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Mini Reviews in Medicinal Chemistry 2023Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in primates, which is predominantly synthesized in the adrenal cortex. A characteristic curve of... (Review)
Review
Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in primates, which is predominantly synthesized in the adrenal cortex. A characteristic curve of growth and decline of its synthesis during life was observed, together with the corresponding formation of its sulphate ester (DHEAS). High levels of plasma circulating DHEA are suggested as a marker of human longevity, and various pathophysiological conditions lead to a decreased DHEA level, including adrenal insufficiency, severe systemic diseases, acute stress, and anorexia. More recent studies have established the importance of DHEA in the central nervous system (CNS). A specific intranuclear receptor for DHEA has not yet been identified; however, highly specific membrane receptors have been detected in endothelial cells, the heart, kidney, liver, and the brain. Research shows that DHEA and DHEAS, as well as their metabolites, have a wide range of effects on numerous organs and organ systems, which places them in the group of potential pharmacological agents useful in various clinical entities. Their action as neurosteroids is especially interesting due to potential neuroprotective, pro-cognitive, anxiolytic, and antidepressant effects. Evidence from clinical studies supports the use of DHEA in hypoadrenal individuals and in treating depression and associated cognitive disorders. However, there is also an increasing trend of recreational DHEA misuse in healthy people, as it is classified as a dietary supplement in some countries. This article aims to provide a critical review regarding the biological and pharmacological effects of DHEA, its mechanism of action, and potential therapeutic use, especially in CNS disorders.
Topics: Animals; Humans; Dehydroepiandrosterone; Endothelial Cells; Dehydroepiandrosterone Sulfate; Brain; Steroids
PubMed: 36121077
DOI: 10.2174/1389557522666220919125817 -
Drugs Jul 2014Dehydroepiandrosterone (DHEA) and its sulfated form dehydroepiandrosterone sulfate (DHEAS) are the most abundant circulating steroid hormones in humans. In animal... (Review)
Review
Dehydroepiandrosterone (DHEA) and its sulfated form dehydroepiandrosterone sulfate (DHEAS) are the most abundant circulating steroid hormones in humans. In animal studies, their low levels have been associated with age-related involuntary changes, including reduced lifespan. Extrapolation of animal data to humans turned DHEA into a 'superhormone' and an 'anti-aging' panacea. It has been aggressively marketed and sold in large quantities as a dietary supplement. Recent double-blind, placebo-controlled human studies provided evidence to support some of these claims. In the elderly, DHEA exerts an immunomodulatory action, increasing the number of monocytes, T cells expressing T-cell receptor gamma/delta (TCRγδ) and natural killer (NK) cells. It improves physical and psychological well-being, muscle strength and bone density, and reduces body fat and age-related skin atrophy stimulating procollagen/sebum production. In adrenal insufficiency, DHEA restores DHEA/DHEAS and androstenedione levels, reduces total cholesterol, improves well-being, sexual satisfaction and insulin sensitivity, and prevents loss of bone mineral density. Normal levels of CD4+CD25(hi) and FoxP3 (forkhead box P3) are restored. In systemic lupus erythematosus, DHEA is steroid-sparing. In an unblinded study, it induced remission in the majority of patients with inflammatory bowel disease. DHEA modulates cardiovascular signalling pathways and exerts an anti-inflammatory, vasorelaxant and anti-remodelling effect. Its low levels correlate with increased cardiovascular disease and all-cause mortality. DHEA/DHEAS appear protective in asthma and allergy. It attenuates T helper 2 allergic inflammation, and reduces eosinophilia and airway hyperreactivity. Low levels of DHEAS accompany adrenal suppression. It could be used to screen for the side effects of steroids. In women, DHEA improves sexual satisfaction, fertility and age-related vaginal atrophy. Many factors are responsible for the inconsistent/negative results of some studies. Overreliance on animal models (DHEA is essentially a human molecule), different dosing protocols with non-pharmacological doses often unachievable in humans, rapid metabolism of DHEA, co-morbidities and organ-specific differences render data interpretation difficult. Nevertheless, a growing body of evidence supports the notion that DHEA is not just an overrated dietary supplement but a useful drug for some, but not all, human diseases. Large-scale randomised controlled trials are needed to fine-tune the indications and optimal dosing protocols before DHEA enters routine clinical practice.
Topics: Adrenal Insufficiency; Aging; Animals; Bone Density; Dehydroepiandrosterone; Dietary Supplements; Humans; Hypersensitivity
PubMed: 25022952
DOI: 10.1007/s40265-014-0259-8 -
European Journal of Clinical... Dec 2000Dehydroepiandrosteone (DHEA) and its sulfate ester (DHEAS) are the major secretory products of the human adrenal glands and serve as precursors for both androgenic and... (Review)
Review
Dehydroepiandrosteone (DHEA) and its sulfate ester (DHEAS) are the major secretory products of the human adrenal glands and serve as precursors for both androgenic and estrogenic steroids. DHEA/S concentrations are particularly high in the brain, and DHEA/S and related steroids can be synthesized de novo in brain glial cells. Therefore, the term 'neurosteroids' has been coined for these compounds. This review summarizes findings in neurosteroid physiology on a cellular and molecular level, and outlines current concepts of how these compounds modulate physiological functions of the brain. Today, despite promising preclinical and human data the present clinical studies provide only weak evidence, if any, in favour of a DHEA replacement therapy.
Topics: Animals; Behavior, Animal; Dehydroepiandrosterone; Humans; Memory; Receptors, GABA-A; Sleep
PubMed: 11281367
DOI: 10.1046/j.1365-2362.2000.0300s3046.x -
The Medical Journal of Australia Aug 1999Dehydroepiandrosterone (DHEA) is a weak androgen, but is one of the main precursors of testosterone. Athletes use it for its androgenic and anticatabolic effects and it... (Review)
Review
Dehydroepiandrosterone (DHEA) is a weak androgen, but is one of the main precursors of testosterone. Athletes use it for its androgenic and anticatabolic effects and it has been described as a "wonder drug", although there is little evidence to support these claims. There are no published studies of the long-term effects of taking DHEA, particularly in the large doses used by athletes, or of its possible interactions with other agents.
Topics: Australia; Dehydroepiandrosterone; Humans; Internet; Sports; Testosterone
PubMed: 10494239
DOI: 10.5694/j.1326-5377.1999.tb123601.x -
Best Practice & Research. Clinical... Sep 2004Dehydroepiandrosterone (DHEA) is the major steroid produced by the adrenal zona reticularis and, in contrast to cortisol and aldosterone, its secretion declines with... (Review)
Review
Dehydroepiandrosterone (DHEA) is the major steroid produced by the adrenal zona reticularis and, in contrast to cortisol and aldosterone, its secretion declines with ageing. This has generated major interest in its putative role as an 'anti-ageing' hormone. However, it is not clear that the age-associated, physiological decline in DHEA secretion represents a harmful deficiency. DHEA exhibits its action mainly by conversion to sex steroids. In addition, DHEA has neurosteroidal properties and may exhibit direct action via specific binding sites on endothelial cells. There is convincing evidence for beneficial effects of DHEA in patients with adrenal insufficiency and future research will hopefully elucidate its role in patients receiving pharmacological glucocorticoid treatment. However, in healthy elderly subjects, current evidence from randomised, controlled trials does not justify the use of DHEA, with no major beneficial effects reported and, in addition, potentially adverse effects on sex steroid-dependent tumour growth need to be considered.
Topics: Adrenal Insufficiency; Aged; Aging; Animals; Body Composition; Bone and Bones; Central Nervous System; Dehydroepiandrosterone; Female; Frail Elderly; Gonadal Steroid Hormones; Hormone Replacement Therapy; Humans; Immunity; Male; Middle Aged
PubMed: 15261843
DOI: 10.1016/j.beem.2004.02.006 -
Vitamins and Hormones 2018The discovery of "oestrus-producing" hormones was a major research breakthrough in biochemistry and pharmacology during the early part of the 20th century. The... (Review)
Review
The discovery of "oestrus-producing" hormones was a major research breakthrough in biochemistry and pharmacology during the early part of the 20th century. The elucidation of the molecular weight and chemical structure of major oxidative metabolites of dehydroepiandrosterone (DHEA) led to the award of the Nobel Prize in 1939 to Adolf Frederick Johann Butenandt and Leopold Ruzicka. Considered a bulk androgen in the circulation, DHEA and its sulfated metabolite DHEA-S can be taken up by most tissues where the sterols are metabolized to active androgenic and estrogenic compounds needed for growth and development. Butenandt's interactions with the German pharmaceutical company Schering led to production of gram quantities of these steroids and other chemically modified compounds of this class. Sharing chemical expertise allowed Butenandt's laboratory at the Kaiser Wilhelm Institute to isolate and synthesize many steroid compounds in the elucidation of the pathway leading from cholesterol to testosterone and estrogen derivatives. As a major pharmaceutical company worldwide, Schering AG sought these new biological sterols as pharmacological agents for endocrine-related diseases, and the European medical community tested these compounds in women for conditions such as postmenopausal depression, and in men for increasing muscle mass. Since it was noted that circulating DHEA-S levels decline as a function of age, experimental pathology experiments in animals were performed to determine how DHEA may protect against cancer, diabetes, aging, obesity, immune function, bone density, depression, adrenal insufficiency, inflammatory bowel disease, diminished sexual function/libido, AIDS/HIV, chronic obstructive pulmonary disease, coronary artery disease, chronic fatigue syndrome, and metabolic syndrome. While the mechanisms by which DHEA ameliorates these conditions in animal models have been elusive to define, even less is known about its role in human disease, other than as a precursor to other sterols, e.g., testosterone and estradiol. Our groups have shown that DHEA and many of its oxidative metabolites serve as a low-affinity ligands for hepatic nuclear receptors, such as the pregnane X receptor, the constitutive androstane receptor, and estrogen receptors α/β (ERα/ERβ) as well as G protein-coupled ER (GPER1). This chapter highlights the founding research on DHEA from a historical perspective, provides an overview of DHEA biosynthesis and metabolism, briefly summarizes the early work on the beneficial effects attributed to DHEA in animals, and summarizes the human trials addressing the action of DHEA as a therapeutic agent. In general, most human studies involve weak correlations of circulating levels of DHEA and disease outcomes. Some support for DHEA as a therapeutic compound has been demonstrated for postmenopausal women, in vitro fertilization, and several autoimmune disorders, and adverse health effects, such as, acne, embryo virilization during pregnancy, and possible endocrine-dependent cancers.
Topics: Animals; Cardiovascular Physiological Phenomena; Dehydroepiandrosterone; Fertility Agents, Female; Glucosephosphate Dehydrogenase; Humans; Hypertension, Pulmonary
PubMed: 30029723
DOI: 10.1016/bs.vh.2018.02.002 -
Seminars in Reproductive Medicine Nov 2004Dehydroepiandrosterone (DHEA) replacement therapy has attracted considerable attention over recent years. Significant beneficial effects of DHEA replacement have been... (Review)
Review
Dehydroepiandrosterone (DHEA) replacement therapy has attracted considerable attention over recent years. Significant beneficial effects of DHEA replacement have been reported in patients representing the pathophysiological model of complete DHEA deficiency, in other words, adrenal insufficiency (AI). This includes effects on well-being, energy levels, mood, and libido, which is usually impaired in AI, particularly in female patients. DHEA exerts its action mainly indirectly via downstream metabolism to sex steroids, and conversion to active androgens is likely to play a major role. In addition, DHEA has well-described neurosteroidal properties, and by exerting anti-gamma aminobutyric acid(GABA)ergic action it may have antidepressive potential. Other patient groups that may benefit from DHEA replacement are patients receiving chronic exogenous glucocorticoid treatment, which invariably leads to persistent suppression of DHEA production. In patients with systemic lupus erythematosus, DHEA has been shown to reduce disease activity and has a glucocorticoid-sparing effect. However, caution is required regarding DHEA treatment in individuals with only a relative decline in circulating DHEA levels. This particularly includes the physiological decline of DHEA and its sulfate ester observed with aging. Even the elderly maintain circulating levels of DHEA that are orders of magnitude higher than what is observed in AI. Even physiological menopause does not necessarily lead to a decrease in circulating androgens while estrogen production invariably ceases. Current evidence from randomized, controlled trials in healthy elderly persons including several cohorts of postmenopausal women does not justify the use of DHEA. However, DHEA may be a suitable option for androgen replacement in women with established androgen deficiency, for example, bilateral oophorectomy and premature menopause.
Topics: Adrenal Insufficiency; Aging; Animals; Autoimmune Diseases; Cognition Disorders; Dehydroepiandrosterone; Female; Hormone Replacement Therapy; Humans; Male; Mood Disorders; Sexual and Gender Disorders
PubMed: 15635505
DOI: 10.1055/s-2004-861554 -
European Journal of Endocrinology Aug 2001
Review
Topics: Adult; Aged; Aging; Dehydroepiandrosterone; Female; Hormone Replacement Therapy; Humans; Male; Middle Aged
PubMed: 11454504
DOI: 10.1530/eje.0.1450103 -
American Journal of Health-system... Nov 2000
Review
Topics: Animals; Dehydroepiandrosterone; Drug Interactions; Humans
PubMed: 11098305
DOI: 10.1093/ajhp/57.22.2048 -
Vitamins and Hormones 2018Type 2 diabetes is a metabolic disorder that is characterized by an impaired capacity to secrete insulin, insulin resistance, or both. Dehydroepiandrosterone (DHEA), a... (Review)
Review
Type 2 diabetes is a metabolic disorder that is characterized by an impaired capacity to secrete insulin, insulin resistance, or both. Dehydroepiandrosterone (DHEA), a steroid hormone produced by the adrenal cortex, has been reported to have beneficial effects on diabetes mellitus and obesity in animal models. DHEA and DHEA-sulfate (DHEA-S) have been reported to increase not only insulin secretion of the pancreas but also insulin sensitivity of the liver, adipose tissue, and muscle. We investigated the effects of DHEA on glucose metabolism in animal models and reported decrease of liver gluconeogenesis. Recently, we reported the effect of DHEA on the liver and muscle by using insulin-stimulated insulin receptor substrate 1 and 2 (IRS1 and IRS2)-deficient mice. DHEA increased Akt phosphorylation in the liver of C57BL6 IRS1- and IRS2-deficient mice fed with a high-fat diet (HFD), which suggests that the increase in DHEA-induced Akt signaling is sufficient in the presence of IRS1 or IRS2. In addition, other studies have also reported the effect of DHEA on diabetes mellitus in the liver, muscle, adipose tissue, and pancreatic β-cell and its effect on obesity in animal models. A meta-analysis in elderly men and women has found that DHEA supplementation has no effects on blood glucose levels. However, DHEA supplementation to patients with type 2 diabetes has not been fully elucidated. Therefore, further studies are needed to provide greater insight into the effect of DHEA on diabetes and obesity in animal and human models.
Topics: Animals; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Diabetes Mellitus, Type 2; Humans; Insulin; Obesity
PubMed: 30029734
DOI: 10.1016/bs.vh.2018.01.008