1. INFERTILITY:
Update on Evaluation &
Treatment
LaTasha B. Craig, M.D.
Assistant Professor
Division of Reproductive Endocrinology
University of Oklahoma Health Sciences
Center

2. 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

3. 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.

4. 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.

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

6. 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

7. 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

8. Ovulation Predictor Kits:

9. What to Expect--Fecundability:
Cumulative pregnancy rate
0
10
20
30
40
50
60
70
80
90
100
% Pregnant
3 mos 6 mos 1 year 2 years
Duration of exposure
Guttmacher, 1956

10. 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

11. Infertility
 Incidence
 Diagnostic
evaluation
 Treatment
options

12. 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.

13. Components of Normal Fertility

14. Etiologies by percent in couples
presenting for infertility

15. 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)

16. Female Infertility Evaluation:
Tubal/Pelvic Factor

17. Hysterosalpingogram (HSG)
Normal Bilateral Blocked Tubes

18. 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

19. Ovarian Aging:
Depletion of primordial follicles
Picture from:
http://embryology.med.unsw.edu.au/Notes/im
ages/week1/ovary/oocytenumber.jpg

20. 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.

21. 2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)

22. 2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)

23.  Female age
 Cycle day 3
FSH &
estradiol
 AMH level
 Vaginal
ultrasound for
antral follicles
Assessment of Ovarian Reserve

24. 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)

25. Treatment Options:
Intrauterine Insemination (IUI)
Picture from Familydoctor.co.uk

26. 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.

27.  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

28. Gonadotropins

29. Polycystic Ovarian
Syndrome (PCOS)

30. 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

31. 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.

32. 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

33. Metformin in PCOS
BeforeBefore AfterAfter
InsulinInsulin
microU/mLmicroU/mL
2626 2222
TestosteroneTestosterone
ng/dLng/dL
6161 4747
Glueck CJ, et al. Metabolism Apr;48(4):511-9, 1999

34. 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

35. 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

36. 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 birth
7.2%7.2% 22.5%22.5% 26.8%26.8%

37. What if all the tests
are normal?
Unexplained Infertility
~10% of couples

38. 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

39. OU Reproductive Medicine IVF
Statistics
( (Delivered per embryo transfer in 2010)
Age group (years)
%PregnantorDelivered
* 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.

40. 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)

41. MDsMDs
LabLab
• Embryology• Embryology
• Andrology• Andrology
• Endocrine• Endocrine
NursingNursing
StaffStaff
Office &Office &
ClinicClinic
StaffStaff
ART Team

42. 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

43. IVF
Luteal Leuprolide Protocol
OCPs
14-28 days
Lupron
24-30 days
Gonadotropins
8-12 days
hCG
Retrieval
Transfer
2
days
3-6
days

44. Monitoring Follicles
IVF Ultrasound


45. Sonographic Egg Recovery

46. Sonographic Egg Recovery

47. Intracytoplasmic sperm
injection—ICSI
 Discovered “by
accident” in 1991
in a Belgian IVF lab
 Successfully treats
almost all forms of
severe male factor
infertility

48. ICSI

49. 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.

50. Embryo Transfer

51. •
Loading Catheter

52. Embryo Transfer

53. Outcomes—
Children

54. Children of ART
Possible Risks
 Multiple pregnancy
 Low birth weight
 Congenital anomalies
 Transmission of parental genetic
abnormalities (e.g., male factor)
 Imprinting defects
 Developmental abnormalities

55. OCTOMOM: Nadya Suleman

56. 2009 Assisted Reproductive Technology Success Rates, National Summary and Fertility Clinic Reports (CDC)

57. Octomom’s Clinic:
West Coast IVF
Clinic, Inc.
In 2007, 19 patients < 35 years old
2 became pregnant
1 delivered
Average # embryos transferred: 4.1

58. 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)

59. A
FE
C D
B
An Atlas of Preimplantation Genetic Diagnosis pg 91

60. 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

61. Trisomy 21 Embryo
Chromosome 21
Chromosome 21
Chromosome 21
An Atlas of Preimplantation Genetic Diagnosis pg

62. 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)

63. 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.

64. 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