Cushing’s SyndromePaper 1: HPA Axis, Normal Cortisol Function and RegulationDr. B. KaluLiberty University BIOM 525: Human Physiology Lecture Section D01Due 22 July 2018? Within the complex structure of the human body, many chemical and electrical processes exist to promote and maintain stable equilibria at levels ranging from a single cell to the entire organism. Homeostasis, or the tendency of the human body to function in an autoregulatory manner, is achieved in part by chemical reactions enabled by the body’s endocrine system, which uses specialized chemicals known as hormones to regulate and control bodily functions. One such hormone with far-reaching effects throughout the human body is called cortisol. A glucocorticoid steroid hormone, cortisol regulates processes that control many different bodily functions and regulate several different bodily systems (appropriate end to introduction).
Upon perception of a stressor, the human body has two immediate responses- first, the sympathetic division of the autonomic nervous system is stimulated. Additionally stimulated is the intricate system of direct signaling and feedback loops between the hypothalamus (a subdivision of the diencephalon), the anterior pituitary gland also located in the diencephalon, and the adrenal glands. This intricate network of glands and signaling pathways designed to regulate bodily function is referred to Hypothalamic-Pituitary-Adrenal (HPA) axis (PMC3288468). While the sympathetic stimulation results in hormone release for immediate physiological response, the longer-term response necessary for proper bodily function stems from the complex neuroendocrine pathway of the HPA Axis. The HPA axis process begins when hypophysiotropic neurons within the paraventricular nucleus, or PVN (a subdivision of the hypothalamus) receive a stimulus and subsequently secrete two hormones, arginine vasopressin (AVP, also known as antidiuretic hormone or ADH) and corticotropin releasing hormone (CRH) (PMC5666832).
Once released by the hypothalamus, both AVP and CRH are transported from the hypothalamus to the anterior pituitary gland via the complex hypophysial portal vessel system. Stimulated by CRH, the anterior pituitary gland releases another hormone called Adrenocorticotropic Hormone, or ACTH (alternatively referred to as corticotropin) (PMC 5666832). One of several melanocortin peptides, ACTH then travels in the bloodstream to the adrenal cortex (the adrenal gland is immediately superior to each kidney). (PMC4436856). Once it arrives in the zona fasciculate region of the adrenal gland, ACTH will bind to melanocortin receptors, known as MCRs, which function as G-Protein Coupled Receptors (GPCRs) on surface cells and stimulate both the production and release of cortisol- the primary stress hormone in the human body.
(PMC4106642). Inside the zona fasculata, cortisol is chemically synthesized from cholesterol, which is either produced in the liver or ingested. At the cellular level, cortisol synthesis, or steroidogenesis, begins and ends inside cellular mitochondria with intermediate chemical reaction steps occurring within the endoplasmic reticulum (PMC2940507).
ACTH additionally serves to upregulate the Cytochrome P450scc (side chain cleavage) enzyme necessary for synthesizing the initial steps of cortisol synthesis (removing the side chains from cholesterol molecules) and CYP11B1, necessary for the final step in cortisol biosynthesis. (PMC4521600). Due to the time needed to undertake these biological processes, cortisol secretion reaches a maximum level approximately 15 minutes after the CNS perceives the stressful event (PMC5563520). In addition to synthesis in the adrenal gland an independent of the HPA Axis, cortisol is also regenerated from coritisone in adipose tissue and within the liver.
(PMC4392802). Negative feedback loops are evident at each stage with the hypothalamic-pituitary-adrenal axis and integral for both regulation of each stage and the overall regulation of the HPA axis as a whole. When circulating cortisol levels rise, ACTH release is inhibited, slowing the synthesis and release of cortisol, which eventually regulates the level of cortisol within the body. Glucocorticoids such as cortisol functionally regulate both the CRH-releasing neurons within the hypothalamus and the ACTH-releasing receptors on the anterior pituitary gland (PMC3288468). As a steroid hormone, cortisol acts upon two types of receptors: mineralcorticoid and glucocorticoid receptors. Although mineralcorticoid and glucocorticoid receptors are similar anatomically, they have different functions that must occur in the correct balance to maintain homeostasis. In most tissues, cortisol activates mineralcorticoid receptors in an unstressed state and activates glucocorticoid receptors in a stressed condition, particularly within heart and brain tissue. Additionally, glucocorticoid receptors are principally bound to cortisol during particular points of the circadian rhythm and during times of stress (PMC4521600).
The binding action to two different types of receptors enables cortisol to facilitate two different types of reactions within the body. While cortisol binding to mineralocorticoid receptors furthers the original sympathetic stress reaction, cortisol bound to glucocorticoid receptors dampens the initial stress reaction and prevents these reactions from causing further damage to the body (PMC5563520). Since the demand for glucocorticoids varies based on cortisol secretion occurs in a circadian manner, varying in a predictable, 24-hour repeating pattern to appropriately modulate bodily functions. Regulated by the hypothalamus, more specifically the suprachiasmatic nucleus, levels of released cortisol in the plasma reach their maximum when an individual wakes up from sleep and diminish over the day, reaching their lowest points in the evening and while the individual is asleep; these varying levels contribute greatly to how cells, organs, and systems throughout the body function (PMC5563520). In addition to cortisol production mechanisms, several mechanisms exist to remove cortisol from the blood and therefore regulate the overall blood cortisol concentration. Glucocorticoids such as cortisol are removed from the blood by corticosteroid binding globulin, or CBG, which binds to cortisol, preventing its breakdown and ensuring that sufficient cortisol is on hand for tissue usage (PMC4521600).
Once cortisol binds as a ligand to a mineralcorticoid or glucocorticoid receptor, scaffolding and chaperone proteins (which affect the probability of a ligand binding to a receptor) are sent to the cellular nucleus and bind to form either homodimers or heterodimers, which in turn bind to chromosomal hormone response elements, regulating the production of effector proteins, which go on to cause physiological response in the target cells (PMC4521600). After being released by the adrenal glands, the effects of cortisol can be observed globally throughout the body-they can be subdivided into several equally important categories: cardiovascular effects, neurocognitive effects, anti-inflammatory properties, glucose metabolism, and sleep regulation. The actions of glucocorticoids such as cortisol on various types of target organs and tissues is determined by two factors- receptor density and the action of two enzymes, 11?-hydroxysteroid dehydrogenase-1 and -2 (abbreviated 11?-HSD1 and 11?-HSD2). ? Figure 1- the HPA Axis (PMC5666832) Figs- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563520/
