INFERTILITY: Update on Evaluation &

Treatment

LaTasha B. Craig, M.D.Assistant Professor

Division of Reproductive EndocrinologyUniversity of Oklahoma Health Sciences

Center

Objectives Understand the different causes of infertility and

the specific evaluations to diagnose each cause.

Comprehend the available infertility treatment options including their chance of pregnancy, complications and chance of multiple gestations.

Have an understanding of the process and success of in vitro fertilization (IVF) & the concerns for long term outcomes of children born from IVF.

Speaker Disclosure I have no financial

relationships or affiliations to disclose.

Many of the medications used in in vitro fertilization are not FDA approved for this indication.

Considerations Pre-Pregnancy Nutritional issues Medical conditions Medications Immunization history Family history and genetic risk Tobacco, alcohol, caffeine & substance use Occupational & environmental exposures

How to time conception Cycle Day (CD) 1 is

the first day of full-flow bleeding

Have intercourse every 2 -3 days (especially between CD 10-20)

Avoid most over-the-counter lubricants

Things to consider: Ovulation Predictor Kits Basal Body

Temperature Charting

Things to avoid: Over the counter

fertility tests Salivary hormone tests Hormonal supplements

Basal Body Temperature Monitoring

Newill RG, Katz M. The basal body temperature chart in artificial insemination by donor pregnancy cycles. Fertil Steril 1982 Oct;38(4):431-8

Ovulation Predictor Kits:

What to Expect--Fecundability: Cumulative pregnancy rate

0102030405060708090

100

% Pregnant

3 mos 6 mos 1 year 2 years

Duration of exposure

Guttmacher, 1956

Definition of Infertility

Failure to conceive after 1 year of unprotected intercourse

The exception: For women ≥ 35 years old, 6 months unprotected intercourse without conception

Infertility Incidence Diagnostic

evaluation Treatment

options

Historical perspective on fertility In 1790 U.S. census, birth

rate was 55 per 1000 population with avg. of 8 births per woman

1995 National Survey of Family Growth (NSGF), birth rate of 15.5 per 1000, with avg. births of 1.2 per woman

Popular explanations for declining U.S. fertility

Changing roles & aspirations for women

Postponement of marriage Delayed age of

childbearing Increasing use of

contraception Liberalized abortion

Speroff. Clinical Gynecologic Endocrinology & Infertility. Sixth edition.

Components of Normal Fertility

Etiologies by percent in couples presenting for infertility

Male Infertility Evaluation: Semen Analysis

Volume 2.0 - 5.0 mL

pH >7.2

Concentration >20 million / mL

Total sperm number >40 million / ejaculate

Motility >50%

Forward progression >2 (scale 0-4)

Sperm morphology >30% normal (WHO 1992)

>14% normal (WHO 1999)

Female Infertility Evaluation: Tubal/Pelvic Factor

Hysterosalpingogram (HSG)

Normal Bilateral Blocked Tubes

Female Infertility Evaluation:

Confirm ovulation by History of regular cycles Symptoms of ovulation Ovulation predictor kits Basal body temperature Progesterone level around

CD 21 Ultrasound monitoring

Ovulation Dysfunction

Ovarian Aging: Depletion of primordial follicles

Picture from: http://embryology.med.unsw.edu.au/Notes/im

ages/week1/ovary/oocytenumber.jpg

Ten various populations ranging from 17th to mid-20th century.

Marital fertility rates by 5-year age groups

Menken J, Trussel J, Larsen U. Age and infertility. Science 1986;23:1389-1394.

2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)

2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)

Female age Cycle day 3

FSH & estradiol

AMH level Vaginal

ultrasound for antral follicles

Assessment of Ovarian Reserve

Treatment Options Directly correct a problem if possible (i.e.

thyroid tx, Bromocriptine, weight loss, etc) If unable to correct the underlying

problem, then use empiric treatment: Intrauterine insemination (IUI or AI) Ovulation Induction Assisted Reproductive Technology (i.e. in vitro

fertilization – IVF)

Treatment Options: Intrauterine Insemination (IUI)

Picture from Familydoctor.co.uk

Treatment Options: Ovulation Induction

By mouth: Clomiphene (Clomid) or Letrozole (Femara) Pregnancy rate is 10% per cycle (higher in

PCOS patients). Risk of twins 8-10% and risk of triplets or

more less than 1% Side Effects: hot flushes, nausea,

headaches, mood swings, blurred vision, thin uterine lining, poor cervical mucus.

Injectable medications: Gonadotropins (FSH, LH) Pregnancy rate is 10-20% each cycle

(controversial) Risk of twins up to 30% and risk of triplets

or more 5-10% Side effects of medication are minimal

because it is a natural hormone. Chance of overstimulation and canceling cycle.

Treatment Options: Ovulation Induction

Gonadotropins

Polycystic Ovarian Syndrome (PCOS)

Adjunct to Ovulation Induction in PCOS 1500-2000 mg/ day May not be covered by

insurance in non-diabetics Re-introduce clomid

Metformin

Ovarian Drilling Ovulation rates, 50-80% Adhesion risk, 10-15% Longest study, 5 year follow-up1

(206 patients) 70% Pregnancy rate (1/2 treated) 50% Live birth rate

1 Naether OG et al., Human Reprod 9(12):2342-9, 1994

Which of the following do you believe: All patients with PCOS should be on

metformin All PCOS patients wanting to conceive

should be on metformin Metformin is only indicated if a patient has

diabetes or impaired glucose tolerance.

Metformin in PCOS

0

10

20

30

40

50

60

70

80

90

placebo placebo+CC metformin met+CC

ovulation

Nestler JE, et al. NEJM 338(26):1876-80, 1998

Metformin in PCOS

BeforeBefore AfterAfter

Insulin Insulin microU/mLmicroU/mL

26 26 2222

TestosteroneTestosterone

ng/dLng/dL

6161 4747

Glueck CJ, et al. Metabolism Apr;48(4):511-9, 1999

Is metformin more effective than clomid?

Randomized controlled trial of metformin 850 mg bid vs. clomiphene citrate 150 mg qd cycle days 5-9

Cumulative ovulation rate not different (63 vs. 67%)

Pregnancy rate/cycle = 15.1% metformin; 7.2% clomiphene (p = 0.009)

Palomba et al. JCEM 90(7): 4068-74, 2005Palomba et al. JCEM 90(7): 4068-74, 2005

Does metformin decrease the spontaneous miscarriage rate in PCOS?

Randomized controlled trial of metformin 850 mg bid vs. clomiphene citrate 150 mg qd cycle days 5-9

Metformin group miscarriage = 3/31 (9.7%) Clomid group miscarriage = 6/16 (37.5%) P = 0.045

Palomba et al. JCEM 90(7): 4068-74, 2005Palomba et al. JCEM 90(7): 4068-74, 2005

Is metformin more effective than clomid?

Legro et al. NEJM 356,6: 551-66, 2007Legro et al. NEJM 356,6: 551-66, 2007

Metformin + Metformin + placeboplacebo

Clomid + placeboClomid + placebo Metformin + Metformin + ClomidClomid

nn 208208 209209 209209

% of cycles that % of cycles that were ovulatorywere ovulatory 29%29% 49%49% 60%60%

% pregnant/ % pregnant/ ovulatory cycleovulatory cycle 8.4%8.4% 13.4%13.4% 13.7%13.7%

% live birth% live birth7.2%7.2% 22.5%22.5% 26.8%26.8%

What if all the tests are normal?

Unexplained Infertility ~10% of couples

Guzick et al. Efficacy of treatment for unexplained infertility.Fertil Steril. 1998 Aug;70(2):207-13.)

Treatment % preg

No treatment 2.6%

IUI 3.8%

Clomiphene 5.6%

Clomiphene+IUI 8.3%

Gonadotropins 7.7%

Gonadotropins+IUI 17.1%

IVFIVF 20.7%20.7%

Treatment Options: Unexplained Infertility

See next slide

OU Reproductive Medicine IVF Statistics

( (Delivered per embryo transfer in 2010)

Age group (years)

% P

reg

nan

t o

r D

eliv

ered

* A comparison of clinic success rates may not be meaningful because patient medical characteristics, treatment approaches and entrance criteria for ART may vary from clinic to clinic.

Treatment Options: In Vitro Fertilization (IVF) & ART

Blocked tubes Severe male factor Unexplained infertility Endometriosis/peritoneal factor infertility Failure to conceive with less aggressive

treatment Ovarian failure/ ovarian reserve (donor eggs)

MDsMDs

LabLab• Embryology• Embryology• Andrology• Andrology• Endocrine• Endocrine

NursingNursingStaffStaff

Office &Office & Clinic Clinic Staff Staff

ART Team

Assisted Reproductive Technology—ART

1978/1981 In vitro fertilization—IVF 1984 Donor oocyte (egg) cycle 1985 Cryopreserved Embryo Transfer 1990 Preimplantation Genetic Diagnosis—PGD 1992 Intracytoplasmic Sperm Injection—ICSI

As of 2004, more than 1 million children born worldwide as a result of ART

IVFLuteal Leuprolide Protocol

OCPs14-28 days

Lupron24-30 days

Gonadotropins8-12 days

hCG

Retrieval

Transfer

2days

3-6days

Monitoring FolliclesIVF Ultrasound

Sonographic Egg Recovery

Sonographic Egg Recovery

Intracytoplasmic sperm injection—ICSI

Discovered “by accident” in 1991 in a Belgian IVF lab

Successfully treats almost all forms of severe male factor infertility

ICSI

Timing of Embryo Transfer

Day 3 Embryo Transfer

Day 5–6 Embryo Transfer “Blastocyst Transfer”

Veeck LL, Zaninovic N. An Atlas of Human Blastocysts. 1st ed. New York: Parthenon Publishing, 2003;118.

Embryo Transfer

•

Loading Catheter

Embryo Transfer

Outcomes—Children

Children of ARTPossible Risks

Multiple pregnancy Low birth weight Congenital anomalies Transmission of parental genetic

abnormalities (e.g., male factor) Imprinting defects Developmental abnormalities

OCTOMOM: Nadya Suleman

2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)

Octomom’s Clinic: West Coast IVF

Clinic, Inc.In 2007, 19 patients < 35 years old

2 became pregnant1 delivered

Average # embryos transferred: 4.1

Preimplantation Genetic Testing Preimplantation Genetic Screening (PGS)

Advanced reproductive age Recurrent pregnancy loss Multiple failed IVF cycles

Preimplantation Genetic Diagnosis (PGD) Sex-linked disorders (FISH or PCR) Single gene disease

Autosomal recessive (PCR) Autosomal dominant (PCR)

Translocations (FISH)

A

FE

C D

B

An Atlas of Preimplantation Genetic Diagnosis pg 91

The Technology: PGS and Chromosome Translocations

Fluorescent In-Situ Hybridization (FISH)

Alternatives in the near future:Comparative Genomic Hybridization (CGH)

Multiple Displacement Amplification

Gene Chips

Pyro Sequencing

Trisomy 21 Embryo

Chromosome 21

Chromosome 21

Chromosome 21

An Atlas of Preimplantation Genetic Diagnosis pg 114

When should you refer your patient:

You’ve been trying to conceive for > 1year

You do not have regular periods

You are > 35 years old You have a history of

sexually transmitted diseases (i.e. chlamydia)

Conclusions Basic Infertility Evaluation Understand the treatment options Understand the complications of treatments

We do not know all of the long-term effects of ART because it is still a relatively young field of study.

THANK YOU

QUESTIONS?

LaTasha B Craig, MD

University of Oklahoma Health Sciences Center

Section of Reproductive Endocrinology & Infertility

Department of Obstetrics & Gynecology

www.OUInfertility.com