Endokrinologi,Dr.novia

ENDOKRINOLOGI KEHAMILAN , PERSALINAN

& LAKTASI

ENDOKRINOLOGI KEHAMILAN , PERSALINAN

& LAKTASI

21 Oktober 2009

Dr. Novia FN, SpOG

Endocrinology in PregnancyEndocrinology 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

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


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 depiction of a blastocyst implanting in the uterus

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

Decidua lines the maternal surface of the intervillous space and secretes protein hormones

Syncytiotrophoblasts line the fetal surface of the inter villous space and interact with the maternal blood supply to secrete placental hormones directly into the circulation

Human placental ultra-structure seen in cross section

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 termThe 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

Circulating maternal steroid hormone levels throughout early pregnancy

The fetal adrenal gland lacks 3-hydroxysteroid dehydrogenase, but has sulfation and 16-hydroxylase capabilitiesLikewise, the placenta lacks 17-hydroxylase activity but contains sulfatase in order to cleave the sulfated fetal products.

The maternal, placental and fetal compartments for estrogen and progesterone synthesis in human pregnancy

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

The Placental Hormones

INDEXHUMAN CHORIONIC GONADOTROPIN (hCG)1

HUMAN PLACENTAL LACTOGEN (hPL)2

HYPOTHALAMIC-LIKE RELEASING HORMONES4

ESTROGENS6

OTHER PLACENTAL PEPTIDE HORMONES5

OTHER PLACENTAL PROTEIN HORMONES3

FETAL ADRENAL GLANDS7

MATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION

8

PROGESTERONE9

The human placenta synthesize an enormous amount of hormones

hPL, hCG, ACTH, PTH-rP, GH variant, calcitonin, relaxin

hypothalamic-like releasing and inhibiting hormones (TRH, GnRH, CRH, somatostatin, GHRH)

inhibins, activins, ANP

HUMAN CHORIONIC GONADOTROPIN

hCG

• “pregnancy hormones”

• produced almost exclusively in the placenta

• detection of hCG in blood or urine

- indication of pregnancy


• glycoprotein

- hCG, FSH, LH, TSH

• two subunits

- α subunits – identical

- β subunits – distinctly different

1. Chemical Characteristics

2. Biosynthesis• single gene (chromosome 6 at q12-q21)

- codes for α-subunit

• eight separate gene (chromosome 19)

- Codes for β-hCG/β-LH family


- complete hCG molecule is synthesized primarily

in the syncytiotrophoblast

3. Cellular Sites of Origin

4. Regulation of hCG Subunit Biosynthesis- The amount of mRNA for hCG in

syncytiotrophoblast

from the first trimester are greater than at term

→ the measurement of hCG in plasma

as a screening procedure to identify

abnormal fetuses

HCG

• 1st detection : 7 1/2 to 9 1/2 days

after the LH surge

• maximal levels : about 8 to 10 weeks

• begin to decline : about 10 to 12 weeks

• nadir : about 20 weeks

• maintained at this lower level

for remainder of pregnancy

5. Concentrations of hCG in Serum & Urine

HCG

• elevated : multiple fetuses, erythroblstotic fetuses,

hydatidiform mole, choriocarcinoma.

Down syndrome

• depressed : ectopic pregnancy impending

spontaneous abortion

6. Elevated or Depressed hCG Levels


- rescue and maintenance of function

of corpus luteum

- stimulate of fetal testis

: to promote male sexual differentiation

- stimulate of maternal thyroid

: increases thyroid activity,

stimulate iodine uptake

- other

: promote relaxin secretion

7. Biological Function


- single non-glycosylated polypeptide chain

- similar to hPRL (prolactin)

1. Chemical Characteristics

◎ hPL

- potent lactogenic and GH-like bioactivity

HUMAN PLACENTAL LACTOGENHUMAN PLACENTAL LACTOGEN

- hPL – on chromosome 17

- hPRL – on chromosome 6

2. Gene Structure

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

HUMAN PLACENTAL LACTOGEN

- stimulated : insulin, cAMP

- inhibited : PGE2, PGF2α

4. Regulation of hPL Biosynthesis

5. Metabolic Actions

① lipolysis and increase FFA

② anti-insulin action

HUMAN PLACENTAL LACTOGEN

1. Chorionic Adrenocorticotropin - ACTH, lipotropin, β-endorphin

2. Chorionic Thyrotropon

3. Relaxin - acts on myometrial smooth muscle

to promote uterine relaxation

4. PTH-rP

5. hGH-variant

OTHER PLACENTAL PROTEIN HORMONES

1. GnRH

HYPOTHALAMIC-LIKE RELEASING HORMONES

• immunoreactive GnRH was present

in cytotrophoblast

2. CRH

• biological function

- fetal adrenal steroidogenesis

- smooth muscle relaxation

- immunosuppression


• level

- nonpregnant – 15 pg/mL

- early third trimester – 250 pg/mL

- last 5 to 6 weeks – 1000 to 2000 pg/mL

• cushing syndrome that developed during pregnancy

with spontaneous resolution after delivery

→ placental CRH stimulated pituitary

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)

OTHER PLACENTAL PEPTIDE HORMONES

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

cholesterolandrostenedione

(taken up granulosa cell)

estradiol 17β synthesis

ESTROGENS

2) pregnant

- neither acetate nor cholesterol,

nor even progesterone can serve as precursor

- C19-steroids convert to estrone

and estradiol-17β

- 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-17β

• adipose tissue

: androstenedione → estrone

• human placenta

① estradiol-17β

② 16α-hydroxyandrostenedione

→ 16α-hydroxyesterone → estriol

FETAL ADRENAL GLANDS

◎ Fetal Adrenal Glands- compared with adult organs, the adrenal cortex is the largest organ of the fetus- more than 85% of fetal gland is normally composed of a peculiar fetal zone (not in adults)

1. Contribution to Placental Estrogen Formation• near term, estradiol-17β produced in placenta - half from maternal - half from fetal plasma


2. Placental Estriol Synthesis

• nonpregnant

urine estriol : estrone + estriol-17β = 1 : 1

• near term, this ratio increases to 10 or more

• 16α-hydroxylated C19-steroids

- converted to estriol by placental tissue

- is synthesized by the fetal adrenal and liver

• near term, fetal source (90&)

maternal source (10%)

An illustration demonstrating generalized pathways for steroid hormone formation in the fetal adrenal gland.

DHA: dehydroepiandrosterone. LDL: low-density lipoprotein cholesterol.


E2

E3

Adrenal

DS

Liver

16α-OH-DS

E2

Placenta

E3

E2Adrenal

DS16α-OH-DS

Liver

16α-OH-DS

E3

MaternalCompartmen

t Fetus


3. Fetal Adrenal Development

• in early embryo, adrenal cortex is composed of cells

- proliferate rapidly prior to vascularization

of pituitary gland

→ comprise fetal zone

• ACTH is secreted by

- fetal pituitary gland

- chorionic ACTH syncytiotrophoblast


4. Enzymatic Considerations

• deficiency of 3β-hydroxysteroid dehydrogenase

→ limit the conversion of

- pregnenolone → progesterone

- 17α-hydroxypregnenolone

→ 17α-hydroxyprogesterone

• very active steroid sulfotransferase


5. Fetal Adrenal Steroid Precursor

- LDL cholesterol

- is synthesized fetal adrenal

→ convert to 16α-OH C19 steroid in fetal liver

→ placenta


6. Fetal Conditions that Affect Estrogen

Production① fetal death

- striking reduction in the levels of

urinary estrogens

② fetal anencephaly (In the absence of the fetal zone)

- limited availability of C19-steroid precursors

→ rate of formation of placental estrogens is

severely limited


③ fetal adrenal hypoplasia

- estrogen formation is very limited

④ placental sulfatase deficiency

- precludes the hydrolysis of C19-steroid sulfates

(X-linked disorder)

⑤ placental aromatase deficiency

- androstenedione could not converted to

estradiol-17β

⑥ down syndrome

- serum unconjugated estriol levels were low

- screening of 2nd trimester


⑦ deficiency in fetal LDL biosynthesis

- lead to no progesterone formation

- estriol levels were also lower than normal

⑧ fetal erythroblastosis

- estrogen levels in maternal plasma are elevated

⑨ decreased fetal adrenal use of LDL

- most common cause of decreased

placental estrogen formation

6. Fetal Conditions that Affect Estrogen Production

① glucocorticosteroid treatment

- inhibit ACTH secretion

→ maternal & fetal adrenal secretion

is decreased

→ causes striking reduction in placental estrogen

② maternal adrenal dysfunction

- estrone and estradiol-17β is decreased

③ maternal ovarian androgen-producing tumors

- precluding transplacental passage


④ maternal renal disease

- lower level of estriol in urine maybe observed

⑤ maternal HTN and DM

- decreased uteroplacental flow

→ fetal formation of dehydroepiandrosterone

is impaired

⑥ gestational trophoblastic disease

- in H-mole or choriocarcinoma, there is no fetal

adrenal source of C19-steroid precursor,

estrogen formation is limited


PROGESTERONE

1. Source of Cholesterol for Placental Progesterone

Biosyntheis

• cholesterol (in mitochondria)

cytochrome P450

→ pregnenolone

→ progesterone

3β-hydroxysteroid dehydrogenase

- 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 Pregnancy① 5α-dihydroprogesterone↑

② progesterone is converted to the potent

mineralocorticosteroid deoxycorticosterone

in pregnant women and in the fetus

Endorinology in parturitionEndorinology in parturition

Norwitz E et al. N Engl J Med 1999;341:660-666

Regulation of Uterine Activity during Pregnancy and Labor

Regulation of Uterine Activity during Pregnancy and Labor

Endocrinology in lactationEndocrinology in lactation

PROLAKTINHUMAN PLASENTAL LACTOGEN

GROWTH HORMON

Overview of the regulation of mammary gland development

During embryonic development, signaling molecules important in epithelial-mesenchymal interactions include PTHrP, FGF- 10, 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.

Prolactin and the Maintenance of Lactation Prolactin is necessary for the maintenance of

lactation, and suckling causes prolactin secretion

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.

Prolactin and the Maintenance of Lactation

1 - 2 months after parturition, mean prolactin levels decline, but suckling continues to result in transient elevations

It appears that the continuous elevations of prolactin early after parturition are important to the initiation of lactation,

…. but that once begun, nursing can be maintained with the lower, transient elevations of prolactin.

However, further lowering of prolactin levels with dopamine agonists will terminate milk production

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

Endokrinologi,Dr.novia

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