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Rat oral mucosa microsomal Δ 4-3-ketosteroid-5α-A-ring reductase enzyme system, reducing testosterone and 4-androstenedione, was found to be inducible by systemic administration of medroxyprogesterone acetate (MPA). MPA, when used in a mixture with testosterone and/ or 4-androstenedione in vitro, acted as a competitive inhibitor of the reduction of these substrates.

In vitro incubation of 7α-3H-testosterone with crushed mandibular bone of castrated male rats shows that the steroid is converted to both androgenic and estrogenicmetabolites. The metabolism to androgens is characterized by formation of Sa-and 5β-reduced compounds. The principal estrogens identified are estradiol and estriol. This study suggests that bonehas the capacity to convert androgens to estrogens. (Endocrinology 94: 325, 1974)

In vivo immune clearance of immunoglobulin G sensitized autologous erythrocytes (rbc) was studied in nine patients who fulfilled American Rheumatism Association (ARA) criteria for systemic lupus erythematosus (SLE). Opsonized rbc were radiolabelled with technetium 99. The rate of radioactive blood clearance was measured, as was organ-specific radioactive uptake utilizing area-of-interest (AOI) measurements in a computerized scintigraphic imaging system. It was shown that dynamic quantitation of an AOI corresponding to the heart generated time-activity curves which approximated blood-clearance curves. Calculation of first order clearance (min per 50% decrease in counts) showed a highly significant correlation between rates derived from heart AOI curves and those derived from blood-clearance curves (r = 0.9483, P = 0.0003). Clearance curves showed a monoexponential slope in most patients. Further exploration of organ-specific AOI curves showed that percent splenic uptake and the nature of the splenic uptake curves varied between patients. These studies point toward a variable splenic role in Fc receptor function for SLE patients and further demonstrate the utility of nuclear imaging in studying immune clearance.

Oral administration of medroxyprogesterone acetate to 4 normal male and 3 normal female subjects was found to produce a significant increase in the metabolic clearance rate of testosterone in 6 of the 7 subjects. The plasma levels and production rates of testosterone decreased markedly in the males. The females tended to show a decrease in the plasma concentration of testosterone with no change in the production rate of the steroid. Although there was an over-all decrease in the percentage binding of testosterone for the group, individual responses were variable in degree and did not necessarily correlate with the alterations in the metabolic clearance rate of the steroid. Plasma LH levels fell during the administration of medroxyprogesterone acetate in 6 of the 7 subjects. Plasma FSH, however, decreased in only 1 subject (postmenopausal female). Medroxyprogesterone acetate increased rat hepatic testosterone A-ring reductase activity almost 4-fold. Moreover, the drug interfered with the growth-pr...

SummaryRabbits treated with D-L penicillamine for 28 days prior to intravenous injection of I131 labeled human serum albumin showed accelerated elimination of the antigen and correspondingly earlier appearance of free antibody, as compared with control animals. Graphic analysis of the radioactive clearance data indicates that the length of the induction period preceding antibody synthesis was shortened. Once immunity commenced, the slopes of the disappearance curves of both experimental and control group were parallel, suggesting no change in the rate of antibody production.

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.

Within 3 hr after the intraperitoneal administration of hydrocortisone to female rats, a new leucine-accepting tRNA and a new leucyl-tRNA synthetase activity appear in the liver cytosol. The new isoaccepting tRNA can be acylated only with the synthetase derived from livers of hormone-treated animals. Both components are transient; by 12 hr after hydrocortisone administration, the isoaccepting tRNA and its synthetase disappear from livers of treated animals.

Male alcoholics often suffer from features of hypogonadism related to abnormal metabolism of sex steroids. Since the activity of testosterone reductases is rate limiting for testosterone metabolism in the liver, the effect of prolonged ethanol consumption by rats and human volunteers on the activities of these microsomal and cytosolic enzymes was studied. In rats, long-term ethanol ingestion doubled microsomal 5alpha-testosterone reductase activity, a major pathway for testosterone metabolism, while in human volunteers the activity was increased two- to fivefold. These changes may play a role in the altered androgenic activity of the chronic alcoholic.

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.

Administration of hydrocortisone causes two- to fourfold increase in the level of activity of tryptophan pyrrolase in human liver, as measured in needle-biopsy specimens. Correlation of the higher levels of the enzyme with the amounts of urinary kynurenine suggests that the tryptophan pyrrolase level, which is regulated by adrenocortical hormones, may be the important variable in the increased excretion of tryptophan metabolites that accompanies various diseases.

Administration of medroxyprogesterone acetate (MPA) to castrated male rats inhibited the testosterone mediated growth of prostate and seminal vesicle. MPA, however, failed to increase the activity of testosterone A-ring reductase in the prostate in contrast to its marked inductive effect on the liver enzyme. MPA treatment caused a diminished uptake of radioactivity by the prostate and seminal vesicle in vivo after a single injection of 3H-testosterone, as well as, a lower plasma level of the labeled hormone. However, in vitro incubation of prostatic tissue derived from MPA treated rats with 3H-testosterone showed no local interference with the uptake of radioactivity. It appears, that the anti-androgenic effect of MPA can be explained on the basis of induction of hepatic testosterone reductase activity which in turn increases the catabolism of the hormone, leading to its lower plasma concentration and consequently to a lower target tissue uptake of testosterone. (Endocrinology 93: 417, 1973)

SummaryRabbits treated with D-L peni-cillamine beginning one day prior to intravenous injection of I131 labeled human serum albumin showed suppression of the immune response. Two-thirds of the animals completely failed to undergo immune elimination of the antigen and to form circulating antibody. The remaining ⅓ of the animals in which immunity did occur exhibited retardation of the onset of antibody synthesis. This observation contrasts with an earlier study in which the drug, if administered for 28 days before sensitization, resulted in accelerated onset of immune responsiveness.

Administration of medroxyprogesterone acetate (MPA) to male rats causes a significant (2-3-fold) increase in the activity of hepatic testosterone A-ring reductase. This was demonstrated by employing assays that measured an increase in disappearance of testosterone and/ or an increase in its reduced metabolites. Progesterone and its derivatives were also capable of increasing the reductase activity. Fasting or fed state, castration or adrenalectomy did not interfere with the effect of MPA, nor did the administration of phenobarbital or cortisol cause a rise in the reductase level. MPA also significantly increased the rate of reduction of Δ4-androstenedione, cortisol, progesterone and MPA itself (all Δ4-3-ketosteroids) when used as substrates in vitro. Cytoplasmic fractionation revealed that the MPA stimulated increase in reductase activity is restricted to the microsomes, indicating that only the Sa-oxidoreductase activity is affected. Simultaneous administration of actinomycin-D with MPA resulted in a com...

6α-Hydroxycortisol was found to have a cortisol-like activity in inducing rat hepatic tryptophan oxygenase. 6β-Hydroxycortisol was without this effect. Neither 6β-hydroxycortisol nor o,p'-DDD had any cortisol inhibitory activity in this enzyme system. (Endocrinology 83: 384, 1968)