1. Female Reproductive Physiology Hope A. Ricciotti, M.D. Associate Professor of Obstetrics, Gynecology and Reproductive Biology Beth Israel Deaconess Medical Center Harvard Medical School

2. At the end of this session you should be able to... Describe hormonal changes of the menstrual cycle. List steps from conception to early pregnancy. Describe major physiologic changes in systems (cardiovascular, renal, hematologic, pulmonary, GI, and breast) during pregnancy. Provide physiologic rationalizations for these changes.

3. Menstrual Cycle

4. ovulation

5. Menstrual Cycle Median duration is 28 days 21-35 days considered normal Luteal phase is constant at 14 days Variability in length of follicular phase

6. 2 key cell types in the ovary: Theca cellsproduce androgens Granulosa cellsproduce estradiol + aromatase

7. Estrogen Production Theca cells produce androgens Granulosa cells produce estradiol + aromatase

8. Fecundity Rate by Age Fecundity Rates by Age 35-39 years30% 27-34 years40% 19-26 years50%

9. If fertilization occurs… Corpus Luteum makes HCG

10. HCG Hormone Composed of 2 subunits – alpha and beta. The alpha subunit is identical to other pituitary hormones – TSH and LH. The beta subunit is more specific.

12. HCG -Pregnancy Testing Produced by the trophoblastic layer shortly after fertilization occurs. Detectable in bloodstream 8 days after conception Detectable in urine 10 days after conception

13. Antibody to HCG plus Color Change Antibody Monoclonal mouse anti-hcg enzyme conjugate Polyclonal anti-hcg antibodies Antimouse antibodies

14. Conception & Implantation

15. Travel to uterus 3 days

16. Blastocyst

17. 3 Days to Implant

18. Major Pregnancy Hormones Estradiol HCG Insulin HPL Progesterone

19. Insulin Anabolic hormone Promotes uptake of glucose by cells A large molecule that does not pass the placenta Pregnancy is a state of relative insulin resistance

20. HPL - Anti-insulin Human placental lactogen Produced by placenta Structure and function similar to growth hormone Modifies metabolic state of pregnancy –creates insulin resistance –results in lypolysis –facilitates glucose transfer to fetus –Glucose passes placenta by diffusion

21. HPL increases as pregnancy progresses

22. Progesterone A smooth muscle relaxant Keeps uterus quiescent until term Has ‘side effects’ all over the body

23. Summary of pregnancy hormones

24. Laboratory results Three hour glucose tolerance test (mg/dl) fasting 110* (105) 1 hr170 (190) 2 hr200* (165) 3 hr130(145) 2/4 abnormal values gives diagnosis of gestational diabetes

25. Treatment Gestational Diabetes Exercise Medical Therapy –Insulin –Oral Agents Peripartum Management –Goal 70-90 mg/dl –Avoid maternal hyperglycemia –Insulin if required

26. HPL Increases as pregnancy progresses

27. Diabetes and Pregnancy If you test positive for diabetes in the first trimester that is actually Type II diabetes 50% of women who have gestational diabetes go on to develop type II diabetes later in life Gestational diabetes is a warning signal that you are at risk and can motivate women to make lifestyle changes

28. Maternal Physiology

29. Cardiovascular Changes in Pregnancy Maternal total body water 6-8 liters Fetus, placenta, amniotic fluid 3.5 liters Total blood volume50% Red cell mass35%

30. Mechanism of Sodium and Water Retention Concentrations of renin and angiotensin are increased in response to vasorelaxation (progesterone effect) Serum level sodium decreases during a normal pregnancy Resetting of the osmotic thresholds for both thirst and antidiuretic hormone release

31. Pregnant women are thirsty Stimulates water intake and dilution of body fluids. Maternal interstitial volume shows its greatest increase in the last trimester.

32. Maternal Blood Volume Plasma volume increases 50% Red cell mass increases 30%-40% Creates a dilutional anemia

33. Increased Heart Rate in Pregnancy Exact mechanism unknown Thought to be a direct effect of hormones on pacemaker in heart Increased 15-20 beats per minute

34. Frank Starling Law and Pregnancy The greater the end diastolic volume, the greater the stroke volume Cardiac Output = SV x HR Cardiac Output increases significantly in pregnancy, reaching a peak at 24 weeks

35. Cardiac Output in Pregnancy

36. Increased Maternal Blood Volume Serves metabolic needs of fetus Increased perfusion of others organs, especially kidneys Compensates for maternal blood loss delivery (vaginal delivery is 500 ml, cesarean delivery about 1000ml)

37. Decreased Peripheral Resistance Progesterone is smooth muscle relaxant Vasorelaxant Results in decreased peripheral resistance/lower blood pressure in pregnancy

38. Summary Cardiovascular Changes in Pregnancy Blood pressure  6-10 mm Hg Heart Rate  12-18 beats/min Stroke volume  10-30% Cardiac Output  33-45%

39. Respiratory Changes in Pregnancy Progesterone levels drive hyperventilation Subjective sense of dyspnea is common Respiratory rate is unchanged Chest wall mechanics are changed

40. Chest Wall Changes Intercostal angle increases from 70 to 100° Transverse diameter of chest increases 2 cm Chest circumference increases by 5-7 cm Lung compliance does not change

41. Respiratory Changes in Pregnancy

42. Pulmonary Function Summary Tidal volume  40% Minute ventilation  40% Respiratory rateunchanged

43. Respiratory System Dyspnea is common even in early pregnancy, before the mechanical effects of an enlarging uterus become significant. Dyspnea during early pregnancy is thought to be a central (“controller”) effect caused by progesterone (which is a respiratory stimulant).

44. Minute Ventilation Formula Volume of air that can be inhaled or exhaled in one minute Tidal Volume x Respiratory Rate (increased)(unchanged) Increased in pregnancy due to TV

45. Arterial Blood Gas Non pregnant normal pHPAO 2 PACO 2 HCO 3 7.40 93-10035-40 23mEq/L Ann’s: pHPAO 2 PACO 2 HCO 3 7.421023218mEq/L

46. A Well Designed System Total oxygen consumption is increased Hyperventilation and respiratory alkalosis Cardiorespiratory responses are so efficient that: –Arteriovenous difference actually DECREASES

47. A-aO2 difference The difference in partial pressure of oxygen between the alveolus and the arterial blood. An abnormally large difference is characteristic of problems with the gas exchanger. In pregnancy, we have the opposite

48. Gastrointestinal Changes Progesterone is a smooth muscle relaxant Decreased GI motility Longer GI transit time Relaxation of the lower esophageal sphincter

49. GI Changes in Pregnancy Constipation Reflux Longer time for gastric emptying

50. Constipation Reduced GI motility due to progesterone Mechanical effect of enlarging uterus on GI motility Prolonged GI transit time, more water absorbed, stool harder Iron supplements compounds issues Most pregnant women are constipated

51. Reflux Relaxation of lower esophageal sphincter Slower stomach emptying time Elevation of stomach by enlarged uterus

52. Renal Physiology

53. Renal Changes in Pregnancy Renal blood flow increases 25%-50% –Increased CO –Decreased vascular resistance Glomerular Filtration Rate increases 50%

54. Pregnancy Changes in Kidney Kidney Size increases Urinary stasis - progesterone Increased susceptibility to infection from stasis

55. Filtration Fraction in Pregnancy Filtration Fraction = GFR/RPF Increased filtration fraction –Increase in GFR > Renal blood flow

56. Substance Excreted in Urine Determined by the equation: (filtered) – (reabsorbed) + (secreted)

57. Pregnant Urinalysis Glycosuria may not be abnormal Trace proteinuria may not be abnormal Explained by increased GFR with overwhelming of tubular reabsorption capacity

58. Sodium Balance Pregnancy

59. Renin-Angiotensin-Aldosterone Pregnancy Decreased resistance/BP in pregnancy stimulate this system Net retention of sodium and water in pregnancy

60. You note that you have developed cankles!

61. Female Reproductive Physiology