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After injection of castrated rams with 600 mg testosterone or testosterone propionate, plasma LH levels were biphasic, with significant decreases at 6-10 and 96 h after treatment. These results support the suggestion that testosterone acts at the hypothalamo-pituitary level by two different mechanisms.
The effect of 10 days i.m. treatment of testosterone propionate (TP) on plasma testosterone and accessory reproductive organs were studied in adult (6 to 6 1/2 kg) male rhesus monkeys, housed under natural light conditions using six different dose levels. The study was scheduled in the month of September and October. To maintain the weight of accessory reproductive organs and testosterone levels in castrates, different dose levels of exogenous testosterone propionate were required: 3.2 mg/d for seminal vesicles, 4.8 mg/d for ventral prostate and 3.2 mg/d for plasma testosterone titer. The levels of so-called "physiological" doses of exogenous testosterone varied for various target organs under consideration. TP at a dose of 0.4 mg/d had a depressing effect on plasma testosterone in intact monkeys. For higher doses, plasma testosterone increased roughly similarly in both intact and castrated monkeys. It suggests that with otherwise "physiological" doses of testosterone propionate, there is an almost complete blockage of endogenous testosterone secretion.
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The final step in the biosynthesis of testosterone is the reduction of androstenedione, which is catalyzed by the microsomal enzyme 17-ketosteroid reductase. Evidence is presented which suggests that there are two distinct 17-ketosteroid reductases in rat testes, one in interstitial tissue and one in seminiferous tubules. The two enzymes have different pH optima, 5.6 for the one from interstitial tissue and 6.5 for the one from seminiferous tubules. At the optimum pH, a 70-fold difference in Km values was observed, 17 muM for the interstitial tissue enzyme and 0.25 muM for the enzyme from seminiferous tubules. Testosterone and metabolites of testosterone have very different effects of each of these enzyme activities. The interstitial tissue enzyme activity is inhibited by testosterone and several 5alpha-reduced metabolites of testosterone and by estrogens. The most potent inhibitor of the steroids investigated was 5alpha-androstane-3alpha, 17beta-diol, followed by 17beta-estradiol approximately equal to dihydrotestosterone greater than testosterone greater than estrone greater than estriol. 5alpha-Androstane-3alpha, 17beta-diol and 17beta-estradiol were shown to act by competitive inhibition with apparent Ki values of 2.2 and 3.7 muM, respectively. In contrast, it was demonstrated that among the above steroids, only dihydrotestosterone inhibits the 17-ketosteroid reductase activity of seminiferous tubules and this inhibition was only observed at very high concentrations of inhibitor. Testosterone stimulated the 17-ketosteroid reductase activity of seminiferous tubules. 5alpha-Androstane-3alpha, 17beta-diol at low concentrations stimulated the enzyme activity from seminiferous tubules, while it had no effect at high concentrations. The remainder of the steroids tested had no effect on the 17-ketosteroid reductase activity of seminiferous tubules. The difference in response of the two enzyme activities suggests a mechanism for local regulation of testosterone synthesis in each testicular compartment that does not involve directly pituitary gonadotropins.
In 18 males (age 49--79 yrs) without endocrine diseases, testosterone, free testosterone fraction, LH, FSH and cortisol (as indicator for stress) were determined in the early stage of an acute myocardia infarction. Blood was taken on admission as well as every 4 hours up to meanly 43 hours. The patients were separated in 2 groups for proving whether alterations of the parameters may depend on the severity of the myocardial infarction (group A=severe infarction; group B=not severe infarction). Testosterone showed a rapid decrease in the first 11 hours after admission, which continued less striking to the end of the investigation. Testosterone was significantly decreased in group A in comparison to group B. LH and FSH in both groups together were remarkably reduced during the whole time. Whereas group A demonstrated a tendency to decreased values in comparison to group B for LH, there were not any essential differences between the two groups for FSH. The free testosterone fraction was not altered. Cortisol in group A was twice as high as in group B during the entire investigation. The systolic pressure in group A was generally lower than in group B during the whole time. The results demonstrate an important reduction of the secretion of testosterone, LH and FSH during the early stage of the acute myocardial infarction. The testosterone suppression seems to be dependent on the severity of the myocardial infarction. These alterations may be caused by a general impaired perfusion as a consequence of myocardial infarction and a suppressive effect of increased cortisol values on testosterone levels.
A rapid quantitative procedure is presented for the separation of testosterone esters from their hydrolysis products through the use of the acetonitrile-infusorial earth column. The method was applied to testosterone cypionate, testosterone enanthate, and testosterone propionate. Recovery and replication of reference standard testosterone and its three esters through the proposed method ranged from 99.1 to 100.3%, and the percent relative standard deviation ranged from 0.6 to 1.0%. Two samples can be separated into testosterone and testosterone ester fractions in about 1.5 hr. The analyses of 20 injectable and one buccal tablet formulations made by 12 different manufacturers are reported.
Testosterone tablets of crystal size 2-5 micrometer were administered orally for 10 dags to 3 human subjects with low endogenous serum testosterone (se-T) levels. Fifty mg testosterone increased se-T slightly, while one daily dose of 200 mg maintained the se-T level within normal range for men for more than 12h. No cumulative effect was seen. Seven further subjects with low androgen production ingested 100 or 200 mg testosterone of crystal size 125-400 micrometer. Blood samples were taken frequently during the 24 h period following administration of the testosterone and se-T levels determined. Testosterone levels in serum increased in 6 patients and was maintained within the normal male range for 5-7 h. In one subject a slight but significant increase in se-T was observed although the level did not reach the normal male range. Although it has been shown that it is possible to use orally administered testosterone to maintain se-T levels in the normal male range, the convenience to the patient must be balanced against the cost and possible side effects of the large doses required.
Total plasma estradiol, progesterone, testosterone, and the binding capacity of testosterone-estradiol-binding globulin (TeBG) were measured and plasma unbound estradiol and testosterone calculated, every second day during nine cycles in six patients with epilepsy. They all received phenytoin as one medication. Some had additionally, phenobarbital or ethosuximide. Plasma concentrations were compared with those of a group of healthy women without medication. Total plasma testosterone and TeBG binding capacity were significantly increased in the treated group, as compared to the control group. However, the unbound testosterone concentration was within the range of the controls. The percentage unbound testosterone of total plasma concentration was clearly below that of the control group. This indicates that there was a primarily increased TeBG binding capacity in patients taking antiepileptic drugs.
The effects of ethynylestradiol or mestranol given in cyclic fashion, with and without a progestational compound (norethindrone acetate, dl-norgestrel, or megestrol acetate), on plasma androgens and their binding were examined in adult women, female baboons, and beagles. The two estrogens are equivalent in their effect, and there were essentially no dose-related differences over the range examined. In human subjects, the estrogens increased total testosterone and testosterone binding, and decreased free testosterone. In baboons, estrogen produced a transient decrease in total testosterone and an increase in binding. The levels of progestational agents used did not affect total testosterone in humans, as is commonly observed with commercial agents, but did decrease it in baboons. Percentage binding was decreased in both species by the 19-nor compounds, but not by megestrol. Androstenedione levels were unaffected in human subjects, but effects of both estrogens and progestins were seen in baboons. Because of the very low levels of androgens in female beagles, this species did not lend itself well to a study of this kind. However, an increase in testosterone binding was induced by estrogen even in the absence of testosterone/estrogen-binding globulin.
Analytical procedures for the measurement of testosterone by mass fragmentography (MF) using trideuterated testosterone (testosterone-19,19,19-d3) are described. For the calculation of plasma testosterone, peak height ratios were measured by MF performed on the molecular ions of the TFA derivative of testosterone (m/e 480) and testosterone-19,19,19-d3 (m/e 483). The sensitivity of the method was judged from the lower limit of detection of the mass spectrometer which was at 10 pg. For the measurement of the precision, the inter- and intra-assay coefficients of variation (C.V.) were calculated by using a pooled plasma sample; they were 3.15% and 1.79%, respectively. The specificity was investigated by the use of 5 alpha-dihydrotestosterone and the MF method was found to afford a highly selective technique. These results obtained by MF have been compared with the results obtained by a radioimmunoassay method.
The long-term effect of single intramuscular injections of various doses of dimeric testosterone and of testosterone enanthate into castrated male rats upon serum testosterone, luteinizing hormone (LH), pituitary LH, and on the weight of the seminal vesicles, the ventral prostate and the levator ani muscle, was investigated. The effect of the enanthate was characterized by a rapid onset and a protracted androgenic action and a suppression of serum LH, while the dimeric testosterone brought about only a moderate but very even depot effect. The injection of 5 mg of the dimeric testosterone caused a positive feedback effectu upon LH release for 16 weeks. The results indicate that the dimeric testosterone may exert is hormonal effects as intact ester.
Subcutaneous Silastic implants were designed to release quantities of testosterone approximating that produced by the rat testis and appropriate testosterone treatment was found to produce a physiologic inhibition of both LH and FSH secretion in orchidectomized rats. In rats bearing such testosterone implants, intravenous injection of an ovine anti-testosterone serum (0.3 cc) was sufficient to completely abolish the inhibitory effects of the testosterone implant for a period of 3 days as judged by the development of typical post-castration increases in serum LH and FSH. When this dose of antiserum was administered to intact adult male rats, the increases in serum LH on days 1, 2, and 3 post-injection were approximately 19%, 15%, and 11% of those observed in untreated castrates. Increases in serum FSH in antiserum injected rats followed a pattern similar to that for serum LH but the response was slightly greater (19%, 23%, and 22% of the castrate response) and there was no indication of a decreasing effect during the three days following injection. In these experiments, passive immunization against testosterone in intact male rats produced a clearcut stimulation of both LH and FSH release, but produced no data to support the suggestion that the intact testis can secrete nonsteroidal compounds capable of producing a differential inhibition of FSH secretion.
On day old male mice received a single injection of oestradiol benzoate, testosterone propionate or cyproterone acetate in order to study their action on testicular development, particularly testosterone secretion. Oestrogenization of newborn males leads, when the animals mature, to a high proportion or cryptorchidism, to atrophy of testes and seminal vesicles, and inhibition of spermatogenesis. Testosterone levels were reduced in the plasma. Testosterone propionate produced moderate reduction of testicular weight but spermatogenesis was not impaired. Plasma testosterone level was reduced. Cyproterone acetate increased significantly testicular testosterone level.
Testosterone (T) and dihydrotestosterone (DHT) have been quantitated by means of radioimmunoassay in Müllerian ducts (CM) from control quail embryos (6 to 8-day male and 6 to 15-day female) and from female embryos injected with 50 nanograms of testosterone propionate (PT) on the 8th day. These hormones are demonstrable in undifferentiated CM from 6-day control embryos. In control males although a highly significant decrease of the CM weight occurs during the CM involution, the detected amounts of androgens remain at a constant level. In control females, the right CM shows a slight increase of the androgen content during the rudimentation, i.e. from day 8 on; in the left CM: the highest steroid levels are found on the 6th day; while the CM differentiate, concentrations decrease and become similar to those found in neutral tissues. Given testosterone propionate on day 8 female embryos: right CM: both testosterone and DHT levels highly increase until day 14; the CM of treated embryos contain 8 times as much steroid as control; left CM: testosterone and DHT increase after injection until day 9,5; they slightly decrease between days 9,5 and 12, and then remain constant on day 14. Differences in concentrations are highly significant between CM of control and of PT - injected embryos. It seems that the binding sites of these androgens are more numerous during the involution and that bound testosterone or DHT could take a part in CM regression in male embryos and right CM rudimentation in female embryos.
This report describes a solid phase method for the characterization of testosterone binding to both albumin and testosterone-estradiol binding globulin (TeBG). TeBG is adsorbed from serum samples onto a solid phase matrix of concanavalin A covalently linked to 4B Sepharose. The binding of testosterone is then examined both in the presence and absence of the endogenous serum albumin. Analysis of the resulting Scatchard plots permits determination of the TeBG binding capacity, TeBG association constant and a parameter of albumin binding equivalent to the product of its affinity and capacity for binding testosterone. Results showed that the TeBG capacity was lower in men than in women (18.4 +/- 5.8 vs. 33.1 +/- 19.2 nM, p less than 0.01). The association constant was greater in men (1.59 +/- 0.35 vs. 1.19 +/- 0.32 x 10(9)M-1, 10(9)M-1, p less than 0.01). There was no difference in the albumin binding parameter (43.8 +/- 18.3 vs. 46.6 +/- 15.5, NS). These parameters can then be used to calculate the distribution of the circulating testosterone into albumin bound, TeBG bound and unbound fractions.
The effects of neonatal testosterone injections on adult male sexual behavior and plasma testosterone levels were investigated in several strains of male house mice. Both sexual behavior and plasma testosterone levels were increased in the testosterone-treated groups from some strains, but the 2 variables did not change concomitantly.
The injection of testosterone propionate for 4 successive days into female rats resulted in an increase of the in vitro conversion of the hydroxylated testosterones from testosterone by the hepatic microsomal fraction, but no change in the content of microsomal cytochrome P-450 occurred. Actinomycin D or puromycin, which was administered for 4 days with injections of testosterone propionate, prevented the enzyme induction.
LH and testosterone release after LH-RH treatment was studied in male calves from 1 week to 8 months of age. Total LH release, LH peak values and duration of the discharge increased from 1 week to 4 months of age by 406, 453 and 110%, respectively. Significant decreases of 54, 48 and 24% were observed at 6 months of age compared to 4 months of age. This was followed by steep increases in those variables of 344, 129 and 69% at 8 months compared to 4 months. A testosterone response following an LH increase was first seen at 4 months of age when a weak discharge occurred in 2 out of 5 calves. In older calves strong and LH-correlated testosterone responses were always observed. In a second experiment the LH response to LH-RH was studied in 6 months old calves castrated 2 months previously. The total LH response was 61% greater than in intact controls. When animals were castrated and pre-treated briefly with testosterone propionate the response was increased by 183% and the time to reach the LH peak was increased by 360%. From these and other results a synthesis of endocrine events during the first year of life is proposed. In particular it seems that the period between 4 and 8 months of age is crucial since interactions between steroid feedback and pituitary sensitivity to LH-RH change and eventually reach an equilibrium.