Clomid and Oral Agents for Ovulation

Oral Agents for Ovulation Induction
Clomiphene Citrate and Letrozole

Clomiphene

What is Clomiphene and How Does It Work?

Clomiphene (Clomid™ is a common brand name) has been used to induce ovulation for more than 40 years. It acts as an antagonist to estrogen in the central nervous system by binding to estrogen receptors. This interference with estrogen signaling results in the hypothalamus (a structure in the base of the brain) stimulating the pituitary gland (a structure in the base of the brain) to increase the production of gonadotropins (i.e. follicle stimulating hormone (FSH) and leutinizing hormone (LH)). The increase in FSH stimulates growth of ovarian follicles (fluid filled structures in the ovary that contain developing oocytes).

Ovulation Induction

Clomiphene is an oral medication that is used to induce ovulation in anovulatory patients. This medication is usually given for five days following the onset of a menstrual period. In this setting, clomiphene is given in variable doses to achieve ovulation. To limit side effects and decrease unwanted consequences such as decreased cervical mucous production and alteration of the endometrium (lining of the uterus), the lowest effective dose of clomiphene is used. About 90% of appropriately chosen patients with anovulation will respond to clomiphene citrate.

Clomiphene Use For Unexplained Infertility

Clomiphene may also be used for some patients with normal ovulation who have unexplained infertility. In this situation, clomiphene therapy is usually combined with intrauterine insemination (IUI). The IUI may be timed by several methods that include monitoring of urine for an LH surge, or by performing vaginal ultrasound examinations to time administration of an injection of hCG which will induce ovulation.

Side Effects of Clomiphene

In the short term, the majority of side effects of clomiphene result from a perceived drop in estrogen by the central nervous system. This may result in hot flushes and mood swings. Less commonly, clomiphene may cause headaches and visual changes. Patients are instructed to notify their physician if headache and visual changes occur as clomiphene therapy may need to be discontinued.

Clomiphene is associated with an increase rate of multiple gestations. In the general population, the rate of twins is roughly 1:90. The rate of twins in patients conceiving with clomiphene is about 5-7%. Triplets in pregnancies conceived using clomiphene occur in about three per thousand pregnancies. In the general population, the rate of triplet pregnancies is approximately 1:8000. Higher order multiple pregnancies (i.e. quadruplets or greater) are quite uncommon with clomiphene.

Monitoring of Patients Taking Comiphene

Ovarian cysts may form in patients taking clomiphene. These cysts are benign and will almost always resolve spontaneously without further therapy. They are referred to as follicular cysts and result from the development of smaller follicles that do not ovulate.

If a patient does not conceive in a given cycle with clomiphene, and a subsequent treatment is planned, patients are seen in the office prior to repeating the therapy. An ultrasound is usually performed to confirm that a significant follicular cyst has not formed. These follicular cysts are a possible side effect of clomiphene treatment. There is a potential risk of stimulating growth of these cysts if clomiphene is given. For this reason, therapy may need to be delayed until the following menstrual cycle and the cyst has resolved

Letrozole

What is Letrozole and How Does It Work?

Letrozole (Femara™ is the brand name) is an aromatase inhibitor that is taken orally. Aromatase is an enzyme that is necessary for the ovaries to produce estrogen. Although this medication is approved for treatment of breast cancer, letrozole is not like most “chemotherapies” for cancer. It is useful for the treatment of breast cancer as these tumors are usually dependent upon estrogen for growth. Letrozole greatly decreases estrogen production.

The decreased estrogen production resulting from letrozole administration leads to ovulation induction. A decrease in estrogen results in the hypothalamus (a structure in the base of the brain) stimulating the pituitary gland (a structure in the base of the brain) to increase the production of gonadotropins (i.e. follicle stimulating hormone (FSH) and leutinizing hormone (LH)). The increase in FSH stimulates growth of ovarian follicles (fluid filled structures in the ovary that contain developing oocytes). Thus, letrozole works along the same pathway as clomiphene by interfering with estrogen stimulation of the central nervous system. Clomiphene inhibits estrogen receptors in the brain (see above), while letrozole inhibits estrogen production.

Use of Letrozole

Letrozole may be used to induce ovulation in anovulatory patients. In addition, it may be used in patients with unexplained infertility.

Side Effects of Letrozole

The majority of side effects of letrozole result from a drop in estrogen. The decreased action of estrogen on the central nervous system may result in hot flushes and mood swings. Less commonly, letrozole may cause headaches. Patients are instructed to notify their physician if headache occurs as letrozole therapy may need to be discontinued.

Letrozole results in the formation of slightly fewer follicles than occurs with clomiphene therapy. Although there is an increased rate of multiple gestations (e.g. twins) with letrozole the rate is expected to be lower than with clomiphene (see above).

Letrozole vs Clomiphene, Which One?

There is a theoretic advantage of letrozole compared with clomiphene. Letrozole is metabolized and eliminated by the body much more quickly than clomiphene. Hence, there may be fewer adverse effects on cervical mucous production and on endometrial receptivity (the ability of the endometrium to allow for implantation of an embryo). Some studies have shown higher pregnancy rates with letrozole than with clomiphene. However, this remains a matter of controversy as other studies have found similar pregnancy rates. Moreover, clomiphene has been used for ovulation induction for a much longer period of time (more than 40 years) than letrozole.

Monitoring of Patients Taking Letrozole

Ovarian cysts may form in patients taking letrozole. Like the cysts that form in patients taking clomiphene (see above), these are benign and will almost always resolve without further therapy.

Like patients taking clomiphene, if a patient does not conceive in a given cycle with letrozole, and a subsequent treatment is planned, patients are seen in the office prior to repeating the therapy. This is done to confirm that there are no residual cysts on the ovary prior to initiating further therapy.

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