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F Labrie

Publications and source records attributed to F Labrie.

At least 37 records · Page 2Linked to original sources
PubMed1997

Long-term inhibitory effects of a novel anti-estrogen on the growth of ZR-75-1 and MCF-7 human breast cancer tumors in nude mice.

The effects of the novel anti-estrogen EM-343 on the growth of 2 hormone-responsive human breast cancer tumors have been examined in athymic nude mice. At the low daily dose of 5 microg, EM-343 administered subcutaneously for 6 months completely blocked the stimulatory effect of endogenous estrogens on the growth of ZR-75-1 and MCF-7 tumors implanted in nude mice. In addition, uterine weight decreased by 60% while ovarian weight increased by 37%. Estrogen receptor (ER) levels measured by [3H]-labeled estrogen binding were markedly reduced (by 96%, 96% and 92%) in ZR-75-1 and MCF-7 tumors, and in the mouse uterus, respectively. Accompanying the decrease in ER, progesterone receptor levels were reduced by 79%, 87% and 76%, respectively, in the above-mentioned tissues following EM-343 treatment. Our data show the pure anti-estrogenic properties of EM-343 and its high potency as an inhibitor of growth of human ZR-75-1 and MCF-7 breast tumors in nude mice.

Animals↗
PubMed1997

Inhibitory effect of the novel anti-estrogen EM-800 and medroxyprogesterone acetate on estrone-stimulated growth of dimethylbenz[a]anthracene-induced mammary carcinoma in rats.

The novel anti-estrogen EM-800 and medroxyprogesterone acetate (MPA) inhibit estrone (E1)-stimulated growth of dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in a rat model. After 65 days, ovariectomy (OVX) decreased total tumor area to 9.6 +/- 3.9% of initial size, while E1 (1.0 microg, s.c., twice daily) stimulated tumor growth to 225 +/- 40.9% of initial size. Daily oral administration of 2.5 mg/kg body weight of EM-800 completely abolished E1-stimulated tumor growth. A low daily dose of EM-800 (0.25 mg/kg body weight) or MPA (1 mg, s.c., twice daily) used alone partially reversed the stimulatory effect of E1 on the growth of DMBA-induced tumors. The combination of both compounds, however, caused a more potent inhibitory effect than each compound used alone. A high dose of EM-800 completely or almost completely inhibited the E1-stimulated vaginal and uterine weights, respectively. The same dose of EM-800 completely reversed the inhibitory effect of E1 on serum luteinizing hormone levels. Uterine, vaginal and tumoral estrogen and progesterone receptor levels were reduced markedly following treatment with EM-800. Our data show that the combination of the pure anti-estrogen EM-800 with the androgenic compound MPA achieves greater inhibition of the growth of DMBA-induced mammary carcinoma than that achieved by each compound used alone.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Comparative effects of 28-day treatment with the new anti-estrogen EM-800 and tamoxifen on estrogen-sensitive parameters in intact mice.

Following 28 days of oral administration, in intact mice, the novel non-steroidal anti-estrogen EM-800 was at least 30-fold more potent than tamoxifen in inhibiting uterine weight. Moreover, the maximal inhibitory effect achieved with tamoxifen on uterine weight was only 40% that with EM-800. The pure anti-estrogenic activity of EM-800 on the hypothalamo-pituitary-gonadal axis is illustrated by the increase in ovarian weight, while tamoxifen, due to its estrogenic activity, decreased ovarian weight. EM-800 is 10- to 30-fold more potent than tamoxifen in inhibiting uterine and vaginal estrogen receptors. Since 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is the key enzyme in estradiol formation, the potent inhibitory effect of EM-800 on uterine 17beta-HSD could play an additional role by decreasing the availability of estradiol in the uterine tissue, while tamoxifen, on the contrary, stimulates activity of the enzyme. The atrophic changes in both the endometrial and myometrial layers achieved with EM-800 almost reached those observed 28 days after ovariectomy. EM-800 also resulted in a marked decrease in the number of ovarian developing follicles and corpora lutea, while the number of atretic follicles was increased. Tamoxifen treatment, on the other hand, produced an increase in both the number and crowding of the endometrial glands and a mild atrophy of the myometrial layer. Tamoxifen caused atrophic changes of the vaginal epithelium, especially at the highest doses, though the atrophy was much less pronounced than that following EM-800 treatment or ovariectomy. In addition to being at least 30-fold more potent than tamoxifen in inhibiting uterine weight, the novel anti-estrogen causes atrophy of the endometrium, stimulates the hypothalamo-pituitary-gonadal axis and inhibits uterine 17beta-HSD activity, while tamoxifen exerts opposite and estrogen-like effects on these parameters.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen-induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro.

Since estrogens play a predominant role in the development and growth of human breast cancer, antiestrogens represent a logical approach to the treatment of this disease. The present study compares the effects of the novel nonsteroidal anti-estrogen EM-800 and related compounds with those of a series of anti-estrogens on basal and 17 beta-estradiol (E2)-induced cell proliferation in human breast cancer cell lines. In the absence of added E2, EM-800 and related compounds failed to change basal cell proliferation, thus showing the absence of intrinsic estrogenic activity in the ER-positive T-47D, ZR-75-1 and MCF-7 cell lines. The stimulation of T-47D cell proliferation induced by 0.1 nM E2 was competitively blocked by a simultaneous incubation with EM-652, EM-800, OH-tamoxifen, OH-toremifene, ICI 182780, ICI 164384, droloxifene, tamoxifen and toremifene at apparent Ki values of 0.015, 0.011-0.017, 0.040-0.054, 0.043, 0.044, 0.243 and 0.735 nM, approx. 10 nM and > 10 nM, respectively. Similar data were obtained in ZR-75-1 and/or MCF-7 cells. Moreover, EM-652 was 6-fold more potent than OH-Tamoxifen in inhibiting the proportion of cycling MCF-7 cells. Our data show that EM-800 and EM-652 are the most potent known antiestrogens in human breast cancer cells in vitro and that they are devoid of the estrogenic activity of OH-tamoxifen and droloxifene suggested by stimulation of cell growth in the absence of estrogens in ZR-75-1 and MCF-7 cells.

Benzopyrans↗
PubMed1997

Blockade of the stimulatory effect of estrogens, OH-tamoxifen, OH-toremifene, droloxifene, and raloxifene on alkaline phosphatase activity by the antiestrogen EM-800 in human endometrial adenocarcinoma Ishikawa cells.

Although temporary benefits of tamoxifen therapy are observed in up to 40% of women with breast cancer, this compound, which is known to possess mixed estrogenic and antiestrogenic activities, has been associated with increased risk of endometrial carcinoma. This study compares the effects of the novel nonsteroidal pure antiestrogen EM-800 and related compounds with those of a series of antiestrogens on the estrogen-sensitive alkaline phosphatase (AP) activity in human endometrial adenocarcinoma Ishikawa cells. Exposure to increasing concentrations of up to 1000 nM EM-800 or its active metabolite EM-652 alone failed to affect basal AP activity. In contrast, incubation with 10 nM (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, or raloxifene increased the value of this estrogen-sensitive parameter by 3.3-, 3.5-, 2.2-, and 1.6-fold, respectively, a stimulatory effect that was completely reversed by simultaneous exposure to 30 nM EM-800. Moreover, the stimulation of AP activity induced by 1 nM 17beta-estradiol was completely reversed by EM-800, EM-652, or ICI-182780, at the IC50 value of 1.98 +/- 0.23, 1.01 +/- 0.16, and 5.64 +/- 0.59 nM, respectively, whereas the partial blockade exerted by (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, or raloxifene was observed at IC50 values of 13.5 +/- 3.80, 41.0 +/- 7.2, and 3.74 +/- 0.43 nM, respectively. Thus, as assessed by their activity in the human Ishikawa endometrial carcinoma cells, EM-800 and EM-652 are the most potent known antiestrogens in Ishikawa cells, and, most importantly, they are devoid of the estrogenic activity observed in these human endometrial cancer cells with (Z)-4-OH-tamoxifen, (Z)-4-OH-toremifene, droloxifene, and raloxifene.

Adenocarcinoma↗
PubMed1997

Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer.

PURPOSE: The aim of the present study is to investigate whether combined androgen blockade associated with radiation therapy for localized prostate cancer decreases at 12 and 24 months the rate of positive follow-up biopsies and serum PSA compared to radiation therapy alone. This is the report of an interim analysis. METHODS AND MATERIALS: One hundred and twenty patients with clinical Stage B1-T2a, B2-T2b/T2c, and C-T3/T4, adenocarcinoma of the prostate were entered in a prospective randomized study. After written informed consent, the subjects were randomly allocated between external beam radiation therapy (EBRT) alone (group 1), 3 months of neoadjuvant combination therapy (LHRH-agonist + Flutamide) prior to EBRT (group 2), and a third group receiving combination therapy 3 months before, during, and 6 months after EBRT. There is no significant difference between the three groups concerning age, stage of disease, grade of tumor, and pretreatment PSA levels. Control transrectal ultrasound (TRUS)-guided needle biopsies (one core was taken from the initial cancer site regardless of the presence or absence of TRUS abnormalities) were done 12 and 24 months after the end of EBRT. Serum PSA measurements were done on schedule visits. RESULTS: Ninety-two and 68 patients underwent biopsies at 12 and 24 months, respectively, after the end of radiation therapy. While 62% of control patients at 12 months in Group 1 disclosed residual neoplasm, only 30% and 4% showed residual disease in groups 2 and 3, respectively (p = 0.00005). When looking at 24 months, 65, 28, and 5% showed residual cancer for groups 1, 2, and 3, respectively (p = 0.00001). The PSA measurements indicate also at 12 months a difference between the three groups (p < 0.0001), except at 24 months, the difference between the group 2 and 3 is no longer significant. CONCLUSION: The preliminary analysis of this clinical trial indicates that patients treated with radiation therapy alone show a significantly higher rate of positive biopsies at 12 and 24 months after the end of radiation therapy as compared with those treated with total antiandrogen blockade (TAB) and radiation therapy. When analyzing the median PSA serum levels, we found the same advantage at 12 months, but, at the time of the analysis at 24 months, the PSA levels are not different between groups 2 and 3.

Aged↗
PubMed1997

Relationships between endogenous steroid hormone, sex hormone-binding globulin and lipoprotein levels in men: contribution of visceral obesity, insulin levels and other metabolic variables.

Excess visceral adipose tissue (AT) and hyperinsulinemia are important correlates of an altered lipoprotein profile. It has also been reported that testosterone, adrenal C19 steroids and sex hormone-binding globulin (SHBG) concentrations are associated with plasma lipoprotein levels. The aim of the present study was to investigate the relative contributions of endogenous steroid hormone and SHBG levels, of visceral AT accumulation measured by computed tomography, and of fasting insulin and free fatty acid (FFA) concentrations to the variation of plasma lipoprotein levels in men. For this purpose, plasma concentrations of testosterone, dehydroepiandrosterone (DHEA), androstene-3beta,17beta-diol (delta5-DIOL), androstenedione (delta4-DIONE), estrone and estradiol, as well as SHBG levels were determined in a sample of 76 men covering a wide range of body fatness values. Higher testosterone levels were associated with a more favorable lipoprotein profile as it showed significant correlations with triglyceride (TG), total cholesterol and LDL-cholesterol (LDL-C) concentrations (r= -0.25, -0.25 and -0.27, respectively; P < 0.05). Higher plasma adrenal C19 steroid levels were also associated with a favorable lipoprotein profile as DHEA, delta4-DIONE and delta5-DIOL levels were negatively correlated with total cholesterol (r = -0.24, -0.33 and -0.24, respectively; P < 0.05) and LDL-C (r = -0.23, -0.31 and -0.28, respectively; P < 0.05). SHBG levels were negatively correlated with TG concentrations (r = -0.33; P < 0.005) whereas delta5-DIOL, testosterone and SHBG were negatively correlated with apolipoprotein B levels (-0.32 < or = r < or = -0.43; P < 0.005). Statistical adjustment for visceral AT area, fasting insulin, fasting free fatty acid (FFA) levels and total body fat mass eliminated most of the correlations between steroid and lipoprotein levels, while SHBG remained significantly correlated with lipoprotein concentrations after such adjustments. Multivariate analyses revealed that SHBG, delta4-DIONE, delta5-DIOL and metabolic variables all contributed to the variance in plasma lipoprotein concentrations (from 10 to 29% of explained variance). Visceral AT, fasting FFA and insulin levels as well as SHBG concentrations appeared to be independent correlates of lipoprotein concentrations. Thus, metabolic and anthropometric variables examined in the present study could have represented important confounding factors in previous studies which have examined the relationship of steroid hormones to plasma lipoprotein concentrations.

Adipose Tissue↗
PubMed1997

The key role of 17 beta-hydroxysteroid dehydrogenases in sex steroid biology.

17 beta-Hydroxysteroid dehydrogenase (17 beta-HSD) controls the last step in the formation of all androgens and all estrogens. This crucial role of 17 beta-HSD is performed by at least five 17 beta-HSD isoenzymes having individual cell-specific expression, substrate specificity, regulation mechanisms, and reductive or oxidative catalytic activity. Both estrogenic and androgenic 17 beta-HSD activities were found in all 25 rhesus monkey and 15 human peripheral intracrine tissues examined. Type 1 17 beta-HSD is a protein of 327 amino acids catalyzing the formation of 17 beta-estradiol from estrone. Its x-ray structure was the first to be determined among mammalian steroidogenic enzymes. Initially crystallized with NAD, the crystal structure of type 1 17 beta-HSD has just been determined as a complex with 17 beta-estradiol, thereby illustrating the conformation of the substrate-binding site. Type 2 17 beta-HSD degrades 17 beta-estradiol into estrone and testosterone into androstenedione, and type 4 17 beta-HSD mainly degrades 17 beta-estradiol into estrone and androst-5-ene-3 beta, 17 beta-diol into dehydroepiandrosterone. Types 3 and 5 17 beta-HSD, on the other hand, catalyze the formation of testosterone from androstenedione in the testis and peripheral tissues, respectively. The various types of human 17 beta-HSD, because of their tissue-specific expression and substrate specificity, provide each peripheral cell with the necessary mechanisms to control the level of intracellular androgens and/or estrogens, a new area of hormonal control that we call intracrinology.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Comparison of in vitro effects of the pure antiandrogens OH-flutamide, Casodex, and nilutamide on androgen-sensitive parameters.

OBJECTIVES: A combination of flutamide (Eulexin) or nilutamide (Anandron) with a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy is the only therapy demonstrated to prolong life in prostate cancer. Recently, the low 50-mg daily dose of Casodex, an analogue of the pure antiandrogen flutamide, was chosen for clinical studies on the basis that the compound was 5 to 10 times more potent than flutamide, as suggested by data obtained in the inappropriate intact rat model. The present study was designed to compare the in vitro antiandrogenic activity of OH-flutamide (OH-FLU), the active metabolite of flutamide, Casodex, and nilutamide. METHODS: The effect of the antiandrogens was tested on two androgen-sensitive parameters, namely proliferation of the SEM-107 clone of Shionogi mouse mammary tumor cells and secretion of the GCDFP-15 (gross cystic disease fluid protein 15 kDa) in T-47D and ZR-75-1 human breast cancer cells. RESULTS: The twofold stimulation of Shionogi cell proliferation caused by a 10-day exposure to 1 nM testosterone was competitively reversed by incubation with OH-FLU, Casodex, or nilutamide, at the respective IC50 values of 72, 243, and 412 nM. Moreover, the marked increase in GCDFP-15 release induced by 1 nM testosterone was blocked by OH-FLU. Casodex, or nilutamide at respective IC50 values of 29, 180, and 87 nM in T-47D cells and at 35, 142, and 75 nM in ZR-75-1 cells. Similar data were detected in 4-androstenedione-induced Shionogi cell proliferation and in dihydrotestosterone-induced GCDFP-15 secretion in T-47D cells. CONCLUSIONS: OH-FLU is 3.1- to 7.8-fold more potent than Casodex, as measured on two in vitro androgen-sensitive parameters, in agreement with our recent in vivo data obtained in the model of castrated rats supplemented with 4-androstenedione implants, in which threefold greater potency of flutamide was observed. The present data, as well as other data from the literature, strongly indicate the need to choose a more appropriate dose of Casodex for the treatment of prostate cancer.

Androgen Antagonists↗
PubMed1997

Neoadjuvant hormonal therapy: the Canadian experience.

OBJECTIVE: To assess the effect of neoadjuvant combination therapy with the antiandrogen flutamide and a luteinizing-hormone-releasing hormone (LHRH) agonist administered for 3 months before radical prostatectomy, compared with surgery alone in early stage prostate cancer on histopathologic findings at surgery and serum prostate-specific antigen (PSA). METHODS: A sample of 161 randomly screened patients diagnosed as having stage B (134 patients) or C (27 patients) prostate cancer were randomly assigned to radical prostatectomy alone or to 3 months of neoadjuvant combination therapy with the antiandrogen flutamide and an LHRH agonist before radical prostatectomy. RESULTS: Neoadjuvant combination therapy before radical prostatectomy decreased cancer-positive surgical margins from 33.8% in the control group to only 7.8%, thus leaving 92.2% of patients with negative margins at surgery. A net 54% improvement of staging was observed in favor of combination therapy. Organ-confined disease, on the other hand, increased from 49.3% to 77.8% of patients after 3 months of combination therapy, for a 57.8% increase in the incidence of organ-confined disease. No cancer was found in 6 (6.7%) prostatectomy specimens from the treated group. A close correlation was found between serum PSA at diagnosis and the stage of the disease at surgery. Upstaging increased from 30% at serum PSA values of 0 to 3.0 ng/mL up to 100% at serum PSA values above 15 ng/mL. CONCLUSIONS: Although long-term follow-up of these patients is required to determine the impact on survival, the marked influence of neoadjuvant combination therapy on the stage of the disease suggests the possibility of a major improvement in the morbidity and mortality from prostate cancer.

Adenocarcinoma↗
PubMed1997

Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity.

OBJECTIVES: Because the large increase in luteinizing hormone secretion induced by flutamide in the intact rat is not found in men, we have used castrated rats and mice supplemented with androstenedione (4-dione) instead of intact animals to measure the activity of the pure antiandrogens flutamide and Casodex. METHODS: We first compared the effect of different schedules of administration of various doses of the two antiandrogens on prostate and seminal vesicle weights in the castrated rat and mice models. RESULTS: For both flutamide and Casodex, no consistent difference was found between the effects of once daily and thrice daily oral dosing in the rat. It was observed, however, that flutamide, especially at the high and therapeutically more effective doses, is about three times more potent than Casodex under both schedules of dosing. When flutamide was administered subcutaneously three times a day, twice a day, once a day, or once every second day in rats and mice, no difference was observed in the degree of inhibition achieved on prostate and seminal vesicle weights. CONCLUSIONS: The present data show that Casodex is about three times less potent than flutamide on the well-recognized parameters of androgen responsiveness in the rat, namely prostate and seminal vesicle weights. Another finding is that once daily dosing with flutamide exhibits an effectiveness comparable to thrice daily dosing; such data may have potential significance in facilitating compliance by administration of flutamide once daily instead of the current thrice daily schedule in men. Moreover, these data, if obtained in a reliable in vivo model, should be helpful in determining the choice of an appropriate dose of Casodex for the treatment of prostate cancer.

Androgen Antagonists↗
PubMed1997

Synthesis and in vitro study of 17 beta-[N-ureylene-N,N'-disubstituted]-4-methyl-4-aza-5 alpha-androstan-3-ones as selective inhibitors of type I 5 alpha-reductase.

A series of 17 beta-(N-ureylene-N,N'-disubstituted)-4-azasteroids as inhibitors of human type I 5 alpha-reductase (5 alpha-Re) were prepared from 17 beta-N-alkyl-4-methyl-4-aza-5 alpha-androstan-3-ones and various isocyanates. For the measurement of 5 alpha-Re activity, 293 cells transfected with human type I 5 alpha-Re, cDNA were used. Azasteroids with an N-cyclopropyl ring exhibited potent inhibitory activity against type I 5 alpha-Re. As the chain length increased, from the N'-ethyl to the N'-butyl chain, activity of compounds also increased and azasteroids with the N'-butyl chain showed strong inhibitory activity (IC50 = 5.3 nM). Branching of alkyl chains decreased the potency of compounds. Introduction of the 1,2-double bond significantly reduced the activity of azasteroids. Replacement of the N'-alkyl chain with the phenyl moiety gave the most active compound of this series (IC50 = 1.3 nM). Other variations such as the replacement of a N-cyclopropyl ring with the N-methyl or the N-butyl chain decreased the activity of compounds (compounds were less active compared with above). The IC50 values of N-methyl-N'-cyclohexyl- and N-butyl-N'-phenyl-ureylenes were 31.5 and 11.5 nM. respectively. In general, all azasteroids were poor inhibitors of Type II 5 alpha-Re.

5-alpha Reductase Inhibitors↗
PubMed1997

Localization of BRCA1 gene expression in adult cynomolgus monkey tissues.

The breast and ovarian cancer susceptibility gene BRCA1 encodes a phosphoprotein of 1863 amino acids containing a highly conserved N-terminal RING finger domain and a C-terminal acidic region typical of several transcription factors. BRCA1 acts as a tumor suppressor that may inhibit the proliferation of breast and ovarian cancer cells. To gain knowledge and to further understand the biological function of BRCA1, we examined its localization and expression in various tissues from 20-year-old male and female cynomolgus monkeys (Macaca fascicularis) by in situ hybridization using a 35S-labeled human BRCA1 DNA probe fragment derived from exon 11. In mammary glands, BRCA1 expression was primarily located in the duct and acinar epithelial cells. In the ovary, strong BRCA1 expression was detected in granulosa cells in maturing follicles and in luteal cells of the corpus luteum, as well as in the epithelial cells overlying the tunica albuginea. Specific signal was also observed in epithelial cells of the oviduct, endometrium, cervix, and vagina. Moreover, BRCA1 was strongly expressed in the germinal epithelium of the seminiferous tubules as well as over interstitial cells of the testis, in the epithelium of the epididymis, and in epithelial cells bordering the glandular lumen of the seminal vesicles. Signal was also detected in both the anterior and posterior lobes of the pituitary. In the adrenal glands, the signal was greater in the zona glomerulosa compared to the two other cortical zones, whereas the medullary cells were weakly labeled. In the stomach, and in small and large intestine, epithelial cells of the crypts usually exhibited stronger positive reaction than that observed over surface epithelial lining cells. BRCA1 expression was also found in diverse types of epithelial cells of the thyroid, pancreas, salivary glands, trachea, urinary bladder, and kidneys. In addition to demonstrating widespread tissue- and cell-specific expression of the BRCA1 gene in primate tissues, primarily in the epithelia, we observed a weaker but specific signal in various other cell types, suggesting a generalized biological function of BRCA1.

Animals↗
PubMed1997

Combined effects of dehydroepiandrosterone and EM-800 on bone mass, serum lipids, and the development of dimethylbenz(A)anthracene-induced mammary carcinoma in the rat.

Although treatment with dehydroepiandrosterone (DHEA) and the antiestrogen EM-800 alone decreased dimethylbenz(A)anthracene (DMBA)-induced mammary tumor incidence from 95% to 57% and 38%, respectively, approximately 9 months after DMBA administration, only two tumors developed in the group of animals that received the combination of DHEA and EM-800, and these two tumors disappeared before the end of the experiment (P < 0.01 vs. DHEA or EM-800 alone). Average tumor number per tumor-bearing animal as well as average tumor area per tumor-bearing animal were further decreased in animals that received the combination therapy compared with the effect of each treatment alone (P < 0.01). DHEA induced 6.9% (P < 0.01), 10.6% (P < 0.05), and 8.2% (P < 0.01) increases in bone mineral density of total skeleton, lumbar spine, and femur, respectively. The addition of EM-800 to DHEA did not affect the enhancing effect of DHEA on bone mass. The combination of the two drugs had important inhibitory effects on the urinary excretion of calcium and phosphorus as well as on the urinary hydroxyproline/creatinine ratio. Serum total alkaline phosphatase was stimulated by DHEA. Treatment with EM-800 decreased both serum triglyceride and cholesterol levels, whereas DHEA had an inhibitory effect on serum triglycerides. Although treatment with EM-800 caused a marked atrophy of the mammary gland, DHEA alone reduced lobular hyperplasia seen in aged intact rats while causing an androgen-specific stimulation of the same structures in animals already receiving the antiestrogen EM-800. The combination of DHEA and EM-800 lowered ovarian weight by 24% (P < 0.01) and decreased serum estradiol concentrations to intact control levels, whereas each compound alone had no effect on ovarian weight and stimulated serum estradiol levels by 45% (P < 0.05) and 46% (P < 0.05), respectively. Treatment with EM-800 caused a marked inhibition of uterine and vaginal weight. The present data show the additive inhibitory effects of DHEA and EM-800 on the development of DMBA-induced mammary carcinoma in the rat, thus suggesting the potential benefits of such a combination for the prevention of breast cancer in women while preserving or even increasing bone mass and maintaining a favorable lipid profile.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Morphological changes induced by 6-month treatment of intact and ovariectomized mice with tamoxifen and the pure antiestrogen EM-800.

The present study compares the effects of tamoxifen and EM-800, both administered at the oral daily dose of 100 microg for 6 months, on the uterus, vagina, and mammary gland in the mouse at histopathological examination. Treatment of intact animals with EM-800 resulted in uterine and vaginal atrophy even greater than that achieved after ovariectomy, while the developmental growth of the mammary gland was completely blocked and serum LH was increased. In ovariectomized animals, treatment with EM-800 decreased uterine and vaginal wt below the values observed in control ovariectomized mice while no significant change was observed on serum LH, thus indicating the lack of estrogenic activity of EM-800. Tamoxifen, on the other hand, showed a stimulatory estrogenic-like action on the mouse uterus in both intact and ovariectomized animals, thus resulting in moderate to severe endometrial hyperplasia. These morphological changes were accompanied by a marked stimulation of both the estrogenic and androgenic 17beta-hydroxysteroid dehydrogenase as well as 5alpha-reductase uterine activities. The histological atrophic changes observed in the vagina after tamoxifen treatment were less pronounced than those seen after treatment with EM-800. The agonistic estrogen-like action of tamoxifen was also illustrated by the suppression of serum LH levels in ovariectomized animals. A marked stimulation of the ovarian stroma, accompanied by a significant reduction in folliculogenic activity, was observed after EM-800 or tamoxifen administration, although the interstitial ovarian hyperplasia was more pronounced after EM-800 treatment. While both antiestrogens blocked the developmental growth of the mammary gland, EM-800 showed more potent antiestrogenic activity than tamoxifen. The highly potent and specific antiestrogenic activity of EM-800 suggests that this compound could improve the therapy of breast cancer while avoiding the undesirable stimulation of the endometrium.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Effect of dehydroepiandrosterone on bone mass, serum lipids, and dimethylbenz(a)anthracene-induced mammary carcinoma in the rat.

The present study investigated the effect of dehydroepiandrosterone (DHEA) on bone mass and serum lipids in the rat with dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma. The animals received DHEA once daily, percutaneously, at the dose of 5, 10, or 20 mg for 9 months following a single dose of 20 mg DMBA at 50-52 days of age. Bone mineral content (BMC) and bone mineral density (BMD) of total skeleton, lumbar spine, and femur were measured by dual energy x-ray absorptiometry. A 9-month treatment with DHEA increased BMC and BMD of total skeleton by 14.2% to 14.5% (all P < 0.01) and 6.7% to 8.3% (all P < 0.01), respectively. Similarly, femoral BMC and BMD were stimulated by 13.6% to 14.7% (all P < 0.05) and by 8.1% to 9.5% (all P < 0.01), respectively. In addition, BMD of lumbar spine was increased by 10.4% to 10.8% (all P < 0.05), whereas the 9.4% to 11.1% increment in BMC of lumbar spine was not statistically significant. Treatment with DHEA led to 26% (NS), 60% (P < 0.01), and 62% (P < 0.01) decreases in serum triglyceride levels at the same doses. On the other hand, no significant change in serum cholesterol concentrations was observed. Two hundred and seventy-nine days after DMBA administration, the incidence of mammary carcinoma had decreased from 95% in control animals to 73% (P < 0.05), 57% (P < 0.01), and 38% (P < 0.01) at the daily percutaneous doses of 5, 10, and 20 mg of DHEA, respectively. Moreover, the mean tumor number per tumor-bearing animal and the mean tumor area per tumor-bearing animal were also reduced by the same treatments. DHEA increased serum total alkaline phosphatase activity and decreased urinary calcium excretion, but had no effect on the urinary ratio of hydroxyproline to creatinine and urinary phosphorus excretion. These data show that DHEA exerts a stimulatory effect on bone mass and an inhibitory effect on serum triglycerides, as well as a preventive effect on the development of mammary carcinoma induced by DMBA in the rat. Such data suggest that while decreasing the risk of breast cancer, DHEA replacement therapy could also exert beneficial effects on the bone and lipid metabolism in women receiving DHEA replacement therapy.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1997

Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women.

The effect of 12-month dehydroepiandrosterone (DHEA) replacement therapy has been evaluated in 14 60- to 70-yr-old women who received daily applications of a 10% DHEA cream. Vaginal epithelium maturation was stimulated by DHEA administration in 8 of 10 women who had a maturation value of zero at the onset of therapy, whereas a stimulatory effect was also seen in all three women who had an intermediate vaginal maturation index before therapy. The estrogenic effect of DHEA observed in the vagina was not observed in the endometrium, which remained atrophic in all women. Most interesting, the bone mineral density significantly increased at the hip from 0.744 +/- 0.021 to 0.759 +/- 0.025 g/cm2 after 12 months of treatment (P < 0.05). These changes in bone mineral density were associated with a significant 20.0% decrease (P < 0.01) in plasma bone alkaline phosphatase and a 28% decrease in the urinary hydroxyproline/creatinine ratio. A 2.1-fold increase over the control value (P < 0.01) in plasma osteocalcin was concomitantly observed. The present data describe for the first time a series of medically important beneficial effects of DHEA therapy in postmenopausal women through transformation of the precursor steroid DHEA into androgens and/or estrogens in specific peripheral intracrine tissues without significant adverse effects. The stimulatory effect on the vaginal epithelium in the absence of stimulation of the endometrium is of particular interest because it eliminates the need for progestin replacement therapy. On the other hand, the stimulatory effect on bone mineral density accompanied by an increase in serum osteocalcin, a marker of bone formation, suggests stimulation of bone formation by the androgenic action of DHEA, a finding of particular interest for both the prevention and treatment of osteoporosis.

Aged↗