CHAPTER 50 DHEA, the most abundant steroid hormone in the body: inhibits glucose-6-phosphate dehydrogenase, inhibits the generation of NADPH, activates the pyruvate dehydrogenase complex and increases oxidative phosphorylation, increases oxidative stress, polarizes the immune system to M1/Th1, inhibits the pathway PI3K/Akt and decreases proliferation and increases apoptosis in cancer José de Felippe Junior DHEA: substance synthesized in the body with multiple actions – Plasma DHEA-sulphate declines from a peak at age maintain health, prevent diseases and help to heal them. JFJ 20, in both men and women. In men, DHEA-s ranges Warning: your adrenal gland is prohibited from making DHEA from 11 to 2.5 microM and in women from 6 to 1 mi- if you live in Brazil. Nonconformist medical doctors croM, from 20 to 80 years respectively (Labrie-1997). The DHEA biological actions involve multiple re- ceptors. DHEA binds to steroid/nuclear receptors (e.g. DHEA in United States of America is considered as a pregnane X receptor/steroid and xenobiotic receptor or food supplement, in Europe as a hormone that requires PXR/SXR), estrogen receptors alpha, beta (ER-alpha medical prescription (Samaras-2013) and in Brazil, for and ER-beta), androgen (AR), cellular membrane re- reasons unknown, it is prohibited the commercializa- ceptors and endothelial cells receptors (activating tion and prescription. G-receptor-coupled proteins – GPCR) (Webb-2006, in Dehydroepiandrosterone – DHEA – is produced in Teng-2015). cortical adrenal gland and activated by sulfation in the It was found in Japanese with over 100 years in- liver and target organs. DHEA is the steroid hormone crease in telomere length in leukocytes, increased adi- or steroid pre-hormone in the highest amount in the ponectin concentration along with normal levels of body: 72% of the total (Ebeling-1994, Traish-2011). If DHEA-sulphate in blood, suggesting the importance of DHEA exists in such a high concentration in blood is this pre-hormone (Aoki-2017). because its importance in our economy is the same car- Most of the hormones in our body under physio- at. We dose in blood the DHEA-sulphate. logical conditions stimulate cell proliferation of normal DHEA-sulphate is the circulating form, and non-sul- cells and neoplastic cells: IGF-I, insulin, aldosterone, phated DHEA is the bioactive form with the various thyroxine, prolactin, estradiol, testosterone, DHEA, functions in cells and organs provided with sulfatases. while melatonin and DHEA- in a supra-physiological Non-sulphated circulating DHEA has no diagnostic dose causes antiproliferative effect in cancer. value in the blood because its effect is in the intimacy of DHEA deserves special attention because in physi- the tissues. Leukocytes, macrophages, peripheral ological doses it increases estrogens and testosterone lymph nodes, and spleen have sulfatases necessary to synthesis, both involved in normal or neoplastic cell convert DHEA-sulphate into DHEA and activate the proliferation. However, in high doses and in the short immune system. term, as in the treatment of neoplasias, DHEA inhibits 367 368 INTEGRATIVE MEDICAL ONCOLOgy – PATHOPHYSIOLOGY AND TREATMENT glucose-6-phosphate dehydrogenase (G6PD) and ease progresses. Therefore, given the importance of this causes anticancer effect by several mechanisms in most hormone or pre-hormone we must be alert to start as human cancer strains. soon as possible its correct replacement. We found studies in which high or above-normal To examine the association between circulating lev- DHEA increases breast cancer risk in postmenopausal els of dehydroepiandrosterone and dehydroepiandros- women (Gomes-1988, Dorgan-1997, Stoll-1999). Well, terone sulfate and the development of gastric cancer, elevated DHEA in the general population happens by the authors measured the serum levels of these steroids uncontrolled replacement or more rarely by adrenal tu- in 13 individuals who donated serum to the Washing- mor. In postmenopausal or not, including in man, ex- ton County Maryland serum bank in 1974 and who cess DHEA inhibits G6PD, which causes a decrease in subsequently developed gastric cancer and in 52 NADPH generation and an increase in free radicals of matched controls. Prediagnostic serum levels of dehy- oxygen in a continuous and uninterrupted manner and droepiandrosterone were 38% lower in cases as com- the consequent continuous and uninterrupted oxida- pared to controls (P = 0.09). The risk of developing tive stress, which causes the increased risk of cancer. It gastric cancer increased with decreasing levels of both is inconsequential and sinful to replace DHEA, like any steroids. Adjustment for confounding factors such as other hormone, without the proper controls. smoking or the interval between blood donation and In physiological doses DHEA increases estrogen time to diagnosis did not alter the findings. These re- generation because it activates the critical enzyme in sults suggest that there may be a role for this steroid in the synthesis process, 3 beta-hydroxysteroid dehydro- the prevention of gastric cancer (Gordon-1993). genase type 1 and when placed in MCF-7 cell cultures Epidemiological studies show that the risk of devel- ER-positive breast cancer causes what it knows to do, oping specific cancers is related to the serum or urinary increased cell proliferation. Thomas showed this in levels of DHEA and DHEA-sulfate. In addition, dehy- 2011. We know that 3 beta-hydroxysteroid dehydroge- droepiandrosterone prevents a variety of spontaneous nase type 1 is a critical enzyme in the conversion of and chemically induced tumors when administered to DHEA to estradiol in breast tumors and also in normal laboratory animals (in-Gordon-1993). cells. The author showed that DHEA in physiological Dehydroepiandrosterone was found to inhibit ex- concentration increases the proliferation of ER-posi- perimental cancer development in mouse and rat lung, tive MCF-7 cells and the inhibition of the critical en- colon and mammary gland. Since DHEA is a potent zyme by two substances, trilostan or epostane, inhibits inhibitor of mammalian G6PD, the hypothesis that the DHEA-induced proliferation (Thomas-2011). compound could inhibit cell proliferation through an The author has shown only something that has inhibition of the pentose phosphate pathway has been been described in the literature since DHEA discovery. formulated. The authors studied the effects of DHEA Recently, in 317 breast cancer patients, there was no on the proliferation in vitro of human lymphocytes in- association between the concentration of DHEA or duced by several mitogens (PHA, ConA and PWM), DHEA-sulphate with breast cancer risk, in situ or inva- measuring 3H-thymidine uptake. DHEA inhibited sive. The relative risk (RR) of DHEA-non-sulphated, up- 3H-thymidine uptake of mitogen-stimulated cells from per limit versus lower quartile was RR, 1.2; (95% CI), both G6PD+ and G6PD- (mediterranean type defi- 0.8-1.8, p = 0.53 and DHEA-sulphate: RR, 1.3; (95% CI), ciency) individuals in a dose-dependent and reversible 0.9-2.0; p = 0.07, that is, non-significant (Tworoger-2006). fashion. These data suggest that the inhibition of thy- DHEA-sulphate was measured in 70 patients with midine uptake induced by DHEA on human lympho- solid tumors (gastrointestinal tract tumors: 28; breast cytes does not depend on the inhibition of G6PD (En- cancer: 24; non-small cell lung cancer: 18), 28 without nas-1987). and 42 with distant metástases. The control group con- It is interesting to note that physical activity in- sisted of 100 age- and sex-matched healthy subjects. creases the serum concentration of DHEA-sulphate in No significant difference in mean serum levels of normal or cancerous people. Particularly in breast can- DHEAS was observed between controls and non-met- cer survivors, twelve weeks of aerobic training im- astatic patients: both presented the expected physio- proves psychosocial health, along with increasing se- logical fall of DHEA-sulphate with advancing age. In rum DHEA-sulphate and decreasing salivary cortisol contrast, metastatic patients, irrespectively of tumor (Di Blasio-2017). histotype, showed significantly lower mean levels of In the general population, low levels of DHEA-sul- DHEAS with respect to either controls or non-meta- phate and increased cortisol/DHEA-s ratio correlates static patients (Lissoni-1998). with the onset of cancer, cardiovascular disease, meta- This study suggests that patients with metastases bolic syndrome, all causes of disease and higher mor- develop with exaggerated DHEA decrease as the dis- tality (Phillips-2010). INTEGRATIVE MEDICAL ONCOLOgy – PATHOPHYSIOLOGY AND TREATMENT 369 The chemical name of DHEA is [(3S, 8R, 9S, 10R, 6. Drastically increases adiponectin gene expression 13S, 14S) -10,13-dimethyl-17-oxo-1,2,3,4,7,8,9,11,12,14 in omentum adipocytes. Adiponectin activates , 15,16-dodecahydrocyclopenta [a] phenanthren-3- AMPK, which inhibits mTOR: antiproliferation, yl] hydrogen sulphate of the formula: C 19 H 28 O 5 S, apoptotic and inhibition of peritumoral autophagy. and molecular weight: 368.5 g/mol. In addition, adipose tissue volume decrease. Other names: DHEA sulphate, Prasterone sulphate; 7. Inhibits the most effective and frequent prolifera- DEHYDROEPIANDROSTERONE SULFATE, Dehy- tive axis PI3K/Akt (Jiang-2005). droisoandrosterone sulphate and DHEAS. 8. DHEA effects are mediated by Akt inhibition and It donates 1 electron and is acceptor of 5 electrons: subsequent activation of GSK-3beta, which causes oxidant molecule. mitochondrial depolarization, increase reactive ox- ygen species, activate membrane-redox-sensitive + O K voltage channels, and decrease intracellular Ca++, all anticancer effects. 9. Low DHEA-sulphate in the blood possibly increas- es the risk of metastases in patients with cancer al- H ready installed (Lissoni-1998). 10. For Hans Nieper DHEA increases serum cholines- O H O H H terase and the higher the concentration of this sub- S O stance, the greater the cancer regression. O 11. TP53 is tumor suppressor gene. DHEA sulfate trans- forms into intracellular DHEA in cells with inactive DHEA-sulphate p53 and triggers its activation (Nyce, 2018).