Fetoplacental unit

1. FETOPLACENTAL UNIT Presenter : Dr AnuPriya J Moderator : Dr Ambarish V

2. Scheme Introduction History Corpus luteum Luteal-placental shift Fetoplacental unit - Synthesis of hormones - Plasma levels - Metabolites - Functions of the hormones Applied aspects

3. The placenta - major source of estrogens and progesterone during pregnancy - cannot synthesize these hormones by itself - requires the assistance of both mother and fetus. Introduction

4. Introduction The fetus, placenta, and mother are interdependent - functional unit – joint effort in steroid biosynthesis – lead to the concept of feto - placento -maternal unit or simply, the fetoplacental unit.

5. Steroid hormones- Estriol 17 β Estradiol Estrone Progesterone and Pregnenolone. Introduction

6. HISTORY The concept of the functional “maternal-placental- fetal unit” or “complex” ( Diczfalusy , 1964). These hormonal relationships are important in terms of fetal growth and development ( Evseenko et al., 2007; Kingdom et al., 2000), the regulation of maternal blood volume in pregnancy (Longo, 1983) The role of the fetal -placental unit as a factor in the initiation of labor ( Beshay et al., 2007; Challis et al., 2001; 2005)

7. ESTROGEN AND PROGESTERONE IN A NON-CONCEPTION CYCLE

8. CORPUS LUTEUM Following ovulation during a normal or nonconception cycle - the cells of the ovarian follicle functionally transform into luteal cells Progesterone(mainly) & estrogens.

9. CORPUS LUTEUM Life span - lasts only ≈ 12 days – then - begins its demise in the presence of declining LH levels. Luteal demise - levels of both progesterone and estrogens decline

10. ESTROGEN AND PROGESTERONE DURING PREGNANCY

11. During pregnancy - maternal levels of progesterone and estrogens( estradiols , estrone , estriol ) increase - reach concentrations substantially higher than those achieved during a normal menstrual cycle.

12. HOW ARE THESE ELEVATED LEVELS ACHIEVED?

13. EARLY IN THE FIRST TRIMESTER

14. Corpus luteum of pregnancy Early in the first trimester ( upto 7 wks after conception ) - hCG that is manufactured by the syncytiotrophoblast rescues the corpus luteum – source of estrogen and progesterone - until fetoplacental unit is able to synthesize its own estrogen and progesterone.

15. hCG - also known as second luteotropic hormone. Actions - similar to LH of anterior pituitary. Maintains functions of corpus luteum upto 7 weeks after conception Corpus luteum of pregnancy

16. hCG converts corpus luteum of menstruation into corpus luteum of pregnancy - stimulates it to secrete 17 alpha hydroxy progesterone and lesser amount of progesterone . ROLE OF hCG

17. AFTER 8 WKS OF GESTATION

18. LUTEAL-PLACENTAL SHIFT

19. Study by Caspo et al – to find the timing of luteal-placental shift - luteectomy before, but not after, the 7 th week of gestation – usually resulted in subsequent abortion LUTEAL-PLACENTAL SHIFT

20. After 8 wks of gestation coordinated biosynthetic activity of the maternal-placental- fetal unit maintains high levels of progesterone and estrogens.

21. Corpus luteum – manufactures the hormones – without assistance from fetus or placenta . The placenta is an imperfect endocrine organ - shortcomings overcome by the fetoplacental unit - shuttling of many of the hormonal substrates.

22. Placenta - does not express SF-1 ( Steroidogenic Factor-1) – a transcription factor – important regulator of genes involved in adrenal & gonadal steroidogenesis . Trophoblasts – reduced levels / lack of certain enzymes

23. NEEDS CONTRIBUTES LACKS MOTHER PROGESTERONE ESTRONE ESTRADIOL ESTRIOL LDL CHOLESTEROL ADEQUATE SYNTHETIC CAPACITY FOR PROGESTERONE & ESTROGENS PLACENTA 3 β HYDROXY STEROID DEHYROGENASE AROMATASE ADEQUATE CHOLESTEROL SYNTHESIZING CAPACITY 17 α HYDROXYLASE 17,20 DESMOLASE 16 α HYDROXYLASE FETUS 17 α HYDROXYLASE 17,20 DESMOLASE 16 α HYDROXYLASE 3 β HYDROXY STEROID DEHYROGENASE AROMATASE

24. Cholesterol uptake by trophoblasts The trophoblast can synthesize cholesterol from acetate - but the amount of hydroxy -methyl- glutaryl -coenzyme A is low in placental microsomes . LDL & VLDL from maternal circulation – receptors in syncytiotrophoblast. Receptor mediated uptake – stimulated by estrogen.

25. PROGESTERONE MOTHER PLACENTA FETUS ACETATE ↓ CHOLESTEROL PROGESTERONE CHOLESTEROL ↓ CYP11A1 PREGNENOLONE ↓ 3 β HSD PROGESTERONE CORTISOL → DHEAS & 16-OH-DHEAS CYP11A1 – CHOLESTEROL SIDE CHAIN CLEAVAGE / DESMOLASE ENZYME 3BHSD – 3 β HYDROXY STEROID DEHYDROGENASE

26. Placenta lacks StAR ( Steroidogenic Acute Regulatory protein) – mediates cholesterol transport from outer to inner mitochondrial membrane – the site where CYP11A1 acts in other sites of steroidogenesis . Therefore, there must be another mitochondrial transport mechanism present in the placenta Pregnancies with StAR mutations – no alterations in placental steroidogenesis .

27. FORMATION OF DHEAS MOTHER PREGNENOLONE FETUS PREGNENOLONE SULFATE 17 HYDROXY-PREGNENOLONE SULFATE DEHYDROXYEPIANDROSTERONE SULFATE 17 α HYDROXYLASE 17,20 DESMOLASE FETAL STEROID SULFOTRANSFERASE

28. ESTRONE & ESTRADIOL 60% 40% E1 – Estrone E2 - Estradiol

29. ESTRIOL

30. ESTRIOL Major estrogen formed in pregnancy Increase to 12-20 ng /ml by term Low affinity for sex hormone binding globulin – cleared more rapidly – therefore, circulating level of estradiol > estriol . Placental estrogens

31. Placental estrogens During pregnancy – a woman produces more estrogen than a normal ovulatory woman produce in more than 150 yrs.( Tulchinsky & Hobel 1973) 90% of 17 β estradiol & estriol secreted by placenta – enters maternal compartment Most of the estrone – enters fetal compartment

32. ESTETROL An estrogen unique to pregnancy 15 α hydroxy derivative of estriol Synthesized in the fetal liver Placental estrogens

33. Maternal environment is protected from testosterone produced by male fetus – placental aromatase enzyme – converts testosterone to estradiol . Placental estrogens

34. Fetal cortisol Fetal adrenal cortex – placental progesterone ---- hydroxylated at C-17, C-21 & C-11 positions – form aldosterone , cortisone & cortisol respectively. Upto 10 weeks of gestation – Placental CRH needed After 10 th week of gestation – Fetal CRH sufficient to produce corticosteroids.

35. Prior to term , there is an effective negative feedback mechanism by which cortisol inhibits fetal ACTH secretion. Estrogen selectively suppresses fetal zone growth during second half of pregnancy. At term , human placental estrogen leads to positive feedback cycle with progressive increase in fetal HPA activity resulting in increase in ACTH and cortisol . Fetal cortisol

36. Plasma levels Progesterone Non-conception cycle Follicular phase ≈ 2.5 mg/day Luteal phase ≈ 25 mg/day By the end of pregnancy Production ≈ 250 mg/day Circulating level ≈ 130 ng /ml

37. ESTROGENS Estriol – first detectable at 9 weeks (0.05 ng /ml) – increases gradually to about 30 ng /ml at term. Secretory curve parallels that of progesterone Maximum plateau – 30 to 40 weeks of gestation At term – oestrogen:progesterone ratio increases. Plasma levels

38. Metabolites Progesterone – pregnanenediol – glucuronised and secreted by kidneys – urine Estrogen – glucuronised and sulfated – urine Catecholestrogens

39. CATECHOLESTROGENS Hydroxylation at the C2 position of the phenolic A ring 2-hydroxy-estrone, 2-hydroxy estradiol , 2-hydroxy-estriol Major product of estrogen metabolism during pregnancy Act as antiestrogens – competes with estrogen for their receptors Metabolites

40. Placental Progesterone Functions Helps to preserve the pregnancy by promoting growth of the endometrium Converts secretory endometrium of luteal phase of menstrual cycle to decidua during pregnancy Marked inhibitory effect on uterine contractions – by acting on uterine smooth muscle - maintains quiescence Development of alveolar system of breast

41. Functions Inhibits uterine prostaglandin production - promotes uterine quiescence & delays cervical ripening. Antagonizes the effect of aldosterone – promotes renal excretion of sodium during pregnancy Precursor for corticosteroid synthesis by the fetal adrenal cortex – therefore helps in growth and development of fetus Inhibits lactation during pregnancy Placental Progesterone

42. Functions Immunosuppressive activity Contributes to the immunologically privileged status of the pregnant uterus – by inhibiting T lymphocyte mediated processes that play a role in tissue rejection. Placental Progesterone

43. Placental Estrogen Functions Enlargement of the uterus, breasts and female external genitalia. Relaxes various pelvic ligaments and makes the pelvis more capacious Development of lactiferous ductal system of breast Stimulates prolactin secretion Production of hormone binding globulins in liver Enhance receptor mediated uptake of LDL

44. Functions Stimulates cell proliferation of fetal tissue Fetal development & organ maturation Helps in increasing fetal lung surfactant production Stimulates Leydig cells of male fetus to produce testosterone ( initial stimulus is by hCG) Increases uteroplacental blood flow – ensures adequate supply of oxygen & nutrients to the fetus. Placental Estrogen

45. Functions Increase in oestrogen:progesterone ratio – progression of the stages of labour Due to the stimulatory effects of estrogen on: Phospholipid synthesis & turnover Prostaglandin production Increases formation of lysosomes in the uterine endometrium Stimulates synthesis of gap junctions between myometrial smooth muscle cells Placental Estrogen

46. Plasma 17 α hydroxy progesterone level - excellent indicator of the activity of corpus luteum of pregnancy . Peak level - 3 to 4 wks after conception. Decrease in 17 α hydroxy progesterone & the dip in progesterone levels – 8 to 10 weeks of gestation – reflect luteal-placental shift Progesterone supplementation required if corpus luteum function is compromised before 9-10 weeks of gestation. Applied aspects

47. Progesterone production continues after fetal death - Fetal adrenals not essential for progesterone production – lacks 3 β HSD Applied aspects

48. Applied aspects Conditions – low estrogen production Genetic disorders - fetal & placental sulfatase deficiencies - fetal & placental aromatase deficiencies Absence of fetal signals from the fetal hypothalamic pituitary adrenal axis – no stimulus for fetal androgen production Absence of a fetus – molar pregnancy, pseudocyesis Fetal demise Anencephaly

49. Placental estrogen synthesis – not essential for maintenance of pregnancy - pregnancy proceeds to term . Changes in the reproductive tract that precede the stages of labour do not occur. Applied aspects

50. Urinary estriol Index of function of fetoplacental unit Use is limited now because of various factors that affect estriol levels: Moment to moment fluctuations – single time plasma measurement is not very conclusive. Body position (bed rest, ambulation) affects blood flow to uterus & kidney. Drugs like glucocorticoids & penicillin. Applied aspects

51. Aromatase deficiency – fetus and mother are virilized – due to diminished aromatization of androgens. Oocyte recipients who have no ovarian function - exogenous progesterone needed only in the first trimester Applied aspects

52. The major estrogen during pregnancy is Estrone Estradiol Estetrol Estriol

53. Major source of estrogen & progesterone during the first 7 weeks of pregnancy Corpus luteum of pregnancy Endometrium Fetoplacental unit Fetal tissue

54. The second luteotropic hormone is Human chorionic gonadotropin Luteinising hormone Human chorionic somatomammotropin Prolactin

55. References Robert K.Creasy , Robert Resnik , Jay D.Iams – Maternal-Fetal medicine - Principles & practice Williams Textbook of Endocrinology, 11th Edition Ganong's Review of Medical Physiology, 24 th Edition Guyton and Hall Textbook of Medical Physiology, 12 th Edition Best & Taylor's Physiological Basis Of Medical Practice, 13/ E. Berne & Levy - Physiology, 6 th Edition Boron & Boulpaep - Medical Physiology, 2 nd Edition Internet References

56. THANK YOU

57. CORTISOL ---CONTINUED PLACENTAL CRH ALSO PLAYS A ROLE ROLE OF FETAL/MATERNAL STRESS IN PREGNANCY BEFORE TERM – COTISOL BINDING GLOBULIN – BINDS WT IT N PREV ITS ACTN LATER – DEC IN CORTISOL BINDING GLOBULIN – CORTISOL FREE TO ACT CRH BINDING PROTEIN – WILLIAMS ENDOCRINOLOGY

58. The progesterone antagonist  mifepristone  - terminate pregnancy because it blocks progesterone action and causes the uterus to contract.  Supplemental progesterone - prevent preterm birth in women who have a history of preterm labor . Applied aspects

59. The addition of mifepristone to the misoprostol regimen for induction increases effectiveness and decreases induction-to-abortion time. Mifepristone is a synthetic steroid that competitively binds to progesterone receptors, and also appears to increase myometrial sensitivity to misoprostol. 19 Administration of mifepristone 24 to 48 hours before misoprostol decreases mean induction times by up to 45%, and it has been suggested that use of adjunctive mifepristone could make induction a day procedure. Applied aspects

60. (1) The placenta cannot synthesize cholesterol from acetate. However, both mother and fetus can do so and the cholesterol so formed diffuses into the placenta, which possesses the enzymes needed to convert cholesterol to progesterone via pregnenolone . The progesterone formed in the placenta diffuses back into the maternal circulation and exerts its physiological actions. Placental progesterone also diffuses into the fetus where it is converted to corticosteroids.

61. (2) The enzyme 17, 20 lyase is essential for the synthesis of DHEA ( dehydroepiandrosterone ), which is the precursor to all estrogens. 17, 20 lyase is absent in the placenta. Hence, for estrogen synthesis, the placenta obtains DHEAS from the maternal and fetal circulation. DHEAS ( dehydroepiandrosterone sulfate ) is deconjugated to DHEA in the placenta before it is converted to estrone and estradiol .

62. (3) Estriol, the major circulating hormone in pregnancy is synthesized from 16-OH-DHEAS. The conversion requires mainly two enzymes: 16a hydroxylase and aromatase . However, 16a- hydroxylase is absent in the placenta. The placenta therefore takes up 16 OH-DHEAS from maternal and fetal circulation, deconjugates it into 16 OH-DHEA and converts it into estriol . Fetal 16 OH-DHEA is the major source of placental estriol and therefore, the urinary excretion of estriol in mother is an index of the health of the fetus.

63. SYNTHESIS OF PLACENTAL ESTROGENS - SUMMARY

64. Parturition Parturition  is the delivery of the infant followed by delivery of the placenta. Estrogen is the most important hormone in preparation for parturition. Estrogen stimulates proliferation in the myometrium , accomplishing the considerable growth that is necessary for the forceful contractions of labor . Importantly, as the time for parturition nears, estrogen stimulates the synthesis of  gap junctions  between myometrial smooth muscle cells. Gap junctions allow electrical activity to travel between cells, so that coordinated contractions can occur. Near term, estrogen stimulates the synthesis of enzymes involved in  prostaglandin  synthesis. Before labor , prostaglandins stimulate  cervical ripening , the breakdown of cervical connective tissue allowing it to become soft and flexible and capable of dilation. During labor , prostaglandins stimulate myometrial contractions. The posterior pituitary hormone  oxytocin  is the strongest stimulator of uterine contractions. As the time of delivery approaches, estrogen increases responsiveness to oxytocin by increasing expression of oxytocin receptors.