Ovulation Induction with Clomiphene Citrate

By Isaac Glatstein, M.D.

Often, we are asked by primary care physicians and obstetrician/gynecologists how far they should go in managing their infertility patients, and when they should refer their couples seeking to conceive to a fertility specialist. One area of particular concern is the proper use of clomiphene citrate. This article is meant to serve as a brief guide to help answer these questions.

Clomiphene citrate, initially synthesized in 1956, was the first fertility medication approved in this country by the FDA in 1967. Its primary indication has been to induce ovulation in normally estrogenized, women whom are not ovulating. Indeed, it is quite effective under these clinical circumstances, and a series of classic studies done in the 1980's have established that pregnancy rates for anovulatory women treated with clomiphene citrate approached that of normal, healthy women. Treatment is typically begun either on day three, or five of menses, starting with a 50mg dose and continuing for five consecutive days. Ovulation is then monitored by either by the patient at home with urine LH test kits, or in the physician's office with blood estradiol and LH testing as well as vaginal ultrasound follicular monitoring. The sperm source may come from either timed intercourse, or else with an intra-uterine insemination in the physician's office.

Severe complications with clomiphene citrate are rare. Nonetheless, it is of utmost importance that infertile couples are properly counseled regarding potential adverse effects associated with use of this medication. Minor side effects include troublesome "hot" flashes, headaches, visual disturbances and abdominal discomfort. Couples should also be counseled about the potential for multiple gestations with a twin rate of approximately 10% and a triplet rate of less than 1%. Additional effects include a potential adverse impact on endometrial thickness as well as on cervical mucus. The most severe adverse effect is the development of ovarian hyperstimulation syndrome (OHSS). Severe OHSS may result in enlarged ovaries in mild cases to rapid fluid accumulation in the abdominal, lung, and chest cavities along with the development of clotting abnormalities in critical cases.

How long should women be treated with clomiphene citrate? The opinion of most authorities, is that the majority of pregnancies occurring with clomiphene take place within the first four to six treatment cycles, and therefore, additional treatments beyond that are unlikely to be of benefit. Of interest, the manufacturer's label recommends treatment up to three cycles only. One area of emerging concern is the potential association of prolonged use of clomiphene and the subsequent risk for the development of ovarian cancer. Although a couple of studies in the epidemiology literature in the early 90's suggested such a link, a number of recent publications critically evaluating this link have concluded that although the long term risk of ovulation inducing medications is unknown, there is probably no strong link between their use and the likelihood of ovarian cancer down the road. Interestingly, these studies do suggest that women with refractory infertility may constitute a high-risk group for the development of ovary cancer, but this is most likely independent o any fertility drug use. In any event, wise and judicious use of these medications is certainly warranted given the lack of clarity on this evolving issue. For all of these reasons, The American Society for Reproductive Medicine recommends no more than six total cycles of clomiphene treatment before moving onto alternative therapy.

How are patients on clomiphene best monitored? In the early days of clomiphene, before the advent of rapid immunoassays, patients would plot their ovulation with basal body thermometer readings. Because of their relative inaccuracy and lack of prospective information about ovulation, temperature reading has largely been abandoned. Newer, and more modern techniques such as home LH kit determinations, and rapid blood LH, estradiol and progesterone determinations as well as vaginal ultrasound monitoring for follicular development are in fairly common use. Additional refinements include the use of a hCG injection to trigger ovulation and allow more accurate timing of an intra-uterine insemination, and luteal phase support with progesterone supplementation. It should be noted that these last two treatments, although widely used, are controversial in terms of actually increasing the pregnancy rate and may also contribute to increasing the cost of providing infertility services.

Who should be treated with clomiphene? There is mounting evidence in the literature that administering clomiphene to normally ovulatory women may actually lower pregnancy rates in infertile couples compared to untreated controls, perhaps due to a negative impact of the clomiphene cervical mucus and endometrial thickness. At a very minimum, consideration should be given to monitoring of endometrial thickness to couples on clomiphene and to performing an intra-uterine insemination if there is a suspicion of an adverse impact of the clomiphene on cervical mucus. Besides ovulatory status, age is also a critical factor. A recent study published out of the UCLA School of Medicine studied the effect of age in women infertility treated with clomiphene. Using a life-table analysis to study pregnancy rates, they concluded that there was a dramatic fall in cumulative pregnancy rates, as well as pregnancy rates per cycle beyond the age of 35 years in clomiphene-treated women. The authors suggest that in this age group it is probably more time and cost effective to proceed with more aggressive treatments such as gonadotrophins or in vitro fertilization (IVF) than to treat with clomiphene citrate.

When should a patient be referred to a reproductive endocrinologist? Patients who clearly need IVF for tubal factor or pelvic adhesive disease or intracytoplasmic sperm injection combined with IVF for profound male factor are candidates for referral to a center specializing in these procedures and with a proven track record of clinical success in terms of pregnancy rates. Other categories of patients who may benefit from a referral are women unresponsive to clomiphene citrate, women more than 35 years with a limited reproductive time frame, women with unexplained infertility, and other complex cases.

How does one find a reproductive endocrinologist? It is important to choose one that you are personally comfortable with and respect as a provider. You should be satisfied with the high level of service received, and pregnancy rates should be at or above the level of other programs in the area. Become familiar with the local centers offering assisted reproductive services. The Internet is an outstanding source of information on where to find a board-certified reproductive endocrinologist. Visit www.asrm.org, the official web site of the American Society. It contains a physician directory, a wide variety of services and information available to patients and professionals, and links to other relevant sites of interest. For a complete listing of board-certified reproductive endocrinologists by state, visit the "clinic nearest you" section of this web site for a map with direct phone numbers and office locations.

Isaac Glatstein, MD is a board certified Reproductive Endocrinologist affilated with the Reproductive Science Center of Boston. He may be reached by e-mail at isaac.glatstein@integramed.com