leakage of fluid from the peritoneal capillariesas well as the ovaries. The leakage of fluid is also critically related to the mass, volume,and surface area of the ovaries. Therefore, the larger the ovaries and the greater the



steroid production, the more severe the condition. Or the syndrome may result fromoverproduction of autocrine/paracrine factors that affect vascular permeability.A growing body of evidence implicates vascular endothelial growth factor (VEGF) in the pathophysiology of the hyperstimulation syndrome. The origin of VEGF is presumed to be the ovarian follicle, and increased capillary permeability and the severity of the

syndrome are correlated with circulating levels of VEGF.142, 143 and 144 Other cytokines, especially the interleukin family, are also believed to be involved in the permeability changes, and it is hypothesized that these agents affect the nitric oxidesystem.145, 146 Large amounts of angiotensin II are present in the ascites produced byovarian hyperstimulation, presumably originating from HCG stimulation of the ovarianrenin-angiotensin system.147The loss of fluid and protein into the abdominal cavity accounts for the hypovolemia andhemoconcentration. This in turn results in low blood pressure and decreased centralvenous pressure. The major clinical complications are increased coagulability anddecreased renal perfusion. Blood loss as the cause of the clinical picture can be easilyruled out since a hematocrit will reveal hemoconcentration. The decreased renal

perfusion leads to increased salt and water reabsorption in the proximal tubule, producingoliguria and low urinary sodium excretion. With less sodium being presented to the distaltubule, there is a decrease in the exchange of hydrogen and potassium for sodium,resulting in hyperkalemic acidosis. A rise in the blood urea nitrogen (BUN) is due todecreased perfusion and increased urea reabsorption. Because it is only filtered,creatinine does not increase as much as the BUN. Thus, the patient is hypovolemic,azotemic, and hyperkalemic. In response to these changes, aldosterone, plasma reninactivity, and antidiuretic hormone levels are all elevated.148Treatment is conservative and empiric. When a patient displays excessive weight gain(usually 10 or more pounds), excessive pain, hemoconcentration (hematocrit over 50%,white blood count over 25,000), oliguria, dyspnea, or postural hypotension, she should behospitalized. Pelvic and abdominal examinations are contraindicated in view of theextreme fragility of the enlarged ovaries. Ovarian rupture and hemorrhage are easily precipitated.Upon admission, the patient is put on bed rest, with daily body weights, strict monitoringof intake and output, and frequent vital signs. Serial studies of the following are obtained:hematocrit, BUN, creatinine, electrolytes, total proteins with albumin:globulin ratio,coagulation studies, and urinary sodium and potassium. The electrocardiogram is utilizedto follow and evaluate hyperkalemia. Fluid and salt restriction is controversial. It isargued that correction of the decreased circulating volume is not necessary as long as theBUN remains stable (an abnormally low urine output can be tolerated).148 Others believe that plasma expanding agents and electrolyte supplements should beadministered.149 Human albumin (safe from viral contamination) is the volume expander of choice. Potassium exchange resins may be necessary. Diuretics are without effect and,indeed, may be disadvantageous. The fluid in the abdominal cavity is not responsive todiuretic treatment, and diuresis may further contract the intravascular volume and produce hypovolemic shock or thrombosis. Arterial and venous thromboses have beenreported in both the upper and lower portions of the body, and anticoagulant therapyshould be considered in severely hemoconcentrated patients.150, 151 and 152 Although both antihistamines and indomethacin have been demonstrated to ameliorate the



hyperstimulation in animal studies, their efficacy and safety in early human pregnancyare unknown. Inhibition of prostaglandin synthesis can worsen renal perfusion.

In severe cases, life-threatening adult respiratory distress syndrome can occur.153 These patients require intensive care monitoring, including central venous and pulmonary

wedge pressures. Adult respiratory distress syndrome is associated with a 50% mortalityrate. Chlorpheniramine maleate, an H-1 receptor blocker, appears to maintain membranestability, allowing the use of fluids and mannitol to retain intravascular volume.154 Withultrasound guidance to avoid the enlarged ovaries, abdominal paracentesis can relievesevere pulmonary compromise. Aspiration of ascites can also be accomplished (and probably more easily) transvaginally (with ultrasound guidance).155, 156 With repeatedaspirations, it is very important to replace the lost plasma proteins (autotransfusion of theascitic fluid has been used in a small number of cases). On the average, repeat aspirationsare necessary in 3 to 5 days.In severe cases, transvaginal aspiration of follicular structures should be considered tointerfere with the intraovarian mechanism responsible for the clinical picture;

progesterone supplementation will be necessary to maintain an on-going pregnancy.157The possibility of ovarian rupture should always be considered, and serial hematocritsmay be the only clue to intraperitoneal hemorrhage. Of course, a falling hematocritaccompanied by diuresis is an indication of resolution, not hemorrhage. Laparotomyshould be avoided in these precarious patients. If surgery is necessary, only hemostaticmeasures should be undertaken and the ovaries should be conserved if possible, since areturn to normal size is inevitable. If torsion of the adnexa is encountered, unwinding theadnexa (and preserving the ovary in an infertile patient) is possible even when the adnexaare already ischemic.The key point is that the hyperstimulation syndrome will undergo gradual resolution withtime. In a patient who is not pregnant, the syndrome will cover a period of approximately7 days. In a patient who is pregnant and in whom the ovaries are restimulated by theemerging endogenous HCG production, the syndrome will last 10–20 days.The syndrome will not develop unless the ovulatory dose of HCG is given. Thus, themajor emphasis in recent years has been to utilize monitoring to avoid hyperstimulation.The relationship between estrogen levels and hyperstimulation is not a perfect one.Hyperstimulation has been found with relatively low estrogen levels, and high estrogen isnot necessarily followed by hyperstimulation. As a general rule, the more follicles present(on ultrasound examination) the greater the risk for hyperstimulation. But this too is not a perfect correlation. Nevertheless, monitoring is the major available deterrent to a potentially life-threatening situation.What to Do With Gonadotropin Failures?At one time, management of the couple who had failed ovulation induction withgonadotropin treatment was difficult, but straightforward. Short of another costly round if funds and emotional reserves were sufficient, nothing was left to offer except adoption.Today, a major option is now available in the assisted reproductive technologies (Chapter 31). Although even more costly and emotionally charged, these methods do offer significant additional opportunities for unsuccessful patients. Nevertheless, guidance toadoption services and emotional support continue to be part of the physician's obligation.



A very important question for patients is: when to stop? All clinicians have beenconfronted by the dismal and frustrating prospects of a woman who has squandered yearsin vain repetitive attempts at ovulation induction, only to arrive at age 40 for interventionwith one of the methods of assisted reproductive technology. If a properly managed set of 6 gonadotropin cycles is unsuccessful, the prudent counsel is to recommend a turn toward

the methods of assisted reproductive technology.Can Failure to Respond Be Predicted?Women who present with “incipient” ovarian failure have elevated FSH levels anddecreased levels of inhibin, but normal levels of estradiol.158, 159 The rise in FSHduring the later years is in response to declining inhibin production.160, 161, 162 and163 Inhibin levels are lower in the follicular phase in women 45–49 years old comparedwith younger women. The specific inhibin involved in this feedback effect on FSHduring the follicular phase is inhibin B.164, 165 In addition, a decline in luteal phaseinhibin A can contribute to a greater rise in FSH during the luteal-follicular transition.166This decline in inhibin begins early, but accelerates after 40 years of age. The rise in FSHis very apparent after age 40, but there is no change in LH levels until menopause. The

changes in the later reproductive years reflect either lesser follicular competence, as the better primordial follicles respond early in life, leaving the lesser follicles for later, or thefact that the total follicular pool is reduced in number (or both factors). Arguing in favor of a role for a reduced follicular pool is the observation that follicular fluid obtained from preovulatory follicles of older women contains amounts of inhibin A and B that aresimilar to that measured in follicular fluid from young women.167These endocrine changes and the decline in ovarian follicles are correlated with adecrease in ovarian volume.168 A measurement of volume by ultrasonography that isequal to or less than 3 cm3 predicts a poor response to ovulation induction.169Testing the Ovarian ReserveThe measurement of baseline hormonal levels provides important and helpful prognosticinformation. Because FSH levels increase with age, elevated FSH levels on cycle day 3(greater than 12 IU/L, but especially greater than 20 IU/L) are associated with poor performance with in vitro fertilization.170 A cycle day 3 FSH level that is 25 IU/L or more, or an age of 44 years or more, are both independently associated with a chance of pregnancy close to zero during ovulation induction or with assisted reproductivetechnologies.171 Values can vary between laboratories, significantly due to differences inantibodies and standards usedto measure gonadotropin levels.172 With the most recent assays, day 3 values above 10IU/L are abnormal and are comparable with values greater than 20 IU/L with older assays.Keep in mind that there is no abrupt change at 40, and, therefore, these changes can applyto younger women. The age of change is determined by the rate of oocyte loss, a rate thatis genetically programmed in most women. An elevated FSH at any age is correlated withfewer available oocytes, and advancing age adds the factor of lesser oocyte quality. Anelevated estradiol level on day 3 (greater than 80 pg/mL) is also predictive of difficulty inachieving pregnancy;173, 174 premature estradiol elevations are associated with ahurried recruitment of follicles in response to increased FSH secretion, changescharacteristic of the years preceding menopause. When both FSH and estradiol areelevated on day 3, ovarian response to stimulation is very poor.



The Clomiphene Challenge Test. Navot and colleagues developed the clomiphenechallenge test as a bioassay of FSH response (which in turn reflects ovarian follicular inhibin capability).175 Clomiphene is administered in a dose of 100 mg/day on days 5–9.The level of FSH on day 10 is compared with the baseline level on day 3. An exaggeratedFSH response of 26 IU/L or more was two standard deviations above the control values

in this study, and this increase in FSH was associated with a significant prospect for failure to achieve pregnancy. Remember that there is a wide variety of FSH assays (thenewer assays provide numbers that are approximately 70% of the older results), and cliniciansmust become familiar with the values provided by their own laboratories. There is a highincidence of abnormal responses in women over age 35, and 85% of women withincreased FSH levels respond poorly to ovarian stimulation.176 In a general infertility population, about 10% of women have an abnormal response to the clomiphene challengetest. As expected, the percentage increased with increasing age (from 3% under age 30 to26% over age 39), and women with unexplained infertility had a 38% incidence of abnormal tests.177 This test of ovarian reserve is more sensitive than just measuring

basal FSH levels in predicting the potential for pregnancy in both assisted and naturalreproduction. An abnormal response to the clomiphene challenge test indicates a poor prognosis no matter the woman's age.178 However, because age alone is an importantfactor (presumably due to other age-related oocyte conditions of quality), older womenwith normal hormone levels and normal responses to clomiphene still have diminishedchances of pregnancy.We believe it is worthwhile to screen all infertile women beginning atage 30, women of any age with unexplained infertility, and women who respond poorlyto ovulation induction with the clomiphene challenge test and a day 3 estradiol level. For practical purposes, equivalent results can be expected on days 2, 3, and 4 of the cycle. Far less certain is the need for these tests in the woman over 40, because even normal tests donot provide reassurance of adequate ovarian reserve. An abnormal test in a woman over 40,however, can be used to bolster advice to consider ovum donation. Although an abnormaltest at any age indicates a very poor prognosis, it does not indicate an absolute inability toachieve pregnancy.Regardless of age, women with elevated day 3 FSH levels and/or abnormal responses tothe clomiphene challenge test should consider in vitro fertilization with young, donatedoocytes. Patients should also be informed that a failure to respond to gonadotropintreatment despite normal screening hormonal levels places them at risk for progressing toovarian failure in a relatively short time.179GnRH Agonist and Gonadotropin Combined TreatmentRecognizing that women with significant estrogen, androgen, and gonadotropin levels donot respond well to induction of ovulation, attention was turned to a method that couldturn off a woman's endogenous reproductive hormone production. The availability of GnRH agonists provided such a method. The thesis underlying the use of a GnRH agonistas an adjunctive therapy in ovulation induction is straightforward: convertnormogonadotropic anovulators to a hypogonadotropic hypogonad state by the process of pituitary GnRH receptor desensitization and down-regulation.180, 181 Premature LHeffects on the follicle and the burden of excess local androgen can be diminished and an



improved therapeutic response achieved. There is reason to believe that women withanovulatory polycystic ovaries have a higher incidence of spontaneous miscarriagefollowing induction of ovulation with gonadotropin;73, 74 and 75 combining the GnRHagonist with gonadotropin not only yields a greater pregnancy rate, but also reduces themiscarriage rate.182 Furthermore, premature LH release is believed to contribute to the

risk of ovarian hyperstimulation in women with polycystic ovaries.183 Combining aGnRH agonist with gonadotropin treatment could reduce (although not eliminate) the risk of this serious complication.Leuprolide acetate (Lupron) is administered twice daily (0.5 mg subcutaneously) for 2weeks.181 Suppression of gonadotropin secretion is confirmed by measurement of theestradiol level; a concentration less than 25 pg/mL should be achieved before treatment isinitiated with gonadotropins. Lupron treatment is maintained throughout thegonadotropin regimen until HCG is administered. It is not unusual to require higher dosesof gonadotropin. With this combination, no difference has been observed in the number of follicles recruited, the rate of rise and final estradiol level achieved, or the number of cycles canceled compared with gonadotropin alone. Hyperstimulation is not avoided, but

per cycle fecundity appears to be modestly increased. Any of the available GnRHagonists can be used for this purpose. Pituitary suppression can be combined with highly purified or recombinant FSH; it appears that very little LH is necessary for normalresponses.184The administration of a GnRH agonist to a woman who has menstrual function willinitially produce a stimulatory response, known as the “flare.” The magnitude of the flareresponse depends upon when in the cycle the agonist is administered. During thefollicular phase or in anovulatory women, the flare is greater, and enlarged follicular cysts can occur. This response can be minimized by beginning therapy during themidluteal phase or by administering a progestational agent (e.g., 10 mgmedroxyprogesterone acetate daily for 10 days) and beginning GnRH agonist treatmentafter 3 days of progestin.During the hypoestrogenic period of time, menopausal-like symptoms are common,especially hot flushes. Forewarning and reassurance are usually sufficient to help patientstolerate these short-lived reactions.Utilization of a GnRH agonist suppresses endogenous LH levels to such a low level that,after ovulation, the corpus luteum requires additional exogenous support. One canadminister HCG (2000 IU) twice, 3 days, and 6 days after ovulation, or progesteronesupplementation beginning 3 days after ovulation (4 days after the LH surge):intravaginal progesterone suppositories, 25 mg twice per day, intramuscular progesterone, 50 mg per day, or oral micronized progesterone, 300 mg per day. The doseof micronized progesterone is relatively high and should be administered at bedtime toavoid side effects. Progesterone in a gel that adheres to the vaginal mucosa (Crinone) isavailable in a prefilled vaginal applicator, applied with one 8% (90 mg progesterone)application daily. Vaginal administration accomplishes targeted delivery to the uteruswithout producing high circulating levels. The pregnancy rates with either HCG or progesterone treatment are the same, but the use of HCG adds to the risk of hyperstimulation.185, 186GnRH Antagonists



More extensive alterations in the GnRH structure yield compounds that bind to the GnRHreceptor and totally block any stimulation of the pituitary gonadotropin-secreting cells.GnRH antagonists can be used concomitantly with gonadotropin induction of ovulationto prevent premature LH surges.187 Because GnRH antagonists are competitiveinhibitors, a GnRH agonist could be used for the ovulatory signal, possible avoiding the

use of HCG and reducing the risk of ovarian hyperstimulation. The optimal use of GnRHantagonists is currently being explored.Adding Growth HormoneAs discussed in Chapter 6, the primate ovarian follicular cycle is very dependent uponautocrine/paracrine factors. In view of the critical role played by insulin-like growthfactor-I, it was quickly recognized that the addition of growth hormone (which stimulatesinsulin-like growth factor-I production), usually in a dose of 24 IU given intramuscularlyevery other day, might facilitate ovulation induction by gonadotropins, and especially,might convert poor responders to good responders. Initial results in poor responders werefavorable, although this may be limited to patients with polycystic ovaries.188, 189 Inwomen with normal responses, however, the addition of growth hormone did not improve

results or reduce the total dose of gonadotropin.190 Thus, in normally respondingwomen, the growth hormone and IGF-I system may be operating at maximal levels. In poorly responding women, concomitant treatment with growth hormone can reduce theamount of gonadotropin necessary, shorten the duration of treatment, and increase thechance of pregnancy. However, not all poorly responding women respond favorably togrowth hormone treatment.191 The effective selection of patients, dosage, and treatmentregimens remains to be standardized, and the extreme cost of growth hormone is asignificant disadvantage. Another approach is to administer growth hormone-releasinghormone. In a small randomized trial (13 women), the addition of growth hormone-releasing hormone to gonadotropin treatment was associated with a higher pregnancyrate.192 However, others have administered 500 µg of growth hormone releasinghormone twice daily to poor responders with little effect, although the dosage of gonadotropin may be reduced.193, 194Induction of Ovulation With Gonadotropin-Releasing Hormone (GnRH) Numerous advantages can be cited in favor of pulsatile GnRH therapy for ovulationinduction. GnRH methodology, once established, is simple to use, requires no extensive(or expensive) follicular monitoring, and, relative to its counterparts, is quite safe.Ovarian hyperstimulation and multiple gestations are rare because only “physiologic”levels of FSH should be generated. Because GnRH serves largely a permissive role, theinternal feedback mechanisms between the ovary and pituitary should be operative,yielding follicular growth and development similar to a normal menstrual cycle inresponse to the “turning on” of the system by GnRH.GnRH is administered constantly in a pulsatile fashion by a programmable portableminipump. Induction of ovulation with the GnRH pump is most effective in women withhypothalamic amenorrhea (absence of menstrual bleeding following a progestinchallenge) where endogenous GnRH is dysfunctional or absent. Unfortunately, althoughit has been successful in some anovulatory women with polycystic ovaries, this success isfar less than anticipated, and these patients are at greater risk for hyperstimulation andmultiple pregnancy, therefore requiring a lower dose (2.5 µg per bolus).195, 196 Nevertheless, the GnRH pump is a safer, less expensive alternative for these patients than



gonadotropin therapy. The GnRH pump is also effective in women withhyperprolactinemia, providing a good alternative if dopamine agonist treatment cannot betolerated.GnRH is available in crystalline form that when reconstituted in the aqueous diluent isstable for at least 3 weeks at room temperature. The pump must be worn constantly

around the clock, requiring some ingenuity for bathing and sleeping. GnRH can beadministered by either the intravenous or subcutaneous routes. The subcutaneous routerequires a higher dose. Failure with subcutaneous administration is associated with a polycystic ovary-like picture, with high LH levels, anovulation, and even symptoms of androgen excess. This is not surprising because subcutaneous administration results in anabsorption curve with a broad base without a definite peak. For intravenousadministration, heparin is added to the GnRH solution in a concentration of 1000 U/mL.We favor starting with the intravenous route. The needle is left in place until there aresigns of local reaction and then changed. Women at risk for bacterial endocarditis should be restricted to the subcutaneous route of administration.Although some argue in favor of near physiologic duplication of the pulse frequency,

similar results can be obtained with empiric 90-minute cycles throughout treatment. Thedose for subcutaneous administration is 20 µg per bolus, for intravenous administration, 5µg per bolus. If the patient fails to respond (assessed by weekly measurement of estradiol), the dose should be increased by 5 µg increments.After ovulation, the luteal phase is maintained by either continuing the pump or administering HCG (2000 IU intramuscularly at the time of the temperature rise and thenevery 3 days for 3 doses). In our experience, most patients would rather discontinue the pump.One of the reasons that the GnRH pump is less expensive is that it reproduces physiologic hormonal events, and intensive monitoring is not necessary. The main problem is knowing with some accuracy when to have intercourse. Usually ovulationoccurs by 14 days of treatment, but the range extends from 10 days to 22 days.Intercourse every other day during this period of time can be a formidable challenge.Ultrasonic monitoring of follicular development may be required, or more conveniently,the couple can use one of the urinary LH test kits to detect the LH surge and haveintercourse for 2–3 days beginning the day of the color change.Side effects with the GnRH pump are minimal, principally related to pump functioningand local reactions to the needle placement. The patient must be educated to pay closeattention to proper function of the pump and maintenance of the GnRH reservoir.Hyperstimulation and multiple births have been encountered, but this is rare andassociated with higher than recommended doses. The risk of dangerous hyperstimulationis essentially zero. Several cases of allergic response with the development of circulatingantibodies have been reported.The pregnancy rate in anovulatory women is 20–30% per treatment cycle, whichapproximates the pregnancy rate of normal couples.197, 198 Persistence with repeatedcycles is rewarded with high cumulative pregnancy rates, approximately 80% after 6cycles and 93% after 12 cycles.199 The miscarriage rate of 20% is typical of allmethodologies. The incidence of multiple pregnancy is low (4–5%). The cumulative pregnancy rate in women with polycystic ovaries is approximately 30–40%. If thismethod is to be used for women with polycystic ovaries, it is recommended that



desensitization and down-regulation of the pituitary with a GnRH agonist precedetreatment (and retreatment will be necessary with each cycle). This approach can yield acumulative pregnancy rate of 60%.200 Even then, obese patients are less likely torespond, and they have higher rates of spontaneous miscarriage.The safety and simplicity of GnRH administration are powerful attractions. Despite the

clear advantages, the GnRH pump has not received wide acceptance by patients. Manyare irrationally fearful of the risk of needle displacement or equipment problemsassociated with the technology. Because of this low acceptance, appropriate pumps for the administration of GnRH are no longer available in many countries.

Ovarian Surgical ProceduresIrving Stein and Michael Leventhal, in 1935, at the Michael Reese Hospital in Chicago,described 7 cases of the syndrome that bears their names.201 They developed wedgeresection of the ovaries when they observed that several of their amenorrheic

(anovulatory) patients with polycystic ovaries menstruated after ovarian biopsies. In their original procedure, they removed 50 to 75% of each ovary. They concluded that thethickened surface of the ovary prevented follicles from reaching the surface. For years,the wedge resection was the only method available to induce ovulation in these patients,and it wasn't until 30–40 years later that an accurate understanding of the mechanism wasachieved.The purpose of wedge resection of the ovaries is to remove a significant amount of hormone-producing tissue. Documentation of hormone changes following wedgeresection indicates that an important change is a sustained reduction in testosteronelevels.202, 203 This suggests that the barrier to ovulation is the intraovarian, atresia- promoting effects of the high testosterone production. Removal of androgen-producingtissue effectively lowers this barrier, and ovulatory cycles can ensue. The success of wedge resection is directly proportional to the volume of androgen-producing tissueremoved. Tissue removal and destruction are the key factors, not the shape and procedureof the “wedge.” Indeed, even a unilateral oophorectomy is followed by resumption of ovulation in anovulatory women with polycystic ovaries.204Another contributing factor is a reduction in circulating levels of inhibin, which followsthe loss of ovarian tissue.205 A rise in FSH occurs in the days after wedge resection;successful ovulation reflects the combined effects of increased FSH and the removal of the local androgen obstruction to the emergence of a dominant follicle.The response to ovarian wedge resection is variable. Some patients resume ovulation permanently. However, most patients return to their anovulatory state. Some patients failto respond at all. Furthermore, the surgical procedure carries with it the potential problemof postoperative adhesion formation.The operative risk, the variable response, and the possibility of postoperative adhesionformation are the liabilities of wedge resection. These must be weighed against theexcellent results obtained with medical induction of ovulation (approximating the normalconception rate when anovulation is the only fertility problem present). It should truly bea rare patient in whom wedge resection of the ovaries is necessary.



Today, a new type of “wedge resection” is available. Using either cautery, diathermy, or laser vaporization by means of the laparoscope, destruction of ovarian tissue at multiplesites (15–20 per ovary) can achieve spontaneous ovulations or an increased sensitivity toclomiphene, ultimately achieving pregnancy rates equivalent to those with gonadotropintreatment (but without the risks of hyperstimulation and multiple pregnancies).206, 207,

208, 209 and 210 These procedures are associated with the same decrease in androgensand inhibin as observed with wedge resection. When clomiphene is reinstituted, 70–80%of patients will ovulate, and approximately 60% will achieve pregnancy. Adhesionformation remains a problem, but perhaps it is less profound than in the traditionalsurgery.210, 211 Second look laparoscopy with lysis of adhesions is indicated if pregnancy does not follow successful ovulations. This therapy can be performed at thetime of a planned diagnostic laparoscopy in a patient with known anovulation and polycystic ovaries. These procedures are worth considering by patients who are reluctantto pursue the more expensive and difficult methods of the assisted reproductivetechnologies. These methods are the modern equivalent of the original ovarian wedgeresection pioneered by Stein and Leventhal.

Superovulation and IUI for Unexplained InfertilityThe methods of assisted reproductive technology and superovulation with intrauterineinsemination (IUI) increase the prospect of pregnancy in couples with unexplainedinfertility. The results with superovulation alone are inferior to those achieved with oneof the assisted reproductive techniques, but the overall cost is also less.212 Studiesindicate that subtle hormonal abnormalities do exist in women with unexplainedinfertility.213, 214 These changes (elevated gonadotropins and estradiol in the follicular phase and decreased luteal phase progesterone) have been attributed to a reduction inovarian reserve as usually seen in older women.214 Thus, there is a rational basis to provide ovarian stimulation.A cumulative pregnancy rate of 40% can be achieved in couples with unexplainedinfertility after 6 cycles of superovulation or 3 cycles of in vitro fertilization.215 Inrandomized, controlled clinical trials, the monthly pregnancy rates in couples withunexplained infertility is increased 2–3-fold (a monthly fecundity rate of 9%) withclomiphene treatment, and with human gonadotropins, the monthly fecundity rate isapproximately 10–15%.216, 217 and 218 Although some studies have failed to yieldincreased pregnancy rates with the empiric use of clomiphene,219, 220 we believecouples with unexplained infertility should beoffered superovulation or one of the assisted reproductive technologies. However,superovulation should be limited to 3 or 4 cycles.The addition of intrauterine insemination of washed sperm (IUI) to clomiphene treatmentincreased fecundity in couples with unexplained infertility or surgically treatedendometriosis, compared with intercourse without hormonal stimulation).217 As withalmost all infertility, success is age-related, with pregnancy rates 3–4-fold greater inwomen under age 20.221 Although the combination of IUI with clomiphene mayenhance the pregnancy rate in couples with unexplained infertility, IUI by itself doesnot.222, 223 and 224The combination of IUI with gonadotropin stimulation provides even better results thanclomiphene and IUI. In two studies, the pregnancy rate per cycle with gonadotropins andIUI was 19% and 14.3% compared to 4% and 7.7% with clomiphene and IUI



respectively.218, 225 In a meta-analysis of randomized trials comparing gonadotropinstimulation with IUI or with timed intercourse, IUI was associated with approximately a2-fold greater pregnancy rate.226 In a randomized trial, superovulation and IUI resultedin a 3-fold greater pregnancy rate compared with intracervical insemination and 2-foldgreater compared with either IUI alone or a combination of superovulation and

intracervical insemination.241The effectiveness of gonadotropin treatment combined with IUI has been repeatedlydemonstrated for a variety of infertility disorders, including endometriosis, cervicalfactor, and unexplained infertility.227, 228 and 229 As with clomiphene, few pregnanciesoccur after 4 cycles of treatment.In summary, a meta-analysis of methods used to treat unexplained infertility, pregnancyrates were estimated to be as follows:

Pregnancy Rate per Cycle169

No treatment1.3–4.1%

IUI3.8%

Clomiphene5.6%

Clomiphene & IUI8.3%

Gonadotropins7.7%

Gonadotropins & IUI17.1%



IVF20.7%

Because it is relatively inexpensive, easy to administer, and not usually burdened withmajor side effects (except for a 2-fold increase in twinning), clomiphene is usually thefirst treatment choice. Patient demand for this treatment is substantial, and it is notunreasonable to respond to that demand with 3–4 clomiphene cycles. The uncertaintyregarding the efficacy of adding IUI to clomiphene influences us to proceed fromclomiphene treatment to the combination of gonadotropins and IUI, with an expectationof achieving a pregnancy rate of 15% per cycle. The combination of clomiphene and IUIis still appropriate in circumstances where cost, time, and avoidance of complications are paramount. The use of IUI alone or gonadotropins without IUI is not recommended for the treatment of unexplained infertility.223, 231The effects of age remain critical whatever the method of ovarian stimulation. In one

series of 136 treatment cycles, no pregnancies were achieved in women who were 43 or older.232 Despite rare successes in older women, it borders on the exploitive to treatwomen over age 40 with superovulation and IUI. Indeed, pregnancy rates begin todecline with this treatment around age 35.221The incidence of multiple births and ovarian hyperstimulation is higher with this empirictreatment. Patients and clinicians undertaking empiric superovulation should have readyrecourse to in vitro fertilization. If gonadotropin stimulation is excessive, several choicesare available: avoiding HCGadministration and cancelling the cycle, aspirating most of the ovarian follicles withultrasound guidance and proceeding with in vitro fertilization.Fertility Drugs and the Risk of Ovarian Cancer An analysis of 3 case-control studies of ovarian cancer conducted in the U.S. from 1987– 1989 concluded that the risk was increased among women who had used fertility drugsand among women who had been exposed to long periods of sexual activity withoutcontraception.233 However, this conclusion was limited by the small number of cases,and the exact drugs and dosage used by these cases were unknown. Concern over thisissue was further fueled by a report that prolonged use of clomiphene (12 or more cycles)was associated with an increased risk of borderline or invasive ovarian tumors.234 Theconclusion in this comparison of a cohort of women with the rate of ovarian tumors in thegeneral population was based on only 5 cases of borderline tumors and 4 cases of invasive tumors. Nevertheless, the idea that superovulation can increase the risk of ovarian cancer is biologically plausible because there is a decreasing risk for invasiveepithelial ovarian cancer associated with those conditions marked by a decrease in thenumber of ovulations: multiparity, increasing duration of breastfeeding, and the use of oral contraception.It is worth noting that a long-term follow-up of 2632 women in Israel who had receiveddrugs for induction of ovulation did not record an increased incidence of ovarian cancer in the subsequent years.235 More recently, stimulated by the above reports, severalepidemiologic studies appeared with the strength of larger case numbers. A study fromIsrael indicated an increased risk, but the relative risk was not statistically significant.236



Two case-control studies from Italy and a Danish case-control study (the largest in size)failed to find a relationship between fertility drugs and the risk of epithelial ovariancancer.237, 238 and 239The best evidence does not indicate an increased risk of ovarian cancer with less than 12months of clomiphene treatment (there is no reason to pursue clomiphene treatment for

more than 12 months), or with gonadotropin treatment. Nulliparity and infertility innulliparous women are associated with a slight increase in the risk of ovarian cancer, butovarian stimulation with fertility drugs does not change this baseline risk.240dChapter References

1.Greenblatt RB, Barfield WE, Jugck EC, Ray AW, Induction of ovulation with MRL/41, preliminary report, JAMA 178:255, 1961.

2.Dickey RP, Holtkamp DE, Development, pharmacology and clinical experience with

clomiphene citrate, Hum Reprod Update 2:483, 1996.

3.Ernst S, Hite G, Cantrell JS, Richardson Jr A, Benson HD, Stereochemistry of geometricisomers of clomiphene: a correction of the literature and a reexamination of structure-activity relationships, J Pharm Sci 65:148, 1976.

4.Clark JH, Markaverich BM, The agonistic-antagonistic properties of clomiphene: areview, Pharmacol Ther 15:467, 1982.

5.Adashi EY, Clomiphene citrate-initiated ovulation: a clinical update, Seminars ReprodEndocrinol 4:255, 1986.

6.Kerin JF, Liu JH, Phillipou G, Yen SSC, Evidence for a hypothalamic site of action of clomiphene citrate in women, J Clin Endocrinol Metab 61:265, 1985.

7.Kettel LM, Roseff SJ, Berga SL, Mortola JF, Yen SSC, Hypothalmic-pituitary-ovarianresponse to clomiphene citrate in women with polycystic ovarian syndrome, Fertil Steril59:532, 1993.

8.de Moura MD, Ferriani RA, de Sa MFS, Effects of clomiphene citrate on pituitaryluteinizing hormone and follicle-stimulating hormone release in women before and after treatment with ethinyl estradiol, Fertil Steril 58:504, 1992.

9.



Kessel B, Hsueh AJW, Clomiphene citrate augments follicle-stimulating hormone-induced luteinizing hormone receptor content in cultured rat granulosa cells, Fertil Steril46:334, 1987.

10.

Birkenfeld A, Beier HM, Schenker JG, The effect of clomiphene citrate on earlyembryonic development, endometrium and implantation, Hum Reprod 1:387, 1986.

11.Li T, Warren MA, Murphy C, Sargeant S, Cooke ID, A prospective, randomised, cross-over study comparing the effects of clomiphene citrate and cyclofenil on endometrialmorphology in the luteal phase of normal, fertile women, Br J Obstet Gynaecol 99:1008,1992.

12.Thompson LA, Barratt CLR, Thornton SJ, Bolton AE, Cooke ID, The effects of

clomiphene citrate and cyclofenil on cervical mucus volume and receptivity over the periovulatory period, Fertil Steril 59:125, 1993.

13.Fritz MA, Holmes RT, Keenan EJ, Effect of clomiphene citrate treatment on endometrialestrogen and progesterone receptor induction in women, Am J Obstet Gynecol 165:177,1991.

14.Mikkelson TJ, Kroboth PD, Cameron WJ, Dittert LW, Chungi V, Manberg PJ, Single-dose pharmacokinetics of clomiphene citrate in normal volunteers, Fertil Steril 46:392,1986.

15.Lavy G, Diamond MP, Polan ML, Reversal by human chorionic gonadotropin of theinhibitory effect of clomiphene on progesterone production by granulosa-luteal cells inculture, Int J Fertil 34:359, 1989.

16.Cunha GR, Taguchi O, Namikawa R, Nishizuka Y, Robboy SJ, Teratogenic effects of clomiphene, tamoxifen, and diethylstilbestrol on the developing human female genitaltract, Hum Pathol 18:1132, 1987.

17.Mills JL, Simpson JL, Rhoads GG, Graubard BI, Hoffman H, Conley MR, Lassman M,Cunningham G, Risk of neural tube defects in relation to maternal fertility and fertilitydrug use, Lancet 336:103, 1990.

18.



Shoham Z, Zosmer A, Insler V, Early miscarriage and fetal malformations after inductionof ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, andgamete intrafallopian transfer, FertilSteril 55:1, 1991.

19.Venn A, Lumley J, Clomphene citrate and pregnancy outcome, Aust N Z J ObstetGynaecol 34:56, 1994.

20.Gorlitsky GA, Kase NG, Speroff L, Ovulation and pregnancy rates with clomiphenecitrate, Obstet Gynecol 51:265, 1978.

21.Downs KA, Gibson M, Clomiphene citrate therapy for luteal phase defect, Fertil Steril39:34, 1983.

22.Huang K-E, The primary treatment of luteal phase inadequacy: progesterone versusclomiphene citrate, AmJ Obstet Gynecol 155:824, 1986.

23.Murray DL, Reich L, Adashi EY, Oral clomiphene citrate and vaginal progesteronesuppositories in the treatment of luteal phase dysfunction; a comparative study, FertilSteril 51:35, 1989.

24.Gysler M, March CM, Mishell Jr DR, Bailey EJ, A decade's experience with anindividualized clomiphene treatment regimen including its effect on the postcoital test,Fertil Steril 37:161, 1982.

25.Wu CH, Winkel CA, The effect of therapy initiation day on clomiphene citrate therapy,Fertil Steril 52:564, 1989.

26.Shepard MK, Balmaceda JP, Leija CG, Relationship of weight to successful induction of ovulation with clomiphene citrate, Fertil Steril 32:641, 1979.

27.Lobo RA, Gysler M, March CM, Goebelsmann U, Mishell Jr DR, Clinical and laboratory predictors of clomiphene response, Fertil Steril 37:168, 1982.

28.



Dickey RP, Taylor SN, Curole DN, Rye PH, Lu PY, Pyrzak R, Relationship of clomiphene dose and patient weight to successful treatment, Hum Reprod 12:449, 1997.

29.Hammond MG, Halme JK, Talbert LM, Factors affecting the pregnancy rate in

clomiphene citrate induction of ovulation, Obstet Gynecol 62:196, 1983.

30.Tiitinen AE, Laatikainen TJ, Seppala MT, Serum levels of insulin-like growth factor binding protein-1 and ovulatory responses to clomiphene citrate in women with polycystic ovarian disease, Fertil Steril 60:58, 1993.

31.Lunenfeld B, Pariente C, Dor J, Menashe Y, Seppala M, Mortman H, Insler V, Modernaspects of ovulation induction, Ann N Y Acad Sci 626:207, 1991.

32.Opsahl MS, Robins ED, O'Connor DM, Scott RT, Fritz MA, Characteristics of gonadotropin response, follicular development, and endometrial growth and maturationacross consecutive cycles of clomiphene citrate treatment, Fertil Steril 66:533, 1996.

33.Smith YR, Randolph Jr JF, Christman GM, Ansbacher R, Howe DM, Hurd WW,Comparison of low-technology and high-technology monitoring of clomiphene citrateovulation induction, Fertil Steril 70:165, 1998.

34.Agarwal SK, Buyalos RP, Corpus luteum function and pregnancy rates with clomiphenecitrate therapy: comparison of human chorionic gonadotrophin-induced versusspontaneous ovulation, Hum Reprod 10:328, 1995.

35.Kousta E, White DM, Franks S, Modern use of clomiphene citrate in induction of ovulation, Hum Reprod Update 3:359, 1997.

36.Dickey RP, Taylor SN, Curole DN, Rye PH, Pyrzak R, Incidence of spontaneousabortion in clomiphene pregnancies, Hum Reprod 11:2623, 1996.

37.Greenland S, Ackerman DL, Clomiphene citrate and neural tube defects: a pooledanalysis of controlled epidemiologic studies and recommendations for future studies,Fertil Steril 64:936, 1995.

38.



Purvin VA, Visual disturbance secondary to clomiphene citrate, Arch Ophthalmol113:482, 1995.

39.Imani B, Eijkemans MJC, te Velde ER, Habbema JDF, Fauser BCJM, Predictors of

patients remaining anovulatory during clomiphene citrate induction of ovulation innormogonadotropic oligoamenorrheic infertility, J Clin Endocrinol Metab 83:2361, 1998.

40.Taubert H-D, Dericks-Tan JE, High doses of estrogens do not interfere with theovulation-inducing effect of clomiphene citrate, Fertil Steril 27:375, 1976.

41.Bateman BG, Nunley Jr WC, Kolp LA, Exogenous estrogen therapy for the treatment of clomiphene citrate-induced cervical mucus abnormalities: Is it effective? Fertil Steril54:577, 1990.

42.Pasquali R, Antenucci D, Casimirri F, Venturoli S, Paradisi R, Fabbri R, Balestra V,Melchiondra N, Barbara L, Clinical and hormonal characteristics of obese amenorrheichyperandrogenic women before and after weight loss,J Clin Endocrinol Metab 68:173, 1989.

43.Kiddy DS, Hamilton-Fairley D, Seppälä M, Koistinen R, James VHT, Reed MJ, FranksS, Diet-induced changes in sex hormone binding globulin and free testosterone in womenwith normal or polycystic ovaries: correlation with serum insulin and insulin-like growthfactor-I, Clin Endocrinol 31:757, 1989.

44.Kiddy DS, Hamilton-Fairley D, Bush A, Short F, Anyaoku V, Reed MJ, Franks S,Improvement in endocrine and ovarian function during dietary treatment of obese womenwith polycystic ovary syndrome, Clin Endocrinol 36:105, 1992.

45.Guzick DS, Wing R, Smith D, Berga S, Winters SJ, Endocrine consequences of weightloss in obese, hyperandrogenic anovulatory women, Fertil Steril 61:598, 1994.

46.Andersen P, Selifeflot I, Abdelnoor M, Arnese H, Dale PO, Lovik A, Birkeland K,Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obesewomen with polycystic ovary syndrome, Metabolism 44:611, 1995.

47.



Jakubowicz DJ, Nestler JE, 17a-Hydroxyprogesterone responses to leuprolide and serumandrogens in obese women with and without polycystic ovary syndrome after dietaryweight loss, J Clin Endocrinol Metab 82:556, 1997.

48.

Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, Norman RJ, Weightloss results in significant improvement in pregnancy and ovulation rates in anovulatoryobese women, Hum Reprod 10:2705, 1995.

49.Hollmann M, Runnebaum B, Gerhard I, Effects of weight loss on the hormonal profile inobese, infertile women, Hum Reprod 11:1884, 1996.

50.Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ, Weight loss in obeseinfertile women results in improvement in reproductive outcome for all forms of fertility

treatment, Hum Reprod 13:1502, 1998.

51.Muscelli E, Camastra S, Catalano C, Galvan AQ, Ciociaro D, Baldi S, Ferrannini E,Metabolic and cardiovascular assessment in moderate obesity: effect of weight loss, JClin Endocrinol Metab 82:2937, 1997.

52.Legro RS, Finegood D, Dunaif A, A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome, J Clin Endocrinol Metab83:2694, 1998.

53.Velázquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ, Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance,hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy, Metabolism 43:647, 1994.

54. Nestler JE, Jakubowicz DJ, Decreases in ovarian cytochrome P450c17 alpha activity andserum free testosterone after reduction of insulin secretion in polycystic ovary syndrome, New Engl J Med 335:617, 1996.

55.Velázquez EM, Mendoza SG, Wang P, Glueck CG, Metformin therapy is associated witha decrease in plasma plasminogen activator inhibitor-1, lipoprotein (a), andimmunoreactive insulin levels in patients with the polycystic ovary syndrome,Metabolism 46:454, 1997.

56.



Veláquez E, Acosta A, Mendoza SG, Menstrual cyclicity after metformin therapy in polycystic ovary syndrome, Obstet Gynecol 90:392, 1997.

57.Diamanti-Kandarakis E, Kouli C, Tsianateli T, Bergiele A, Therapeutic effects of

metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome,Eur J Endocrinol 138:269, 1998.

58. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R, Effects of metformin on spontaneousand clomiphene-induced ovulation in the polycystic ovary syndrome, New Engl J Med338:1876, 1998.

59.Crave J-C, Fimbel S, Lejeune H, Cugnardey N, Dechaud H, Pugeat M, Effects of diet andmetformin administration on sex hormone-binding globulin, androgens, and insulin in

hirsute and obese women, J Clin Endocrinol Metab 80:2057, 1995.

60.Ehrmann DA, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky KS, Effectsof metformin on insulin secretion, insulin action, and ovarian steroidogenesis in womenwith polycystic ovary syndrome, J ClinEndocrinol Metab 82:524, 1997.

61.Açbay O, Gündogdu S, Can metformin reduce insulin resistance in polycystic ovarysyndrome? Fertil Steril 65:946, 1996.

62. Nestler JE, Jakubowicz DJ, Lean women with polycystic ovary syndrome respond toinsulin reduction with decreases in ovarian P450c17a activity and serum androgens, JClin Endocrinol Metab 82:4075, 1997.

63.Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R, The insulin-sensitizing agenttroglitazone improves metabolic and reproductive abnormalities in the polycystic ovarysyndrome, J Clin Endocrinol Metab 81:3299, 1996.

64.Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosenfield RL,Polonsky KS, Troglitazone improves defects in insulin action, insulin secretion, ovariansteroidogenesis, and fibrinolysis in women with polycystic ovary syndrome, J ClinEndocrinol Metab 82:2108, 1997.

65.



Lobo RA, Paul W, March CM, Granger L, Kletzky OA, Clomiphene and dexamethasonein women unresponsive to clomiphene alone, Obstet Gynecol 60:497, 1982.

66.Daly DC, Walters CA, Soto-Albers CE, Tohan N, Riddick DH, A randomized study of

dexamethasone in ovulation induction with clomiphene citrate, Fertil Steril 41:844, 1984.

67.Hoffman D, Lobo RA, Serum dehydroepiandrosterone sulfate and the use of clomiphenecitrate in anovulatory women, Fertil Steril 43:196, 1985.

68.Trott EA, Plouffe Jr L, Hansen K, Hines R, Brann DW, Mahesh VB, Ovulation inductionin clomiphene-resistant anovulatory women with normal dehydroepiandrosterone sulfatelevels: beneficial effects of the addition of dexamethasone during the follicular phase,Fertil Steril 66:484, 1996.

69.Lobo RA, Granger LR, Davajan V, Mishell Jr DR, An extended regimen of clomiphenecitrate in women unresponsive to standard therapy, Fertil Steril 37:762, 1982.

70.O'Herlihy C, Pepperell RJ, Brown JB, Smith MA, Sandri L, McBain JC, Incrementalclomiphene therapy: a new method for treating persistent anovulation, Obstet Gynecol58:535, 1981.

71.Fluker MR, Wang IY, Rowe TC, An extended 10-day course of clomiphene citrate (CC)in women with CC-resistant ovulatory disorders, Fertil Steril 66:761, 1996.

72.Genazzani AD, Petraglia F, Battaglia C, Gamba O, Volpe A, Genazzani AR, A long-termtreatment with gonadotropin-releasing hormone agonist plus a low-dose oralcontraceptive improves the recovery of the ovulatory function in patients with polycysticovary syndrome, Fertil Steril 67:463, 1997.

73.Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS, Influence of serum luteinisinghormone concentrations on ovulation, conception, and early pregnancy loss in polycysticovary syndrome, Br Med J 297:1024, 1988.

74.Regan L, Owen EJ, Jacobs HS, Hypersecretion of luteinising hormone, infertility, andmiscarriage, Lancet 336:1141, 1990.

75.



Watson H, Kiddy DS, Hamilton-Fairley D, Scanlon MJ, Barnard C, Collins WP, BonneyRC, Franks S, Hypersecretion of luteinizing hormone and ovarian steroids in women withrecurrent early miscarriage, HumReprod 8:829, 1993.

76.Clifford K, Rai R, Watson H, Franks S, Regan L, Does suppressing luteinising hormonesecretion reduce the miscarriage rate? Br Med J 312:1508, 1996.

77.Padilla SL, Person GK, McDonough PG, Reindollar RH, The efficacy of bromocriptinein patients with ovulatory dysfunction and normoprolactinemic galactorrhea, Fertil Steril44:695, 1985.

78.Falaschi P, Rocco A, del Pozo E, Inhibitory effect of bromocriptine treatment on

luteinizing hormone secretion in polycystic ovary syndrome, J Clin Endocrinol Metab62:348, 1986.

79.Soto-Albers CE, Daly DC, Walters CA, Ying YK, Riddick DH, Titrating the dose of bromocriptine when treating hyperprolactinemic women, Fertil Steril 43:485, 1985.

80.Rains CP, Bryson HM, Fitton A, Cabergoline. A review of its pharmacological propertiesand therapeutic potential in the treatment of hyperprolactinemia and inhibition of lactation, Drugs 49:255, 1995.

81.Colao A, Di Sarno A, Sarnacchiaro F, Ferone D, Di Renzo G, Merola B, Annunziato L,Lombardi G, Prolactinomas resistant to standard dopamine agonists respond to chroniccabergoline treatment, J Clin Endocrinol Metab 82:876, 1997.

82.Ciccarelli E, Giusti M, Miola C, Potenzoni F, Sghedoni D, Camanni F, Giordano G,Effectiveness and tolerability of long term treatment with cabergoline, a new long-lastingergoline derivative, in hyperprolactinemic patients, J Clin Endocrinol Metab 69:725,1989.

83.Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Scanlon MF, for the CabergolineComparative Study Group, A comparison of cabergoline and bromocriptine in thetreatment of hyperprolactinemic amenorrhea, New Engl J Med 331:904, 1994.

84.



Biller BMK, Molitch ME, Vance ML, Cannistraro KB, Davis KR, Simons JA,Schoenfelder JR, Klibanski A, Treatment of prolactin-secreting macroadenomas with theonce-weekly dopamine agonist cabergoline, J Clin Endocrinol Metab 81:2338, 1996.

85.

Colao A, Di Sarno A, Landi ML, Cirillo S, Sarnacchiaro F, Gacciolli G, Pivonello R,Cataldi M, Merola B, Annuziato L, Lombardi G, Long-term and low-dose treatment withcabergoline induces macroprolactinoma shrinkage, J Clin Endocrinol Metab 82:3574,1997.

86.Robert E, Musatti L, Piscitelli G, Ferrari CI, Pregnancy outcome after treatment with theergot drivative, cabergoline, Reprod Toxicol 10:333, 1996.

87.Motta T, deVincentiis S, Marchinin M, Colombo N, D'Alberton A, Vaginal cabergoline

in the treatment of hyperprolactinemic patients intolerant to oral dopaminergics, FertilSteril 65:440, 1996.

88.Porcile A, Gallardo E, Venegas E, Normoprolactinemic anovulation nonresponsive toclomiphene citrate: ovulation induction with bromocriptine, Fertil Steril 53:50, 1990.

89.Suginami H, Hamada K, Yano K, Kuroda G, Matsuura S, Ovulation induction with bromocriptine in normoprolactinemic anovulatory women, J Clin Endocrinol Metab62:899, 1986.

90.Weight CS, Steele SJ, Jacobs HS, Value of bromocriptine in unexplained primaryinfertility: a double-blind controlled trial, Br Med J i:1037, 1979.

91.DeVane GW, Guzick DS, Bromocriptine therapy in normoprolactinemic women withunexplained infertility and galactorrhea, Fertil Steril 46:1026, 1986.

92.Germond M, Dessole S, Senn A, Loumaye E, Howles C, Beltrami V, Successful in-vitrofertilisation and embryo transfer after treatment with recombinant FSH, Lancet 339:1170,1992.

93.Farine D, Dor J, Lupovici N, Lunenfeld B, Mashiach S, Conception rate after gonadotropin therapy in hyperprolactinemia and normoprolactinemia, Obstet Gynecol65:658, 1985.



94.Out HJ, Driessen SGAJ, Mannaerts BMJL, Coelingh Bennink HJT, Recombinantfollicle-stimulating hormone (follitropin beta, Puregon®) yields higher pregnancy rates inin vitro fertilization than urinary gonadotropins, Fertil Steril 68:138, 1997.

95. Noci I, Biagiotti R, Maggi M, Ricci F, Cinotti A, Scarselli G, Low day 3 luteinizinghormone values are predictive of reduced response to ovarian stimulation, Hum Reprod13:531, 1998.

96.van der Meer M, Hompes PGA, de Boer JAM, Schats R, Schoemaker J, Cohort sizerather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome, J Clin Endocrinol Metab 83:423, 1998.

97.

Homburg R, Levy T, Ben-Rafael Z, A comparative prospective study of conventionalregimen with chronic low-dose administration of follicle-stimulating hormone for anovulation associated with polycystic ovary syndrome, Fertil Steril 63:729, 1995.

98.White DM, Polson DW, Kiddy D, Sagle P, Watson H, Gilling-Smith C, Hamilton-FairleyD, Franks S, Induction of ovulation with low-dose gonadotropins in polycystic ovarysyndrome: an analysis of 109 pregnancies in 225 women, J Clin Endocrinol Metab81:3821, 1996.

99.Dale PO, Tanbo T, Haug E, Åbyholm T, The impact of insulin resistance on the outcomeof ovulation induction with low-dose follicle stimulating hormone in women with polycystic ovary syndrome, Hum Reprod 13:567, 1998.

100.Gindoff PR, Jewelewicz R, Use of gonadotropins in ovulation induction, N Y State JMed 85:580, 1985.

101.Chong AP, Rafael RW, Forte CC, Influence of weight in the induction of ovulation withhuman menopausal gonadotropin and human chorionic gonadotropin, Fertil Steril 46:599,1986.

102.Diamond MP, DeCherney AH, Baretto P, Lunenfeld B, Multiple consecutive cycles of ovulation inductions with human menopausal gonadotropins, Gynecol Endocrinol 3:237,1989.

103.



Silverberg KM, Klein NA, Burns WN, Schenken RS, Olive DL, Consecutive versusalternating cycles of ovarian stimulation using human menopausal gonadotrophins, HumReprod 7:940, 1992.

104.

Haning Jr RV, Levin RM, Behrman HR, Kase NG, Speroff L, Plasma estradiol windowand urinary estriol glucuronide determination for monitoring menotropin induction of ovulation, Obstet Gynecol 54:442, 1979.

105.Haning Jr RV, Boehnlein LM, Carlson IH, Kuzma DL, Zweibel WJ, Diagnosis-specificserum 17b-estradiol (E2) upper limits for treatment with menotropins using a 125I directE2 assay, Fertil Steril 42:882, 1984.

106.Wilson EA, Jawad MJ, Hayden TL, Rates of exponential increase of serum estradiol

concentrations in normal and human menopausal gonadotropin-induced cycles, FertilSteril 37:46, 1982.

107.Ritchie WGM, Ultrasound in the evaluation of normal and induced ovulation, Fertil Steril43:167, 1985.

108.Leerentueld R, Van Gent I, Der Stoep M, Wladimiroff J, Ultrasonographic assessment of Graffian follicle growth under monofollicular and multifollicular conditions inclomiphene citrate stimulated cycles, Fertil Steril 43:565, 1985.

109.March CM, Improved pregnancy rate with monitoring of gonadotropin therapy by threemodalities, Am J Obstet Gynecol 156:1473, 1987.

110.Tal J, Paz B, Samberg I, Lazarov N, Sharf M, Ultrasonographic and clinical correlates of menotropin versus sequential clomiphene citrate: menotropin therapy for induction of ovulation, Fertil Steril 44:342, 1985.

111.Blankstein J, Shalev J, Sasdon T, Kukia EE, Rabinovici J, Pariente C, Lunenfeld B, Serr DM, Mashiach S, Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory follicles, Fertil Steril 47:597, 1987.

112.Ueno J, Oehninger S, Brzyski RG, Acosta AA, Philput B, Muasher SJ, Ultrasonographicappearance of the endometrium in natural and stimulated in-vitro fertilization cycles andits correlation with outcome, Hum Reprod 6:901, 1991.



113.Shoham Z, Di Carlo C, Patel A, Conway GS, Jacobs HS, Is it possible to run a sucessfulovulation induction program based solely on ultrasound monitoring? The importance of endometrial measurements, Fertil Steril 56:836, 1991.

114.Dickey RP, Olar TT, Taylor SN, Curole DN, Matulich EM, Relationship of endometrialthickness and pattern to fecundity in ovulation induction cycles: effect of clomiphenecitrate alone and with human menopausal gonadotropin, Fertil Steril 59:756, 1993.

115.Shapiro H, Cowell C, Casper RF, The use of vaginal ultrasound for monitoringendometrial preparation in a donor oocyte program, Fertil Steril 59:1055, 1993.

116.

Isaacs Jr JD, Wells CS, Williams DB, Odem RR, Gast MJ, Strickler RC, Endometrialthickness is a valid monitoring parameter in cycles of ovulation induction withmenotropins alone, Fertil Steril 65:262, 1996.

117.Akin JW, Shepard MK, The effects of baseline ovarian cysts on cycle fecundity incontrolled ovarian hyperstimulation, Fertil Steril 59:453, 1993.

118.March CM, Tredway DR, Mishell Jr DR, Effect of clomiphene citrate upon amount andduration of human menopausal gonadotropin therapy, Am J Obstet Gynecol 125:699,1976.

119.Ho Yuen B, Pride SM, Burch-Callegari P, Leroux AM, Moon YS, Clinical and endocrineresponse to pulsatile intravenous gonadotropins in refractory anovulation, Obstet Gynecol74:763, 1989.

120. Nakamura Y, Yoshimura Y, Yamada H, Ubukata Y, Yoshida K, Tamaoka Y, Suzuki M,Clinical experience in the induction of ovulation and pregnancy with pulsatilesubcutaneous administration of human menopausal gonadotropin: a low incidence of multiple pregnancy, Fertil Steril 51:423, 1989.

121.Ho Yuen B, Pride S, Induction of ovulation with exogenous gonadotropins in anovulatoryinfertile women, Seminars Reprod Endocrinol 8:1861, 1990.

122.



Fluker MR, Urman B, MacKinnon M, Barrow SR, Pride SM, Ho Yuen B, Exogenousgonadotropin therapy in World Health Organization Groups I and II ovulatory disorders,Obstet Gynecol 83:189, 1994.

123.

Balen AH, Braat DDM, West C, Patel A, Jacobs HS, Cumulative conception and live birth rates after the treatment of anovulatory infertility: safety and efficacy of ovulationinduction in 200 patients, Hum Reprod 9:1563, 1994.

124.Fernandez H, Coste J, Job-Spira N, Controlled ovarian hyperstimulation as a risk factor for ectopic pregnancy, Obstet Gynecol 78:656, 1991.

125.Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S, Association of moderateobesity with a poor pregnancy outcome in women with polycystic ovary syndrome

treated with low dose gonadotropin, Br J Obstet Gynaecol 99:128, 1992.

126.Keenan JA, Moghissi KS, Luteal phase support with hCG does not improve fecundityrate in human menopausal gonadotropin-stimulated cycles, Obstet Gynecol 79:983, 1992.

127.Kurinczuk JJ, Pemberton RJ, Binns SC, Parsons DE, Stanley FJ, Singleton and twinconfinements associated with infertility treatments, Aust N Z J Obstet Gynaecol 35:27,1995.

128.Ho ML, Chen JY, Ling UP, Chen JH, Huang CM, Chang CC, Su PH, Changingepidemiology of triplet pregnancy: etiology and outcome over twelve years, Am JPerinatol 13:269, 1996.

129.Corchia C, Mastroiacovo P, Lanni R, Mannazzu R, Curro V, Fabris C, What proportionof multiple births are due to ovulation induction? A register-based study in Italy, Am JPublic Health 86:851, 1996.

130.Derom C, Derom R, Vlietink R, Van Den Berghe H, Thiery M, Increased monozygotictwinning rate after ovulation induction, Lancet i:1236, 1987.

131.Bohrer M, Kemmann E, Risk factors for spontaneous abortion in menotropin-treatedwomen, Fertil Steril 48:571, 1987.

132.



Ben-Rafael Z, Mashiach S, Oelsner G, Farine D, Lunenfeld B, Serr DM, Spontaneous pregnancy and its outcome after human menopausal gonadotropin/human chorionicgonadotropin-induced pregnancy, Fertil Steril 36:560, 1981.

133.

Aboulghar MA, Mansour RT, Serour GI, Rizk P, Riad R, Improvement of spontaneous pregnancy rate after stopping gonadotropin therapy for anovulatory infertility, FertilSteril 55:722, 1991.

134.Evans MI, Dommergues M, Timor-Tritsch I, Zador IE, Wapner RJ, Lynch L, Dumez Y,Goldberg JD, Nicolaides KH, Johnson MP, Golbus MS, Boulot P, Aknin AJ,Monteagudo A, Berkowitz RL, Transabdominal versus transcervical and transvaginalmultifetal pregnancy reduction: international collaborative experience of more than onethousand cases, Am J Obstet Gynecol 170:902, 1994.

135.Kol S, Levron J, Lewit N, Drugan A, Itskovitz-Eldor J, The natural history of multiple pregnancies after assisted reproduction: is spontaneous fetal demise a clinicallysignificant phenomenon? Fertil Steril 60:127, 1993.

136.Engel T, Jewelewicz R, Dyrenfurth I, Speroff L, Vande Wiele RL, Ovarianhyperstimulation syndrome: report of a case with notes on pathogenesis and treatment,Am J Obstet Gynecol 112:1052, 1972.

137. Navot D, Bergh PA, Laufer N, Ovarian hyperstimulation syndrome in novel reproductivetechnologies: prevention and treatment, Fertil Steril 58:249, 1992.

138.Schenker JG, Prevention and treatment of ovarian hyperstimulation, Hum Reprod 8:653,1993.

139.Mashiach S, Bider D, Moran O, Goldenberg M, Ben-Rafael Z, Adnexal torsion of hyperstimulated ovaries in pregnancies after gonadotropin therapy, Fertil Steril 53:76,1990.

140.Rizk B, Smitz J, Ovarian hyperstimulation syndrome after superovulation using GnRHagonists for IVF and related procedures, Hum Reprod 7:320, 1992.

141.



Morris RS, Paulson RJ, Sauer MV, Lobo RA, Predictive value of serum oestradiolconcentrations and oocyte number in severe ovarian hyperstimulation syndrome, HumReprod 10:811, 1995.

142.

Neulen J, Yan Z, Raczek S, Weindel K, Keck C, Weich Ha, Marme D, Breckwoldt M,Human chorionic gonadotropin-dependent expression of vascular endothelial growthfactor/vascular permeability factor in human granulosa cells: importance in ovarianhyperstimulation syndrome, J Clin Endocrinol Metab 80:1967, 1995.

143.Abramov Y, Barak V, Nisman B, Schenker JG, Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulationsyndrome, Fertil Steril 67:261, 1997.

144.

Lee A, Christenson LK, Stouffer RL, Burry KA, Patton PE, Vascular endothelial growthfactor levels in serum and follicular fluid of patients undergoing in vitro fertilization,Fertil Steril 68:305, 1997.

145.Revel A, Barak V, Lavy Y, Anteby E, Abramov Y, Schenker JJ, Amit A, Finci-YeheskelZ, Mayer M, Simon A, Laufer N, Hurwitz A, Characterization of intraperitonealcytokines and nitrites in women with severe ovarian hyperstimulation syndrome, FertilSteril 66:66, 1996.

146.Abramov Y, Schenker JG, Lewin A, Friedler S, Nisman B, Barak V, Plasmainflammatory cytokines correlate to the ovarian hyperstimulation syndrome, Hum Reprod11:1381, 1996.

147.Delbaere A, Bergmann PJM, Gervy-Decoster C, Deschodt-Lanckman M, de Maertelaer V, Staroukine M, Camus M, Englert Y, Increased angiotensin II in ascites during severeovarian hyperstimulation syndrome: role of early pregnancy and ovarian gonadotropinstimulation, Fertil Steril 67:1038, 1997.

148.Haning Jr RV, Strawn EY, Nolten WE, Pathophysiology of the ovarian hyperstimulationsyndrome, Obstet Gynecol 66:220, 1985.

149.Rizk B, Aboulghar M, Modern management of ovarian hyperstimulation syndrome, HumReprod 6:1082, 1991.

150.



Rizk B, Meagher S, Fisher AM, Severe ovarian hyperstimulation syndrome andcerebrovascular accidents, Hum Reprod 5:697, 1990.

151.Fournet N, Surrey E, Kerin J, Internal jugular vein thrombosis after ovulation induction

with gonadotropins,Fertil Steril 56:354, 1991.

152.Stewart JA, Hamilton PJ, Murdoch AP, Thromboembolic disease associated with ovarianstimulation and assisted conception techniques, Hum Reprod 12:2167, 1997.

153.Zosmer A, Katz Z, Lancet M, Konichezky S, Schwartz-Shoham Z, Adult respiratorydistress syndrome complicating ovarian hyperstimulation syndrome, Fertil Steril 47:524,1987.

154.Kirshon B, Doody MC, Cotton DB, Gibbons W, Management of ovarianhyperstimulation syndrome with chlorpheniramine maleate, mannitol, and invasivehemodynamic monitoring, Obstet Gynecol 71:485, 1988.

155.Padilla SA, Zamaria S, Baramki TA, Garcia JE, Abdominal paracentesis for the ovarianhyperstimulation syndrome with severe pulmonary compromise, Fertil Steril 53:365,1990.

156.Aboulghar MA, Mansour RT, Serour GI, Sattar MA, Amin YM, Elattar I, Managementof severe ovarian hyperstimulation syndrome by ascitic fluid aspiration and intensiveintravenous fluid therapy, Obstet Gynecol 81:108, 1993.

157.Fakih H, Bello S, Ovarian cyst aspiration: a therapeutic approach to ovarianhyperstimulation syndrome, Fertil Steril 58:829, 1992.

158.Cameron IT, O'Shea FC, Rolland JM, Hughes EG, de Kretser DM, Healy DL, Occultovarian failure: a syndrome of infertility, regular menses, and elevated follicle-stimulating hormone concentrations, J Clin Endocrinol Metab 67:1190, 1986.

159.Buckler HM, Evans A, Mamlora H, Burger HG, Anderson DC, Gonadotropin, steroidand inhibin levels in women with incipient ovarian failure during anovulatory andovulatory ‘rebound' cycles, J Clin Endocrinol Metab 72:116, 1991.



160.Lenton EA, de Kretser DM, Woodward AJ, Robertson DM, Inhibin concentrationsthroughout the menstrual cycles of normal, infertile, and older women compared withthose during spontaneous conception cycles, J Clin Endocrinol Metab 73:1180, 1991.

161.McNaughton J, Banah M, McCloud P, Hee J, Burger H, Age related changes in folliclestimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin inwomen of reproductive age, Clin Endocrinol 36:339, 1992.

162.Pellicer A, Marí M, de los Santos MJ, Simón C, Remohí J, Tarín JJ, Effects of aging onthe human ovary: the secretion of immunoreactive a-inhibin and progesterone, FertilSteril 61:663, 1994.

163.

Burger HG, Cahir N, Robertson DM, Groome NP, Dudley E, Green A, Dennerstein L,Serum inhibins A and B fall differentially as FSH rises in perimenopausal women, ClinEndocrinol 48:809, 1998.

164.Klein NA, Illingworth PJ, Groome NP, McNeilly AS, Battaglia DE, Soules MR,Decreased inhibin B secretion is associated with the monotropic FSH rise in older,ovulatory women: a study of serum and follicular fluid leavels of dimeric inhibin A andB in spontaneous menstrual cycles, J Clin Endocrinol Metab 81:2742, 1996.

165.Hofmann GE, Danforth DR, Seifer DB, Inhibin-B: the physiologic basis of theclomiphene citrate challenge test for ovarian reserve screening, Fertil Steril 69:474, 1998.

166.Danforth DR, Arbogast LK, Mroueh J, Kim MH, Kennard EA, seifer DB, Friedman CI,Dimeric inhibin: a direct marker of ovarian aging, Fertil Steril 70:119, 1998.

167.Klein NA, Battaglia DE, Miller PB, Branigan EF, Giudice LC, Soules MR, Ovarianfollicular development and the follicular fluid hormones and growth factors in normalwomen of advanced reproductive age, J Clin Endocrinol Metab 81:1946, 1996.

168.Lass A, Silye R, Abrams D-C, Krausz T, Hovatta O, Margara R, Winston RML,Follicular density in ovarian biopsy of infertile women: a novel method to assess ovarianreserve, Hum Reprod 12:1028, 1997.

169.



Lass A, Skull J, McVeigh E, Margara R, Winston RM, Measurement of ovarian volume by transvaginal sonography before human menopausal gonadotrophin superovulation for in-vitro fertlization can predict poor response, Hum Reprod 12:294, 1997.

170.

Toner JP, Philput CB, Jones GS, Muasher SJ, Basal follicle-stimulating hormone level isa better predictor of in vitro fertilization performance than age, Fertil Steril 55:784, 1991.

171.Pearlstone AC, Fournet N, Gambone JC, Pang SC, Buyalos RP, Ovulation induction inwomen age 40 and older: the importance of basal follicle-stimulating hormone level andchronological age, Fertil Steril 58:674, 1992.

172.Scott Jr RT, Hofmann GE, Prognostic assessment of ovarian reserve, Fertil Steril 63:1,1995.

173.Smotrich DB, Widra EA, Gindoff PR, Levy MJ, Hall JL, Stillman RJ, Prognostic valueof day 3 estradiol on in vitro fertilization outcome, Fertil Steril 64:1136, 1995.

174.Buyalos RP, Daneshmand S, Brzechffa PR, Basal estradiol and follicle-stimulatinghormone predict fecundity in women of advanced reproductive age undergoing ovulationinduction therapy, Fertil Steril 68:272, 1997.

175. Navot D, Rosenwaks Z, Margalioth EJ, Prognostic assessment of female fecundity,Lancet ii:645, 1987.

176.Tanbo T, Dale PO, Lunde O, Norman N, Abyholm T, Prediction of response tocontrolled ovarian hyperstimulation: a comparison of basal and clomiphene citrate-stimulated follicle-stimulating hormone levels, Fertil Steril 57:819, 1992.

177.Scott Jr RT, Leonardi MR, Hofmann GE, Illions EH, Neal GS, Navot D, A prospectiveevaluation of clomiphene citrate challenge test screening of the general infertility population, Obstet Gynecol 82:539, 1993.

178.Scott Jr RT, Opsahl MS, Leonardi MR, Neal GS, Illions EH, Navot D, Life table analysisof pregnancy rates in a general infertility population relative to ovarian reserve and patient age, Hum Reprod 10:1706, 1995.

179.



Farhi J, Homburg R, Ferber A, Orvieto R, Ben Rafael Z, Non-response to ovarianstimulation in normogonadotrophic, normogonadal women: a clinical sign of impendingonset of ovarian failure pre-empting the rise in basal follicle stimulating hormone levels,Hum Reprod 12:241, 1997.

180.Dodson WC, Gonadotropin releasing analogues as adjunctive therapy in ovulationinduction, Seminars Reprod Endocrinol 8:198, 1990.

181.Dodson WC, Hughes CL, Whitesides DB, Haney AF, The effect of leuprolide acetate onovulation induction with human menopausal gonadotropins in polycystic ovarysyndrome, J Clin Endocrinol Metab 65:95, 1987.

182.Homburg R, Levy T, Berkovitz D, Farchi J, Feldberg D, Ashkenazi J, Ben-Rafael Z,

Gonadotropin-releasing hormone agonist reduces the miscarriage rate for pregnanciesachieved in women with polycystic ovarian syndrome, Fertil Steril 59:527, 1993.

183.Mizunuma H, Andoh K, Yamada K, Takagi T, Kamijo T, Ibuki Y, Prediction and prevention of ovarian hyperstimulation by monitoring endogenous luteinizing hormonerelease during purified follicle-stimulating hormone therapy, Fertil Steril 58:46, 1992.

184.Devroey P, Mannaerts B, Smitz J, Coelingh Bennink H, Van Steirteghem A, Clinicaloutcome of a pilot efficacy study on recombinant human follicle-stimulating hormone(Org 32489) combined with various gonadotrophin-releasing hormone agonist regimens,Hum Reprod 9:1064, 1994.

185.Smitz J, Devroey P, Camus M, Deschacht J, Khan I, Staessen C, Van Waesherghe L,Wisanto A, Van Steirteghem AC, The luteal phase and early pregnancy after combinedGnRH-agonist/hMG treatment for superovulation in IVF and GIFT, Hum Reprod 3:585,1988.

186.McClure N, Leya J, Radwanska E, Rawlins R, Haning Jr RV, Luteal phase support andsevere ovarian hyperstimulation syndrome, Hum Reprod 7:758, 1992.

187.Albano C, J, Camus M, Riethmüller-Winzen H, Siebert-Weigel M, Diedrich K, VanSteirteghem AC, Devroey P, Comparison of different doses of gonadotropin-releasinghormone antagonist Cetrorelix during controlled ovarian hyperstimulation, Fertil Steril67:917, 1997.



188.Ibrahim ZHZ, Lieberman BA, Matson PL, Buck P, The use of biosynthetic growthhormone to augment ovulation induction with buserelin acetate/human menopausalgonadotrophin in women with a poor ovarian response,Fertil Steril 55:202, 1991.

189.Owen EJ, Shoham Z, Mason BA, Ostergaard H, Jacobs HS, Cotreatment with growthhormone, after pituitary suppression, for ovarian stimulation in in vitro fertilization: arandomized, double-blind, placebo-control trial, Fertil Steril 56:1104, 1991.

190.Hughes SM, Huang ZH, Matson PL, Buck P, Lieberman BA, Morris ID, Clinical andendocrinological changes in women following ovulation induction using buserelinacetate/human menopausal gonadotrophin augmented with biosynthetic human growthhormone, Hum Reprod 7:770, 1992.

191.Levy T, Limor R, Villa Y, Eshel A, Eckstein N, Vagman I, Lidor A, Ayalon D, Another look at co-treatment with growth hormone and human menopausal gonadotrophins in poor ovarian responders, Hum Reprod 8:834, 1993.

192.Tulandi T, Galcone T, Guyda H, Hemmings R, Billiar R, Morris D, Effects of syntheticgrowth hormone-releasing factor in women treated with gonadotrophin, Hum Reprod8:525, 1993.

193.Hugues JN, Torresani T, Herve F, Martin-Point B, Tamboise A, Sanarelli J, Interest of growth hormone-releasing hormone administration for improvement of ovarianrepsonsiveness to gonadotropins in poor responder women, Fertil Steril 55:945, 1991.

194.Volve A, Coukos G, Barreca A, Giordano G, Artini PG, Genazzani AR, Clinical use of growth hormone-releasing factor for induction of superovulation, Hum Reprod 6:1228,1991.

195.Bunger CW, Korsen TJM, Hompes PGA, Vankessel H, Schoemaker J, Ovulationinduction with pulsatile LHRH in women with clomiphene resistant polycystic ovary-likedisease: clinical results, Fertil Steril 46:1045, 1986.

196.Filicori M, Flamigni C, Meriggiola MC, Ferrari P, Michelacci L, Campaniello E,Valdiserri A, Cognigni G, Endocrine response determines the clinical outcome of



pulsatile gonadotropin-releasing hormone ovulation induction in different ovulatorydisorders, J Clin Endocrinol Metab 72:965, 1991.

197.Carr JS, Reid RL, Ovulation induction with gonadotropin-releasing hormone (GnRH),

Seminars Reprod Endocrinol 8:174, 1990.

198.Filicori M, Flamigni C, Dellai P, Cognigni G, Michelacci L, Arnone R, Sambataro M,Falbo A, Treatment of anovulation with pulsatile gonadotropin-releasing hormone: prognostic factors and clinical results in 600 cycles,J Clin Endocrinol Metab 79:1215, 1994.

199.Braat DD, Schoemaker R, Schoemaker J, Life table analysis of fecundity of intravenously gonadotropin-releasing hormone-treated patients with normogonadotropic

and hypogonadotropic amenorrhea, Fertil Steril 55:266, 1991.

200.Filicori M, Flamigni C, Campaniello E, Meriggiola MC, Michelacci L, Valdiserri A,Ferrari P, Polycystic ovary syndrome: abnormalities and management with pulsatilegonadotropin-releasing hormone and gonadotropin-releasing hormone analogs, Am JObstet Gynecol 163:1737, 1990.

201.Stein IF, Leventhal ML, Amenorrhea associated with bilateral polycystic ovaries, Am JObstet Gynecol 29:181, 1935.

202.Judd HL, Rigg LA, Anderson DC, Yen SSC, The effect of ovarian wedge resection oncirculating gonadotropin and ovarian steroid levels in patients with polycystic ovarysyndrome, J Clin Endocrinol Metab 43:347, 1976.

203.Katz M, Carr PJ, Cohen BM, Milhin RP, Hormonal effects of wedge resection of polycystic ovaries, Obstet Gynecol 51:437, 1978.

204.Kaaijk EM, Beek JF, Hamerlynck JVTH, van der Veen F, Unilateral oophorectomy in polycystic ovary syndrome: a treatment option in highly selected cases? Hum Reprod12:2370, 1997.

205.Kovacs G, Buckler H, Gangah M, Burger H, Healy D, Baker G, Phillips S, Treatment of anovulation due to polycystic ovarian syndrome by laparoscopic ovarian electrocautery,Br J Obstet Gynaecol 98:30, 1991.



206.Daniell JF, Miller W, Polycystic ovaries treated by laparoscopic laser vaporization, FertilSteril 51:232, 1989.

207.Gadir A, Mowafi RS, Alnaser HMI, Alrashid AH, Alonezi OM, Shaw RW, Ovarianelectrocautery versus human menopausal gonadotrophins and pure follicle stimulatinghormone therapy in the treatment of patients with polycystic ovarian disease, ClinEndocrinol 33:585, 1990.

208. Naether OGJ, Fischer R, Weise HC, Geiger-Kotzler L, Delfs T, Rudolf K, Laparoscopicelectrocoagulation of the ovarian surface in infertile patients and polycystic ovariandisease, Fertil Steril 60:88, 1993.

209.Armar NA, Lachelin GCL, Laparoscopic ovarian diathermy: an effective treatment for anti-oestrogen resistant anovulatory infertility in women with polycystic ovariansyndrome, Br J Obstet Gynaecol 100:161, 1993.

210.Campo S, Ovulatory cycles, pregnancy outcome and complications after surgicaltreatment of polycystic ovary syndrome, Obstet Gynecol Survey 53:297, 1998.

211. Naether OGJ, Fischer R, Adhesion formation after laparoscopic electrocoagulation of theovarian surface in polycystic ovary patients, Fertil Steril 60:95, 1993.

212.Crosignani PG, Walters DS, Soliani A, Addendum to the ESHRE multicentre trial: asummary of the abortion and birth statistics, Hum Reprod 7:286, 1992.

213.Tummon IS, Macklin VM, Radwanska E, Binor Z, Dimowski WP, Occult ovulatorydysfunction in women with minimal endometriosis or unexplained infertility, Fertil Steril50:716, 1988.

214.Leach RE, Moghissi KS, Randolph JF, Reame NE, Blacker CM, Ginsburg KA, DiamondMP, Intensive hormone monitoring in women with unexplained infertility: evidence for subtle abnormalities suggestive of diminished ovarian reserve, Fertil Steril 68:413, 1997.

215.Simon A, Laufer N, Unexplained infertility: a reappraisal, Assist Reprod Rev 3:26, 1993.



216.Glazener CMA, Coulson C, Lambert PA, Watt EM, Hinton RA, Kelly NG, Hull MGR,Clomiphene treatment for women with unexplained infertility: placebo-controlled studyof hormonal responses and conception rates,

Gynecol Endocrinol 4:75, 1990.

217.Deaton JL, Gibson N, Blackmer KM, Nakajima ST, Badger GJ, Brumsted JR, Arandomized, controlled trial of clomiphene citrate and intrauterine insemination incouples with unexplained infertility, Fertil Steril 54:1083, 1990.

218.Karlstrom P-O, Bergh T, Lundkvist O, A prospective randomized trial of artificialinsemination versus intercourse in cycles stimulated with human menopausalgonadotropin or clomiphene citrate, Fertil Steril 59:554, 1993.

219.Martinez AR, Bernardos RE, Voorhorst FJ, Vermeiden JPW, Schoemaker J, Intrauterineinsemination does and clomiphene citrate does not improve fecundity in couples withinfertility due to male or idiopathic factors: a prospective, randomized, controlled study,Fertil Steril 53:847, 1990.

220.Fujii S, Fukui A, Fukushi Y, Kagiya A, Sato S, Saito Y, The effects of clomiphene citrateon normal ovulatory women, Fertil Steril 68:997, 1997.

221.Agarwal SK, Buyalos RP, Clomiphene citrate with intrauterine insemination: is iteffective therapy in women above the age of 35 years? Fertil Steril 65:759, 1996.

222.Serhal PF, Katz M, Little V, Woronowski H, Unexplained infertility — the value of pergonal superovulation combined with intrauterine insemination, Fertil Steril 49:602,1988.

223.Chaffkin LM, Nulsen JC, Luciano AA, Metzger DA, A comparative analysis of the cyclefecundity rates associated with combined human menopausal gonadotropin (hMG) andintrauterine insemination (IUI) versus either hMG or IUI alone, Fertil Steril 55:252,1991.

224. Nulsen JC, Walsh S, Dumez S, Metzger DA, A randomized and longitudinal study of human menopausal gonadotropin with intrauterine insemination in the treatment of infertility, Obstet Gynecol 82:780, 1993.



225.Kemmann E, Bohrer M, Shelden R, Fiasconaro G, Beardsley L, Active ovulationmanagement increases the monthly probability of pregnancy occurrence in ovulatorywomen who receive intrauterine insemination, Fertil Steril 48:916, 1987.

226.Zeyneloglu HB, Arici A, Olive DL, Duleba AJ, Comparison of intrauterine inseminationwith timed intercourse in superovulated cycles with gonadotropins: a meta-analysis,Fertil Steril 69:486, 1998.

227.Dodson WC, Whitesides DB, Hughes Jr CL, Easley III HA, Haney AF, Superovulationwith intrauterine insemination in the treatment of infertility: a possible alternative togamete intrafallopian transfer and in vitro fertilization, Fertil Steril 48:441, 1987.

228.Dodson WL, Haney AF, Controlled ovarian hyperstimulation and intrauterineinsemination for treatment of infertility, Fertil Steril 55:457, 1991.

229.DiMarzo SJ, Kennedy JF, Young PE, Hebert SA, Rosenberg DC, Villanueva B, Effectsof controlled ovarian hyperstimulation on pregnancy rates after intrauterine insemination,Am J Obstet Gynecol 166:1607, 1992.

230.Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, Steinkampf MP, Efficacy of treatment of unexplained infertility, Fertil Steril 70:207, 1998.

231.Hughes EG, The effectiveness of ovulation induction and intrauterine insemination in thetreatment of persistent infertility: a meta-analysis, Hum Reprod 12:1865, 1997.

232.Corsan G, Trias A, Trout S, Kemmann E, Ovulation induction combined with intrauterineinsemination in women 40 years of age and older: is it worthwhile? Hum Reprod11:1109, 1996.

233.Whittemore AS, Harris R, Itnyre J, and the Collaborative Ovarian Cancer Group,Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II: Invasive epithelial ovarian cancers in white women, Am J Epidemiol136:1184, 1992.

234.



Rossing MA, Daling JR, Weiss NS, Moore DE, Self SG, Ovarian tumors in a cohort of infertile women, New EnglJ Med 331:771, 1994.

235.

Ron E, Lunenfeld B, Menczer J, Blumstein T, Katz L, Oelsner G, Serr D, Cancer incidence in a cohort of infertile women, Am J Epidemiol 125:780, 1987.

236.Shushan A, Paltiel O, Iscovich J, Elchalal U, Peretz T, Schenker JG, Human menopausalgonadotropin and the risk of epithelial ovarian cancer, Fertil Steril 65:13, 1996.

237.Franceschi S, La Vecchia C, Negri E, Guarneri S, Montella M, Conti E, Parazzini F,Fertility drugs and risk of epithelial ovarian cancer in Italy, Hum Reprod 9:1673, 1994.

238.Parazzini F, Negri E, La Vecchia C, Moroni S, Franceschi S, Crosignani PG, Treatmentfor infertility and risk of invasive epithelial ovarian cancer, Hum Reprod 12:2159, 1997.

239.Mosgaard BJ, Lidegaard Ø, Kjaer SK, Schou G, Andersen AN, Infertility, fertility drugs,and invasive ovarian cancer: a case-control study, Fertil Steril 67:1005, 1997.

240.Mosgaard BJ, Lidegaard Ø, Andersen AN, The impact of parity, infertility and treatmentwith fertility drugs on the risk of ovarian cancer, Acta Obstet Gynecol Scand 76:89,1997.

241.Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Staimkampf MP,Hill JA, Mastroianni Jr L, Buster JE, Nakajima ST, Vogel DL, Canfield RE, for the National Cooperative Reproductive Medicine Network, Efficacy of superovulation andintrauterine insemination in the treatment of infertility, New Engl J Med 340:177, 1999.

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