1. Infertility Edward A. Rose, M.D., M.S.A. North Oakland Medical Centers Pontiac, MI

2. Description of Case 29 y o G 0 concerned about not getting pregnant 29 y o G 0 concerned about not getting pregnant Unprotected sex X 1 ½ years Unprotected sex X 1 ½ years PMHx negative PMHx negative No other complaints No other complaints

3. Further History? Frequency of intercourse, use of lubricants (e.g., K-Y gel) that could be spermicidal, use of vaginal douches after intercourse, or presence of any sexual dysfunction such as anorgasmia or dyspareunia Frequency of intercourse, use of lubricants (e.g., K-Y gel) that could be spermicidal, use of vaginal douches after intercourse, or presence of any sexual dysfunction such as anorgasmia or dyspareunia Menstrual history, frequency, and patterns since menarche; weight changes, hirsutism, frontal balding, acne Menstrual history, frequency, and patterns since menarche; weight changes, hirsutism, frontal balding, acne

4. History (continued) Male partners: previous spermogram results, history of impotence, premature ejaculation, change in libido, history of testicular trauma, previous relationships, history of any previous pregnancy, existence of offspring from previous partners Male partners: previous spermogram results, history of impotence, premature ejaculation, change in libido, history of testicular trauma, previous relationships, history of any previous pregnancy, existence of offspring from previous partners History of sexually transmitted diseases; surgical contraception (e.g. vasectomy, tubal ligation); lifestyle; consumption of alcohol, tobacco, and recreational drugs; occupation; physical activities History of sexually transmitted diseases; surgical contraception (e.g. vasectomy, tubal ligation); lifestyle; consumption of alcohol, tobacco, and recreational drugs; occupation; physical activities

5. History (continued) Either partner currently under medical treatment, the reason, and whether they have a history of allergies Either partner currently under medical treatment, the reason, and whether they have a history of allergies Complete review of systems may be helpful to identify any endocrinological or immunological problem Complete review of systems may be helpful to identify any endocrinological or immunological problem

6. Your Patient History of weight gain, acne, facial hair, irregular menses History of weight gain, acne, facial hair, irregular menses ROS + for an elevated glucose and elevated BP a few months ago ROS + for an elevated glucose and elevated BP a few months ago Exam shows android body habitus, weight 205#, acne on face and back, some facial hair Exam shows android body habitus, weight 205#, acne on face and back, some facial hair Diagnosis, first years? Diagnosis, first years?

7. Definition Inability to conceive after one year of intercourse without contraception Inability to conceive after one year of intercourse without contraception Counsel patience! Counsel patience!

8. Causes of Infertility

9. Male Factor Male partner should be evaluated simultaneously with female partner Male partner should be evaluated simultaneously with female partner Causes of male infertility: Causes of male infertility: –Reversible conditions (varicocele, obstructive azoospermia) –Not reversible, but viable sperm available (ejaculatory dysfunction, inoperative obstructive azoospermia) –Not reversible, no viable sperm (hypogonadism) –Genetic abnormalities –Testicular or pituitary cancer

10. Ovulatory Dysfunction Causes 18% of infertility Causes 18% of infertility Diagnosed by Diagnosed by –Menstrual irregularities –Basal body temperatures –Ovulation prediction kits –Serum progesterone levels (18-24 days after onset of menses; level > 3 ng/ml is diagnostic of ovulation)

11. BBT Kit

12. Completed Sample BBT Chart

13. Evaluation of Ovarian Reserve Assessed in women > 35 or younger women with risk factors for premature ovarian failure Assessed in women > 35 or younger women with risk factors for premature ovarian failure Day 3 FSH and CCCT (clomiphene citrate challenge test) Day 3 FSH and CCCT (clomiphene citrate challenge test) –Administer 100 mg clomiphene on cycle days 5-9 –Measure FSH on days 3 and 10; maybe estradiol on day 3 (conflicting data) –Normal test not useful, but abnormal test virtually assures that pregnancy will not occur even with treatment Ultrasound may also be used Ultrasound may also be used

14. Causes of Ovulatory Dysfunction Polycystic ovary syndrome Polycystic ovary syndrome Hypothalamic anovulation Hypothalamic anovulation Hyperprolactinemia Hyperprolactinemia Premature and age-related ovarian failure Premature and age-related ovarian failure Luteal phase defect Luteal phase defect –Abnormalities of corpus luteum resulting in inadequate production of progesterone –Based on finding of 2 consecutive endometrial biopsy specimens showing histology > 2 days out-of-phase with actual biopsy date –Relevance is controversial

15. Polycystic Ovarian Syndrome Oligomenorrhea/amenorrhea and hyperandrogenism Oligomenorrhea/amenorrhea and hyperandrogenism Prevalence: 5% Prevalence: 5% Among women with ovulatory dysfunction, 70% have PCOS Among women with ovulatory dysfunction, 70% have PCOS Clinical evidence: hirsutism, acne, obesity Clinical evidence: hirsutism, acne, obesity Lab evidence: elevated testosterone, elevated DHEA-S Lab evidence: elevated testosterone, elevated DHEA-S “Polycystic ovaries” supportive, not diagnostic “Polycystic ovaries” supportive, not diagnostic

16. PCOS Treatment Approach Weight loss if BMI > 30 Weight loss if BMI > 30 Clomiphene to induce ovulation Clomiphene to induce ovulation If DHEA-S > 2, clomiphene + glucocorticoid (dexamethasone) If DHEA-S > 2, clomiphene + glucocorticoid (dexamethasone) If clomiphene alone unsuccessful, try metformin + clomiphene If clomiphene alone unsuccessful, try metformin + clomiphene

17. Hypothalamic Anovulation Low levels of GnRH, low or normal levels of FSH/LH, low levels of endogenous estrogen Low levels of GnRH, low or normal levels of FSH/LH, low levels of endogenous estrogen Associated factors: low BMI (< 20), high- intensity exercise, extreme diets, stress Associated factors: low BMI (< 20), high- intensity exercise, extreme diets, stress Treatment: lifestyle modification Treatment: lifestyle modification

18. Hyperprolactinemia Causes: pituitary adenoma, psych meds Causes: pituitary adenoma, psych meds Test for pregnancy, thyroid disease Test for pregnancy, thyroid disease Imaging: MRI for macro vs. microadenoma Imaging: MRI for macro vs. microadenoma Treatment: Bromocriptine (dopamine agonist) Treatment: Bromocriptine (dopamine agonist) After treatment, 80% of women will ovulate, 80% will get pregnant After treatment, 80% of women will ovulate, 80% will get pregnant Discontinue treatment once pregnancy established Discontinue treatment once pregnancy established

19. What Can I Do?

20. History and Physical - Female History History –Menarche, puberty –Menstrual history –Pregnancies, abortions, birth control –Dyspareunia, dysmenorrhea –STDs, abdominal surgery, galactorrhea –Weight loss/gain –Stress, exercise, drugs, alcohol, psychological Physical Physical –Weight/BMI –Thyroid –Skin (striae, acanthosis nigricans) –Pelvic (vaginal mucosa, masses, pain) –Rectal (uterosacral nodularity)

21. History and Physical - Male History History –Prior fertility –Medications –History of diabetes, mumps, undescended testes –Genital surgery, trauma, infections –ED –Drug/alcohol use, stress –Underwear, hot tubs, frequent coitus Physical Physical –Habitus, gynecomastia –Sexual development –Testicular volume (5x3 cm) –Epididymis, vas, prostate by palpation –Check for varicocele

22. How Long To Wait Before Work-up For young patients, wait a year For young patients, wait a year Don’t wait a year if: Don’t wait a year if: –Irregular menses; intermenstrual bleeding –History of PID –History of appendicitis with rupture –History of abdominal surgery –Dyspareunia –Age > 35 –Male factors

23. On The First Visit Semen analysis Semen analysis Confirm ovulation Confirm ovulation –Basal body temperature charting –Ovulation predictor kits (detect LH surge) –Consider serum progesterone on day 21 Labs: Labs: –TSH and prolactin –DHEA-S if concern for PCOS –FSH and estradiol on cycle day 3 and 10 if >35y –Cervical cultures prn

24. Three Months Later Hysterosalpingogram Hysterosalpingogram –Evaluates tubal patency and uterine cavity shape –Noninvasive but involves a tenaculum –Not a painless test –Performed by radiology with gynecology supervision –Diagnostic and therapeutic

25. Hysterosalpingogram

26. Limited Clinical Utility Postcoital test Postcoital test –Limited diagnostic potential, poor predictive value Endometrial biopsy (luteal phase defect) Endometrial biopsy (luteal phase defect) BBTs BBTs –Very inexpensive but interpretation difficult –Temperature changes too late to be useful for timing intercourse Zona-free hamster oocyte penetration test Zona-free hamster oocyte penetration test –Not sure if hamster oocytes predict human oocytes Immune testing for antiphospholipid, antisperm, antinuclear, antithyroid antibodies Immune testing for antiphospholipid, antisperm, antinuclear, antithyroid antibodies Routine cervical cultures Routine cervical cultures –Mycoplasma hominis or Ureaplasma urealyticum Karyotype Karyotype

27. Clomiphene Citrate Effective for anovulatory patients Effective for anovulatory patients –Also used in unexplained fertility, but no data to support –Most effective for women with normal FSH and estrogen, least effective in hypothalamic amenorrhea or elevated FSH Induces ovulation by unknown mechanism Induces ovulation by unknown mechanism Most pregnancies occur in first 3 cycles Most pregnancies occur in first 3 cycles 80% will ovulate, 40% will become pregnant in 3 cycles 80% will ovulate, 40% will become pregnant in 3 cycles

28. Clomiphene - Complications 7% twin gestations, 0.3% triplet gestations 7% twin gestations, 0.3% triplet gestations Miscarriage rate = 15% Miscarriage rate = 15% Birth defect rate unchanged from controls Birth defect rate unchanged from controls Side effects: hot flashes, adnexal tenderness, nausea, headache, blurry vision Side effects: hot flashes, adnexal tenderness, nausea, headache, blurry vision Contraindications: pregnancy, ovarian cysts Contraindications: pregnancy, ovarian cysts

29. Clomiphene - Administration 50 mg daily, cycle day 3 through 7 50 mg daily, cycle day 3 through 7 –Induce bleeding first with progesterone if amenorrheic Intercourse QOD cycle days 12 - 17 Intercourse QOD cycle days 12 - 17 Track ovulation with BBT or ovulation detection kits Track ovulation with BBT or ovulation detection kits Increase dose to 100 mg daily, then 150, if no ovulation occurs Increase dose to 100 mg daily, then 150, if no ovulation occurs

30. Thank You!