Infertility: Help for Couples Huntington, MD, Phd Sioux Falls Family Medicine Residency Starts with You Program, Center for Family Medicine (Drs

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Heather J. Bell, MD; Fredrick H. Thanel, MD, MPH; Mark K. Infertility: Help for couples Huntington, MD, PhD Sioux Falls Family Medicine Residency starts with you Program, Center for Family Medicine (Drs. Bell, Thanel, and Huntington) A patient tells you she’s “starting to worry” that getting and Department of Family Medicine, Sanford School pregnant won’t be as easy as she’d hoped. Before you of Medicine of The University of South provide a referral, look for clues in the couple’s histories. Dakota, Sioux Falls (Drs. Thanel and Huntington)

[email protected] Practice uring an annual visit, a patient confides in you that The authors reported no potential conflict of interest recommendations she and her husband have been trying to get preg- relevant to this article. › Evaluate the fallopian D nant for a year, but haven’t had any success. She tells tubes and their patency when you that she’s starting to get worried. menstruation is normal. How do you advise her? What are your next steps? Also, consider arranging for The approach to evaluating infertility complaints is usu- a hysterosalpingogram. B ally straightforward and can lead to a positive outcome. Not › Suspect polycystic ovarian surprisingly, the dialogue often begins with you, the family syndrome when adipos- physician. Your attention to clues in each partner’s history ity, acne, and hirsutism can do much to get to the heart of the problem. And even if with menstrual irregu- a couple requires a specialty referral, it’s best to be familiar larity are factors. B with the more extensive evaluation and management options › Suspect androgen defi- they’ll encounter to help them anticipate likely discussions ciency when a man’s arm in their consultations. In this article, we review the best evi- span is >2 cm longer than dence for the care of your patients who want to conceive. his height, or when he has experienced a loss of pubic, axillary, or facial hair. C Who’s affected?

Strength of recommendation (SOR) Infertility difficulties may be attributable to one or both partners, may be multifactorial, or may be unexplained (TABLE). A Good-quality patient-oriented evidence In women, infertility is the inability to conceive after B Inconsistent or limited-quality 1 year of unprotected regular intercourse in those younger patient-oriented evidence 1 C Consensus, usual practice, than 35 years, and after 6 months in those 35 years and older. opinion, disease-oriented Fecundability is the probability of achieving pregnancy in evidence, case series 1 menstrual cycle. Normal fecundability with a single menstrual cycle is ~20%, peaking between the ages of 20 and 24 years.2 Fecundability decreases slightly at age 32 and declines progressively and more rapidly after age 40. Spontane- ous miscarriage is a factor; its rate in younger women is ~10% and in women >40 years is ~40%.2 Overall, approximately 13% of women between the ages of 15 and 44 have fecundity impairment, with more than 6 million women in the United States affected.2 About 24% of all cases of infertility are due to male factors—seminiferous dysfunction, including problems with

82 The Journal of Family Practice | February 2012 | Vol 61, No 2 TABLE Consider these factors in cases of suspected infertility3,6,21,23,40,41

Major causes of infertility Infertility risk factors Female Cause Contribution

Endocrine factors 45%-55% • Advanced endometriosis • Autoimmune disease PCOS 21%-28% • E xposure to cytotoxic drugs or radiation Thyroid 10%-20% therapy Diabetes mellitus 10%-20% • F amily history of premature ovarian failure Prolactinemia 7% or menopause Tubal and peritoneal pathology 30%-40% • Inability to conceive with past partners • Previous ovarian surgery • Smoking Ovulatory dysfunction* 15% • Suspected uterine or tubal disease

Cervical and uterine factors <5%

Male Cause Contribution With normal • Adult mumps menses, Seminiferous tubule dysfunction 60%-80% • Chemotherapy and/or radiation • Drug use ovulatory Posttesticular defects 10%-20% • History of testicular trauma dysfunction • Erectile or sexual dysfunction is an unlikely • Inability to conceive with past partners Primary hypogonadism 10%-15% cause of • STIs infertility. • GU infections Hypothalamic pituitary disease 1%-2% • H istory of surgical procedures to inguinal and/or scrotal area

*Assuming appropriate ovarian reserve, indicated by follicle-stimulating hormone (FSH) level <10 mIU/mL, FSH-to-luteinizing hormone ratio <2, and estradiol level <50 pg/mL. GU, genitourinary; PCOS, polycystic ovarian syndrome; STIs, sexually transmitted infections. motility, morphology, and volume of sperm; become pregnant. More time may be all they primary hypogonadism; posttesticular de- need to achieve pregnancy. Educate them on fects; and hypothalamic pituitary disease.3 reproductive cycles and optimal timing to Recent observational trends show declines in achieve pregnancy. Some women experience fertility among men older than 40, and among lower abdominal pain (mittelschmerz) signi- men from different areas in the country, thus fying release of an egg from the ovary, which raising the issue of the role that environmen- can help identify the time of ovulation. tal pollutants or toxins may play. Supposed Remember, too, the role that a couple’s increases in urogenital abnormalities and psychological state can play; worries over testicular cancers may also contribute to de- suspected infertility may cause anxiety, an- clining fertility rates.4,5 ger, depression, and marital troubles.

Zero in on these areas of the history As with any diagnostic work-up, the most im- Is it her? portant aspect of an infertility evaluation is Regular menstrual cycles—menses occurring the history. Document menstrual cycle length every 21 to 35 days—carry an ovulation prob- and regularity and the timing of intercourse. ability of 95% with each cycle.6 With normal (Ideally, this would be done when a couple menses, ovulatory dysfunction is an unlikely first decides to conceive.) It’s important to cause of infertility. If menstrual cycles are know how long the couple has been trying to irregular, ovulatory function is not normal

jfponline.com Vol 61, No 2 | FEBRUARY 2012 | The Journal of Family Practice 83 and cyclical. Explore the woman’s medical, The patient must record temperatures at ex- surgical, and gynecologic histories, looking actly the same time each day. Have her log particularly for thyroid disease, galactorrhea, the temperatures and watch for a spike that hirsutism, pelvic or abdominal pain, dys- occurs 1 to 2 days after the LH surge. The av- menorrhea, dyspareunia, pelvic inflamma- erage woman’s temperature rises above 98ºF tory disease (PID), and abdominal or pelvic in progressing from the follicular to the luteal surgery. phase. Since the spike occurs 1 to 2 days after z The fallopian tubes. When menstrua- ovulation, this method is best used for many tion is normal, evaluate the fallopian tubes months so the woman can predict her cycle.11 and their patency; 30% to 40% of infertility Once timing of ovulation has been es- cases can be related to peritoneal patholo- tablished, you can check lab results at Day 3 gy.3,7 Inability to conceive in a previous rela- of the woman’s cycle for follicle-stimulating tionship, history of PID, or prior tubal surgery hormone (FSH), LH, estradiol, thyroid- all correlate to infertility. Ten percent of pa- stimulating hormone (TSH), prolactin, and tients with a history of one PID episode and 2-hour fasting glucose tolerance. In addition 54% to 75% of patients with 3 episodes will to polycystic ovarian syndrome (PCOS), pa- have patency issues.7 tients may have ovulatory dysfunction sec- Consider arranging for a hysterosalpin- ondary to glucose intolerance. gogram (HSG) in all patients as part of an A clomiphene (Clomid) challenge can When initial work-up for infertility.8 HSG is useful help in assessing ovarian reserve. Administer menstruation in evaluating tubal patency and the uterine 100 mg clomiphene on Days 5 through 9 of is normal, cavity, and it can be therapeutic. HSG is not the patient’s cycle, and check FSH and estra- evaluate the useful in detecting peritubal adhesions or en- diol levels on Day 10. With diminished ovar- fallopian tubes dometriosis; patients in whom you suspect ian reserve, FSH will increase to >12 mIU/mL and their these conditions should undergo diagnostic and estradiol to >300 pg/mL.12 If this occurs, patency. laparoscopy. If abnormalities are found on consider referring for an ultrasound mea- HSG, refer patients to a reproductive endo- surement of antral follicle count. The pres- crinologist to evaluate treatment options. ence of 4 to 10 follicles measuring 2 to 10 mm Chlamydia trachomatis IgG antibody in diameter suggests adequate reserve.13 testing can predict the presence of tubal dis- Although not widely available in the ease. For women with low risk of tubal dis- United States, the test for antimüllerian hor- ease, it may be more cost effective to test for mone (AMH) levels may be useful in reflect- the Chlamydia antibody and proceed with ing the size of the primordial follicle pool. At HSG if the result is positive. Antibody test- menopause, the level is undetectable. A level ing is also useful for women with an allergy above 0.5 ng/mL correlates with good ovar- to contrast dye who cannot undergo an HSG. ian reserve; levels <0.15 ng/mL suggest poor If the antibody test result is positive, consider response to in vitro fertilization (IVF).14 arranging for a sonohysterogram to evaluate z Endocrine factors account for 45% to for the presence of fluid in the cul-de-sac, or 55% of female infertility and include thyroid an intrauterine infusion of saline to evaluate disease, PCOS, diabetes mellitus, prolac- the patency of at least one tube.9 tinemia, and luteal phase defects. Subclinical z Ovulatory function. To assess ovula- hypothyroidism, often evidenced only by high tory function, measure a midluteal-phase levels of TSH, decreases the chance of a suc- serum progesterone level, drawn 1 week be- cessful pregnancy. This can occur even if the fore the expected day of menses (Day 21 of a dysfunction is not severe enough to affect cycle 28-day cycle). A level >3 ng/mL is evidence regularity.15 Clinical hypo- or hyperthyroidism of ovulation. Over-the-counter ovulation kits can affect ovulation by interfering with normal detect the luteinizing hormone (LH) surge hormonal feedback loops, and correcting thy- but have false-positive and false-negative roid disease can improve fertility. rates of 5% to 10%, respectively.10 Recording Galactorrhea discovered during the his- basal body temperature is a noninvasive and tory and physical may be caused by elevated inexpensive means of evaluating ovulation. prolactin levels, which also inhibit normal

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ovulatory function. Chronically elevated pro- and pH; microscopic debris and agglutination; lactin levels in patients with PCOS can be sperm concentration, motility, and morphol- attributed to elevated estrogen levels. Adi- ogy; leukocyte count; and immature germ posity, acne, and hirsutism with menstrual cells. Have the man abstain from sex for 2 to irregularity can indicate PCOS as the primary 7 days before semen collection. If collection is cause, and your work-up should focus on a not possible to do in the office, the patient can hyperandrogenic state.16 Low or normal FSH drop it off at a lab within an hour of collection. levels are common in patients with PCOS. Analyze 2 samples at least 2 weeks apart.22 Also test for 17a-hydroxyprogestrone and se- More detailed semen analysis can be rum testosterone levels.17 done, especially if evaluation of the female z Endometriosis. How endometriosis af- partner does not reveal a cause of infertility. fects fertility is controversial. One hypothesis Tests include sperm autoantibodies, sperm is that it is associated with overproduction biochemistry, semen culture, sperm function of prostaglandins, metalloproteinases, cyto- tests, and sperm-cervical mucus interaction. kines, and chemokines. The inflammatory Typically, these tests and further evaluation process impairs ovarian, peritoneal, tubal, of the male partner after an abnormal semen and endometrial function.18 analysis are best done by a urologist special- z Discourage the use of the postcoital izing in reproduction. test. Patients may inquire about this test, in Oligospermia or azoospermia point to- which the cervical mucus is obtained after ward hypogonadism. Elevated morning FSH Subclinical intercourse to assess stretch ability and and low total testosterone correlate with pri- hypothyroidism sperm motility. This test has been used for mary hypogonadism, whereas low levels of can decrease more than a century, but has poor predictive both hormones correlate with secondary hy- the chances value and is not recommended.19 pogonadism. Hyperprolactinemia is a cause of a successful of secondary hypogonadism.3 Low volume of pregnancy— semen can be further evaluated by testing a even if it is not Or is it him? postejaculatory urinalysis and transrectal ul- severe enough Inquire about sexual development and medi- trasonography to rule out retrograde ejacula- to affect cycle cal history, including mumps orchitis or tion and ejaculatory duct obstruction.23 regularity. other infections, sinopulmonary symptoms suggesting cystic fibrosis, sexually transmit- Fixing the problem ted infections (STIs) and genitourinary infec- Focus initial counseling for couples on life- tions, and surgical procedures of the inguinal style modifications. Advise patients to quit and scrotal areas. Also ask about prescription smoking, reduce excessive caffeine and alco- and illicit drug use, environmental exposures, hol consumption, and engage in intercourse and sexual history. every day or every other day around ovula- z Physical exam. Look for signs of an- tion. Patients should also avoid lubricants drogen deficiency, such as an arm span and douching as they can interfere with >2 cm longer than height (eunuchoidal pro- sperm deposition. portions), or loss of pubic, axillary, or facial hair.20 Examine the external genitalia to evaluate for complete sexual development Managing female infertility (Tanner stage of 5). The scrotum can provide z Tubal, pelvic, and uterine infertility. Pa- clues to disorders that can affect sperm mat- tients with bilateral tubal obstruction may uration and transport. Examination may re- wish to undergo tubal reconstruction, espe- veal absence of the vas deferens, epididymal cially if IVF treatments are not readily avail- thickening, varicocele, or hernia.21 Testicu- able to them. Counsel them that surgery for lar volume, if <15 mL with testicular length proximal tubal occlusion is not effective and <3.6 cm, can point to a decreased number of the risk of ectopic pregnancy in the future is seminiferous tubules.21 high, at approximately 20%.24 Because of the z Semen analysis. If the physical exami- low efficacy of surgery and high ectopic rate, nation is normal, analyze semen for volume most patients with tubal disease favor IVF. Pa-

jfponline.com Vol 61, No 2 | FEBRUARY 2012 | The Journal of Family Practice 85 tients with endometriosis sometimes benefit ple births, primarily twinning, occur at a rate from laser ablation or surgical resection, but of 8% to 13%.33 If clomiphene is unsuccess- often do well with intrauterine insemination ful, refer patients to a reproductive endocri- (IUI) or IVF in conjunction with ovulation nologist for evaluation for IVF and injectable induction.25 Uterine abnormalities including ovulation-inducing agents. submucous fibroid, endometrial polyp, sep- tate uterus, or uterine synechiae frequently benefit from surgical correction.26 Patients Managing male infertility with irreparable defects may want to consider Men who have hyperprolactinemic infertility a surrogate. can often be treated with dopaminergic agents z Ovulatory dysfunction. Anovulation such as bromocriptine. Inform them that nor- can be hypogonadotropic hypogonadal (sec- mal spermatogenesis can take 3 to 6 months. ondary to functional factors such as exercise Gonadotropin therapy may be effective for and weight), normogonadotropic normoes- patients with hypothalamic or pituitary dis- trogenic with PCOS, or hypergonadotropic eases. Surgery may correct obstruction, but hypoestrogenic infertility (premature ovarian may not actually increase pregnancy rates. failure). Repairing a varicocele, for instance, increases A body mass index >17 and <27 kg/m2 sperm counts but not conception rates.34 is optimal to achieve fertility and to sus- Other obstructive problems may need sperm Discourage tain a healthy pregnancy.27 Individuals who extraction followed by IUI or IVF, with or with- patients from are obese or very thin or who overexercise out intracytoplasmic sperm injection, where considering the and do not respond to behavioral modifi- the sperm is injected into the ovum in the lab postcoital test, cation are known to benefit from pulsatile before implantation.34 which has poor gonadotropin-releasing hormone therapy. predictive value. This treatment, however, is not available in the United States.28 Managing unexplained infertility Dopaminergic agents can restore nor- Fifteen percent of infertility is unexplained.35 mal ovulation in patients with hyperprolac- Assisting these patients is challenging. Per- tinemia,29 but they should receive ovulation forming IUI with or without clomiphene, or induction first. Patients who have glucose giving clomiphene alone is often attempted. intolerance may benefit from an insulin-sen- Pregnancy rates are 2% for expectant man- sitizing agent such as metformin. It is par- agement, 5% for IUI alone, 9.5% for clomi- ticularly useful if patients also have PCOS; phene alone, and 19% for combined IUI with however, it is not an FDA-approved indication clomiphene.36 Gonadotropins are no more for the medication. Clomiphene has recently effective in achieving conception than clo- been shown to result in a higher rate of ovula- miphene, but gonadotropin injection and tion, but not pregnancy, than metformin.30 IUI together are more effective than no treat- Most patients with ovulatory dysfunc- ment.37 IVF, if successful, leads to pregnancy tion are best treated with clomiphene.31 Give in the shortest amount of time. But it is the 50 mg of the drug on cycle Days 3 through 7; most costly intervention and the most likely ovulation occurs between Days 10 through to result in multiple births. In randomized 15.12 If, after the first cycle, pregnancy has not controlled trials, however, IVF has not proved occurred, increase the dose by 50 mg with beneficial for unexplained infertility.38 each cycle, to a maximum of 150 mg daily.32 Higher doses are not FDA approved, nor are Trends likely to affect fertility treatment they more effective. Clomiphene is most ef- Currently in the United States, there is little fective in the first 6 cycles, and the American regulation to guide reproductive technolo- Congress of Obstetricians and Gynecologists gies. But there is a trend, varying by state, recommends limiting its use to fewer than 12 toward legislation similar to child protection cycles due to the risk of ovarian neoplasm.33 laws and adoption services, under which Clomiphene yields an ovulation rate of 73% couples are evaluated for suitability as par- and a pregnancy rate of 36% per cycle. Multi- ents for the potential child’s safety.39 Other

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countries have acts regulating reproductive ment of infertility. Education and household technologies and infertility services. England income correlate with the amount of money focuses on the child’s welfare; Australia re- spent on fertility care. JFP stricts access by eligibility requirements.39 In the United States we may see similar policies, Correspondence especially as controversy grows regarding Heather Bell, MD, Center for Family Medicine, 1115 East multiple births. Cost is a factor in the treat- 20th Street, Sioux Falls, SD 57105; [email protected]

References 1. Practice Committee of the American Society for Reproductive 22. World Health Organization Department of Reproductive Medicine. Definitions of infertility and recurrent pregnancy Health and Research. World Health Organization Laboratory loss. Fertil Steril. 2008;90(suppl):S60. Manual for the Examination and Processing of Human Semen. 2. Boivin J, Bunting L, Collins JA, et al. International estimates 5th ed. Geneva, Switzerland: World Health Organization; of infertility prevalence and treatment-seeking: potential 2010. need and demand for infertility medical care. Hum Reprod. 23. Male Infertility Best Practice Policy Committee of the Ameri- 2007;22:1506-1512. can Urological Association; Practical Committee of the 3. Hull MGR, Glazener CMJ, Kelly NJ, et al. Population stud- American Society for Reproductive Medicine. Report on ies of causes, treatment, and outcome of infertility. BMJ. optimal evaluation of the infertile male. Fertil Steril. 2004;82 1985;291:1693-1697. (suppl 1):S123-S130. 4. Carlsen E, Giwercman A, Keiding N, et al. Evidence for de- 24. Honoré GM, Holden AE, Schenken RS. Pathophysiology creasing quality of semen during past 50 years. BMJ. 1992;305: and management of proximal tubal blockage. Fertil Steril. 609-613. 1999;71:785-795. 5. de La Rochebrochard E, Thonneau P. Paternal age >or=40 25. Tummon IS, Asher LF, Martin JS, et al. Randomized con- years: an important risk factor for infertility. Am J Obstet trolled trial of superovulation and insemination for infertility In the United Gynecol. 2003;189:901-905. associated with minimal or mild endometriosis. Fertil Steril. 1997;68:8-12. 6. Behre HM, Kuhlage J, Gassner C, et al. Prediction of ovula- States, we may tion by urinary hormone measurements with the home use 26. Heinonen PK, Saarikoski S, Pystynen P. Reproductive perfor- see reproductive ClearPlan Fertility Monitor: comparison with transvaginal mance of women with uterine anomalies. An evaluation of 182 ultrasound scans and serum hormone measurements. Hum cases. Acta Obstet Gynecol Scand. 1982;61:157-162. technology Reprod. 2000;15:2478-2482. 27. Frisch RE. The right weight: body fat, menarche and ovulation. policies similar 7. Brassard M, AinMelk Y, Baillargeon J. Basic infertility includ- Baillieres Clin Obstet Gynaecol. 1990;4:419-439. ing polycystic ovary syndrome. Med Clin North Am. 2008; 28. Abraham S, Mira M, Llewellyn-Jones D. Should ovulation be to those in other 92:1163-1192. induced in women recovering from an eating disorder or who countries— 8. Papaioannou S, Bourdrez P, Varma R, et al. Tubal evaluation are compulsive exercisers? Fertil Steril. 1990;53:566-568. in the investigation of subfertility: a structured comparison of 29. Crosignan PG. Management of hyperprolactinemia in infertil- especially as tests. BJOG. 2004;111:1313-1321. ity. J Reprod Med. 1999; 44(12 suppl):1116-1120. controversy 9. Mol BW, Collins JA, Van Der Veen F, et al. Cost-effectiveness of 30. Baran S, Api M, Godsedef BP, et al. Comparison of metformin hysterosalpingography, laparoscopy, and Chlamydia antibody and clomiphene citrate therapy for induction in the polycystic grows regarding testing in subfertile couples. Fertil Steril. 2001;75:571-580. ovary syndrome. Arch Gynecol Obstet. 2010;282:439-443. multiple births. 10. Corson SL. Self-prediction of ovulation using a urinary lu- 31. Kerin JF, Liu JH, Phillipou G, et al. Evidence for a hypothalamic teinizing hormone test. J Reprod Med. 1986;31(8 suppl): site of action of clomiphene citrate in women. J Clin Endocri- 760-763. nol Metab. 1985;61:265-268. 11. Kambic R, Gray RH. Interobserver variation in estimation of 32. Huang KE. The primary treatment of luteal phase inadequacy: day of conception intercourse using selected natural family progesterone versus clomiphene citrate. Am J Obstet Gynecol. planning charts. Fertil Steril. 1989;51:430-434. 1986;155:824-828. 12. Wu CH, Winkel CA. The effect of therapy initiation day on clo- 33. Homburg R. Clomiphene citrate—end of an era? A mini- miphene citrate therapy. Fertil Steril. 1989;52:564-568. review. Hum Reprod. 2005;20:2043-2051. 13. Chang MY, Chiang CH, Hsieh TT, et al. Use of the antral follicle 34. Hirsh A. Male subfertility. BMJ. 2003;327:669-672. count to predict the outcome of assisted reproductive tech- 35. Collins JA, Crosignani PG. Unexplained infertility: a review of nologies. Fertil Steril. 1998;69:505-510. diagnosis, prognosis, treatment efficacy and management. Int 14. de Vet A, Laven JS, de Jong FH, et al. Antimüllerian hormone J Gynaecol Obstet. 1992;39:267-275. serum levels: a putative marker for ovarian aging. Fertil Steril. 36. Fisch P, Casper RF, Brown SE, et al. Unexplained infertility: 2002;77:357-362. evaluation of treatment with clomiphene citrate and human 15. De Sutter P. Rational diagnosis and treatment in infertility. Best chorionic gonadotropin. Fertil Steril. 1989;51:828-833. Pract Res Clin Obstet Gynaecol. 2006;20:647-664. 37. Verhulst SM, Cohlen BJ, Hughes E, et al. Intra-uterine insemi- 16. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. nation for unexplained subfertility. Cochrane Database Syst 2005;352:1223-1236. Rev. 2006;(4):CD001838. 17. Azziz R, Zacur HA. 21-Hydroxylase deficiency in female hy- 38. Pandian Z, Bhattacharya S, Vale L, et al. In vitro fertilization perandrogenism, screening and diagnosis. J Clin Endocrinol for unexplained subfertility. Cochrane Database Syst Rev. Metab. 1989;69:577-584. 2005;(2):CD003357. 18. Bulun SE. Endometriosis. N Engl J Med. 2009;360:268-279. 39. Liu C. Restricting access to infertility services: what is a justi- 19. van der Steeg JW, Steures P, Eijkemans MJ, et al. Should the fied limitation on reproductive freedom?Minn J Law Sci Tech- post-coital test (PCT) be part of the routine fertility work-up? nol. 2009;10:291. Available at: http://mjlst.umn.edu/uploads/ Hum Reprod. 2004;19:1373-1379. QJ/WD/QJWDUZ1D-pV28sHvArqp6A/101_liu.pdf. Accessed 20. Themmen APN, Huhtaniemi IT. Mutations of gonadotropins May 4, 2011. and gonadotropin receptors: elucidating the physiology and 40. Practice Committee of the American Society for Reproductive pathophysiology of pituitary-gonadal function. Endocr Rev. Medicine. Optimal evaluation of the infertile female. Fertil 2000;21:551-583. Steril. 2006;86(suppl 1):S264-S267. 21. Rowe PJ. WHO Manual for the Standardization Investiga- 41. Practice Committee of the American Society for Reproduc- tion and Diagnosis of the Infertile Couple. New York, NY: tive Medicine. Current evaluation of amenorrhea. Fertil Steril. Cambridge University Press; 1993. 2004;82(suppl 1):S33-S39.

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