Inhumans and otheranimals, theadrenocortical hormones arehormones produced by theadrenal cortex, the outer region of theadrenal gland. These polycyclicsteroid hormones have a variety of roles that are crucial for the body's response tostress (for example, thefight-or-flight response), and they also regulate otherfunctions in the body. Threats tohomeostasis, such asinjury,chemical imbalances,infection, orpsychological stress, can initiate a stress response. Examples of adrenocortical hormones that are involved in the stress response arealdosterone andcortisol. These hormones also function in regulating theconservation of water by thekidneys andglucose metabolism, respectively.[1]
Adrenocortical hormones are divided into three classes by function:mineralocorticoids,glucocorticoids, andandrogens.
Adrenocortical hormones are consideredsteroid hormones because of the shared characteristic of acholesterol backbone. The structures of different steroids differ by the types and locations of additional atoms on acholesterol backbone.[4] Thecholesterol backbone consists of fourhydrocarbon rings, threecyclohexane rings and onecyclopentane, that contribute to its insolubility in aqueous environments. However, thehydrophobic nature allows them to readily diffuse through theplasma membrane of cells.[3] This is important to the function ofsteroid hormones as they rely on cellular response pathways to restore thehomeostatic imbalance that initiated the hormone release.
The synthesis of adrenocorticalsteroid hormones involves a chain ofoxidation-reduction reactions catalyzed by a series of enzymes. Synthesis begins with a molecule ofcholesterol. Through shared intermediates and pathways branching off those shared intermediates, the different classes of steroids are synthesized. Steroids are synthesized fromcholesterol in their respective regions of theadrenal cortex. The process is controlled bysteroidogenic acute regulatory protein (StAR) which sits in themitochondrial membrane and regulates the passage ofcholesterol.[3] This is the rate-limiting step ofsteroid biosynthesis. Once StAR has transportedcholesterol into themitochondria, thecholesterol molecule undergoes a string ofoxidation-reduction reactions catalyzed by a series of enzymes from the family ofcytochrome P450 enzymes. Acoenzyme system calledadrenodoxin reductase transfers electrons to theP450 enzyme which initiates theoxidation-reduction reactions that transformcholesterol into thesteroid hormones.[5] Though synthesis is initiated insidemitochondria, precursors are shuttled to theendoplasmic reticulum for processing by enzymes present in theendoplasmic reticulum. The precursors are shuttled back to themitochondria in the region of theadrenal cortex within which synthesis initially began and it is there that synthesis is completed.[6]
Cushing's syndrome arises from the repeatedhypersecretion ofglucocorticoids. It can be caused by either anadrenal tumor or byhypersecretion ofadrenocorticotropic hormone (ACTH) from theanterior pituitary gland.[2] It is predominantly due to an excess of theglucocorticoidcortisol. Secretion is typically regulated by thehypothalamus which secretescorticotropin-releasing hormone (CRH) to thepituitary gland, stimulating thepituitary to secreteadrenocorticotropic hormone (ACTH).ACTH then travels to theadrenal glands and induces the release ofcortisol into the bloodstream.[7] InCushing's syndrome, this process occurs in excess. Some symptoms of an individual withCushing's syndrome include low tissue protein levels, due to muscle and bone atrophy, and high blood glucose levels. Sodium levels also see an increase which results in fluid retention in tissues and elevated blood pressure. In addition tohypersecretion ofcortisol, excessandrogens are secreted.[8] In females, increased secretion ofandrogens, such astestosterone, results inmasculinization which may present as facial hair growth and a deepened voice.[2]
Treatment forCushing's syndrome aims to reduce the high levels ofcortisol circulating through the human body. The course of action ultimately depends on the cause of thehypersecretion. Cushing's can be induced by repeated synthetic steroid use to treatinflammatory diseases, or it can also be caused by a tumor in thepituitary gland oradrenal gland. In either case, treatment may rely on removal of the tumor or of theadrenal glands.[8] Without theadrenal glands, the human body is unable to supply the hormones it produces and therefore requireshormone replacement therapy.
Addison's disease is anautoimmune disorder that affects theadrenal cortex such that it is unable to efficiently secrete hormones. The immune system specifically targets the cells of theadrenal cortex and destroys them, butAddison's disease can also be caused by a severe infection such astuberculosis. Some symptoms includehypoglycemia and decreased blood sodium levels and increased blood potassium levels caused by a deficiency ofaldosterone. These electrolyte imbalances induce nerve and muscle issues. Other symptoms include fatigue, salt cravings, weight loss, and increasedskin pigmentation.[2] Increasedskin pigmentation is caused by a deficiency of the adrenocortical hormonehydrocortisone. Its normal behavior would be asnegative feedback at thepituitary gland, stimulating thepituitary gland to decrease secretion ofcorticotropin. Becausehydrocortisone is not able to be produced inAddison's disease, thepituitary gland continues to secretecorticotropin which binds to the receptor formelanocyte-stimulating hormone. It then causesmelanocytes to produce more pigment, thus darkening the skin tone.[9]
The standard treatment forAddison's disease ishormone replacement therapy for themineralocorticoids andglucocorticoids that are no longer able to be synthesized.[12] Former U.S. PresidentJohn F. Kennedy is a well-known individual who suffered fromAddison's disease throughout his presidency. Due to the availability ofhormone replacement therapy, he and his staff were able to cover up his condition.[2]
Recent studies have discovered a pathway that links stress to the onset of disease through the activation of certain genes.[10] The experience of psychological stress activatestranscription factors that activate genes. In a study by Cole et al., it was concluded thatGABA-1 transcription factor activates theinterleukin-6-gene. This gene codes for a protein that activates the inflammatory response which directs animmune response to the site of the inflammation.[9]Chronic inflammation makes an individual more susceptible to diseases such ascancer,heart disease, anddiabetes.
Another study found that physical stress caused increasedcortisol:DHEAS (dehydroepiandrosterone sulphate) molar ratios which may contribute to reduced immunity, especially in the elderly for whomcortisol:DHEAS ratios are already increased. This is becauseDHEAS levels decrease with age whilecortisol levels do not. This high ratio was found to suppress the activity ofneutrophils and raise susceptibility forinfection.[11]
