Large Doses Of Testosterone Research Articles

Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped

<h3>Objective.</h3> —To study the changes in body composition produced by large doses of testosterone and reversal of changes when the drug is discontinued. <h3>Design.</h3> —Weekly injections of testosterone enanthate were given to young adult male volunteers for 12 weeks. Repeated assays of lean body mass (LBM) by potassium 40 counting were made during this period and at intervals during the ensuing 5 to 6 months. <h3>Participants and Setting.</h3> —Subjects who were living on their own, who were known to be free of significant disease, and who volunteered as controls for a study of patients with neuromuscular disease. Assays were done in the Clinical Research Center. <h3>Main Outcome Measures.</h3> —Changes in body weight, LBM, and (by subtraction) body fat. <h3>Results.</h3> —Testosterone treatment produced a progressive increase in LBM and a progressive decrease in body fat. Body composition reverted slowly toward normal when the injections were stopped; thus, the effects of testosterone lingered for some time. The magnitude of the observed changes in LBM was in keeping with the change in urinary creatinine excretion reported for these same subjects. <h3>Conclusion.</h3> —Testosterone is a powerful anabolic agent that also serves to reduce body fat content. (<i>JAMA</i>. 1992;267:397-399)

Sequence of Changes in Body Composition Induced by Testosterone and Reversal of Changes After Drug Is Stopped

--To study the changes in body composition produced by large doses of testosterone and reversal of changes when the drug is discontinued. --Weekly injections of testosterone enanthate were given to young adult male volunteers for 12 weeks. Repeated assays of lean body mass (LBM) by potassium 40 counting were made during this period and at intervals during the ensuing 5 to 6 months. --Subjects who were living on their own, who were known to be free of significant disease, and who volunteered as controls for a study of patients with neuromuscular disease. Assays were done in the Clinical Research Center. --Changes in body weight, LBM, and (by subtraction) body fat. --Testosterone treatment produced a progressive increase in LBM and a progressive decrease in body fat. Body composition reverted slowly toward normal when the injections were stopped; thus, the effects of testosterone lingered for some time. The magnitude of the observed changes in LBM was in keeping with the change in urinary creatinine excretion reported for these same subjects. --Testosterone is a powerful anabolic agent that also serves to reduce body fat content.

Seminal plasma LDH-X in testosterone rebound therapy.

The changes in seminal plasma LDH-X isoenzyme were investigated in 27 oligozoospermic patients treated with large doses of testosterone. The increase in this isoenzyme, proven to occur prior to the sperm count elevation, might possibly serve as a predictor enabling the choice of an optimal term for affecting conception. A high percentage of responders has been found in patients with severe oligozoospermia (less than 0.1 x 10(6) spermatozoa/ml), but with a high initial relative percentage of seminal plasma LDH-X. The determination of this parameter could be one of the criteria for the selection of patients who will probably respond to the therapy.

LH and testosterone cause the development of seminiferous tubule contractile activity and the appearance of testicular oxytocin in hypogonadal mice.

Immunoreactive oxytocin is present in the testis and it has been shown that this hormone increases the contractility of seminiferous tubules. We have investigated the relationship between testicular oxytocin, tubular movements and the effects of LH and testosterone using, as a model, the hypogonadal (hpg/hpg) mouse, which is deficient in hypothalamic LH-releasing hormone (LHRH). Whilst both testicular oxytocin and seminiferous tubule movements, resembling those seen in the rat, can be found in normal adult mice, neither can be found in hypogonadal mice. After 2 weeks of treatment with LH (200 ng to 100 micrograms daily) low levels of testicular oxytocin and tubular movements were observed. Treatment with large doses of testosterone for 2-12 weeks led to higher concentrations of testicular oxytocin and tubular movements resembling those seen in the normal adult mouse. The results support the evidence that testicular oxytocin modulates seminiferous tubule movements. We suggest that testosterone may play a part in the accumulation of oxytocin in the testis.

Inhibition of prolactin secretion by moderate and high doses of testosterone.

The effects of different doses of testosterone on basal and stimulated secretion of prolactin (PRL) were investigated. Intact female mice of the S/W strain were injected sc with 0, 1, 10, 20, 50, 250, 500, 1000, 2500, or 5000 micrograms of testosterone propionate (TP) once daily for 4 weeks. Serum testosterone concentrations of TP injected mice rose 2- to 5-fold above those of controls at 1- to 50-micrograms doses, and 25- to 600-fold over controls in mice given higher doses of the steroid. Administration of 1 microgram of TP, the lowest dose tested, had no significant effects on basal serum PRL concentrations and only slightly inhibited the release of PRL induced by perphenazine, but the weight and PRL concentration of the pituitary gland were significantly depressed. However, at doses of 10, 20, and 50 micrograms TP, perphenazine-induced PRL release, pituitary PRL concentration, and pituitary gland weight were all reduced in a dose-related manner. The basal serum PRL concentrations decreased by the time the dose of TP reached 50 micrograms. In contrast, higher doses of TP (250 micrograms and above) reversed the suppression of these parameters: pituitary gland weight and basal serum PRL levels were restored to control levels, whereas pituitary PRL concentrations and perphenazine-induced PRL release were partially restored. These results suggest that administration of moderate and large doses of testosterone may suppress natural episodic and acute releases of PRL.

Effect of testosterone on the rate of myofibrillar protein breakdown in castrated and adrenalectomized male rats measured by the urinary excretion of 3-methylhistidine

Urinary output in N τ-methylhistidine (3-MeHis) was used to evaluate changes in myofibrillar protein breakdown rate in the skeletal muscles of castrated and adrenalectomized-castrated young male rats, and the responses of breakdown to testosterone and corticosterone replacement. The castrated rats grew less well than intact control rats and excreted significantly less 3-MeHis. Administration of low and high doses of testosterone restored the weight of the levator ani of the castrated animals but failed to affect growth rate or 3-MeHis output. Although this might suggest that testosterone has an indirect effect on muscle turnover through changes in growth rate, this parallelism was not confirmed by studies on adrenalectomized-castrated rats. Adrenalectomy of castrated rats caused a further reduction in growth rate and in output of 3-MeHis, but administration of testosterone now reduced 3-MeHis output still further while stimulating growth. Treatment of the adrenalectomized-castrated rats with low doses of corticosterone increased growth modestly, while depressing 3-MeHis output, and again output of this metabolite was further reduced when testosterone was added to the treatment, although growth rate was unaffected. Finally, large doses of testosterone given to adrenalectomized-castrated rats receiving excessive amounts of corticosterone did not prevent the growth failure or the increased output of 3-MeHis due to the corticosteroid, though it appeared to reduce the magnitude of the response to corticosterone alone. It is concluded that the effects of testosterone on growth and on 3-MeHis output are not necessarily associated and that the functional status of the adrenal cortex modifies the response of myofibrillar breakdown rate to testosterone treatment.

Gonadal hormones and sexual behavior in groups of adult talapoin monkeys ( Miopithecus talapoin)

Three heterosexual groups of six to eight monkeys were studied; all females were ovariectomized, whereas males were either intact or castrated. Aggressive hierarchies were evident in all groups, with females generally outranking males. When females were treated with estradiol, all males looked more frequently at the latters' sexual skin swellings, but only one male who was both dominant and intact copulated with them. Thus, either castration or low rank resulted in decreased levels of sexual behavior in male talapoins. The sexual behavior of dominant castrated males was restored by testosterone therapy, whereas subordinate castrates never copulated, even after large doses of testosterone, though penile erections and ejaculatory reflex (during masturbation) were restored. Following removal of a dominant male, the sexual behavior of the next male in rank was restored, provided he was not castrated and untreated. In contrast to males, female talapoins showed no consistent correlation between their rank and sexual activity. Estradiol therapy was without overall effect upon the frequency of female mounting behavior, though some females mounted and presented to one another more often. Estradiol treatment also caused females to present to males more frequently, but only to those that were sexually active (i.e., who mounted females).

Testosterone Rebound Therapy in the Treatment of Male Infertility

Large doses of testosterone were used to cause degeneration of the testicular germinal epithelium and a subsequent rebound of spermatogenesis, to produce improved seminal fluid. A 29% pregnancy rate was obtained by 131 patients treated for idiopathic oligospermia, and an 8% pregnancy rate was obtained by 12 patients treated for azoospermia. The seminal fluid of three patients (2%) was permanently damaged by the therapy.

Androgen binding proteins in different testis compartments

Two different high-affinity androgen binding proteins have been demonstrated in the rat testis. The smaller protein (ABP, MW 90,000) is produced in the testis, and transported with the testicular fluid into the epididymis. ABP is found in tubules but not in interstitial tissue or in testicular lymph. Destruction of the spermiogenic cells by physical or chemical agents does not decrease the concentration of ABP in the testis, indicating Sertoli cells to be the site of production. ABP disappears from the testis following hypophysectomy, but reappears following FSH treatment. Other pituitary hormones have no effect. Another androgen binding component, different from ABP, has also been recovered from rat testis tubules. This protein shows characteristics different from ABP but identical to cytoplasmic receptors of epididymis and prostate, indicating the presence of androgen target cells in the testis. Large doses of testosterone or dihydrotestosterone are known to maintain spermatogenesis in the hypophysectomized rat. We postulate that a major action of FSH on spermatogenesis may be mediated by ABP. ABP may facilitate androgen transport into the seminiferous tubules and provide the germ cells with the milieu of androgenic hormones which is required for normal spermatogenesis.

Persistent postpubertal elevation of activity of steroid 5alpha-reductase in the adrenal of rat pseudohermaphrodites and correction by large doses of testosterone or DHT.

The development of adrenal androgen metabolizing enzymes with androstenedione and testosterone as substrates has been studied in the rat pseudohermaphrodite and its King-X Holtzman male littermates and females. Enzymatic activity has been determined by the separation and quantitation of the products formed from the labeled androgen substrates by a partition system on thin-layer chromatography, and by trimethylsilylether derivative formation and radio-gas-liquid chromatography. The separations have been confirmed by recrystallization. Serum corticosterone is significantly higher in the pseudohermaphrodite than in males or females indicating intact corticoidogenic enzymes. The development of adrenal androgen metabolizing enzymes in the pseudohermaphrodite differs from that of its littermate male primarily by a persistent postpubertal elevation of activity of 5α-reductase and a failure of a postpubertal rise in 17-ketoreductase, the enzyme converting the 17-ketone of androstenedione to the 17β-alcohol of tes...

A high-affinity androgen-binding protein (ABP) in rat testis: evidence for secretion into efferent duct fluid and absorption by epididymis.

An androgen-binding protein (ABP) was detected in 105,000 × g supernatants of rat testis homogenates after removal of endogenous steroids by charcoal extraction. The ABP was identical to that previously demonstrated in highspeed supernatants of epididymis homogenates. When the exocrine secretion of the testis was blocked by ligation of efferent ducts, ABP increased in testis supernatant in proportion to the retention of testicular fluid while at the same time it disappeared from epididymis supernatant, first from the caput and later from the cauda. Treatment with large doses of testosterone did not alter the disappearance from epididymis. ABP disappeared almost completely from caput supernatant within three days after efferent duct ligation. When efferent ducts and corpus epididymidis were ligated simultaneously to block the flow of luminal fluid into and out of the caput, the disappearance of ABP from caput supernatant was only partially prevented. This finding suggested that a major portion of ABP is ei...

Ultrastructural effects of testosterone on epiphyseal cartilage.

Although experimental and clinical experience indicates that large doses of testosterone lead to premature cessation of growth, the exact mechanism and precise site of action of this hormone on the growth apparatus of long bones remain unknown. In this study, plateaued male rats were injected with supraphysiologic doses of testosterone to observe the submicroscopic effects on the various zones of the epiphyseal cartilage. In the zone of cell division there were increased numbers of dividing cells. The maturing cells accumulated larger amounts of secretory products at earlier stages of their life cycle, and appeared to undergo a more abrupt hypertrophy. In the zone of prehypertrophy, the interterritorial matrix contained foci of early and premature calcification and thicker and longer collagen fibers than at comparable levels in controls. It is concluded that in intact animals, even large doses of testosterone initially cause a stimulation of chondrocyte proliferation, prior to promoting maturation processes.

Androgen Insensitivity in Male Pseudohermaphrodite Rats1

Determinations were made of the citrate and nitrogen content of urine from male pseudohermaphrodite rats before and after injection with testosterone propionate. Controls were normal male and female siblings of pseudohermaphrodite males, and normal maternal carriers for the mutant gene for male pseudohermaphroditism. Testosterone caused an increase in weight of all normal animals, male and female, whereas that of male pseudohermaphrodites remained relatively stable. The citrate and nitrogen content decreased in the urine of all normal animals while testosterone was administered, but they did not undergo a significant change in that of male pseudohermaphrodites subjected to the same treatment. Since testosterone has a protein anabolic effect and the citrate and nitrogen titer in urine reflects the rate of metabolism, the preceding results indicate that many tissues of male pseudohermaphrodite rats are insensitive to androgen, whereas those in normal rats are not. (Endocrinology 89: 615, 1971) I THE RAT and many other species, the administration of testosterone increases the rate of protein anaboKsm. In animals so treated, the rate of excretion of urinary nitrogen and citric acid decreases (1). Following large doses of testosterone, patients with the complete form of testicular feminization fail to exhibit changes in their urinary nitrogen, phosphorus and citric acid (2). Male pseudohermaphrodite rats are genetic males which exhibit a female phenotype. Affected animals lack wolffian and mullerian derivatives except for a blind vagina which varies from a dimple to about 2 mm in depth. They exhibit a pair of inguinal testes. The mutation is passed by the mother to one half of her male offspring. They are produced in relatively large numbers from a King-Holtzman strain in the Stanley-Gumbreck colony at the Received October 6, 1970. Supported by NIH Grants HD 01921-02 and HD 03909-02. 1 Presented in part at the 82nd Annual Session of the American Association of Anatomists and the 52nd Meeting of The Endocrine Society. 2 Present address: Department of Anatomy, University of Tennessee College of Medicine, Memphis, Tenn. 38103. University of Oklahoma Medical Center. In many respects, the conditions manifested in the male pseudohermaphrodite rat resemble those seen in testicular feminization in man (3, 4). Insensitivity to androgen appears to be a phenomenon shared by both (5, 6). The present work was undertaken in order to show the result of measuring citric acid and nitrogen in urine of male pseudohermaphrodite rats before and after the administration of testosterone propionate. Materials and Methods Two groups of rats were used. There were 20 animals in group 1 and 15 in group 2. Both groups included 4 types of animals. The types and number of each type in each group are indicated in Table 1. All rats belonged to the King-Holtzman strain from the Stanley-Gumbreck colony. Each rat in group 1 was given a sc injection of 0.25 ml of sesame oil daily for 22 days. On the eleventh day, 4 mg of testosterone propionate was added to each daily dose of sesame oil. During the first and last 10 days of this entire regimen, the urine from these animals was analyzed for citric acid content. Group 2 contained 3 subgroups according to the number of days the members therein were treated. Those in subgroup 1 received subcutaneous injecTABLE 1. Number and type of animals used Male pseudohermaphrodites Normal males Normal females Mothers of pseudohermaphrodites Group 1 (citrate) Group 2 (nitrogen)

Treatment of cyclic neutropenia with testosterone

A case of periodic neutropenia in which the patient was treated with large doses of testosterone before and after splenectomy is reported. Testosterone therapy before splenectomy caused subjective and objective improvement. Splenectomy alone failed to alleviate the patient's symptoms or to alter the cyclic neutropenia. Retreatment with testosterone again abolished the patient's symptoms and ameliorated the cyclic neutropenia. The effect of testosterone on the marrow granulocytic reserve is discussed.

Effect of Large Doses of Testosterone on Body Fat of Elderly Men

Effect of Large Doses of Testosterone on Body Fat of Elderly Men

An endocrine mechanism involved in testicular changes produced by a dl-ethionine supplemented diet: a study of morphologic changes and endocrine dysfunction.

The endocrine-morphological relationship in testicular lesions of rats treated with ethionine and testosterone was investigated. This was done through indirect evaluation of the androgenic activity by the estimation of urinary 17-KS excretion. It has been found that small and large doses of testosterone (12 clays of treatment) prevent histologic testicular changes clue to ethionine. However small doses of testosterone given over a longer period (24 days) did not prevent ethionine-induced testicular histologic changes. Large doses of testosterone did not prevent damage to spermatogenesis during continuous ethionine administration, but did prevent Leydig cell hyperplasia. Ethionine alone stopped spermatogenesis, and induced Leydig cell hyperplasia. Leydig cell hyperplasia therefore may have been compensatory. Ethionine treatment decreased the excretion of 17-KS prior to the appearance of any testicular morphological changes. Therefore ethionine presumably affected the androgenic activity directly if 17-KS excretion may be used as an index of androgenic activity. Intraperitoneal (I.P.) administration of ethionine diminished the 17-KS excretion by two thirds. Since I.P. ethionine diminished in 12 days the excretion of 17-KS in the absence of histologic testicular changes and was followed by an increase in the excretion of 17-KS associated with Leydig cell hyperplasia after 24 days, this would suggest that functional changes precede histologic changes. Morphological liver changes were demonstrable within 24 days after initiating oral ethionine therapy but not after I.P. ethionine. Gastrointestinal versus systemic absorption of the administered ethionine may be a factor. Finally, it may be concluded that an endocrine-morphological relationship exists in the pathogenetic effect of ethionine on testicular changes observed in albino rats.

Treatment of male infertility with large doses of testosterone.

• The administration of a standard course of testosterone in a series of subfertile male patients resulted, as a rule, in the disappearance of spermatozoa from the semen after 12 weeks. After termination of this treatment, spermatozoa reappeared in two or three months. While in some cases the sperm counts returned to the pretratment level, in others they failed to reach it during the period of observation and in some they exceeded it (rebound phenomenon). The selection of patients must be governed by determinations of urinary gonadotropin excretion and by testicular biopsy, especially the latter. In one initially azoospermic patient the rebound phenomenon was observed twice and a peak count of 30 million spermatozoa per cubic centimeter was achieved. In this instance a pregnancy followed, with subsequent normal childbirth.

Studies in sperm hormones: demonstration of estrogenic activity.

THE mechanism by which the testes exert a regulatory influence on the anterior pituitary is still an obscure physiologic phenomenon. While large doses of testosterone may depress the pituitary gonadotrophins, it is now generally agreed that physiologic quantities of this hormone do not inhibit the secretion of gonadotrophin to a significant extent. This would indicate that, either there are other testicular hormones capable of inhibiting gonadotrophins, or that some other mechanism, of pituitary control is involved. The first of these hypotheses received some measure of support as it became evident that the testis is capable of producing estrogenic hormones. Such evidence came from the isolation of estrogens from the testes of the stallion (Beall, 1940), hog (Ruzicka, 1943; Haines et al., 1948), and more recently from human testes by Goldzieher and Roberts (1952). Since estrogens are known to be powerful pituitary inhibitors, these isolation experiments add support to the view that these hormones may play...

THE COMPOSITION OF BONES OF MICE RECEIVING ESTROGENS AND ANDROGENS1

FOLLOWING the injection of large amounts of estrogens, the marrow cavities of the femurs of mice are invaded and largely replaced by bone (5, 13). Similar changes occurred elsewhere in the skeleton except at the pubic symphyses (4). The changes took place more slowly in males and were prevented by large doses of testosterone (6). This investigation was designed to determine whether these anatomical changes were associated with changes in chemical composition of the osseous tissues. Determinations of ash, total calcium and total phosphorus were made on the femurs and pelves of control mice and of mice receiving estradiol bensoate, testosterone propionate and estradiol bensoate plus testosterone propionate. The mice of both sexes were of 4 groups: a), control animals, some of which received injections of cholesterol; b), animals receiving weekly or biweekly injections of 16.6 micrograms of estradiol benzoate; c), animals receiving weekly or biweekly injections of 1.25 mg. testosterone propionate and d), ani...

MORPHOLOGICAL CHANGES IN FEMALE MICE RECEIVING LARGE DOSES OF TESTOSTERONE

The action of oestrogen overdosage has been studied by numerous investigators, and it was found that besides influencing the development of the sex organs, these substances exert a marked influence on the pituitary, the adrenals, the liver, &c. [Hohlweg, 1934; Wolfe, 1935 a, b; Selye, Collip, and Thomson, 1935; Selye, Harlow, and Collip, 1936; and Selye, 1938, 1939 a]. Since relatively few observations have been made up to the present along similar lines with chemically pure androgens, it appeared of interest to make a systematic study of the morphological changes produced by large doses of testosterone. As most of our previous work with the oestrogens was performed on female animals, we decided to use females for this work also, so as to make experimental conditions comparable. The findings of previous investigators concerning the action of androgens on various organs are rather contradictory, partly because they used impure preparations, and partly