Endokrinologi, Dr. Novia Fransiska Ngo, Sp.og

ENDOKRINOLOGI KEHAMILAN , PERSALINAN& LAKTASI 21 Oktober 2009

Dr. Novia FN, SpOG

Endocrinology in PregnancyThe 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

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 lactationEndocrinology in Pregnancy

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

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 pregnancyHUMAN CHORIONIC GONADOTROPIN

glycoprotein - hCG, FSH, LH, TSH two subunits - subunits identical - subunits distinctly different1. Chemical Characteristics2. Biosynthesis single gene (chromosome 6 at q12-q21) - codes for -subunit eight separate gene (chromosome 19) - Codes for -hCG/-LH familyHUMAN CHORIONIC GONADOTROPIN

complete hCG molecule is synthesized primarily in the syncytiotrophoblast3. Cellular Sites of Origin4. 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 pregnancy5. Concentrations of hCG in Serum & UrineHCG

elevated : multiple fetuses, erythroblstotic fetuses, hydatidiform mole, choriocarcinoma. Down syndrome

depressed : ectopic pregnancy impending spontaneous abortion6. Elevated or Depressed hCG LevelsHUMAN CHORIONIC GONADOTROPIN

- 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 secretion7. Biological FunctionHUMAN CHORIONIC GONADOTROPIN

- single non-glycosylated polypeptide chain- similar to hPRL (prolactin)1. Chemical Characteristics hPL - potent lactogenic and GH-like bioactivityHUMAN PLACENTAL LACTOGENHUMAN PLACENTAL LACTOGEN

- hPL on chromosome 17- hPRL on chromosome 62. Gene Structure3. 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 weeksHUMAN PLACENTAL LACTOGEN

- stimulated : insulin, cAMP- inhibited : PGE2, PGF24. Regulation of hPL Biosynthesis5. Metabolic Actions lipolysis and increase FFA anti-insulin actionHUMAN PLACENTAL LACTOGEN

1. Chorionic Adrenocorticotropin - ACTH, lipotropin, -endorphin2. Chorionic Thyrotropon

3. Relaxin - acts on myometrial smooth muscle to promote uterine relaxation4. PTH-rP5. hGH-variantOTHER PLACENTAL PROTEIN HORMONES

1. GnRHHYPOTHALAMIC-LIKE RELEASING HORMONES immunoreactive GnRH was present in cytotrophoblast2. CRH biological function - fetal adrenal steroidogenesis - smooth muscle relaxation - immunosuppression

HYPOTHALAMIC-LIKE RELEASING HORMONES 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

HYPOTHALAMIC-LIKE RELEASING HORMONES 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

ESTROGENS1. Biosynthesis1) nonpregnant : produced in the ovarian follicle(in theca cell)acetatecholesterolandrostenedione(taken up granulosa cell)estradiol 17 synthesis

ESTROGENS2) 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

ESTROGENS2. 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

ESTROGENS3. Secreted Estrogens ovary : androstenedione estrone estradiol-17 adipose tissue : androstenedione estrone human placenta estradiol-17 16-hydroxyandrostenedione 16-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-17 produced in placenta - half from maternal - half from fetal plasma

FETAL ADRENAL GLANDS2. Placental Estriol Synthesis nonpregnant urine estriol : estrone + estriol-17 = 1 : 1 near term, this ratio increases to 10 or more 16-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.

FETAL ADRENAL GLANDS

FETAL ADRENAL GLANDS3. 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

FETAL ADRENAL GLANDS4. Enzymatic Considerations deficiency of 3-hydroxysteroid dehydrogenase limit the conversion of - pregnenolone progesterone - 17-hydroxypregnenolone 17-hydroxyprogesterone

very active steroid sulfotransferase

FETAL ADRENAL GLANDS5. Fetal Adrenal Steroid Precursor- LDL cholesterol

- is synthesized fetal adrenal convert to 16-OH C19 steroid in fetal liver placenta

FETAL ADRENAL GLANDS6. Fetal Conditions that Affect Estrogen Production fetal death - striking reduction in the levels of urinary estrogens fetal anencephaly (In the absence of the fetal zone) - limited availability of C19-steroid precursors rate of formation of placental estrogens is severely limited

FETAL ADRENAL GLANDS fetal adrenal hypoplasia - estrogen formation is very limited placental sulfatase deficiency - precludes the hydrolysis of C19-steroid sulfates (X-linked disorder) placental aromatase deficiency - androstenedione could not converted to estradiol-17 down syndrome - serum unconjugated estriol levels were low - screening of 2nd trimester

FETAL ADRENAL GLANDS deficiency in fetal LDL biosynthesis - lead to no progesterone formation - estriol levels were also lower than normal fetal erythroblastosis - estrogen levels in maternal plasma are elevated decreased fetal adrenal use of LDL - most common cause of decreased placental estrogen formation6. Fetal Conditions that Affect Estrogen Production

glucocorticosteroid treatment - inhibit ACTH secretion maternal & fetal adrenal secretion is decreased causes striking reduction in placental estrogen maternal adrenal dysfunction - estrone and estradiol-17 is decreased maternal ovarian androgen-producing tumors - precluding transplacental passageMATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION

maternal renal disease - lower level of estriol in urine maybe observed maternal HTN and DM - decreased uteroplacental flow fetal formation of dehydroepiandrosterone is impaired gestational trophoblastic disease - in H-mole or choriocarcinoma, there is no fetal adrenal source of C19-steroid precursor, estrogen formation is limitedMATERNAL CONDITIONS THAT AFFECT PLACENTAL ESTROGEN FORMATION

PROGESTERONE1. Source of Cholesterol for Placental Progesterone Biosyntheis cholesterol (in mitochondria) cytochrome P450 pregnenolone progesterone 3-hydroxysteroid dehydrogenase- 6 to 7 weeks of gestation produced in the ovary

PROGESTERONE2. 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

PROGESTERONE3. Progesterone Metabolism During Pregnancy

5-dihydroprogesterone

progesterone is converted to the potent mineralocorticosteroid deoxycorticosterone in pregnant women and in the fetus

Endorinology in parturition

Norwitz E et al. N Engl J Med 1999;341:660-666Regulation of Uterine Activity during Pregnancy and LaborRegulation of Uterine Activity during Pregnancy and Labor

Endocrinology in lactationPROLAKTINHUMAN PLASENTAL LACTOGENGROWTH 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.

Overview of the regulation of mammary gland developmentMammary 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.

Overview of the regulation of mammary gland development 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.

LACTOGENESISMammary 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

LACTOGENESISPRL 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

LACTOGENESISThe 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 LactationProlactin 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 Lactation1 - 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

INVOLUTIONThe 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

INVOLUTIONLack 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

Figure 1. Regulation of Uterine Activity during Pregnancy and Labor. The regulation of uterine activity during pregnancy and labor can be divided into four distinct physiologic phases -- quiescence, activation, stimulation, and involution -- that are or may be influenced by a number of stimulatory and inhibitory factors. Question marks indicate a possible influence. Adapted from Challis and Gibb5 with the permission of the publisher.