Metabolic Clearance Rate Of Testosterone Research Articles

Effect of Adrenocorticotropin on Production Rates and Metabolic Clearance Rates of Testosterone and Estradiol*

Using the constant infusion technique, [7-3H]testosterone and [4-l4C]estradiol were infused into six men and two women and [7-3H]androstenedione and [4-l4C]estrone were infused into two men before and after the administration of 60 U ACTH every 12 h for four doses. Measurements of the MCRs, plasma levels of endogenous hormones, and blood production rates (PBs) were performed before and after ACTH. The fraction of infused androgen converted to and measured as estrogen ([ρ]AND,ESTBB) was also determined before and after ACTH. In all six men, ACTH caused a significant rise in the mean value for the MCR of testosterone from 900 ± 80 to 1250 ± 80 (SE) liters/day, a significant decrease in the mean value for levels of testosterone from 5.2 ± 0.9 to 2.0 ± 0.6 ng/ml, and a significant decrease in the PB of testosterone from 4.5 ± 0.5 to 2.3 ± 0.6 mg/day. In both women, MCR of testosterone rose, the plasma levels remained essentially unchanged, and the PBS increased. In the men, ACTH administration resulted in a nonsignificant rise in the MCR of estradiol from 1760 ± 50 to 2010 ± 120 liters/day, and no change in the circulating level (30 ± 2 to 26 ± 2 pg/ml) or the PB (53 ± 4 to 54 ± 6 μg/day). The fractional conversion of testosterone to estradiol, [ρ]T,2BB, did not change (0.0032 ± 0.0006 to 0.0032 ± 0.0004). In both women, the MCR for estradiol rose, but the changes in levels and estradiol PB were divergent. In both men, although the MCRs for androstenedione and estrone did not change appreciably, the circulating levels and PBS rose. The mean level of LH in six men did not change under these conditions (51 ± 11 before and 57 ± 11 ng/ml after ACTH). We conclude that in men, ACTH increases the metabolism of testosterone and decreases its circulating level, synthesis, and production rate. During the course of the study, LH levels did not rise in response to the fall in testosterone. The circulating level and PB of estradiol remain unchanged because ACTH results in increased production of androstenedione and estrone, both of which are converted to estradiol. In women, the PB of testosterone does not fall after ACTH, presumably because of the increased PB of androstenedione.

Inhibition of Testicular Steroids by Antibodies — A Feasible Approach to Male Contraception

The biological and immunological effects of immunisation against testosterone are reviewed and considered in regard to potential applications in male fertility control. In experimental animals active immunization with testosterone causes atrophy of the accessory reproductive glands, loss of sexual activity, increase in gonadotrophins, decrease in metabolic clearance rate of testosterone and prevention of fetal sexual differentiation. These findings can be described as “immunological castration”. Paradoxically, hyperplasia of the Leydig cells with excessively high testosterone levels in circulating blood occurs, while spermatogenesis remains intact. Thus infertility is achieved but at the expense of peripheral actions of testosterone. In addition, in actively immunized animals a high degree of immune complex nephritis is observed. Therefore, although a valuable research tool, immunization with testosterone does not represent a feasible approach to male fertility control.

Pathophysiology of spironolactone-induced gynecomastia.

Peripheral blood levels of testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone and the metabolic clearance rates of testosterone and estradiol, as well as the peripheral conversion of testosterone into estradiol, were measured in 16 patients with hypertension. Six of these patients were treated with spironolactone and developed gynecomastia. The other 10 patients served as control subjects. The blood testosterone level in the spironolactone-treated group (2.7 +/- 0.5 ng/ml) was significantly less (P less than 0.02) than in the control group (4.4 +/- 0.4 ng/ml). On the other hand, blood estradiol levels in the spironolactone group (30 +/- 4 pg/ml) were significantly greater (P less than 0.01) than in the control group (13 +/- 2 pg/ml). These changes were primarily due to significant increases in the metabolic clearance rate of testosterone (P less than 0.02) and in the rate of peripheral conversion of testosterone into estradiol (P less than 0.001) in the spironolactone-treated group. Thus, spironolactone does alter the peripheral metabolism of testosterone resulting in changes in the ratio of testosterone to estradiol, which could contribute to the production of gynecomastia.

Effect of alcohol (ethanol) administration on sex-hormone metabolism in normal men.

To determine whether ethanol per se affects testosterone metabolism, alcohol was administered to normal male volunteers for periods up to four weeks, resulting in an initial dampening of the episodic bursts of testosterone secretion followed by decreases in both the mean plasma concentration and the production rate of testosterone. The volunteers received adequate nutrition and none lost weight during the study, which tended to exclude a nutritional disturbance as the cause of the decreased testosterone levels. The changes in plasma luteinizing hormone suggested both a central (hypothalamus-pituitary) and gonadal effect of alcohol. In addition, alcohol consumption increased the metabolic clearance rate of testosterone in most subjects studied, probably owing to the combined effects of a decreased plasma binding capacity for the androgen and increased hepatic testosterone A-ring reductase activity. These results indicate that alcohol markedly affects testosterone metabolism independently of cirrhosis or nutritional factors.

A Study of the Endocrine Manifestations of Hepatic Cirrhosis

The clinical features and hormonal abnormalities were surveyed in 117 men with cirrhosis of the liver. Compared with healthy men of similar ages, the patients had significantly lower metabolic clearance rates, plasma production rates and total and free levels of testosterone, reduced testosterone responses to human chorionic gonadotrophin stimulation, higher oestradiol, luteinizing hormone and follicle stimulating hormone levels and higher binding capacities of sex steroid binding globulin. The peripheral conversion of testosterone to oestradiol was also found to be significantly increased. However, the metabolic clearance and plasma production rates of oestradiol were not significantly different from those of healthy men. Patients who were severely ill with liver failure and one with haemochromatosis had low levels of luteinizing hormone and follicle stimulating hormone and sub-normal responses to clomiphene and luteinizing hormone-releasing hormone. Higher plasma oestradiol levels were found in patients with gynaecomastia and spider naevi than in those without these signs. However, the clinical features of androgen deficiency—that is, testicular atrophy, impotence and loss of secondary sex hair—were only poorly related to the low testosterone levels, and production rates and longtitudinal studies indicated that the hormonal levels, endocrine features and severity of the liver disease could change independently. It is concluded that the clearance of oestradiol from plasma is not limited by liver disease in all patients, and that reduced degradation of oestrogens is not the initial event in the sequence leading to the hormonal abnormalities of cirrhosis. While gonadotrophin deficiency occurs with liver failure and in some patients with haemo-chromatosis, the more usual findings are of elevated gonadotrophin levels and a poor Leydig cell response to chorionic gonadotrophin. These suggest that the hypo-gonadism is primary in most patients with cirrhosis. The causes of the high oestradiol levels were not discovered. Increased peripheral conversion of precursors to oestradiol or increased testicular secretion of oestradiol are possibilities. The high binding capacities of sex steroid binding globulin were not significantly correlated with either the low testosterone or high oestradiol level and the cause of this abnormality remains uncertain. The low metabolic clearance rates of testosterone appeared to result from the increased plasma protein binding of testosterone. The discrepancies in the expected relationships between the hormone and clinical changes suggest that factors other than those studied are also involved in the genesis of the endocrine features of hepatic cirrhosis.

A Study of the Endocrine Manifestations of Hepatic Cirrhosis

The clinical features and hormonal abnormalities were surveyed in 117 men with cirrhosis of the liver. Compared with healthy men of similar ages, the patients had significantly lower metabolic clearance rates, plasma production rates and total and free levels of testosterone, reduced testosterone responses to human chorionic gonadotrophin stimulation, higher oestradiol, luteinizing hormone and follicle stimulating hormone levels and higher binding capacities of sex steroid binding globulin. The peripheral conversion of testosterone to oestradiol was also found to be significantly increased. However, the metabolic clearance and plasma production rates of oestradiol were not significantly different from those of healthy men. Patients who were severely ill with liver failure and one with haemochromatosis had low levels of luteinizing hormone and follicle stimulating hormone and sub-normal responses to clomiphene and luteinizing hormone-releasing hormone. Higher plasma oestradiol levels were found in patients with gynaecomastia and spider naevi than in those without these signs. However, the clinical features of androgen deficiency--that is, testicular atrophy, impotence and loss of secondary sex hair--were only poorly related to the low testosterone levels, and production rates and longtitudinal studies indicated that the hormonal levels, endocrine features and severity of the liver disease could change independently. It is concluded that the clearance of oestradiol from plasma is not limited by liver disease in all patients, and that reduced degradation of oestrogens is not the initial event in the sequence leading to the hormonal abnormalities of cirrhosis. While gonadotrophin deficiency occurs with liver failure and in some patients with haemochromatosis, the more usual findings are of elevated gonadotrophin levels and a poor Leydig cell response to chorionic gonadotrophin. These suggest that the hypogonadism is primary in most patients with cirrhosis. The causes of the high oestradiol levels were not discovered. Increased peripheral conversion of precursors to oestradiol or increased testicular secretion of oestradiol are possibilities. The high binding capacities of sex steroid binding globulin were not significantly correlated with either the low testosterone or high oestradiol level and the cause of this abnormality remains uncertain. The low metabolic clearance rates of testosterone appeared to result from the increased plasma protein binding of testosterone. The discrepancies in the expected relationships between the hormone and clinical changes suggest that factors other than those studied are also involved in the genesis of the endocrine features of hepatic cirrhosis.

Hormonal studies in Klinefelter's syndrome.

Some aspects of the hormonal abnormalities of Klinefelter's syndrome have been studied in nineteen patients. As a group the plasma production rate, the total and free levels of testosterone, and the metabolic clearance rates of testosterone and oestradiol were low. Plasma oestradiol, LH and FSH levels were elevated and there was increased peripheral conversion of testosterone to oestradiol. The production rates of oestradiol and the binding capacities of the sex steroid binding globulin were normal. There were fluctuations in the blood levels of LH, FSH, testosterone and oestradiol, but these appeared to be less marked than in healthy men. Both LH and FSH levels were suppressed by acute or prolonged testosterone administration and there was no evidence for a differential effect on LH. It is suggested that the threshold for suppression of LH and FSH is increased in hypergonadotrophic states. Although no statistically significant relationships were found between the hormonal and clinical abnormalities of the syndrome it is probable that the hyperoestrogenism and androgen deficiency are linked to the development of the signs of feminization and hypogonadism.

Studies of the relation of plasma androgen levels to androgen action in women

Testosterone-estradiol-binding-globulin (TEBG) is a major determinant of androgen disposition and action. TEBG levels, but not free testosterone levels, correlate with the metabolic clearance rate (MCR) of testosterone in normal women. This suggests that the testosterone MCR reflects androgen removal by the liver, an organ which removes a large fraction of steroid on a single passage, rather than the concentration of unbound androgen. Consequently, testosterone production seems more closely related to androgen catabolism than to androgen action. In support of this concept, we have studied a hirsute woman in whom testosterone clearance and production were elevated in the presence of a normal free testosterone level; her hirsutism seems related to androgens other than testosterone. Although testosterone is of major importance, androgen action seems to result from the net effect of several free plasma 17β-hydroxysteroids, including particularly androstenediol and dihydrotestosterone. About 25% of women with moderate male-pattern hirsutism have normal total and free plasma testosterone levels. In most such cases total 17β-hydroxysteroids are also normal. However, an abnormally low fraction of all these 17β-hydroxysteroids is bound to TEBG. As a result, an increase in the plasma “total androgenicity index” is present in this group of patients. Such women do not necessarily evidence increased testosterone production. Obesity appears to be another important determinant of androgen disposition and action. The testosterone MCR correlates well with adiposity independently of the TEBG levels in normal women. In addition, hyperandrogenism is frequently present with minimal or no hirsutism in obese women. This finding suggests that obesity increases the apparent “threshold” at which hirsutism appears in response to androgen or that obesity is a result of slight hyperandrogenism.

Testosterone secretion and plasma luteinizing hormone concentration during a sexual cycle in the Pekin duck, and after thyroxine treatment

Plasma testosterone and luteinizing hormone concentrations, together with the metabolic elearance rate for testosterone, were measured in Pekin ducks exposed to a natural cycle of day length, to artificial long day lengths, and to treatment with thyroxine. Long day lengths led to increases in testicular size and in plasma testosterone and LH levels. Under natural photoperiods a dissociation was observed between these parameters with the plasma testosterone concentration reaching a peak some months before the time of maximal testicular size and LH concentration. It is suggested that the fall in testosterone concentration, in the absence of a concomitant fall in luteinizing hormone, may reflect (a) an increase in testosterone metabolic clearance rate due to thyroxine, and (b) a decrease in sensitivity of the interstitial cells to LH through the breeding season. Exogenous thyroxine increases the testosterone MCR but has no consistent effect on plasma luteinizing hormone.

Increased steroid metabolic clearance rate in anephric patients.

ABSTRACT The control of plasma aldosterone level depends on the secretion rate and on the metabolic clearance rate (MCR) of the hormone. The rate of aldosterone metabolism was measured in 6 anephric patients in comparison with normal volunteers. Unexpected high aldosterone MCR's were found in the anephric patients: 2700 ± 265 1/24 h (M ± sem), as compared to the normals (1600 ± 57). Passive 45° tilting did not significantly change aldosterone MCR's in both the normal and anephric patients. This increase in aldosterone MCR might be explained by a high hepatic plasma flow due to a high cardiac output. The haemodynamic condition of these patients could also explain the high testosterone MCR found in 3 male anephric patients, although testosterone-oestradiol binding globulin was in the high normal male range.

Thyroid gonadal interactions in the male domestic duck in relationship with the sexual cycle

The annual variations of the plasma testosterone concentrations (PT), and the metabolic clearance rate (MCR) of 3H-testosterone, that permits evaluation of the secretion rate (SR = PT × MCR) of the hormone, have been measured in Pekin ducks reared outdoors. Three salient features were observed: (1) during the progressive phase of the reproductive cycle, there is no close parallelism between the testis weight (spermatogenetic activity) and the SR of testosterone; in 1971–1972 both rhythms followed a particularly asynchronous course; (2) in late May the PT falls down to almost autumnal values when the testis weight is still high; (3) this breakdown of the PT is concomitant with a 80% rise in the MCR of testosterone, which contributes, together with a depressed SR to lower the PT. The two latter events (lowered PT in association with an enhanced MCR) can be reproduced by thyroxine administration (0.1 mg or 1 mg/day over 9 days) either during the vernal progressive phase, or during autumn in ducks photo-stimulated by “long days.” The recently evidenced increase in thyroid function in May–June in ducks reared under similar conditions led to the assumption that a seasonal hyperthyroidism may, at least partially, account for the characteristic pattern of testosterone secretion and metabolism at the onset of the regressive phase of the sexual cycle. The postnuptial molt occurs once this peculiar endocrine balance (hyperthyroidism associated to hypoandrogenism) is fulfilled.

Androgen metabolism in cirrhosis of the liver

Androgen metabolism was studied in male patients with cirrhosis of the liver. The plasma level, metabolic clearance, and production rates of testosterone were decreased while the conversion ratio and rate transport constant of testosterone to androstenedione was increased. Administration of testosterone produced a marked increase in the metabolic clearance rate of testosterone indicating that parenchymal hepatic dysfunction per se was not the cause for the reduced clearance rate. Moreover, the patients were found to have normal testicular reserve for the biosynthesis of testosterone as indicated by an almost fourfold increase in the plasma concentration of testosterone following the administration of human chorionic gonadotropin. These data demonstrate that the reduced production rate of testosterone in male cirrhotics is not due primarily to testicular disease but possibly reflects hypothalamic-pituitary suppression secondary to increased circulating estrogens. The increase in the rate of conversion of testosterone to androstenedione, found in the present study, is consistent with this hypothesis. The present investigation thus provides quantitative data on the hypogonadal state in cirrhosis and suggests possible mechanisms for the alteration in androgen metabolism.

Rabbit testosterone-binding-globulin. II. Effect on androgen metabolism in-vivo.

Sexually mature Fauve de Bourgogne rabbits were investigated to determine the role of Testosterone—Binding—Globulin (R—TeBG) on androgen metabolism. The binding capacity of R—TeBG, determined by polyacrylamide gel electrophoresis, was elevated, and not significantly different in 9 males (3.46 ± 1.22 (SD) μg steroid bound/100 ml) and in 7 females (4.85 ± 2.53). The metabolic clearance rate of testosterone (MCRT) was similar in 6 males (1.63 ± 0.27 (SD) liter/Kg/hr) and 4 females (1.96 d= 0.73). The MCR of androstenedione was 4 times higher than MCRT in both sexes. The MCR of dihydrotestosterone in 2 males and 2 females was equal to MCRT. Plasma concentration and blood production rate of testosterone were: 549 ± 384 (SD) ng/100 ml and 9.62 ± 7.62 M-g/kg/hr, respectively, in males; 22.5 ± 7.1 and 0.48 ± 0.29 in females. A significant correlation (p < 0.05) was found between unbound plasma testosterone and MCRT in males, but not in females. It is concluded that MCRT depends mainly upon specific binding to R—T...

Effets du jeûne et de la castration sur la cinétique du métabolisme de la testosterone chez le Canard

The plasma concentration (PC) of testosterone in the duck, and the metabolic clearance rate (MCR) of the hormone were measured, respectively, by gas chromatography and by a constant infusion procedure of 3H-testosterone, under the following conditions: (1) intact controls, in winter (low gonadal activity) or spring (reproductive period); (2) light-stimulation (18L-6D) in winter; (3) castration in winter or spring; (4) castration in winter, and testosterone treatment (5 mg/day im); (5) light-stimulation in winter, and 17 days' starvation; (6) castration in winter and 17 days' starvation. The MCR of testosterone in intact ducks was found to range between 95 and 120 ml/min/kg, whatever the endogenous testosterone secretion might be. The testosterone production rate (PR = PC x MCR) is 6–7 times higher in light-stimulated winter birds or in spring birds than in control winter birds. The testosterone MCR of light-stimulated ducks is unaffected by chronic starvation. However, starvation inhibits completely the stimulation of testosterone PC and PR in winter birds exposed to “long days.” Castration induces a 50% (winter) to 100% (spring) elevation of the testosterone MCR. Chronic starvation inhibits the increase of testosterone MCR in castrates. A possible involvement of testosterone-thyroid inter-relationships in these results is discussed.

Hyperthyroidism and gynecomastia: metabolic studies.

ABSTRACT The testosterone plasma concentration, metabolic clearance rate of testosterone, sexual binding protein (S.B.P.) concentration and the conversion of iv injected labeled testosterone to urinary androstanediols (androstanediol and 5βandrostanediol) have been evaluated in a hyperthyroid subject with gynecomastia. Results have been compared with those obtained in normal men, in a man treated with estrogen and in a hypogonadal subject. The thyrotoxic state is a very particular condition where, in spite of an elevated S.B.P. concentration, the conversion of testosterone to urinary androstanediol is not reduced. The cutaneous 5α-reductase activity for testosterone, which may be considered as the ratio of potential conversion of percutaneously administered testosterone to the conversion of intravenously injected testosterone to androstanediol, is not very different in the hyperthyroid subject compared to that observed in normal males. Gynecomastia is possibly explained by an elevated concentration of pla...

The effect of medroxyprogesterone acetate on androgen metabolism in the polycystic ovary syndrome.

Medroxyprogesterone acetate was administered to six patients with the polycystic ovary syndrome. The drug resulted in a significant reduction in serum LH, plasma concentration and plasma production rate of testosterone in each patient. In addition, five of the six patients showed a significant increase in the metabolic clearance rate of testosterone. This study also confirms previous findings by others of an increase in serum LH in the syndrome.

Some studies on the biological significance of free testosterone

It is generally admitted that the free, non-protein-bound, hormone fraction represents the biologically active fraction in plasma. As far as testosterone is concerned, there exists some indirect clinical evidence and a few experimental data supporting this hypothesis, but a more direct approach to this problem is hampered by difficulties in estimating the free fraction. Using equilibrium dialysis of diluted plasma and extrapolating the results to undiluted plasma, using a mathematical model, the authors determined the apparent free testosterone concentration (AFTC), which corresponds in first approximation to the free testosterone concentration in vivo. This AFTC was determined in normal adult, (pre)adolescent and hypogonadal males, in male diabetics, as well as in hirsute and pregnant women, and in hyperthyroid patients of both sexes; the values were compared with total plasma testosterone levels. The AFTC in normal males aged 20–50 yr varied between 5.5 and 20 ng/100 ml and decreased with age; this decrease was already significant in the age group 50–70 yr, whereas total testosterone concentration in these subjects was not different from younger adults. In females, the AFTC varied between 0.2 and 0.75 ng/100 ml. In (pre)adolescent males plasma testosterone levels and AFTC increased as a function of sexual maturity, but whereas sometimes adult plasma testosterone levels were already observed before full sexual development was achieved, adult AFTC levels were only obtained in subjects with full sexual maturity. In male hypogonadism, the decrease in AFTC was more pronounced than the decrease in total testosterone. In female hirsutism, plasma testosterone levels and AFTC were variable, but the AFTC was increased more frequently than total plasma testosterone. In pregnancy, whereas plasma testosterone levels were increased, the AFTC was normal or moderately decreased. In hyperthyroidism, finally, plasma testosterone levels were often increased, but the AFTC was normal. The above-mentioned results support the hypothesis that only the free fraction is biologically active. In order to test this hypothesis more directly, the authors investigated whether there exists a parallel between the free fraction and the metabolic clearance rate of testosterone. This was confirmed within the same subject and within a group of subjects of the same sex. Finally a significant correlation was observed between the AFTC and the formation of 5α-androstanediol. As the latter is formed essentially in peripheral target tissues, this suggests that target tissues metabolize only the free non-protein-bound fraction.

Suppression of the pituitary-Leydig cell axis and sebum production in normal men by medroxyprogesterone acetate (provera).

ABSTRACT In four normal men, the pituitary-Leydig cell axis was challenged before and during administration of large doses of medroxyprogesterone acetate (Provera). After 9–10 days of Provera, testosterone production rates decreased from 6.1 to 2.9 mg/day, and a comparable decrease in sebum production was observed. No changes were noted in the metabolic clearance rates of testosterone. Fluoxymesterone given along with Provera resulted in lower plasma testosterone concentrations than obtained by Provera alone, and sebum production was stimulated. When clomiphene (Clomid) was given along with Provera, there was no stimulation of testosterone production, but a striking increase in sebum production, suggesting that Clomid has a direct effect on sebum independent of its usual stimulatory action on LH and testosterone production. Human chorionic gonadotrophin resulted in brisk increases of plasma testosterone concentrations both before and during Provera treatment. Since the suppressive effects of Provera on sebum production could be overcome by exogenous and endogenous androgens, and since steroidogenesis remained intact, it seems unlikely that Provera blocks androgens at their peripheral sites of action. It is thus concluded that the suppressive effect of Provera on the pituitary-Leydig cell axis can be explained entirely by its antigonadotrophic properties.

Human hepatic testosterone A-ring reductase activity: effect of medroxyprogesterone acetate.

ABSTRACT Testosterone A-ring reductase activity was measured in human liver obtained from 6 normal volunteers by aspiration liver biopsy. The base line enzyme activity varied between 62 and 132 nmoles of testosterone metabolized per hr per mg liver protein. Administration of medroxyprogesterone acetate resulted in a 200–500% increase in reductase activity. This was associated with a 28–58% rise in the metabolic clearance rate of testosterone. Medroxyprogesterone acetate appears to increase the metabolic clearance rate of testosterone by raising the A-ring reductase activity.

EFFECT OF ESTROGEN ADMINISTRATION ON ANDROGEN PRODUCTION AND PLASMA LUTEINIZING HORMONE IN HIRSUTE WOMEN

ABSTRACT Large doses of estrogens were given for 10–200 days to 11 hirsute women in an attempt to suppress LH production, and thus androgen production originating from the ovaries. In only 2 of 7 patients did estrogen result in suppression of plasma LH. In the remaining 5 women, LH levels were unchanged, and abnormalities of androgen production persisted. Estrogen treatment was noted to decrease the metabolic clearance rates of testosterone (MCRT) in all 11 patients independent of its effect on testosterone production rate . AS a result, plasma T remained unchanged, increased or decreased, and was an unreliable parameter of the effect of estrogen on testosterone production. No consistent change was noted in MCR of androstenedione (MCRΔ) after estrogen treatment. These studies demonstrate that estrogen administration 1) does not suppress LH in the majority of hirsute women, and 2) alters the peripheral metabolism of testosterone such that measurement of plasma T can lead to erroneous conclusions. The use, ...