Popovic V, Simic M, Ilic L, Micic D, Damjanovic S, Djurovic M, Obradovic S, Dieguez C, Casanueva F
Institute of Endocrinology, University Clinical Center, Belgrade, Yugoslavia.
Clin Endocrinol (Oxf). 1998 Jan;48(1):103-8. doi: 10.1046/j.1365-2265.1998.00360.x.
Growth hormone-releasing peptides (GHRPs) are potent GH releasers which act at both pituitary and hypothalamic levels through specific G-protein coupled receptors, recently cloned. A synergistic effect from the simultaneous administration of GHRH + GHRP-6 on GH release is observed in normal subjects, while it is absent in patients with hypothalamo-pituitary disconnection. We studied the effects of GHRH, GHRP-6 and both secretagogues on GH release in patients harbouring pituitary tumours that may be reduced in size by medical treatment.
Analysis of peak GH response to GHRH, GHRP-6 and GHRH plus GHRP-6 in patients with micro- and macroprolactinomas. Integrated GH response over 2 hours calculated as AUG-GH mU/l x 120 min. Analysis of delta PRL above the basal level in response to the same GH releasers.
Eleven patients with macroprolactinomas aged 41.2 +/- 4.8 years (range 24-75), nine patients with microprolactinomas aged 31.5 +/- 3.4 (range 22-53) and 13 healthy subjects aged 42.1 +/- 4.7 years (range 22-64) were studied. Prolactinoma patients were then treated with bromocriptine (15-20 mg orally) for 6-24 months. Tests were repeated when there was evidence of tumour shrinkage and normalized plasma prolactin concentrations.
Peak GH response before treatment in macroprolactinoma patients was 4.9 +/- 0.9 mu/l after GHRH, 8 +/- 4 mU/l after GHRP-6 and 18 +/- 5 mU/l after GHRH + GHRP-6. Synergism was absent. AUC were 390 +/- 90; 500 +/- 100 and 1100 +/- 300 mU/l x 120 min respectively. These values were all significantly different (P < 0.05) from normal subjects and patients with microprolactinomas with peak GH 16.8 +/- 0.9 mU/l after GHRH; 43 +/- 6 mU/l after GHRP-6 and 130 +/- 10 mU/l after GHRH + GHRP-6. AUC-GH was 1200 +/- 400 after GHRH, 2200 +/- 400 after GHRP-6 and 9000 +/- 1000 mU/l x 120 min after GHRH + GHRP-6. As in normal subjects, synergism was preserved in patients with microprolactinoma (P > 0.05). After treatment with bromocriptine peak GH in patients with macroprolactinoma was 8 +/- 4 mU/l after GHRH, 22 +/- 5 mU/l after GHRP-6 and 70 +/- 20 mU/l after GHRH + GHRP-6. AUC-GH was 800 +/- 300, 1100 +/- 300 and 3500 +/- 800 mU/l x 120 min, respectively. The response of GH after GHRP-6 and GHRH + GHRP-6 improved significantly (P < 0.05) in treated patients with macroprolactinoma. There was no significant change in GH response in microprolactinoma patients after treatment with bromocriptine. Peak GH after GHRH was 30 +/- 20 mU/l, after GHRP-6 it was 75 +/- 8 mU/l and after GHRH + GHRP-6 it was 200 +/- 30 mU/l. AUC-GH was 1500 +/- 700 after GHRH, 4500 +/- 500 after GHRP-6 and 15,100 +/- 600 mU/l x 120 min. Delta prolactin after GHRP-6 did not change before and after bromocriptine treatment in patients with macroprolactinoma or microprolactinoma.
GH release after GHRP-6 or GHRH + GHRP-6 is fully preserved in patients with microprolactinomas and does not differ before and after treatment with bromocriptine. Patients with macroprolactinoma have blunted responses of GH after GHRH and GHRP-6 and synergism is severely compromised. GH responsiveness to and synergistic interaction between GHRH and GHRP-6 recovers after shrinkage of macroprolactinoma with bromocriptine. Prolactin release stimulated by intravenous administration of GHRP-6 in healthy subjects was not seen in patients with micro- or macroprolactinomas.
生长激素释放肽（GHRPs）是强效的生长激素释放剂，通过最近克隆出的特异性G蛋白偶联受体作用于垂体和下丘脑水平。在正常受试者中观察到同时给予生长激素释放激素（GHRH）+生长激素释放肽-6（GHRP-6）对生长激素释放有协同作用，而在下丘脑-垂体分离的患者中则不存在这种协同作用。我们研究了GHRH、GHRP-6以及这两种促分泌素对垂体肿瘤患者生长激素释放的影响，这类垂体肿瘤患者可能通过药物治疗使肿瘤体积缩小。
分析微泌乳素瘤和大泌乳素瘤患者对GHRH、GHRP-6以及GHRH加GHRP-6的生长激素峰值反应。以生长激素增加值（AUG-GH，mU/l）×120分钟计算2小时内的生长激素综合反应。分析对相同生长激素释放剂反应时高于基础水平的泌乳素变化量（delta PRL）。
研究了11例年龄为41.2±4.8岁（范围24 - 75岁）的大泌乳素瘤患者、9例年龄为31.5±3.4岁（范围22 - 53岁）的微泌乳素瘤患者以及13名年龄为42.±4.7岁（范围22 - 64岁）的健康受试者。泌乳素瘤患者随后接受溴隐亭（口服15 - 20 mg）治疗6 - 24个月。当有肿瘤缩小及血浆泌乳素浓度正常化的证据时重复进行测试。
大泌乳素瘤患者治疗前对GHRH的生长激素峰值反应为4.9±0.9 μ/l；对GHRP-6为8±4 mU/l；对GHRH + GHRP-6为18±5 mU/l。不存在协同作用。曲线下面积（AUC）分别为390±90；500±100和1100±300 mU/l×120分钟。这些值与正常受试者及微泌乳素瘤患者均有显著差异（P < 0.05），微泌乳素瘤患者对GHRH的生长激素峰值为16.8±0.9 mU/l；对GHRP-6为43±6 mU/l；对GHRH + GHRP-6为130±10 mU/l。GHRH后的AUC-GH为1200±400，GHRP-6后为2200±400，GHRH + GHRP-6后为9000±1000 mU/l×120分钟。与正常受试者一样，微泌乳素瘤患者保留了协同作用（P > 0.05）。溴隐亭治疗后大泌乳素瘤患者对GHRH的生长激素峰值为8±4 mU/l，对GHRP-6为22±5 mU/l，对GHRH + GHRP-6为70±20 mU/l。AUC-GH分别为800±300、1100±300和3500±800 mU/l×120分钟。接受治疗的大泌乳素瘤患者对GHRP-6和GHRH + GHRP-6后的生长激素反应显著改善（P < 0.05）。溴隐亭治疗后微泌乳素瘤患者的生长激素反应无显著变化。对GHRH的生长激素峰值为30±20 mU/l，对GHRP-6为75±8 mU/l，对GHRH + GHRP-6为200±30 mU/l。GHRH后的AUC-GH为1500±700，GHRP-6后为4500±500，GHRH + GHRP-6后为15100±600 mU/l×120分钟。大泌乳素瘤或微泌乳素瘤患者溴隐亭治疗前后GHRP-6后的泌乳素变化量无改变。
微泌乳素瘤患者对GHRP-6或GHRH + GHRP-6后的生长激素释放完全保留，且溴隐亭治疗前后无差异。大泌乳素瘤患者对GHRH和GHRP-6后的生长激素反应减弱，协同作用严重受损。溴隐亭使大泌乳素瘤缩小后，生长激素对GHRH和GHRP-6的反应性及协同相互作用得以恢复。在健康受试者中静脉注射GHRP-6刺激释放的泌乳素在微泌乳素瘤或大泌乳素瘤患者中未观察到。
