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36 Review Articles

THE EFFECTS OF TREATMENT WITH (DHEA) ON CIRCULATING , BODY COMPOSITION AND MUSCLE STRENGTH IN MEN AND WOMEN

S. S. Ivanova1, K. Ivanov1, S. A. Ivanova1, S. Papanov1, D. Obreshkova2 1Medical University – Plovdiv, Faculty of Pharmacy, Department Pharmacognosy and Pharmaceutical Chemistry, Plovdiv, Bulgaria 2Medical University – Sofia, Faculty of Pharmacy, Department Pharmaceutical Chemistry, Sofia, Bulgaria

Abstract. Nowadays many individuals are using “performance-enhancing” nutritional supple- ments. Many professional and nonprofessional athletes take the popular supplements, containing the DHEA (Prasterone), to increase their levels and improve their perfor- mance. Even DHEA has been considered as a hormone with multiple effects, it is sold as a in many countries. (DHEA), a 19-carbon , is situated along the steroid . It is the most abundant circulating hormone in the body and can be converted to either or . The physiological function of Dehydroepian- drosterone remains poorly understood and not enough analyzed. In this work we have analyzed the beneficial effects of a supplementation with Prasterone in order to alleviate its decrease in and improve well-being. We have summarized the results of clinical trials including more than 1000 women and men.

Key Words: Dehydroepiandrosterone; Dehydroepiandrosterone ; Prasterone; physical performance; muscle strength; sport; ; hormones; androgens; food supplements.

Abbreviation: Dehydroepiandrosterone (DHEA), Dehydroepiandrosterone sulphate (DS), -like -I (IGF-I), muscle strength (MedX), binding (GHBP), mineral density (BMD), testosterone (T), physical performance test (PPT), an- drostenedione (A), growth hormone binding protein (GHBP).

Introduction: DHEA was isolated from the blood, and in 1959 the Human and some other primates are unique since chemist E. Baulieu discovered that DHEA-S, which their adrenals secrete large amounts of dehydroepi- is the most abundant form of the hormone found in (DHEA) and its sulfate (DHEA-S), human plasma. In 1965, De Neve and Vermeulen re- which are converted into (4-dione) ported an association between DHEA-S levels and and then into potent androgens and estrogens in pe- aging; it was found that as people age, DHEA-S ripheral tissues, therefore providing autonomous in- levels decline in a linear fashion [20][21]. This dis- tracrine control to target tissues that can adjust the covery led to numerous studies that focused on the formation and of active steroids link between DHEA and DHEA-S levels and the according to local requirements. [25] Dehydroepi- aging process.[18] DHEA is readily conjugated to androsterone (DHEA) is an endogenous steroid that its sulphate DHEAS, and they are designated is produced by the of the adrenal as DHEA(S) here when used together. Its secretion cortex.[19] It was first isolated in 1934 from reaches a peak in early adulthood and thereafter by Butenandt and Dannenbaum. In 1944, Dehydroe- decreases, until approximately age 70 years when piandrosterone sulfate (DHEA-S), DHEA’s sulfated it reaches a concentration of approximately 20%. , was isolated from the urine. In 1954, The effects of treatment with prasterone (dhea) on circulating... PHARMACIA, vol. 62, No. 4/2015 37

Many hormonal changes may take place with aging this steroid and are reviewed here. Since the levels of but none is as marked as this. This “relative DHEA DHEA correlate with general good health, and aging deficiency” resulted in DHEA being enthusiastically is associated with a decline in the secretion of this labeled by some as a fountain of youth or an antidote steroid, a growing interest in replacement of DHEA to aging that would prove to be the panacea they are in elderly people has developed.[4] Administration seeking. Its use was also taken up enthusiastically by of Dehydroepiandrosterone (DHEA), a precursor of the athletic community and used as a prohormone in sex steroid hormones, reduces total and visceral fat the belief or hope that it would be converted mainly mass and elevates adipocytic ex- to testosterone in the body.[6] Dehydroepiandroste- pression.[5] Prasterone supplementation has been re- rone (DHEA) is a weak also used to ele- ported to increase testosterone and fat-free mass in vate testosterone levels, and is advertised as an an- nontrained populations.[22] ti- and anti-aging supplement capable of im- proving , vitality and immunity levels.[7] The Clinical studies, analyzing the effects of age-related decline of Dehydroepiandrosterone and DHEA supplementation its sulfate ester levels is thought to be related to the Dehydroepiandrosterone, also known as andro- development of age-associated usual modifications, stenolone or prasterone is an important endogenous such as neuromuscular function impairments. It is of- .[16] Oral absorption of DHEA is ten claimed that individuals can enhance their mus- excellent. The volume of distribution is 17.0-38.5 cular capacity by boosting Dehydroepiandrosterone L for DHEA and 8.5-9.3 L for DHEAS. DHEA and levels through oral supplementation.[3] Dehydroepi- DHEAS are converted into several active , androsterone (DHEA) and DHEA-sulfate (DHEAS) including androstenedione, testosterone, , es- represent the major androgens secreted by the adre- tradiol, and (Figure 1). The elimination half- nal gland. Various functions including metabolic, im- life of DHEA is 15-38 minutes, whereas the half-life mune, and cognitive effects have been attributed to of DHEAS is 7-22 hours. Renal accounts

Figure 1. DHEA metabolism 38 PHARMACIA, vol. 62, No. 4/2015 S. S. Ivanova, K. Ivanov, S. A. Ivanova, S. Papanov, D. Obreshkova for 51-73% of the elimination of DHEAS and its me- of DHEA and DHEA sulfate found in advanc- tabolites.[26,27,28,29] DHEA and DHEAS serve as ing age have been correlated with a myriad of the precursors of approximately 50% of androgens health conditions. Also, some studies suggest in men, 75% of active estrogens in premenopausal gender-specific actions of endogenous and ex- women, and 100% of active estrogens after meno- ogenous DHEA.[23] We have summarized the pause.[30] results of some clinical trials included over 1000 Dehydroepiandrosterone (DHEA) therapy is men and women. In table 1 could be seen the de- controversial due to sensationalized reports of sign of these studies and the conclusions. epidemiologic studies and the over-the-count- Physiological replacement dosages of oral er availability of DHEA. Human clinical trials DHEA in healthy people older than 40 years have investigated the potential of DHEA are in the range of 20-50 mg/day for men and therapy in multiple conditions with resultant in- 10-30 mg/ day for women.[30] The researchers consistencies in findings. DHEA is unique com- Tummala and Svec have described that incre- pared with other adrenal steroids because of the mental increases in serum DHEA and DHEAS fluctuation in serum levels found from birth into levels appear to plateau at an oral DHEA dosage advancing age. The lower endogenous levels

Table 1. Clinical studies about the beneficial effects of Prasterone (DHEA) supplementation.

Design of the study and measurements Results Ref. Prospective, randomized, double-blind, and A time- and dose-dependent improvement of the four [17] placebo-controlled phase III has domains of sexual function was observed. At the 12- evaluated the effect of daily local intravaginal week time interval, the 1.0% DHEA dose led, compared application of Prasterone for 12 weeks on with placebo, to 49% (P = 0.0061) and 23% (P = 0.0257) the domains of , namely, improvements of the desire domains in the desire/interest, arousal, orgasm, and pain at Specific Quality of Life and Abbreviated Sex Function sexual activity, in 216 postmenopausal women questionnaires, respectively. Compared with placebo, the with moderate to severe symptoms of vaginal Abbreviated Sex Function arousal/sensation domain was atrophy. improved by 68% (P = 0.006), the arousal/lubrication domain by 39% (P = 0.0014), orgasm by 75% (P = 0.047), and dryness during intercourse by 57% (P = 0.0001). By a local action in the , DHEA applied daily at doses at which serum steroids remain well within normal postmenopausal values exerts relatively potent beneficial effects on all four aspects of sexual dysfunction. Healthy non-obese age-advanced (50-65 A daily oral 100 mg dose of DHEA for 6 months resulted [1] years of age) men (n = 9) and women (n = in elevation of circulating DHEA and DS concentrations 10) were randomized into a double-blind and the DS/ ratio. Biotransformation to potent placebo-controlled cross-over trial. Sixteen androgens near and slightly above the range of their subjects completed the one-year study of six younger counterparts occurred in women with no months of placebo and six months of 100 mg detectable change in men. Given this hormonal milieu, oral DHEA daily. Fasting early morning blood an increase in serum IGF-I levels was observed in both samples were obtained. Serum DHEA, DS, sex genders but dimorphic responses were evident in fat steroids, IGF-I, IGFBP-1, IGFBP-3, growth body mass and muscle strength in favour of men. These hormone binding protein (GHBP) levels and differences in response to DHEA administration may profiles as well as body composition reflect a gender specific response to DHEA and/or the (by DEXA) and muscle strength (by MedX presence of confounding factor(s) in women such as testing) were measured at baseline and after replacement therapy. each treatment. The effects of treatment with prasterone (dhea) on circulating... PHARMACIA, vol. 62, No. 4/2015 39

Design of the study and measurements Results Ref. Double-blind, randomized, placebo-controlled Eighty-seven women (88%) completed 6 months. There [2] trial. Hormone levels, bone mineral density were no significant changes in BMD or bone turnover (BMD), bone turnover markers, body markers. DHEA supplementation resulted in gains in composition, upper and lower extremity lower extremity strength (from 459 ± 121 N to 484 ± strength, physical performance. 147 N; P=.01). There was also improvement in Short Physical Performance Battery score, a composite score that focuses on lower extremity function, in those taking DHEA (from 10.1 ± 1.8 to 10.7 ± 1.9; P=.02). There were significant changes in all hormone levels, including DHEAS, , estrone, and testosterone, and a decline in -binding globulin levels in those taking DHEA. DHEA supplementation improved lower extremity strength and function in older, frail women involved in a gentle program of chair aerobics or yoga. No changes were found in BMD either due to small sample size, short duration of study or no effect. The physical function findings are promising and require further evaluation as frail women are at high risk for falls and fracture. It was performed on 280 healthy ambulatory The results give evidence that Dehydroepiandrosterone [3] and independent men and women aged administration restores Dehydroepiandrosterone sulfate 60 to 80 years. The study design was a serum concentrations to the normal range for young adults double-blind placebo-controlled trial. (aged 20-50 years). However, no positive effect inherent Dehydroepiandrosterone sulfate serum to Dehydroepiandrosterone treatment was observed either concentration, handgrip strength, isometric on muscle strength or in muscle and fat cross-sectional and isokinetic knee muscle strength, and thigh areas. (fat and muscle) cross-sectional area were analyzed before and just after 12 months of placebo or Dehydroepiandrosterone treatment. This manuscript examines the relationships All hormones exhibited significant age-adjusted positive [24] of total testosterone (T), bioavailable T, association with PPT score below, but not necessarily DHEA, and DHEA sulfate (DHEAS) to above, the thresholds. DHEA was positively associated measures of physical performance in a large, with chair stand score below, but was not above the population-based, random sample of men. In threshold. None of the hormones studied was significantly the most recent wave of the Massachusetts associated with grip strength. Up to certain critical Male Aging Study, measures of strength and concentrations, elevated levels of TT, total T, bioavailable physical performance [seven-item physical T, DHEA, and DHEA sulfate are associated with performance test (PPT), timed chair stand test, increased physical performance, as indicated by the PPT. and grip strength] were made in 684 men, aged However, levels beyond those critical concentrations, as 55–85 years. Complete hormone data were might be achieved through exogenous supplementation, also obtained. Initial graphical exploration do not appear to confer any additional benefit. In general, of performance outcomes as a function of hormone concentrations do not appear to be meaningfully hormone levels showed linear increases in associated with grip strength or chair stand scores. physical performance up to certain threshold hormone concentrations, beyond which the associations were diminished. 40 PHARMACIA, vol. 62, No. 4/2015 S. S. Ivanova, K. Ivanov, S. A. Ivanova, S. Papanov, D. Obreshkova

Design of the study and measurements Results Ref. A randomized, placebo-controlled, double- Despite a small increase in (0.8 +/- 0.4 [9] blind design was used to study 40 healthy, and 0.5 +/- 0.3 kg) and mean strength (6.8 +/- 2.7 and trained (>1 year weight training) male 5.7 +/- 2.4 kg) in both D and A groups respectively, subjects (mean +/- SD: age 48.1 +/- 3.9 these changes were not significantly different from P. In years; weight 79.8 +/- 9.8 kg). Subjects were D, there was a significantly greater increase in DHEA-S randomly assigned to one of three groups: levels than in P (P < 0.05). There were no adverse side placebo (P), DHEA (D), or androstenedione effects demonstrated during D or A supplementation (A). Supplements (50 mg capsules) were including significant changes in PSA, function, or ingested two times daily for 12 weeks. All lipid levels (P < 0.05).The results of this study suggest testing, including venous blood samples, body that supplementation with 100 mg x d(-1) of either composition, and performance, was conducted androstenedione or DHEA does not independently elicit at three time points: presupplementation (1 d), a statistically significant increase in lean body mass, at 6 week, and postsupplementation (12 week). strength, or testosterone levels in healthy adult men over a 12-wk period.

Table 2. Food additives containing Prasterone (Dehydroepiandrosterone).

1. DHEA (Blade Nutrition Test Booster), 180 caps. 25 mg.

2. DHEA (MRM), 90 caps. 25 mg.

3. DHEA (Natrol), 300 tabl. 25 mg.

4. DHEA Fast Dissolve (Natrol), 30 tabl. 25 mg.

5. DHEA MAX (Nutraceutics), 60 tabl. 25 mg.

6. DHEA (Ultimate Nutrition), 100 caps. 25 mg.

7. DHEA (Healthy ‚N Fit), 100 caps. 50 mg.

8. DHEA (MRM), 60 caps. 50 mg.

9. DHEA (Natrol), 60 tabl. 50 mg.

10. DHEA (S.A.N.), 90 caps. 50 mg.

11. DHEA (Ultimate Nutrition), 100 caps. 50 mg.

12. DHEA (PharmaFreak), 28 caps. 60 mg.

13. DHEA (Maximum Nutrients), 60 caps. 100 mg. The effects of treatment with prasterone (dhea) on circulating... PHARMACIA, vol. 62, No. 4/2015 41 of 300 mg/day and inferred that doses greater misuse of drugs legislation“ in UK. DHEA is a than this have little additional therapeutic val- Class C Controlled Drug drug under the Misuse ue. [31] Sometimes professional and nonprofes- of Drugs Act. In Bulgaria Prasterone (DHEA) is sional athletes take inhibitors when legal to sell as a dietary supplement. DHEA is a they take Prasterone for increasing testosterone prohibited substance under the World Anti-Dop- levels. These sportsman take also aromatase in- ing Code of the World Anti-Doping Agency. hibitors when they make an anabolic steroidal [13] In January 2011, NBA player O.J. Mayo cycle. The function of the aromatase inhibitors was given a 10-game suspension after testing is to prevent . Aromatase inhibitors positive for DHEA. Mayo termed his use of are classified as either steroidal or , DHEA as “an honest mistake,” saying the DHEA or as first, second or third generation. Steroidal was in an over-the-counter supplement and that inhibitors such as and he was unaware the supplement was banned by inhibit aromatase activity by mimicking the sub- the NBA.[14] 2008 Olympic 400 meter cham- strate androstenedione. Nonsteroidal in- pion Lashawn Merritt has also tested positive hibitors such as and inhibit for DHEA and was banned from the sport for 21 enzyme activity by binding with the iron months.[15] of the enzyme. First-generation aromatase inhib- itors such as are relatively Conclusion weak and nonspecific; they can also block other Undoubtedly the intake of Prasterone gives steroidogenic necessitating adrenal ste- benefits but to put a definitive evaluation are need- roid supplementation.[32] Although aromatase ed more specific studies. The researches show that inhibition by anastrozole and letrozole is report- Prasterone (DHEA) may have a role in hormone re- placement therapy in patients with low endogenous ed to be close to 100%, administration of these DHEA and DHEAS. Many clinical trials suggest inhibitors to men will not suppress plasma estra- that doses of 30–50mg of oral DHEA may produce diol levels completely. In men third-generation physiologic androgen levels. These studies report a aromatase inhibitors will decrease the mean plas- dose-dependent effect and lack of accumulation of ma estradiol/testosterone ratio by 77%.[33,34 ] It serum androgen levels. These studies also reveal a is important to note that the use of the aromatase gender-specific response to DHEA therapy such that inhibitors for sport purpose is over the counter, testosterone levels are increased in women but not it is not supported by the today`s medicine. in men. The trials show that supplementation with Prasterone restores Dehydroepiandrosterone sulfate Legality serum concentrations to the normal range for young DHEA is legal to sell in the as adults (aged 20-50 years). Although the DHEA sup- plementation is well widely practiced by athletes, the a dietary supplement. DHEA is specifically ex- trials have consistently shown that DHEA supple- empted from the Control Act mentation does not increase statistically significant of 1990 and 2004.[10] It is banned from use in testosterone levels, enhance muscle mass or muscle athletic competition. In , DHEA is a Con- strength. The DHEA supplementation gives improve- trolled Drug listed under Section 23 of Sched- ment in short physical performances. The conditions ule IV of the Controlled Drugs and Substances in which Dehydroepiandrosterone could preserve or Act and as such is available by prescription only. improve muscle strength and morphological features [11] In it is a controlled drug. Austra- still need to be determined and more clinical studies lian customs classify DHEA as an “anabolic ste- are needed. roid[s] or precursor[s]” and, as such, it is only possible to carry DHEA into the country through Acknowledgement customs if one possesses an import permit which This work was supported by Medical Univer- may be obtained if one has a valid prescription sity of Plovdiv, project DP 13/2015. for the hormone.[12] DHEA is includes in the “List of drugs currently controlled under the 42 PHARMACIA, vol. 62, No. 4/2015 S. S. Ivanova, K. Ivanov, S. A. Ivanova, S. Papanov, D. Obreshkova

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 Corresponding author: Stanislava Ivanova Department Pharmagognosy and Pharmaceutical Chemistry Faculty of Pharmacy, Medical University – Plovdiv, Plovdiv, Bulgaria Mobile: +359 (0)879 061053 e-mail: [email protected]