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Menopause (New York, N.Y.) Jun 2017To illustrate the marked differences between classical endocrinology that distributes hormones to all tissues of the body through the bloodstream and the science of... (Review)
Review
OBJECTIVE
To illustrate the marked differences between classical endocrinology that distributes hormones to all tissues of the body through the bloodstream and the science of intracrinology, whereby each cell of each peripheral tissue makes a small and appropriate amount of estrogens and androgens from the inactive precursor dehydroepiandrosterone (DHEA), DHEA being mainly of adrenal origin. Because only the inactivated sex steroids are released in the blood, influence in the other tissues is avoided.
METHODS
Molecular biology has been used for the identification/characterization of the steroid-forming and steroid-inactivating enzymes, whereas steroids have been measured by mass spectrometry-based assays validated according to the US Food and Drug Administration guidelines.
RESULTS
Evolution over 500 million years has engineered the expression of about 30 steroid-forming enzymes specific for each peripheral tissue. These tissue-specific enzymes transform DHEA into the appropriate small amounts of estrogens and androgens for a strictly intracellular and local action. Humans, contrary to species below primates, also possess intracellular steroid-inactivating enzymes, especially glucuronyl transferases and sulfotransferases, which inactivate the estrogens and androgens at their local site of formation, thus preventing the release of a biologically significant amount of estradiol (E2) and testosterone in the circulation. Since DHEA becomes the unique source of sex steroids after menopause, serum E2 and testosterone are thus maintained at low biologically inactive concentrations with no activity outside the cells of origin. DHEA secretion, unfortunately, starts decreasing at about the age of 30 at various rates in different women. Moreover, there is no feedback mechanism to increase DHEA secretion when the concentration of serum DHEA decreases. Considering this mechanism is unique to the human, it seems logical to replace DHEA locally in women suffering from vulvovaginal atrophy (genitourinary syndrome of menopause). The clinical data obtained using a small dose of intravaginal DHEA (prasterone) confirm the mechanisms of intracrinology mentioned above which avoid biologically significant changes in serum E2 and testosterone.
CONCLUSIONS
The symptoms and signs of vulvovaginal atrophy (genitourinary syndrome of menopause) can be successfully treated by the intravaginal administration of DHEA without safety concerns. This strategy exclusively replaces in the vagina the missing cell-specific intracellular estrogens and androgens. This approach avoids systemic exposure and the potential risks of estrogen exposure for the tissues other than the vagina.
Topics: Androgens; Atrophy; Dehydroepiandrosterone; Enzyme Inhibitors; Enzymes; Estrogens; Female; Humans; Intracellular Space; Postmenopause; Vagina
PubMed: 28098598
DOI: 10.1097/GME.0000000000000808 -
FP Essentials Aug 2023Given their association with aging, growth hormone (GH), dehydroepiandrosterone (DHEA), and melatonin (-acetyl-5-methoxytryptamine) have been evaluated as potential...
Given their association with aging, growth hormone (GH), dehydroepiandrosterone (DHEA), and melatonin (-acetyl-5-methoxytryptamine) have been evaluated as potential antiaging treatments. It has been hypothesized that declining endocrine function, specifically the decreases in hormone production and secretion seen with aging, plays a role in development of frailty. This physiologic decrease in hormone levels differs from a pathologic decrease due to a condition or disease. However, the signs and symptoms can be similar. Hormone replacement therapy is a well-established treatment for many conditions, but its role in the healthy aging process remains unclear. Off-label use of these hormones has shown some short-term benefits, such as improved body composition, mood, neurocognition, and sexual function and decreased oxidative stress. However, there are no recommendations for routine measurement of these hormone levels or for hormone replacement therapy because of a lack of high-quality evidence. Long-term studies are needed to evaluate the efficacy and safety of GH, DHEA, and melatonin if they are to be used as antiaging therapies.
Topics: Humans; Melatonin; Hormone Replacement Therapy; Aging; Dietary Supplements; Dehydroepiandrosterone
PubMed: 37603882
DOI: No ID Found -
Steroids Oct 2019Osteoarthritis (OA) is the most common form of degenerative arthropathy, and the primary symptom is chronic joint pain. Dehydroepiandrosterone (DHEA) exerts a... (Review)
Review
Osteoarthritis (OA) is the most common form of degenerative arthropathy, and the primary symptom is chronic joint pain. Dehydroepiandrosterone (DHEA) exerts a chondroprotective effect against OA and has been reported to have potent structure-modifying effects on osteoarthritic cartilage, thereby attenuating disease progression. However, the ability of DHEA to modulate OA-related pain has not yet been verified. Recent evidence suggests that there may be a link between the pharmacological effects of DHEA and pain generation. For example, DHEA synthesized in the adrenal gland interferes directly with nerve growth factor (NGF) receptors, a major biochemical contributor to peripheral hypersensitivity. Similarly, endogenous DHEA produced in the spinal cord exerts a regulatory effect on nociception in neuropathic rats. In this short review, we discuss recent studies concerning crucial signalling cascades and molecular mechanisms involved in pain generation as well as the potential link between DHEA activity and nociception. Particular attention is given to the putative molecular mechanisms underlying the favourable efficacy of DHEA against pain generation. Elucidating the molecular mechanisms of DHEA against osteoarthritic pain may pave the way for the discovery and development of novel anti-OA drugs, as effective drugs for OA treatment are not currently available.
Topics: Animals; Dehydroepiandrosterone; Humans; Osteoarthritis; Pain
PubMed: 31229511
DOI: 10.1016/j.steroids.2019.108433 -
The Journal of Steroid Biochemistry and... Oct 2018Dehydroepiandrosterone (DHEA), a 19-carbon steroid hormone primarily synthesized in the adrenal gland, exerts a chondroprotective effect against osteoarthritis (OA) and... (Review)
Review
Dehydroepiandrosterone (DHEA), a 19-carbon steroid hormone primarily synthesized in the adrenal gland, exerts a chondroprotective effect against osteoarthritis (OA) and has been considered an effective candidate of disease-modifying OA drugs (DMOADs) that slow disease progression. We and others previously demonstrated that DHEA exerted a beneficial effect on osteoarthritic cartilage by positively modulating the balance between anabolic and catabolic factors (e.g., MMPs/TIMP-1, ADAMTS/TIMP-3 and cysteine proteinases/cystatin C), inhibiting catabolic signaling pathways (e.g., Wnt/β-catenin), and suppressing proinflammatory cytokines-mediated low-grade synovial inflammation (e.g., IL-1β). However, the full picture of the pharmacological molecular mechanism(s) underlying the activity of DHEA against OA is still incomplete, and a comprehensive and up-to-date review article in this field is unavailable. In this review, recent findings (apart from the well documented pathogenesis of OA) regarding disease-related mechanisms involving low grade synovial inflammation, cartilage matrix stiffness, chondrocyte autophagy and the roles of a variety of catabolic cellular signaling pathways are discussed. Moreover, the possible relationship between these disease-related mechanisms and DHEA action is discussed. Emerging evidence from in vivo and in vitro studies were scrutinized and are concisely presented to demonstrate the investigational and putative mechanisms underlying the anti-OA potential of DHEA.
Topics: Adjuvants, Immunologic; Animals; Dehydroepiandrosterone; Humans; Osteoarthritis; Signal Transduction
PubMed: 29787833
DOI: 10.1016/j.jsbmb.2018.05.004 -
Vitamins and Hormones 20183βHSD2 enzyme is crucial for adrenal and gonad steroid biosynthesis. In enzyme deficiency states, due to recessive loss-of-function HSD3B2 mutations, steroid flux is... (Review)
Review
3βHSD2 enzyme is crucial for adrenal and gonad steroid biosynthesis. In enzyme deficiency states, due to recessive loss-of-function HSD3B2 mutations, steroid flux is altered and clinical manifestations result. Deficiency of 3βHSD2 activity in the adrenals precludes normal aldosterone and cortisol synthesis and the alternative backdoor and 11-oxygenated C19 steroid pathways and the flooding of cortisol precursors along the Δ5 pathway with a marked rise in DHEA and DHEAS production. In gonads, it precludes normal T and estrogen synthesis. Here, we review androgen-dependent male differentiation of the external genitalia in humans and link this to female development and steroidogenesis in the developing adrenal cortex. The molecular mechanisms governing postnatal adrenal cortex zonation and ZR development were also revised. This chapter will review relevant clinical, hormonal, and genetic aspects of 3βHSD2 deficiency with emphasis on the significance of alternate fates encountered by steroid hormone precursors in the adrenal gland and gonads. Our current knowledge of the process of steroidogenesis and steroid action is derived from pathological conditions. In humans the 3βHSD2 deficiency represents a model of nature that reinforces our knowledge about the role of the steroidogenic alternative pathway in sex differentiation in both sexes. However, the physiological role of the high serum DHEAS levels in fetal life as well as after adrenarche remains to be elucidated.
Topics: Dehydroepiandrosterone; Gene Expression Regulation; Genotype; Humans; Progesterone Reductase; Sexual Development
PubMed: 30029738
DOI: 10.1016/bs.vh.2018.05.002 -
Maturitas Feb 2023Normal aging is linked to various endocrine gland changes, including changes in the adrenal glands. Aging is linked to alterations of the hypothalamic-pituitary-adrenal... (Review)
Review
Normal aging is linked to various endocrine gland changes, including changes in the adrenal glands. Aging is linked to alterations of the hypothalamic-pituitary-adrenal (HPA) axis, including an increase in cortisol levels, a disruption of the negative cortisol feedback, and attenuation of cortisol's diurnal pattern. In addition, secretion of aldosterone and adrenal androgens [dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS)] from the adrenal cortex decreases with aging. In this review, we describe normal adrenal function, the adrenal response to stress and immunomodulation in aging individuals as well as the effects of adrenal aging on body composition, metabolic profile, bone health and cognition.
Topics: Humans; Dehydroepiandrosterone; Hydrocortisone; Immunosenescence; Aging; Adrenal Cortex Hormones; Dehydroepiandrosterone Sulfate
PubMed: 36370489
DOI: 10.1016/j.maturitas.2022.10.006 -
The Journal of Steroid Biochemistry and... Jan 2015The importance of intracrinology, or in situ production of steroids from circulating precursors, in breast cancer has been firmly established in estrogen actions on... (Review)
Review
The importance of intracrinology, or in situ production of steroids from circulating precursors, in breast cancer has been firmly established in estrogen actions on postmenopausal patients. Expression levels of various steroid synthesizing and/or metabolizing enzymes have been examined in human breast cancer tissues by a number of groups. The enzymes examined include those capable of converting circulating DHEA-S to sex steroids (STS and 3βHSDΔ4-5 isomerase), the group of enzymes that modulate the strength of both androgens and estrogens (17βHSD family) as well as the androgenic 5αR enzymes and the estrogenic aromatase enzyme. In addition to these DHEA-related metabolism pathways, other intracrine pathways involving progesterone and cholesterol have also been examined. Some risk factors of breast cancer development, including obesity, have also been postulated to interact with steroid metabolising pathways. In this review, we aimed to summarise the current state of knowledge regarding intracrine metabolism including expression levels of various enzymes and receptors, focusing particularly upon the importance of the production of biologically potent steroids from circulating sulfated precursors such as DHEA-S. In addition, we attempted to summarise the factors, both steroidal and non-steroidal, involved in the regulation of these enzymes and propose future directions for research in this particular field. The concept of intracrinology was first proposed over 20 years ago but there still remain many unanswered questions which could open new horizons for the understanding of intracrine metabolism in the breast. This article is part of a Special Issue entitled 'Essential role of DHEA'.
Topics: Androgens; Aromatase; Breast; Breast Neoplasms; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estrogens; Female; Gene Expression Regulation, Neoplastic; Humans; Obesity; Risk Factors; Steroids
PubMed: 24751707
DOI: 10.1016/j.jsbmb.2014.04.004 -
American Family Physician Jan 2019
Review
Topics: Adjuvants, Immunologic; Administration, Intravaginal; Dehydroepiandrosterone; Dyspareunia; Female; Humans; Postmenopause; Randomized Controlled Trials as Topic
PubMed: 30633482
DOI: No ID Found -
Biochemistry. Biokhimiia Sep 2022Cholesterol oxidase is a highly demanded enzyme used in medicine, pharmacy, agriculture, chemistry, and biotechnology. It catalyzes oxidation of 3β-hydroxy-5-ene- to...
Cholesterol oxidase is a highly demanded enzyme used in medicine, pharmacy, agriculture, chemistry, and biotechnology. It catalyzes oxidation of 3β-hydroxy-5-ene- to 3-keto-4-ene- steroids with the formation of hydrogen peroxide. Here, we expressed 6xHis-tagged mature form of the extracellular cholesterol oxidase (ChO) from the actinobacterium Nocardioides simplex VKM Ac-2033D (55.6 kDa) in Escherichia coli cells. The recombinant enzyme (ChO) was purified using affinity chromatography. ChO proved to be functional towards cholesterol, cholestanol, phytosterol, pregnenolone, and dehydroepiandrosterone. Its activity depended on the structure and length of the aliphatic side chain at C17 atom of the steroid nucleus and was lower with pregnenolone and dehydroepiandrosterone. The enzyme was active in a pH range of 5.25÷6.5 with the pH optimum at 6.0. Kinetic assays and storage stability tests demonstrated that the characteristics of ChO were generally comparable with or superior to those of commercial ChO from Streptomyces hygroscopicus (ChO). The results contribute to the knowledge on microbial ChOs and evidence that ChO from N. simplex VKM Ac-2033D is a promising agent for further applications.
Topics: Actinobacteria; Cholestanols; Cholesterol Oxidase; Dehydroepiandrosterone; Hydrogen Peroxide; Phytosterols; Pregnenolone; Steroids
PubMed: 36180991
DOI: 10.1134/S0006297922090048 -
Endocrine Regulations Sep 2021The pathophysiology of COVID comprises an exaggerated pro-inflammatory response. Hypothalamic-pituitary-adrenal (HPA) axis has a crucial role in various inflammatory... (Review)
Review
The pathophysiology of COVID comprises an exaggerated pro-inflammatory response. Hypothalamic-pituitary-adrenal (HPA) axis has a crucial role in various inflammatory conditions and modulated immunological response. Limited evidence is available regarding the incidence and the effect of HPA dysfunction in COVID-19. Although the cortisol levels have only been estimated in a few studies, the dehydroepiandrosterone sulfate (DHEAS) release from the adrenal gland has not been explored yet. In this mini review, the authors discuss the role of dehydroepiandrosterone (DHEA) and DHEAS in the acute stress response and immunological modulation. Various effects of DHEAS have been demonstrated in different diseases. The specific inhibitory effect of DHEA on interleukin 6 (IL-6) could be of paramount importance in COVID-19. Further, DHEA supplementation has already been proposed in inflammatory conditions, like rheumatoid arthritis. DHEAS levels in COVID-19 may help to understand the HPA axis dysfunction as well as the possibility of repurposing DHEA as a drug for mitigating the pro-inflammatory COVID-19.
Topics: COVID-19; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Humans; Hypothalamo-Hypophyseal System; Immunologic Factors; COVID-19 Drug Treatment
PubMed: 34523302
DOI: 10.2478/enr-2021-0019