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Progesterone increase under DHEA-substitution in males
Abstract
Two case reports of men suffering from excessive fatigue and depression are presented, both treated with 50 or 25 mg DHEA per day over a period of 1 year. Under DHEA treatment one subject reported being less tired and the other experienced improved well-being without depressive episodes and an increase in libido. Investigations of sex hormone parameters in plasma before and under treatment revealed a decrease of testosterone and an increase of progesterone in both, possibly dose-dependent to DHEA application. It is hypothesised that the increase of progesterone is parallel to an increase of its metabolite allopregnanolone (which was not determined), that might explain the improvement in well-being. The increase of progesterone under DHEA supplementation in males should receive further attention.
... Their samples presented varied characteristics, different ages and both genders. In addition, the dosages used were not consistent among the studies [55][56][57][58] . ...
... In men, testosterone showed a decrease in two studies, yet an increase in most male carriers of Addison's disease, although less expressive than in women 55 . Estradiol was only assessed in one man, and there was an increase 58 . ...
... HIV þ individuals witnessed an improvement in libido; however, this improvement was always associated with a mood enhancement, and was not specifically associated with the effect of DHEA on sexual function 57 . In a case report of two patients, an elderly subject complained of loss of libido whilst a younger patient with depression reported an improvement of depression and libido 58 . ...
Objective:
Faced with the growing interest about the action of dehydroepiandrosterone (DHEA) and its benefits, as well as the negative impacts that sexual dysfunctions have on people's quality of life, this systematic review was undertaken with the objective of evaluating the effect of DHEA use on aspects of sexual function.
Method:
An electronic search was conducted in the databases of PubMed, ISI Web of Science and Virtual Health Library (VHL) combining the terms 'DHEA treatment' and 'DHEA use' with terms such as 'sexual dysfunction', 'sexual frequency' and 'libido'. No limits on time and language were imposed. Clinical studies were considered eligible where individuals for any reason made use of DHEA and if they had any aspect of sexual function assessed. Preclinical studies and systematic reviews were considered ineligible.
Results:
The search identified 183 references and 38 were considered eligible. DHEA improved aspects such as sexual interest, lubrication, pain, arousal, orgasm and sexual frequency. Its effect was better in populations with sexual dysfunction, especially in perimenopausal and postmenopausal women.
Conclusion:
Considering the studies currently published, DHEA is effective in improving several aspects of sexual function, but this effect did not reach all the populations studied.
... DHEA can increase the function and activity of mitochondria, reduce the apoptosis and of transcription factors (27). CYP17A1 is an integral membrane protein in the endoplasmic reticulum that transfers electrons from NADPH to CYP17A1 (28). DHEA of sulfuric acid can be generated in the adrenal cortex through the 3βʹ-hydroxyl group. ...
Diminished ovarian reserve (DOR) refers to the decline in fertility caused by the loss of normal ovarian function. DOR is associated with adverse reactions to ovarian stimulation during in vitro fertilization and embryo transfer (IVF-ET), increasing cycle cancellation rates and reducing pregnancy rates. Although it is well known that dehydroepiandrosterone (DHEA) can be used as a dietary supplement for age-related diseases, its potential has gradually been shown for many diseases. In this review, we focus on the effects of DHEA on DOR, briefly analysing its clinical benefits and limitations and describing the mechanism of function and the clinical trials conducted. Therefore, we summarize the mechanisms and indications of DHEA for DOR.
... Furthermore, our results showed a correlation between DHEAS and progesterone levels only in the non-catatonic state but not in the catatonic state. The fact that progesterone is produced in the adrenal cortex at this patient's age and that DHEA supplementation increases progesterone levels in males [7] suggests that the conversion of DHEA to progesterone occurs. Therefore, it is speculated that changes in DHEA metabolism in the catatonic state, such as the conversion rate between DHEAS and DHEA, alter the secretion of progesterone. ...
Catatonia is an abnormal psychological and behavioral state related to stress. The treatment strategy suggests the involvement of neuroactive steroids in its pathophysiology. We report a hospitalized patient with schizophrenia in whom a catatonic state occurred 7 times in 5.5 years. Blood levels of steroid hormones and adrenocorticotropic hormone (ACTH) were measured during the catatonic state and in the intervals between catatonic states (non-catatonic states). Cortisol and dehydroepiandrosterone sulfate (DHEAS) were significantly higher during catatonia than in the non-catatonic state. Cortisol significantly correlated with the ACTH level, whereas blood DHEAS and progesterone correlated only during the non-catatonic state. In addition, the cortisol to DHEAS ratios did not differ between catatonic and non-catatonic states. Although the correlating elevations of ACTH and cortisol implied activation of the hypothalamic-pituitary-adrenal axis (HPA-axis) in the catatonic state, DHEAS levels did not seem to increase in a manner dependent on the HPA-axis or the production of progesterone. The results suggest that the catatonic state was a neuroendocrinological state of HPA-axis activation with comparable increases in DHEAS levels.
... • Decrease of cortisol levels during DHEA treatment [180] and antiglucocorticoid properties of DHEA [184,185] • Direct modulation of GABA A , NMDA and s-1 receptors by DHEA [181,182] • Metabolization of DHEA to other neuroactive steroids with GABAergic effects [186,187] • Increased testosterone and androgen levels during DHEA treatment, particularly in women with improvement of libido and mood [188] • Neurotrophic effects of DHEA with enhancement of synaptic plasticity [189,166,190] ...
According to the corticoid receptor hypothesis of depression, hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the major pathophysiological factors for the development of depression and opens a broad range of new antidepressant treatment options that are related to direct interventions in HPA system regulation in depressed patients. These new therapy strategies include inhibition of hypothalamic corticotropin-releasing hormone (CRH) release, antagonism at CRH1 receptors, antagonism at vasopressin V1b receptors, inhibition of cortisol synthesis, antiglucocorticoid treatment with dehydroepiandrosterone and treatment with glucocorticoid receptor antagonists. Although preclinical data support the view that CRH1 receptor antagonists are useful in the treatment of depression, currently no controlled studies are available that demonstrate clinical efficacy in depressed patients. The use of the antiglucocorticoid neuroactive steroid dehydroepiandrosterone, the cortisol synthesis inhibitor metyrapone and the glucocorticoid receptor antagonist mifepristone in depression has been demonstrated in some small, double-blind, placebo-controlled studies. However, three recently completed Phase III trials failed to significantly separate mifepristone from placebo in depression. Thus, it is unclear at present to what extent new, clinically effective antidepressant therapies can be developed based on the corticoid receptor hypothesis of depression.
... However, direct modulation of GABA A , NMDA and sigma 1 receptors as well as a metabolism to other steroids (Bloch et al. 1999;Nadjafi-Triebsch et al. 2003;Schmidt et al. 2005) may also account for the antidepressive potential of this neuroactive steroid. Furthermore, even DHEAinduced increases in 3α, 5α-THP levels may contribute to its beneficial effects in the treatment of depressive symptoms. ...
Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABAA) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety- and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of 3alpha-reduced neuroactive steroids have been observed during major depression. This disequilibrium can be corrected by successful treatment with antidepressant drugs. However, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition independently from the clinical response. Further research is needed to clarify whether enhancement of neuroactive steroid levels might represent a new therapeutical approach in the treatment of affective disorders. Nevertheless, the first studies investigating the therapeutical effects of exogenously administered dehydroepiandosterone revealed promising results in the treatment of major depression. In addition, in various anxiety disorders alterations of neuroactive steroid levels have been observed. In panic disorder, in the absence of panic attacks, neuroactive steroid composition is opposite to that seen in depression, which may represent counter-regulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimentally induced panic attacks, there was a pronounced decline in GABAergic neuroactive steroids, which might contribute to the pathophysiology of panic attacks. In conclusion, neuroactive steroids contribute to the pathophysiology of affective disorders and the mechanisms of action of antidepressants. They are important endogenous modulators of depression and anxiety and may provide a basis for the development of novel therapeutic agents in the treatment of affective disorders.
... However, the observation of decreased cortisol plasma levels after DHEA administration (Wolkowitz et al., 1999b) and its potential antiglucocorticoid effects in vivo (Browne et al., 1993;Araneo and Daynes, 1995) might play a role for the beneficial effects especially in hypercortisolemic depressed patients. However, also direct modulation of GABA A , NMDA and sigma 1 receptors as well as a metabolism to other steroids (Bloch et al., 1999;Nadjafi-Triebsch et al., 2003;Schmidt et al., 2005) have been suggested to play a role for the antidepressive potential of this neuroactive steroid. ...
Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of such neuroactive steroids have been observed during major depression and in several anxiety disorders, suggesting a pathophysiological role in such psychiatric conditions. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Furthermore, alterations of 3alpha-reduced pregnane steroids during major depression were corrected by successful treatment with antidepressant drugs. However in contrast, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. In addition, changes in neuroactive steroid concentrations after mirtazapine therapy occurred independently from the clinical response, thereby suggesting that changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of antidepressants rather than clinical improvement in general. Nevertheless, the effects of antidepressant pharmacotherapy on the composition of neuroactive steroids may contribute to the alleviation of certain depressive symptoms, such as amelioration of anxiety, inner tension or sleep disturbances. Moreover, first studies investigating the therapeutical effects of dehydroepiandrosterone revealed promising results in the treatment of major depression. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.
... Administration of DHEA to depressed patients improves their symptoms (Wolkowitz et al, 1997(Wolkowitz et al, , 1999, with daily treatment improving the overall well-being of the patient by preventing depressive episodes, decreasing fatigue, and increasing libido (Nadjafi-Triebsch et al, 2003). Significant improvement also occurs in men and women with midlifeonset major or minor depression upon treatment with DHEA for 6 weeks, according to the Hamilton Depression Rating Scale and the Center for Epidemiologic Studies Depression Scale ratings (Schmidt et al, 2005). ...
Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate gamma-aminobutyric-acid-type-A (GABA(A)R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (sigma 1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitive-line (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the delta-subunit of GABA(A), but not of sigma 1R mRNA, in FSL rats compared to SD rats. The delta-subunit controls the sensitivity of the GABA(A)R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA(A) agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA(A)), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA(A)Rs in the NAc and VTA.
... The EC 50 for progesterone activation of mPRα, mPRβ and mPRγ in yeast is between 1–3 nM, values that are consistent with the K d 's for progesterone binding to mPRs (~ 5 nM) determined by Thomas et al.[56] These EC 50 values are also close to the physiological concentration of progesterone in human serum, which has been estimated to be between 1–10 nM in men and non-pregnant women in the follicular phase of the menstrual cycle.[57,58] Thus, our data suggests that human mPRα, mPRβ and mPRγ are most responsive to progesterone at physiologically relevant hormone concentrations and would likely function as legitimate progesterone receptors. ...
The nuclear progesterone receptor (nPR) mediates many of the physiological effects of progesterone by regulating the expression of genes, however, progesterone also exerts non-transcriptional (non-genomic) effects that have been proposed to rely on a receptor that is distinct from nPR. Several members of the progestin and AdipoQ-Receptor (PAQR) family were recently identified as potential mediators of these non-genomic effects. Membranes from cells expressing these proteins, called mPRalpha, mPRbeta and mPRgamma, were shown to specifically bind progesterone and have G-protein coupled receptor (GPCR) characteristics, although other studies dispute these findings. To clarify the role of these mPRs in non-genomic progesterone signaling, we established an assay for PAQR functional evaluation using heterologous expression in Saccharomyces cerevisiae. Using this assay, we demonstrate unequivocally that mPRalpha, mPRbeta and mPRgamma can sense and respond to progesterone with EC(50) values that are physiologically relevant. Agonist profiles also show that mPRalpha, mPRbeta and mPRgamma are activated by ligands, such as 17alpha-hydroxyprogesterone, that are known to activate non-genomic pathways but not nPR. These results strongly suggest that these receptors may indeed function as the long-sought-after membrane progesterone receptors. Additionally, we show that two uncharacterized PAQRs, PAQR6 and PAQR9, are also capable of responding to progesterone. These mPR-like PAQRs have been renamed as mPRdelta (PAQR6) and mPRvarepsilon (PAQR9). Additional characterization of mPRgamma and mPRalpha indicates that their progesterone-dependent signaling in yeast does not require heterotrimeric G-proteins, thus calling into question the characterization of the mPRs as a novel class of G-protein coupled receptor.
A whole “orchestra” of hormones and enzymes are required in order to achieve an optimal hormonal supply for bodily functions. Progesterone appears to be the key-factor for health not only in women, but also in men and children, in patients with depression, sleep disorders, multiple sclerosis, spinal cord-neurodegeneration, brain trauma, CVA, epileptic seizures, prostate hyperplasia, erectile dysfunction and more. Progesterone has anti-inflammatory and anti-oxidative effects, is a mild diuretic, a natural anti-convulsive, supports thyroid function, helps to normalize the blood-sugar level, normalizes zinc–and copper-levels.
The translocator protein (TSPO) is a five transmembrane domain protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans. The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders.
Alterations in neurosteroid secretion have been implicated in the efficacy of antidepressants. In a previous study, the adrenal androgen DHEA, a precursor of the neurosteroid androsterone, produced antidepressant and libido-enhancing effects in patients with midlife depression. To investigate the mechanisms underlying DHEA's behavioral effects in this same patient group, we examined plasma levels of four additional neurosteroids implicated in the regulation of affective behavior.
Blood samples were assayed for neurosteroids in men (n = 13) and women (n = 10) with midlife depression who previously participated in a crossover study in which DHEA and placebo were administered for 6 weeks each. Depression severity was measured by the Center for Epidemiologic Studies Depression Scale (CES-D). Plasma levels of androsterone (ADT), allopregnanolone, pregnanolone, and pregnenolone were measured by GC-MS at baseline and week 6 of each treatment phase. Data were analyzed with repeated measures analysis of variance (ANOVA-R) and Bonferroni t tests.
ADT levels (but not allopregnanolone, pregnanolone, and pregnenolone) increased after DHEA but not after placebo (F 2,42 = 3.3, p < 0.05). Post-DHEA ADT levels were higher in women than men [t 63 = 2.9, p < 0.05]. However, in both men and women who met criteria for clinical response on the CES-D, baseline ADT levels significantly increased post-DHEA, and the magnitude of the ADT increase post-DHEA treatment was similar in men and women. Consequently, it was the non-responders who accounted for the sex difference in post-DHEA plasma ADT levels, a difference that was driven by values in two women (the only female non-responders).
The small sample size notwithstanding, these data emphasize the potential behavioral relevance of ADT in humans, which may include contribution to the antidepressant effects of DHEA.
The translocator protein (TSPO) is a five transmembrane domain protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans.
The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders.
'Classical' genomic progesterone receptors appear relatively late in phylogenesis, i.e. it is only in birds and mammals that they are detectable. In the different species, they mediate manifold effects regarding the differentiation of target organ functions, mainly in the reproductive system. Surprisingly, we know little about the physiology, endocrinology, and pharmacology of progesterone and progestins in male gender or men respectively, despite the fact that, as to progesterone secretion and serum progesterone levels, there are no great quantitative differences between men and women (at least outside the luteal phase). In a prospective cohort study of 1026 men with and without cardiovascular disease, we were not able to demonstrate any age-dependent change in serum progesterone concentrations. Progesterone influences spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the Leydig cells. Other progesterone effects in men include those on the central nervous system (CNS) (mainly mediated by 5alpha-reduced progesterone metabolites as so-called neurosteroids), including blocking of gonadotropin secretion, sleep improvement, and effects on tumors in the CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system, kidney function, adipose tissue, behavior, and respiratory system. A progestin may stimulate weight gain and appetite in men as well as in women. The detection of progesterone receptor isoforms would have a highly diagnostic value in prostate pathology (benign prostatic hypertrophy and prostate cancer). The modulation of progesterone effects on typical male targets is connected with a great pharmacodynamic variability. The reason for this is that, in men, some important effects of progesterone are mediated non-genomically through different molecular biological modes of action. Therefore, the precise therapeutic manipulation of progesterone actions in the male requires completely new endocrine-pharmacological approaches.
The term "neurosteroid" (NS) was introduced by Baulieu in 1981 to name a steroid hormone, dehydroepiandrosterone sulfate (DHEAS), that was found at high levels in the brain long after gonadectomy and adrenalectomy, and shown later to be synthetized by the brain. Later, androstenedione, pregnenolone and their sulfates and lipid derivatives as well as tetrahydrometabolites of progesterone (P) and deoxycorticosterone (DOC) were identified as neurosteroids. The term "neuroactive steroid" (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. NASs bind and modulate different types of membrane receptors. The GABA and sigma receptor complexes have been the most extensively studied, while glycine-activated chloride channels, nicotinic acetylcholine receptors, voltage-activated calcium channels, although less explored, are also modulated by NASs. Within the glutamate receptor family, N-methyl-d-aspartate (NMDA) receptors, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors have also been demonstrated to be a target for steroid modulation. Besides their membrane effects, once inside the neuron oxidation of Ring A reduced pregnanes, THP and THDOC, bind to the progesterone intracellular receptor and regulate gene expression through this path. The involvement of NASs on depression syndromes, anxiety disorders, stress responses to different stress stimuli, memory processes and related phenomena such as long-term potentiation are reviewed and critically evaluated. The importance of context for the interpretation of behavioral effects of hormones as well as for hormonal levels in body fluids is emphasized. Some suggestions for further research are given.
1. Neuroactive steroids are steroid hormones that exert rapid, nongenomic effects at ligand-gated ion channels. There is increasing awareness of the possible role of these steroids in the pathology and manifestation of symptoms of psychiatric disorders. The aim of this paper is to review the current knowledge of neuroactive steroid functioning in the central nervous system, and to assess the role of neuroactive steroids in the pathophysiology and treatment of symptoms of schizophrenia, depression, and anxiety disorders. Particular emphasis will be placed on GABAA receptor modulation, given the extensive knowledge of the interactions between this receptor complex, neuroactive steroids, and psychiatric illness.
2. A brief description of neuroactive steroid metabolism is followed by a discussion of the interactions of neuroactive steroids with acute and chronic stress and the HPA axis. Preclinical and clinical studies related to psychiatric disorders that have been conducted on neuroactive steroids are also described.
3. Plasma concentrations of some neuroactive steroids are altered in individuals suffering from schizophrenia, depression, or anxiety disorders compared to values in healthy controls. Some drugs used to treat these disorders have been reported to alter plasma and brain concentrations in clinical and preclinical studies, respectively.
4. Further research is warranted into the role of neuroactive steroids in the pathophysiology of psychiatric illnesses and the possible role of these steroids in the successful treatment of these disorders.
Aging in humans is accompanied by a progressive decline in the secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate (DS), paralleling that of the GH-insulin-like growth factor-I (GH-IGF-I) axis. Although the functional relationship of the decline of the GH-IGF-I system and catabolism is recognized, the biological role of DHEA in human aging remains undefined. To test the hypothesis that the decline in DHEA may contribute to the shift from anabolism to catabolism associated with aging, we studied the effect of a replacement dose of DHEA in 13 men and 17 women, 40-70 yr of age. A randomized placebo-controlled cross-over trial of nightly oral DHEA administration (50 mg) of 6-month duration was conducted. During each treatment period, concentrations of androgens, lipids, apolipoproteins, IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, insulin sensitivity, percent body fat, libido, and sense of well-being were measured. A subgroup of men (n = 8) and women (n = 5) underwent 24-h sampling at 20-min intervals for GH determinations. DHEA and DS serum levels were restored to those found in young adults within 2 weeks of DHEA replacement and were sustained throughout the 3 months of the study. A 2-fold increase in serum levels of androgens (androstenedione, testosterone, and dihydrotestosterone) was observed in women, with only a small rise in androstenedione in men. There was no change in circulating levels of sex hormone-binding globulin, estrone, or estradiol in either gender. High density lipoprotein levels declined slightly in women, with no other lipid changes noted for either gender. Insulin sensitivity and percent body fat were unaltered. Although mean 24-h GH and IGFBP-3 levels were unchanged, serum IGF-I levels increased significantly, and IGFBP-1 decreased significantly for both genders, suggesting an increased bioavailability of IGF-I to target tissues. This was associated with a remarkable increase in perceived physical and psychological well-being for both men (67%) and women (84%) and no change in libido. In conclusion, restoring DHEA and DS to young adult levels in men and women of advancing age induced an increase in the bioavailability of IGF-I, as reflected by an increase in IGF-I and a decrease in IGFBP-1 levels. These observations together with improvement of physical and psychological well-being in both genders and the absence of side-effects constitute the first demonstration of novel effects of DHEA replacement in age-advanced men and women.
This study was designed to assess possible antidepressant effects of dehydroepiandrosterone (DHEA), an abundant adrenocortical hormone in humans.
Twenty-two patients with major depression, either medication-free or on stabilized antidepressant regimens, received either DHEA (maximum dose = 90 mg/day) or placebo for 6 weeks in a double-blind manner and were rated at baseline and at the end of the 6 weeks with the Hamilton Depression Rating Scale. Patients previously stabilized with antidepressants had the study medication added to that regimen; others received DHEA or placebo alone.
DHEA was associated with a significantly greater decrease in Hamilton depression scale ratings than was placebo. Five of the 11 patients treated with DHEA, compared with none of the 11 given placebo, showed a 50% decrease or greater in depressive symptoms.
These results suggest that DHEA treatment may have significant antidepressant effects in some patients with major depression. Further, larger-scale trials are warranted.
To evaluate basal allopregnanolone and progesterone in both phases of the menstrual cycle in women suffering from premenstrual syndrome (PMS) and their response to a GnRH test.
We selected 56 women (28 patients with PMS and 28 controls) aged between 18 and 32 years. Blood samples were drawn in both follicular and phases. Twenty-eight women (14 patients with PMS and 14 controls) underwent a GnRH test in the luteal phase.
We evaluated allopregnanolone by RIA, using a specific antibody. Serum progesterone and oestradiol were determined using a commercially available RIA kit.
Luteal phase allopregnanolone concentrations were significantly lower in patients with PMS than in controls. Progesterone concentrations were significantly lower in patients with PMS in both the follicular and the luteal phase. Serum oestradiol concentrations were in the normal range in both groups of women, although slightly greater in those with PMS. Allopregnanolone and progesterone responses to a GnRH test were significantly blunted in women with PMS.
Diminished concentrations of allopregnanolone and progesterone, its precursor, and a blunted response to the GnRH test lead us to hypothesise that patients with PMS may suffer from an inadequate production of ovarian neuroactive steroids, especially in the luteal phase. This would lead to an impaired anxiolytic GABA(A)-mediated response in stressful physiological and psychological conditions, and may in part explain various psychoneuroendocrine symptoms that arise during PMS.
The secretion and the blood levels of the adrenal steroid dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) decrease
profoundly with age, and the question is posed whether administration of the steroid to compensate for the decline counteracts
defects associated with aging. The commercial availability of DHEA outside the regular pharmaceutical–medical network in the
United States creates a real public health problem that may be resolved only by appropriate long-term clinical trials in elderly
men and women. Two hundred and eighty healthy individuals (women and men 60–79 years old) were given DHEA, 50 mg, or placebo,
orally, daily for a year in a double-blind, placebo-controlled study. No potentially harmful accumulation of DHEAS and active
steroids was recorded. Besides the reestablishment of a “young” concentration of DHEAS, a small increase of testosterone and
estradiol was noted, particularly in women, and may be involved in the significantly demonstrated physiological–clinical manifestations
here reported. Bone turnover improved selectively in women >70 years old, as assessed by the dual-energy x-ray absorptiometry
(DEXA) technique and the decrease of osteoclastic activity. A significant increase in most libido parameters was also found
in these older women. Improvement of the skin status was observed, particularly in women, in terms of hydration, epidermal
thickness, sebum production, and pigmentation. A number of biological indices confirmed the lack of harmful consequences of
this 50 mg/day DHEA administration over one year, also indicating that this kind of replacement therapy normalized some effects
of aging, but does not create “supermen/women” (doping).
Previous studies from this laboratory have shown that progesterone (PROG) treatment in ovariectomized rats produces an anti-anxiety response similar to that observed after the administration of prototypical anxiolytic benzodiazepine (BDZ) compounds. The PROG-induced anxiolytic response was highly correlated with an increased level of 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in the blood and brain, and was also associated with a facilitation of GABA-stimulated chloride ion (Cl-) influx in cortical synaptoneurosomes. This correlative evidence suggested that the anxiolytic effect of PROG was a result of its in vivo reduction to the neuroactive steroid, allopregnanolone. In this report, a series of studies was conducted to determine the mechanism(s) by which PROG alters behavior in animal models of anxiety. In the first experiment, ovariectomized rats were injected with PROG (1 mg/0.2 ml, SC) 4 h prior to a test in the elevated plus-maze. Some animals also received an injection of picrotoxin (0.75 mg/kg, IP), a GABAA receptor-gated Cl- channel antagonist, whereas other animals were pretreated with RU 38486 (5 mg/0.2 ml, SC), a progestin receptor antagonist. PROG elicited anxiolytic behavior in the plus-maze, an effect that was blocked by picrotoxin administration. Pretreatment with RU 38486 was not effective in altering PROG-induced anxiolytic behavior in the plus-maze. In a second experiment, the effect of PROG on behavior in the plus-maze was determined in the presence of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide (4-MA; 10 mg/0.2 ml, SC), a 5 alpha-reductase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
The discovery that the endogenous steroid derivatives 3α-hydroxy-5α-pregnan-20-one (allopregnanolone, or 3α,5α-TH PROG) and 3α,21-dihydroxy-5α-pregnan-20-one (allotetrahydrodeoxycorticosterone, or 3α, 5α-TH DOC) elicit marked anxiolytic and anti-stress effects and selectively facilitate γ-aminobutyric acid (GABA)-mediated neurotransmission in the central nervous system (see Chapter 3) has provided new perspectives for our understanding of the physiology and neurobiology of stress and anxiety. Evidence indicating that various stressful conditions that downregulate GABAergic transmission and induce anxiety-like states (Biggio et al., 1990) also induce marked increases in the plasma and brain concentrations of these neuroactive steroids (Biggio et al., 1996, Biggio et al., 2000) has led to the view that stress, neurosteroids, and the function of GABAA receptors are intimately related. Changes in the brain concentrations of neurosteroids may play an important role in the modulation of emotional state as well as in the homeostatic mechanisms that counteract the neuronal overexcitation elicited by acute stress. Indeed, neurosteroids not only interact directly with GABAA receptors but also regulate the expression of genes that encode sub-units of this receptor complex. This chapter summarizes observations from our laboratories and others, suggesting that neurosteroids and GABAergic transmission are important contributions to the changes in motional state induced bu environmental stress.
In a cross-sectional study, serum dehydroepiandrosterone sulfate (DS) concentrations were measured in 981 men and 481 women, aged 11-89, yr. The resulting data were asymetrically distributed and were normalized by logarithmic transformation and analyzed by 5-yr age grouping (e.g. 15-19 yr, 20-24 yr, etc.). The DS concentration peaked at age 20-24 yr in men (logarithmic mean, 3470 ng/ml) and at age 15-19 yr in women (log mean, 2470 ng/ml). Mean values then declined steadily in both sexes (log mean at greater than 70 yr of age, 670 ng/ml in men and 450 ng/ml in women) and were significantly higher in men than women at ages from 20-69 yr. Analysis of 517 randomly selected sera (from women) which had been stored frozen for 10-15 yr gave results indistinguishable from values obtained from fresh specimens. In a supplementary study, a longitudinal analysis of weekly specimens from 4 normal men, aged 36-59 yr, revealed individual variability (mean coefficient of variation, 19%) and failed to demonstrate any monthly, seasonal, or annual rhythmicity. Based on the above analyses, a table of normal serum DS ranges for adult men and women is presented for use as a clinical reference.
Dehydroepi-androsterone (DHEA) exhibits various behavioral effects in mammals, at least one of which is enhancement of memory that appears to be mediated by an interaction with the gamma-aminobutyric acidA (GABAA) receptor complex. We investigated the effects of a single oral dose of DHEA (500 mg) on sleep stages, sleep stage-specific electroencephalogram (EEG) power spectra, and concurrent hormone secretion in 10 healthy young men. DHEA administration induced a significant (P < 0.05) increase in rapid eye movement (REM) sleep, whereas all other sleep variables remained unchanged compared with the placebo condition. Spectral analysis of five selected EEG bands revealed significantly (P < 0.05) enhanced EEG activity in the sigma frequency range during REM sleep in the first 2-h sleep period after DHEA administration. In contrast, the EEG power spectra of non-REM sleep were not affected, nor were the nocturnal time course curves of plasma cortisol, growth hormone, or testosterone concentration. The results suggest that DHEA administration has a mixed GABAA-agonistic/antagonistic effect, exerted either directly or through DHEA-induced changes in steroid metabolism. Because REM sleep has been implicated in memory storage, its augmentation in the present study suggests the potential clinical usefulness of DHEA in age-related dementia.
The secretion of both growth hormone (GH) and androgens declines with age which may play a role in the senescent changes in body composition and organ function. Among healthy adults abdominal adiposity is an important negative determinant of GH secretion. Surprisingly, abdominal or android obesity seems inversely correlated with testosterone levels in males but not in females. The ability of GH to promote lipolysis and preserve or increase lean body mass has been reappraised in substitution studies in GH-deficient adults. By comparison, adequately controlled studies of androgen replacement in hypogonadal and/or elderly males are few. In view of the physiological and clinical relevance of obtaining information about the aging process, there is a need for controlled experiments addressing similarities and differences between the action of GH and sex steroids in adults.
Progesterone administration induces a reduction of the vigilance state in humans during wakefulness. It has been been suggested that this effect is mediated via neuroactive metabolites that interact with the gamma-aminobutyric, acidA (GABAA) receptor complex. To investigate the effects of progesterone administration on the sleep electroencephalogram (EEG) in humans we made polysomnographic recordings, including sleep stage-specific spectral analysis, and concomitantly measured plasma concentrations of progesterone and its GABA-active metabolites 3 alpha-hydroxy-5 alpha-dihydroprogesterone (allopregnanolone) and 3 alpha-hydroxy-5 beta-dihydroprogesterone (pregnanolone) in nine healthy male subjects in a double-blind placebo-controlled crossover study. Progesterone administration at 9:30 PM induced a significant increase in the amount of non-rapid eye movement (REM) sleep. The EEG spectral power during non-REM sleep showed a significant decrease in the slow wave frequency range (0.4-4.3 Hz), whereas the spectral power in the higher frequency range (> 15 Hz) tended to be elevated. Some of the observed changes in sleep architecture and sleep-EEG power spectra are similar to those induced by agonistic modulators of the GABAA receptor complex and appear to be mediated in part via the conversion of progesterone into its GABA-active metabolites.
To evaluate the anxiolytic 3alpha-5alpha-reduced progesterone metabolite allopregnanolone in the luteal phase of the menstrual cycle in women with premenstrual syndrome (PMS) and controls.
Thirty-five women with prospectively documented PMS and 36 controls were evaluated. Serum progesterone and allopregnanolone levels were measured on days 19 and 26 of the cycle as determined by urinary LH detection kits. Analysis of variance and Student t tests were used to analyze the data.
Allopregnanolone levels were significantly lower on day 26 in the PMS group than in controls (3.6 +/- 0.8 versus 7.5 +/- 1.3 ng/mL; P < .04). Significant differences in the ratio of the metabolite to progesterone also were noted, with a smaller ratio in the PMS subjects (0.9 +/- 0.3 versus 3.2 +/- 1.3 ng/mL; P < .05). There were no significant differences between the PMS and control groups with respect to serum progesterone levels.
Subjects with PMS manifested lower levels of the anxiolytic metabolite allopregnanolone in the luteal phase when compared with controls. Diminished concentrations of allopregnanolone in women with PMS may lead to an inability to enhance gamma aminobutyric acid-mediated inhibition during states of altered central nervous system excitability, such as ovulation or physiologic or psychological stress. The lowered metabolite levels could contribute to the genesis of various mood symptoms of the disorder, such as anxiety, tension, and depression.
Prior to three months of age there is little melatonin (MLT) secretion in humans. MLT production then commences, becomes circadian, and reaches its highest nocturnal blood levels between the ages of one to three years. During the remainder of childhood, nocturnal peak levels drop progressively by 80%. In adults, these levels show an additional drop of some 10%, mainly during senescence. The large drop in serum MLT during childhood is probably the result of the increase in size of the human body, despite a constant MLT production after infancy. The additional decline of MLT with higher age may be due to a yet unidentified physiological mechanism accompanying senescence. The biological significance of these MLT alterations remains unknown. Since the discovery of MLT, an immediate sedative action of this hormone has been known. A number of recent studies have demonstrated that MLT indeed exerts a sleep-promoting action by accelerating sleep initiation, improving sleep maintenance, and marginally altering sleep architecture. The potential of MLT in the treatment of insomnia is being explored, and the results are promising. Although in most of these studies pharmacological dosages of MLT have been used, preliminary data suggest that similar effects can also be achieved by physiological hormone concentrations. The latter observation raises the question of whether MLT might be involved in the physiological control of sleep.
Oral dehydroepiandrosterone (DHEA) replacement therapy may have a multitude of potential beneficial effects and exerts its action mainly via peripheral bioconversion to androgens (and estrogens). A daily dose of 50-mg DHEA has been shown by us and others to restore low endogenous serum DHEA concentrations to normal youthful levels followed by an increase in circulating androgens and estrogens. As the hepatic first-pass effect may lead to a non physiological metabolism of DHEA after oral ingestion we studied the influence of two single DHEA doses (50 and 100 mg) on the excretion of steroid metabolites in 14 elderly males [age 58.8+/-5.1 years (mean +/- SEM)] with endogenous DHEAS levels <1500 ng/ml and in 9 healthy females (age 23.3+/-4.1 years) with transient suppression of endogenous DHEA secretion induced by dexamethasone (dex) pretreatment (4x0.5 mg/day/4 days). Urinary steroid profiles in the elderly males were compared to the steroid patterns found in 15 healthy young men (age 28.9+/-5.1 years). In the females the results were compared to their individual baseline excretion without dex pretreatment. Urinary steroid determinations were carried out by semiautomatic capillary gas-liquid chromatography. In both genders DHEA administration induced significant increases in urinary DHEA (females: baseline vs. 50 mg vs. 100 mg: 361+/-131 vs. 510+/-264 vs. 1541+/-587 microg/day; males: placebo vs. 50 mg vs. 100 mg: 434+/-154 vs. 1174+/-309 vs. 4751+/-1059 microg/day) as well as in the major DHEA metabolites androsterone (A) and etiocholanolone (Et). Fifty mg DHEA led to an excretion of DHEA and its metabolites only slightly above baseline levels found in young females and in young men, respectively, whereas 100 mg induced clearly supraphysiological values. After 50 mg DHEA the ratios of urinary DHEA metabolites (A/DHEA, Et/DHEA) were not significantly different between elderly males vs. young male volunteers and young healthy females versus their individual baseline levels. In conclusion, an oral dose of 30 to 50 mg DHEA restores a physiological urinary steroid profile in subjects with DHEA deficiency without evidence for a relevant hepatic first-pass effect on urinary metabolites.
Oestrogens and androgens stimulate collagen matrix synthesis, while progesterone is a competitive inhibitor for the 5 alpha-reduction of testosterone to 5 alpha-dihydrotestosterone (DHT). The anti-androgen finasteride is a specific inhibitor of the 5 alpha-reductase type 2 isoenzyme, associated with anabolic functions. The aim of this investigation is to study the effects of progesterone and finasteride on 5 alpha-reduction of androgen substrates by human gingival fibroblasts. Monolayer cultures of human gingival fibroblasts (HGF) of the 4th 9th passage were established in Eagle's minimum essential medium (MEM). Duplicate incubations were performed with 14C-testosterone/14C-4-androstenedione as substrates and progesterone (P) or finasteride (F), at concentrations of 0.5, 1, 3 and 5 microg/ml, alone and in combination, for 24 h. Similarly, the effects of the alkaline phosphatase inhibitor levamisole (L, 30 microg/ml) and P were studied. Steroid metabolites were analysed and quantified, using a radioisotope scanner. Progesterone inhibited DHT synthesis in HGF from 14C-testosterone by 24-62% (n = 8; p < 0.01). Finasteride caused 59 82% inhibition (n=8;p<0.01). The combination of P+F showed a similar degree of inhibition (68-78%) of DHT synthesis to that of F alone (n = 8; p<0.01). There was 35-56% stimulation of 17beta-HSD (hydroxysteroid dehydrogenase) activity by P, F and P + F (n = 8; p < 0.01). When 14C-4-androstenedione was used as substrate there was 47% inhibition of 5 alpha-reductase activity at higher concentrations of P and 63 and 44% stimulation at 0.5 and 1 microg/ml (n = 8;p < 0.01). F and P + F caused 40-67% inhibition of this activity. P, F and P + F caused 2-2.7-fold stimulation of 17beta-HSD activity in response to all concentrations studied. L inhibited DHT synthesis from both substrates by 36-38%, with further inhibition of 55-70% (n = 4; p < 0.01), with P; this is suggestive of ligand-independent alkaline phosphatase activity mediated by 5 alpha-reductase. Inhibition of 5 alpha-reductase activity by finasteride in gingival fibroblasts is suggestive of target tissue anabolic functions in gingivae and competitive inhibition by progesterone, is suggestive of regulation of hormone mediated tissue responses during repair.
The adrenal production of the delta 5-androgens, dehydroepiandrosterone (DHEA) and its sulfate ester dehydroepiandrosterone sulfate (DHEAS), declines linearly with aging. The evidence that DHEA or DHEAS administration may alleviate some of the problems related to aging has opened new perspectives for clinical research. The present study aims to investigate the effects of a 6-month DHEA supplementation in early and late postmenopausal women, with normal or overweight body mass index (BMI), on the level of circulating steroids, sex hormone binding globulin (SHBG), beta-endorphin and gonadotropins, and on the adrenal gland response to dexamethasone suppression and adrenocorticotropic hormone (ACTH) stimulation. Early postmenopausal women (50-55 years) both normal weight (BMI 20-24, n = 9) and overweight (BMI 26-30, n = 9) and late postmenopausal women (60-65 years) both of normal weight and overweight, were treated with oral DHEA (50 mg/day). Circulating DHEA, DHEAS, 17-OH pregnenolone, progesterone, 17-OH progesterone, allopregnenolone, androstenedione, testosterone, dihydrotestosterone, estrone, estradiol, SHBG, cortisol, luteinizing hormone, follicle stimulating hormone and beta-endorphin levels were evaluated monthly and a Kupperman score was performed. The product/precursor ratios of adrenal steroid levels were used to assess the relative activities of the adrenal cortex enzymes. Before and after 3 and 6 months of therapy, each women underwent an ACTH stimulating test (10 micrograms i.v. in bolus) after dexamethasone administration (0.5 mg p.o.) to evaluate the response of cortisol, DHEA, DHEAS, androstenedione, 17-OH pregnenolone, allopregnanolone, progesterone and 17-OH progesterone. The between-group differences observed before treatment disappeared during DHEA administration. Levels of 17-OH pregnenolone remained constant during the 6 months. Levels of DHEA, DHEAS, androstenedione, testosterone and dihydrotestosterone increased progressively from the first month of treatment. Levels of estradiol and estrone significantly increased after the first/second month of treatment. Levels of SHBG significantly decreased from the second month of treatment only in overweight late postmenopausal women, while the other groups showed constant levels. Progesterone levels remained constant in all groups, while 17-OH progesterone levels showed a slight but significant increase in all groups. Allopregnanolone and plasma beta-endorphin levels increased progressively and significantly in the four groups, reaching values three times higher than baseline. Levels of cortisol and gonadotropins progressively decreased in all groups. The product/precursor ratios of adrenal steroid levels at the sixth month were used to assess the relative activities of the adrenal cortex enzymes and were compared to those found before therapy. The 17,20-desmolase, sulfatase and/or sulfotransferase, 17,20-lyase and 5 alpha-reductase activities significantly increased, while the 3 beta-hydroxysteroid-oxidoreductase activity did not vary. On the contrary, the 11-hydroxylase and/or 21-hydroxylase activities showed a significant decrease after 6 months of treatment. In basal conditions, dexamethasone significantly suppressed all the adrenal steroids and this suppression was greater after 3 and 6 months of treatment for DHEA, DHEAS and allopregnanolone, while it remained unchanged for other steroids. Before treatment, ACTH stimulus induced a significant response in all parameters; after the treatment, it prompted a greater response in delta 5- and delta 4-androgens, progesterone and 17-OH progesterone, while cortisol responded less in both younger and older normal-weight women. The endometrial thickness did not show significant modifications in any of the groups of postmenopausal women during the 6 months of treatment. Treatment with DHEA was associated with a progressive improvement of the Kupperman score in all groups, with major effects on the vasomotor symptoms in
The term neurosteroids applies to those steroids that are both synthesized in the nervous system, either de novo from cholesterol or from steroid hormone precursors, and that accumulate in the nervous system to levels that are at least in part independent of steroidogenic gland secretion rates. Glial cells play a major role in neurosteroid formation and metabolism. Several neurosteroids are involved in either auto- or paracrine mechanisms involving both regulation of target gene expression and effects on membrane receptors (including those of neurotransmitters). The neuromodulatory role of neurosteroids in regulating the estrous cycle and pregnancy, stress, memory, and developmental as well as aging processes awaits further investigation.
A multidisciplinary approach for the evaluation and the treatment of androgen deficiency in aging men (ADAM), Organon symposium at the second world congress on the aging male
- J Maillhot
Maillhot J. A multidisciplinary approach for the evalua-tion and the treatment of androgen deficiency in aging men (ADAM), Organon symposium at the second world congress on the aging male, Geneva, Switzerland, 2000.
Acute anxiolytic effect of oral administration of progesterone in men: a double-blind crossover study. Presented at the second international symposium on premenstrual, postpartum and menopausal mood disorders
- B De Lignieres
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Anti Aging Sprechstunde Alexander Rö mmler
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- Progestagene
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DHEA: a comprehensive review In: Proceedings of a workshop by the international health foundation, The Netherlands
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Thijssen JHH, Nieuwenhuyse H. DHEA: a comprehensive review. In: Proceedings of a workshop by the international health foundation, The Netherlands. Parthenon Publishing Group, 1997:1999.
Das männliche Klimakterium oder die besten Jahre des Mannes. Über Wechselwirkungen von hormonellen Veränderungen und physischer Befindlichkeit
- Degenhardt
Degenhardt A, Thiele A. Das mä Klimakterium oder die besten Jahre des Mannes. U ¨ ber Wechselwirkun-gen von hormonellen Verä und physischer Befindlichkeit. Forschung Frankfurt 4 Sammelband Med-izin 1997;15:99 Á/109.
Presented at tenth world congress on the menopause
- A R Genazzani
- Neurosteroids
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Hormonprofilveränderungen unter DHEA-substitution bei Patienten mit erektiler Dysfunktion.
- Reiter W.J.
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- Pycha A.
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Chronic administration of dehydroepiandrosterone (DHEA) does not increase serum testosterone or prostatic specific antigen (PSA) in normal men
- Vaughn
Neurosteroids:biosynthesis and function
- Robel
Hormonprofilveränderungen unter DHEA-substitution bei Patienten mit erektiler Dysfunktion
- Reiter
Progestagene sind nicht Progesteron, In: Anti Aging Sprechstunde Alexander Römmler; Alfred S Wolf (Hrsg.) Teil 1.Leitfaden für Einsteiger
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