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LITHUANIAN UNIVERISTY OF HEALTH SCIENCES
FACULTY OF MEDICINE
Divin Varughese Mathai
LITERATURE REVIEW: CLINICAL SIGNIFICANCE OF
DHEA/DHEA-S BASED OF CURRENT MEDICAL DATA
Department of Endocrinology
Submitted in partial fulfillment of the requirements
for the degree of
Master of Medicine
Supervisor:
Valentinas Matulevičius
MD. PhD. Habil Dr. Assoc. Prof.
June 2017
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Table of Contents
Page
1. Title page………. 1
2. Table of contents……….. 2
3. Summary ………. 3
4. Summary in Lithuanian……….... 4
5. Acknowledgements……….. 5
6. Conflicts of interest……….. 5
7. Abbreviations ……….. 6
8. Terms ……….. 7
9. Introduction………... 8
10. Aim and objectives………. 9
11. Literature review ……… 10
12. Methods……….. 21
13. Results and discussion………. 22
14. Conclusions……….. 34
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Summary
Authors Name: Divin Varughese Mathai
Title: Literature review- Clinical significance of DHEA/DHEA-S based on current medical data. Aim and objectives: The aim of this review is to clarify the clinical significance of DHEA/DHEAS based on current medical findings. The objectives raised are as follows. 1. To describe an overview of synthesis and metabolism of DHEA/ DHEA-S in humans. 2. To describe mechanism of action, 3. To describe clinical significance of DHEA/ DHEA-S in various organs and/ or pathologies. 4. To describe role of DHEA/S in treatment. 5. To make an inventory of relevant case reports involving DHEA/ DHEA-S from year 2000 onwards.
Methods: Search of PubMed using keywords such as “DHEA”, “DHEA-S”, “Dehydroepiandrosterone”and “Dehydroepiandrosterone- Sulfate” was conducted and 40 articles were selected based on their relevance to the topics. In addition to this 40 case reports that describe DHEA was identified and were tabulated. Results: Out of the 40 case reports, 7 described the use of DHEA/DHEAS as a treatment and 2 of these reports showed negative effects. 33 case reports described laboratory values of DHEA (some of them high and some of the undetectable or low). 12 instances of adrenal tumors were noticed.
Conclusions: Clinical significance is varied in that DHEA has stimulatory effects on bone mineral density, protective role in cardiovascular diseases [16]. Positively affects memory, mood, energy and indirect physical activity [8]. Raised levels of DHEAS are found in plasma of patients with adrenal tumors or with congenital adrenal hyperplasia (CAH). In adrenal insufficiency or panhypopituitarism DHEAS levels may usually be undetectable or low [5]. DHEA therapy is promising in patients with impaired well-being, mood or sexuality. In elderly population, DHEA use shows favorable outcomes in body composition, skin hydration increase bone mass density. DHEA use is advocated in replacement of pathophysiological defined DHEA deficiency, such as in adrenal insufficiency or glucocorticoid treated patients. Although every aspect of DHEA physiological role is yet to found, certain positive effects have been established and the impact it’s causing is promising.
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Santrauka
Literatūros apžvalga- DHEA/ DHEA-S klinikinė reikšmė, remiantis dabartinės medicinos duomenimis. Tikslas ir uždaviniai: išsiaiškinti DHEA / DHEAS klinikinę svarbą,
remiantis šiuolaikinės medicinos duomenimis.
Išvada: DHEA turi stimuliuojantį poveikį kaulų mineraliniam tankiui, apsaugo nuo širdies ir kraujagyslių ligų [16]. Teigiamai veikia atmintį, nuotaiką, energiją ir fizinį aktyvumą [8]. Padidėjęs DHEAS yra randama kraujo plazmoje pacientams, sergantiems antinksčių navikais. Esant įgimtai antinksčių hiperplazijai, antinksčių nepakankamumui arba panhipopituitarizmui,
DHEAS koncentracija paprastai gali būti neaptinkama arba žema [5].
DHEA terapija gali tikti pacientams su sutrikusia gyvenimo kokybe, esant nuotaikos ar seksualumo sutrikimams. Senyviems gyventojams DHEA naudojimas gerina kūno sudėtį, didina odos hidrataciją ir kaulų masę bei tankį.
DHEA naudotinas, esant patofiziologiškai spėjamam jo kiekio sumažėjimui, kaip antai antinksčių nepakankamumui arba gliukokortikoidus naudojantiems pacientams.
Kartais gaunami teigiami rezultatai ligoniams su autoimuninėmis ligomis, tokių kaip sisteminė raudonoji vilkligė [4].
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Acknowledgements
I would like to express my sincere gratitude to Dr. Valentinas Matulevičius, my supervisor who enabled me to complete this review.
Conflicts of Interest
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Abbreviations
DHEA: Dehydroepiandrosterone
DHEA-S: Dehydroepiandrosteone – sulfate RCT: Randomized Controlled Trial
GABA: Gamma-aminobutyric acid
StAR: Steroidogenic acute regulatory enzyme
DHEA-ST: Dehydroepiandrosterone sulfotransferase STS: Steroid sulfatase
CRH: Corticotropin releasing hormone AVP: Arginine vasopressin
ACTH: Adrenocorticotropic hormone DHT: Dehydrotestosterone
MCR: metabolic clearance rate BMD: Bone mass density CVD: Cardiovascular disease IGF: insulin like growth factor SLE: Systemic lupus erythematosus
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Terms
Chemoprotective: Protecting healthy tissue from toxic effects of anticancer drugs
Neurosteroids: endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors.
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Introduction
Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone sulfate (DHEA-S) are two of the most abundant precursor steroids in human circulation [1]. The concentration of DHEA-S is 100- to 500- fold greater than that of testosterone and 1000 to 10,000 times higher than estradiol. Despite being in such abundance in circulation both DHEA and DHEA-S does not possess any intrinsic estrogenic or androgenic activity, and are precursor steroids that are converted to androgens and/ estrogens in peripheral tissues [2]. The adrenal secretion of DHEA and DHEA-S increases in children at ages 6 to 8, reaching a maximum concentration during the second and third decades of life and the levels are markedly decreased henceforth. At around age 70, the serum levels of DHEA-S are at estimated 20 percent of their peak value and can further decrease by 95 percent by the age of 80 to 90 years [3]. This decrease of serum DHEA levels with age in healthy individuals has led to suggestions that DHEA might be useful in the anti-ageing process and it gained quite an interest in the 1990’s. Therefore, it has often been advertised as “fountain of youth” and is freely available as a food supplement, without a medical prescription. This has thus led to the widespread and uncontrolled use of DHEA in the USA among many other countries. [4][5]
The age related decline of serum DHEA &DHEA-S has been suggested to cause the development of diseases that are usually associated with the ageing process. Some recent studies have hypothesized the effect of low DHEA include insulin resistance, obesity, cardiovascular diseases, cancer, reduction of immune defenses and psychosocial problems such as depression and a general deterioration in sensation of wellbeing [2]. For instance, animal studies on rat models of type 2 diabetes have shown treatment with DHEA could result in insulin- induced glucose uptake and moderate the severity of diabetes. Few randomized controlled trials (RCT) have positively reported on the effects of DHEA supplementation on reducing body fat and improving glucose metabolism. However studies investigating association between DHEA and DHEAS and type 2 diabetes have been scarce [6].
Recently, there have been many studies done to understand DHEA as a neurosteroid and to determine the relationship between DHEA and cognitive function. DHEA has also been postulated to have opposite effects to glucocorticoids and also as a modulator of neurotransmission as it can affect serotonin, γ-amino butyric
acid (GABA), glutamate and dopamine levels. Research has concluded, DHEA might play a relevant role in the expressions of stress response, anxiety, cognitive deficits and physical health in schizophrenia [7]. Although the numerous aspects of DHEA have been extensively studied, there has not yet been any conclusive data regarding the use of DHEA as treatment or as a supplement in various diseases mentioned
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above. This review focusses on understanding the clinical significance of DHEA/ DHEA-S based on current medical findings, to also discuss the synthesis, mechanism of action, clinical significance and its role in treatment.
Aim and objectives
The aim of this review is to clarify the clinical significance of DHEA/ DHEA-S based on current medical findings. To achieve this the following objectives are raised:
1. To describe an overview of synthesis and metabolism of DHEA/DHEA-S in humans. 2. To describe mechanism of action
3. To describe the clinical significance of DHEA/ DHEA-S in various organs and/ or pathologies. 4. To describe role of DHEA/DHEA-S in treatment
5. To make an inventory of relevant case reports involving DHEA/ DHEAS from the year 2000 and onwards
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Literature Review
1. Overview of synthesis & metabolism
DHEA is primarily synthesized in the zona reticularis i.e. the inner zone of the adrenal cortex [8]. The first, rate-limiting and hormonally regulated step in the biosynthesis of all steroid hormones is the conversion of cholesterol to pregnenolone [9] (See fig. 1). Steroidogenic acute regulatory enzyme (StAR) is one of the proteins that regulate the transfer of cholesterol within the mitochondria [8]. The cytochorome P450 side-chain cleavage enzyme (CYP11A1) is located in the inner membrane of the mitochondria and catalyzes the conversion of cholesterol to pregnenolone by the cleavage of the cholesterol side chain [9] [10]. In the zona reticularis, pregnenolone is converted to DHEA by the enzyme cytochrome P450c17; this single enzyme catalyzes both the 17α-hydroxylation reaction converting pregnenolone to 17-OH
pregnenolone and the 17, 20-lyase reaction converting 17-OH pregnenolone to DHEA. The sulfation of DHEA into its more stable sulfate ester DHEAS is catalyzed by the enzyme hydroxysteroid sulfotransferase (HST, SULT2A1), commonly known as DHEA sulfotransferase (DHEA-ST). DHEAS can be converted back into DHEA by steroid sulfatase (STS) [11]. This is an important biological function of adipose in post-menopausal women whose major source of estradiol is from adrenal DHEA-S conversion to estrogens in fat tissue [12].
Figure 1. Schematic of DHEA/ DHEAS synthesis and physiologically relevant metabolites. Dashed lines indicate that intermediate structures in the conversion are not shown. Bold arrows indicate greater quantity. 3-b-HSD: 3-b-hydroxysteroid dehydrogenase; 5-a-R: 5-a-reductase; 11-b-OH: 11-bhydroxylase; 17-a-OH/ly:17-a-hydroxylase/17,20-lyase; 17-b-HSD:17-b-hydroxysteroid dehydrogenase; 21-a-OH: 21-a- hydroxylase; AROM: aromatase; SSC: side-chain cleavage enzyme; StAr: steroidogenic acute regulatory protein.
“Binello E, Gordon CM. Clinical uses and misuses of dehydroepiandrosterone. Current Opinion in Pharmacology 2003 Dec; 3(6): 635-641.”
11 The synthesis of DHEA is controlled by the hormonal signaling cascade of the hypothalamic-pituitary-adrenal axis. From the anterior pituitary gland, corticotrophin- releasing hormone (CRH) and also arginine vasopressin (AVP), to a lesser extent, stimulates the release of adrenocorticotropin (ACTH). ACTH, in turn stimulates the adrenal cortex to secrete DHEA and DHEA-S, in addition to cortisol. Cortisol provides negative feedback on CRH, AVP, and ACTH. Yet, there is no evidence of feedback exerted by DHEA and DHEAS on the hypothalamic- pituitary- adrenal axis [5].
DHEA is metabolized to the active androgens, testosterone, 5-dihydrotestosterone (DHT) and estradiol in the peripheral tissues, gonads and adrenals. In both men and women, DHT and testosterone can be metabolized to estradiol (E2) or estrone by aromatase (CYP19A1) [13]. In women the adrenal glands are the main source of these steroids, whereas in men only 5% of DHEAS and 10 – 25% of DHEA is secreted by the testes [5]. The contribution of DHEA to circulating testosterone represents a very small fraction, less than 5% of the total testosterone in men with normal testis function. In castration or other instances where
12 testis-derived testosterone is absent, adrenal androgens are the only important precursors to maintain DHT levels in the prostrate [14]. While, pre-menopausal women, derive 40-75% of circulating testosterone from the metabolism of DHEA-S, post-menopausal, derive 90% of their estrogen from the peripheral metabolism of DHEA-S [13].
DHEA is released in to circulation as DHEAS, and the half-life of DHEA is estimated at 15 – 30 minutes, with a metabolic clearance rate (MCR) of 2000 l/day, whereas the half-life of DHEAS is significantly longer at 7 – 10 hours with MCR of 5-20 l/day. Both DHEA and DHEAS are widely distributed throughout the body, however the amount of DHEAS in the brain exceeds that of the spleen, adrenals, kidney, liver and plasma (in descending order). Renal excretion accounts for 51- 73% of the elimination of DHEAS and its metabolites [5].
1.1 Changes of physiological concentration of DHEA with age
DHEA- S is the most abundant circulating sterol in humans. Plasma levels of DHEA-S during fetal development are around 100- 200 μg/dL (3-7 μM) and decrease dramatically after birth due to involution of the fetal adrenal zone but reach a low point at 6 months post-partum [15]. From 6 months post-partum to age 6- 8 years the DHEAS levels remains low since adrenal fetal zone and zona reticularis are absent. The DHEAS levels gradually start increasing at adrenarche and reaching a peak at 20 – 30 years and then gradually decrease in both genders (1-4% for men and 2 % for women) to about 20% of the maximal value [8].
2. Mechanism of action
DHEA exerts is action through indirect and direct mechanisms. Indirectly, it acts mainly through its metabolites. Estradiol, testosterone 5-dihydrotestosterone (DHT) are some of the most well-known and best characterized metabolites and each hormone produces its effect in their respective sites. Other important metabolites of DHEAS that have important function may be eventually be recognized. On the other hand, DHEA exerts its direct action through interaction either with a nuclear or a membrane receptor. Some of these receptors are constitutive aldosterone receptor β (CARβ), pregnane X receptor (PXR), peroxisomal
proliferator-activated receptor (PPAR).In the brain, DHEA-S serves as a gamma – aminobutyric acid type A (GABAA) antagonist and a Sigma 1 (σ1) agonist and can also potentiate N-methyl-D-aspartate receptor
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3. Clinical significance
3.1 Bones
Androgens play a prominent role in bone physiology as documented by numerous studies, and some have also shown a stimulatory effect of DHEA on bone mineral density (BMD), especially in post-menopausal women. In men, due to lower degree of sex steroid deficiency, significant effects on BMD have been observed less frequently or not at all. Whereas on the other hand, some studies show positive correlation between BMD and serum DHEA levels [16]. A cross-sectional study done in Korean population showed a positive correlation between serum DHEAS and femur BMD, which suggested that maintaining serum levels of DHEA may reduce age related BMD decline in Koreans [17]. Another randomized controlled trial conducted showed improved hip BMD in older adults and spine BMD in older women after 1 year of DHEA replacement therapy with daily dose of 50 mg [18]. Other reviews also show that DHEA through its conversion into androgens stimulates bone formation. Also, DHEA by activating both androgen and estrogen receptors present in osteoblast population, increases trabecular thickness, cortical thickness and cortical density. [16]
3.2 Cardiovascular diseases
There has been extensive research evidence that suggests a beneficial effect of DHEA on cardiovascular function [19]. Studies have observed that high serum DHEA is associated with decreased deaths and CVD. Data indicates that in humans, DHEA inhibits atherosclerosis, reduces cardiovascular risk markers and improves endothelial function. Low serum DHEAS has also been found to be associated with the incidence of cardiovascular events, thus showing that DHEAS has a protective role on cardiovascular diseases [16]. Another study found that DHEA increases endothelial cell proliferation in vitro and improve endothelial function in vivo in post-menopausal women by mechanisms that are independent from androgen and estrogen receptors. Also, DHEA administration over 3 months increased endothelium-mediated vascular reactivity in both large and small blood vessels, with no change in blood pressure and a decrease in total cholesterol. These data show that peripheral vasculature is a potential site of DHEA action and may contribute to improvement of CVD [20].
DHEA also inhibits apoptosis in endothelial cells under serum privation conditions, which suggest that DHEA acts as a survival factor in these cells. Also, effects of DHEA were estrogen receptor (ER) independent and were mediated through Gαi-PI3K/Akt-Bcl-2 module, which shows a novel mechanism of
14 DHEA action in vascular endothelial cells [21]. A population- based study of 1032 non-smoking men and women over age of 55 years of age found no clear association between DHEA-S levels and presence of severe aortic atherosclerosis. However, in men, a protective effect of DHEA-S was postulated but did not represent a statistically significant effect [22]. Also low DHEA-S concentrations were associated with atrial fibrillation in men [1].
Since DHEA is a well-tolerated molecule and inexpensive drug, DHEA supplementation may prove useful for clinical management of some types of cardiovascular diseases, however, assessing the clinical efficacy of DHEA in CVD, requires additional multi-centric clinical studies [19].
3.3 Brain
DHEA and DHEA-S are true neurosteroids, differing in their influence on brain function and also modulating them in a variety of ways through multitude of different mechanisms [8]. DHEA, in addition to reaching the brain through circulation via blood-brain barrier, it can be locally synthesized. DHEA can then be converted in to estrogens and /or androgens modulating neuronal activity. Some of the reported actions of DHEA in the brain are increased neuronal excitability, gamma-aminobutyric acid (GABA) type A receptor antagonistic properties and changes in synaptic transmission in hippocampus. DHEA can act directly with N-methyl –D- aspartate (NMDA) receptors as well as GABA and sigma receptors [16]. The decline of DHEA with age has been linked to loss of memory and cognitive function. The role of DHEA has been proposed in the etiology and treatment of neuronal damage induced by Alzheimer’s disease. The hippocampus, which is the region in the brain involved in learning, cognition and memory, shows pronounced changes during aging and Alzheimer’s disease. Estrogens and DHEA which can form estrogens locally in the brain show to enhance memory and learning functions. Also studies show that DHEA-S can influence brain function and positively affect memory mood, energy and indirect physical activity. In humans, long-term memory test have been improved by DHEA administration and also oral administration of 25 mg DHEA per day for 12 months in aging males with partial androgen deficiency improved mood and fatigue in addition to join pain [16].
DHEA has potential therapeutic in the treatment of depression. In a randomized, double blinded, placebo- controlled trial, supplementation with DHEA had favorable outcomes in patient with major depression [23]. A different randomized clinical trial found that DHEA was beneficial agent for treatment of classic schizophrenic symptoms and also alleviated co-morbid depression and anxiety in these patient. DHEA appeared to be safe in this group, and did not exacerbate mania or other adverse effect. However another
15 randomized trial using the same DHEA doses and treatment intervals in Alzheimer’s patients found there was no improvement in cognitive performance or changes in symptoms. This study was surprising, because many other basic studies showed a correlation between decreased levels of DHEA-S and Alzheimer’s [1]. Despite the considerable increase in DHEA-S research and discovery of its biochemical mechanisms of action, its role in neuropsychiatric diseases and clinical therapeutics remain uncertain [11].
3.4 Cancer
The potential of DHEA as an anticancer agent has been long advertised among many other benefits [1]. DHEA is well known to exert anti-proliferative effects and there has been evidence on preclinical chemopreventive efficacy of DHEA [16]. A series of studies have shown that DHEA, instead of being carcinogenic as shown for estrogens, exerts an opposite effect, namely an anti-carcinogenic effect. Also there have been studies that show DHEA confers significant protection against prostate carcinogenesis [16] DHEA treatment in a model of colon carcinogenesis has decreased the number of cancer precursors, although it did not affect malignant potential. Another study examining the association of DHEAS levels in serum to melanoma and squamous cell carcinoma of the skin found no statistically significant trend toward protection or risk [1].
Anti-carcinogenic effect of DHEA in breast cancer can be attributed to the predominant formation of androgens over estrogens from DHEA in breast tissue, thus providing a higher influence of androgens which are well known inhibitors of mammary gland proliferation in vitro, as well as in vivo in animal models and in women [24].
3.5 Skin
DHEA is known to have important effects on the skin of aged individuals, one of them being an increase in sebum production and the other noticed effect is of skin surface hydration. Sebum secretion was increased to up to 79 % after 12 months of DHEA therapy with a return to pre-treatment values 3 months after cessation. This DHEA – induced increase in sebum production can be due to the fact that sebaceous glands contain all the steroidogenic enzymes necessary to catalyze the transformation of DHEA into androgen DHT (DHT being the main stimulator of sebaceous gland activity [16]. In a study done where male and female subjects between ages of 60 and 79 where administered 50 mg DHEA, once daily for a year, skin hydration significantly increased for the whole DHEA –treated population examined after 12 months of treatment. DHEA also significantly decreased facial skin pigmentation (yellowness) for the whole population. This decrease was more pronounced in women aged >70 years [25].
16 3.6 Mortality
There is significant amount of data that supports the association of low serum DHEA with increased risk of death in men, including CVD. In the Rancho Bernardo Study, a correlation between high serum DHEA-S levels and low cardiovascular risk in men aged 50 years or older. The PAQUID study has also shown higher mortality in men having lower serum DHEA [16]. Also in the InCHIANTI study, low serum DHEA-S levels were associated with higher mortality, when adding one or two other anabolic hormones (such as testosterone, DHEA-S, IGF-1) the risk of mortality increases [26]. The decrease in serum testosterone, DHEA-S and insulin- like growth factor (IGF-1) may be associated with decrease in muscle mass, increase in fat deposition, development of insulin resistance and other medical conditions which affect mortality [16]. A study done in Sweden in 2644 men of median age 75.4, followed for 4.5 year, during which 328 deaths occurred, low serum DHEA and DHEA-S have been found to be associated with 49% and 46% increased risk of all deaths when the 25% of men having lowest levels of serum DHEA were compared with rest of cohort [hazard ratio (HR) of 1.49 with 95% confidence interval (CI) of 1.18- 1.88]. When deaths from ischemic heart disease was considered, 25% of men having lowest DHEA and DHEA-S levels had 72% and 61% higher risks of cardiovascular death, the corresponding increasing risk of death from ischemic heart disease were 94% and 75%, respectively for low DHEA and DHEA-S [16] [27] .In men there are also studies that report no correlation between serum DHEA and mortality. There is also data that suggest lower serum DHEA in oophorectomized women is involved in increased mortality [16]. To gain a better understanding on the true nature of this association between endogenous DHEA-S levels and risk of death, the solution is to apply genetics and Mendelian randomization approach [28].
3.7 Inflammatory diseases
DHEAS is known to have immunomodulatory functions, and low levels of DHEAS have been associated with specific changes such as decrease in major T cell subsets, increase in natural killer cells and activated T cell phenotype. Also, in severe critical conditions caused by septic shock and multiple trauma, low DHEA-S levels represented a prognostic marker for poor outcome [29] [1]. Two gender biased, autoimmune diseases: rheumatoid arthritis and systemic lupus erythematosus were investigated if DHEA-S had a role to play. A retrospective study of patients with rheumatoid arthritis showed that patients had higher levels of DHEA, but not DHEA-S, compared with healthy control subjects. The authors of this study concluded that although absolute levels of DHEA were higher, these levels in relation to inflammatory markers were low [30]. Also there is controlled clinical trials published that test the effect of DHEA treatment in rheumatoid arthritis. Another clinical trial examined the effect of DHEA supplementation in women with systemic lupus
17 erythematosus. A daily oral dose of DHEA (200mg) on 10 female patients with mild to moderate SLE, after 6 months of treatment, a significant decrease in both disease activity and corticosteroid requirement was seen [30][31]. This led to other studies that further investigated the clinical benefits of DHEA supplementation in SLE, like a randomized double blind placebo controlled trial in 120 adult women with active SLE, treated with 200mg/day DHEA for 6 months, revealed that the treatment could significantly reduce number of SLE flares and improve patient assessment of disease activity [32][31]. Exactly how DHEA mediates these effects is still unclear, but its ability to reduce immune cell apoptosis and rectify cytokine imbalance that underlies SLE pathology may offer some explanation [31]. With the exception of this success of reducing clinical symptoms in patients with SLE, there have not been any case of human based studies on effects of DHEA on immune function.
3.8 Endocrine Pathologies
DHEA secretion is physiologically regulated by the hypothalamic-pituitary-adrenal axis, therefore any pathological states that affects any of these organs can profoundly affect serum DHEA-S levels [1]. Clinical trials in patients with adrenal insufficiency reports benefits in mood and well-being, as well as in sexual interest and satisfaction [4]. This has prompted the recommendation of DHEA administration as part of treatment regimen for patients with Addison’s disease [33] and more multicenter trials are underway to determine role of DHEA administration as part of routine hormonal replacement therapy [4]. A randomized, double-blind, placebo-controlled trial in hypopituitary androgen-deficient women treated with low dose DHEA (20-30mg/day depending on age) showed androgenic effects on skin axillary and pubic hairs, as well as improved alertness, stamina and initiative in sexual relations during 6 month period [34] [1].
A study of osteoblasts from post-menopausal women indicate that DHEA is converted to estrogen and positively regulated by glucocorticoids and 1, 25-dihyroxyvitamin D3. This prompts interest in administering low dose DHEA and vitamin D3 for post-menopausal patients with osteoporosis. Also this study showed a positive correlation between BMD and DHEA-S [1] [35]. Although DHEA therapy in patient with endocrinological pathologies have some positive effects, the long-term benefit in these pathologies and other areas need to be established.
3.9 Sexual function
The intravaginal administration of DHEA in post-menopausal women suffering from sexual dysfunction had important beneficial effect. Local DHEA, through local androgen and estrogen formation causes a reversal of the symptoms and signs of vaginal atrophy with no or minimal change in serum steroid levels
18 [16]. Another study focused on 70 post-menopausal women, daily treated with 50 mg DHEA for 12 months and they showed improved libido and sexual function in addition to many other effects [25]. However, in another study, where DHEA was administered at 50 mg daily to 17 women and 13 men for 3 months, reported no significant effect on sexual function. Only improved physical and psychological well-being was observed [24].
3.10 Diabetes
DHEAS is often reported to have anti-diabetic effects. Although the exact mechanism of the relationship has been discussed there is no concrete evidence for pathophysiological explanation [36]. In a large prospective population based cohort study, serum level of DHEA was inversely associated with risk of type 2 diabetes, independent of established diabetes risk factors which include, BMI, fasting glucose, insulin etc. However, there was no independent association found between DHEAS, androstenedione or DHEAS to DHEA ratio and risk of type 2 diabetes [6]. Also a study in post-menopausal women showed no effect between the DHEA levels and risk of type 2 diabetes [37]. In another case controlled study of 718 post-menopausal women, inverse association between DHEAS and diabetes risk was seen, but was only of borderline significance. This also indicates that if there are any effects of DHEAS they may be small [38]. Studies in animals have shown therapeutic effects of DHEA in mice used as a model of diabetes, however these data should not be translated to human physiology directly [6]. Overall although numerous studies have been done to find association between risk of diabetes and DHEA levels, because of conflicting data, no concrete evidence can be put forth for such an association.
4. Role of DHEA in treatment
Serum DHEA is unique from other adrenal steroids in that it significantly decreases with age. This has triggered the advertisement of DHEA as an anti-aging drug and was often self-administered in USA and other countries [4]. It is considered to be a food supplement and this may lead to people misusing this hormone.
However, recently there has been a lot more placebo controlled studies that show the use of DHEA in various diseases as previously mentioned above in clinical significance. DHEA supplementation has proven beneficial in deficient states such as adrenal insufficiency [39], systemic lupus erythematosus [32], and other depressive states. However in perimenopausal women who complains of altered mood and well-being, no specific effect of DHEA supplementation was seen with all subjects improving after DHEA and placebo
19 treatment [4]. DHEA administration in elderly people showed increased sebum secretion, suggesting androgenic activity of DHEA, it also improved the skin hydration in the elderly [16].
Apart from the replacement of a pathophysiological defined DHEA deficiency, as in adrenal insufficiency or chronic glucocorticoid- treated patients, DHEA therapy is promising in patients with impaired well-being, mood or sexuality, also post-menopausal women who suffer from sexual dysfunction may also benefit from use of DHEA to reverse signs and symptoms of vaginal atrophy. Furthermore, in elderly population use of DHEA treatment show favorable outcomes in body composition, skin hydration, and slight increases in bone mass density [4].
Serious adverse of DHEA treatment have not been reported in any published data. Some of the side effects reported include possible androgenic effects such as oily sin, acne, deepening of voice, mild hair loss and facial or body hair growth [40].
Methods
To achieve the objectives laid out in this literature review, the electronic medical database PubMed was used to search relevant medical literature for publications related to DHEA/ DHEA-S. For this literature search, a variety of keywords and terms (including synonyms, abbreviations and closely related words) such as: “DHEA”, “DHEA-S”, “Dehydroepiandrosterone”, “Dehydroepiandrosterone sulfate”, “Prasterone”, “androstenolone”, “DHEA synthesis”, “DHEA metabolism”, “DHEA action”, “DHEA significance”, “DHEA treatment” , “DHEA concentrations”, “DHEA treatment”, “adrenal hormones” were used to identify relevant articles. Article types that were mainly searched for were reviews and systematic reviews. The titles and abstract associated with these searches were reviewed for references to DHEA/ DHEA-S synthesis, mechanism of action, clinical significance and treatment, and if found relevant, full texts of those articles were retrieved. Addition studies were retrieved also be reviewing bibliographies of articles identified through search terms.
In addition to this, case reports that involve DHEA/DHEA-S were also reviewed. These case reports were searched using PubMed database, keywords used were “DHEA”, “DHEA-S”, “DHEAS pathology”, and case reports from the year 2000 and onwards were reviewed. The abstract of the case report were reviewed for changes in DHEA levels, and/ or uses of DHEA as treatment. And if case report was found relevant, full texts were retrieved.
20 Case reports and articles that were excluded include foreign language articles and case reports. Also Case reports and articles published earlier than year 2000 were excluded.
Results and their Discussion
987 articles were found during initial search results for articles related to DHEA/ DHEAS from the year 2000 till 2017. After adding filters for human species the list was narrowed down to 932. 40 articles were identified that were considered eligible for the scope of this review (depending on whether the articles discussed about DHEA/ DHEAS synthesis, mechanism of action, clinical significance and treatment) A review of those articles were performed and have been elaborated on in the literature review section of this document. A table summarizing the role of DHEA in various disease states is shown below.
Table 1. Summary of role of DHEA on various systems and pathologies mentioned in literature review.
System/ process Disease/ tissue DHEA/DHEAS Role
Musculoskeletal Bone Stimulatory effect on BMD, esp. in post-menopausal women. By activating both androgen and estrogen receptors present in osteoblast population increases trabecular thickness, cortical thickness and cortical density.[16]
Cardiovascular Atherosclerosis, atrial fibrillation, endothelial cells
DHEA inhibits atherosclerosis, reduces cardiovascular risk markers and improves endothelial function [16]. Low DHEAS conc. Associated with atrial fibrillation
Nervous Depression,
Alzheimer’s, schizophrenia
Increased neuronal excitability, GABA type A receptor antagonist properties. Supplementation with DHEA showed favorable outcomes in major depression [23]. Study in Alzheimer’s patients with DHEA supplementation found no improvement or changes in symptoms [1]
Cancer Skin, breast Serum DHEA levels and association to melanoma and squamous cell carcinoma found no significant trend towards protection or risk. [1] Anti carcinogenic effect in breast cancer attributed to formation of androgens over estrogens from DHEA in breast tissue.
Skin Skin Important effects on skin of aged individuals- increased
sebum production and skin surface hydration with DHEA therapy [16].
Mortality CVD Low serum DHEA in association with increased risk of
death.
Inflammatory diseases
Rheumatoid arthritis, SLE
Patients with Rheumatoid arthritis showed higher levels of DHEA, but not DHEAS, However these results in respect to inflammatory markers were low [30]. Oral dose of DHEA in patients with SLE showed decreased disease activity and reduced SLE flares.[31]
21
Endocrine Adrenal insufficiency, osteoporosis, Diabetes.
Clinical trials in patients with adrenal insufficiency report benefits in mood and well-being [4]. No independent relation between DHEAS and risk of type 2 diabetes[6]
Sexual function Sexual dysfunction Local DHEA through androgen and estrogen formation causes reversal of symptoms and signs of vaginal atrophy [16]. Treatment with 50 mg DHEA for 12 months in post-menopausal women showed improved libido and sexual function [25]. But other studies with same treatment reported no significant sexual function [24]
A list of 190 case reports were identified initially which were narrowed to 40 case reports to meet the scope of this review. A detailed list of these case reports is mentioned below in table 2.
Table 2. List of case reports involving DHEA/DHEAS from the year 2000 onwards. No . Author Disease/ pathology Age / Sex
Case specifics DHEA/D HEA-S levels Comments 1. Dissanayake et al., 2017 [41] Hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome) 1/ F Spontaneous epistaxis, pulmonary arterio venous malformation, oral telangiectasia, masculine habitus, elevated testosterone
low Low DHEA-S levels could be due to impaired sulfation of DHEA due to portocaval shunting of blood, leading to hyperandrogenemia 2. Hatano et al., 2016 [42] adrenocortical carcinoma 60/ M Gynecomastia, right hypochondriac pain, adrenal tumor on CT
High This report describes a case of feminizing adrenocortical
carcinoma and elevated levels of DHEAS, and estradiol.
3. Ohashi et al., 2016 [43] Adrenocortical carcinoma 67/F History of DM, Hypertension and referred for evaluation of Hypopotassemia, right adrenal tumor and huge liver tumor.
High Rare case where adrenocortical
carcinoma increases aldosterone, in addition to DHEA and cortisol
22 4. Sacerdote et al., 2015 [44] Hepatocellular carcinoma 53/F Cushing syndrome, elevated DHEA, DHEAS, cortisol levels were seen
High Rare case of Cushing syndrome associated with cortisol-secreting and DHEA -secreting hepatocellular carcinoma. 5. Monno et al., 2015 [45] Bilateral cortisol-secreting adenomas 39/F Symptoms of Cushing’s syndrome with amenorrhea and hirsutism
High Rare case of bilateral cortisol secreting adenomas with unilateral over secretion of DHEAS. 6. Kozan et al., 2014 [46] Leydig cell tumor of Ovary 55/F Post-menopausal woman with frontal balding, virilization, history of sleep apnea. Recurrent pulmonary embolism and unexplained secondary erythrocytosis High Virilization in postmenopausal women is mostly due to tumors of ovary or, less commonly adrenal. This tumor explains the cause of elevated testosterone and DHEAS levels.
7. Subbiah et al., 2013 [47] Adrenocortical oncocytoma 3/F Premature pubarche, clitoromegaly
High Rare case of
functioning adrenocortical oncocytoma with increased DHEA-S and testosterone 8. Siepmann et al., 2011 [48] Hypogonadism and erectile dysfunction associated with soy product consumption 19/ M Loss of libido, erectile dysfunction after ingestion of large quantities of soy based products in vegan style diet. Low testosterone levels.
High First reported case of relation between decreased free testosterone and increased DHEA blood concentrations and soy-rich diet. 9. Akishima – Fukasawa et al., 2011 [49] Malignant adrenal rest tumor 31/F Symptoms of Cushing’s syndrome including hirsutism, leg edema. Cortisol, DHEA-S were
High Rare case which demonstrated
steroidogenic capacity in malignant adrenal rest tumor, show by elevated levels of DHEA-S and cortisol.
23 elevated, and low
levels of ACTH 10. Faria et al., 2011 [50] Leydig cell tumor of Ovary 33/F History of secondary amenorrhea, and progressive worsening signs of virilization. Elevated serum free testosterone levels
Normal Evaluation of DHEA-S levels are helpful for differential diagnosis of hyperandrogenism when very high levels of testosterone are present. 11. Ghayee et al., 2011 [51] Macronodular hyperplasia of adrenal zona reticularis 29/ M Incidental discovery of bilateral adrenal enlargement
High Very high levels of DHEA were observed, which could be explained by the hyperplasia of the adrenal zona reticularis. 12. Biliatis et al., 2010 [52] Ovarian follicular cyst 2/F Signs of precocious puberty, advanced bone age. Increased estradiol and DHEAS levels
High The report concluded that the elevated DHEAS levels maybe the cause of the ovarian follicle formation. 13. Fichna et al., 2010 [53] Adrenal hypoplasia congenita 20/ M
low body mass, lack of puberty, skeletal immaturity Undetecta ble DHEA and testosterone levels were undetectable which is common in adrenal failure. 14. Unuvar et al., 2010 [54] Testicular tumor of adrenogenital syndrome due to 11-beta-hydroxylase deficiency 2/M Presence of pubic hair for 6 months and progressive penile
enlargement.
High Elevated DHEA levels showed tumor involvement in adrenal glands. 15. Lim et al., 2010 [55] Adrenocortical oncocytoma
14/F Virilization High Rare case of virilization, elevated
DHEA and
testosterone levels due to functioning adrenocortical
24 16. Chiu et al., 2010 [56] 17 alpha-hydroxylase deficiency 20/F female pattern hair loss Low Deficiency of 17- alpha hydroxylase causes low levels of cortisol, and other androgens including DHEA 17. Li et al., 2010 [57] 17- alpha-hydroxylase deficiency 16/F Primary amenorrhea, lack of secondary sexual characteristics.
Low The deficiency of 17-alpha-hydroxylase causes low levels of DHEA and also testosterone. 18. Arlt W. 2009 [58] Primary adrenal insufficiency 20/ M fever, lack of energy, dizziness, hyperpigmentatio n Low/ undetecta ble
DHEA levels will be low or undetectable in adrenal insufficiency 19. Herrera et al., 2009 [59] Testosterone - secreting sertoli-leydig cell tumor associated with
DHEAS-secreting adrenal adenoma
59/F gradual increase in facial and body hair, male pattern baldness,
deepening of voice
High First reported case of coincidental DHEA-S secreting adenoma and testosterone secreting serotli-leydig cell tumor. 20. Karp et al., 2009 [60] generalized seizures 30/F Seizure attack. Using supplementary DHEA (75mg/day) prior to seizure no data given
This report describes the first published case of association between new onset epilepsy and the use of DHEA
21. Gupta et al., 2008 [61] Ovarian steroid cell tumor 9/F Weight gain, hypertension, mass in lower abdomen, signs of Cushing’s syndrome
High Ovarian steroid cell tumors usually secrete gonadal steroids, however in this case both glucocorticoids and gonadal steroids are secreted. 22. Balkan et al., 2008 [62] Translocation between chromosomes 3 and 4 : 46, XY, t 1/M Abnormal location of urethral meatus
Low Unique case of hypospadias in patient with translocation of chromosomes 3 and 4.
25 (3,4) (p25;q31.3) 23. Diab et al., 2008 [63] Ovarian Leydig cell tumor 49/F Hirsutism, obesity, male pattern baldness, and left adrenal mass on CT
Low Case of virilizing ovarian leydig cell tumor in patient with subclinical Cushing syndrome. 24. Von Puttkamer et al., 2008 [64] McCune- Albright Syndrome 6/M Premature pubarche, fibrous dysplasia of the forehead, growth hormone and prolactin producing pituitary adenoma.
High Report concluded that increased production of DHEAS may have caused pubarche. And this increase in DHEA is caused due to a mutation of a hormone receptor in zona reticularis of adrenal glands leading to increase in sulfotransferase activity and increased DHEAS production. 25. Golkowski et al., 2007 [65] Adrenocortical oncocytoma 51/ M Weight loss, general asthenia and abdominal pain, adrenal mass on CT, high DHEA-S and cortisol levels.
High Rare case of malignant and functioning adrenocortical oncocytic tumor reported 26. Suzuki et al., 2007 [66] Adrenal adenoma 35/F Persistent hypertension with hypokalemia, serum aldosterone levels high, adrenal tumor on radiological examination.
Low Case of primary aldosteronism with low basal ACTH and DHEAS. 27. Nakamura et al., 2007 [67] Adrenocortical adenoma 39/F Hirsutism, obesity, DM, and hypertension. Adrenal tumor on CT High In histopathological examination of resected tumor, steroidogenic enzymes particularly dehydroepiandrosteron e sulfotransferase (DHEA-ST) were expressed. This
26 explains high level of
DHEA-S 28. Mann et al., 2007 [68] Adrenocortical tumor 2/M Persistent acne, since 6 months of age, signs of virilization and accelerated growth. High DHEA and testosterone
High Elevated levels of DHEA/DHEAS should prompt evaluation for adrenocortical tumor especially in infants. 29. Ikarashi et al., 2006 [69] Preclinical Cushing syndrome with diurnal rhythms of ACTH and cortisol in blood 50/ M Incidental right adrenal tumor associated with hyperglycemia and hypertension
Normal In patients with preclinical and clinical Cushing syndrome, serum conc. of DHEA is decreased. This case is rare in that DHEA is normal 30. Sun et al., 2006 [70] Ovarian Sertoli- Leydig cell tumors 14/F progressive abdominal pain, constipation, early satiety, CT revealed right adnexal mass
High Although patient had increased serum androgen and DHEA-S, there was no obvious virilization, possibly due to seeming rapid growth of tumor. 31. Larizza et al., 2006 [71] Juvenile granulosa cell tumor 16/F Spontaneous menarche at 12 yr, after this no menstrual bleeding for 4 years. No clinical signs of virilization. High DHEA, 17 OH-P and low FSH and high LH after GnRh.
High Unusual case where hormonal secretion consisted mainly of androgens even though clinical signs of virilization were not present. Increased DHEA levels were due to tumor. 32. Barad et al., 2005 [72] improved ovarian reserve after DHEA supplementation 42/F Severely decreased ovarian reserve. Patient started DHEA supplementation (75mg/day) and no data given
positive response can be attributed to an interaction of DHEA, gonadotropin
stimulation and acupuncture treatment
27 weekly acupuncture voluntarily 33. Nadjafi-Triebsch et al., 2003 [73] Progesterone increase under DHEA - substitution 75/ M Excessive fatigue, depression. Patient received 50 mg DHEA for depressive mood Increased after suppleme ntation
There was an increase in progesterone under DHEA substitution 34. Nadjafi-Triebsch et al., 2003 [73] Progesterone increase under DHEA - substitution 48/ M Fatigue, depression, moodiness. Patient received 50 mg DHEA for depressive mood Increased after suppleme ntation Increase in progesterone under DHEA substitution 35. Klebl et al., 2003 [74] Pouchitis treatment with DHEA 35/F Signs of chronic active pouchitis. Treated with DHEA 200 mg/day No data given Positive effect of DHEA in pouchitis. 36. Takahashi et al., 2002 [75] Adrenal adenoma 21/F Primary amenorrhea, hyperprogesteron emia without virilization. Mass in adrenal gland on CT
High Steroid secreting adrenal adenoma, after resection steroid levels were normalized except for DHEA-S. This high level of DHEA-S after operation can be explained by possible complication of PCOS. 37. Wit et al., 2001 [76]
Atrichia pubis F atrichia pubis was treated with daily
dosage of DHEAS 10 mg/m2 body surface in addition to their regular substitution therapy no data given Oral administration of DHEAS in a dosage of 15mg/m2 o.d. is quite an efficacious treatment for atrichia pubis. 38. Bozbora et al., 2000 [77] Functional adrenal tumor 23/F Hirsutism and fatigue nine
High Androgen secreting tumors explains high
28 months after delivery. High testosterone. Large tumor on CT level of DHEA. Prognosis is poor due to aggressive nature. 39. Lin et al., 2000 [78] Ovarian steroid cell tumor 3/F telarche at 2 yr, pubarche and accelerated growth velocity 4 months later. Ultrasound showed multicystic mass DHEAS- high, DHEA - normal
The elevated DHEAS secretion by the tumor associated with elevated estradiol levels can account for
pubic hair
development in this girl
40. C.E.Dean.,
2000 [79]
Mania after use of DHEA
31/ M
Patient was using DHEA several weeks prior to his
mood and
behavior changes
no data given
This study concluded that use of DHEA under the age for 35 maybe risky and questionable as endogenous DHEA peaks at 20 - 30 years.
Out of the 40 case reports, 7 (namely no. 20, 32, 33, 34, 35, 37 and 40) were describing the use of DHEA/ DHEA-S as a treatment. Furthermore, 2 reports (no. 20 and 40) showed negative effects after the use of DHEA as treatment and the rest (no. 32, 33, 34, 35, 37) showed satisfactory and even effective therapeutic action after the use of DHEA. 33 case reports described the use of DHEA/ DHEAS as a laboratory test where, in some diseases the levels were high and in others the levels were undetectable or low. 12 instances of adrenal tumors were found.
In general we can say that, raised levels of DHEAS are found in the plasma of patients with adrenal tumors or with congenital adrenal hyperplasia (CAH). In addition to this it may also be elevated in patients with polycystic ovary syndrome (PCOS). In adrenal insufficiency or panhypopituitarism DHEAS levels may usually be undetectable. [5]. these were similar findings to what is observed in the table 1.
29
Conclusion
In the recent past there has been tremendous progress in the field of DHEA research. Numerous articles that were reviewed in this modest literature review and the objectives set out has been achieved. On the synthesis and metabolism, it is clear that DHEA is synthesized in the zona reticularis [8] and is controlled by hormonal signaling cascade of the hypothalamic-pituitary- adrenal axis. The most important step is the conversion of cholesterol to pregnenolone, which in turn is converted to DHEA. The sulfation of DHEA into DHEA-S is catalyzed by DHEA sulfotransferase. [8][9][10]. DHEA is metabolized to active androgens, testosterone, 5 dihydrosterstosterone and estradiol. [13]. DHEA-S levels few months after birth are quite low and remain as such until adrenarche, following which there is an increase until the second or third decade of life. There after there is an age related decline in both genders to about 20% of maximal value. [8].
The clinical significance of DHEA/ DHEAS is quite varied. Studies show a stimulatory effect of DHEA on bone mineral density, especially in post-menopausal women. High serum DHEA is also associated with decreased deaths and CVD, thus showing a protective role on cardiovascular diseases. [16] DHEA and DHEA-S are true neurosteroids, their decline has been linked to loss of memory and cognitive function, and also studies show that it can positively affect memory mood, energy and indirect physical activity. However, its absolute role in neuropsychiatric diseases and clinical therapeutic are uncertain. [8] [16] DHEA supplementation in inflammatory diseases such as SLE showed positive effects.
DHEA therapy is promising in patients with impaired well-being, mood or sexuality. In elderly population, DHEA use shows favorable outcomes in body composition, skin hydration increase bone mass density [4]. Also in replacement of pathophysiological defined DHEA deficiency, such as in adrenal insufficiency or glucocorticoid treated patients. There has not been any data on serious adverse effects of DHEA treatment and some of the side effects include oily skin, acne, deepening of voice, mild hair loss, facial and body hair loss. [40]
It can be concluded that although every aspect of DHEA physiological role is not known, certain positive effects have been established in certain disease states.
30
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