Fertility Treatment for Polycystic Ovarian Disease

Halina Wiczyk, M.D.
Associate Professor of Obstetrics & Gynecology
Tufts University School of Medicine

Chief, Reproductive Endocrinology
Baystate Medical Center
Springfield, Massachusetts

Background

Polycystic ovarian syndrome (PCOS) is the most common cause of chronic anovulation (no menses) or oligo-ovulation (infrequent menses). It is also the most heterogeneous syndrome in its presentations. Patients can present with the classic triad of obesity, hirsutism, and anovulation. Or, they can be slim, have no excess hair, and minimal menstrual irregularities. The ovaries can also be seen as being polycystic in appearance on ultrasound in normal, regular cycling women. These patients can have an exaggerated response to stimulation with fertility drugs.

Androgens (male hormones) are produced in women by the adrenal gland and by the ovaries. Testosterone is the most biologically active hormone that is produced by these two organs with 25% coming from each. The remaining 50% is derived from conversion to testosterone in peripheral tissues (other than ovary or adrenal). The most common presentation in PCOS is elevated androgens, although it does not necessarily mean that excess hair is always present. How the hair follicle responds to elevated androgens is more genetically related. Aside from an increase in androgens, women with PCOS have been found to have insulin resistance (increased levels) and glucose intolerance. These abnormalities can occur in obese as well as non-obese women. The glucose intolerance is not totally related to androgen excess. Women whose androgens are decreased to a normal level will still continue to have increased levels of insulin. Some women who have a higher level of insulin resistance are more at risk to develop diabetes mellitus and cardiovascular disease later on in life.

Treatments

Women who have had a significant weight gain in their adult years can change their chronic anovulatory state with weight loss alone. Weight loss is also strongly encouraged for improvement in overall health, as well as better response to fertility treatments. In the past, elevated androgens were treated with low dose steroids in an effort to suppress their levels. Spontaneous ovulations have occurred on this treatment alone.

More recently, evidence has shown that decreasing insulin resistance and glucose intolerance can also lead to spontaneous ovulations. Patients need to be tested to evaluate their fasting glucose/insulin ratio <4.5 to determine if they are candidates for treatment. A lipid profile should also be done. Metformin (a drug used in diabetes) is given in an effort to lower insulin resistance in those patients. Although these women are not overtly diabetic, when the ratio is <4.5, there is evidence of glucose intolerance, even with normal fasting glucose levels. Metformin alone (at a dose of 1500 mg to 1700 mg/day) can restore normal ovulatory cycles to those women. Alternatively, if spontaneous ovulation does not occur, clomiphene citrate (CC) can be added to the treatment regimen.

Clomiphene citrate is a first line drug in anovulatory patients. It acts as an antiestrogen at the level of the hypothalamus (an organ in the brain that controls ovulation). The drug binds to estrogen receptors in the hypothalamus and blocks a negative feedback role that estrogen exerts there. Therefore, the hypothalamus is "tricked" into releasing gonadotropin-releasing hormones which stimulate the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland (also in the brain). These hormones in turn act on the ovary to increase estrogen production and develop a follicle. Clomiphene citrate is started at a dose of 50 mg for 5 days, either days 3-7 or days 5-9. The dose can be increased to 100 or 150 mg/day and the length of treatment can be extended to 7 days. The dose should only be increased if ovulation has not occurred, not if there is no conception. An ovulation predictor kit (LH kit) can then be used to determine ovulation and ti med intercourse. Once an ovulatory response (an ovulatory progesterone level) has been achieved, most conceptions will occur in the first 6 ovulatory cycles. A hysterosalpingogram may need to be performed to evaluate the patency of the fallopian tubes.

Because CC is an antiestrogen, it can have a negative effect on cervical mucus, as well as the endometrium. Also, these anovulatory patients may have elevated levels of endogenous LH which may interfere with ability to interpret an LH predictor kit. Therefore, more aggressive monitoring and treatment can be added. Ultrasound can be performed around day 14 to determine follicular development as well as endometrial thickness. When a follicle reaches approximately 19 mm in average diameter, an injection of human chorionic gonadotropin (hCG) can be given. This will trigger ovulation and can be combined with an intrauterine insemination (IUI) of washed sperm.

If CC does not work or the patient does not have an ovulatory response, it is necessary to move to the next step, gonadotropins. These drugs were originally derived from the urine of postmenopausal women. Human menopausal gonadotropins given intramuscularly (hMG, Pergonal, Humegon) were originally used starting in 1952. In the early 1990s, a purified preparation of follicle stimulating hormone (FSH, Metrodin) became available and was used extensively until an ultrapurified FSH was developed (Fertinex). Today, recombinant technology is in use for the production of FSH (Follistim, Gonal-F). These drugs are given as a subcutaneous injection which has greatly eased patient use.

When using gonadotropins, patients need to be monitored closely. Treatment is usually begun on cycle day 3 (either a spontaneous cycle or progestin-induced). A baseline ultrasound is performed to determine the ovarian status regarding cysts or persistent follicles. Injection of medication is typically taken in the evening starting with 1 or 2 ampules (75-150 International Units) of FSH. After five days, an early morning ultrasound and blood test (estradiol, E2) are performed to determine response to medication. Patients are then notified in the afternoon to either continue with medication (and dosage) or to take the hCG trigger. Intrauterine insemination or intercourse should occur 36 hours later.

Complications

Ovarian hyperstimulation syndrome (OHSS) is the most frequent complication with the use of gonadotropins in these patients. The reason this occurs has not been totally elucidated but it is known that it is triggered by hCG. If the E2 level is greater than 2000 pg/ml in an insemination cycle, the hCG injection may be withheld and the cycle canceled to avoid ovarian hyperstimulation syndrome. If gonadotropin use repeatedly causes over stimulation, the couple may consider in vitro fertilization or surgical ovarian drilling procedure (a laparoscopic surgery involving cauterization of the ovarian capsule).

Ovarian hyperstimulation syndrome can be mild, moderate, or severe. The most common presentation is mild OHSS where ovarian enlargement can be up to 8 cm with some discomfort but no other significant clinical symptoms. Moderate OHSS can present with ovarian enlargement (8-12 cm) with pain and discomfort. Severe OHSS which occurs in less than 1-2% of patients usually requires hospitalization. Ovarian enlargement is >12 cm and there is fluid in the abdominal cavity (ascites). Patients may experience nausea, vomiting, and difficulty with urination. Pain control and fluid management are key in the treatment of this condition. If conception occurs, the OHSS can persist for several weeks before it gets better.

Multiple pregnancy occurs in about 30-35% of pregnancies when gonadotropins are used. If there are too many follicles in response to FSH, the cycle should be canceled because of the significantly increased risk of multiple pregnancy, especially a 3-5% chance of more than twins.

Spontaneous abortion occurs somewhat more in these patients (12-29%). It is not known why this is and closer observations in these patients could be a factor. Subtle hormonal imbalances (LH>FSH) may also play a role in this.

Assisted Reproduction

In many patients with PCOS, ovulation induction can be quite difficult and challenging. The response to gonadotropins may be too brisk to safely proceed with hCG and intrauterine insemination. These patients are then better served with in vitro fertilization (IVF). In this way, the oocytes can be retrieved and a decision can be made regarding embryo transfer. Only two embryos can be transferred, thereby decreasing the multiple pregnancy rate. Alternatively, if the patient's E2 level is high and there are multiple follicles (these patients typically can have a huge response), the oocyte retrieval can be performed and all the resulting embryos frozen. This option eliminates the chance of conception and shortens the course of OHSS. These embryos can then be transferred into the uterus during a frozen-thaw cycle.

In conclusion, PCOS is a challenging condition that has several options for treatment. Conception can occur quickly or patients need to proceed with the various options. However, the success rate with these patients can be excellent and most rewarding.