DEFINITION AND PREVALENCE
Infertility has traditionally been defined as the inability to conceive after 12 months of unprotected sexual intercourse. In women who ultimately conceived, pregnancy occurred in ~50% within 3 months, 75–82% within 6 months, and 85–92% within 12 months. The World Health Organization (WHO) considers infertility as a disability (an impairment of function) and thus access to health care falls under the Convention on the Rights of Persons with Disability. Thirty-four million women, predominantly from developing countries, have infertility resulting from maternal sepsis and unsafe abortion. In populations <60 years old, infertility is ranked the fifth highest serious global disability. In the United States, the rate of infertility in married women age 15–44 is 6% based on the National Survey of Family Growth, although prospective studies suggest that it may be as high as 12–15%. The infertility rate has remained relatively stable over the past 30 years in most countries. However, the proportion of couples without children has risen, reflecting both higher numbers of couples in childbearing years and a trend to delay childbearing. This trend has important implications because of an age-related decrease in fecundability: the incidence of primary infertility increases from ~8% between the ages of 18 and 38 to 25% and 30% between the ages of 35 and 39 and 40 and 44, respectively. It is estimated that 14% of couples in the United States have received medical assistance for infertility; of these, two-thirds received counseling, ~12% underwent infertility testing of the female and/or male partner, and 17% received drugs to induce ovulation.
The spectrum of infertility ranges from reduced conception rates or the need for medical intervention to irreversible causes of infertility. Infertility can be attributed primarily to male factors in 25% of couples and female factors in 58% of couples and is unexplained in about 17% of couples (Fig. 14-1). Not uncommonly, both male and female factors contribute to infertility. Decreases in the ability to conceive as a function of age in women has led to recommendations that women >34 years old who are not at increased risk of infertility seek attention after 6 months, rather than 12 months as suggested for younger women, and receive an expedited work-up and approach to treatment.
Causes of infertility. FSH, follicle-stimulating hormone; LH, luteinizing hormone.
APPROACH TO THE PATIENT: Infertility INITIAL EVALUATION
In all couples presenting with infertility, the initial evaluation includes discussion of the appropriate timing of intercourse and discussion of modifiable risk factors such as smoking, alcohol, caffeine, and obesity. The range of required investigations should be reviewed as well as a brief description of infertility treatment options, including adoption. Initial investigations are focused on determining whether the primary cause of the infertility is male, female, or both. These investigations include a semen analysis in the male, confirmation of ovulation in the female, and, in the majority of situations, documentation of tubal patency in the female. In some cases, after an extensive workup excluding all male and female factors, a specific cause cannot be identified, and infertility may ultimately be classified as unexplained. PSYCHOLOGICAL ASPECTS OF INFERTILITY
Infertility is invariably associated with psychological stress related not only to the diagnostic and therapeutic procedures themselves but also to repeated cycles of hope and loss associated with each new procedure or cycle of treatment that does not result in the birth of a child. These feelings are often combined with a sense of isolation from friends and family. Counseling and stress-management techniques should be introduced early in the evaluation of infertility. Importantly, infertility and its treatment do not appear to be associated with long-term psychological sequelae. FEMALE CAUSES
Abnormalities in menstrual function constitute the most common cause of female infertility. These disorders, which include ovulatory dysfunction and abnormalities of the uterus or outflow tract, may present as amenorrhea or as irregular or short menstrual cycles. A careful history and physical examination and a limited number of laboratory tests will help to determine whether the abnormality is (1) hypothalamic or pituitary (low follicle-stimulating hormone [FSH], luteinizing hormone [LH], and estradiol with or without an increase in prolactin), (2) polycystic ovary syndrome (PCOS; irregular cycles and hyperandrogenism in the absence of other causes of androgen excess), (3) ovarian (low estradiol with increased FSH), or (4) a uterine or outflow tract abnormality. The frequency of these diagnoses depends on whether the amenorrhea is primary or occurs after normal puberty and menarche (see Fig. 15-2).
The approach to further evaluation of these disorders is described in detail in Chap. 15. Ovulatory Dysfunction
In women with a history of regular menstrual cycles, evidence of ovulation should be sought (Chap. 13). Even in the presence of ovulatory cycles, evaluation of ovarian reserve is recommended for women age >35 years if they are interested in fertility. Measurement of FSH on day 3 of the cycle (an FSH level <10 IU/mL on cycle day 3 predicts adequate ovarian oocyte reserve) is the most cost-effective test. Other tests include measurement of FSH in response to clomiphene citrate (blocks estrogen negative feedback on FSH), antral follicle count on ultrasound, and anti-müllerian hormone (AMH; <0.5 ng/mL predicts reduced ovarian reserve although there is variability between labs). Tubal Disease
Tubal dysfunction may result from pelvic inflammatory disease (PID), appendicitis, endometriosis, pelvic adhesions, tubal surgery, previous use of an intrauterine device (IUD), and a previous ectopic pregnancy. However, a cause is not identified in up to 50% of patients with documented tubal factor infertility. Because of the high prevalence of tubal disease, evaluation of tubal patency by hysterosalpingogram (HSG) or laparoscopy should occur early in the majority of couples with infertility. Subclinical infections with Chlamydia trachomatis may be an underdiagnosed cause of tubal infertility and requires the treatment of both partners. Endometriosis
Endometriosis is defined as the presence of endometrial glands or stroma outside the endometrial cavity and uterine musculature and accounts for 40% of infertility not due to ovulatory disorders, tubal obstruction, or male factor. Its presence is suggested by a history of dyspareunia (painful intercourse), worsening dysmenorrhea that often begins before menses, or a thickened rectovaginal septum or deviation of the cervix on pelvic examination. Mild endometriosis does not appear to impair fertility; the pathogenesis of the infertility associated with moderate and severe endometriosis may be multifactorial with impairments of folliculogenesis, fertilization, and implantation, as well as adhesions. Endometriosis is often clinically silent, however, and can only be excluded definitively by laparoscopy. Male Causes
Known causes of male infertility include primary testicular disease, genetic disorders (particularly Y chromosome microdeletions), disorders of sperm transport, and hypothalamic-pituitary disease resulting in secondary hypogonadism (See also Chap. 11). However, the etiology is not ascertained in up to one-half of men with suspected male factor infertility. The key initial diagnostic test is a semen analysis. Testosterone levels should be measured if the sperm count is low on repeated examination or if there is clinical evidence of hypogonadism. Gonadotropin levels will help to determine a gonadal versus a central cause of hypogonadism.
In addition to addressing the negative impact of smoking on fertility and pregnancy outcome, counseling about nutrition and weight is a fundamental component of infertility and pregnancy management. Both low and increased body mass index (BMI) are associated with infertility in women and with increased morbidity during pregnancy. Obesity has also been associated with infertility in men. The treatment of infertility should be tailored to the problems unique to each couple. In many situations, including unexplained infertility, mild-to-moderate endometriosis, and/or borderline semen parameters, a stepwise approach to infertility is optimal, beginning with low-risk interventions and moving to more invasive, higher risk interventions only if necessary. After determination of all infertility factors and their correction, if possible, this approach might include, in increasing order of complexity: (1) expectant management, (2) clomiphene citrate or an aromatase inhibitor (see below) with or without intrauterine insemination (IUI), (3) gonadotropins with or without IUI, and (4) in vitro fertilization (IVF). The time used for evaluation, correction of problems identified, and expectant management can be longer in women age <30 years, but this process should be advanced rapidly in women age >35 years. In some situations, expectant management will not be appropriate. OVULATORY DYSFUNCTION
Treatment of ovulatory dysfunction should first be directed at identification of the etiology of the disorder to allow specific management when possible. Dopamine agonists, for example, may be indicated in patients with hyperprolactinemia (Chap. 5); lifestyle modification may be successful in women with obesity, low body weight, or a history of intensive exercise.
Medications used for ovulation induction include agents that increase FSH through alteration of negative feedback, gonadotropins, and pulsatile GnRH. Clomiphene citrate is a nonsteroidal estrogen antagonist that increases FSH and LH levels by blocking estrogen negative feedback at the hypothalamus. The efficacy of clomiphene for ovulation induction is highly dependent on patient selection. In appropriate patients, it induces ovulation in ~60% of women with PCOS and has traditionally been the initial treatment of choice. Combination with agents that modify insulin levels such as metformin does not appear to improve outcome. Clomiphene citrate is less successful in patients with hypogonadotropic hypogonadism. Aromatase inhibitors have also been investigated for the treatment of infertility. Studies suggest they may have advantages over clomiphene, but these medications have not been approved for this indication.
Gonadotropins are highly effective for ovulation induction in women with hypogonadotropic hypogonadism and PCOS and are used to induce the development of multiple follicles in unexplained infertility and in older reproductive-age women. Disadvantages include a significant risk of multiple gestation and the risk of ovarian hyperstimulation, particularly in women with polycystic ovaries, with or without other features of PCOS. Careful monitoring and a conservative approach to ovarian stimulation reduce these risks. Currently available gonadotropins include urinary preparations of LH and FSH, highly purified FSH, and recombinant FSH. Although FSH is the key component, LH is essential for steroidogenesis in hypogonadotropic patients, and LH or human chorionic gonadotropin (hCG) may improve results through effects on terminal differentiation of the oocyte. These methods are commonly combined with IUI.
None of these methods are effective in women with premature ovarian failure, in whom donor oocyte or adoption is the method of choice. TUBAL DISEASE
If hysterosalpingography suggests a tubal or uterine cavity abnormality or if a patient is age ≥35 at the time of initial evaluation, laparoscopy with tubal lavage is recommended, often with a hysteroscopy. Although tubal reconstruction may be attempted if tubal disease is identified, it is generally being replaced by the use of IVF. These patients are at increased risk of developing an ectopic pregnancy. ENDOMETRIOSIS
Although 60% of women with minimal or mild endometriosis may conceive within 1 year without treatment, laparoscopic resection or ablation appears to improve conception rates. Medical management of advanced stages of endometriosis is widely used for symptom control but has not been shown to enhance fertility. In moderate and severe endometriosis, conservative surgery is associated with pregnancy rates of 50 and 39%, respectively, compared with rates of 25 and 5% with expectant management alone. In some patients, IVF may be the treatment of choice. MALE FACTOR INFERTILITY
The treatment options for male factor infertility have expanded greatly in recent years (Chap. 11). Secondary hypogonadism is highly amenable to treatment with gonadotropins or pulsatile gonadotropin-releasing hormone (GnRH) where available. In vitro techniques have provided new opportunities for patients with primary testicular failure and disorders of sperm transport. Choice of initial treatment options depends on sperm concentration and motility. Expectant management should be attempted initially in men with mild male factor infertility (sperm count of 15 to 20 × 106/mL and normal motility). Moderate male factor infertility (10 to 15 × 106/mL and 20–40% motility) should begin with IUI alone or in combination with treatment of the female partner with ovulation induction, but it may require IVF with or without intracytoplasmic sperm injection (ICSI). For men with a severe defect (sperm count of <10 × 106/mL, 10% motility), IVF with ICSI or donor sperm should be used. If ICSI is performed because of azoospermia due to congenital bilateral absence of the vas deferens, genetic testing and counseling should be provided because of the risk of cystic fibrosis. ASSISTED REPRODUCTIVE TECHNOLOGIES
The development of assisted reproductive technologies (ARTs) has dramatically altered the treatment of male and female infertility. IVF is indicated for patients with many causes of infertility that have not been successfully managed with more conservative approaches. IVF or ICSI is often the treatment of choice in couples with a significant male factor or tubal disease, whereas IVF using donor oocytes is used in patients with premature ovarian failure and in women of advanced reproductive age. Success rates are influenced by cause of infertility and age, varying between 15 and 40%. Success rates are highest in anovulatory women and lowest in women with decreased ovarian reserve. In the United States, success rates are higher in white than in black, Asian, or Hispanic women. Although often effective, IVF is expensive and requires careful monitoring of ovulation induction and invasive techniques, including the aspiration of multiple follicles. IVF is associated with a significant risk of multiple gestation, particularly in women age <35, in whom the rate can be as high as 30%, which has led to specific recommendations for numbers of embryos or blastocysts to transfer based on age and specific prognostic factors.