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Combined inhibition of types I and II 5 alpha-reductase selectively augments the basal (nonpulsatile) mode of testosterone secretion in young men.

CONTEXT: Testosterone (Te) is metabolized in the hypothalamus and pituitary gland, where untransformed steroid and activated products participate in feedback regulation of GnRH and LH secretion. Genetic inactivation of 5 alpha-reductase type I remains undescribed clinically, whereas deficiency of the type II isoenzyme elevates both LH and Te concentrations. OBJECTIVE: The aim of this study was to test the combined feedback contribution of 5 alpha-reduced steroids. SETTING/DESIGN/INTERVENTION: In a university setting, nine young men received placebo and a dual (type I/type II) 5 alpha-reductase inhibitor, dutasteride. METHODS/OUTCOMES: LH and Te dynamics were assessed by: 1) 10-min blood sampling for 26 h; 2) GnRH stimulation (100 ng/kg iv); 3) discrete peak detection; 4) deconvolution analysis; 5) cosinor analyses of 24-h rhythmicity; and 6) pattern regularity. RESULTS: Compared with placebo, dutasteride lowered 5 alpha-dihydro Te concentrations by 80% (P = 0.009), but did not alter any measure of LH dynamics. Conversely, dutasteride augmented: 1) total, bioavailable and free Te concentrations (0.002 < P < 0.032) without changing estradiol or SHBG concentrations; 2) nadir Te concentrations (P = 0.025); and 3) basal (P = 0.013) and thereby total (basal plus pulsatile) (P = 0.003) Te secretion. CONCLUSION: Combined antagonism of types I and II 5 alpha-reductase preferentially drives nonpulsatile Te secretion in healthy men. The concomitant stability of LH outflow could indicate that intragonadal 5 alpha-reduced androgens repress basal Leydig-cell steroidogenesis.

Adult↗

Single dose long-term suppression of testosterone secretion by a gonadotropin-releasing hormone antagonist (Antide) in male monkeys.

This study was designed to find the minimal single dose of Antide (Nal-Lys GnRH antagonist) that would provide long-term inhibition of serum testosterone levels in adult male monkeys. At 3 mg/kg (sc), Antide blocked testosterone secretion for only a few days. However, when the dose of Antide was raised to 10 mg/kg, some of the males manifested testosterone inhibition lasting more than 60 days, while shorter durations of action were found in others. These preliminary findings increase our interest in studying Antide as a potential male contraceptive agent, when combined with androgen replacement therapy, as well as for therapeutic applications in men having prostatic carcinoma. Importantly, Antide lacks the sometimes deleterious "flare" effect known to occur when GnRH agonists are used to treat these patients.

Animals↗

Effect of mammalian gonadotropins on testosterone secretion in male alligators.

Male farm-reared alligators were injected with mammalian FSH, LH, hCG, prolactin, or saline. A blood sample was taken immediately prior to injection of hormone and at 24 h postinjection. Testosterone concentrations in the plasma were then determined by radioimmunoassay. Only the alligators injected with FSH showed a significant increase in plasma testosterone. In a second series of experiments male alligators were injected with ovine LH, ovine FSH, or saline and bled at 0, 2, 4, 16, and 24 h postinjection. Again, only the alligators injected with FSH showed significant increases in plasma testosterone at 16 and 24 h postinjection. Mammalian LH does not appear to stimulate testosterone secretion in male alligators.

Alligators and Crocodiles↗

On the zeros of a third degree exponential polynomial with applications to a delayed model for the control of testosterone secretion.

In this paper, we first study the distribution of the zeros of a third degree exponential polynomial. Then we apply the obtained results to a delay model for the control of testosterone secretion. It is shown that under certain assumptions on the coefficients the steady state of the delay model is asymptotically stable for all delay values. Under another set of conditions, there is a critical delay value, the steady state is stable when the delay is less than the critical value and unstable when the delay is greater than the critical value. Thus, oscillations via Hopf bifurcation occur at the steady state when the delay passes through the critical value. Numerical simulations are presented to illustrate the results.

Animals↗

Intratesticular factors and testosterone secretion: the effect of treatment with ethane dimethanesulphonate (EDS) and the induction of seminiferous tubule damage.

The role of seminiferous tubule dysfunction in regulating the levels of a factor (or factors) in testicular interstitial fluid (IF) which stimulates Leydig cell testosterone secretion in vitro, was assessed by injecting rats with the Leydig cell toxin, EDS. Within 72 h of treatment EDS destroyed the Leydig cells and concomitantly reduced IF testosterone to undetectable levels. This was associated with nearly a 2-fold increase (P less than 0.001) in levels of the IF-factor(s) as judged by the enhancement of hCG-stimulated testosterone production (= IF bioactivity). By 3 weeks, and thereafter up to 10 weeks post-EDS, Leydig cells regenerated within the testis, and testosterone levels returned to control values, but IF-bioactivity remained significantly increased. The latter was associated with seminiferous tubule dysfunction as indicated initially by testicular morphology, raised serum levels of FSH and reduced testicular weight. For animals with normal testosterone levels, there was a significant negative correlation (r = -0.57, N = 46; P less than 0.001) between testicular weight and IF bioactivity. A similar increase in IF bioactivity in the presence of normal testosterone levels was observed in rats in which patchy severe seminiferous tubule damage had been induced by short-term cryptorchidism. It is concluded that, in addition to testosterone, seminiferous tubule function may dictate the intratesticular levels of the testosterone-stimulating factor(s) in IF.

Animals↗

Testosterone secretion and pharmacological spermatozoal recovery in the cane toad (Bufo marinus).

The cane toad (Bufo marinus) was used as a model to study male anuran reproductive endocrinology and to develop a protocol for non-invasive sperm recovery. Circulating testosterone concentrations in 6-hourly samples did not vary significantly (P < 0.05) over a 24 h period although there was a tendency (P = 0.06) for testosterone to be elevated at 19:00 h relative to other times of the day, which may be related to the nocturnal activity pattern of this species. Testosterone secretion after intraperitoneal (IP) injection of either a GnRH agonist (5 microg IP) or hCG (1000 IU) was also examined. While the GnRH agonist did not produce a significant increase above basal plasma testosterone (0.29, 95% C.I. of 0.05-1.10 ng/ml), injection of hCG resulted in an increase (P < 0.01) of plasma testosterone with peak concentrations at approximately 120 min (4.17, 95% C.I. of 2.69-7.44 ng/ml) after injection. Non-invasive pharmaceutical sperm recovery was attempted following IP injection of graded doses of GnRH agonist, hCG or FSH. Urine was collected at 3, 6 and 12 h after treatment to assess sperm quality and quantity. The optimal protocol for sperm recovery in cane toads was injection of either 1000 or 2000 IU hCG; there was no significant difference in the quality of the spermic urine samples obtained using either dose of hCG or with respect to collection time. The findings indicated that hCG can be used to assess testicular steroidogenic status and also to induce sperm recovery in the cane toad. The hCG protocols developed in this study will have application in studies on the reproductive biology of rare and endangered male anurans.

Animals↗

Testosterone secretion by Mongolian gerbil interstitial cells during short-term incubation depends on androgen precursors and serum proteins but not on gonadotrophins.

Interstitial cells from the testes of the Mongolian gerbil have been used to investigate the effects of serum proteins on testosterone production stimulated by hCG and steroidal precursors. Short-term incubation of interstitial cells with progesterone or DHEA resulted in a rapid increase of testosterone secretion; this effect was even more pronounced in the presence of calf serum. On the other hand, addition of hCG (10 mIU) had no significant effect on testosterone release during the 30-min incubation. These results demonstrate that the magnitude of the steroidogenic response of short-term incubated interstitial cells is a complex function, mainly of precursor concentrations and binding capacities of serum proteins but not of gonadotrophins.

Androgens↗

Delayed luteolysis and suppression of testosterone secretion after recombinant ovine interferon treatment in goats (Capra hircus).

Oxytocin at a dose of 100 iu injected s.c. daily into goats (Capra hircus) between day 3 and day 6 of the oestrous cycle caused a significant increase in testosterone secretion and luteolysis compared with saline-treated animals. Intrauterine administration of recombinant ovine interferon tau (80, 160 or 320 micrograms day-1) between days 12 and 18 of the oestrous cycle, or concomitantly (80 micrograms day-1) with oxytocin between day 3 and day 7, delayed luteolysis and blocked the increased release of testosterone. It is suggested that recombinant ovine interferon tau can act as an antiluteolytic agent in goats.

Administration, Cutaneous↗

Seasonal changes in the endocrine responsiveness of the pituitary and tests of male sheep in relation to their patterns of gonadotropic hormone and testosterone secretion.

Pituitary and testicular endocrine responses to exogenous gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH), respectively, were assessed for adult rams in an investigation of the regulation of seasonal changes in the patterns of episodic LH and testosterone secretion. Concurrent variations in testis size and in circulating levels of follicle stimulating hormone (FSH) and prolactin (PRL) were also examined. On 10 occasions throughout the year, serum hormone levels were assessed over 6- to 8-h periods during which time rams were left untreated (day 1) or were injected (iv) with single doses of either 10 micrograms synthetic GnRH (day 2) or 30 micrograms NIH-LH-S18 (day 3); blood samples were collected from the jugular vein at 10- to 20-min intervals. Testicular redevelopment during the summer, as indicated by increasing testis diameter measurements, was associated with increases in mean FSH level and was preceded by a springtime rise in mean PRL level; "spontaneously" occurring LH pulses and those produced in response to GnRH treatment were relatively large during this period. Increases in the magnitude of testosterone elevations in response to both endogenously and exogenously produced LH pulses occurred in August. Mean testosterone levels were elevated fourfold in the fall as a consequence of relatively frequent and small LH pulses stimulating a more responsive testis to produce more frequent and larger testosterone elevations; endogenous LH pulses, however, did not appear to stimulate the testes maximally at this time.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Stress-induced suppression of testosterone secretion in male alligators.

In order to test the effect of acute stress on gonadal hormone secretion in reptiles, six mature male alligators were captured, and a blood sample was taken within 5 min of capture. Additional blood samples were taken at timed intervals for up to 41 hr, and plasma testosterone and corticosterone were measured by radioimmunoassay. Plasma testosterone declined to 50% of the initial value by 4 hr and dropped to less than 10% of initial by 24 hr. Plasma corticosterone increased during the first 12 hr, declined at 24 hr, and rose again at 40 hr. Blood samples from male alligators collected in North and South Carolina, south Florida, and in south Louisiana in two consecutive breeding seasons were also assayed for testosterone and corticosterone. In these populations there were significant differences in mean plasma testosterone and corticosterone levels. Elevated corticosterone levels were consistently seen in alligators caught in traps and from which a blood sample was taken several hours later. Plasma testosterone, although consistently lower in trapped alligators, did not show a negative correlation with plasma corticosterone. Farm-reared alligators bled once, released, and bled again at 24 hr also showed a highly significant suppression of testosterone secretion. These results demonstrate that stress has a rapid and dramatic effect on testicular steroid secretion in both farm-reared and wild alligators.

Alligators and Crocodiles↗

Suppression of pulsatile luteinizing hormone and testosterone secretion during short term food restriction in the adult male rhesus monkey (Macaca mulatta).

To determine whether signals occurring during the early stages of undernutrition can have a suppressive effect on the central drive to the reproductive axis, the effects of 1 day of fasting on pulsatile LH and testosterone secretion were examined in adult male rhesus monkeys. Monkeys were maintained with chronic indwelling venous catheters on tether/swivel systems. One day of fasting caused a small weight loss of 0.1-0.2 kg, which represented a loss of 1-3% of the initial body weight. On a day of normal feeding monkeys showed a mean of 4.57 +/- 0.53 LH pulses/12 h (measured from 1900-0700 h). On a subsequent day of fasting LH pulse frequency was significantly reduced to 1.86 +/- 0.46 pulses/12 h (P less than or equal to 0.05). Likewise, there was a similar decrease in testosterone pulse frequency on a day of fasting. The substantial decrease in LH/testosterone pulse frequency was not caused by the intensive blood-sampling regimen, in that collection of blood samples for 12 h on 2 consecutive days of normal feeding did not result in a decrease in either LH or testosterone pulse frequency. Administration of exogenous GnRH in doses of 0.05-0.3 microgram/kg caused LH pulses of similar magnitudes on a day of normal feeding and a day of fasting, suggesting that the decrease in LH pulse frequency during the day of fasting reflects a decrease in GnRH stimulation of the pituitary rather than a loss of pituitary sensitivity to GnRH. Measurement of pulsatile LH across 3 consecutive days (e.g. a day of normal feeding, a day of fasting, and a day of refeeding) indicated that LH pulse frequency is slow before the time that the meal is missed on the second day and remains low throughout the day of fasting (normal feeding, 7 +/- 1.16 pulses/24 h; fasting, 3.33 +/- 0.33 pulses/24 h). Refeeding a normal meal at 1100 h on the third day resulted in an immediate and sustained increase in pulsatile LH secretion above normal frequency (11.07 +/- 0.33 pulses/24 h). These results indicate that very brief periods of undernutrition can significantly suppress the central drive to the reproductive axis in male rhesus monkeys, and this suppression can be rapidly reversed by refeeding. These findings argue against the hypothesis that undernutrition only suppresses central drive to the reproductive axis once a substantial amount of body weight has been lost.

Animals↗

Endothelin stimulates testosterone secretion by rat Leydig cells.

The present study was designed to evaluate the effects of endothelin (ET) on rat testicular steroidogenesis in vitro and the involvement of prostaglandins (PG) and extracellular calcium in its mechanism of action. To this purpose we examined the effects of ET-1 and ET-3 on basal testosterone secretion, the influence of ET-1 on PGE2 release, the interaction of ET-1 and ET-3 with human chorionic gonadotrophin (hCG) and the interference of indomethacin (an inhibitor of cyclooxygenase) and nifedipine (a calcium-channel blocker) in purified rat Leydig cells. The data indicate that ET-1 and ET-3 stimulate basal and hCG-induced testosterone production although the effects of ET-3 were less marked. In addition, a concomitant release of PGE2 was observed after exposure to ET-1. A synergistic interaction between ET-1 and hCG in stimulating testicular steroidogenesis was revealed. Indomethacin was ineffective in modifying ET-1 evoked testosterone output, while in the presence of nifedipine the stimulatory effect of ET-1 was completely abolished. Since it has been shown by others that ET-1 is produced by rat Sertoli cells and specific binding sites are present in Leydig cells, the results of our study indicate that such a peptide may be regarded as a new paracrine factor able to influence steroidogenesis in Leydig cells. The action of ET-1 requires the activity of voltage-operated Ca2+ channels, while PGE2 activation is not essential for its steroidogenic effect.

Animals↗

Blockade of neonatal activation of the pituitary-testicular axis: effect on peripubertal luteinizing hormone and testosterone secretion and on testicular development in male monkeys.

The objective of this study was to examine the effect of blockade of neonatal activation of the pituitary-testicular axis, using a GnRH agonist, on sexual development in male rhesus monkeys. Monkeys were treated with either a GnRH agonist (10 micrograms/day; n = 8) or vehicle (n = 9) for 112 days using osmotic minipumps beginning at 10-13 days of age. In control monkeys serum LH and testosterone concentrations during the first 3 postnatal months were similar to those in adults; they then declined to very low levels. GnRH agonist administration caused an immediate and precipitous decline in serum LH and testosterone concentrations to very low levels, and both remained low throughout the rest of the agonist administration period. Neither group had any significant elevation in serum LH or testosterone concentrations during the next 2 yr. In the control monkeys serum LH and testosterone began to rise during the third year, with a rapid increase occurring during the fall coincident with the breeding season. This peripubertal rise of LH and testosterone secretion was associated with rapid enlargement of the testes and the appearance of sperm in ejaculates. The monkeys who had received GnRH agonist had subnormal serum LH and testosterone increases, and testicular enlargement was also attenuated compared to that in the control animals during the third year of life. Semen samples were recovered from only 50% of the GnRH agonist-treated monkeys during this period, and the sperm count per ejaculate was suppressed. The serum LH responses of the GnRH agonist-treated monkeys to an iv bolus dose of GnRH (5 micrograms/kg BW) during the third year were normal. These results suggest that the induction of reversible hypogonadotropin-hypogonadism in neonatal male monkeys alters subsequent testicular development and peripubertal endocrine changes. Thus, neonatal activation of the pituitary-testicular axis may be a critical developmental event in the process of sexual development in male primates.

Animals↗

Intratesticular factors and testosterone secretion. Effect of treatments that alter the level of testosterone within the testis.

The authors recently have reported the presence of a nongonadotropic polypeptide factor in rat testicular interstitial fluid that can exert marked stimulatory effects on Leydig cell testosterone production. To assess the potential physiologic significance of this factor, its effective levels in rat interstitial fluid have been investigated in response to treatments that either markedly reduce interstitial fluid testosterone concentrations (anti-LH treatment; transient or chronic experimental cryptorchidism; destruction of Leydig cells with ethane dimethanesulphonate) or that significantly elevate testosterone levels in interstitial fluid by injection of hCG. The possible relationship between this factor and changes in testicular weight, serum LH and FSH, and interstitial fluid volume also were monitored. When testosterone levels in interstitial fluid were decreased by 75 to 99% either acutely (5-72 hours) or chronically (20-75 days), there was an accompanying increase (P less than 0.001) in the levels of the interstitial fluid factor(s), as determined by the ability of charcoal-stripped interstitial fluid from individual rats to enhance hCG-stimulated testosterone production by Percoll-purified Leydig cells in vitro. Anti-LH treatment increased the levels of the interstitial fluid factor(s) over the ensuing 5 to 48 hours. In abdominal testes from rats made unilaterally or bilaterally cryptorchid for 20 or 55 days, a decrease in interstitial fluid testosterone levels was associated with increased levels of the interstitial fluid factor(s). The same inverse relationship was found 72 hours after treatment with ethane dimethanesulphonate in which Leydig cells had disappeared from the testis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effects of N-methyl-D,L-aspartate on LH, GH, and testosterone secretion in goat bucks maintained under long or short photoperiods.

Photoperiod modulates reproduction in goats. We tested the hypothesis that the excitatory glutamatergic tone is reduced in the photoinhibited goat. The objectives of this study were to determine the effect of photoperiod and glutamatergic stimulation on LH, GH, and testosterone (T) secretion in goat bucks. Eight mature, intact bucks were used in two simultaneous 4 x 4 Latin square designs. Variables were two photoperiod regimens (short day; SD, 10 h light:14 h dark, n = 4; vs long day; LD, 16 h light:8 h dark, n = 4) and four doses of N-methyl-D-L-aspartate (NMA; 0, 1, 2 and 4 mg/kg BW, i.v.). Venous blood was obtained for 2 h before and after NMA injection, followed by GnRH injection and then a final 1 h of sampling. Injection of NMA increased (P < 0.002) LH secretion within 20 min. This increase was sustained for 120 min, but the response was most pronounced in LD goats. The increase in mean LH was associated with a concomitant dose-dependent increase in pulse frequency (P < 0.006). However, NMA treatment had no effect (P > 0.10) on LH pulse amplitude. The release of LH after injection of GnRH was not affected by photoperiod. Exposure of bucks to LD reduced T secretion relative to that of SD bucks (P < 0.01). However, GH secretion was enhanced in LD bucks (P< 0.001). The response of GH to NMA was dependent on photoperiod history. A highly significant immediate and sustained increase (P < 0.001) was observed in LD but not in SD bucks within 10 min. Overall, a dose-dependent increase (P < 0.01) in T secretion was stimulated by NMA in both LD and SD bucks. These results indicate that NMA receptors may be involved in the regulation of LH, GH, and testosterone secretion in the goat. Furthermore, length of day influences GH secretion in the goat and NMA receptor activation had divergent effects on the secretion of this hormone.

Animals↗

Seasonal pattern of LH and testosterone secretion in adult male fallow deer, Dama dama.

At monthly intervals during the year blood samples were collected every 20 min for 12 h from 4 entire and 2 prepubertally castrated adult fallow deer bucks. In the entire bucks there were seasonal changes in mean concentrations and pulse frequencies of plasma LH. Mean concentrations in late summer and autumn were 3-6 times higher than during other seasons. LH pulse frequency was low (0-1 pulses/12 h) during most of the year and increased only during the 2-month period (January and February) that marked the transition from the non-breeding season to the autumn rut. During this period there was a close temporal relationship between pulses of LH and testosterone. However, during the rutting period (March and April) episodic secretion of testosterone, manifest as surges in plasma concentrations of 4-6 h duration, was not associated with any detectable pulses in LH although mean plasma concentrations of LH remained elevated. During the rut, the surges of plasma testosterone occurred at similar times of the day. Plasma profiles in May indicated very low concentrations of LH and testosterone secretion in the immediate post-rut period. Castrated bucks exhibited highly seasonal patterns of LH secretion, with mean plasma LH concentrations and LH pulse frequency being lowest in November (early summer) and highest in February and March (late summer-early autumn). Mean concentrations and pulse frequency of LH in castrated bucks were higher than for entire bucks at all times of the year.

Animals↗

Enhanced testosterone secretion in adult rams after establishment of a high-frequency, low-amplitude pattern of LH pulses in the nonbreeding season occurs without changes in the number or binding affinity of testicular LH receptors.

When the LH signal in the ram is changed from one of large and infrequent pulses to one of small and frequent pulses, the testes quickly become more responsive to LH and testosterone secretion is elevated, perhaps because the number and (or) binding affinity of testicular LH receptors have increased. An experiment was undertaken in the nonbreeding season (July) with 10 adult Dorset x Leicester x Suffolk rams that were about 3.5 years of age and 69 +/- 2 kg in body weight. Rams were given injections into the jugular vein of either 5 micrograms NIH-LH-S24 (in 1 ml saline) or vehicle every 80 min for 6 days. LH treatment produced a series of LH pulses that occurred three times more frequently and were 70% less in amplitude than pulses in the control rams, without causing mean LH concentration to increase. Endogenously produced LH pulses were not evident in the treated rams after LH injection began. The modified LH-pulse pattern elevated mean testosterone concentration by 150% (assessed on days 2 and 5), and caused the cumulative testosterone response to LH pulses, estimated by multiplying testosterone-pulse amplitude by frequency per 6 h, to increase progressively by 180% (days -2 through 5). Enhanced testicular steroidogenic activity, presumably due to greater enzymatic activity and cholesterol availability within Leydig cells, was not associated with increases in either the concentration or affinity of LH-binding sites in the testis (assessed on days 3 and 6).

Animals↗

Gonadotropin-releasing hormone-induced changes in testosterone secretion in normal women.

This study investigated the pattern of testosterone (T) secretion in spontaneous (n = 14) and gonadotropin-releasing hormone (GnRH)-treated (n = 6) menstrual cycles in normal women. In spontaneous cycles, T was found to increase progressively over the follicular phase (P less than or equal to 0.001), with the peak T value occurring on cycle day 0 (luteinizing hormone [LH] surge). The mean (+/- standard error of the mean [SEM]) T values on cycle day -14 and cycle day 0 were 35 +/- 4 and 51 +/- 4 ng/dl, respectively. GnRH was administered intravenously to six women at 1.3 to 1.7 micrograms per dose every 30 minutes in a study that assessed the ovarian effects of a rapid gonadotropin pulse frequency. In three of the women, the T levels followed a normal follicular phase pattern, whereas in the remaining three GnRH-treated women, there were marked increases in T with peak levels of 97, 123, and 81 ng/dl on day 0. The GnRH-treated subgroup with increased T levels had significantly increased follicular levels of LH, follicle-stimulating hormone (FSH), LH-bio and number of preovulatory ovarian follicles. This study demonstrated that increased levels of LH, FSH, and LH/FSH are capable of acutely increasing the secretion of ovarian androgens.

Adult↗