Use of clomiphene citrate in women
2003; Elsevier BV; Volume: 80; Issue: 5 Linguagem: Inglês
10.1016/s0015-0282(03)01184-1
ISSN1556-5653
AutoresThe Practice Committee of the American Society for Reproductive Medicine,
Tópico(s)Reproductive System and Pregnancy
ResumoOvulatory dysfunction is one of the most common causes of reproductive failure in subfertile and infertile couples. In the absence of other significant infertility factors, successful ovulation induction often will restore normal fertility. Clomiphene citrate (CC) is the best initial treatment for the large majority of anovulatory infertile women. The first clinical trial of CC therapy demonstrated successful ovulation induction in 80% of women, half of whom achieved pregnancy during treatment (1Greenblatt R.B. Chemical induction of ovulation.Fertil Steril. 1961; 12: 402-404Abstract Full Text PDF PubMed Google Scholar). In subsequent years, results of CC treatment have not changed appreciably, despite the advent of modern immunoassays for steroid hormones, advances in ultrasound technology for cycle monitoring, and the introduction of commercial test kits that allow detection of the midcycle luteinizing hormone (LH) surge in urine. This guideline will first describe the pharmacology, mode of action, and indications for CC treatment. Second, it will outline the pretreatment evaluation, standard and combination treatment regimens, and alternative strategies for the CC-resistant patient. Lastly, it will summarize the methods for monitoring therapy and review the results, side effects, and risks of CC treatment. Chemically, CC (like tamoxifen) is a nonsteroidal triphenylethylene derivative that exhibits both estrogen agonist and antagonist properties (2Clark J.H. Markaverich B.M. The agonistic-antagonistic properties of clomiphene a review.Pharmacol Ther. 1982; 15: 467-519Crossref Scopus (183) Google Scholar). In general, estrogen agonist properties are manifest only when endogenous estrogen levels are extremely low. Otherwise, CC acts solely as a competitive estrogen antagonist. CC is cleared through the liver and excreted in stool. About 85% of an administered dose is eliminated after approximately 6 days, although traces may remain in the circulation for much longer (3Mikkelson T.J. Kroboth P.D. Cameron W.J. Dittert L.W. Chungi V. Manberg P.J. Single-dose pharmacokinetics of clomiphene citrate in normal volunteers.Fertil Steril. 1986; 46: 392-396Abstract Full Text PDF PubMed Google Scholar). As currently manufactured, CC is a racemic mixture of two distinct stereoisomers, enclomiphene and zuclomiphene. Available evidence indicates that enclomiphene is the more potent isomer and the one primarily responsible for the ovulation inducing actions of CC (2Clark J.H. Markaverich B.M. The agonistic-antagonistic properties of clomiphene a review.Pharmacol Ther. 1982; 15: 467-519Crossref Scopus (183) Google Scholar, 4Van Campenhout J. Borreman E. Wyman H. Antaki A. Induction of ovulation with cisclomiphene.Am J Obstet Gynecol. 1973; 115: 321-327Abstract Full Text PDF PubMed Scopus (21) Google Scholar). Enclomiphene levels rise rapidly after administration and fall to undetectable concentrations soon thereafter. Zuclomiphene is cleared far more slowly. Levels of this less active isomer remain detectable in the circulation for more than a month after treatment and may accumulate over consecutive cycles of treatment, but there is no evidence of any important clinical consequence (5Young S.L. Opsahl M.S. Fritz M.A. Serum concentrations of enclomiphene and zuclomiphene across consecutive cycles of clomiphene citrate therapy in anovulatory infertile women.Fertil Steril. 1999; 71: 639-644Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Structural similarity to estrogen allows CC to bind to estrogen receptors (ER) throughout the reproductive system. However, in contrast to estrogen, CC binds nuclear ER for an extended period of time and ultimately depletes ER concentrations by interfering with the normal process of ER replenishment (2Clark J.H. Markaverich B.M. The agonistic-antagonistic properties of clomiphene a review.Pharmacol Ther. 1982; 15: 467-519Crossref Scopus (183) Google Scholar). The drug's effectiveness in ovulation induction can be attributed to actions at the hypothalamic level. Depletion of hypothalamic ER prevents correct interpretation of circulating estrogen levels. Reduced levels of estrogen negative feedback trigger normal compensatory mechanisms that alter pulsatile hypothalamic GnRH secretion to stimulate increased pituitary gonadotropin release that, in turn, drives ovarian follicular activity. In ovulatory women, CC treatment increases GnRH pulse frequency (6Kerin J.F. Liu J.H. Phillipou G. Yen S.S. Evidence for a hypothalamic site of action of clomiphene citrate in women.J Clin Endocrinol Metab. 1985; 61: 265-268Crossref PubMed Scopus (120) Google Scholar). In anovulatory women with polycystic ovary syndrome (PCOS) in whom the GnRH pulse frequency is already abnormally high, CC treatment increases pulse amplitude, but not frequency (7Kettel L.M. Roseff S.J. Berga S.L. Mortola J.F. Yen S.S. Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome.Fertil Steril. 1993; 59: 532-538PubMed Google Scholar). During CC treatment, levels of both LH and FSH rise, falling again after the typical 5-day course of therapy is completed (8Rebar R. Judd H.L. Yen S.S.C. Rakoff J. VandenBerg G. Naftolin F. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome.J Clin Invest. 1976; 57: 1320-1329Crossref PubMed Scopus (494) Google Scholar). In successful treatment cycles, one or more dominant follicles emerge and mature, generating a rising tide of estradiol that ultimately triggers the midcycle LH surge and ovulation. Not surprisingly, tamoxifen also has been used successfully to induce ovulation in anovulatory infertile women (9Boostanfar R. Jain J.K. Mishell Jr, D.R. Paulson R.J. A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction.Fertil Steril. 2001; 75: 1024-1026Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Given its structural similarity to CC, its mechanism of action presumably is also similar (10Tajima C. Fukushima T. Endocrine profiles in tamoxifen-induced ovulatory cycles.Fertil Steril. 1983; 40: 23-30Abstract Full Text PDF PubMed Scopus (27) Google Scholar). Recent evidence suggests that letrozole, an orally active aromatase inhibitor, may have potential as an ovulation-inducing agent (11Mitwally M.F. Casper R.F. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate.Fertil Steril. 2001; 75: 305-309Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar, 12Fisher S.A. Reid R.L. Van Vugt D.A. Casper R.F. A randomized double-blind comparison of the effects of clomiphene citrate and the aromatase inhibitor letrozole on ovulatory function in normal women.Fertil Steril. 2002; 78: 280-285Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). In contrast to the central actions of CC and tamoxifen, letrozole acts in the periphery to inhibit ovarian follicular estradiol production, but the end result is similar—a decrease in central estrogen feedback action that stimulates a compensatory increase in pituitary gonadotropin secretion. The causes of anovulation are many and varied. Whenever possible, treatment should be directed at correcting the underlying cause. Correct diagnosis may suggest specific treatment, and many conditions may have longer-term health consequences. Thyroid disease, pituitary tumors, eating disorders, extremes of weight loss and exercise, hyperprolactinemia, PCOS, and obesity may be identified, but very often the immediate cause of anovulation cannot be confidently defined. CC is the initial treatment of choice for most anovulatory or oligo-ovulatory infertile women. However, given its hypothalamic site of action, CC is often ineffective in women with hypogonadotropic hypogonadism (hypothalamic amenorrhea). Women with other demonstrable endocrinopathies (diabetes mellitus, thyroid disorders, hyperprolactinemia, congenital adrenal hyperplasia) should first receive specific treatment and be offered CC only when that therapy fails to restore regular ovulatory cycles. Given that the corpus luteum derives from the follicle that ovulates, its functional capacity is, at least in part, dependent on the quality of preovulatory follicle development. In that context, CC is one logical treatment option for luteal phase deficiency (LPD) (13Quagliarello J. Weiss G. Clomiphene citrate in the management of infertility associated with shortened luteal phases.Fertil Steril. 1979; 31: 373-377Abstract Full Text PDF PubMed Scopus (29) Google Scholar). Progesterone levels are typically higher after CC treatment than in spontaneous cycles, reflecting improved preovulatory follicle and corpus luteum development and/or the combined hormone production of more than one corpus luteum (14Guzick D.S. Zeleznik A. Efficacy of clomiphene citrate in the treatment of luteal phase deficiency quantity versus quality of preovulatory follicles.Fertil Steril. 1990; 54: 206-210PubMed Google Scholar). In couples whose infertility remains unexplained after careful and thorough evaluation, empiric treatment with CC may be justified, particularly in young couples with a short duration of infertility and in those unwilling or unable to pursue more aggressive therapies involving greater costs, risks, and logistical demands (15Fisch P. Casper R.F. Brown S.E. Wrixon W. Collins J.A. Reid R.L. et al.Unexplained infertility evaluation of treatment with clomiphene citrate and human chorionic gonadotropin.Fertil Steril. 1989; 51: 828-833Crossref PubMed Google Scholar, 16Glazener C.M. Coulson C. Lambert P.A. Watt E.M. Hinton R.A. Kelly N.G. et al.Clomiphene treatment for women with unexplained infertility placebo-controlled study of hormonal responses and conception rates.Gynecol Endocrinol. 1990; 4: 75-83Crossref PubMed Scopus (71) Google Scholar). The efficacy of empiric CC treatment may be attributed to correction of subtle and unrecognized ovulatory dysfunction and/or “superovulation” of more than a single ovum (16Glazener C.M. Coulson C. Lambert P.A. Watt E.M. Hinton R.A. Kelly N.G. et al.Clomiphene treatment for women with unexplained infertility placebo-controlled study of hormonal responses and conception rates.Gynecol Endocrinol. 1990; 4: 75-83Crossref PubMed Scopus (71) Google Scholar). CC treatment is most effective when it is combined with properly timed intrauterine insemination (IUI), all in an effort to bring together more than the usual numbers of ova and sperm at the optimal time (17Deaton J.L. Gibson M. Blackmer K. Nakajima S.T. Badger G.J. Brumsted J.R. A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis.Fertil Steril. 1990; 54: 1083-1088Crossref PubMed Google Scholar, 18Guzick D.S. Sullivan M.W. Adamson G.D. Cedars M.I. Falk R.J. Peterson E.P. et al.Efficacy of treatment for unexplained infertility.Fertil Steril. 1998; 70: 207-213Abstract Full Text Full Text PDF PubMed Scopus (231) Google Scholar). Infertile women who rarely or never ovulate are candidates for CC treatment. Diagnosis of ovulatory dysfunction may be established by: •Basal body temperature recordings•Timed serum progesterone determinations•Monitoring urinary LH excretion•Timed endometrial biopsy•Serial transvaginal ultrasound examinations However, specific tests of ovulation are unnecessary when menstrual history alone is diagnostic (amenorrhea, oligomenorrhea). Once identified, anovulatory infertile women merit additional pretreatment evaluation to identify any underlying systemic illness that may require additional tests, counseling, or specific treatment. A detailed medical history and physical examination may reveal evidence of other endocrine or metabolic disease. Acanthosis nigricans is often observed in women with underlying insulin resistance or frank diabetes and merits formal evaluation to exclude these diagnoses (19Practice Committee ReportUse of insulin sensitizing agents in the treatment of polycystic ovary syndrome. American Society for Reproductive Medicine, Birmingham, AL2000Google Scholar). Screening for hypothyroidism (serum TSH) and hyperprolactinemia (serum prolactin) is reasonable since both disorders are best treated with medications other than CC (20Cuellar F.G. Bromocriptine mesylate (Parlodel) in the management of amenorrhea/galactorrhea associated with hyperprolactinemia.Obstet Gynecol. 1980; 55: 278-284PubMed Google Scholar, 21Lincoln S.R. Ke R.W. Kutteh W.H. Screening for hypothyroidism in infertile women.J Reprod Med. 1999; 44: 455-457PubMed Google Scholar). Hirsutism that is severe or rapid in progression warrants specific additional evaluation to exclude non-classic congenital adrenal hyperplasia (CAH) and androgen-producing tumors of the ovary or adrenals (22Practice Committee ReportEvaluation and treatment of androgen excess. American Society for Reproductive Medicine, Birmingham, AL2000Google Scholar). Attempts at ovulation induction are generally futile in women with elevated serum FSH levels. Those with hypothalamic/pituitary dysfunction are also unlikely to respond to CC as its mechanism of action requires a functional hypothalamic/pituitary/ovarian feedback axis. Alternative treatments that will reestablish normal hypothalamic/pituitary communication (pulsatile exogenous GnRH) or stimulate the ovary directly (exogenous gonadotropins) will generally be required. Ovulation induction has little value when severe male, uterine, or tubal factors are also present. Semen analysis should be performed to identify seminal abnormalities that also may require treatment. Hysterosalpingography is indicated when clinical history raises suspicion of uterine or tubal pathology (pelvic infection or surgery, ectopic pregnancy, inflammatory bowel disease), but may otherwise be reserved for those who fail to conceive within three to six ovulatory treatment cycles. An HSG is also prudent in older women (over 35 years) to avoid ineffective treatment at a time when fertility is steadily declining. CC is administered orally, typically starting on the third to fifth day after the onset of spontaneous or progestin-induced menses; ovulation rates, conception rates, and pregnancy outcome are similar regardless whether treatment begins on cycle day 2, 3, 4, or 5 (23Wu C.H. Winkel C.A. The effect of therapy initiation day on clomiphene citrate therapy.Fertil Steril. 1989; 52: 564-568Crossref PubMed Scopus (84) Google Scholar). Although the dose required to achieve ovulation correlates with body weight, there is no reliable way to accurately predict what dose will be required in an individual woman (24Lobo R.A. Gysler M. March C.M. Goebelsmann U. Mishell Jr, D.R. Clinical and laboratory predictors of clomiphene response.Fertil Steril. 1982; 37: 168-174Crossref PubMed Google Scholar). Consequently, CC induction of ovulation amounts to an empiric incremental titration in efforts to establish the lowest effective dose for each individual. Treatment typically begins with a single 50-mg tablet daily for 5 consecutive days, increasing by 50-mg increments in subsequent cycles until ovulation is induced. The effective dose of CC ranges from 50 mg/day to 250 mg/day, although doses in excess of 100 mg/day are not approved by the Food and Drug Administration (FDA). Lower doses (e.g., 12.5 mg/day to 25 mg/day) deserve a trial in women who demonstrate exquisite sensitivity to CC or consistently develop large ovarian cysts that interfere with efficient cyclic treatment (25Dodge S.T. Strickler R.C. Keller D.W. Ovulation induction with low doses of clomiphene citrate.Obstet Gynecol. 1986; 67: 63S-65SCrossref PubMed Scopus (10) Google Scholar). Most women ovulate in response to treatment with 50 mg (52%) or 100 mg (22%); higher doses have been used, but also are less often successful (150 mg, 12%; 200 mg, 7%; 250 mg, 5%) (26Gysler M. March C.M. Mishell Jr, D.R. Bailey E.J. A decade's experience with an individualized clomiphene treatment regime including its effect on the postcoital test.Fertil Steril. 1982; 37: 161-167Abstract Full Text PDF PubMed Google Scholar). Some CC-resistant anovulatory women who fail to respond to a standard 5-day treatment regimen may respond to longer courses (8 days) of CC treatment (27Lobo R.A. Granger L.R. Davajan V. Mishell Jr, D.R. An extended regimen of clomiphene citrate in women unresponsive to standard therapy.Fertil Steril. 1982; 37: 762-766Abstract Full Text PDF PubMed Scopus (52) Google Scholar), but such treatment should be considered only when alternative treatment with exogenous gonadotropins is rejected. Many women who prove resistant or refractory to standard CC treatment may ovulate in response to alternative treatment regimens. A choice among them should not be arbitrary, but based on specific elements of the patient's history, results of laboratory evaluation, and/or observations in previous unsuccessful CC treatment cycles. These regimens also should not be considered as a prerequisite for use of more aggressive treatment strategies (e.g., exogenous gonadotropins). They are merely useful alternatives that merit consideration, depending on the patient's age, goals, available resources, and risk tolerance. Insulin resistance and hyperinsulinemia are common features in women with PCOS. Most women with PCOS will respond to CC, but many prove resistant and ultimately require alternative treatment. Among these, a large majority will have demonstrable insulin resistance (28Legro R.S. Finegood D. Danaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome.J Clin Endocrinol Metab. 1998; 83: 2694-2698Crossref PubMed Scopus (671) Google Scholar). Insulin sensitizing agents (e.g., metformin) alone can restore menses and cyclic ovulation in many amenorrheic PCOS women (29Heard M.J. Pierce A. Carson S.A. Buster J.E. Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome.Fertil Steril. 2002; 77: 669-673Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 30Nestler J.E. Jakubowicz D.J. Evans W.S. Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.N Engl J Med. 1998; 338: 1876-1880Crossref PubMed Scopus (716) Google Scholar), although they are not currently approved by the FDA for this indication. Based on observations from open trials, some advocate metformin as primary therapy in anovulatory infertile PCOS women (1,000 mg/day to 2,000 mg/day in divided doses) and add CC only in those who fail to respond (29Heard M.J. Pierce A. Carson S.A. Buster J.E. Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome.Fertil Steril. 2002; 77: 669-673Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Given the greater costs and complexity of metformin treatment and the frequency of severe gastrointestinal side effects (e.g., nausea, vomiting, diarrhea), others prefer to reserve metformin treatment for those who first prove resistant to CC. In either case, many who fail to ovulate in response to either alone will respond when the two are used in combination (29Heard M.J. Pierce A. Carson S.A. Buster J.E. Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome.Fertil Steril. 2002; 77: 669-673Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 30Nestler J.E. Jakubowicz D.J. Evans W.S. Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.N Engl J Med. 1998; 338: 1876-1880Crossref PubMed Scopus (716) Google Scholar, 31Velazquez E. Acosta A. Mendoza S.G. Menstrual cyclicity after metformin therapy in polycystic ovary syndrome.Obstet Gynecol. 1997; 90: 392-395Crossref PubMed Scopus (274) Google Scholar). Because metformin therapy may have hepatic toxicity or be complicated by lactic acidosis, liver and renal functions must be evaluated before treatment and monitored periodically thereafter. Although the safety of metformin treatment in pregnancy has not been established, preliminary evidence suggests that it may reduce the incident risk of spontaneous abortion and gestational diabetes in women with PCOS (32Glueck C.J. Phillips H. Cameron D. Sieve-Smith L. Wang P. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion a pilot study.Fertil Steril. 2001; 75: 46-52Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar, 33Glueck C.J. Wang P. Kobayashi S. Phillips H. Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome.Fertil Steril. 2002; 77: 520-525Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar). Although exogenous hCG has been used to trigger ovulation and define the optimal time to perform IUI in CC-induced cycles, the practice is difficult to justify on a routine basis. Treatment requires costly monitoring with serial transvaginal ultrasound examinations that are otherwise unnecessary. The mean peak diameter of the preovulatory follicle in successful CC-induced ovulatory cycles ranges between 19 and 30 mm (median diameter: 25 mm) (34Opsahl M.S. Robins E.D. O'Connor D.M. Scott R.T. Fritz M.A. Characteristics of gonadotropin response, follicular development, and endometrial growth and maturation across consecutive cycles of clomiphene citrate treatment.Fertil Steril. 1996; 66: 533-539Abstract Full Text PDF PubMed Google Scholar), and the optimum time to administer hCG is therefore difficult to determine. Most importantly, two randomized trials have demonstrated that IUI after exogenous hCG-triggered ovulation in CC-induced cycles is no more effective than IUI performed after detection of the endogenous LH surge (35Deaton J.L. Clark R.R. Pittaway D.E. Herbst P. Bauguess P. Clomiphene citrate ovulation induction in combination with a timed intrauterine insemination the value of urinary luteinizing hormone versus human chorionic gonadotropin timing.Fertil Steril. 1997; 68: 43-47Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 36Zreik T.G. Garcia-Velasco J.A. Habboosh M.S. Olive D.L. Arici A. Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropin-timed versus urinary luteinizing hormone-timed intrauterine inseminations in clomiphene citrate-stimulated treatment cycles.Fertil Steril. 1999; 71: 1070-1074Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Therefore, use of exogenous hCG is perhaps best limited to those women who require IUI and in whom a midcycle LH surge cannot reliably be detected. In some CC-resistant PCOS women, addition of glucocorticoids (e.g., dexamethasone 0.5 mg or prednisone 5 mg hs) to the CC treatment regimen may induce ovulation when CC alone has failed (37Daly D.C. Walters C.A. Soto-Albors C.E. Tohan N. Riddick D.H. A randomized study of dexamethasone in ovulation induction with clomiphene citrate.Fertil Steril. 1984; 41: 844-848Abstract Full Text PDF PubMed Scopus (122) Google Scholar, 38Isaacs Jr, J.D. Lincoln S.R. Cowan B.D. Extended clomiphene citrate (CC) and prednisone for the treatment of chronic anovulation resistant to CC alone.Fertil Steril. 1997; 67: 641-643Abstract Full Text PDF PubMed Scopus (25) Google Scholar). Adjunctive glucocorticoid treatment may be based on the serum DHEA-S concentration (>200 μg/dL) (37Daly D.C. Walters C.A. Soto-Albors C.E. Tohan N. Riddick D.H. A randomized study of dexamethasone in ovulation induction with clomiphene citrate.Fertil Steril. 1984; 41: 844-848Abstract Full Text PDF PubMed Scopus (122) Google Scholar) or empiric (38Isaacs Jr, J.D. Lincoln S.R. Cowan B.D. Extended clomiphene citrate (CC) and prednisone for the treatment of chronic anovulation resistant to CC alone.Fertil Steril. 1997; 67: 641-643Abstract Full Text PDF PubMed Scopus (25) Google Scholar). Treatment may be continued (three to six cycles) when it is successful and should be promptly discontinued when it is not. There is no evidence that glucocorticoid treatment has any important side effects or risks when used in the doses or for the duration indicated. CC-resistant anovulatory women who ultimately require exogenous gonadotropins to achieve ovulation and those with unexplained infertility might benefit from a trial of sequential CC/gonadotropin therapy using either traditional menotropins (hMG) or purified or recombinant FSH (39March C.M. Tredway D.R. Mishell Jr, D.R. Effect of clomiphene citrate upon the amount and duration of human menopausal gonadotropin therapy.Am J Obstet Gynecol. 1976; 125: 699-704Abstract Full Text PDF PubMed Scopus (33) Google Scholar). Given the costs and risks of exogenous gonadotropin therapy, treatment should be offered only by those having the requisite training or experience. The typical cycle includes a standard CC treatment regimen (50 mg/day to 100 mg/day, cycle days 5–9), followed by low-dose hMG or FSH (75 IU/day, cycle days 9–12). Treatment is individualized thereafter, in the same way as with traditional gonadotropin therapy, based on transvaginal ultrasound examinations. Cycle fecundity with this approach is similar to that achieved with gonadotropins alone, but the dose and duration of treatment and the associated costs of monitoring may be significantly reduced. Treatment with exogenous gonadotropins alone is the obvious alternative. CC-resistant anovulatory women are often very sensitive to low doses of gonadotropins and treatment should be aimed at achieving ovulation of but a single mature follicle if possible. There is no indication for purposeful superovulation in the anovulatory infertile woman. A contemporary version of the classic ovarian wedge resection is another treatment option in CC-resistant, hyperandrogenic, anovulatory women (e.g., PCOS). The technique involves laparoscopic cautery, diathermy, or laser vaporization of the ovaries at multiple sites, the objective being to decrease circulating and intraovarian androgen levels by reducing the volume of ovarian stroma. Data derived from randomized controlled trials suggest that initial ovulation and pregnancy rates after ovarian drilling are similar to those achieved by treatment with exogenous gonadotropins, and the risk of multiple pregnancy is lower (40Farquhar C, Vandekerckhove P, Lilford R. Laparoscopic “drilling” by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2001:CD001122Google Scholar). When it does not result in spontaneous ovulation, ovarian drilling may help to restore sensitivity to CC treatment. Ovarian drilling is a reasonable option for clomiphene-resistant anovulatory women, but the temporary effects of treatment and the risks of postoperative adhesions or diminished ovarian reserve should be carefully considered. Objective evidence of ovulation and normal luteal function is key to successful treatment. Ovulation can be documented using any one of a number of methods. The choice may vary and should be tailored to meet the needs of the individual patient. Basal body temperature (BBT) recordings provide a simple and inexpensive method for evaluating response to treatment, but may be tedious. Test kits that can identify the midcycle LH surge in urine more precisely define both the interval of peak fertility and luteal phase duration (41Wilcox A.J. Weinberg C.R. Baird D.D. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby.N Engl J Med. 1995; 333: 1517-1521Crossref PubMed Scopus (830) Google Scholar). The surge is typically observed between 5 and 12 days after treatment is completed, most often on cycle day 16 or 17 when CC is administered on days 5–9 (34Opsahl M.S. Robins E.D. O'Connor D.M. Scott R.T. Fritz M.A. Characteristics of gonadotropin response, follicular development, and endometrial growth and maturation across consecutive cycles of clomiphene citrate treatment.Fertil Steril. 1996; 66: 533-539Abstract Full Text PDF PubMed Google Scholar). Whereas any progesterone level greater than 3 ng/mL provides presumptive evidence of ovulation (42Wathen N.C. Perry L. Lilford R.J. Chard T. Interpretation of single progesterone measurement in diagnosis of anovulation and defective luteal phase observations on analysis of the normal range.BMJ. 1984; 288: 7-9Crossref PubMed Scopus (90) Google Scholar), a midluteal phase concentration offers more information regarding the quality of luteal function. Best results are observed when concentrations exceed 10 ng/mL (43Hull M.G. Savage P.E. Bromham D.R. Ismail A.A. Morris A.F. Value of a single serum progesterone measurement in the miduteal phase as a criterion of a potentially fertile cycle (“ovulation”) derived from treated and untreated conception cycles.Fertil Steril. 1982; 37: 355-360Abstract Full Text PDF PubMed Scopus (137) Google Scholar). Endometrial biopsy revealing a secretory endometrium also provides evidence of ovulation. Endometrial “dating” using established histologic criteria may reveal evidence of LPD (44Noyes R.W. Hertig A.T. Rock J. Dating the endometrial biopsy.Fertil Steril. 1950; 1: 3-25Crossref Google Scholar), although controversies persist regarding the accuracy of traditional diagnostic criteria. Serial transvaginal ultrasound can reveal the size and number of developing follicles and provide presumptive evidence of ovulation (progressive follicular growth, sudden collapse of the preovulatory follicle, and an increase in cul-de-sac fluid volume) and luteiniz
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