Babies Without a Test-TubeBabies Without a Test-Tube

Dan C. Martin, M.D.Dan C. Martin, M.D.

University of Tennessee Health Science CenterUniversity of Tennessee Health Science CenterMemphis, TennesseeMemphis, Tennessee

Babies Without a Test-TubeBabies Without a Test-Tube

www.www.DanMartinMD.com/bmhwbwtt.htmDanMartinMD.com/bmhwbwtt.htm

Learning ObjectivesLearning 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

PatientsPatients

• Irregular Menses

• Dysmenorrhea

• Normal History and Physical

PatientsPatients

• Irregular Menses PCOS

• Dysmenorrhea Endometriosis

• Normal History and Physical

EvaluationEvaluation

• Months– 6 Months– 12 Months– 36 Months

• Available Resources

• Age– 28– 38– 45

DisclosureDisclosure

• None

Off-Label DiscussionOff-Label Discussion

• Clomiphene Citrate

• Oral hypoglycemics

• Estradiol

• Progestins

GoalsGoals

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

EvaluationEvaluation

• History• Physical• General Lab

– Pregnancy Test, Pap Smear, GC and Chlamydia– CBC, TSH, prolactin, rubella, vitamin D*

• Fertility Lab– Semen Analysis– Luteal Progesterone

* Vitamin D deficiency is associated with pre-eclampsia and C-section for small pelvis

EvaluationEvaluation

• 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

GeneralGeneral

• Prenatal Vitamins• Pregnancy test before any medication

– Clomiphene Class X• Includes neural tube defects.

Day 18 to 30 after ovulationUse folic acid up to 5 mg dailyStart 96 hours to 6 months before pregnant

– Femara Class X

AgingAging

Windows of OpportunityWindows of Opportunity

Cervix (Tube) - Sex

Ampulla - Fertilization

Endometrium -Implantation

Windows of OpportunityWindows 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

Windows of OpportunityWindows 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

Estrogenized Cervical Mucus

BasicsBasics

• 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.

BasicsBasics

• Ovary

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

BasicsBasics

• Cervix

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

BasicsBasics

• Peritoneum

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

BasicsBasics

• Tubes

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

BasicsBasics

• Uterus

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

Ovulation Predictor KitsOvulation Predictor Kits

OvulationOvulation

• 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.

OvulationOvulation

• 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.

PatientsPatients

• Irregular Menses

• Dysmenorrhea

• Normal History and Physical

Ovulation DisordersOvulation Disorders

• PCOS

• Hypothyroidism

• Hyperprolactinemia

• Weight Loss / Weight Gain

PCOSPCOS

PCOSPCOS• Diagnosis is more clinical than lab.

– Androgenism (hirsute, acne, central obesity)

– Oligo-anovulatory

– PCOM – polycystic morphology• > 12 follicles at 2 - 9 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

PCOSPCOS

• 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

PCOSPCOS

• 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

Yee 2003

Letrozole and ClomipheneLetrozole and ClomipheneBirth DefectsBirth 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

ClomipheneClomiphene

• Four ovarian responses to clomiphene– Ovulatory response– Anovulatory response– Ovulatory dysfunction– Luteinized unruptured follicle (LUF)

• Ultrasound characteristics of ovulation

Ovulation MonitoringOvulation Monitoring

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

collapse.

Sonographic CollapseSonographic 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

Luteinized Unruptured FollicleLuteinized Unruptured Follicle

• No Collapse

• May respond to 10,000 to 20,000 IU HCG

Clomiphene CitrateClomiphene Citratefor PCOSfor 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

PatientsPatients

• Irregular Menses

• Dysmenorrhea

• Normal History and Physical

EndometriosisEndometriosis

Minimum Maximum

Theoretical 1% 99%

Family Practice 1% 15%

Gyn Practice 30% 72%

Powder Burn?Powder Burn?

1) Infiltrating dark and scarred or

2) Surface vesicles and hemosiderin.

These lesions have different histology and behavior.

TheoriesTheories

• Retrograde Menstruation - Implantation

• Mullerian Tissue Present at Birth

• Coelomic Metaplasia

• Vascular Metastasis

• Lymphatic Metastasis

TheoriesTheoriesImplantation

Nisolle 1997

Nisolle 1997

TheoriesTheories• Retrograde Menstruation

– Pelvis

– Bowel

– Bladder

– Appendix

– Vagina

– Sciatic Nerve

– Diaphragm (Lungs)

Natural ProgressionNatural Progressioni f P r o g r e s s i n gi 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

Histological DiagnosisHistological Diagnosis

Histological DiagnosisHistological Diagnosis

Histological DiagnosisHistological Diagnosis

Fibromuscular Scar

Stroma

Glandular Epithelium Old Blood

Pelvic AdhesionsPelvic Adhesions

• TerminologyNo consistent definitions– Dense or Filmy– Thick or Thin– Opaque or Translucent– Vascular or Avascular.

Normal AnatomyNormal Anatomy

Filmy AdhesionsFilmy Adhesions

Fitz-Hugh Curtis AdhesionsFitz-Hugh Curtis Adhesions

Curtis 1930 and Fitz-Hugh 1934

Dense and Filmy AdhesionsDense and Filmy Adhesions

PatientsPatients

• Irregular Menses

• Dysmenorrhea

• Normal History and Physical

OptionsOptions

• Evaluate and Treat Specific Problems– 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.

Marcoux NEJM 337:217, 1997Marcoux NEJM 337:217, 1997

Marcoux NEJM 337:217, 1997

Pregnancy After LaparoscopyPregnancy 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 198336 Weeks 36 Months

Empirical ClomipheneEmpirical Clomiphene3 Month Fecundability3 Month Fecundability

Monthly6.8% 8.7%1% 3.38%

Empirical ClomipheneEmpirical Clomiphene3 Month Fecundability3 Month Fecundability

• Monthly– 6.8% 8.7%– 1% 3.38%

• Walgreens 3 months for $12– $ 114 to $303 per baby

Babies Without a Test-TubeBabies Without a Test-Tube

www.www.DanMartinMD.com/bmhwbwtt.htmDanMartinMD.com/bmhwbwtt.htm