Robert A. MacLaughlin

Prostatic Cancer and Sch-13521: II. Histological Alterations and the Pituitary Gonadal Axis

We herein report on the results of treatment of 13 men with stage D prostatic carcinoma with a non-steroidal compound, SCH-13521 (flutamide). The dosage of the drug was 750 mg. in 3 divided doses daily and treatment extended for 2 to 20 months. Two patients failed to respond in any fashion, 7 had objective evidence of response and the others had varying degrees of subjective response. Plasma testosterone was never suppressed and sexual potency was not altered by the drug. Gynecomastia occurred in several patients, 1 patient had intractable vomiting and 2 had thromboembolic disease. In tissue biopsies after therapy, cytotoxic changes in some acinar cells were noted but healthy-appearing neoplastic cells were always abundant. These observations suggest the pre-treatment existence of autonomous cells that no conventional hormonal manipulation will succeed in destorying. However, the palliation that flutamide seems to afford makes it important to conduct an appropriately designed study that will compare it in a suitable fashion to the effectiveness of diethylstilbestrol.

Endocrine changes after diethylstilbestrol therapy Effects on prostatic neoplasm and pituitary-gonadal axis

This study was undertaken to determine the effects of DES (diethylstilbestrol) on prostatic neoplasms and of different dosage levels on the pituitary-gonadal axis. It is recommended that when DES is chosen for treatment plasma testosterone be monitored carefully and for long periods of time to evaluate the ability of the dose to achieve levels comparable to castration in each patient.

Dehydroepiandrosterone-sulfate/cortisol ratio in panic disorder

We hypothesized that the dehydroepiandrosterone-sulfate (DHEA-S)/cortisol ratio, which has been used as an index of adrenocortical function, would be altered in panic disorder patients and would change after treatment. We evaluated 10 male and 14 female outpatients meeting DSM-III-R criteria for panic disorder. Of these 24 subjects, 13 were treated with clonazepam, 8 were treated with alprazolam, and 3 were treated with placebo as part of a double-blind study. The DHEA-S/cortisol ratio values in the 24 patients with panic disorder (mean = 20.5, SD = 11.6) were significantly higher than those of a group of 60 normal controls (mean = 11.5, SD = 6.01) and were also significantly higher than those of a group of 22 depressed patients (mean = 10.6, SD = 6.33). Although there was no significant difference in the pretreatment DHEA-S/cortisol ratio values between male (mean = 23.6, SD = 11.8) and female (mean = 18.2, SD = 11.3) panic disorder patients, the effects of treatment on this ratio differed between the two sexes. In fact, in the female patients there was a significant decrease in the DHEA-S/cortisol ratio at the end of the study (mean = 15.1, SD = 7.9), while in the male patients there was no significant change in this ratio at the end of the study (mean = 30.2, SD = 21.4). No significant differences were noted between pretreatment and posttreatment DHEA-S/cortisol ratio values in patients treated with alprazolam (n = 8), in patients treated with clonazepam (n = 13), or in patients treated with placebo (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

In Vitro Uptake of 3H Testosterone and its Conversion to Dihydrotestosterone by Prostatic Carcinoma and Other Tissues

Needle biopsies of normal, benign hyperplastic, neoplastic and metastatic prostatic tissues were used to study the uptake of 3H testosterone by these tissues and their ability to convert testosterone to dihydrotestosterone. Histological quantification is important because stroma is active in both of these areas of biochemical activity. The 3H testosterone uptake by the tissues is relatively similar but benign prostatic hyperplasia and normal tissue consistently convert more testosterone to dihydrotestosterone than do neoplastic tissues. The least active in this regard are pure biopsies of neoplastic cells obtained from nodal metastases, suggesting extensive loss or repression of 5-alpha-reductase activity. Further, this defect is present in neoplastic tissues even if the patient has had an orchiectomy and/or received hormonal therapy. It is not known whether testosterone may substitute for dihydrotestosterone in the neoplastic nucleus. Our studies indicate that animal models that yield data on suppresion of 5-alpha-reductase activity by certain agents may have limited relevance to the tissues of human prostatic carcinoma.

Psychological behavioral and biochemical risk factors for coronary artery disease among American and Italian male corporate managers

Differences in psychological, behavioral and biochemical risk factors for coronary artery disease (CAD) among male corporate managers of 2 countries (United States and Italy), with very different age-specific rates of mortality for CAD were evaluated. In all, 129 American (mean age 43 +/- 7 years) and 80 Italian (mean age 45 +/- 7 years) managers volunteered to participate in this study. Each subject was administered several questionnaires assessing various psychological and behavioral risk factors for CAD, and all 129 Americans and 55 of 80 Italians had their blood drawn between 8:00 and 9:30 AM after overnight fasting for the measurement of plasma levels of dehydroepiandrosterone-sulfate (DHEA-S), total cholesterol, triglycerides, and apolipoproteins A-I and B. Italian managers reported significantly more cynicism and hostility, and less enjoyment in leisure activities than did American ones. Furthermore, 40 Italian (51%) and only 18 American (14%) managers were smokers (this difference being statistically significant). Although no significant differences were found in factors positively related with CAD (cholesterol, triglycerides and apolipoprotein B), there were clear differences in parameters inversely correlated with the incidence of CAD. Italian managers had significantly lower levels of plasma DHEA-S and apolipoprotein A-I than did American ones. In conclusion, this study found that Italian managers had a significantly more unhealthy psychological and behavioral profile than did American ones, and had lower levels of those biochemical parameters (apolipoprotein A-I and DHEA-S) thought to have a protective role against development of CAD.

Neuroendocrine effects of S-adenosyl-L-methionine, a novel putative antidepressant

S-adenosyl-L-methionine (SAMe), a putative antidepressant, is a naturally occurring substance whose mechanism of action is still a matter of speculation. It has been recently postulated that SAMe may increase the dopaminergic tone in depressed patients. Since dopamine inhibits both thyrotropin (TSH) and prolactin secretion, we investigated the effects of treatment with SAMe on the TSH and prolactin response to thyrotropin-releasing-hormone (TRH) stimulation in 7 depressed outpatient women (mean age: 46.1 +/- 7.2 years) and 10 depressed outpatient men (mean age: 38.0 +/- 10.0 years) participating in a six-week open study of oral SAMe in the treatment of major depression. At the end of the study, there was a significant reduction after treatment with SAMe in the response of both prolactin and TSH to TRH stimulation in the group of depressed men compared to pre-treatment values. On the other hand, in the group of depressed women, the posttreatment prolactin response to TRH did not appear to change when compared to pre-treatment and the TSH response to TRH challenge tended even to augment slightly after treatment with SAMe. Our results, at least in depressed men, seem to support the hypothesis of a stimulating effect of SAMe on the dopaminergic system.

Physiologic benefits of a stress reduction program for healthy middle-aged army officers ☆

Stress reduction programs (SRPs) can reduce morbidity and mortality in patients with coronary artery disease (CAD). This study evaluated the effect of an SRP on metabolic and hormonal risk factors for CAD. Twenty army officers participating in an SRP, Group I, and a comparison group of seventeen SRP nonparticipants, Group C, volunteered to undergo measurement of dehydroepiandrosterone-sulfate (DHEA-S), cortisol, DHEA-S/cortisol ratio, testosterone, apolipoprotein-A1, apolipoprotein-B, triglycerides, cholesterol, fibrinogen, and leukocyte count both before and after the SRP period. No differences in the changes in biochemical risk factors for CAD were found between participant and nonparticipant except for DHEA-S. While Group C had a marked reduction in DHEA-S levels, Group I had a small increase. Previous studies indicate DHEA-S is inversely associated with extent of CAD and age-adjusted DHEA-S levels below 3.78 mumol/l confer an increased risk for CAD mortality. SRP participation appears to effect DHEA-S levels, possibly partially accounting for the benefits observed in SRPs among CAD patients.

Altered Androgen Metabolism in Metastatic Prostate Cancer

Admixture of androgen-sensitive elements from normal or hyperplastic prostatic tissue interferes with biochemical studies of prostate cancer in its primary site. Heterogeneity of cancer tissues, varying in stromal and epithelial elements, also complicates interpretation of data relating to androgen metabolism. Accordingly, we have compared metastatic deposits composed of epithelial cancer cells to the primary biopsies of 4 patients in respect to uptake of 3H-testosterone and its conversion to 5-alpha-dihydrotestosterone during in vitro incubation. 3H-testosterone uptake was similar for both tissue sites but 3H-dihydrotestosterone formation was reduced by 76% in the metastases compared to primary tissues. This group was not large enough to show statistical significance, whereas a total of 11 such primary studies compared to 6 metastatic specimens was significant. When either primary or secondary tissue results were compared to 12 cases of benign prostatic hyperplasia similarly studied the differences were highly significant. These results demonstrate a major impairment in the formation of dihydrotestosterone by metastatic prostatic cancer and a similar but less evident alteration in the primary site. This abnormality in testosterone metabolism is of major importance in the attempt to obtain effective hormonal control of human prostatic cancer.

Effect of dexamethasone on cortisol and prolactin responses to meals in bulimic and normal women

In normal individuals, serum cortisol and prolactin concentrations have been shown to rise following a mid-day meal. To determine whether abnormalities of the hypothalamo-pituitary-adrenal axis in bulimics lead to a disrupted hormonal response to eating, cortisol and prolactin responses to meals (600 kcal, 30% protein, 30% fat, 40% carbohydrate) were studied on two consecutive days in six normal weight bulimics and six normal volunteers. Dexamethasone (1 mg orally) was administered at 2330 h after baseline sampling. During baseline sampling, cortisol concentrations were significantly higher in the bulimics (18.2 +/- 0.9 micrograms/dl, mean +/- SEM) than in the normals (12.1 +/- 0.4 micrograms/dl) (p less than 0.001). Post-dexamethasone cortisol concentrations also were higher in the bulimics (5.7 +/- 0.3 micrograms/dl) than in the normals (1.2 +/- 0.2 micrograms/dl) (p less than 0.001). The three bulimics with a major depressive disorder had higher peak post-dexamethasone cortisol concentrations than the nondepressed bulimics. Dexamethasone significantly enhanced the prolactin response to meals among both bulimics (at 90 min post onset of eating) and normals (at 60, 75 and 90 min post onset of eating). This enhancement of the prolactin response to meals by dexamethasone is opposite to the inhibitory effect of dexamethasone on stress-induced prolactin release and suggesting that stress-induced and meal-induced prolactin release involve different neuroendocrine mechanisms.