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

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

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

Patients Irregular Menses Dysmenorrhea Normal History and Physical

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

Evaluation Months Age 6 Months 12 Months 36 Months Available Resources 28 38 45

Disclosure None

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 2004. 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.

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

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. 9 3517-3522, 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. 3 940-945 2009 * Vitamin D deficiency is associated with pre-eclampsia and C-section for small pelvis

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

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

Aging

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

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

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

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.

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

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

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

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

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

Ovulation Predictor Kits

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.

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.

Patients Irregular Menses Dysmenorrhea Normal History and Physical

Ovulation Disorders PCOS Hypothyroidism Hyperprolactinemia Weight Loss / Weight Gain

PCOS

PCOS 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

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

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

Yee 2003

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

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

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.

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

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

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

Patients Irregular Menses Dysmenorrhea Normal History and Physical

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* 0.00015% 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, 1986. 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, 1999. pp 233-239. Evers, J.L.H. 1994. Endometriosis does not exist; all women have endometriosis. Hum. Reprod. 9: 2206-2209. Brosens, I.A. 1994. Is mild endometriosis a progressive disease? Hum. Reprod. 9: 2209-2211.

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.

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

Theories Implantation Nisolle 1997 Nisolle1997 Nisolle 1997

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. 2006 88 (6):547-9

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

Histological Diagnosis 400 / 200 μm circled

Histological Diagnosis

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

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

Normal Anatomy

Filmy Adhesions

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

Dense and Filmy Adhesions

Patients Irregular Menses Dysmenorrhea Normal History and Physical

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.

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

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

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

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

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