Studies of the human testis. XVII. Gonadotropin regulation of intratesticular testosterone and estradiol in infertile men

Serum levels of LH and FSH and the intratesticular concentrations of testosterone (T) and estradiol (E) were measured in biopsy tissue from 40 infertile men, aged 21-36 yr, of whom 21 were oligospermic men with varicocele and 19 were men with idiopathic oligospermia. Intratesticular T and E concentrations were negatively correlated (P less than 0.001) with testicular volumes, as measured with a calibrated orchidometer, suggesting that differences in measured intratesticular steroid levels in part reflect altered relative Leydig cell density as seminiferous tubular volume changes. To gather information about the regulation of intratesticular T and E by gonadotropins, we calculated an index of intratesticular steroid content by multiplying steroid concentration by testicular volume and compared these values with circulating LH and FSH levels. Highly significant positive correlations were found between both serum LH and FSH and intratesticular E content and between LH and FSH and intratesticular T content. Multivariant stepwise regression analysis revealed that while serum FSH is a strong predictor of intratesticular E (r = 0.72; P less than 0.001), serum LH is not (partial r = 0.00 when controlling for the influence of FSH). Instead, the apparent relationship between Serum LH and intratesticular E results from the highly positive correlation between serum LH and FSH in the patients studied (r = 0.71; P less than 0.001). Similarly, circulating LH levels are independently related to intratesticular T content (r = 0.67; P less than 0.001), whereas the relationship between FSH and T is indirect (partial r = 0.06 when controlling for the influence of LH). We believe that these associations suggest that the major regulator of intratesticular T content is LH and that FSH may be the important gonadotropin regulating intratesticular E.     

Diminished luteinizing hormone pulse frequency and amplitude with aging in the male rat

Aging in the male rat is associated with a reduction in circulating testosterone levels. One possible cause of this decline is an age-related alteration of central nervous system-mediated LH secretion. To examine the effects of age on the hypothalamo-hypophyseal system, in the absence of gonadal steroid feedback, we studied the pattern of pulsatile LH secretion in castrate male Sprague-Dawley rats, aged 3 months (young), 8 months (middle-aged), and 26 months (old). All animals were castrated, and after 3 weeks, they were implanted with indwelling atrial catheters. One day later, duplicate 25 microliters blood samples were obtained at 4-min intervals for 4 h, while the animals were awake and unrestrained. Serum levels of LH, FSH, and testosterone were measured in animals before castration, and blood LH levels were measured in the postcastration, repeated sampling studies. After castration, middle-aged and old animals exhibited significantly lower mean serum LH levels, associated with a diminished amplitude of LH secretory episodes compared to young rats. In the oldest group, LH pulse frequency was significantly lower compared to middle-aged and young animals. Since the control of LH secretory episodes resides in the central nervous system, we propose that alterations in frequency of LH pulses observed in the aged, castrate male rat are the result of a diminished functional capacity of LHRH-containing neurons or of neurotransmitters that modulate their activity in the aging brain.     

Do androgens directly regulate gonadotropin secretion in the polycystic ovary syndrome?

This study was designed to investigate whether androgens directly, independent of their aromatization to estrogens, disrupt gonadotropin secretion in hyperandrogenic women with the polycystic ovary syndrome (PCO). Pulsatile gonadotropin release and gonadotroph sensitivity to GnRH were determined on consecutive study days basally and during a primed continuous infusion of testosterone (T; n = 4; 100 micrograms/h; twice the mean production rate of T in PCO) or dihydrotestosterone (DHT; n = 5; 50 micrograms/h). To determine if the gonadotropin secretory changes during T infusion were secondary to spontaneous variation, four patients had two consecutive basal studies, and all patients received DHT on the third study day. T infusion that increased mean plasma T levels from 76 +/- 12 (+/- SE) to 315 +/- 28 ng/dl produced no significant changes in the amount or pattern of LH release or in LH sensitivity to GnRH. Mean plasma FSH levels decreased slightly but significantly during T infusion (basal, 242 +/- 29 vs. T 226 +/- 30 ng/ml LER-907; P less than 0.05 by two-tailed paired t test), but the pulsatile pattern of FSH release and FSH sensitivity to GnRH did not change. DHT infusion increased plasma DHT levels from 17 +/- 3 to 244 +/- 31 ng/dl, but did not alter the mean levels, pulsatile patterns, or sensitivity to GnRH of LH or FSH. These data suggest that androgens do not directly alter gonadotropin release in PCO. Thus, regulation of the hypothalamic-pituitary axis in women with PCO is different from that in men despite chronic exposure to hyperandrogenemia.     

The influence of chronic morphine treatment on the negative feedback regulation of gonadotropin secretion by gonadal steroids

The influence of continuous stimulation of opiate receptors with morphine (M) on the negative feedback effects of testosterone (T), 5 alpha-dihydrotestosterone (DHT), and 17 beta-estradiol (E2) on LH and FSH secretion was studied in rats that had been castrated 2 weeks previously. In the absence of gonadal steroids, 4 days of continuous M exposure did not alter LH or FSH levels. Similarly, Silastic capsules containing crystalline T (5 mm) or E2 [5 mm long (75 micrograms E2/ml) to 7.5 mm long (300 micrograms E2/ml)] alone had little effect on LH or FSH release. However, in M-exposed rats, T reduced serum LH by greater than 90%, and E2 reduced LH by more than 75%. Among the doses of DHT evaluated, only the highest dose (7.5-mm Silastic capsules packed with crystalline DHT) reduced LH secretion, and M exposure only slightly enhanced this suppression. M or gonadal steroids alone produced little change in FSH levels in castrated rats. However, the combination of M plus E2 or DHT further reduced FSH levels. Evaluation of pituitary responses to LHRH revealed that when administered alone, T did not alter, DHT reduced, and E2 enhanced the LH response to the decapeptide. Neither M treatment alone nor M plus T or DHT altered the pituitary LH response to LHRH. On the other hand, M appeared to enhance the stimulatory effects of E2 on pituitary responsiveness to LHRH. These findings suggest that the interaction of M and gonadal steroids at the level of the pituitary could not explain the observed marked suppression of gonadotropin secretion by suboptimal T or E2 during opiate receptor stimulation with M. Collectively, these observations are in accord with the view that endogenous opioid peptides may play a role in modulating the sensitivity of the hypothalamus to the negative feedback effects of gonadal steroids.     

The effects of aging in normal men on bioavailable testosterone and luteinizing hormone secretion: response to clomiphene citrate

Serum testosterone (T) levels in men decline with age while serum LH levels, as measured by RIA, increase. To assess if the decline in serum T levels in healthy aging men is paralleled by an age-related decline in the bioavailable non-sex hormone-binding globulin (SHBG)-bound fraction of T and to determine whether there are age-related changes in LH secretion or LH control of T production, we studied 29 young (aged 22-35 yr) and 26 elderly (aged 65-84 yr) healthy men. All men had single random blood samples drawn, and 14 men in each age group underwent frequent blood sampling for 24 h, both before and after 7 days of clomiphene citrate (CC) administration. Both mean 24-h serum total T levels and non-SHBG-bound T were reduced in elderly men compared to those in young men (P less than 0.05), while estradiol and SHBG levels were similar in the 2 age groups. Serum FSH determined by RIA and LH by RIA and bioassay were higher in the elderly men compared to those in young men (P less than 0.05), but the ratios of LH bioactivity to immunoreactivity and the LH pulse frequency and amplitude were similar. After CC administration, mean serum total T and non-SHBG-bound levels in young men increased by 100% and 304%, respectively, while in older men these values increased by only 32% and 8%, respectively. However, CC-stimulated LH pulse characteristics and serum levels of estradiol, SHBG, FSH, and bioactive and immunoreactive LH were similar in the 2 groups. Thus, both at baseline and after CC stimulation, elderly men had significantly lower serum total T and non-SHBG-bound (bioavailable) T levels than did young men, despite similar or increased levels of bioactive LH and similar bioactive to immunoreactive LH ratios and LH pulse characteristics. These results suggest that major age-related changes in the hypothalamic-pituitary-testicular axis occur at the level of the testes and are manifested by decreased responsiveness to bioactive LH. Administration of CC to young and elderly men resulted in similar changes in LH pulse characteristics and LH bioactivity and immunoreactivity, suggesting preserved hypothalamic-pituitary responsiveness in the elderly.     

Plasma 5 alpha-dihydrotestosterone and testosterone in the bullfrog, Rana catesbeiana: stimulation by bullfrog LH.

Effects of purified bullfrog (Rana catesbeiana) LH and FSH on plasma levels of the androgens, testosterone (T), and 5α-dihydrotestosterone (DHT), were studied using adult male bullfrogs. Rana LH was considerably more potent than Rana FSH in stimulating increased plasma androgen levels in hypophysectomized and intact animals. Simultaneous injection of Rana FSH or ovine PRL with Rana LH, over a 10-day period, did not alter the LH-induced increase in plasma androgens. More DHT than T was present in plasma after LH injection. Castration abolished plasma DHT and greatly reduced plasma T. Results indicate that DHT is a major testicular steroid, and that testicular androgen secretion is stimulated primarily by LH in the bullfrog.     

Ontogeny of serum and pituitary gonadotrophins in male rats treated with low doses of 5 alpha-dihydrotestosterone

The effect of s.c. daily injections of 10 or 1000 ng 5 alpha-dihydrotestosterone (DHT)100 g body weight from birth to day 21, or from days 26 to 117 of age, on the changes in concentration of serum and pituitary gonadotrophins was investigated in male rats. Treatment with 10 ng DHT from days 1 to 21 depressed serum FSH, but not LH, at day 7, while 1000 ng DHT depressed both serum LH and FSH. Treatment with both doses of DHT reduced pituitary levels of LH and FSH at day 7, with FSH being more depressed than LH. Treatment with 10 ng DHT from days 26 to 117 increased serum FSH from days 82 to 117, while 1000 ng DHT did not have this effect. Treatment with 1000 ng, but not 10 ng, DHT between days 26 and 117 reduced pituitary levels of LH and FSH at day 40. Rats treated with the two doses of DHT from days 26 to 117 showed a difference in the responsiveness of the pituitary to LH-releasing hormone (LHRH). Treatment with 10 ng DHT enhanced LHRH-induced release of LH without affecting FSH release, while 1000 ng DHT depressed LHRH-induced release of FSH but not of LH. These findings support the view that DHT may play a modulatory role in the ontogeny of serum gonadotrophins and the responsiveness of the pituitary to LHRH during the onset of puberty in the male rat.     

Studies on the feedback regulation of gonadotropin concentrations in male rats. (III). The effects of testosterone and its metabolites on gonadotropin secretion from rat pituitary cells in culture

To determine whether dihydrotestosterone (DHT) or estradiol (E2) exerts negative or positive feedback effects on rat pituitary gland, Testosterone (T) metabolite (T, DHT, 5 alpha-androstane-3 alpha, 17 beta-diol:3 alpha-diol or E2) was added to the cultured pituitary cells. Anterior pituitary glands were obtained from 6-week-old male rats. Pituitary cells were prepared by trypsin digestion and incubated with various concentrations of steroid hormones for 72 h to determine the effects of steroid hormones on basal secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) after 48 h preculture without steroids. Then 10 nM luteinizing hormone-releasing hormone (LH-RH) with appropriate concentrations of these steroid hormones was added to the pituitary cells in culture and incubated for another 6h to determine the effects of steroid hormones on LH-RH induced gonadotropin release. After the incubation, pituitary cells were lysed with 0.1% Triton X100 to measure the intracellular gonadotropin content. The concentration of LH and FSH was determined by radioimmunoassay. T, DHT and 3 alpha-diol stimulated basal FSH but not basal LH secretion, and inhibited both the release of FSH and LH from cultured pituitary cells during incubations with LH-RH in a dose-dependent fashion. Intracellular content of both FSH and LH were increased, and total FSH and not LH was also increased by the addition of DHT in a dose-dependent manner. E2 did not exert any of such effects on pituitary cells in culture. These studies suggest that 5 alpha-reduced metabolites but not aromatized metabolite of T play an important role on feedback regulation of gonadotropin secretion at pituitary level. DHT directly acts on pituitary gland not only to stimulate the production of FSH but also to suppress FSH and LH secretion induced by LH-RH.     

Effects of 10 days administration of percutaneous dihydrotestosterone on the pituitary-testicular axis in normal men

Dihydrotestosterone (DHT) was administered percutaneously in a dose of 125 mg twice daily for 10 days to 12 normal men. Basal plasma levels of testosterone (T), 17 beta-estradiol (E2), and LH were measured every 2 days in these men and every 5 days in subjects from a control group receiving placebo. The daytime course of plasma hormone levels between two DHT applications was studied in six men. LRH tests were performed in nine men before and on day 10 of DHT administration. Plasma levels of free T and free E2, and T - E-binding globulin capacity and affinity were measured in six men before and on days 5 and 10 of DHT administration. Before DHT administration, there was no difference in basal plasma levels of T, DHT, E2, and LH between the control and the DHT-treated group. In the latter group, plasma DHT levels increased sharply from 0.52 +/- (+/- SE) to 3.70 +/- 0.92 ng/ml on day 2 (P less than 0.001) during DHT treatment. Plasma T, E2, and LH levels decreased significantly from 7.33 +/- 0.74 to 1.33 +/- 0.54 ng/ml (P less than 0.001), from 46 +/- 5 to 20 +/- 3 pg/ml (P less than 0.01), and from 7.8 +/- 1 to 4.2 mIU/ml (P less than 0.05), respectively. Except for a small decrease in plasma DHT (P less than 0.05) 12 h after the previous DHT application, hormone levels were stable during the time between the two DHT treatments. The responses of LH and FSH to LRH were not different before and on day 10 of DHT administration. Plasma levels of free T and free E2 as well as those of total T and E2 decreased; however, the percentages of unbound T and E2 were not different before and during DHT administration. T - E-binding globulin capacity and affinity were not modified by DHT administration. Changes in plasma DHT levels were negatively correlated with those in The results of this study demonstrate that 10-days DHT administration has an inhibitory effect on the hypothalamo-pituitary-testicular axis in normal men.     

Effects of age on hormone levels and in vitro steroidogenesis by rat ovary and adrenal

In order to evaluate age-related changes in ovarian and adrenal steroid production, in vitro steroid production by adrenal glands and ovaries from young (3-4 mo) and middle-aged (10-11 mo) cycling rats was compared to serum steroid and gonadotropin levels on each morning of the estrous cycle. Basal LH levels were not different between young and mid-aged cycling rats except on estrus, when elevated estrogen (E) levels were correlated with depressed LH in the mid-aged rats. Basal FSH levels were generally elevated in mid-aged cycling and mid-aged constant estrus (CE) rats, but the FSH rise on estrus morning was not seen in the mid-aged rats. Serum progesterone levels were not changed with age or reproductive state, although in vitro ovarian progesterone secretion was decreased in mid-aged CE rats. Adrenal progesterone secretion increased significantly with age. Serum total testosterone was similar in young and mid-aged cycling and mid-aged CE rats, despite a highly significant increase in in vitro testosterone secretion by the CE ovary. Serum estradiol (E2) levels were significantly elevated on proestrus and estrus in the mid-aged rats. Although estrone (E1) levels appeared higher in the mid-aged than in the young cycling rats, the differences were not significant. Mid-aged CE rats had significantly elevated serum levels of both E1 and E2. In vitro ovarian estrone production was depressed in mid-aged cycling rats. Adrenal total estrogen production was similar in young and mid-aged animals. These results demonstrate that serum gonadotropin and steroid levels are altered in aging female rats prior to the loss of reproductive cycles. Changes in serum steroid levels are probably due to changes in circulating LH and FSH levels or the ovarian response to these gonadotropins, but changes in vitro basal steroid production suggest that intrinsic ovarian function may also change with advancing age. As rats enter a CE state, alterations in basal ovarian and adrenal steroid production are seen and may be partially responsible for maintenance of the acyclic state.     

Quantitating genetic and nongenetic factors that determine plasma sex steroid variation in normal male twins

We have observed that familial factors have a decided influence on the plasma content of sex steroids in men both in the general population and in men of families with prostatic cancer. The contribution of genetic and nongenetic familial factors on the variation of plasma sex steroid content and action has now been investigated in 75 pairs of normal male monozygotic (MZ) twins and 88 pairs of dizygotic (DZ) twins. Zygosity was determined by measuring ten blood proteins and enzymes. The mean plasma values for testosterone (T), dihydrotestosterone (DHT), estradiol (E2), estrone (E1), and 3 alpha-androstanediol glucuronide (3 alpha-diol G), free T, LH, FSH, SHBG, age, and degree of adiposity were all similar between the groups of twins. Familial factors (P less than 0.01) accounted for 50% or more of the variation in plasma hormone levels in MZ twins (3 alpha-diol G, 84%; T/DHT, 70%; T, 63%; E1, 63%; free T, 61%; E2, 57%; DHT, 56%; LH, 55%; and FSH, 54%) except for SHBG, which was 30%. The familial influence was greater in MZ twins than in DZ twins for all measurements except for SHBG. The heritability of the variation of hormone levels in plasma was determined from the equation: 2[rMZ(intraclass correlation) - rDZ]. Genes regulate 25% to 76% of the total variation of plasma content of the hormones except for DHT (12%) and SHBG (less than 1%). Genetic regulation of tissue DHT formation was suggested by observing a 48% genetic effect on the plasma content of 3 alpha-diol G.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gonadotropin gene expression and secretion in gonadotropin-releasing hormone antagonist-treated male rats: effect of sex steroid replacement.

The possibility of direct pituitary effects of sex steroids on gonadotropin gene expression and synthesis was studied in male rats. The animals were treated with a potent GnRH antagonist, Ac-D-pClPhe-D-pClPhe-D-Trp-Ser-Tyr-D-Arg-Leu-Arg-Pro-D-Ala-+ ++NH2CH3COOH (Org 30276; 0.5 mg/kg BW, sc, twice daily) for 10 days. Groups of the antagonist-treated rats were implanted at the beginning of the injections with Silastic capsules containing testosterone (T), 5 alpha-dihydrotestosterone (DHT), or diethylstilbestrol (DES). Groups treated with the antagonist alone or vehicle served as controls. The antagonist treatment decreased unoccupied pituitary receptors of GnRH by 93% (P less than 0.001), serum LH by 34% (P less than 0.01), and serum FSH by 30% (P less than 0.05), and serum T became undetectable (less than 0.10 nmol/liter). Compared to antagonist treatment alone, no further effects on serum or pituitary LH levels found after steroid replacements. In contrast, the antagonist-induced decreases in serum and pituitary FSH (30% and 70%, respectively; P less than 0.05-0.01) were totally reversed by the T and DHT implants, but not by DES. Pituitary levels of the LH beta-subunit mRNA were decreased by 60% (P less than 0.01) after antagonist treatment. Combination treatment with androgens had no further effect on this mRNA, whereas DES partially reversed this suppression (P less than 0.05). In contrast, the pituitary mRNA level of the FSH beta-subunit, which decreased with antagonist treatment by 90% (P less than 0.01), returned to the control level with T and DHT replacements, but only partially with DES. The pituitary mRNA level of the common alpha-subunit was significantly suppressed only by combined antagonist plus DHT treatment (P less than 0.01). However, combination of DES with the antagonist increased alpha-subunit mRNA levels 2.4-fold (P less than 0.05) compared to antagonist treatment alone. It is concluded that the suppression of gonadotropin secretion by GnRH antagonist treatment is accompanied in male rats by a parallel reduction in mRNA levels of the gonadotropin beta-subunits. Sex steroid replacement of the antagonist-treated animals selectively reverses some of the mRNA changes. Androgens (T and DHT) increase the mRNA of FSH beta-subunit, but have no effect on the LH beta-subunit. Estrogen increases the mRNA levels of common alpha- and LH beta-subunits and slightly increases that of FSH beta.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition

CONTEXT: Aging in men is associated with a decline in serum testosterone (T) levels. OBJECTIVE: Our objective was to assess whether decreased T in aging might result from increased estradiol (E2) negative feedback on gonadotropin secretion. DESIGN AND SETTING: We conducted a comparative intervention study (2004) in the Outpatient Endocrinology Clinic, Ghent University Hospital. PARTICIPANTS: Participants included healthy young and elderly men (n = 10 vs. 10). INTERVENTIONS: We used placebo and letrozole (2.5 mg/d) for 28 d, separated by 2 wk washout. MAIN OUTCOME MEASURES: We assessed changes in serum levels of free E2, LH, and FSH, free T, SHBG, and gonadotropins response to an i.v. 2.5-microg GnRH bolus. RESULTS: As assessed after 28 d of treatment, letrozole lowered E2 by 46% in the young men (P = 0.002) and 62% in the elderly men (P < 0.001). In both age groups, letrozole, but not placebo, significantly increased LH levels (339 and 323% in the young and the elderly, respectively) and T (146 and 99%, respectively) (P value of young vs. elderly was not significant). Under letrozole, peak LH response to GnRH was 152 and 52% increase from baseline in young and older men, respectively (P = 0.01). CONCLUSIONS: Aromatase inhibition markedly increased basal LH and T levels and the LH response to GnRH in both young and elderly men. The observation of similar to greater LH responses in the young compared with the elderly does not support the hypothesis that increased restraining of LH secretion by endogenous estrogens is instrumental in age-related decline of Leydig cell function.     

老年男性骨密度的增龄改变与骨代谢有关激素的相关性研究

目的探讨老年男性增龄与骨密度(BMD)及骨代谢有关激素的关系。方法123例老年男性按年龄分成3组,分别测定骨密度及血清甲状旁腺素(PTH)、睾酮(T)、雌二醇(E2)、卵泡刺激素(FSH)、黄体生成素(LH)并进行比较。结果老年男性BMD随增龄而减少,在股骨近端和髋关节处更为明显(P<0.05),在腰椎不确定;老年男性T、E2处于低水平,而FSH、LH及PTH随增龄而增高,FSH更为明显(P<0.05)。结论随着增龄,老年男性MBD下降,T、E2水平低下,而FSH、LH和PTH水平增高。提示体内骨代谢有关激素的变化,可能是老年男性骨质疏松症发病的重要机制之一。     

Evidence that testosterone can suppress pituitary gonadotropin secretion independently of peripheral aromatization.

Testosterone (T) was given to normal men with and without the concomitant administration of the aromatase inhibitor, delta 1-testolactone (Teslac), to examine the role of peripheral aromatization of T in gonadotropin regulation. When T was administered alone by continuous iv infusion (15 mg/day for 4 days), serum T increased 3-fold (P less than 0.01) and estradiol (E) increased by 50% (P less than 0.01). These changes were associated with a 50% decrease in serum LH and FSH concentrations (P less than 0.01). When T was infused into men taking Teslac (2000 mg/day), serum T levels doubled (P less than 0.01), but E levels did not change (13.4 +/- 1.5 vs. 13.5 +/- 1.0 pg/ml; P = NS). This pattern of plasma steroids, increased T and unchanged E, was also associated with significantly decreased serum LH and FSH concentrations (14.5 +/- 0.4 vs. 8.0 + 0.4 mIU/ml and 9.9 +/- 2.5 vs. 5.8 +/- 0.1 mIU/ml, respectively; P less than 0.01). These data support the hypothesis that T or one of its metabolites can modulate LH and FSH secretion independently of peripheral aromatization to E.     

Adrenal and gonadal steroids and pituitary response to LHRH in girls. I. Delayed puberty.

Plasma levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), dehydroepiandrosterone (DHA), dehydroepiandrosterone-sulphate (DHA-S), 17-hydroxyprogesterone (17P), androstenedione (A), testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) were measured in basal conditions in eleven young women from 16 to 25 years of age characterized by delayed puberty. The gonadotropin response to LHRH (50 microgram iv) was also tested in these cases. The results, as far as gonadotropins and E2 are concerned, indicate that delayed pubertyin girls is a heterogeneous disorder: an impairment in the negative feedback between E2 and FSH coexists with a reduced ovarian response to endogenous gonadotropins. All cases showed evidence of a more or less pronounced delayed adrenarche, which was demonstrated by the markedly reduced levels of DHA-S and DHA (with the exception of this latter steroid in two cases with idiopathic hirsutism). Furthermore, the very low plasma progesterone (P) levels in all cases suggest the existence of impaired delta 5 - delta 4 isomerase activity in the adrenal cells. Despite the low levels of A and T, DHT is within the upper limits of the normal range in all cases.     

Dopaminergic control of gonadotropin secretion in male senescence]

To verify the role of the dopaminergic mechanism in the control of gonadotropin secretion and aging of this mechanism in men, we studied serum gonadotropin response to LH-RH (100 micrograms i.v.) in basal condition and during dopamine infusion (DA 4 micrograms/kg/min). Seven young males (24-29yr.) and twenty aged males (50-80yr.) without endocrinological diseases were included in the present study. Aged male subjects were divided into hyperresponders, in whom maximal LH response to LH-RH without DA infusion exceeded 153.5mIU/ml (mean + 2SD of young male subjects), and non-hyperresponders, in whom maximal LH responses to LH-RH without DA infusion were less than 153.5mIU/ml. In hyperresponders, serum LH response at 30 minutes after LH-RH administration was significantly (p less than 0.05) suppressed by DA infusion. In non-hyperresponders and young male subjects, however, serum LH response to LH-RH was not affected by DA infusion. Basal levels of serum LH and FSH in hyperresponders tended to be higher than that of non-hyperresponders. Total serum testosterone, free testosterone and estradiol levels of hyper and non-hyperresponders failed to reveal any significant differences. These observations suggest that 1) DA directly suppresses gonadotroph responsiveness to LH-RH, 2) in aging men, inhibitory tone imposed on gonadotrophs by DA is decreased, and 3) this decline of DA system can cause hypergonadotropism in aging men, independent of serum sex steroids levels.     

Administration of dihydrotestosterone to rhesus monkeys inhibits gonadotropin-stimulated ovarian steroidogenesis

Androgens, in addition to serving as a substrate for estrogen biosynthesis, exert autocrine/paracrine actions on ovarian function. However, much of the information regarding the actions of androgens on the ovary has been obtained using rodents, and the extent to which these results can be extrapolated to higher primates is uncertain. The current study was initiated to determine the effects of dihydrotestosterone (DHT) and testosterone (T) on the responsiveness of the rhesus monkey ovary to exogenous FSH and LH in vivo. Rhesus monkeys whose spontaneous gonadotropin secretion was interrupted with a GnRH antagonist received s. . implants of either DHT or T for 5 d before and continuing throughout a 15-d i.v. infusion of human FSH and LH. Neither T nor DHT treatment synergized with FSH/LH to stimulate estrogen production or increases in ovarian weight. Rather, administration of DHT significantly reduced estrogen secretion and the augmentation of ovarian weight in response to exogenously administered FSH and LH. These results indicate that high concentrations of DHT are antagonistic to gonadotropin-stimulated ovarian function in primates.     

Hormonal responses to a potent gonadotropin hormone-releasing hormone antagonist in normal elderly men

GnRH analogs, both agonists and antagonists, have potential use in androgen-dependent diseases of older men, such as prostatic cancer and benign prostatic hyperplasia. Previous experience with agonists of GnRH has suggested that GnRH analogs may be more effective in aged men than in young men, but little is known about GnRH antagonists in older men. Therefore, we evaluated the hormonal effects of a single dose and a short course of a GnRH antagonist (Nal-Glu) in normal elderly men. Six young men (25-34 yr old) and six older men (66-76 yr) each received single morning injections of Nal-Glu (25, 75, and 250 micrograms/kg), separated by 2 weeks. Serum levels of testosterone (T), immunoreactive LH (LH RIA) and FSH (FSH RIA), and bioactive LH (LH BIO) were evaluated periodically for 7 days after each injection. In addition, six elderly men received 25 and 75 micrograms/kg.day Nal-Glu for 10 consecutive mornings each, and serum levels of T, inhibin, LH RIA, LH BIO, FSH RIA, and bioactive FSH were evaluated. Nal-Glu in all three single doses caused a significant (P less than 0.01) decline in serum levels of T and gonadotropins that was similar in extent in the elderly and young men. For example, T declined to a level of 19% of baseline after the 250 micrograms/kg dose of Nal-Glu in both age groups. For both the young and elderly men, the major effect of increasing the Nal-Glu dose was a prolongation of the period of suppression. Multiple Nal-Glu injections in the elderly men also resulted in a rapid decline in T, inhibin, and bioactive and immunoreactive gonadotropins. For both LH and FSH, bioactivity decreased to a greater extent than immunoreactivity. Local side-effects of Nal-Glu tended to be fewer and of less intensity in the elderly men compared to those in the young men. These results demonstrate that the response to Nal-Glu in healthy elderly men is similar to that in younger men, and extended administration of Nal-Glu in elderly men effectively suppresses gonadal and pituitary function. These results suggest that the role of GnRH antagonists in the effective treatment of androgen-dependent disease in the aging male needs to be explored further.     

Selective suppression of follicle-stimulating hormone by 3 alpha-hydroxy-4-pregnen-20-one, a steroid found in Sertoli cells

Previous reports have not identified a naturally occurring steroid that selectively inhibits FSH secretion without also inhibiting LH secretion. The effect of 3 alpha-hydroxy-4-pregnen-20-one (3-HP), a steroid produced in Sertoli cells, on gonadotropin secretion in intact and castrate male and female, prepubertal and adult rats and in cultures of anterior pituitary cells was investigated. Intact prepubertal male rats were treated with a single sc injection of 0.2 mg/kg 3-HP, and castrate male and female rats were given a daily sc injection of 0.2 mg/kg 3-HP for 4 days. Serum FSH levels were suppressed by 26-44% (P less than 0.001-0.05), with no similar effect on serum LH levels. The acetyl derivative of 3-HP (3-HPA), administered to castrate prepubertal and adult rats for 4 days (0.625 mg/kg), resulted in significant decreases (P less than 0.001) in serum FSH to 45% and 19% of castrate control levels, respectively, without a significant effect on LH levels. Treatment of castrate prepubertal male rats with various doses of 3-HPA (0.001-0.625 mg/kg X day) for 4 days resulted in a dose-related suppression of serum FSH. Similar results were obtained with chronic (14-day) treatment of intact male rats with 3-HPA. Treatment of young (15-day-old) intact males with either 3-HP or 17 beta-hydroxy-5 alpha-androstan-3-one (DHT) for 14 days showed that DHT resulted in significant increases in prostate and seminal vesicle weights, while 3-HP showed no apparent androgenic activity. The effects of treatment with 3-HP, 3 beta-HP, 17 beta-estradiol, and DHT (0.025-0.625 mg/kg X day) were compared. Treatment with 3 beta-HP resulted in significant increases in serum FSH levels; 17 beta-estradiol and DHT suppressed both gonadotropins (at the higher doses administered), while 3-HP suppressed only FSH. 3-HP (3.16 X 10(-11) M) and/or LHRH (3 X 10(-8) M) were employed in primary cultures of anterior pituitary cells. Addition of LHRH resulted in 6- to 8-fold increases in the secretion of FSH and LH, while 3-HP suppressed basal (P less than 0.05) and LHRH-stimulated (P less than 0.001) FSH secretion by 26% and 77%, respectively. We conclude that 3-HP selectively suppresses FSH secretion and may be involved in the normal regulation of FSH secretion in the male.