Most fertility drugs work as ovulation-inducing agents. This includes Clomid (clomiphene citrate), which works at the hypothalamus located at the base of the brain, and FSH, which stimulates the ovaries directly.
Clomid
Clomid is a first-line fertility drug, often prescribed by OB/GYNs. It should only be used for three ovulatory cycles. Unfortunately, many physicians prescribe Clomid for longer periods, even though it is clear that success will most likely come within three cycles. The response to Clomid, unlike FSH, is not dose-dependent, so there is no advantage to increasing the dose once ovulation is occurring regularly.
Letrozole
Letrozole belongs to the class of drugs known as aromatase inhibitors. It causes a lowering of estrogen levels, like Clomid, although by a different mechanism. Clomid works at the hypothalamus to block estrogen receptors, whereas Letrozole blocks the conversion of androgens to estrogen hormones. This is particularly important in PCOS patients who have increased androgen production.
Letrozole produces fewer side effects, such as emotional instability and cervical mucus thinning that can be seen with Clomid. However, Letrozole can seriously damage a developing fetus and must not be used without a negative pregnancy test prior to each treatment cycle.
Letrozole and other aromatase inhibitors do not yet have an indication for ovulation induction, but they are being used for that purpose by infertility specialists.
Follicle Stimulating Hormone (FSH, gonadotropins, Menopur, Bravelle, Repronex, Follistim, Gonal-F and others)
FSH stimulates the ovaries to produce multiple follicles (each containing one egg), which are needed in assisted reproductive technology cycles (IVF). FSH is also used for ovarian stimulation in intrauterine insemination cycles.
Gonadotropin hormones have been used for many years to stimulate and regulate ovulation. FSH stimulates the ovaries directly. The ovarian response to gonadotropin number depends on many factors, and women with diminished ovarian reserve may not respond well to FSH.
Pergonal was the first gonadotropin hormone approved by the Federal Drug Administration for ovulation induction in women. Pergonal is extracted from the urine of post-menopausal women and contains equivalent amounts of both FSH and luteinizing hormone (LH). The second class of gonadotropins released were the urofollitropins, which includes Metrodin and Bravelle. These products are highly purified natural products (derived from urine) that contain FSH and only trace amounts of LH.
The product development cycle continued to move away from “impure” mixes of FSH and LH, with the goal of reducing and eventually eliminating LH. The next step in the purification process was the introduction of follitropin alfa under the trade names of Gonal-F and Follistim. These products are pure FSH, manufactured using advanced genetic engineering processes, that instructs mammalian cells to produce FSH in culture. They are 100 percent pure. These are the first FSH products that are not derived from the urine of post-menopausal women.
There has been extensive debate about the role of LH in ovulation induction, and many physicians believe better stimulation is achieved when small amounts of LH are present and the FSH dosage requirements are lower. Still others believe that pure FSH provides a better quality egg.
Each patient receives a personalized ovulation induction protocol that specifies the type of gonadotropin to be used, the dosage, and other information. Dosage adjustments are made based upon the female’s response, as well as ultrasound and estradiol monitoring. If a woman does not respond well to one protocol, she may be switched to another for a subsequent treatment cycle.
Patients undergoing ovulation induction with FSH must receive regular ultrasound examinations and have their estradiol blood levels checked to avoid side effects and to determine the correct medication dosage. Ultrasound is used to view the follicles as they develop on the ovaries, measure the width of the endometrium, and examine other internal organs.
Healthy follicles secrete estrogen as they develop. However, highly elevated levels of estrogen may indicate a potentially serious side effect known as hyperstimulation syndrome (OHSS). OHSS can best be avoided by vigilant monitoring and management of the cycle by a trained reproductive endocrinologist/infertility specialist. In fact, the physician information sheets for Gonal-F and Follistim specifically state that only a specialist should administer these products.
Luveris (LH), Ovidrel (hCG), Pregnyl (hCG)
In a natural cycle, once the follicles are mature and ready for ovulation, the hypothalamus signals the pituitary gland to release a surge of luteinizing hormone (LH). This surge initiates the final stages of egg development. In stimulated cycles, Lupron or Ganirelix may be used to control ovulation by blocking the LH surge seen in natural cycles. This prevents the eggs from being ovulated before they are ready or retrieved in IVF cycles.
The body recognizes hCG as LH, and hCG initiates ovulation in the same manner. Therefore, an injection of hCG is given in stimulated cycles once the physician judges the follicles are mature. Once the injection is given, the egg retrieval (or insemination in IUI cycles) is scheduled. Pregnyl, Novarel, Profasi, and others are all hCG products. Ovidrel is a highly purified form of hCG.
Luveris is a newly released product. It is a genetically engineered form of pure LH used in women who have severe LH deficiencies, as in hypogonadotropic hypogonadism. It is currently not indicated for use in ovulation induction, but is being used “off label” by many physicians.
Metformin (glucophage)
Metformin belongs to a class of drugs known as antihyperglycemics and is used to control insulin levels in type II diabetes. These patients have hyperglycemia, meaning the pancreas produces too much insulin for a given quantity of glucose. When a patient is “insulin resistant,” it means that the body tries to compensate for lower insulin levels by overproducing insulin. When the cells are “sensitized” to insulin by using metformin, circulating levels of insulin decline.
Patients with polycystic ovarian syndrome (PCOS) have chronically elevated insulin levels, leading to increased androgen (male hormones) production by the ovaries. Increased androgen levels can lead to irregular or no ovulation, excess body hair, increased LH, infertility, and other PCOS symptoms.
Metformin normalizes insulin levels, which in many cases reduces the level of androgens. Once androgens are reduced, ovulation will often occur spontaneously, and the other symptoms of PCOS mentioned above abate. Unlike FSH and Clomid, which stimulate ovulation, metformin reverses an abnormal state and allows normal ovulation to resume.
Many patients remain on metformin for the rest of their lives to counter the risks of chronically elevated androgen levels, which include increased risk for cardiovascular disease and diabetes.
Progesterone
Sometimes the endometrium will not thicken and develop properly to accept a developing embryo. When this occurs it is often termed a “luteal phase defect.” Externally administered progesterone will usually offset the deficiency and cause the endometrium to develop normally.
Gonal-F or Lupron are used in virtually all assisted reproductive technology cycles to control ovulation. A side effect is that these drugs interfere with the body's natural progesterone production; for this reason, progesterone is administered in virtually all assisted reproductive cycles.
Bromocriptine (Parlodel)
When a woman has an elevated prolactin level, it can cause ovulatory irregularities or failure. Prolactin is the hormone responsible for breast milk production in pregnant women and is often elevated in non-pregnant women because of a small tumor on the pituitary gland. This tumor is usually not malignant, and may sometimes be surgically removed. Bromocriptine lowers prolactin levels and is often an effective treatment for hyperprolactenemia.
