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 of dehydroepiandrosterone (DHEA). This conversion is reversibly catalyzed primarily in the adrenal glands, liver, and small intestine by sulfotransferase (SULT2A1). DHEA sulfate can also be reversed back to DHEA by steroid sulfatases. In the blood, most DHEA exists as DHEAS, at concentrations approximately 300 times higher than free DHEA. Orally ingested DHEA is converted to sulfate as it passes through the intestines and liver. DHEAS levels do not exhibit diurnal variation. In both men and women, the conversion of DHEAS to DHEA, and then to testosterone, requires the catalysis of 17β-hydroxysteroid dehydrogenase.

Toxicity Summary
While DHEA (produced from DHEAS) primarily functions as an endogenous precursor to more potent androgens such as testosterone and dihydroxytestosterone, studies have found that DHEA itself also possesses androgenic activity, acting as a weak partial agonist with low affinity (Ki = 1 μM) for androgen receptors. DHEA has also been found to bind to and activate ERα and ERβ estrogen receptors with Ki values of 1.1 μM and 0.5 μM, respectively. When sufficient amounts of DHEAS are ingested, masculinizing effects can occur. DHEAS is considered a precursor to androgenic steroids because testosterone (and its products) is an androgen or male hormone. In both men and women, the conversion of DHEAS to testosterone requires the catalysis of 17β-hydroxysteroid dehydrogenase. Testosterone plays a crucial role in the development of male reproductive tissues such as the testes and prostate and promotes the development of secondary sexual characteristics, such as muscle growth, bone mass increase, and body hair growth. High levels of testosterone can lead to masculinization in women or precocious puberty in boys. High levels of testosterone in adults over a long period can lower levels of high-density lipoprotein cholesterol (good cholesterol), increasing the risk of heart attack, stroke, and blood clots. Gynecomastia, also known as male breast development (usually caused by excessively high levels of estradiol in the circulation), is due to aromatase promoting the conversion of testosterone to estradiol. Men may also experience decreased libido and temporary infertility.

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Toxicity Overview
Although DHEA (produced from DHEAS) primarily functions as an endogenous precursor to more potent androgens such as testosterone and dihydroxytestosterone, studies have found that DHEA itself also possesses androgenic activity, acting as a weak partial agonist with low affinity (Ki = 1 μM) for androgen receptors. DHEA has also been found to bind to and activate ERα and ERβ estrogen receptors with Ki values of 1.1 μM and 0.5 μM, respectively. When adequate amounts of DHEAS are ingested, masculinizing effects can occur. DHEAS is considered a precursor to androgen steroids because testosterone (and its products) is an androgen or male hormone. In both men and women, the conversion of DHEAS to testosterone requires the catalysis of 17β-hydroxysteroid dehydrogenase. Testosterone plays a crucial role in the development of male reproductive tissues such as the testes and prostate, and promotes the development of secondary sexual characteristics, such as muscle growth, bone mass increase, and body hair growth. High levels of testosterone can lead to masculinization in women or precocious puberty in boys. Long-term high levels of testosterone in adults can lower levels of high-density lipoprotein (good cholesterol), thereby increasing the risk of heart attack, stroke, and blood clots. Gynecomastia (often caused by excessively high levels of circulating estradiol) is due to aromatase promoting the conversion of testosterone to estradiol. Men may also experience decreased sexual function and temporary infertility.

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Health Effects
Some researchers believe that DHEAS supplementation may actually increase the risk of breast cancer, prostate cancer, heart disease, diabetes, and stroke. DHEAS may stimulate the growth of tumors in certain hormone-sensitive cancers, such as certain types of breast cancer, uterine cancer, and prostate cancer. DHEAS may worsen prostate swelling in men with benign prostatic hyperplasia (BPH, or enlarged prostate). High doses of DHEAS may cause symptoms in women such as aggression, irritability, sleep disturbances, and increased body or facial hair. It may also cause amenorrhea and lower high-density lipoprotein ("good" cholesterol) levels, increasing the risk of heart disease. Other reported side effects include acne, arrhythmias, liver problems, hair loss (dandruff), and oily skin. In women, DHEAS may cause breast shrinkage, a deeper voice, enlarged vulva, menstrual irregularities, oily skin, and abnormal hair growth. In men, DHEAS may cause aggression, breast tenderness or enlargement, testicular shrinkage, and urinary urgency. DHEAS may interfere with the way the body processes certain substances using the liver's cytochrome P450 enzyme system. Long-term high levels of dehydroepiandrosterone sulfate have been associated with male pseudohermaphroditism with gynecomastia.

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Exposed route: Endogenous, ingested

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Symptoms
In women, DHEAS may cause breast shrinkage, voice deepening, genital enlargement, menstrual irregularities, oily skin, and abnormal hair growth. In men, DHEAS may cause aggression, breast tenderness or enlargement, testicular shrinkage, and urinary urgency.

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Intraperitoneal LD50 in mice: 655 mg/kg², Yu Biyun, Reproduction and Contraception, 13(414), 1993
Intravenous LD50 in mice: 293 mg/kg², Yu Biyun, Reproduction and Contraception, 13(414), 1993

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Lowest risk level
Dehydroepiandrosterone sulfate levels above 1890 μmol/L or 700-800 μg/dL are highly indicative 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 (DHEA-S) is a steroidal steroid, a 3-sulfonoxy derivative of dehydroepiandrosterone. It is an EC 2.7.1.33 (pantothenic acid kinase) inhibitor and a metabolite in humans and mice. It is a steroidal steroid and a 17-oxosteroid. Its function is related to dehydroepiandrosterone. It is the conjugate acid of dehydroepiandrosterone sulfate (1-). Dehydroepiandrosterone sulfate is the major steroidal steroid of the fetal adrenal gland. DHEA-S is the major adrenal androgen, co-secreted with cortisol under the regulation of adrenocorticotropic hormone (ACTH) and prolactin. Hyperprolactinemia can lead to elevated DHEA-S levels. Studies have reported the presence of dehydroepiandrosterone sulfate in both humans and honeybees. Dehydroepiandrosterone sulfate (DHEAS) is the sulfated form of dehydroepiandrosterone (DHEA). This sulfation reaction is reversibly catalyzed primarily by sulfotransferase 2A1 (SULT2A1) in the adrenal glands, liver, and small intestine. Most DHEA in the blood exists as DHEAS, at levels approximately 300 times higher than free DHEA. Orally ingested DHEA is converted to sulfate as it passes through the intestines and liver. DHEA levels typically peak in the morning, while DHEAS levels do not exhibit diurnal variation. From a practical standpoint, DHEAS measurement is superior to DHEA because DHEAS levels are more stable. DHEA (a precursor to DHEAS) is a natural steroid hormone synthesized from cholesterol by the adrenal glands, gonads, adipose tissue, brain, and skin (through autocrine mechanisms). DHEA is a precursor to androstenedione, which can be further converted into the androgens testosterone and the estrogens estrone and estradiol. DHEA is also a potent σ-1 receptor agonist. DHEAS can serve as a precursor to testosterone, androstenedione, estradiol, and estrone. Serum dehydroepiandrosterone sulfate (DHEA-S) is a classic marker of adrenal gland development, reflecting individual hormone levels. DHEA-S is an endogenously produced sex steroid believed to have anti-aging effects. It is also negatively correlated with the development of atherosclerosis (A3325, A3326, A3327). DHEA-S is the primary adrenal androgen, co-secreted with cortisol under the regulation of adrenocorticotropic hormone (ACTH) and prolactin. Hyperprolactinemia can lead to elevated DHEA-S levels. DHEA-S is the circulating form of a major C19 steroid primarily produced by the adrenal cortex. DHEA-S is a precursor to testosterone, androstenedione, and estradiol.

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Drug Indications
It has been studied for the treatment of asthma, burns, and burn infections.

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Mechanism of Action
Low levels of dehydroepiandrosterone sulfate (DHEA-S) are associated with adverse levels of several strong risk factors for cardiovascular disease, such as blood lipids and dyslipidemia (a component of metabolic syndrome) and insulin levels. DHEA-S deficiency is a risk factor for obesity and insulin resistance, but it is unclear whether this potential effect exists independently.

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.)