Question 25. I have PCOS and am still not having normal cycles with metformin. What comes next

PCOS is not at all an uncommon problem in our fertility practice. Although many OB GYN physicians advertise that they treat infertility, some really do not approach this common problem in a logical way. Instead, they give the patient a prescription for metformin or clomid and push the patient out the door. However, I still believe that having a logical plan is very important. My wife finds this hard to believe because according to her I am constantly flying by the seat of my pants. But that is my little secret and gets me off the hook for being responsible for many household chores....

So as we await the arrival of the heat and humidity here in Washington DC please take a minute to read this latest installment in my effort to keep up with the 2nd Edition of 100 Questions and Answers about Infertility.

25. I have PCOS and am still not having normal cycles with metformin. What comes next?


In our experience, most patients who will resume regular cycles on metformin will demonstrate regular cycles within 4 months of starting this medication. Patients who fail to respond to metformin may require ovulation induction with either clomiphene citrate (Clomid) or injectable fertility medications (gonadotropins).

Clomid has been an FDA-approved treatment for anovulation since the late 1960s. This anti-estrogen has been used successfully in millions of women with few complications. Clomid binds to estrogen receptors in the brain, causing the pituitary gland to resume normal release of FSH, and thereby inducing follicles to grow and ultimately release an egg. Patients should take the lowest effective dose of Clomid needed to induce ovulation. With increasing doses, the anti-estrogen side effects can reduce fertility by altering the cervical mucus and leading to a thinner endometrial lining. Many physicians initially prescribe a dose of 50 mg of Clomid to be taken on cycle days 5 to 9. The physician may perform ultrasound monitoring after day 12. Most patients will ovulate around day 17. If no dominant follicle emerges by this day, then an increased dose of 100 mg should be considered in the next cycle. A dose of 150 mg is rarely prescribed, because the vast majority of Clomid-responsive patients will ovulate while taking the 50- or 100-mg dose. Patients who ovulate rarely or not at all can be given medroxyprogesterone acetate (Provera) for 10 days to induce bleeding. By convention, the first day of this bleeding is referred to as cycle day #1 (eventhough it was an induced bleed and not the result of a normal cycle) and clomiphene is prescribed as noted above.

Women with PCOS who fail to respond to Clomid can be treated with injectable fertility hormones called gonadotropins. Such hormone medications are prepared either using recombinant DNA technology (Follistim, Gonal-F) or by isolating these hormones from the urine of postmenopausal women (Bravelle, Menopur). By following a very-low-dose protocol (37.5 IU as the starting dose), approximately 90% of patients will achieve a single dominant follicle. If the treatment produces multiple follicles, however, the woman’s risk of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS) may lead to cycle cancellation. Alternatives to canceling the cycle and withholding HCG include conversion to IVF or performing a follicle aspiration procedure to reduce the number of follicles to a reasonable number but without fertilizing the eggs that were removed by the aspiration procedure. Almost all of the high-order multiple pregnancies (e.g., sextuplets) born today result from PCOS patients who took gonadotropins and demonstrated an excessive follicular response (think Jon and Kate Plus Eight).