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 sometimes elevated in non-pregnant women, which can be due to a non-malignant tumor on the pituitary gland. If a tumor is present, it may be removed surgically by a neurosurgeon. Bromocriptine and Cabergoline lower prolactin levels and are often effective medical treatments for hyperprolactenemia.
Clomid was one of the first ovulation induction agents introduced. Clomid is used widely by OB/GYN’s as a first line treatment for infertility. Clomid is used to induce or regulate ovulation.
Infertility specialists complete a thorough workup to establish the cause(s) of infertility prior to starting therapy with Clomid or other fertility drugs. Male infertility must be ruled out before any female therapy begins.
Clomid does not directly stimulate the ovaries; rather, it works in the brain at the hypothalamus and pituitary gland. The hypothalamus is the part of the brain that produces gonadotropin releasing hormone (GnRH) to stimulate the pituitary gland to release follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH then act on the ovary to stimulate development of eggs. Each egg is surrounded by cells and fluid that support development (a follicle).
When the hypothalamus measures lower levels of estrogen (produced by developing follicles), it responds by releasing GnRH to increase FSH production. Clomid works by “blocking” estrogen receptors at the hypothalamus. This blockade by Clomid causes the hypothalamus to “measure” lower estrogen levels thus increasing FSH production. Once ovulation is occurring regularly on Clomid there is no advantage to increasing the dosage.
Clomid should generally be used for a short time period. Clomid is usually started at 50mg per day on cycle days 3, 4, or 5 calculated from the first day of the menstrual period and continued for 5 days. If ovulation does not occur at 50mg, the dosage can be increased in 50mg increments to 150mg.
Historically, Clomid has sometimes been prescribed for long periods by generalists, which can lead to deleterious side effects. Pregnancy is most likely to occur during the first three months and after this period success rates decline precipitously. Infertility specialists usually move to the next therapy, such as stimulated IUI, after 3 failed Clomid cycles.
Clomid can cause thickening of the cervical mucus making it more difficult for the sperm to reach the eggs, and it can produce other side effects such as moodiness, hot flashes, vaginal dryness, and headache.
Many infertility specialists are using Femara (letrozole) as an ovulation induction drug, particularly for patients who have side effects with Clomid. Letrozole is an aromatase inhibitor. Aromatase synthesizes the conversion of androgens to estrogen, so blockage lowers estrogen levels causing the hypothalamus to release GnRH thus increasing FSH. Letrozole is less likely to adversely affect the cervical mucus or endometrium. Its use for ovulation induction is growing, but use of it for this purpose is considered “off label”, as it has not approved by the FDA for this specific purpose.
Letrozole must not be given to pregnant women. It has a shorter half-life in the body and fewer side effects compared to Clomid, so its advantage is that patients can begin a second cycle of Letrozole in the month following the first cycle, with no drug leftover in the body.
Clomid is a useful first line fertility drug when used judiciously after a complete evaluation of the female and male.
The fertility drug FSH stimulates the ovaries to produce multiple follicles (each containing one egg), which are needed in assisted reproductive technology cycles (IVF) and stimulated IUI. FSH is produced by the pituitary gland.
Fertility drugs containing gonadotropin hormones (FSH, LH) have been used for many years to stimulate ovarian follicular development. FSH stimulates the ovaries directly and the response depends on many factors.
Pergonal was the first FSH containing fertility drug 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 gonadotropin fertility drugs released were the urofollitropins, which includes Metrodin and Bravelle. These fertility drugs are highly purified natural products (derived from urine) that contain FSH and only trace amounts of LH.
Fertility drug development 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 fertility drugs are pure FSH, manufactured using advanced genetic engineering processes that instructs mammalian cells to produce FSH in culture. They are 100 percent pure.
Based on your specific diagnosis, at Baystate Reproductive Medicine, we may use all FSH or a mix of FSH and LH to achieve optimal results for you.
Each patient receives a personalized ovulation induction protocol that specifies the fertility drugs, their dosages, administration, and other information. Dosage adjustments are made based upon the response, which is monitored by ultrasound, estradiol levels, and physical exam. Monitoring reduces the incidence of fertility drug side effects and helps measures follicular development. If a woman does not respond well to one protocol, she may be switched to another for a subsequent treatment cycle.
Healthy follicles secrete estrogen as they develop. However, highly elevated levels of estrogen may signal a potentially serious side effect known as ovarian 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 an infertility specialist should administer these products. Fortunately, the incidence of serious side effects is low when these drugs are administered by a reproductive endocrinologist.
Letrozole belongs to a class of drugs known as aromatase inhibitors, originally introduced to treat breast cancer, and it is now being used "off label" as a fertility drug. Letrozole 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. This "estrogen lowering effect" causes the hypothalamus to signal increased FSH production by the pituitary. Letrozole may be an important fertility drug for ovulation regulation in PCOS patients who have increased androgen production. Letrozole produces fewer side effects than Clomid, such as fewer hot flashes and less moodiness.
The fertility drug Lupron was originally introduced to treat endometriosis in women and prostate cancer in men. Lupron works by inhibiting the production of gonadotropin releasing hormone (GnRH). GnRH signals the pituitary to produce FSH and LH, and estrogen levels increase. Endometriosis cells are dependent upon estrogen for growth, and when GnRH is inhibited, estrogen levels fall causing a reduction in endometriosis implants. While Lupron is often effective, many women will need laparoscopic surgery to remove extensive endometriosis and cut scar tissue.
Lupron is used in stimulated cycles (IVF and sometimes in IUI) to allow the specialist to control follicular development and prevent premature ovulation. FSH is administered and follicular development is followed via ultrasound and estradiol hormone levels. In a natural cycle, a surge of LH causes ovulation but this is blocked by Lupron's actions. In IVF, ovulation must not occur prior to egg retrieval or the cycle would be cancelled. Once the follicles mature, an injection of hCG is administered to finally prepare the eggs and retrieval is scheduled.
Ganirelix and Cetrotide (GnRH antagonists) are also fertility drugs that block release of the egg. The difference is that ovulation can be blocked more quickly with GnRH antagonists, so they are usually started only a couple of days before follicles are mature. However, since the body's production of FSH is lowered more than it is in Lupron cycles, higher doses of FSH are sometimes required. With Lupron, final maturation of the eggs cannot occur until an injection of hCG is given.
In FSH stimulated cycles, the fertility drugs 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 mature or can be retrieved for the IVF cycle. 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 and causes ovulation.
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 large enough to cause final egg maturation. Once the injection is given, the egg retrieval (or insemination in IUI cycles) is scheduled. The fertility drugs Pregnyl, Novarel, Profasi, and others are hCG products. Ovidrel is a genetically engineered pure hCG fertility drug.
Metformin belongs to a class of fertility 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 inability of the cells to take up glucose and insulin 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 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 may abate. Metformin may also help patients reduce weight, which increases the chance for spontaneous ovulation. Unlike FSH and Clomid, which stimulate ovulation, metformin reverses an abnormal state and allows normal ovulation to resume.
Many patients remain on metformin for years to counter the risks of chronically elevated glucose and insulin, which may help reduce the risk for diabetes and cardiovascular disease.
Sometimes the endometrium does not thicken and become more vascular in preparation for a developing embryo. Externally administered progesterone will usually offset the deficiency and cause the endometrium to develop normally. Progesterone is always used in cycles where patients are "downregulated" with drugs such as Lupron or Antagon. These drugs block the body's natural progesterone production.