Endocrine Disorders During Pregnancy Sarita Bajaj, Rajesh Rajput, Jubbin J Jacob
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Endocrine Physiology in Pregnancy1

Sarita Bajaj
 
INTRODUCTION
Pregnancy is a dynamic and an anabolic state. The endocrinological processes of gestation comprise various endocrine and metabolic changes as a consequence of physiological modifications at the fetoplacental boundary between the mother and the fetus. The neuroendocrine events and their timing in the placental, fetal, and maternal compartments are critical for initiation and maintenance of pregnancy, for growth and development of fetus, as well as for parturition.1,2 Within several weeks of conception, a new endocrine organ, the placenta, is formed that secretes hormones which affect the metabolism of all nutrients.1
The endocrine system is amongst the earliest system that develops in the fetus, and remains functional from early intrauterine existence to the prime of life. The fetal endocrine system, to some extent, relies on the precursors secreted by either placenta or in the mother's body for its regulation. As the fetus develops, its own endocrine system matures and eventually becomes more independent to prepare it to cope with extrauterine life.2
 
THE PLACENTA AND ITS HORMONAL ROLE
The development of human placenta is as uniquely intriguing as the embryology of the fetus. The fetus, during its brief intrauterine existence, depends on placenta for pulmonary, hepatic, and renal functions. The placenta, through its unique anatomical association with the mother, accomplishes these functions.3
The corpus luteum and placenta secrete hormones, which maintain pregnancy and influence metabolism.1 The placenta functions partly as a hypothalamic-pituitary-end organ-like entity with stimulatory and inhibitory feedback mechanisms to regulate dynamic factors affecting fetal growth and development under a variety of conditions.2 2The production of steroid and protein hormones by human trophoblasts is greater in amount and diversity than that of any single endocrine tissue in the whole mammalian physiology.3 Placental steroidogenesis takes place in the syncytiotrophoblast, and synthesis and secretion of estrogen and progesterone increase throughout pregnancy in concert with an increase in the trophoblast mass.4
The human placenta also synthesizes an enormous amount of protein and peptide hormones as much as 1 g of human placental lactogen (HPL) every 24 hours, massive quantities of human chorionic gonadotropin (hCG), adrenocorticotropic hormone (ACTH), growth hormone variant (GH-V), parathyroid hormone-related protein (PTH-rP), calcitonin, relaxin, inhibins, activins and atrial natriuretic peptide, as well as a variety of hypothalamic-like releasing and inhibiting hormones, such as thyrotropin releasing hormone (TRH), gonadotropin releasing hormone (GnRH), corticotropin releasing hormone (CRH), somatostatin, and growth hormone-releasing hormone (GHRH) (Table 1-1).3
 
Progesterone
After 6–7 weeks of gestation, small amounts of progesterone are produced in the ovary.5 After about 8 weeks, the placenta replaces the ovary as the source of progesterone and continues its production in such a way that there is a gradual increase in the levels throughout the remaining pregnancy. By the end of pregnancy, maternal levels of progesterone are 10–5,000 times than those in nonpregnant women, depending on the stage of the ovarian cycle. The daily production rate of progesterone in late, normal, singleton pregnancy is about 250 mg.3 The trophoblast preferentially use maternal low-density lipoprotein (LDL) cholesterol for progesterone biosynthesis. Progesterone appears to have multiple functions during pregnancy, the most important being preparation of the uterus for implantation and maintenance of the pregnancy.
Table 1-1   Steroid Production Rates in Nonpregnant and Near-term Pregnant Women
Steroid
Production rates (mg/24 hours)
Nonpregnant
Pregnant
17-Estradiol
0.1–0.6
15–20
Estriol
0.02–0.1
50–150
Progesterone
0.1–40
250–600
Aldosterone
0.05–0.1
0.250–0.600
Deoxycorticosterone
0.05–0.5
1–12
Cortisol
10–30
10–20
Adapted from Maternal Physiology. In: Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap LC III, Wenstrom KD, Editors. Williams Obstetrics, 22nd edition, McGraw-Hill Publications; 2007.
3Progesterone also serves as an important substrate for fetal adrenal glucocorticoid and mineralocorticoid synthesis and maintenance of myometrial quiescence, possibly through inhibition of prostaglandin formation. A possible role for the high concentrations of progesterone present at the trophoblast-decidua junction is suppression of cell-mediated rejection of the fetus, which expresses paternal antigens, by maternal T lymphocytes.6
 
Estrogen
The placenta produces huge amount of estrogen using blood-borne steroidal precursors from the maternal and fetal adrenal glands. Near term, normal human pregnancy is a hyperestrogenic state of major proportions. The amount of estrogen produced each day by syncytiotrophoblast during the last few weeks of pregnancy is equivalent to that produced in 1 day by the ovaries of not less than 1,000 ovulatory women. The estrogen levels continually increase as pregnancy progresses and terminate abruptly after parturition.3 By the seventh week, more than 50% of estrogen entering the maternal circulation is produced by the placenta. During pregnancy, estrogen has several actions as stated below:4
  • Enhances receptor-mediated uptake of LDL cholesterol, which is important for normal placental steroid production
  • Increases uteroplacental blood flow
  • Increases endometrial prostaglandin synthesis
  • Prepares the breasts for lactation.
 
Human Chorionic Gonadotropin
hCG, the so-called pregnancy hormone, is a glycoprotein with biological activity very similar to luteinizing hormone (LH), both of which act via the plasma membrane LH–hCG receptor. hCG is produced almost exclusively in the placenta but is also synthesized in fetal kidney, and a number of fetal tissues may produce the β-subunit or intact hCG molecule.7 The intact hCG molecule is detectable in the plasma of pregnant women about 7–9 days after the midcycle surge of LH that precedes ovulation. Thus, it is likely that hCG enters maternal blood at the time of blastocyst implantation. Blood levels increase rapidly, doubling every 2 days, with maximal levels being attained at about 8–10 weeks of gestation. The best-known biological function of hCG is the so-called rescue and maintenance of function of the corpus luteum, i.e., continued progesterone production.3
 
Human Placental Lactogen
HPL is synthesized and secreted by the syncytiotrophoblast and is detected in the maternal serum between 20 and 40 days of gestation.8 Maternal plasma concentration 4rises steadily until about 34–36 weeks, and this rise is linked mainly to the placental mass. The serum concentration reaches higher levels in late pregnancy (5–15 g/mL) than that of any other known protein hormone. HPL has putative actions in a number of important metabolic processes. These include:9
  • Maternal lipolysis and an increase in the levels of circulating free fatty acids, thereby, providing a source of energy for maternal metabolism and fetal nutrition
  • An anti-insulin or “diabetogenic” action leading to an increase in maternal levels of insulin, which favors protein synthesis and provides a readily available source of amino acids for transport to the fetus
  • A potent angiogenic hormone, it also may play an important role in the formation of fetal vasculature.
 
PITUITARY GLAND
The maternal anterior pituitary gland enlarges by an average of 36% during pregnancy primarily because of a tenfold increase in lactotroph size and number. This enlargement results in an increase in height and convexity of the pituitary on magnetic resonance imaging (MRI). There are reduced number of somatotrophs and gonadotrophs and no changes in corticotrophs or thyrotrophs.10 The posterior pituitary gland diminishes in size during pregnancy.11 The maternal pituitary gland is not essential for maintenance of pregnancy.3
The marked increase in estrogen levels during pregnancy enhances prolactin synthesis and secretion, and maternal prolactin serum levels increase in parallel with the enlargement of the lactotrophs (Figure 1-1). At term, the mean serum prolactin concentration is 207 ng/mL (range 35–600 ng/mL), in contrast to a mean of 10 ng/mL in nonpregnant premenopausal women.12 The principal function of maternal serum prolactin is to ensure lactation.13 Prolactin levels return to the baseline level of nonpregnancy approximately 7 days after delivery in the absence of breastfeeding. With breastfeeding, the basal prolactin levels remain elevated for several months but gradually decrease; however, with suckling, there is a brisk rise in prolactin levels within 30 minutes.10
Growth hormone (GH) levels in maternal serum remain unchanged throughout pregnancy, although the source of immunoreactive GH during gestation does change. Relaxin, secreted by the corpus luteum of pregnancy and estrogen stimulate GH secretion during early pregnancy.14 During the first trimester, GH is secreted predominantly from the maternal pituitary gland and concentrations in serum and amniotic fluid are within nonpregnant values of 0.5–7.5 ng/mL.15 As early as 8 weeks, GH-V secreted from the placenta becomes detectable.16 By about 17 weeks, placenta is the principal source of GH-V secretion.175
zoom view
Figure 1-1: Effect on prolactin secretion by increased estrogen secretion during pregnancy.
Maternal serum concentration of insulin-like growth factor-1 (IGF-1) is elevated during the second half of pregnancy, probably through the combined effect of placental GH-V and HPL. Although the placenta synthesizes and secretes biologically active GnRH, pituitary gonadotropin production decreases during pregnancy.10 Mean TSH concentrations during the first trimester are significantly lower than in the second and third trimesters or in the nonpregnant state.18 Most of this early decrease may be due to the intrinsic thyrotropic activity of hCG. A reduction in serum levels of LH and follicle-stimulating hormone (FSH) is also seen. During pregnancy, maternal ACTH levels rise fourfold over concentration in the nonpregnant state between 7 and 10 weeks of gestation. There is a further gradual rise till 33–37 weeks, when a mean fivefold increase over prepregnancy values is found, followed by a 50% drop just before parturition and a marked fifteenfold increase during the stress of delivery.19 The ACTH concentration returns to the prepregnancy levels within 24 hours of delivery.
6
Arginine vasopressin (AVP) or antidiuretic hormone (ADH) concentrations in the maternal serum are similar to those in nonpregnant women.20 Oxytocin levels progressively increase in the maternal blood and parallels the increase in maternal serum estradiol and progesterone. The levels increase further with cervical dilation and vaginal distension during labor and delivery, stimulating contraction of the uterine smooth muscles and enhancing fetal ejection.21 Uterine oxytocin receptors also increase throughout pregnancy, resulting in a hundredfold increase in oxytocin binding at term in the myometrium.22
 
THYROID GLAND
Evidence of fetal thyroid gland development is apparent early during gestation. Thyroglobulin synthesis can be detected by 4–6 weeks, iodine trapping by 8–10 weeks, and thyroxine (T4) and, to a lesser extent, triiodothyronine (T3) synthesis by 12 weeks. Hypothalamic TRH synthesis can be demonstrated by 6–8 weeks and TSH secretion by 12 weeks of gestation. The bilobed-shape of thyroid gland is evident by 7 weeks and thyroid follicles containing colloid by 10 weeks of gestation. There is evidence that transplacental passage of maternal thyroid hormones play an important role in fetal brain development in the first trimester.23 In light of increased renal clearance of iodine, the status of maternal iodine levels become vital for the development of fetus, as iodine is an essential component for the synthesis of thyroid hormones. The growth and development of the fetus, neurodevelopment in particular, is essentially related to maintenance of maternal euthyroid state. In the first trimester, the fetus relies solely on thyroid hormones and iodine from the mother. Even subtle changes in the thyroid function of the pregnant and lactating woman can cause detrimental effects on the fetus.24 Fetal T4 production gradually rises from mid-gestation to term.25 Fetal serum T3 levels are relatively lower, owing to placental type 3 deiodinase activity, which converts T4 to reverse T3. Maturation of the hypothalamic-pituitary-thyroid axis feedback relationships occurs during the second half of gestation, but it is not complete until after birth. Immediately after birth, there is a TSH surge to 60–80 mIU/L, likely a result of the stress of delivery and clamping of the cord.26
The thyroid gland enlarges by an average of 18% during pregnancy. Important changes in thyroidal economy occur due to 3 modifications in the regulation of thyroid hormones. Firstly, pregnancy induces a marked increase in circulating levels of thyroxine-binding globulin (TBG) in response to increasingly high estrogen levels. Secondly, several factors, which have a stimulatory effect on thyroid gland are produced in excess. Lastly, pregnancy is accompanied by a decreased availability of iodine for the maternal thyroid. This occurs because of increased renal clearance and excretion that results in a relative iodine-deficiency state. Thus, there is a twofold increase in TBG and increased total T4 and T3 levels in maternal serum throughout pregnancy, whereas for most of the gestation, free T4 and free T3 concentrations remain normal.187
 
PARATHYROID GLANDS
During pregnancy, approximately 30 g of calcium is transferred from the maternal compartment to the fetus, with most of the transfer occurring during the last trimester. Maternal total serum calcium levels decrease during pregnancy, with a nadir at 28–32 weeks. This phenomenon is related to the decrease in albumin levels that accompanies the increase in vascular volume.27 Parathyroid hormone (PTH) plasma concentrations decrease during the first trimester and then increase progressively throughout the remaining pregnancy.28 Increased levels likely result from the lower calcium concentration in the pregnant woman. Pregnancy and lactation cause profound calcium stress, and during these times, calcitonin levels are appreciably higher than in nonpregnant women. The net result of these actions is a physiological hyperparathyroidism of pregnancy in order to supply the fetus with adequate calcium. The serum levels of 25-hydroxy vitamin D [25(OH)D] are unchanged during pregnancy, but the estrogen-induced rise in vitamin D–binding globulin results in a twofold increase in 1, 25-dihydroxy vitamin D3 [1,25(OH)2D3] concentrations in maternal serum.27
 
ADRENAL GLANDS
During fetal life, there is a remarkable increase in the size of the adrenal glands mainly due to the presence of a well-developed inner zone that involutes after birth.29 The fetal adrenals are disproportionately large and are larger than the fetal kidneys at mid-gestation.2 This inner zone comprises 80% of the fetal adrenal cortex at term.29 The adrenals are as large as those of adults, weighing 10 g or more at term.2 There is a convincing evidence that the fetal adrenal cortex synthesizes a considerable part of the precursors for estrogen, which are eliminated in the maternal urine during pregnancy. The fetal adrenal glands secrete large quantities of steroid hormones (up to 200 mg daily) near term, and the rate of steroidogenesis is, thus, 5 times of that observed in the adrenal glands of resting adults. Also, the fetal adrenal cortex is one of the main users of placental progesterone in its synthesis of adrenocortical hormones.29 As clinically evidenced, ACTH is the primary trophic hormone of the fetal adrenal glands. ACTH-related peptides, growth factors, and other hormones have been suggested as possible contributory trophic hormones for the fetal zone. The adrenal glands shrink to almost 50% in size, because of regression of fetal zonal cells after birth.2
In normal pregnancy, the maternal adrenal glands undergo little, if any, morphological change.3 As a result of the hyperestrogenemia of pregnancy, hepatic production of cortisol-binding globulin is increased. The increased production results in doubling of the maternal serum levels of cortisol-binding globulin, which in turn results in 8decreased metabolic clearance of cortisol and a threefold rise in total plasma cortisol by 26 weeks, when the levels reach a plateau until they rise at the onset of labor. The enhanced cortisol production is due to an increase in the maternal plasma ACTH concentrations and hyperresponsiveness of the adrenal cortex to ACTH stimulation during pregnancy.19 Cortisol secretion follows that of ACTH, and the diurnal rhythm is maintained during pregnancy. Despite the elevated free cortisol levels, pregnant women do not develop the stigma of glucocorticoid excess, possibly because of the antiglucocorticoid activities of the elevated concentrations of progesterone.30
As early as 15 weeks, the maternal adrenal glands secrete considerably increased amounts of aldosterone. By the third trimester, about 1 mg/day is secreted. If sodium intake is restricted, aldosterone secretion is elevated even further.31 At the same time, levels of renin and angiotensin II substrate normally are increased, especially during the latter half of pregnancy. This scenario gives rise to increased plasma levels of angiotensin II, which by acting on the zona glomerulosa of the maternal adrenal glands, accounts for the markedly elevated aldosterone secretion. It has been suggested that the increased aldosterone secretion during normal pregnancy affords protection against the natriuretic effect of progesterone and atrial natriuretic peptide.
Maternal plasma androstenedione and testosterone are increased in pregnancy. These hormones are converted to estradiol in placenta, which increases their clearance rates. Conversely, the increased sex hormone-binding globulin (SHBG) in plasma of pregnant women retards testosterone clearance.3
Adrenal medullary function remains normal throughout pregnancy. Thus, 24-hour urine catecholamine and plasma epinephrine and norepinephrine levels are similar to concentrations in the nonpregnant state.32
 
PANCREAS
Hyperplasia and hypertrophy of β cells in the islets of Langerhans are probably the result of stimulation by estrogen and progesterone.33 During early pregnancy, the glucose requirement of the fetus leads to enhanced transport of glucose across the placenta by facilitated diffusion, and maternal fasting hypoglycemia may be present. Although basal insulin levels may be normal, there is hypersecretion of insulin in response to a meal. Because the half-life of insulin is not altered during pregnancy,34 this increase represents an increase in synthesis and secretion. This results in enhanced glycogen storage and decreased hepatic glucose production.
As pregnancy progresses, the levels of HPL rise, as do the levels of glucocorticoids, leading to insulin resistance (IR) found during the last half of pregnancy.35 Thus, in late pregnancy, glucose ingestion results in higher and more sustained levels of glucose and insulin and a greater degree of glucagon suppression than in the nonpregnant state.9
 
CONCLUSION
The maternal endocrinological activities and processes play a vital as well as critical role in the initiation and maintenance of pregnancy. The interplay of these processes is essential in the complete period of pregnancy and the requirements of the fetus, even after birth. Progesterone and estrogen are primarily concerned with the maintenance of the gestational period and preparing the mother for further requirements and necessities of the fetus. While hCG is responsible for the continued progesterone production during gestation, HPL ensures fetal nutrition and angiogenesis. Thyroid hormones are responsible for the growth and development, especially neurodevelopment of the fetus, and hyperparathyroidism ensures adequate availability of calcium to the fetus. ACTH ensures the maintenance of the diurnal rhythm during pregnancy, and aldosterone provides protection against natriuretic effect of the progesterone and atrial natriuretic peptide. All the maternal hormones, thus, synchronize with each other and result in the evolution of a new life.
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