Ovulation Induction Strategies for Infertility ManagementWHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Approximately 20% of infertile women have ovulatory disorders. When anovulation is the only infertility factor, the prognosis for pregnancy is very good because modern ovulation induction strategies are highly effective. When anovulation can be attributed to a specific treatable cause, ovulation induction can achieve pregnancy rates comparable to those observed in the normal population. When a specific cause cannot be defined, as in most anovulatory women, ovulation induction becomes an organized, empiric, incremental titration intended to identify the successful treatment regimen associated with the least cost and risk. When treatment fails to achieve ovulation or induces ovulation but fails to achieve pregnancy, more aggressive therapies often succeed, but the associated costs and risks are substantially greater. Advances in reproductive endocrinology allow the generalist obstetricians and gynecologists to provide treatment those results in successful ovulatory stimulation and pregnancy in most women with ovulatory disorders.
The purpose of this document is to understand various modalities of ovulation induction. Anovulation is among the most common causes of infertility, and clinicians caring for infertile couples must have a thorough understanding of the many treatment options, their indications, and their risks. With these goals in mind, this article reviews the principles that guide both the traditional therapies and more recently described treatment strategies.
Ovulatory dysfunction is likely to be present in women with polymenorrhea or oligomenorrhea and is almost always present in women with amenorrhea (except in patients with uterine disease, such as uterine synechiae or Asherman's syndrome). Regular menstrual cycles, with a cycle length between 22 and 35 days, and the presence of premenstrual bloating, dysmenorrhea, and breast tenderness suggest the presence of ovulatory cycles. The causes of anovulation are many and varied. Thyroid disease, hyperprolactinemia, adrenal disease, pituitary or ovarian tumors, eating disorders, extremes of weight loss or exercise, polycystic ovary syndrome, and obesity are all commonly associated with ovulatory dysfunction. Because chronic anovulation is associated with increased risk for endometrial hyperplasia and neoplasia, endometrial sampling also merits serious consideration before induction of ovulation, depending on the menstrual history.
Laboratory methods for determining ovulation include the basal body temperature chart (BBT), urine testing for the luteinizing hormone (LH), properly timed measurement of serum progesterone, and endometrial biopsy. Serial pelvic ultrasonography also may be able to identify the growth and rupture of a follicle, suggesting that ovulation has occurred (1). Ovulatory cycles are typically associated with a classic biphasic basal body temperature (BBT) pattern that when present is not difficult to recognize. Chaotic BBT recording in which there is no apparent mid-cycle thermogenic shift or sustained interval of temperature elevation preceding the onset of menses strongly suggest anovulation. Contrary to popular belief and practice, cycle day 21 is not always the best time to measure the serum progesterone concentration and the threshold level that indicates ovulation is not 10 ng/mL. A midluteal phase serum progesterone concentration over 10 ng/mL certainly indicates normal luteal function, but not when the luteal phase is grossly short. A progesterone level less than 10 ng/mL can be entirely normal, even during the midluteal phase, because corpus luteum progesterone secretion is distinctly pulsatile and random sampling can coincide with a transient nadir in circulating levels.
Evaluation of Other Infertility Factors:
Before starting any form of ovulation induction, at least one screening semen analysis should always be obtained. Male factors are an important contribution in 20-40% of infertile couple. Early recognition of a coexisting male factor and other potential explanation for infertility can help to avoid wasted time, effort, expense, and associated frustration. Preliminary hysterosalpingogram (HSG) and transvaginal ultrasonography are recommended when the medical history or physical examination raises suspicion of coexisting uterine or tubal infertility factors, for women over age 35, and when ovulation induction requires treatment with exogenous gonadotropins. Laparoscopy and hysteroscopy are unnecessary for most women, but certainly appropriate for those with an abnormal HSG or signs or symptoms of advanced pelvic disease. As the ovarian follicular pool depletes with age, the remaining follicles appear to be less capable of fertilization and establishing a successful pregnancy. If initial attempts at ovulation do not result in a pregnancy in women older than 37 years, consultation with an infertility specialist may be advisable to develop a plan for assisted reproductive procedures, such as In-Vitro Fertilization (IVF) or oocyte donation should be pursued.
Diagnosis of Anovulation:
The most common causes of ovulatory dysfunction are (2):
- Polycystic ovary syndrome (PCOS) -- approximately 70% of cases of ovulatory dysfunction.
- Hypothalamic amenorrhea, also known as hypogonadotropic hypogondism -- approximately 10% cases.
- Hyperprolactinemia -- approximately 10% of cases.
- Premature ovarian failure -- approximately 10% of cases.
Hypothalamic anovulation (hypogonadotropic hypogonadism) usually is associated with low levels of GnRH secretion, low or normal levels of LH and FSH secretion, and low levels of endogenous estrogen secretion. Diseases associated with hypothalamic anovulation include anorexia nervosa, Kallmann's syndrome, and hypothalamic tumors and cysts. These women typically exhibit hypogonadotropic hypogonadism with low follicle-stimulating hormone (FSH) and estrogen levels and normal prolactin levels. In the past, one option for ovulation induction for hypogonadotropic hypogondism was the parenteral administration of GnRH in pulses using a portable programmable pump. It was associated with monofollicular ovulation and a high rate of singleton pregnancy but the pump is not commercially available in the United States (3). In women with a high BMI, abnormal hypothalamic GnRH secretion, pituitary gland LH and FSH secretion, insulin resistance, an anovulation are common. Many of the women resume ovulation after weight loss (4). Weight reduction is best achieved by a combination of diet and exercise.
The most common causes of hyperprolactinemia are a prolactin-secreting pituitary gland tumor and the use of psychiatric medications. The presence of hyperprolactinemia should be confirmed if there is any question about the timing of the blood test or the quality of the assay; blood should be drawn after the patient has fasted and preferably not after a breast examination or breast stimulation. All women with hyperprolactinemia should be tested for hypothyroidism and pregnancy. An imaging study (MRI or CT-scan) of the central nervous system and the pituitary gland should be obtained in all women with hyperprolactinemia unless there is an obvious cause, such as hypothyroidism, that makes a pituitary gland tumor unlikely. Women with large pituitary gland tumors may have undiagnosed adrenal insufficiency, a condition that poses significant health risks (5).
Premature Ovarian Failure:
This includes women with amenorrhea and elevated serum FSH concentrations, indicating ovarian failure. An elevated random FSH level in amenorrheic or severely oligomenorrheic women or an elevated day-3 FSH level in women with menses is highly sensitive and specific for identifying women with a depleted ovarian follicular pool. Treatments proposed to induce ovulation in women with premature ovarian failure include 1) oral contraceptive suppression of gonadotropins followed by discontinuation of the oral contraceptive to allow a rebound in gonadotropin secretion and ovarian function; 2) GnRH-agonist suppression of gonadotropin injections; and 3) glucocorticoid suppression of the immune system. None of these treatments has demonstrated efficacy in randomized clinical trials for inducing ovulation in women with premature ovarian failure (6).
Luteal Phase Deficiency:
It is a theoretical disorder in which ovulation occurs, but there is insufficient progesterone production by the corpus luteum to allow for successful implantation. Luteal phase deficiency is thought to cause recurrent pregnancy loss, especially in the first trimester, and is believed to be responsible for a subset of cases of infertility. However, women who have regular menstrual cycles may have luteal phase abnormalities in as many as 31% of their cycles. Methods to diagnose and treat luteal phase deficiencies are largely speculative. Because current infertility treatment often includes empiric treatment for unexplained infertility, most women who have luteal phase deficiencies and are infertile will receive treatment that includes controlled ovarian hyperstimulation. Therefore, a therapy specific to luteal phase deficiency is not being aggressively pursued. Clomiphene citrate, therefore, is both a logical and effective choice for treatment. Progesterone levels are typically higher in clomiphene-induced ovulatory cycles than in normal spontaneous cycles, likely because the preovulatory follicular development is optimized and also because treatment may result in more than just one corpus luteum (7).
Age is an important consideration. Ideally, the woman undergoing ovulation induction is 34 or younger. The best information available today suggests that by the time woman is in her early 40s, the chance has declined to just a few percentage points, reflecting the fact that the ability to conceive declines slowly until age 38 or so and then decreases rapidly thereafter. For women in their early 40s, proceeding directly to in-vitro fertilization (IVF) usually makes more sense than attempting ovulation induction over the course of a few cycles -- those two or three cycles may represent 10% to 20% of patient's remaining productive life. Because older women are more susceptible to endometrial carcinoma and have a higher incidence of anovulatory disorders, endometrial cavity evaluation should precede ovulation induction when a patient over age 35 has unexplained uterine bleeding or other signs of possible endometrial pathology, particularly when therapy will involve the administration of injectable gonadotropins.
Clomiphene Citrate -- the precise mechanism of action of clomiphene citrate is not completely understood. The administration of clomiphene to anovulatory women with endogenous estrogen secretion often is followed by an increase in both hypothalamic GnRH secretion and pituitary LH and FSH secretion, which causes follicle growth, triggering the LH surge and ovulation. Anovulatory women in whom the anterior pituitary gland, adrenals, ovaries, and thyroid are relatively healthy are the best candidates for clomiphene citrate. Patients with polycystic ovary syndrome (PCOS) or irregular menses also may benefit. When primary pituitary or ovarian failure is present, however, clomiphene will be ineffective. Obesity and hyperandrogenism also significantly reduce the chances that the drug will induce ovulation. Clomiphene may be used alone or in combination with estrogen or gonadotropins. When used in tandem with intrauterine insemination (IUI), pregnancy rates generally are boosted over those associated with either modality alone. This combination of clomiphene citrate and IUI is particularly advisable when treating women with unexplained infertility. Clomiphene treatment is most effective in women with normal FSH levels and adequate endogenous production of estrogen and is least effective in women with hypothalamic amenorrhea or in women with an elevated basal FSH concentration (8).
Most clomiphene-induced pregnancies occur within the first three menstrual cycles, and the vast majority occurs within 6 months. There is no benefit to increasing the dosage once ovulation has occurred or to continuing beyond 6 months of treatment. The risk of multiple-gestation is low compared with other ovarian-stimulation methods, ranging from about 5% to 10%. The potential side effects of clomiphene citrate include ovarian enlargement, ovarian cysts, hot flashes, bloating, weight gain, headache, nausea, fatigue, and blurred vision. The main contraindications to the use of clomiphene are pregnancy, hypersensitivity to the medication, and ovarian cysts.
FDA has approved clomiphene dosages of 50 mg or 100 mg daily for a maximum of 5 days per cycle. After spontaneous menses or the induction of menses with a progestin withdrawal, clomiphene is started on cycle day 3, 4, or 5 at 50 mg daily for 5 days. Starting clomiphene on cycle day 3 or 5 does not appear to influence the pregnancy rate. If lower doses are not successful in inducing ovulation, many clinicians prescribe 150 mg daily for 5 days; a few have used dosage as high as 250 mg daily for 5 days. Of those women who ovulate while taking clomiphene, between 40% and 80% will become pregnant. The rate of spontaneous abortions is noted to be 15% and the incidence of birth defects is similar to that seen in spontaneous pregnancy.
Gonadotropins -- it can be administered using human urinary menopausal gonadotropins (hMG), which contain both LH and FSH, or by using recombinant FSH. Both types of gonadotropins are effective in treating anovulation in women with PCOS. Although more expensive than clomiphene citrate and also involve greater potential for side effects. For these reasons, they usually are given when clomiphene citrate has proved unsuccessful. Because even anovulatory patients are likely to have enough endogenous LH to produce estradiol in a developed follicle, FSH containing little or no LH is adequate for hMG (menotropins) therapy. An exception would be a patient who has had her pituitary gland removed. Such a patient would require exogenous LH as well as FSH. Menotropins have been on the market for more than 30 years. Today, highly purified FSH products also are available. This purer compound ensures that dosages are of consistent potency, and can be given subcutaneously. Women with hypothalamic anovulation who have a baseline serum LH level lower than 0.5 IU/L should be treated with both gonadotropins. Women with hypothalamic amenorrhea and a baseline LH level higher than 0.5 IU/L can be successfully treated with FSH alone (9).
Metformin -- it is an oral biguanide antihyperglycemic agent approved for the treatment of adult-onset diabetes mellitus. It is category-B drug used by some clinicians to treat diabetes mellitus in pregnant women. Metformin is not approved by the U.S. Food and Drug Administration (FDA) for ovulation induction. Numerous studies have examined the effects of metformin on ovulation rates in anovulatory women with polycystic ovary syndrome. Metformin treatment regimens have varied little, ranging from 1,500 mg to 1,700 mg daily (500-850 mg 2-3 times daily). Most studies, but not all, have observed that metformin treatment alone can induce ovulation in anovulatory women with polycystic ovary syndrome. Ovulation rates in metformin-treated women have varied widely among studies, ranging from a low of 8% to a high of 82%; overall, the observed ovulation rate is approximately 40% (10).
Dopamine Agonists -- the drugs (bromocriptine, pergolide, cabergoline) are the treatment of choice for ovulation induction in women with hyperprolactinemia. These drugs directly suppress prolactin production by the tumor and cause an increase in endogenous GnRH secretion, which stimulates pituitary gland secretion of LH and FSH and consequently induces follicle development and ovulation. In addition, dopamine agonists decrease the size of prolactin-secreting pituitary gland tumor (11). Normalization of prolactin levels is the therapeutic goal, as well as assuring that the tumor is responding to the dopamine agonists. With dopamine-agonist therapy, a near-maximal decrease in serum prolactin levels should be achieved after 4-weeks of treatment. Serum prolactin levels should be measured approximately 1 month after initiating therapy and about 1 month after a change in the dosage or drug. Following correction of hyperprolactinemia, about 80% of women will ovulate, and cumulative pregnancy rates of 80% are commonly observed. Treatment usually is discontinued once pregnancy is diagnosed. However, in women with a macroprolactinoma, therapy should be continued throughout pregnancy to decrease the risk of tumor growth and neurosurgical complications, such as compression of the optic nerve. In small percentage of women with hyperprolactinemia who do not respond to dopamine-agonist therapy, standard ovulation induction therapy with clomiphene citrate may be considered. In rare cases, gonadotropin therapy may be considered.
Ovulation Induction and Multiple-Gestation:
Multiple-gestation is a growing problem. Public awareness is increasing about the hazards associated with multiple births, as well as the long-term costs and consequences. Monofolliculogenesis is the goal of therapy in infertile patients. The potential for multiple-gestation with gonadotropin therapy ranges near 30% (particularly when IUI is involved). When treatment is aggressive, the rate may approach 50%. Patients should receive extensive counseling in this regard, and should understand and accept the risks entailed in whatever treatment strategy they select. To decrease the risk of multiple-gestation, treatments associated with low rates of multiple-gestation should be used. When using gonadotropin injections, the use of low-dose regimens appears to be associated with lower rates of multiple-gestation than the use of standard dose regimens. In addition, the risk of multiple-gestation with FSH injections can probably be decreased by withholding hCG and prescribing a barrier contraceptive whenever more than three follicles greater than 15 mm in diameter are detected with pelvic ultrasonography. Multiple pregnancies are high-risk pregnancies at any age because they are frequently complicated by preterm delivery, low birth weight, gestational diabetes, and preeclampsia, and are associated with high infant mortality and morbidity. Their clinical management often requires extended hospitalization, cesarean delivery, and neonatal intensive care, and the associated health care costs are enormous, for both individual couples and society. In fact, the combined costs associated with multifetal pregnancies and their complications now exceed those of all the treatments from which they derive.
Ovarian Hyperstimulation Syndrome:
It is an iatrogenic complication of ovulation induction with exogenous gonadotropins. This disorder also occasionally can be observed in clomiphene-induced cycles. Risk factors for ovarian hyperstimulation syndrome include young age, low body weight, polycystic ovary syndrome, higher doses of gonadotropins, and previous episodes of hyperstimulation. Risk increases with serum estradiol levels and the number of developing ovarian follicles and when supplemental doses of hCG are administered after ovulation for luteal-phase support. Ovarian hyperstimulation syndrome has a broad pathophysiologic spectrum ranging from mild illness to severe disease. It has traditionally been classified as mild, moderate, or severe. Mild illness is characterized by ovarian enlargement, lower abdominal discomfort, and mild nausea and vomiting, diarrhea, and abdominal distention, and occurs in up to one-third of super-ovulation cycles. In general only oral analgesics and counseling to alert affected women to the signs and symptoms of progressive illness are required. Intercourse may be painful and is best avoided to limit the risk of ovarian rupture. Hospitalization for more careful monitoring and aggressive treatment should be given serious consideration in women with severe abdominal pain or peritoneal signs, intractable nausea and vomiting, severe oliguria, tense ascites, dyspnea or tachypnea, dizziness or syncope, severe hyponatremia (sodium less than 135 mEq/L) or hyperkalemia (potassium greater than 5 mEq/L), hemoconcentration (hematocrit greater than 45%), or abnormal renal functions (serum creatinine greater than 1.2 mg/dL; creatinine clearance less than 50 mL/min) or abnormal liver functions (elevated transaminases). Knowledge and prompt recognition of the risk factors for ovarian hyperstimulation are essential for its prevention.
Ovarian and Breast Cancer Risks with Induction Agents:
The risk of ovarian cancer is increased in women who are nulligravid (voluntarily and involuntarily) and women with a strong family history of ovarian cancer. Preliminary studies reported ovulation-inducing medications may be associated with a small increase in the risk of ovarian tumors (borderline tumors and cancer) and that the risk may increase with the extended use of ovulation-inducing agents for many months (12). Although most studies have found no evidence that fertility drug use increases overall breast cancer risk, the results of some studies suggest that prolonged or repeated use of exogenous gonadotropins (6 cycles or more) may increase risk. Overall, the available data are quite reassuring. No causal relationship between exogenous gonadotropin treatment and breast or ovarian cancer has been established. Prolonged treatment is best avoided when there is little hope for success.
Compared with even 10 years ago, there are fortunately a very broad armamentarium of agents, technologies, and knowledge upon which to draw, in helping our patients pursue their goal of parenthood. Knowing which therapy is best suited for which patient, and at which time, is one of the keys to the success in helping patients realize that goal. Knowing when to stop ovulation-induction regimens is as important as knowing when to begin them.
- Ecochard R, Marret H, Rabilloud M et al. Sensitivity and specificity of ultrasound indices of ovulation in spontaneous cycles. Eur J Obstet Gynecol Reprod Bio. 2000;91:59-64.
- ACOG Practice Bulletin. Management of Infertility Caused by Ovulatory Dysfunction. Number 34, February 2002.
- Martin KA, Hall JE, Adam JM et al. Comparison of exogenous gonadotropins and pulsatile gonadotropin-releasing hormone for induction of ovulation in hypogonadotropic amenorrhea. J Clin Endocrinol Metab. 1993;77:125-129 (Level II-3).
- American Society for Reproductive Medicine. Effectiveness and treatment for unexplained infertility. A practice committee report, Birmingham, AL, 2000.
- Gsponer J, De Tribolet N, Deruaz JP et al. Diagnosis, treatment, and outcome of pituitary tumors and other abnormal instrasellar masses. Retrospective analysis of 353 patients. Medicine (Baltimore) 1999;78:236-269 (Level II-2)
- Van Kasteren YM, Hoek A, Schoemaker J. Ovulation induction in premature ovarian failure: a placebo-controlled randomized trial combining pituitary suppression with gonadotropin stimulation. Fertil Steril. 1995;64:273-278 (Level II-1)
- Guzick DS, Sullivan MW, Adamson GD et al. Efficacy of treatment for unexplained infertility. Fertil Steril. 1998;70:207-210
- Barbieri RL. Induction of ovulation in infertile women with hyperandrogenism and insulin resistance. Am J Obstet Gynecol. 2000;183:1412-1418 (Level III)
- Yen SS. Chronic anovulation due to CNS-hypothalamic-pituitary dysfunction. In: Yen SS, Jaffe RB, Barbieri RL, eds. Reproductive endocrinology: physiology, pathophysiology, and clinical management. 4th ed. Philadelphia: WB Saunders, 1999: 516-561 (Level III)
- Kocak M, Caliskan E, Simsir C et al. Metformin therapy improves ovulatory rates, cervical scores, and pregnancy rates in clomiphene citrate-resistant women with polycystic ovary syndrome. Fertil Steril. 2002;77:101-110
- Gsponer J, De Tribolet N, Deruaz JP et al. Diagnosis, treatment, and outcome of pituitary tumors, and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine (Baltimore) 1999;78:236-269 (Level II-2)
- Rossing MA, Daling JR, Weiss NS et al. Ovarian tumors in a cohort of infertile women. N Engl J Med. 1994;331:771-776 (Level II-2)
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