Fertility Drugs

Clomid

Clomid was one of the first medications employed as an ovulation-inducing agent and enjoys widespread use by obstetrician/gynecologists and reproductive endocrinology & infertility specialists. Interestingly, Clomid was first studied as a potential birth control agent. Clomid exerts it actions at the hypothalamus, which is a small gland at the base of the brain.

The hypothalamus can be thought of as the “reproductive hormone production” regulator. It monitors the levels of various hormones including estrogen, FSH, and LH and adjusts production accordingly. For example, as levels of estrogen increase the hypothalamus signals a corresponding reduction in FSH production. This relationship is known as the “hypothalamic pituitary adrenal axis”.

The hypothalamus produces gonadotropin-releasing hormone, (GnRH) which travels to the pituitary and causes increased production of gonadotropin hormones (i.e. FSH). Clomid works by “blocking” estrogen receptors at the hypothalamus thus causing increased production of GnRH, which stimulates continued FSH production by the pituitary. Increased FSH stimulates follicular recruitment and development.

Clomid is very often overused. Many well controlled studies have demonstrated that pregnancy is most likely to occur during the first 3-6 ovulatory cycles of Clomid and therapy beyond that time is not recommended. Yet, we still see women who have been on Clomid for much longer times, sometimes without a semen analysis. No therapy of the female should be initiated until a semen analysis has been performed.

Clomid is used primarily in women who ovulate irregularly or not at all and in some cases of unexplained infertility. For women aged 35 and older, it is advisable to undergo a complete fertility evaluation prior to beginning Clomid therapy. Sometimes fertility declines very rapidly in this age group.

Rarely, women using Clomid will have "thin" cervical mucus or a poorly developed endometrial lining during stimulation. This can be easily overcome with the use of injectable medication (such as Gonal-F, Follistim, Repronex, Bravelle, Menopur) in combination with clomiphene citrate. The combination of clomiphene citrate and injectable medication will quadruple the pregnancy rates while minimizing the monitoring with pelvic ultrasound and blood levels of estradiol.

Most women experience no side effects with Clomid therapy. See the Clomid manufacturers Web site for a complete listing of potential side effects.

Letrozole

The fertility drug letrozole is as an aromatase inhibitor and is used to induce ovulation. Letrozole is used in women who do not ovulate or in women with unexplained infertility. It works by blocking the enzyme that converts androstendione and testosterone to estrone and estradiol.

By lowering circulating estrogen it will release the hypothalamus from the negative feedback of estrogen causing an increase in GNRH (Gonadotropin releasing hormone) which leads to an increase in FSH (Follicle stimulating hormone) and LH (leutinizing hormone) secretion. The secretion of these two hormones stimulates the growth of ovarian follicles.

A second mechanism of action of letrozole in promoting ovulation is increased ovarian follicle sensitivity to FSH. Letrozole has also been shown to not have the adverse effects on the endometrium that is typically seen with Clomid.

Letrozole may be particularly useful in women withPCOS (Polycystic Ovarian Syndrome) who fail to ovulate with Clomid. The number of follicles achieved with letrozole appear to be less than clomid leading to a very low multiple pregnancy rate of less than 5%.
Letrozole can also be used in combination with injectable gonadotropins (FSH or FSH and LH) to induce ovulation. This combination has been shown to reduce the total amount of injectable medication used while improving ovarian response to FSH stimulation.

Letrozole Side Effects

Side effects from letrozole are rare but some of the effects described below have been described:

• Hot flashes
• Headaches
• Leg cramps

One case report of increased risk of congenital anomalies in 6 of 150 pregnancies

Follicle Stimulating Hormone (FSH)- Gonal-F, Follistim, Repronex, Bravelle, Menopur

FSH causes the recruitment, and supports the development, of the ovarian follicles, each of which contains an egg. The pituitary gland produces FSH after it is stimulated with gonadotropin releasing hormone (GnRH), which is released by the hypothalamus.
Injectable FSH is used in assisted reproductive technology cycles, usually for 7-10 days, to stimulate the recruitment and development of multiple eggs, which are needed for procedures such as IVF andIVF/ICSI.

Patients undergoing ovulation induction with FSH are carefully monitored using vaginal probe ultrasound and E2 hormone measurements to insure follicular development and avoid serious side effects. The ultrasound determines follicle size and count. It is also used to assess the thickness of the endometrium (lining of the uterus), and monitor follicular development. If the lining is thin, it may indicate a hormonal problem.
Dosages of FSH are adjusted based upon the information from estradiol levels and ultrasound evaluation.

The first “FSH containing product” was Pergonal, which consisted of 75 IU of FSH and 75 IU of LH. Newer products include Gonal-F and Follistim which are pure FSH products (no LH or other impurities) derived using genetic recombinant technology. Repronex is a natural product extracted from the urine of postmenopausal women, which contains both FSH and luteinizing hormone (LH). The major advantage of Repronex is that it is less expensive. These medications can be administered subcutaneously.

The most severe adverse effect associated with FSH is ovarian hyperstimulation syndrome (OHSS) which occurs in approximately 1% if cases. These drugs must always be administered by a specialist (reproductive endocrinologist) thoroughly trained in their use.

Symptoms of OHSS usually occur one week pos hCG injection and an include:

• Ovarian enlargement
• Pelvic pain
• Weight gain
• Abdominal swelling

The risk for ovarian hyperstimulation is increased in-patients diagnosed with polycystic ovarian syndrome (PCOS)

hCG (human chorionic gonadotropin)-Pregnyl, Novarel; r-hCG Ovidrel, Luveris (r-LH)

Once the ovarian follicles mature, the hypothalamus signals the pituitary gland to release a surge of luteinizing hormone (LH). This surge of LH is responsible for initiating ovulation of the mature eggs. The ovary responds to a spike in human chorionic gonadotropin (hCG) in the same manner as LH, thus ovulation will occur after an injection, or spike, of hCG.

hCG is available as Pregnyl and Novarel, which are natural products, derived from placental tissue. hCG is also available as Ovidrel, which is pure r-hCG, manufactured using genetic recombinant technology. The major advantage of Pregnyl and Novarel is that they are less expensive than Ovidrel.

Luveris is recombinant LH (r-LH) and is indicated for the treatment of patients with severe hypothalamic hypogonadism (extremely low levels of LH). Luveris may offer an advantage in “sweetening” FSH protocols or inducing ovulation but this remains to be demonstrated.

Progesterone

Progesterone is a hormone that supports the development of the endometrium, which is the lining of the uterus. The endometrium must thicken and become more vascular to support the growth of a developing embryo. When the endometrium does not develop properly it is sometimes due to inadequate progesterone during the luteal phase, known as a luteal phase defect.

Once the follicles mature and are ovulated, the remaining follicular structure on the ovary is known as the “corpus luteum”. The corpus luteum begins production of progesterone to support initial embryonic development. Once the placenta forms it begins progesterone production to support the growth of the fetus. IVF patients receive progesterone because medications such as Lupron or Ganirelex interfere with its natural production.

Progesterone can be given in many forms including injection, vaginal troche, vaginal suppositories and oral micronized capsules.

Parlodel (bromocriptine)

Once a woman becomes pregnant, the pituitary gland increases the production of prolactin, which is known as the "breast milk" hormone. As the name implies, prolactin is responsible for stimulating the production of breast milk in pregnant women.

When the prolactin level is elevated in women who are not pregnant, the condition is known as hyperprolactinemia, which can lead to irregular, or no ovulation. In some cases, hyperprolactinemia is caused by a small non-malignant tumor within the pituitary gland. When a tumor is present, surgical removal is usually the "first line" treatment. In other cases, bromocriptine is administered to medically lower prolactin levels.

Lupron (GnRH Agonist), Ganirelix, Cetrotide (GnRH antagonist)

GnRH is produced by the hypothalamus and travels through the bloodstream to the pituitary where it controls the production of FSH and LH. The hypothalamus works like a “thermostat” and increases, or decreases, the production of GnRH based upon hormone levels. For example, as estrogen levels increase signaling follicular development, the hypothalamus begins to reduce FSH production.

Lupron, a commonly used fertility drug, works by competing with receptors at the hypothalamus while Cetrotide and Ganirelix work to directly block GnRH at the pituitary. Since Ganirelix and Cetrotide block GnRH, they produce a more profound, and quicker, down regulation. Patients undergoing ovulation induction with the fertility drug FSH must come to our office regularly for estradiol hormone measurements and ultrasound evaluation.

In order for ovulation to occur, the hypothalamus must signal the pituitary gland to release a surge of LH. This cannot occur while a patient is taking Lupron, Ganirelix or Cetrotide because the action of GnRH on the pituitary is blocked. This is the primary reason these drugs are used in assisted reproductive technology (ART) cycles. Ovulation must not occur prior to egg retrieval or the stimulation cycle would be “lost”. When the eggs are mature an injection of hCG (the body reacts to hCG like LH) is given and retrieval is scheduled.

One characteristic of Lupron therapy is that there is an initial spike in FSH production when the drug is first started followed by dramatic suppression. The “flare protocol” makes use of this physiologic characteristic by beginning FSH during the initial suppression resulting in higher initial FSH levels.

Metformin

The fertility drug metformin (glucophage) first enjoyed widespread use in patients with diabetes because it sensitizes the cells in the pancreas to insulin, thus lowering insulin production to normal levels.

Glucophage (metformin) is being used to treat anovulatory (don’t ovulate) women with polycystic ovarian syndrome (PCOS), a relatively common cause of female infertility. Between 40-70% of women with PCOS will be hyperinsulinemic meaning they have chronically elevated insulin levels.

PCOS patients usually have elevated androgens (male hormones, i.e. testosterone) which are responsible for many of the symptoms of PCOS. Symptoms can include excess body hair (hirsuitism), hyperinsulinemia, increased chance of miscarriage, obesity, classic pear shaped body appearance, and ovaries typically covered with numerous small cysts.

The chronic elevation of insulin leads to the overproduction of androgens and LH by the ovaries ultimately leading to irregular, or failed, ovulation. Hyperinsulinemic patients don’t respond appropriately to a given level of insulin and continually secrete insulin to try and reach the appropriate physiologic “balance”. Thus, a cycle of continuing anovulation is established.

Metformin does not stimulate, or cause, ovulation like other fertility drugs including Clomid and FSH. It establishes a correct physiologic balance by causing insulin production to decrease to normal levels. When this is achieved, the ovaries no longer “over produce” androgens and ovulation will often resume.

Metformin is usually administered at a dose of 500 mg three to four times daily (1500-2000 mg daily). Metformin in combination with Clomid or letrozole has been shown to have substantial improvement in ovulation and higher pregnancy rates compared to Clomid or metformin alone.

For women with PCOS, metformin has been shown to decrease miscarriages, improve pregnancy rates and decrease the risk of gestational diabetes mellitus. Long term benefits of metformin include decrease in the risk of diabetes mellitus, improvement of hyperandrogenism, includinghirsutism, and normalizing the menstrual cycle.