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Biomedical subjects

A Dupont

Publications and source records attributed to A Dupont.

At least 37 records · Page 2Linked to original sources
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

Combination therapy for prostate cancer. Endocrine and biologic basis of its choice as new standard first-line therapy.

RESULTS. All double-blind randomized and prospective clinical trials in advanced prostate cancer have shown that combination therapy using a nonsteroidal antiandrogen in association with a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy has significant benefits according to all the subjective and objective parameters used, the most important being a prolongation of survival ranging from 5.4-15.0 months compared with LHRH agonists or orchiectomy alone (standard therapy). The benefits observed are probably the result of the blockade by the antiandrogenic agents of the androgens of adrenal origin, which represent, on average, 40% of the total androgens in men and which, otherwise, are left free to continue to stimulate prostate cancer after castration. These data are supported well by the demonstration of the expression of the genes encoding all enzymes required for the formation of active androgens in prostatic tissue from the inactive adrenal steroid precursors; this new specialty is called intracrinology. Both fundamental and clinical data indicate that low androgen levels cause changes in the cancer cells that lead to no or a poor response to antihormonal therapy. CONCLUSIONS. It is thus imperative that combination therapy be used as first treatment in all patients in whom endocrine therapy is indicated. Prior exposure to monotherapy shortens the patient's life by many months and produces a poor quality of life.

Adrenal Cortex Hormones↗
PubMed1993

Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy.

The effect of flutamide withdrawal was studied in 40 patients with stage D2 prostate cancer showing progression of the disease after an initial and long (average 3.9 years) period of positive response to combination therapy with flutamide associated with medical (luteinizing hormone-releasing hormone agonist) or surgical castration. Using the criteria of response of the United States National Prostatic Cancer Project, 1 complete, 3 partial and 26 stable responses were observed, while 10 patients continued to have progression after discontinuation of flutamide. The average durations of previous treatment with combination therapy were 1,794 days for the 30 responders (complete, partial and stable responses), compared to 1,726 days for the 10 nonresponders. The average duration of response after the arrest of flutamide was 440 days. Serum prostate specific antigen, which was elevated in all patients, decreased by 90% or more in 19 of the 30 responders (63%) and returned to normal in 17 (57%). The concentration of testosterone binding globulin increased after discontinuation of flutamide, thus also suggesting the suppression of an androgenic influence, while the serum levels of testosterone and dihydrotestosterone, as well as their main metabolites, did not change after withdrawal of flutamide. Alteration of local sensitivity to androgens is a probable explanation for the paradoxical positive response to the arrest of flutamide suggested in the present preliminary study.

Adenocarcinoma↗
PubMed1993

Combination therapy with flutamide and the LHRH agonist [D-Trp6, des-Gly-NH(2)10]LHRH ethylamide in stage C prostatic carcinoma.

A series of 115 previously untreated patients displaying clinical stage C prostatic carcinoma with no evidence of distant metastases received combination therapy using the antiandrogen flutamide and the LHRH agonist [D-Trp6, des-Gly-NH(2)10]LHRH ethylamide; the average follow-up was 3.9 years. Twenty-eight patients showed treatment failure with a probability of disease-free survival of 91.2% at 2 years. Twenty patients died from prostate cancer and 10 from other causes, the survival probability being 93.4% at 2 years. Local control was achieved rapidly in all patients. Urinary obstruction and hydronephrosis were corrected in all cases. When compared with data obtained after single endocrine therapy (orchiectomy or oestrogens) or radiotherapy, the treatment failure rate at 2 years was more than 3.0-fold lower after combination therapy (8.8%) than monotherapy (28.4%). The death rate 2 years after the start of combination therapy was 6.6% and was on average 22.2% (3.6-fold higher) in the studies using monotherapy (orchiectomy or oestrogens) or radiotherapy. The present data suggest that treatment of prostate cancer with combination therapy before clinical evidence of dissemination of disease permits more efficient control of local disease and a decreased rate of progression to metastatic disease.

Aged↗
PubMed1993

Intracrinology: the basis for the rational design of endocrine therapy at all stages of prostate cancer.

Adrenal androgens contribute 40% of total androgens in adult men. The inactive precursor steroids dehydroepiandrosterone (DHEA) and DHEA-sulfate are secreted in large amounts by the adrenals and reach the prostate and other peripheral target tissues, where they are transformed into the potent androgen dihydrotestosterone (DHT). We have cloned and sequenced the cDNAs and/or genes which encode the enzymes responsible for the transformation of DHEA into DHT, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase. Blockade of DHT synthesized by these enzymes, with a pure antiandrogen of the class of flutamide, prolongs life in advanced prostate cancer, the effect being much more important when a small number of metastases is present. Most importantly, 3-month combination therapy reduces cancer-positive margins at radical prostatectomy, from 38.5% in control patients to only 13% in those who received combination therapy. Combined with an efficient strategy for detection of early-stage prostate cancer, the present approach could offer the possibility of a cure to more than 80% of prostate cancer patients, compared with the present situation where a cure can be offered to less than 20% of patients, since the first diagnosis of prostate cancer is usually made at a late stage of the disease.

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↗
PubMed1993

Science behind total androgen blockade: from gene to combination therapy.

Probably the most important finding in the endocrine therapy of prostate cancer is that the testicles and adrenals contribute approximately equal amounts of dihydrotestosterone (DHT), the active androgen that stimulates normal and cancerous prostatic cell growth and function. Structure of the cDNAs and genes encoding most of the enzymes responsible for the transformation of the adrenal precursor dehydroepiandrosterone (DHEA) into DHT have recently been elucidated, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase, and 5 alpha-reductase. With the action of these enzymes, DHT is then made locally in the prostate from circulating DHEA of adrenal origin. Given such an important role of the adrenals, it is essential to use a pure antiandrogen for maximal blockade of the interaction of DHT with the androgen receptor while the testicles are blocked by orchiectomy or treatment with a luteinizing hormone-releasing hormone (LHRH) super-agonist. This combination therapy was first developed to treat advanced prostate cancer. The multicenter clinical data recently obtained confirm our original data and demonstrate the major importance of the intracrine or in situ formation of androgens in the human prostate from the inactive adrenal steroid precursors. Combination therapy thus permits, for the first time, to prolong life in advanced prostate cancer and, most importantly, offers the possibility of a major improvement in the efficacy of a curative therapy, namely, radical prostatectomy in early stage disease.

Aged↗
PubMed1993

Major advantages of "early" administration of endocrine combination therapy in advanced prostate cancer.

Combination therapy with the antiandrogen flutamide and the luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide or orchiectomy was administered to 268 patients with previously untreated metastatic stage D2 prostate cancer for an average of 1,191 d (3.26 y). Only 17 of the 268 evaluable patients (6.5%) showed no objective positive response to the combination therapy assessed according to the National Prostatic Cancer Project objective criteria of response. The median duration of the disease-free response was 2.23 y and median overall survival was 3.58 y. The median survival for patients with only 1-5 bone metastases was not yet reached at 8 y, but for patients with 6-10 bone lesions, 11-40 bone lesions, and multiple bone metastases (superscan), median survival was markedly reduced to 3.56, 2.36, and 1.76 y, respectively. Analysis of patients according to general symptomatology, pain, and performance status showed median survivals of 5.47, 2.71, and 2.1 y for minimal, moderate, and severe symptoms, respectively. The present data demonstrate that administration of combination therapy to stage D2 prostate cancer patients having 1-5 bone metastases adds a minimum of 4.4 y of good quality life compared with patients whose disease is slightly more advanced. Our findings clearly demonstrate the major importance of starting combination therapy as soon as possible after diagnosis of metastatic prostatic cancer.

Androgen Antagonists↗
PubMed1993

Downstaging of localized prostate cancer by neoadjuvant therapy with flutamide and lupron: the first controlled and randomized trial.

Although the only opportunity to cure prostate cancer is treatment at an early stage, radical prostatectomy has remained relatively unpopular because 40-50% of prostate cancers estimated at diagnosis as confined to the prostate are found to be at a more advanced stage following histopathological analysis of the surgical specimen. This first prospective, randomized trial investigated the potential advantages of 3-month neoadjuvant combination therapy with flutamide and lupron before radical prostatectomy vs. prostatectomy alone in early stage prostate cancer. Cancer-positive margins were reduced from 38.5% (25 of 65) in control patients to only 13.0% (10 of 77) in men who received neoadjuvant combination therapy with the antiandrogen flutamide and the luteinizing hormone-releasing hormone (LHRH) super-agonist Lupron before radical prostatectomy (p = 0.006). Moreover, comparison of the final stage determined by histopathological examination of the surgical specimen with that estimated at diagnosis showed that a more advanced stage (upstaging) was found in 53.8% of controls, but patients who received combination therapy had an opposite effect: a more favorable stage than expected at diagnosis was found in 23.4% of cases (downstaging), a 77.2% advantage of neoadjuvant combination therapy. The concern about radical prostatectomy, underestimation of stage, is thus markedly improved by 3-month neoadjuvant therapy with flutamide and a LHRH superagonist. Cancer-negative margins are expected to be accompanied by a life expectancy not different from that of men of similar age with no prostate cancer; therefore, the present data, combined with efficient detection of early stage prostate cancer, offer the basis for dramatic improvement in the morbidity and mortality of prostate cancer.

Adenocarcinoma↗
PubMed1992

Incidence of liver toxicity associated with the use of flutamide in prostate cancer patients.

PURPOSE: The incidence of flutamide-related liver toxicity was studied in 1,091 consecutive patients treated for stage C or D prostate cancer with the antiandrogen flutamide and the luteinizing hormone-releasing factor (LHRH) agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide. PATIENTS AND METHODS: Liver function tests, namely measurement of serum aspartate amino-transferase (AST) and alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GT), and prothrombin and thromboplastin times, were performed at 4, 8, and 12 weeks and every 3 months thereafter. Clinical signs and symptoms of liver dysfunction were also sought. The causal link between the antiandrogen used and liver injury was assessed on the basis of the temporal relationship with the use of the drug in the absence of other possible causes and, in two patients, through rechallenge of the putative causative drug after a period of normalization of liver function. RESULTS: An increase in AST and ALT at fourfold or more above upper normal limits was observed in only four patients (0.36%). Total serum bilirubin and alkaline phosphatase were elevated in only one patient at 126 mmol/L and 640 IU/L, respectively. Among the four patients, only two developed clinical manifestations of liver disease (0.18%). Biopsy was performed in one patient, and the histopathologic findings showed a mixed pattern of cytotoxic and cholestatic changes. All clinical and biologic manifestations of liver toxicity rapidly disappeared upon discontinuation of flutamide alone. No sequelae were observed in the long-term follow-up at 18, 22, 31, and 62 months. The 1,087 remaining patients experienced no or mild (less than fourfold upper normal limit) and transient elevation in aminotransferase serum levels during the first 6 months of treatment, with normalization at later time intervals. CONCLUSION: Despite the fact that the cases reported so far, along with our large series, indicate that the incidence of flutamide-induced liver toxicity is very low, we recommend serial blood aminotransferase measurements at 2 and 4 weeks of treatment in order to detect early signs of possible flutamide-induced hepatic injury, thus avoiding the low potential risk of clinically significant liver toxicity.

Adenocarcinoma↗
PubMed1992

Simultaneous liver and lung toxicity related to the nonsteroidal antiandrogen nilutamide (Anandron): a case report.

We report the case of a 69-year-old patient treated for stage C adenocarcinoma of the prostate with the combination of the luteinizing hormone-releasing hormone agonist [D-Trp6, des-Gly-NH2(10)] LHRH ethylamide and the antiandrogen nilutamide (Anandron) who developed simultaneous liver and lung toxicity. Investigation revealed an abnormal chest radiograph accompanied by altered respiratory function tests, suggesting the diagnosis of interstitial lung disease. This diagnosis was confirmed by an open chest biopsy. At the same time, liver function tests yielded abnormal results. All toxic manifestations disappeared after cessation of treatment with Anandron.

Adenocarcinoma↗
PubMed1992

Transrectal ultrasound evaluation of local prostate cancer in patients treated with LHRH agonist and in combination with flutamide.

We followed total prostate and prostatic tumor volumes in patients who received combination endocrine therapy with the antiandrogen flutamide and the LHRH agonist [D-Trp6,des-Gly-NH2(10)]LHRH ethylamide. Twenty-three men with proved prostatic adenocarcinoma (Stages B1 to D2) were subjected to a transrectal ultrasound (TRUS) study before and after a three-month period of combination antihormonal therapy. A total prostatic volume reduction ranging from 17 percent to 70 percent (median 47%, p less than 0.0001) was observed. An even greater effect was observed on tumor volume which was reduced by 20 percent to 91 percent (median 81%, p less than 0.01). After treatment, the original suspicious zone became nonvisible in 4 cases. The TRUS measurements were confirmed by direct examination of the radical prostatectomy specimen in 7 cases. TRUS is thus a precise, sensitive, and valid method for evaluating the effect of combined antihormonal therapy on normal and tumoral prostatic tissues. These data indicate that combination therapy induces a rapid and marked reduction in glandular and tumoral prostatic volume which could well improve the success of radical prostatectomy and increase the changes of cure of localized prostatic cancer.

Adenocarcinoma↗
PubMed1992

Serum prostate specific antigen as pre-screening test for prostate cancer.

Prostate cancer has become the most common cancer and the second cause of death due to cancer in men in North America. Since curative therapies are limited to early stages of the disease, the availability of an efficient, easy to perform, widely acceptable and cost-effective method of early detection of prostate cancer is particularly important. Thus, digital rectal examination, transrectal ultrasonography of the prostate as well as measurements of serum prostate specific antigen (PSA) were performed independently in a series of 1,002 men between 45 and 80 years old randomly selected from the electoral rolls of Quebec City and its vicinity as part of a screening program for prostate cancer. Using this population of randomly chosen men, various cutoff serum PSA values were selected in an attempt to find the optimal decision threshold that would indicate a much greater risk of having prostatic cancer. At a threshold value of 3.0 micrograms./l. the sensitivity and specificity of the test are 80.7 and 89.6%, respectively, while the area under the receiver operating characteristic curve reflecting the accuracy of the test is 87.8 +/- 3.3% (plus or minus standard deviation). Moreover, the negative predictive value was estimated at 98.6%, thus leaving only a 1.4% chance of missing cancer when the serum PSA value was 3.0 micrograms./l. or less. Most importantly, such a threshold level of serum PSA retains only 19% of the whole cohort as candidates for transrectal ultrasonography and expensive diagnostic procedures, thus leading to the finding of 1 prostate cancer of 4 such examinations. The present data indicate that simple measurement of serum PSA can be used efficiently as a pre-screening test for prostate cancer in the general population to identify, at a low cost, the subpopulation of men at a much greater risk of having prostate cancer, and who should then be submitted to the more elaborate and expensive diagnostic procedures.

Age Factors↗
PubMed1992

[Primary malignant teratoma of the thyroid. Two cases involving immunohistochemical and ultrastructural studies].

Two cases of primary malignant teratoma of the thyroid are reported. The first case, which occurred in a 21-year-old female, was mostly composed of tumoral neural tissue and foci of foetal cartilage. The patient died with lung metastases within 5 months after the first symptoms. The second case, which occurred is a 8-year-old infant female, had epithelial and mesenchymal components without neural tissue. This case had a better prognosis with survival of four years after initial diagnosis. The different tumoral components were identified by a thorough histopathological examination of the thyroidectomy with immunological and ultrastructural studies. As for other teratomas, presence of immature neural tissue bore a poor prognosis. The clinical, histopathological features and the histogenesis of this rare tumour are described and literature is reviewed.

Adult↗
PubMed1991

Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women.

Sixty-three healthy post-menopausal women participated in the study aimed at determining the efficiency of percutaneous administration of estradiol (E2) giving physiological plasma levels of the estrogen to provide an efficient relief of climacteric and urogenital symptoms. Among these women, 31 had previous hysterectomy and were randomly allocated to one of the two estrogen replacement therapies while, similarly, the 32 women having an uterus were randomly divided between two groups who received in addition to estrogens, micronized oral progesterone. As estrogen, women received either E2 by percutaneous administration (Oestrogel) or oral conjugated estrogens (Premarin). With Oestrogel, serum E2 and estrone levels were within those seen during premenopause and showed a ratio close to 1.0. Climacteric symptoms were reduced or eliminated similarly in all groups. No changes was noticed on the concentration of serum angiotensinogen with Oestrogel therapy while a 2.5-fold increase was found in women receiving Premarin. As indicated by the 24-week endometrial biopsy, the progestational response induced by oral progesterone at the dose used was sufficient in twenty out of thirty-two women to cause endometrial atrophy, thus suggesting the need for higher amounts of micronized progesterone in a proportion of women. The present data also indicate that Oestrogel provides efficient relief of climacteric and urogenital symptoms without exerting any detectable effect on hepatic function while maintaining the ratio of serum E2/E1 at the physiological value of 1.0.

Administration, Cutaneous↗
PubMed1991

Steroid glucuronides: human circulatory levels and formation by LNCaP cells.

We studied the relationship between circulating androsterone glucuronide, androstane-3 alpha, 17 beta-diol glucuronide and androstane-3 beta, 17 beta-diol glucuronide concentrations and adrenal as well as testicular C-19 steroids in men. Among the three 5 alpha-reduced steroid glucuronides, androsterone glucuronide is the predominant C-19 steroid glucuronide measured in plasma and its levels are markedly elevated compared to those of the non-conjugated steroid. The marked rise in testosterone during puberty was strongly correlated with the increase in both androsterone glucuronide and androstane-3 alpha, 17 beta-diol glucuronide, thus suggesting that testicular C-19 steroids are the main precursors of the steroid glucuronides. We also found that the presence of testicular androgen in plasma contributes to approx. 70% of plasma androsterone glucuronide and androstane-3 alpha, 17 beta-diol glucuronide. Our data suggest that the adrenal C-19 steroids remaining in circulation after castration in men are converted into potent androgen which are then glucuronidated by UDP-glucuronyltransferase. We also demonstrated that the human prostate cell line LNCaP is capable of converting to a large extent androstenedione into androsterone glucuronide. Our data further confirm that glucuronidation is a major pathway of steroid metabolism in steroid target tissues.

Adolescent↗