From the FDA Drug Label
The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-beta-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine
The adrenal pathway involves the production of cortisol and corticosterone in the adrenal cortex, which is regulated by the hypothalamic-pituitary-adrenal (HPA) axis. The key steps in this pathway are:
- Production of adrenocorticotropic hormone (ACTH) by the pituitary gland
- Stimulation of the adrenal cortex by ACTH to produce cortisol and corticosterone
- Inhibition of ACTH production by cortisol through a negative feedback mechanism
- Production of 11-desoxycortisol and desoxycorticosterone as precursors to cortisol and corticosterone The adrenal pathway is crucial for regulating the body's response to stress, maintaining blood pressure, and controlling electrolyte balance 1.
From the Research
The adrenal pathway is a complex hormonal cascade that begins with the hypothalamus and ends with the release of adrenal hormones, playing a crucial role in maintaining homeostasis and responding to stress, as evident from recent studies such as 2 and 3. The pathway starts when the hypothalamus secretes corticotropin-releasing hormone (CRH) in response to stress or low blood cortisol levels. CRH then stimulates the anterior pituitary gland to release adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH travels to the adrenal glands, which sit atop the kidneys, and triggers the adrenal cortex to produce and release cortisol and other glucocorticoids. Some key points to consider in the adrenal pathway include:
- The role of ACTH in stimulating cortisol production, as seen in cases of ACTH-producing pheochromocytoma 4, 2, 3
- The importance of negative feedback in regulating the pathway, where elevated cortisol levels signal the hypothalamus and pituitary to reduce CRH and ACTH production 5
- The potential for chronic activation of the pathway to lead to health problems like hypertension, immune suppression, and metabolic disorders 5, 6 Additionally, stress can activate the sympathetic nervous system, causing the adrenal medulla to release catecholamines like epinephrine (adrenaline) and norepinephrine. These hormones prepare the body for "fight or flight" by increasing heart rate, blood pressure, and blood glucose levels while diverting blood flow to essential organs. It is essential to note that the adrenal pathway is regulated through negative feedback, where elevated cortisol levels signal the hypothalamus and pituitary to reduce CRH and ACTH production, thereby preventing excessive hormone secretion, as supported by the most recent and highest quality study 2.