Editorial Robert l. Barbieri, mD Editor in Chief ClOmIPhEnE failuRE? Try adding dexamethasone to your clomiphene infertility regimen Clomiphene-resistant women often ovulate, and then become pregnant, when treated with a combination of clomiphene and dexamethasone CASE Infertility Dx: PCOS, For women who have PCOS and work-up shows severely abnormal anovulation anovulatory infertility, approaches to semen parameters or bilateral tubal You have been treating a 33-year-old ovulation induction include: disease, consultation with a fertility G0P0 woman who has polycystic ovary • weight loss specialist, and IVF, might be a more syndrome (PCOS) and anovulatory in- • clomiphene appropriate course than undertaking fertility with clomiphene citrate for three • metformin ovulation induction with clomiphene. cycles, at escalating doses of 50 mg, • follicle-stimulating hormone (FSH) Further work-up of anovulatory 100 mg, and 150 mg daily. She has not injection infertility. First obtain measure- ovulated, however, as determined by • laparoscopic ovarian drilling ments of serum thyroid-stimulating appropriately timed serum progester- • in vitro fertilization (IVF). hormone (TSH), follicle-stimulating one measurement. Women who fail to ovulate at hormone (FSH), and prolactin; ab- What is your next step? standard dosages of clomiphene are normalities of these hormones might labeled “clomiphene-resistant.” A contraindicate clomiphene for ovu- novulation is a common consensus panel of expert fertility spe- lation induction. cause of infertility; approxi- cialists recommended that, for such Next, measurement of total se- A mately 70% of cases of anovu- women, the most appropriate next rum testosterone and dehydroepi- latory infertility are caused by PCOS. steps in treatment include FSH injec- androsterone sulfate (DHEAS) might tion or laparoscopic ovarian drilling.1 be useful to determine if your patient’s For many women, however, those op- clomiphene resistance is caused by Instant Poll tions are prohibitively expensive. significantly elevated androgen levels. For a clomiphene-resistant wom- Then, if your clomiphene- an who has PCOS, then, what afford- resistant patient has a normal hystero- able treatment can you prescribe? salpingogram (HSG) and normal TSH, A woman seeking One answer is that many clomi- FSH, and prolactin test results, and pregnancy has PCOS and phene-resistant women will ovulate her partner has a normal semen anal- anovulatory infertility, and is clomiphene-resistant. What if they are treated with a combination ysis, consider that she might benefit 2–6 is your preferred next step in of clomiphene and dexamethasone. from treatment with a combination of management? Here is a stepwise approach to using clomiphene and dexamethasone. clomiphene with dexamethasone. Tell us—at STEP 2 Induce ovulation [email protected]. STEP 1 Review the infertility with clomiphene plus Please include your name and work-up dexamethasone city and state. The standard infertility work-up in- One cause of clomiphene resistance cludes hysterosalpingography, semen is an elevated serum testosterone analysis, and test of ovulation. If the level.7 Other causes include an 10 OBG Management | May 2012 | Vol. 24 No. 5 obgmanagement.com Editorial Plotting a cycle of clomiphene plus dexamethasone, and accompanying testing Clomiphene, 100 mg Dexamethasone, 2 mg Urine luteinizing hormone test Serum progesterone test g Pregnancy test (if no menses) g 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Cycle day elevated body-mass index and ad- early morning adrenocorticotropic asleep. I recommend that patients vanced age. Dexamethasone can im- (ACTH) surge, which stimulates ad- take dexamethasone in the morning. prove the efficacy of clomiphene by renal androgen production. I have Note: Before initiating a clomi- reducing androgen levels. found, however, that, for many wom- phene plus dexamethasone cycle, What trials have demonstrated. en, a nighttime dose of dexametha- many experts 1) obtain a pregnancy Two randomized clinical trials have sone energizes them and causes test to rule out ongoing pregnancy shown that, in clomiphene-resistant difficulty falling, and remaining, and then 2) prescribe progestin women, dexamethasone plus clomi- phene increases ovulation and the pregnancy rate, compared with clo- miphene alone.2,3 Reluctant to use dexamethasone plus clomiphene? One regimen that has been re- Try this. ported to be successful is to treat the clomiphene-resistant woman with Consider estrogen-progestin for 2 months, leading up to a clomiphene cycle clomiphene, 100 mg daily, for cycle Another treatment option that can enhance the efficacy of clomiphene in women Days 3 to 7, and simultaneously treat who are resistant to the drug is to prescribe 2 months of an estrogen–progestin her with dexamethasone, 2 mg dai- contraceptive, then stop the contraceptive and prescribe a standard cycle of ly, for cycle Days 3 to 12 (FIgure).2 clomiphene. A randomized trial has demonstrated the effectiveness of this regi- 1 Treatment with dexamethasone re- men for clomiphene-resistant patients. In the report of the trial by Branigan and Estes,1 women who failed to ovulate duces the serum concentration of with clomiphene, 150 mg/d for 5 days, were randomized to: androgens, thereby increasing the • 42 to 50 days of ethinyl estradiol, 0.03 mg, plus desogestrel (Desogen), efficacy of clomiphene. 0.15 mg, before a clomiphene cycle (Group 1) or In the randomized trial that • no treatment before a clomiphene cycle (Group 2, controls). used this regimen to treat clomi- After a withdrawal bleed (Group 1) or spontaneous menses (Group 2), all subjects phene-resistant women, the ovula- were treated with clomiphene, 100 mg/d, for cycle Days 5 to 9. Women in Group 1 exhibited a 55% mean decrease in serum testosterone (P <.001); women tion rate was 75% in the clomiphene in the control group had a 6% mean decrease in serum testosterone (no signifi- plus dexamethasone group and cant change). Across six treatment cycles, the pregnancy rate was 54% (Group 1) 15% in the clomiphene-only group and 4% (Group 2) (P <.001). (P <.001). The pregnancy rate was The researchers’ conclusion? Lowering serum testosterone with estrogen– 40% in the clomiphene plus dexa- progestin pretreatment might improve responsiveness to clomiphene-induced ovulation. methasone group and 5% in the clomiphene-only group (P <.05). Reference Many clinicians instruct their 1. Branigan EF, Estes MA. A randomized clinical trial of treatment of clomiphene-resistant anovulation with the use of oral contraceptive pill suppression and repeat clomiphene citrate treatment. Am J Obstet Gynecol. patients to take the dexametha- 2003;188(6):1424–1430. sone at night to maximally blunt the 12 OBG Management | May 2012 | Vol. 24 No. 5 obgmanagement.com withdrawal. A commonly used agent pregnancy test. If the combination She became pregnant, and delivered a for progestin withdrawal is medroxy- of clomiphene, 100 mg/d for 5 days, singleton newborn, at term. progesterone acetate (Provera), plus dexamethasone does not cause 10 mg/d for 5 days. The first day of ovulation, prescribe a cycle of clomi- full withdrawal flow after cessation phene, 150 mg/d for cycle Days 3 to 7, of progestin treatment is considered plus dexamethasone. Day 1 of the cycle. If that regimen does not cause [email protected] During the clomiphene plus ovulation, advise the patient to con- dexamethasone treatment cycle, sider other options for ovulation the patient can take urine lutein- induction—such as weight loss, FSH References izing hormone (LH) measurements injection, laparoscopic ovarian drill- 1. The Thessalonkiki ESHRE/ASRM-sponsored PCOS Consensus Workshop Group. Consen- at home to identify the preovula- ing, and IVF. sus on infertility treatment related to polycys- tory LH surge, which typically occurs Caution on the duration of ther- tic ovary syndrome. Fertil Steril. 2008;89(3): 505–522. 5 to 12 days after the last day of clo- apy. Experts recommend that clo- 2. Elnashar A, Abdelmageed E, Fayed M, Sharaf miphene medication (FIgure). The miphene therapy for infertility be M. Clomiphene citrate and dexamethasone in treatment of clomiphene citrate-resistant poly- woman’s maximal fertile span is the limited to no more than approxi- cystic ovary syndrome: a prospective placebo- day before the LH surge, the day of mately 6 to 12 cycles; the concerns controlled study. Hum Reprod. 2006;21(7):1805– the LH surge, and the day following are that prolonged clomiphene 1808. 3. Parsanezhad ME, Alborzi S, Motazedian S, Om- the LH surge. Coitus should occur on treatment may increase the risk of rani G. Use of dexamethasone and clomiphene at least 2 of these 3 days. ovarian neoplasm8 and that the preg- citrate in the treatment of clomiphene citrate- resistant patients with polycystic ovary syndrome If the patient prefers not to mea- nancy rate per cycle may decrease and normal dehydroepiandrosterone sulfate sure urine LH, recommend that with prolonged use of clomiphene. levels: placebo-controlled trial. Fertil Steril. 2002;78(5):1001–1004. she have coitus every other day for Women who use clomiphene 4. Isaacs JD, Lincoln SR, Cowan BD. Extended clo- 8 days, beginning 5 days after the last should also be aware that approxi- miphene citrate (CC) and prednisone for the treatment of chronic anovulation resistant to CC clomiphene tablet. mately 8% of clomiphene-induced alone. Fertil Steril. 1997;67(4):641–643. pregnancies are twin gestations and 5. Daly DC, Walters CA, Soto-Albors CE, Tohan N, STEP 3 measure serum <0.5% are triplet gestations. Riddick DH. A randomized study of dexametha- sone in ovulation induction with clomiphene ci- progesterone approximately trate. Fertil Steril. 1984;41(6):844–848. 6. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes 7 to 10 days after the lh surge CASE Resolved, on labor and delivery E. Clomiphene and anti-estrogens for ovulation Evidence of successful ovulation is The clomiphene-resistant woman de- induction in PCOS.