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B Candas

Publications and source records attributed to B Candas.

36 records · Page 2Linked to original sources
PubMed1997

Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging.

The present data show a dramatic decline in the circulating levels of dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), androst-5-ene-3 beta,17 beta-diol (5-diol), 5-diol-sulfate, 5-diol-fatty acid esters, and androstenedione in both men and women between the ages of 20-80 yr. In the 50- to 60-yr-old group, serum DHEA decreased by 74% and 70% from its peak values in 20- to 30-yr-old men and women, respectively. the serum concentrations of the conjugated metabolites of dihydrotestosterone (DHT), namely androsterone (ADT)-G, androstane-3 alpha,17 beta-diol (3 alpha-diol-G), androstane-3 beta,17 beta-diol (3 beta-diol-G), and ADT-sulfate are the most reliable parameters of the total androgen pool in both men and women, whereas serum testosterone and DHT can be used as markers of testicular secretion in men and interstitial ovarian secretion in women. The serum concentration of these various conjugated androgen metabolites decreased by 40.8% to 72.8% between the 20- to 30-yr-old and 70- to 80-yr-old age groups in men and women, respectively, thus suggesting a parallel decrease in the total androgen pool with age. As estimated by measurement of the circulating levels of these conjugated metabolites of DHT, it is noteworthy that women produce approximately 66% of the total androgens found in men. In women, most of these androgens originate from the transformation of DHEA and DHEA-S into testosterone and DHT in peripheral intracrine tissues, whereas in men the testes and DHEA and DHEA-S provide approximately equal amounts of androgens at the age of 50-60 yr. An additional potentially highly significant observation is that the majority of the marked decline in circulating adrenal C19 steroids and their resulting androgen metabolites takes place between the age groups of 20- to 30-yr olds and 50- to 60-yr-olds, with smaller changes are observed after the age of 60 yr.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology.

This study analyzes in detail the serum concentration of the active androgens and estrogens, as well as a series of free and conjugated forms of their precursors and metabolites, after daily application for 2 weeks of 10 mL 20% dehydroepiandrosterone (DHEA) solution on the skin to avoid first passage through the liver. In men, DHEA administration caused 175%, 90%, 200% and 120% increases in the circulating levels of DHEA and its sulfate (DHEA-S), DHEA-fatty acid esters, and androst-5-ene-3 beta,17 beta-diol, respectively, with a return to basal values 7 days after cessation of the 14-day treatment. Serum androstenedione increased by approximately 80%, whereas serum testosterone and dihydrotestosterone (DHT) remained unchanged. In parallel with the changes in serum DHEA, the concentrations of the conjugated metabolites of DHT, namely androsterone glucuronide, androstane-3 alpha,17 beta-diol-G, and androstane-3 beta,17 beta-diol-G increased by about 75%, 50%, and 75%, respectively, whereas androsterone-sulfate increased 115%. No consistent change was observed in serum estrone (E1) or estradiol (E2) in men receiving DHEA, whereas serum E1-sulfate and E2-sulfate were slightly and inconsistently increased by about 20%, and serum cortisol and aldosterone concentrations were unaffected by DHEA administration. Almost superimposable results were obtained in women for most steroids except testosterone, which was about 50% increased during DHEA treatment. This increase corresponded to about 0.8 nM testosterone, an effect undetectable in men because they already have much higher (approximately 15 nM) basal testosterone levels. In women, the serum levels of the conjugated metabolites of DHT, namely androsterone glucuronide, androstane-3 alpha,17 beta-diol-G, androstane-3 beta,17 beta-diol-G, and androsterone-sulfate were increased by 125%, 140%, 120% and 150%, respectively. The present study demonstrates that the serum concentrations of testosterone, DHT, E1, and E2 are poor indicators of total androgenic and estrogenic activity. However, the esterified metabolites of DHT appear as reliable markers of the total androgen pool, because they directly reflect the intracrine formation of androgens in the tissues possessing the steroidogenic enzymes required to transform the inactive precursors DHEA and DHEA-S into DHT. As well demonstrated in women, who synthesize almost all their androgens from DHEA and DHEA-S, supplementation with physiological amounts of exogeneous DHEA permits the biosynthesis of androgens limited to the appropriate target tissues without leakage of significant amounts of active androgens into the circulation. This local or intracrine biosynthesis and action of androgens eliminates the inappropriate exposure of other tissues to androgens and thus minimizes the risks of undesirable masculinizing or other androgen-related side effects of DHEA.

Administration, Cutaneous↗
PubMed1996

Diagnosis of advanced or noncurable prostate cancer can be practically eliminated by prostate-specific antigen.

OBJECTIVES: To determine the percentage of localized and potentially curable prostate cancers diagnosed at follow-up screening visits compared with the first screening visit. METHODS: Within the context of a prospective screening study performed in randomly chosen men aged between 45 and 80 years, up to 6-year follow-up screening visits have been performed with serum prostate-specific antigen (PSA) measurement and digital rectal examination (DRE) followed by transrectal ultrasonography of the prostate when PSA or DRE is abnormal. RESULTS: Of the 117 prostate cancers diagnosed at 14,554 annual follow-up visits, only 1 cancer (0.9%) was metastatic compared with 8% (26/322) at 8029 first visits. Moreover, 97% of the cancers detected at follow-up visits could be identified by PSA alone compared with 86% at first visit. The incidence of 0.8% per year during 15 years of screening between the ages of 55 and 70 years would diagnose localized prostate cancer in 12% of the population, a value not too different from the 10% diagnosed with prostate cancer during life-time in the absence of screening. CONCLUSIONS: The present data show that annual screening with PSA diagnoses clinically localized prostate cancer in more than 95% of cases, thus almost completely eliminating the diagnosis of metastatic prostate cancer. Moreover, the number of prostate cancers diagnosed is not significantly increased by screening.

Aged↗
PubMed1996

Effect of neoadjuvant endocrine therapy (combined androgen blockade) on normal prostate and prostatic carcinoma. A randomized study.

The morphologic changes induced by neoadjuvant combination endocrine therapy were evaluated in prostatectomy specimens from patients diagnosed with localized prostate cancer. These patients participated in a prospective, randomized clinical trial investigating the effect of 3 months of combination therapy with flutamide and an LHRH agonist prior to radical prostatectomy versus radical prostatectomy alone. Ninety-six radical prostatectomy specimens processed according to the same protocol were evaluated without knowledge of prior treatment. Forty-seven patients were randomly assigned to the neoadjuvant combination therapy group and 49 to the control arm. Compared with the control group, several changes were strongly and significantly associated with exposure to neoadjuvant combination therapy. The nonmalignant prostatic tissue showed strong prominence and hyperplasia of the basal cell layer, accompanied by epithelial cell vacuolization and markedly reduced occurrence of prostatic intraepithelial neoplasia (p < 0.001) after combination therapy. Prostate cancer tissue, on the other hand, showed smaller nucleoli (p < 0.001), cell vacuolization (p < 0.001), rare intraluminal crystalloids (p < 0.001), higher Gleason grade (p < 0.001), lower prevalence of capsular penetration (p < 0.001), and less frequent invasion of the perineural spaces (p < 0.001) and surgical margins (p = 0.002). Tumor volume, was also reduced by more than 40% in the treated group (p = 0.007). The present findings show that preoperative endocrine combination therapy induces highly characteristic changes in both nonmalignant and cancerous prostatic tissue. Furthermore, following endocrine treatment, the surgical margins are less likely to be involved by cancer and capsular penetration is reduced.

Adult↗
PubMed1995

Equilibrium model in an in vitro poly(ADP-ribose) turnover system.

Poly(ADP-ribose) metabolism plays an important role in numerous DNA-related functions. This homopolymer is synthesized by poly(ADP-ribose) polymerase and is degraded mainly by the poly(ADP-ribose) glycohydrolase. The activities of these two enzymes in the nucleus are closely coordinated. To better understand the interactions between these enzymes, we designed an in vitro system in which both enzymes are present at the same time. In this work, we report a model describing the synthesis and degradation of the poly(ADP-ribose) in turnover conditions. Because the half-life of the polymer in the cell is close to 1 min, we studied the very early kinetic interactions of these two enzymes.

Adenosine Diphosphate Ribose↗
PubMed1995

Combination of screening and preoperative endocrine therapy: the potential for an important decrease in prostate cancer mortality.

Prostate cancer is the second cause of cancer death in men in the Western world; its medical and social impact is comparable to that of breast cancer in women. Although it is well recognized that early treatment is the only possibility for reducing the high rate of death from prostate cancer, screening and even early treatment are controversial issues due mainly to arguments based upon old literature and lack of awareness of the significant advances recently made in this field. As it is well known that surgical removal of organ-confined prostate cancer cures the disease, and it has been demonstrated that annual screening with prostate-specific antigen coupled with digital rectal examination followed, when indicated, by transrectal ultrasonography of the prostate more than doubles the proportion of organ-confined disease, screening alone offers the possibility of at least doubling the number of patients curable from prostate cancer or the potential for a cure to an estimated 45% of prostate cancer patients compared to a maximum of 20% in the absence of screening. It is important to mention that screening does not detect small and insignificant cancers, especially when random biopsies are not performed routinely. The critical volume of prostate cancer is estimated at 0.3 cm or a tumor 7.5 mm in diameter, if spherical. Such a tumor should increase serum prostate-specific antigen by 0.5 ng/mL. Contrary to the belief that screening detects cancers that are too small, the fact is that screening detects prostate cancer too late or nonorgan- or nonspecimen-confined cancer in 35-50% of cases. There is, thus, a narrow window when prostate cancer can be detected at a curable stage, and even the best available screening techniques cannot succeed in all cases. It should be mentioned that the recent improvements of the technique of radical prostatectomy have markedly improved the acceptability of surgery. Concerning the recent publicity related to watchful waiting, it is essential to indicate that all such reports support the notion that prostate cancer grows slowly, but steadily and irremediably, with increasing malignancy and risk of distant metastases and death if sufficient time is allowed. Another serious limitation of watchful waiting is that the available prognostic factors have a large margin of error and cannot predict with certainty the rate of progression of the tumor.(ABSTRACT TRUNCATED AT 400 WORDS)

Androgen Antagonists↗
PubMed1995

Downstaging by combination therapy with flutamide and an LHRH agonist before radical prostatectomy.

A total of 161 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 anti-androgen flutamide and an LHRH agonist before radical prostatectomy. 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 for a 39.2% increase in specimen confined disease. Although on average the final stage determined at histopathological examination of the surgical specimen was more advanced than predicted at initial diagnosis in 33.8% of control patients, an opposite observation was made in the group of men who received the 3 month neoadjuvant combination therapy where the final stage, instead of being more advanced, was less advanced than at diagnosis in an average of 21.1% of men for a net 54.9% improvement of staging in favour of combination therapy. On the other hand, organ confined disease increased from 49.3% to 77.8% of patients after 3 months of combination therapy, for a 57.9% increase in the incidence of organ confined disease. 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.

Aged↗
PubMed1994

An adaptive plasma glucose controller based on a nonlinear insulin/glucose model.

The design of plasma glucose controllers traditionally relies on linear approaches. The implementation of an appropriate nonlinear model of the insulin/glucose regulatory system into an adaptive controller should predict the insulin-dependent glucose removal more reliably and hence provide better control over a wide spectrum of insulin signals. A discretized form of the model leads to a two-step procedure. First, the measured plasma glucose levels associated with the exogenous glucose infusion rates are used in the estimation of the past removal rates which, in turn, can be expressed as a weighted sum of past insulin inputs and previous values of the removal rate. Parameters of the sum are adjusted on-line by a recursive method of estimation which features a prefiltering of data to account for a corrupting coloured process noise. The same equation is in turn used to predict the time course of the insulin-dependent fractional rate of glucose removal. The performance of the controller, tested in vivo in three pigs, is presented for various intravenous or subcutaneous rapid injections and staircase infusions of insulin. Plasma glucose is maintained at an average level of 99.9 +/- 8.7% of the target value (% set point +/- coefficient of variation). The controller reacts promptly to large and rapid variations in insulin action. Although control improves with the number of glucose measurements, the prediction of glucose removal allows for some flexibility in the monitoring of the plasma glucose. Sampling frequency varied from a 2 min interval during transient periods to 7 min as steady states were reached.

Algorithms↗
PubMed1994

Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men.

It is well recognized that aging in men is accompanied by a decline in the serum levels of some adrenal and testicular steroids, but little or no attention has focused on the multiple steroid metabolites that are formed by steroid-converting enzymes in target tissues. In the present study, we have examined in detail the serum concentrations of a large series of adrenal and testicular steroids and their most significant metabolites produced in intracrine peripheral tissues. The serum concentrations of 26 conjugated and unconjugated C21-, C19-, and C18-steroids were measured in 2423 men aged 40-80 yr. The serum concentrations of the major circulating adrenal C19-steroids, namely dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), androst-5-ene-3 beta, 17 beta-diol and its sulfate, and androstenedione, decreased by about 60% between the ages of 40-80 yr. The small decrease in the serum concentrations of progesterone and pregnenolone in the presence of increased levels of cortisol and markedly decreased levels of DHEA, androst-5-ene-3 beta, 17 beta-diol, and their polar metabolites suggests that adrenal 17,20-lyase is particularly affected by aging. In addition to a marked decline in the serum concentrations of adrenal C19-steroids, a smaller, but significant, decrease occurred in serum testosterone. However, serum dihydrotestosterone levels remained constant, but the glucuronidated derivatives of dihydrotestosterone metabolites (androstane-3 alpha, 17 beta-diol glucuronide, androstane-3 beta, 17 beta-diol glucuronide, and androsterone glucuronide) were reduced by 45-50%, suggesting that 5 alpha-reductase activity in peripheral tissues may show a compensatory increase during aging. Analysis of the fatty acid esters of DHEA (DHEA-FA) also revealed that these nonpolar steroids markedly decrease between 40-80 yr of age, although such a decrease in DHEA-FA levels was smaller than that in DHEA and DHEA-S, suggesting that the formation of DHEA-FA may be specifically increased during aging. In summary, the present study suggests that in contrast to the marked decline in activity of steroidogenic enzymes in the adrenals and the small decrease in the testis, the activity of the steroid-converting enzymes present in peripheral tissues does not decrease during aging. In fact, the marked decrease in DHEA formation by the adrenals leads to a decrease of about 50% in total androgens in men between the ages of 40-80 yr. Such a decrease probably affects many physiological processes during aging.

Adrenal Glands↗
PubMed1993

Optimized strategy for detection of early stage, curable prostate cancer: role of prescreening with prostate-specific antigen.

In 1,002 men aged 45-80 y, 81% of the cancers detectable by serum prostate-specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasonography (TRUS) were present in a subpopulation (19% of total) identified by serum PSA above the threshold value of 3.0 micrograms/L. This study was extended to 7,350 men using serum PSA and DRE as first approach, followed by TRUS only when 1 of these 2 tests was abnormal. Because the aim of prostate cancer detection is to find cancers at an early, potentially curable stage, it is of major interest that 71.8% of evaluable cancers were clinical stage B; 8.4% and 10.7% were stages C1 and C2, respectively; only 9.2% were stage D (metastatic) at first visit while none was at stage D at follow-up visits. This study, the first performed in an unselected, unscreened population, shows that serum PSA is the most sensitive technique to identify men at high risk of having prostate cancer and that 12% more cancers can be found at first visit by doing DRE in addition to PSA. Follow-ups can be done every second year using serum PSA alone, as 97% of the cancers detected at annual follow-up by DRE + PSA were PSA+. Cancers are discovered by the present approach at an estimated cost of $2,665 per cancer. Such cancers are potentially curable in at least 80% of cases detected at first visit and in 97% of cases at follow-up. This strategy offers the possibility to improve markedly morbidity and mortality from prostate cancer, presently the second leading cause of cancer death in North American men.

Aged↗
PubMed1990

Model of the distribution and metabolism of a GnRH superagonist in dogs.

The plasma kinetics of [D-Trp6, des-Gly-NH2(10)]gonadotropin-releasing hormone (GnRH) ethylamide was assessed in eight dogs over a period of 8 h after rapid intravenous or subcutaneous injection. Each animal received doses of 0.2, 2, and 20 micrograms/kg body wt iv and 1 and 10 micrograms/kg body wt sc. A two-compartment structure, to which a source compartment was added to represent the subcutaneous route, adequately fits the five kinetics when the apparent volume of distribution follows a plasma concentration-dependent sigmoid function. Despite the nonlinearity, the apparent volume of distribution can be approximated by a constant value of 280 ml/kg body wt for the dynamics corresponding to the three lowest and more physiological doses. The metabolic clearance rate is 4.63 ml.min-1.kg body wt-1. The two exponential components that characterize the two-compartment structure are equal to 0.0348 +/- 0.0053 and 0.00470 +/- 0.00060 min-1, respectively. The agonist injected subcutaneously diffuses to plasma at a fractional rate of 0.0265 +/- 0.0029 min-1. Disposal occurs at a maximal rate of 0.017 and 0.0055 min-1 of the amount of agonist present in the central and peripheral compartments, respectively. The highest fractional exchange rate between compartments reaches 0.01 min-1. As simulated with the model, a continuous infusion of 4.63 ng.min-1.kg body wt-1 leads to a steady state of 1 ng/ml plasma; 90% of that level is reached 7 h after the onset of the subcutaneous input signal. The kinetics of plasma [D-Trp6, des-Gly-NH2(10)]GnRH ethylamide is many times slower than that of the native hormone and of the other GnRH agonists.

Animals↗
PubMed1990

Model of the distribution and metabolism of the gonadotropin-releasing hormone (GnRH) agonist [D-Trp6,Des-Gly-NH2(10)]GnRH ethylamide in man.

The kinetics of plasma immunoreactive [D-Trp6,Des-Gly-NH2(10)]GnRH ethylamide, a potent GnRH agonist, was assessed in nine normal adult men over a period of 24 h after a rapid sc injection of 1 or 10 micrograms peptide/kg BW. The specific RIA of the GnRH agonist is characterized by a minimum detectable dose of 5.0 +/- 0.5 pg peptide, while the midrange effective dose is 73 +/- 8 pg. The within- and between-assay coefficients of variation range from 2-7% and from 10-15%, respectively. When the volume of the central compartment is set proportional to the logarithm of the plasma concentration of the GnRH agonist, the time courses of both doses are statistically well represented by a two-compartment model to which a source compartment is added to represent the sc route of administration. The sc diffusion to plasma is 5 times faster than any other fractional transport rate of the model (5%/min). Disposal occurs at a maximum rate of 0.55%/min from the central compartment, which includes plasma, and 0.25%/min from the peripheral compartment. As simulated with the model, 90% of the steady state is reached 13 h and 45 min after the onset of a sc continuous infusion. A molecule spends, on the average, from 6 h to 9 h and 45 min in the whole organism; 30-50% of this period is accounted for by residence in the central compartment. The volume of the central compartment reaches 208 mL/kg BW, and the MCR is estimated at 1.18 mL/min.kg BW for a steady state of 1 ng/mL plasma. The plasma dynamics of [D-Trp6,Des-Gly-NH2(10)]GnRH ethylamide in men are at least 10 times slower than those reported for the natural GnRH, thus indicating the relevance of its clinical use in suppressive therapy of LH secretion.

Adult↗
PubMed1989

Trait anxiety, submaximal physical exercise and blood androgens.

This study evaluates the relationship between trait anxiety and both androgen and gonadotrophic hormone levels at rest and during severe physical exercise. Twelve volunteers were selected among 160 untrained male collegial students and classified as anxious (N = 6) or non-anxious (N = 6) subjects according to their scores on three trait-anxiety tests (STAI, IPAT, 16 PF). Serum delta 4-androgen (testosterone and delta 4-androstenedione), delta 5-androgen (DHEA and DHEA-SO4) and gonadotrophin (LH and FSH) concentrations were measured by radioimmunoassay before, during and after 20 minutes of intensive bicycle exercise (80% of maximal heart rate). Results indicate significantly lower serum delta 4-androgens in anxious subjects before exercise. However, for each subject and irrespective of his anxiety level, all measured serum androgen concentrations increased significantly during exercise, although delta 4-androstene-dione remained lower in anxious subjects than in non-anxious ones. Serum LH concentrations (but not FSH) were significantly higher in anxious subjects throughout the observation periods. However, exercise induced in each subject a significant decrease in the serum level of both gonadotrophic hormones. The results suggest that trait anxiety level may constitute an important factor that affects both pre-exercise and exercise serum androgen concentrations in untrained subjects.

Adult↗
PubMed1988

A model of the distribution and metabolism of corticotropin-releasing factor.

The aim of this study is the selection of the number of compartments required for a model to represent the distribution and metabolism of corticotropin-releasing factor (CRF) in rats. The dynamics of labeled rat CRF were measured in plasma for seven rats after a rapid injection. The sampling schedule resulted from the combination of the two D-optimal sampling sets of times corresponding to both rival models. This protocol improved the numerical identifiability of the parameters and consequently facilitated the selection of the relevant model. A three-compartment model fits adequately to the seven individual dynamics and better represents four of them compared with the lower-order model. It was demonstrated, using simulations in which the measurement errors and the interindividual variability of the parameters are included, that his four-to-seven ratio of data sets is consistent with the relevance of the three-compartment model for every individual kinetic data set. Kinetic and metabolic parameters were then derived for each individual rat, their values being consistent with the prolonged effects of CRF on pituitary-adrenocortical secretion.

Animals↗
PubMed1986

Distribution and metabolism of corticotropin-releasing factor in the rat.

To develop a mathematical model of the distribution and metabolism of rat corticotropin-releasing factor (rCRF), the time course of 125I-labelled rCRF in plasma was measured in male Sprague-Dawley rats (i) following a rapid injection of 24 ng rCRF/100 g body weight (BW), or (ii) following a rapid injection of 424 ng rCRF/100 g BW, or (iii) during an infusion at a rate ranging from 0.28 to 0.73 ng rCRF X min-1 X 100 g BW-1. The comparison of the one-, two-, and three-compartment models shows that the two-pool structure fits better to the dynamics of CRF in plasma as measured in each rat. Following a rapid injection the decay curve occurs in a biphasic manner; the early phase of disappearance is 25 times faster than the late one. There is no significant difference between the estimates of the metabolic clearance rate following both amplitudes of injection (0.40 +/- 0.06 and 0.48 +/- 0.05 mL X min-1 X 100 g BW-1). The volume of the first pool, 16.8 +/- 1.1 mL/100 g BW, is four times larger than the plasma volume. It would thus appear that CRF is rapidly distributed from plasma into several tissues which are represented in the first pool of the model. The mean residence time of every CRF molecule in the second compartment, from the moment of secretion to its elimination, is from three to four times longer than in the first one. It stays, on average, between 140 min and 3 h in the system before an irreversible exit.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging.

Human and some other primates are unique since their adrenals secrete large amounts of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), which are converted into androstenedione (4-dione) and then into potent androgens and estrogens in peripheral tissues, therefore providing autonomous intracrine control to target tissues that can adjust the formation and metabolism of active sex steroids according to local requirements. Knowledge in this area has recently made rapid progress with the elucidation of the structure of most of the tissue-specific cDNAs and genes that encode the steroidogenic enzymes responsible for the transformation of these inactive precursor steroids into androgens and/or estrogens. It is estimated that 30 to 50% of total androgens in men are synthesized in peripheral intracrine tissues from inactive adrenal precursors while, in women, peripheral estrogen formation is even more important, the best estimate being 75% before menopause and 100% after menopause. The marked reduction in the formation of DHEA-S by the adrenals during aging, especially before the age of 50 years, results in a dramatic fall in the formation of active sex steroids in peripheral target tissues, a situation which is thought to be associated with a long series of age-related decreases such as insulin resistance, obesity, osteoporosis, cardiovascular diseases, loss of muscle mass, cancer and other diseases. We have demonstrated for the first time a series of medically important beneficial effects of DHEA administered for 12 months to post-menopausal women. Most interestingly, the bone mineral density significantly increased. This relatively rapid change was associated with an increase in plasma osteocalcin, a marker of bone formation, while a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel. In addition, the estrogenic stimulation of vaginal cytology in the absence of any sign of stimulatory effect on the endometrium is also of potentially major interest for the prevention and management of menopause. Furthermore, the inhibitory effect of DHEA on the growth of human breast cancer xenografts in vivo in nude mice supports the beneficial use of DHEA as hormone replacement therapy in women.

Aging↗
PubMedDate not supplied

EM-652 (SCH 57068), a third generation SERM acting as pure antiestrogen in the mammary gland and endometrium.

Breast cancer is the most frequent cancer in women while it is the second cause of cancer death. Estrogens are well recognized to play the predominant role in breast cancer development and growth and much efforts have been devoted to the blockade of estrogen formation and action. The most widely used therapy of breast cancer which has shown benefits at all stages of the disease is the use of the antiestrogen Tamoxifen. This compound, however, possesses mixed agonist and antagonist activity and major efforts have been devoted to the development of compounds having pure antiestrogenic activity in the mammary gland and endometrium. Such a compound would avoid the problem of stimulation of the endometrium and the risk of endometrial carcinoma. We have thus synthesized an orally active non-steroidal antiestrogen, EM-652 (SCH 57068) and the prodrug EM-800 (SCH57050) which are the most potent of the known antiestrogens. EM-652 is the compound having the highest affinity for the estrogen receptor, including estradiol. It has higher affinity for the ER than ICI 182780, hydroxytamoxifen, raloxifene, droloxifene and hydroxytoremifene. EM-652 has the most potent inhibitory activity on both ER alpha and ER beta compared to any of the other antiestrogens tested. An important aspect of EM-652 is that it inhibits both the AF1 and AF2 functions of both ER alpha and ER beta while the inhibitory action of hydroxytamoxifen is limited to AF2, the ligand-dependent function of the estrogen receptors. AF1 activity is constitutive, ligand-independent and is responsible for mediation of the activity of growth factors and of the ras oncogene and MAP-kinase pathway. EM-652 inhibits Ras-induced transcriptional activity of ER alpha and ER beta and blocks SRC-1-stimulated activity of the two receptors. EM-652 was also found to block the recruitment of SRC-1 at AF1 of ER beta, this ligand-independent activation of AF1 being closely related to phosphorylation of the steroid receptors by protein kinase. Most importantly, the antiestrogen hydroxytamoxifen has no inhibitory effect on the SRC-1-induced ER beta activity while the pure antiestrogen EM-652 completely abolishes this effect, thus strengthening the need to use pure antiestrogens in breast cancer therapy in order to control all known aspects of ER-regulated gene expression. In fact, the absence of blockade of AF2 by hydroxytamoxifen could explain why the benefits of tamoxifen observed up to 5 years become negative at longer time intervals and why resistance develops to tamoxifen. EM-800, the prodrug of EM-652, has been shown to prevent the development of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat, a well-recognized model of human breast cancer. It is of interest that the addition of dehydroepiandrosterone, a precursor of androgens, to EM-800, led to complete inhibition of tumor development in this model. Not only the development, but also the growth of established DMBA-induced mammary carcinoma was inhibited by treatment with EM-800. An inhibitory effect was also observed when medroxyprogesterone was added to treatment with EM-800. Uterine size was reduced to castration levels in the groups of animals treated with EM-800. An almost complete disappearance of estrogen receptors was observed in the uterus, vaginum and tumors in nude mice treated with EM-800. EM-652 was the most potent antiestrogen to inhibit the growth of human breast cancer ZR-75-1, MCF-7 and T-47D cells in vitro when compared with ICI 182780, ICI 164384, hydroxytamoxifen, and droloxifene. Moreover, EM-652 and EM-800 have no stimulatory effect on the basal levels of cell proliferation in the absence of E2 while hydroxytamoxifen and droloxifene had a stimulatory effect on the basal growth of T-47D and ZR-75-1 cells. EM-652 was also the most potent inhibitor of the percentage of cycling cancer cells. (ABSTRACT TRUNCATED)

Animals↗