Peripheral Metabolism Of Testosterone Research Articles

Serum androgen levels in senescent Cr1:CD-1 (ICR)BR mice: effects of castration and testosterone treatment.

Serum levels of dehydroepiandrosterone, androstenedione, testosterone, and dihydrotestosterone were measured in intact, orchiectomized and orchiectomized-androgen-treated CD-1 mice. Although dehydroepiandrosterone was not detectable in the serum of old mice, approximately half of the very substantial serum concentration of this hormone found in the mature mice appeared to be of adrenal origin. In contrast to dehydroepiandrosterone, serum levels of testosterone and, when detectable, the other androgens, were the same in mature and senescent intact males. Serum levels responded similarly to castration and testosterone replacement. Seminal vesicle weights reflected the similar serum androgen levels found in both age groups. The results indicate that there is neither an age-associated decline in the serum concentration of testosterone nor an apparent alteration in the hepatic and/or peripheral metabolism of testosterone in aging CD-1 male mice.

Diurnal variations in plasma testosterone concentrations in the male lesser mouse lemur (Microcebus murinus).

In 6 isolated adult male lesser mouse lemurs, concentrations of testosterone in plasma were determinated at 6-h intervals over a 24-h period. Blood samples were collected at monthly intervals and for a period of 12 months under natural photoperiod. In this nocturnal prosimian, there were no apparent diurnal changes in testosterone concentrations during the non-breeding season (autumn). During seasonal sexual activity (January-August), diurnal changes in testosterone concentrations were characterized by a significant rise during the light phase. The daily testosterone peak occurred about 8.5 h after sunrise from February to July, but at the beginning (January) or at the end (August) of the breeding season, the daily testosterone peak was displaced to the morning. A circannual testosterone rhythm occurred with the highest testosterone values in May/June and the lowest values 6 months later. The dramatic fall in testosterone concentrations after the summer solstice may be associated with a change in the peripheral metabolism of testosterone.

Testosterone and the incidence of boar taint: Effects of testosterone or testosterone propionate on the incidence of boar taint in implanted barrows

Boars, barrows and barrows implanted with testosterone or testosterone propionate via polydimethylsiloxane (Silastic) capsules were placed on test in individual pens at 10 weeks of age. Each animal was slaughtered at 110 kg and evaluated for growth rate, efficiency of feed utilization, carcass merit and the incidence of objectionable odors (boar taint). Five capsules of testosterone or testosterone propionate were used in barrows since they substantially elevated concentrations of serum testosterone, decreased serum LH and stimulated weights of the accessory sex glands. Large variations within and between litters of pigs were found for performance and carcass traits; thus, the influences of castration and testosterone replacement therapy on these traits were inconclusive. In contrast, the effects of castration and hormone treatment on the incidence of boar taint were more definitive. The incidence of boar taint was relatively high in boars, according to a consumer taste panel. This characteristic odor was appreciably lower in barrows and was not reinstated with either testosterone or testosterone propionate implants. These results suggest that testosterone is not itself responsible for boar taint and that 5α-androstenone, the pheromone most closely associated with boar taint, is not produced by peripheral metabolism of testosterone. Additional studies are warranted to provide insight into the regulation of testicular steroid secretion in the boar and the contribution of these steroids to boar taint and protein anabolism.

Peripheral metabolism of testosterone during the annual reproductive cycle in the male hedgehog, a hibernating mammal

The seasonal cycle of plasma testosterone levels in hedgehogs of midwestern France shows large variations and different successive sequences: a resting period in autumn, an increase during winter in January, continued high levels from midwinter to midsummer that are characterized by an important spring peak, a regular decrease in May–June, a shorter but regular summer peak, and an involution beginning at the end of summer. To elucidate (i) the increase of plasma testosterone levels in January during hibernation and (ii) the regular decrease of plasma testosterone levels in May–June during the activity period, the seasonal cycles of metabolic clearance and production rates of testosterone were studied, using [3H]testosterone in a single injection technique. The rate of peripheral metabolism of testosterone was reduced in autumn but increased in January during hibernation, simultaneously with the endocrine activity of the testis; it was maximum in February–March, then fluctuated but stayed at a high level during spring and summer, and decreased in September. In these hedgehogs there is a clear annual cycle of testosterone production with two maxima, and only the decrease of plasma testosterone levels observed in June can be explained by an increase of the metabolic clearance rate.

Gynecomastia in Men Following Antineoplastic Therapy

\s=b\Six men had painful gynecomastia develop during or following the administration of cytotoxic chemotherapy. Alternative causes of gynecomastia were not delineated in any patient. Sharp increases in levels of plasma follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were noted in five patients. Plasma testosterone concentrations were within or above the normal range in all five patients in whom they were determined. In three patients, plasma estradiol concentrations were modestly increased. One patient was studied prospectively: painful gynecomastia developed at a time when plasma FSH and LH levels were elevated, serum testosterone was decreasing from supranormal to low-normal concentrations, and plasma estradiol was rising to high levels. Plasma prolactin levels were increased in one of four patients in whom they were measured. The mechanisms leading to gynecomastia following cytotoxic chemotherapy were not defined. Damage to germinal epithelium and Leydig cells as well as changes in the peripheral metabolism of testosterone and estrogen may be important. Gynecomastia may occur following cytotoxic chemotherapy and does not necessarily represent recurrent or progressive cancer. (Arch Intern Med 1982;142:511-513) Amenorrhea, oligoazoospermia, disturbances in gonadal ^ estrogen and androgen secretion, and increased plas¬ ma content of gonadotropins are recognized consequences of the administration of cytotoxic drugs.15 Pubertal male subjects have been noted to have gynecomastia develop following the administration of cytotoxic chemotherapy; however, gynecomastia has been thought not to occur in adult men following cytotoxic therapy.6i7 This report de¬ scribes six adults in whom painful gynecomastia developed after cytotoxic therapy. The importance of recognizing this potential complication of cytotoxic chemotherapy is dis¬ cussed. REPORT OF CASES Case 1.—Six months following right orchiectomy and retroperitoneal node dissection for an embryonal carcinoma of the testis, this 19-year-old man had asymptomatic pulmonary metastases develop. Serum content of the beta subunit of human chorionic gonadotropin (/3HCG) was normal and reproductive hormone data were as noted in the Figure. Systemic chemotherapy using cisplatin, vinblastine sulfate, and bleomycin sulfate was initiated and administered monthly for four months. Pulmonary metastases resolved and therapy was discontinued after four months. Six weeks following the administration of the last cycle of chemotherapy, bilateral tender gynecomastia developed. The patient was taking no medications at this time and evaluation for recurrent testis cancer revealed no abnormalities. Sequential reproductive hormone data were obtained during therapy and are depicted in the Figure. The patient has been followed up for 14 months since the onset of gynecomastia. Breast tenderness has diminished but persists and there is no evidence of recurrent testis cancer. Case 2.—One year following left inguinal orchiectomy and retroperitoneal node dissection for an embryonal carcinoma of the testis, this 33-year-old man had asymptomatic pulmonary metastases develop. Serum content of /3HCG was normal. Administra¬ tion of combination chemotherapy (cyclophosphamide, vinblas¬ tine, bleomycin, dactinomycin, and cisplatin[VAB III]) resulted in a complete remission after two months. Maintenance chemother¬ apy (vinblastine, dactinomycin, and cisplatin) was begun and two months later painful enlargement of both breasts developed. Prochlorperazine (30 to 40 mg/mo) and two to four marijuana cigarettes per month were the only other drugs ingested during this time. Complete reevaluation failed to reveal evidence of recurrent testis cancer. Reproductive hormone data obtained are outlined in the Table. Maintenance therapy was completed and the patient remains free of disease years after the initiation of chemotherapy. Breast tenderness has resolved, though palpable breast tissue persists. Case 3.—At age 31, this patient underwent right inguinal orchiectomy and retroperitoneal lymph node dissection for a teratocarcinoma. Gynecomastia and increased urinary excretion of HCG were noted before orchiectomy, and both resolved follow¬ ing lymph node dissection. One and one-half years later, a pulmonary nodule was discovered. Gynecomastia and breast ten¬ derness had returned and the serum concentration of 0HCG was increased. A biopsy specimen of the pulmonary nodule confirmed the presence of teratocarcinoma. Combination chemotherapy (VAB III) was administered in the fashion described in case 2. Breast tenderness resolved over the next two months and the chest roentgenogram returned to normal. However, five months after the initial chemotherapy, pain and further enlargement of both breasts developed. Evaluation did not reveal recurrence of testis cancer. Prochlorperazine (30 to 40 mg/mo) and marijuana (four to six cigarettes per month) were the only other drugs ingested during this time. Reproductive hormone data are out¬ lined in the Table. Maintenance chemotherapy was completed and over the next six months gynecomastia and pain diminished. Three years after the initiation of chemotherapy, the patient is free of testis cancer; mildly painful gynecomastia persists.

Gynecomastia in Men Following Antineoplastic Therapy

Six men had painful gynecomastia develop during or following the administration of cytotoxic chemotherapy. Alternative causes of gynecomastia were not delineated in any patient. Sharp increases in levels of plasma follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were noted in five patients. Plasma testosterone concentrations were within or above the normal range in all five patients in whom they were determined. In three patients, plasma estradiol concentrations were modestly increased. One patient was studied prospectively: painful gynecomastia developed at a time when plasma FSH and LH levels were elevated, serum testosterone was decreasing from supranormal to low-normal concentrations, and plasma estradiol was rising to high levels. Plasma prolactin levels were increased in one of four patients in whom they were measured. The mechanisms leading to gynecomastia following cytotoxic chemotherapy were not defined. Damage to germinal epithelium and Leydig cells as well as changes in the peripheral metabolism of testosterone and estrogen may be important. Gynecomastia may occur following cytotoxic chemotherapy and does not necessarily represent current or progressive cancer.

Métabolisme périphérique de la testostérone en relation avec le cycle annuel de la testostérone et de la 5α-dihydrotestostérone plasmatiques chez le Blaireau européen (Meles meles L.) et le Renard roux (Vulpes vulpes L.)

Seasonal variations in plasma contents of testosterone, 5α-dihydrotestosterone (5α-DHT) and other parameters related to the peripheral metabolism of testosterone have been determined in adult foxes and badgers, in natural climatic conditions.In both species, testosterone reaches peak levels in winter, but whereas the fox takes a sexual break beginning in spring (April), the badger has high concentrations of hormones until the summer. The mean annual concentration of testosterone is four times higher in the badger than in the fox; the annual mean value of 5α-dihydrotestosterone is identical in both species and levels of 5α-DHT are significantly higher during the breeding period.The annual cycle of testosterone peripheral metabolism in the fox is characterized by a decreased rate during summer and fall and an increased rate during winter (breeding period). In the badger, the metabolic clearance rate is high at the end of the fall and at the onset of the breeding period (October to January) and low during the peak reproduction period (February to April) and then increases as the period of sexual break approaches.The annual cycle of testosterone production rate is characterized in both species by a fall or prewinter increase; in the fox, this increase is followed by a decrease at the end of the winter, whereas the badger keeps pretty well the same rate of production until the summer.Seasonal variations of hormone peripheral metabolism are examined and discussed in relation to the fluctuations in testosterone levels and the hormone-specific protein linkage capacity.[Journal Translation]

17β-hydroxysteroid dehydrogenase activity in the mucosa of rat and human small intestine

Although circulating plasma concentrations of androgens are determined in pan by peripheral interconversion in a variety of non-endocrine tissues, the role of the gastrointestinal tract in the peripheral metabolism of testosterone has not been established. Oxidation of testosterone to androstenedione was the predominant conversion by homogenates of rat and human small intestinal mucosa. Reduction of testosterone was not observed. The conversion of testosterone to androstenedione was independent of intestinal bacteria since it was effected by homogenates of germ-free rat jejunal mucosa. The conversion conformed to the kinetics of an enzyme-mediated reaction, with an apparent Michaelis constant for testosterone of 2.8 × 10 −6 M. Assay conditions for the enzyme responsible for this conversion, 17β-hydroxysteroid dehydrogenase (17β-HSD; E.C. 1.1.1.51) were determined. Specific activity of 17β-HSD in the intestinal mucosa was similar to testis and lung but greater than skeletal muscle or ventral prostate. The estimated total 17β-HSD capacity of the rat small intestinal mucosa was considerably greater than both testis and lung, suggesting that the small intestine may make significant contribution to the peripheral oxidative metabolism of testosterone. In addition, the high specific activity of 17β-HSD in the small intestinal mucosa may be an important factor leading to testosterone's lack of oral potency.

Peripheral metabolism of testosterone during puberty in the male guinea-pig.

Variations in the metabolic clearance rate and the production rate of testosterone during puberty in the male guinea-pig were established by single injection and constant infusion methods. Similar results were obtained; MCR (1/24h) increases from Day 20 to Day 70 and then stabilizes between Days 70 and 90 to levels comparable to those of a 6-month-old adult. MCR as 1/24 h/100 g decreases steadily between Days 20 and 60. The evolution of the testosterone production rate (PR: ng/24 h) is characterized by a marked rise between Days 20 and 70, and then a decrease up to Day 90, continuing until 6 months. PR as ng/24 h/100 g increases between Days 20 and 40, remains stable until Day 70, then decreases. Testosterone half-life is stable throughout the pubertal period. The rate of conversion of testosterone to androstenedione remains stable except for a rise between Days 50 and 60. We conclude that the increase in testosterone concentrations during puberty is due to a rise in the production rate and not to a decrease of clearance rate.

The effect of flutamide on testosterone metabolism and the plasma levels of androgens and gonadotropins.

Flutamide, a nonsteroidal antiandrogen, was given to 11 men with prostate cancer, in doses of 750 to 1500 mg daily for 0.5--7 months. Four patients had a clinical remission and seven showed no response. All the patients showed a profound change in the peripheral metabolism of testosterone: markedly increased conversion to androsterone (A) and correspondingly decreased conversion to etiocholanolone (E); the A/E ratio rose to levels never before observed consistently in any group of healthy or diseased humans. This change was probably due to alteration by flutamide of the relative activities of steroid 5alpha and 5beta reductase in favor of the former. 24-Hour mean plasma testosterone was increased in five of the six patients studied for this parameter, for the group as a whole, testosterone rose from 279 ng/dl to 484 ng/dl (P less than .05). 24-Hour mean values for plasma dihydrotestosterone, dehydroisoandrosterone, LH and FSH showed no significant change, for the group as a whole, in the same six patients. Since flutamide did not change the metabolic clearance rate or volume of distribution of testosterone tracers, the increased plasma levels of the hormone were probably due to increased production.

Biochemical determinants in Gender identity.

The purpose of this communication is to report cognate studies which suggest that the nature of the peripheral metabolism of testosterone may impart gender direction to thought construction and motive. In patients with the complete testicular feminizing syndrome [4], the XO/XY syndrome [4], female trans-sexualism [4] and testicular agenesis [5] HCG-tests of 3 days duration were performed, and plasma and urinary testosterone, urinary excretion of 5 alpha-androstane, 3 alpha, 17 beta-diol (5 alpha-diol), 5 beta-androstane, 3 alpha, 17 beta-diol (5 beta-diol) and epiandrosterone before and after stimulation were measured. In addition steroid transformation was examined by incubation studies with human fetal brain tissue. The results of the latter method presented here are in agreement with published work. It seems clear therefore that the peripheral levels of androgens, oestrogens and their metabolites combine with cerebral steroid transformation, metabolism and possible also synthesis in order to establish gender identity. Exploration of the role of peripheral hormones as stimulators of both gender identity and gender function has dictated the need for a new approach to therapy for gender abnormalities in psyche and soma.

The influence of age and sex on the metabolism of testosterone.

The influence of age and sex on the peripheral metabolism of testosterone was studied by giving intravenous tracers of 14C-testosterone to 21 prepubertal children (13 boys and 8 girls), 39 young adults 18-43 years old (23 men and 16 women), and 10 elderly adults 68-86 years old (6 men and 4 women). Studies were also carried out in 2 sexually immature young adults, one 18-year-old 45 XO phenotypic female with gonadal agenesis and one 18-year-old 45 XO, 46 XX mosaic female with gonadal dysgenesis; the latter was restudied after prolonged estrogen-progestagen therapy. Age and sex influences were observed only with respect to the androsterone/etiocholanolone (A/E) ratio; a sex difference in diol metabolite formation was not observed. Prepubertal children showed no sex difference in A/E ratio, which averaged 1.7 +/- 0.28 in boys and 1.9 +/- 0.42 in girls. Young adult men showed a slightly lower A/E ratio, averaging 1.5 +/- 0.10, while females showed a much greater decrease in A/E ratio, to 0.9 +/- 0.09, so that there was a highly significant (P less than .001) sex difference in this age group. The decreased averages were due to disappearance of the higher end of the ranges seen in prepubertal children; the lower limit of the ranges remained the same. Elderly adult men showed a further fall in the A/E ratio, to 1.0 +/- 0.11, and elderly women also showed a further fall, to 0.4 +/- 0.04; a highly significant (P less than .005) sex difference remained. Once again, the fall in average A/E ratio from young adults to elderly adults was due to disappearance of the higher end of the ranges in the former, the lower limits of the ranges were the same in both groups. Of the 2 sexually immature young women, one showed an A/E ratio of 1.3, just below the upper limit for young adult women, and the other showed a ratio of 1.8, well above that limit and thus typical of prepubertal girls. Estrogen-progestagen therapy of the second girl decreased the A/E ratio to 1.4, the upper limit for young adult women. It was concluded that there is a fundamental aging effect in both sexes which causes a gradual progressive decrease of the mean A/E ratio as a result of progressive disappearance of the higher individual A/E values while the lower end of the range of values remains constant; superimposed on this gradual decrease is an acute pubertal decrease in females, probably mediated by the development of the estrogen-progestagen milieu characteristic of sexually mature women.