Differential Effect of Oral Dehydroepiandrosterone-Sulphate on Metabolic Syndrome Features in Pre- and Postmenopausal Obese Women

Cecilia Gómez-Santos; Juan José Hernández-Morante; Francisco Javier Tébar; Esteban Granero; Marta Garaulet

Disclosures

Clin Endocrinol. 2012;77(4):548-554. 

In This Article

Discussion

The present study was performed to evaluate the usefulness of DHEA-S replacement therapy in pre- and postmenopausal women for the treatment of metabolic syndrome (MetS). In this regard, our data indicate that, at least in postmenopausal obese women, DHEA-S treatment might be a good therapeutic alternative against this syndrome.

The primary finding of this study was that DHEA-S treatment significantly decreased most of the obesity-related parameters in the women studied, being particularly effective in helping weight loss. As has been shown in numerous studies, DHEA-S has fat-reducing properties. Moreover, DHEA-S reduces adipogenesis. Indeed, DHEA-S treatment seems to enhance lipid mobilization and reduce lipid storage. In 1995, Tagliaferro and co-workers mentioned that glycerol release (a consequence of lipolysis) was higher in adipose tissue from Wistar rats treated with DHEA, indicating increased lipolytic activity.[25] Furthermore, the nature of DHEA-S as a potent stimulator of lipolysis has also been demonstrated in primary cultures of human adipocytes.[15]

However, it is important to highlight that in the current work, the decrease in waist circumference, the key point of the MetS definition, was only significant in postmenopausal women, in whom the decrease reached 7–10 cm in some cases. Several authors have described that replacement therapy with this hormone inhibits fat accumulation in the abdominal region, one of the main factors responsible for metabolism impairment.[10] However, there is still great controversy in this regard, because other authors found no changes in body fat distribution.[26,27] Such differences may be related to the menopausal status of the women studied, as is shown in the current work.

Furthermore, our data revealed that the dietary administration of DHEA-S induced a decrease in glycaemia and was strongly correlated with improved insulin sensitivity in the postmenopausal group, as demonstrated by the normalization of the HOMA index.

It has been widely described that DHEA and DHEA-S act as modulators of glucose metabolism in humans and that the protective action of DHEA-S against insulin resistance may result from the combination of different mechanisms, like the secondary effect of reduced fat accumulation, a counteraction of glucocorticoid action, or the direct stimulation of glucose uptake.[28]

Moreover, this improvement in insulin sensitivity after DHEA-S treatment may reflect intracrine effects, a contention supported by the close association seen between insulin sensitivity and the adrenal androgens DHEA-S derivatives, such as dihydrotestosterone, androstenedione and androstenetriol glucoronidate.[29] These data agree with previous results suggesting that high plasma DHEA-S levels are correlated with a reduction in age-related increases in insulin levels, insulin resistance and blood glucose.[10,30,31] In our opinion, these results are important, because it has been proposed that insulin resistance is the previous step to the development of MetS, and additionally, early diagnosis and treatment of insulin resistance could be an important factor in preventing the development of MetS.[32]

Summarizing, the role of DHEA-S as waist circumference and insulin resistance lowering agent not only confirms its important role in MetS treatment, but also suggests that it might serve as a promising prophylactic agent.

As we have mentioned, the present work was performed to assess the usefulness of DHEA-S against MetS as a whole. In this regard, oral DHEA-S treatment exerted a positive effect against MetS, significantly reducing the MetS score, although this effect was confined to postmenopausal women.

It is important to note that, while DHEA-S replacement could be useful for weight loss in both pre- and postmenopausal women, DHEA-S replacement should only be recommended to postmenopausal women to treat MetS. In fact, in the current study, none of the parameters related to MetS improved significantly in premenopausal women. These results coincide with the findings of Oliver et al. in 1997, who did not find any effect on MetS measures in young and healthy adults after DHEA-S treatment. Following the indication of Oliver et al.,[33] it may be that DHEA-S administration is useful, at least in the case of MetS, only in women with decreased baseline levels of this hormone.

Plasma leptin levels also decreased after DHEA-S treatment both in pre- and postmenopausal women. Previous observations suggested that subjects with MetS have higher leptin levels than subjects without MetS.[34] In addition, because hyperleptinaemia has been proposed as a component of MetS, it may be speculated that subjects with relatively high levels of leptin develop MetS at an earlier stage. In this regard, the antidiabetic effect of DHEA-S may be due to a decrease in leptin levels, as suggested by Apostolova et al.[35] As a consequence, the beneficial effects of DHEA-S observed in the present study may be exerted, at least in part, via decreasing plasma leptin levels.

With respect to the other hormones related to obesity and food intake, such as adiponectin and ghrelin, our results pointed a differential effect of this hormone in pre- and postmenopausal women, which could be related to the initial basal levels of the hormone in both groups of women. Indeed, with menopause, there is a gradual decrease of several plasma sexual hormones, including DHEA-S, which is about 2/3 lower in postmenopausal women.[36] Moreover, it has been demonstrated that androgens are related to muscle mass maintenance, increased insulin sensitivity, greater energy expenditure and lower obesity.[26] This may explain why in the postmenopausal women studied DHEA-S replacement was followed by a better metabolic status. Furthermore, differences in both the sexual hormones synthesis and in the transformation degree of androgens to estrogens between pre- and postmenopausal women could be involved in the differential effect of the exogenous DHEA-S treatment.

It is important to note that, paradoxically, DHEA-S plasma levels were reduced after replacement treatment in premenopausal women, a decrease that may be determined by several circumstances. Firstly, in premenopausal women, plasma hormone levels vary significantly depending on the menstrual cycle. On the other hand, the exogenous administration of DHEA-S could lead to the reduced secretion of luteinizing hormone and, as a consequence, a feedback inhibition of DHEA-S release by the ovaries.[37] Moreover, taking into account that DHEA-S plasma levels are high in premenopausal women, external supplementation of DHEA-S could encourage hyperandrogenism in these women, because it has been postulated that women with high sex hormone levels have an increased 5 beta-reductase activity, which could finally increase DHEA-S clearance and urinary excretion.[38]

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