Chapter 3 – Adrenal Androgens

Updated January 12, 2012

INTRODUCTION

The adrenal androgens (AAs), normally secreted by the fetal adrenal zone, the zona fasciculata and the zona reticularis of the adrenal cortex are steroid hormones with weak androgenic activity. The adrenal androgens are DHEA, DHEA sulfate and androstenedione. DHEA and DHEA sulfate are secreted  in greater quantities, although androstenedione is more important, because it is more readily converted peripherally to testosterone. Production of testosterone (T) by these glands is minimal (1).  Although AAs do not appear to play a major role in the fully androgenized adult man, they seem to play a role in the adult woman and in both sexes before puberty.  Girls, women, and prepubertal boys may be negatively affected by AA hypersecretion in contrast to adult men. This capter reviews AA biosynthesis, regulation, physiology and biological action.

ADRENAL ANATOMY AND ANDROGEN BIOSYNTHESIS

Adrenal gland anatomy

The adrenal glands, consisting of cortex and medulla, have a roughly pyramidal shape, lie above the upper poles of the kidneys in the retroperitoneum and weigh approximately 4g each. They are well supplied with arterial blood from branches of the phrenic arteries, the aorta, and the renal arteries, which give rise to the superior, middle, and inferior adrenal arteries, respectively. Arterial blood enters from the outer cortex, flows through fenestrated capillaries between the cords of cells, and drains into venules in the medulla. On the right side, the adrenal vein directly enters the inferior vena cava; on the left side, it usually drains into the left renal vein. The adrenal cortex is divided into three histologic and functional zones: the outer, aldosterone-secreting, called zona glomerulosa; the intermediate, cortisol and androgen secreting, zona fasciculata; and the inner, androgen and cortisol secreting zona reticularis. Each one is characterized by the expression of specific steroidogenic enzymes, which result in the production of different steroid hormones. The outer zona glomerulosa produces aldosterone and constitutes about 15% of cortical volume. The zona fasciculata is the thickest part of the adrenal cortex, making up about 75% of the cortex and produces cortisol as well as small amounts of androgens and estrogens. The inner zona reticularis surrounds the medulla and produces the adrenal androgens and small amounts of cortisol and estrogens (2). The zona glomerulosa is deficient in 17a – hydroxylase activity and thus cannot produce cortisol and androgens (figure 1). Whereas the zona glomerulosa is primarily regulated by angiotensin II and ACTH, both the zona fasciculata and the zona reticularis are regulated by corticotropin (ACTH) (3). Both of these zones become hypofunctional and atrophic when corticotropin is deficient. On the other hand, they become hypertrophic and hyperplastic when corticotropin is secreted in excess.

Fetal adrenal and development

The fetal adrenal cortex arises from mesodermal cells migrating from the coelomic epithelium very early in the embryonic period. It consists of the two adult adrenal zona glomerulosa and fasciculata and an inner large adrenal zone, which degenerates rapidly after birth (4). Thus, adrenocortical tissue can be found in the ovaries, spermatic cord and testes. The adrenal medulla originates from ectodermal tissue. At 2 months of gestation, the adrenal cortex is identifiable as a separate organ and is composed of a fetal zone and a definitive zone similar to the adult adrenal cortex. At mid gestation the adrenal cortex is considerably larger than the kidney and much larger than the adult gland in relation to total body mass. The active secretion of steroids occurs by week 6 from the provisional zone, which represents the functional cortex in the fetal period. Remaining cell foci from the fetal adrenal zone presumably give rise to the adrenal zona reticularis starting at the age of 4 to 5 years in both sexes, clinically expressed as adrenarche (5). The growth of this zone continues until young adulthood (20 to 25 years), remains at a plateau for 5 to 10 years, and regresses gradually after  the reproductive period of life.(6,7) Aging results in alterations within the adrenal cortex with no significant difference in the total width of the cortex. More specifically, there is a reduction in the size of the zona reticularis and a relative increase in the outer cortical zones (8).

Biosynthesis of adrenal androgens

All human steroid hormones derive from cholesterol. Plasma lipoproteins are the major source of adrenal cholesterol. Low –density lipoprotein accounts for about 80% of cholesterol delivered to the adrenal gland. There are specific cell surface LDL receptors on the adrenal tissue. Synthesis within the gland from acetyl-coenzyme A also occurs. A small pool of free cholesterol within the adrenal is available for acute response when stimulation occurs. Acute stimulation leads to hydrolysis of stored cholesteryl esters to free cholesterol, increased uptake from plasma lipoproteins and increased cholesterol synthesis within the gland (9). In addition, there is evidence that the adrenal can utilize HDL cholesterol through the recently reported HDL receptor, SR-B1(10).
The conversion of cholesterol to pregnenolone is the major site of ACTH action on the adrenal. This occurs in the mitochondria with two hydroxylations and then the side chain cleavage of cholesterol. The enzyme CYP11A1 mediates this process. These reactions require molecular oxygen and a pair of electrons. The electrons are donated by NADPH to adrenodoxin reductase (flavoprotein) and then to adrenodoxin (an iron-sulfur protein) and finally to CYP11A1. Electron transport to microsomial cytochrome P450 involves the enzyme P450 reductase (figure 2).

 

The steroid hormones produced by the adrenal cortex are members of a large family of compounds derived from the cyclopentanoperhydrophenanthrene ring structure that comprises three cyclohexane rings and one cyclopentane ring. DHEA, DHEA-S, and 4-A (figure 4) are 19-carbon compounds.
Androgens, as all steroid hormones, share an initial step in their biosynthesis, which is the conversion of cholesterol to pregnenolone. Cholesterol is released and enters steroid hormone synthesis by the action of the enzyme cholesterol esterase. The conversion of cholesterol to pregnenolone requires the action of cytochrome P450 side-chain cleavage enzyme (P450scc), which is present in the inner mitochondrial membrane of all steroidogenic cells. Free cholesterol is transferred from the outer mitochondrial membrane to the inner mitochondrial membrane by STeroid Acute Regulatory (STAR) protein. This transport is followed by the conversion of cholesterol to pregnenolone by P450scc enzyme. This conversion is the first step in the synthesis of steroid hormones. Pregnenolone undergoes 17α-hydroxylation by 17α-hydroxylase. The product is 17α- hydroxypregnenolone, which is converted to 17α-OH-progesterone by 3β-hydroxysteroid dehydrogenase. Thereafter, 17α-hydroxyprogresterone is converted to 11-deoxycortisol by the enzyme 21-hydroxylase and finally 11-deoxycortisol is converted to cortisol by the enzyme 11β-hydroxylase (figure 3).

ADRENAL ANDROGEN REGULATION AND PHYSIOLOGY

Regulation

Adrenal androgens are secreted by the adrenal glands in response to ACTH, a 39-amino acid peptide synthesized and secreted by the anterior pituitary (figure 5). It is derived from  proopiomelanocortin (POMC), a large precursor molecule from which β-lipotropin hormone and/or β-endorphin are also derived (15,16). Corticotropin (1-39) is the predominant form of corticotropin in plasma and has a half- life of approximately 10 minutes (17). Its synthesis and secretion are primarily regulated by corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP), both of which are produced by parvocellular neurons of the paraventricular nucleus of the hypothalamus and act in synergy with each other (18,19). Under ACTH regulation, adrenal androgens are secreted synchronously with cortisol. There are three mechanisms of neuroendocrine control: [1] episodic secretion and the circadian rhythm of ACTH, [2] stress responsiveness of the hypothalamic-pituitary-adrenal axis (HPA), [3] feedback inhibition by cortisol of ACTH secretion. [1] The circadian rhythm  is the episodic secretion, as a result of the central nervous system regulation of CRH and ACTH secretory episodes. Cortisol secretion is low in the late evening. The major secretory episodes begin in the sixth to eighth hours of sleep and then begin to decline as wakefulness occurs. Cortisol secretion then gradually declines during the day with fewer secretory episodes (20). The circadian rhythm of the adrenal androgens is typical of the different physiologic and pathologic conditions. Patients with nonclassic 21-hydroxylase deficiency, for example, have a distinct pattern of adrenal steroid secretion characterized by a high-frequency 17-hydroxyprogesterone release accompanied by a relative nocturnal cortisol deficiency (21,22). [2] Plasma ACTH and cortisol secretion are secreted within minutes following the onset of physical stress. This response abolishes circadian periodicity if the stress is prolonged. Stress responses originate in the CNS and result to CRH and ACTH secretion. [3] Corticotropin-stimulated cortisol exerts major feedback inhibitory influences at the level of both the hypothalamus and the anterior pituitary by suppressing CRH, AVP, and corticotropin synthesis and secretion. Plasma DHEA, 4-A, and T concentrations  parallel closely the circadian rhythm in plasma cortisol. Plasma DHEA-S levels do not exhibit a circadian rhythm because of the much longer circulating half-life of this sulfated steroid (23,24).

Numerous other endocrine signals (25) were proposed as coregulators of adrenal androgen secretion. Among these are prolactin (PRL) (26), estrogen (27-31), epidermal growth factor (32), prostaglandins (33), angiotensin (34), GH (35), gonadotropins (36,37), β-lipotropin, and β-endorphin.  Glasow et al. reported the presence of PRL receptors in the human adrenal gland and suggested a direct effect of PRL on adrenal steroidogenesis that may be of particular relevance in clinical disorders characterized by hyperprolactinemia (38). Interestingly, adults with hyperprolactinemia have increased secretion of AAs by the zona reticularis, which is corrected by reduction of PRL secretion with bromocriptine (39). In women with PRL-secreting tumors there is a correlation between PRL levels and DHEA-S (40).
Pabon et al. (41) have detected the presence of LH- hCG receptors in zona reticularis and fasciculata. The receptor bearing cells were positive for steroidogenic enzymes, indicating that the receptors could be coupled to DHEAS secretion (42,43,44).
Cytokines interfere with steroidogenesis at the level of the adrenals, testes and ovaries. Within the adrenal adrenocortical and chromaffin cells produce cytokines such as IL-1, IL-6, TNFa, leukemia inhibitory factor (LIF) and IL-18 which have a key role in the immune-adreno-cortical communication. Thus, in autoimmune and inflammatory diseases an adequate adrenal stress response is observed. In addition cytokines such as IL-8 and MCP-1 (monocyte chemotactic protein-1) are involved in steroidogenesis.(45)
Interleukin-6 also is known to activate the HPA axis by stimulating both the CRH - and the AVP -secreting neurons of the paraventricular nucleus of the hypothalamus, and their terminals at the median eminence, the cotricotrophs of the anterior pituitary, and the cortisol-secreting adrenal cells in rats. In the latter it acts through specific receptors expressed mainly in the zona fasciculata and reticularis, but also with lower density in the zona glomerulosa (46,47). The ability of IL-6 to stimulate glucocorticoids, mineralocorticoids, and androgens suggests that this cytokine might have a role in coordinating the response of all adrenocortical zones. Its secretion is regulated by different substances, such as CRH, ACTH, angiotensin II, or immune products such as IL-1/ indicating that IL-6 may play a major role in the interaction of the adrenal function with the immune system (48).
Interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) regulate the activity of HPA axis at several levels. Studies investigate their action on adrenal steroidogenesis and indicate that IL-1α and IL-1β increase cortisol, androstenedione, DHEA, DHEAS production and the accumulation of mRNAs for steroidogenic acute regulatory protein (STAR), 17α-hydroxylase/17,20-lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase 2 (HSD3B2) in these cells. TNF-α induced cortisol production (49).
Both corticotropin and PRL stimulate AAs secretion by the fetal adrenal zone. In addition, placental CRH appears to play a major role in sustaining this zone and stimulating androgen secretion together with corticotropin and/or PRL (50).

Physiology

AAs are secreted in small amounts during infancy and early childhood, and their secretion gradually increases with age, paralleling the growth of the zona fasciculata and the zona reticularis. Disturbances in both enzymatic activity in zona fasciculata and reticularis and its regulators (ACTH or peptides of hypothalamic – pituarity origin, such as PRL) may result in syndromes of hirsustism and virilization in female or feminization in men. The adrenal cortex normally secretes the adrenal androgens in increasing amounts beginning at about 6-7 years of age in girls and 7-8 years of age in boys. This continued rise in adrenal androgen secretion continues until late puberty. Adrenarche (secretion of adrenal androgens) occurs years before gonadarche (secretion of gonadal sex steroids) . The appearance of pubic hair (pubarche) results from a rise in adrenal androgen levels (adrenarche) (51,52). The mechanism(s) by which the zona fasciculata and reticularis develop with age, as well as the regulation of adrenarche onset are not understood. The biochemical hallmark of adrenarche is accelerated DHEAS production from the adrenal gland. The axillary and pubic hair regions are the most sensitive androgen-dependent regions and they represent the clinical manifestation of adrenarche. Children with premature pubarche have hormonal responses to CRH stimulation test similar in magnitude to those of prepubertal children of comparable age, ruling out a prominent role of CRH in premature pubarche (53). Gell et al. suggested that as children mature, a decrease of 3-hydroxysteroid dehydrogenase activity in the adrenal reticularis occurs, leading to an increased production of DHEA and DHEA-S, as seen during adrenarche, by shifting pregnenolone through the 17-hydroxylase /17, 20 lyase pathway (54), (fig.4). Activation of the type I Insulin-like Growth Factor (IGF) receptor was shown to enhance steroidogenic responsiveness of the fetal zone cells to ACTH by modulating the ACTH signal transduction pathway at some point downstream from ACTH receptor binding (55). Also, locally produced IGF-II modulates fetal adrenocortical cells function by increasing responsiveness to ACTH via activation of the type I IGF receptor and increases the capacity of those cells for androgen synthesis by directly augmenting the expression of P450c17 (55). Thus, IGF-II may play a pivotal role in AA production, both physiologically in utero and at adrenarche, as well as in conditions of hyperandrogonemia (55). All together, these data indicate that the IGF system is important in the regulation of the differential function of adult human adrenocortical cells (56).
The rise in plasma concentrations of the AAs at adrenarche occurs in the presence of constant levels of cortisol, suggesting that factors other than corticotropin are involved. The influences of sex and age are minor in the modulation of adrenal steroidogenesis and support the concept that extra-adrenal factors dominate in the differential modulation of AAs and cortisol (57). These may include POMC-derived or other still uncovered peptides.
An increased serine phosphorylation of human P450c17 might have a role in the development of both the excessive adrenarche and hyperandrogenism of patients with the polycystic ovary syndrome resulting in a substantial increase in 17-20-lyase activity (58,59,60), (fig.4). P450c17 is the key enzyme that regulates androgen synthesis (61). It is the only enzyme known to be able to convert C21-precursors to the androgen pro-hormones, the 17-ketosteroids. It is a single enzyme with two activities, 17 a-hydroxylase and 17,20-lyase (fig.4) and serine phosphorylation appears to modulate the activity of P450c17. In particular, it promotes the 17,20-lyase activity, and at the same time it inhibits the activity of the insulin receptor (59,62-65). It was postulated that a single abnormal serine kinase might hyperphosphorylate both P450c17 and the insulin receptor, accounting for the hyperandrogenism and hyperinsulinism responsible for both premature pubarche and later in life for PCOS (66). In vitro studies, however, failed to find evidence for hyperphosphorylation of the insulin receptor-b chain and P450c17 in PCOs (67). The reason for this might be related to the many different factors needed for P450c17 optimal activity and not normally expressed in the cell line used for that study (68).

CIRCULATION, PERIPHERAL CONVERSION AND METABOLISM

Adrenal androgens are secreted from the adrenal cortex in an unbound state. Bound steroids are biologically inactive. Androstenedione, DHEA and DHEA sulfate bind mainly to albumin. About 90% of adrenal androgens are bound to albumin and 3% approximately is bound to sex hormone-binding globulin (SHBG). The binding globulins have high affinity and low capacity, whereas, albumin has low affinity and high capacity for steroids.
Adrenal androgens can lead to two different pathways after entering the circulation. Their metabolism can result either in degradation and inactivation or the peripheral conversion to their more potent derivatives testosterone and dihydrotestosterone.
The AAs and their metabolites are inactivated or degraded in various tissues, including the liver and kidneys (69). Major biochemical routes for inactivation and excretion are conjugation of androgens to glucuronate or sulfate residues to produce hydrophilic glucuronides or sulfates that are excreted in the urine (figure 6A).
DHEA, DHEA-S, and 4-A are converted to the potent androgens T and DHT in peripheral tissues. Major conversions are those of 4-A to T and T to DHT by the enzymes 17β -hydroxysteroid dehydrogenase (17β-HSD) and 5-reductase, respectively. Major peripheral sites of androgen conversion are the hair follicles, the sebaceous glands (fig.6A), the prostate,the external genitalia and the adipose tissue. (70,71). DHEAS is the sulfated version of DHEA. This conversion is catalyzed by sulfotransferase (SULT2A1) primarly in the adrenals, the liver, the kidney and small intestine. The levels of DHEAS in the circulation are about 300 times higher than those of free DHEA. DHEAS levels show no diurnal variation, whereas DHEA levels reach their peak in the early morning hours. DHEA secreted by the adrenal gland can be also converted to Δ4-androstenedione. Both  DHEA and DHEAS are also metabolized to  7α  and 16α – hydroxylated derivatives and by 17β reduction to Δ5-androstenediol and its sulfate. Androstenedione is converted either to testosterone or by reduction of its 4,5 double bond to etiocholanolone or androsterone. Testosterone is converted to DHT in androgen-sensitive tissues by 5β reduction. The product is mainly metabolized by 3α reduction to androstanediol. The metabolites of these androgens are conjugated either as glucuronides or sulfates and excreted in the urine.
Active uptake of androgens and in situ estrogen synthesis occur in peripheral adipose tissue (figure 6B) through the enzymes 17β-HSD and aromatase, respectively (72-75). Peripheral conversion contributes significantly to circulating T levels in women, but not in men, in whom T is largely produced by the testis.
Three main enzyme complexes are involved in the synthesis of estrogens in peripheral tissues (76-78):

• Aromatase for the aromatization of androstenedione to estrone.
• Estrone sulfatase (E1-STS), which catalyses the formation of estrone from estrone sulfate.
• Estradiol-17-β-hydroxysteroid dexydrogenase (17β-HSD) Type 1 which is responsible for the reduction of estrone to the biologically active estrogen, estradiol.

ANDROGEN RECEPTOR

The inactive androgen precursors secreted by the adrenal glands are converted to T and 5-dihydrotestosterone (DHT) and exert their effects in most peripheral tissues by interacting with high-affinity receptor proteins. The androgen receptor (AR), member of the steroid receptor superfamily, also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4) is a type of nuclear receptor that is activated by binding of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus. The androgen receptor is most closely related to the progesterone receptor and progestins in higher dosages can block the androgen receptor. The androgen receptors are encoded by the AR gene located on the X-chromosome at Xq11-12. (79). This gene contains a polymorphic CAG microsatellite repeat within exon 1, encoding for a variable length of polyglutamine chain at the aminoterminal, the transactivation domain of the AR protein. Triplet-repeat DNA sequences can be sites of genetic instability, and their expansion in a variety of genes has been associated with human genetic diseases, such as fragile X-syndrome (80,81) and myotonic dystrophy (82). In the case of the AR gene, an inverse correlation of the number of CAG repeats with the risk for prostate cancer was described (83-86), and its expansion was documented in Kennedy's disease (spinal and bulbar muscular atrophy), a disorder associated with primary hypogonadism (87). In vitro studies showed that progressive expansion of the repeat length in the AR was associated with a linear decrease in its transactivation function (88). These observations support the idea that there is an optimal number of repeats, which varies in the population from 11 to 31 (average size: 21 + 2) (83).
Methylation of deoxycytosine residues is another process involved in the modulation of gene expression. Belmont et al. (89) showed that the methylation of HpaII and HhaI sites near the polymorphic CAG repeats in the first exon of the human AR (HUMARA) locus correlated with X-inactivation.
Patients with idiopathic hirsutism were shown to have a normal number of CAG repeats but with a preponderance of the shortest and most active alleles (90). These patients had also a preferential methylation of the longer AR allele compared to normal subjects, leading to inactivation of the functionally weaker gene. This skewing could allow the shorter, more active AR allele (84,88) to be preferentially expressed explaining the peripheral hypersensitivity to androgens in hirsute patients.
Multiple "coactivators" were identified enhancing transcription of the AR gene (91), including AP-1 (92), Smad3 (93,94), nuclear factor kB (NF-kB) (95,96), sex-determining region Y (SRY) (97), and the Ets family of transcription factors (98). The relative importance of these molecules for any particular cell type remains unclear, since the ability of a putative coregulator to alter the transcriptional activity is typically examined in transient transfection experiments. Although AR is normally thought to function as a homodimer, it was also shown to heterodimerize with other nuclear receptors including the estrogen receptor (ER) (99), glucocorticoid receptor (GR) (100) and testicular orphan receptor 4 (TR4) (101). One of the major mechanisms through which coregulators might function is by forming a bridge between the DNA-bound nuclear receptor and the basal transcriptional machinery (type I regulators) (102). Coactivators may also facilitate ligand binding, promote receptor nuclear translocation, or mediate signal transduction (type II coregulators).
The role of "corepressors" in AR function is poorly defined. Three corepressors of androgen-bound AR have been identified to date, cyclin D1, calreticulin, and HBO1. However, relatively little is known about the mechanism of their repressive effect.
The role of androgens and their receptors (AR) in breast cancer etiology and progression has been less profoundly studied and remains an unanswered question. There is evidence showing that androgens can directly stimulate the growth of human breast cancer cell lines. In addition, both retrospective and prospective studies have reported statistically significant associations between increased levels of testosterone and higher breast cancer risk in both pre- and postmenopausal women (103,104). A recent study (105) confirms that AR are commonly expressed in breast cancer. Researchers found a specific value of AR expression to be a prognostic indicator in breast cancer. The functional role of AR in these neoplasms is still unclear and further data are needed to clarify their biological signification in breast cancer (106,107).
Androgen receptor may explain male dominance in liver cancer. A recent study (108) showed that the AR promotes liver cancer when hepatitis B is present by altering DNA replication of  the virus. Thus, men with HBV are much more likely to develop cancer than women with the same infection. Researchers investigate the role of the AR pathway as a potential new treatment target for liver cancer. (109-112)
For decades Chang et al has focused on the particular role of the AR in human health. In 1988 (113,114) he successfully cloned AR, which led to breakthroughs in several AR-related diseases such as prostate (115-119) and bladder cancer (120), and Kennedy's neuron disease, a rare and progressive motor disorder, similar to Lou Gehrig's disease that affects only men. In addition, Chang has shown that mice without AR have dramatically lower rates of bladder cancer, a cancer that strikes men three times more often than women (121).
SARMs (selective androgen receptor modulators) are molecules which provide the benefits of traditional anabolic/androgenic steroids such as testosterone, while showing a lower tendency of side effects. They are a class of molecules currently under development for treatment of a variety of diseases, which were previously treated with anabolic steroids and other medications. SARMs take the place of the androgen in the androgen/receptor bound. SARMs generally have fewer unwanted side-effects on non- target tissues such as the prostate, hairline, sebaceous glands and secondary sexual organs. At this stage of development there are no SARMs available in the pharmaceutical market, although they may be available in the black market as doping agents (122,123).

BIOLOGIC EFFECTS

In adult men, the conversion of adrenal 4-A to testosterone accounts for less than 5% of the production rate of the latter, making its participation in the physiologic androgenization of the male negligible. Excessive AA secretion appears to have no major clinical consequences in the adult man, although this may be debated. AA hypersecretion in prepubertal boys, on the other hand has clearly been associated with isosexual precocious puberty.
In adult women, adrenal 4-A and 4-A generated from peripheral conversion of DHEA contribute substantially to total androgen production and effect. In the follicular phase of the menstrual cycle, adrenal precursors account for two thirds of testosterone production and half of dihydrotestosterone production. In the midcycle, the ovarian contribution increases, and the adrenal precursors account for 40% of testosterone production. In women, increased AA production may be manifested as cystic acne, hirsutism, male type baldness, menstrual irregularities, oligoovulation or anovulation, infertility, and/or frank virilization. Excessive adrenal androgen secretion in prepubertal or pubertal girls can cause heterosexual precocious puberty.
Abnormalities in the timing and intensity of adrenarche are associated with PCOs, CAH and insulin resistance conditions.
Studies conducted over the past few years have used DHEA to treat female infertility (124,125).  Women with poor ovarian reserve, after DHEA supplementation 4 to 12 weeks prior an IVF cycle, had a 50-80% reduction in miscarriages (126).
DHEA supplementation has been long investigated during the past twenty years and it remains controversial (127-129). Reports demonstrate DHEA as a replacement therapy in the elderly (130,131). At 70-80 years of age, peak DHEA concentrations are about 10-20% of those in young adults. These reports suggest DHEA as replacement treatment in menopausal women and it has been reported to restore both the androgenic and estrogenic environment and reduce most of the symptoms of menopause (132-134). Other reports have suggested that oral DHEA in doses of 25-50 mg/d may restore plasma testosterone levels to normal in some women with hypopituitarism who have diminished libido despite adequate estrogen therapy (135-137). In addition DHEA replacement   therapy is investigated for the conditions of adrenopause and adrenal insufficiency (138-141).
Other studies investigate the role of DHEA and DHEAS in the immune response and suggest that adrenal androgens have opposite biological effects to those of corticosteroids (142). DHEA is a cortisol antagonist (143). Research studies indicate DHEA supplementation has an anti-depressant effect (144-146).
Recently, we have shown that in postmenopausal PCOS women, androgen levels at baseline are higher in PCOS than control women and remain increased after ACTH stimulation (147). While the dexamethasone suppression test results in postmenopausal PCOS women suggest that DHEAS and total T are partially of adrenal origin. Although the ovarian contribution was not fully assessed, increased Δ(4)A production suggests that the ovary also contributes to hyperandrogenism in postmenopausal PCOS women. In conclusion, this study indicates that postmenopausal PCOS women are exposed to higher adrenal and ovarian androgen levels than non-PCOS women (147).
Both gonadal and AAs contribute to the positive impact of androgenic steroids on bone cell metabolism in vitro (148). Interestingly, a study found that the potential anabolic effect of androgens on bone might not be mediated at the level of the mature osteoblast but at the level of fetal, less differentiated, osteoblastic cell lines (149).

CONCLUSION

DHEA is the most prevalent steroid hormone in the body. DHEA levels drop dramatically with aging. There are pronounced differences in the average DHEA levels of men and women, with women on average having lower DHEA levels. DHEA replacement therapy can restore youthful DHEA levels. Many of the studies examining DHEA have found an overall benefit among study subjects on specific diseases, including: female infertility, hypopituitarism, menopause, adrenopause, adrenal insufficiency, diseases of the immune system, osteoporosis and bone metabolism, depression, Alzheimer’s disease and other neurological conditions. Recent studies have shown that DHEA replacement therapy might be beneficial in cardiovascular diseases, diabetes mellitus and chronic inflammation conditions. On the other hand, some studies have shown no effect of oral DHEA therapy for women. The spectrum of women and men that would benefit from DHEA therapy is not clearly defined.
Further studies are needed to investigate the side effects of the DHEA replacement therapy in these diseases and to define the range of dosage that is more effective without complications. Another point that needs to be investigated is the comparison and evaluation of the DHEA replacement therapy with the existing treatments for each disease. Additionally, accurate indications and counter- indications must be given. The aim of further studies should be to give information to all the unanswered issues, which make the DHEA replacement therapy a topic of controversy.