When I was an Intern in Ob Gyn at Stanford, my friend and Senior Resident Jan Rydfors shared with me a helpful saying: “Like treats like.” He was referring to patients with polycystic ovarian syndrome (PCOS) and how to induce them to ovulate. He explained to me that since PCOS was a hormonal problem, its treatment should be with hormones (not surgery).
Surgery for patients with PCOS was popular for many years and prior to the introduction of clomiphene, one could indeed help women with PCOS by performing bilateral ovarian wedge resection. My father, a general surgeon, who trained when gynecology was still part of general surgery, performed many of these procedures and some of the patients did indeed begin to cycle normally and conceived. Unfortunately, the surgery sometimes caused tubal damage and pelvic adhesions, trading one reproductive problem for another. Surgeons also have a helpful saying: “A chance to cut is a chance to cure.” Doctors in non-surgical specialties have some pithy quips about surgeons, such as orthopedic surgeons are “big as a tree and half as smart.”
Although laparoscopic ovarian drilling has emerged as the modern form of ovarian wedge resection, few patients are forced to resort to this approach as our understanding of PCOS has improved. About 90% of patients will ovulate on metformin or metformin and clomiphene in combination. The remaining 10% usually respond to injectible fertility drugs but here one has to be careful about OHSS and multiples. So here is today’s Question of the Day from the book that my Mother thinks all women of reproductive age need to read: 100 Questions and Answers about Infertility.
25. I have PCOS and am still not having normal cycles with metformin. What comes next?
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 used 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.
Women with PCOS who fail to respond to Clomid can be treated with injectable fertility medications. Gonadotropins 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. 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.