Beruflich Dokumente
Kultur Dokumente
21 Oktober 2009
Endocrinology in Pregnancy
The endocrinology of human pregnancy involves endocrine and metabolic changes that result from physiological alterations at the boundary between mother and fetus. feto-placental unit (FPU), a major site of protein and steroid hormone production and secretion Many of the endocrine and metabolic changes that occur during pregnancy can be directly attributed to hormonal signals originating from the FPU
Endocrinology in Pregnancy
The initiation and maintenance of pregnancy depends primarily on the interactions of neuronal and hormonal factors Proper timing of these neuro-endocrine events within and between the placental, fetal and maternal compartments is critical in directing fetal growth and development and in coordinating the timing of parturition
Endocrinology in Pregnancy
Maternal adaptations to hormonal changes directly reflect the development of the fetus and placenta Gestational adaptations in pregnancy include : implantation and the maintenance of early pregnancy modification of the maternal system in order to provide adequate nutritional support for the developing fetus prearation for parturition and subsequent lactation
Syncytiotrophoblasts, the principal site of placental steroid and protein hormone biosynthesis, have a large surface area and line the intervillous space which exposes them directly to maternal bloodstream without the vascular endothelium and basement membrane which separates them from the fetal circulation This anatomic arrangement explains why placental proteins are secreted almost exclusively into the maternal circulation in concentrations much higher than those in the fetus
A longitudinal section of a chorionic villus at the feto-maternal interface at about 10 weeks' gestation The villous serves as a bridge between maternal and fetal compartments
A shift in progesterone production from the corpus luteum to the placenta occurs at approximately the 7- 9th week of gestation The small, shaded area represents the estimated duration of this functional transition.
Relative values of circulating concentrations of progesterone and 17a-progesterone during the course of human pregnancy from conception to term The data displayed demonstrates values before and after the luteinizing hormone (LH) surge
Synthesis of estrogen and progesterone within and between the maternal, placental & fetal compartment
The maternal, placental and fetal compartments for estrogen and progesterone synthesis in human pregnancy
The fetal adrenal gland lacks 3-hydroxysteroid dehydrogenase, but has sulfation and 16-hydroxylase capabilities Likewise, the placenta lacks 17-hydroxylase activity but contains sulfatase in order to cleave the sulfated fetal products.
KEY POINTS
Steroidogenesis in pregnancy is characterized by enzymatic deficiencies within the placental and fetal compartments which foster interdependent transfer of precursors among compartments for the synthesis of steroid hormones Redundancy in protein hormone receptor interactions such as hPL and hPGH serve to insure that adequate nutrition is supplied to the developing fetus
KEY POINTS
A relatively insulin resistant state is generated within the maternal compartment to supply glucose and free fatty acids for fetal nutrition Human parturition exemplifies the interplay between placental, fetal, and maternal compartments, characterized by increased responsiveness of the myometrium to prostaglandins and oxytocin
INDEX
1 2 3 4 5 6 7 8 9
HUMAN CHORIONIC GONADOTROPIN (hCG) HUMAN PLACENTAL LACTOGEN (hPL) OTHER PLACENTAL PROTEIN HORMONES HYPOTHALAMIC-LIKE RELEASING HORMONES OTHER PLACENTAL PEPTIDE HORMONES ESTROGENS FETAL ADRENAL GLANDS MATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION PROGESTERONE
hPL, hCG, ACTH, PTH-rP, GH variant, calcitonin, relaxin hypothalamic-like releasing and inhibiting hormones (TRH, GnRH, CRH, somatostatin, GHRH) inhibins, activins, ANP
2. Biosynthesis
single gene (chromosome 6 at q12-q21) - codes for -subunit eight separate gene (chromosome 19) - Codes for -hCG/-LH family
HCG
3. Cellular Sites of Origin
- complete hCG molecule is synthesized primarily
in the syncytiotrophoblast
HCG
5. Concentrations of hCG in Serum & Urine
1st detection : 7 1/2 to 9 1/2 days after the LH surge
spontaneous abortion
1. Chemical Characteristics
- single non-glycosylated polypeptide chain
3. Serum Concentration
demonstrable in placenta within 5 to 10 days
after conception detected as early as 3 weeks after fertilization rises until about 34 to 36 weeks
5. Metabolic Actions
lipolysis and increase FFA anti-insulin action
2. Chorionic Thyrotropon
3. Relaxin
- acts on myometrial smooth muscle to promote uterine relaxation
4. PTH-rP 5. hGH-variant
1. GnRH
immunoreactive GnRH was present in cytotrophoblast
2. CRH
biological function - fetal adrenal steroidogenesis - smooth muscle relaxation - immunosuppression
ACTH formation
positive feedback
: placental CRH placental ACTH glucocorticosteroid formation placental CRH expression
1. Neuropeptide-Y
2. Inhibin and Activin 3. Atrial Natriuretic Peptide (ANP)
ESTROGENS
placenta produce huge amounts of estrogen and progesterone near term: hyperestrogenic state produced by syncytiotrophoblast
ESTROGENS
1. Biosynthesis
1) nonpregnant : produced in the ovarian follicle (in theca cell) acetate cholesterol
androstenedione
(taken up granulosa cell) estradiol 17 synthesis
ESTROGENS
2) pregnant - neither acetate nor cholesterol, nor even progesterone can serve as precursor - C19-steroids convert to estrone and estradiol-17 - C19-steroids : dehydroepiandrosterone, androstenedione, and testosterone - plasma C19-steroids are estrogen precursors
ESTROGENS
2. Placental Aromatase Enzyme
enzyme complex that catalyze estrogen formation from androstenedione - Cyt P-450 monooxygenase - aromatase cytochrome P-450 - flavoprotein - NADPH-cytochrome P-450 reductase
ESTROGENS
3. Secreted Estrogens
ovary
: androstenedione estrone estradiol-17 adipose tissue : androstenedione estrone human placenta estradiol-17 16-hydroxyandrostenedione 16-hydroxyesterone estriol
An illustration demonstrating generalized pathways for steroid hormone formation in the fetal adrenal gland.
DHA: dehydroepiandrosterone. LDL: low-density lipoprotein cholesterol.
E2
Adrenal
E2 E2
Placenta
Adrenal
DS
Liver
DS 16-OH-DS
Liver
16-OH-DS
E3
16-OH-DS
E3
E3
ACTH is secreted by
- fetal pituitary gland - chorionic ACTH syncytiotrophoblast
17-hydroxyprogesterone
very active steroid sulfotransferase
PROGESTERONE
- 6 to 7 weeks of gestation produced in the ovary
PROGESTERONE
2. Progesterone Synthesis and Fetal Well-Being
relationship between fetal well-being and placental
estrogen cannot be demonstrated in the case of progesterone thus, progesterone biosynthesis may persist for long periods after fetal death
PROGESTERONE
3. Progesterone Metabolism During Pregnancy
5-dihydroprogesterone progesterone is converted to the potent
mineralocorticosteroid deoxycorticosterone
in pregnant women and in the fetus
Endorinology in parturition
Endocrinology in lactation
During embryonic development, signaling molecules important in epithelial-mesenchymal interactions include PTHrP, FGF10, LEF-1, and Msx2 Under the influence of maternal PRL and PL, the neonatal mammary gland undergoes transient functional differentiation and produces witch's milk.
Mammary gland development proceeds slowly after birth until puberty, when E and GH stimulate rapid ductal elongation. During pregnancy, progesterone stimulates alveologenesis and lactogenesis 1. At parturition, the withdrawal of progesterone is required for initiation of lactogenesis 2.
Prolactin promotes lactogenesis 2 and, along with oxytocin, maintains lactation. The withdrawal of prolactin and oxytocin causes involution of the mammary gland to a mature virgin-like state. MFP, mammary fat pad; TEB, terminal end bud.
The percentage of human mammary epithelial cells that are estrogen or progesterone receptor positive (ER/PR +), proliferating, ER/PR + and proliferating This graph illustrates that steroid receptor expression and proliferation infrequently occur in a single mammary epithelial cell at a given time. Receptor positive cells are found in close juxtaposition to proliferating cells, suggesting a paracrine mechanism for the mitogenic action of estrogen and progesterone on mammary epithelial cells
Stimulation of ER/PR + cells (lower panel) could release a paracrine factor that either stimulates adjacent luminal epithelial cells to proliferate or causes proliferation of the responder cells by eliciting a secondary response through stromal cells.
LACTOGENESIS
Mammary gland differentiation leads to full lactation Lactogenesis is traditionally divided into two stages Lactogenesis 1 starts around mid-pregnancy, when some of the genes encoding milk proteins are first expressed Lactogenesis 2 occurs at about the time of parturition, and is characterized by increased expression of milk proteins, the formation of tight junctions between mammary epithelial cells, and the expulsion of lipid droplet and casein micelles into the lumen
LACTOGENESIS
PRL promotes lactogenesis 1 & required for lactogenesis 2 and for maintenance of lactation
Lowering prolactin levels using dopamine agonists (bromocriptine) will prevent lactogenesis 2 and suppresses milk production in both rodents and women
LACTOGENESIS
The importance of placental lactogen to human lactation is questionable because women with placental lactogen deficiency can lactate normally, whereas women with low PRL levels cannot lactate
In fact, GH is dispensable for lactogenesis in mice and humans, as GHR knockout mice and human dwarfs with mutations in either GH or GHR can lactate
A, time course of plasma prolactin or HGH levels in eight nursing mothers from 8-41 d postpartum and six women between 63-194 days postpartum A sharp suckling-induced increase in prolactin was seen in the 8-41 days postpartum group, while this response was diminished in the 63-194 days postpartum group. HGH levels did not increase with suckling. B, profile of prolactin concentrations in three women between 22 and 26 days postpartum who played with their infants before nursing. In all three women, milk let down began shortly after they started interacting with the infants. However, prolactin levels did not rise until suckling began.
Unlike oxytocin, prolactin is not released by psychological stimuli in anticipation of suckling, but. begin to rise within 10 mnt after suckling begins peak by 30 - 60 m after the nursing stimulus
Initially, prolactin levels are elevated after parturition and suckling causes further elevations.
INVOLUTION
The last stage of the mammary life cycle involves the removal of the differentiated mammary epithelial cells and the remodeling of the gland to a duct system similar to that in the mature virgin
When no longer needed, the milk-producing machinery is destroyed, to be recapitulated in a subsequent pregnancy in preparation for another round of lactation Involution of the mammary gland is triggered by the combination of milk stasis and a fall in prolactin levels
INVOLUTION
Lack of suckling and milk stasis results in a rapid, but reversible induction of apoptosis within the differentiated population of mammary epithelial cells
If the lack of suckling is prolonged, prolactin levels decline below a threshold level and apoptosis is accompanied by a tissue-remodeling phase involving the induction of matrix-degrading enzymes and inflammatory cell infiltration
INVOLUTION
Once the transition to the alveolar remodeling phase begins, the process of involution cannot be reversed
The end result of this process is the elimination of all lobuloalveolar structures leaving behind a simple ductal tree