Infertility

Author: Keith A. Frey, MD, Chair, Department of Family Medicine, Mayo Clinic, Scottsdale, Ariz.

Editor's Note—Infertility is a common condition and usually presents to the primary care physician initially. Infertility is defined as 1 year of unprotected intercourse in which a pregnancy has not been achieved. Fifteen to twenty percent of couples in the United States are infertile, and this rate has remained relatively stable since the early 1980s. Aging has an effect on fertility, and studies in different populations show a correlation between a decline in fertility rates and an increase in women’s age.

The causes of infertility include abnormalities of any portion of the male or female reproductive system. Although infertility results from a single cause in the majority of couples, more than 1 factor contributes to infertility in as many as 25% of couples. It is usually the female partner who presents initially for an infertility problem, often in the context of an annual well women appointment. It is advisable to meet both individually with each partner and with the couple together when possible. The physician should arrange a meeting with the couple early in the diagnostic work-up. This provides an important opportunity to review reproductive biology and the rationale for subsequent laboratory test results.

In addition to a comprehensive history and physical examination, each couple must be evaluated by a series of routine laboratory tests and appropriately timed studies to evaluate each major reproductive factor that may be contributing to the infertility. This comprehensive diagnostic survey can and should be completed for most couples in 6-12 months. Each couple’s evaluation must be individualized based on the findings of the history and the physical examination. However, an initial survey of each major reproductive factor is necessary in all couples and can be coordinated by the primary care physician.

Infertility is often associated with intense emotional issues for couples. The primary care physician should anticipate and discuss the range of emotional responses, including depression, anxiety, anger, and marital discord.

Case

A new 31-year-old female patient presents to your office for her annual well women exam. When asked about her contraceptive needs, she tears up and states that she and her husband have been attempting unsuccessfully to get pregnant for 2 years. She was hoping to undergo an evaluation for her infertility and is looking to you for guidance.

Definition

Infertility is defined as 1 year of unprotected intercourse in which a pregnancy has not been achieved. Fecundability is the probability of achieving a pregnancy within 1 menstrual cycle. The fucundability of a normal’ couple is approximately 25%. Infertility is considered primary if neither partner has achieved a successful pregnancy.1 Secondary infertility relates to those couples where there has previously been a pregnancy but there is current difficulty with conception. A subset category of infertility is the female patient with recurrent or habitual spontaneous abortions.

Epidemiology

Fifteen to twenty percent of couples in the United States are infertile, and this rate has remained relatively stable since the early 1980s.1,2 It is estimated that approximately 25% of women will have an episode of infertility during their childbearing years. In recent years, there has been an increase in demand for infertility services. This increased demand appears to be related to a societal trend toward delayed marriage and childbirth, greater awareness of treatment options, and increased societal acceptance of infertility as a medical condition.1

Aging has an effect on fertility, and studies in different populations show a correlation between a decline in fertility rates and an increase in women’s age. Additionally, there is an increased risk of spontaneous abortion and chromosomal nondisjunction and associated aneuploidy with age.2

Etiology

The causes of infertility include abnormalities of any portion of the male or female reproductive system. Although infertility results from a single cause in the majority of couples, more than 1 factor contributes to infertility in as many as 25% of couples. "Unexplained" infertility, in which no specific cause is identified, occurs in approximately 20% of infertile couples. The following causes of infertility have been identified:1-3

  • Male factors (40% of infertile couples).
  • Ovulatory dysfunction (25% of infertile couples).
  • Tubal and pelvic pathology (35% of infertile couples).
  • Unusual problems (5% of infertile couples).

Pathophysiology

Male factors. The most commonly encountered cause of male infertility is a varicocele, a network of palpably distended veins of the pampiniform plexus of the spermatic cord. Studies suggest that larger varicoceles have a greater effect on fertility.4 Other causes include oligospermia or azoospermia,5 disorders of sperm function or motility (asthenospermia), and abnormalities of sperm morphology (teratospermia). Approximately 13% of men with nonobstructive azoospermia have been shown to have Y-chromosome microdeletions. Men with a congenital bilateral absence of the vas deferens have an approximately 70% chance of being carriers of cystic fibrosis mutations.6 High levels of "reactive oxygen species" (oxidants) may have an effect on sperm quality and function, and further studies are currently underway.7

Ovulatory dysfunction. The possible causes of anovulation may be grouped into 4 major categories.8

  1. Hypothalamic anovulation. Specific examples include: psychogenic trauma, anorexia nervosa, pseudocyesis, pharmacologic agents, anatomic defects, and congenital defects.
  2. Pituitary anovulation, such as pituitary tumors or ischemia.
  3. Ovarian anovulation, such as ovarian dysgenesis, premature ovarian failure, or ovarian tumors.
  4. Integrative anovulation, such as polycystic ovarian syndrome or nonpsychogenic weight disturbances.

Tubal and pelvic pathology. Infertility may be associated with tubal damage or adnexal adhesions. Tubal obstruction may result from acute salpingitis, although many cases of tubal occlusion are encountered in which no episodes of salpingitis are recalled. Anatomic distortion of adnexal structures may also be caused by endometriosis. The chronic inflammation associated with endometriosis may disrupt normal conception by causing tubal damage or by secretion of toxic substances,9 though the exact mechanisms remain controversial.10

Unusual problems. Cervical mucus abnormalities occur if, at the time of ovulation, the mucus is either insufficient in quantity or poor in quality. Factors contributing to the formation of such "hostile" (unreceptive) cervical mucus include cervical infections, previous cervical surgery or cautery, and clomiphene therapy.8

Clinical Features

It is usually the female partner who presents initially for an infertility problem, often in the context of an annual well women appointment (such as the case at the beginning). The generalist physician providing such preventive care should regularly inquire about a woman’s intent to conceive. These office visits provide the opportunity to counsel women both about optimizing their preconception health11,12 and normal reproductive physiology.1,2,13,14 The general time requirements for achieving a pregnancy have been studied and defined. As noted earlier, the fucundability rate is approximately 25% in normal’ couples. Additionally, the number of months during which conception was attempted and the percentage of resultant pregnancies is, respectively: at 3 months, 57% of couples achieved pregnancy; at 6 months, 72%; at 12 months, 85%; and at 24 months, 93%.3

Infertility is often associated with intense emotional issues for couples. The primary care physician should anticipate and discuss the range of emotional responses, including depression, anxiety, anger, and marital discord. Infertility differs from other medical conditions in that it is always a problem for both members of the relationship, even if an infertility factor is identified in only 1 partner. Openness about infertility has been shown to be a positive factor in the ability of a couple to cope with involuntary childlessness.1,8

It is advisable to meet both individually with each partner and with the couple together when possible. The physician should arrange a meeting with the couple early in the diagnostic work-up. This provides an important opportunity to review reproductive biology and the rationale for subsequent laboratory test results. The optimal frequency of intercourse is every 1-2 days around the time of expected ovulation.15 The commercially available lubricants are generally considered spermatotoxic and their use should be discouraged.6,16 Since infertility may arise from 1 or more areas of the reproductive system, it requires a comprehensive diagnostic evaluation. The initial assessment of both the male and the female partner consists of a thorough history and physical examination. Specific areas requiring extra attention in the medical history are outlined in Table 1. The purpose of the physical examination is to evaluate each partner for evidence of systemic disease, genetic abnormalities, or androgen dysfunction.2 Specific areas of attention in the male and female physical examination are outlined in Table 2.

In addition to a comprehensive history and physical examination, each couple must be evaluated by a series of routine laboratory tests (see Table 3) and appropriately timed studies (see Table 4) to evaluate each major reproductive factor that may be contributing to the infertility. This comprehensive diagnostic survey can and should be completed for most couples in 6-12 months.1 Each couple’s evaluation must be individualized based on the findings of the history and the physical examination. However, an initial survey of each major reproductive factor is necessary in all couples and can be coordinated by the primary care physician.1,2,8

Table 4.
The Infertility Work-up: Timed Diagnostic Tests

It is helpful for the primary care physician to organize the work-up of the infertile couple into "factors," or the components of human reproductive systems:

1. Male factors. Erectile dysfunction may contribute to male factor infertility and should be investigated if present.18 Evidence of oligospermia or azoospermia after 2 semen analyses will require further diagnostic evaluation. The additional tests will be dependent upon the presence of some sperm (oligospermia) vs absence of sperm (azoospermia) and may include blood levels for follicle-stimulating hormone (FSH), testosterone, genetic evaluation, and testicular biopsy.6,16,19

2. Tubal and pelvic pathology. The female partner must undergo an evaluation for tubal patency. If the history or the physical examination do not indicate evidence of previous tubal damage, proceed with a hysterosalpingogram (HSG). Generally performed by radiologists, the hysterosalpingography involves the instillation of dye into the uterus via an intracervical catheter. Under gentle pressure and while under fluoroscopy, the dye outlines the endometrial cavity, tubes, and eventual free spill into the peritoneal cavity. If the woman’s history strongly suggests prior tubal damage (previous pelvic inflammatory disease or endometriosis), the patient should instead undergo a laparoscopy with intraoperative instillation of tubal dye. If uterine structure abnormalities are suspected or noted on the HSG, a hysteroscopy will be necessary.20 Referral to a gynecologist experienced in infertility evaluation is advised.

3. Ovulatory dysfunction. Anovulation or inconsistent ovulation is strongly suggested by a history of irregular menses and a nonbiphasic basal body temperature pattern (ie, absence of a luteal phase elevation of temperature of approximately 1°F for at least 10 days). Observation of several cycles is recommended with confirmation by abnormally low serum progesterone levels during the luteal phase, or a late luteal phase endometrial biopsy. Patients with polycystic ovary syndrome (PCOS) must meet the following diagnostic criteria: 1) clinical or biochemical evidence of hyperandrogenism; 2) oligo-ovulation; and 3) exclusion of other known disorders, such as adrenal hyperplasia or hyperprolactinemia.21

4. Cervical mucus factors. When a significant number of white blood cells are noted on cervical mucus samples at the time of expected ovulation (mid-cycle), a specific bacteriologic diagnosis should be sought and treated. The postcoital test, historically an important test in the evaluation of the infertile couple, has now been shown to have limited value.22

Management

The comprehensive diagnostic survey should be completed prior to initiating therapy. As noted earlier, the work-up can usually be completed within 6 months. When the female partner is 35 years or older, the diagnostic evaluation should be completed as quickly as feasible due to the limited ovarian reserve.23 The male and female partners should be managed as a couple, and therapy should proceed at a rate that the couple finds comfortable.

Specific Management Issues

Male factors. Infections of the male genitourinary tract (such as prostatitis and epididymitis) are treated as usual with the indicated antibiotics. Abnormalities of sperm count and/or motility due to a varicocele will often improve following a varicocelectomy,4,24 and a urology referral is warranted. Other causes of oligospermia require referral to an infertility specialist for consideration of intrauterine insemination (IUI) or advanced reproductive technology, such as intracytoplasmic sperm injection (ICSI), a technique in which a single sperm is injected directly into the oocyte.

Ovulatory dysfunction. When anovulation or oligo-ovulation is diagnosed, absent additional contributing infertility factors, clomiphene citrate therapy may be initiated. Chronic anovulation and unexplained infertility patients attempting to conceive are among the patients best suited for clomiphene.25,26 Patients with other causes of anovulation generally respond best to specific therapy, such as surgery for a pituitary tumor. Patients with polycystic ovarian syndrome are uniquely sensitive to clomiphene citrate and gonadotropins, with higher risks of ovarian hyperstimulation and multiple gestations. Referral of these PCOS patients to an infertility subspecialist is therefore recommended.21

Clomiphene treatment. A careful evaluation for galactorrhea and a prolactin level should precede treatment. The risk of multiple gestation (primary twinning) and the common side effects should be reviewed with the patient prior to beginning treatment. The usual starting dose is 50 mg/d orally on days 3 through 7 of the menstrual cycle. A home ovulation kit can help guide the timing of intercourse. The dose may be increased to 100 mg daily (again Day 3 through 7) after 2-3 unsuccessful cycles at 50 mg. Common side effects include vasomotor flushes (10%), abdominal or pelvic discomfort (5.5%), nausea (2.2%), and breast tenderness (2%).1,3

Expected results. Ovulation should be expected 5-10 days after the treatment ends; this should be confirmed by biphasic basal body temperature (BBT) and an elevated level of serum progesterone on day 21. If ovulation does not occur despite clomiphene therapy, consultation with a reproductive endocrinologist is recommended.

Tubal and pelvic pathology. Tubal blockage or deformity may necessitate surgical correction. The management of endometriosis in a woman desiring to achieve pregnancy depends on the degree and location of endometrial deposits. Conservative surgical treatment may enhance fertility potential by destroying endometrial implants and endometriomas. Laparoscopic conservative surgical treatment should be considered as a treatment option for mild endometriosis-associated infertility.27 For patients with more severe tubal and pelvic pathology, referral for assisted reproductive technologies is warranted and have higher rates of successful pregnancy than extensive surgery.

Unusual problems. For cervical mucus abnormalities, antibiotics should be used to treat the specific bacterial cause of the problem. Low-dose estrogens (0.625 mg of conjugated estrogen from menstrual day 3 through 14) may be used for poor cervical mucus that does not result from infectious causes.1,3 However, intrauterine insemination (IUI) is the best treatment option for a cervical factor.

Recurrent pregnancy loss. Most pregnancy losses are due to random genetic events and occur in the first trimester. Habitual miscarriage, or abortion, is defined as 3 consecutive losses. The clinical evaluation of these couples should be based on the woman’s age and her apprehension about future loss, not the total number. The evaluation should include a detailed family and genetic history, and a search for other specific causes. The prognosis after even 3 consecutive losses is still hopeful at approximately 60%.2

Additional Aspects

The work-up, diagnosis, and treatment of infertility can precipitate intense emotional reactions. The sensitive primary care physician should discuss and provide support for such emotions as anger, guilt, self-doubt, depression, and grief with the couple. The actions described below may also prove beneficial.1,8

  • Help the couple understand their motives for parenting, which may include desires 1) to parent; 2) to experience a pregnancy; 3) to meet the expectations of others; and 4) to promote genetic continuity.
  • Assist the couple in the development of mutual support and an adaptive "couple-coping" style. Discuss sexual issues, and encourage the couple to nurture their intimacy; they will need its strength to deal with the problems associated with infertility. Periodic meetings with the couple to review diagnostic progress provide further opportunity to reinforce coping skills.
  • Help the couple broaden their support systems, including self-help groups, such as Resolve, Inc. (see RESOLVE National Home Page at www.resolve.org.)

Disposition/Prognosis

The exact prognosis of infertility is difficult to define because of the multiple potential causes. For most of these, conception will not be achieved without specific treatment. However, with specific therapy, subsequent pregnancy rates have been studied and the results are favorable. "Unexplained" infertility is the persistent inability to conceive after a comprehensive diagnostic assessment of the couple fails to establish a specific diagnosis. Couples with infertility of 4 years or more tend to have a poor prognosis.2,3 If a comprehensive diagnostic work-up fails to identify a cause, or if the appropriate treatment at the primary care level is unsuccessful, the physician should refer the patient to an infertility subspecialist for further evaluation and consideration of advanced reproductive techniques.

References

1. Petrie K, Frey KA. Preconception care/infertility. Monograph, Edition No. 234, Home Study Self-Assessment program. Kansas City, Mo.: American Academy of Family Physicians, November 1998.

2. Whitman-Elia GF, Baxley EG. A primary care approach to the infertile couple. J Am Board of Fam Pract. 2001;14:33-45.

3. Speroff L, et al. Infertility chapter. In: Speroff L, Glass RH, Kase NG, eds. Clinical Gynecologic Endocrinology and Infertility. 5th ed. Baltimore, Md: Williams & Wilkins; 1994.

4. Steckel J, et al. Relationship between varicocele size and response to varicocelectomy. J Urol. 1993;149:769-771.

5. Guzick DS, et al. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med. 2001;345:1388-1393.

6. Kolettis PN. Evaluation of the subfertile man. Am Fam Physician. 2003;67:2165-2172.

7. Agarwal A, Saleh RA. Role of oxidants in male infertility: Rationale, significance, and treatment. Urol Clin N Am. 2002;29:817-827.

8. Frey KA. Infertility. In: Mengel MB, Schwiebert LP, eds. Ambulatory Medicine: Primary Care Families. New York, NY: McGraw-Hill/Appleton & Lange; 2000.

9. Osuga Y, et al. Role of laparoscopy in the treatment of endometriosis-associated infertility. Gynecol Obstet Invest. 2002;53(suppl 1):33-39.

10. Witz CA, Burns WN. Endometriosis and infertility: Is there a cause and effect relationship? Gynecol Obstet Invest. 2002; 53(suppl 1):2-11.

11. Hargreave TB, Mills JA. Investigating and managing infertility in general practice. BMJ. 1998;316:1438-1441.

12. Frey KA. Preconception care. Primary Care Reports. 2002;8: 222-227.

13. Falcone T. What the internist needs to know about infertility. Cleve Clin J Med. 2001;68:65-72.

14. Himmel W, et al. Management of involuntary childlessness. Br J Gen Pract. 1997;47:111-118.

15. Wilcox AJ, et al. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med. 1995;333: 1517-1521.

16. Sigman M, Lipshultz LI, Howard SS. Evaluation of the subfertile male. In: Lipshultz LI, Howards SS, eds. Infertility in the Male. 3rd ed. St. Louis, Mo: Mosby; 1997:173-193.

17. World Health Organization. Reference values of semen variables. In: WHO Laboratory Manual for the Examination of Human Semen and Sperm-Cervical Mucus Interaction. 4th ed. Cambridge, Mass: Cambridge University Press; 1999:60-61.

18. Wijesinha S. Male reproductive health—what is the GP’s role? Aust Fam Physician. 2003;32:408-411.

19. Schoor RA, et al. The role of testicular biopsy in the modern management of male infertility. J Urol. 2002;167:197-200.

20. Revel A, Shushan A. Investigation of the infertile couple. Hysteroscopy with endometrial biopsy is the gold standard investigation for abnormal uterine bleeding. Human Reproduction. 2002; 17:1947-1949.

21. Richardson MR. Current perspectives in polycystic ovary syndrome. Am Fam Physician. 2003;68:697-704.

22. Oei SG, et al. Effectiveness of the postcoital test: Randomized controlled trial. BMJ. 1998;317:502-505.

23. Broekmans FJ, et al. Ovarian reserve tests in infertility practice and normal fertile women. Maturitas. 1998;30:205-214.

24. Seftel AD, et al. Effects of subinguinal varicocele ligation on sperm concentration, motility, and Kruger morphology. J Urol. 1997;158:1800-1803.

25. Hughes E, et al. Clomiphene citrate for unexplained subfertility in women. In: Cochrane Database of Systematic Reviews. (3): CD000057, 2000.

26. Hughes E, et al. Clomiphene citrate for ovulation induction in women with oligo-amenorrhoea. In: Cochrane Database of Systematic Reviews. (2): CD000056, 2000.

27. Jacobson TZ, et al. Laparoscopic surgery for subfertility associated with endometriosis. In: Cochrane Database of Systematic Reviews. (4): CD001398, 2002.

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