Plasma Dihydrotestosterone Concentrations Research Articles

Pharmacokinetics and pharmacodynamics of TF-505, a novel nonsteroidal 5alpha-reductase inhibitor, in normal subjects treated with single or multiple doses.

To assess the tolerability, pharmacokinetics and pharmacodynamics of a novel nonsteroidal and noncompetitive inhibitor of type I and type II 5alpha-reductases, (-)-(S)-4-[1-[4-[1-(4-isobutylphenyl) butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), after single and multiple oral doses in healthy volunteers. In the single-dose study, six young adult males in each dose group received 25 mg or 50 mg of TF-505, and six older males (>or= 40 years) in each dose group received 75 mg or 100 mg of TF-505. The subjects were given the drug in ascending dose and in the fasting state. Six subjects also received 50 mg of TF-505 after breakfast in a two-period crossover manner. In the multiple-dose study, six older males in each dose group received 12.5 mg or 25 mg TF-505 after breakfast daily for 7 days. Plasma concentrations of TF-505, dihydrotestosterone (DHT) and testosterone were measured. The pharmacokinetics of TF-505 were analysed by a compartment model with first-order absorption, first-order elimination and a lag time. Pharmacokinetic and pharmacodynamic relationships were evaluated by indirect response modelling with inhibition of input. Maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) increased proportionately after the single dose up to 50 mg and with the multiple doses. Linearity was not detected between 75 and 100 mg of TF-505. Dose dependency was also noted for the effect of TF-505 on DHT concentrations following single doses up to 50 mg and multiple doses. Plasma DHT concentrations decreased maximally to 58.2, 49.5, 54.2 and 49.8% of basal values at 8-12 h after single administration of 25, 50, 75 and 100 mg TF-505, respectively, and to 60.5 and 49.4% at the 7th and 5th dose following multiple doses of 12.5 and 25 mg TF-505, respectively. The predicted effect curves matched the observed data when the indirect response model was applied to the time course of the suppressant effect of TF-505 on plasma DHT concentrations after both the single and multiple studies. Fifty percent inhibitory concentrations (IC50) of 0.82, 1.48, 1.31 and 0.88 micro g ml(-1), zero-order rate constants for the onset of plasma DHT concentration changes (kin) of 17.8, 17.4, 17.0 and 10.7% h(-1) and first-order rate constants for increase in plasma DHT concentrations to basal values (kout) of 0.17, 0.16, 0.17 and 0.10 h(-1) for the single study at doses of 25, 50, 75 and 100 mg, respectively, were attained. In the multiple-dose study, IC50s were 1.74 and 1.49 micro g ml(-1) for the 12.5 and 25 mg doses, respectively. No serious adverse events related to TF-505 were observed. TF-505 was well tolerated in healthy male volunteers. Accumulation of TF-505 in plasma was not observed during multiple dosing. The indirect response model described the relationships between pharmacokinetics and pharmacodynamics of TF-505. Such modelling is expected to yield an appropriate dosage regimen in subsequent clinical trials.

Plasma Dihydrotestosterone Concentrations and Phallus Size in Juvenile American Alligators (A. mississippiensis) from Contaminated and Reference Populations

Evidence increasingly suggests that some environmental pollutants are able to permanently affect development of the endocrine system in wildlife. Embryonic and neonatal exposure to these endo- crine-disrupting contaminants can cause structural and functional abnormalities of the reproductive system. It has recently been hypothesized that demasculinization of a population of male juvenile American alli- gators (Alligator mississippiensis) from Lake Apopka, Florida, could result from exposure to antiandrogenic contaminants. The persistent pesticide contaminant p.p'-DDE interacts with the mammalian androgen recep- tor and antagonizes androgen action in vivo. Wildlife from Lake Apopka, which has been contaminated through agriculture and an industrial accident, exhibit elevated levels of p.p.'-DDE, among other pesticide residues. This study provides further evidence of reproductive dysfunction in Lake Apopka juvenile alli- gators by comparison with a reference population from a relatively uncontaminated lake nearby, Lake Woodruff National Wildlife Refuge. Phallus size correlated strongly with plasma dihydrotestosterone (DHT) concentrations or body size in juvenile males from Lake Woodruff In contrast, males from Lake Apopka had significantly smaller phalli (adjusted for body size) than those from Lake Woodruff, and correlations with body size or plasma DHT concentrations were weak or absent. Plasma DHT concentrations did not differ significantly between juvenile males from the two lakes. In contrast, plasma DHT concentrations were significantly higher in females from Lake Apopka compared to those from Lake Woodruff This is the first report of masculinized female juvenile alligators from Lake Apopka and suggests that juveniles of both sexes exhibit altered endocrine and reproductive parameters.

Transient Neonatal Hypothyroidism Alters Plasma and Testicular Sex Steroid Concentration in Puberal Rats

The stimulatory and inhibitory effects on testicular steroidogenesis of transient neonatal hypothyroidism from day 1 postpartum through different postnatal developmental events on testis at puberal age (60 days old) were studied in vivo. Hypothyroidism was induced in neonates by feeding the lactating mother or directly with 0.05% methimazole (MMI) through drinking water from the day of parturition to 10, 15, 30, 40 and 60 days, and were killed at day 60 postpartum. Plasma and testicular interstitial fluid (TIF) progesterone, testosterone, dihydrotestosterone (DHT) and estradiol concentrations were assessed. Testis weight and volume significantly increased in rats subjected to 10 and 15 days of hypothyroidism, decreased in rats subjected to 30, 40 and 60 days of hypothyroidism. A consistent increase in Leydig cell number was seen in puberal rats subjected to transient neonatal hypothyroidism but decreased in 60 days hypothyroid rats. Peritubular myoid cell number was consistently decreased in all experimental rats. Leydig cell diameter decreased consistently in all experimental groups. Persistent hypothyroidism (60 days hypothyroid) consistently decreased both plasma and TIF sex steroids. In transient hypothyroid rats, progesterone concentration decreased in both plasma and TIF. Transient hypothyroidism from birth to day 10 postnatal age maintained normal titre of plasma testosterone, whereas a significant increase in TIF testosterone concentration was evident when compared with controls. All other groups of rats subjected to transient neonatal hypothyroidism had consistently low titres of plasma and TIF testosterone. Plasma DHT concentrations in rats subjected to transient neonatal hypothyroidism remained unaltered. However, TIF DHT increased in 10 days hypothyroids, decreased in 30 and 40 days hypothyroid rats and remained unaltered in 15 days hypothyroids. Transient hypothyroidism registered normal titres of plasma estradiol in all groups except in 30 days hypothyroids, which registered an increase, while a consistent increase in TIF estradiol concentration was observed. The present study indicates that transient neonatal hypothyroidism, when restricted up to 10 days of postnatal life, at puberal age Stimulates testosterone, DHT and estradiol secretion and when extended beyond 10 days of postnatal life shifts towards estradiol secretion.

Effects of exogenous androgen on brain androgen receptors of the fetal rhesus monkey.

Testosterone secreted by the fetal testes masculinizes and defeminizes the nonhuman primate brain during a defined prenatal critical period. We previously demonstrated the presence of high-affinity, specific androgen receptors (AR) in the developing rhesus monkey brain, but did not present data concerning their capacity for activation. To achieve this end, we analyzed the AR content in brains from intact and gonadectomized rhesus monkey fetuses at approximately 125 days of gestation, 2 h after injection of either 500 micrograms dihydrotestosterone (DHT) or vehicle directly into the fetus. After treatment, plasma DHT concentrations increased five-fold in the fetal circulation. In gonad-intact fetuses, cytosolic AR decreased in preoptic area, medial basal hypothalamus, and septum following DHT treatment. No significant effect of DHT treatment on nuclear AR was seen. In contrast, the increased level of DHT in the maternal circulation decreased cytosolic AR and increased nuclear AR of the maternal myometrium. In gonadectomized fetuses, DHT treatment decreased cytosolic AR as it did in the intact group. In contrast, a significant increase in nuclear AR was seen in preoptic area, medial basal hypothalamus, and tegmentum of these fetuses. Thus AR in fetal rhesus brain can be activated by DHT when the gonads are removed, but not in the intact fetuses. These data suggest that AR in the developing nervous system of rhesus macaques can be activated by exogenous androgen and hence are probably functional.

Oral testosterone undecanoate in the management of delayed puberty in boys: pharmacokinetics and effects on sexual maturation and growth.

Therapeutic induction of puberty using oral testosterone (T) undecanoate (TU) 40 mg daily was performed in 4 pubertal boys aged 12.7-17.1 yr with constitutional delayed puberty and/or short stature. Single-dose pharmacokinetics study was performed on matched plasma and saliva samples obtained half-hourly for 10 h after the first dose and then repeated 3 and 6 months later. Treatment was continued for 15-21 months. Peak plasma total T concentration was achieved at 255 +/- 51 (SEM) min after the first 40 mg dose of TU, 300 +/- 76 min at 3 months, and 293 +/- 103 min at 6 months, the levels remaining elevated above baseline for at least 8 h after a single oral dose. Total T levels were initially high (mean 13.0 +/- 2.5; peak 38.7 +/- 4.2 nmol/L) but dropped significantly at 3 months (mean 8.3 +/- 1.8; peak 23.6 +/- 5.6 nmol/L) and at 6 months (mean 9.2 +/- 1.6; peak 24.8 +/- 3.5 nmol/L) paralleled by a dramatic fall in sex hormone binding globulin (73.9 +/- 18.0 to 35.1 +/- 9.7 at 3 month and 29.2 +/- 6.0 nmol/L at 6 month). Mean concentrations of unbound and free T (non-sex hormone binding globulin-bound T, free T, and salivary T) were below the normal adult range and remained unchanged over the same period. Plasma dihydrotestosterone concentrations were elevated after the first dose (mean 5.4 +/- 1.3; peak 11.0 +/- 2.5 nmol/L), the extent of this rise being less after 6 months (mean 4.1 +/- 0.8; peak 7.1 +/- 1.1 nmol/L) as was the case with mean estradiol (51.5 +/- 8.9 to 38.1 +/- 3.7 pmol/L). Signs of virilization progressed to Tanner stage G3 PH2-3 with testicular volumes increasing to 3-4 mL at 12 months, and G4 PH4-5 with further testicular growth to 6-10 mL at 24 months. Height velocity rose from 3.2 +/- 0.3 cm/yr (pretreatment) to 7.2 +/- 1.0 cm/yr in the first year and was maintained at 7.3 +/- 0.4 cm/yr despite cessation of therapy during the second year. Bone age advanced by 1.1 +/- 0.1 yr at 12 months and a further 0.8 +/- 0.3 yr at 24 months. Predicted adult height remained unchanged. No side effects were observed. Our preliminary data suggest that oral TU is a well accepted, effective, and safe treatment for the initiation of male puberty without disproportionate skeletal maturation. Continued pubertal advance was evident after cessation of treatment in all patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Treatment of Persistent Pubertal Gynecomastia With Dihydrotestosterone Heptanoate

Four boys with persietent pubertal gynecomastla were given intramuscular dihydrotesiosterone heptanoate (DHT-hp) at 2 to 4-week intervals for 16 weeks. By the end of treatment, breast size in all four boys had decreased 67% to 78%. Initial plasma levels of gonadotropins, estradlol, testosterone, and dihydrotestosterone (DHT) were normal. Mean plasma DHT concentration rose with the injections of DHT-hp, and remained elevated throughout the treatment period Estradiol, LH, FSH, and testosterone decreased during treatment, as did 24-hour urinary LH and FSH. No regrowth of breast tissue was observed 6 to 15 months after treatment, although hormone concentrations had returned to near pretreatment values by 2 months after the last injection. DHT-hp has potential to be an effective medical therapy for persistent pubertal gynecomastia.

Treatment of persistent pubertal gynecomastia with dihydrotestosterone heptanoate

Four boys with persistent pubertal gynecomastia were given intramuscular dihydrotestosterone heptanoate (DHT-hp) at 2 to 4-week intervals for 16 weeks. By the end of treatment, breast size in all four boys had decreased 67% to 78%. Initial plasma levels of gonadotropins, estradiol, testosterone, and dihydrotestosterone (DHT) were normal. Mean plasma DHT concentration rose with the injections of DHT-hp, and remained elevated throughout the treatment period. Estradiol, LH, FSH, and testosterone decreased during treatment, as did 24-hour urinary LH and FSH. No regrowth of breast tissue was observed 6 to 15 months after treatment, although hormone concentrations had returned to near pretreatment values by 2 months after the last injection. DHT-hp has potential to be an effective medical therapy for persistent pubertal gynecomastia.

Long term effects of administration of a gonadotropin-releasing hormone superagonist analog in men with prostatic carcinoma.

Administration of the superagonist analog of GnRH, D-Leu6-GnRH proethylamide, profoundly reduced plasma LH, FSH, testosterone, and dihydrotestosterone levels when given for 6-11 weeks to adult men with prostatic carcinoma. Since patients with prostatic carcinoma can be expected to receive this analog for as long as 3-4 yr, we questioned whether the same degree of reduction could be maintained during chronic administration. In 22 men who had received D-Leu6-GnRH proethylamide for at least 1 yr, LH and testosterone remained at the initial low levels. Plasma dihydrotestosterone concentrations, on the other hand, gradually fell further with long term administration. FSH levels reached a nadir of 5.7 +/- 0.94 (+/- SEM) mIU/ml at 10-11 weeks. Unexpectedly, the plasma levels of this gonadotropin then gradually increased, and between 25 and 97 weeks were approximately 10-15 mIU/ml. This pattern occurred identically in patients receiving either 1 or 10 mg D-Leu6-GnRH proethylamide daily. These data indicate persistent suppression of LH and androgen levels during prolonged therapy and suggest that D-Leu6-GnRH-induced "medical castration" can be maintained with chronic administration.

Alterations in daily rhythms of testosterone and progesterone in old male rats.

Studies were undertaken to characterize the daily patterns of secretion of testosterone (T), progesterone (P) and dihydrotestosterone (DHT) in young (3-4 months old) and old (19-20 months old) male Sprague-Dawley rats. In young rats, plasma T concentrations show dramatic daily variations with peak and nadir levels at 1130 and 2330 h, respectively. In old male rats, no such rhythmic pattern in plasma T was observed. Plasma P concentrations varied significantly in both young and old male rats, with peak levels occurring 8 h (1930 h) after the plasma T peak in young rats. Additionally, in old male rats, the daily increase in plasma P was significantly larger and was sustained for a longer period than in young rats. Plasma DHT concentrations were similar and changed little during the day in both young and old animals. In view of the known P influence on gonadal secretion, the possible significance of these age-related changes in daily patterns in plasma P and T are discussed.