The document discusses the fetoplacental unit, which refers to the functional relationship between the fetus, placenta, and mother in steroid hormone biosynthesis during pregnancy. The placenta relies on assistance from the mother and fetus to synthesize hormones like estrogens and progesterone. In early pregnancy, the corpus luteum provides these hormones, while later the placenta takes over with support from maternal cholesterol and fetal precursors. Key functions of placental progesterone and estrogens include maintaining pregnancy and promoting fetal growth and development.

1. FETOPLACENTAL UNIT
Presenter : Dr AnuPriya J

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 7th 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 3βHYDROXY 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
3βHYDROXY STEROID
DEHYROGENASE
AROMATASE

25. 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.

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

27. • 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.

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

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

30. ESTRIOL

31. 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

32. 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 17β estradiol & estriol secreted by placenta –
enters maternal compartment
• Most of the estrone – enters fetal compartment

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

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

35. 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 10th week of gestation – Fetal CRH sufficient to
produce corticosteroids.

36. • 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

37. 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

38. 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

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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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

47. • 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

48. • Progesterone production continues after fetal
death - Fetal adrenals not essential for
progesterone production – lacks 3βHSD
Applied aspects

49. 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

50. • 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

51.  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

52. • 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

53. The major estrogen during pregnancy is
• Estrone
• Estradiol
• Estetrol
• Estriol

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

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

56. 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, 24th Edition
Guyton and Hall Textbook of Medical Physiology, 12th
Edition
Best & Taylor's Physiological Basis Of Medical Practice,
13/ E.
Berne & Levy - Physiology, 6th Edition
Boron & Boulpaep - Medical Physiology, 2nd Edition
Internet References

58. 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

60. • 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

61. • 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.19Administration 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

63. (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.

64. • (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.

65. • (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.

66. SYNTHESIS OF PLACENTAL ESTROGENS
- SUMMARY

71. • 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.