Infertility is frequently caused by anovulation. The affected women present with irregular menstrual cycles and the most common diagnosis is polycystic ovary syndrome. Ovulation induction is commonly used to treat these women. Clomiphene citrate (a selective estrogen receptor modulator or SERM) remains the most used medication for treating this condition. Alternatives that have been used include other SERMs such as tamoxifen, aromatase inhibitors, insulin sensitizing agents, and ovarian drilling. Evidence for and against the effectiveness of these agents has fluctuated over the last decade. Controversies surrounding the use of ovulation induction such as development of functional cysts, high-order multiple births, and development of ovarian cancer have been further studied and some controversies have almost been laid to rest in the last decade.
Infertility secondary to anovulation
Causes for infertility can be broadly categorized into male factor or female factor. Anovulation is one of the leading causes contributing to female factor infertility.
The most common cause for anovulation or oligoovulation is polycystic ovary syndrome (PCOS) and it may be the most common cause for female infertility. In addition to infertility, women with PCOS may present with irregular menses and/or hirsutism.
Multiple criteria (1990 NIH/NICHD, 2003 ESHRE/ASRM, and 2006 AE/PCOS society) have been proposed to diagnose PCOS and it is beyond the scope of this article to address the controversy surrounding these different criteria. All 3 statements emphasize the importance of excluding other causes of anovulation and hyperandrogenism such as thyroid dysfunction, hyperprolactinemia, congenital adrenal hyperplasia, androgen secreting tumor, Cushing syndrome, and idiopathic hirsutism. Even though all the above conditions should be considered clinically, no clear consensus exists on which of the patients need to have laboratory testing to exclude the conditions. We check thyroid function and serum prolactin levels in all patients with oligomenorrhea. Serum 17-hydroxy progesterone levels are checked in women with hyperandrogenism to exclude nonclassical congenital adrenal hyperplasia.
The 2003 Rotterdam Criteria jointly proposed by European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine is 1 of the 3 used by gynecologists to diagnose PCOS. The patient must have 2 of the following 3 criteria to be diagnosed with PCOS:
- 1
Oligoovulation defined as 8 or less menstrual cycles per year;
- 2
Hyperandrogenism diagnosed either clinically (hirsutism) or biochemically (raised serum testosterone levels); and
- 3
Polycystic-appearing ovaries on vaginal sonogram defined by the presence of 12 or more antral follicles in an ovary or an ovarian volume of >10 mL. Antral follicles are defined as measuring between 2 and 9 mm diameter.
Although oligoovulation and polycystic ovaries were defined clearly, hyperandrogenism was deliberately defined vaguely as consensus could not be reached among participants at the 2003 conference on definition of clinical and biochemical hyperandrogenism.
It is important to note that some patients may have oligoovulation in the absence of other criteria for PCOS and would still benefit from induction of ovulation. Ratio of serum luteinizing hormone (LH) to follicle-stimulating hormone (FSH) is no longer an accepted criterion for diagnosing PCOS.
Amenorrhea or severe oligomenorrhea should prompt evaluation for hypothalamic or pituitary causes for anovulation by measuring serum FSH and estradiol levels. Hypothalamic or pituitary cause for the amenorrhea must be considered if FSH levels are low or in the normal range and estradiol level is <30 pg/mL. Gonadotropins are currently the only available drugs in the United States for treating these patients.
Consideration should also be given to evaluating the male partner using semen analysis and the uterine cavity and fallopian tubes using hysterosalpingography.
Methods for ovulation induction
The focus of this opinion is on ovulation induction. Management of other symptoms/conditions associated with PCOS or hypothalamopituitary failure is not considered here.
Selective estrogen receptor modulators (SERMs)
Clomiphene citrate and tamoxifen are the agents in this class that have been used for ovulation induction. Clomiphene citrate remains the most widely prescribed of the 2 and has been extensively studied for the last 50 years. It is commonly prescribed at the dose of 50 to 150 mg per day for 5 days in the early follicular phase of the menstrual cycle. The start day can be cycle day 2 through day 5 without any significant difference in its effectiveness. In the United States, it is commonly prescribed for use from cycle days 3 through 7. It has been estimated that only 44% of women respond to the 50 mg dose and smaller percentages of the population will respond to higher doses. There is little advantage to prescribing the medication at doses higher than 150 mg. However, some women may require a lower (25 mg a day) dose if they are sensitive to the 50 mg dose. Overall, it is estimated that 73% of patients will ovulate on clomiphene and 36% will get pregnant.
Approximately 20% of patients are resistant to clomiphene and adjuvant agents have been tried in the hope of making these patients responsive to clomiphene. Insulin sensitizing agents for this purpose are reviewed later. Another agent that has been advanced as an adjunct is dexamethasone. In the last decade, a few trials have been published showing benefit to adding dexamethasone in women with PCOS. A recent review has shown a significant benefit to adding dexamethasone as an adjunct based on these trials. The dose of the clomiphene used in these trials varied from 150 mg to 200 mg administered for 5 days starting on days 3 through 5. The dexamethasone was administered continuously at a dose of 0.5 mg daily or intermittently at a dose of 2 mg daily starting on the same day as clomiphene and administered for 10 days.
The possible complications of ovulation induction are discussed later. Briefly, clomiphene citrate (CC) has a relatively low multiple pregnancy rate and ovarian hyperstimulation rate.
Insulin sensitizing agents
Insulin sensitizing agents were expected to be the panacea for PCOS when it was realized that many of these patients had insulin resistance and impaired glucose tolerance. The most commonly used agent is metformin at the dose of 1500 to 2000 mg in divided daily doses. Multiple metaanalyses including the previous versions of the Cochrane review suggested that these agents, by themselves or in conjunction with clomiphene, can significantly improve ovulation rates in PCOS women. Subsequent publication of randomized controlled trials, notably the Reproductive Medicine Network trial served to dampen this enthusiasm. This was a randomized controlled trial involving 626 PCOS women. They were randomly assigned to receive clomiphene plus placebo, metformin plus placebo, or both metformin and clomiphene for up to 6 months. The live birth rate was 7.2% in the metformin group, 22.5% in the clomiphene group, and 26.8% in the combined therapy group. The difference between the latter 2 groups was not statistically significant. The authors concluded that clomiphene is superior to metformin in achieving live birth rate in infertile women in PCOS. The latest version of the Cochrane review has also tempered its recommendation based on the new data and concludes that the use of metformin in improving reproductive outcomes in women with PCOS appears to be limited. Another metaanalysis concluded that combination of clomiphene and metformin is superior to clomiphene alone.
Metformin therapy is frequently accompanied by nausea, vomiting, and diarrhea. This can be overcome by slow increase in dosage over a period of 3 to 4 weeks. Considering these side effects and the doubts raised about its efficacy, it may be used as an adjunct to CC in those women who are resistant to CC alone for ovulation induction.
Aromatase inhibitors
Letrozole and anastrozole are the 2 agents in this class that have been used for ovulation induction. Letrozole has been more widely used and studied. Letrozole, a third generation aromatase inhibitor, is as effective as CC in ovulation induction. Studies that use letrozole in women resistant to clomiphene have shown that letrozole can induce ovulation in some of these women suggesting that letrozole may be superior to clomiphene. It is commonly used at the dose of 2.5, 5, or 7.5 mg. The start days and the number of days used in the cycle mirror those of clomiphene use.
Although there was some controversy (possibility of increased congenital cardiac anomalies in an abstract presentation that was never published in a peer reviewed journal) over the use of aromatase inhibitors for ovulation induction, a larger study confirmed lower cardiovascular anomalies rates in pregnancies resulting from letrozole use. However, it is not approved by the Federal Drug Administration (FDA) for ovulation induction and any use for this purpose has to be off-label in United States. FDA has categorized the medication as pregnancy category D and the label states that it is contraindicated in women of premenopausal endocrine status, including pregnant women.
Ovarian drilling
Wedge resection of the ovary was the classical management strategy proposed by Stein in his seminal paper on management of PCOS. This has to a large extent been replaced by the use of ovulation inducing agents. However, there is still a place for the modern version of wedge resection, namely, laparoscopic ovarian drilling, in a select group of patients who are unwilling or unable to move on to gonadotropin treatment or in vitro fertilization (IVF) when they are resistant to clomiphene for induction of ovulation. The ovarian drilling is effective for a few months after the drilling and the multiple pregnancy rate is the lowest among methods used for ovulation induction. Approximately 50% of women will have a live birth and 16% miscarry after the procedure. Postoperative adhesion formation has been documented and concerns regarding the effect on long-term ovarian function remain to be addressed.
Weight loss
Classic teaching has been that even a 5-10% loss of weight can achieve resumption of ovulation in obese women. Body mass index (BMI) plays an important part in the ability of PCOS women to respond to clomiphene. A complex relationship between BMI, free androgen index, and whether the patient is oligomenorrheic or amenorrheic determines the chance of ovulation using clomiphene. A longer duration of stimulation and higher doses of gonadotropins are needed for successful ovulation in women with higher BMI.
Regardless of the benefit for ovulation induction, emphasis on weight loss needs to be continued in obese women to decrease the intrapartum and postpartum morbidity, in addition to improving the long-term outlook for general health including risk for development of diabetes and cardiac disease. It has been advocated that women with BMI higher than 35 kg/m 2 be prescribed a contraceptive and all efforts made to reduce their weight before instituting infertility treatment.
Diagnosis of ovulation
On instituting treatment, diagnosing ovulation is important to advise the couple on when to have intercourse to achieve the pregnancy they desire. Ideally, the sperm should be present in the genital tract before the arrival of the oocyte to have the maximum chance at fertilization. Therefore, it is critical to predict ovulation rather than confirm it afterward.
Diagnosis of ovulation has traditionally been by use of basal body temperature (BBT) measurements. The physiologic basis of this test is the rise in basal body temperature caused by higher serum levels of progesterone after ovulation. Therefore, ovulation can only be inferred after the event using this method. The cumbersome nature of measuring and documenting BBT, combined with availability of other methods, has considerably decreased the use of this method in practice. The change in consistency of cervical mucus has also been used to diagnose ovulation and although useful, it is not as sensitive as the BBT measurement.
Urine LH detection kits detect the LH surge that occurs before ovulation and therefore allow prediction of ovulation. This has to a great extent replaced the above 2 methods in practice. These urine LH kits are useful in most patients. However, use of these kits in conjunction with ovulation-inducing agents can be frustrating to some patients as the elevated levels of endogenous LH may give rise to persistently positive or ambivalent results. Daily serum LH monitoring is another cumbersome, expensive but available option in some patients.
Serum progesterone levels can be used to confirm ovulation. It is not useful to predict ovulation. Serum progesterone levels can be measured either a week after urine LH surge or approximately 7 days before the next menses (if onset of menses can be predicted). Progesterone levels more than 3 ng/dL are indicative of ovulation.
Serial pelvic ultrasound monitoring can confirm ovulation but is seldom used solely for diagnostic purposes. It is usually used when intrauterine insemination is also advocated for management of the infertility. In this circumstance, ultrasound monitoring is frequently used to determine the time of administration of human chorionic gonadotropin discussed later.
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