Is dehydroepiandrosterone a hormone? Labrie, F; Luu-The, V; Bélanger, A ...
Journal of Endocrinology/Journal of endocrinology,
11/2005, Volume:
187, Issue:
2
Journal Article
Peer reviewed
Open access
Dehydroepiandrosterone (DHEA) is not a hormone but it is a very important prohormone secreted in large amounts by the adrenals in humans and other primates, but not in lower species. It is secreted ...in larger quantities than cortisol and is present in the blood at concentrations only second to cholesterol. All the enzymes required to transform DHEA into androgens and/or estrogens are expressed in a cell-specific manner in a large series of peripheral target tissues, thus permitting all androgen-sensitive and estrogen-sensitive tissues to make locally and control the intracellular levels of sex steroids according to local needs. This new field of endocrinology has been called intracrinology. In women, after menopause, all estrogens and almost all androgens are made locally in peripheral tissues from DHEA which indirectly exerts effects, among others, on bone formation, adiposity, muscle, insulin and glucose metabolism, skin, libido and well-being. In men, where the secretion of androgens by the testicles continues for life, the contribution of DHEA to androgens has been best evaluated in the prostate where about 50% of androgens are made locally from DHEA. Such knowledge has led to the development of combined androgen blockade (CAB), a treatment which adds a pure anti-androgen to medical (GnRH agonist) or surgical castration in order to block the access of the androgens made locally to the androgen receptor. In fact, CAB has been the first treatment demonstrated to prolong life in advanced prostate cancer while recent data indicate that it can permit long-term control and probably cure in at least 90% of cases of localized prostate cancer. The new field of intracrinology or local formation of sex steroids from DHEA in target tissues has permitted major advances in the treatment of the two most frequent cancers, namely breast and prostate cancer, while its potential use as a physiological HRT could well provide a physiological balance of androgens and estrogens, thus offering exciting possibilities for women's health at menopause.
The present article summarizes some of the studies available on steroid hormone conversion through the specific expression of steroidogenic enzymes in adipose tissue (adipose tissue intracrinology) ...and discusses the potential impact of local adipose tissue steroid metabolism on the regulation of adipocyte function and other metabolic parameters. Several studies have demonstrated significant steroid hormone uptake and conversion by adipose tissues from various body sites and in various cell fractions. Activities and/or mRNAs of aromatase, 3beta-hydroxysteroid dehydrogenase (HSD), 3alpha-HSD, 11beta-HSD, 17beta-HSD, 7alpha-hydroxylase, 17alpha-hydroxylase, 5alpha-reductase and UDP-glucuronosyltransferase 2B15 have been detected in adipose tissue or adipose cells. These studies have demonstrated potentially important roles for these enzymes in obesity, central fat accumulation, and the metabolic syndrome. Future studies on adipose tissue intracrinology will contribute further to our understanding of steroid action in adipocytes.
It is well documented that oestrogen suppresses food intake by an action at the hypothalamic level. Using in situ hybridisation, we studied the effect of castration (CX) and short‐term administration ...of oestradiol (E2) in CX female mice for three neuropeptides involved in feeding behaviour: two anorexigenic peptides, (i) the pro‐opiomelanocortin (POMC)‐derived peptide α‐melanocyte‐stimulating hormone and (ii) corticotrophin‐releasing hormone (CRH), and the orexigenic peptide, (iii) neuropeptide Y (NPY). POMC‐expressing neurones were mostly laterally located in the arcuate nucleus. POMC mRNA expression was decreased following CX and a single injection of E2 induced an increase in mRNA levels at 12‐ and 24‐h time intervals. In the parvocellular area of the paraventricular nucleus, CRH mRNA levels were similarly decreased after CX and completely restored to normal levels at 12 and 24 h following E2 injection. On the other hand, the levels of NPY mRNA expressed in neurones located in the inner zone of the arcuate nucleus were increased by CX and decreased to the levels observed in intact animals by E2 injection (3–24 h). The present data suggest that oestrogen might exert an anorexigenic action by stimulating POMC and CRH mRNA expression and decreasing NPY mRNA expression in the hypothalamus.
A new understanding of the endocrinology of menopause is that women, at menopause, are not only lacking estrogens resulting from cessation of ovarian activity but have also been progressively ...deprived for a few years of androgens and some estrogens originating from adrenal DHEA and androstenedione (4-dione). In fact, serum DHEA decreases by about 60% between the maximal levels seen at 30 years of age to the age of menopause. This decreased secretion of DHEA and DHEA-S by the adrenals is responsible for a parallel decrease in androgen and estrogen formation in peripheral tissues by the steroidogenic enzymes specifically expressed in each cell type in individual target tissues. This new field of endocrinology, called intracrinology, describes the local synthesis of androgens and estrogens made locally in each cell of each peripheral tissue from the adrenal precursors DHEA and 4-dione. These androgens and estrogens exert their action in the same cells where their synthesis takes place and they are released from these target cells only after being inactivated. To further understand the effect of DHEA in women, DHEA has been administered in postmenopausal women for 12 months. Such treatment resulted in increased bone formation and higher bone mineral density accompanied by elevated levels of osteocalcin, a marker of bone formation. Vaginal maturation was stimulated, while no effect was observed on the endometrium. Preclinical studies, on the other hand, have shown that, due to its predominant conversion into androgens, DHEA prevents the development and inhibits the growth of dimethylbenz(a)anthracene-induced mammary carcinoma in the rat, a model of breast cancer. DHEA also inhibits the growth of human breast cancer ZR-75-1 xenografts in nude mice. The inhibitory effect of DHEA on breast cancer is due to an androgenic effect of testosterone and dihydrotestosterone made locally from DHEA. When used as replacement therapy, DHEA is free of the potential risk of breast and uterine cancer, while it stimulates bone formation and vaginal maturation and decreases insulin resistance. The combination of DHEA with a fourth generation SERM, such as EM-652 (SCH 57068), a compound having pure and potent antiestrogenic activity in the mammary gland and endometrium, could provide major benefits for women at menopause (inhibition of bone loss and serum cholesterol levels) with the associated major advantages of preventing breast and uterine cancer. A widely used application of intracrinology is the treatment of prostate cancer where the testicles are blocked by an LHRH agonist while the androgens made locally in the prostate from DHEA are blocked by a pure antiandrogen. Such treatment, called combined androgen blockade, has led to the first demonstration of a prolongation of life in prostate cancer.
In women and men, an important proportion of estrogens and androgens are synthesized locally at their site of action in peripheral target tissues. This new field of endocrinology has been called ...intracrinology. In postmenopausal women, 100% of active sex steroids are synthesized in peripheral target tissues from inactive steroid precursors while, in adult men, approximately 50% of androgens are made locally in intracrine target tissues. The last and key step in the formation of all estrogens and androgens is catalyzed by members of the family of 17beta-hydroxysteroid dehydrogenases (17 beta-HSDs) while different 17 beta-HSDs inactivate these steroids in the same cell where synthesis takes place. To date, seven human 17 beta-HSDs have been cloned, sequenced and characterized. The 17 beta-HSDs provide each cell with the means of precisely controlling the intracellular concentration of each sex steroid according to local needs.
Serum androgens as well as their precursors and metabolites decrease from the age of 30–40 yr in women, thus suggesting that a more physiological hormone replacement therapy at menopause should ...contain an androgenic compound. It is important to consider, however, that most of the androgens in women, especially after menopause, are synthesized in peripheral intracrine tissues from the inactive precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) of adrenal origin. Much progress in this new area of endocrine physiology called intracrinology has followed the cloning and characterization of most of the enzymes responsible for the transformation of DHEA and DHEA-S into androgens and estrogens in peripheral target tissues, where the locally produced sex steroids are exerting their action in the same cells in which their synthesis takes place without significant diffusion into the circulation, thus seriously limiting the interpretation of serum levels of active sex steroids. The sex steroids made in peripheral tissues are then inactivated locally into more water-soluble compounds that diffuse into the general circulation where they can be measured. In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation. In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no significant side effects. The advantage of DHEA over other androgenic compounds is that DHEA, at physiological doses, is converted into androgens and/or estrogens only in the specific intracrine target tissues that possess the appropriate physiological enzymatic machinery, thus limiting the action of the sex steroids to those tissues possessing the tissue-specific profile of expression of the genes responsible for their formation, while leaving the other tissues unaffected and thus minimizing the potential side effects observed with androgens or estrogens administered systemically.
In postmenopausal women, almost 100% of active sex steroids are synthesized in peripheral target tissues from inactive steroid precursors and, in adult men, approximately 50% of androgens are made ...locally in target tissues. This new field of endocrinology has been called intracrinology. The last and key step in the formation of all estrogens and androgens is catalyzed by a series of substrate-specific, cell-specific and unidirectional 17β -hydroxysteroid dehydrogenases (17β -HSDs). To date, seven human 17β -HSDs have been cloned, sequenced and characterized. The 17β -HSDs provide each cell with the means of precisely controlling the intracellular concentration of each sex steroid according to local needs.
Androgen receptors (AR) are highly expressed in female reproductive organs. In order to define the possible involvement of estrogens in the regulation of AR expression in the uterus and vagina, we ...have studied the effect of short-term administration of 17beta-estradiol (E2) to ovariectomized adult mice on AR mRNA levels. Seven days after ovariectomy, the mice received a single injection of E2 (0.05 microg/mouse) 3, 12 or 24 h before they were killed. The levels of AR mRNA were measured in the different uterine and vaginal compartments using quantitative in situ hybridization. In the uterus, AR mRNA was expressed in the luminal and glandular epithelial cells, stromal cells and smooth muscle cells. In the vagina, AR mRNA was localized in both epithelial and stromal cells. In the uterus after ovariectomy, AR mRNA levels were decreased by 18% in the epithelial cells, 23% in the stromal cells and 50% in the myometrial cells. AR mRNA levels were completely restored as early as 3 h after E2 administration in the epithelium and stroma, and at the 12-h time-interval in the myometrium. In the vaginal epithelium, ovariectomy induced a 70% decrease in AR mRNA expression. No effect could be detected 3 h after E2 administration, while at the longest time-intervals (12 and 24 h) there was an increase in mRNA levels corresponding to 70% of the levels observed in intact animals. In the vaginal stroma, ovariectomy was responsible for a 55% decrease in mRNA levels. While no significant changes were observed at the 3-h time-interval, a complete restoration of AR mRNA levels in stromal cells could be recorded at the longest time-intervals after E2 administration. The data obtained indicated that, in adult mice, estrogens exert a positive regulation of AR mRNA expression in the different compartments of both the uterus and the vagina.
We had previously shown that in rat spinal cord motoneurons urotensin II (UII) precursor mRNA was down-regulated by androgens. Very recently, a gene encoding the precursor of a UII analog, termed ...UII-related peptide (URP), has been identified. Using
in situ hybridization, we studied the localization of UII and URP precursor as well as androgen receptor (AR) mRNA in the male mouse thoracic spinal cord. We also evaluated the androgenic regulation of the two peptide precursor and AR mRNA expression in the ventral horn of the mouse thoracic spinal cord. The results revealed that URP precursor mRNA was localized in motoneurons and that the vast majority of the motoneurons expressed both peptide precursor as well as AR mRNA. Seven-day castration induced an increase in UII and URP precursor and AR mRNA levels. Short term (3–24 h) administration of dihydrotestosterone to castrated animals restored the three protein mRNA levels to the levels observed in intact animals. These results suggest that in the ventral horn of the mouse spinal cord both UII and URP precursor and AR mRNA are expressed by the same neurons and that circulating androgens are exerting a down-regulation of the three protein mRNA expression, possibly by a direct action on motoneurons.
The neurohypophysial nonapeptides vasopressin (VP) and oxytocin (OT) modulate a broad range of cognitive and social activities. Notably, in amphibians, vasotocin (VT), the ortholog of mammalian VP, ...plays a crucial role in the control of sexual behaviors. Because several neurosteroids also regulate reproduction-related behaviors, we investigated the possible effect of VT and the OT ortholog mesotocin (MT) in the control of neurosteroid production. Double immunohistochemical labeling of frog brain sections revealed the presence of VT/MT-positive fibers in close proximity of neurons expressing the steroidogenic enzymes 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase (3beta-HSD) and cytochrome P450 17alpha-hydroxylase/c17, 20-lyase (P450(C17)). High concentrations of VT and MT receptor mRNAs were observed in diencephalic nuclei containing the 3beta-HSD and P450(C17) neuronal populations. Exposure of frog hypothalamic explants to graded concentrations of VT or MT produced a dose-dependent increase in the formation of progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone. The stimulatory effect of VT and MT on neurosteroid biosynthesis was mimicked by VP and OT, as well as by a selective V1b receptor agonist, whereas V2 and OT receptor agonists had no effect. VT-induced neurosteroid production was completely suppressed by selective V1a receptor antagonists and was not affected by V2 and OT receptor antagonists. Concurrently, the effect of MT on neurosteroidogenesis was markedly attenuated by selective OT and V1a receptor antagonists but not by a V2 antagonist. The present study provides the first evidence for a regulatory effect of VT and MT on neurosteroid biosynthesis. These data suggest that neurosteroids may mediate some of the behavioral actions of VT and MT.
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