1. Christopher R. Graber, MD Salina Women’s Clinic 10 Dec 2010

2. Overview Definitions and Numbers Indications for evaluation Causes of infertility Ovulatory dysfunction Tubal and pelvic Male factor Laboratory evaluation Treatment with Clomid When to refer

3. Definitions Infertility – 1 year of unprotected intercourse without conception (10-15% of couples) Fecundability – probability that a single cycle will result in pregnancy (20-25% if normal)

4. Lies, Damn Lies and Statistics Time required for conception in couples who will attain pregnancy Exposure % Pregnant 3 mo57 6 mo72 1 yr85 2 yr93

5. Indications for Evaluation Education should be offered to any couple who seeks it – even without trying first Any couple who is infertile Any woman older than 35yo with irregular or infrequent menses Women with a history of PID Men with known or suspected poor quality semen

6. Causes of Infertility Ovulatory dysfunction – 15-20% PCOS, ovarian failure Tubal and peritoneal pathology – 30-40% Congenital malformations, fibroids, tubal scarring, intrauterine adhesions (Asherman’s) Male factors – 30-40% Unexplained – 10-15%

7. Ovulatory Dysfunction 20% of infertile women have ovulatory disorders The cause of anovulation will guide treatment Symptoms polymenorrhea, oligomenorrhea, amenorrhea Regular menstrual cycles (22-35d) with presence of premenstrual symptoms is highly suggestive of ovulation (~95%)

8. Ovulatory Dysfunction Differential diagnosis PCOS (70%) Hypothalamic amenorrhea (10%) aka hypogonadotropi c hypogonadism Low GnRH, LH, FSH, Estrogen Hyperprolactinemia (10%) Can be caused by hypothyroid (TRH acts as PRF) Premature ovarian failure/insufficiency (10%) aka hypergonadotropic hypoestrogenic anovulation

9. PCOS Must have 2 of 3 diagnostic criteria “polycystic ovaries” on sono Clinical or lab evidence of increased testosterone Oligo- or amenorrhea Diagnosis of exclusion thyroid/prolactin disorders Testosterone secreting tumor, non-typical congenital adrenal hyperplasia (CAH), Cushing’s syndrome

10. Other Ovulatory Dysfunction Hypothalamic amenorrhea aka hypogonadotropic hypogonadism Low GnRH, LH, FSH, Estrogen Frequently found in athletes and women with very low BMI – consider eating disorders Hyperprolactinemia Can be caused by hypothyroid (TRH acts as PRF) MRI to look for prolactinoma of pituitary

11. Other Ovulatory Dysfunction Premature ovarian failure/insufficiency aka hypergonadotropic hypoestrogenic anovulation Premature if less than 35 to 40yo Usually not complete “failure” High FSH and LH but low estrogen levels Signs that the ovaries are not responding Rule out chromosomal abnormalities Y chromosome, Turner’s syndrome, Fragile X

12. Ovulatory Dysfunction Eval Physical exam (after a very thorough history) Galactorrhea, thyroid eval Acanthosis nigricans, hirsutism, acne BMI (>30 or <20) Laboratory evaluation for ovulation Basal body temperature Urine testing for LH surge (seen after ovulation) Pelvic sono

13. Tubal and Peritoneal Pathology Cervical factor – post-coital test not common Uterine factor Fibroids: size, symptoms, sono Intrauterine adhesions – Asherman’s syndrome Painful, short menses Classically after a D&C, may also be after infection

14. Tubal and Peritoneal Pathology Tubal factor History of PID (or untreated STI) Abdominal/pelvic surgery Endometriosis – painful menses

15. Tubal and Peritoneal Pathology Evaluation Pelvic sono Hysterosalpingography (HSG) Sonohysterography (SHG) Hysteroscopy Laparoscopy with tubal dye instillation

16. Male Factor Semen analysis Volume 1.5 – 5ml pH > 7.2 Concentration > 20 mil/ml Total number > 40 mil Percent motile >50% Normal morphology – lab: 14%, 30%, or 50% If abnormal, repeat then refer if still abnormal

17. Laboratory Evaluation For ovulatory dysfunction Basal body temperature, urinary LH TSH Prolactin (ideal conditions if first test abnormal) Cycle day 3 labs FSH, Estradiol Consider other screening Pap, Rubella, STI, genetics

18. Clomiphene Citrate Clomid – estrogen agonist and antagonist Binds to nuclear estrogen receptors Circulating estrogen levels perceived as low Stimulates increased pituitary gonadotropins Increases ovarian follicular development Side effects Antiestrogenic Multiples: 7% twins, 1% triplets

19. Clomiphene Citrate Who to give Anovulatory woman with normal TSH, PRL Normal estradiol or menstrual response to progesterone challenge Unexplained fertility How to give 50mg PO qday on cycle days 3-7 (or 5-9) New prescription every month Scheduled intercourse QOD days 10-18

20. Clomiphene Citrate When it fails (no menses and not pregnant) Double check a pregnancy test (usually CD 33-35) Induce menses with progesterone challenge Provera 5mg PO qday x 5 days Increase dose of CC by 50 mg Max dose 150 mg – 250 mg How long to give 3 to 6 to 9 months – patient and provider specific

21. Other options Insulin sensitizers Metformin 500 – 875 mg, BID to TID Letrozole (Femara) Aromatase inhibitor 2.5 mg PO on cycle days 3-7 Laparoscopic ovarian drilling Injectible gonadotropins

22. When to refer Right away Advanced age Previous treatment Upon patient request Non-ovulatory dysfunction Tubal or peritoneal factory, male factor When Clomid doesn’t work 3 to 6 to 9 months

23. Questions?