Dehydroepiandrosterone and its Sulfate
Joint Statement by the German Society for Gynecological Endocrinology and Reproductive Medicine [DGGEF] and the German Professional Association of Gynecologists [BVF])

Journal für Reproduktionsmedizin und Endokrinologie - Journal of Reproductive Medicine and Endocrinology 2015; 12 (4): 318-341

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Keywords: Benefit,  DHEA,  Doping,  future perspectives,  side effects

Dehydroepiandrosterone (DHEA) is the most frequent circulating steroid hormone in humans. It is formed in the reticular zone of the adrenal glands to 90– 95% and, to a lower extent in the gonads and the brain where DHEA acts as neuro-steroid. There is an interconversion of DHEA to DHEAS in both directions. DHEAS levels in the blood are approximately 300 times higher in comparison to free DHEA levels. The DHEA peak levels are reached in the early morning hours whereas DHEAS is not subject to a circadian rhythm. Hence, DHEAS is well suitable for analysis in serum. DHEA is a universal precursor for the formation of androgen and estrogen in peripheral tissues. They contain enzyme systems such as 3beta-HSDH for the formation of androstenedione, 17alpha-hydroxysteroid dehydrogenase for the synthesis of testosterone and aromatase for estrogen-synthesis. Maximum levels of DHEA/DHEAS are reached between 20 and 30 years of age. At the age of 70 or older DHEAS levels can be up to 75% lower.
Mode of action: DHEA acts predominantly as steroid precursor in the biosynthesis of androgenic and estrogenic sex steroids. There have been no DHEA/ DHEAS receptors identified yet. DHEA and DHEAS bind and activate several receptors including ER-alpha and ER-beta, peroxisome-proliferator activated receptors, PXR (pregnant-X-receptor), AUTO (constitutive androstane receptor) and beyond that membrane receptors as neuro-steroids like NMDA receptors (N-methyl- D-aspartate, glutamate) as positive allosteric modulator of the GABAA receptor and negative allosteric modulator. DHEA/DHEAS has a variety of dose independent effects like immune-modulation, effects on haemostasis, the lipid- and carbohydrate metabolism, bone health and mental health.
Pharmacology: The pharmacokinetic of DHEA depends on gender, dosing (25–50, 100 or 300 mg/day oral, no further increase of DHEA or DHEAS concentrations, respectively), and the route of application (oral, transdermal, vaginal). The oral adsorption is excellent. DHEA is converted in DHEAS by sulphation in the intestines and the liver after oral intake. DHEA and DHEAS were converted in several biologically active metabolites, including androstenedione, testosterone, estrone, estradiol and estriol. The elimination half-life of DHEA is 15–38 minutes; the half-life of DHEAS is 7–22 hours. Clearance of 51–73% of DHEAS and its metabolites is achieved by renal excretion.
Route of administration:
– Oral: Females take initially (10)–25 mg in the morning with dose reduction depending on clinical symptoms and DHEA levels in the blood. Dose adjustment is required for long-term treatments (e.g. 15–25 mg/day for females and 25–50 mg/day in males). Blood levels should be checked regulary and should range from 20 to 30 nmol/l (5.6–8.6 ng/ml).
Supplements:
– Oral: There are several international vendors offering compounds with 10, 20, 50 and 100 mg (off-label in Germany on prescription). Physiological doses of DHEA when taken per oral in healthy men > 40 years of age are between 20–50 mg for males and 10–30 mg for females. US pharmacists recommend 50– 200 mg daily despite some studies investigated doses above and below these ranges.
– Transdermal: There is a 10% DHEA cream for transdermal administration available. 3–5 g cream per day are usually applied resulting in 300–500 mg DHEA applied to the skin.
– Intravaginal: According to Cleveland Clinic: http://www.clevelandclinicwellness.com/Features/Pages/DHEA-Suppository.aspx 25 mg suppository for use at night.
Side effects: Most of unwanted side effects are mild and occur due to the androgenic effect of DHEA. Increased sebum production, increased facial hair and changes in androgenic hair might occur in females. Changes of the voice have not been observed yet.
Advantages and risks:
– No health-advantage detectable: There is no evidence that DHEA treatment can be used to prevent cardiovascular diseases, cognitive disorders, depression or to improve well-being. Most workgroups did not find any positive effects of DHEA on general well-being and physical strength. Small sample sizes and short observational periods may play a role there. So far, there is no evidence that DHEA has positive effects in patients wishing to become pregnant: premature ovarian insufficiency reduced ovarian reserve, poor response to stimulation in the context of ART. – Potential health-advantages: DHEA substitution might play a role in women with low DHEA levels, e. g. adrenal insufficiency: Beside the substitution with gluco- and mineral corticosteroids, one might consider DHEAS substitution in single cases. – Anorexia nervosa: DHEA has positive effects on bones, also in women with a lack of estrogen in fertile ages, as for example in patients with anorexia nervosa. – Vaginal atrophy: Treatment with vaginal DHEA suppositories results in a rapid relief of symptoms of vaginal atrophy with only minimal to no changes in serum steroids. There are no concerns of systemic side effects, as observed in estrogen therapy. However, local administration is required daily. Approved alternative treatment options such as low dose intravaginal estriol treatment or oral administration of novel SERMs (Ospemifen) should be preferred. – Health hazards: DHEA can be metabolized to testosterone as well as to estrogen. There is increasing evidence on a potential correlation between low DHEA levels and a cardiovascular risk as well as to high DHEA levels and the risk to develop breast cancer.
Precautions:
– Doping: DHEA is a prohibited substance according to the World Anti-Doping Code by the World Anti-Doping Agency.
– Drug-drug interactions: for example tamoxifen – concomitant DHEA administration might lead to tamoxifene-resistance.
– DHEA is commonly used as prescription-free food supplement or anti-ageing drug in the United States. This does not necessarily mean that the product is safe since there are no corresponding long-term studies.
– Informed consent: Patients must be informed thoroughly about potential risks and benefits of DHEA treatment.
– Males: DHEA should not be used by persons suffering from prostate- or testicular cancer.
– All patients: Patients with severe diseases or hormonal disorders should take DHEA only after seeking competent medical advice and surveillance.
Future perspectives:
– Oral DHEA treatment might be indicated in special clinical indications as, in single cases, in patients with adrenal insufficiency, particularly in women.
– Intravaginal application in cases of vaginal atrophy is an interesting therapeutic option in this disorder.
– Positive effects of DHEA treatment on well-being, disturbances of memory, psychosexual disorders and bone-health were observed in studies investigating DHEA in other indications.
– Clinical trials with new DHEA metabolits e.g. 7-keto-DHEA are still ongoing.