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R S Swerdloff

Publications and source records attributed to R S Swerdloff.

At least 19 recordsLinked to original sources
PubMed1997

Androgen-behavior correlations in hypogonadal men and eugonadal men. I. Mood and response to auditory sexual stimuli.

Mood and response to auditory sexual stimuli were assessed in 33 hypogonadal men receiving testosterone (T) replacement therapy, 10 eugonadal men receiving T in a male contraceptive clinical trial, and 19 eugonadal men not administered T. Prior to and after 6 weeks of hormone administration, men completed a mood questionnaire, rated sexual arousal to and sexual enjoyment of auditory sexual stimuli, and performed a dichotic listening task measuring selective attention for sexual stimuli. Mood questionnaire results suggest that T has positive effects on mood in hypogonadal men when hormone levels are well below the normal male range of values, but does not have any effects on mood when hormone levels are within or above the normal range. However, increased sexual arousal and sexual enjoyment were associated with T administration regardless of gonadal status. Eugonadal men administered T also increased in the bias to attend to sexual stimuli. In contrast, the comparison group of eugonadal men not administered T showed no mood or sexual behavior changes across the two test sessions. These data support a positive relationship between T and sexual interest, sexual arousal, and sexual enjoyment in men.

Administration, Sublingual↗
PubMed1997

Oligozoospermia induced by exogenous testosterone is associated with normal functioning residual spermatozoa.

OBJECTIVE: To determine the functional capacity of residual spermatozoa in semen samples from normal men with T enanthate-induced oligozoospermia. DESIGN: Prospective clinical study. SETTING: Academic research center. PATIENT(S): Twelve healthy men were studied while participating in a multicenter T enanthate contraceptive efficacy study. Data were analyzed from only eight subjects, whose sperm concentrations were between 1.3 and 10 x 10(6)/mL at the suppression phase. INTERVENTION(S): Testosterone enanthate (200 mg) was administered IM weekly during the suppression and treatment (efficacy) phases (total 15 months). MAIN OUTCOME MEASURE(S): Sperm function tests (stimulated acrosome reaction, sperm hyperactivation [HA], and zona-free hamster oocyte penetration tests) were performed during the pretreatment, suppression (usually after 6 to 10 weeks of treatment, when sperm concentration was anticipated to decrease to < 10 x 10(6)/mL), and recovery phases. Studies were not done during the contraceptive efficacy phase because only one of the subjects was not azoospermic. RESULT(S): Mean sperm concentration was reduced but sperm motility, motility characteristics, and morphology were not affected by T enanthate treatment. The residual spermatozoa in the ejaculate could acrosome react, exhibited normal HA, and maintained the capacity to penetrate and fuse with the oocyte. CONCLUSION(S): Suppression of spermatogenesis to moderate oligozoospermia (< 10 x 10(6)/mL) with exogenous T enanthate administration was not associated with impaired sperm function of the residual spermatozoa. The study did not exclude the possibility that disorders of sperm function might occur when spermatogenesis is suppressed further to very severe oligozoospermia (< 1 x 10(6)/mL), commonly observed in hormonal male contraceptive clinical trials.

Adult↗
PubMed1997

Effect of increased scrotal temperature on sperm production in normal men.

OBJECTIVE: To determine whether application of polyester-lined athletic supports to bring the testes closer to the abdomen increases scrotal temperature and decreases sperm production. DESIGN: Prospective clinical study. SETTING: University academic medical center. PATIENT(S): Twenty-one healthy male volunteers. INTERVENTION(S): The study consisted of a pretreatment period of 6 weeks, a treatment phase of 52 weeks, and a recovery phase until return to normal sperm production. During the treatment phase, the men wore polyester-lined athletic supports (single layer, double layer, or double layer impregnated with aluminum) throughout the day. MAIN OUTCOME MEASURE(S): Semen parameters and sperm function tests. RESULT(S): In all three groups of subjects, scrotal temperature was consistently increased by 0.8 to 1 degree C while the subjects were wearing the athletic supports. Mean sperm concentration; sperm motility, morphology, and viability; sperm hyperactivation; and ability of spermatozoa to penetrate zone-free hamster oocytes were not affected by the increase in scrotal temperature. CONCLUSION(S): The increase in scrotal temperature induced by polyester-lined athletic supports was insufficient to cause significant suppression of spermatogenesis or alteration of sperm function.

Adult↗
PubMed1997

Separation of germ cell apoptosis from toxin-induced cell death by necrosis using in situ end-labeling histochemistry after glutaraldehyde fixation.

In situ end-labeling of fragmented DNA is routinely being used to detect apoptotic cells in various tissues including the testis. In this study, we examined the influence of various fixatives (neutral buffered formalin, paraformaldehyde, and glutaraldehyde) on the testicular structural integrity and immunoreactivity of fragmented DNA in apoptotic germ cells of the adult rat. Accelerated apoptosis of germ cells was induced in the adult rate by gonadotropin deprivation. Visualization of apoptotic DNA fragmentation in individual germ cells was achieved by direct immunoperoxidase detection of digoxigenin-labeled genomic DNA. Glutaraldehyde fixation significantly improved the in situ detection of apoptotic germ cells while maintaining excellent morphological preservation. The labeling is also specific for apoptosis since necrotic germ cells show no specific signals. Fixed tissues could be processed for electron microscopy for further characterization of germ cell death using morphological criteria. Thus, glutaraldehyde fixation is advantageous for recognition of apoptotic germ cells with high sensitivity and specificity on a cell-by-cell basis. It should also be applicable to detect apoptosis in other cells and tissues.

Animals↗
PubMed1997

The interaction between beta-endorphin and gonadal steroids in regulation of luteinizing hormone (LH) secretion and sex steroid regulation of LH and proopiomelanocortin peptide secretion by individual pituitary cells.

Reported studies using the conventional pituitary cell culture technique suggest that beta-endorphin (B-EP) produced locally in the pituitary or reaching it from the hypothalamus acts in conjunction with estradiol (E2) to initiate and in conjunction with progesterone (P4) to terminate the midcycle surge of LH. In addition, the reverse hemolytic plaque assay (RHPA) was used to investigate the effects of E2 and P4 on the secretory activity of individual pituitary cells. The results of these experiments indicate that 1) E2 enhances the secretion of LH, ACTH, and B-EP by individual pituitary cells; 2) E2 increases the number of secreting cells for each of the three hormones; 3) the rise in B-EP and ACTH secretion antecede that of LH; 4) P4 augments ACTH and B-EP secretion by individual pituitary cells; and 5) P4 has dual effects, acutely (1 h) potentiating LH secretion from already active cells and subsequently (8 h) recruiting cells that formerly had little or no secretory activities. Collectively, the above studies support a role for steroid hormones in regulation of midcycle LH secretion at the pituitary level. The results also suggest that intrapituitary (paracrine/autocrine) and extrapituitary (endocrine) B-EP modulates gonadal steroid effects on LH secretion by pituitary gonadotrophs.

Adrenocorticotropic Hormone↗
PubMed1996

Androgens are not major down-regulators of androgen receptor levels during growth of the immature rat penis .

This study was undertaken to investigate the prevalent hypothesis that androgens are responsible for the organ-specific down-regulation of penile androgen receptors (ARs) and decline of penile growth in the rat during sexual maturation. Sexually immature male rats (21 days old) were castrated and treated for 3 days ("short-term"), with high doses of: (a) testosterone and the alpha-reductase inhibitor finasteride (T/F); (b) dihydrotestosterone (DHT); or (c) finasteride alone (F). Intact and castrate controls received vehicle only. PolyA + RNA was analysed by Northern blot hybridization and ARs were estimated in the penis and ventral prostates by (3-H)R-1881 binding in the cytosol. Short-term castration, with or without F, increased penile AR mRNA, whereas high doses of T/F and DHT reduced it considerably. Although penile cytosol AR concentration in the control castrates, with or without F, paralleled the AR mRNA rise, treatment with androgens left cytosol AR content per organ and AR concentration above those of the intact rat penis despite the drop in AR mRNA. A "long-term" treatment (10 days) on 19-day-old rats with either medium or high doses of T/F and DHT also failed to down-regulate penile cytosol ARs below the intact controls. Western blot analysis of penile cytosol AR levels confirmed these results. Block of pituitary FSH and LH release by a GnRH antagonist in castrates receiving T/F or DHT at high doses did not modify the response. In the case of intact rats, high doses of T/F or DHT actually increased penile cytosol AR content. No difference was observed between T/F and DHT effects. In contrast to what occurs during sexual maturation, the prostate ARs and growth rate responded to all treatments in a similar way to what was observed in the penis. Our results suggest that increases in serum T or DHT are not major factors in the physiological down-regulation of ARs and androgen-dependent growth in the rat corpora cavernosa.

Androgens↗
PubMed1996

Testosterone replacement therapy improves mood in hypogonadal men--a clinical research center study.

The effect of testosterone (T) replacement on changes in mood was studied for 60 days in 51 hypogonadal men. All patients were withdrawn from their prior T replacement for at least 6 weeks before enrollment. Of these patients, 18 received T enanthate 200 mg im every 20 days, 16 received sublingual T cyclodextrin (SLT) at a dose of 2.5 mg three times daily, and 17 received SLT at a dose of 5.0 mg three times daily. The total treatment period was 60 days. The patients were asked to respond to a questionnaire on 7 consecutive days before the start of treatment and on 7 consecutive days before their visits to the clinic on days 21, 41, and 60 of treatment. The following mood parameters were assessed using a 7-point Likert rating scale: angry, alert, irritable, full of pep (energy), sad/blue, tired, friendly, nervous, and well/good. When compared with the baseline period, T replacement led to significant decreases in anger (P = 0.0045), irritability (P = 0.0009), sadness (P = 0.0033), tiredness (P = 0.0035), and nervousness (P = 0.0291), and significant improvement in energy level (P = 0.0020), friendliness (P = 0.0072), and sense of well-being (P = 0.024) in all subjects as a group. Analyses of the area under the curve (AUC) of baseline serum T levels before T replacement showed significant positive correlations between serum T (AUC) and friendliness (r = 0.29, P < 0.05) and sense of well-being (r = 0.27, P < 0.05), and significant negative correlations with nervousness (r = -0.27, P < 0.05), irritability (r = -0.29, P < 0.05) and tiredness (r = -0.28, P < 0.05). Similar correlations were found between serum dihydrotestosterone (DHT) and some of the mood parameters. After T replacement in the hypogonadal men, these correlations between AUC of serum T levels and the positive and negative mood scores disappeared. These results were corroborated in a subsequent study in which 30 hypogonadal men were supplemented with SLT 5 mg three times daily for 6 months. The patients were less nervous (P = 0.0025) and more alert (P = 0.0004), friendly (P = 0.042), and energetic (P = 0.0001) during the 6-month treatment period compared with baseline. We conclude that T replacement therapy in hypogonadal men improved their positive mood parameters, such as energy, well/good feelings, and friendliness and decreased negative mood parameters including anger, nervousness, and irritability, and direct correlations between serum T and DHT with mood scores were only observed in the baseline period when serum androgen levels were below the normal range. The latter observation suggests that once a minimally adequate serum T/DHT level was achieved by T replacement therapy, further increases in serum T/DHT levels did not further contribute to the improvement in mood variables.

Administration, Sublingual↗
PubMed1996

Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men--a clinical research center study.

To study the effects of androgen replacement therapy on muscle mass and strength and bone turnover markers in hypogonadal men, we administered sublingual testosterone (T) cyclodextrin (SLT; 5 mg, three times daily) to 67 hypogonadal men (baseline serum T, < 8.4 nmol/L) recruited from 4 centers in the U.S.: Torrance (n = 34), Durham (n = 12), New York (n = 9), and Salem (n = 12). Subjects who had received prior T therapy were withdrawn from injections for at least 6 weeks and from oral therapy for 4 weeks. Body composition, muscle strength, and serum and urinary bone turnover markers were measured before and after 6 months of SLT. We have shown previously that this regimen for 60 days will maintain adequate serum T levels and restore sexual function. Total body (P = 0.0104) and lean body mass (P = 0.007) increased with SLT treatment in the 34 subjects in whom body composition was assessed. There was no significant change in total body fat or percent fat. The increase in lean body mass was mainly in the legs; the right leg lean mass increased from 8.9 +/- 0.3 kg at 0 months to 9.2 +/- 0.3 kg at 6 months (P = 0.0008). This increase in leg lean mass was associated with increased leg muscle strength, assessed by leg press (0 months, 139.0 +/- 4.0 kg; 6 months, 147.7 +/- 4.2 kg; P = 0.0038). SLT replacement in hypogonadal men led to small, but significant, decreases in serum Ca (P = 0.0029) and the urinary calcium/creatinine ratio (P = 0.0066), which were associated with increases in serum PTH (P = 0.0001). At baseline, the urinary type I collagen-cross linked N-telopeptides/creatinine ratio [75.6 +/- 7.9 nmol bone collagen equivalents (BCE/mmol] was twice the normal adult male mean (41.0 +/- 3.6 nmol BCE/mmol) and was significantly decreased in response to SLT treatment at 6 months (68.2 +/- 7.7 nmol BCE/mmol; P = 0.0304) without significant changes in urinary creatinine. Serum skeletal alkaline phosphatase did not change. In addition, SLT replacement caused significant increases in serum osteocalcin (P = 0.0001) and type I procollagen (P = 0.0012). Bone mineral density did not change during the 6 months of SLT treatment. We conclude that SLT replacement therapy resulted in increases in lean muscle mass and muscle strength. Like estrogen replacement in hypogonadal postmenopausal females, androgen replacement therapy led to decreased bone resorption and urinary calcium excretion. Moreover, androgen replacement therapy may have the additional benefit of increasing bone formation. A longer term study for several years duration would be necessary to demonstrate whether these changes in bone turnover marker levels will result in increased bone mineral density decreased fracture risks, and reduced frailty in hypogonadal men.

Administration, Sublingual↗
PubMed1995

Temporal and stage-specific effects of recombinant human follicle-stimulating hormone on the maintenance of spermatogenesis in gonadotropin-releasing hormone antagonist-treated rat.

Despite considerable attention to the hormonal regulation of spermatogenesis, the role of FSH in adult mammals remains controversial. This is mainly due to the unavailability until recently of FSH preparations free of contaminating LH and discrepant results in various species. Using LH-free recombinant human FSH (rhFSH), we sought to determine if FSH is able to maintain spermatogenesis in rats in which both LH and FSH, but not other pituitary hormones, are markedly suppressed by GnRH-A treatment. Groups of five adult SD rats were given daily sc injections of vehicle, Nal-Glu-GnRH-A (1.25 mg/kg BW) or GnRH-A + 10 IU rhFSH for up to 4 weeks. In agreement with our previous report, GnRH-A treatment for 1 week led to a significant (P < 0.05) reduction in testis weight (26.6%) and in the number of specific germ cells involving preleptotene (27.7%) and pachytene spermatocytes (36.7%) and step 7 spermatids (30.3%) at stage VII of the seminiferous epithelial cycle. The number of advanced spermatids declined by 44.3%. Concomitant administration of rhFSH for 1 week resulted in a significant increase in testicular weight, tubular areas at stage VII-VIII, and in the absolute volumes of seminiferous tubules and their lumens compared to GnRH-A alone. Most importantly, FSH replacement to GnRH-A-treated rats fully attenuated the early (1 week) GnRH-A-induced reduction in germ cell numbers at stage VII as well as the number of advanced (steps 17-19) spermatids, and effectively prevented GnRH-A-induced reduction in the number of pachytene spermatocytes and step 7 spermatids for 2 weeks. In addition, FSH replacement to GnRH-A-treated rats was able to increase the number of B spermatogonia available for entry into meiosis and maintain the number of preleptotene spermatocytes throughout the treatment period. The observed beneficial effects of rhFSH on spermatogenesis in GnRH-A-treated rats are most likely not due to the stimulation of the Leydig cell function (via paracrine interaction between Sertoli and the Leydig cells), because FSH addition to GnRH-A had no discernible effect on intratesticular or plasma T levels, accessory organs weight, and the total volume of the Leydig cells when compared with GnRH-A alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Involvement of apoptosis in the induction of germ cell degeneration in adult rats after gonadotropin-releasing hormone antagonist treatment.

In adult mammals, including man, germ cell death is conspicuous during spermatogenesis and plays a pivotal role in sperm output. The possible mechanism(s) underlying this phenomenon remains, however, poorly understood. Apoptosis is a programmed physiological process by which cells die either spontaneously or in response to changes in the levels of specific physiological stimuli. Previously, we reported that early deprivation of gonadotropin and testosterone by GnRH antagonist (GnRH-A) treatment is followed by a stage-specific degeneration of germ cells in the testis. In this study, we examined the possible involvement of apoptosis in the induction of germ cell degeneration. Adult male rats were given a daily injection of Nal-Glu GnRH-A (1 mg/kg BW) for 0 (control), 2, or 5 days. The onset of germ cell degeneration was assessed by high resolution light microscopy as well as by a germ cell degeneration assay. The occurrence of apoptosis was characterized by 1) detection of internucleosomal DNA fragmentation after agarose gel electrophoresis, and 2) direct immunoperoxidase detection of digoxigenin-labeled genomic DNA in specific cell types. The earliest morphological signs of germ cell degeneration involving preleptotene and pachytene spermatocytes, step 7 spermatids (at stage VII), and step 19 spermatids (at both stages VII and VIII) were detected 5 days after the commencement of GnRH-A treatment. The onset of germ cell degeneration was further accompanied by a significant increase in the degree of low mol wt DNA fragmentation. In situ detection of apoptosis within this time frame fully corroborates the observed stage-related degeneration of specific germ cells. These results suggest that apoptosis provides the basic mechanism by which germ cells die in the testis in response to a lack of hormonal stimulation.

Animals↗
PubMed1995

Pharmacokinetics, bioefficacy, and safety of sublingual testosterone cyclodextrin in hypogonadal men: comparison to testosterone enanthate--a clinical research center study.

We studied and compared the pharmacokinetics and bioefficacy of two doses of sublingual testosterone cyclodextrin (SLT; 2.5 and 5.0 mg, administered three times per day) with testosterone enanthate (TE; 200 mg) given once every 20 days by im injections over a 60-day study period in 63 hypogonadal men. After SLT administration, serum testosterone (T) levels peaked at 20 min and then fell, reaching baseline levels by 360 min. The calculated half-lives were 60.3 +/- 7.5 and 68.8 +/- 5.0 min after a single dose of 2.5 and 5.0 mg SLT, respectively. The mean area under curve (AUC) of serum T was computed over 20-day periods for the 3 treatment groups. The mean net AUC of serum T after TE administration was about 4- and 2-fold higher than that in the 2.5 and 5 mg groups over the last 20 days. Serum estradiol and dihydrotestosterone followed the same pattern as serum T. Serum estradiol to T ratios decreased after T replacement in all 3 groups, whereas serum dihydrotestosterone to T ratios were not significantly changed by T treatment. Suppression of serum LH and FSH levels was more marked in the patients treated with TE than in those given SLT. Similarly, serum sex hormone-binding globulin levels showed significant decreases with androgen replacement only in the TE and SLT 5.0 mg range groups. There were no significant adverse effects based on comprehensive physical examinations, urea, electrolytes, and renal or liver function tests. Hematocrit levels increased in the TE-treated group, but remained slightly lower than baseline levels in the SLT groups. Serum high density lipoprotein cholesterol showed a small, but significant, decrease with time of treatment in all groups. Despite the differences in the AUC of serum T levels achieved by different androgen replacement therapies, all patients showed significant improvements in sexual motivation and performance, with no significant difference between the treatment groups. We conclude that SLT may be a useful addition to the currently available injectable and transdermal delivery systems for treatment of hypogonadal men. Because of the ease of administration, rapid reversibility of effects, and lower AUC of serum T levels achieved compared to those of TE injections, SLT may be especially suitable for treatment of boys with delayed puberty and older men with androgen deficiency.

Administration, Sublingual↗
PubMed1994

Time course of recovery of spermatogenesis and Leydig cell function after cessation of gonadotropin-releasing hormone antagonist treatment in the adult rat.

This study examined the time course of recovery of spermatogenesis and its relationship to the temporal changes in circulating levels of gonadotropin and testosterone (T) and intratesticular T levels after cessation of treatment with a potent GnRH antagonist (GnRH-A). Adult male rats were given a daily sc injection of Nal-Glu-GnRH antagonist (1250 micrograms/kg BW) for 4 weeks and killed in groups of five 0, 1, 2, 3, 4, and 6 weeks after discontinuation of treatment. After cessation of treatment, plasma FSH levels returned to control values by 6 weeks, whereas LH levels returned to control values within 1 week. Both circulating as well as intratesticular levels of T returned to normal levels by 3 and 4 weeks, respectively. Interestingly, a rebound in both FSH and intratesticular T, but not in plasma T, beyond control levels occurred early in the recovery phase. The total volume of Leydig cells, which was only 15% of control values, increased 4.3-fold within 1 week and was not significantly different from control values (92% recovery) by 2 weeks posttreatment. Enumeration of earlier phases of germ cells as well as homogenization-resistant advanced (steps 17-19) spermatids revealed a progressive increase in germ cell numbers with time. Complete restoration of the numbers of preleptotene spermatocytes, pachytene spermatocytes, step 7 spermatids, and advanced spermatids occurred 1, 3, 4, and 6 weeks, respectively, after termination of GnRH-A treatment. There was also a complete reversal of GnRH-A-induced changes in testicular weight, tubule diameter, and volume of seminiferous tubules and their lumens by 6 weeks posttreatment, paralleling the recovery of spermatogenesis. These results suggest that 1) complete recovery of spermatogenesis and various other testicular parameters can be achieved in GnRH-A-treated rats after cessation of treatment; 2) the progression of various germ cells during the recovery period follows the normal time schedule of germ cell development; and 3) the recovery of spermatogenesis is preceded by supranormal levels of FSH and intratesticular T. These findings further emphasize the suitability of antagonistic analogs of GnRH for male fertility control.

Animals↗
PubMed1993

Up-regulation of the levels of androgen receptor and its mRNA by androgens in smooth-muscle cells from rat penis.

Smooth-muscle cells cultured from the penis of sexually immature (I-PSMC) and adult (A-PSMC) rats express similar high levels of the androgen receptor (AR) mRNA. This contrasts with the marked in vivo decline of both AR mRNA and androgen binding in the penile smooth muscle of adult rats, which appears to be responsible for the cessation of androgen-dependent penile growth upon sexual maturation. PSMC is therefore a good model to study putative down-regulators of AR expression as a function of cell proliferation in the smooth muscle of androgen-responsive vascular tissue. In order to determine whether AR protein levels in PSMC correlate with AR mRNA levels, the immunocytochemical detection of ARs and their androgen binding capacity were compared between I- and A-PSMC. The number of ARs and their protein half-lives suggested similar levels of translation of the AR mRNA in both cell lines. The effect of the synthetic analog methyltrienolone (R-1881) on androgen binding was studied in contact-inhibited androgen-deprived PSMC. In contrast to the postulated role of androgens as down-regulators of AR expression in rat penis, ARs were up-regulated in A-PSMC by R-1881. Contact inhibition of A-PSMC combined with serum depletion and androgen deprivation down-regulated AR mRNA levels, and dihydrotestosterone (DHT) counteracted this effect. These results suggest that the loss in A-PSMC of the age-dependent down-regulation of ARs observed in vivo in adult corpora cavernosa smooth muscle is related to the in vitro resumption of cell proliferation and that DHT acts directly on the penile smooth muscle as a positive modulator of AR levels.

Actin Cytoskeleton↗
PubMed1993

Testosterone down-regulates the levels of androgen receptor mRNA in smooth muscle cells from the rat corpora cavernosa via aromatization to estrogens.

Androgens down-regulate the levels of androgen receptors (AR) and AR mRNA in the penis and prostate of castrated rats, and are assumed to cause their decrease during sexual maturation in the penile smooth muscle of intact rats. In order to determine whether these effects occur directly at the target cell level, and to what extent they are due to testosterone (T) or to their metabolites, we have measured AR mRNA in cultures of smooth muscle cells from the adult rat corpora cavernosa treated in vitro with sex steroids. T at high concentrations (100 nM) acted like dihydrotestosterone (DHT) in increasing moderately the levels of AR mRNA in both proliferating and contact-inhibited cells. However, when conversion of T to DHT was blocked by the 5-alpha reductase inhibitor finasteride, the levels of AR mRNA were considerably down-regulated by T (10-500 nM), particularly in the contact-inhibited cells. Finasteride by itself was inactive. These effects in both types of cultures were inhibited by platelet derived growth factor (PDGF) (20 ng/ml), a growth factor that up-regulates AR mRNA levels, and by fadrozole (100 nM), an aromatase inhibitor of the T/estrogen conversion. Estradiol (50 nM) was even more potent than T in decreasing AR mRNA levels. With the exception of PDGF none of the treatments affected significantly cell growth, as measured by DNA synthesis and content. Our results indicate that it is possible to modulate in vitro AR mRNA levels in the penile smooth muscle cells, and that under normal conditions DHT and T act as moderate up-regulators. When DHT formation is inhibited, the aromatization pathway of T to estradiol will prevail and induce a pronounced down-regulation of AR mRNA levels. We assume that the in vivo AR down-regulation in the penile smooth muscle by androgens is an indirect effect mediated by a paracrine or endocrine mechanism elicited in another tissue.

Animals↗
PubMed1993

Leydig cell neoplasia in a patient with Reifenstein syndrome.

We present the rare coincidence of a Leydig cell tumor in both testicles of a patient with partial androgen insensitivity syndrome (PAIS). The clinical picture with perineoscrotal hypospadia, micropenis, gynecomastia and delayed puberty and the serum hormone levels with elevated concentrations of testosterone, luteinising hormone (LH) and follicle-stimulating hormone were entirely consistent with PAIS. Ultimately, the diagnosis was confirmed by determination of genital skin fibroblast androgen receptor binding capacity for 5 beta-dihydrotestosterone, which demonstrated a qualitatively abnormal androgen receptor. At 44 years of age, a nodule in the left testis led to orchidectomy. At that time, the right testis was inconspicuous sonographically. But 3 years later the right testis developed nodules and was removed. Review of testicular histology revealed the presence of Leydig cell hyperplasia (LCH), multifocal nodular hyperplasia and Leydig cell neoplasia (LCN) in both testes. Many micronodules of Leydig cells in transition from hyperplasia to neoplasia were also identified. The simultaneous development of histologically identical nodes of LCN independently from each other and a different sites of both tests indicates the presence of a tumorigenic factor acting on the Leydig cells. Furthermore, the observation of multiple foci of cells in all stages of transition from hyperplasia to neoplasia demonstrates the persistent process of transformation. We speculate, that in this patient the grossly elevated LH levels present over 30 years have enhanced, if not provoked, the formation of LCN. In addition, the defective androgen receptor might have prevented suppressive effects of androgens on the Leydig cells.

Disorders of Sex Development↗
PubMed1993

Temporal and stage-specific changes in spermatogenesis of rat after gonadotropin deprivation by a potent gonadotropin-releasing hormone antagonist treatment.

GnRH antagonists (GnRH-As) rapidly and reversibly inhibit testicular functions in a variety of experimental models as well as man. Their potential for human male contraception is currently being tested in many centers, including our own. This study was undertaken to provide comprehensive quantitative information on the testes and to document the temporal and stage-specific changes in the kinetics of germ cell degeneration in rats treated daily with the Nal-Glu GnRH-A (1250 micrograms/kg body wt) for up to 4 weeks. Plasma levels of testosterone (T) and the concentrations of testicular T declined to 20.7% and 5.4% of control values, respectively, by 1 week and remained suppressed throughout the treatment period. Preleptotene and pachytene spermatocytes, and step-7 and step-19 spermatids at stage VII were the first germ cells to degenerate soon after (1 week) GnRH-A treatment. Germ cell counts at stage VII also revealed a significant (P < 0.05) reduction in number of preleptotene (25.6%), pachytene (35.4%), and step-7 spermatids (29.1%) in comparison with controls. The number of homogenization-resistant advanced spermatids decreased by 70%. A further progressive loss of spermatogenic activity occurred with time. Treatment with GnRH-A for 4 weeks caused advanced spermatids to decline to nearly undetectable, Step-7 spermatids to decline to 17.7% of the normal level, and the P and PL to decline to 28.6% and 67.7%, respectively, of control values. The number of Sertoli cells and A1 spermatogonia remained unchanged throughout the experimental period. The effects of GnRH-A treatment on spermatogenesis were identical to that of hypophysectomy. These results suggest that: 1) early deprivation of gonadotropins and/or intratesticular T by GnRH-A treatment is followed by stage-specific degeneration of germ cells; 2) pituitary secretions other than LH and FSH have little primary influence on spermatogenesis during early regression; and 3) the GnRH-A-treated rat would be an excellent animal model for studying the targeted effects of LH, FSH, and T on the regulation of spermatogenesis.

Animals↗
PubMed1993

Androgen deficiency and aging in men.

Androgen levels decrease with age in men. Androgen deficiency in men older than 65 years leads to asthenia, a decrease in muscle mass, osteoporosis, and a decrease in sexual activity. Androgen deficiency has been reported to cause changes in mood and cognitive function. The combination of these factors results in impaired quality of life in older men. Androgen replacement therapy in hypogonadal men increases bone and muscle mass, enhances muscle and cardiovascular function, and improves sexual function and general well-being; whether elderly men experience benefits of androgen replacement is not known. These benefits have to be weighed against the possible adverse effects of prostate and cardiovascular diseases. Careful long-term studies are needed to assess the risk-to-reward ratios of androgen or other hormone replacement therapy before treatment strategies similar to estrogen therapy for postmenopausal women are implemented.

Aged↗