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Basic and Clinical Endocrinology 7th International student edition Edition

16

The Endocrinology of Pregnancy

Robert N. Taylor MD, PhD

Dan I. Lebovic MD, MA

Throughout pregnancy, the fetal-placental unit secretes protein and steroid hormones into the mother's bloodstream, and these apparently or actually 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 polycystic ovary syndrome.

The endocrine changes associated with pregnancy are adaptive, allowing the mother to nurture the developing fetus. Although maternal reserves are usually adequate, occasionally, as in the case of gestational diabetes or hypertensive disease of pregnancy, a woman may develop overt signs of disease as a direct result of pregnancy.

Aside from creating a satisfactory maternal environment for fetal development, the placenta serves as a repository endocrine gland as well as a respiratory, alimentary, and excretory organ. Measurements of fetal-placental products in the maternal serum provide one means of assessing fetal well-being. This chapter will consider the changes in maternal endocrine function in pregnancy and during parturition as well as fetal endocrine development. The chapter concludes with a discussion of some endocrine disorders complicating pregnancy.

CONCEPTION & IMPLANTATION

Fertilization

In fertile women, ovulation occurs approximately 12–16 days after the onset of the previous menses. The ovum must be fertilized within 24–48 hours if conception is 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 conduit for sperm. Following intercourse, sperm that are to survive penetrate the cervical mucus within minutes and can remain viable there until the mucus character changes, approximately 24 hours following ovulation. Sperm begin appearing in the outer third of the uterine

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tube (the ampulla) 5–10 minutes after coitus and continue to migrate to this location from the cervix for about 24–48 hours. Of the 200 × 106sperm that are deposited in the vaginal fornices, only approximately 200 reach the distal uterine tube. Fertilization normally occurs in the ampulla.

Implantation

Implantation in the uterus does not occur until 8–10 days after ovulation and fertilization, when the conceptus is a blastocyst. In most pregnancies, the dates of ovulation and implantation are not known. Weeks of gestation (“gestational age”) are by convention calculated from the first day of the last menstrual period. Within 24 hours after implantation, or at about 3 weeks of gestation, human chorionic gonadotropin (hCG) is detectable in maternal serum. Under the influence of increasing hCG production, the corpus luteum continues to secrete steroid hormones in increasing quantities. Without effective implantation and subsequent hCG production, the corpus luteum survives for only about 14 days following ovulation.

Symptoms & Signs of Pregnancy

Breast tenderness, fatigue, nausea, absence of menstruation, softening of the uterus, and a sustained elevation of basal body temperature are all attributable to hormone production by the corpus luteum and developing placenta.

Ovarian Hormones of Pregnancy

The hormones produced by the corpus luteum include progesterone, 17-hydroxyprogesterone, and estradiol. The indispensability of the corpus luteum in early pregnancy has been demonstrated by ablation studies, in which luteectomy or oophorectomy before 42 days of gestation results in precipitous decreases in levels of serum progesterone and estradiol, followed by abortion. Exogenous progesterone will prevent abortion, proving that progesterone alone is required for maintenance of early pregnancy. After about the seventh gestational week, the corpus luteum can be removed without subsequent abortion owing to compensatory progesterone production by the placenta.

Because the placenta does not produce appreciable amounts of 17-hydroxyprogesterone, this steroid provides a marker of corpus luteum function. As shown in Figure 16-1, the serum concentrations of estrogens and total progesterone exhibit a steady increase, but the concentration of 17-hydroxyprogesterone rises and then declines to low levels that persist for the duration of the pregnancy. The decline of corpus luteum function occurs despite the continued production of hCG; in fact, corpus luteum production of 17-hydroxyprogesterone declines while hCG is still rising to maximal levels. Whether this is due to down-regulation of corpus luteal hCG receptors is not known.

Another marker of corpus luteum function is the polypeptide hormone relaxin, a protein with a molecular mass of about 6000. It is similar in its tertiary structure to insulin. Relaxin becomes detectable at about the same time as hCG begins to rise, and it maintains a maximum maternal serum concentration of about 1 ng/mL during the first trimester. The serum concentration then falls approximately 20% and is constant for the remainder of the pregnancy.

Pharmacologically, relaxin ripens the cervix, softens the pubic symphysis, and acts synergistically with progesterone to inhibit uterine contractions. A major physiologic role for relaxin in human gestation has not been established. Luteectomy after 7 weeks of gestation does not interfere with gestation in spite of undetectable relaxin levels. Extraluteal production of relaxin by the decidua and placenta has been demonstrated, however, and local effects may be exerted without alteration of systemic hormone concentrations.

FETAL-PLACENTAL-DECIDUAL UNIT

The function of the placenta is to establish effective communication between the mother and the developing fetus while maintaining the immune and genetic integrity of both individuals. Initially, the placenta functions autonomously. By the end of the first trimester, however, the fetal endocrine system is sufficiently developed to influence placental function and to provide some hormone precursors to the placenta. From this time, it is useful to consider the conceptus as the fetal-placental unit.

The fetal-placental unit will be considered in three separate but related categories: (1) as a source of secretion of protein and steroid hormones into the maternal circulation; (2) as a participant in the control of fetal endocrine function, growth, and development; and (3) as a selective barrier governing the interaction between the fetal and maternal systems.

Within 8 days after fertilization, implantation begins. The alpha-v-beta-3 integrin vitronectin receptor may serve as a link between the maternal and embryonic epithelia. The trophoblast invades the endometrium, and two layers of developing placenta can be demonstrated. Columns of invading cytotrophoblasts anchor the placenta to the endometrium. The differentiated syncytiotrophoblast, also derived from precursor cytotrophoblasts, is in direct contact with the maternal circulation. The syncytiotrophoblast is the major source of hormone production, containing the

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cellular machinery needed for synthesis, packaging, and secretion of both steroid and polypeptide hormones.

 

Figure 16-1. Maternal serum hormone changes during pregnancy.

The decidua is the endometrium of pregnancy. Recent investigation has shown that the decidual cells are capable of synthesizing a variety of polypeptide hormones, including prolactin (PRL), relaxin, and a variety of paracrine factors, in particular IGF-binding protein I. The role of the decidua as an endocrine organ has not been established, but its role as a source of prostaglandins during labor is certain (see Endocrine Control of Parturition, below).

Modern methods of screening for fetal chromosomal aneuploidy, particularly trisomy 21 (Down's syndrome), utilize circulating biochemical markers. Screening by maternal age alone (> 35 years) led to the prenatal identification of only about 25% of aneuploid fetuses. As an aneuploid chromosome complement affects both fetal and placental tissues, their protein and steroid products have been evaluated. A combination of alpha-fetoprotein, hCG, and unconjugated estriol concentrations, secreted into and measured in maternal serum between 15 and 18 weeks' gestation, can be used to identify fetal Down's syndrome and trisomy 18 with a detection rate of 60% over all age groups.

POLYPEPTIDE HORMONES

Human Chorionic Gonadotropin

The first marker of trophoblast differentiation and the first measurable product of the placenta is chorionic gonadotropin (hCG). hCG is a glycoprotein consisting of about 237 amino acids. It is quite similar in structure to the pituitary glycoproteins in that it consists of two chains: an alpha chain, which is species-specific; and a beta chain, which determines receptor interaction and ultimate biologic effect. The alpha chain is identical in sequence to the alpha chains of the hormonal glycoproteins TSH, FSH, and LH. The beta chain has significant sequence homology with LH but is not identical; of the 145 amino acids in β-hCG, 97 (67%) are identical to those of β-LH. In addition, the placental hormone has a carboxyl terminal segment of 30 amino acids not found in the pituitary LH molecule. Carbohydrate constitutes approximately 30% by weight of each subunit. Sialic acid alone accounts for 10% of the weight of the molecule and confers a high degree of resistance to degradation and consequently a long plasma half-life of about 24 hours.

In the early weeks of pregnancy (up to 6 weeks), the concentration of hCG doubles every 1.7–2 days, and serial measurements provide a sensitive index of early trophoblast function. Maternal plasma hCG peaks at about 100,000 mIU/mL during the tenth gestational week and then declines gradually to about 10,000 mIU/mL in the third trimester. Peak concentrations correlate temporally with the establishment of maternal blood flow in the intervillous space (Figure 16-1).

These characteristics of hCG all contribute to the possibility of diagnosing pregnancy several days before any symptoms occur or a menstrual period has been missed. Without the long plasma half-life of hCG (24 hours), the tiny mass of cells comprising the blastocyst could not produce sufficient hormone to be detected in the peripheral circulation within 24 hours of implantation. Antibodies to the unique β-carboxyl terminal segment of hCG do not cross-react significantly with any of the pituitary glycoproteins. As little as 5 mIU/mL (1 ng/mL) of hCG in plasma can be detected without interference from the higher levels of LH, FSH, and TSH.

Like its pituitary counterpart LH, hCG is luteotropic, and the corpus luteum has high-affinity receptors for hCG. The stimulation of increased amounts of progesterone production by corpus luteum cells is driven by increasing concentrations of hCG. Steroid synthesis can be demonstrated in vitro and is mediated by the cAMP system. hCG has been shown to enhance placental conversion of maternal low-density lipid cholesterol to pregnenolone and progesterone.

The concentration of hCG in the fetal circulation is less than 1% of that found in the maternal compartment. However, there is evidence that fetal hCG is an important regulator of the development of the fetal adrenal and gonad during the first trimester.

hCG is also produced by trophoblastic neoplasms such as hydatidiform mole and choriocarcinoma, and the concentration of hCG or its beta subunit is used as a tumor marker, for diagnosis, and for monitoring the success or failure of chemotherapy in these disorders. Women with very high hCG levels due to trophoblastic disease may become clinically hyperthyroid and revert to euthyroidism as hCG is reduced during chemotherapy.

Human Placental Lactogen

A second placental polypeptide hormone, also with homology to a pituitary protein, is termed placental lactogen (hPL). hPL is detectable in the early trophoblast, but detectable serum concentrations are not reached until 4–5 gestational weeks (Figure 16-1). hPL is a protein of about 190 amino acids whose primary, secondary, and tertiary structures are similar to those of growth hormone (GH). The two molecules cross-react in immunoassays and in some receptor and bioassay systems. However, hPL has only some of the biologic activities of GH. Like GH, hPL is diabetogenic, but it

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has minimal growth-promoting activity as measured by standard GH bioassays. hPL also shares many structural features with prolactin (PRL).

The physiologic role of hPL during pregnancy remains controversial, and normal pregnancy without detectable hPL production has been reported. Although not clearly shown to be a mammotropic agent, hPL contributes to altered maternal glucose metabolism and mobilization of free fatty acids; causes a hyperinsulinemic response to glucose loads; appears to directly stimulate pancreatic islet insulin secretion; and contributes to the peripheral insulin resistance characteristic of pregnancy. Along with prolonged fasting and insulin-induced hypoglycemia, pre-beta-HDL and apoprotein A-I are two factors that stimulate release of hPL. hPL production is roughly proportionate to placental mass. Actual production rates may reach as much as 1–1.5 g/d. The disappearance curve shows multiple components but yields a serum half-life of 15–30 minutes. Serum hPL concentration had been proposed as an indicator of the continued health of the placenta, but the range of normal values is wide, and serial determinations are necessary. hPL determinations have largely been replaced by biophysical profiles, which are more sensitive indicators of fetal jeopardy.

Other Chorionic Peptide Hormones & Growth Factors

Other chorionic peptides have been identified, but their functions have not yet been defined. One of these proteins is a glycoprotein with partial sequence and functional homology to TSH. Its existence as a separate entity from hCG has been debated in the literature, with some reports suggesting that chorionic TSH is a protein with a molecular weight of about 28,000, structurally different from hCG, with weak thyrotropic activity. Similarly, ACTH-like, lipotropin-like, and endorphin-like peptides have been isolated from placenta, but they have low biologic potency and undetermined physiologic roles. A chorionic FSH-like protein has also been isolated from placenta but has not yet been detected in plasma. Good evidence exists that the cytotrophoblast produces a human chorionic gonadotropin-releasing hormone that is biologically and immunologically indistinguishable from the hypothalamic GnRH. The release of hCG from the syncytiotrophoblast may be under the direct control of this factor, in a fashion analogous to the hypothalamic control of anterior pituitary secretion of gonadotropins. Preliminary evidence is also available for similar paracrine control of syncytiotrophoblastic release of TSH, somatostatin, and corticotropin by analogous cytotrophoblastic releasing hormones. Activin, inhibin, corticotropin-releasing factor, and multiple peptide growth factors, including fibroblast growth factor (FGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and the insulin-like growth factors (IGFs)—and many of their cognate receptors—have all been isolated from placental tissue. Placental EGF and the related TGFα have been suggested to play a role in fetal growth.

STEROID HORMONES

In contrast to the impressive synthetic capability exhibited in the production of placental proteins, the placenta does not appear to have the capability to synthesize steroids de novo. All steroids produced by the placenta are derived from maternal or fetal precursor steroids.

No tissue, however, even remotely approaches the syncytiotrophoblast in its capacity to efficiently interconvert steroids. This activity is demonstrable even in the early blastocyst, and by the seventh gestational week, when the corpus luteum has undergone relative involution, the placenta becomes the dominant source of steroid hormones.

Progesterone

The placenta relies on maternal cholesterol as its substrate for progesterone production. Fetal death has no immediate influence on progesterone production, suggesting that the fetus is a negligible source of substrate. Enzymes in the placenta cleave the cholesterol side chain, yielding pregnenolone, which in turn is partially isomerized to progesterone; 250–350 mg of progesterone is produced daily by the third trimester, and most enters the maternal circulation. The maternal plasma concentration of progesterone rises progressively throughout pregnancy and appears to be independent of factors that normally regulate steroid synthesis and secretion (Figure 16-1). Whereas exogenous hCG increases progesterone production in pregnancy, hypophysectomy has no effect. Administration of ACTH or cortisol does not influence progesterone concentrations, nor does adrenalectomy or oophorectomy after 7 weeks.

Progesterone is necessary for establishment and maintenance of pregnancy. Insufficient corpus luteum production of progesterone may contribute to failure of implantation, and luteal phase deficiency is implicated in some cases of infertility and recurrent pregnancy loss. Furthermore, progesterone, along with nitric oxide (NO), seems to maintain uterine quiescence during pregnancy. Progesterone also may act as an immunosuppressive agent in some systems and inhibits T cell-mediated tissue rejection. Thus, high local concentrations of progesterone may contribute to immunologic

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tolerance by the uterus of invading embryonic trophoblast tissue.

Estrogens

Estrogen production by the placenta also depends on circulating precursors, but in this case both fetal and maternal steroids are important sources. Most of the estrogens are derived from fetal androgens, primarily dehydroepiandrosterone sulfate (DHEA sulfate). Fetal DHEA sulfate, produced mainly by the fetal adrenal, is converted by placental sulfatase to the free dehydroepiandrosterone (DHEA) and then, through enzymatic pathways common to steroid-producing tissues, to androstenedione and testosterone. These androgens are finally aromatized by the placenta to estrone and estradiol, respectively.

Placental corticotropin-releasing hormone (CRH) may be an important regulator of fetal adrenal DHEA sulfate secretion. The greater part of fetal DHEA sulfate is metabolized to produce a third estrogen: estriol. Estriol is a weak estrogen with one-tenth the potency of estrone and one-hundredth the potency of estradiol. While serum estrone and estradiol concentrations are increased during pregnancy about 50-fold over their maximal prepregnancy values, estriol increases approximately 1000-fold. The key step in estriol synthesis is 16α-hydroxylation of the steroid molecule (Figure 13-4). The substrate for the reaction is primarily fetal DHEA sulfate, and the vast majority of the production of the 16α-hydroxy-DHEA sulfate occurs in the fetal adrenal and liver, not in maternal or placental tissues. The final steps of desulfation and aromatization to estriol occur in the placenta. Maternal serum or urinary estriol measurements, unlike measurements of progesterone or hPL, reflect fetal as well as placental function. Normal estriol production, therefore, reflects the integrity of fetal circulation and metabolism as well as adequacy of the placenta. Rising serum or urinary estriol concentrations are the best available biochemical indicator of fetal well-being (Figure 16-1). 17-Hydroxysteroid dehydrogenase type II prevents fetal exposure to potent estrogens by catalyzing the conversion of estradiol to less potent estrone.

There are some circumstances in which decreased estriol production is the result of congenital derangements or iatrogenic intervention. Maternal estriol remains low in pregnancies with placental sulfatase deficiency and in cases of fetal anencephaly. In the first case, DHEA sulfate cannot be hydrolyzed; in the second, little fetal DHEA is produced because fetal adrenal stimulation by ACTH is lacking. Maternal administration of glucocorticoids inhibits fetal ACTH and lowers maternal estriol. Administration of DHEA to the mother during a healthy pregnancy increases estriol production. Antibiotic therapy can reduce estriol levels by interfering with bacterial glucuronidases and maternal reabsorption of estriol from the gut. Estetrol, an estrogen metabolite with a fourth hydroxyl at the 16 position, is unique to pregnancy.

Cases of aromatase deficiency and estrogen receptor mutations indicate that estrogen action is not mandatory for the maintenance of pregnancy. Homozygous mutant mice with disrupted estrogen receptor genes undergo apparently normal blastocyst, fetal, and placental development. This observation has been corroborated by a clinical case of a spontaneous missense mutation of the estrogen receptor in a man.

MATERNAL ADAPTATION TO PREGNANCY

As a successful “parasite,” the fetal-placental unit manipulates the maternal “host” for its own gain but normally avoids imposing excessive stress that would jeopardize the “host” and thus the “parasite” itself. The prodigious production of polypeptide and steroid hormones by the fetal-placental unit directly or indirectly results in physiologic adaptations of virtually every maternal organ system. These alterations are summarized in Figure 16-2. Most of the commonly measured maternal endocrine function tests are radically changed. In some cases, true physiologic alteration has occurred; in others, the changes are due to increased production of specific serum binding proteins by the liver or to decreased serum levels of albumin. Additionally, some hormonal changes are mediated by altered clearance rates owing to increased glomerular filtration, decreased hepatic excretion of metabolites, or metabolic clearance of steroid and protein hormones by the placenta. The changes in endocrine function tests are summarized in Table 16-1. Failure to recognize normal pregnancy-induced alterations in endocrine function tests can lead to unnecessary diagnostic tests and therapy that may be seriously detrimental to mother and fetus.

Maternal Pituitary Gland

The mother's anterior pituitary gland hormones have little influence on pregnancy after implantation has occurred. The gland itself enlarges by about one-third, with the major component of this increase being hyperplasia of the lactotrophs in response to the high plasma estrogens. PRL, the product of the lactotrophs, is the only anterior pituitary hormone that rises progressively during pregnancy and peaks at the time of delivery, with contributions from both the anterior pituitary and the decidua. In spite of the high serum concentrations,

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pulsatile release of PRL and nocturnal and food-induced increases persist. Hence, the normal neuroendocrine regulatory mechanisms appear to be intact in the maternal adenohypophysis. Pituitary ACTH and TSH secretion remain unchanged. Serum FSH and LH fall to the lower limits of detectability and are unresponsive to GnRH stimulation. GH concentrations are not significantly different from nonpregnant levels, but pituitary response to provocative testing is markedly altered. GH response to hypoglycemia and arginine infusion is enhanced in early pregnancy but thereafter becomes depressed. Established pregnancy can continue in the face of hypophysectomy, and in women hypophysectomized prior to pregnancy, induction of ovulation and normal pregnancy can be achieved with appropriate replacement therapy. In cases of primary pituitary hyperfunction, the fetus is not affected.

 

Figure 16-2. Maternal physiologic changes during pregnancy.

Maternal Thyroid Gland

The thyroid becomes palpably enlarged during the first trimester, and a bruit may be present. Thyroid iodide clearance and thyroidal 131I uptake, which are clinically contraindicated in pregnancy, have been shown to be increased. These changes are due in large part to the increased renal clearance of iodide, which causes a relative iodine deficiency. While total serum thyroxine is elevated as a result of estrogen-stimulated increased thyroid hormone-binding globulin (TBG), free thyroxine and triiodothyronine are normal (Figure 16-1). High circulating concentrations of hCG, particularly asialo-hCG, which has weak TSH-like activity, contributes to the thyrotropic action of the placenta in early pregnancy. In fact, there is often a significant though transient biochemical hyperthyroidism associated with hCG stimulation in early gestation.

Maternal Parathyroid Gland

The net calcium requirement imposed by fetal skeletal development is estimated to be about 30 g by term. This is met by hyperplasia of the parathyroid glands and elevated serum levels of parathyroid hormone. The maternal serum calcium concentration declines to a nadir at 28–32 weeks, largely owing to the hypoalbuminemia of pregnancy. Ionized calcium is maintained at normal concentrations throughout pregnancy.

Maternal Pancreas

The nutritional demands of the fetus require alteration of maternal metabolic homeostatic control, which results in both structural and functional changes in the maternal pancreas. The size of pancreatic islets increases, and insulin-secreting β cells undergo hyperplasia. Basal levels of insulin are lower or unchanged in early pregnancy but increase during the second trimester. Thereafter, pregnancy is a hyperinsulinemic state, with resistance to the peripheral metabolic effects of insulin. The increased concentration of insulin has been shown to be a result of increased secretion rather than decreased metabolic clearance. The measured half-life for insulin is unchanged in pregnant women. The effects of pregnancy on the pancreas can be mimicked by appropriate treatment with estrogen, progesterone, hPL, and corticosteroids.

Pancreatic production of glucagon remains responsive to usual stimuli and is suppressed by glucose loading, although the degree of responsiveness has not been well evaluated.

The major role of insulin and glucagon is the intracellular transport of nutrients, specifically glucose, amino acids, and fatty acids. These concentrations are regulated during pregnancy for fetal as well as maternal

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needs, and the pre- and postfeeding levels cause pancreatic responses that act to support the fetal economy. Insulin is not transported across the placenta but rather exerts its effects on transportable metabolites. During pregnancy, peak insulin secretion in response to meals is accelerated, and glucose tolerance curves are characteristically altered. Fasting glucose levels are maintained at low normal levels. Excess carbohydrate is converted to fat, and fat is readily mobilized during decreased caloric intake.

Amino acid metabolism is also altered during pregnancy at the expense of maternal needs. Because alanine, the key amino acid for gluconeogenesis, is preferentially transported to the fetus, maternal hypoglycemia leads to lipolysis.

Table 16-1. Effect of pregnancy on endocrine function tests.

 

Test

Result

Pituitary
  FSH, LH

GnRHstimulation

Unresponsive from third gestational week until puerperium

  GH

Insulin tolerance text

Response increases during the first half of pregnancy and then is blunted until the puerperium

Arginine stimulation

Hyperstimulation during the first and second trimesters, then suppression

  TSH

TRH stimulation

Response unchanged

Pancreas

 

      Insulin

Glucose tolerance

Peak glucose increases, and glucose concentration remains elevated longer

Glucose chal lenge

Insulin concentration increases to higher peak levels

Arginine infusion

Insulin response is blunted in mid to late pregnancy

Adrenal

 

      Cortisol

ACTH infusion

Exaggerated cortisol and 17-hydroxycorticosterone responses

Metyrapone

Diminished response

      Mineralocorticoids

ACTH infusion

No DOC response

Dexamethasone suppression

No DOC response

The normal result of pregnancy, then is to reduce glucose levels modestly but to reserve glucose for fetal needs while maternal energy requirements are met increasingly by the peripheral metabolism of fatty acids. These changes in energy metabolism are beneficial to the fetus and innocuous to the mother with an adequate diet. Even modest fasting, however, causes ketosis, which is potentially injurious to the fetus.

Maternal Adrenal Cortex

  1. GLUCOCORTICOIDS

Plasma cortisol concentrations increase to three times nonpregnant levels by the third trimester. Most of the increase can be accounted for by a doubling of corticosteroid-binding globulin (CBG). The increased estrogen levels of pregnancy account for the increase in CBG, which, in turn, is sufficient to account for decreased catabolism of cortisol by the liver. The result is a doubling of the half-life of plasma cortisol. The actual production of cortisol by the zona fasciculata also is increased in pregnancy. The net effect of these changes is an increase in plasma free cortisol, which is approximately doubled by late pregnancy. Whether this increase is mediated through ACTH or by other mechanisms is not known. In spite of cortisol concentrations approaching those found in Cushing's syndrome, diurnal variation in plasma cortisol is maintained. The elevated free cortisol probably contributes to the insulin resistance of pregnancy and possibly to the appearance of striae, but most signs of hypercortisolism do not occur in pregnancy. It is possible that high progesterone levels act as a glucocorticoid antagonist and prevent some cortisol effects.

  1. MINERALOCORTICOIDS AND THE RENIN-ANGIOTENSIN SYSTEM

Serum aldosterone is markedly elevated in pregnancy. The increase is due to an eight- to tenfold increased production of aldosterone by the zona glomerulosa and not to increased binding or decreased clearance. The peak in aldosterone production is reached by mid pregnancy and is maintained until delivery. Renin substrate is increased owing to the influence of estrogen on hepatic synthesis, and renin also is increased.

The increases in both renin and renin substrate inevitably lead to increases in renin activity and angiotensin. In spite of these dramatic changes, normal pregnant women show few signs of hyperaldosteronism. There is no tendency to hypokalemia or hypernatremia, and blood pressure at mid pregnancy—when changes in the aldosterone-renin-angiotensin system are maximal—tends to be lower than in the nonpregnant state.

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Although the quantitative aspects of this apparent paradox are not fully understood, a qualitative explanation is possible. Progesterone is an effective competitive inhibitor of mineralocorticoids in the distal renal tubules. Exogenous progesterone (but not synthetic progestins) is natriuretic and potassium-sparing in intact humans, whereas it has no effect in adrenalectomized subjects not receiving mineralocorticoids. Progesterone also blunts the response of the kidney to exogenous aldosterone—thus, the increases in renin and aldosterone may simply be an appropriate response to the high gestational levels of progesterone. The concomitant increase in angiotensin II as a result of increased plasma renin activity apparently does not normally result in hypertension, because of diminished sensitivity of the maternal vascular system to angiotensin. Even during the first trimester, exogenous angiotensin provokes less of a rise in blood pressure than in the nonpregnant state.

It is clear that the high levels of renin, angiotensin, and aldosterone in pregnant women are subject to the usual feedback controls, because they respond appropriately to changes in posture, dietary sodium, and water loading and restriction in qualitatively the same way as they do in nonpregnant women. Finally, in patients with preeclampsia, the most common form of pregnancy-related hypertension, serum renin, aldosterone, and angiotensin levels are lower than in normal pregnancy, thus ruling out any primary role for the renin-angiotensin system in this disorder. Production of the mineralocorticoid 11-deoxycorticosterone (DOC) rises throughout pregnancy, and plasma levels six to ten times normal are achieved by term. In contrast to the nonpregnant state, DOC production in pregnancy is unaffected by ACTH or glucocorticoid administration. Fetal pregnenolone-3,21-disulfate may serve as a placental precursor of maternal DOC. DOC is not elevated in hypertensive disorders of pregnancy.

  1. ANDROGENS

In normal pregnancy, the maternal production of androgens is slightly increased. The most important determinant of plasma levels of specific androgens, however, appears to be whether or not the androgen binds to sex hormone-binding globulin (SHBG). Testosterone, which binds avidly to SHBG, increases to the normal male range by the end of the first trimester, but free testosterone levels are actually lower than in the non-pregnant state. Dehydroepiandrosterone sulfate (DHEA sulfate) does not bind significantly to SHBG, and plasma concentrations of DHEA sulfate actually decrease during pregnancy. The desulfation of DHEA sulfate by the placenta and the conversion of DHEA sulfate to estrogens by the fetal-placental unit also are important factors in its increased metabolic clearance.

FETAL ENDOCRINOLOGY

Because of the inaccessibility of the fetus, much of our information about fetal endocrinology is derived indirectly. Most early studies of fetal endocrinology relied upon observations of infants with congenital disorders or inferences from ablation studies or acute manipulation in experimental animals. The development of effective cell culture methods, sensitive immunoassays, and the ability to achieve stable preparations of chronically catheterized monkey fetuses have increased our understanding of the dynamics of intrauterine endocrine events.

Study of the fetal endocrine system is further complicated by the multiplicity of sources of the various hormones. The fetus is exposed to maternal and placental hormones as well as to those it produces itself. Amniotic fluid contains a variety of hormones of mixed fetal and maternal origin, and these hormones are of uncertain importance. Inferences from the behavior of adult endocrine systems are not transferable to the fetus, because target organs, receptors, modulators, and regulators develop at different times. Study of the isolated fetus, even if possible, would thus be of little physiologic relevance.

Dating of events in fetal development is usually given in “fetal weeks,” which begin at the time of ovulation and fertilization. Thus, fetal age is always 2 weeks less than gestational age.

Human fetal growth is influenced by endocrine and hemodynamic factors that dictate the partitioning of nutrients between the mother and the conceptus. The main metabolic substrates for fetal and placental growth are glucose, lactate, amino acids, and lipids. A variety of placental transport proteins regulate the partitioning of these nutrients. In addition, placental hormones such as hPL, GH-variant, and IGF-I and IGF-II are secreted into the maternal and fetal circulations where they modulate energy metabolism and fetal growth.

The endocrine system is among the first to develop in fetal life. Differentiation of the gonads is crucial for normal male sexual development and reproductive potential. Primary testis differentiation begins with development of the Sertoli cells at 8 weeks' gestation. SRY is the sex-determining locus on the Y chromosome which directs the differentiation of the Sertoli cells, which are the sites of müllerian-inhibiting substance (MIS) synthesis. MIS, a member of the TGFβ family of growth factors, specifically triggers the ipsilateral resorption of the müllerian tract in males. Embryonic androgen production begins in the developing Leydig cells at about 10 weeks, coincident with the peak production of placental hCG. The ovarian counterpart in the female is smaller and less differentiated at this stage of embryonic

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life. Oogonia mitosis is active and steroid-producing theca cell precursors are identifiable at 20 weeks. This corresponds with peak gonadotropin levels from the fetal pituitary. Activin and inhibin peptide subunits are expressed in the midtrimester human testis but not in the midtrimester human ovary. In contrast to the male fetus, ovarian steroid production is not essential for female phenotypic development (see Chapter 14).

Fetal Anterior Pituitary Hormones

The characteristic anterior pituitary cell types are discernible as early as 8–10 fetal weeks, and all of the hor-mones of the adult anterior pituitary are extractable from the fetal adenohypophysis by 12 weeks. Similarly, the hypothalamic hormones thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), and somatostatin are present by 8–10 weeks. The direct circulatory connection between hypothalamus and pituitary develops later, with capillary invasion initially visible at about 16 weeks.

The role of the fetal pituitary in organogenesis of various target organs during the first trimester appears to be negligible. None of the pituitary hormones are released into the fetal circulation in large quantities until after 20 fetal weeks. Even growth hormone (GH) appears not to be influential, and in fact total absence of GH is consistent with normal development at birth. Development of the gonads and adrenals during the first trimester appears to be directed by hCG rather than by fetal pituitary hormones.

During the second trimester, there is a marked increase in secretion of all of the anterior pituitary hormones, which coincides with maturation of the hypophysial portal system. Observations include a marked rise in production of GH and an increase in fetal serum TSH, with a concomitant increase in fetal thyroidal iodine uptake. Gonadotropin production also increases, with the female achieving higher FSH levels in both pituitary and serum than does the male. The fetal gonadotropins do not direct the events of early gonadal development but are essential for normal development of the differentiated gonads and external genitalia. ACTH rises significantly during the second trimester and assumes an increasing role in directing the maturation of the differentiated adrenal, as shown by the anencephalic fetus, in which the fetal zone of the adrenal undergoes atrophy after 20 weeks. Fetal PRL secretion also increases after the 20th fetal week, but the functional significance of this hormone, if any, is unknown.

During the third trimester, maturation of feedback systems modulating hypothalamic release signals causes serum concentrations of all of the pituitary hormones except PRL to decline.

Fetal Posterior Pituitary Hormones

Vasopressin and oxytocin are demonstrable by 12–18 weeks in the fetal posterior pituitary gland and correlate with the development of their sites of production, the supraoptic and paraventricular nuclei, respectively. The hormone content of the gland increases toward term, with no evidence of feedback control.

During labor, umbilical artery oxytocin is higher than umbilical vein oxytocin. It has been suggested that the fetal posterior pituitary may contribute to the onset or maintenance of labor.

Fetal Thyroid Gland

The thyroid gland develops in the absence of detectable TSH. By 12 weeks the thyroid is capable of iodine-concentrating activity and thyroid hormone synthesis.

During the second trimester, TRH, TSH, and free T4 all begin to rise. The maturation of feedback mechanisms is suggested by the subsequent plateau of TSH at about 20 fetal weeks. Fetal T3 and reverse T3 do not become detectable until the third trimester. The hormone produced in largest amount throughout fetal life is T4, with the metabolically active T3 and its inactive derivative, reverse T3, rising in parallel to T4 during the third trimester. At birth, conversion of T4 to T3 becomes demonstrable.

The development of thyroid hormones occurs independently of maternal systems, and very little placental transfer of thyroid hormone occurs in physiologic concentrations. This prevents maternal thyroid disorders from affecting the fetal compartment but also prevents effective therapy for fetal hypothyroidism through maternal supplementation. Goitrogenic agents such as propylthiouracil are transferred across the placenta and may induce fetal hypothyroidism and goiter.

The function of the fetal thyroid hormones appears crucial to somatic growth and for successful neonatal adaptation. Many auditory maturational events may be regulated by thyroid hormones.

Fetal Parathyroid Gland

The fetal parathyroid is capable of synthesizing parathyroid hormone by the end of the first trimester. However, the placenta actively transports calcium into the fetal compartment, and the fetus remains relatively hypercalcemic throughout gestation. This contributes to a suppression of parathyroid hormone, and fetal serum levels in umbilical cord have been reported to be low or undetectable. Fetal serum calcitonin levels are elevated, enhancing bone accretion. Fetal vitamin D levels reflect maternal levels but do not appear to be significant in fetal calcium metabolism.

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Fetal Adrenal Cortex

The fetal adrenal differs anatomically and functionally from the adult gland. The cortex is identifiable as early as 4 weeks of fetal age, and by the seventh week, steroidogenic activity can be detected in the inner zone layers.

By 20 weeks, the adrenal cortex has increased to a mass that is considerably larger than its relative postnatal size. During gestation, it occupies as much as 0.5% of total body volume, and most of this tissue is composed of a unique fetal zone that subsequently regresses or is transformed into the definitive (adult) zone during the early neonatal period. The inner fetal zone is responsible for the majority of steroids produced during fetal life and comprises 80% of the mass of the adrenal. During the second trimester, the inner fetal zone continues to grow, while the outer zone remains relatively undifferentiated. At about 25 weeks, the definitive (adult) zone develops more rapidly, ultimately assuming the principal role in steroid synthesis during the early postnatal weeks. This transfer of function is accompanied by involution of the fetal zone, which is completed during the first months of neonatal life.

Fetal Gonads

The testis is a detectable structure by about 6 fetal weeks. The interstitial or Leydig cells, which synthesize fetal testosterone, are functional at this same stage. The maximal production of testosterone coincides with the maximal production of hCG by the placenta; binding of hCG to fetal testes with stimulation of testosterone release has been demonstrated. Other fetal testicular products of importance are the reduced testosterone metabolite dihydrotestosterone and müllerian-inhibiting substance. Dihydrotestosterone is responsible for development of the external genital structures, whereas müllerian-inhibiting substance prevents development of female internal structures.

Little is known about fetal ovarian function. By 7–8 weeks of intrauterine life, the ovaries become recognizable, but their importance in fetal physiology has not been established, and the significance of the steroids produced by the ovaries remains unclear.

ENDOCRINE CONTROL OF PARTURITION

During the last few weeks of normal pregnancy, two processes herald approaching labor. Uterine contractions, usually painless, become increasingly frequent, and the lower uterine segment and cervix become softer and thinner, a process known as effacement, or “ripening.” Although false alarms are not uncommon, the onset of true labor is usually fairly abrupt, with the establishment of regular contractions every 2–5 minutes, leading to delivery in less than 24 hours. There is a huge literature describing the physiologic and biochemical events that occur during human labor, but the key inciting event has eluded detection. For sheep, it is the fetus that controls the onset of labor. The initial measurable event is an increase in fetal plasma cortisol, which, in turn, alters placental steroid production, resulting in a drop in progesterone. Cortisol reliably induces labor in sheep, but in humans, glucocorticoids do not induce labor and there is no clear drop in plasma progesterone prior to labor. Furthermore, exogenous progesterone does not prevent labor in humans. Emerging primate data suggest that at the time of parturition, an increase in the ratio of the potent repressor progesterone receptor-A to the active progesterone receptor-B may lead to functional suppression of progesterone action and subsequent parturition.

A role for placental CRH in the regulation of parturition is suspected given the sharp increase in placental CRH mRNA from 28 weeks of gestation until delivery. Three weeks before the onset of labor, the exponential rise in plasma CRH is accompanied by an abrupt fall in CRH-binding protein. Glucocorticoids enhance placental CRH expression—thus, the rise in placental CRH that precedes parturition could result from the rise in fetal glucocorticoids that occurs at this time. The increase in placental CRH may stimulate—via stimulation of fetal pituitary ACTH—a further rise in fetal glucocorticoids, completing a positive feedback loop that would be terminated by delivery. Further evidence for a role of CRH in parturition is seen in studies showing CRH receptors in the myometrium and fetal membranes, CRH-stimulating prostaglandin release from human decidua and amnion, and, finally, the CRH-induced augmentation of oxytocin and prostaglandin F2 actions.

The difficulty in identifying a single initiating event in human labor suggests that there is more than one. Approaching the matter in a different way, one could ask: What are the factors responsible for maintenance of pregnancy, and how can they fail?

Sex Steroids

Progesterone is essential for maintenance of early pregnancy, and withdrawal of progesterone leads to termination of pregnancy. Progesterone causes hyperpolarization of the myometrium, decreasing the amplitude of action potentials and preventing effective contractions. In various experimental systems, progesterone decreases alpha-adrenergic receptors, stimulates cAMP production, and inhibits oxytocin receptor synthesis. Progesterone also inhibits estrogen receptor synthesis, promotes the storage of prostaglandin precursors in the

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decidua and fetal membranes, and stabilizes the lysosomes containing prostaglandin-synthesizing enzymes. Estrogen opposes progesterone in these actions and may have an independent role in ripening the uterine cervix and promoting uterine contractility. Thus, the estrogen:progesterone ratio may be an important parameter. In a small series of patients, an increase in the estrogen:progesterone ratio has been shown to precede labor. Thus, for some individuals, a drop in progesterone or an increase in estrogen may initiate labor. The cause of the change in steroids may be placental maturation or a signal from the fetus, but there are no data to support either thesis. It has been shown that an increase in the estrogen:progesterone ratio increases the number of oxytocin receptors and myometrial gap junctions; this finding may explain the coordinated, effective contractions that characterize true labor as opposed to the nonpainful, ineffective contractions of false labor.

Oxytocin

Oxytocin infusion is commonly used to induce or augment labor. Both maternal and fetal oxytocin levels increase spontaneously during labor, but neither has been convincingly shown to increase prior to labor. Data in animals suggest that oxytocin's role in initiation of labor is due to increased sensitivity of the uterus to oxytocin rather than increased plasma concentrations of the hormone. Even women with diabetes insipidus are able to deliver without oxytocin augmentation; thus a maternal source of the hormone is not indispensable.

Prostaglandins

Prostaglandin F administered intra-amniotically or intravenously is an effective abortifacient as early as 14 weeks of gestation. Prostaglandin E2 administered by vagina will induce labor in most women in the third trimester. The amnion and chorion contain high concentrations of arachidonic acid, and the decidua contains active prostaglandin synthetase. Prostaglandins are almost certainly involved in maintenance of labor once it is established. They also probably are important in initiating labor in some circumstances, such as in amnionitis or when the membranes are “stripped” by the physician. They probably are part of the“final common pathway” of labor.

Prostaglandin synthetase inhibitors abolish premature labor, but their clinical usefulness has been restricted by their simultaneous effect of closing the ductus arteriosus, which can lead to fetal pulmonary hypertension.

Catecholamines

Catecholamines with α2-adrenergic activity cause uterine contractions, whereas β2-adrenergics inhibit labor. Progesterone increases the ratio of beta receptors to alpha receptors in myometrium, thus favoring continued gestation. There is no evidence that changes in catecholamines or their receptors initiate labor, but it is likely that such changes help sustain labor once initiated. The beta-adrenergic drug ritodrine has proved to be a valuable agent in the management of premature labor. Alpha-adrenergic agents have not been useful in inducing labor, because of their cardiovascular side effects.

Nitric Oxide

Uterine smooth muscle may also be affected by nitric oxide (NO), which may act as a uterine smooth muscle relaxant. Some laboratory findings suggest that uterine NO production decreases at term and that inhibitors of NO synthesis might some day be used to initiate or augment human labor.

ENDOCRINOLOGY OF THE PUERPERIUM

Extirpation of any active endocrine organ leads to compensatory changes in other organs and systems. Delivery of the infant and placenta causes both immediate and long-term adjustment to loss of the pregnancy hormones. The sudden withdrawal of fetal-placental hormones at delivery permits determination of their serum half-lives and some evaluation of their effects on maternal systems.

Physiologic & Anatomic Changes

Some of the physiologic and anatomic adjustments that take place after delivery are hormone-dependent, whereas others are themselves responsible for hormonal changes. For example, major readjustments of the cardiovascular system occur in response to the normal blood losses associated with delivery and to loss of the low-resistance placental shunt. By the third postpartum day, blood volume is estimated to decline to about 84% of predelivery values. These cardiovascular changes influence renal and liver clearance of hormones.

Reproductive Tract Changes

The uterus decreases progressively in size at the rate of about 500 g/wk and continues to be palpable abdominally until about 2 weeks postpartum, when it reoccupies its position entirely within the pelvis. Nonpregnant size and weight (60–70 g) are reached by 6 weeks. The

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reversal of myometrial hypertrophy occurs with a decrease in size of individual myometrial cells rather than by reduction in number. Uterine discharge also changes progressively during this period, with the mixture of fresh blood and decidua becoming a serous transudate and then ceasing in 3–6 weeks.

The endometrium, which is sloughed at the time of delivery, regenerates rapidly; by the seventh day, there is restoration of surface epithelium, except at the placental site. By the second week after delivery, the endometrium resembles normal proliferative-phase endometrium, except for the characteristic hyalinized decidual areas. The earliest documented appearance of a secretory endometrium occurred on day 44 in one series of daily biopsies. These rapid regenerative changes do not apply to the area of placental implantation, which requires much longer for restoration and retains pathognomonic histologic evidence of placentation indefinitely.

The cervix and vagina also recover rapidly from the effects of pregnancy, labor, and delivery. The cervix regains tone over the first week; by 6 weeks postpartum, it usually exhibits complete healing of trauma sustained at the time of delivery. Histologically, involution may continue beyond 6 weeks, with stromal edema, leukocytic infiltration, and glandular hyperplasia still apparent. Similarly, the vagina regains muscular tone following delivery, and rugae appear as early as 3 weeks. However, in women who nurse, the vaginal mucosa may remain atrophic for months, sometimes resulting in dyspareunia and a watery discharge.

Endocrine Changes

  1. STEROIDS

With expulsion of the placenta, the steroid levels decline precipitously, their half-lives being measured in minutes or hours. As a consequence of continued low-level production by the corpus luteum, progesterone does not reach basal prenatal levels as rapidly as does estradiol. Plasma progesterone falls to luteal-phase levels within 24 hours after delivery but to follicular-phase levels only after several days. Removal of the corpus luteum results in a fall to follicular levels within 24 hours. Estradiol reaches follicular-phase levels within 1–3 days after delivery.

  1. PITUITARY HORMONES

The pituitary gland, which enlarges during pregnancy owing primarily to an increase in lactotrophs, does not diminish in size until after lactation ceases. Secretion of FSH and LH continues to be suppressed during the early weeks of the puerperium, and stimulus with bolus doses of GnRH results in subnormal release of LH and FSH. Over the ensuing weeks, responsiveness to GnRH gradually returns to normal, and most women exhibit follicular-phase serum levels of LH and FSH by the third or fourth postpartum week.

  1. PROLACTIN

Serum prolactin (PRL), which rises throughout pregnancy, falls with the onset of labor and then exhibits variable patterns of secretion depending upon whether breast feeding occurs. Delivery is associated with a surge in PRL, which is followed by a rapid fall in serum concentrations over 7–14 days in the nonlactating mother.

In nonlactating women, the return of normal cyclic function and ovulation may be expected as soon as the second postpartum month, with the initial ovulation occurring at an average of 9–10 weeks postpartum. In lactating women, PRL usually causes a persistence of anovulation. Surges of PRL are believed to act on the hypothalamus to inhibit GnRH secretion. Administration of exogenous GnRH during this time induces normal pituitary responsiveness, and occasional ovulation may occur spontaneously even during lactation. The average time for ovulation in women who have lactated for at least 3 months is about 17 weeks. The percentage of nonlactating women who have resumed menstruation increases linearly up to 12 weeks, by which time 70% will have restored menses. In contrast, the linear increase for lactating women exhibits a much shallower slope, and 70% of lactating women will have menstruated by about 36 weeks.

Lactation

Development of the breast alveolar lobules occurs throughout pregnancy. This period of mammogenesis requires the concerted participation of estrogen, progesterone, PRL, GH, and glucocorticoids. hPL may also play a role but is not indispensable. Milk secretion in the puerperium is associated with further enlargement of the lobules, followed by synthesis of milk constituents such as lactose and casein.

Lactation requires PRL, insulin, and adrenal steroids. It does not occur until unconjugated estrogens fall to nonpregnant levels at about 36–48 hours postpartum.

PRL is essential to milk production. Its action involves induced synthesis of large numbers of PRL receptors; these appear to be autoregulated by PRL, since PRL increases receptor levels in cell culture and since bromocriptine, an inhibitor of PRL release, causes a decrease in both PRL and its receptors. In the absence of PRL, milk secretion does not take place; but even in the

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presence of high levels of PRL during the third trimester, milk secretion does not take place until after delivery, owing to the blocking effect of high levels of estrogen.

Galactopoiesis, or the process of continued milk secretion, is also dependent upon the function and integration of several hormones. Evidence from GH-deficient dwarfs and hypothyroid patients suggests that GH and thyroid hormone are not required.

Milk secretion requires the additional stimulus of emptying of the breast. A neural arc must be activated for continued milk secretion. Milk ejection occurs in response to a surge of oxytocin, which induces a contractile response in the smooth muscle surrounding the gland ductules. Oxytocin release is occasioned by stimuli of a visual, psychologic, or physical nature that prepare the mother for suckling, while PRL release is limited to the suckling reflex arc.

ENDOCRINE DISORDERS & PREGNANCY PITUITARY DISORDERS

In women of reproductive age, small tumors of the anterior pituitary are not uncommon (see also Chapter 5). While most are nonfunctional and asymptomatic, the most common symptom of pituitary microadenomas is amenorrhea, frequently accompanied by galactorrhea. In the past, few affected women became pregnant, but now most can be made to ovulate and to conceive with the aid of clomiphene citrate, menotropins and hCG, or bromocriptine. Before ovulation is induced in any patient, serum PRL should be determined. Modest elevations of PRL warrant checking IGF-I levels, since hyperprolactinemia occurs in 25% of patients with GH-producing adenomas. If it is elevated, the sella turcica should be evaluated by magnetic resonance imaging (MRI) or by high-resolution CT scanning with contrast. About 10% of women with secondary amenorrhea will be found to have adenomas, while 20–50% of women with amenorrhea and galactorrhea will have detectable tumors.

The effect of pregnancy on pituitary adenomas depends on the size of the adenoma. Among 216 women with microadenomas (< 10 mm in diameter), fewer than 1% developed progressive visual field defects, 5% developed headaches, and none experienced more serious neurologic sequelae. Of 60 patients who had macroadenomas and became pregnant, 20% developed abnormal changes in their visual fields or other neurologic signs, usually in the first half of their pregnancies. Many of these required therapy. Monitoring of patients with known PRL-secreting adenomas during pregnancy is primarily based on clinical examination. The normal gestational increase in PRL may obscure the increase attributable to the adenoma, and radiographic procedures are undesirable in pregnancy.

Visual disturbances are usually experienced as “clumsiness” and are objectively found to be due to visual field changes. The most frequent finding is bitemporal hemianopia, but in advanced cases the defect can progress to concentric contraction of fields and enlargement of the blind spot.

Since the pituitary normally increases in size during pregnancy, headaches are common and bitemporal hemianopia not uncommon in patients with adenomas. These changes almost always revert to normal after delivery, so that aggressive therapy for known pituitary adenomas is not indicated except in cases of rapidly progressive visual loss.

Management

Management of the pregnant woman with a small pituitary adenoma includes early ophthalmologic consultation for formal visual field mapping and repeat examinations once a month or every other month throughout pregnancy.

If visual field disturbances are minimal, pregnancy may be allowed to proceed to term. If symptoms become progressively more severe and the fetus is mature, labor should be induced. If symptoms are severe and the fetus is immature, management may consist of transsphenoidal resection of the adenoma or medical treatment with bromocriptine. While bromocriptine inhibits both fetal and maternal pituitary PRL secretion, it does not affect decidual PRL secretion. Bromocriptine appears not to be teratogenic, and no adverse fetal effects have been reported. In most cases it is probably preferable to surgery. The newer, selective dopamine D2 receptor agonist cabergoline has given excellent results in normalizing PRL levels, inducing tumor shrinkage, and minimizing side effects. The data available on pregnancies in which cabergoline was used do not show adverse effects; however, since the data are limited compared with the large numbers for bromocriptine safety, the latter is recommended during pregnancy. Radiation therapy should not be used in pregnancy.

Management of PRL-secreting tumors in women who want to become pregnant is controversial. Surgical resection by surgeons with experience in transsphenoidal procedures results in reduction of PRL levels and resumption of normal ovulation in 60–80% of women with microadenomas and 30–50% of women with macroadenomas. The incidence of recurrence is at least 10–16% and will probably increase with further follow-up. Bromocriptine is usually well tolerated and is successful in achieving normal menstrual cycles and lowering PRL levels in 40–80% of patients. Bromocriptine

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also causes a marked decrease in tumor size, but the original size of the tumor is usually regained within days or weeks after discontinuing therapy. In the case of large tumors, combined medical and surgical management may often be appropriate. Radiation therapy has an important role in arresting growth of tumors that are resistant to other management, particularly large tumors that involve the cavernous sinuses and tumors that secrete both GH and PRL (see Chapter 5).

Lymphocytic adenohypophysitis is an enigmatic autoimmune inflammation of the pituitary that classically occurs in women in late pregnancy or during the puerperium. The clinical presentation is difficult to distinguish from that of a large prolactin-secreting adenoma. Expectant conservative medical management with corticosteroids is sometimes possible, with vigilant postpartum observation to prevent consequences of pituitary insufficiency.

Prognosis & Follow-Up

There appears to be no increase in obstetric complications associated with pituitary adenomas, and no fetal jeopardy. The rate of prematurity increases in women with tumors requiring therapy, but this is probably due to aggressive intervention rather than to spontaneous premature labor.

The postpartum period is characterized by rapid relief of even severe symptoms, with less than 4% of untreated tumors developing permanent sequelae. In some cases, tumors improve following pregnancy, with normalization or lowering of PRL relative to prepregnancy values. Management should include radiography and assessment of PRL levels 4–6 weeks after delivery. There are no contraindications to breast-feeding.

Sheehan's Syndrome

Postpartum pituitary necrosis, or Sheehan's syndrome, is preceded by obstetric hemorrhage leading to severe circulatory collapse. Theoretically, severe hypotension predisposes the enlarged pituitary to ischemia. The posterior pituitary is usually spared, and the most common clinical feature is inability to lactate as a result of deficient PRL production. Loss of axillary and pubic hair is also a common sign. Other manifestations include hypothyroidism and hypocortisolism. Damage is variable, and in some instances there is return to normal fertility.

PREGNANCY & BREAST CANCER

Breast cancer complicates one in 1600–5000 pregnancies. Only one-sixth of breast cancers occur in women of reproductive age, but of these, one in seven is diagnosed during pregnancy or the puerperium. Pregnancy and breast cancer have long been considered such an ominous combination that only one in 20 young women who have had breast cancer have later become pregnant. It now appears, however, that pregnancy has little effect on growth of breast cancer, though it presents problems of detection and management of the cancer.

Influence of Pregnancy on Breast Cancer

Pregnancy is not an etiologic factor in breast cancer. Indeed, there is good evidence that pregnancy at an early age actually reduces the risk of developing mammary cancer, and multiple pregnancies may also make the disease less likely. Moreover, contemporary concepts of the rate of tumor growth suggest that a tumor becomes clinically evident only 8–10 years after its inception. Thus, a tumor cannot arise and be discovered during the same pregnancy. In view of the increased glandular proliferation and blood flow and marked increase in lymph flow that occur during pregnancy, it could be argued that pregnancy accelerates the appearance of previously subclinical diseases, but this has not been demonstrated.

Probably the most important influence of pregnancy on breast cancer is the delay it may cause in making the diagnosis and starting therapy. In some series, the interval between initial symptoms and treatment was 6–7 months longer than in the absence of pregnancy. Larger tumors may be misdiagnosed as galactoceles, and inflammatory carcinoma in the puerperium is liable to be misdiagnosed as mastitis.

At the time of diagnosis, 60% of pregnancy-associated breast cancers have metastasized to regional lymph nodes, and an additional 20% have distant metastases. Stage for stage, however, survival rates following appropriate therapy are comparable to those achieved in nonpregnant patients. Termination of pregnancy, either by abortion or by early delivery, does not influence maternal survival.

Pregnancy After Treatment for Cancer

Pregnancy following definitive treatment of breast cancer has no adverse effect on survival. Indeed, women who become pregnant following stage I or stage II breast cancer have a somewhat better 5-year survival rate than matched controls who did not become pregnant but who survived at least as long as their match before becoming pregnant.

Women who have had breast cancer are frequently advised to avoid pregnancy for 5 years. Because most fertile women with breast cancer are in their mid 30s, such a plan virtually precludes pregnancy. Because pregnancy is not known to influence the rate of cancer recurrence, the only reasons for proscribing pregnancy are to avoid the possibility that management of a recurrence

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will be complicated by the pregnancy or to avoid the problem of producing motherless children. For a couple strongly desiring pregnancy, these risks may become acceptable in a much shorter time than 5 years, especially if the original lesion was small and the spread of disease minimal.

Estrogen Receptors in Breast Cancer

Determinations of soluble estrogen and progesterone receptors are frequently used in breast cancer to predict whether the tumor is likely to respond to endocrine therapy. There is also evidence that the presence of estrogen receptor-positive tumors is correlated with a lower risk of early recurrence. In the pregnant patient, however, high progesterone levels inhibit estrogen and progesterone receptor synthesis, and high levels of both hormones cause their receptors to become tightly associated with the nuclear fraction. Thus, when soluble receptors are quantified, all breast cancers arising in pregnancy appear to be receptor-negative, making such measurements in pregnancy at best worthless and at worst dangerously misleading. The introduction of immunohistochemical assays, which allow identification of occupied nuclear receptors, provides a more reliable assessment.

Treatment of Breast Cancer in Pregnancy

Once the diagnosis of cancer is made, the patient must be treated surgically without delay. In view of the large percentage of patients with positive nodes, the procedure should be one that provides adequate sampling of the axillary nodes, such as modified radical mastectomy. Simple mastectomy with axillary irradiation should be avoided. Therapeutic abortion is not routinely indicated. If, on the basis of surgical staging, adjuvant therapy is considered advisable, the decision must be made either to terminate the pregnancy by abortion or early delivery or to postpone chemotherapy to the second or third trimester. Since delay in treatment is the principal known reason for the poorer prognosis of breast cancer in pregnancy, delivery should be accomplished as soon as there is a substantial probability of good fetal outcome—usually at 32–34 weeks. Many of the drugs used in cytotoxic therapy of breast carcinoma are contraindicated in pregnancy. Radiation can be given with appropriate shielding, but the dose to the fetus will not be negligible.

HYPERTENSIVE DISORDERS OF PREGNANCY

Hypertension associated with pregnancy is generally categorized as chronic, in which elevated blood pressures antedate the pregnancy or are clinically recognized prior to the 20th week, or gestational, when the onset is beyond 20 weeks of gestation. If the latter is complicated by proteinuria and generalized edema, the triad is referred to as preeclampsia. When seizures accompany this syndrome, the condition is termed eclampsia. The incidence of preeclampsia is about 7%. Women at highest risk include primigravidas under 18 years old, multiparous women over 35 years old, and women with twin gestations, diabetes, hydramnios, pregnancy obesity, or prepregnancy hypertension. As many as half of women with prepregnancy hypertension develop exacerbations of hypertension in the third trimester.

Course of Hypertension in Pregnancy

In normal pregnancies, as well as those complicated by mild essential hypertension, diastolic blood pressure decreases 10–16 mm Hg in the second trimester. Hypertensive patients first seen at that time may be mistakenly identified as having preeclampsia when the blood pressure again increases in the third trimester. Clinically, preeclampsia usually appears after the 32nd week of gestation and, most frequently, during labor. In severe cases, especially those complicated by essential hypertension, acute rises in blood pressure may occur as early as 26 weeks. If hypertension appears in the first or early second trimester, it is associated either with gestational trophoblastic disease or an underlying disorder such as an acute flare-up of lupus nephritis. Occasionally, the onset of hypertension is recognized during the 24 hours following delivery.

In normal pregnancies, all of the components of the renin-angiotensin-aldosterone system are markedly elevated. In pregnancies complicated by chronic hypertension or preeclampsia, these components are slightly reduced toward normal nonpregnant levels, suggesting an appropriate feedback response. The most consistent finding in women with preeclampsia is the increased sensitivity to vasopressor agents compared to women with normal pregnancy. In pregnancies destined to be complicated by preeclampsia, an increase in arteriolar response to angiotensin that becomes statistically significant by 18–22 weeks of gestation-long before changes in blood pressure are detectable. The cause of this increase in vascular sensitivity to angiotensin is not known. Considerable evidence suggests that dyslipidemia, oxidative stress, and endothelial cell dysfunction may explain many of the pathophysiologic features of preeclampsia.

Treatment of Chronic Hypertension

Women with chronic hypertension who become pregnant require special management. Roberts's recommendations are probably the best:

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(1) Diastolic pressures under 100 mm Hg should not be treated. However, if a woman is receiving antihypertensive therapy when first seen in pregnancy, therapy should be continued. If she is taking propranolol, consideration may be given to switching to a more specific β1-antagonist such as metoprolol or atenolol. The rare patient who has been taking ganglionic blockers should receive another form of therapy instead. Owing to a transient decrease in blood volume and placental perfusion associated with thiazide diuretics, use of these agents should usually not be initiated during pregnancy; however, if a woman is already receiving such therapy, it may be continued. Angiotensin-converting enzyme inhibitors may be associated with adverse fetal and neonatal effects, including death.

(2) Diastolic pressures above 100 mm Hg discovered during pregnancy call for antihypertensive management. Initial therapy should be with methyldopa, 250 mg orally at bedtime. This may be increased 1 g twice daily as required. If unacceptable drowsiness lasting more than 2–3 days occurs, the dosage may be reduced, and hydralazine, beginning at 10 mg orally twice daily and increasing up to 100 mg twice daily, may be added. If hydralazine is not tolerated, prazosin may be gradually added to the methyldopa therapy.

(3) Accelerated hypertension at any stage of gestation should be managed with bed rest and, if necessary, intravenous hydralazine. Unless diastolic pressure can be reduced to 110 mm Hg promptly, delivery should be performed regardless of gestational age.

Symptoms & Signs of Preeclampsia

Signs of preeclampsia include sustained blood pressure increase to levels of 140 mm Hg systolic or 90 mm Hg diastolic and proteinuria exceeding 300 mg daily. Symptoms include headaches, visual disturbances, and epigastric pain. Eclampsia may occur even with mild elevation of blood pressure and is associated with a maternal mortality rate as high as 10%. Deaths occur most frequently from cerebral hemorrhage, renal failure, disseminated intravascular coagulopathy, acute pulmonary edema, or hepatic failure. The fetal perinatal mortality rate is in excess of 30%, and the risk of perinatal morbidity due to hypoxia is even higher.

Treatment of Preeclampsia

The only definitive therapy for preeclampsia is delivery. If a modest increase in blood pressure first occurs in association with proteinuria at 32–36 weeks of gestation, bed rest, preferably in the left lateral decubitus position, is frequently effective in temporarily inducing diuresis and controlling progression of the disease, thus gaining time for the developing fetus. If labor occurs or induction of labor is attempted, parenteral magnesium sulfate should be used to prevent seizures and should be continued for 24 hours following delivery. Moderate hypertension need not be treated with antihypertensive agents; however, diastolic blood pressure above 110 mm Hg must be controlled to reduce the risk of intracranial hemorrhage. The agent of choice is hydralazine, 5 mg intravenously at 16- to 20-minute intervals, until the diastolic pressure is approximately 100 mm Hg. If hydralazine is unsuccessful, labetalol, verapamil, or nifedipine, may be used, but these agents are rarely required. Recent trials using low-dose aspirin revealed minimal to no benefit in preventing the development of preeclampsia.

Prognosis

Both preeclampsia and transient hypertension (late-gestation hypertension without proteinuria) are associated with an increased risk of chronic hypertension in later life.

HYPERTHYROIDISM IN PREGNANCY

Pregnancy mimics hyperthyroidism. There is thyroid enlargement, increased cardiac output, and peripheral vasodilation. Owing to the increase in thyroid hormone-binding globulin (TBG), total serum thyroxine is in the range expected for hyperthyroidism. Free thyroxine, the free thyroxine index, and TSH levels, however, remain in the normal range (see Chapter 7).

True hyperthyroidism complicates one or two per 1000 pregnancies. The most common form of hyperthyroidism during pregnancy is Graves' disease. Hyperthyroidism is associated with an increased risk of premature delivery (11–25%) and may modestly increase the risk of early abortion. In Graves' disease, thyroid-stimulating immunoglobulin (TSI), a 7S immune gamma globulin, crosses the placenta and may cause fetal goiter and transient neonatal hyperthyroidism, but these effects rarely jeopardize the fetus.

Treatment

The treatment of maternal hyperthyroidism is complicated by pregnancy. Radioiodides are strictly contraindicated. Iodide therapy can lead to huge fetal goiter and is contraindicated except as acute therapy to prevent thyroid storm before thyroid surgery. All antithyroid drugs cross the placenta and may cause fetal hypothyroidism and goiter or cretinism in the newborn. However, propylthiouracil in doses of 300 mg/d or less has been shown to be reasonably safe, although even at low doses about 10% of newborns will have a detectable goiter. Propranolol has been used to control maternal cardiovascular symptoms but may result in fetal bradycardia, growth retardation, premature labor,

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and neonatal respiratory depression. Partial or total thyroidectomy, especially in the second trimester, is a reasonably safe procedure except for the risk of premature labor.

  1. PROPYLTHIOURACIL

A reasonable plan of management is to begin therapy with propylthiouracil in doses high enough to bring the free T4 index into the mildly hyperthyroid range and then to taper the dose gradually. Giving thyroxine along with propylthiouracil in the hope that it will cross the placenta in sufficient quantities to prevent fetal hypothyroidism is not effective and serves only to increase the amount of propylthiouracil required. If the maintenance dose of propylthiouracil is above 300 mg/d, serious consideration should be given to partial thyroidectomy.

  1. PROPRANOLOL

Propranolol may be used transiently to ameliorate cardiovascular symptoms while control is being achieved.

Management of Newborn

Newborns should be observed carefully. In infants of mothers given propylthiouracil, even equivocal evidence of hypothyroidism is an indication for thyroxine replacement therapy. Neonatal Graves' disease, which may present as late as 2 weeks after delivery, requires intensive therapy (see Chapter 7).

HYPOTHYROIDISM IN PREGNANCY

Hypothyroidism is uncommon in pregnancy, since most women with the untreated disorder are oligo-ovulatory. As a practical matter, women taking thyroid medication at the time of conception should be maintained on the same or a slightly larger dose throughout pregnancy, whether or not the obstetrician believes thyroid replacement was originally indicated. Physiologic doses of thyroid are innocuous, but maternal hypothyroidism is hazardous to the developing fetus. Women with a personal or family history of thyroid disease or with symptoms suggestive of hypothyroidism should be tested for TSH prior to conception. The correlation between maternal and fetal thyroid status is poor, and hypothyroid mothers frequently deliver euthyroid infants. The strongest correlation between maternal and newborn hypothyroidism occurs in areas where endemic goiter due to iodide deficiency is common. In these regions, dietary iodide supplementation in addition to thyroid hormone treatment of the mother may be of the greatest importance in preventing cretinism.

REFERENCES

General

Burrow GN, Duffy TP (editors): Medical Complications During Pregnancy, 5th ed. Saunders, 1999.

Haig D: Genetic conflicts in human pregnancy. Q Rev Biol 1995; 68:495.

Jaffe RB: Endocrine-metabolic alterations induced by pregnancy. In: Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 4th ed. Yen SSC, Jaffe RB, Barbieri RL (editors). Saunders, 1999.

Norwitz ER, Schust DJ, Fisher SJ: Implantation and the survival of early pregnancy. N Engl J Med 2001;345:1400.

Chorionic Proteins and Pregnancy Tests

Lessey BA: Endometrial integrins and the establishment of uterine receptivity. Hum Reprod 1998;13(Suppl 3):247.

Lin LS, Roberts VJ, Yen SS: Expression of human gonadotropin-releasing hormone receptor gene in the placenta and its functional relationship to human chorionic gonadotropin secretion. J Clin Endocrinol Metab 1995;80:580.

Meuris S et al: Temporal relationship between the human chorionic gonadotrophin peak and the establishment of intervillous blood flow in early pregnancy. Hum Reprod 1995;10: 947.

O'Connor JF et al: Recent advances in the chemistry and immunochemistry of human chorionic gonadotropin: Impact on clinical measurements. Endocr Rev 1994;15:650.

Wilcox AJ, Baird DD, Weinberg CR: Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 1999; 340:1796.

Ovarian Proteins

Bani D: Relaxin: a pleiotropic hormone. Gen Pharmacol 1997; 28:13.

Steroid Hormones

Couse JF, Korach KS: Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev 1999; 20:358.

Mesiano S, Jaffe RB: Human fetal adrenal cortical function in pregnancy and parturition. Curr Probl Obstet Gynecol Fertil 1999;22:195.

Miller WL: Steroid hormone biosynthesis and actions in the materno-feto-placental unit. Clin Perinatol 1998;25:799.

Pepe GJ, Albrecht ED: Actions of placental and fetal adrenal steroid hormones in primate pregnancy. Endocr Rev 1995; 16:608.

Strauss JF 3rd, Martinez F, Kiriakidou M: Placental steroid hormone synthesis: unique features and unanswered questions. Biol Reprod 1996;54:303.

Fetal Endocrinology

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Fisher DA: Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 1997;40:16.

Gluckman PD: The endocrine regulation of fetal growth in late gestation: The role of insulin-like growth factors. J Clin Endocrinol Metab 1995;80:1047.

Haddow JE et al: Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549.

Rabinovici J, Jaffe RB: Development and regulation of growth and differentiated function in human and subhuman primate fetal gonads. Endocr Rev 1990;11:532.

Sinclair AH et al: A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990;346:240.

Wald NJ, Watt HC, Hackshaw AK: Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters. N Engl J Med 1999;341:461.

Parturition

Chwalisz K, Garfield RE: Antiprogestins in the induction of labor. Ann N Y Acad Sci 1994;734:387.

Haluska GJ et al: Progesterone receptor localization and isoforms in myometrium, decidua, and fetal membranes from rhesus macaques: evidence for functional progesterone withdrawal at parturition. J Soc Gynecol Investig 2002;9:125.

Weiss G: The role of the time of labor is complex and involves interactions of the mother, the fetus and the placenta, plus membranes. J Clin Endocrinol Metab 2000;854421.

Puerperium and Lactation

Crowley WR, Armstrong WE: Neurochemical regulation of oxytocin secretion in lactation. Endocr Rev 1992;13:33.

McNeilly AS, Tay CC, Glasier A: Physiological mechanisms underlying lactational amenorrhea. Ann N Y Acad Sci 1994;709: 145.

Pituitary Adenomas

Colao A, Lombardi G: Prolactinomas resistant to standard dopamine agonists respond to chronic cabergoline treatment. J Clin Endocrinol Metab 1997;82:876.

Molitch ME: Disorders of prolactin secretion. Endocrinol Metab Clin North Am 2001;30:585.

Molitch ME: Pituitary disease in pregnancy. Semin Perinatol 1998;22:457.

Breast Cancer and Pregnancy

Bernik SF et al: Carcinoma of the breast during pregnancy: a review and update on treatment options. Surg Oncol 1998;7:45.

Berry DL et al: Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999;17:855.

Berry DL et al: Influence of pregnancy on the outcome of breast cancer: a case-control study. Societ Franaise de Srologie et de Pathologie Mammaire Study Group. Int J Cancer 1997; 4:720.

Hypertensive Disorders

Dekker GA, Sibai BM: Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998;179:1359. [PMID:]

Hubel CA: Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med 1999;222:222. Review.

Roberts JM: Pregnancy-related hypertension. In: Maternal-Fetal Medicine: Principles and Practice, 4th ed. Creasy RK, Resnick R (editors). Saunders, 1998.

Hyperthyroidism in Pregnancy

Burrow GN, Fisher DA, Larsen PR: Maternal and fetal thyroid function. N Engl J Med 1994;331:1072.

Foulk RA et al: Does human chorionic gonadotropin have human thyrotropic activity in vivo? Gynecol Endocrinol 1997;11:195.

Haddow JE et al: Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549.


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