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Home , Infertility, Male infertility, Mittelschmerz, Ovulation induction, Vaginal discharge

Infertility ALAINA B. JOSE-MILLER, M.D., University of Arizona, Tucson, Arizona JENNIFER W. BOYDEN, M.D., and KEITH A. FREY, M.D., Mayo Clinic, Scottsdale, Arizona

Infertility is defined as failure to achieve during one year of frequent, unprotected intercourse. Evaluation generally begins after 12 months, but it can be initiated earlier if infertility is suspected based on history or if the female partner is older than 35 years. Major causes of infertility include male factors, ovarian dysfunction, tubal disease, , and uterine or cervical factors. A careful history and physical examination of each partner can suggest a single or multifactorial etiology and can direct further investigation. can be documented with a home uri- nary kit. and pelvic ultrasonography can be used to screen for uterine and disease. Hysteroscopy and/or laparoscopy can be used if no abnormalities are found on initial screening. Women older than 35 years also may benefit from testing of follicle-stimulating hormone and levels on day 3 of the , the clomiphene citrate challenge test, or pelvic ultrasonography for antral follicle count to determine treatment options and the likelihood of success. Options for the treatment of male factor infertility include therapy, intrauterine , or in vitro fertilization. Infertility attributed to ovulatory dysfunction often can be treated with oral ovulation-inducing agents in a primary care setting. Women with poor ovar- ian reserve have more success with oocyte donation. In certain cases, tubal disease may be treatable by surgical repair or by in vitro fertilization. Infertility attributed to endometriosis may be amenable to surgery, induction of ovulation with intrauterine insemination, or in vitro fertilization. may be managed with , intrauterine insemination, or both. The overall likelihood of successful pregnancy with treatment is nearly 50 percent. (Am Fam 2007;75:849-56, 857-8. Copyright © 2007 American Academy of Family .) ▲ Patient information: nfertility is defined as one year of fre- be considered when historical factors, such A handout on infertility, written by the authors of quent, unprotected intercourse during as previous pelvic inflammatory disease or this article, is provided on which pregnancy has not occurred. , suggest infertility, although page 857. According to data from the National physicians should be aware that earlier evalu- ISurvey of Family Growth, an estimated ation may lead to unnecessary testing and 10 to 15 percent of couples in the United treatment in some cases.3,4 Evaluation also States are infertile.1 Many of these couples may be initiated earlier when the female present first to their primary care physician, partner is older than 35 years, because fertil- who may initiate evaluation and treatment. ity rates decrease and spontaneous miscar- Infertility can be attributed to any abnor- riage and chromosomal abnormality rates mality in the female or male reproductive increase with advancing maternal age.5,6 system. In most cases, the etiology is dis- Partners should be evaluated together and tributed fairly equally among male factors, separately, because each person may want to ovarian dysfunction, and tubal factors. A reveal information about which their partner smaller percentage of cases are attributed to endometriosis, uterine or cervical fac- tors, or other causes. In approximately one table 1 fourth of couples, the cause is uncertain and Etiology of Infertility is referred to as “unexplained infertility” 2 (Table 1). The etiology is multifactorial for Unexplained (28 percent) some couples. Male factors (24 percent) Ovarian dysfunction (21 percent) Evaluation Tubal factors (14 percent) In general, an infertility evaluation is initi- Other (13 percent) ated after 12 months of unprotected inter- course during which pregnancy has not Information from reference 2. been achieved.3,4 Earlier investigation may

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Evidence Clinical recommendation rating References

Men with low-volume ejaculate may benefit from postejaculatory urinalysis and transrectal C 4 ultrasonography to rule out retrograde and obstruction. Transvaginal ultrasonography can be used to obtain an antral follicle count and predict ovarian C 5, 19 response to gonadotropin stimulation. Postcoital testing has not been shown to improve pregnancy outcome. B 21 repair has not been shown to increase the likelihood of conception. A 26, 27 Laparoscopic for ovulation induction may be beneficial in women with polycystic A 29, 32 syndrome who have not responded to other therapies. To achieve ovulation, clomiphene citrate (Clomid) in an initial dosage of 50 mg per day is C 29 administered starting on day 3 to day 5 of the menstrual cycle and continued for five days. Women with endometriosis may benefit from laparoscopic ablation, laparotomy, or ovulation A 35-38 induction with or without intrauterine insemination and in vitro fertilization. Women with unexplained infertility may benefit from intrauterine insemination, clomiphene citrate A 39, 40 therapy, or intrauterine insemination with either clomiphene citrate or gonadotropin therapy.

A = consistent, good quality patient-oriented evidence; B = inconsistent or limited quality patient-oriented evidence; C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For more information about the SORT evidence rating system, see page 789 or http://www.aafp.org/afpsort.xml.

is unaware, such as previous pregnancy or prognosis and may help in determining sexually transmitted disease.7 etiology.2,7

evaluation of the couple evaluation of the male partner Important topics to address include the fre- Any condition that results in impaired quency and timing of intercourse, and the quality, quantity, or both can lead use of lubricants or other products that may to male factor infertility. Testicular failure impair .8-10 The duration of infertil- or dysfunction, also referred to as primary ity and history of previous fertility for the , is the most common iden- couple and for each partner individually also tifiable cause.11 Less common causes are need to be addressed, because they affect hypothalamic-pituitary dysfunction, also

table 2 Causes of Male Factor Infertility

Unknown (40 to 50 percent) Altered sperm transport (10 to 20 percent) Primary hypogonadism (30 to 40 percent) Absent or obstruction Androgen insensitivity Epididymal absence or obstruction Congenital or developmental testicular disorder (e.g., ) Secondary hypogonadism (1 to 2 percent) Medication (e.g., alkylating agents, , Androgen excess state (e.g., tumor, exogenous administration) [Tagamet], ketoconazole [Nizoral], Congenital idiopathic hypogonadotropic hypogonadism [Aldactone]) excess state (e.g., tumor) , including orchitis Infiltrative disorder (e.g., sarcoidosis, ) Radiation Medication effect Systemic disorder Multiorgan (e.g., Prader-Willi syndrome) Testicular trauma Varicocele Trauma Y chromosome defect

Information from references 4, 7, and 11 through 13.

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referred to as secondary hypogonadism, and of 22 to 35 days suggests ovulatory cycles, conditions that affect sperm transport.11 The as does the presence of and etiology remains unclear in nearly one half of premenstrual symptoms.14 During review of cases (Table 2).4,7,11-13 the woman’s substance use history, caffeine Important historical and physical exami- intake should be assessed; high levels of caf- nation details and laboratory tests in the feine use by the female partner have been evaluation of the male partner are outlined associated with lower fertility rates.15 in Table 3.4,7,12,13 Normal parameters, charting is a simple as established by the World Health Organi- zation, are shown in Table 4.12 If hypogonad- ism is suspected based on the table 3 (severe or ), eval- Key Elements of Infertility Evaluation in Men uation of morning follicle-stimulating hor- mone (FSH) and total serum History levels can help distinguish between primary Coital practices and secondary causes.7 Elevated levels of Developmental history FSH in the presence of low testosterone levels Medical history (e.g., genetic disorders, chronic illness, genital trauma, orchitis) correlate with primary hypogonadism. Low Medications (e.g., [Azulfidine], methotrexate, colchicine, levels of both hormones suggest secondary cimetidine [Tagamet], spironolactone [Aldactone]) hypogonadism. Measurement of Potential sexually transmitted disease exposure, symptoms of genital levels is indicated if secondary hypogonad- inflammation (e.g., urethral discharge, dysuria) ism is suspected, to rule out hyperprolac- Previous fertility 7 tinemia as the underlying cause. Recent high fever In patients with a low volume of ejaculate, Substance use postejaculatory urinalysis and transrectal Surgical history (e.g., previous genitourinary surgery) ultrasonography may be performed to rule Toxin exposure out retrograde ejaculation and ejaculatory Physical examination 4 duct obstruction, respectively. Scrotal ultra- Genital (e.g., discharge, tenderness) sonography also can be helpful in evaluating Hernia suspected testicular and scrotal abnormali- Presence of vas deferens 13 ties such as and tumors. Spe- Signs of (e.g., increased body fat, decreased muscle cialized semen tests, including testing for mass, decreased facial and body hair, small testes, Tanner stage < 5) sperm vitality, sperm culture, and analysis Testicular mass of sperm biochemistry and function, should Varicocele be considered if evaluation of the female Laboratory evaluation/specialized tests partner fails to reveal a cause.12 Complete blood cell count (if infection suspected) Follicle-stimulating hormone, testosterone levels (if hypogonadism evaluation of the female partner suspected) As previously noted, causes of infertility in and cultures, urinalysis (if genital infection the female partner include disorders of ovu- suspected) lation, tubal disease, and uterine or cervical Other laboratory studies based on history and physical examination findings factors.2,3 Endometriosis also has been impli- Postejaculatory urinalysis (if retrograde ejaculation suspected) cated as an independent cause of infertility Renal and liver function studies (Table 5).2,3,7,14,15 Scrotal ultrasonography Important historical and physical exami- Semen analysis (two or more samples) nation details, laboratory tests, and addi- Specialized sperm studies (if initial evaluation of both partners tional studies to consider for the female unrevealing) 3,5,7,8,16-21 partner are outlined in Table 6. Transrectal ultrasonography (if ejaculatory duct obstruction suspected) Details of the menstrual cycle can help determine whether the cycles are ovulatory Information from references 4, 7, 12, and 13. or anovulatory. A menstrual cycle length

March 15, 2007 ◆ Volume 75, Number 6 www.aafp.org/afp American Family Physician 851 Infertility table 5 Causes of Female Factor Infertility

Ovulation disorders (40 percent) and inexpensive means of documenting Aging ovulation. In ovulatory cycles, the first Diminished ovarian reserve morning body temperature often increases Endocrine disorder (e.g., hypothalamic from 97°F to 98°F (36.1°C to 36.6°C) to amenorrhea, hyperprolactinemia, greater than 98°F as a woman’s menstrual disease, adrenal disease) cycle progresses from the Polycystic ovary syndrome to the . The rise in temperature Premature ovarian failure is generally noted two days after a surge Tobacco use in luteinizing hormone (LH) occurs.3,22 In Tubal factors (30 percent) recent years, basal body temperature chart- Obstruction (e.g., history of pelvic inflammatory disease, tubal surgery) ing for documentation of ovulation has Endometriosis (15 percent) largely been replaced by use of the less cum- Other (about 10 percent) bersome urinary LH prediction kit. Dur- Uterine/cervical factors (more than 3 percent) ing ovulatory cycles, an LH surge can be Congenital uterine anomaly detected in the urine 14 to 48 hours before Fibroids ovulation.8,16 Additionally, a single mid- Polyps luteal progesterone level, measured at the Poor cervical mucus quantity/quality (caused midpoint between ovulation and the start by , infection) of the next menstrual cycle, can provide Uterine synechiae further confirmation as well as informa- tion about the adequacy of the luteal phase. Information from references 2, 3, 7, 14, and 15. A level greater than 6 ng per mL (19 nmol per L) implies ovulation and normal corpus luteal production of progesterone.17 Of the or normal FSH levels are most common in three tests, the urinary LH kit provides the patients with polycystic ovary syndrome greatest accuracy in predicting ovulation.17 (PCOS) and hypothalamic amenorrhea.18 If ovulatory dysfunction is suspected based The presence or absence of and on the results of initial evaluation, focused androgenization, generally occurring in laboratory investigation and other testing women with PCOS, can be used to dis- can help determine the underlying cause. tinguish between the two disorders.18 The Testing in patients with amenorrhea, irregu- usefulness of the progesterone challenge lar menses, or should involve test is limited because of high false-positive checking FSH, prolactin, and thyroid- and false-negative rates with respect to the stimulating hormone (TSH) levels.7,18 Low presence or absence of estrogen produc- tion.18 A high FSH level correlates with ovarian failure.18 Evaluation of prolactin TABLE 4 level is useful to rule out pituitary tumor, World Health Organization 1999 Seminal Fluid Analysis and measurement of TSH is necessary to Reference Values rule out .18 Measurement of 17α-hydroxyprogesterone and serum testos- Variable Measurement terone levels is helpful in evaluating patients with for late-onset con- Volume More than 2 mL genital adrenal hyperplasia and androgen- Sperm concentration More than 20 million per mL secreting tumors.23 Total sperm number More than 40 million per ejaculate Women older than 35 years may benefit More than 50 percent motile and/or more than from testing of FSH and estradiol levels on 25 percent progressively motile day 3 of their menstrual cycle to assess Sperm morphology More than 14 percent normal forms using strict 5 criteria ovarian reserve. An FSH level of less than 10 mIU per mL (10 IU per L), combined Information from reference 12. with an estradiol level of less than 80 pg per mL (294 pmol per L), suggests favorable

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follicular potential.5 The clomiphene citrate (i.e., clear, stringy), or both, may be the most challenge test, in which the FSH level is helpful in determining optimal timing of obtained on day 3 of the cycle, then again on intercourse, because they reflect the increase day 10 after administration of clomiphene in estrogen before the LH surge and are more citrate (Clomid; 100 mg per day) on days prospective than basal body temperature 5 to 9, also can be helpful in assessing ovarian charting or the urinary LH kit.8 reserve.5 Normal and abnormal values vary The importance of avoiding lubricants by laboratory. Obtaining an antral follicle and douches should be stressed.10 Both part- count via transvaginal ultrasonography can ners should be encouraged to avoid alco- be useful in evaluating ovarian reserve; it hol consumption and use of tobacco and also can help predict ovarian responsiveness to gonadotropin stimulation, which is useful when considering treatment options.5,19 The table 6 optimal test to assess ovarian reserve has not Key Elements of Infertility Evaluation in Women yet been determined.5 Circulating inhibin B levels and the gonadotropin-releasing hor- History mone test are not recommended for routine Coital practices use in the assessment of ovarian reserve Medical history (e.g., genetic disorders, endocrine disorders, history of because of limited data regarding their prog- pelvic inflammatory disease) nostic value.5 Medications (e.g., hormone therapy) If the initial history and physical exami- Menstrual history nation suggest tubal dysfunction or a uter- Potential sexually transmitted disease exposure, symptoms of genital ine abnormality, or if other testing has failed inflammation (e.g., , dysuria, abdominal , fever) to reveal an etiology, hysterosalpingography Previous fertility is indicated.3,7 The contour of the uterine Substance use, including caffeine cavity, including the presence or absence of Surgical history (previous genitourinary surgery) any abnormalities, as well as tubal patency Toxin exposure can be assessed. Ultrasonography can also Physical examination be used to evaluate for pelvic pathology.3 Breast formation If abnormalities are detected, hysteroscopy Galactorrhea and/or laparoscopy, depending on the loca- Genitalia (e.g., patency, development, masses, tenderness, discharge) tion of the abnormality, can be pursued Signs of hyperandrogenism (e.g., hirsutism, acne, clitoromegaly) 3,7 for confirmation and further assessment. Laboratory evaluation/specialized tests Laparoscopy may be performed as a final To document ovulation: measurement of mid-luteal progesterone level, step in the infertility evaluation because it urinary luteinizing hormone using home prediction kit, and basal body can reveal additional causes not otherwise temperature charting seen, including endometriosis and pelvic To determine etiology if ovulatory dysfunction suspected: adhesions.3,7,20 The use of postcoital testing measurement of FSH, prolactin, thyroid-stimulating hormone, 17α-hydroxyprogesterone (if hyperandrogenism suspected), to evaluate for factors of cervical mucus has testosterone (if hyperandrogenism suspected) been abandoned by most physicians because To assess ovarian reserve (women older than 35 years): measurement of 21 of its lack of effect on pregnancy outcome. FSH and estradiol levels on day 3 of the menstrual cycle, clomiphene citrate (Clomid) challenge test, or transvaginal ultrasonography for Management antral follicle count treatment of the couple To assess tubes, , and : transvaginal ultrasonography, Ideal coital frequency, consisting of inter- hysterosalpingography if tubal dysfunction suspected or evaluation otherwise unrevealing, hysteroscopy if results of hysterosalpingography course on multiple days during the “fertile suggest intrauterine abnormality, laparoscopy if results of window,” which includes the five days pre- hysterosalpingography abnormal or evaluation otherwise unrevealing ceding and the day of anticipated ovulation, should be reviewed with the couple.8 Using FSH = follicle-stimulating hormone. the Clear Plan Easy Fertility Monitor, check- Information from references 3, 5, 7, 8, and 16 through 21. ing for E-type vaginal mucous discharge

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street and, as mentioned earlier, the otherwise correctable, the condition can woman should be counseled to limit caffeine be managed with use of the oral ovulation- intake.3,4,7,15 The use of fertility-impairing inducing agent clomiphene citrate.29 Clomi- medications should be avoided by both part- phene citrate can be used in patients with ners if possible (Tables 3 and 6).2,3,7,12,14,15 PCOS as well, with or without the coad- The couple should be offered emotional ministration of insulin-sensitizing agents.31 support because infertility often produces Treatment with clomiphene citrate is inef- significant stress and sadness in one or both fective in patients with ovulatory dysfunc- partners. Groups such as RESOLVE: the tion caused by hypothalamic amenorrhea, National Fertility Association can provide however, because its mechanism of action additional support and information to assist occurs at the .29 These patients the couple (http://www.resolve.org). are more likely to respond to gonadotro- pin therapy.14 Women with limited ovarian management of male factor infertility reserve also are unlikely to benefit from Dopamine agonists such as bromocriptine ovulation induction. Currently, only oocyte (Parlodel) can be useful in patients with donation has been proven successful for hyperprolactinemia.24 Agents to treat erectile these patients.5 dysfunction can be employed if indicated.25 Clomiphene citrate is generally well toler- If obstruction or a varicocele is found to be ated and effective; 80 percent of appropri- associated with seminal fluid abnormalities, ately selected patients will ovulate with this surgical repair may be pursued. Varicocele treatment.29 Major risks associated with the repair has been shown to improve semen use of clomiphene citrate include ovarian parameters, although it has not yet been shown hyperstimulation syndrome and twinning. to increase the chance of conception.26,27 In Higher-order multiple gestation is a rare general, seminal fluid abnormalities warrant consequence.29 Generally, a dosage of 50 mg referral to a fertility specialist for treatment. per day is administered starting on day 3 to Depending on findings, treatment options day 5 of the menstrual cycle and is continued available to the specialist include gonadotro- for five days.29 Documentation of ovulation pin injections, intrauterine insemination, and can be accomplished fairly easily with basal in vitro fertilization (IVF) with or without body temperature charting or use of a uri- intracytoplasmic sperm injection, using tes- nary LH kit.29 If a dosage of 50 mg per day ticular sperm extraction if indicated.25,28 is insufficient to induce ovulation, it can be increased to 100 mg per day. Higher dosages management of ovulatory dysfunction generally should be managed by a fertility Underlying causes of ovulatory dysfunc- specialist because 100 mg per day is the tion, such as thyroid dysfunction, should be maximal dosage approved by the FDA.29 If corrected if possible.29 As with men, women clomiphene citrate therapy is unsuccessful, who have hyperprolactinemia can be treated additional treatment options include IVF with dopaminergic agents, which may restore and injectable ovulation-inducing agents ovulation.30 Insulin-sensitizing agents, most such as menopausal gonadotropin, commonly (Glucophage), have exogenous FSH, and gonadotropin-releas- been shown to increase ovulation and preg- ing hormone.33 nancy rates in patients with PCOS, although these agents are not yet approved by the U.S. management of tubal, uterine, and pelvic disease Food and Administration (FDA) for the treatment of infertility.31 Laparoscopic Tubal disease may be treated with tubal ovarian drilling for ovulation induction also reparative surgery, although success rates may be considered for patients with PCOS if are generally low and are compromised other treatments are unsuccessful.29,32 by increased risk of subsequent ectopic In most women with ovulatory dysfunc- pregnancy.14,34 IVF is an alternative, espe- tion without evident cause or that is not cially in patients with markedly damaged

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tubes.14 Patients with endometriosis may KEITH A. FREY, M.D., M.B.A., is chair of the Department benefit from laparoscopic ablation or lapa- of Family Medicine, Mayo Clinic, Scottsdale, and an associate professor of family medicine at Mayo Clinic rotomy, depending on the severity of dis- School of Medicine. He received his medical degree from ease.35,36 Ovulation induction with or without the Medical College of Virginia, Virginia Commonwealth intrauterine insemination and IVF also can University, Richmond, and completed a residency in fam- be used in these patients.35,37,38 ily practice at the U.S. Air Force Medical Center, Scott Air Force Base, Ill. management of unexplained or Address correspondence to Alaina B. Jose-Miller, M.D., persistent infertility Dept. of Family and Community Medicine, University of Arizona, 707 N. Alvernon Way, Suite 101, Tucson, AZ Options for patients with unexplained infer- 85711. Reprints are not available from the authors. tility include intrauterine insemination, clo- Author disclosure: Nothing to disclose. miphene citrate therapy, and intrauterine insemination with either clomiphene citrate or gonadotropin therapy.39,40 To date, the REFERENCES benefit of IVF has not been proven in patients 1. Mosher WD, Bachrach CA. Understanding U.S. fertility: with unexplained infertility.41 IVF may be continuity and change in the National Survey of Family Growth, 1988-1995. Fam Plann Perspect 1996;28:4-12. useful in patients with persistent infertility in 2. Hull MG, Glazener CM, Kelly NJ, Conway DI, Foster PA, whom treatments for specific diagnoses have Hinton RA, et al. Population study of causes, treatment, been unsuccessful.14 and outcome of infertility. Br Med J 1985;291:1693-7. 3. Practice Committee of the American Society for Repro- prognosis ductive Medicine. Optimal evaluation of the infertile female. Fertil Steril 2004;82(suppl 1):S169-72. The overall likelihood of successful treat- 4. Best Practice Policy Committee of the ment for infertility is nearly 50 percent, but American Urological Association for the Practice Com- this varies by cause, age of the female part- mittee of the American Society for Reproductive Medi- cine. Report on optimal evaluation of the infertile male. ner, history of previous fertility, and dura- Fertil Steril 2004;82(suppl 1):S123-30. 42 tion of infertility. Of the various etiologies, 5. Practice Committee of the American Society for Repro- infertility attributed to ovulatory dysfunc- ductive Medicine. Aging and infertility in women. Fertil tion has the best prognosis, with treatment Steril 2004;82(suppl 1):S102-6. 6. Pal L, Santoro N. Age-related decline in fertility. Endo- success rates approaching 50 percent overall. crinol Metab Clin North Am 2003;32:669-88. Infertility caused by tubal factors or severe 7. Rowe PJ. WHO Manual for the Standardized Investiga- endometriosis has the least likelihood for tion and Diagnosis of the Infertile Couple. New York, success (i.e., 21 and 17 percent, respec- N.Y.: Cambridge University Press, 1993. tively).42 A shorter duration of infertility 8. Stanford JB, White GL, Hatasaka H. Timing intercourse to achieve pregnancy: current evidence. Obstet Gyne- and previous fertility increase the chance of col 2002;100:1333-41. achieving pregnancy, as does age younger 9. Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual than 30 years in the female partner.2,7,42 intercourse in relation to ovulation. Effects on the prob- ability of conception, survival of the pregnancy, and sex of the baby. N Engl J Med 1995;333:1517-21. The Authors 10. Kutteh WH, Chao CH, Ritter JO, Byrd W. Vaginal lubri- cants for the infertile couple: effect on sperm activity. ALAINA B. JOSE-MILLER, M.D., is an assistant clinical Int J Fertil Menopausal Stud 1996;41:400-4. professor in the Department of Family and Community 11. De Kretser DM. Male infertility. Lancet 1997;349: Medicine at the University of Arizona, Tucson. Dr. Jose- 787-90. Miller received her medical degree from Loyola University 12. World Health Organization. WHO Laboratory Manual Chicago Stritch School of Medicine, Maywood, Ill., and for the Examination of Human Semen and Sperm- completed a family medicine residency at the Good Cervical Mucus Interaction. 4th ed. New York, N.Y.: Samaritan Family Practice Program, Phoenix, Ariz. Cambridge University Press, 1999. JENNIFER W. BOYDEN, M.D., is a consultant in the 13. Jarow JP. Role of ultrasonography in the evaluation of Department of Family Medicine at the Mayo Clinic, the infertile male. Semin Urol 1994;12:274-82. Scottsdale, Ariz., and an assistant professor of fam- 14. Adamson GD, Baker VL. Subfertility: causes, treatment ily medicine at the Mayo Clinic School of Medicine, and outcome. Best Pract Res Clin Obstet Gynaecol Scottsdale. She received her medical degree from the 2003;17:169-85. University of Utah Medical School, Salt Lake City, and 15. Jensen TK, Henriksen TB, Hjollund NH, Scheike T, completed residency training at Mayo Clinic, Scottsdale, Kolstad H, Giwercman A, et al. Caffeine intake and Family Practice Residency. fecundability: a follow-up study among 430 Danish

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couples planning their first pregnancy. Reprod Toxicol 29. Practice Committee of the American Society for Repro- 1998;12:289-95. ductive Medicine. Use of clomiphene citrate in women. 16. Miller PB, Soules MR. The usefulness of a urinary LH Fertil Steril 2004;82(suppl 1):S90-6. kit for ovulation prediction during menstrual cycles of 30. Crosignani PG. Management of hyperprolactinemia in normal women. Obstet Gynecol 1996;87:13-7. infertility. J Reprod Med 1999;44(12 suppl):1116-20. 17. Guermandi E, Vegetti W, Bianchi MM, Uglietti A, Ragni 31. Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz G, Crosignani P. Reliability of ovulation tests in infertile DJ. Strategies for the use of insulin-sensitizing drugs women. Obstet Gynecol 2001;97:92-6. to treat infertility in women with polycystic ovary syn- drome. Fertil Steril 2002;77:209-15. 18. Practice Committee of the American Society for Repro- ductive Medicine. Current evaluation of amenorrhea. 32. Farquhar C, Lilford RJ, Marjoribanks J, Vandekerckhove Fertil Steril 2004;82(suppl 1):S33-9. P. Laparoscopic “drilling” by diathermy or laser for ovula- tion induction in anovulatory polycystic ovary syndrome. 19. Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans Cochrane Database Syst Rev 2005;(3):CD001122. FJ. Antral follicle count in the prediction of poor ovarian 33. Hughes E, Collins J, Vandekerckhove P. Clomiphene response and pregnancy after in vitro fertilization: a citrate for ovulation induction in women with oligo- meta-analysis and comparison with basal follicle-stimu- amenorrhoea. Cochrane Database Syst Rev 1996;(1): lating hormone level. Fertil Steril 2005;83:291-301. CD000056. 20. Cundiff G, Carr BR, Marshburn PB. Infertile couples 34. Lavy G, Diamond MP, DeCherney AH. Ectopic preg- with a normal hysterosalpingogram. Reproductive out- nancy: its relationship to tubal reconstructive surgery. come and its relationship to clinical and laparoscopic Fertil Steril 1987;47:543-56. findings. J Reprod Med 1995;40:19-24. 35. Practice Committee of the American Society for Repro- 21. Oei SG, Helmerhorst FM, Bloemenkamp KW, Hol- ductive Medicine. Endometriosis and infertility. Fertil lants FA, Meerpoel DE, Keirse MJ. Effectiveness of Steril 2004;82(suppl 1):S40-5. the postcoital test: randomised controlled trial. BMJ 1998;317:502-5. 36. Jacobson TZ, Barlow DH, Koninckx PR, Olive D, Far- quhar C. Laparoscopic surgery for subfertility associ- 22. McCarthy JJ Jr, Rockette HE. Prediction of ovulation ated with endometriosis. Cochrane Database Syst Rev with basal body temperature. J Reprod Med 1986;31(8 2002;(4):CD001398. suppl):742-7. 37. Tummon IS, Asher LJ, Martin JS, Tulandi T. Randomized 23. Azziz R, Zacur HA. 21-Hydroxylase deficiency in female controlled trial of superovulation and insemination for hyperandrogenism: screening and diagnosis. J Clin infertility associated with minimal or mild endometrio- Endocrinol Metab 1989;69:577-84. sis. Fertil Steril 1997;68:8-12. 24. Laufer N, Yaffe H, Margalioth EJ, Livshin J, Ben-David 38. Kodama H, Fukuda J, Karube H, Matsui T, Shimizu M, Schenker JG. Effect of bromocriptine treatment on Y, Tanaka T. Benefit of in vitro fertilization treatment male infertility associated with hyperprolactinemia. for endometriosis-associated infertility. Fertil Steril Arch Androl 1981;6:343-6. 1996;66:974-9. 25. Hirsh A. Male subfertility [Published correction appears 39. Hughes E, Collins J, Vandekerckhove P. Clomiphene in BMJ 2003;327:1165-a]. BMJ 2003;327:669-72. citrate for unexplained subfertility in women. Cochrane 26. Evers JL, Collins JA. Surgery or embolisation for vari- Database Syst Rev 2000;(1):CD000057. cocele in subfertile men. Cochrane Database Syst Rev 40. Practice Committee of the American Society for Repro- 2004;(3):CD000479. ductive Medicine. Effectiveness of treatment for unex- 27. Male Infertility Best Practice Policy Committee of the plained infertility. Fertil Steril 2004;82(suppl 1):S160-3. American Urological Association for the Practice Com- 41. Pandian Z, Bhattacharya S, Vale L, Templeton A. In mittee of the American Society for Reproductive Medi- vitro for unexplained subfertility. Cochrane cine. Report on varicocele and infertility. Fertil Steril Database Syst Rev 2005;(2):CD003357. 2004;82(suppl 1):S142-5. 42. Collins JA, Van Steirteghem A. Overall prognosis with 28. Hopps CV, Goldstein M, Schlegel PN. The diagnosis current treatment of infertility. Hum Reprod Update and treatment of the azoospermic patient in the age of 2004;10:309-16. intracytoplasmic sperm injection. Urol Clin North Am 2002;29:895-911.

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