Korbonits M, Jacobs R A, Aylwin S J, Burrin J M, Dahia P L, Monson J P, Honegger J, Fahlbush R, Trainer P J, Chew S L, Besser G M, Grossman A B
Department of Endocrinology, St. Bartholomew's Hospital, London, United Kingdom.
J Clin Endocrinol Metab. 1998 Oct;83(10):3624-30. doi: 10.1210/jcem.83.10.5210.
Synthetic GH secretagogues (GHSs; GH-releasing peptides and their nonpeptide mimetics) stimulate GH release, activate the hypothalamo-pituitary-adrenal axis, and release PRL in vivo. Patients with acromegaly show an exuberant GH response to GHSs, whereas patients with pituitary-dependent ACTH-secreting tumors show an exaggerated rise in ACTH and cortisol. We, therefore, studied the presence of GHS receptor (GHS-R) messenger ribonucleic acid (RNA) in 38 human pituitary tumors of different cell types, 3 ectopic ACTH-secreting tumors, a pancreatic gastrinoma, 3 insulinomas, and a non-secreting thymic carcinoid as well as in 7 normal pituitary glands. Certain pituitary tumors were also studied by in vitro cell culture with measurement of secreted GH, ACTH, PRL, FSH, LH, alpha-subunit, and TSH. RNA was extracted from tissue samples and, after RT, a duplex PCR reaction with primers for the GHS-R gene and for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was performed, allowing semiquantitation of GHS-R expression. All the somatotroph adenomas (n = 8) showed a 2-10 times higher expression of the GHS-R gene compared to normal pituitaries. Higher than normal expression was shown in 5 of 18 tumors from patients with ACTH-secreting pituitary adenomas and in 1 of 3 ectopic ACTH-secreting carcinoid tumors. Two of the pituitary ACTH-secreting adenoma samples showed completely absent expression of the GHS-R, 8 showed expression similar to that of normal pituitary tissue, and 3 of the corticotroph adenoma tissue samples and 2 ectopic ACTH-secreting tumors showed a very low level of expression. One of 4 prolactinoma samples showed a high level of expression, 1 showed expression similar to that of normal pituitary, and 2 samples showed a very low level of expression. Nonfunctioning pituitary adenoma samples showed either absent or very low level expression of the GHS-R. The pancreatic gastrinoma sample showed expression similar to that of normal pituitary tissue, whereas 3 insulinomas showed low level expression of the GHS-R gene; a nonsecreting thymic carcinoid tumor showed no detectable expression. In summary, although GHS-R messenger RNA is abundant in human somatotroph adenomas, it is also present in other pituitary adenomas, particularly ACTH-secreting tumors. These findings may explain the in vivo responses to GHSs in patients harboring such tumors. It also appears from our study that GHS-R may be expressed in other neuroendocrine tumors.
合成生长激素促分泌素（GHSs；生长激素释放肽及其非肽类模拟物）可刺激生长激素释放，激活下丘脑-垂体-肾上腺轴，并在体内释放催乳素。肢端肥大症患者对GHSs表现出旺盛的生长激素反应，而垂体依赖性促肾上腺皮质激素分泌肿瘤患者的促肾上腺皮质激素和皮质醇则出现过度升高。因此，我们研究了38例不同细胞类型的人垂体肿瘤、3例异位促肾上腺皮质激素分泌肿瘤、1例胰腺胃泌素瘤、3例胰岛素瘤和1例无分泌功能的胸腺类癌以及7个正常垂体中生长激素促分泌素受体（GHS-R）信使核糖核酸（RNA）的存在情况。还通过体外细胞培养并测量分泌的生长激素、促肾上腺皮质激素、催乳素、促卵泡激素、促黄体生成素、α亚基和促甲状腺激素，对某些垂体肿瘤进行了研究。从组织样本中提取RNA，反转录后，使用针对GHS-R基因和管家基因甘油醛-3-磷酸脱氢酶的引物进行双重PCR反应，以对GHS-R表达进行半定量分析。所有生长激素细胞腺瘤（n = 8）与正常垂体相比，GHS-R基因表达高2至10倍。分泌促肾上腺皮质激素的垂体腺瘤患者的18个肿瘤中有5个以及3个异位促肾上腺皮质激素分泌类癌肿瘤中有1个显示出高于正常的表达。垂体促肾上腺皮质激素分泌腺瘤样本中有2个显示GHS-R完全不表达，8个显示与正常垂体组织相似的表达，促肾上腺皮质激素细胞腺瘤组织样本中有3个和2个异位促肾上腺皮质激素分泌肿瘤显示出极低水平的表达。4个催乳素瘤样本中有1个显示高水平表达，1个显示与正常垂体相似的表达，2个样本显示极低水平的表达。无功能垂体腺瘤样本显示GHS-R表达缺失或极低。胰腺胃泌素瘤样本显示与正常垂体组织相似的表达，而3个胰岛素瘤显示GHS-R基因低水平表达；1个无分泌功能的胸腺类癌肿瘤未检测到表达。总之，虽然GHS-R信使RNA在人生长激素细胞腺瘤中丰富，但也存在于其他垂体腺瘤中，尤其是促肾上腺皮质激素分泌肿瘤。这些发现可能解释了患有此类肿瘤的患者在体内对GHSs的反应。我们的研究还表明，GHS-R可能在其他神经内分泌肿瘤中表达。
