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Short-term aromatase-enzyme blockade unmasks impaired feedback adaptations in luteinizing hormone and testosterone secretion in older men.

The mechanisms subserving hypoandrogenemia and relative hypogonadotropism in older men are not known. The present study tests the clinical hypothesis that aging impairs hypothalamopituitary adaptations to feedback withdrawal induced by antagonism of estrogen biosynthesis. To this end, we appraised gonadal axis responses to estrogen depletion induced by anastrozole (a potent and selective aromatase inhibitor) in nine older and 11 young men vs. placebo in 17 other older and eight young men. The study design comprised a prospectively randomized, double-blind, parallel-cohort intervention. To monitor LH release, blood was sampled every 10 min for 24 h; LH concentrations were assayed by two-site monoclonal immunoradiometric assay; pulsatile LH release quantitated by a model-free discrete peak-detection technique (Cluster); feedback-dependent orderliness of LH secretion via the approximate entropy statistic; and 24-h rhythmicity of LH concentrations by cosine analysis. At baseline, older men had comparable estradiol and testosterone but lower LH concentrations than young controls. Exposure to anastrozole reduced (24-h pooled) serum estradiol concentrations by 50% (P < 0.001) and elevated mean LH concentrations by 2.1-fold (P < 0.001) in both the young and older cohorts. However, older men failed to achieve young adult augmentation of the following: 1) total testosterone concentrations (P < 0.01) or molar testosterone to SHBG ratios (P < 0.01); 2) incremental LH pulse amplitude (P < 0.001) and LH peak area (P < 0.01); 3) mean LH pulse frequency (P = 0.0044); and 4) quantifiable irregularity (approximate entropy) of LH release patterns (P < 0.001). FSH concentrations became comparable in the two age cohorts. In summary, administration of a potent and selective aromatase antagonist reduces estradiol and elevates mean LH concentrations equivalently in young and older men. The low estrogen-feedback state in elderly men unmasks diminished incremental LH pulse amplitude and area; absence of further acceleration of LH pulse frequency; impaired regulation of the orderliness of LH release; and reduced testosterone to SHBG ratios. Thus, aging alters expected hypothalamopituitary-gonadal adaptations to short-term partial estrogen depletion in healthy men.

Adaptation, Physiological↗

Intratesticular factors and testosterone secretion: the role of luteinizing hormone in relation to changes during puberty and experimental cryptorchidism.

Testicular interstitial fluid (IF) from the rat contains a nongonadotropic polypeptide factor (or factors) which can enhance human CG (hCG)-stimulated testosterone production by Percoll-purified Leydig cells in vitro. The potential importance of this factor has been investigated by measuring its effective levels in testicular IF from individual rats during sexual maturation or after the induction of unilateral cryptorchidism (UCD). In both situations, the effect of modulating LH drive to the testis was also assessed. In abdominal testes from UCD rats, levels of the IF factor were nearly doubled (P less than 0.001) when compared to levels in the contralateral scrotal testis; this was associated with more than an 85% reduction in IF testosterone levels. Further lowering of testosterone levels by the injection of an antiserum to LH beta, raised levels of the IF factor by 30-40% (P less than 0.01) in both scrotal and abdominal testes. Conversely, raising of testosterone levels by injection of hCG caused more than a 90% reduction (P less than 0.001) in levels of the IF factor in both scrotal and abdominal testes. During sexual maturation, levels of the IF factor doubled (P less than 0.01) between 30 and 40 days of age, remained high until 70 days of age, and then decreased to the lower levels found in adult rats. High pubertal levels of the IF factor were associated with the most rapid phase of testicular growth and with a steady increase in the IF levels of testosterone. Injection of pubertal or adult rats with antiserum to ovine LH (oLH) reduced testosterone levels by approximately 85% and doubled (P less than 0.01) levels of the IF factor(s) in both groups. It is concluded that levels of the IF-factor are influenced: by testosterone levels and/or LH drive and by the maturational and/or functional status of the testis. These results also suggest that changing levels of the IF factor may be of physiological significance during puberty.

Animals↗

Cobalt-protoporphyrin suppresses testosterone secretion by multiple interactions within the brain-pituitary-testicular axis.

Administration of large doses of cobalt-protoporphyrin (CoPP), a synthetic heme analogue, to adult male rats leads to a rapid decline in serum concentrations of testosterone and luteinizing hormone (LH). Hypothalamic luteinizing hormone-releasing hormone (LHRH) contents are not affected by CoPP. The pituitary LH response to exogenous LHRH is attenuated by CoPP both in vivo and in vitro in pituitary cultures. Additionally, CoPP directly inhibits synthesis or release of testosterone by the testes. These effects are specific to CoPP and not shared by heme, inorganic cobalt or tin-protoporphyrin. Castration of CoPP-treated rats leads to a normal rise in LH concentrations, but this can be abolished by using testosterone implants to elevate serum testosterone concentrations to the low levels (approximately 0.4 ng/ml) typical of CoPP-treated intact rats. Thus, CoPP appears to be a pharmacological model for testing the mechanisms which underlie an enhanced negative feedback efficacy of testosterone on pituitary LH release.

Animals↗

Isosexual precocious pseudopuberty secondary to a testosterone-secreting Leydig cell testicular tumour: true isosexual development early after surgery.

The paper reports on a 6-year-old boy with precocious pseudopuberty due to androgen hypersecretion by a testicular interstitial cell tumour. Steroidogenesis, characterized by high testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone and 17-hydroxyprogesterone plasma levels, was not modified by ACTH, dexamethasone or HCG administration. Gonadotropins were subnormal and unresponsive to LRH stimulation. TSH and prolactin levels were normal both in basal and dynamic conditions. The hormonal profile progressively returned to prepubertal value and persisted normal for 6 months after removal of the tumour. The patient entered puberty spontaneously at 7,6/12 years showing a normal pubertal basal and LRH stimulated FSH and LH and a pubertal circadian rhythm of both gonadotropins and testosterone.

17-alpha-Hydroxyprogesterone↗

Relationship between rapid eye movement sleep and testosterone secretion in normal men.

The relation between the pituitary-gonadal hormones' rhythm and sleep physiology in men is not fully elucidated. To examine whether the reproductive hormones are correlated with sleep architecture, we determined the nocturnal serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in six healthy young men. Serum hormone levels were obtained every 15 minutes from 1900 to 0700 hours with simultaneous polysomnographic sleep recordings. Hourly testosterone levels were lowest when subjects were awake (1900-2200 hours) than during sleep (2300-0700 hours). Testosterone nocturnal rise antedated the first REM by about 90 minutes. The rise in testosterone levels was slower when REM latency was longer. Mean nocturnal testosterone levels did not correlate with the number of rapid eye movement (REM) episodes. Also, pre-non-REM (NREM) testosterone levels were higher as compared with the pre-REM periods and lower during the first NREM period as compared with other nocturnal NREM periods. Serum LH levels disclosed a nocturnal rise that preceeded a similar rise in testosterone by about an hour. We conclude that in young adult men, testosterone levels begin to rise on falling asleep, peak at about the time of first REM, and remain at the same levels until awakening.

Activity Cycles↗

Capillary blood flow in the tests and testosterone secretion in the starved rat.

The average capillary blood flow in the testes was found to be 181 microliter/min/g testis tissue (n = 19) in rats starved for 5 days and 273 microliter/min/g (n = 18, p less than 0.01) in the control group. Plasma testosterone was significantly decreased in the starved animals (1.00 +/- 0.06 ng/ml vs 5.43 +/- 0.63 ng/ml). When starved and control rats were stimulated with human chorion gonadotropin, testosterone values in plasma were greatly increased in both groups. The capillary blood flow was not altered. The date indicate that human chorion gonadotropin can stimulate testosterone production in the starved rat without influencing the reduced capillary blood flow.

Animals↗