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Biomedical subjects

F Labrie

Publications and source records attributed to F Labrie.

At least 307 records · Page 17Linked to original sources
PubMed1991

Endocrine therapy for prostate cancer.

Prostate cancer is the most frequent cancer in men. A discovery of major importance in the endocrinology of prostate cancer is that the testes contribute only 60% of total androgens in adult men; the remaining 40% are synthesized in peripheral tissues, including the normal and cancerous prostate, from inactive androgen precursors of adrenal origin. Using a combination therapy that includes a pure blocker of the androgen receptor or antiandrogen and castration (medical with luteinizing hormone-releasing hormone agonist or surgical by orchiectomy), the duration of response and survival have been demonstrated to be prolonged for the first time in advanced prostate cancer.

Androgen Antagonists↗
PubMed1991

Combination of an antiandrogen and a 5 alpha-reductase inhibitor: a further step towards total androgen blockade?

While the elimination of androgens of testicular origin can be easily achieved by orchiectomy or medical castration with LHRH agonists, the action of adrenal androgen precursors which are converted into the active androgen 5 alpha-dihydrotestosterone (DHT) in the prostatic tissue itself can be partially neutralized by antiandrogens which compete with DHT for binding to the androgen receptor. In order to increase the efficiency of androgen blockade, we have used 4-MA, an inhibitor of 5 alpha-reductase, the enzyme which converts testosterone into DHT, to reduce intracellular DHT concentrations and thus facilitate the action of the antiandrogen Flutamide. The present data show that the inhibitory effects of 4-MA (17 beta, N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and of the antiandrogen Flutamide are additive on prostatic growth and on androgen-sensitive prostatic binding protein mRNA levels in the rat, thus clearly suggesting that such a combination could provide the basis for a further improvement in the therapy of prostate cancer.

5-alpha Reductase Inhibitors↗
PubMed1990

Combination therapy with flutamide and medical (LHRH agonist) or surgical castration in advanced prostate cancer: 7-year clinical experience.

Three hundred and sixty-three patients with clinical stage D2 prostate cancer who had not received previous endocrine therapy or chemotherapy were treated with the combination therapy using the pure antiandrogen Flutamide and the LHRH agonist [D-Trp6,des-Gly-NH2(10)]LHRH ethylamide (or orchiectomy) for an average of 771 days (24-2607 days). Only 31 of the 308 evaluable patients (10.1%) did not show an objective positive response at the start of the combination therapy compared with an average of 18% in five recent studies using monotherapy. The median survival achieved using monotherapy is approximately 24 months while, in the present study, it is increased to 41.2 months, thus giving an additional 17 months of survival with the combination therapy. It should be mentioned that at the time of relapse, combination therapy is continued and, in addition, further blockade of adrenal androgen secretion is achieved with aminoglutethimide and hydrocortisone. While our studies showing the advantages of combination therapy with pure antiandrogen in advanced prostate cancer have been confirmed by independent large-scale randomized studies, our preliminary data clearly suggest the interest of downstaging early stage prostate cancer by temporary combination therapy prior to radical prostatectomy.

Adenocarcinoma↗
PubMed1990

Ontogeny of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) in human adrenal gland performed by immunocytochemistry.

Human foetal adrenal plays a major role in the synthesis and secretion of steroids which are essential to several physiological events during foetal development. Since 3 beta-hydroxysteroid dehydrogenase 5-ene-4-ene isomerase (3 beta-HSD) is involved in the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens and estrogens, knowledge of the ontogeny of 3 beta-HSD should lead to a better understanding of steroidogenesis in the foetal adrenal. Polyclonal antibodies raised against purified human placental 3 beta-HSD were used to localize the enzyme in 22-week, 28-week, and term foetal adrenals as well as in the adrenals of 2-month-, 8-month- and 2-year-old infants. 3 beta-HSD has been identified in the outer cortex, neocortex and zona glomerulosa zone of foetal adrenal, respectively. In 2-month- and 8-month-old infant adrenals, the enzyme was localized in the zona glomerulosa and zone fasciculata while in 2-year-old infants, the immunoreaction was observed also in the zona reticularis, the medulla being devoid of any reaction.

Adrenal Glands↗
PubMed1990

Characterization of human 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase gene and its expression in mammalian cells.

Three beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD) catalyze the oxidative conversion of delta 5-3 beta-hydroxysteroids to the delta 4-3-keto configuration and is therefore essential for the biosynthesis of all classes of hormonal steroids, namely progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. Using human 3 beta-HSD cDNA as probe, a human 3 beta-HSD gene was isolated from a lambda-EMBL3 library of leucocyte genomic DNA. A fragment of 3 beta-HSD genomic DNA was also obtained by amplification of genomic DNA using the polymerase chain reaction. The 3 beta-HSD gene contains a 5'-untranslated exon of 53 base pairs (bp) and three successive translated exons of 232, 165, and 1218 bp, respectively, separated by introns of 129, 3883, and 2162 bp. The transcription start site is situated 267 nucleotides upstream from the ATG initiating codon. DNA sequence analysis of the 5'-flanking region reveals the existence of a putative TATA box (ATAAA) situated 28 nucleotides upstream from the transcription start site while a putative CAAT binding sequence is located 57 nucleotides upstream from the TATA box. Expression of a cDNA insert containing the coding region of 3 beta-HSD in nonsteroidogenic cells shows that the gene encodes a single 42-kDa protein containing both 3 beta-hydroxysteroid dehydrogenase and delta 5-delta 4-isomerase activities. Moreover, all natural steroid substrates tested are transformed with comparable efficiency by the enzyme. In addition to its importance for studies of the regulation of expression of 3 beta-HSD in gonadal as well as peripheral tissues, knowledge of the structure of the human 3 beta-HSD gene should permit investigation of the molecular defects responsible for 3 beta-HSD deficiency, the second most common cause of adrenal hyperplasia in children.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

Opposite effects of estrogen and the progestin R5020 on cell proliferation and GCDFP-15 expression in ZR-75-1 human breast cancer cells.

We have recently demonstrated that physiological concentrations of androgens caused a marked inhibition of basal and 17 beta-estradiol (E2)-induced cell growth in ZR-75-1 human breast cancer cells. Moreover, these steroids exert effects on GCDFP-15 (gross cystic disease fluid protein-15) expression that are opposite to their above-indicated actions on cell proliferation. The synthetic progestin R5020 (17.21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione), on the other hand, causes a potent inhibition of E2-induced ZR-75-1 cell growth. In order to further characterize the hormonal regulation of GCDFP-15 expression and to better understand the antagonism between progestin and estrogen action in breast cancer cells, we have studied the effect of R5020 on both GCDFP-15 expression and cell growth in ZR-75-1 cells. After a 10-day incubation, the 4-fold stimulatory effect of 1 nM E2 on cell growth was 60% decreased by maximal effective concentrations of R5020 (greater than 1 nM) while, in the absence of E2, R5020 had no effect. The mitogenic action of E2 was accompanied by a 75% inhibition of GCDFP-15 secretion while nanomolar concentrations of R5020 induced 1.4- and 5.2-fold increases in GCDFP-15 secretion in control and E2-treated ZR-75-1 cells, respectively. While E2 caused a marked inhibition of GCDFP-15 mRNA levels, R5020 induced a maximal 2- to 3-fold increase (above control) in GCDFP-15 mRNA accumulation in cells simultaneously incubated with E2.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins↗
PubMed1990

Effects of human chorionic gonadotropin (hCG) and prolactin (PRL) on 3 beta-hydroxy-5-ene-steroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) expression and activity in the rat ovary.

Using a recently cloned rat ovary 3 beta-HSD cDNA and antibodies raised against purified human placental 3 beta-HSD, we have studied the effects of treatment with human chorionic gonadotropin (hCG) and hyperprolactinemia achieved by pituitary implants, alone or in combination, on the expression and activity of ovarian 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) in intact adult rats. 32P- and 35S-labeled cDNA probes were used to evaluate the effects of treatments on 3 beta-HSD mRNA levels by dot blot and in situ hybridization, respectively, while enzymatic activity was measured by the conversion of [14C]dehydroepiandrosterone into [14C]androstenedione. The present data show that hCG exerts a marked trophic effect on rat corpora lutea with an increase in total ovarian 3 beta-HSD mRNA levels, 3 beta-HSD protein content as well as enzymatic activity, resulting in an increase in serum progesterone levels. Prolactin-secreting pituitary implants alone, on the other hand, while exerting small effects on 3 beta-HSD expression and activity, led to a marked potentiation of the stimulatory effect of hCG on all parameters. The present data show that hCG and PRL act synergistically to stimulate ovarian progesterone secretion via an increase in 3 beta-HSD mRNA levels, protein content and enzymatic activity.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

Regulation of proopiomelanocortin messenger ribonucleic acid content by sex steroids in the arcuate nucleus of the female rat brain.

It has been recently demonstrated that sex steroids can negatively regulate beta-endorphin content as well as proopiomelanocortin (POMC) mRNA levels in the rat basal hypothalamus. In order to verify whether or not all the POMC neurons are equally affected by sex steroids, we arbitrarily divided the arcuate nucleus rostro-caudally into four equal portions and used an in situ hybridization technique to evaluate POMC gene expression in these different regions of the arcuate nucleus in the female rat. It was shown that ovariectomy induced an increase in mRNA levels in the most rostral region of the arcuate nucleus, an effect which was reversed by the concurrent administration of estradiol and dihydrotestosterone. On the other hand, estrogen administration to ovariectomized animals produced a marked depression of mRNA levels in all the regions of the arcuate nucleus with the exception of the most caudal one. These results suggest that sex steroids exert their action in subpopulations of POMC neurons.

Animals↗
PubMed1990

Synthetic progestins stimulate prostatic binding protein messenger RNAs in the rat ventral prostate.

In order to assess the intrinsic androgenic activity of the synthetic progestins currently used as antiandrogens for the treatment of prostate cancer and other androgen-sensitive diseases, cyproterone acetate (CPA), medroxyprogesterone acetate (MPA) and megestrol acetate (MEG) were administered for 4 days to adult rats castrated 4 days previously. The effects of these compounds were measured on highly specific and sensitive markers of androgen action in the rat ventral prostate, namely the levels of messenger RNAs encoding the C1 (PBP-C1) and C3 (PBP-C3) components of rat prostatic binding protein (PBP). Steady-state mRNA levels were measured by dot-blot hybridization as well as by in situ hybridization. Treatment with CPA or MEG, at the twice daily dose of 10 mg, caused respective 2- and 4.5-fold increases in the steady-state levels of mRNA encoding PBP-C1. MPA, at the dose of 0.45 mg, twice daily, was approximately 40 times as potent as MEG, leading to an 8-fold increase in PBP-C1 mRNA levels. While the pure nonsteroidal antiandrogen flutamide (10 mg, twice daily) did not cause accumulation of PBP mRNAs when administered to castrated rats, it completely reversed the stimulatory effects of the synthetic progestins CPA, MPA and MEG. The results obtained by in situ hybridization were similar to those obtained by dot-blot analysis. Moreover, the synthetic progestins caused similar androgenic effects on PBP-C3 mRNA levels. The present data indicate that all three synthetic progestins currently used for the treatment of prostate cancer possess significant intrinsic androgenic activity as evidenced by their stimulatory effects on the accumulation of mRNAs sensitive to androgen action. Consequently, as indicated by this sensitive and androgen-specific in vivo rat model, such compounds are not recommended for the treatment of conditions requiring an optimal blockade of androgens, especially prostate cancer.

Androgen-Binding Protein↗
PubMed1990

Derivatives of ethynylestradiol with oxygenated 17 alpha-alkyl side chain: synthesis and biological activity.

The coupling reaction of an acetylide ion with alkyl bromide or delta-valerolactone was used to synthesize twelve 17 alpha-derivatives of ethynylestradiol having various 17 alpha-side chain lengths and, except one, having mono- or di-oxygenated function on the side chain. All compounds had low (0.01-1.79%) relative binding affinity (RBA) for the rat uterine estrogen receptor. The highest RBA were obtained for compounds 26 (1.79%), 30 (1.55%) and 19 (0.42%). The length and polarity of the side chain decreases the affinity for the estrogen receptor. The in vivo estrogenic activity was measured on mouse uterine weight and was found to range from 0 to 35%, except for compound 30 (100%). The antiuterotrophic activity was measured by inhibition of estradiol-induced stimulation of uterine weight and was found to be 39% for compound 19, 25% for compound 26 and 0% for all other compounds. These two compounds (19 and 26) possess mixed agonist and antagonist activity.

Animals↗
PubMed1990

Wide spectrum of steroids serving as substrates for the formation of lipoidal derivatives in ZR-75-1 human breast cancer cells.

Recently, several natural steroids have been found to be esterified to long-chain fatty acids (FAE) in various mammalian tissues. The purpose of the present study was to determine the ability of a series of 3H-labeled steroids to serve as substrates for the formation and accumulation of such non-polar derivatives in intact cells, using the hormone-responsive ZR-75-1 human breast cancer cell line as model. All 14 steroids tested were found to be converted, directly or following further metabolism, to lipoidal ester derivatives. The percentage of intracellular steroids recovered as FAE derivatives was usually substantial (14-90%), especially in the case of C-19 steroids (75-90%). The composition of the lipoidal steroid fractions recovered from the labeled cell extracts was characterized by chromatographic comparison with synthetic steroid FAEs and by saponification of the steroid FAEs and identification of the released steroidal moieties. Following metabolism, most steroid substrates were converted into multiple lipoidal esters. Furthermore, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 alpha-androstane-3 beta, 17 beta-diol, as well as androst-5-ene-3 beta, 17 beta-diol formed lipoidal diesters in addition to the monoester form. The high level of intracellular steroid FAE accumulation reported in this study suggests that these yet poorly known steroid derivatives may play important functions in the regulation of steroid hormone metabolism and action.

Breast Neoplasms↗
PubMed1990

Treatment of hirsutism with the pure antiandrogen flutamide.

The effectiveness of the antiandrogen flutamide in combination with an oral contraceptive was studied in 20 patients with moderate to severe hirsutism. Eight patients had no previous therapy, whereas 12 had failed to respond to oral contraceptives, spironolactone, or dexamethasone therapy. Treatment with the antiandrogen flutamide (250 mg twice daily) and an oral contraceptive (Ortho 1/35) resulted in a particularly rapid and marked decrease in the total hirsutism score, which reached the normal range at 7 months. Seborrhea, acne, and hair loss score were also rapidly corrected. Treatment was associated with a decrease in plasma luteinizing hormone, progesterone, and estradiol levels. Plasma sex hormone-binding globulin levels were initially low in 18 to 20 patients but increased significantly during therapy. No clinically significant side effects were observed.

Adult↗
PubMed1990

Levels of eighteen non-conjugated and conjugated steroids in human breast cyst fluid: relationships with cyst type.

The present study investigates the levels of a large series of 18 non-conjugated or conjugated steroids in 71 samples of human breast cyst fluid (BCF) as divided into three groups corresponding to different electrolyte composition. In the type 1 group, the K+/Na+ ratio was higher than 1.5, while in type 2 it was lower than 0.66 and finally type 3 had an intermediate ratio. Pregnenolone (PREG) and progesterone (PROG) levels were approximately 2-fold higher (P less than 0.05) in the type 2 than in the type 1 group while both 17-OH-pregnenolone (17-OH-PREG) and 17-OH-progesterone (17-OH-PROG) concentrations were similar in these two groups. Most of the C-19 steroids analyzed, namely dehydroepiandrosterone sulfate (DHEAS), androst-5-ene-3 beta, 17 beta-diol (5-ene-DIOL), testosterone (TESTO), dihydrotestosterone (DHT), androstane-3 alpha, 17 beta-diol (3 alpha-DIOL), androsterone (ADT), androstane-3 alpha, 17 beta-diol glucuronide (3 alpha-DIOL-G) and androsterone glucuronide (ADT-G) were 180-360% (P less than 0.05) higher in type 1 than in type 2 cysts while no difference in C-18 steroid and C-18 steroid glucuronide levels was observed. A small or no difference was seen in steroid levels between types 2 and 3. We conclude that the arbitrary division according to the electrolyte composition of BCF permits identification of different patterns of steroid concentrations in BCF. However, the mechanism responsible for both sets of parameters remain unclear.

Adult↗
PubMed1990

Inhibitory effect of synthetic progestins, 4-MA and cyanoketone on human placental 3 beta-hydroxysteroid dehydrogenase/5----4-ene-isomerase activity.

Human placental 3 beta-hydroxysteroid dehydrogenase/5----4-ene isomerase (3 beta-HSD) purified from human placenta transforms C-21 (pregnenolone and 17 alpha-hydroxy pregnenolone) as well as C-19 (dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol) steroids into the corresponding 3-keto-4-ene-steroids and is thus involved in the biosynthesis of all classes of hormonal steroids. Trilostane, epostane and cyanoketone are potent inhibitors of 3 beta-HSD with Ki values of approximately 50 nM. 4-MA, a well known 5 alpha-reductase inhibitor, is also a potent inhibitor of 3 beta-HSD with a Ki value of 56 nM. Synthetic progestin compounds such as promegestone and RU2323 show relatively strong inhibitory effects with Ki values of 110 and 190 nM, respectively. Cyproterone acetate, a progestin used in the treatment of hirsutism, acne and prostate cancer as well as norgestrel and norethindrone that are widely used as oral contraceptives also inhibit 3 beta-HSD activity at Ki values of 1.5, 1.7 and 2.5 microM, respectively.

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

Unconjugated and glucuronide steroid levels in human breast cyst fluid.

The present report deals with the concentrations of C-21, C-19 and C-18 steroids as well as steroid glucuronides, namely androstane-3 alpha,17 beta-diol glucuronide, androsterone glucuronide, estradiol glucuronide, and estrone glucuronide (E1-G) in breast cyst fluid (BCF). The concentration of the gross breast cystic disease protein 15 (GCDFP-15) was also measured and its value was correlated with concentrations of unconjugated steroids as well as steroid conjugates. The present data indicate that for a large number of unconjugated steroids (namely pregnenolone, progesterone, dehydroepiandrosterone (DHEA), androsterone, androstane-3 alpha,17 beta-diol, estrone and estradiol) there is an important accumulation in BCF. Our data permit us to demonstrate a statistical relationship between the concentrations of DHEA and its metabolites (namely, androstenedione [4-ene-Dione]), thus suggesting an activity of the enzyme 3 beta-hydroxysteroid dehydrogenase-4-ene-5-ene-isomerase in the breast tissue. Further examination of the relationship between the concentrations of 4-ene-Dione and its metabolites, namely testosterone and 5 alpha-reduced steroid metabolites, as well as their glucuronide derivatives, strongly suggests that the metabolism of androgens in the breast tissue occurs mainly via 5 alpha-reductase and glucuronyl transferase activities. The concentration of GCDFP-15 in BCF found in the present investigation was 2745 +/- 234 micrograms/ml and we have shown that a negative relationship exists in the BCF between E1-G and GCDFP-15 levels.

Exudates and Transudates↗