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R S Rittmaster

Publications and source records attributed to R S Rittmaster.

At least 19 recordsLinked to original sources
PubMed1998

Insulin-like growth factor binding protein 5 is associated with involution of the ventral prostate in castrated and finasteride-treated rats.

BACKGROUND: Insulin-like growth factor binding protein (IGFBP)-5 has been proposed as a signal for apoptosis in the ovary. To determine the relationship between IGFBP-5 and apoptosis during regression of the androgen-deprived prostate, rats were castrated or treated with the 5alpha-reductase inhibitor finasteride for 4, 9, 14, 21, and 28 days. METHODS: Ventral prostate tissue was immunostained for IGFBP-5, and apoptotic cells were identified by in situ end-labeling of fragmented DNA (TUNEL). To compare the distribution of IGFBP-5 with the distribution of apoptotic cells, mirror-image serial sections of prostate tissues from normal and day 4 finasteride-treated rats were examined. RESULTS: In normal rats, 4+/-1% of prostate epithelial cells stained positively for IGFBP-5, and 0.1+/-0.03% demonstrated DNA fragmentation. IGFBP-5 staining peaked at day 9 with 93 +/-2% and 64+/-13% of epithelial cells staining positively in castrated and finasteride-treated rats, respectively. In contrast, DNA fragmentation peaked at day 4 in tissues from both castrated and finasteride-treated rats with 7+/-1% and 0.7+/-0.3% of epithelial cells, respectively, staining. In the serial sections, TUNEL and IGFBP-5 staining were not usually expressed in the same cells. CONCLUSIONS: Prostatic involution involves both programmed cell death and inhibition of cell growth. Because of the distribution of staining and the delayed expression of IGFBP-5 relative to initiation of apoptosis, we postulate that IGFBP-5 functions as an inhibitor of cell proliferation rather than as a signal for apoptosis.

Animals↗
PubMed1998

Role of the ovary in the adrenal androgen excess of hyperandrogenic women.

OBJECTIVE: To test the hypothesis that ovarian hormones in women with hyperandrogenism alter adrenocortical steroidogenesis. DESIGN: Combination of two prospective studies. SETTING: Academic medical centers. PATIENT(S): Eighteen hyperandrogenic patients demonstrating hirsutism with either hyperandrogenemia, oligomenorrhea, or both. Eighteen healthy nonhirsute eumenorrheic untreated women served as controls. INTERVENTIONS: Blood sampling basally and after acute adrenal stimulation with ACTH, before and after 20-24 weeks of leuprolide administration. Nine patients also received 0.625 mg/d of oral conjugated esterified estrogens and 10 mg of medroxyprogesterone acetate days 1-12 of the month (i.e., estrogen replacement therapy [ERT]), whereas the remaining nine did not. MAIN OUTCOME MEASURE(S): Before and after the administration of the GnRH agonist (GnRH-a), the basal concentrations of DHEAS; and the levels of androstenedione (A4), DHEA, androstenediol, 11 beta-hydroxyandrostenedione (11-OHA4), and cortisol before and 60 minutes after acute adrenal stimulation, were measured. RESULT(S): Levels of DHEAS, androstenediol, and 11-OHA4 decreased by 15%-30%, regardless of whether patients initially had or did not have DHEAS excess. However, only hyperandrogenic patients with elevated levels of DHEAS showed a significant decrease in basal DHEA levels. No statistically significant difference in the response of either androgen to ACTH (1-24) stimulation was noted with ovarian suppression, regardless of initial DHEAS level or use of ERT. CONCLUSION(S): We found no evidence that ovarian hormone secretion affected adrenal steroidogenesis, and those women with the highest adrenal androgen levels had the least response to GnRH-a suppression. These findings further support the concept of an intrinsic, and possibly primary, abnormality of adrenocortical steroidogenesis in a subset of hyperandrogenic women that is independent of ovarian abnormalities.

Adolescent↗
PubMed1998

Effect of methimazole, with or without L-thyroxine, on remission rates in Graves' disease.

Medical treatment of Graves' disease involves antithyroid drugs with or without the addition of exogenous T4. There have been conflicting reports as to whether the addition of T4 improves remission rates or delays relapse. To evaluate this issue in a North American population, 199 patients were treated with methimazole until they were euthyroid. They were then randomized to either methimazole alone in a dose sufficient to normalize TSH (group 1), or to 30 mg methimazole daily plus sufficient T4 to maintain TSH in the upper normal range (group 2), or to 30 mg methimazole daily plus sufficient T4 to suppress TSH below 0.6 mIU/L (group 3). After 18 months, methimazole was stopped, and T4 was continued in groups 2 and 3. Because not all patients in groups 2 and 3 achieved their target TSH concentration, they were reassigned to group A (TSH > or = 1.0) or group B (TSH < 1.0), based on the mean TSH achieved during methimazole treatment. One hundred forty-nine patients have been followed for at least 6 months after stopping methimazole (mean 27 months). Fifty-eight percent of patients have relapsed. There were no significant differences in relapse rates after stopping methimazole. Among those patients who did relapse, however, there was a significant difference in the months to relapse after stopping methimazole between groups B and 1 (group 1: 3.3 +/- 0.7, group A: 5.6 +/- 0.8, group B: 7.4 +/- 1.7; P = 0.01 for the comparison between groups B and 1). We conclude that the addition of T4 to methimazole does not improve long-term remission rates in Graves' disease.

Adult↗
PubMed1998

Testolactone-associated high androgen levels, a pharmacologic effect or a laboratory artifact?

Testolactone, an aromatase inhibitor, blocks conversion of androgens to estrogens. In familial male precocious puberty, slowing of pubertal progression and growth velocity occurs with testolactone and spironolactone. Girls with McCune-Albright syndrome, given testolactone, respond similarly. A 2-yr-old female (case 1) on testolactone for non-McCune-Albright gonadotropin independent precocious puberty had marked elevations of androstenedione (18 ng/mL, normal: 0.2-3.1) and testosterone (3.6 ng/mL, normal < 0.2) but no virilization. Investigations were undertaken to determine whether elevations in testosterone and androstenedione were caused by interference in these RIAs. After a single oral dose of testolactone (5 mg/kg in case 1; 4 mg/kg in case 2, a 3-yr-old boy with familial male precocious puberty; 10 mg/kg in a healthy postmenopausal control), serum testosterone and androstenedione were measured serially by RIA for 24 h. Androstenedione went from normal to a mean peak of 45.4 ng/mL at 1-2 h and returned to baseline by 24 h. Testosterone, undetectable at baseline (case 1 and control) or 1.8 ng/mL (case 2) rose to a mean peak of 6.9 ng/mL and returned to baseline by 24 h. Testolactone, in serial dilutions, cross-reacted in the testosterone assay. Testolactone significantly interferes in these serum RIAs, making their use unreliable in follow-up of patients treated with testolactone.

Androstenedione↗
PubMed1997

Hirsutism.

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Androgens↗
PubMed1996

Relative potency of testosterone and dihydrotestosterone in preventing atrophy and apoptosis in the prostate of the castrated rat.

Although dihydrotestosterone (DHT) is the principal androgen in the prostate, testosterone can also act as an androgen in this tissue. To determine the relative potencies of testosterone and DHT in preventing prostate regression, castrated rats were implanted for 4 d with varying doses of testosterone in the presence or absence of the 5alpha-reductase inhibitor finasteride. In the absence of finasteride, testosterone in the prostate is converted to DHT, creating an intraprostatic DHT dose response. In the presence of finasteride, this conversion is blocked, and an intraprostatic testosterone dose response is achieved. DHT was 2.4 times more potent than testosterone at maintaining normal prostate weight and duct lumen mass, a measure of epithelial cell function. The two androgens were equipotent at preventing DNA fragementation and expression of testosterone-repressed prostate message, two measures of apoptosis (cell death). The intraprostatic testosterone concentration that results from finasteride treatment in rats is sufficient to inhibit apoptosis but will not maintain normal epithelial cell activity. In conclusion, whereas DHT is more potent than testosterone at stimulating prostate epithelial cell function as measured by ductal mass, the two androgens are equipotent at preventing prostate cell death after castration. These results explain why finasteride causes prostate involution in the rat with minimal evidence of prostate cell death.

Animals↗
PubMed1996

Dose-response effect of depot leuprolide acetate on serum androgens in hirsute women.

OBJECTIVE: To determine the dose of leuprolide acetate (LA) needed to maximally suppress serum androgens in hirsute women. DESIGN: Prospective, dose-escalation study. SETTING: Outpatient endocrinology clinic. PATIENTS: Eight hyperandrogenic women with moderate to severe hirsutism. INTERVENTIONS: A LA dose-response study was done in women receiving depot LA plus estrogen-progestin replacement. MAIN OUTCOME MEASURES: Serum concentrations of T, androstenedione (A), and basal and GnRH-stimulated LH. RESULTS: The lowest LA dose (3.75 mg/mo) suppressed serum T by 62% +/- 6% and A by 56% +/- 7%. No further decrease in serum androgens was seen with doses up to 15 mg/mo. Maximal suppression of basal and stimulated LH was also seen with the lowest dose of LA. CONCLUSIONS: As opposed to results previously published in children with precocious puberty, the 3.75 mg dose of depot LA is sufficient to maximally suppress serum androgens in hyperandrogenic women.

Adolescent↗
PubMed1996

Evidence for atrophy and apoptosis in the prostates of men given finasteride.

Finasteride, a 5 alpha-reductase inhibitor, decreases prostate size and improves symptoms in men with benign prostatic hyperplasia. However, little is known about prostate histopathology in men taking finasteride. To determine the mechanism by which finasteride reduces prostate size, tissue was collected at the time of prostatectomy from men taking either no medication (n = 10) or 5 mg finasteride daily for 6-18 days (n = 6; group 1), 23-73 days (n = 5; group 2), or 3 months to 4 yr (n = 5; group 3). To assess whether finasteride causes epithelial atrophy, morphometric measurement of epithelial cell and duct width was used. The mean epithelial cell width in control prostates (mean +/- SEM, 21 +/- 0.7 microns) decreased with duration of treatment to 19 +/- 1 microns in group 1, 15 +/- 2 microns in group 2, and 8 +/- 0.3 microns in group 3. Mean duct width decreased from 135 +/- 6 microns in the control prostates to 128 +/- 10 microns in group 1, 103 +/- 3 microns in group 2, and 63 +/- 6 microns in group 3. To assess whether prostate cell death was occurring, sections were in situ end labeled for DNA breaks and immunostained for tissue transglutaminase (tTG), a marker of apoptosis (programmed cell death). The percentage of epithelial cells staining for DNA breaks was 0.4 +/- 0.2 in control prostates, 2.8 +/- 0.9 in group 1, 1.7 +/- 0.5 in group 2, and 0.7 +/- 0.3 microns in group 3. Anti-tTG staining of epithelial cells was graded on a scale of 0-4. In control prostates, 3 +/- 1% of the ducts were grade 3 or 4 (> 50% of epithelial cells staining). In finasteride-treated prostates, 2 +/- 2% of the prostates in group 1, 13 +/- 4% of the prostates in group 2, and 0.5 +/- 0.5% of the prostates in group 3 were grade 3-4. These results indicate that a progressive decrease in epithelial cell size and function occurs during the first several months in the prostates of men treated with finasteride. The staining for DNA breaks and the tTG staining also indicate that an increased rate of apoptosis is occurring transiently in these prostates. We conclude that finasteride causes prostate involution through a combination of atrophy and cell death.

5-alpha Reductase Inhibitors↗
PubMed1996

Effect of methimazole with or without exogenous L-thyroxine on serum concentrations of thyrotropin (TSH) receptor antibodies in patients with Graves' disease.

Medical treatment of Graves' disease involves use of antithyroid drugs with or without the addition of exogenous L-T4. There have been conflicting reports as to whether the addition of T4 reduces TSH receptor antibodies and improves remission rates more than antithyroid drugs alone. To further examine the effect of drug therapy on serum concentrations of TSH receptor antibodies. 70 patients with Graves' disease were treated with methimazole (Tapazole) alone until they were euthyroid. Then they were randomized to receive either: 1) methimazole alone in a dose sufficient to normalize TSH (0.3-5.4 mIU/L; Group 1); 2) 30 mg methimazole daily plus sufficient T4 (Synthroid) to maintain TSH in the high-normal range (2.0-5.4 mIU/L; Group 2); or 3) 30 mg methimazole daily plus sufficient T4 to suppress TSH to below 0.6 mIU/L (Group 3). The duration of treatment in all groups was 18 months. At baseline and after 6 and 18 months, TSH receptor antibodies were measured both by the ability of patients' sera to stimulate cAMP production by FRTL-5 cells (thyroid-stimulating Ig) and by the ability of patients' sera to inhibit binding of radiolabeled TSH to solubilized porcine thyroid membranes (TSH-binding, inhibiting Ig). Thyroid-stimulating Ig(TSI) and TSH-binding, inhibiting Ig(TBII) concentrations were similar among the three groups at baseline. Mean baseline TSI (expressed as the percent of normal control) for all patients combined was 306 +/- 21%. Mean baseline TBII (expressed as percent inhibition of TSH binding) was 38 +/- 2%. TSI was elevated in 85% and TBII was elevated in 75% of patients at baseline. After 18 months, TSI was elevated in 64% of patients, and TBII was elevated in 28%. Serum TSI decreased by 36 +/- 5% during the study, and there was no significant difference in the degree of reduction among the three groups (P = 0.99). Serum TBII decreased by 59 +/- 3%, and there also was no significant difference among the groups (P = 0.83). At baseline, serum TBII correlated with free T4 (r = 0.33, P < 0.01), total T3 (r = 0.55, P < 0.01), and thyroid size (r = 0.35, P < 0.01). There was no correlation between TSI and any of the baseline parameters or between TSI and TBII at any timepoint. In conclusion, we found that the addition of T4 to methimazole does not result in a greater decrease in TSH receptor antibody concentrations than treatment with methimazole alone. From these results, we would predict no difference in remission rates among these patients, but confirmation of this prediction will need to await long-term follow-up of these subjects.

Adolescent↗
PubMed1995

Clinical relevance of testosterone and dihydrotestosterone metabolism in women.

Androgens are part of normal female physiology. When they are secreted in excess or when they cause unwanted symptoms such as hirsutism and male-pattern baldness, the term hyperandrogenism is used. In many hyperandrogenic women, there is no well-defined hormonal abnormality, but the women are simply on one end of a normal spectrum of androgen secretion and cutaneous androgen sensitivity. To be active in the skin, testosterone must be converted to dihydrotestosterone by the enzyme 5 alpha-reductase. Androgen sensitivity is determined, in part, by 5 alpha-reductase activity in the skin. This is a localized phenomenon, and there is no generalized increase in 5 alpha-reductase activity in these women. Dihydrotestosterone can be converted to glucuronide and sulfate conjugates, including androstanediol glucuronide. These androgen conjugates have been proposed to be serum markers of cutaneous androgen metabolism, but recent evidence indicates that they arise from adrenal precursors and are more likely to be markers of adrenal steroid production and metabolism. Antiandrogens (androgen receptor blockers) are the best medical treatment of cutaneous hyperandrogenism. 5 alpha-Reductase inhibitors have recently been approved for the treatment of benign prostatic hyperplasia, and research is currently underway to determine their effectiveness in treating hirsutism and male-pattern baldness.

Cholestenone 5 alpha-Reductase↗
PubMed1995

Evidence for atrophy and apoptosis in the ventral prostate of rats given the 5 alpha-reductase inhibitor finasteride.

Castration causes cell loss in the rat ventral prostate through a process called apoptosis. Although 5 alpha-reductase inhibition also causes prostate cell loss, the mechanisms involved have been debated. To investigate this question further, we have evaluated the histological responses of the rat ventral prostate to both castration and 5 alpha-reductase inhibition. Rats were left intact, castrated, or given the selective 5 alpha-reductase inhibitor finasteride. After 4, 9, 14, and 21 days the prostates were excised, the androgen and DNA content determined, and the tissue was subjected to histological and histomorphometric analysis. Finasteride and castration decreased prostate weight at day 21 by 65% and 93%, respectively. Castration decreased DNA content (micrograms per prostate) by a maximum of 88% at 14 days. Finasteride had no significant effect on DNA content after 4 days and decreased DNA content by a maximum of 52% at 14 days. When castrate prostate sections were stained for tissue transglutaminase, a marker of apoptotic cell death, a maximum of 23% of epithelial cells were stained by day 14 with a return to control levels by day 21. Finasteride caused a less intense increase in staining in which 16% of epithelial cells stained for tissue transglutaminase on day 9 with a return to baseline by day 14. When prostate sections were stained for DNA breaks, another marker of cell death, castration, caused a peak of staining on day 4 with 6% of epithelial cells staining and a return to near control levels by day 21. Finasteride-induced staining was less intense with peak staining at day 4 (0.7% of epithelial cells) and a return to control values by day 9. Morphometrics were used to assess the effect of castration and finasteride on prostate duct size and epithelial cell mass. After 4 days of finasteride treatment, the mean ductal mass decreased by 47%, with no significant change thereafter. The mean epithelial cell mass decreased by 15% on day 4 and 60% on day 9, with no further decrease thereafter. Castration caused a more rapid and greater decrease in both morphometric parameters with a 95% reduction in the mass of prostate ducts and a 93% decrease in epithelial cell mass by day 9. We conclude that castration induces a more profound involution of the rat ventral prostate than does 5 alpha-reductase inhibition. Cell loss occurs in both groups, but the degree of cell loss is less with finasteride.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Clinical review 73: Medical treatment of androgen-dependent hirsutism.

Although hirsutism is more a cosmetic and psychosocial problem than a disease, hirsute women are often some of the most grateful patients in an endocrinologist's practice. The combination of mechanical hair removal and judicious use of medications will improve hair growth in most women. Unfortunately, no drug is approved by regulatory agencies in North America for treatment of hirsutism. Well designed comparative studies with objective end points are needed to demonstrate which drugs work best in which hirsute women. Because pharmaceutical companies are reluctant to market drugs for women of child-bearing age, there has been little industry support for such studies.

Adrenal Glands↗
PubMed1994

Finasteride.

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Acne Vulgaris↗
PubMed1993

Androgen metabolism in men receiving finasteride before prostatectomy.

Oral administration of finasteride, a 5 alpha-reductase inhibitor, affects intraprostatic androgens by suppressing dihydrotestosterone and increasing testosterone. This study was designed to determine the correlation of these effects of finasteride with changes in serum dihydrotestosterone, testosterone and androstanediol glucuronide. In a double blind, placebo-controlled study, 27 men with symptomatic benign prostatic hyperplasia were treated with placebo or 1 or 5 mg. per day finasteride for 6 to 8 weeks before transurethral resection of the prostate. There was no significant change in serum testosterone in any group, or in serum dihydrotestosterone or androstanediol glucuronide in the placebo group. There was a decrease in serum dihydrotestosterone by 66 +/- 4% and 70 +/- 8% (p = 0.32), and of serum androstanediol glucuronide by 78 +/- 3% and 86 +/- 3% (p = 0.012) in the 1 and 5 mg. finasteride groups, respectively. Intraprostatic dihydrotestosterone in the placebo group decreased from 18.6 +/- 1.4 nmol./kg. to 3.8 +/- 1.0 nmol./kg. and 1.7 +/- 0.7 nmol./kg. with 1 mg. and 5 mg. finasteride, respectively (p = 0.049 between 1 mg. and 5 mg. finasteride). Intraprostatic testosterone in the placebo group increased from 1.1 +/- 0.2 nmol./kg. to 7.6 +/- 1.0 nmol./kg. and 8.3 +/- 0.7 nmol./kg. with 1 mg. and 5 mg. finasteride, respectively (no significant difference between 1 mg. and 5 mg. finasteride). Serum and intraprostatic dihydrotestosterone correlated (p = 0.002). There was no correlation between intraprostatic dihydrotestosterone and serum androstanediol glucuronide. We conclude that 5 mg. of finasteride cause greater inhibition of intraprostatic 5 alpha-reductase than 1 mg. and that serum dihydrotestosterone is a better marker of intraprostatic dihydrotestosterone than androstanediol glucuronide.

Androstane-3,17-diol↗