Basic Female Infertility for the Primary Care Physician Molly Moravek, MD, MPH Director, Fertility Preservation Program Assistant Professor Reproductive Endocrinology and Infertility Department of Obstetrics and Gynecology

Objectives Recognize common causes of female infertility Understand the basic female infertility workup be able to interpret the results Briefly describe treatment options

Definitions Fertility The ability to conceive and produce offspring Infertility The inability to conceive after 12 months of frequent intercourse without contraception Fecundability The probability that a single cycle will result in pregnancy Fecundity The probability that a single cycle will result in a live birth

Epidemiology (CDC 2011-2013) Women aged 15-44 with impaired fecundity: 7.5 million (12.3%) Married women aged 15-44 that are infertile: 1.0 million (6.1%) Women aged 15-44 who have ever used infertility services: 6.9 million (11.3%)

Normal Reproduction Education on normal human reproductive efficiency can help provide important perspective for an infertile couple In normally fertile couples, cycle fecundability is ~20% and does not exceed 35%, even with carefully timed intercourse 3 months of “trying”  57% will become pregnant 6 mo  72% 1 yr  85% 2 yrs  93%

Tubal and Pelvic Pathology Ovulatory Dysfunction Female Infertility Tubal and Pelvic Pathology 40% Ovulatory Dysfunction 40% Male Causes 35% Female Causes 50% Unexplained Causes 15% Unusual Problems 10% Unexplained Infertility 10%

Evaluation – Female Infertility History General Physical Exam Endocrine blood tests Evaluation of uterine cavity/tubal patency

Key Components + + =

Tests of Ovarian Reserve Day 3 FSH/E2 FSH > 10 to 15 IU/L on day 2 or 3 is considered DOR Anti-mullerian hormone (AMH) Antral follicle count (AFC)

Age and Reproduction Data from natural populations suggest that fertility in women peaks between 20-24yo, decreases gradually until 30-32yo, then declines more rapidly Overall, fertility rates are: 4-8% lower in women aged 25-29yo 15-19% lower in women aged 30-34yo 26-46% lower in women aged 35-39yo Up to 95% lower in women aged 40-45yo As women age, miscarriage rates also increase e.g. Hutterites

Other Endocrine Testing TSH – goal <2.5 mU/L Prolactin? Androgens? Midluteal progesterone?

Hyperprolactinemia Eating Medications Hypothyroidism Pituitary Disorders Chest wall stimulation Hyperprolactinemia Stress Breastfeeding Infiltrative Diseases Adrenal Insufficiency Idiopathic Intercourse

Anatomical Evaluation Hysterosalpingogram (HSG) Saline infusion sonogram (SIS) Pelvic ultrasound

Hysterosalpingogram #1

Hysterosalpingogram #2

Saline Infusion Sonography

Semen Analysis Parameter WHO 1999 WHO 2010 Volume 2 ml 1.5 ml Concentration 20 million/ml   15 million/ml Progressive motility 50% 32% Normal forms 14%   4%

Hypothalamic Amenorrhea Most common cause of hypogonadotropic amenorrhea Categorized by: Low/normal gonadotropins Low E2 Normal prolactin/TSH levels Normal imaging evaluation of the sella turcica Failure to demonstrate withdrawal bleeding Associated with eating disorders, excessive exercise, extreme stress Every women’s set point Is somewhere different for amount of weight loss or amount of stress/exercise that will shut down HPO axis. May be less than you think. It is thought that minimum body fat necessary to initiate menarche is 17%.

PCOS Most common endocrine disorder Rotterdam Criteria (2 of 3): Oligo-/Anovulation Hyperandrogenism Polycystic ovaries Increased risk of endometrial hyperplasia or carcinoma Increased insulin resistance, NIDDM – 2hr GTT Metabolic syndrome/Central obesity - Lipids

It is imperative to rule out other causes of hyperandrogenism before diagnosing PCOS

Evaluation of Androgen Excess Testosterone (LCMS) Elevation consistent with PCO Very high levels >200 ng/dL suggest tumor DHEAS Elevated levels indicate adrenal source (>700ug/dL) 17-hydroxyprogesterone Assess in follicular phase, AM Elevated level could indicate CAH

PCOS Treatment Cycle Regulation/Endometrial protection Hyperandogenism OCPs Cyclic progesterone Hyperandogenism Spironolactone Insulin Resistance/Hyperlipidemia Infertility Letrozole likely superior to clomiphene

Unexplained infertility Diagnosis of exclusion Incidence 10-30% among infertile populations 2 potential explanations There truly is NO abnormality and the couple’s natural fertility is at the extreme lower end of normal range There is a specific cause, but not one that we can identify with the existing tests

Recurrent Pregnancy Loss Pregnancy occurs in ~15% of clinical pregnancies Age dependent Majority SAB <10 weeks’ gestation due to random chromosome errors >90% of conceptions with nl karyotype will continue <5% of women have 2 consecutive miscarriages Only ~1% experience 3 or more Diagnosis made and treated in about 50% of women with RPL

Recurrent Pregnancy Loss Recurrent pregnancy loss defined as 3+ (do not have to be consecutive) Evaluation warranted after 2 losses (preferably documented), especially when: Fetal heart activity noted prior to loss Nl karyotype on POC Age >35 Infertility

Etiology Undisputed: Not so firmly established: Genetic: Balanced translocation in either partner, maternal age, oocyte quality, random mutations Anatomic: Congenital and acquired uterine anomalies (usually later losses) Immunologic: Thrombotic complications of antiphospholipid syndrome Not so firmly established: Alloimmunopathology Inherited thrombophilias, e.g. FVL Endocrinopathies: Thyroid, DM, luteal phase defects Infections: Genital mycoplasma Environmental: tobacco, alcohol, caffeine

Management options

Lifestyle Changes Weight loss if BMI > 30 Smoking cessation Drug use cessation Decrease in caffeine Decrease in life stressors

Ovulation Induction/Superovulation Clomiphene citrate Letrozole Gonadotropins +/- IUI

In Vitro Fertilization (IVF)

Preimplantation Genetic Diagnosis

Third Party Reproduction Donor Oocytes Donor Embryos Gestational Carrier

Shameless Plug for the Fertility Preservation Program 

Cancer and Fertility Survival rates are at an all-time high Treatment is often detrimental to reproductive function Resumption of menses ≠ fertility An infertility diagnosis has equivalent psychosocial effects as a cancer diagnosis Treatment of these cancers is often detrimental to reproductive function

Options Females Males Embryo Cryopreservation Oocyte Cryopreservation Ovarian Shielding Ovarian Transposition GnRH Agonist Ovarian Tissue Cryopreservation Sperm banking Testicular sperm extraction Testicular shielding Testicular tissue cryopreservation

If you’re just waking up…. Evaluate women >1 year without conception (>6 months if >35yo), 2+ miscarriages, oligo-/amennorhea Basic infertility workup prior to referral: Day 3 FSH and E2 AMH, TSH Other labs as indicated by history Semen analysis

Thank You!