All of the following are changes due to age-related decreases in endocrine secretions, except

Introduction

The endocrine system is one of two main systems in the body responsible for communication and regulation of body functions, coordinating functions such as growth, metabolism, and reproduction. The other main communication and regulation system is the nervous system. The endocrine system utilizes hormones for communication and regulation, and these are typically released into the blood. In contrast, the nervous system utilizes primarily cell-to-cell synaptic communication. While divisions are helpful for classification and specification, it is important to bear in mind the multitude of bidirectional effects between all the major systems of the body, including those between the endocrine system and the nervous system.

Hormones are chemical messengers derived from the major classes of compounds used by the body more generally, such as proteins and lipids. Endocrine coordination via the release of hormones into the blood stream presents unique problems of production, distribution, and mechanisms for action. Receptors on cell surfaces and in the nuclei of cells play a critical role in the endocrine system. Without the active participation of receptors, hormones would be incapable of executing their wide-ranging effects. Another critical aspect of the endocrine system to be discussed is regulation of hormone action via feedback loops.

Over- or under-production of hormones, autoimmune diseases, and genetic mutations can lead to a variety of endocrine disorders, some of which are life-threatening if left untreated. Diseases to be discussed below are those that are most likely to influence infant and child development, including diabetes, growth disorders, thyroid disease, adrenal insufficiency, and the rare disorder, Cushing’s syndrome.

Endocrine functions also change across the lifetime, so that unique endocrine processes and profiles are found during pregnancy, in the fetus, during puberty, and in aging. Those changes that accompany pregnancy and those that are important during the fetal period will be discussed.

2.2 Endocrine System

The endocrine system consists of a variety of glands that secrete hormones. Hormones are chemical substances that are released into the bloodstream, stimulate receptors in target cells, and alter the behavior of those cells. Ample evidence exists that neuroendocrine substances influence immune cells. For example, immune cells react to many hormones, including cortisol, substance P, vasoactive intestinal peptide, prolactin, and growth hormone. Many of the cells involved in the immune response carry surface receptors for a number of hormones, allowing them to respond to signals from the brain as well as from other organ systems.

Introduction

The endocrine system, along with the nervous system, comprise the primary regulators of body metabolism. While the nervous system acts through electrical impulses and neurotransmitters, the endocrine system operates through chemical messengers called hormones. Hormone production is regulated by a chain of choreographed interactions of many endocrine organs. As a response to physiological and environmental stress, hormones are synthesized and secreted in a timely and quantitative manner. They travel in the bloodstream to different parts of the body to elicit characteristic cellular responses through hormone-specific receptors in target endocrine organs. Upon binding to receptors at target organs, the hormone–receptor complex initiates a cascade of signal transduction reactions, which ultimately modulate expressions of genes, thus regulating physiological and cellular reactions that are essential for reproduction, growth, development, immune reactions, and neurobehavioral functions.

Furthermore, hormone production is controlled by negative feedback mechanisms. When there is sufficient concentration of a hormone in circulation, a control mechanism will send signals back to the hormone-producing organ to inhibit further hormone production. This mechanism prevents excessive stimulation and maintains the stability of the cellular status.

Many environmental factors, including the light cycle, temperature, naturally occurring ingredients in food, and anthropogenic pollutants, interact with the endocrine system and influence hormone production. Substances with the ability to interfere with hormone levels in the endocrine system, however, do not necessarily pose any health risk for humans and other organisms. The endocrine system has the capacity to tolerate moderate external challenges by evoking the above-described adaptable control/feedback mechanisms, thus maintaining functional homeostasis of the body. However, deleterious health effects could occur when the control mechanisms of equilibrium are overwhelmed by excessive amounts of exposure to endocrine disruptors.

Endocrine dysfunction could result from having either an excessive or insufficient amount of hormone production or failure to induce proper cellular responses. Excessive amounts of hormones may be caused by overproduction, rapid release from storage, decreased rate of metabolism or decreased excretion, while insufficient amount of hormone production may be caused by decreases in hormone synthesis or release, increased rate of metabolism or rapid excretion. Cellular injury of endocrine organs and altered enzymatic activities of hormone synthesis and metabolism could be the underlying etiology of endocrine toxicity. Endocrine dysfunction may also result from exposure to substances with structures similar to hormones that are capable of binding to receptors, thus either mimicking the function of a hormone or inhibiting the function of the normal hormone–receptor complex. An endocrine toxic substance may also change the way hormones are transported in circulation by adhering to or changing the amount of hormone-binding protein. In such cases, either the total concentration of a hormone or the amount in free form (i.e. biologically available form) can be altered. Furthermore, hormones are also involved in the differentiation and development of interrelated endocrine organs and the nervous systems. The potential of a substance to cause developmental effects depends not only on the amount of exposure, but also on the timing of exposure in an organism’s stage of life. During gestation and prepuberty, morphological and functional development in a fetus and young animal are highly sensitive to endocrine-disrupting agents.

Age-Related Hormone Decline

Endocrine system activity is known to change markedly with age. Because of decreased releases of gonadotropin and decreased secretions at the gonadal level, a gradual decline in serum testosterone levels occurs during aging.27 Testosterone plays a key role in maintaining body composition.28 Low levels of serum testosterone have been shown to have an independent relationship with frailty.29 Insulin-like growth factor-1 (IGF-1) is primarily produced by the liver; production is regulated by growth hormone secreted from the pituitary gland. The amount of growth hormone secreted from the pituitary gland declines gradually with age. In parallel, levels of circulating IGF-1 decrease with aging.30 The primary function of IGF-1 is to promote growth and development, including muscle protein synthesis. As a crucial regulator of muscle mass, IGF-1 levels are associated with muscle strength and mobility.31 Dehydroepiandrosterone (DHEA) and its sulfate form (DHEAS) are secreted from the adrenal gland. Adrenocortical cells that produce hormones decrease in activity in aging.32 DHEAS is converted to androgenic and estrogenic steroid in peripheral tissues, and represents another hormone that has significant trophic effects on skeletal muscles.32 Low circulating DHEAS levels have been shown to be independently linked to frailty.33

INTRODUCTION

The endocrine system consists of several glands that synthesize and secrete hormones into the circulatory system. These hormones control a variety of metabolic processes throughout the body. The secretions of some of these glands affect the growth and maintenance of skeletal tissue. Abnormal secretions, either too little or too much, can affect the shape, size, and biomechanical strength of bone. Although there is considerable overlap in the skeletal manifestations of endocrine diseases, it is possible to diagnose some endocrine problems on the basis of the abnormalities apparent in archeological human skeletal remains. The endocrine glands associated with skeletal pathology include (1) pituitary, (2) thyroid, (3) parathyroid, (4) adrenal, (5) ovaries, and (6) testis.

Skeletal growth and maturation is mainly controlled by an intricate interrelationship between the pituitary and thyroid. The pituitary mainly controls growth and the thyroid maturation of bone (Asling and Evans 1956). The parathyroid glands play a crucial role in the maintenance of calcium and phosphate ion concentrations in serum. Parathyroid hormone stimulates the action of osteoclasts, which release calcium and phosphate into the bloodstream. Excessive amounts of the hormone secreted by the adrenal glands (adrenocortical glucocorticoid steroids) increase the activity of osteoclasts relative to osteoblasts and result in osteoporosis (Resnick 1995c:2076). Inadequate secretions by the ovaries or testis can result in deficient growth. (For a general discussion of endocrine-skeletal relations, see Putschar (1960:405-414)).

Introduction

The endocrine system comprises several glands that synthesize and secrete hormones into the circulatory system. These hormones control a variety of metabolic processes throughout the body. The secretions of some of these glands affect the growth and maintenance of skeletal tissue. Abnormal secretions, either too little or too much, can affect the shape, size, and biomechanical strength of bone. Although there is considerable overlap in the skeletal manifestations, it is possible to diagnose some endocrine problems on the basis of the abnormalities apparent in archeological human skeletal remains. The endocrine glands associated with skeletal pathology include: (1) the pituitary, (2) the thyroid, (3) the parathyroid, (4) the adrenals (cortex), (4) the ovaries, and (6) the testes.

Normal skeletal growth and maturation is mainly controlled by an intricate interrelationship between the pituitary and thyroid glands. The pituitary mainly controls growth, while the thyroid controls maturation of bone (Urist, 2012). The parathyroid glands play a crucial role in the maintenance of calcium and phosphate concentrations in serum. Parathyroid hormone stimulates the action of osteoclasts, which release calcium and phosphate into the bloodstream. Excessive amounts of the hormone secreted by the adrenal glands (adrenocortical glucocorticoid steroids) increase the activity of osteoclasts while depressing osteoblasts, resulting in osteoporosis (Canalis et al., 2007). Inadequate secretions by the ovaries or testes can result in deficient growth.

Energy Production, Utilization, and Storage

The endocrine system is the preeminent mediator of substrate flux and the conversion of food into energy production or storage. In the anabolic state, excess fuel is stored as glycogen and fat under the influence of insulin. In the catabolic state, as in starvation or fasting, glucagon and other counterregulatory hormones induce glycogen breakdown and mobilize amino acids and free fatty acids as substrates for gluconeogenesis.

The functionality of hormones does not simply relate to the idea of one hormone for one particular job or function. The effects of hormones are complex, as a single hormone can have different effects in various tissues and in the same tissue at different times of life. Similarly, some biological processes are under the control of a single hormone while others require complex interactions among several hormones for the full biological effect to be realized.

An example of a hormone with multiple effects is testosterone. While its predominant actions are involved in the development of the male external genitalia in embryogenesis, it also acts to develop the secondary sexual characteristics of puberty. One of the most important aspects of testosterone action is that it can be explained by binding of the hormone or its more active metabolite, dihydrotestosterone, to a single receptor. The diverse effects of the hormone are due in large part not to different mechanisms of action but rather to the fact that different cells at different stages of development are programmed to respond to the hormone receptor complex in different ways.

It is commonplace to think of hormones and their actions in isolation, but virtually all complex processes under endocrine regulation are influenced by more than one hormone. Plasma glucose concentrations are maintained within a very narrow range in humans, but such regulation is not accomplished by a single hormone (Figure 2). Primary control is through the secretion of insulin, which modulates hepatic glucose production and enhances glucose transport into cells. The process for elevating blood glucose concentrations, however, utilizes another hormone from the pancreas, glucagon, which stimulates glucose production in the liver by breakdown of stored glycogen. Because low blood glucose or hypoglycemia is a greater risk to life than hyperglycemia, a backup set of glucose-raising hormones is released as the plasma glucose concentration falls below about 3.5 mmol/L (normal range for blood glucose concentrations are 3.5–7.0 mmol/L). These include the catecholamines cortisol and growth hormone. Overall, about six hormones play important roles in directly maintaining the plasma glucose concentration.

The existence of such complex control mechanisms has two major implications. First, there can be a remarkable degree of fine-tuning, in that blood glucose concentrations can be maintained within normal limits under nutritional conditions that vary in the extreme. Second, complex control mechanisms for vital functions may provide safety insofar as alternative mechanisms can take over should one hormone in the series fail. In the case of the glucose–insulin axis, there is little redundancy, as there are additional hormones to raise blood glucose concentrations but only one (insulin) to reduce values, hence loss of insulin leads immediately to disease – diabetes mellitus.

METABOLIC CHANGES, CARDIOVASCULAR DISEASE, AND OTHER EVIDENCE OF CHANGING PHYSIOLOGY

Metabolic endocrine systems show age-related changes that are similar to those experienced in humans, with increasing risk of prediabetic symptoms and changing metabolic function. Body composition in rhesus also parallels changes observed in humans. Fat mass, particularly abdominal fat, increases with age while lean body mass declines (Schwartz and Kemnitz, 1992). As in humans, rhesus can develop diet-dependent obesity and diabetes, thereby providing an excellent model for testing antiobesity and antidiabetic treatments. Other studies have shown the potential therapeutic value of antidiabetic and antiobesity drugs in obese or insulin-resistant rhesus monkeys (Roth et al., 1995; Oliver et al., 2001; Bodkin et al., 2003). Metabolic Syndrome includes several characteristics known to be associated with increased cardiovascular risk (Scuteri et al., 2005). Studies of the characteristics associated with Metabolic Syndrome in nonhuman primates will provide crucial information about efficacy of potential interventions and the age at which they are most effective. Furthermore, early preventive measures may be identified and then tested in nonhuman primates to attenuate or prevent cardiovascular disease.

Cardiovascular disease poses a major threat to aging individuals. The rhesus monkey has been used extensively in the development of diagnostic methods for cardiovascular disease (Neemen et al., 2004). In women, there is increased incidence of heart disease after the age of 50, presumably associated with the loss of estradiol in postmenopause (Campos et al., 1988). The other suspected problem contributing to the onset of this condition is altered lipoprotein profiles, with increased (10–15%) low density lipoproteins (LDL) in menopausal women. Research in monkeys has shown that hormone replacement therapy (HRT) decreased the severity of atherosclerosis in controlled experiments in monkeys (Mikkola and Clarkson, 2002). Once the data are gathered in the monkey, then it will be important to establish if HRT administered during the perimenopausal transition decreases the risk of cardiovascular disease in women (Speroff and Fritz, 2005).

The resilience of the skin also declines during aging, partially due to glycation, which occurs in a similar manner in rhesus skin proteins to that in humans (Sell et al., 1996). Another evidence of the loss of resilience of the skin is that there is an age-related decrease in wound healing ability (Roth et al., 1997).

Summary

1.

The endocrine system is composed of:

Dedicated hormone-producing glands (pituitary, thyroid, parathyroid, and adrenal)

Testes and ovaries, whose intrinsic endocrine function is absolutely necessary for gametogenesis

Hypothalamic neuroendocrine neurons

Scattered endocrine cells that exist as clusters of endocrine-only cells (islets of Langerhans) or as cells within organs that are have a nonendocrine primary function (pancreas, GI tract, kidney)

Endocrine signaling involves the secretion of a chemical messenger, called a hormone, that circulates in the blood and reaches an equilibrium with the extracellular fluid. Hormones alter many functions of their target cells, tissues, and organs through specific, high-affinity interactions with their receptors.

Protein/peptide hormones:

Are produced on ribosomes, become inserted into the cisternae of the endoplasmic reticulum, transit the Golgi apparatus, and finally are stored in membrane-bound secretory vesicles. The release of these vesicles represents a regulated mode of exocytosis. Each hormone is first made as a prehormone, containing a signal peptide that guides the elongating polypeptide into the cisternae of the endoplasmic reticulum.

Are frequently synthesized as preprohormones. After removal of the signal peptide, the prohormone is processed by prohormone convertases.

Typically do not cross cell membranes and act through transmembrane receptors (see later).

Mostly circulate as free hormones, and are excreted in the urine or cleared by receptor-mediated endocytosis and lysosomal degradation.

Catecholamine hormones:

Include the hormones, epinephrine (Epi) and norepinephrine (Norepi). Epi and Norepi are derivatives of tyrosine, which is enzymatically modified by several reactions. Ultimately, Epi and Norepi are stored in a secretory vesicle and are released in through regulated exocytosis.

Act through transmembrane GPCRs receptors called adrenergic receptors.

Steroid hormones:

Include cortisol (glucocorticoid), aldosterone (mineralocorticoid), testosterone, and dihydrotestosterone (androgens), estradiol (estrogen), progesterone (progestin), and 1,25 dihydroxy-vitamin D3 (secosteroid).

Are derivatives of cholesterol, which is modified by a series of cell-specific enzymatic reactions.

Are lipophilic and cross membranes readily. Thus, steroid hormones cannot be stored in secretory vesicles. Steroid production is regulated at the level of synthesis. Several steroid hormones are produced to a significant extent by peripheral conversion of precursors.

Circulate bound to transport proteins. Steroid hormones are cleared by enzymatic modifications that increase their solubility in blood and decrease their affinity for transport proteins. Steroid hormones and their inactive metabolites are excreted in the urine.

Act through intracellular receptors, which are members of the nuclear hormone receptor family. Most steroid hormone receptors reside in the cytoplasm and are translocated to the nucleus after ligand (hormone) binding. Each steroid hormone regulates the expression of numerous genes in their target cells.

Thyroid hormones are:

Iodinated derivatives of thyronine. The term thyroid hormone typically refers to 3,5,3′,5′-tetraiodothyronine (T4 or thyroxine) and 3,5,3′-triiodothyronine (T3). T4 is an inactive precursor of T3, which is produced by 5′-deiodination of T4.

Synthesized and released by the thyroid epithelium (see Chapter 6 for more detail)

Circulate tightly bound to transport proteins

Lipophilic and cross cell membranes. T3 binds to one of several isoforms of thyroid hormone receptors (THRs), which form heterodimers with retinoid X receptor (RXR) and reside bound to their response elements in the nucleus in the absence of hormone. Hormone binding induces an exchange in the co-regulatory proteins that interact with the THRs.

Protein, peptide, and catecholamine hormones signal through transmembrane receptors and use several common forms of informational transfer:

Conformational change

Binding by activated G proteins

Binding by Ca2 + or Ca2 +-calmodulin. IP3 is a major lipid messenger that increases cytosolic Ca2 + levels through binding to the IP3 receptor.

Phosphorylation and dephosphorylation, using kinases and phosphatases, respectively. The phosphorylation state of a protein affects activity, stability, subcellular localization, and recruitment binding of other proteins. Note that phosphorylated lipids such as PIP3 also play a role in signaling.

Transmembrane receptor families:

G-protein-coupled receptors (GPCRs) act as guanine nucleotide exchange factors (GEFs) to activate the Gα subunit of the heterotrimeric α/β/γ G-protein complex. Depending on the type of Gα subunit that is activated, this will increase cAMP levels, decrease cAMP levels, or increase protein kinase C activity and Ca2 + levels. All catecholamine receptors (adrenergic receptors) are GPCRs. GPCRs are internalized by a receptor-mediated endocytosis that involves GRK and β-arrestin. Endocytosis results in the lysosomal clearance of the hormone. The receptor may be digested in the lysosome or may be recycled to the cell membrane.

The insulin receptor is a tyrosine kinase receptor that activates the Akt/PKB pathway, the G-protein TC10-related pathway, and the MAPK pathway. The insulin receptor uses the scaffolding protein insulin receptor substrate (IRS; four isoforms) as part of its signaling to these three pathways.

Some protein hormones (e.g., growth hormone, prolactin) bind to transmembrane receptors that belong to the cytokine receptor family. This are constitutively dimerized receptors that are bound by janus kinases (JAKs). Hormone binding interacts with both extracellular domains and induces JAK-JAK cross-phosphorylation, followed by recruitment and binding of STAT proteins. Phosphorylation of STATs activates them and induces their translocation to the nucleus, where they act as transcription factors.

Hormones that are related to transforming growth factor-β (TGF-β), such as antimüllerian hormone, signal through a co-receptor (receptor I and receptor II) complex that ultimately signals to the nucleus through activated Smad proteins.

Atrial natriuretic peptide (and related peptides) bind to a transmembrane receptor that contains a guanylyl cyclase domain within the cytosolic domain. These receptors signal by increasing cGMP, which activates protein kinase G (PKG) and cyclic nucleotide-gated channels. cGMP also regulates selective phosphodiesterases.

Steroid hormones bind to members of the nuclear hormone transcription factor family. Steroid hormone receptors usually reside in the cytoplasm. Hormone binding induces nuclear translocation, dimerization, and DNA binding. Steroid hormone receptor complexes regulate many genes in a target cell.

Thyroid hormone (T3) receptors (THRs) are related to steroid hormone receptor, but they constitutively remain in the nucleus bound to thyroid hormone response DNA elements. T3 binding typically induces an exchange of co-regulatory proteins and altered gene expression.

Endocrine Axes

A major part of the endocrine system is organized into endocrine axes (Fig. 5-10), which contain three levels of hormonal output: The highest level of hormonal output is actually neurohormonal, and is made up of several hypothalamic nuclei, collectively referred to as the hypophysiotropic region of the hypothalamus, that regulate the adenohypophysis. These nuclei are distinguished from the magnocellular neurons of the PVN and SON that project to the pars nervosa in that they have small parvicellular neuronal cell bodies that project axons to the median eminence. Parvicellular neurons release neurohormones called releasing hormones at the median eminence (Fig. 5-11). The median eminence is like the pars nervosa in that it represents another neurovascular organ. Releasing hormones secreted from axonal endings at the median eminence enter a primary plexus of fenestrated capillaries. Hypothalamic-releasing hormones are then conveyed from the median eminence to a second capillary plexus located in the pars distalis by the hypothalamohypophyseal portal vessels (a “portal” vessel is defined as a vessel that begins and ends in capillaries without going through the heart). With one exception (see later) all releasing hormones are short-lived peptides (see Table 5-2) and reach significant levels only in the private portal system between the hypothalamus and the pituitary gland. At the secondary capillary plexus, the releasing hormones diffuse out of the vasculature and bind to their specific receptors on specific cell types within the anterior pituitary.

Clinical Box 5-4

The neurovascular link (i.e., the pituitary stalk) between the hypothalamus and pituitary is somewhat fragile and can be disrupted by physical trauma, surgery, or hypothalamic disease. Damage to the stalk and subsequent functional isolation of the anterior pituitary result in the decline of all anterior pituitary tropic hormones except prolactin (see later).

The cells of the anterior pituitary make up the second, intermediate level of an endocrine axis. The anterior pituitary secretes protein hormones that are referred to as tropic hormones—adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), growth hormone (GH), and prolactin (PRL) (see Table 5-2). With a few exceptions, tropic hormones bind their receptors on peripheral endocrine glands. Because of this arrangement, pituitary tropic hormones generally do not directly regulate physiologic responses.

The third level of an endocrine axis involves the peripheral endocrine organs, which include the thyroid gland, the adrenal cortex, the ovary, the testis, and the liver. These peripheral endocrine glands are stimulated by pituitary tropic hormones to secrete thyroid hormone, cortisol, estrogen, progesterone, testosterone, and insulin-like growth factor-1 (IGF-1). Thus, we refer to the following endocrine axes: hypothalamus-pituitary-adrenal axis, hypothalamus-pituitary-thyroid axis, hypothalamus-pituitary-ovary axis, hypothalamus-pituitary-testis axis, and hypothalamus-pituitary-liver axis. These axes, through the peripheral hormones they regulate, have a broad range of effects on growth, metabolism, homeostasis, and reproduction, as discussed in Chapters 6, 7, 9, and 10. The endocrine axes have the following important features:

The activity of a specific axis is normally maintained at a set-point (which in truth is a normal range of activity). The set-point is determined primarily by the integration of hypothalamic stimulation and peripheral hormone negative feedback. Importantly, the negative feedback is not exerted primarily by the physiologic responses regulated by a specific endocrine axis, but rather from the peripheral hormone acting on the pituitary and hypothalamus (see Fig. 5-10). Thus, if the level of a peripheral hormone drops, the secretion of hypothalamic-releasing hormones and pituitary tropic hormones will increase. As the level of peripheral hormone rises, the hypothalamus and pituitary will decrease secretion owing to negative feedback. Although some nonendocrine physiologic parameters (e.g., acute hypoglycemia) can regulate some endocrine axes, the axes function semiautonomously with respect to the physiologic changes they produce. This configuration means that a peripheral hormone (e.g., thyroid hormone) can evolve to regulate multiple organ systems, without those organ systems exerting competing negative feedback regulation on the hormone. Clinically, this partial autonomy means that multiple aspects of a patient's physiology are at the mercy of whatever derangements exist within a specific axis.

Hypothalamic hypophysiotropic neurons often secrete in a pulsatile manner and are entrained to daily and seasonal rhythms through CNS inputs. Additionally, hypothalamic nuclei receive various neuronal inputs from higher and lower levels of the brain. These can be short term (e.g., various stresses/infections) or long term (e.g., onset of reproductive function at puberty). Thus, the inclusion of the hypothalamus in an endocrine axis allows for the integration of a considerable amount of information in determining or changing the set-point of that axis.

The loss of a peripheral hormone (e.g., thyroid hormone) may be due to a defect at the level of the peripheral endocrine gland (e.g., thyroid), the pituitary gland, or the hypothalamus, which are referred to as primary, secondary, and tertiary endocrine disorders, respectively (see Fig. 5-10). A thorough understanding of the feedback relationships within an axis allows the physician to determine where the defect lies. Primary endocrine deficiencies tend to be the most severe because they often involve complete absence of the peripheral hormone. Disorders can also be due to excessive secretion at the primary, secondary, or tertiary level of an axis. This is usually due to a hormone-producing tumor (e.g., Cushing disease is due to an ACTH-producing pituitary tumor).

Clinical Box 5-5

Clinically, the inclusion of the hypothalamus within an endocrine axis means that a broad range of complex, neurogenic states can alter pituitary function. Psychosocial dwarfism is a striking example of this, in which children who are abused or under intense emotional stress have lower growth rates as a result of decreased growth hormone secretion by the pituitary gland.