In 1934, Adolf Buteiiandt and Hand Dannenbaum first discovered Dehydroepiandrosterone (DHEA) as a urinary metabolite. 10 years late, DHEA 3-sulfate (DHEA-S), the stored form of DHEA was identified
(Butemandt A, Dannenbaum H. Munson P L, Gallagher T F, Koch F C. ).
It was not until 1954 and 1960, when DHEA and DHEA-S respectively, was isolated from serum (Baulieu E E. .; Migeon C J, Plager J E. ).
DHEA and DHEA-S, is the most abundant endogenous sex-steroid hormone (Baulieu et al.) , with circulating levels at peak age being 10nM (DHEA) and10uM (DHEA-S) (Longcope 1995; Migeon, 1957; Orentreich et al. 1992).
Large amounts of DHEA and DHEA-S are produced during fetal development ({Rainey:2002vm}). After an initial rapid decline immediately after birth.{Rainey:2002vm}; {Saltzman:2006cb}, synthesis resumes when andrenache occurs between the ages 6-8, initially with no sex differences long before any clinical signs of puberty (de Peretti E, Forest MG, 1976). Rising DHEA and DHEA-s levels are the biochemical hallmarks of adrenache {Smith:1975vd}, with the increase occurring before oestrogen and androgen concentrations (Ducharme et al., 1976). Conversely, cortisol and ACTH concentration do not change during this peroid, indicating that adenacrhe is not only a global activation of the of the pituitary-adrenal axis {Rainey:2008jb}.
DHEA and DHEA-S levels continue to rise throughout puberty and peak during the second decade of life with absolute levels of circulating DHEA-S is lower in females than males throughout life {Smith:1975vd}, (Orentreich et al., 1984) (Ducharme et al., 1976).
By the third decade of life, DHEA and DHEA-s level decline with ageing {Kiechl:2000wc}, with levels being as little as 10-20% of peak by the eighth decade {Jarrar:2001kl}.
The Bruneck study {Kiechl:2000wc}, demonstrated the life long age-related decline occurs in both genders. This decline with increasing age occurs at an approximately constant rate of 29% and 44% per decade in men and women respectively with DHEA-S {Kiechl:2000wc}. (Fig 1.).
Figure 1. Effects of age in 40- to 79-year-old men and women on serum concentration of DHEAS. Values given are retransformed averages 2 SEM of log-transformed DHEAS levels in age strata of 5 years each. Lines depict regression lines. indicates •men; º, women. (Taken from Kiechl et al. )
The Kiechl and colleagues noted that the age-adjusted levels of DHEA-S were higher among alcohol consumers (17% [men] and 12% [women], P 0.01); subjects with hypertension (21% [men] and 13% [women], P 0.05), and male smokers (9%, P 0.05) and lower among subjects with chronic respiratory infections (-16% [men] and 21% [women], P 0.05) and diabetic men (-35%, P 0.01).
The implications of this age-related decline, as well as in certain disease states has yet to be fully understood and investigated.
Chemistry
Isomers and Structure
DHEA is an androstane, with a molecular formula of C19H28O2, and molecular weight of 288.43. DHEA is a C19 steroid with a gonane core, chemically know as 3β-Hydroxy-5-Androstene-17-one. It is the 5-dehydro analogue of epiandrosterone and may also be referred to as 5-dehydroepiandrosterone. DHEA has a similar skeletal backbone to that found in cholesterol, the difference due to the side-chain being replaced with a ketone group.
DHEA per se, does not signify the location of the molecules hydrogen atoms are vacant. DHEA is 5-dehydroepiandrosterone or 5,6-didehydroepiandrosterone
Naturally occurring isomers do exist and exert very similar functions, e.g. 1-dehydroepiandrosterone (1-androsterone) and 4-dehydroepiandrosterone.
Clinically utilised C3ß esters of DHEA are: 1. Fluasterone and 2. Prasterone Enanthate and 3. Prasterone Sodium Sulfate.
This is the biological process, that occur throughout different tissues, by which androgen, oestrogens, progestogens and corticosteroids are synthesised from cholesterol. Steroids are important for the maintenance, integrity and fluidity of the cell membrane and in signalling and activating the hormone receptors of cells. The ‘nucleus’ of all steroids is that of the nomenclature, gonane.
Steroid Classification
Steroids may be classified into the following categories:
1. Corticosteorids
a. Glucocoticoids
b. Mineralocoticoids
2. Sex Steroids
a. Progesterone
b. Androgens
c. Oestrogens
3. Neurosteroids
4. Aminosteroids
5. Secosteoirds (‘broken ring’ steoird)
Corticosteroids
Sub-categorised into the glucocorticoids and mineral corticoids, these steroid hormones are produced in the adrenal cortex.
Involved in vertebrate physiological processes
Steroidogenesis
Insert Steroid pathway
Synthesis Of DHEA
Synthesis from cholesterol to DHEA may be seen in the figure XX
DHEA is produced in the primarily in the zona reticularis and to a lesser extent in the fasciculate of the adrenal cortex {Rainey:2002vm}under the control of adrenocorticotropic hormone (ACTH). Expression of steroidogenic acute regulatory protein (StAR) has been observed to be the different in both cells, but production being greater in the reticularis. StAR is the protein responsible for cholesterol transport into the mitochondria. DHEA is also synthesised in small quantities (~10%) in the gonads under the control of gonadotropin-releasing hormone (GnRH).
DHEA is synthesised from cholesterol via the cholesterol side-chain cleavage enzyme (CYP11A1; P450scc) to pregnenolone, and hydroxylation of the side chain at the C20 and C22 position. This occurs via two intermediates, 22R-hydroxycholesterol and 20α,22R-dihydroxycholesterol, with all three stages in the transformation catalyzed by P450scc.
This is the first step in the process of steroidogenesis and therefore this enzyme is considered essential for life.
Pregnenolone itself is an endogenous steroid, and in a metabolic intermediate to the progestogens, androgens, glucocorticoids and mineralocorticoids (REF?), as well as a neurosteroid in its own right.
Pregnanolone is then hydroxylated (at the C17alpha position) via 17 alpha-hydrolase (CYP17A1) to hydroxypregnenolone, a pregnane (C21) steroid. CYP17A, which is also a member of the cytochrome P450 superfamily of enzymes, has 17,20-lyase activity and may convert hydroxypregnenolone to dehydroepiandrosterone (DHEA).
Metabolism of DHEA to androgenic and oestrogenic hormones
DHEA is sulfonated by sulfotransferase enzyme (SULT2A1) at position C3ß to DHEA-S {Rainey:2008jb} in the adrenal cortex and during first-pass metabolism in the liver.
This therefore has implications, as any exogenous supply of DHEA would be converted immediately to the sulphated version of DHEA, in the form of an oral supplement.
The levels of DHEA-S, about 200-300 times higher than its desulphated counterpart , in circulation act as a reservoir for DHEA and may be converted by steroid sulfatase (STS) in the endoplasmic reticulum (Ghosh, 2007). Terminal half-life of DHEA-S is 7-10 hours, compare to that of DHEA which is a maximum of 30 minutes. (White et al., 2013). DHEA-S can therefore act as a reservoir and extend the duration of DHEA ()
In circulation, DHEA is predominantly weakly bound to albumin, with decreasing amounts bound to sex horomone-bind globulin (SHBG) and unbound to any protein {Ahn:2007km}({Vining:1987ta}). DHEA-S is not bound to SHBG (Coates) but has a high affinity with albumin and hence the reason for this more longer terminal half-life (Becker, 2001; White & Porterfield, 2013) but is not bound to
In addition to DHEA-S, DHEA also has its own down-stream metabolites 7α-hydroxy-DHEA, 7β-hydroxy-DHEA, 7-keto-DHEA, 7α-hydroxyepiandrosterone, and 7β-hydroxyepiandrosterone, as well as androstenediol and androstenedione
The alcohol oxidorecturase, 17β-Hydroxysteroid dehydrogenases (17β-HSD, HSD17B), catalyses the reduction of all 17-ketosteroids, of which DHEA to androstendiol is one, and the dehydrogenation of the 17β-Hydroxysteroids (REF_ WIKI).
Androstendiol, also known as androst-5-ene-3β,17β-diol, is a weak androgen and oestrogen steroid hormone. Androstendiol also has a role as an intermediate in the biosynthesis of testosterone from DHEA, as well as a stimulator of the immune system.
3β-Hydroxysteroid dehydrogenase/Δ5-4 isomerase (3β-HSD) converts androstendiol to testosterone via oxidative conversion ().3β-HSD, is also responsible for androstadienol to androstadienone, which may then also be converted by 17β-HSD to testosterone.
Testosterone, predominantly bound to SHBG and weakly bound to albumin, produced in the Leydig cells of the testes, is the primary anabolic and male sex steroid hormone. It has multiple roles within the body such as development of the reproductive organs and promoting secondary sexual characteristics (Moordian et al., 1987). It may also influence platelet aggregation, via the thromboxane A2 receptors on megakaryocytes (a large bone marrow cell) (Ajay x2).
Age, resistive exercise, nutrients, weight loss and sleep have been documented to affect the levels of testosterone in humans. Biologically, testosterone is also important for the regulation of acute Hypothalamic-Pituitary-Gonadal-Axis (HPG axis), which will be discussed later.
40% of testosterone is metabolised equally between etiocholanolone and 17-ketosteroids androsterone (Wecker; Melmed; Becker) with approximately half of circulating testosterone being conjugated in the liver by glucuronosyltransferases and sulfotransferases to testosterone glucuronide and testosterone sulfate (Melmed;).
5-7% of Testosterone may then be irreversibly reduced to form 5alpha-Dihydrotestosterone (DHT) via 5alpha reductase , predominantly in the liver and skin, but also the genitals, hair follicules and brain (Melmed).
200-300ug of DHT, the most potent androgenic hormone, is synthesised per day (Melmed).
Despite circulating in much lower levels that testosterone, DHT may be up to 10 times that of testosterone in the tissues where 5-alpha reductase is expressed, like the prostate (Hay et al).
Although being a potent androgenic hormone, exogenous supplementation does not confer and anabolic advantage (Llewellyn, 2009) as it is readily inactivated in the muscle, adipose and liver by 3a-hydroxysteroid dehydrogenase and 3b-hydroxysteroid dehydrogenase (Melmed, Swerdloff et al.; Jin et al.Rizner et al.,) to 3α-androstanediol and 3β-androstanediol.
DHT cannot be aromatized into an oestrogen like testosterone and therefore has no oestrongenic effects (WIKI REF).
Both testosterone and androstendione may be aromatized to the 18 carbon Oestradiol and estrone respectively. Aromatase, also known as estrogen synthetase or estrogen synthase, is the enzyme that is responsible for this biosynthesis of oestrogens, via the oxidation of the C-19 methyl group to formic acid.
This enzyme, a member of the P450 superfamily (CYP19A1), is found in high concentrations endoplasmic reticulum of the gonads, brain, adipose tissue, blood vessels, skin and bone (WIKI REF). Age, obesity, insulin, gonadotrophins and alcohol that all increase the activity of aromatase and therefore why its association with disease and disorders such as endometriosis, endometrial cancer, breast cancer and uterine fibroids (REF).
Aromatase activity may be decreased by prolactin, anti-Mullerian Hormone and the broad-spectrum herbicide, glyphosate (Gasiner et al.).
DELETE _ CYP19A1 mutations, inherited in an autosomal dominant manner, causes excess in puberty, may cause gynaecomastia in boys or precocious puberty and gigantomastia in girls, with both suffering from short stature due to early epiphyseal closure (Fukami, et al., x2 ).
DELETE _ Conversely, CYP19A1 mutations in an autosomal recessive manner at puberty may led to delayed menses and sexual maturation. Post-puberty, primary amenorrhea and osteoporosis may also prevail. In pregnant females, accumulation of androgens, via lack of aromatase may lease to virilisation. However, it is the tall stature that tends to be evident in both males and females.
The primary female sex steroid hormone, Oestradiol, is essential for the development of secondary sexual characteristics during puberty, and the maintenance of these female biological functions throughout life.
The most potent of the three oestrogens (X and X being the other two), levels in the premenopausal women vary throughout the menstrual cycle (Becker), but tend to be 20-80pg/mL. This is followed by a general increase over the preceding weeks, prior to a surge of circulating levels between 130 – 400pg/mL pre-ovulation(REF). Levels in the early to mid luteal phase tend to plateau, between 100-150pg/mL and as low as 40pg/mL during menstruation (Becker, von Schoultz).
Oestradiol its self may be metabolised in to (see figure) the following metabolites.
Two of these metabolites are oestriol and estrone. Oestriol, produced via the 16α-hydroxylation of estradiol and estrone by cytochrome P450 enzymes (e.g., CYP3A4) mainly in the liver (Henderson ). Poorly bound to SHBG (Buchaumn,), levels of circulating Oestriol are low, but concentrations in the urine are high, due to its rapid clearance (Henderson). Although reportedly undetectable in some females, it is during pregnancy that oestriol levels, synthesised in the placenta, up to a 1000-fold, meaning that it becomes the predominant hormone at this time (Jerome; Goodman; Rosamaria et al., ).
Finally, oestrone. Predominantly bound to albumin in circulation (80%), it has a poor affinity to SHBG (16%) (Hornstein, 2012). Principally converted by aromatase from androstendione in the gonads and adipose tissue (Hornstein, 2012). , oestrones potency comes via the reversibly converted to oestradiol by 17B-HSD primarily in the liver (Kuhl 2005).
Synthesis of Progestogens, Mineralocorticoids and Glucocorticoids
The first two metabolites of this process are the same as that of the synthesis of DHEA. Pregnenolone and hydroxypregnenolone are the primary progestogens synthesis from cholesterol.
Pregnenolone which also exist in a sulphated form, are neurosteroids. Like DHEA and DHEAS, they are of interest to researchers due to its hypothesised affect upon synaptic function, myelination (REF) and memory function (Vailee et al., 2001).
3β-HSD, which was previously outlined in its role of conversion of DHEA to Androstendione and Androstenediol to testosterone, is necessary of the oxidation Pregnenolone and hydroxypregnenolone to progesterone and 17α-hydroxyprogesterone