Ovulatory Dysfunction

Some women do not develop and release a mature egg every month. This is known as ovulatory dysfunction. Ovulatory dysfunction is likely when a women has irregular menses, infrequent menses or no menses at all. A small fraction of women who have regular menses may have ovulatory dysfunction.

	Polycystic Ovarian Syndrome
	Ovulation Induction
	Clomiphene Citrate
	Clomiphene Citrate with Intrauterine Insemination
	Superovulation Intrauterine Insemination (IUI)

Polycystic Ovarian Syndrome

Some women with ovulatory dysfunction may also have increased hair growth, increased acne and/or increased male hormone level in their blood. They have a condition called polycystic ovary syndrome (PCOS). PCOS is a common disorder with a prevalence rate of three to seven percent in the general population and as high as 20 percent in the infertile population. A significant number of women with PCOS have insulin resistance. Their bodies require a high level of insulin to keep their blood glucose normal. They are at risk for developing diabetes, high cholesterol, stroke and heart disease later in life. PCOS occurs in both lean and obese females. Women with PCOS who are also overweight or obese can improve their condition by diet and exercise. Studies have shown that weight loss of as little as 5% may provide benefit in their ovulation, insulin resistance and long-term health.

Ovulation Induction

Women with ovulatory dysfunction need medication to stimulate egg development (ovulation induction). The most commonly used medication is clomiphene citrate (also known as Serophene® or Clomid®). Patients with PCOS and insulin resistance may respond to a drug called metformin (also known as Glucophage®). This is a drug that has been used for patients with diabetes for many years. It is safe to be on this drug when trying to get pregnant. The current recommendation is to discontinue its use once pregnant.

Injectable follicle-stimulating hormone FSH (also known as Gonal-F®, Puregon® or Menopur®) can be utilized if clomiphene citrate is ineffective. When FSH is used to induce ovulation this is called superovulation.

Clomiphene Citrate

Clomiphene citrate (also known as Serophene® or Clomid®) has been widely used as a first line treatment to induce and augment ovulation. Clomiphene Citrate works at the hypothalamus in the brain and stimulates the production of gonadotropin releasing hormone which in turn stimulates the pituitary gland to produce follicle stimulating hormone (FSH). FSH, as its name implies, stimulates the development of the ovarian follicles. Ovarian follicles are structures in which eggs reside and mature. Clomiphene Citrate is an oral medication. Clomiphene Citrate is typically administered for five days a month starting on either day 3 or 5 of the menstrual cycle with day one being the first day of normal menstrual flow. The starting does is usually 50 mg per day. If ovulation is not achieved at this dose, the dose can be gradually increased by 50 mg per day till ovulation occurs. The effective dose of clomiphene citrate varies from individual to individual. Ovulation usually occurs 5-8 days after the last tablet is taken. Couples are advised to have intercourse every other day at this time. Clomiphene citrate is also given to augment ovulation to optimize the success rate of intrauterine insemination.

The physician will determine how clomiphene citrate cycles should be monitored. Early in treatment, it is common for patients to take clomiphene for 5 days each month and have blood drawn for a progesterone level on day 21 of their cycle to monitor for ovulation. This permits the dosage to be titrated appropriately. In some situations the physician may wish to monitor the cycles more closely by utilizing ovulation predictor kits and/or ultrasounds. This provides additional information on the number of developing follicles and their rate of growth. A number of patients may not have spontaneous ovulation despites follicular development. In such case, ultrasound monitoring (also known as follicular tracking) allows us to pinpoint the optimal timing so ovulation can be triggered artificially by the administration of a medication called HCG (Chorionic Gonadotropin®).

Clomiphene citrate has been used since 1960 and is considered a safe and effective medication. Side-effects of clomiphene citrate may include abdominal discomfort, hot flashes, vaginal dryness, moodiness, headache and visual disturbances. Very rarely, clomiphene citrate can cause significant enlargement of the ovary a condition called ovarian hyperstimulation syndrome. Clomiphene citrate is associated with a 5-8% incidence of multiple births. The vast majority of these are twin pregnancies. There is no increased risk of birth defects with the use of clomiphene citrate. There has been some suggestion of an association between the use of clomiphene citrate for more than twelve cycles and ovarian cancer. To date, various studies have shown conflicting data. It appears that there is an association between female infertility and ovarian cancer, and this may be a confounding factor in the association between the use of clomiphene citrate and ovarian cancer. The risk of ovarian cancer in clomiphene citrate users, if any is extremely small.

If clomiphene citrate has not produced a pregnancy within 3-6 cycles an alternate mode of treatment will be considered. The literature strongly supports that using Clomiphene Citrate beyond 6 cycles is unlikely to result in pregnancy.

Clomiphene Citrate with Intrauterine Insemination

Clomiphene Citrate corrects ovulation abnormalities in patients who do not ovulate well and may increase the number of eggs produced by the ovaries in patients who are already ovulating normally. When more eggs are produced and more sperms reach the fallopian tubes, the pregnancy rate per cycle increases. Clomiphene Citrate combined with IUI significantly improves the pregnancy rate compared with Clomiphene Citrate and natural intercourse. Clomiphene Citrate may cause the cervical mucous of some women to thicken thus hindering passage of sperm through the mucous. The addition of intrauterine insemination overcomes this negative effect of Clomiphene Citrate. The combination of Clomiphene Citrate and IUI can also be an effective treatment for mild male factor infertility.

Navigating your IUI Cycle

Superovulation Intrauterine Insemination (IUI)

Gonadotropins are injectable follicle-stimulating hormones that are identical to the hormone FSH produced by the body. This treatment results in the recruitment and growth of multiple follicles and eggs. In addition to increasing the number of eggs, the timing of ovulation can be controlled to maximize the chances of pregnancy by the administration of HCG (Chorionic Gonadotropin®) when the follicles have grown to a size consistent with egg maturity. Intrauterine insemination (injection of sperm into the uterus) is always performed in combination with superovulation and has been shown to optimize the pregnancy rates in superovulation cycles.

Several preparation of gonadotropins are available include Gonal-F®, Puregon® and Menopur®. Gonadotropins are also used in IVF cycles where many eggs are required.

All gonadotropin superovulation cycles must be administered and monitored by an infertility specialist. They are monitored with blood estrogen levels and pelvic ultrasounds to assess follicular growth. These tests are performed every few days in the early part of the stimulation cycle. Towards the end of the cycle they are performed more frequently, depending upon each patient's individual response. Ovulation induction cycles are followed by an injection of HCG to trigger ovulation. Intrauterine inseminations are performed 36-38 hours after hCG administration. In an IVF cycle, egg retrievals are also timed using hCG.

The most common side effects with superovulation include discomfort or "fullness" in the lower abdomen, bloating, headache or fatigue. The most significant potential risks are multiple pregnancies and ovarian hyperstimulation. The majority of multiple pregnancies are twins; however, more than two fetuses can sometimes develop. Pregnancy with three or more fetuses places both the mother and fetus at high risk of miscarriage, preterm delivery and bleeding. The risk of high order multiples is higher in superovulation cycles than IVF cycles because the number of eggs ovulated cannot be precisely controlled.

Ovarian hyperstimulation typically occurs 5-7 days after hCG injection and occurs in 1-2% of superovulation cycles. If pregnancy results, the ovarian enlargement may persist for up to six weeks. In general, the symptoms associated with ovarian hyperstimulation are mild and may include lower abdominal pain, heaviness and bloating. Sometimes shortness of breath may also develop. It is less common for hyperstimulation to result in severe medical problems. Close monitoring of the ovarian stimulation by ultrasound and laboratory tests are used to minimize the risk of ovarian hyperstimulation.