Leonello Cusan

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.

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.

Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women

Despite the long series of cohort studies performed during the last 20 years, the correlation between serum testosterone and any clinical situation believed to be under androgen control in women has remained elusive. This is likely related to the recent finding that the androgens made locally in large amounts in peripheral tissues from the precursor dehydroepiandrosterone (DHEA) act in the same cells where synthesis takes place and are not released in significant amounts in the circulation, thus making unreliable the measurement of serum testosterone as marker of total androgenic activity. The objective is to determine if serum androgen glucuronides can be replaced by testosterone or another steroid as measure of androgenic activity. Since the glucuronide derivatives of androgens are the obligatory route of elimination of all androgens, these metabolites were measured by liquid chromatography tandem mass spectrometry under basal conditions in 377 healthy postmenopausal women aged 55-65 years as well as in 47 premenopausal women aged 30-35 years while testosterone was assayed by gas chromatography mass spectrometry. No correlation was found between the serum concentration of testosterone and that of androsterone glucuronide (ADT-G) or androstenediol glucuronide (3alpha-diol-G), the androgen metabolites which account for the total pool of androgens. The present data show that measurement of the total pool of androgens reflected by the serum levels of ADT-G and 3alpha-diol-G cannot be replaced by serum testosterone or any other steroid, including DHEA or DHEA sulphate. These findings may have implications for women with androgen deficiency involving osteoporosis, obesity, type 2 diabetes, sexual dysfunction, loss of muscular strength and a series of other clinical situations affecting womens health. Measuring ADT-G and 3alpha-diol-G might identify cases of true androgen deficiency and provide an opportunity to offer appropriate androgen therapy.

Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women

Objective: The objective of this study was to provide evidence that the transformation of DHEA into both androgens and/or estrogens locally in cells of the three layers of the vagina (epithelium, lamina propria, and muscularis) would have effects of greater impact, including effects on sexual function, than only effects on superficial epithelial cells as achieved with estrogens. Methods: This prospective, randomized, double-blind, and placebo-controlled phase III clinical trial has evaluated the effect of daily local intravaginal application of Prasterone (dehydroepiandrosterone; DHEA) for 12 weeks on the domains of sexual dysfunction, namely, desire/interest, arousal, orgasm, and pain at sexual activity, in 216 postmenopausal women with moderate to severe symptoms of vaginal atrophy. Results: A time- and dose-dependent improvement of the four domains of sexual function was observed. At the 12-week time interval, the 1.0% DHEA dose led, compared with placebo, to 49% (P = 0.0061) and 23% (P = 0.0257) improvements of the desire domains in the Menopause Specific Quality of Life and Abbreviated Sex Function questionnaires, respectively. Compared with placebo, the Abbreviated Sex Function arousal/sensation domain was improved by 68% (P = 0.006), the arousal/lubrication domain by 39% (P = 0.0014), orgasm by 75% (P = 0.047), and dryness during intercourse by 57% (P = 0.0001). Conclusions: By a local action in the vagina, DHEA applied daily at doses at which serum steroids remain well within normal postmenopausal values exerts relatively potent beneficial effects on all four aspects of sexual dysfunction. Such data indicate that combined androgenic/estrogenic stimulation in the three layers of the vagina exerts important beneficial effects on sexual function in women without systemic action on the brain and other extravaginal tissues.

Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy

Objective: Because the secretion of dehydroepiandrosterone (DHEA), the exclusive source of sex steroids in postmenopausal women, is already decreased by 60% and continues to decline at the time of menopause, the objective of this study was to examine the effect of intravaginal DHEA on the symptoms and signs of vaginal atrophy. Methods: This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of Prasterone (DHEA) applied locally in the vagina on the signs and symptoms of vaginal atrophy in 216 postmenopausal women. Results: All three doses (0.25%, 0.5%, and 1.0%) of DHEA ovules applied daily intravaginally induced a highly significant beneficial change in the percentage of vaginal parabasal and superficial cells and pH as well as in the most bothersome symptom at 2 weeks. At the standard 12-week time interval, 0.5% DHEA caused a 45.9 ± 5.31 (P < 0.0001 vs placebo) decrease in the percentage of parabasal cells, a 6.8 ± 1.29% (P < 0.0001) increase in superficial cells, a 1.3 ± 0.13 unit (P < 0.0001) decrease in vaginal pH, and a 1.5 ± 0.14 score unit (P < 0.0001) decrease in the severity of the most bothersome symptom. Similar changes were seen on vaginal secretions, color, epithelial surface thickness, and epithelial integrity. Comparable effects were observed at the 0.25% and 1.0% DHEA doses. Conclusions: Local Prasterone, through local androgen and estrogen formation, causes a rapid and efficient reversal of all the symptoms and signs of vaginal atrophy with no or minimal changes in serum steroids, which remain well within the normal postmenopausal range. This approach avoids the fear of systemic effects common to all presently available estrogen formulations and adds a novel physiological androgenic component to therapy.

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.

Treatment of hirsutism with the pure antiandrogen flutamide

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

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.

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.

Metabolism of DHEA in postmenopausal women following percutaneous administration

The marked decline in serum dehydroepiandrosterone (DHEA) with age is believed to play a role in health problems associated with aging, these health issues being potentially preventable or reversible by the exogenous administration of DHEA. In the present study, liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and gas chromatrography/mass spectrometry (GC/MS) were used to measure the serum levels of DHEA and 11 of its metabolites in seventy-five 60-65-year-old Caucasian women who received 3g of 0.1%, 0.3%, 1.0% or 2.0% DHEA cream or placebo applied twice daily on the face, upper chest, arms and legs. The serum levels of DHEA increased 574% over control at the 2.0% DHEA dose while the sum of the androgen metabolites androsterone glucuronide (ADT-G), 3alpha-androstenediol-3G (3alpha-diol-3G) and 3alpha-diol-17G increased by only 231%. On the other hand, serum testosterone and dihydrosterone were increased by 192% and 275%, respectively, above basal levels compared to 139% and 158% for estrone and estradiol. Such data show that the transformation of exogenous DHEA in postmenopausal women is preferentially into androgens rather than into estrogens. On the other hand, the present data indicate that serum DHEA measurements following DHEA supplementation in postmenopausal women are an overestimate of the formation of active androgens and estrogens and suggest a decreased efficiency of transformation of DHEA into androgens and estrogens with aging.