Clomid was one of the first fertility medications introduced in the United States. Interestingly, it was first studied as a means of birth control. Clomid is prescribed by obstetrician/gynecologists and reproductive endocrinologist/infertility specialists to regulate or induce ovulation.

Clomid exerts it ovulatory effects indirectly by its actions at the hypothalamus. The hypothalamus is located at the base of the brain and serves as the regulator for the reproductive hormone system known as the hypothalamic-pituitary-adrenal axis. In order to understand Clomid’s actions, it is necessary to have a basic understanding of this system.

The hypothalamus manufactures several specific hormones known as gonadotropin releasing hormones or GnRH. GnRH stimulates the pituitary production of follicle stimulating hormone (FSH). FSH directly stimulates the recruitment of ovarian follicles, each of which contains one egg. As healthy follicles develop, they produce increasing amounts of estrogen which is monitored by the hypothalamus. As estrogen levels increase, the hypothalamus adjusts the production of FSH.

Once the follicles reach maturity, the hypothalamus produces GnRH which travels to the pituitary and stimulates a surge in the production of luteinizing hormone (LH). LH initiates the final processes of follicular maturation and stimulates ovulation 34-36 hours later.

After successful ovulation, the remaining follicular structure, known as the corpus luteum, begins to produce progesterone. Progesterone is needed for the proper thickening and vascularization of the lining of the uterus (endometrium). The lining must develop to properly support an implanting embryo and later the fetus.

Clomid works by competing for estrogen binding sites at the hypothalamus. When Clomid occupies these receptor sites, estrogen cannot attach to them and the hypothalamus measures lower estrogen levels leading to increased production of FSH.

The major limitation to Clomid’s use is its limited ability to produce a pregnancy after three ovulatory cycles of treatment. Numerous studies demonstrate that pregnancy is most likely to occur during the first three ovulatory cycles. Clomid can also produce side effects such as thickening of the cervical mucus which can impede the sperms progress. Clomid has also been linked to an increased chance of multiple birth, ovarian enlargement and pain, and others side effects.

Even though Clomid’s use beyond three to six ovulatory cycles is not recommended, we see patients who have been taking it for 8 months or much longer. The chance of a Clomid pregnancy in these patients is extremely low and the treatment is expensive. Most reproductive endocrinologist/infertility specialists move patients on to other therapies such as stimulated IUI or IVF.

We also see patients who have taken Clomid in the absence of a male semen analysis. No treatment in the female is effective without enough good quality sperm to initiate a pregnancy. The semen analysis is a mandatory part of the initial infertility workup.

Clomid is usually prescribed as 50 mg per day on the cycle days indicated by the physician. If ovulation does not occur on the 50 mg the dose is increased to 100 mg and to a maximum of 150 mg/day.

Letrozole bellows to a class of drugs known as aromatase inhibitors which decrease estrogen production by the ovaries. The hypothalamus measures this decrease in estrogen levels and concomitantly signals the pituitary to increase FSH production. Because of its estrogen lowering effect, letrozole has been used to treat endometriosis and induces ovulation.

Clomid also reduces estrogen levels by competing with estrogen binding sites at the hypothalamus. Letrozole does not cause the “cervical mucus thickening” seen with Clomid.

Studies with patients who failed Clomid therapy indicate that letrozole may work in many of these cases. Letrozole may also augment Clomid therapy since both drugs “reduce estrogen” albeit by different mechanisms. It has also been used successfully in combination with FSH reducing the total amount of FSH required. One additional clinical finding is that endometrial development seems to be enhanced by letrozole.