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Steroids Mar 2022Although DHEA sulfate (DS) is the most abundant steroid in the circulation, breast fluid contains an approximately 80-fold greater concentration than serum. Transport of... (Review)
Review
Although DHEA sulfate (DS) is the most abundant steroid in the circulation, breast fluid contains an approximately 80-fold greater concentration than serum. Transport of DS into cells requires organic anion transporting polypeptides (OATPs), which are specific for cell type, cell location, and substrate, but may have a broader specificity for housekeeping functions. Specific classes, which may be modified by soluble factors including neutral steroids, have been identified in the breast. After transport, DS may be cleaved to DHEA by ubiquitous sulfatases, which may be modified by the cell milieu, or DHEA may enter by diffusion. Synthesis from cholesterol does not occur because CYP17B12 and cytochrome b5 are lacking in breast tissues. Case-control studies reveal a positive association of serum DS with risk of breast cancer. The association is even greater with DHEA, particularly in postmenopausal women with HR + invasive tumors. Metabolites of DHEA, androstenedione and testosterone, are associated with breast cancer but DHEA is likely to have an independent role as well. Mechanisms by which DHEA may promote breast cancer relate to its effect in increasing circulating IGF-I, by inhibiting the suppressive effect of glucocorticoids, and by promoting retention of pre-adipocytes with aromatase activity. In addition, DHEA may interact with the G-protein coupled receptor GPER for stimulation of miR-21 and subsequent activation of the MAPK pathway. DHEA also has antitumor properties that relate to stimulation of immunity, suppression of inflammation, and elevation of adipose tissue adiponectin synthesis. The net effect may depend on the which factors predominate.
Topics: Androstenedione; Breast Neoplasms; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Humans; Testosterone
PubMed: 35122788
DOI: 10.1016/j.steroids.2022.108970 -
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 -
Vitamins and Hormones 2018DHEA and DHEA-S have numerous associations with multiple aspects of immune function and are often characterized as beneficial and supportive of immunocompetence.... (Review)
Review
DHEA and DHEA-S have numerous associations with multiple aspects of immune function and are often characterized as beneficial and supportive of immunocompetence. However, closer inspection of these studies reveals confusion regarding the immunological components modified, the mechanisms of action, and degree of impact, and even whether these hormones even have direct action or are mediated by metabolites and interactions with other hormones and hormone receptors. Additionally, much of the research is conducted on rodent models using very high concentrations of hormone supplements, which may not be representative of the effects of these hormones in natural circulating concentrations, or may not translate to human physiology in a meaningful way. Here, we review the effects of DHEA and DHEA-S on immune function and examine the potential roles these hormones play on specific components of immune function. Drawing from the literature on hormone supplementation, as well as studies examining the natural circulating levels of DHEA and DHEA-S on specific immunological components and disease processes, we argue that DHEA has differential actions on human immune function, and that its effects are further shaped by concentrations of other hormones. Of particular interest is the role of DHEA as an antiglucocorticoid, and for its actions on both androgen and estrogen receptors. With additional research, DHEA may be useful as a therapeutic, particularly in diseases with high levels of inflammation, or where adrenal production is altered. The convoluted nature of DHEA-immune interactions makes direct effects difficult to interpret, and future research needs to consider direct, intracrine, and downstream effects of these hormones.
Topics: Cytokines; Dehydroepiandrosterone; Gene Expression Regulation; Humans; Immunomodulation; Infections
PubMed: 30029724
DOI: 10.1016/bs.vh.2018.01.023 -
The Journal of Steroid Biochemistry and... Jan 2015Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the most abundant steroid hormones in the humans. However, their physiological significance, their... (Review)
Review
Dehydroepiandrosterone (DHEA) and its sulfate ester, DHEAS, are the most abundant steroid hormones in the humans. However, their physiological significance, their mechanisms of action and their possible roles as treatment are not fully clarified. Biological actions of DHEA(S) in the brain involve neuroprotection, neurite growth, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion, as well as anti-oxidant, anti-inflammatory and antiglucocorticoid effects. In addition, DHEA affects neurosteroidogenis and endorphin synthesis/release. We also demonstrated in a model of ovariectomized rats that DHEA therapy increases proceptive behaviors, already after 1 week of treatment, affecting central function of sexual drive. In women, the analyses of clinical outcomes are far from being conclusive and many issues should still be addressed. Although DHEA preparations have been available in the market since the 1990s, there are very few definitive reports on the biological functions of this steroid. We demonstrate that 1 year DHEA administration at the dose of 10mg provided a significant improvement in comparison with vitamin D in sexual function and in frequency of sexual intercourse in early postmenopausal women. Among symptomatic women, the spectrum of symptoms responding to DHEA requires further investigation, to define the type of sexual symptoms (e.g. decreased sexual function or hypoactive sexual desire disorder) and the degree of mood/cognitive symptoms that could be responsive to hormonal treatment. In this regard, our findings are promising, although they need further exploration with a larger and more representative sample size. This article is part of a Special Issue entitled: Essential role of DHEA.
Topics: Affect; Animals; Anxiety; Brain; Cognition; Cognition Disorders; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Depression; Female; Humans; Male; Mood Disorders; Neurobiology; Neurotransmitter Agents; Sexual Behavior
PubMed: 24892797
DOI: 10.1016/j.jsbmb.2014.04.012 -
Climacteric : the Journal of the... Oct 2015Dehydroepiandrosterone (DHEA) and its sulfate represent the most abundant sex steroid in humans. In addition to age-related reduction, serum DHEA shows large...
Dehydroepiandrosterone (DHEA) and its sulfate represent the most abundant sex steroid in humans. In addition to age-related reduction, serum DHEA shows large interindividual variability. Although cross-sectional studies suggest that lower levels are associated with cardiovascular, cognitive and sexual impairment in women, clinical trials of oral DHEA replacement have failed to show benefits. However, current evidence is too imprecise to draw definite conclusions.
Topics: Adjuvants, Immunologic; Dehydroepiandrosterone; Estrogen Replacement Therapy; Female; Humans; Middle Aged; Postmenopause
PubMed: 25961114
DOI: 10.3109/13697137.2015.1042337 -
Current Opinion in Endocrinology,... Jun 2022Dehydroepiandrosterone (DHEA) is an androgen produced by the zona reticularis of the adrenal gland. Patients with adrenal insufficiency will have a deficiency of DHEA.... (Review)
Review
PURPOSE OF REVIEW
Dehydroepiandrosterone (DHEA) is an androgen produced by the zona reticularis of the adrenal gland. Patients with adrenal insufficiency will have a deficiency of DHEA. Unlike glucocorticoid and mineralocorticoid replacement, DHEA supplementation is not considered essential for life and is therefore not routinely replaced in adrenal failure. DHEA deficiency is associated with morbidity, including adverse impacts on metabolic function, quality of life and sexuality in multiple studies. The role for replacement, however, remains unclear.
RECENT FINDINGS
The benefits of DHEA supplementation have been definitively demonstrated in a number of historical studies of patients with primary and secondary adrenal insufficiency. Beneficial impacts on quality of life, body composition, bone health and metabolic markers have been demonstrated. However, published data are inconsistent; controversies persist around the exact role of DHEA replacement and around which patient cohorts are most likely to benefit. There is also a paucity of recent randomized controlled trials in the medical literature to inform on optimal dose and duration of DHEA replacement in adrenal failure.
SUMMARY
Here, we review the evidence for DHEA supplementation in patients with adrenal insufficiency. We highlight knowledge gaps in the medical literature and areas that should be prioritized for future research endeavours.
Topics: Adrenal Insufficiency; Androgens; Dehydroepiandrosterone; Hormone Replacement Therapy; Humans; Quality of Life
PubMed: 35621180
DOI: 10.1097/MED.0000000000000728 -
The vagina as source and target of androgens: implications for treatment of GSM/VVA, including DHEA.Climacteric : the Journal of the... Aug 2023The vagina is traditionally thought of as a passive organ in the female reproductive system, serving primarily as a passageway for menstrual blood, sexual intercourse... (Review)
Review
The vagina is traditionally thought of as a passive organ in the female reproductive system, serving primarily as a passageway for menstrual blood, sexual intercourse and childbirth. However, recent research has shed light on the vagina's role as an endocrine organ that plays a crucial role in female hormonal balance and overall health. Particularly, growing evidence shows that the human vagina can be considered both as source and target of androgens, in view of the novel concept of 'intracrinology'. Besides the well-known role of estrogens, androgens are also crucial for the development and maintenance of healthy genitourinary tissues in women. As androgen levels decline with age, and estrogen levels fall during the menopausal transition, the tissues in the vagina, together with those in the urinary tract, become thinner, drier and less elastic, leading to a variety of uncomfortable and sometimes painful symptoms, clustered in the genitourinary syndrome of menopause (GSM). Given the lack of testosterone-based or androstenedione-based products approved by regulatory agencies to treat GSM, the possibility of using intravaginal prasterone, which works by providing a local source of dehydroepiandrosterone (DHEA) to the vaginal tissues, appears to be a targeted treatment. Further studies are needed to better assess its safety and efficacy.
Topics: Female; Humans; Androgens; Dehydroepiandrosterone; Dyspareunia; Administration, Intravaginal; Vagina; Menopause; Estrogens; Atrophy
PubMed: 37288964
DOI: 10.1080/13697137.2023.2213827 -
Biomolecules Nov 2022Androgens are steroids that modulate various processes in the body, ranging from reproduction, metabolism, and even immune response. The main androgens are testosterone,... (Review)
Review
Androgens are steroids that modulate various processes in the body, ranging from reproduction, metabolism, and even immune response. The main androgens are testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA). These steroids modulate the development and function of immune response cells. Androgens are generally attributed to immunosuppressive effects; however, this is not always the case. Variations in the concentrations of these hormones induce differences in the innate, humoral, and cell-mediated immune response, which is concentration dependent. The androgens at the highest concentration in the organism that bind to the androgen receptor (AR) are DHEA and testosterone. Therefore, in this work, we review the effects of DHEA and testosterone on the immune response. The main findings of this review are that DHEA and testosterone induce similar but also opposite effects on the immune response. Both steroids promote the activation of regulatory T cells, which suppresses the Th17-type response. However, while testosterone suppresses the inflammatory response, DHEA promotes it, and this modulation is important for understanding the involvement of androgens in infectious (bacterial, viral and parasitic) and autoimmune diseases, as well as in the sexual dimorphism that occurs in these diseases.
Topics: Testosterone; Dehydroepiandrosterone; Androgens; Dihydrotestosterone; Adaptive Immunity
PubMed: 36551196
DOI: 10.3390/biom12121768 -
Expert Opinion on Pharmacotherapy Jan 2023Genitourinary syndrome of menopause is caused by climacteric estrogens drop and leads to bothersome and progressive genital and urinary symptoms. Considering the high... (Review)
Review
INTRODUCTION
Genitourinary syndrome of menopause is caused by climacteric estrogens drop and leads to bothersome and progressive genital and urinary symptoms. Considering the high frequency in the population and the impact on quality of life, it is crucial to find a safe and effective treatment. Pharmacological therapies aim to modulate the hormonal system and reverse tissue changes due to hypoestrogenism and consequently the symptoms.
AREAS COVERED
We analyzed the scientific evidence concerning the main pharmacological treatments, which include systemic and topical estrogens, prasterone and ospemifene. This literature review focused on recent safety and efficacy findings in an attempt to identify the best treatment choice for each individual patient.
EXPERT OPINION
There are encouraging data regarding the efficacy of all currently available pharmacological options and concerning their short and long-term safety. There are still doubts regarding best treatment choice for oncological high-risk population, in particular for breast cancer survivors, and some issues relative to patients' poor compliance and treatment adherence. For these reasons further studies need to be conducted with a patient-tailored focus.
Topics: Female; Humans; Quality of Life; Menopause; Breast Neoplasms; Estrogens; Dehydroepiandrosterone; Syndrome; Vagina; Atrophy
PubMed: 36444726
DOI: 10.1080/14656566.2022.2152326 -
Life Sciences Oct 2023The present study aims to investigate the impact of the gut microbiota and serum metabolites on the regulation of liver dysfunction in PCOS.
AIMS
The present study aims to investigate the impact of the gut microbiota and serum metabolites on the regulation of liver dysfunction in PCOS.
MATERIALS AND METHODS
PCOS rat models were established by treating Sprague Dawley (SD) rats with DHEA (an androgen, 60 mg/kg) and LET (a nonsteroidal aromatase inhibitor, 1 mg/kg) for 90 days. Hematoxylin and eosin staining (H&E), Western blotting, and radioimmunoassay were employed to test ovarian and liver functions. Gut microbiome and serum metabolites were assessed using 16S rRNA amplicon sequencing and non-targeted metabolomics, respectively. The association between gut microbiota and serum metabolites was examined using Spearman analysis. Finally, using HepG2 cells to investigate the function of the serum metabolite rosmarinic acid (RA).
KEY FINDINGS
Both Dehydroepiandrosterone (DHEA) and letrozole (LET) treatments induced a PCOS phenotype and liver dysfunction. However, LET resulted in more severe lipid accumulation and liver cell apoptosis than DHEA. 16S rRNA sequencing and non-targeted metabolomics analysis revealed significant differences in beta diversity and serum metabolite profiles among the three groups. Furthermore, among the significantly changed metabolites, RA was found to have a significant correlation with the levels of serum aspartate transaminase (AST) and lactate dehydrogenase (LDH) and could promote HepG2 cell apoptosis.
SIGNIFICANCE
Restoring gut microbiota, altering serum metabolites and/or decreasing RA may provide a new insight to treat this complication.
Topics: Humans; Female; Rats; Animals; Polycystic Ovary Syndrome; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Rats, Sprague-Dawley; Letrozole; Liver Diseases; Dehydroepiandrosterone; Rosmarinic Acid
PubMed: 37423380
DOI: 10.1016/j.lfs.2023.121912