1. Babies Without a Test-Tube Dan C. Martin, M. D
Babies Without a Test-Tube Dan C. Martin, M.D University of Tennessee Health Science Center Memphis, Tennessee

2. Babies Without a Test-Tube www.DanMartinMD.com/bmhwbwtt.htm

3. Learning Objectives
Following the presentation “Babies With Test Tube” participants should be able to:
Understand initial infertility evaluation.
Clarify evaluation and therapy with:
Normal History and Physical
Irregular Menses
Dysmenorrhea

6. Patients
Irregular Menses
Dysmenorrhea
Normal History and Physical

7. Patients Irregular Menses  PCOS Dysmenorrhea  Endometriosis
Normal History and Physical

8. Evaluation Months Age 6 Months 12 Months 36 Months Available Resources28 38 45

9. Disclosure
None

10. Off-Label Discussion Clomiphene Citrate Oral hypoglycemics Estradiol
Progestins
Depo-SubQ Provera 104TM
Depo-subQ provera 104 received FDA approval for use as a contraceptive in December Injected every three months, depo-subQ provera 104 provides better efficacy than the original DEPO-PROVERA Contraceptive Injection, but with 30 percent less hormone. Women who use depo-subQ provera 104 may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of depo-subQ provera 104 during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk of osteoporotic fracture in later life. Depo-subQ provera 104 should be used as a long-term birth control method (e.g., longer than two years) only if other birth control methods are inadequate. In the clinical trials, the most common side effect was irregular menstrual bleeding, typically followed by amenorrhea (loss of monthly menstrual period). The average weight gain after one year of use was 3.5 pounds. Depo-subQ provera 104 does not protect against sexually transmitted diseases, including HIV (AIDS). Depo-subQ provera 104 is contraindicated in patients with known or suspected pregnancy or with undiagnosed vaginal bleeding, known or suspected breast malignancy, current or past thromboembolic or cerebral vascular disorders, or significant liver disease. Depo-subQ provera 104 may be considered among the possible risk factors for the development of osteoporosis. The risk of osteoporosis should be assessed for women with multiple risk factors. Depo-subQ provera 104 does not require dosing adjustments based on body type, body mass index or weight.

11. Goals One healthy baby Twins can be a major complication.
Triplets are often a major complication.

12. Evaluation History Physical General Lab Fertility Lab
Pregnancy Test, Pap Smear, GC and Chlamydia
CBC, TSH, prolactin, rubella, vitamin D*
Fertility Lab
Semen Analysis
Luteal Progesterone
Vitamin D deficiency –
Lisa M. Bodnar, et al. Vitamin D deficiency early in pregnancy is associated with a five-fold increased risk of preeclampsia. Journal of Clinical Endocrinology and Metabolism. The Journal of Clinical Endocrinology & Metabolism Vol. 92, No , 2007
Anne Merewood - The term rachitic pelvis has fallen into disuse, but an association has been noted between cesarean birth and a narrow pelvis.  Journal of Clinical Endocrinology & Metabolism Vol. 94, No
* Vitamin D deficiency is associated with pre-eclampsia and C-section for small pelvis

13. Evaluation Day 3 FSH and E2 if age ≥38 (≥35)
HIV, RPR, fasting glucose, Type and Rh, free testosterone, testosterone, DHEAS, 17 OHP (follicular)
Sonogram
Sonohysterogram
Hysterosalpingogram (HSG)
Hysteroscopy
Diagnostic Laparoscopy

14. General Prenatal Vitamins Pregnancy test before any medication
Clomiphene Class X
Includes neural tube defects. Day 18 to 30 after ovulation Use folic acid up to 5 mg daily Start 96 hours to 6 months before pregnant
Femara Class X

15. Aging

16. Windows of Opportunity
Endometrium -Implantation
Ampulla - Fertilization
Cervical sperm survival – 2 to 8 days
Tubal sperm survival – 2 to 8 days?
Ampullary fertilization of egg – 6 to 7 hours
Implantation in endometrium – 6 to 7 days after LH surge
Cervix (Tube) - Sex

17. Windows of Opportunity
Cervical sperm survival – 2 to 8 days
Tubal sperm survival – 2 to 8 days?
Ampullary fertilization of egg – 6 to 7 hours
Implantation in endometrium – 6 to 7 days after LH surge
Cervical sperm survival – 2 to 8 days
Tubal sperm survival – 2 to 8 days?
Ampullary fertilization of egg – 6 to 7 hours
Implantation in endometrium – 6 to 7 days after LH surge

18. Windows of Opportunity
Cervix – 2 to 8 days Tubal Sperm also?
Ampullary Egg – 6 to 7 hours
Implantation – 6 to 7 days
Estrogenized Tubal Environment
Egg Release
Estrogen proliferation and
Progestin maturation of
Endometrium
Cervical sperm survival – 2 to 8 days
Tubal sperm survival – 2 to 8 days?
Ampullary fertilization of egg – 6 to 7 hours
Implantation in endometrium – 6 to 7 days after LH surge
Estrogenized Cervical Mucus

19. Basics
Sperm
An adequate number of spermatozoa must be deposited at or near the cervix at or near the time of ovulation, ascend into the fallopian tubes, and fertilize an ovum.

20. Basics
Ovary
A mature ovum must be released from the ovaries, ideally on a regular, predictable, cyclic basis.

21. Basics
Cervix
The cervix must capture, nurture, and release spermatozoa into the uterus that then travel into the fallopian tubes.

22. Basics
Peritoneum
The fallopian tubes must have a functional anatomic relationship with the adjacent ovaries to facilitate travel and capture.

23. Basics
Tubes
The fallopian tubes must be patent and also capable of timely transport of an embryo to the uterine cavity.

24. Basics
Uterus
The uterus must be receptive to embryo implantation and capable of supporting subsequent normal growth and development.

25. Ovulation Predictor Kits

26. Ovulation
An LH (luteinizing hormone) surge begins 24 to 36 hours prior to ovulation and peaks 12 to 24 hours before ovulation.
Follicular rupture = It is the ovary’s job to make a cyst and rupture it.
Progesterone is increasingly produced after the LH surge
Secretory changes occur in the endometrium due to progesterone.

27. Ovulation Pregnancy is absolute proof of ovulation.
Serum progesterones are 99%+
8 days after a positive ovulation test
7 days after ovulation on a monitor
Day 21 and 24 if ovulation day is uncertain.

28. Patients
Irregular Menses
Dysmenorrhea
Normal History and Physical

29. Ovulation Disorders PCOS Hypothyroidism Hyperprolactinemia
Weight Loss / Weight Gain

30. PCOS

31. PCOS Diagnosis is more clinical than lab.
Androgenism (hirsute, acne, central obesity)
Oligo-anovulatory
PCOM – polycystic morphology
> 12 follicles at mm in at least 1 ovary
Volume > 10cc
Does not apply if on BCPs
If a follicle is >10mm, repeat scan next cycle
Elevated androgens
Androgens decrease with age
Decreased HDL and SHBG

32. PCOS Treatment Weight loss and exercise
Clomid (clomiphene citrate) (3 months)
Femara (aromatase inhibitor) (3 months)
Metformin (6 months)
Note that the combination of Metformin and Clomid are more productive at months 4-6 compared with months 1-3 .
Gonadotropins

33. PCOS Weight loss Poor results if BMI > 50
Requires a dedicated program of diet and exercise
Use dieticians who work with diabetics
Liposuction of cutaneous fat is not the same as loss of visceral weight

34. Yee 2003

35. Letrozole and Clomiphene Birth Defects
There is no increase in birth defects for letrozole or clomiphene if used when not pregnant.
Letrozole associated with fewer birth defects than clomiphene but this is not statistically significant.
Tulandi T. Fertil Steril 85:1761, 2006

36. Clomiphene Four ovarian responses to clomiphene
Ovulatory response
Anovulatory response
Ovulatory dysfunction
Luteinized unruptured follicle (LUF)
Ultrasound characteristics of ovulation

37. Ovulation Monitoring Basal body temperature charting (BBTC)
Mid luteal phase serum progesterone
Urine LH hormone detection (ovulation kits)
Serial ultrasounds for follicular growth and collapse.

38. Sonographic Collapse
Collapse at 24 mm maximum or 21 mm mean with no stimulation – 2 to 3 mm larger with clomiphene
Scan 1 to 2 days after collapse

39. Luteinized Unruptured Follicle
No Collapse
May respond to 10,000 to 20,000 IU HCG

40. Clomiphene Citrate for PCOS
Ovulatory rate - 80%
Pregnancy rate - 40%
Multiple rate
Twins - 5%
Triplets - < 1%
80% of pregnancies occur in 4 cycles
85% at 3 months if IUI

41. Patients
Irregular Menses
Dysmenorrhea
Normal History and Physical

42. Endometriosis Minimum Maximum Theoretical 1% 99%
Family Practice 1% 15%
Gyn Practice 30% 72%
Adapted from:
Minimum Maximum
Theoretical ? 99%
Family Practice 1% 15%
Gyn Practice 30% 72%
Infiltrating in Gyn 5% 25%
Bowel in Gyn* 0.5% 12%
Vaginal in Gyn* 0.17% 4%
Deep Vaginal in Gyn* % 0.04%
* Increased chance of colostomy if surgery
D’Hooghe et al. Hum Reprod is on repetitive cycles in monkeys in Kenya
25% Recurrent observations with no endometriosis
51% Single observation with no endometriosis
87% Single observation with 13 of 15 with stage I
100% with stage II, III and IV
Liu DTY and Hitchcock A. Br J Ob Gyn 93:859, These are single observations in humans
76% with no endo
97% with endo
Martin DC. Recurrent or Persistent Endometriosis. In Lemay, A; R Maheux (Editors) Advances in Research and Practice, New York: The Parthenon Publishing Group, pp
Evers, J.L.H Endometriosis does not exist; all women have endometriosis. Hum. Reprod. 9:
Brosens, I.A Is mild endometriosis a progressive disease? Hum. Reprod. 9:

43. Powder Burn? 1) Infiltrating dark and scarred or
Surface vesicles and hemosiderin.
Infiltrating dark and scarred.
The lesions have differing histology and behavior.
Other possibilities?
1) Infiltrating dark and scarred or
2) Surface vesicles and hemosiderin.
These lesions have different histology and behavior.

44. Theories Retrograde Menstruation - Implantation
Mullerian Tissue Present at Birth
Coelomic Metaplasia
Vascular Metastasis
Lymphatic Metastasis

45. Theories
Implantation
Nisolle 1997
Nisolle1997
Nisolle 1997

46. Theories Retrograde Menstruation Pelvis Bowel Bladder Appendix Vagina
Sciatic Nerve
Diaphragm (Lungs)
Pre-existing or acquired diaphragmatic defects and endometrial implants.
Annabelle C Leong, Aman S Coonar, Loïc Lang-Lazdunski
Catamenial pneumothorax: surgical repair of the diaphragm and hormone treatment.
Ann R Coll Surg Engl (6):547-9

47. Natural Progression i f P r o g r e s s i n g
Implantation
Clear Blisters
Red Polypoid Blisters
Scarring and Blood Trapping
Collection of Old Blood
More Scar
Deep Infiltration
From Time Related Observation Data

48. Histological Diagnosis
400 / 200 μm circled

49. Histological Diagnosis

50. Histological Diagnosis
Glandular Epithelium 
Old Blood 
Stroma 
Fibromuscular Scar 

51. Pelvic Adhesions Terminology No consistent definitions Dense or Filmy
Thick or Thin
Opaque or Translucent
Vascular or Avascular.

52. Normal Anatomy

53. Filmy Adhesions

54. Fitz-Hugh Curtis Adhesions
Curtis 1930 and Fitz-Hugh 1934

55. Dense and Filmy Adhesions

56. Patients
Irregular Menses
Dysmenorrhea
Normal History and Physical

57. Options Evaluate and Treat Specific Problems Clomiphene IUI
PCO
Prolactinemia, etc
Clomiphene
IUI
Clomiphene IUI
Empirical Trials
hMG IUI
Assisted Reproductive Technologies These are not today’s subject since few of my patients can afford them.

58. Marcoux NEJM 337:217, 1997
Marcoux NEJM 337:217, 1997

59. Pregnancy After Laparoscopy
Comparative cumulative pregnancy curves using the two-parameter exponential model for stage I and II endometriosis patients with no other infertility factors.
Olive Fertil Steril 1987
Guzick Fertil Steril 1983
36 Weeks
36 Months

60. Empirical Clomiphene 3 Month Fecundability
Monthly
6.8%  8.7%
1%  3.38%

61. Empirical Clomiphene 3 Month Fecundability
Monthly
6.8%  8.7%
1%  3.38%
Walgreens 3 months for $12
$ 114 to $303 per baby

62. Babies Without a Test-Tube www.DanMartinMD.com/bmhwbwtt.htm