The majority of patients seeking ovulation induction are women with polycystic ovarian syndrome (PCOS). An ovulation induction treatment algorithm for women with polycystic ovarian syndrome can be seen in Figure Ovulation induction treatment algorithm for polycystic ovarian syndrome (PCOS).

Weight Loss

Weight loss can restore ovulatory cycles for many women with polycystic ovarian syndrome (PCOS). Approximately 80% of women with polycystic ovarian syndrome are obese, which is associated with hyperinsulinemia. The increased insulin has a direct effect on the ovary, resulting in increased androgen production. Weight loss of >5% has been shown to restore ovulation in some polycystic ovarian syndrome women. In addition, polycystic ovarian syndrome women who did not conceive with previous treatment and had a mean weight loss of 10.2 kg went on to have a 77% pregnancy rate with treatment. While this is an often overlooked mode of treatment, it should be considered first line treatment for overweight women with polycystic ovarian syndrome (PCOS).

Figure Ovulation induction treatment algorithm for polycystic ovarian syndrome (PCOS)

Figure Ovulation induction treatment algorithm for polycystic ovarian syndrome (PCOS). DHEAS, dehydroepiandrosterone sulfate; IVF, in vitro fertilization

Clomiphene Citrate

Clomiphene citrate (clomiphene citrate) is an estrogen analog that was first shown to induce ovulation in 1961 and was approved for clinical use in the United States in 1967. Clomiphene belongs to a family of compounds known as selective estrogen receptor modulators (SERMs). Other well-known SERMs include tamoxifen (breast cancer treatment) and raloxifene (osteoporosis treatment). Clomiphene is used for ovulation induction or controlled ovarian hyperstimulation in patients with normal endogenous estrogen levels.

Clomiphene exerts both estrogen agonist and antagonist effects. Clomiphene blocks the negative feedback of endogenous estrogen at the hypothalamic and pituitary levels. This results in a >50% increase in endogenous follicle stimulating hormone which subsequently stimulates follicular growth. Ovulation rates approach 80%, with cumulative pregnancy rates of 30-40% over the course of a few cycles. This discrepancy between ovulation and pregnancy rates is thought to be due to the estrogen antagonist effects on the endometrium and cervical mucus. This may be detected by an endometrial thickness of <7 mm on ultrasound, which would suggest other forms of ovulation induction would be more effective.

Clomiphene citrate is administered in a dose of 50-150 mg/day for 5 days, starting on day 2, 3, 4, or 5 of the menstrual cycle. The lowest starting dose is used initially and is only increased in subsequent cycles if the patient remains anovulatory at a given dose. While some physicians have used longer treatment regimens and higher doses, there is little evidence for effectiveness at doses greater than 150 mg. Once a patient is ovulatory with clomiphene citrate treatment, it is usually continued for up to 3-6 ovulatory cycles. Approximately 75% of conceptions occur in the first three treatment cycles. Ovulation can be confirmed with a single mid-luteal (7 days after ovulation) serum progesterone level of >5 ng/ml.

Monitoring of clomiphene citrate cycles may be managed using ovulation prediction kits, basal body temperature monitoring, or ultrasound monitoring. If the woman is attempting conception in conjunction with timed intercourse, the fertile period is a 6-day period which is generally the day of ovulation and the 5 days preceding ovulation, and intercourse every second day is recommended. If ovulation induction is used in conjunction with intrauterine insemination (IUI), then the intrauterine insemination should be performed the day of, or the day following a positive ovulation predictor test. Ultrasound monitoring of clomiphene citrate stimulated cycles has demonstrated that on the day of spontaneous luteinizing hormone surge, the preovulatory follicles are usually slightly larger than in natural, unstimulated cycles. If ultrasound monitoring is used in conjunction with intrauterine insemination (IUI), human chorionic gonadotropin (5,000-10,000 IU) is typically administered when the lead follicle is >18 mm, and intrauterine insemination is performed 36 hours later. While high-technology monitoring has not been shown to increase pregnancy rates over low-technology monitoring, ultrasound monitoring adds additional information on the endometrial effects of clomiphene citrate.

Complications of clomiphene citrate include ovarian hyperstimulation syndrome and multiple pregnancies. Original reports demonstrated twin pregnancy rates of 10% and higher order multiple rate (triplets or greater) of 1%. Clinically significant ovarian hyperstimulation syndrome is uncommon in clomiphene citrate stimulated cycles. Side effects of clomiphene citrate include breast tenderness, bloating, hot flashes, abdominal discomfort, and mood changes. A rare side effect is changes in vision or sensitivity to light, which requires immediate discontinuation of the medication, as continuation may cause permanent visual changes.

Metformin

There has been a plethora of evidence that polycystic ovarian syndrome is associated with hyperinsulinemia, which leads to the widespread use of insulin sensitizing agents for treatment. The most studied agent is the oral biguanide, metformin. The exact mechanism of action of metformin in polycystic ovarian syndrome is unclear, but may be related to weight loss or direct suppression of androgen production by the ovary. Metformin is typically used at doses between 1500-2000 mg/day, and the main side effect is GI upset.

Metformin may be used alone or in conjunction with clomiphene citrate. When metformin is used alone as an ovulation induction agent, ovulation rates are typically between 30-40%, but evidence for a significant increase in pregnancy rates is lacking. When metformin and clomiphene citrate are used together, ovulation rates approach 90%. In patients who did not previously ovulate with clomiphene citrate therapy, ovulation rates are approximately 75% when treated with clomiphene citrate plus metformin. A recent meta-analysis suggests that clomiphene citrate plus metformin has an approximately 3-fold greater pregnancy rate in polycystic ovarian syndrome women than clomiphene citrate alone. In clinical practice, metformin is usually used in conjunction with clomiphene citrate in obese polycystic ovarian syndrome patients or in patients who do not respond to clomiphene citrate. Currently, a large, randomized, double-blind, clinical trial comparing pregnancy rates in patients treated with clomiphene citrate, metformin, or clomiphene citrate plus metformin, is ongoing. This trial should determine the best treatment regimen for achieving pregnancy.

Aromatase Inhibitors

Aromatase inhibitors are orally active agents that inhibit estrogen biosynthesis by inhibiting the aromatase enzyme, resulting in decreased circulating levels of es-tradiol. Under low estrogen conditions, there is decreased negative feedback and greater pituitary follicle stimulating hormone release. While this medication is not approved for ovulation induction, it is increasingly being used for this purpose. The most commonly used aromatase inhibitor given for ovulation induction is letrozole. It is typically administered at a dose of 2.5-7.5 mg/day for a 5-day regimen, starting on day 3 of the menstrual cycle or occasionally as a single 20 mg dose given on day 3. While aromatase inhibitors have not been shown to be superior to clomiphene citrate, there are some studies that suggest they may be useful in patients who do not respond to clomiphene citrate.

Laparoscopic Ovarian Diathermy

Laparoscopic ovarian diathermy (LOD) is an endoscopic surgical procedure that has been found to be an effective mode of ovulation induction. This procedure involves creating 3-10 holes per ovary with an electric current or laser. Its use has primarily been in the clomiphene citrate resistant population, and a randomized, controlled study in this population has shown similar pregnancy rates in patients undergoing laparoscopic ovarian diathermy compared to gonadotropin therapy. Furthermore, laparoscopic ovarian diathermy has been shown to have equivalent pregnancy rates after 6-12 months when compared to 3-6 cycles of gonadotropin therapy with significantly lower multiple pregnancy rates in the laparoscopic ovarian diathermy group. A recent study comparing metformin treatment versus laparoscopic ovarian diathermy in a clomiphene citrate resistant population demonstrated similar ovulation rates, but higher pregnancy rates in the metformin group. With an expanding number of ovulation induction agents, the role of laparoscopic ovarian diathermy in contemporary ovulation induction appears to be limited.

Glucocorticoids

While not an ovulation induction agent on its own, glucocorticoids (namely dexamethasone) have occasionally been used in conjunction with clomiphene citrate in women who are unresponsive to clomiphene citrate. A subset of patients with polycystic ovarian syndrome have increased adrenal androgen production, reflected by elevated DHEAS levels. Administration of dexamethasone suppresses adrenal androgen production and can increase the ovulation rate among women with DHEAS levels >200 µg/dl. The most widely used protocol includes dexamethasone administered at nighttime in a dose of 0.5 mg orally in conjunction with clomiphene citrate treatment.

Pulsatile Gonadotropin Releasing Hormone

Gonadotropin releasing hormone (GnRH) was first identified in 1971 and is the hypothalamic releasing hormone responsible for follicle stimulating hormone and luteinizing hormone synthesis and release from the pituitary. While it is rarely used in clinical practice, it is the most physiological method of ovulation induction for WHO group I ovulatory disorders, namely women who have hypogonadotropic hypogonadism. These women typically do not have the pulsatile gonadotropin releasing hormone secretion required for the synthesis and release of gonadotropins from the pituitary that are responsible for ovarian folliculogenesis and regular, cyclic menses. gonadotropin releasing hormone is typically administered in doses from 2.5-20 µg every 60-120 minutes. gonadotropin releasing hormone pulsatile therapy may be administered intravenously (IV) or subcutaneously (SC) but appears to be more effective by IV route. The luteinizing hormone surge and subsequent ovulation occur spontaneously, therefore not requiring an injection of human chorionic gonadotropin to induce follicular maturation, and pulsatile gonadotropin releasing hormone can be continued in the luteal phase to provide support for the corpus luteum. Ovulation rates are typically 75%/cycle, with pregnancy rates of 23%/ovulatory cycle and multiple pregnancy rate of 3.8%/cycle. The low multiple pregnancy rate is due to monofollicular development using this method of ovulation induction. In spite of high pregnancy rates and low multiple pregnancy rates, due to the need for a pump and indwelling catheter, this method of ovulation induction is not frequently used.

Dopamine Agonists

Dopamine agonists are the first-line therapy for patients with anovulation related to hyperprolactinemia. Hyperprolactinemia is often due to prolactin-secreting pituitary adenomas. Hyperprolactinemia interferes with gonadotropin releasing hormone pulsatile secretion, thereby causing anovulation. Dopamine inhibits prolactin secretion, and administration of dopamine agonists results in both a decrease in tumor volume and restoration of ovulatory cycles. The most commonly used dopamine agonist for ovulation induction is bromocriptine, which is administered in a dose of 2.5-10 mg, daily in divided doses. Cabergoline is another dopamine agonist with a better side-effect profile and patient tolerability and is administered in a dose of 0.25-1 mg, given twice weekly. Cumulative pregnancy rates of 80% can be expected with bromocriptine treatment for anovulation due to hyperprolactinemia. Dopamine agonists are typically stopped once conception has occurred.

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