Fertility drugs and their mechanism of action
Normally, a single egg ovulates from a single follicle mid-way through a cycle that is 26 to 32 days in length. The processes of follicle growth, ovulation, and production of progesterone from the corpus luteum are controlled by hormones produced in the pituitary gland called gonadotropins. The principle gonadotropin of the first part of the cycle (follicular phase) is follicle stimulating hormone (FSH). FSH is responsible for the growth of the follicle and with its production of estradiol (the principle estrogen of the ovary). A second gonadotropin, luteinizing hormone (LH), is responsible for the final stages of oocyte development, ovulation and the conversion of the follicle to the corpus luteum (luteinization). LH is present in small quantities, except at mid-cycle when a burst, or “surge,” is released.
In PCOS, the normal mechanisms of hypothalamic-pituitary-ovarian (HPO) axis and therefore, follicle growth and ovulation, are disturbed. “Fertility drugs” are commonly used in an attempt to temporarily override the problem and facilitate ovulation. The traditional fertility agents, clomiphene citrate (CC) (Clomid, Serophene) and various preparations of injectable gonadotropins, both create a “super”-physiologic situation where an ‘extra push’ is given for follicular development. All fertility drugs increase the stimulation of the ovary by increasing the concentration of gonadotropins available to stimulate the ovary. CC causes a release of the body’s own gonadotropin stores and indirectly stimulates the ovaries, while the injectable gonadotropins stimulate the ovaries directly.
One of the drawbacks of all fertility drugs is that they tend to work in only one cycle (month). The developing follicle may take as long as three months (cycles) to go through the entire process of growth and maturation. For the PCOS patients, this means that the follicle and its egg have progressed through its early stages of growth in an abnormal hormonal environment that may contribute to poorer egg quality despite aggressive stimulation.
Clomiphene citrate (CC) CC probably is the first-line therapy in PCOS patients who want to become pregnant. In comparison, it is quite safe, inexpensive, easy to use and offers chance of pregnancy in the initial month of use. It works by a pharmacological trick that promotes the release of the pituitary gland’s own storage of gonadotropins (FSH and LH). CC is not a hormone, but a synthetic “anti”-estrogen. As such, it ‘fools’ the body’s regulatory mechanisms into perceiving that more estrogen is needed. This challenge is met by gonadotropin release and hopefully a breakdown in the barriers to successful follicle growth with resultant ovulation. However, this antiestrogenic action is a double edge sword and extends to other ‘target’ organs such as the lining of the uterus (endometrium) and cervix. CC retards endometrial development and may decrease the possibility of implantation of the embryo. CC also markedly decrease the amount and quality of cervical mucus, which may impede sperm, transport. Some investigators have proposed a detrimental affect of CC on the follicle, egg, or embryo, but this is much less well substantiated. Still, it is clear that many more patients on CC will ovulate than will get pregnant.
Except under very specific circumstances, CC therapy should not be used more than six months. More than 70 percent of pregnancies are achieved during the first three months of use. In the first three cycles an expectation of five to 25 percent is not unreasonable. There generally is reported to be a cumulative pregnancy rate of about 30 percent after six cycles.
The lowest dose of CC that results in ovulation should be used. The ‘more is better’ rule does not apply here because higher doses of CC increase the negative antiestrogenic effects. The dose may need to be adjusted according to patient weight. After several cycles, a “wash-out” period may be useful. CC will accumulate over time in fat cells with a potential of increasing its negative effects. CC is usually begun on cycle days two through five, and given for five days. Each physician will have a preference, but there is no conclusive evidence that one regimen is superior to the others. The dose is usually increased by one pill (50 mg.) (50 mg. for five days then 100 mg for five days) until ovulation is achieved. Success is usually limited at doses over 150 mg (three tablets per day). There is some evidence that a ten day trial at 50 or 100 mg. may be effective in some PCOS patients that are otherwise unresponsive.
This anti-estrogenic effects of CC is the reason some women will have hot flashes during its use. Other side effects include headache (about 29 percent), visual disturbance such as blurred or double vision, mood alteration and breast tenderness. Since the drug is used for a brief time, these side-effects are generally considered more of a nuisance than serious and resolve quickly. There is one report that there is an increase in ovarian cancer in patients that have completed 12 or more cycles of CC. This study must be questioned because of the extended use of clomiphene, but also it would seem to be more related to the patient with recalcitrant infertility and ovarian dysfunction than to the drug it self.
The risk of twins is reported at five to 10. Triplets and greater are uncommon (fewer than one percent) when used in the prescribed way. Ovarian hyperstimulation is also uncommon and may be more related to stimulation of residual cysts from the previous cycle rather than multiple cystic development in a current cycle.
It is probably good advice to have a baseline ultrasound scan performed before the first CC cycle. This will usually exclude ovarian cysts and some other pelvic abnormality that may complicate therapy or make it less effective. Some form of exam, ultrasound or bimanual (pelvic) should be performed each time CC is used, although this may be modified depending on the particular circumstances.
In some cases use of CC can alter the ovulation detection kit by causing it to be falsely positive on the first day of use. Some PCOS patients have repeatedly positive ovulation detection kits because of their elevated LH. If the first measurement is negative, other tests should be reliable. Some centers aggressively monitor CC cycles while others do not. In some cases, use of CC can alter the ovulation detection kit by causing it to be falsely positive on the first day of use. The advantage of close supervision is that, if the drug is not effective, therapy can be modified. Monitoring can also offer the patient and clinician a better understanding of the dynamics of ovarian function. The disadvantage is cost and inconvenience.
Initially Gonadotropin Injections, for use as fertility agents, were extracted from the urine of post-menopausal women who produce large quantities of these hormones. The first well known human menopausal gonadotropin (HMG) preparation was Pergonal. More recently, other companies have marketed HMG, as Humegon and Repronex, which should be available at slightly lower costs. All of these HMG preparations consist of equal quantities of FSH and LH and should be identical in action.
In many PCOS patients there is excessive production of LH. Normally only a small amount of LH except at mid-cycle is produced. Since most women are thought to have sufficient naturally produced LH for follicular development, a purified HMG product from which most of the LH had been removed was introduced, (Metrodin). Later, a further purification of Metrodin led to Fertinex, which had the additional advantage of self-administration by a superficial skin injection.
A major change in the way gonadotropins were obtained was made possible by genetic engineering and recombinant DNA technology. Here, specific cells that produce massive amounts of absolutely pure hormone are cultured in the laboratory. This type of production has obvious advantages, but at present, the disadvantage of higher cost.
Presently, the FSH preparations available in the U.S. are Gonal F and Follistim. Although there are many claims, to date, no specific formulation or product has emerged as superior for controlled ovarian stimulation. Some patients respond better to one drug, but it has been impossible to predict this in advance. The amount of gonadotropin to be given is determined by expected and previous response. The amount of drug needed may be difficult to predict in advance.
Gonadotropin injections have three major disadvantages. First, they are injections. While relatively simple and painless as injections go, they are inconvenient. Second, their cost rages from $40-80 per ampule and usually five to 40 ampules are used in each cycle. And third, they carry a significant risk of ovarian hyperstimulation and multiple pregnancies. It is usually suggested that the twinning rate is about 20 percent and larger order pregnancies occur in about five percent of cycles. While cyst formation and abdominal enlargement is common, some patients develop ovarian hyperstimulation syndrome (OHMS). Here large amounts of fluid are leaked form the ovaries and can represent a medical emergency.
In vitro fertilization (IVF)
The American Society for Reproductive Medicine (ASRM) states “in vitro fertilization for infertility, not solvable by other means, is considered ethical.” IVF is increasingly being used for treatment of PCOS. The major factor limiting even greater use of assisted reproduction is its high cost. IVF offers several distinct advantages that may make it more cost-effective than it might seem initially.
Perhaps the largest benefit, a desire shared by both clinician and patient, is to evaluate the capacity of the oocyte to be fertilized. As expected, the chance of fertilization failure is higher in PCOS patients than in patients with anatomic abnormalities. Lack of fertilization in one cycle does not necessarily prove that by altering the stimulating regimen, or timing, that fertilization will fail in subsequent cycles. It may be more the environment in which the oocyte develops than the oocyte itself. An additional advantage is that a more aggressive approach can be taken toward ovarian stimulation. With PCOS, hyperstimulation is somewhat less of an issue because the preovulatory size follicles are aspirated and a limited number of embryos are replaced. Not only does this decrease the chance of multiple pregnancies, it reduces the risk of more pronounced cystic change. Many PCOS patients either over stimulate, or under stimulate, with gonadotropin therapy. The use of GnRH analogs and gonadotropins in conjunction with IVF may maximize control and ensure the greatest chance of pregnancy in any one cycle.