Editorial Robert L. Barbieri, MD Editor in Chief

Clomiphene failure? Try adding dexamethasone to your clomiphene 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 anovulatory infertility, approaches to semen parameters or bilateral tubal You have been treating a 33-year-old 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 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 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 , 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 , 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. 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. 7 to 10 days after the LH surge CASE Resolved, on labor and delivery 6. Brown J, Farquhar C, Beck J, Boothroyd C, Hughes E. Clomiphene and anti-estrogens for ovulation Evidence of successful ovulation is The clomiphene-resistant woman de- induction in PCOS. Cochrane Database Syst Rev. an appropriately drawn serum pro- scribed at the beginning of the Edi- 2009;(4):CD002249. 7. Imani B, Eijkemans MJ, te Velde ER, Habbema gesterone level >8 ng/mL; in most torial underwent HSG that showed JDF, Fauser BC. A nomogram to predict the clomiphene cycles in which success- bilaterally patent tubes, of normal probability of live birth after clomiphene ci- trate induction of ovulation in normogonado- ful ovulation has occurred, the serum caliber. Her partner’s semen analysis tropic oligoamenorrheic infertility. Fertil Steril. progesterone level is >20 ng/mL. was normal. 2002;77(1):91–97. She was treated with clomiphene 8. Rossing MA, Daling JR, Weiss NS, Moore DE, Self If menses does not occur within SG. Ovarian tumors in a cohort of infertile wom- 17 days after the LH surge, obtain a plus dexamethasone, and ovulated. en. N Engl J Med. 1994;331(12):771–776.

Did you ›› Update on Fertility see these G. David Adamson, MD; Mary E. Abusief, MD (February 2012) related ›› Ovarian stimulation ups risk of ovarian tumors in later life articles? (November 2011) ›› Can ovulation induction be accelerated in women who have PCOS-related infertility? Richard S. Legro, MD (Examining the Evidence, September 2009)

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