Chapter 14 - Study Guide

The Approach

1. First read the summary and questions.

2. Next read bolded headings.

3. Finally read the chapter–once through, look up unfamiliar words in the chapter’s key terms.

4. Lastly, re-read the chapter a second time using the support given below.

Consider the expectations of Chapter 14

The essentials from Chapter 14:

a) The endocrine system (hypothalamic–pituitary–peripheral organ axis; HPA) plus the pancreas, parathyroid gland and pineal gland, assure consistency of the internal environment (called homeostasis).

b) The HPA fails for poorly understood reasons. The results are: menopause; prolonged exposure to adrenal stress steroids; and declines in growth hormone, insulin growth factor-1(IGF-1), and adrenal androgens. The most overt of these is the multiplicity of changes that occur with menopause.

c) The endocrine theory of aging is a systems theory (in contrast to a molecular or cellular theory, such as the oxidative theories). It proposes that aging occurs with dysregulation of the endocrine system that is permissive for elevated levels of adrenal steroids, reduced levels of other hormones (e.g., estrogen, GH, IGF-1), and changes in responsiveness of tissues to hormones.

Understand the concept of an endocrine gland, the various endocrine glands and the hormone(s) that each produces. That will give you an outline of the variety of functions that are regulated by this system. All hormones must bind to and activate a specific receptor in order to bring about a response.

One easy way to understand dysregulation of the HPA is to first learn the HPA organ members, and then to realize that one of the major control mechanisms is the negative feedback loop. It is this loop that weakens in aging.

You will need to study Table 14.1. The neuroendocrine glands are regulated (at least in part) by negative feedback inhibition. Here’s how this works: the master gland is the hypothalamus, which produces releasing hormones that stimulate the pituitary gland. Following stimulation, the pituitary gland releases stimulating hormones that activate peripheral endocrine glands: thyroid, adrenal, ovaries, testes, liver. When these endocrine glands are stimulated, they release their specific hormones that act on appropriate tissues. Here’s the important part: as the hormone levels from the peripheral endocrine glands increase in the blood, they circulate back to the pituitary and the hypothalamus. When peripheral hormone levels are high, the pituitary and hypothalamus reduce/stop production of releasing and stimulating hormones, and the blood levels of hormones from the peripheral glands fall (as they are no longer stimulated). This is the negative feedback that results in reliable levels of hormones.

Aging of the neuroendocrine system, the HPA

Hypothalamus–pituitary–ovary axis

The most dramatic change occurs in females, when the regulation of the ovaries via the pituitary and the hypothalamus deteriorates, resulting in menopause (unique to humans). From sexual maturation to menopause, the menstrual cycle is tightly regulated by hormone pulses and surges from the hypothalamus and pituitary to assure the production of estrogen and progesterone for the production of a viable ovum and potential implantation in the uterus. Menopause changes all of that to achieve a loss of fertility. The cause for menopause is still somewhat debated; however, it is presently thought to derive from an evolutionarily fixed and limited supply of the follicular cells. These cells give rise to the ovum, and when there are no more reproduction ceases.

Menopause takes time–there is a transition phase (hormone level disruption begins) followed by one year of amenorrhea (no menstrual periods). Symptoms relate to the loss of estrogen–hot flushes (details in Table 14.2), atrophy of reproductive tissue, osteopenia, accelerated aging of the skin.

The results of three large RCTs initially concluded that hormone replacement therapy (HRT; the use of systemic estrogen/progesterone, E/P) in menopausal women not only failed to prevent CV disease and preserve cognitive function, mood and libido, but also caused an increased incidence of adverse effects (stroke, clots, breast cancer, etc.; see Table 14.3). Unfortunately, a year or two following the publication of these trial results it became apparent that these trials had a MAJOR DESIGN FLAW in that HRT was given to women 10–12 years after menopause. Without a retrial, there is no information as to whether HRT protects against CV disease.

Hypothalamus-pituitary-testes axis

Andropause–there is evidence of dysregulation of the HPA regarding the production of testosterone (T) which tends to decline, but to label it andropause is absurd. Supporting androgens (produced by the adrenal glands) such as the dihydroandrosterones (DHEAs) fall dramatically. The existence of the condition called ‘low T’ is controversial, and unless there are specific symptoms it does not warrant therapy with T. HPA dysfunction does contribute to benign prostatic hypertrophy, which may progress to urinary problems or possibly cancer.

Hypothalamus–pituitary–adrenal axis

The HPA experiences dysregulation, but somewhat differently than the above two systems. There is a slight change in the circadian rhythm of adrenal steroids (e.g., cortisol, high in the morning and low at night), and there is an issue with the stress response that pumps out cortisol. With age, cortisol ‘hangs around’ longer, which means that feedback inhibition is lessening. The consequence of this is that it exposes immune cells, bone cells, and nerve cells to the potential toxicity of cortisol, causing cell death or senescence. The precursors of testosterone and estrogen are the DHEAs, and they (for unknown reasons) decline precipitously with age. Regardless of the advertising, DHEAs (RCT results) are not anti-aging.

Hypothalamus–pituitary–thyroid gland axis

The changes here are confusing due to confounding variables in the measurements of thyroid tests. If they are excluded (a big ‘if’), thyroid-stimulating hormone and the active form of the thyroid hormones (T3) decline with age. Whether to treat this with replacement therapy is debated.

Hypothalamus–pituitary–liver (HPL) axis

Aging of this axis is called somatopause (rightly or wrongly). Growth hormone (GH) works with an assistant, insulin growth factor-1 (IGF-1) produced in the liver. The HPL axis changes with age such that less releasing hormone from the hypothalamus and more inhibitor, somatostatin, are produced. Tissue response to GH also seems to diminish, perhaps due to receptor disappearance. Some of the decline in GH level appears dependent on stochastic factors such as adiposity, diet, and exercise.

Other endocrine glands

Pineal gland

Aging of the eye (lens, iris reduces blue light) is thought in part responsible for changing melatonin secretion from the pineal gland with age (melatonin levels fall with age). Melatonin appears to play a beneficial role not only in sleep regulation but also in preservation of the immune system, anti-inflammatory, and antioxidative effects.

Parathyroid gland

The gland produces the parathyroid hormone that maintains the homeostatic level of free calcium in the blood. It removes calcium from bone, and with vitamin D assures increased GI absorption and decreased urinary loss of calcium. Few studies here, but basal levels may be influenced by diet, vitamin D efficiency and possible reduction in calcium absorption (kidney and GI tract).


From previous chapters it should be apparent that insulin is an important hormone in aging. Consider all the caloric restriction (CR) studies that showed an increase in lifespan with a decrease in calories that always produced a decrease in insulin and glucose levels. Know the actions of insulin on the uptake and storage of sugar. Reduced sensitivity of insulin sets the stage for pre-diabetes and thereafter type 2 diabetes (T2D). The incidence of this disease is unnecessarily high. Age contributes modestly, while life style choices (sarcopenia, increased abdominal circumference, inactivity, diet) contribute in a major way.

Neuroendocrine theory of aging

Associated with this system is an old theory that still has some credibility today. The theory states: Dysregulation of the hypothalamic–pituitary–peripheral gland axis leads to a loss of homeostasis (inability to return to normal after encountering a stress). This leads to organ damage (aging) and a vulnerability to disease. There is a detrimental effect with poor regulation of each of the peripheral endocrine glands, and eventually even very small stress will create disproportionally large damage and result in disease/death.