Fertility Evaluation and Treatment for the Non-

Gynecologist

Albert Asante, MD MPH Fellow Reproductive Endocrinology & Infertility Mayo Clinic asante.albert@mayo.edu

Disclosures

• No financial conflicts of interest

Objectives

• Identify when a couple is infertile

• Use a very rational strategy for evaluating an infertile couple

• Determine when, and how, to treat and when to refer patients for subspecialty care

Case Vignette

• A 31 year old woman

• Unable to conceive a child x 3 yrs

• GynHx: menarche 13yrs, menses q 28 days, no hx of STIs, no abnl paps

• Sexual hx: no dyspareunia, regular intercourse

• PM/SHx: unremarkable

• Partner: 35 year old male

• Has never fathered a child

• No significant PM/SHx

Infertility

• One year of attempting conception without success

• Primary: No previous pregnancies

• Secondary: Patient has had previous pregnancies, but now infertile

• ASRM Revision September 2008: evaluate after 6 months for women over age 35 years

Scope of The Problem

• ~15% of couples with reproductive-age women considered infertile

• > 15% in developing countries (Demographic Health Survey, WHO 2004)

• Number of infertility services more than doubled from 1996 - now

• 2004: >1 Million Americans

underwent some form of

fertility treatment

• $3 Billion dollar industry

Source: Adapted from The New York Times, February 12, 2009

Normal Fecundability

0

5

10

15

20

25

30

35

1 2 3 4 5 6 7 8 9 10 11 12

Pre

gn

an

cy

Ra

te (

%)

Cycle Number

• 200 couples attempting pregnancy

• Followed prospectively

Zinaman, et al. Fertil Steril 1996

Most pregnancies occurred in first 6 months

Pregnancy rate ≤3% at 12 months

Causes of Infertility

Evaluation of the Infertile Couple

• Evaluation of both partners should begin at the same time

• Initial consultation should include:

• Complete medical and menstrual history

• Targeted physical examination

• Preconception counseling

• Instruction on optimizing coital timing

Optimization of Coital Timing

Source: Fertil Steril 2008; 90:S1-S6

• Fertile window: 6-day interval ending in ovulation • Viability and survivability of sperm and oocytes maximal during that time • No significant difference in pregnancy rates between daily (37%) and QOD intercourse (33%)

• Source: Wilcox AJ, NEJM 1995; 333:1517-1521

Recommendation: Intercourse QOD from cycle days 10 - 20

Objectives of Management

• Diagnose any definite cause of infertility

• Discuss treatment appropriate to the couple’s needs (by age, duration, wishes)

• Give a realistic prognosis

• Provide support and counseling (to cope with the stress of Tx and possible failure)

• Discuss valid alternatives

• Arrange prompt referrals when appropriate

Diagnostic Tests: The Big 3

• The EGG: Assessment of ovulatory status and ovarian reserve

• The TUBES: Evaluation of tubal patency and uterine cavity

• The SPERM: Semen analysis

Assessment of Ovulatory Status

• Menstrual history: May be enough

• Mid-Luteal phase progesterone: >3 ng/ml

• LH predictor kits

• Serial transvaginal US

• Basal body temperature charting: Retrospective evidence of ovulation

• Endometrial biopsy for dating: Not useful

Ovulatory Disorders: WHO Classification

• Group I: Hypothalamic-Pituitary Failure

• Hypogonadotropic hypogonadism

• Kallmann’s syndrome, Pituitary tumors

• Group II: Hypothalamic-Pituitary Dysfunction

• Eugonadotropic hypogonadism

• Polycystic Ovary Syndrome (PCOS)

• Group III: End Organ Failure

• Hypergonadotropic hypogonadism

• Premature ovarian failure (POI)

• Hyperprolactinemia

Ovulatory Disorders: Gonadotropin and Estradiol Measurements

FSH/LH Estradiol

Group 1:

Hypogonadotropic hypogonadism

Low

(<5 IU/L)

Low

(<25 pg/mL)

Group 2:

Eugonadotropic hypogonadism

Normal

(5-20 IU/L)

Normal

(25-300 pg/mL)

Group 3:

Hypergonadotropic hypogonadism

High

(>20 IU/L)

Low

(<25 pg/mL)

GnRH

Evaluation of A Woman with Ovulatory Dysfunction

• Pregnancy test

• TSH, Prolactin

• FSH, Estradiol

• If PCOS suspected:

• Serum androgens, 17-OHP, Serum Progesterone, Pelvic ultrasound

Diagnostic Tests: The Big 3

• The EGG: Assessment of ovulatory status and ovarian reserve

• The TUBES: Evaluation of tubal patency and uterine cavity

• The SPERM: Semen analysis

Assessing Ovarian Reserve

Human Oocytes Across the Lifespan

Source: http://php.med.unsw.edu.au/embryology/index.php?title=Menstrual_Cycle

Ovarian Reserve Testing

• Cycle day 3 FSH and Estradiol

• FSH: ≤14 IU/L

• Estradiol: ≤50 pg/mL

• Abnormal results:

• Low FSH/High estradiol Diminished reserve

• High FSH/Low estradiol Even worse

• U/S for antral follicle count (AFC)

• ≥14 considered normal

• Anti-Mullerian Hormone (AMH)

Ovarian Reserve Testing Recommendations

• Which patients?

• Women >35, younger women with indications

• When?

• FSH and Estradiol Cycle Day 3

• Ultrasound for AFC Follicular phase

• AMH Anytime in the cycle

Diagnostic Tests: The Big 3

• The EGG: Assessment of ovulatory status and ovarian function

• The TUBES: Evaluation of tubal patency and uterine cavity

• The SPERM: Semen analysis

Evaluation of Fallopian Tube Patency and Uterine Cavity

• Hysterosalpingogram (HSG)

• Ideal timing: CD 7–10

• Between end of menses and ovulation

• Slight increase in pregnancy rate during cycle HSG performed

• Infection risk: 2-4%

• Doxycycline 100 mg po BID x 5 days

Normal Hysterosalpingogram

Endometrial Polyp Asherman syndrome

Uterus Didelphys Hydrosalpinx

Diagnostic Tests: The Big 3

• The EGG: Assessment of ovulatory status and ovarian function

• The TUBES: Evaluation of tubal patency and uterine cavity

• The SPERM: Semen analysis

Semen Analysis

• Critical early component

• Abstinence: 2-7 days

• Sample collected on site

• Examined within one hour

• WHO: New guidelines introduced in 2010

• If abnormal Repeat

Who should treat the infertile couple?

Infertility Treatment

• Ovulation Induction: Make one egg per cycle

• Superovulation: Make more than one egg at a time

• Intrauterine Insemination (IUI): Concentrate sperm and place closer to egg(s) at ovulation

• Combination of above

• In Vitro Fertilization (IVF)

Treat or Refer?

• Ovulatory dysfunction: Depends

• PCOS; Hyperprolactinemia; Thyroid disorder: Treat

• Hypogonadotropic hypogonadism: Refer

• Diminished ovarian reserve: Refer

• Bilateral fallopian tube blockage: Refer

• Unilateral blockage: Possibly treat

• Uterine cavity lesion: Refer for surgical correction

• Abnormal semen analysis: Refer

• Endometriosis: Treat for ≤6 months

• Unexplained: Treat for ≤6 months

How do you Treat?

• Thyroid disease: Correct as appropriate

• Goal TSH: 2.5 mIU/L or less

• Hyperprolactinemia: Correct as appropriate

• Cabergoline

• PCOS: Ovulation induction

• Endometriosis: Superovulation x < 6mths

• Unexplained: Superovulation x < 6mths

Ovulation Induction / Superovulation Strategies

GnRH

Block negative

feedback of

estrogen to

hypothalamus

and pituitary

Clomiphene

citrate

Aromatase

inhibitors

Stimulate ovaries

directly with

supraphysiologic

amounts of FSH/LH

Exogenous

gonadotropins

Clomiphene Citrate (Clomid)

• Oral administration

• Given CD 3-7

• Dose: 50-150 mg daily

• 75% of women respond to 50 mg

• 22% respond to 100 mg

• Side effects: Twins (5-8%), hot flashes, mood changes, breast tenderness, pelvic pressure/pain, nausea

Monitoring Response

• Ovulation predictor kits

• Detect urinary surge of LH

• Ovulation will be ~36-40 hours later

• Begin using on CD 12

• Timed intercourse every other day CD 10-20

• Mid-luteal progesterone

• Ultrasound monitoring of follicle

• If no ovulation: Increase by 50 mg in next cycle

• Treat for ≤6 months before referral or alternate treatment

Aromatase Inhibitors

• Block peripheral conversion of androgens to estrogen

• Dose: Letrozole 2.5-10 mg daily

• Oral administration; CD 3-7

• Off-label use

• Pregnancy rates similar to clomiphene; risk of multiples lower

Injectable Gonadotropins

• Synthetic FSH/LH

• Daily SC injection, beginning CD3

• Usual dose: 75-225 IU daily

• Must monitor follicle development with serial estradiol levels and ultrasounds

• Goal: 1-3 follicles that are >18 mm diameter

• hCG administered to trigger oocyte release

• Intercourse or IUI 36 hours later

• High risk for multiples if not used carefully

In Vitro Fertilization (IVF)

• High doses of gonadotropins given to recruit a cohort of oocytes to develop

• Follicle growth monitored with serial estradiol levels and ultrasounds

• hCG given to trigger final oocyte maturation

• Oocytes harvested before ovulation

• Oocytes fertilized in laboratory Embryos

• Embryos transferred to uterus 2-5 days later

www.TMZ.com www.radaronline.com

Tread Carefully…………………………

Success Rates

• Normal fertility: 20-25% pregnancy per month

• Infertile couples: ≤3% pregnancy per month

• Pregnancy rates with aromatase inhibitors are similar to Clomiphene

Treatment % Pregnancy per Month

IUI alone 4%

Clomiphene + Timed IC

5-8%

Clomiphene + IUI

10-12%

Gonadotropins + Timed IC

10%

Gonadotropins + IUI

15-20%

IVF Up to 65%

Take Home Points…….

Natural Human Fertility Is Low

• Set realistic expectations

• Clomid is the usual first-line therapy, but it is not appropriate for everyone

• No matter what treatment, re-evaluate if no success after 4-6 months

Male Factor Infertility

• 30-40% of the time

• Get the Semen Analysis early

Role of Laparoscopy

• No longer routine

• Only if other indication (pain, adnexal mass, hydrosalpinx)

Fertility Vitamins?

• NO

• Generic prenatals

Lifestyle Factors

• Coital position: No effect on fecundability or gender

• Lubricants: Water-based inhibit sperm motility by 60-100% within 60 mins of incubation with sperm

• Includes: AstroGlide® and KY®

• Recommend hydroxyethylcellulose-based (Pre-Seed®)

Lifestyle Factors, con’t

• Diet: No specific diet recommended

• Smoking: QUIT!

• Menopause 1-4 years earlier in smokers

• Semen parameters also affected

• Alcohol: Mixed data, <2 drinks daily probably okay

• Caffeine: Mixed data, ≤200 mg daily probably okay

• Marijuana use: QUIT!

• Hot tub use: Okay for both partners

…………back to our Case Vignette

• 31 y.o. female with primary infertility

• Diagnostic tests

• Semen analysis

• Cycle day 21 Progesterone or LH surge kit

• HSG

• +/- Cycle day 3 FSH/E2

• Management

• Preconception counseling

• Discuss timed intercourse (TIC)

• Superovulation with TIC or IUI x 3-4 cycles

Thank You!