FSH is produced by the pituitary gland and stimulates ovarian follicular recruitment and development. Each follicle contains one egg that must mature prior to ovulation. Inadequate FSH hampers follicular development and leads to irregular, or no, ovulation.
FSH is commonly administered to induce ovulation in stimulated intrauterine insemination (IUI) and IVF cycles. FSH is used in IVF to cause the development of numerous eggs, which are needed for the procedure.
FSH products can be divided into two categories: 1) urinary derived or natural and 2) pure products manufactured using genetic recombinant technologies. One of the major differences in these categories is the amount of luteinizing hormone present.
Urinary products, such as Repronex, are derived from the urine of postmenopausal women and each ampule contains 75 IU of FSH and 75 IU of LH. Bravelle is also a highly purified urinary product which contains 75 IU of FSH and only 2% LH. Several different brands of these products are available.
Throughout product development the trend has been to increase FSH purity while eliminating "impurities", including LH. Gonal-F and Follistim were the latest market entries and both are pure FSH produced using genetic recombinant technologies. They are identical to the FSH produced by the body and notably contain no LH.
LH is required for adequate estrogen production and endometrial development. There is much debate over the need for additional LH in ovulation induction (IVF) cycles because patients are down regulated meaning they do not produce FSH or LH.
Some believe that pure FSH products produce higher quality eggs and others feel that adding small amounts of LH, by using products such as Repronex, leads to a better stimulation cycle by replacing the LH that would be produced normally.
Drug protocols are individualized and different medications are employed by the infertility specialist dependent upon each patient's response and other factors. A protocol may include pure FSH (Gonal-F, Follistim), a urinary product (Repronex), or both. Most of these products can be administered subcutaneously.
Originally introduced to treat breast cancer, letrozole belongs to a class of drugs known as aromatase inhibitors. Aromatase inhibitors block the conversion of androgens into estrogenic hormones. Letrozole's ultimate effect is to lower estrogen levels as does Clomid albeit by different mechanisms. Lower estrogen levels signal the hypothalamus to increase FSH production by the pituitary.
Letrozole seems to minimize the number of eggs produced in ovulation induction which is particularly important in patients with PCOS.
Clomid competes for estrogen receptors at the hypothalamus but also effects receptors at the cervical glands which can lead to "poor" cervical mucus.
Clomid can also lead to impaired endometrial development. One benefit of letrozole is that it does not appear to harm the cervical mucus or endometrium because it does not bind the estrogen receptors.
Letrozole may be harmful to a developing baby and must not be given during pregnancy. A pregnancy test is performed prior to initiating therapy. The usual dose of Femara is 2.5 mg. on cycle days 3-7 and it is sometimes combined with FSH.
Lupron was initially introduced to treat endometriosis and prostate cancer in men. Lupron works by inhibiting the production of gonadotropin releasing hormone (GnRH). GnRH normally signals the pituitary to produce FSH and LH and estrogen levels increase. Endometrial cells are dependent upon estrogen and when GnRH is inhibited, estrogen levels fall effectively "starving" the endometrial tissue.
Lupron is used in stimulated cycles (IVF) 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 cycles. In IVF, ovulation must not occur prior to egg retrieval or the cycle would be "lost". Once the follicles mature, an injection of hCG, or LH, is administered to finally prepare the eggs and retrieval is scheduled.
Ganirelix and Cetrotide (GnRH antagonists) produce the same down regulation results as Lupron. The difference is that rather than inhibit GnRH production, it is "blocked" at the pituitary gland. This leads to a "stronger" down regulation and a shorter treatment period. However, since the body's production of FSH is completely blocked, higher doses of FSH are sometimes required.
Like Lupron, ovulation cannot occur until an injection of hCG or LH is given.
Metformin is classified as an antihyperglycemic and is used to treat Type II diabetes. These diabetic patients have elevated insulin levels, a condition known as hyperinsulenemia. Metformin works by increasing the pancreatic cells sensitivity to insulin thus lowering insulin production.
Patients with polycystic ovarian syndrome (PCOS) usually have chronically elevated insulin levels. When this occurs, the physiologic effect is to cause the ovaries to produce more androgens (male hormones). Clinical findings in PCOS patients are reflective of higher androgen levels and can include ovaries covered by numerous unruptured cysts, increased body hair, obesity, lowering of the voice, irregular or no ovulation (infertility), increased LH levels, and others.
Since metformin causes lower insulin levels, androgen production by the ovaries in PCOS patients is diminished thus often allowing normal ovulation to resume.
This is unlike other drugs, such as FSH, that stimulate ovulation. Chronically elevated insulin levels can lead to negative long term health consequences such as cardiovascular disease. For this reason, patients sometimes continue metformin therapy after infertility treatment.
hCG is normally produced by the placenta once pregnancy is established. The body responds to a surge of hCG in the same manner as LH thus causing ovulation. hCG is administered in cycles down regulated by Lupron, Ganirelix, or Cetrotide where the body's production of LH is blocked. In IVF, hCG is given to finally prepare the eggs for retrieval which is scheduled after the injection. In stimulated IUI, hCG is often given to initiate ovulation and facilitate timing of the inseminations.
Luveris is pure LH produced using genetic recombinant technologies and is approved for use in combination with FSH in women with severe FSH and LH deficiencies. Many times drugs are used by physicians in conditions where they may not be specifically indicated.
Some believe that adding small amounts of LH to the stimulation protocol results in a better stimulation (higher estrogen levels). Luveris is also used in place of hCG to stimulate ovulation. The major disadvantage to using recombinant LH is increased cost.
The role of progesterone is to support endometrial development. The endometrium must thicken and become more vascular to support the developing embryo. Initially, progesterone is produced by the follicular structure, known as the corpus luteum, remaining after ovulation. After pregnancy is established, progesterone is produced by the placenta.
Sometimes the endometrium will not develop properly during the luteal phase, a condition known as a luteal phase defect. Progesterone is often administered to correct this defect by promoting endometrial development.
Progesterone is administered in IVF cycles because Lupron/Ganirelix/Cetrotide interferes with its natural production.
Prolactin stimulates the production of breast in pregnant women. Hyperprolactenemia exists when a non-pregnant woman has abnormally high levels of prolactin which can lead to irregular or no ovulation. It is sometimes due to a small nonmalignant tumor on the pituitary gland which may require surgical removal.
Parlodel reduces the level of prolactin allowing normal ovulation to resume.