Developmental Endocrinology

Endocrine Systems

A few key concepts of cell communication will be presented here to help build a foundation of knowledge to understand hormonal abnormalities in neonates.

In the process of communication, cells emit signals that act locally or distally. If a cell emits signals that are received by the cell itself, this is termed autocrine regulation . If a cell emits signals that are received by neighboring cells, this is termed paracrine regulation . Finally, if the cell signal travels through the bloodstream to distant cells and organs, this is termed endocrine regulation .

A feature of endocrine systems is that the hormonal signals are present in the bloodstream at very low concentrations, and even small changes in hormone concentration can elicit a robust response from receiving cells. The released endocrine hormones can be either water-soluble peptide hormones that must bind to receptors on the extracellular surface of the cell or fat-soluble steroid-like molecules that can pass through the cell membrane directly into the cell's nucleus to bind its receptor to regulate gene transcription. On binding to their specific cell membrane receptor, peptide hormones activate downstream signaling transduction pathways in the cell to induce biological responses. These responses can be immediate; for instance, thyroid-stimulating hormone (TSH), when bound to the TSH receptor on thyroid follicular cells, cause iodine transport into the cell to increase. It can also induce relatively delayed cell responses, such as an increase in gene transcription of enzymes involved in thyroglobulin production. In contrast, steroid-like molecules, such as cortisol, when bound to their respective receptors, induce a biological response by causing an increase in the transcription of various genes. These induce longer-term, broader changes in the target cell function by modulating which genes the cells express and, thus, the proteins they produce.

Many hormonal systems exhibit a hierarchy of hormone signals that allow strict regulation of system function. The hypothalamic-pituitary-end gland system is an example of this multitier hormonal system. In this system, a hormone released by the upstream hypothalamus travels through the portal circulation of the pituitary and binds to the corresponding receptor on the dedicated pituitary cell. Once bound, this receptor induces the cell to synthesize and release the corresponding pituitary hormone. This hormone then travels through the systemic circulation to the endocrine gland to bind to the hormone's dedicated receptor on the target gland. The binding of the hormone to its receptor induces the target organ to release its dedicated end hormone. This hormone then travels through the bloodstream to multiple organs to affect cell function. End hormones use negative feedback to regulate their own production. That is, the hypothalamus and pituitary sense the end hormone concentration, adjusting the release of the upstream regulatory hormone cascade to fine-tune end hormone production. Negative feedback is a unique and consistent property of hormonal systems and is useful in interpreting the adequate response of a hormonal cascade to perturbation in the system.

Endocrine Organ Development and Perinatal Transition

Early in fetal development, fetal hormonal gland development is driven by fetal genotype. However, later in fetal development, the hormonal responsiveness of target tissues is dependent not only on fetal genotype but also on the complex fetal hormonal milieu, which comprises fetal, maternal, and placental hormones. Placental hormones may be influenced by maternal and fetal genotype, as well as maternal prepregnancy and pregnancy health and nutrition. Thus the fetal hormonal environment is dependent on a complex interplay between fetal and maternal factors.

In evaluating hormonal disorders in newborns, one needs to consider both maternal and fetal factors and keep the following principles in mind. First, human fetal endocrine organ development begins predominantly independently of maternal hormones. This independence is possible because the placenta is a barrier to many (but not all) maternal hormones, including steroids, peptides, and glycoproteins. Second, although endocrine organ development may be normal, perturbations in the maternal hormonal milieu may still affect fetal development for the rare hormone that crosses the placenta. An example is disorders of thyroid hormone production. Maternal-fetal transfer of thyroxine (T ₄ ) may result in 25% to 50% of neonatal plasma levels of T _4. This transfer allows children with athyrosis to have good neurodevelopmental outcomes if treatment is initiated within 2 weeks of birth, as the maternal thyroid hormone crossed the placenta and allowed normal fetal neurodevelopment and growth. In contrast, children born to mothers with untreated or undertreated hypothyroidism during pregnancy have poor neurodevelopmental outcomes because of the hypothyroxinemia early in gestation before T ₄ production by the fetal thyroid. Third, alterations in transplacental substrate transfer can modify the late development of the fetal and, thus, neonatal hormonal pathways and feedback mechanisms. This can be seen in neonates born from pregnancies with uncontrolled diabetes, in which the transplacental passage of glucose induces robust insulin release and subsequent β-cell hypertrophy in the still-developing pancreas. This leads to transient neonatal hyperinsulinemic hypoglycemia due to the abrupt fall in glucose supply at birth. This is also seen in the placental transfer of hormonal agents or maternal antibodies that affect neonatal endocrine gland function. Examples include the transplacental crossing of maternal TSH antibodies causing neonatal hyperthyroidism. Fourth, when interpreting research on endocrine developmental biology from animal fetal physiology models and gene manipulation studies, one must consider similarities and differences between animal and human fetuses and newborns. The maturational state at birth differs widely among species. For many species, including rodents and some large animals, the maturational state of the newborn is relatively immature (altricial). Organ systems in humans, in contrast, are relatively more developed at birth (precocial). This is especially true in neuroendocrine and most endocrine systems. Thus a study of hormonal physiology in nonhuman species may yield insights, but they may not be immediately applicable to human newborns.

The Maternal-Placental-Fetal Unit

During pregnancy, the mother, fetus, and placenta function in concert as a steroidogenic unit for estrogen and progesterone production. Most steroidogenic activity is exerted in the fetal zone (FZ) of the human fetal adrenal (HFA) gland, where large amounts of adrenal androgens are produced to be used by the placenta for estrogen biosynthesis. Estrogen promotes placental trophoblast differentiation into syncytiotrophoblast and upregulates key enzymes in progesterone biosynthesis.

Cortisol may act as a “two-edged sword” for the fetus; it promotes the maturation of fetal organs necessary for extrauterine life, but it can also adversely influence fetal growth and postnatal development. Therefore, cortisol production in the fetoplacental unit is strictly regulated to protect the fetus from hypercortisolism effects. Fetal access to maternal glucocorticoid is restricted, and a maternal-fetal gradient is maintained by the enzyme 11β-hydroxysteroid dehydrogenase type 2, which converts cortisol to inactive cortisone. Maternal cortisol levels are usually 5 to 10 times higher than fetal cortisol levels. Fetal protection is also achieved through other mechanisms in the HFA by regulation of 3β-hydroxysteroid dehydrogenase/Δ isomerase type 2, the key steroidogenic enzyme for cortisol biosynthesis, and in fetal membranes by control of 11β-hydroxysteroid dehydrogenase type 1 activity, which converts inactive cortisone to cortisol. A single course of glucocorticoids is accepted as standard therapy for pregnant women at risk of preterm delivery to accelerate fetal lung maturation and reduce morbidity and mortality in preterm infants. However, multiple courses of prenatal glucocorticoids (more than 2) may be associated with decreased weight, length, and head circumference at birth and are currently not recommended because of concerns for maternal and fetal harm.

Placental corticotropin-releasing hormone (CRH) is one of the key determinants of the timing of parturition. Near term, CRH levels increase and directly stimulate the HFA by increasing its responsiveness to adrenocorticotropic hormone (ACTH) and secretion of cortisol and dehydroepiandrosterone (DHEA) and its sulfonated form, precursors of placental estrogen. Cortisol, in turn, stimulates placental CRH production, forming a positive feedback loop and generating more cortisol and estrogen near term. Estrogen upregulates contraction-associated proteins and transforms the myometrium into a contractile state, preparing for successful uterine contractions and parturition. Cortisol also promotes the maturation of fetal organs (e.g., the lung) and stimulates the production of prostaglandins necessary for parturition. Increased levels of estrogen, cortisol, and CRH, together with functional progesterone withdrawal, are thought to contribute to the initiation of parturition ( Fig. 82.1 ).

From this perspective, one would expect that the lower cortisol levels seen in preterm infants may have adverse consequences. This is not confirmed. Some studies showed no adverse effects related to low cortisol levels in preterm infants, while others correlated low cortisol levels to increased severity of illness, hypotension, mortality, and development of bronchopulmonary dysplasia. Selective hydrocortisone supplementation could be beneficial for survival in very preterm infants but with possible increased risks of spontaneous gastrointestinal perforation and late-onset sepsis.

Umbilical plasma estradiol and progesterone levels are quite high and fall approximately 100-fold during the first day after birth. The consequences of estradiol and progesterone withdrawal earlier in premature infants remain largely unknown. Pilot studies of estradiol and progesterone supplementation in extremely low-birth-weight infants have shown trends toward increased bone mineralization and a decrease in the incidence of chronic lung disease. Adequately powered clinical trials are needed to determine the benefits and risks of hormonal replacement in preterm infants.

Hypothalamic and Pituitary Development

The anterior and posterior pituitary glands have different embryonic origins. The anterior lobe arises from the oral ectoderm, and the posterior pituitary arises from the infundibulum of the developing central nervous system. A section of the oral ectoderm thickens very early in development, forming an invagination termed a Rathke pouch . As the Rathke pouch invaginates further, the adjacent neural ectoderm evaginates to form the infundibulum ( Fig. 82.2A ). With further evagination, the Rathke pouch and the infundibulum directly contact each other. This close contact is essential for subsequent anterior and posterior pituitary development. The Rathke pouch later “pinches off” from the remaining oral ectoderm to form the anterior pituitary gland. In humans, this occurs by 5 to 6 weeks of gestation.

The hypothalamus comprises a diverse collection of neurons that regulate pituitary hormone release, thirst, body temperature, blood pressure, and serum osmolality. Although the location of the diverse neurons within the hypothalamus is well delineated, the development of these neuron populations within the hypothalamus has yet to be elucidated. The complexity of the anatomy and neuronal cell types makes it difficult to elucidate the developmental cascade of events. Nevertheless, it is known that the hypothalamic nuclei, which contain the individual neuron types, are fully developed with projections to the median eminence (with subsequent release of hormones into the pituitary portal circulation) by 15 to 18 weeks’ gestation.

In contrast, knowledge regarding differentiation of the anterior pituitary is well delineated. Differentiation of Rathke pouch cell progenitors into the pituitary cell types (corticotrophs, gonadotrophs, lactotrophs, thyrotrophs, and somatotrophs) is tightly regulated by a cascading series of transcription factors (see Fig. 82.2B ). Knowledge of the series of events comes from knockout studies in mice as well as genetic studies in humans with congenital hypopituitarism. The pituitary cell types arise in a temporally and spatially specific pattern as directed by the transcription factors, occurring between week 7 and week 16 of human gestation. If one transcription factor of the developmental series malfunctions or is expressed out of series, as is seen in clinical syndromes of hypopituitarism ( Table 82.1 ), then a very typical pattern of pituitary hormone deficiency is manifest.

Each mature pituitary cell type synthesizes and secretes a corresponding hormone that is regulated by a hypothalamic peptide: corticotrophs secrete ACTH in response to CRH; gonadotrophs secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in response to gonadotropin-releasing hormone (GnRH); lactotrophs secrete prolactin in response to dopamine; thyrotrophs secrete thyrotropin (TSH) in response to thyrotropin-releasing hormone (TRH; and somatotrophs secrete growth hormone in response to growth hormone-releasing hormone and somatostatin.

The mature pituitary cell types contain secretory granules by 10 to 12 weeks’ gestation, and the hormones can be measured by 12 to 17 weeks’ gestation. The pituitary portal circulation is mature by 12 to 17 weeks, and thus regulation of pituitary hormone release by the corresponding hypothalamic peptide may be operational by that time. However, the negative feedback mechanisms that finely tune hypothalamic-pituitary-end hormone release may not be fully mature until later in gestation. At birth, the negative feedback mechanisms are fully mature, which is crucial in the diagnostic evaluation of infants with suspected pituitary hormone disorders.

The neurohypophysis (posterior pituitary), formed by the evagination of the neuroectoderm, is fully developed by 10 to 12 weeks of gestation and contains granules of arginine vasopressin (AVP) and oxytocin. The neurohypophysis comprises the axonal terminals of hypothalamic neurons whose cell bodies are in the mature paraventricular nuclei and supraoptic nuclei. These neurons generate AVP or oxytocin separately and are thus regulated by separate factors. AVP-releasing neurons integrate signals from plasma osmolality sensors and baroreceptors in the carotid sinus and aortic arch to release AVP and thus regulate serum osmolality and systemic blood pressure. AVP acts on the renal collecting duct via V ₂ receptors to induce water reabsorption. AVP also acts on V _1A receptors on endothelial cells to increase arterial and venous constriction and thus increase blood pressure. Serum osmolality is tightly controlled between 280 and 295 milliOsmoles (mOsm)/kg water in adults. With even a slight increase in serum osmolality, AVP release increases exponentially to induce renal water reabsorption to a maximum urine osmolality of 800 to 1200 mOsm/kg water (maximum urine osmolality depends on the osmolality of the upstream kidney medulla). In neonates, however, the urine-concentrating ability of the kidney is impaired to a maximum of 300 mOsm/kg water because of the relative immaturity of the renal tubules rather than lack of AVP release; AVP is present in the fetus and neonate, and V ₂ receptors are functional.

Diseases of Hypothalamic or Pituitary Maldevelopment

Given the overlapping developmental windows of important cranial midline structures, a diagnosis of congenital hypopituitarism in a neonate should be considered if there are intracranial or extracranial midline defects. For instance, hypopituitarism has been reported in children with cleft lip or palate or central incisors. Hypopituitarism and diabetes insipidus can be encountered in neonates with holoprosencephaly. Children who have intracranial abnormalities along the spectrum of optic nerve hypoplasia, with or without septo-optic dysplasia, commonly have congenital hypopituitarism.

Neonates with congenital hypopituitarism because of a mutation in a gene important in pituitary differentiation may or may not have obvious defects in midline structures (see Table 82.1 ). In the absence of these clinical signs, hypopituitarism may be suspected in neonates with micropenis and normal testicular descent (caused by growth hormone with or without gonadotropin deficiency), prolonged hypoglycemia (caused by combined growth hormone and cortisol deficiency), or rarely, cholestatic giant cell hepatitis (caused by combined growth hormone, thyroid hormone, and cortisol deficiency). As fetal growth is independent of growth hormones, children with congenital hypopituitarism are of normal size and weight at birth. If a newborn screen uses T ₄ levels as the screen for congenital hypothyroidism, then low T ₄ levels may be a diagnostic clue; if a newborn screen measures thyrotropin (also known as thyroid-stimulating hormone, TSH) to screen a newborn for congenital hypothyroidism, the central hypothyroidism of hypopituitarism will not be detected. After 2 months of life, a clue to optic nerve hypoplasia may be a disconjugate gaze. If diabetes insipidus is diagnosed, then full evaluation of the remaining pituitary hormones is mandatory.