Clomiphene citrate (Clomid) is by far the most commonly used fertility drug in the world. Used in the right circumstances and with appropriate application, it can be and is effective in assisting conception. Ideally the use of clomiphene use should be confined to younger women (under 35 years) who have normal “ovarian reserves” (as evidenced by normal day-3 FSH and AMH levels) and accordingly are likely to respond by producing the multiple follicles (at least 3), necessary to override the “antiestrogenic” effects of clomiphene (see below). In my opinion, if used for longer than 3 consecutive months, clomiphene is not only ineffective, but actually starts to function as a “relative” contraceptive! This could come as a shocking revelation to many women who have often many more consecutive cycles of Clomiphene without success.  Few realize that the rate of conception with clomiphene therapy is about 20%-30% lower than the natural fertility rate for any given age and about 25% lower than when gonadotropin stimulation is used. This problem increases significantly with advancing age.Consider the fact that in women under 35 years, the pregnancy rate with clomiphene treatment is about 10% per cycle , about 5% between 35 and 40 years and <3% after age 40Y. Here are a few reasons why this is so:

  • Clomiphene through its “antiestrogen effect” tricks an area in the brain (the hypothalamus) that regulates release of FSH and LH by the pituitary gland, into “thinking” that ovarian estrogen levels are low. In response, the pituitary gland reacts by releasing exaggerated amounts of follicle-stimulating hormone (FSH), which stimulates development of the follicles, ultimately resulting in ovulation. The growing ovarian follicles secrete estrogen into the bloodstream, thus closing the feedback circle that the hypothalamus initiated in response to the anti-estrogen properties of Clomiphene. Unfortunately, however, at the same time the pituitary also releases large amounts of LH which causes the ovary to produce large amounts of the male hormone, testosterone. In high local ovarian concentrations, testosterone can compromise egg quality and thus ultimately the chance of having a baby. The older the woman, the greater this adverse effect of clomiphene will be.
  • Clomiphene’s anti-estrogenic effects often manifest as an over-thin uterine lining that is incapable of supporting a healthy pregnancy, thickening of the cervical mucus, making sperm migration via the uterus to the awaiting egg in the fallopian tube difficult or impossible. This antiestrogenic effect will invariably build to such a degree over 3 consecutive back-to back cycles of clomiphene therapy (that regardless of age or “ovarian reserve”) most women will manifest with such effects by the 4th month of back-to-back cycles of stimulation. This is why, in my opinion, no woman using clomiphene should do more than three consecutive cycles of treatment without taking at least some break from therapy. Fortunately, the cessation of Clomiphene treatment for only one month is usually sufficient to completely reverse such highly undesirable side effects. The same anti-estrogen effects can occur with the very first clomiphene treatment cycle. This usually happens in women over 35 years and those with elevated FSH levels (poor responders) who cannot produce enough follicles that would produce sufficient estrogen to overcome the anti-estrogenic effects of clomiphene. When this happens or when the woman fails to conceive following (at most) 3 cycles of clomiphene stimulation, it is time to move on to a different method of treatment.
  • About 20% of clomiphene cycles are associated with trapped ovulation (LUF syndrome). This means that in spite of hormone changes suggesting that ovulation has occurred, the egg remains trapped in the ovary. Obviously this is not condusive to the establishment of a successful pregnancy.

The above serves to explain why I strongly hold that Clomiphene should not be prescribed to women over 35 years of age, never to women with diminished ovarian reserve or women over 40 years, and should be avoided in IVF (alone or in combination with gonadotropins). The results are simply too poor to validate such practices.