Clomid is an oral medication that induces, or regulates, ovulation. Understanding how Clomid works is important to understanding how most fertility drugs effect ovulation. Clomid exerts its effects at the hypothalamus, the gland that signals the pituitary to produce FSH, LH, and estrogen. FSH products stimulate the ovaries directly and the response is dose related.

Clomid competes for estrogen receptors causing the hypothalamus to “read” lower estrogen levels. Healthy follicles produce estrogen which is monitored by the hypothalamus and FSH production is increased/decreased based upon estrogen levels. As estrogen levels increase, FSH production decreases. Conversely, lower estrogen levels cause an increase in FSH and subsequent follicular stimulation.

Clomid was one of the first infertility drugs in clinical use and was originally studied as a potential birth control medication. Clomid’s ovulation induction properties were discovered and physicians began to use it in women who ovulated irregularly or not at all. As Clomid usage continued, physicians discovered side effects including hot flashes, enlarged ovaries, abdominal discomfort, nausea, vomiting, visual disturbances, headache, and others. Clomid side effects are usually not severe and cease once Clomid is withdrawn.

Clomid does not stimulate the ovaries directly and once ovulation is occurring regularly there is no reason to increase the Clomid dose. If ovulation does not occur at 50mg of Clomid, physicians will often increase the dose to 100mg to 150mg. Pregnancies usually occur within the first three ovulatory cycles and Clomid therapy beyond this time is not recommended. Sometimes it takes one to two ovulatory cycles to establish the ovulatory dose for individual patients. Clomid cycles may be monitored by ultrasound to establish the proper timing of intercourse, or in cases of IUI, when to schedule the procedure. The ovarian follicles and the lining of the uterus are measured using transvaginal ultrasound. Proper growth of the follicles can be demonstrated using ultrasound and by measuring the estradiol hormone level.

Clomid is known to be effective usually within the first 3-6 cycles, however, we still see women who have been on Clomid for a year or longer. (Why it is important to see a fertility specialist especially if you have been taking Clomid) This extended Clomid treatment is unlikely to work, is expensive, and can cause deleterious side effects. Clomid is also used to treat PCOS but many specialists are now employing metformin which can facilitate normal ovulation by correcting insulin levels and thus lowering androgens (male hormones). Clomid is sometimes prescribed by non specialists without a male semen analysis. Infertility specialists always order a semen analysis prior to any treatment of the female. Some degree of male infertility is present in up to half of all infertile couples and it must be ruled out before beginning female therapy.

Clomid does not directly stimulate the ovaries; rather, Clomid facilitates ovulation and usually does not result in a high number of eggs. In fact, once ovulation is occurring regularly, there is no advantage to increasing the dosage.

Unlike Clomid, FSH does stimulate the ovaries directly and causes the recruitment and development of many eggs which are needed for an IVF cycle. FSH dosages and follicular development are monitored carefully by the fertility specialist and frequent dosage adjustments may be necessary.

Dependent upon many couple specific factors, FSH IUI may be attempted; however, IVF is often the “treatment of first choice”. Clomid may sometimes be used in IUI but it is less effective than FSH.

Letrozole, Femara
Many fertility specialists have begun to use Letrozole (Femara®) to facilitate ovulation sometimes in place of Clomid. Letrozole belongs to the class of drugs known as aromatase inhibitors which are currently approved by the FDA only for prevention of recurrent breast cancer.

However, research has demonstrated that Femara might be a useful fertility drug exerting its actions primarily by facilitating ovulation. Aromatase inhibitors work by blocking the enzymatic conversion of androgenic hormones to estrogenic hormones thus lowering the levels of estrogen. As discussed earlier, the hypothalamus measures the estrogen decreases and modulates the continued production of FSH. This usually leads to a fewer number of eggs being released during ovulation which is very important in PCOS patients.

Clomid seems to produce more deleterious side effects than Femara. Clomid side effects include decreased cervical mucus, thinning of the endometrial lining, psychological irritability, and others. The incidence of twins is 2-3% with Femara compared to 10% with Clomid. The addition of FSH injections to either Clomid or letrozole can increase the risk of multiples.

Letrozole may be harmful to a developing baby if taken while pregnant. A pregnancy test must be conducted prior to each treatment cycle. Further research is warranted in order to confirm that aromatase inhibitors are safe for use as ovulation agents.