ACTH Adrenocorticotropic hormonecAMP Cyclic adenosine monophosphateCBG Corticosteroid-binding globulinCRH Corticotropin-releasing hormoneDHEA DehydroepiandrosteroneDOC DeoxycorticosteroneEGF Epidermal growth factorFGF Fibroblast growth factorFSH Follicle-stimulating hormoneGH Growth hormoneGnRH Gonadotropin-releasing hormoneGTN Gestational trophoblastic neoplasiahCG Human chorionic gonadotropinhPL Human placental lactogenIGF Insulin-like growth factorLH Luteotropic hormoneMIS Müllerian-inhibiting substancePDGF Platelet-derived growth factorPlGF Placental growth factorPRL ProlactinSHBG Sex hormone-binding globulinTBG Thyroid hormone-binding globulinTRH Thyrotropin-releasing hormoneTSH Thyroid-stimulating hormone(thyrotropin)VEGF Vascular endothelial growth factor

Throughout pregnancy, the fetal-placental unit secretes protein and steroid hormones into the mother’s bloodstream, and these alter the function of every endocrine gland in her body. Both clinically and in the laboratory,pregnancy can mimic hyperthyroidism, Cushing’s disease,pituitary adenoma, diabetes mellitus, and polycysticovary syndrome.The endocrine changes associated with pregnancy areadaptive, allowing the mother to nurture the developingfetus. Although maternal reserves are usually adequate,occasionally, as in the case of gestational diabetes orhypertensive disease of pregnancy, a woman may developovert signs of disease as a direct result of pregnancy.Aside from creating a satisfactory maternal environmentfor fetal development, the placenta serves as arepository endocrine gland as well as a respiratory, alimentary,and excretory organ. Measurements of fetal-placentalproducts in the maternal serum provide one meansof assessing fetal well-being. This chapter will considerthe changes in maternal endocrine function in pregnancyand during parturition as well as fetal endocrine development.The chapter concludes with a discussion of someendocrine disorders complicating pregnancy.CONCEPTION & IMPLANTATIONFertilizationIn fertile women, ovulation occurs approximately 12–16 days after the onset of the previous menses. Theovum must be fertilized within 24–48 hours if conceptionis to result. For about 48 hours around ovulation,cervical mucus is copious, nonviscous, slightly alkaline,

and forms a gel matrix that acts as a filter and conduitfor sperm. Following intercourse, sperm that are to survivepenetrate the cervical mucus within minutes andcan remain viable there until the mucus characterchanges, approximately 24 hours following ovulation.Sperm begin appearing in the outer third of the uterinetube (the ampulla) 5–10 minutes after coitus and continueto migrate to this location from the cervix forabout 24–48 hours. Of the 200 106 sperm that aredeposited in the vaginal fornices, only approximately200 reach the distal uterine tube. Fertilization normallyoccurs in the ampulla.ImplantationEmbryonic invasion of the uterus occurs during a specificwindow of implantation 8–10 days after ovulationand fertilization, when the conceptus is a blastocyst. Inmost pregnancies, the dates of ovulation and implantationare not known. Weeks of gestation (“gestationalage”) are by convention calculated from the first day ofthe last menstrual period. Within 24 hours afterimplantation, or at about 3 weeks of gestation, humanchorionic gonadotropin (hCG) is detectable in maternalserum. Under the influence of increasing hCG production,the corpus luteum continues to secrete steroidhormones in increasing quantities. Without effective

implantation and subsequent hCG production, the corpusluteum survives for only about 14 days followingovulation (see Chapter 14).Symptoms & Signs of PregnancyBreast tenderness, fatigue, nausea, absence of menstruation,softening of the uterus, and a sustained elevation ofbasal body temperature are all attributable to hormoneproduction by the corpus luteum and developing placenta.Ovarian Hormones of PregnancyThe hormones produced by the corpus luteum includeprogesterone, 17-hydroxyprogesterone, and estradiol.The indispensability of the corpus luteum in early pregnancyhas been demonstrated by ablation studies, inwhich luteectomy or oophorectomy before 42 days ofgestation results in precipitous decreases in levels ofserum progesterone and estradiol, followed by abortion.Exogenous progesterone will prevent abortion, provingthat progesterone alone is required for maintenance ofearly pregnancy. After about the seventh gestationalweek, the corpus luteum can be removed without subsequentabortion owing to compensatory progesteroneproduction by the placenta.Because the placenta does not produce appreciableamounts of 17-hydroxyprogesterone, this steroid providesa marker of corpus luteum function. As shown inFigure 17–1, the serum concentrations of estrogens andtotal progesterone exhibit a steady increase, but theconcentration of 17-hydroxyprogesterone rises and thendeclines to low levels that persist for the duration of the

pregnancy. The decline of corpus luteum functionoccurs despite the continued production of hCG; infact, corpus luteum production of 17-hydroxyprogesteronedeclines while hCG is still rising to maximal levels.Whether this is due to down-regulation of corpusluteal hCG receptors is not known.Another marker of corpus luteum function is thepolypeptide hormone relaxin, a protein with a molecularmass of about 6000. It is similar in its tertiary structureto insulin. Relaxin becomes detectable at about thesame time as hCG begins to rise, and it maintains amaximum maternal serum concentration of about 1 ng/mL during the first trimester. The serum concentrationthen falls approximately 20% and is constant for theremainder of the pregnancy.Pharmacologically, relaxin ripens the cervix, softensthe pubic symphysis, promotes decidual angiogenesis,and acts synergistically with progesterone to inhibituterine contractions. A major physiologic role forrelaxin in human gestation has not been established.Luteectomy after 7 weeks of gestation does not interferewith gestation in spite of undetectable relaxin levels.Extraluteal production of relaxin by the decidua andplacenta has been demonstrated, however, and localeffects may be exerted without alteration of systemichormone concentrations.FETAL-PLACENTAL-DECIDUAL UNITThe function of the placenta is to establish effective communicationbetween the mother and the developing fetuswhile maintaining the immune and genetic integrity ofboth individuals. Initially, the placenta functions autonomously.By the end of the first trimester, however, thefetal endocrine system is sufficiently developed to replaceplacental function and to provide some hormone precursorsto the placenta. From this time, it is useful to considerthe conceptus as the fetal-placental unit.The fetal-placental unit will be considered in threeseparate but related categories: (1) as a source of secretionof protein and steroid hormones into the maternalcirculation; (2) as a participant in the control of fetalendocrine function, growth, and parturition; and (3) asa selective barrier governing the interaction between thefetal and maternal systems.Within 8 days after fertilization, implantation begins.The alpha-v-beta-3 integrin vitronectin receptor may serveas a link between the maternal and embryonic epithelia.The trophoblast invades the endometrium, and two layersof developing placenta can be demonstrated. Columns ofinvading cytotrophoblasts anchor the placenta to theendometrium. The differentiated syncytiotrophoblast,derived from fusion of cytotrophoblasts, is in direct contactwith the maternal circulation. The syncytiotrophoblastis the major source of hormone production, containingthe cellular machinery needed for synthesis andsecretion of both steroid and polypeptide hormones.

The decidua is the endometrium of pregnancy. Decidualcells are capable of synthesizing a variety of polypeptidehormones, including prolactin (PRL), relaxin, and avariety of paracrine factors, in particular insulin-likegrowth factor (IGF)-binding protein I. The role of thedecidua as an endocrine organ has not been established,but its role as a source of prostaglandins during labor iscertain (see Endocrine Control of Parturition, below).Modern methods of screening for fetal chromosomalaneuploidy, particularly trisomy 21 (Down’s syndrome),utilize circulating biochemical markers. Screeningby maternal age alone (> 35 years) led to the prenatalidentification of only about 25% of aneuploidfetuses. As an aneuploid chromosome complementaffects both fetal and placental tissues, their protein andsteroid products have been evaluated. A combination ofalpha-fetoprotein, hCG, and unconjugated estriol concentrations,secreted into and measured in maternalserum between 15 and 18 weeks’ gestation, can be usedto identify fetal Down’s syndrome and trisomy 18 witha detection rate of 60% over all age groups.

POLYPEPTIDE HORMONESHuman Chorionic GonadotropinThe first marker of trophoblast differentiation and thefirst measurable product of the placenta is hCG, a glycoproteinconsisting of 237 amino acids. It is similar instructure to the pituitary glycoprotein hormones in thatit consists of two chains: a common alpha chain, which isspecies-specific; and a beta chain, which determinesreceptor interaction and ultimate biologic specificity.The alpha chain is identical in sequence to the alphachains of thyroid-stimulating hormone (TSH), folliclestimulatinghormone (FSH), and luteinizing hormone(LH). The beta chain has significant sequence homologywith LH but is not identical; of the 145 amino acids in-hCG, 97 (67%) are identical to those of -LH. Inaddition, the placental hormone has a carboxyl terminalsegment of 30 amino acids not found in the pituitary LHmolecule. Carbohydrate constitutes approximately 30%by weight of each subunit. Sialic acid alone accounts for10% of the weight of the molecule and confers a highdegree of resistance to degradation and consequently along plasma half-life of about 24 hours.In the early weeks of pregnancy (up to 6 weeks), theconcentration of hCG doubles every 1.7–2 days, andserial measurements provide a sensitive index of earlytrophoblast function. Maternal plasma hCG peaks atabout 100,000 mIU/mL during the tenth gestationalweek and then declines gradually to about 10,000mIU/mL in the third trimester. Peak concentrationscorrelate temporally with the establishment of maternalblood flow in the intervillous space (Figure 17–1).The long plasma half-life of hCG (24 hours) allowsthe tiny mass of cells comprising the blastocyst to produce

sufficient hormone to be detected in the peripheralcirculation within 24 hours of implantation. Thus,pregnancy can be diagnosed several days before anysymptoms occur or a menstrual period has been missed.Antibodies to the unique -carboxyl terminal segmentof hCG do not cross-react significantly with any of thepituitary glycoproteins. As little as 5 mIU/mL (1 ng/mL) of hCG in plasma can be detected without interferencefrom the higher levels of LH, FSH, and TSH.Like its pituitary counterpart LH, hCG is luteotropic,and the corpus luteum has high-affinity receptorsfor hCG. The stimulation of increased amounts ofprogesterone production by corpus luteum cells isdriven by increasing concentrations of hCG. Steroidsynthesis can be demonstrated in vitro and is mediatedby the cyclic adenosine monophosphate (cAMP) system.hCG has been shown to enhance placental conversionof maternal low-density lipid cholesterol to pregnenoloneand progesterone.The concentration of hCG in the fetal circulation isless than 1% of that found in the maternal compartment.However, there is evidence that fetal hCG is animportant regulator of the development of the fetaladrenal and gonad during the first trimester.hCG is also produced in gestational trophoblasticneoplasia (GTN) by hydatidiform mole and choriocarcinoma,and the concentration of -hCG is used as atumor marker, for diagnosis, and for monitoring thesuccess or failure of chemotherapy in these disorders.Women with very high hCG levels due to GTN maybecome clinically hyperthyroid and revert to euthyroidismas hCG is reduced during chemotherapy.Human Placental LactogenA second placental polypeptide hormone, also withhomology to a pituitary protein, is termed placental lactogen(hPL). hPL is detectable in the early trophoblast,but detectable serum concentrations are not reacheduntil 4–5 gestational weeks (Figure 17–1). hPL is a proteinof 190 amino acids whose primary, secondary, andtertiary structures are similar to those of growth hormone(GH) and PRL. The molecules cross-react inimmunoassays and in some receptor and bioassay systems.hPL is diabetogenic and lactogenic but it hasminimal growth-promoting activity as measured bystandard GH bioassays.The physiologic role of hPL during pregnancyremains controversial, and normal pregnancy withoutdetectable hPL production has been reported. Althoughnot clearly shown to be a mammotropic agent, hPLcontributes to altered maternal glucose metabolism andmobilization of free fatty acids; causes a hyperinsulinemicresponse to glucose loads; appears to directly stimulatepancreatic islet insulin secretion; and contributes tothe peripheral insulin resistance characteristic of pregnancy.Along with prolonged fasting and insulininduced

hypoglycemia, pre-beta-HDL and apoproteinA-I are two factors that stimulate release of hPL. hPLproduction is roughly proportionate to placental mass.Actual production rates may reach as much as 1–1.5 g/d. The disappearance curve shows multiple componentsbut yields a serum half-life of 15–30 minutes.Serum hPL concentrations were used historically asa clinical indicator of the health of the placenta, but therange of normal values was wide, and serial determinationswere necessary. hPL determinations have beenreplaced by biophysical profiles, which are more sensitiveindicators of fetal jeopardy.Other Chorionic Peptide Hormones& Growth FactorsOther chorionic peptides have been identified, but theirfunctions remain poorly defined. One of these proteins isa glycoprotein with partial sequence and functionalhomology to TSH. Its existence as a separate entity fromsuggesting that chorionic TSH is a protein with a molecularweight of about 28,000, structurally different fromhCG, with weak thyrotropic activity. Similarly, adrenocorticotropichormone (ACTH)-like, lipotropin-like, andendorphin-like peptides have been isolated from placenta,but they have low biologic potency and undeterminedphysiologic roles. A chorionic FSH-like protein has alsobeen isolated from placenta but has not yet been detectedin plasma. Strong evidence exists that the cytotrophoblastproduces a human chorionic gonadotropin-releasing hormonethat is biologically and immunologically indistinguishablefrom the hypothalamic gonadotropin-releasinghormone (GnRH). The release of hCG from the syncytiotrophoblastmay be under the direct control of this factor,in a fashion analogous to the hypothalamic control ofanterior pituitary secretion of gonadotropins. Preliminaryevidence is also available for similar paracrine control ofsyncytiotrophoblastic release of TSH, somatostatin, andcorticotropin by analogous cytotrophoblastic releasinghormones. Activin, inhibin, corticotropin-releasing factor,and multiple peptide growth factors, including fibroblastgrowth factor (FGF), epidermal growth factor (EGF),platelet-derived growth factor (PDGF), and the IGFs—and many of their cognate receptors—have all been isolatedfrom placental tissue. Placental growth factor (PlGF)and the related vascular endothelial growth factor (VEGF)have been suggested to play a role in placental angiogenesis,preeclampsia, and fetal growth.STEROID HORMONESIn contrast to the impressive synthetic capability exhibitedin the production of placental proteins, the placentadoes not appear to have the capability to synthesize steroidsde novo. All steroids produced by the placenta arederived from maternal or fetal precursor steroids.No cells, however, even remotely approach the trophoblastsin their capacity to efficiently interconvert steroids.This activity is demonstrable even in the early blastocyst,

and by the seventh gestational week, when thecorpus luteum has undergone relative involution, the placentabecomes the dominant source of steroid hormones.ProgesteroneThe placenta relies on maternal cholesterol as its substratefor progesterone production. Fetal death has no immediateinfluence on progesterone production, suggesting that thefetus is a negligible source of substrate. Enzymes in the placentacleave the cholesterol side chain, yielding pregnenolone,which in turn is isomerized to progesterone;250–350 mg of progesterone is produced daily by the thirdtrimester, and most enters the maternal circulation. Thematernal plasma concentration of progesterone rises progressivelythroughout pregnancy and appears to be independentof factors that normally regulate steroid synthesis andsecretion (Figure 17–1). Whereas exogenous hCG stimulatesprogesterone production in early pregnancy, hypophysectomy,adenalectomy, or oophorectomy has no effectafter the luteo-placental shift, which occurs between 7–9weeks gestation. Likewise, the administration of ACTH orcortisol does not influence placental progesterone secretion.Progesterone is necessary for establishment andmaintenance of pregnancy. Luteal phase deficiency isimplicated in some cases of infertility and recurrentpregnancy loss. Insufficient production of progesteronemay contribute to failure of implantation and pretermdelivery. Progesterone, along with nitric oxide, maintainsuterine quiescence during pregnancy. Progesteronealso may act as an immunosuppressive agent insome systems and inhibits T cell-mediated tissue rejection.Thus, high local concentrations of progesteronemay contribute to immunologic tolerance by the uterusof invading embryonic trophoblast tissue.EstrogensEstrogen production by the placenta also depends oncirculating precursors, but in this case both fetal andmaternal steroids are important sources. Most of theestrogens are derived from fetal androgens, primarilydehydroepiandrosterone (DHEA) sulfate. Fetal DHEAsulfate, produced mainly by the fetal adrenal, is convertedby placental sulfatase to the free DHEA andthen, through enzymatic pathways common to steroidproducingtissues, to androstenedione and testosterone.These androgens are finally aromatized by theplacenta to estrone and estradiol, respectively.Placental corticotropin-releasing hormone (CRH)may be an important regulator of fetal adrenal DHEAsulfate secretion. The greater part of fetal DHEA sulfateis metabolized to produce a third estrogen: estriol. Estriolis a weak estrogen with one-tenth the potency of estroneand one-hundredth the potency of estradiol. Serumestrone and estradiol concentrations are increased duringpregnancy about 50-fold over their maximal prepregnancyvalues, but estriol increases approximately 1000-fold. The substrate for the reaction is 16-hydroxy-

DHEA sulfate produced in the fetal adrenal and liver,not in maternal or placental tissues. The final steps ofdesulfation and aromatization to estriol occur in the placenta.Maternal serum or urinary estriol measurements,unlike measurements of progesterone or hPL, reflect fetalas well as placental function. Normal estriol production,therefore, reflects the integrity of fetal circulationand metabolism as well as adequacy of the placenta.Rising serum or urinary estriol concentrations are thebest available biochemical indicator of fetal well-being(Figure 17–1). 17-Hydroxysteroid dehydrogenase type IIprevents fetal exposure to potent estrogens by catalyzingthe conversion of estradiol to less potent estrone. There are some circumstances in which decreasedestriol production is the result of congenital derangementsor iatrogenic intervention. Maternal estriolremains low in pregnancies with placental sulfatase deficiencyand in cases of fetal anencephaly. In the firstcase, DHEA sulfate cannot be hydrolyzed; in the second,little fetal DHEA is produced because fetal adrenalstimulation by ACTH is lacking. Maternal administrationof glucocorticoids also inhibits fetal ACTH andlowers maternal estriol. Administration of DHEA tothe mother during a healthy pregnancy increases estriolproduction. Antibiotic therapy can reduce estriol levelsby interfering with bacterial glucuronidases and maternalreabsorption of estriol from the gut. Estetrol, anestrogen metabolite with a fourth hydroxyl at the 16position, is unique to pregnancy.Cases of aromatase deficiency indicate that fetalestrogen action is not mandatory for the maintenanceof pregnancy. Homozygous mutant mice with disruptedestrogen receptor alpha or beta genes undergoapparently normal blastocyst, fetal, and placental development.This observation has been corroborated by aclinical case of a spontaneous missense mutation of theestrogen receptor alpha gene in a man.MATERNAL ADAPTATIONTO PREGNANCYAs a successful “parasite,” the fetal-placental unitmanipulates the maternal “host” for its own gain butnormally avoids imposing excessive stress that wouldjeopardize the pregnancy. The prodigious productionof polypeptide and steroid hormones by the fetal-placentalunit directly or indirectly results in physiologicadaptations of virtually every maternal organ system.These alterations are summarized in Figure 17–2. Mostof the commonly measured maternal endocrine functiontests are radically changed. In some cases, truephysiologic alteration has occurred; in others, thechanges are due to increased production of specificserum binding proteins by the liver or to decreasedserum levels of albumin. In addition, some hormonalchanges are mediated by altered clearance rates due toincreased glomerular filtration, decreased hepatic excretion

of metabolites, or metabolic clearance of steroidand protein hormones by the placenta. The changes inendocrine function tests are summarized in Table 17–1.Failure to recognize normal pregnancy-induced alterationsin endocrine function tests can lead to unnecessarydiagnostic tests and therapy that may be seriouslydetrimental to mother and fetus.Maternal Pituitary GlandThe mother’s anterior pituitary gland hormones havelittle influence on pregnancy after implantation hasoccurred. The gland itself enlarges by about one-third,with the major component of this increase beinghyperplasia of the lactotrophs in response to the highplasma estrogens. PRL, the product of the lactotrophs,is the only anterior pituitary hormone that rises progressivelyduring pregnancy and peaks at the time ofdelivery, with contributions from both the anteriorpituitary and the decidua. In non-lactating women,maternal PRL decreases to pre-gestational levels withinthree months. In spite of the high serum concentrations,pulsatile release of PRL and nocturnal and foodinducedincreases persist. Hence, the normal neuroendocrineregulatory mechanisms appear to be intact inthe maternal adenohypophysis. Pituitary ACTH andTSH secretion remain unchanged. Serum FSH andLH fall to the lower limits of detectability and areunresponsive to GnRH stimulation. GH concentrationsare not significantly different from nonpregnantlevels, but pituitary response to provocative testing ismarkedly altered. GH response to hypoglycemia andarginine infusion is enhanced in early pregnancy butthereafter becomes depressed. Established pregnancycan continue in the face of hypophysectomy, and inwomen hypophysectomized prior to pregnancy, inductionof ovulation and normal pregnancy can beachieved with appropriate replacement therapy. Incases of primary pituitary hyperfunction, the fetus isnot affected.Maternal Thyroid GlandThe thyroid becomes palpably enlarged during the firsttrimester, and a bruit may be present. Thyroid iodideclearance and thyroidal 131I uptake, which are clinicallycontraindicated in pregnancy, have been shown to beincreased. These changes are due in large part to theincreased renal clearance of iodide, which causes a relativeiodine deficiency. Although total serum thyroxineis elevated as a result of estrogen-stimulated increasedthyroid hormone-binding globulin (TBG), free thyroxineand triiodothyronine are normal (Figure 17–1).High circulating concentrations of hCG, particularlyasialo-hCG, which has weak TSH-like activity, contributesto the thyrotropic action of the placenta in earlypregnancy. In fact, there is often a significant thoughtransient biochemical hyperthyroidism associated withhCG stimulation in early gestation.

Maternal Parathyroid GlandThe net calcium requirement imposed by fetal skeletaldevelopment is estimated to be about 30 g by term. Thisis met by hyperplasia of the maternal parathyroid glandsand elevated serum levels of parathyroid hormone. Thematernal serum calcium concentration declines to a nadirat 28–32 weeks, largely due to the hypoalbuminemia ofMaternal PancreasThe nutritional demands of the fetus require alterationof maternal metabolic homeostatic control, whichresults in both structural and functional changes in thematernal pancreas. The size of pancreatic islets increases,and insulin-secreting cells undergo hyperplasia. Basallevels of insulin are lower or unchanged in early pregnancybut increase during the second trimester. Thereafter,pregnancy is a hyperinsulinemic state, with resistanceto the peripheral metabolic effects of insulin.The increased concentration of insulin has been shownto be a result of increased secretion rather thandecreased metabolic clearance. The measured half-lifefor insulin is unchanged in pregnant women. Theeffects of pregnancy on the pancreas can be mimickedby appropriate treatment with estrogen, progesterone,hPL, and corticosteroids.Pancreatic production of glucagon remains responsiveto usual stimuli and is suppressed by glucose loading,although the degree of responsiveness has not beenwell evaluated.The major role of insulin and glucagon is the intracellulartransport of nutrients, specifically glucose, aminoacids, and fatty acids. These concentrations are regulatedduring pregnancy for fetal as well as maternal needs, andthe pre- and postfeeding levels cause pancreatic responsesthat act to support the fetal economy. Insulin is nottransported across the placenta but rather exerts its effectson transportable metabolites. During pregnancy, peakinsulin secretion in response to meals is accelerated, andglucose tolerance curves are characteristically altered.Fasting glucose levels are maintained at low normal levels.Excess carbohydrate is converted to fat, and fat isreadily mobilized during decreased caloric intake.

Amino acid metabolism also is altered during pregnancyat the expense of maternal needs. Because alanine,the key amino acid for gluconeogenesis, is preferentiallytransported to the fetus, maternal hypoglycemialeads to lipolysis.The normal metabolic effects of pregnancy are toreduce glucose levels modestly but to reserve glucose forfetal needs while maternal energy requirements are metincreasingly by the peripheral metabolism of fatty acids.These changes in energy metabolism are beneficial tothe fetus and innocuous to the mother with an adequatediet. Even modest fasting, however, can causeketosis, which is potentially injurious to the fetus.

Maternal Adrenal CortexA. GLUCOCORTICOIDSTotal plasma cortisol concentrations increase to threetimes nonpregnant levels by the third trimester. Mostof the change can be explained by increased corticosteroid-binding globulin (CBG). The increased estrogenlevels of pregnancy cause an increase in CBG, which, inturn, is sufficient to account for decreased catabolism ofcortisol by the liver. The result is a doubling of the halflifeof plasma cortisol. The actual production of cortisolby the zona fasciculata also is increased in pregnancy.The net effect of these changes is an increase in plasmafree cortisol, which is approximately doubled by latepregnancy. Whether this increase is mediated throughACTH or by other mechanisms is not known. In spiteof cortisol concentrations approaching those found inCushing’s syndrome, diurnal variation in plasma cortisolis maintained. The elevated free cortisol probablycontributes to the insulin resistance of pregnancy andpossibly to the appearance of striae, but most signs ofhypercortisolism do not occur in pregnancy. It is suggestedthat high progesterone levels act to antagonizeglucocorticoid effects.B. MINERALOCORTICOIDS AND THERENIN-ANGIOTENSIN SYSTEMSerum aldosterone is markedly elevated in pregnancy.The increase is due to an eight-fold increased productionof aldosterone by the zona glomerulosa and not toincreased binding or decreased clearance. The peak inaldosterone production is reached by midpregnancyand is maintained until delivery. Renin substrate isincreased due to the influence of estrogen on hepaticsynthesis, and renin also is increased.The increases in both renin and renin substrate inevitablylead to increases in renin activity and angiotensin.In spite of these dramatic changes, normal pregnantwomen show few signs of hyperaldosteronism. There isno tendency to hypokalemia or hypernatremia, andblood pressure at midpregnancy—when changes in thealdosterone-renin-angiotensin system are maximal—tends to be lower than in the nonpregnant state.Although the quantitative aspects of this apparentparadox are not fully understood, a qualitative explanationis possible. Progesterone is an effective competitiveinhibitor of mineralocorticoids in the distal renaltubules. Exogenous progesterone (but not synthetic progestins)is natriuretic and potassium-sparing in intacthumans, whereas it has no effect in adrenalectomizedsubjects not receiving mineralocorticoids. Progesteronealso blunts the response of the kidney to exogenousaldosterone—thus, the increases in renin and aldosteronemay simply be an appropriate response to the highgestational levels of progesterone. The concomitantincrease in angiotensin II as a result of increased plasmarenin activity does not normally result in hypertension,

because of diminished sensitivity of the maternal vascularsystem to angiotensin. Even during the first trimester,exogenous angiotensin provokes less of a rise inblood pressure than in the nonpregnant state.It is clear that the high levels of renin, angiotensin,and aldosterone in pregnant women are subject to theusual feedback controls, because they respond appropriatelyto changes in posture, dietary sodium, and waterloading and restriction in qualitatively the same way asthey do in nonpregnant women. Finally, in patientswith preeclampsia, the most common form of pregnancy-related hypertension, serum renin, aldosterone,and angiotensin levels are unchanged or even lowerthan in normal pregnancy, thus ruling out any primaryrole for the renin-angiotensin system in this disorder.Production of the mineralocorticoid 11-deoxycorticosterone(DOC) rises throughout pregnancy, and plasmalevels six to ten times normal are achieved by term. Incontrast to the nonpregnant state, DOC production inpregnancy is unaffected by ACTH or glucocorticoidadministration. Fetal pregnenolone-3,21-disulfate servesas a placental precursor of maternal DOC. DOC is notelevated in hypertensive disorders of pregnancy.C. ANDROGENSIn normal pregnancy, the maternal production ofandrogens is slightly increased. The most importantdeterminant of plasma levels of specific androgens, however,appears to be whether or not the androgen binds tosex hormone-binding globulin (SHBG). Testosterone,which binds avidly to SHBG, increases to the normalmale range by the end of the first trimester, but free testosteronelevels are actually lower than in the nonpregnantstate. DHEA sulfate does not bind significantly toSHBG, and plasma concentrations of DHEA sulfateactually decrease during pregnancy. The desulfation ofDHEA sulfate by the placenta and the conversion ofDHEA sulfate to estrogens by the fetal-placental unit areimportant factors in its increased metabolic clearance.

FETAL ENDOCRINOLOGYBecause of the physical inaccessibility of the fetus,much of our information about fetal endocrinology isderived indirectly. Most early studies of fetal endocrinologyrelied on observations of infants with congenitaldisorders or inferences from ablation studies or acutemanipulation in experimental animals. The developmentof effective cell culture methods and sensitiveimmunoassays, as well as the ability to achieve stablepreparations of chronically catheterized monkey fetuses,has increased our understanding of the dynamics ofintrauterine endocrine events.Study of the fetal endocrine system is further complicatedby the multiplicity of sources of the varioushormones. Inferences from the behavior of adult endocrinesystems are not transferable to the fetus, because

target organs, receptors and other modulators developat different times.Dating of events in fetal development is usuallygiven in “fetal weeks,” which begin at the time of fertilization.Thus, fetal age is always 2 weeks less than gestationalage.Human fetal growth is influenced by endocrine andhemodynamic factors that dictate the distribution ofnutrients between the mother and the conceptus. Themain metabolic substrates for fetal and placental growthare glucose, lactate, amino acids, and lipids. A variety ofplacental transport proteins regulate the partitioning ofthese nutrients. In addition, placental hormones such ashPL, GH-variant, and IGF-I and IGF-II are secretedinto the maternal and fetal circulations where theymodulate energy metabolism and fetal growth.The endocrine system is among the first to developin fetal life. Differentiation of the gonads is crucial fornormal male sexual development and reproductivepotential in both sexes.Fetal Anterior Pituitary HormonesThe characteristic anterior pituitary cell types are discernibleas early as 8–10 fetal weeks, and all of the hormonesof the adult anterior pituitary are extractablefrom the fetal adenohypophysis by 12 weeks. Similarly,the hypothalamic hormones thyrotropin-releasing hormone(TRH), GnRH, and somatostatin are present by8–10 weeks. The direct circulatory connection betweenhypothalamus and pituitary develops later, with capillaryinvasion initially visible at about 16 weeks.The role of the fetal pituitary in organogenesis of varioustarget organs during the first trimester appears to benegligible. None of the pituitary hormones are releasedinto the fetal circulation in large quantities until after 20fetal weeks. Even GH appears not to be influential, andin fact total absence of GH is consistent with normaldevelopment at birth. Development of the gonads andadrenals during the first trimester appears to be directedby hCG rather than by fetal pituitary hormones.During the second trimester, there is a markedincrease in secretion of all of the anterior pituitary hormones,which coincides with maturation of the hypophysialportal system. Observations include a markedrise in production of GH and an increase in fetal serumTSH, with a concomitant increase in fetal thyroidaliodine uptake. Gonadotropin production also increases,with the female achieving higher FSH levels in bothpituitary and serum than does the male. The fetalgonadotropins do not direct the events of early gonadaldevelopment but are essential for normal developmentof the differentiated gonads and external genitalia.ACTH rises significantly during the second trimesterand assumes an increasing role in directing the maturationof the differentiated adrenal, as shown by the anencephalicfetus, in which the fetal zone of the adrenal

undergoes atrophy after 20 weeks. Fetal PRL secretionalso increases after the 20th fetal week, but the functionalsignificance of this hormone, if any, is unknown.During the third trimester, maturation of feedbacksystems modulating hypothalamic release signals causesserum concentrations of all of the pituitary hormonesexcept PRL to decline.Fetal Posterior Pituitary HormonesVasopressin and oxytocin are demonstrable by 12–18weeks in the fetal posterior pituitary gland and correlatewith the development of their sites of production, thesupraoptic and paraventricular nuclei, respectively. Thehormone content of the gland increases toward term,with no evidence of feedback control.During labor, umbilical artery oxytocin is higherthan umbilical vein oxytocin. It has been suggested thatthe fetal posterior pituitary may contribute to the onsetor maintenance of labor.Fetal Thyroid GlandThe thyroid gland develops in the absence of detectableTSH. By 12 weeks the thyroid is capable of iodine-concentratingactivity and thyroid hormone synthesis.During the second trimester, TRH, TSH, and freeT4 all begin to rise. The maturation of feedback mechanismsis suggested by the subsequent plateau of TSH atabout 20 fetal weeks. Fetal T3 and reverse T3 do notbecome detectable until the third trimester. The hormoneproduced in largest amount throughout fetal lifeis T4, with the metabolically active T3 and its inactivederivative, reverse T3, rising in parallel to T4 during thethird trimester. At birth, conversion of T4 to T3

becomes demonstrable.The development of thyroid hormones occurs independentlyof maternal systems, and very little placental

transfer of thyroid hormone occurs in physiologic concentrations.This prevents maternal thyroid disordersfrom affecting the fetal compartment but also preventseffective therapy for fetal hypothyroidism throughmaternal supplementation. Goitrogenic agents such aspropylthiouracil are transferred across the placenta andmay induce fetal hypothyroidism and goiter.The function of the fetal thyroid hormones appearscrucial to somatic growth and for successful neonataladaptation. Many auditory maturational events may beregulated by thyroid hormones.Fetal Parathyroid GlandThe fetal parathyroid is capable of synthesizing parathyroidhormone by the end of the first trimester. However,the placenta actively transports calcium into thefetal compartment, and the fetus remains relativelyhypercalcemic throughout gestation. This contributesto a suppression of parathyroid hormone, and fetalserum levels in umbilical cord have been reported to below or undetectable. Fetal serum calcitonin levels are

elevated, enhancing bone accretion. Fetal vitamin Dlevels reflect maternal levels but do not appear to beimportant in fetal calcium metabolism.Fetal Adrenal CortexThe fetal adrenal differs anatomically and functionallyfrom the adult gland. The cortex is identifiable as earlyas 4 weeks of fetal age, and by the seventh week, steroidogenicactivity can be detected in the inner zonelayers.By 20 weeks, the adrenal cortex has increased to amass that is considerably larger than its relative postnatalsize. During gestation, it occupies as much as 0.5% oftotal body volume, and most of this tissue is composed ofa unique fetal zone that subsequently regresses or is transformedinto the definitive (adult) zone during the earlyneonatal period. The inner fetal zone is responsible forthe majority of steroids produced during fetal life andcomprises 80% of the mass of the adrenal. During thesecond trimester, the inner fetal zone continues to grow,while the outer zone remains relatively undifferentiated.At about 25 weeks, the definitive (adult) zone develops,ultimately assuming the principal role in steroid synthesisduring the early postnatal weeks.Fetal GonadsThe testis is an identifiable structure by about 6 fetalweeks. Primary testis differentiation begins with developmentof the Sertoli cells at 8 weeks’ gestation. SRY is thesex-determining locus on the Y chromosome whichdirects the differentiation of the Sertoli cells, the sites ofmüllerian-inhibiting substance (MIS) synthesis. MIS, amember of the transforming growth factor family ofgrowth factors, specifically triggers the ipsilateral resorptionof the müllerian tract in males and prevents developmentof female internal structures. Embryonic androgenproduction begins in the developing Leydig cells at about10 weeks, coincident with the peak production of placentalhCG. Binding of hCG to fetal testes with stimulationof testosterone release has been demonstrated in thelaboratory. Other fetal testicular products of importanceare inhibin and the reduced testosterone metabolite dihydrotestosterone.Dihydrotestosterone is responsible fordevelopment of the external genital structures.Little is known about fetal ovarian function, but by7–8 weeks of intrauterine life the ovaries become recognizable.Oogonia mitosis is active and steroid-producingtheca cell precursors are identifiable at 20 weeks.This corresponds with peak gonadotropin levels fromthe fetal pituitary. Activin and inhibin peptide subunitsare expressed in the midtrimester human testis but notin the midtrimester human ovary. In contrast to themale fetus, ovarian steroid production is not essentialfor female phenotypic development (see Chapter 14).ENDOCRINE CONTROL OF PARTURITIONDuring the last few weeks of normal pregnancy, twoprocesses herald approaching labor. Uterine contractions,

usually painless, become increasingly frequent,and the lower uterine segment and cervix become softerand thinner, a process known as effacement, or “ripening.”Although false alarms are not uncommon, theonset of true labor is usually fairly abrupt, with theestablishment of regular contractions every 2–5 minutes,leading to delivery in less than 24 hours. An extensiveliterature describes the physiologic and biochemicalevents that occur during human labor, but the keyinciting event has eluded detection. In sheep, the fetuscontrols the onset of labor. The initial measurable eventis an increase in fetal plasma cortisol, which, in turn,alters placental steroid production, resulting in a dropin progesterone. Cortisol reliably induces labor insheep, but in humans, glucocorticoids do not inducelabor and there is no clear drop in plasma progesteroneprior to labor. Emerging primate data suggest that atthe time of parturition, an increase in the ratio of therepressor progesterone receptor-A to the active progesteronereceptor-B may lead to functional suppression ofprogesterone action and subsequent parturition. Recentclinical trials have indicated that the administration of17-hydroxyprogesterone caproate can reliably preventpreterm delivery in high-risk pregnancies, but this agentis ineffective once the labor cascade is initiated.A role for placental CRH in the regulation of parturitionis suspected, given the sharp increase in placentalCRH mRNA from 28 weeks of gestation until delivery.Three weeks before the onset of labor, the exponentialrise in plasma CRH is accompanied by an abrupt fall in

CRH-binding protein. Glucocorticoids enhance placentalCRH expression—thus, the rise in placentalCRH that precedes parturition could result from therise in fetal glucocorticoids that occurs at this time. PlacentalCRH may stimulate—via an increase in fetalpituitary ACTH—a rise in fetal glucocorticoids, completinga positive feedback loop that would be terminatedby delivery. Further evidence for a role of CRHin parturition is seen in studies showing CRH receptorsin the myometrium and fetal membranes, CRH-stimulatingprostaglandin release from human decidua andamnion, and, finally, the CRH-induced augmentationof oxytocin and prostaglandin F2 actions.Failure to identify a single initiating event in humanlabor suggests that there is more than one. Approachingthe matter in a different way, one could ask: What arethe factors responsible for maintenance of uterine quiescence,and how do they fail?Sex SteroidsProgesterone is essential for maintenance of early pregnancy,and withdrawal of progesterone leads to terminationof pregnancy. Progesterone causes hyperpolarization of themyometrium, decreasing the amplitude of action potentialsand preventing effective contractions. In various experimental

systems, progesterone decreases alpha-adrenergicreceptors, stimulates cAMP production, and inhibits oxytocinreceptor synthesis. Progesterone also inhibits estrogenreceptor synthesis in uterine epithelium, promotes the storageof prostaglandin precursors in the decidua and fetalmembranes, and stabilizes the lysosomes containing prostaglandin-synthesizing enzymes. Estrogen opposes progesteronein many of these actions and may have an independentrole in ripening the uterine cervix and promotinguterine contractility. Thus, the estrogen:progesterone ratiomay be an important parameter. In a small series ofpatients, an increase in the estrogen:progesterone ratio hasbeen shown to precede labor. Thus, for some individuals, adrop in progesterone or an increase in estrogen may initiatelabor. The cause of the change in steroids may be placentalmaturation or a signal from the fetus, but there are no datato support either thesis. It has been shown that an increasein the estrogen:progesterone ratio increases the number ofoxytocin receptors and myometrial gap junctions; this findingmay explain the coordinated, effective contractions thatcharacterize true labor as opposed to the nonpainful, ineffectivecontractions of false labor.OxytocinOxytocin infusion is commonly used to induce or augmentlabor. Both maternal and fetal oxytocin levelsincrease spontaneously during labor, but neither has beenconvincingly shown to increase prior to labor. Data inanimals suggest that oxytocin’s role in initiation of labor isdue to increased sensitivity of the uterus to oxytocinrather than increased plasma concentrations of the hormone.Even women with diabetes insipidus are able todeliver without oxytocin augmentation; thus a maternalsource of the hormone is not indispensable. Clinical studiesusing the oxytocin receptor inhibitor, atosiban, havedemonstrated a delay of delivery for 24–48 hours.ProstaglandinsProstaglandin F2administered intra-amniotically orintravenously is an effective abortifacient as early as 14weeks of gestation. Prostaglandin E2 administered byvagina induces labor in most women in the third trimester.The amnion and chorion contain high concentrationsof arachidonic acid, and the decidua containsactive prostaglandin synthetase. Prostaglandins arealmost certainly involved in maintenance of labor onceit is established. They also probably are important ininitiating labor in some circumstances, such as inamnionitis or when the membranes are “stripped” bythe physician. They are believed to be the “final commonpathway” of labor.Prostaglandin synthetase inhibitors can suppress pretermlabor, but their clinical usefulness has been restrictedby their simultaneous effect of closing the ductus arteriosus,which can lead to fetal pulmonary hypertension.CatecholaminesCatecholamines with 2-adrenergic activity cause uterine

contractions, whereas 2-adrenergics inhibit labor. Progesteroneincreases the ratio of beta receptors to alphareceptors in myometrium, thus favoring continued gestation.There is no evidence that changes in catecholaminesor their receptors initiate labor, but it is likely that suchchanges help sustain labor once initiated. The betaadrenergicdrug ritodrine was once used in the managementof preterm labor. Alpha-adrenergic agents have notbeen useful in inducing labor, because of their cardiovascularside effects.Nitric OxideUterine smooth muscle also may be affected by nitricoxide, which acts as a uterine smooth muscle relaxant.Some laboratory findings suggest that uterine nitric oxideproduction decreases at term and that inhibitors of nitricoxide synthesis might some day be used to initiate oraugment human labor.ENDOCRINOLOGY OFTHE PUERPERIUMExtirpation of any active endocrine organ leads to compensatorychanges in other organs and systems. Delivery