Medical Professionals in Infertility - Fertility CARE

Advances in the Treatment of Ovulatory Dysfunction

Etiologies And Diagnostic Approach To Ovulatory Dysfunction
(PART TWO OF TWO)
(April 2005)

Mark P. Trolice, M.D., FACOG, FACS
Board Certified, Reproductive Endocrinology And Infertility
Director, Fertility C.A.R.E.

Overview Of Treatment

Ovulatory dysfunction represents one of the most common causes of female infertility. Once the diagnostic evaluation has been completed patients desiring fertility may be treated to induce ovulation.

The first step in ovulation induction is to encourage achievement of ideal body weight as ovulatory problems are more frequent with body weight less than 95 percent or greater than 120 percent of ideal. If indicated underlying disorders such hyper prolactinemia, thyroid dysfunction or excessive androgen production should also be adequately addressed.

Pharmacologic approaches to ovulation will vary according to the nature of the underlying disorder. These include steroidal agents such as Clomiphene citrate and tamoxifen. Currently available non-steroidal agents to induce ovulation include the gonadotropins, letrozole, and the insulin sensitizing agent metformin. Part 1 of this 2 part series reviewed the etiologies and diagnostic approach to ovulatory dysfunction. Part 2 will outline current treatment options as well as several recent pharmacologic advances.

Clomiphene Citrate

Clomiphene citrate is the initial agent of choice and is the most commonly used pharmacologic agent for inducing ovulation in patients with normal endogenous estrogen production and intact pituitary-hypothalamic function. These Group ll patients typically have withdrawal bleeding following progestin challenge. Clomiphene is preferred because of its simplicity and relatively high success rates. Clomiphene induces ovulation by stimulating the pituitary to release gonadotropins, namely FSH, in much the same manner that GnRH does.

Side effects from Clomiphene are rare and include hot flushes, mild dysphoria and abdominal bloating.

Treatment is usually initiated after spontaneous or induced menses beginning on cycle day 3 to 5 with a starting dose of 50 mg. Expected success rates include ovulation in 60 to 80 percent of patients with cumulative pregnancy rates of up to 50 percent. Multiple pregnancies are noted in 8 - 10 percent of conceptions the vast majority being twins. If unsuccessful treatment is discontinued after 3 to 6 cycles. Side effects from Clomiphene are rare and include hot flushes, mild dysphoria and abdominal bloating. Ten to fifteen percent of patients treated with Clomiphene demonstrate significant antiestrogenic effects including thinning of the endometrial lining and decrease in cervical mucous. In these patients Tamoxifen or Letrazole are efficacious alternatives to Clomiphene.

Gonadotropins

In contrast to the above agents, gonadotropins must be administered by subcutaneous or intramuscular injection. These preparations contain recombinant FSH or a urinary derived combination of FSH and LH. Both types of gonadotropins are effective in women with Clomiphene resistant anovulation and the treatment of hypothalamic anovulation. Because of the high risk of adverse outcomes including ovarian hyperstimulation and high order multiple gestation, treatment with injectable gonadotropins should only be used by physicians with additional training in fertility management.

Side effects from metformin include gastrointestinal symptoms in 20% of patients that can be reduced by a gradual increase to the desired dosage.

Metformin

Metformin is an orally active antihyperglycemic agent that increases insulin sensitivity. A growing body of evidence has demonstrated increased insulin resistance in many patients with polycystic ovarian syndrome. Although metformin is not currently approved for ovulation induction by the U.S. Food and Drug Administration, an increasing number of studies have documented its effectiveness in inducing ovulation in properly selected patients.

In some hyperinsulinemic clomiphene resistant patients, simultaneous administration of metformin and clomiphene result in improvement of insulin resistance and ovulation. Side effects from metformin include gastrointestinal symptoms in 20% of patients that can be reduced by a gradual increase to the desired dosage. Thiazolidinediones are another category of insulin sensitizing agents, but concerns of teratogenicity preclude their use in fertility patients.

Letrozole

In recent years, research on a novel ovulation induction protocol has been published. Letrozole, an aromatase inhibitor and breast cancer treatment, blocks the conversion of androgens to estrogens thereby increasing pituitary FSH and LH stimulation to the ovary. Comparable to clomiphene approximately 60 -80% of patients will ovulate with letrozole, however the latter does not have the antiestrogen disadvantage of clomiphene, i.e. underdeveloped endometrium and poor cervical mucus. As with all fertility medications, multiple gestation is a risk. Letrozole is not FDA approved for ovulation induction and has not been linked to teratogenicity.

Laparoscopic Ovarian Drilling

Surgical treatment of anovulation results in temporary normalization of ovarian function with a cumulative pregnancy rate of 60 to 70 percent. Ovarian wedge resection at laparotomy has been replaced by laparoscopic ovarian follicular puncture. Although concern remains for the post-operative formation of pelvic and periovarian adhesions, this occurrence does not appear to diminish pregnancy rates. Additionally, maintenance of ovulation has been demonstrated for up to 20 years.

In-vitro Fertilization

The most aggressive treatment for ovulation dysfunction, IVF allows for a "mechanical" ovulation after gonadotropin stimulation of multifollicular ovarian development by office transvaginal cyst aspiration. This procedure rarely is unsuccessful in the treatment of anovulation with a national pregnancy rate of approximately 35% with rates varying based on the female's age. IVF actually allows for a reduced risk of multiple gestation since the number of embryos exposed to the uterus can be controlled as opposed to ovulation induction with intrauterine insemination.

Future developments for treating ovulation dysfunction will presumably focus on limiting the risk of multiple gestation. Fortunately, with clinician vigilance during a treatment cycle, this complication can be kept to a minimum.

Read Part One of this article to learn more about the etiologies and diagnostic approach to ovulatory dysfunction.