Infertility: A Generalist s Perspective

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Huddleston, MD Assistant Adjunct Professor UCSF Center for Reproductive Health anovulatory When to

1 Infertility: A Generalist s Perspective Learning Objectives Fertility and Lifestyle: Patient education Describe the basic infertility workup Basic treatment strategies unexplained Heather Huddleston, MD Assistant Adjunct Professor UCSF Center for Reproductive Health anovulatory When to refer Case Patient Education 34 yo Here for routine care Interested in conceiving in the future Age Smoking Body Weight 1

2 Knowledge Gap: Age and Fertility Fecundability decline with age Survey by American Fertility Association ,382 women responded to 15 questions 1 responded correctly to all More than ½ of all questions answered incorrectly 85% overestimated by 5-10 years the point at which fertility declines Menken, et al., Science 1986, 233: Apparent fecundability and natural fertility in humans Chance of Natural Conception per Month Percent chance per month 25% 24% 22% 20% 18% 16% 13% 10% 7% 5% 3% 2% Age Homan, G.F. et al. Hum Reprod Update : ; 2

3 Live birth from IVF by age Miscarriage Rate by Age 44% 45% 44% 42% 41% 35% 30% 23% 14% 7% 10% 10% 10% 12% 18% 34% 54% > National Clinic Data for Adapted from P.R. Gindoff and R. Jewelewicz. Reproductive potential in the older woman. Fertility and Sterility. 46:989;1986. Abnormalities in the oocyte increase with age Patient Education Information on fertile window can be delivered during routine gynecologic care Convey non-directional, factual information Pellestor et al, Eur J Med Genet

4 Age Smoking Body Weight Patient Education 100% Percent of women with knowledge of health association with smoking 99% Respiratory Diseases 99% 90% 91% Lung cancer n=388 hospital employees Heart Disease Pregnancy complications 27% Infertility 17% Early menopause 24% 30% Cervical Cancer Osteoporosis Roth and Taylor (Am J Obstet Gynecol 2001;184:934-9.) Smoking and Fertility Smoking and Fertility Average age of menopause 3-4 years earlier than non-smokers Numerous studies indicate longer time to conception in smokers Nicotine and Cotinine found in follicular fluid Direct damage to oocytes/follicles suspected 4

9 No Smoking <10/per day >10 per day Odds Ratio of infertility in smokers: 2.27 (1.34,1.91).

5 Smoking and Fertility Metanalysis: smoking and fertility Average Time to Conceive by Smoking Status Months No Smoking <10/per day >10 per day Odds Ratio of infertility in smokers: 2.27 (1.34,1.91). Smoking and Fertility Advise women of connection between infertility and smoking Future fertility is a strong motivator to quit for many women Patient Education Age Smoking Body Weight 5

6 Body Weight and Fertility Body Weight and Fertility 1,200 consecutive pregnant women. 25 Adjusted Months to Conception BMI Adj RR Infertility p A questionnaire inquiring about time to pregnancy Contraceptive use, pregnancy planning, previous subfertility/pregnancies, age, and lifestyle characteristics examined < >39 BMI < ( ) ( ) <0.001 > ( ) <0.001 Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004 Hassan and Killick Fertility and Sterility. VOL. 81, NO. 2, FEBRUARY 2004 Lifestyle Factors Alcohol Evidence that >7 drinks per week is deleterious to fertility Exercise No evidence that moderate exercise is deleterious Case 35 yo trying to conceive two month no success. 6

7 Optimal Timing Average Time to Conceive Two days prior to and day of ovulation have highest chance of conception 80% 20% 43% 57% 25% 20% 75% 80% 15% 85% 1 month 3 month 6 month 9 month 12 month 7% 93% 24 month Not pregnant Pregnant Wilcox et al NEJM 1333; , 1995 From Guttmacher, JAMA 161:855, 1956 Cycle Fecundability over time #of women at start of each cycle # of pregnancies in each cycle Per-cycle pregnancy rate The Infertility Evaluation <35 years old: after one year of trying to conceive >35 years old: after six months Adapted from Zinaman et al, fertil steril,1996 7

Causes of Infertility The Basic Infertility Work-up Male Tubal Ovulatory Male Male Age Ovary Tubes Semen Lifestyle Uterine Endometriosis Unexplained Ovulation Ovulation Endocrine Regular Cycles

8 Causes of Infertility The Basic Infertility Work-up Male Tubal Ovulatory Male Male Age Ovary Tubes Semen Lifestyle Uterine Endometriosis Unexplained Ovulation Ovulation Endocrine Regular Cycles with moliminal symptoms Timing of ovulation: Basal body temperature Ovulation predictor kits TSH Prolactin Day 21 Progesterone Anovulation suggested by cycle length 36 Lack of moliminal symptoms 8

9 The Basic Infertility Work-up Ovarian Reserve Ovary Tubes Semen Lifestyle Antral Follicle Count Day 3 FSH/ Estradiol Ovulation Ovarian Reserve Clomid Challenge Test FSH levels and pregnancy outcome The Basic Infertility Work-up Ovary Tubes Semen Lifestyle Patent? HSG 9

Tubal/Uterine Factor The Basic Infertility Work-up Ovary

Blocked Tube Septum Semen Analysis Volume 1.

Repeat The Basic Infertility Work-up Ovary Tubes Semen

10 Tubal/Uterine Factor The Basic Infertility Work-up Ovary Tubes Semen Lifestyle Normal Filling Defect Semenanalysis Blocked Tube Septum Semen Analysis Volume 1.5-5ml Concentration>20million/ml Motility>50% If Abnormal Repeat The Basic Infertility Work-up Ovary Tubes Semen Lifestyle Smoking Coffee Alcohol Hot tubs (male) Biking (male) WHO,1992 Weight 10

11 Treatment Treatment Male Factor Tubal Factor Referral Oligoovulatory/PCOS Unexplained Treatment: Anovulation/PCOS Weight Loss and Lifestyle Change Clomid Letrozole Metformin Ovulation Induction: Mechanism FSH LH Pituitary Gland Clomid Tamoxifen E2 Letrozole Metformin Weight Loss Improve insulin sensitivity 11

12 Lifestyle Changes Treatment of Anovulatory Infertility 87 women - obese - 79 % PCOS 6 month group program - regular exercise - gradual dietary changes 67 patients completed program Mean change in BMI % spontaneous conception 53% conceived with assistance Increased self esteem Decreased anxiety/depression 20 patients dropped out No changes in BMI No conceptions C la Medications: Clomid: taken for five days Metformin: taken continuously r k e Results from the Reproductive Medicine Network (RMN) Treatment of Anovulatory Infertility: RMN Trial 626 women with PCOS Percent chance of conception randomized 30% 38% Clomiphene Metformin Metformin and Note: relatively large (BMI = 34-3) and androgenized (FM ) population Clomiphene 12% Clomid Metformin Clomid and Metformin Legro et al NEJM 2007 p <.001 p <.001 Legro et al NEJM

13 Treatment of Anovulatory Infertility: RMN Trial Treatment of Anovulatory Infertility 26% Miscarriage Rate 40% 30% Clomid Metformin Clomid and Metformin Non-significant Legro et al NEJM 2007 Clomid more effective than Metformin in ovulation induction in PCOS population Clomid continues to be first line Unexplained Infertility Stepwise Approach Failure to find abnormalities in sperm, tubes, ovulation, ovarian reserve Expectant Management Clomid Clomid + IUI Injectable FSH/LH with IUI IVF Minimal efficacy Increasing efficancy Lower cost Higher cost Minimal invasiveness More invasive Minimal Risk More Risk 13

14 FSH LH Mechanism of Ovarian stimulation drugs Pituitary Gland Clomid Tamoxifen E2 Clomid for Unexplained Infertility 100 mg for five days (typical: 3-7) Acts as estrogen antagonist Assist in production >1 oocyte Letrozole Risks/Side Effects: Headache Hot Flash Mood Changes Ovarian Cysts Twins Practice committee ASRM, Fertil Steril, 2004 Unexplained Infertility: Clomid & Intercourse Unexplained Infertility: Clomid & IUI Three comparable randomized controlled trials: Meta-analysis Pregnancy rate per Cycle 5.2% 2.8% Clomid Placebo P=0.02 Randomized Controlled Trial 298 cycles 67 patients with unexplained Infertility Pregnancy rate per Cycle 9.5% 3.3% Clomid and IUI Timed Intercourse Modest Treatment Effect Number of cycles to achieve one pregnancy: 40 (95% CI, ) Practice committee ASRM, Fertil Steril, 2006 Number of cycles to achieve one pregnancy: 16 Deaton et al, Fertil Sterility 54:

15 Treatment of Unexplained Infertility Treatment of Unexplained Infertility o Treatment effect of clomid without IUI is quite modest compared to timed intercourse o Recommend for patients if: No time constraints (ie young) Patients who wish to avoid additional intervention o Treatment effect of clomid with IUI has more reasonable efficacy. Due to low cost and relative ease, recommend as first step. Final Points Education regarding factors impacting fertility is important in routine gynecologic care Basic evaluation of infertility includes: tubes, ovulation, ovarian reserve, semenanalysis Initial treatment of anovulatory and may be lifestyle Final Points Clomid alone remains a useful first step in the treatment of ovulatory infertility Clomid alone (no IUI) has only marginal benefit in unexplained infertility. Consider adding IUI s 15

16 Fecundability over time Thank You Cycle #of women at start of each cycle # of pregnancies in each cycle Per-cycle pregnancy rate Adapted from Zinaman et al, fertil steril,

Infertility in Women over 35. Alison Jacoby, MD Dept. of Ob/Gyn UCSF

Infertility in Women over 35. Alison Jacoby, MD Dept. of Ob/Gyn UCSF Infertility in Women over 35 Alison Jacoby, MD Dept. of Ob/Gyn UCSF Learning Objectives Review the effect of age on fertility Fertility counseling for the patient >35 - timing - lifestyle - workup Fertility