fertility news

First introduced in 1961, clomiphene citrate (CC) has been used as an initial oral therapy for the induction of ovulation in patients who do not ovulate. Clomiphene citrate acts by preventing correct interpretation of circulating estrogen levels. Reduced levels of estrogen trigger normal compensatory mechanisms to stimulate increased pituitary gonadotropin release (LH & FSH) that drives follicular growth in the ovaries. Levels of both LH and FSH rise and then fall after the typical five day course is completed. If the therapy is successful one or more dominant follicles will emerge and mature, generating a rising tide of estradiol that ultimately triggers the mid-cycle LH surge and ovulation.

CC is the initial treatment choice for the following patients:

• Women who have luteal phase defects
• Women who are do not ovulate or those who ovulate infrequently
• Couples who are young with a short duration of unexplained infertility
• Couples who are averse to more aggressive therapies that are costlier, involve greater risk and logistical demands

The drug is contraindicated in women with poor ovarian reserve, those with hypothalamic/pituitary dysfunction, severe male factor, uterine or tubal factors. Clomiphene citrate is considered the minimal stimulation approach for patients attempting pregnancy by timed intercourse or intrauterine insemination that are designed to bring sperm and eggs together at the optimal time. Clomiphene produces effective results when combined with ultrasound monitoring. Treatment usually starts with a single 50mg tablet daily for a 5 day interval and increases, by 50mg in subsequent cycles until ovulation is achieved. Most women who respond do so at 50-100mg.

Some women will ovulate spontaneously using only clomiphene. However, for those who do not exogenous hCG (taken intramuscularly or subcutaneously) is used to trigger ovulation. Using exogenous hCG is best for women who require IUI and whose midcycle LH surge cannot be reliably detected. For those women not requiring IUI, basal body temperature (BBT) or ovulation predictor kits (OPK) may be recommended to determine ovulation. The surge is typically observed between 5-12 days after treatment when CC is given cycle days 5-9.

Among anovulatory infertile women who ovulate in response to CC, the overall pregnancy rate per cycle is ~15%. In couples with no other fertility factors, who ovulate in response to CC, the cumulative pregnancy rate over 6-9 cycles can be 70-75%. The failure to conceive in 5-6 normal ovulatory cycles is indicative of problems that require further evaluation. At this point, the infertility assessment should be expanded to exclude other infertility factors. Factors such as advanced maternal age (>35 years of age), may require a more immediate change in treatment strategy rather than waiting the six months.

The main disadvantage of the drug is a thickening of cervical mucus, which may make it impenetrable to sperm. This effect is dose dependent which is why the lowest effective dose should be used. Approximately 10% of patients receiving clomiphene experience transient “hot flashes” and abdominal-pelvic discomfort/distention/bloating. Another disadvantage is the thinning of the endometrial lining when the drug is used for an extended period of time. This effect occurs infrequently and is also dose dependant. Visual disturbances, including blurring and double vision, occur less commonly.

The use of treatments (such as clomiphene citrate) should be reassessed if pregnancy does not occur within the timeline established initially by the patient and physician. Your health care provider, who is the best source of information about the use of clomiphene, can answer any questions you may have and determine if it is right for you.

References:
ASRM Practice Committee Report: Use of clomiphene citrate in women 2003.
Available at: http://www.asrm.org/membersonly/practice/clomiphene.pdf

Deaton JL, Gibson M, Blackmer K, Nakajima ST, Badger GJ, Brumsted JR. A randomized, controlled trial of clomiphene citrate and intrauterine insemination in couples with unexplained infertility or surgically corrected endometriosis. Fertil Steril 1990;54:1083–8.

Fisch P, Casper RF, Brown SE, Wrixon W, Collins JA, Reid RL, et al.Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin. Fertil Steril 1989;51:828–33.

Glazener CM, Coulson C, Lambert PA, Watt EM, Hinton RA, Kelly NG, et al. Clomiphene treatment for women with unexplained infertility: placebo-controlled study of hormonal responses and conception rates. Gynecol Endocrinol 1990;4:75–83.

Greenblatt RB. Chemical induction of ovulation. Fertil Steril 1961;12: 402–4.

Guzick DS, Sullivan MW, Adamson GD, Cedars MI, Falk RJ, Peterson EP, et al. Efficacy of treatment for unexplained infertility. Fertil Steril 1998;70:207–13.

Gysler M, March CM, Mishell DR Jr, Bailey EJ. A decade’s experience with an individualized clomiphene treatment regime including its effect on the postcoital test. Fertil Steril 1982;37:161–7.

Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligomenorrheic infertility. J Clin Endocrinol Metab 1999;84:1617–22.

Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. Fertil Steril 2002;77:91–7.

Quagliarello J, Weiss G. Clomiphene citrate in the management of infertility associated with shortened luteal phases. Fertil Steril 1979;31: 373–7.

Rebar R, Judd HL, Yen SSC, Rakoff J, VandenBerg G, Naftolin F. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J Clin Invest 1976;57:1320–9.

Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility. 7th ed. Philadelphia, PA, USA: Lippincott Williams & Wilkins; 2005.

Wu CH, Winkel CA. The effect of therapy initiation day on clomiphene citrate therapy. Fertil Steril 1989;52:564–8.