The regulation of the fetal endocrine system, as is true for the placenta, is not entirely independent but relies, to some extent, on precursors secreted by the placenta or maternal tissues. As the fetus develops, its endocrine system begins matures and eventually becomes more independent, preparing the fetus for extrauterine life.
Fetal Hypothalamus and Pituitary
The fetal hypothalamus differentiates from the forebrain during the first few weeks of fetal life. By 12 weeks' gestation, hypothalamic development is well advanced. Most of the hypothalamic-releasing hormones, including gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), corticotrophin-releasing hormone (CRH), as well as dopamine, norepinephrine, and somatostatin, can be identified as early as 6-8 weeks of gestation. The portal-vessel system that delivers the releasing hormones to the anterior pituitary is fully developed by 18 weeks of gestation.
The anterior pituitary cells that develop from those cells lining Rathke's pouch are capable of secreting growth hormone (GH), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and adrenocorticotropic hormone (ACTH), in vitro, as early as 7 weeks of fetal life (Figure 12).
Fig_12_Fetal serum pituitary hormone levels.jpg
Figure 12. Fetal serum pituitary hormone levels. PrL indicates prolactin; TSH, thyroid-stimulating hormone; ACTH, corticotropin; GH, growth hormone; LH/FSH, luteinizing hormone/follicle stimulating hormone.
The placenta is relatively impermeable to thyroid-stimulating hormone (TSH) and thyroxine (T4), so the fetal hypothalamic-pituitary-thyroid axis develops and functions independently of the mother's. The levels of TSH and T4 are relatively low in fetal blood until mid-gestation. At 24-28 weeks' gestation, serum T4 and reverse tri-iodothyronine (rT3) concentrations begin to rise progressively until term while the TSH concentration peaks. At birth, there is an abrupt release of TSH, T4, and T3. The relative hyperthyroid state of the newborn is believed to facilitate thermoregulatory adjustments for extrauterine life.
The pattern of luteinizing hormone (LH) levels in fetal plasma parallels that of follicle-stimulating hormone (FSH). The decline in pituitary gonadotropin content, and plasma concentration of gonadotropins after mid-gestation is believed to result from the maturation of the hypothalamic-pituitary-gonadal axis. The hypothalamus becomes progressively more sensitive to sex steroids originating from the placenta, and circulating in fetal blood. Occurring at 7 weeks' gestation in the male, fetal testosterone secretion begins soon after differentiation of the gonad into the testis and Leydig cells. Maximum levels of fetal testosterone are observed at about 15 weeks and decrease thereafter. Early secretion of fetal testosterone is important in initiating sexual differentiation in males. Human chorionic gonadotropin (hCG), supplemented by fetal LH, is believed to be the primary stimulus effecting the early development and growth of Leydig cells as well as stimulating the subsequent peak of testosterone production. In females, the fetal ovary is involved primarily in the formation of follicles and germ cells and less involved in hormone secretion.
The human fetal adrenal gland is a remarkable organ due to its incredible capacity for steroid biosynthesis in utero, and because of its unique morphologic features. The human fetal adrenals are disproportionately large, and at mid-pregnancy their size exceeds that of the fetal kidneys. At term, the adrenals are as large as those of adults are, weighing 10 grams or more. The region that ultimately develops into the adult adrenal cortex, the outer or definitive zone, accounts for only about 15% of the fetal gland (Figure 13). The unique inner or fetal zone comprises 80-85% of the volume of the adrenal in utero, and is largely responsible for the tremendous secretory capacity of this organ. The fetal zone rapidly undergoes involution at parturition and by one year it has completely disappeared. Changes in the fetal adrenal volume throughout fetal life and into young adulthood are graphically depicted in Figure 14.
The adrenal function of 10 preterm infants of gestational age 27-34 weeks was assessed for up to 80 days after delivery. The changes in steroid excretion with time in preterm infants of gestation over 28 weeks reflect involution of the fetal adrenal zone at a similar rate to term infants. These findings are consistent with the removal at birth of the inhibitory effects of oestrogen on the 3 beta-hydroxysteroid dehydrogenase enzyme. The continued function of the adrenal fetal zone beyond the first month in preterm infants of less than 28 weeks gestation may however be due to persistence of some other fetal regulatory adrenal mechanism. This suggests that it is gestation that determines fetal zone activity rather than birth.
The fetal adrenal gland secretes large quantities of steroid hormones (up to 200-mg daily) near term. The rate of steroidogenesis is 5-times that observed in the adrenal glands of adults at rest. The principal steroids secreted are C-19 steroids (mainly DHEAS), which serve as substrates for estrogen biosynthesis by the placenta (Figure 13).
The fetal adrenal gland contains a zone, unique to in-utero fetal life, that accounts for the rapid growth of the adrenal gland; this zone regresses during the first few weeks after birth. In addition to the fetal zone, an outer layer of cells forms the adrenal cortex (definitive zone). The fetal zone differs not only histologically, but also biochemically from the cortex (i.e., the fetal zone is deficient in 3b-hydroxysteroid dehydrogenase enzyme activity and, therefore, secretes C-19 steroids (mainly DHEAS); the cortex secretes primarily cortisol).
Fig_13_Steroid hormone formation in the fetal adrenal gland.jpg
Figure 13.
An illustration demonstrating generalized pathways for steroid hormone formation
in the fetal adrenal gland.
DHA: dehydroepiandrosterone.
DHAS: dehydroepiandrosterone sulfate.
LDL: low-density lipoprotein cholesterol.
Fig_14_Changes in the fetal adrenal volume .jpg
Figure 14. Changes in the fetal adrenal volume throughout fetal life and into young adulthood.
Research involving the fetal adrenal gland has attempted to determine the factors that stimulate and regulate fetal adrenal growth and steroidogenesis. Other work has focused on the mechanisms responsible for fetal zone atrophy after delivery. All investigations have shown that, in vitro, adrenocorticotropic (ACTH) stimulates steroidogenesis. Furthermore, there is clinical evidence that, in vivo, ACTH is the major trophic hormone of the fetal adrenal gland. For example, in anencephalic fetuses, the plasma levels of ACTH are very low and the fetal zone is markedly atrophic. Maternal glucocorticoid therapy suppresses fetal adrenal steroidogenesis by suppressing fetal ACTH secretion. Despite these observations, ACTH -related peptides, growth factors and other hormones have been proposed as possible trophic hormones for the fetal zone. After birth, the adrenal gland shrinks in size by more than 50% because of the regression of fetal zone cells.
Fetal Parathyroid Glands and Calcium Homeostasis
In the fetus calcium concentrations, are regulated by the movement of calcium, across the placenta, from the maternal compartment. In order to maintain fetal bone growth, the maternal compartment undergoes adjustments that provide a net transfer of sufficient calcium to the fetus. Maternal compartment changes that permit calcium accumulation include increases in maternal dietary intake, increases in maternal 1,25-dihydroxyvitamin D3 levels, and increases in parathyroid hormone levels. Actually, levels of total calcium and phosphorus decline in maternal serum, but ionized calcium levels remain unchanged. A placental calcium pump creates a gradient of calcium and phosphorus that favors the fetus. Thus, circulating fetal calcium and phosphorus levels increase steadily throughout gestation. Furthermore, fetal levels of total and ionized calcium, as well as phosphorus, exceed maternal levels at term.
By 10-12 weeks' gestation, the fetal parathyroid glands secrete parathyroid hormone (PTH). Fetal plasma levels of parathyroid hormone are low during gestation, but increase after delivery. In contrast to unchanged maternal calcitonin levels, the fetal thyroid gland produces increasing levels of calcitonin. Since there is no transfer of parathyroid hormone across the placenta, changes noted in fetal calcium levels are related to changes in these hormones (PTH and calcitonin), and consistent with an adaptation to conserve and stimulate bone growth within the fetus. After birth, neonatal serum calcium and phosphorus levels fall. Parathyroid hormone levels start to rise within 48 hours after birth. Calcium and phosphorus levels steadily increase over the following several days, with some dependence on dietary intake of milk.
The fetal pancreas appears during the 4th week of fetal life. The alpha cells, which contain glucagon, and the beta cells, which contain somatostatin, develop before the beta cells differentiate; however, insulin can be recognized in the developing pancreas before beta cell differentiation is apparent. Human pancreatic insulin and glucagon concentrations increase with advancing fetal age, and are higher than concentrations found in the adult pancreas. In vivo studies of umbilical cord blood obtained at delivery and fetal scalp blood samples obtained at term show that fetal insulin secretion is low and tends to be relatively unresponsive to acute changes in glucose. In contrast, fetal insulin secretion, in vitro, is responsive to amino acids and glucagon as early as 14 weeks' gestation. In maternal diabetes mellitus, fetal islet cells undergo hypertrophy such that the rate of insulin secretion increases.
Alpha-fetoprotein is a glycoprotein synthesized, in sequence, by the yolk sac, gastrointestinal tract and fetal liver. After entering the fetal urine, it is readily detected in amniotic fluid. Amniotic fluid AFP (afAFP) peaks between 10-13 weeks gestation, and then declines from 14-32 weeks. In the fetus, AFP peaks at 12-14 weeks, and steadily decreases until term. The fall in fetal plasma AFP (fpAFP) is most likely due to the combination of increasing fetal blood volume and a decline in fetal production. The concentration gradient between fpAFP and msAFP is approximately 150- to 200-fold. Detectable as early as 7 weeks' gestation, msAFP reaches peak concentrations between 28-32 weeks. The seemingly paradoxical rise in msAFP in association with decreasing afAFP and fetal serum levels can be accounted for by the increasing placental permeability to fetal plasma proteins that occurs with advancing gestational age. Alpha-fetoprotein acts as an osmoregulator to help adjust fetal intravascular volume. It may also be involved in certain immunoregulatory functions (159). Amniotic fluid AFP and maternal serum AFP are clinically important because they are elevated in association conditions such as neural tube defects (160). Additionally, msAFP is decreased in pregnancies in which the fetus has Down syndrome (trisomy 21).
Dr Mahmoud Ahmad Fora
Last Updated Mar 25, 2005