Definition and Prevalence
Infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse. In a study of 5574 English and American women who ultimately conceived, pregnancy occurred in 50% within 3 months, 72% within 6 months, and 85% within 12 months. These findings are consistent with predictions based on fecundability, the probability of achieving pregnancy in one menstrual cycle (approximately 20–25% in healthy young couples). Assuming a fecundability of 0.25, 98% of couples should conceive within 13 months. Based on this definition, the National Survey of Family Growth reports a 14% rate of infertility in the United States in married women aged 15–44. The infertility rate has remained relatively stable over the past 30 years, although the proportion of couples without children has risen, reflecting a trend to delay childbearing. This trend has important implications because of an age-related decrease in fecundability, which begins at age 35 and decreases markedly after age 40. It is estimated that ˜8% of women in the United States have received medical assistance for infertility; of these, 74% received counseling, ˜60% underwent infertility testing of the female and/or male partner, and ˜46% used ovulation-inducing medication.
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%, female factors in 58%, and is unexplained in about 17% of couples (Fig. 347-9). Not uncommonly, both male and female factors contribute to infertility.
Causes of infertility. FSH, follicle-stimulating hormone; LH, luteinizing hormone.
Approach to the Patient: Infertility
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.
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 FSH, LH, and estradiol with or without an increase in prolactin), (2) PCOS (irregular cycles and hyperandrogenism in the absence of other causes of androgen excess), (3) ovarian (low estradiol with increased FSH), or (4) 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. 50-2).
The approach to further evaluation of these disorders is described in detail in Chap. 50.
In women with a history of regular menstrual cycles, evidence of ovulation should be sought as described above. An endometrial biopsy to exclude luteal phase insufficiency is no longer considered a usual part of the infertility workup. Even in the presence of ovulatory cycles, evaluation of ovarian reserve is recommended for women aged >35 years. Measurement of FSH on day 3 of the cycle (an FSH level <10 IU/mL on cycle day 3 predicts adequate ovarian oocyte reserve) or in response to clomiphene (blocks estrogen negative feedback on FSH), antral follicle count and serum levels of inhibin B and AMH have all been used for this purpose.
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 is defined as the presence of endometrial glands or stroma outside the endometrial cavity and uterine musculature. Its presence is suggested by a history of dyspareunia (painful intercourse), worsening dysmenorrhea that often begins before menses, or by a thickened rectovaginal septum or deviation of the cervix on pelvic examination. The pathogenesis of the infertility associated with endometriosis is unclear but may involve effects on fertilization, normal function of the endometrium, as well as adhesions. Endometriosis is often clinically silent, however, and can only be excluded definitively by laparoscopy.
(See also Chap. 346) Known causes of male infertility include primary testicular disease, disorders of sperm transport, and hypothalamic-pituitary disease resulting in secondary hypogonadism. 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 critical part 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 (see below) with or without intrauterine insemination (IUI), (3) gonadotropins with or without IUI, and (4) in vitro fertilization (IVF). The time used to complete the evaluation, correction, and expectant management can be longer in women aged <30 years, but this process should be advanced rapidly in women aged >35 years. In some situations, expectant management will not be appropriate.
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. 339); lifestyle modification may be successful in women with obesity, low body weight, or a history of intensive exercise (Chap. 79).
Medications used for ovulation induction include clomiphene citrate, 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. It induces ovulation in ˜60% of women with PCOS and is the initial treatment of choice. It may be combined with agents that modify insulin levels such as metformin. Clomiphene citrate is less successful in patients with hypogonadotropic hypogonadism. Aromatase inhibitors have also been investigated for the treatment of infertility. Initial studies are promising, 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. 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. Though FSH is the key component, there are growing data that the addition of some LH (or hCG) may improve results and this is particularly important in hypogonadotropic patients.
None of these methods are effective in women with premature ovarian failure in whom donor oocyte or adoption are the methods of choice.
If hysterosalpingography suggests a tubal or uterine cavity abnormality, or if a patient is aged ≥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.
Though 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-to-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.
The treatment options for male factor infertility have expanded greatly in recent years (Chap. 346). Secondary hypogonadism is highly amenable to treatment with pulsatile GnRH or gonadotropins. 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 clomiphene or gonadotropins, 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 depend on the age of the woman and the cause of the infertility. The number of cycles canceled increases from approximately 10% in women aged <35 years to 24% in women aged >40 while the birth rate decreases from ˜39% of cycles in which embryos were transferred in women aged <35 to 24% in women aged 38-40 and only 10% in women aged >40. Though 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 aged <35, in whom it can be as high as 40%.