CLOMID: When and How to Use It and When to Stop

Suheil J. Muasher, MD, F.A.C.O.G.
Professor of Obstetrics and Gynecology
Medical Director, The Muasher Center
for Fertility and IVF, Fairfax,VA

CLOMID, (Clomiphene Citrate)
is the most used and abused medication for infertility treatment. It was introduced to the clinical market in 1967 and almost immediately replaced the surgical procedure - wedge resection of the ovaries - for primary treatment of anovulation in patients with polycystic ovarian disease (PCOD, Clomid and PCOS).

Clomid is still widely used by gynecologists for that purpose and others. It is important to remember that proper use of the



medication will usually yield gratifying results while expanding its use to lesser indications may be counterproductive and often results in unsuccessful outcomes.

Clomid's best and most common indication is for induction of ovulation in euestrogenic, normoprolactinemic, and anovulatory patients. The majority of these patients will have PCOD, which is a clinical diagnosis of chronic anovulation with symptoms and signs of Hyperandrogenism.

The definition implies that there is adequate endogenous estrogen production and that hyperprolactinemia has been excluded. Patients with hypoestrogenic anovulation are not good candidates for Clomid as it works as an antiestrogen at the hypothalamus level.

Examples of patients with hypoestrogenism are those with premature ovarian failure, exercise-related amenorrhea, and low body weight with anorexia. Clomid does not work well in patients who are overweight. The second indication for clomiphene use is for the purpose of superovulation, in ovulating patients, in conjunction with assisted reproduction such as intrauterine insemination (IUI) or in-vitro fertilization (IVF).

Clomid may also be used to treat patients with luteal phase defects in conjunction with progesterone supplementation in the luteal phase. The wide use of Clomid to treat patients with unexplained infertility can be counterproductive as Clomid can have adverse effects on the cervical mucus and on implantation at the endometrial level.

Clomid can be considered in young patients (< 30 years) but certainly for no longer than three cycles and with proper monitoring. (Patients should be on a basal body temperature chart and a post coital test should be performed.)Clomid is started at a dose of 50 mg / day for 5 days in anovulatory patients. It is important to remember that these patients do not have cycles and the conventional "cycle day 5 - 9" should not be used. Rather, the first day of clomiphene use can be conveniently called day 1 of the cycle. Patients should look for ovulation, wither by a BBT chart or using an ovulation predictor urinary test, 7 to 10 days after the last clomiphene pill or on days 12 - 15 of the clomiphene cycle (first day of Clomid is day 1).

Clomid in some thin patients dosed at 25 mg / day for five days can be adequate. A post coital test can be performed in the first cycle of clomiphene use to check for adequate mucus production. f patients ovulate on the 50 mg clomiphene dose, they should be kept on it for 3 - 4 months before re-evaluation. If patients do not ovulate on the lower dosage,clomiphene should be increased in increments of 50 mg / day for subsequent cycles.

It is important to remember that 70 -80% of patients who will respond to Clomid will ovulate on the 50 - 100 mg dosage and of those who get pregnant 80 - 90% will do so within 3 - 4 ovulatory cycles.
What to do about Clomiphene failures? When clomiphene fails, it is extremely important to distinguish between ovulation and conception failure

.1.Clomid Ovulation Failure: This is arbitrary defined as failure to ovulate on doses of 150 mg / day for 5 days (even though 10 - 20% of patients can ovulate on higher dosages, it is important to re-evaluate the patient at this stage. Clomiphene is also approved by the FDA for a maximum dose of 750 mg / cycle.)

What are our options to induce ovulation for these patients?

a)Clomid doses can be increased to a maximum of 250 mg / day for five days or consider increasing the duration (100 mg / day for 8 days).

b) Clomid does not work well in extremely obese patients (> 200 lbs or BMI > 30).These patients usually have insulin resistance and those patients should be highly encouraged to lose weight before induction of ovulation. Insulin sensitizing agents such as Metformin (Glucophage) should be the primary treatment. Metformin can be started at the dose of 500 mg / day for one week, increased to 500 mg p.o., b.i.d. for the next week, and maintained at 500 mg p.o. t.i.d. from the third week onwards.

Patients should be placed on a BBT chart while on Metformin therapy. Approximately, 35 % of patients will ovulate on Metformin and weight loss only within 2 to 3 months of therapy. For those patients who fail to ovulate on Metformin alone, Clomid can be added at a dosage of 50 mg / day for five days. 80-90% of those patients will ovulate on Metformin and clomiphene therapy.

c) Low dosage gonadotropin treatment (75 IU / day) can be used for those patients who fail to ovulate using the above regimens. It is important not to increase this dose for at least 12-14 days as the object in these patients is to make them ovulate and not to super-ovulate them. This treatment should only be used by a reproductive endocrinologist with experience in the use of Gonadotropins.

d) Laparoscopy with multiple electrocoagulations of the follicles (modern day wedge resection or "golfball" procedure) on the surface of the ovaries can be considered as a last resort as it is a surgical procedure and ovarian adhesions can result from it.

e) IVF can also be considered for these patients who should be watched for multiple pregnancy and ovarian hyperstimulation syndrome (OHSS).

2. Clomid Conception Failure:
This is defined as failure to conceive after six documented ovulatory cycles on clomiphene. These patients become like any other patients with unexplained infertility and care should be taken to complete the infertility work-up if it has not been done yet including a semen analysis, HSG, post coital test, endometrial biopsy and laparoscopy to check for pelvic adhesions and or / endometriosis.
What are our opinions for these patients:

a) Low dose gonadotropin use with IUI can be considered although these patients are at risk for multiple pregnancy and OHSS.

b) IVF should be strongly considered, as this can be a diagnostic as well as a therapeutic procedure.

Clomid patients should be properly monitored to maximize the success and guard against potential side effects, including adverse affects on the cervical mucus and ovarian cyst formation. Patients should not be put on Clomid for more than 3 cycles before re-evaluating the treatment.

Clomid use for longer than 12 cycles has been associated with an increase incidence of ovarian cancer; therefore, the medication should be used judiciously and whenever the benefits outweigh the risks.

Clomid is usually successful within 3 to 4 ovulatory cycles.Use beyond this time frame is generally not recommended. As such it is extremely important for the gynecologist to be familiar with the proper indications and the limitations of this therapy.

There are excellent discussions on Clomid at the Reproductive Care Center Web site and Huntington's Clomid domain. The Center for Human Reproduction, North Shore Long Island Jewish fertility center has Clomid information and several fertility videos.

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