Testosterone is the primary and most talked about male sex hormone. When in balance, testosterone is associated with energy, sex drive, and an overall sense of well-being. It is mainly secreted from the gonads or “testes” in males with a small amount being secreted from the adrenal glands. Testosterone is involved in development of the male reproductive tissues and in secondary sexual characteristics such as the testicles, prostate, muscle and bone strength, and body hair. Men are not the only ones who produce testosterone, women also produce some of the hormone in the ovaries. In women testosterone has an impact on the reproductive system, strength, and overall health. Too much or too little testosterone can cause issues in both men and women. Testosterone Production Testosterone production is regulated by the hypothalamus and the pituitary which are located in the brain and send signals to the testes. Together this hormone regulating system is known as the hypothalamus-pituitary-gonadal (HPG) axis. The axis allows for the body to monitor the amount of testosterone in the body and adjust the amount produced according to development age and physical factors. Gonadotropin-releasing hormone (GNRH) is the hormone that regulates the sex hormones. GNRH is low in childhood and increases in puberty when sex hormones are needed for maturation and sexual urges.

Cortisol is a steroid hormone belonging to the corticosteroid class known as glucocorticoids. It is produced and secreted by the adrenal gland and is involved in a variety of functions including the stress response, immune response, inflammation and carbohydrate metabolism. Cortisol is also available as a pharmaceutical therapeutic known as hydrocortisone.  This paper provides an overview of cortisol, its involvement in disease and its use as a therapeutic. Although cortisol is involved in a variety of functions, it is best known as the stress hormone. So it is not surprising that cortisol production is induced by stressors that activate the hypothalamic-pituitary-adrenal (HPA) axis—a system of interactions and feedback loops between three major glands that secrete hormones into the bloodstream. Following stress, the hypothalamus secretes corticotropin-releasing hormone (CRH). CRH then stimulates CRH receptors (CRHRs) in the pituitary gland to produce another hormone called adrenocorticotropin, or ACTH. Some stressors, such as hypoglycemia, hemorrhage and immune stimuli, can trigger the release of vasopressin—another hypothalamic substance that promotes ACTH production. ACTH then stimulates the adrenal cortex to produce cortisol. Other factors such as cytokines and fat cells can also stimulate the HPA at any level. The produced cortisol is bound to corticosteroid-binding globulin (CBG) or cortisol-binding protein (CBP), which transports it through circulation to different tissues.

Cortisol and Circadian rhythm Cortisol levels vary throughout the day and follow a circadian (24-hour) rhythm. Cortisol levels begin to increase significantly in the early morning, peaking around mid-morning. Their levels then gradually decline throughout the day until they reach their lowest levels during nighttime sleep. Approximately 77% of people also experience the cortisol awakening response (CAR), which is a sharp increase in cortisol 30min after waking that is independent of the normal circadian rhythm. Cortisol and Stress Stress is anything that strains homeostasis, which is the capacity of the body to maintain its biological processes such as temperature or heart rate. Stress can be external factors such as work and social stressors or internal such as dysregulation of vital processes. In response to these factors the body typically engages a stress response that serves to return it to a state of normalcy. This response involves increased cognition, lower sensitivity to painful stimuli, an increase in blood sugar levels, increased breakdown of fats and other lipids and an inhibition of reproduction.

While a short-term stress response can be beneficial, a prolonged response can have negative impacts on the body. Too much cortisol over an extended period of time can lead to fatigue, obesity, and other medical conditions like cushions disease. Below is a summary of medical conditions that can result from dysregulation of cortisol. Cushing’s Syndrome Cushing’s syndrome, or hypercortisolism, is a rare condition in which the patient experiences an excess of glucocorticoids, primarily cortisol. It is usually caused by prescription steroids (glucocorticoids) that are used as anti-inflammatories. However, it can also be caused by tumors on the adrenal or pituitary gland. Common symptoms include weight gain, insulin resistance, muscle weakness, high blood concentration of lipids, such as cholesterol (hyperlipidemia), high blood pressure (hypertension), high blood sugar (hyperglycemia), osteoporosis and thin skin. If left untreated, Cushing disease can be life threatening. Prognosis for patients with untreated Cushing’s syndrome is approximately 50% for 5-year survival. Fortunately, the Cushings is treatable. When caused by medications it can be remedied by reducing the dosage or stopping the medication. When caused by tumors, treatment typically revolves around removal of the tumors through surgery or radiation. Metabolism Disorders Recent studies have suggested that morbidity associated with obesity and other metabolic syndromes may be due to the dysregulation of cortisol.

There are several tretments in development to rectify dysregulation of cortisol. One is tissue-specific inhibitors of 11β-HSD1. Clinical trials have revealed that treatment with these inhibitors can reduce body weight, and blood pressure. However, these results have been inconsistent (Shah, et al., 2011; Feig, et al., 2011; Rosenstock, et al., 2010). Another option is inhibition of cortisol production in the adrenal gland. This method is typically used to treat Cushing syndrome. Inhibitors of aldosterone synthase may also reduce cortisol since aldosterone synthase is similar to the enzymes that produce cortisol. These inhibitors would be particularly useful in conditions in which both aldosterone and cortisol are dysregulated. The final option utilizes antagonists for the GRs and MRs. MR inhibitors are easily accessible, have low side effects and are currently used to improve survival following heart failure. Blocking this receptor has the additional benefit of blocking activation due to both cortisol and aldosterone. It has already been shown to stave off hypertension and abnormalities in the muscles of the heart in patients with metabolic syndrome.