Clomiphene Citrate

Clomiphene citrate is an oral ovulation induction drug. If a fertility problem stems from infrequent or absent ovulation, clomiphene citrate may be the first fertility treatment recommended. Because clomiphene citrate is relatively inexpensive, some physicians will go ahead and prescribe treatment after the initial battery of infertility tests. Most patients who are going to respond to therapy (i.e. ovulate) will do so in the first cycle, with three cycles being a sufficient trial for this drug therapy. If there is no evidence of ovulation after three cycles, further treatment with this drug is not recommended, and your diagnosis should be re-evaluated.

If clomiphene alone is not successful, doctors might combine it with other drugs. Some of these drugs, such as bromocriptine, dexamethasone (for high androgen levels), or gonadotropins might be used alone or in combination with other drugs.

Before this drug therapy is prescribed, ovulatory dysfunction should be confirmed through standard techniques, which may include basal body temperature (BBT) curves, cervical mucous monitoring, serial vaginal smears, endometrial biopsy, and an assessment of both adequate estrogen levels and the steroid pregnanediol. Any abnormal or excessive bleeding should be carefully assessed. Tests to rule out possible early pregnancy, liver dysfunction, pituitary problems, primary ovarian failure, diabetes, thyroid or adrenal disorders, or any mechanical impediments to conception (i.e. tubal blockage) should also be performed prior to beginning this drug therapy. A pelvic examination should be performed before each course of treatment to rule out the presence of ovarian cysts. Male factor infertility should also be ruled out by a semen analysis (or other examination if necessary).

While clomiphene may be a useful drug for women with ovulatory problems, it is not always suitable or successful in women with PCOS because these women may have an exaggerated response to usual doses.

How It Works

Clomiphene appears to facilitate ovulation by competing with the estrogen in your body for action on the pituitary gland. This is thought to increase the pituitary’s output of the gonadotropins FSH and LH, which in turn stimulate follicle growth and maturation.

Some women taking clomiphene may also receive an injection of hCG (human chorionic gonadotropin) to stimulate the corpus luteum, a cyst that forms on the ovary after ovulation, to produce progesterone. Others may be given  supplemental progesterone to ensure that the uterine lining is adequately prepared.

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How To Take It

Clomiphene is taken orally for 5 days, generally starting on or about day 5 of your cycle (day 1 is the first day of full menstrual bleeding). Progress can be monitored at home by tracking basal body temperatures (BBT) or using an over-the-counter ovulation predictor kit, however the healthcare provider should determine the best strategy for monitoring the drug’s effect. Some prefer that their patients visit the office, because multiple follicles may develop in response to clomiphene. A transvaginal ultrasound can be performed to monitor follicular development.

Couples are advised to have intercourse every other day for one week beginning a few days after the last day of medication, because an ovulatory surge of luteinizing hormone (an important gonadotropin) can occur six to twelve days after the last day the drug is taken.

The recommended dosage for treatment is starting at 50 milligrams daily for five days. Because the pregnancy rate may be only slightly higher at twice the dosage, starting at a high dosage is not recommended as the risks of ovarian overstimulation and other side effects may be expected to increase. However, if the first cycle does not cause ovulation, the second cycle will be at 50 milligrams higher – 100 milligrams daily for 5 days. If ovulation is not achieved at 100 milligrams, clomiphene failure will be cited, and new options will be explored.

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Side Effects

Side effects associated with clomiphene citrate are not prominent and infrequently interfere with treatment. Some concerns have been expressed over prolonged use of clomiphene. Short-term, closely monitored treatment is recommended.

More common side effects include hot flushes, abdominal discomfort, ovarian enlargement, and visual blurring.

A side effect that may interfere with response to this treatment is the blockage of the favourable effect of estrogen on mucous production by the cervix and vagina during drug administration and for several days afterwards. In some patients, cervical mucous may become ‘hostile’ and inhibit the ability of the sperm to swim from the vagina through the uterus and into the fallopian tubes where fertilization normally occurs. The absence of this side effect can be confirmed by a simple post-coital test that evaluates the nature of the cervical mucous and the ability of the sperm to enter and penetrate the mucous.

A more serious condition associated with clomiphene citrate (alone or in combination with gonadotropins) is ovarian hyperstimulation syndrome (OHSS). Symptoms of OHSS include abdominal pain and distension, nausea, vomiting, diarrhea, and weight gain. Severe OHSS is rare in patients receiving treatment with clomiphene citrate, but may result in severe ovarian enlargement, fluid in the abdomen or around the lungs, gastrointestinal symptoms, decreased urine output, and difficulty breathing.

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In properly selected patients, approximately 80% can be expected to ovulate, however not all women who ovulate on this therapy will become pregnant. The likelihood of success declines with increasing age, body mass index and amount of androgens. The discrepancy between ovulation and pregnancy may be due to other factors or lack of persistence.

Approximately 75% of pregnancies that do occur on clomiphene do so in the first three treatment cycles. The rate of twin pregnancies with this treatment is approximately 8-13%.

Couples shouldn’t be discouraged if clomiphene cycles do not result in a pregnancy, since this is one of several approaches. If treatment doesn’t result in a successful pregnancy, healthcare providers might combine clomiphene with other drugs, or try a different approach altogether, such as the use of gonadotropins.

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