ACTIONS OF TESTOSTERONE ON THE AGING MALE GH AXIS

最近以病人为导向的调查表明，进行性促性腺功能减退和性腺功能减退始终伴随着健康的老龄化。在老年男性中，GH的每日分泌和睾酮的输出伴随着减少，使得到生命的第六至第八十个十年，这些激素的生物利用度降低约50%。随之而来的所谓的体衰和性腺衰包括与衰老的整体脆弱性相关的体征和症状的集合;例如，体能和耐力有限，肌肉质量和力量降低，骨矿物质含量损失，内脏肥胖增加，相对血脂异常，性欲和潜能下降，以及认知、健康感和生活质量受损。基于新的和令人信服的初步神经内分泌数据（见Bkgd），在这里，我们探讨了特定的调节理论，即驱动伴随的躯体aause和aonadoause的aathoahvsioloclical机制在老年男性中是因果联系的。特别地，我们假设：I。通过脉动静脉输注rh GH短期恢复年轻成人GH的可用性将缓解LH驱动的Leydig细胞睾酮分泌与年龄相关的下降;相反，II。在老年男性中短期补充睾酮通过特定的神经调节作用放大GH分泌，这解释了其独特的双重刺激GH和IGF-I的同时产生（与绝经后女性中的雌激素作用不同）;即：(i)GH的自负反馈抑制的沉默;（ii）GHRH前馈驱动的增强;（iii）GH分泌的生长抑素能抑制的缓解;和/或（iv）内源性GHRP（GH释放肽）-配体途径的促进。上述关键的临床假设将通过一种新的干预策略（目标I）和补充神经调节实验（目标II）的组合进行测试。这些临床机制研究的结果应进一步阐明导致老年男性促生长激素和性腺轴关节衰竭的病理生理学性质，从而开始阐明预防策略的潜在靶点，以限制人类双激素衰竭和与衰老相关的衰弱。

Recent patient-oriented investigations establish that progressive hyposomatotropism and hypogonadism consistently accompany healthy aging. The daily secretion of GH and the output of testosterone wane concomitantly in older men, such that by the sixth through eighth decades of life the bioavailability of these hormones is reduced by approximately 50%. The ensuant so-called somatopause and gonadopause encompass an ensemble of signs and symptoms associated with the overall frailty of aging; e.g., limited physical performance and stamina, reduced muscle mass and strength, loss of bone mineral content, increased visceral adiposity, relative dyslipidemia, declining libido and potentia, and variably impaired cognition, sense of well being and quality of life. Based on new and compelling preliminary neuroendocrine data (see Bkgd), here we explore the specific regulatory thesis that the aathoahvsioloclical mechanisms that drive the concomitant somatoaause and aonadoaause are linked causally in the aging male. In particular, we postulate that: I. Short-term restoration of young-adult GH availability by pulsatile i.v. infusions of rh GH will mitigate the age-related decline in LH-driven Leydig-cell testosterone secretion; and, conversely, II. Short-term supplementation with testosterone in older men amplifies GH secretion by way of specific neuroregulatory actions, which explicate its unique twofold stimulation of simultaneous GH and IGF-I production (unlike estrogen action in postmenopausal women); viz.,: (i) muting of GH's autonegative feedback restraint; (ii) enhancement of GHRH feedforward drive; (iii) relief of somatostatinergic inhibition of GH secretion; and/or (iv) facilitation of the endogenous GHRP (GH-releasing peptide)-ligand pathway. The foregoing pivotal clinical postulates will be tested via the combination of a novel interventional strategy (Aim I) and complementary neuroregulatory experiments (Aim II). The outcomes of these clinical mechanistic investigations should clarify further the nature of the pathophysiology subserving joint failure of the somatotropic and gonadal axes in aging men, and thereby begin to illuminate potential targets for preventive strategies desired to limit bihormonal failure and aging- associated frailt in the human.