Nolan L A, Thomas C K, Levy A
Henry Wellcome Labs for Integrative Neuroscience and Endocrinology, University of Bristol, Dorothy Hodgkin Building, Whitson St, Bristol BS1 3NY, UK.
J Endocrinol. 2004 Jan;180(1):35-43. doi: 10.1677/joe.0.1800035.
The anterior pituitary is active mitotically and apoptotically under basal conditions and in response to a variety of physiological and pathophysiological stimuli. Hypothyroidism in man is associated with a modest but very occasionally dramatic increase in overall pituitary size. The mechanisms underlying this reversible phenomenon remain obscure. In the present study we have examined young adult rat anterior pituitary following surgical thyroidectomy and subsequent thyroid hormone treatment and withdrawal using an extremely accurate system for quantifying directly identified mitotic and apoptotic events. Despite the expected increase in the number and/or proportion of immunohistochemically identifiable thyrotrophs three weeks after thyroidectomy, mitotic and apoptotic activity remained unchanged, as did pituitary wet weight, in comparison with sham-operated and intact controls. In contrast, mitotic but not apoptotic activity was enhanced by treatment of thyroidectomized animals with thyroid hormones (triiodothyronine (T3) and thyroxine (T4) 1.8 microg and 3.6 microg/100 g body weight per day respectively), and once again declined to levels seen in intact animals within 72 h of subsequent thyroid hormone withdrawal. Thyroid hormone-induced enhancement of mitotic activity was also seen in intact rats treated with similar doses of thyroid hormones for 7 days and in thyroidectomized rats treated for a similar period with very low dose thyroid hormone replacement at a level that had no effect on raised hypothalamic TRH- or pituitary TSHbeta-transcript prevalence (0.018 microg T3 plus 0.036 microg T4/100 g body weight per day). Thus changes in mitotic and apoptotic activity are unlikely to be the principle mechanism for the apparent increase in thyrotrophs up to 4 weeks after thyroidectomy. In contrast, the data indicate that thyroid hormones have a permissive effect on anterior pituitary mitotic activity in thyroidectomized male rats. Thyroid hormone-induced enhancement of mitotic activity in intact rats further suggests that in euthyroid rats, ambient thyroid hormone levels are a limiting factor for anterior pituitary mitotic activity. In summary, this time course study of young, male rats has shown for the first time that thyroidectomy, thyroid hormone replacement and subsequent withdrawal has no significant effect on anterior pituitary apoptotic activity. Secondly, it has shown that the anterior pituitary mitotic response to thyroidectomy is blocked by complete thyroid hormone deprivation, but can be restored by very low level thyroid hormone replacement, and thirdly that in intact animals thyroid hormone levels significantly limit anterior pituitary mitotic activity.
在基础状态下以及对各种生理和病理生理刺激作出反应时，腺垂体存在有丝分裂和凋亡活性。人类甲状腺功能减退与垂体整体大小适度但偶尔显著增加有关。这种可逆现象背后的机制仍不清楚。在本研究中，我们使用一种极其精确的系统直接量化已识别的有丝分裂和凋亡事件，对成年幼鼠在手术切除甲状腺以及随后进行甲状腺激素治疗和撤药后的腺垂体进行了研究。尽管在甲状腺切除术后三周，免疫组化可识别的促甲状腺激素细胞数量和/或比例预期会增加，但与假手术和完整对照组相比，有丝分裂和凋亡活性、垂体湿重均保持不变。相反，用甲状腺激素（三碘甲状腺原氨酸（T3）和甲状腺素（T4），分别为每天1.8微克和3.6微克/100克体重）治疗甲状腺切除的动物可增强有丝分裂活性，但不增强凋亡活性，并且在随后撤药72小时内，有丝分裂活性再次降至完整动物所见水平。在用相似剂量甲状腺激素治疗7天的完整大鼠以及用非常低剂量甲状腺激素替代治疗相似时间段（该剂量对升高的下丘脑促甲状腺激素释放激素（TRH）或垂体促甲状腺激素β（TSHβ）转录本患病率无影响，即每天0.018微克T3加0.036微克T4/100克体重）的甲状腺切除大鼠中，也观察到甲状腺激素诱导的有丝分裂活性增强。因此，在甲状腺切除术后长达4周的时间里，有丝分裂和凋亡活性的变化不太可能是促甲状腺激素细胞明显增加的主要机制。相反，数据表明甲状腺激素对甲状腺切除的雄性大鼠腺垂体有丝分裂活性具有允许作用。甲状腺激素在完整大鼠中诱导的有丝分裂活性增强进一步表明，在甲状腺功能正常的大鼠中，周围甲状腺激素水平是腺垂体有丝分裂活性的限制因素。总之，这项针对年轻雄性大鼠的时间进程研究首次表明，甲状腺切除、甲状腺激素替代及随后撤药对腺垂体凋亡活性无显著影响。其次，研究表明甲状腺完全切除会阻断腺垂体对甲状腺切除的有丝分裂反应，但极低水平的甲状腺激素替代可使其恢复，第三，在完整动物中，甲状腺激素水平显著限制腺垂体有丝分裂活性。
