Endogenous Metabolite

Dehydroepiandrosterone sulfate (DHEAS) increases the length of neurites that carry the dendritic marker MAP-2 [1]. Dehydroepiandrosterone sulfate (DHEAS) has been shown to increase neuronal excitability (firing rate) when given directly to preseptopic neurons [1]. The human adrenal gland produces substantial amounts of dehydroepiandrosterone (DHEA), principally as 3-sulfoconjugated DHEA sulfate (DS), throughout intrauterine life [2]. Dehydroepiandrosterone sulfate (DHEAS) is generally non-toxic and does not cause negative effects even when administered for an extended period of time [3].

Performance is affected by long-term DHEAS treatment in a dose-dependent manner [3].
The goal of the current study was to test the hypothesis that dehydroepiandrosterone-sulfate (DHEAS), a pro-excitatory neurosteroid, could facilitate recovery of function in male rats after delayed treatment following TBI. DHEAS has been found to play a major role in brain development and aging by influencing the migration of neurons, arborization of dendrites, and formation of new synapses. These characteristics make it suitable as a potential treatment to enhance neural repair in response to CNS injury. In our study, behavioral tests were conducted concurrently with DHEAS administration (0, 5, 10, or 20 mg/kg) starting seven days post-injury (PI). These assays included 10 days of Morris Water Maze testing (MWM; 7d PI), 10 days of Greek-Cross (GC; 21d PI), Tactile Adhesive Removal task (TAR; PI days: 6, 13, 20, 27, 34), and spontaneous motor behavior testing (SMB; PI days: 2, 4, 6, 12, 19, 26, 33). Brain-injured rats showed an improvement in performance in all tasks after 5, 10, or 20 mg/kg DHEAS. The most effective dose of DHEAS in the MWM was 10 mg/kg, while in the GC it was 20 mg/kg, in TAR 5 mg/kg, and all doses, except for vehicle, were effective at reducing injury-induced SMB hyperactivity. In no task did DHEAS-treated animals perform worse than the injured controls. In addition, DHEAS had no significant effects on behavioral performance in the sham-operates. These results can be interpreted to demonstrate that after a 7-day delay, the chronic administration of DHEAS to injured rats significantly improves behavioral recovery on both sensorimotor and cognitive tasks. [3]

Dehydroepiandrosterone (DHEA) is produced in prodigious quantities by the human adrenal, principally as the 3-sulfoconjugate DHEA sulfate (DS) during intrauterine life. The fetal zone and neocortex cells of the fetal adrenal express large amounts of DHEA sulfotransferase and minimal amounts, at least until very near the end of gestation, of 3beta-hydroxysteroid dehydrogenase. This pattern of enzyme expression favors substantial secretion of DHEA/DS with minimal cortisol produced; the DHEA/DS serves as the major precursor for placental estrogen formation in human pregnancy. Aside from adrenocorticotropin, other physiologic regulators of growth and steroidogenesis in the fetal adrenal have been postulated to exist, but have yet to be identified. Whereas intrauterine stressors may activate adrenal cortisol secretion, the fetal adrenal responds to many pregnancy conditions by suppressing DHEA/DS formation. After birth, the human adrenal undergoes reorganization whereby the large, inner fetal zone regresses, and DHEA/DS production is diminished. Just prior to gonadal maturation, the human adrenal undergoes morphologic and functional changes (adrenarche) that give rise to a prominent zona reticularis that is characterized by the presence of DHEA sulfotransferase, the absence of 3beta-hydroxysteroid dehydrogenase, and an enhancement of DHEA/DS production. The adrenal of the adult responds to stress in many instances like that of the fetus: increased cortisol secretion and diminished DHEA/DS secretion. The mechanisms for this divergence in the adrenocortical pathway is unknown. With aging, there is suppression of DHEA/DS secretion, possibly as the consequence of an involution of the zona reticularis, but corticosteroid production continues unabated. [2]

Animal/Disease Models: Sixty-four male SD (Sprague-Dawley) rats, approximately 90 days of age (300-400 g)[3].
Doses: 5, 10, or 20 mg/kg.
Route of Administration: subcutaneous (sc) injection starting 7 days post-surgery and 1 h prior to all behavioral testing.
Experimental Results: Dramatically effective in improving latency to reach the platform as compared to injured rats receiving vehicle.

Metabolism / Metabolites
Dehydroepiandrosterone sulfate (DHEAS) is the sulfate ester of DHEA. This conversion is reversibly catalyzed by sulfotransferase (SULT2A1) primarily in the adrenals, the liver, and small intestine. DHEA sulfate can also be back-converted to DHEA through the action of steroid sulfatase. In the blood, most DHEA is found as DHEAS with levels that are about 300 times higher than those of free DHEA. Orally ingested DHEA is converted to its sulfate when passing through intestines and liver. DHEAS levels show no diurnal variation. In males and females, conversion of DHEAS to DHEA and then to testosterone requires the enzyme 17β-hydroxysteroid dehydrogenase.

Toxicity Summary
Although it predominantly functions as an endogenous precursor to more potent androgens such as testosterone and dihydroxytestosterone, DHEA (which is produced from DHEAS) has been found to possess some degree of androgenic activity in its own right, acting as a low affinity (Ki = 1 μM), weak partial agonist of the androgen receptor. DHEA has also been found to bind to and activate the ERα and ERβ estrogen receptors with Ki values of 1.1 μM and 0.5 μM, respectively. When taken in sufficient quantities DHEAS can cause masculinizing effects. DHEAS is considered an androgenic steroid precursor because testosterone (its product) is an androgen or male hormone. In males and females, conversion of DHEAS to testosterone requires the enzyme 17β-hydroxysteroid dehydrogenase. Testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass, and the growth of body hair. High levels of testosterone can lead to masculinization in females or premature puberty in young boys. Chronically high levels in adults increase the incidence of heart attack, stroke and blood clots by lowering the level of HDL (good cholesterol). The development of breast tissue in males, a condition called gynecomastia (which is usually caused by high levels of circulating estradiol), arises because of increased conversion of testosterone to estradiol by the enzyme aromatase. Reduced sexual function and temporary infertility can also occur in males.

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Toxicity Summary
Although it predominantly functions as an endogenous precursor to more potent androgens such as testosterone and dihydroxytestosterone, DHEA (which is produced from DHEAS) has been found to possess some degree of androgenic activity in its own right, acting as a low affinity (Ki = 1 μM), weak partial agonist of the androgen receptor. DHEA has also been found to bind to and activate the ERα and ERβ estrogen receptors with Ki values of 1.1 μM and 0.5 μM, respectively. When taken in sufficient quantities DHEAS can cause masculinizing effects. DHEAS is considered an androgenic steroid precursor because testosterone (its product) is an androgen or male hormone. In males and females, conversion of DHEAS to testosterone requires the enzyme 17β-hydroxysteroid dehydrogenase. Testosterone plays a key role in the development of male reproductive tissues such as the testis and prostate as well as promoting secondary sexual characteristics such as increased muscle, bone mass, and the growth of body hair. High levels of testosterone can lead to masculinization in females or premature puberty in young boys. Chronically high levels in adults increase the incidence of heart attack, stroke and blood clots by lowering the level of HDL (good cholesterol). The development of breast tissue in males, a condition called gynecomastia (which is usually caused by high levels of circulating estradiol), arises because of increased conversion of testosterone to estradiol by the enzyme aromatase. Reduced sexual function and temporary infertility can also occur in males.

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Health Effects
Some researchers believe DHEAS supplements might actually raise the risk of breast cancer, prostate cancer, heart disease, diabetes and stroke. DHEAS may stimulate tumor growth in types of cancer that are sensitive to hormones, such as some types of breast, uterine, and prostate cancer. DHEAS may increase prostate swelling in men with benign prostatic hyperplasia (BPH), an enlarged prostate gland. High doses of DHEAS may cause aggressiveness, irritability, trouble sleeping, and the growth of body or facial hair on women. It also may stop menstruation and lower the levels of HDL ('good' cholesterol), which could raise the risk of heart disease. Other reported side effects include acne, heart rhythm problems, liver problems, hair loss (from the scalp), and oily skin. In women, DHEA may cause decreased breast size, a deep voice, increased genital size, irregular periods, oily skin, and unnatural hair growth. In men, DHEAS may cause aggression, breast tenderness or enlargement, decreased testes size, and urinary urgency. DHEAS may interfere with the way the body processes certain agents using the liver's cytochrome P450 enzyme system. Chronically high levels of Dehydroepiandrosterone sulfate are associated with male pseudohermaphrodism with gynecomastia.

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Exposure Routes: Endogenous, ingestion

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Symptoms
In women, DHEAS may cause decreased breast size, a deep voice, increased genital size, irregular periods, oily skin, and unnatural hair growth. In men, DHEAS may cause aggression, breast tenderness or enlargement, decreased testes size, and urinary urgency.

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mouse LD50 intraperitoneal 655 mg/kg Shengzhi Yu Biyun. Reproduction and Contraception., 13(414), 1993
mouse LD50 intravenous 293 mg/kg Shengzhi Yu Biyun. Reproduction and Contraception., 13(414), 1993

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Minimum Risk Level
Dehydroepiandrosterone sulfate levels above 1890 micromol/L or 700-800 µg/dL are highly suggestive of adrenal dysfunction.

[1]. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4089-91.

[2]. Dehydroepiandrosterone and dehydroepiandrosterone sulfate production in the human adrenal during development and aging. Steroids. 1999 Sep;64(9):640-7.

[3]. The delayed administration of dehydroepiandrosterone sulfate improves recovery of function after traumatic brain injury in rats. J Neurotrauma. 2003 Sep;20(9):859-70.

Dehydroepiandrosterone sulfate is a steroid sulfate that is the 3-sulfooxy derivative of dehydroepiandrosterone. It has a role as an EC 2.7.1.33 (pantothenate kinase) inhibitor, a human metabolite and a mouse metabolite. It is a steroid sulfate and a 17-oxo steroid. It is functionally related to a dehydroepiandrosterone. It is a conjugate acid of a dehydroepiandrosterone sulfate(1-).
DHEA sulfate is the major steroid of the fetal adrenal. DHEA-S is the principal adrenal androgen and is secreted together with cortisol under the control of ACTH and prolactin. DHEA-S is elevated with hyperprolactinemia.
Dehydroepiandrosterone sulfate has been reported in Homo sapiens and Apis cerana with data available.
Dehydroepiandrosterone sulfate or DHEAS is the sulfated form of dehydroepiandrosterone (DHEA). This sulfation is reversibly catalyzed by sulfotransferase 2A1 (SULT2A1) primarily in the adrenals, the liver, and small intestine. In the blood, most DHEA is found as DHEAS with levels that are about 300 times higher than those of free DHEA. Orally-ingested DHEA is converted to its sulfate when passing through intestines and liver. Whereas DHEA levels naturally reach their peak in the early morning hours, DHEAS levels show no diurnal variation. From a practical point of view, measurement of DHEAS is preferable to DHEA, as levels are more stable. DHEA (from which DHEAS comes from) is a natural steroid prohormone produced from cholesterol by the adrenal glands, the gonads, adipose tissue, brain and in the skin (by an autocrine mechanism). DHEA is the precursor of androstenedione, which can undergo further conversion to produce the androgen testosterone and the estrogens estrone and estradiol. DHEA is also a potent sigma-1 agonist. DHEAS can serve as a precursor for testosterone; androstenedione; estradiol; and estrone. Serum dehydroepiandrosterone sulfate is a classic marker for adrenarche and, subsequently, for the individual hormonal milieu Dehydroepiandrosterone sulfate is an endogenously produced sex steroid that has been hypothesized to have anti aging effects It also has been inversely associated with development of atherosclerosis (A3325, A3326, A3327). DHEA-S is the principal adrenal androgen and is secreted together with cortisol under the control of ACTH and prolactin. DHEA-S is elevated with hyperprolactinemia.
The circulating form of a major C19 steroid produced primarily by the ADRENAL CORTEX. DHEA sulfate serves as a precursor for TESTOSTERONE; ANDROSTENEDIONE; ESTRADIOL; and ESTRONE.

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Drug Indication
Investigated for use/treatment in asthma and burns and burn infections.

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Mechanism of Action
The low levels of dehydroepiandrosterone sulfate(DHEA-S)is associated with unfavorable levels of several strong cardiovascular disease risk factors, such as lipids and blood pleasure, which are components of the metabolic syndrome, and insulin levels. DHEA-S deficiency is risk factors of obesity and insulin resistance, but it is not clear, whether this possible influence is independent.

C19H28O5S

368.48762

368.166

C, 61.93; H, 7.66; O, 21.71; S, 8.70

651-48-9

78590-17-7 (sodium);651-48-9 (free acid);

12594

White to off-white solid powder

1.1763 g/ml

190-192 °C (lit.)

4.787

1

5

2

25

721

6

C[C@]12CC[C@H]3[C@H]([C@@H]1CCC2=O)CC=C4[C@@]3(CC[C@@H](C4)OS(=O)(=O)O)C

CZWCKYRVOZZJNM-USOAJAOKSA-N

InChI=1S/C19H28O5S/c1-18-9-7-13(24-25(21,22)23)11-12(18)3-4-14-15-5-6-17(20)19(15,2)10-8-16(14)18/h3,13-16H,4-11H2,1-2H3,(H,21,22,23)/t13-,14-,15-,16-,18-,19-/m0/s1

[(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-yl] hydrogen sulfate

Prasterone sulfate; DEHYDROEPIANDROSTERONE SULFATE; DHEA sulfate; 651-48-9; Dehydroisoandrosterone sulfate; Dehydroepiandrosterone sulphate; DHEAS; Dehydroandrosterone sulfate;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~271.38 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.78 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.78 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)