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J Rajfer

Publications and source records attributed to J Rajfer.

At least 145 records · Page 8Linked to original sources
PubMed1986

Hormonal effects of ketoconazole in vivo in the male rat: mechanism of action.

Ketoconazole, an antifungal agent, has been shown to lower serum testosterone (T) in man. Measurements of circulating precursors of T suggest that ketoconazole may inhibit 17,20-desmolase activity in the testis. To further elucidate its mechanism of action in vivo, we studied its effects on the pituitary-gonadal axis in the male rate. Two groups of normal male Sprague-Dawley rats were treated with either oil or 25 mg ketoconazole in oil by im injection every 8 h for 21 days. Serum ketoconazole concentrations in the rat 2 h after the 25-mg dose were similar to those after oral administration of a much lower (1/33rd) dose to man. Ketoconazole treatment led to 50% suppression of serum T and prostate and seminal vesicle weights. Testis weights were not significantly affected. Intratesticular T concentrations showed a 50% decrease below the control level. Testicular 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase activities in the ketoconazole-treated animals were significantly decreased in proportion to the decreases in serum and intratesticular T concentrations. Elevations of serum LH and FSH concentrations in the ketoconazole-treated rats were not proportionate to the decline in serum T concentration. Therefore, to exclude an additional inhibitory effect of ketoconazole at the pituitary level, we treated two groups of castrated male Sprague-Dawley rats with the same dose of ketoconazole or oil for 3 days. Serum LH and FSH concentrations were not significantly different in the two groups. In separate experiments, combined treatment of intact rats with GnRH agonist and ketoconazole for 21 days led to lower mean serum T concentrations and accessory organ weights than those achieved with either agent alone. We conclude that ketoconazole inhibits T synthesis, primarily by inhibiting the activity of multiple enzymes in the T biosynthetic pathway and has no direct effect at the pituitary level; ketoconazole metabolism in the rat is considerably different from that in man; and ketoconazole enhances the inhibitory effects of GnRH agonist.

Aldehyde-Lyases↗
PubMed1986

Mechanism of inhibition of human testicular steroidogenesis by oral ketoconazole.

To determine the antisteroidogenic effect of ketoconazole (KTZ) in the human testis, we measured the plasma delta 5-pregnenolone, delta 5-17 alpha-hydroxypregnenolone, dehydroepiandrosterone (DHEA), progesterone, 17 alpha-hydroxyprogesterone, androstenedione (A), and testosterone (T) concentrations in three men with previously untreated metastatic prostate cancer at various time intervals for 24 h before and 48 h after the administration of 200 mg oral KTZ every 8 h. The adrenal glands of these three patients were suppressed (as measured by the plasma cortisol levels) by the administration of 1.0 mg dexamethasone daily for 7 days before and during the study. After six doses of KTZ, bilateral orchiectomy was performed, and the intratesticular concentration of the aforementioned seven steroids and the intratesticular activities of the 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase enzymes in the delta 4-steroidogenic pathway were determined. These seven intratesticular steroids and three intratesticular enzyme activities were compared to those in five men with previously untreated prostate cancer who underwent orchiectomy as primary treatment for their disease. Plasma A, DHEA, and T all significantly decreased during KTZ therapy. There was no significant change in the other four steroids in the plasma. In the testis, delta 5-pregnenolone, delta 5-17 alpha-hydroxypregnenolone, and delta 4-17 alpha-hydroxyprogesterone were all significantly elevated, whereas intratesticular DHEA, A, and T were significantly decreased in the three KTZ-treated patients compared to levels in the five non-KTZ-treated patients. Measurement of the enzyme activities demonstrated a significant reduction in both 17 alpha-hydroxylase and 17,20-desmolase, but no change in 17 beta-hydroxysteroid dehydrogenase, in the KTZ-treated patients compared to the levels in the non-KTZ-treated patients. We conclude that oral KTZ decreases testicular T production by inhibiting the 17,20-desmolase and also the 17 alpha-hydroxylase steps in both the delta 4- and delta 5-T biosynthetic pathways.

Administration, Oral↗
PubMed1985

Assay system for simultaneous measurement of three steroidogenic enzyme activities in rat and human testis--effect of human chorionic gonadotropin.

An assay system that measures the enzymatic activities (17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase) in the delta 4 pathway of testosterone biosynthesis using rat and human testicular homogenate was examined. This system involves the simultaneous separation of the steroid intermediates by a three-step TLC procedure. The observed Rf values were 0.78 for progesterone (P), 0.59 for 17 alpha-hydroxyprogesterone (17 alpha-HP), 0.70 for androstenedione (A), 0.5 for testosterone, 0.64 for dihydrotestosterone, and 0.45 for 3 alpha, 17 beta-androstanediol. The identification of these steroid intermediates was further accomplished by acetylation and rechromatography of the representative samples along with the authentic standards and by recrystallization to constant specific activity until three consecutive crystallizations were within +/- 5% of the mean value. Incubation time up to 30 min and increasing protein concentrations showed a linear relationship with respect to these three enzymatic activities. The optimum temperature for these enzymatic activities varied from 32 to 34 degrees C, with a sharp decline between 37 and 40 degrees C. The Michaelis constants (Km) for the rat testis homogenate samples were 0.17 microM for P, 0.22 microM for 17 alpha-HP, and 2.5 microM for A, while for the human testis the Km values were 1.2, 2.2, and 2.3 microM, respectively, for these substrates. The concentrations of the endogenous steroid substrates present in these homogenate samples did not alter the Km or Vmax values. The effect of human chorionic gonadotropin (hCG) in vitro on these steroidogenic enzyme activities was also studied. In the rat testis, 10 IU of hCG produced a significant rise in all the three enzyme activities whereas in the human testis 10 and 30 IU of hCG showed no significant change in any of these enzymatic activities. However, 100 IU of hCG resulted in a significant increase in 17 alpha-hydroxylase and 17,20-desmolase activities in the human testis. These studies suggest that this assay system for the measurement of these enzymatic activities using a testicular homogenate sample provides consistent and reproducible results. Based on the sensitivities of the measurements and our experience with testicular biopsy technique, we conclude that a routine testicular biopsy in the human should provide sufficient tissue to run these enzymatic assays.

17-Hydroxysteroid Dehydrogenases↗
PubMed1985

Impaired testosterone biosynthesis in cryptorchidism.

In an attempt to determine whether the production and synthesis of testosterone (T) by the testis is impaired by the cryptorchid state, the ability of the cryptorchid rat testis to form T was assessed at various time periods into adulthood after the surgical induction of cryptorchidism in the newborn period. The intratesticular T content of the descended testis rose from 0.3 ng/testis at 14 days of age to 71.2 ng/testis at adulthood (day 56); whereas in the cryptorchid testis, the values were 0.4 ng/testis and 2.0 ng/testis, respectively, at the same ages (P less than 0.001). For determination of the site of inhibition of T biosynthesis in the cryptorchid testis, the enzymatic activities (17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase) in the delta 4T biosynthetic pathway were measured. All these enzyme activities in the cryptorchid testis were inhibited at 56 days of age by about 80% when compared with the descended testis (P less than 0.01). These data suggest that cryptorchidism exerts a deleterious effect on the ability of the Leydig cells to synthesize T and may in part explain the abnormal morphology and resultant infertility seen in patients with cryptorchidism.

17-Hydroxysteroid Dehydrogenases↗
PubMed1985

In vitro inhibition of testosterone biosynthesis by ketoconazole.

Oral ketoconazole has been demonstrated to lower plasma testosterone in man. Measurement of blood precursors of testosterone suggest that ketoconazole may have its effect inhibiting the 17,20-desmolase enzyme within the testis. To substantiate this, a series of in vitro experiments was conducted using the rat testis to determine where in the testosterone biosynthetic pathway ketoconazole has its effect. To accomplish this, an assay system to measure 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase activities involved in the delta 4-testosterone biosynthetic pathway was developed. It was demonstrated from dose-response and time-course experiments that a dose of approximately 10 micrograms/ml ketoconazole was sufficient to inhibit in vitro testicular steroidogenesis. Using dosages between 10 and 300 micrograms/ml ketoconazole, a marked inhibition of both the 17 alpha-hydroxylase and the 17,20-desmolase activities occurred. Ketoconazole under these conditions had no effect on 17 beta-hydroxysteroid dehydrogenase activity. Ketoconazole also inhibited the increased activity of these enzymes induced by hCG (1 IU). These data confirm the observation that in vitro ketoconazole has a direct inhibitory effect on 17,20-desmolase activity. These results further suggest that ketoconazole has more than one site of action in inhibiting testosterone biosynthesis in the testis and may indeed be a suitable agent for the treatment of patients with disseminated prostate cancer.

17-Hydroxysteroid Dehydrogenases↗
PubMed1985

UCLA conference. Infertility in the male.

Male infertility is a common and distressing problem in which reproductive abnormalities frequently play an important role. Assessment requires an understanding of the control of spermatogenesis and factors responsible for normal sperm function. Standard tests for assessment of semen quality frequently fail to detect impaired function, but newer tests are now available to measure sperm movement and their ability to penetrate the ovum. Algorithmic approaches based on laboratory data can be used to characterize subgroups of infertile men, but many patients have subtle abnormalities. Treatment of male infertility is ideally directed to a specific pathogenic mechanism; nonspecific therapies have produced disappointing results. Surgery is indicated for certain types of ductal obstruction, but whether internal spermatic vein ligation should be used to treat varicocele remains uncertain.

Acrosome↗
PubMed1985

Recurrent respiratory disease, azoospermia, and nasal polyposis. A syndrome that mimics cystic fibrosis and immotile cilia syndrome.

Three adult men with chronic sinopulmonary disease, nasal polyposis, and azoospermia were studied. All had normal sweat chloride values and pancreatic function. The azoospermia was due to a block in the epididymis that was distinguishable from the defect in the vas deferens seen in cystic fibrosis. Cilia structure was normal in sperm tails from testicular biopsy specimens and in cilia from tracheal biopsy specimens. These cases represent a clinical entity distinct from cystic fibrosis and known immotile cilia disorders.

Adult↗
PubMed1984

Testicular histology following chronic gonadotropin-releasing hormone agonist treatment.

The histologic appearance of the testes of men exposed to chronic gonadotropin-releasing hormone agonist (GnRH-A) therapy has not been previously documented. Herein, we report on the histologic features of the testes of four patients with disseminated prostatic carcinoma who received at least 1 year of daily treatment with (D-Leu6, des-Gly-NH2(10), proethylamide9)-GnRH (leuprolide, Abbott Laboratories, North Chicago, IL) for their disease, and subsequently underwent bilateral orchiectomy. In marked contrast to the testes from five control patients, the testes of these agonist-treated patients demonstrated absence of spermatogenesis, Leydig cell hypoplasia, and Leydig cell inactivity. These data provide direct histologic evidence that the chronic administration of GnRH agonists may be suitable as a potential male contraceptive.

Aged↗
PubMed1984

Silicate urolithiasis.

Urinary tract silicate calculi are rare. Occurrence is limited strictly to patients who ingest magnesium trisilicate antacids. We report a case of a renal silicate calculus and review the subject of silicate stones.

Adolescent↗
PubMed1984

Role of the gubernaculum and intraabdominal pressure in the process of testicular descent.

In an attempt to more accurately define the role of the gubernaculum in the descent of the testis, a series of microsurgical procedures was performed in the newborn rat and the incidence of testicular descent was noted 4 weeks later. When the proximal attachment of the gubernaculum to the testis/epididymis was severed, descent occurred in 17 of 17 (100 per cent) of the testes. When the distal attachment of the gubernaculum to the scrotum was severed, 0 of 10 (0 per cent) of the testes descended. When the entire gubernaculum was removed, 0 of 18 (0 per cent) of the testes descended. When the gubernaculum on 1 side and the testis on the contralateral side were both excised, the solitary testis descended into the contralateral hemiscrotum in 34 of 45 (76 per cent) animals. When 1 testis was excised and only the attachment between the contralateral testis and its gubernaculum was severed, the solitary testis was capable of descending into either hemiscrotum. When 1 gubernaculum was completely excised leaving both testes and a solitary gubernaculum present, either 1 or both testes were capable of descending into the hemiscrotum containing the intact gubernaculum. In addition, if a testis was excised prior to normal testicular descent and a silicone prosthesis was placed intraabdominally, the prosthesis was capable of migrating into the scrotum 55 per cent (11 of 20) of the time. These data suggest that in the rat, 1) the gubernaculum with an intact distal attachment is a necessary prerequisite for testicular descent, 2) contraction of the gubernaculum is most likely not the mechanism by which testicular descent occurs and 3) intraabdominal pressure appears to play a major role in testicular descent.

Abdomen↗
PubMed1984

Effects of chronic D-Leu6, des-Gly10-gonadotropin releasing hormone ethylamide on male sex tissues.

The chronic administration of superactive agonists of gonadotropin releasing hormone (GnRH-A) have been reported to have a direct inhibitory effect on the sex tissues of the male rat. In an attempt to confirm or refute this statement, adult male rats were either left intact or were castrated and then treated daily for 14 days with either testosterone (T), dihydrotestosterone (DHT) or sesame oil (vehicle). Half of the intact and castrate animals also received daily injections of 200 ng of the GnRH agonist, D-Leu6, des-Gly10-GnRH ethylamide for 14 days. Twenty-four hours after completing treatment, blood levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and T were measured by radioimmunoassay and the ventral prostate gland (VP), seminal vesicle (SV) and penis were weighed. After 2 weeks of GnRH-A treatment, the plasma T level was reduced from 2506 +/- 170 (pg/ml +/- SEM) in the intact, nontreated animals to 907 +/- 69 in the intact, GnRH-A-treated group, indicating that the dosage of GnRH-A used in this study had an inhibiting effect on T secretion. No differences were observed in the VP, SV and penile weights between the castrate, GnRH-A and the castrate, nontreated groups. When exogenous T or DHT was given for 14 days to these castrated animals, the concomitant administration of GnRH-A did not appear to have any effect on the plasma T levels or the sex accessory tissue weights. These data suggest that GnRH-A itself does not appear to have a direct inhibitory or stimulatory effect on the sex tissues of the adult male rat.

Animals↗
PubMed1984

Interstitial Tamm-Horsfall protein in rejecting renal allografts. Identification and morphologic pattern of injury.

In a study of renal allografts with acute rejection primarily or exclusively of the cellular type, extratubular Tamm-Horsfall protein was identified in 63.6% of the specimens, representing 76.1% of the patients whose tissues were examined. There was no evidence of extrarenal obstruction in any patient. This high incidence has not been previously reported. A pattern of development of this phenomenon was determined using combined light and electron microscopies and specific anti-Tamm-Horsfall antiserum. Interstitial lymphocytes and monocytes infiltrated into the walls of tubules causing disruptions of basement membranes, thereby creating free communications between lumina and interstitium. In distal tubules with casts, the matrices extended into the interstitium where they were admixed with leukocytes and few erythrocytes. In a small number of specimens, polyps of Tamm-Horsfall protein were identified in veins or interstitial capillaries. Extratubular Tamm-Horsfall protein was not associated with diminished graft survival. These findings delineate, in detail, one of several mechanisms of escape of Tamm-Horsfall protein from tubules into the interstitium; they may be applicable for the genesis of this abnormality in other forms of acute interstitial nephritis.

Biopsy, Needle↗
PubMed1983

Effect of GnRH superactive analogs (alone and combined with androgen) on testicular function in man and experimental animals.

GnRH long acting agonists, when given chronically, are potent inhibitors of testicular function in both man and experimental animals. Administration of these agents to male rats and to men results in suppression of testosterone secretion and diminished sperm counts. Despite the similarity of these observations the mechanisms by which these agents effect the testes appear to be different in the two species. In man GnRH analogs have an early stimulatory effect on LH and FSH secretion with down regulation evident by the 10th day of daily treatment. Longer treatment results in suppressed LH, FSH and testosterone levels. In the rat the stimulatory phase of GnRH analogs on LH and FSH secretion persisted for a much longer period of time (20-60 days). In the rat, direct testicular effects of analogue were the most likely cause of early suppression of testosterone and impaired sperm production. In both species combined testosterone and GnRH analog had additive effects on gonadotropin hormone suppression; combined therapy is being tested as a male contraceptive regimen.

Animals↗
PubMed1983

Urethral reconstruction before renal transplantation.

Herein we report the first case of reconstruction of a long-standing transected proximal urethra, following a pelvic fracture and resultant rectourethral fistula before renal transplantation. This case supports the viewpoint that before creation of a supravesical diversion in potential transplant patients with lower urinary tract dysfunction, reconstruction of the lower urinary tract should be attempted when there is a reasonable chance for successful outcome.

Follow-Up Studies↗
PubMed1983

The use of computerized tomography scanning to localize the impalpable testis.

To determine the usefulness of computerized tomography scanning in the preoperative localization of the impalpable undescended testis 5 patients with 8 impalpable testes were studied. In 2 patients the scan correctly outlined 3 impalpable testes inside the internal inguinal ring, in 2 patients the scan correctly localized 4 impalpable testes at or just inside the external inguinal ring and in 1 patient the scan failed to demonstrate a testis, a finding corroborated at an operation. These results suggest that computerized tomography scanning appears to be an effective, simple and less hazardous method to localize impalpable undescended testes than other currently available techniques.

Adolescent↗
PubMed1983

Synergy of abdominal pressure and androgens in testicular descent.

The potential synergistic activity between intra-abdominal pressure and androgens in facilitating testicular descent was investigated in the rat. In the rat, the testis normally descends on or about the 21st day of age. If one testis is excised at 14 days of age and replaced by a silicone prosthesis, the silicone prosthesis will descend into the scrotum in approximately 11/20 (55%) of the animals by 28 days of age. If both testes are excised at 14 days of age and a solitary silicone prosthesis is then placed into the abdominal cavity, the prosthesis will descend into the scrotum in approximately 4/18 (22%) of the animals. However, if both testes are excised at 14 days of age and a silicone prosthesis is placed into the abdominal cavity but the animals are treated daily from Day 14 to Day 27 of age with 2 mg of dihydrotestosterone, the prosthesis will at 28 days of age descend into the scrotum in 10/16 (63%) of the animals treated. These data suggest that: 1) androgens do not appear to be solely responsible for testicular descent in the rat; 2) another mechanism such as intra-abdominal pressure may be operative in facilitating testicular descent in this animal species; and 3) there may be some synergism between androgens and intra-abdominal pressure in promoting testicular descent.

Abdomen↗