Dehydroepiandrosterone sulfate explained

Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepiandrosterone (DHEA) and circulates in far greater relative concentrations than DHEA. The steroid is hormonally inert and is instead an important neurosteroid and neurotrophin.

Biological activity

Neurosteroid activity

Similarly to other conjugated steroids, DHEA-S is devoid of hormonal activity, lacking affinity for the steroid hormone receptors.[1] However, DHEA-S retains activity as a neurosteroid and neurotrophin.[2] It has been found to act as a positive allosteric modulator of the NMDA receptor (50 nM–1 μM), negative allosteric modulator of the GABAA and glycine receptors, and weak agonist of the sigma-1 receptor (Kd > 50 μM).[3] In addition, DHEA-S has been found to directly bind to and activate the TrkA and p75NTR – receptors of neurotrophins like nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) – with high affinity (around 5 nM).[4] [5] [6]

Hormonal activity

Although DHEA-S itself is hormonally inert, it has been thought that it can be converted back into DHEA,[7] which is weakly androgenic and estrogenic, and that DHEA in turn can be transformed into more potent androgens like testosterone and dihydrotestosterone (DHT) as well as estrogens like estradiol.[8] As such, it has been thought that DHEA-S is a prohormone with the potential for androgenic and estrogenic effects. However, a 2005 study found that DHEA could be converted into DHEA-S but found no evidence of conversion of DHEA-S into DHEA.[9]

Other activity

DHEA-S has also been found to inhibit the TRPV1 and TRPC5 transient receptor potential channels and to inhibit the P2X receptor.

Biochemistry

Biosynthesis

DHEA and DHEA-S are produced in the zona reticularis of the adrenal cortex under the control of adrenocorticotropic hormone (ACTH).[10] DHEA is synthesized from cholesterol via the enzymes cholesterol side-chain cleavage enzyme (CYP11A1; P450scc) and 17α-hydroxylase/17,20-lyase (CYP17A1), with pregnenolone and 17α-hydroxypregnenolone as intermediates.[11] Then, DHEA-S is formed by sulfation of DHEA at the C3β position via the sulfotransferase enzymes SULT2A1 and to a lesser extent SULT1E1.[12] [13] Whereas DHEA is derived mostly from the adrenal cortex but is also secreted to a lesser extent by the gonads (10%),[14] DHEA-S is almost exclusively produced and secreted by the adrenal cortex, with 95 to 100% originating from the adrenal cortex in women.[15] [16] Approximately 10 to 15 mg of DHEA-S is secreted by the adrenal cortex per day in young adults.[17]

Distribution

Unlike DHEA, which is weakly bound to albumin, DHEA-S is strongly bound to albumin (i.e., with very high affinity), and this is the reason for its much longer comparative terminal half-life.[18] [19] In contrast to DHEA, DHEA-S is not bound to any extent to sex hormone-binding globulin (SHBG).[20]

Whereas DHEA easily crosses the blood–brain barrier into the central nervous system,[21] DHEA-S poorly crosses the blood–brain barrier.[22]

Metabolism

DHEA-S can be converted back into DHEA via steroid sulfatase (STS). In premenopausal women, 40 to 75% of circulating testosterone is derived from peripheral metabolism of DHEA-S, and in postmenopausal women, over 90% of estrogens, mainly estrone, are derived from peripheral metabolism of DHEA-S. A study found that administration of exogenous DHEA-S in women who were pregnant increased circulating levels of estrone and estradiol.[23] DHEA-S serves as a depot for potent androgens like testosterone and dihydrotestosterone in prostate cancer, which fuel the growth of this cancer.[24]

The elimination half-life of DHEA-S is 7 to 10 hours, which is far longer than that of DHEA, which has an elimination half-life of only 15 to 30 minutes.

Elimination

DHEA-S is excreted in the urine via the kidneys.[25]

Levels

DHEA and DHEA-S are the most abundant circulating steroids in the body.[26] Plasma levels of DHEA-S are 100 or more times higher than those of DHEA, 5 to 10 times higher than those of cortisol, 100 to 500 times those of testosterone, and 1,000 to 10,000 times higher than those of estradiol.[27] [28]

Levels of DHEA and DHEA-S vary throughout life. They remain low during childhood until adrenarche around 6 to 8 years of age, at which point they markedly increase,[29] eventually peaking at around 20 to 30 years of age. From the third decade of life on, DHEA and DHEA-S levels gradually decrease. By the age of 70, levels of DHEA and DHEA-S are 80 to 85% lower than those of young adults, and in people more than 80 years of age, DHEA and DHEA-S levels can reach 80 to 90% lower than those of younger individuals.

DHEA-S levels are higher in men than in women.

Reference ranges

Reference ranges for DHEA-S in females[30]
Tanner stage and average age Lower limit Upper limit Unit
Tanner stage I>14 days 16 96 μg/dL
Tanner stage II10.5 years 22 184
Tanner stage III11.6 years <15 296
Tanner stage IV12.3 years 17 343
Tanner stage V14.5 years 44 332
18–29 years44 332
30–39 years31 228
40–49 years18 244
50–59 years<15 200
> or =60 years<15 157
Reference ranges for DHEA-S in males
Tanner stage and average age Lower limit Upper limit Unit
Tanner stage I>14 days <15 120 μg/dL
Tanner stage II11.5 years <15 333
Tanner stage III13.6 years <15 312
Tanner stage IV15.1 years 29 412
Tanner stage V18.0 years 89 457
18–29 years89 457
30–39 years65 334
40–49 years48 244
50–59 years35 179
> or =60 years25 131

Medical use

Deficiency

The Endocrine Society recommends against the therapeutic use of DHEA-S in both healthy women and those with adrenal insufficiency, as its role is not clear from studies performed so far.[31] The routine use of DHEA-S and other androgens is discouraged in the treatment of women with low androgen levels due to hypopituitarism, adrenal insufficiency, menopause due to ovarian surgery, glucocorticoid use, or other conditions associated with low androgen levels; this is because there are limited data supporting improvement in signs and symptoms with therapy and no long-term studies of risk.[31]

In otherwise elderly women, in whom an age-related fall of DHEA-S may be associated with menopausal symptoms and reduced libido, DHEA-S supplementation cannot currently be said to improve outcomes.[32]

Childbirth

See main article: Prasterone sulfate.

As the sodium salt, prasterone sodium sulfate, DHEA-S is used as a pharmaceutical drug in Japan in the treatment of insufficient cervical ripening and cervical dilation during childbirth.[33] [34] [35] [36] [37] [38] [39]

Diagnostic use

DHEA-S levels above 1890 μM or 700 to 800 μg/dL are highly suggestive of adrenal dysfunction because DHEA-S is made by the adrenal glands[40] [41] and also synthesized in the brain.[42] The presence of DHEA-S is therefore used to rule out ovarian or testicular origin of excess androgen.

Women with hirsutism commonly present with mildly elevated DHEA-S levels.[43] Common etiologies for hirsutism include ovarian dysfunction (polycystic ovary syndrome) and adrenal dysfunction (congenital adrenal hyperplasia, cushing's syndrome, androgen secreting tumors); 90% of these cases are caused by PCOS or are idiopathic in nature. However, severely increased DHEA-S levels (>700 μg/dL) necessitate further workup and are almost stem from benign or malignant adrenal alterations.

Chemistry

See also: List of neurosteroids.

DHEA-S, also known as androst-5-en-3β-ol-17-one 3β-sulfate, is a naturally occurring androstane steroid and the C3β sulfate ester of DHEA.

Notes and References

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  2. Prough RA, Clark BJ, Klinge CM . Novel mechanisms for DHEA action . J. Mol. Endocrinol. . 56 . 3 . R139–55 . 2016 . 26908835 . 10.1530/JME-16-0013 . free .
  3. Book: Steven R. King. Neurosteroids and the Nervous System. 9 November 2012. Springer Science & Business Media. 978-1-4614-5559-2. 1, 12.
  4. Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, Calogeropoulou T, Castanas E, Gravanis A . Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis . PLOS Biol. . 9 . 4 . e1001051 . 2011 . 21541365 . 3082517 . 10.1371/journal.pbio.1001051 . free .
  5. Pediaditakis I, Iliopoulos I, Theologidis I, Delivanoglou N, Margioris AN, Charalampopoulos I, Gravanis A . Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors . Endocrinology . 156 . 1 . 16–23 . 2015 . 25330101 . 10.1210/en.2014-1596 . free .
  6. Gravanis A, Calogeropoulou T, Panoutsakopoulou V, Thermos K, Neophytou C, Charalampopoulos I . Neurosteroids and microneurotrophins signal through NGF receptors to induce prosurvival signaling in neuronal cells . Sci Signal . 5 . 246 . pt8 . 2012 . 23074265 . 10.1126/scisignal.2003387 . 26914550 .
  7. Book: Robert Morfin. DHEA and the Brain. 2 September 2003. CRC Press. 978-0-203-30121-0. 28–.
  8. Book: Marc A. Fritz. Leon Speroff. Clinical Gynecologic Endocrinology and Infertility. 28 March 2012. Lippincott Williams & Wilkins. 978-1-4511-4847-3. 545–.
  9. Hammer F, Subtil S, Lux P, Maser-Gluth C, Stewart PM, Allolio B, Arlt W . No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies . J. Clin. Endocrinol. Metab. . 90 . 6 . 3600–5 . 2005 . 15755854 . 10.1210/jc.2004-2386 .
  10. Book: Risto Erkkola. The Menopause. 2006. Elsevier. 978-0-444-51830-9. 5–.
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  18. Book: Kenneth L. Becker. Principles and Practice of Endocrinology and Metabolism. 2001. Lippincott Williams & Wilkins. 978-0-7817-1750-2. 712–.
  19. Book: Bruce Alan White. Susan P. Porterfield. Endocrine and Reproductive Physiology, Mosby Physiology Monograph Series (with Student Consult Online Access),4: Endocrine and Reproductive Physiology. 2013. Elsevier Health Sciences. 978-0-323-08704-9. 164–.
  20. Book: Paul M. Coates. M. Coates Paul. Marc Blackman . Marc R. Blackman, Gordon M. Cragg, Mark Levine, Jeffrey D. White, Joel Moss, Mark A. Levine. Encyclopedia of Dietary Supplements (Print). 29 December 2004. CRC Press. 978-0-8247-5504-1. 170–.
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  24. Penning TM . Dehydroepiandrosterone (DHEA)-SO4 Depot and Castration-Resistant Prostate Cancer . Vitam. Horm. . 108 . 309–331 . 2018 . 30029732 . 6226251 . 10.1016/bs.vh.2018.01.007 . Vitamins and Hormones . 9780128143612 .
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  28. Book: Walter K.H. Krause. Cutaneous Manifestations of Endocrine Diseases. 30 November 2008. Springer Science & Business Media. 978-3-540-88367-8. 79–. Plasma DHEA-S levels in adult men and women are 100-500 times higher than those of testosterone and 1000-10000 times higher than those of estradiol..
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  30. http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/8493 Dehydroepiandrosterone Sulfate (DHEA-S), Serum
  31. Wierman. Margaret E.. Arlt. Wiebke. Basson. Rosemary. Davis. Susan R.. Miller. Karen K.. Murad. Mohammad H.. Rosner. William. Santoro. Nanette. Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 99. 10. 3489–510. 10.1210/jc.2014-2260. 25279570. 2014. free.
  32. Elraiyah. Tarig. Sonbol. Mohamad Bassam. Wang. Zhen. Khairalseed. Tagwa. Asi. Noor. Undavalli. Chaitanya. Nabhan. Mohammad. Altayar. Osama. Prokop. Larry. Montori. Victor M.. Murad. Mohammad Hassan. The Benefits and Harms of Systemic Dehydroepiandrosterone (DHEA) in Postmenopausal Women With Normal Adrenal Function: A Systematic Review and Meta-analysis. The Journal of Clinical Endocrinology & Metabolism. 99. 10. 3536–42. 10.1210/jc.2014-2261. 25279571. 2014. 5393492.
  33. Book: J. Elks. The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014. Springer. 978-1-4757-2085-3. 641–.
  34. Book: John W. Blunt. Murray H. G. Munro. Dictionary of Marine Natural Products with CD-ROM. 19 September 2007. CRC Press. 978-0-8493-8217-8. 1075–.
  35. Book: A. Kleemann. J. Engel. B. Kutscher . D. Reichert. Pharmaceutical Substances, 5th Edition, 2009: Syntheses, Patents and Applications of the most relevant APIs. 14 May 2014. Thieme. 978-3-13-179525-0. 2441–2442.
  36. Book: Martin Negwer. Hans-Georg Scharnow. Organic-chemical drugs and their synonyms: (an international survey). 2001. Wiley-VCH. 978-3-527-30247-5. 1831. 3β-Hydroxyandrost-5-en-17-one hydrogen sulfate = (3β)-3-(Sulfooxy)androst-5-en-17-one. R: Sodium salt (1099-87-2). S: Astenile, Dehydroepiandrosterone sulfate sodium, DHA-S, DHEAS, KYH 3102, Mylis, PB 005, Prasterone sodium sulfate, Teloin.
  37. Jianqiu Y . 1992 . Clinical Application of Prasterone Sodium Sulfate . Chinese Journal of New Drugs . 5 . 015 .
  38. Sakaguchi M, Sakai T, Adachi Y, Kawashima T, Awata N . The biological fate of sodium prasterone sulfate after vaginal administration. I. Absorption and excretion in rats . J. Pharmacobio-Dyn. . 15 . 2 . 67–73 . 1992 . 1403604 . 10.1248/bpb1978.15.67. free .
  39. 1992 . The Biological Fate of Sodium Prasterone Sulfate after Vaginal Administration II: Distribution after Single and Multiple Administration to Pregnant Rats . 薬物動態 . 7 . 1. 87–101 . 10.2133/dmpk.7.87. Sakai . Takanori . Sakaguchi . Minoru . Adachi . Yoshiko . Kawashima . Tsuneo . Awata . Norio .
  40. Somani N, Harrison S, Bergfeld WF . The clinical evaluation of hirsutism . Dermatologic Therapy . 21 . 5 . 376–91 . 2008 . 18844715 . 10.1111/j.1529-8019.2008.00219.x. 34029116 .
  41. Web site: Polycystic Ovarian Syndrome Workup. eMedicine. 25 October 2011. 19 November 2011.
  42. 2011 . Neurosteroid Biosynthesis in the Brain of Amphibians . Frontiers in Endocrinology . 2 . 79 . 10.3389/fendo.2011.00079 . 22649387 . 3355965 . Vaudry . H. . Do Rego . J. L. . Burel . D. . Luu-The . V. . Pelletier . G. . Vaudry . D. . Tsutsui . K. . free .
  43. Sachdeva. Silonie. 2010. Hirsutism: Evaluation and Treatment. Indian Journal of Dermatology. 55. 1. 1. 3–7. 10.4103/0019-5154.60342. 2856356. 20418968 . free .

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