1. Infertility: What the Family Physician Needs to Know Heather L. Paladine MD, Med, FAAFP January 23, 2016 1

2. What You Need to Know Who to evaluate Focused history and physical Evaluation and treatment of women Evaluation and treatment of men Treatment side effects Integrative medicine Patient resources

3. Infertility Facts - 85% of couples will conceive within 1 year, therefore up to 15% may need evaluation - Opportunity for preconception counseling Sources: The Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril 2012; 98(2): 302-7. The Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 2015; 103: e18-25.

4. Who to Evaluate? - No conception after 1 year of regular intercourse - Consider evaluation after six months if the female partner is >= age 35 - Also discuss options with same sex couples, transgender patients, people who are lacking reproductive organs (congenital or surgical)

5. History and Physical Ask specifically about previous pregnancies/conceptions, frequency of intercourse, STDs, medical history, substance use/tobacco - exam focusing on endocrine and reproductive systems - for women: detailed menstrual history

6. Common Causes in Couples Female factors - 40-50% Male factors - 20% Joint or unknown - 30-40%

7. Women - Causes of Infertility Ovulatory dysfunction - most common Tubal abnormalities - second most common Uterine abnormalities Peritoneal factors (Cervical factors)

8. Ovulatory Dysfunction - 15% of couples - Usually identified on history - Important to confirm ovulation as a first step

11. Ovulatory Dysfunction Step 1: Confirm ovulation (or not) Anovulation may be obvious Ovulation should be confirmed with progesterone level one week before next expected menses (level >3) BBT charting not recommended Can use at-home ovulation predictor kits Step 2: Evaluate the cause of anovulation History and exam TSH, prolactin, FSH/estradiol on day #3 of menses

12. WHO Groups I: Hypothalamic/pituitary insufficiency II: Problems w/hypothalamic/pituitary/ovarian axis III: Ovarian insufficiency Source: ESHRE Capri Workshop Group. Health and fertility in World Health Organization group 2 anovulatory women. Human Reproduction Update 2012; 0(0):1 –14.

13. Group I: Hypothalamic/Pituitary Insufficiency Low/normal FSH, low estradiol Underweight, excessive exercise, hyperprolactinemia Treatment depends on the underlying cause

14. Group II: Problems with the Hypothalamic/Pituitary/Ovarian Axis Most common cause of ovulatory dysfunction Normal FSH and estradiol Primarily women with PCOS Improved fertility with weight loss +/- metformin Possible treatments: –Ovulation induction (clomiphene citrate) –Gonadotropin therapy –IVF

15. Group III: Ovarian Insufficiency High FSH, low estradiol Congenital causes: Turner’s syndrome Acquired causes: premature ovarian failure, chemotherapy May require ovum donation

16. Ovulatory Dysfunction - Treatment Treat the underlying cause when possible Clomiphene citrate - oral –Blocks estrogen receptors in the hypothalamus, resulting in upregulation of GNRH Gonadotropin therapy - injectable GNRH or FSH/LH analogs IVF - combined with ovulation induction

17. Clomiphene Citrate Use Use progesterone to induce menses Start with clomiphene 50mg daily for days 2-5 Use home ovulation detection kit to confirm ovulation (usually 5-12 days after last dose) Increase dose to 100mg if not effective Do not use for longer than 3-6 cycles Ultrasound not needed Sources: The Practice Committee of the American Society for Reproductive Medicine. Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril 2013;100:341–8. https://www.asrm.org/uploadedFiles/ASRM_Content/News_and_Publications/Practice_Guidelines/Co mmittee_Opinions/use_of_clomiphene(1).pdf

18. Side Effects of Infertility Treatments Clomiphene citrate: mood swings, hot flashes, ovarian cysts, multiple gestation (8-10%) Injectable gonadotropins: ovarian hyperstimulation (vomiting, ascites, can be severe), multiple gestation (33%) IVF: highest risk of multiple gestation (34% or higher), perinatal morbidity/mortality, may need to consider selective abortion

19. Tubal Abnormalities Also common History: STDs/PID, ectopic pregnancy, tubal surgery Traditionally evaluated by HSG May require IVF

20. Uterine Abnormalities Uncommon Polyps, septa, etc. Should be evaluated with US, HSG, or sonohysterography Treatment is via hysteroscopy

21. Peritoneal Factors Suspect endometriosis or adhesions by history/exam May need laparoscopy for evaluation and treatment

22. Cervical Factors Uncommon Thought to be incompatibility between sperm and cervical mucous No specific test

23. Evaluation of the Male Partner Should begin at the same time History and physical exam Semen analysis Oligospermia or azoospermia: check testosterone and FSH to differentiate between primary and secondary hypogonadism Look for structural causes, like congenital absence of the vas deferens (almost all men with CF)

24. Primary Hypogonadism Genetic: Klinefelter’s syndrome Cryptorchidism Testicular trauma Mumps Varicocele Autoimmune Alcohol Basaria S. Male hypogonadism. Lancet 2014; 383 (9924): 1250-1263.

25. Secondary Hypogonadism Obesity Diabetes Hyperprolactinemia Infection/infiltration (TB, sarcoid, hemochromatosis) Medications (opioids, steroids) Excessive exercise or underweight

26. Varicocele Examine pt while standing, Valsalva Indications for surgical treatment: –Couple with infertility –No female cause or treatable female cause –Varicocele is palpable on exam –Abnormal semen analysis Source: Practice Committee of the American Society for Reproductive Medicine. Report on varicocele and infertility: a committee opinion. Fertility and Sterility 2014; 102(6): 1556-1560.Fertility and Sterility

27. Treatment of the Male Partner Referral to Urology or Reproductive Endocrinology if semen analysis or exam are abnormal and no reversible cause is found Treatment may include IVF

28. Integrative Medicine and Infertility Traditional Chinese Medicine: meta-analysis showed increased pregnancy rate in women with ovulatory dysfunction, but studies were low quality Acupuncture is used with IVF but Cochrane review found no benefit Sources: Tan L, Tong Y, Sze SCW et al. Chinese Herbal Medicine for Infertility with Anovulation: A Systematic Review. Journal of Alternative and Complementary Medicine 2012; 18(12): 1087- 1100. Cheong YC, Dix S, Hung Yu Ng E, Ledger WL, and Farquhar C. Acupuncture and assisted reproductive technology. Cochrane Database of Systematic Reviews 2013; Issue 7.

29. Patient Support Higher levels of stress, anxiety, and depression Psychosocial interventions can decrease stress and may increase pregnancy rate Sources: Vahratian A, Flynn H, Dorman M, Smith YR. Infertility treatment and psychosocial health status. Fertility and Sterility 2008; 90: S383.Fertility and Sterility 2008; 90: S383. Frederiksen Y, Farver-Vestergaard I, Skovgård N, Ingerslev HJ, Zachariae R (2015) Efficacy of psychosocial interventions for psychological and pregnancy outcomes in infertile women and men: a systematic review and meta-analysis.

30. Patient Resources Resolve.org - national advocacy group, can search for local support groups by zip code Womenshealth.gov - fact sheets for patients in English and Spanish Familydoctor.org - patient handout on male infertility in English and Spanish Reproductivefacts.org - ASRM patient education site Be Fruitful by Victoria Maizes - book on integrative medicine and fertility

31. Practice Recommendations Couples should be evaluated if they have not become pregnant after one year of regular intercourse. Consider evaluation after six months if the female partner is >= 35 (SORT: C) Evaluation of the male and female partner should begin at the same time (SORT: C) Recommended tests to confirm ovulation are progesterone levels or urinary LH/ovulation detection kits (SORT: C)

32. Contact Information Heather L. Paladine, MD, Med, FAAFP hlp222@gmail.com @paladineh on Twitter