Androgenic action of dehydroepiandrosterone (DHEA) on nerve density in the ovariectomized rat vagina.

Introduction: We have recently reported that dehydroepiandrosterone (DHEA) increases the density of nerve fibers in the ovariectomized (OVX) rat vagina.

Aim: To better define the mechanism of action of DHEA, we have examined the effect of DHEA, conjugated estrogens (premarin) and the potent blocker of estrogen action acolbifene on the innervation in the lamina propria in the OVX rat vagina.

Methods: Female Sprague-Dawley rats (10-12 weeks old) were used.

Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland.

Novel agents for the endocrine therapy of breast cancer are needed, especially in order to take advantage of the multiple consecutive responses observed in metastatic progressing breast cancer following previous hormone therapy, thus delaying the use of cytotoxic chemotherapy with its frequent poor tolerance and serious side effects. Acolbifene (ACOL) is a novel and unique antiestrogen which represents a unique opportunity to achieve the most potent and specific blockade of estrogen action in the mammary gland and uterus while exerting estrogen-like beneficial effects in other tissues, especially the bones. To better understand the specificity of action of ACOL, we have used Affymetrix GeneChips containing 45,000 probe sets to analyze 34,000 genes to determine the specificity of this compound compared to the pure antiestrogen fulvestrant, as well as to the mixed antagonists/agonists tamoxifen and raloxifene to block the effect of estradiol (E(2)) and to induce effects of their own on the genomic profile in the mouse mammary gland.

Hormonal therapy of prostate cancer.

Of all cancers, prostate cancer is the most sensitive to hormones: it is thus very important to take advantage of this unique property and to always use optimal androgen blockade when hormone therapy is the appropriate treatment. A fundamental observation is that the serum testosterone concentration only reflects the amount of testosterone of testicular origin which is released in the blood from which it reaches all tissues. Recent data show, however, that an approximately equal amount of testosterone is made from dehydroepiandrosterone (DHEA) directly in the peripheral tissues, including the prostate, and does not appear in the blood.

DHEA, important source of sex steroids in men and even more in women.

A major achievement from 500 million years of evolution is the establishment of a high secretion rate of dehydroepiandrosterone (DHEA) by the human adrenal glands coupled with the indroduction of menopause which stops secretion of estrogens by the ovary. Cessation of estrogen secretion at menopause eliminates the risks of endometrial hyperplasia and cancer which would result from non-opposed estrogen stimulation during the post-menopausal years. In fact, from the time of menopause, DHEA becomes the exclusive and tissue-specific source of sex steroids for all tissues except the uterus.

The intracrine sex steroid biosynthesis pathways.

There is an increasing number of differences reported between the steroidogenesis pathways described in the traditional literature related to gonadal steroidogenesis and the more recent observations achieved using new technologies, especially molecular cloning, pangenomic expression studies, precise quantification of mRNA expression using real-time PCR, use of steroidogenic enzymes stably transfected in cells, detailed enzymatic activity analysis in cultured cell lines and mass spectrometry analysis of steroids. The objective of this chapter is to present steroidogenesis in the light of new findings that demonstrate pathways of biosynthesis of estradiol (E(2)) and dihydrotestosterone (DHT) from adrenal dehydroepiandrosterone (DHEA) in peripheral intracrine tissues which do not involve testosterone as intermediate as classically found in the testis and ovary. Steroidogenic enzymes different from those of the ovary and testis act in a tissue-specific manner to catalyze the transformation of DHEA into active sex steroids.