Biomedical subjects

R S Rittmaster

Publications and source records attributed to R S Rittmaster.

At least 55 records · Page 3Linked to original sources

PubMed1992

Effect of finasteride, a 5 alpha-reductase inhibitor, on serum gonadotropins in normal men.

Testosterone exerts negative feedback control on gonadotropin secretion either directly, after aromatization to estradiol, or after 5 alpha-reduction to dihydrotestosterone (DHT). Conflicting data exist as to the role of DHT in the modulation of this negative feedback. To determine whether suppression of endogenous DHT alters gonadotropin secretion, we gave the selective 5 alpha-reductase inhibitor finasteride (5 mg daily), or placebo, to 20 healthy men for 28 days. Basal and GnRH-stimulated LH, bioactive LH, FSH, testosterone, and DHT levels were measured before and after 14 and 28 days of treatment. Basal DHT fell from 1.1 +/- 0.2 to 0.15 +/- 0.04 nmol/L after 28 days of finasteride treatment. A significant rise in baseline testosterone from 17.6 +/- 2.0 to 18.3 +/- 2.3 nmol/L was seen at 14 days (P = 0.046), but not at 28 days. No significant changes were seen in either basal or GnRH-stimulated gonadotropin levels on any day. We conclude that suppression of serum DHT levels with 5 mg finasteride daily in healthy young men has no discernible effect on serum gonadotropin levels.

Adult↗

PubMed1991

Predictors of clinical response in hirsute women treated with spironolactone.

OBJECTIVE: To examine the clinical efficacy of low dose spironolactone in hirsute women. DESIGN: Retrospective. SETTING: Outpatient endocrinology clinic. PATIENTS: One hundred nine consecutive women prescribed 75 to 100 mg/d spironolactone for at least 4 months in whom adequate follow-up data were available. RESULTS: Hirsutism improved in 72% of the women. Women with regular menses, whether or not they used oral contraceptives (OCs), had the highest response rate to spironolactone (78%), whereas women with irregular menses who did not use an OC had the lowest response rate (55%). Favorable responses were associated with increased severity of hirsutism (P = 0.04) and lower serum dehydroepiandrosterone sulfate levels (P = 0.05). Responders and nonresponders did not differ significantly in age (P = 0.10), duration of hirsutism (P = 0.14), pretreatment serum testosterone (T) (P = 0.48), or body mass index (P = 0.11). However, when each parameter was divided into subsets, trends toward decreasing response were observed with increasing age, duration of hirsutism over 15 years, and increasing serum T level. CONCLUSION: Low-dose spironolactone improves hirsutism in a majority of hirsute women, irrespective of age, severity or duration of hirsutism, menstrual status, or serum hormone levels.

Adolescent↗

PubMed1991

A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome.

To determine whether hyperinsulinemia can directly reduce serum sex hormone-binding globulin (SHBG) levels in obese women with the polycystic ovary syndrome, six obese women with this disorder were studied. Before study, ovarian steroid production was suppressed in each woman by the administration of 7.5 mg of a long-acting GnRH agonist, leuprolide depot, im, on days -56, -28, and 0. This resulted in substantial reductions in serum concentrations of testosterone (from 1.72 +/- 0.29 nmol/L on day -56 to 0.32 +/- 0.09 nmol/L on day 0), non-SHBG-bound testosterone (from 104 +/- 16 pmol/L on day -56 to 19 +/- 5 pmol/L on day 0), androstenedione (from 7.25 +/- 1.65 nmol/L on day -56 to 2.78 +/- 0.94 nmol/L on day 0), estrone (from 371 +/- 71 pmol/L on day -56 to 156 +/- 29 pmol/L on day 0), estradiol (from 235 +/- 26 pmol/L on day -56 to 90 +/- 24 pmol/L on day 0), and progesterone (from 0.28 +/- 0.12 nmol/L on day -56 to 0.08 +/- 0.02 nmol/L on day 0). Serum SHBG levels, however, did not change (18.8 +/- 2.8 nmol/L on day -56 vs. 17.8 +/- 2.6 nmol/L on day 0). While continuing leuprolide treatment, the women were administered oral diazoxide (300 mg/day) for 10 days to suppress serum insulin levels. Diazoxide treatment resulted in suppressed insulin release during a 100-g oral glucose tolerance test (insulin area under the curve, 262 +/- 55 nmol/min.L on day 0 vs. 102 +/- 33 nmol/min.L on day 10; P less than 0.05) and deterioration of glucose tolerance. Serum testosterone, androstenedione, estrone, estradiol, and progesterone levels did not change during combined diazoxide and leuprolide treatment. In contrast, serum SHBG levels rose by 32% from 17.8 +/- 2.6 nmol/L on day 0 to 23.5 +/- 2.0 nmol/L on day 10 (P less than 0.003). Due primarily to the rise in serum SHBG levels, serum non-SHBG-bound testosterone levels fell by 43% from 19 +/- 5 pmol/L on day 0 to 11 +/- 4 pmol/L on day 10 (P = 0.05). These observations suggest that hyperinsulinemia directly reduces serum SHBG levels in obese women with the polycystic ovary syndrome independently of any effect on serum sex steroids.

Adult↗

PubMed1991

Clinical and biochemical parameters of androgen action in normal healthy Caucasian versus Chinese subjects.

Stimulation of androgen-sensitive hair follicles is mediated by dihydrotestosterone (DHT), which is formed in these tissues by 5 alpha-reduction of testosterone. A possible mechanism for increased body hair in some human populations might, therefore, be an increase in 5 alpha-reductase activity, resulting in elevated tissue levels of DHT. If present, this finding could have other important clinical implications, since the 5 alpha-reductase enzyme is pivotal in the pathophysiology of prostatic disease. To explore differences in clinical and biochemical parameters of androgen action, we conducted a study of 184 caucasian and Chinese subjects in whom we evaluated chest hair density and serum levels of androgen precursors and 5 alpha-reduced androgen metabolites. Differences in chest hair density were most notable in the men, in whom comparative mean chest hair scores (using a scale of 0-4) were 3.0 vs. 0.8 (P less than 0.0001), caucasian vs. Chinese. Levels of 5 alpha-reduced androgen products were also strikingly higher in the caucasian vs. Chinese subjects. Serum 3 alpha-androstanediol glucuronide levels (nanomoles per L) were 34.7 +/- 2.4 vs. 19.7 +/- 0.9 (P less than 0.001) for the men and 21.5 +/- 3.2 vs. 9.4 +/- 0.6 (P less than 0.001) for the women, and serum levels of androsterone glucuronide (nanomoles per L) were 179 +/- 26 vs. 107 +/- 7 (P less than 0.01) for the caucasian vs. Chinese men and 173 +/- 23 vs. 81 +/- 9 (P less than 0.001) for the women. Serum levels of total and bioavailable testosterone did not differ between the racial groups, but serum levels of the precursor androgens, dehydroepiandrosterone sulfate and androstenedione, were significantly higher in the caucasian vs. Chinese men, but not in the women. We conclude that increased serum levels of 5 alpha-reduced androgen metabolites in caucasians vs. Chinese subjects provide circumstantial evidence for a racial difference in 5 alpha-reductase activity and suggest a mechanism for the increased body hair observed in the caucasian men. Increased levels of precursor androgens may also play a role.

Adolescent↗

PubMed1991

Differential effect of 5 alpha-reductase inhibition and castration on androgen-regulated gene expression in rat prostate.

Castration reduces prostate size and causes intraprostatic testosterone (T) and dihydrotestosterone (DHT) to fall to very low levels. 5 alpha-Reductase inhibition also reduces prostate size, but results in a marked increase in intraprostatic T levels. To compare the effects of 5 alpha-reductase inhibition and castration on prostate physiology, male Sprague-Dawley rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride for up to 9 days. To be sure that finasteride itself did not directly affect gene expression, an additional group of rats was castrated and given finasteride for 4 days. The prostates were weighed, intraprostatic RNA, DNA, and androgen levels were measured, and mRNAs for two androgen-regulated genes, prostate steroid-binding protein (PSBP; an androgen-induced gene) and testosterone-repressed prostate message (TRPM-2), were quantitated by Northern and slot blot analyses. Finasteride caused a 95% reduction in intraprostatic DHT levels and a 10-fold increase in intraprostatic T levels. Finasteride, as expected, caused a pronounced decrease in prostate weight (45% on day 4). DNA content fell correspondingly (48% on day 4). Intraprostatic DNA (micrograms of DNA per gland) on day 4 was 328 +/- 53 in control rats, 171 +/- 10 in finasteride-treated rats (P less than 0.001 compared to controls), 115 +/- 2 in castrated rats (P less than 0.05 compared to finasteride), and 107 +/- 43 in finasteride-treated plus castrated rats (P = NS compared to castration alone). There were no significant differences in DNA levels among the groups when expressed per mg prostate tissue, indicating that mean prostate cell size was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

5-alpha Reductase Inhibitors↗

PubMed1990

Synthesis of new steroid haptens for radioimmunoassay--VIII. Development and validation of a specific radioimmunoassay for serum 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide.

5 alpha-Androstane-3 alpha, 17 beta-diol glucuronide (androstanediol-G) is a dihydrotestosterone metabolite whose serum levels are elevated in hirsute women. Current assay methods do not distinguish between the two androstanediol-G isomers, androstanediol 3-G and androstanediol 17-G. Since the production of these isomers may be influenced by different factors, we have developed a specific radioimmunoassay for androstanediol 17G. The antibody was raised against 5 alpha-androstane-3 alpha, 17 beta-diol 17-G conjugated to bovine serum albumin (BSA). [9,11(-3H]5 alpha-Androstane-3 alpha, 17 beta-diol 17-G was used for determination of procedural losses and as the labeled ligand in the assay. Unlabeled androstanediol 17-G was used as assay standard. Serum levels of total androstanediol-G, androstanediol 3-G and androstanediol 17-G were measured in 8 normal men. Total androstanediol-G levels were 16.5 +/- 5.2 nmol/l, androstanediol 17-G levels were 12.9 +/- 5 nmol/l, and androstanediol 3-G levels were 3.3 +/- 1.8 nmol/l. 77 +/- 13% of total androstanediol-G was androstanediol 17-G. These results confirm our previous findings that androstanediol 17-G is the predominant androstanediol-G isomer in human serum and suggests that 5 alpha-dihydrotestosterone (DHT) is preferentially metabolized to androstanediol 17-G.

Androstane-3,17-diol↗

PubMed1990

Androsterone glucuronide is a marker of adrenal hyperandrogenism in hirsute women.

Androsterone glucuronide (Andros-G), a dihydrotestosterone metabolite, is present in serum at concentrations at least tenfold greater than those of androstanediol glucuronide. To investigate the significance of serum androsterone glucuronide, we developed a direct radioimmunoassay for this compound and measured its levels in normal women, women with mild or severe idiopathic hirsutism (IH), hirsute women with polycystic ovarian syndrome (PCO), and non-hirsute obese women. To determine the source of Andros-G precursors, serum levels were measured before and after selective ovarian suppression with leuprolide, combined ovarian and adrenal suppression with leuprolide and dexamethasone, and adrenal stimulation with ACTH. Androsterone glucuronide levels (nmol/l; mean +/- SD) were significantly higher (P less than 0.025) in women with mild idiopathic hirsutism (IH) (185 +/- 91), severe IH (173 +/- 97), and hirsute women with polycystic ovarian syndrome (PCO) (178 +/- 102) than in normal women (110 +/- 26). Levels in non-hirsute obese women (64 +/- 19) were lower than in normal women (P less than 0.01). Baseline levels (mean +/- SEM) in hirsute women given 20 micrograms/kg/day leuprolide for 5-9 months (171 +/- 15) were not significantly changed after leuprolide alone (153 +/- 18), and were decreased after adding dexamethasone (19 +/- 6; P less than 0.001). Andros-G levels did not increase significantly in normal women 60 min after i.v. ACTH (112 +/- 14 to 126 +/- 19), but rose in IH (170 +/- 24 to 216 +/- 26; P less than 0.001) and in PCO (179 +/- 26 to 238 +/- 31; P = 0.002). We conclude that Andros-G in women arises primarily from adrenal gland precursors and is elevated in hirsute women as a group. Its levels do not correlate with the severity of hirsutism, or the presence or absence of PCO, but reflect an increased production of adrenal androgens in both IH and PCO.

Adrenal Glands↗

PubMed1990

Effect of leuprolide and dexamethasone on hair growth and hormone levels in hirsute women: the relative importance of the ovary and the adrenal in the pathogenesis of hirsutism.

Ten hirsute women with polycystic ovarian syndrome (PCO) and nine with idiopathic hirsutism (IH) underwent selective ovarian suppression with leuprolide for 5-6 months and then were randomized to receive, in addition, dexamethasone or placebo for 4 more months. Serum hormone levels and hair growth rates were determined before and after each treatment period. During the initial treatment period with leuprolide alone, testosterone decreased by 54 +/- 6% (mean +/- SEM) in PCO and by 36 +/- 3% in IH (P = 0.02). Androstenedione decreased by 53 +/- 6% in PCO and by 31 +/- 7% in IH (P = 0.02). Androstanediol glucuronide (Adiol-G) decreased by 14 +/- 6% in PCO and by 7 +/- 3% in IH. There was no change in dehydroepiandrosterone sulfate (DHEAS). While initial serum androgen levels were higher in PCO than in IH, they were similar after ovarian suppression in the two groups. After ovarian suppression, Adiol-G was more consistently correlated with testosterone and androstenedione than was DHEAS, suggesting that Adiol-G may be a better marker than DHEAS of adrenal androgen secretion. Hair growth rates decreased by 37 +/- 6% in PCO and by 14 +/- 10% in IH (P = 0.07). The change in hair growth correlated with the change in androstenedione (r = 0.66; P = 0.002), but not significantly with the change in testosterone (r = 0.29; P = 0.2). After the addition of dexamethasone therapy (0.5 mg daily), testosterone, androstenedione, and DHEAS levels fell to near or below assay detection limits, while Adiol-G decreased by 80 +/- 3%. Hair growth rates decreased slightly more in women during dexamethasone (46 +/- 6%) than during placebo (26 +/- 9%; P = 0.18). In summary, the ovary was the major source of circulating testosterone and androstenedione in PCO. The adrenal contributed a substantial minority of these hormones in PCO and was the major source of androgen secretion in IH. Adrenal hyperandrogenism was common in both IH and PCO. Hair growth rates correlated best with changes in serum androstenedione levels. Adiol-G, which was derived primarily from adrenal precursors, was a better marker of adrenal androgen secretion than was DHEAS in these subjects.

Adolescent↗

PubMed1990

Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers.

Finasteride, a 5 alpha-reductase inhibitor, was administered to normal male volunteers in a blinded placebo-controlled study at daily oral doses of 25, 50, and 100 mg for 11 days (part 1) and daily oral doses of 0.04, 0.12, 0.2, and 1.0 mg for 14 days (part 2). Results from part 1 showed a significant reduction in dihydrotestosterone (DHT) at all doses and a significant increase in both testosterone (T) and delta 4-androstenedione at the 50- and 100-mg doses. No change was seen in LH, FSH, cortisol, or estradiol levels. Serum lipids, including total cholesterol, low density lipoprotein, high density lipoprotein, and triglycerides were not affected by treatment. Results from part 2 again showed significant reduction in DHT at all doses. DHT levels returned to pretreatment values within 14 days of discontinuing treatment. Significant increases in T were observed only in the 1.0 mg group and only during the first 8 days of treatment. The T/DHT ratio increased with all doses and returned to baseline when drug was discontinued. The DHT metabolites and androstanediol glucuronide and androsterone glucuronide were significantly reduced at all doses. There were no significant adverse experiences reported during part 1 or 2. In conclusion, finasteride is well tolerated by normal volunteers and results in significant suppression of serum DHT at all doses tested.

Adult↗

PubMed1989

Androgen glucuronyl transferase activity in rat liver, evidence for the importance of hepatic tissue in 5 alpha-reduced androgen metabolism.

To elucidate the role of the liver in 5 alpha-reduced androgen metabolism, we used a rat liver glucuronyl transferase assay to determine the conversion of 17 beta-hydroxy-5 alpha-androstane-3-one (DHT), 5 alpha-androstane-3 alpha, 17 beta-diol (androstanediol), and androsterone to their glucuronide metabolites. Serum levels of the two isomers of androstanediol glucuronide (androstanediol 3- and 17-glucuronide) were also measured. Using 5 microM unconjugated steroid as substrate, the production rate (pmol/mg/min) for each product from its respective unconjugated steroid was 6.9 +/- 0.4 for DHT glucuronide, 101 +/- 3.3 for androstanediol 3-glucuronide, 71 +/- 2.0 for androstanediol 17-glucuronide, and 181 +/- 11 for androsterone glucuronide. Production rates for androstanediol glucuronide were 800 times greater for rat liver than for rat prostate, when examined under similar conditions. In the presence of either 0 or 5 microM unlabeled androstanediol, about 60% of the androstanediol glucuronide formed by rat liver was androstanediol 3-glucuronide. In normal male rat serum, 69 +/- 8% (mean +/- SEM) of total androstanediol glucuronide was androstanediol 3-glucuronide. We have previously shown that rat prostate forms androstanediol 17-glucuronide, but not androstanediol 3-glucuronide. The results from the present study indicate that rat liver forms both androstanediol glucuronide isomers, and does so in about the same ratio as is found in rat serum. The rate of glucuronidation is also much greater in rat liver than in rat prostate. While other sites of glucuronidation are possible, these results are consistent with the hypothesis that DHT and other unconjugated androgens formed in rat prostate are conjugated to glucuronic acid mainly in the liver.

Androgens↗

PubMed1988

Preferential metabolism of dihydrotestosterone to androstanediol 17-glucuronide in rat prostate.

Androstanediol glucuronide (Adiol G), a marker of peripheral dihydrotestosterone (DHT) metabolism and action, may be conjugated through the hydroxyl group at either the 3-carbon (Adiol 3-G) or 17-carbon (Adiol 17-G) position. Adiol 17-G is the predominant Adiol G isomer derived from DHT in normal men. To determine whether peripheral tissues may be responsible for this selective conversion of DHT to Adiol 17-G, a glucuronyl transferase assay was developed using rat prostate cells. Adiol 17-G was separated from Adiol 3-G by HPLC and selective precipitation with an antibody specific for Adiol 3-G. Using androstanediol (Adiol) as a substrate, enzyme kinetics were linear with respect to time and enzyme concentration. In the presence of 0 or 5 microM Adiol and 1 microCi [3H]Adiol, greater than 99% of the resulting Adiol G was Adiol 17-G. The percent conversions of DHT, Adiol, and androsterone to their glucuronide conjugates were 0.22%, 3.5%, and 0.24%/10(6) prostate cells, respectively. Using DHT as an inhibitor of Adiol glucuronidation, the Ki was 39.1 microM, compared to an apparent Km for Adiol of 15 microM. We conclude that rat prostate cells can selectively convert Adiol to Adiol 17-G, and that Adiol glucuronidation is favored over that of DHT or androsterone under these experimental conditions. Since DHT and Adiol are readily interconvertable, these results suggest that Adiol 17-G is the major DHT metabolite in the rat prostate.

Androstane-3,17-diol↗

PubMed1988

Androstanediol glucuronide isomers in normal men and women and in men infused with labeled dihydrotestosterone.

3 alpha-Androstanediol glucuronide (Adiol G) is a major metabolite of dihydrotestosterone (DHT). Adiol G actually represents 2 different compounds, since the glucuronide can be conjugated at the 3-carbon position (Adiol 3-G) or at the 17-carbon position (Adiol 17-G). To determine which glucuronide represents the predominant physiological DHT metabolite and which isomer is the major circulating form, we developed a RIA to directly measure Adiol 3-G in serum extracts. In 10 normal men, mean serum Adiol 3-G and total Adiol G levels were 4.44 +/- 0.49 (+/- SE) nmol/L (208 +/- 23 ng/dL) and 27.9 +/- 2.8 nmol/L (1310 +/- 129 ng/dL), respectively (13.9 +/- 3.0% of Adiol G was Adiol 3-G). In 10 normal women sampled during the early follicular phase, mean serum Adiol 3-G and total Adiol G levels were 2.64 +/- 0.64 nmol/L (124 +/- 30 ng/dL) and 14.9 +/- 1.5 nmol/L (697 +/- 69 ng/dL), respectively (17.4 +/- 3.6% of Adiol G was Adiol 3-G). In 4 normal men infused for 8 h with tritiated DHT, 17.4 +/- 3.4% of the resulting tritiated Adiol G was Adiol 3-G. These results indicate that Adiol 17-G is the predominant circulating form of Adiol G in normal men and women and that it is also the major Adiol G isomer derived from DHT.

Adult↗

PubMed1988

Effect of daily and alternate day low dose prednisone on serum cortisol and adrenal androgens in hirsute women.

To test the hypothesis that alternate day prednisone treatment more effectively suppresses adrenal androgen secretion (compared to cortisol secretion) than daily prednisone treatment, we measured serum dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and cortisol concentrations during these two prednisone treatment schedules in eight hirsute women. The women were assigned randomly to receive either a daily nighttime dose of prednisone (100 micrograms/kg) or an alternate nighttime prednisone dose (200 micrograms/kg) for 4 months. During the following 4 months the women received the other schedule. Serum hormone levels were measured 0, 4, and 8 months before and after iv administration of 25 U synthetic ACTH. To optimally compare the daily and alternate day prednisone regimens, hormonal determinations were made on 2 successive days (days 1 and 2) after the last dose of prednisone. We found no evidence for greater suppression of adrenal androgens or lesser suppression of cortisol with alternate day prednisone treatment. Basal serum DHEA and DHEAS concentrations were suppressed to a greater degree than was cortisol during both daily and alternate day prednisone treatments. ACTH-stimulated DHEA and cortisol concentrations were equally suppressed. Only two of the eight women noted improvement in hirsutism during the study, and four women gained weight. Thus, adrenal androgen secretion was more easily suppressed than was cortisol secretion by this low dose of glucocorticoid, but there was no advantage to alternate day therapy.

Adrenal Glands↗

PubMed1988

Differential suppression of testosterone and estradiol in hirsute women with the superactive gonadotropin-releasing hormone agonist leuprolide.

To determine the dose of the GnRH agonist leuprolide necessary to maximally suppress ovarian testosterone secretion, 10 moderately to severely hirsute women (5 with idiopathic hirsutism and 5 with polycystic ovarian syndrome) were given gradually increasing leuprolide doses, starting with either 5 or 10 micrograms/kg.day. Serum testosterone and estradiol, basal LH, and the LH response to GnRH were measured before and at the end of each treatment period, until maximal suppression of estradiol and testosterone occurred. Leuprolide was then continued for a total of 6 months to assess its clinical efficacy. Hirsutism scores and hair growth rates were determined before and after therapy. Serum estradiol and the LH response to GnRH were maximally or near-maximally suppressed in all women by the lowest doses of leuprolide used. Basal serum LH was not maximally suppressed in all women until a dose of 15 micrograms/kg.day was reached, and maximal testosterone suppression required 15 micrograms/kg.day or more in 7 of the 10 women. The addition of 0.5 mg dexamethasone daily for 4 weeks at the end of the study in 5 of the women reduced serum testosterone to undetectable levels. Symptomatic improvement in hirsutism occurred in 9 women, hirsutism scores decreased by at least 3 points in 5 women, and hair growth rates decreased in 8 women. These data indicate that low doses of leuprolide were sufficient to maximally suppress serum estradiol and the LH response to exogenous GnRH. Higher leuprolide doses were needed to maximally suppress serum testosterone and the basal LH levels. Leuprolide (20 micrograms/kg.day) effectively reduced hair growth in the majority of these women.

Adult↗

PubMed1987

The effect of 4MA, a potent inhibitor of 5 alpha-reductase, on the growth of androgen-responsive human genitourinary tumors grown in athymic nude mice.

The five alpha-reductase inhibitors are a newly developed family of compounds that block the intracellular conversion of testosterone (T) to dihydrotestosterone (DHT). 17-beta-N, N-Diethylcarbamoyl-4-methyl-4-aza-5-alpha-androstan-3-one (4MA), the most widely studied of these compounds, has been shown to inhibit the androgen-dependent growth of both normal animal tissues and of the Noble tumor, an experimental, hormone-responsive rat neoplasm. 4MA has been found to inhibit androgen-dependent growth without altering plasma levels of T or DHT. In the present study, we assessed the efficacy of 4MA in inhibiting the growth of PC-82 and R198, human androgen-responsive genitourinary malignancies. In the first experiment, 4MA was administered subcutaneously at a dose of 6 mg/kg/day to castrated and hormonally replaced groups of PC-82-bearing male athymic nude mice. 4MA therapy when compared to control therapy caused significant PC-82 growth inhibition in three different groups of hormonally replaced castrated mice: physiologic T-replaced (P less than .001), supraphysiologic T replaced (P less than .001), and supraphysiologic T and DHT replaced (P less than .001). There was no difference between the post therapy plasma levels of T or DHT in the control-treated and 4MA-treated mice. In the second experiment, the effect of 4MA (6 mg/kg/day S.Q.) was compared to that of castration and control therapy on the growth of R198. Both castration and 4MA therapy effectively inhibited R198 growth when compared to control therapy (P = .01 and .02, respectively), but there was no difference in the degree of growth inhibition seen with 4MA or castration (P = .45). Castration and 4MA-therapy significantly lowered plasma T levels when compared to control therapy; castration also significantly lowered plasma DHT levels, while 4MA and control therapy did not. These studies suggest that 4MA is effective in inhibiting the growth of human androgen-responsive tumors grown in athymic nude mice and that further studies with other 5 alpha-reductase inhibitors are indicated.

5-alpha Reductase Inhibitors↗

PubMed1987

Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization independent of GH pool depletion.

Continuous infusions of growth hormone-releasing hormone (GHRH) attenuate the subsequent growth hormone (GH) response to GHRH. To test whether this phenomenon can occur in the absence of GH pool depletion, we examined the effects of continuous infusions of 10 nM GHRH and of 10 nM somatostatin (SRIH), separately or in combination, on dispersed, perifused rat anterior pituitary cells. Columns of these cells were given either GHRH alone for 5 h, GHRH and SRIH together for 3 h followed by GHRH alone, or SRIH alone for 3 h followed by GHRH or medium. SRIH blunted both basal GH release and the GH response to GHRH, without affecting the subsequent GH responses to GHRH. The GHRH infusions attenuated the subsequent GH response to GHRH, even when GH release was initially prevented by the concurrent infusion of SRIH. Furthermore, the degree of attenuation was similar in the presence or absence of SRIH, suggesting that pool depletion plays little role in the desensitization process under these experimental conditions. The results are consistent with the hypothesis that a short-term infusion of GHRH leads to attenuation of the GH response in rat anterior pituitary cells primarily through receptor effects rather than through GH pool depletion.

Animals↗

PubMed1987

The relationship of saline-induced changes in vasopressin secretion to basal and corticotropin-releasing hormone-stimulated adrenocorticotropin and cortisol secretion in man.

To investigate the effect of endogenous arginine vasopressin (AVP) on ACTH secretion, normal subjects were given infusions of either hypertonic saline (HS) or isotonic saline (NS) combined with human corticotropin-releasing hormone (CRH) or placebo. Basal plasma AVP was 2.3 +/- 0.3 (+/- SE) pg/ml, did not change with NS treatment, and rose to 5.4 +/- 0.6 pg/ml during HS infusion (P less than 0.01). Both basal and CRH-stimulated plasma ACTH and cortisol concentrations increased during HS infusion. Peak plasma ACTH and cortisol levels were 11.4 +/- 1.5 pg/ml and 8.6 +/- 0.8 micrograms/dl, respectively, during the HS (plus placebo) infusion. During the NS (plus placebo) infusion, plasma ACTH and cortisol gradually declined to 6.8 +/- 0.5 pg/ml and 2.6 +/- 0.4 micrograms/dl. The timing of the rise in ACTH during the HS infusion paralleled the rise in AVP. When an iv dose of 1 microgram/kg CRH was administered during the saline infusions, peak plasma ACTH and cortisol levels were 27.7 +/- 6.3 pg/ml and 17.5 +/- 1.0 micrograms/dl, respectively, during the HS infusion and 15.6 +/- 1.7 pg/ml and 13.4 +/- 1.2 micrograms/dl during the NS infusion. When the areas under the hormone response curves were compared, CRH stimulated ACTH and cortisol secretion to a greater extent than did HS (P less than 0.05). The hormonal stimulation due to combined CRH and hypertonic saline was greater than that attributable to either factor alone (P less than 0.025), but was not different than the sum of the effects of the individual factors. These results indicate that increases in endogenous AVP produced by HS are associated with increases in both basal and CRH-stimulated ACTH and cortisol release. The effect of HS appears to be additive to but not consistently synergistic with the effect of CRH.

Adrenocorticotropic Hormone↗

PubMed1987

The effects of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide, a 5 alpha-reductase inhibitor and antiandrogen, on the development of baldness in the stumptail macaque.

We used a primate model of male-pattern baldness to test the efficacy of a topically applied 5 alpha-reductase inhibitor and antiandrogen (4-MA) in the prevention of baldness. Six periadolescent stumptail macaques were given daily topical applications of either 4-MA in dimethylsulfoxide or dimethylsulfoxide alone for 27 months. The three control monkeys developed varying degrees of baldness, while the three 4-MA-treated monkeys retained their juvenile pattern of hair growth. The percentage of actively growing hair follicles in the frontal scalp did not change in the 4-MA-treated group [46 +/- 6 (+/- SE) vs. 48 +/- 4], while a significant decrease occurred in the control group (63 +/- 6 vs. 25 +/- 12; P less than 0.025). Skin 5 alpha-reductase activity was reduced in the scalp of the 4-MA-treated monkeys. We conclude that topical 4-MA can prevent the development of baldness in the stumptail macaque, a primate model of androgen-dependent baldness.

Alopecia↗