Transdifferentiation of somatotrophs to thyrotrophs in the pituitary of patients with protracted primary hypothyroidism
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Thyrotropic cell
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Abstract The effects of hemithyroidectomy (hemiTX) and complete thyroidectomy (TX) on the cellular composition and the mitotic activity of the anterior pituitary gland were examined in genetically thyrotropin (TSH)‐deficient female Snell dwarf mice (dw/dw) and in phenotypically normal female mice (?/+) from the same strain. In normal (nondwarf) mice, both hemiTX and TX reduced the percentage of acidophilic (orange G‐positive) cells and increased the percentage of thyrotropic (aldehyde fuchsin [AF]‐positive) cells, whereas the percentage of gonadotrophs (PAS‐positive cells) and chromophobes (unstained cells) was not affected. Both interventions increased the mean mitotic activity rate (MMAR) of the anterior pituitary lobe. This effect was related to the enhancement of the MMAR of acidophilic cells and, particularly, thyrotropic cells. The MMAR of thyrotrophs in thyroidectomized normal mice was significantly higher than that in sham‐TX controls or in hemithyroidectomized animals. In Snell dwarf mice, neither hemiTX nor TX affected the percentage of the various cell categories (PAS‐positive, unstained, and extremely rare AF‐positive cells) in the anterior pituitary lobe. Furthermore, neither hemiTX nor TX substantially influenced the MMAR of the gland. No mitotic figures were found in the AF‐positive cells. Since the AF‐positive cells in the anterior pituitary of dwarf mice completely failed to respond to hemiTX or TX, we believe they are not true thyrotropic cells. Using electron microscopy, we confirmed a lack of somatotrophs, mammotrophs, and normal thyrotrophs in the anterior pituitary of Snell dwarf mice. The results provide morphological evidence of inactivity of the hypothalamo‐pituitary‐thyroid axis in Snell dwarf mice.
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目的 观察阿尔采默病(AD)患者皮肤基底细胞α-微管蛋白的变化.方法取患者背部皮肤,用免疫细胞化学和胶体金免疫电镜技术观察,并进行定量分析.结果免疫细胞化学染色显示,对照组皮肤免疫阳性染色主要位于表皮层基底细胞的胞质内,棘细胞层和颗粒层可见少量的阳性细胞;AD组基底细胞内着色深,棘细胞层和颗粒层亦有表达,但数量少.胶体金标记结果显示,对照组基底细胞可见较丰富的微管,标记的胶体金散在于胞质.AD组微管较对照组减少;标记的金颗粒数量较对照组明显增多.定量结果显示,AD组α-微管蛋白免疫细胞化学染色的AOD值(1.165±0.079)、VIOD值(186.000±15.853)均较对照组(0.814±0.152,96.020±14.755)明显增高(P＜0.01);α-微管蛋白胶体金标记颗粒数目AD组(20.74±3.99)亦较对照组(15.50±3.41)增多明显(P＜0.01).结论AD患者皮肤基底细胞内微管数量的减少,结构破坏,对皮肤组织的观察可能间接反映神经组织的改变。
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Congenitally primary hypothyroid growth-retarded (grt) mice exhibit a characteristic growth pause followed by delayed onset of pubertal growth. We characterized the developmental pattern of somatotropes, lactotropes and thyrotropes in the anterior pituitary, as well as plasma levels of their secretory hormones, in grt mice. Compared with normal mice, the weight of grt pituitary gland was similar at 8 weeks of age but significantly heavier after 12 weeks of age. Compared with normal mice, there were significantly fewer somatotropes in the grt pituitary until 8 weeks of age, but the number gradually increased up to 48 weeks. The number of lactotropes in grt mice was consistently lower than that in normal mice from 2 through 48 weeks, whereas the number of thyrotropes in the grt pituitary was consistently higher than in the normal pituitary. Thyrotropes in the grt pituitary exhibited hypertrophy and hyperplasia with less intensive thyroid-stimulating hormone (TSH) immunoreactivity than normal thyrotropes. In normal mice, the sum of the relative proportions of these cells plateaued at 8 weeks, where it remained up to 48 weeks of age. In grt mice, these proportions almost reached normal levels at 12 weeks of age but gradually declined after 24 weeks. Plasma growth hormone concentrations did not differ between grt and normal mice until 24 weeks of age. Compared with normal mice, grt mice exhibited significantly lower plasma prolactin and thyroxine levels but higher TSH levels. These findings indicate that development of somatotropes, lactotropes and thyrotropes in grt mice is impaired, being followed by altered hormone secretion.
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Somatotroph and thyrotroph pituitary cells share a common precursor cell expressing the transcription factor Pit1 in ontogeny. Cells expressing both thyrotropin (TSH) and growth-hormone (GH) are found in adult rat pituitary and in human pituitary adenomas in acromegaly, and these tumors contain both thyrotropin-releasing hormone (TRH) and the TRH receptors (TRHR). It has been shown that stimulation of TSH expression in primary hypothyroidism promotes changes suggestive of somatotroph to thyrotroph cell transdifferentiation. We tested this hypothesis and the role of TRH in experimental primary hypothyroidism in rats. Adult female Long-Evans rats, 6 months old, were administered the antithyroid drug methimazole (0.1% w/v) in the drinking water for 42 days. Animals were sacrificed by perfusion fixation under anaesthesia at weekly intervals and pituitary tissue processed in acrylic resin for immunofluorescence and immuno-electronmicroscopy for TSH, GH and TRHR. In the hypothyroid rat pituitary immunofluorescent somatotrophs were greatly reduced in number and gradually replaced by thyrotrophs during methimazole administration. Colocalization of GH and TSH in the same cell was noted. Immunoelectronmicroscopy demonstrated the development of enlarged thyrotrophs with dilated rough endoplasmic reticulum containing an electron-dense material and intracisternal granules, both of which are immunoreactive for TSH ('thyroidectomy cells'). The somatotrophs showed reduced GH immunoreactivity and also the presence of TSH-type, small-size secretory granules. This suggests that the greatly increased number of TSH-cells in methimazole-induced-hypothyroidism is due, at least partially, to the transdifferentiation of somatotroph into thyrotroph cells. TRHR immunofluorescence was expressed in many somatotrophs in normal rat pituitary and unlike immunoreactive GH, its expression was enhanced during hypothyroidism. The number of TRHR-immunoreactive cells increased in parallel with the number of TSH-immunoreactive cells. This indicates a role for TRH stimulation in the transdifferentiation process. Taken together, these data suggest that, in addition to the cell mutation mechanism involving an early totipotential progenitor cell, transdifferentiation of existing somatotroph cells also plays a part in the pathogenesis of multihormonal GH-secreting adenomas.
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Abstract The question of whether thyroxine (T 4 ) and TRH have a mitogenic effect on pituitary thyrotrophs and somatotrophs in thyroidectomized rats was investigated. Mitoses were counted in hematoxylin–eosin-stained or periodic acid–Schiff–hematoxylin-stained pituitary slides or immunostained for TSH or GH using male rats thyroidectomized for 5 months. Ten days before they were killed groups of rats were injected with different doses of T 4 (0·5, 3 or 10 μg i.m. every second day for 10 days), TRH alone (100 ng s.c. three times a day for 10 days), or T 4 plus TRH (same doses as above). Mitoses (stopped with colchicine) were counted in 1 mm 2 areas at a magnification of × 1000. In thyroidectomized rats, mitoses were not significantly increased and treatment with TRH or 0·5 μg T 4 alone in thyroidectomized rats did not affect mitotic counts. In thyroidectomized rats treated with higher doses of T 4 , mitoses were increased in a dose-dependent fashion. Simultaneous administration of TRH and T 4 had a significant synergistic effect on pituitary mitoses in a T 4 dose-dependent manner. The treatments also had differential effects on the relative percentages of cellular types in mitosis. Thus, 60% somatotrophs and 12·5% thyrotrophs were found in the euthyroid group. In thyroidectomized and thyroidectomized plus TRH groups, no somatotrophs in mitosis were seen, while thyrotrophs were 28·5% and 33·3% respectively. In thyroidectomized rats treated with low doses of T 4 , somatotrophs and thyrotrophs in mitosis increased to 38·4% and 80% respectively and, with simultaneous administration of a low dose of T 4 plus TRH, although less effective than T 4 alone, mitosis increased in somatotrophs and thyrotrophs to 11·1% and 54·5% respectively. A high dose of T 4 alone did not increase the mitotic figures in somatotrophs (38·8%), while it diminished the percentage of thyrotrophs to 25%. The administration of high doses of T 4 plus TRH had an opposite effect on the mitotic figures of somatotrophs and thyrotrophs and thus the percentage of somatotrophs increased to 50% while thyrotrophs decreased to 5·5%. Ten days of treatment with T 4 were insufficient to reverse the histology to euthyroidism. It can be concluded that in long-standing hypothyroidism: (1) thyroid hormone replacement elicits a dose-dependent and differential proliferative response on pituitary thyrotrophs and somatotrophs, (2) TRH is devoid of mitogenic effects when administered alone and (3) the proliferative response of somatotrophs to T 4 is enhanced by its co-administration with TRH, suggesting a permissive and/or synergistic effect of the thyroid hormone and TRH. Journal of Endocrinology (1997) 154, 149–153
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