infertility.(by craig)
TRANSCRIPT
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INFERTILITY: Update on Evaluation &
Treatment
LaTasha B. Craig, M.D.Assistant Professor
Division of Reproductive EndocrinologyUniversity of Oklahoma Health Sciences
Center
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With Kind Regards I have reproduced this topic as such in
origion for the benefit of students only. I express my sincere thanks and kind
regards to the author from deepest core of my heart.
Prof, M.C.Bansal
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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.
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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.
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Considerations Pre-Pregnancy Nutritional issues Medical conditions Medications Immunization history Family history and genetic risk Tobacco, alcohol, caffeine & substance use Occupational & environmental exposures
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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
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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
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Ovulation Predictor Kits:
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What to Expect--Fecundability: Cumulative pregnancy rate
0102030405060708090
100
% Pregnant
3 mos 6 mos 1 year 2 years
Duration of exposure
Guttmacher, 1956
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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
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Infertility Incidence Diagnostic
evaluation Treatment
options
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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.
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Components of Normal Fertility
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Etiologies by percent in couples presenting for infertility
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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)
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Female Infertility Evaluation: Tubal/Pelvic Factor
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Hysterosalpingogram (HSG)
Normal Bilateral Blocked Tubes
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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
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Ovarian Aging: Depletion of primordial follicles
Picture from: http://embryology.med.unsw.edu.au/Notes/im
ages/week1/ovary/oocytenumber.jpg
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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.
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2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)
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2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)
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Female age Cycle day 3
FSH & estradiol
AMH level Vaginal
ultrasound for antral follicles
Assessment of Ovarian Reserve
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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)
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Treatment Options: Intrauterine Insemination (IUI)
Picture from Familydoctor.co.uk
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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.
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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
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Gonadotropins
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Polycystic Ovarian Syndrome (PCOS)
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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
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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.
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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
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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
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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
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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
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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%
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What if all the tests are normal?
Unexplained Infertility ~10% of couples
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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
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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.
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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)
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MDsMDs
LabLab• Embryology• Embryology• Andrology• Andrology• Endocrine• Endocrine
NursingNursingStaffStaff
Office &Office & Clinic Clinic Staff Staff
ART Team
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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
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IVFLuteal Leuprolide Protocol
OCPs14-28 days
Lupron24-30 days
Gonadotropins8-12 days
hCG
Retrieval
Transfer
2days
3-6days
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Monitoring FolliclesIVF Ultrasound
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Sonographic Egg Recovery
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Sonographic Egg Recovery
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Intracytoplasmic sperm injection—ICSI
Discovered “by accident” in 1991 in a Belgian IVF lab
Successfully treats almost all forms of severe male factor infertility
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ICSI
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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.
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Embryo Transfer
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•
Loading Catheter
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Embryo Transfer
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Outcomes—Children
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Children of ARTPossible Risks
Multiple pregnancy Low birth weight Congenital anomalies Transmission of parental genetic
abnormalities (e.g., male factor) Imprinting defects Developmental abnormalities
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OCTOMOM: Nadya Suleman
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2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)
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Octomom’s Clinic: West Coast IVF
Clinic, Inc.In 2007, 19 patients < 35 years old
2 became pregnant1 delivered
Average # embryos transferred: 4.1
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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)
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A
FE
C D
B
An Atlas of Preimplantation Genetic Diagnosis pg 91
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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
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Trisomy 21 Embryo
Chromosome 21
Chromosome 21
Chromosome 21
An Atlas of Preimplantation Genetic Diagnosis pg 114
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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)
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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.
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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