human chorionic gonadotropin (HCG) must appear by postovulatory day 10 to rescue corpus luteum
in non fertilized state, the CL degenerates on day 14
similarities of LH and HCG
: both are glycoproteins, same a and b chains and dimeric structure, both bind same receptor, only intact hormone binds receptor, both promote progesterone secretion
unique qualities of HCG
: 30 additional C-terminal amino acids on b chain; HCG has 10-20x more polysaccharide side chains, Ý half life (T1/2 for HCG = 32 hours, T1/2 for LH = 2 hours, enhanced receptor binding and activation); only HCG can rescue LH
HCG Synthesis
Þ syncytiotrophoblast
identifiable in preimplantation embryo, first detectable in serum 1-2 days after implantation (~ 8th ovulatory day)
Corpus luteum products
25 mg progesterone/day
0.5 mg estradiol/day
Relaxin a 6 kD heterooligomer protein hormone; found only in corpus luteum of pregnancy and in placenta; secretion stimulated by HCG; causes
ß myometrial activity (progesterone has same effect on myometrium) and increased flexibility of the pubic symphysis
Progesterone and Transition to Placenta
Progesterone Synthesis
corpus luteum required up to 7th postmenstrual week
rate-limiting step in corpus luteum progesterone production is availability of LDL cholesterol
transition to placenta occurs during 7-10 wk; serum progesterone levels surge at 10-11 wks as placental output increases; placenta progesterone secretion continues regardless of fetal health Þ up to 250 mg/d at term
Actions of Progesterone
ß
myometrial contractility (synergistic with relaxin)
inhibits T-lymphocyte mediated tissue rejection helps to maintain immunologic privilege of fetus
inhibits 3-
b hydroxysteroid dehydrogenase (3-b HSD) in fetal adrenals
serves as
d 4 steroid precursor for fetal synthesis of glucocorticoids, mineralcorticoids, and androgens
Synthesis and Roles of Estrogens of Pregnancy
Fetal production of estrogen requires integration of the fetus, placenta and mother
Placenta limitations: placenta lacks 17 hydroxylase and 17-20 desmolase and therefore cannot produce estrogen from progesterone and requires androgens (19-carbon steroids) from another source
also lacks 16-hydroxylase necessary to make estriol
Fetal limitations: fetus lacks 3-b hydroxysteroid dehydrogenase (3-b HSD) and therefore cannot convert pregnenolone to progesterone
fetal adrenal gland contains large fetal cortex that accounts for bulk of the gland (involutes after birth)
placenta and fetus produce pregnenolone from LDL cholesterol; fetal adrenal gland produces 17a OH pregnenolone
due to lack of 3-b HSD, fetal adrenal glands then produce dehydroepiandrosterone (DHEA) produce 90% of DHEA used for estriol synthesis
fetal adrenal rapidly sulfates DHEA Þ DHEAS; this is initiated by HCG and maintained by fetal ACTH (>20 wks)
fetal liver 16 hydroxylates DHEAS Þ 16a OH-DHEAS
16a OH-DHEAS is then transported back to the placenta where the sulfate group is removed Þ 16a OH-DHEA
16a OH-DHEA is aromatized to form estriol in the placenta which is released into the mothers circulation
estriol accounts for 90% of estrogens produced during pregnancy: levels 1000x higher than non-pregnant placental sulfatase deficiency yields low-estriol pregnancies Þ often undergo spontaneous labor
Ý
DHEAS in amniotic fluid and cord blood, sulfatase located on short arm of X csome Þ X linked inheritance
ß
sulfatase also causes icthosis
Biologic Roles of Estrogen
Ý uterine blood flow Þ may be principle action during pregnancy; role in parturition mechanism not clear; prepares breast for lactation
Protein Hormones of the Placenta
HCG secretion
by syncytiotrophoblasts with peak levels at 60-90 days post conception, then drop to lower static level for remainder of pregnancy
wide variation in HCG among individuals at gestation, but a consistent rise in levels seen in 1st trimester; Ý of 66% every 48 hrs with slower rise suggesting incipient spontaneous abortion or ectopic pregnancy
HCG Actions
rescues corpus luteum (CL); stimulates production of LDL-cholesterol binding sites; stimulates conversion of maternal LDL to progesterone in placenta; stimulates placental aromatization of fetal androgens; initiates fetal endocrine development and hormone production
Ý
fetal gonadal testosterone secretion, stimulates development of "fetal zone" of fetal adrenal; stimulates fetal adrenal production of DHEAS
HCG acts in lieu of slow maturing fetal hypothalamic-pituitary axis for first 14 20 wks
pituitary cells differentiated by 8-10 wks; basal secretion of pituitary hormones by 14 wks; organization of hypothalamus by 14-20 wks and intact and functioning hypothalamus by 19-20 wks.
Other Placental Peptides
which may have similar effects on fetus and mother:
human chorionic thyrotropin, human chorionic corticotropin, b -endorphin (Ý levels during delivery), GnRH (part of placental feedback system, somatostatin
Human Placental Lactogen
(HPL) a.k.a. human chorionic somatomammotropin (HCS)
Characteristics
: single chain polypeptide hormone, T1/2 12 min., 96% structural homology with growth hormone (GH), but only 3% of its growth-stimulating ability
Lactogenic activity 50% of prolactin, similar to GH
Secretion
: secreted by syncytiotrophoblast, amount secreted in proportion to placenta size
: maintains maternal metabolism in favor of fetal nutrition; Ý during prolonged fasting and during insulin-induced hypoglycemia, causes maternal release of free fatty acids during fasting; diabetogenic potential
Maternal Changes During Pregnancy
Maternal Pituitary Changes during Pregnancy
:
prolactin Ý gradually throughout pregnancy
hypertrophy and hyperplasia of lactotrophs cause an Ý in gross pituitary size
Ý
nighttime secretion; pre-pregnancy 5-20 ng/ml; up to 200 ng/ml at term
postpartum
Þ baseline levels remain elevated for 2-3 mos., hormone surges with suckling
LH and FSH rapidly
ß
ß
sensitivity of ACTH to negative feedback of cortisol leads to Ý free cortisol
Maternal Breast Changes during Pregnancy
three phases:
(1) Mammogenesis
steroid hormones of pregnancy act with maternal prolactin and other maternal hormones to develop the ducts and alveolar systems of the breast; mature lobulalveolar system includes well developed glands encased in layers of myoepithelial cells and capillaries
prolactin is the most important hormone; cortisol is less important: required for mammogenesis and lactogenesis, completes cellular differentiation and development of lactogenic capacity
estrogens stimulate ductal development Þ development begins at puberty
progesterone needed to complete mammogenesis of alveolar system
insulin required for multiplication of epithelial cells and development of lobulalveolar architecture
(2) Lactogenesis
milk synthesis; prevented until placental steroids cleared from maternal system 3-4 days postpartum
progesterone interferes with casein (major milk protein) synthesis
estrogens interfere with lactogenic effect of prolactin
prolactin stimulates synthesis of casein and stabilizes its mRNA; continued normal maternal endocrine levels and Ý prolactin necessary for milk production
(3) Galactogenesis
(milk letdown), caused by activation of neurosensory reflex
afferent stimuli from suckling reach posterior pituitary Þ oxytocin release; oxytocin causes contraction of myoepithelial cells, ejecting milk into the ductal system for delivery during feeding
afferent stimuli also cause a dramatic Ý in prolactin secretion early in puerperium (period from termination of labor to involution of the uterus » 42 days) necessary for milk production
prolactin spikes occur with each feeding up to 2-3 mos. pospartum; once milk is established, prolactin spikes are no longer necessary as long as frequent suckling continues
cortical inputs may trigger letdown (e.g. thinking of baby or hearing baby cry)