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Labrie F.,EndoCeutics Inc
Journal of Steroid Biochemistry and Molecular Biology | Year: 2015

Following the arrest of estradiol secretion by the ovaries at menopause, all estrogens and all androgens in postmenopausal women are made locally in peripheral target tissues according to the physiological mechanisms of intracrinology. The locally made sex steroids exert their action and are inactivated intracellularly without biologically significant release of the active sex steroids in the circulation. The level of expression of the steroid-forming and steroid-inactivating enzymes is specific to each cell type in each tissue, thus permitting to each cell/tissue to synthesize a small amount of androgens and/or estrogens in order to meet the local physiological needs without affecting the other tissues of the organism. Achieved after 500 million years of evolution, combination of the arrest of ovarian estrogen secretion, the availability of high circulating levels of DHEA and the expression of the peripheral sex steroid-forming enzymes have permitted the appearance of menopause with a continuing access to intratissular sex steroids for the individual cells/tissues without systemic exposure to circulating estradiol. In fact, one essential condition of menopause is to maintain serum estradiol at biologically inactive (substhreshold) concentrations, thus avoiding stimulation of the endometrium and risk of endometrial cancer. Measurement of the low levels of serum estrogens and androgens in postmenopausal women absolutely requires the use of MS/MS-based technology in order to obtain reliable accurate, specific and precise assays. While the activity of the series of steroidogenic enzymes can vary, the serum levels of DHEA show large individual variations going from barely detectable to practically normal "premenopausal" values, thus explaining the absence of menopausal symptoms in about 25% of women. It should be added that the intracrine system has no feedback elements to adjust the serum levels of DHEA, thus meaning that women with low DHEA activity will not be improved without external supplementation. Exogenous DHEA, however, follows the same intracrine rules as described for endogenous DHEA, thus maintaining serum estrogen levels at substhreshold or biologically inactive concentrations. Such blood concentrations are not different from those observed in normal postmenopausal women having high serum DHEA concentrations. Androgens, on the other hand, are practically all made intracellularly from DHEA by the mechanisms of intracrinology and are always maintained at very low levels in the blood in both pre- and postmenopausal women. Proof of the importance of intracrinology is also provided, among others, by the well-recognized benefits of aromatase inhibitors and antiestrogens used successfully for the treatment of breast cancer in postmenopausal women where all estrogens are made locally. Each medical indication for the use of DHEA, however, requires clinical trials performed according to the FDA guidelines and the best rules of clinical medicine. © 2014 Elsevier Ltd. Source


Trademark
Endoceutics Inc. | Date: 2015-09-21

Pharmaceutical preparations for the prevention and treatment of vaginal atrophy, decreased libido and sexual dysfunction.


Pelletier G.,Laval University | Ouellet J.,Laval University | Martel C.,EndoCeutics Inc | Labrie F.,Laval University | And 2 more authors.
Journal of Sexual Medicine | Year: 2012

Introduction. One mechanism by which low sexual steroid activity observed after menopause could cause sexual dysfunction is by deficient vaginal innervation. Recently, it has been shown that intravaginal administration of dehydroepiandrosterone (DHEA) could produce beneficial effects on sexual dysfunction in postmenopausal women. Aim. The goal of this study was to determine if DHEA could modify innervation in the rat vagina. Main Outcome Measures. The area occupied by the nerve fibers immunoreactive for protein gene product 9.5 (PGP 9.5), a panneuronal marker or tyrosine hydroxylase (TH), a sympathetic nerve fiber marker, in the lamina propria and muscular layers, respectively, as well as the total area of each of these 2 layers were measured by stereological analysis. Methods. The innervation of the rat vagina was examined 9 months after ovariectomy (OVX) compared to intact animals and treatment of OVX animals with DHEA (80mg/kg). Four sections from each vagina (5 animals/groups) were immunostained. Results. In OVX animals, the lamina propria area was decreased to 44%, an effect which was reversed by DHEA to 69% of the intact value. OVX also caused a 59% decrease in the area of PGP 9.5 fibers, an effect which was prevented by DHEA, thus showing a 68% stimulatory effect of DHEA on the density of PGP 9.5 fibers in the lamina propria compared to OVX animals. Following OVX, the muscular layer area was decreased by 61%. DHEA treatment induced 118% and 71% increases in TH fiber area compared to OVX and intact animals, respectively. The density of TH fibers was 182% increased over intact controls by DHEA treatment of OVX animals. Conclusions. The relatively potent stimulatory effect of DHEA on intravaginal nerve fiber density provides a possible explanation for the beneficial effects of intravaginal DHEA on sexual dysfunction observed in postmenopausal women. © 2012 International Society for Sexual Medicine. Source


Labrie F.,EndoCeutics Inc | Labrie F.,Laval University | Martel C.,EndoCeutics Inc | Balser J.,Veristat Inc.
Menopause | Year: 2011

Objective: Because the exclusive source of sex steroids (at least estrogens) after menopause is recognized to be dehydroepiandrosterone (DHEA), this study examines the interindividual variability of serum DHEA and its metabolites as well as the contribution of the ovary to global sex steroid physiology in postmenopausal women. Methods: Serum levels of DHEA and 11 of its metabolites were measured by gas or liquid chromatography/mass spectrometry in 442 intact and 71 ovariectomized postmenopausal women aged 42 to 74 years. Results: With a mean ± SD concentration of 2.03 ± 1.33 ng/mL, serum DHEA in intact postmenopausal women is highly variable with 5th and 95th centiles at 0.55 and 4.34 ng/mL, respectively, for a 7.9-fold difference. A comparable variability is observed for the 11 metabolites of DHEA. The 22.3% higher serum DHEA in intact compared with ovariectomized women is accompanied by parallel differences for all the other steroids, thus indicating that all sex steroids originate from circulating DHEA in postmenopausal women with no direct secretion of active estrogens or androgens by the postmenopausal ovary. Conclusions: The 7.9-fold difference between low and high serum DHEA levels provides an explanation for the lack of signs of hormone deficiency in some women, whereas most of them have symptoms or signs. The approximately 20% contribution of the ovary to the total pool of DHEA with no direct secretion of estrogens or androgens in the circulation could possibly explain the reported negative effect of oophorectomy on longevity, especially from coronary heart disease events. © 2011 by The North American Menopause Society. Source


Bertin J.,EndoCeutics Inc | Dury A.Y.,EndoCeutics Inc | Ouellet J.,EndoCeutics Inc | Pelletier G.,Laval University | Labrie F.,EndoCeutics Inc
Journal of Sexual Medicine | Year: 2014

Introduction: To better understand the mechanisms underlying the beneficial effects of the intravaginal administration of dehydroepiandrosterone (DHEA) observed in postmenopausal women on sexual dysfunction. Aims: To identify the distribution of the androgen-synthesizing enzymes as well as androgen receptor (AR) and measure steroid levels in the monkey vagina. Methods: The cynomolgus monkey (Macaca fascicularis), the closest model to the human, has been used to measure the expression levels of steroidogenic enzymes and androgen receptor by quantitative reverse transcription polymerase chain reaction (n=4), confirmed by immunohistochemistry, and immunofluorescence (n=3). DHEA and its androgenic metabolites were quantified by LC-MS/MS (n=4). Main Outcome Measures: The presence of SRD5A1, SRD5A2, HSD17B3, AR as well as nerve fibers (PGP9.5) was investigated, and steroid levels were measured. Results: AR is widely distributed within the vaginal epithelium and also in the lamina propria with a lower expression in the muscularis layer and blood vessel walls. Androgen-forming enzymes, on the other hand, are expressed in the vaginal stratified squamous epithelium at a relatively high level where they are uniformly distributed from the basal membrane up to the superficial keratinized cells. The enzymes are at a lower level in blood vessel walls and zona muscularis where nerve fibers are localized. DHEA and its androgen metabolites are present at biologically significant concentrations in the monkey vagina. Conclusion: The enzymes responsible for androgen formation as well as AR are at the highest level in the superficial layer of the stratified epithelium and muscularis layers of the vagina. These data provide a potential explanation for the described role of androgens in regulating vaginal lubrication, smooth muscle activity, blood flow, and the neuronal activity potentially involved in the correction of sexual dysfunction. Bertin J, Dury AY, Ouellet J, Pelletier G, and Labrie F. Localization of the androgen-synthesizing enzymes, androgen receptor, and sex steroids in the vagina: Possible implications for the treatment of postmenopausal sexual dysfunction. J Sex Med 2014;11:1949-1961. © 2014 International Society for Sexual Medicine. Source

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