Influence of Hypothyroidism Duration on Developmental Changes in the Hypothalamic Factors Implicated in Growth Hormone Secretion in the Male Rat

Abstract

The effects of hypothyroidism duration on several factors implicated in GH secretion control were studied in the male rat at different maturity stages, ranging from the peripuberal period to adulthood. Thyroid ablation was performed on 22-day-old Wistar male rats maintained on a low iodine diet (T group). Age-paired controls (C group) were fed with the same diet, supplemented with potassium iodide. Subgroups of T and C animals (aged 32, 42, 52, 82 and 112 days) were studied 10, 20, 30, 60 and 90 days after surgery. After pentobarbital anesthesia, jugular blood was withdrawn before and 5 min after an intravenous TRH stimulus, for GH assay. Hypothalamic and pituitary tissues were obtained in order to measure GH, immunoreactive somatostatin (IR-SRIF) and growth hormone-releasing factor (IR-GRF). Growth rate and serum testosterone confirmed that C rats reached sexual maturity by day 30 of the study. Mean ± SE serum GH (ng/ml) increased (p < 0.05) in C animals from day 10 (38.5 ± 5) to day 30 (67.4 ± 7.3), with no significant variations thereafter. The same time sequence pattern was observed in pituitary GH concentrations. In T rats, both serum and pituitary GH decreased progressively from day 10 to 90, being significantly lower than in C at all times of the study. No GH response to TRH could be found in C groups. In contrast, GH increased significantly (p < 0.05) in T animals after TRH at days 20 and 30. Hypothalamic IR-SRIF concentrations (ng/mg protein) increased (p < 0.05) to adult levels in C rats between days 10 (15.7 ± 3) and 30 (26.3 ± 2.8), remaining unchanged thereafter. T animals showed the same pattern up to day 60. On day 90, IR-SRIF decreased abruptly in T (9.7 ± 2.9) as compared to both normal peers (30.8 ± 7.2; p < 0.01) and 60-day T rats (24.3 ± 5.1; p < 0.05). Hypothalamic IR-GRF (ng/mg protein) also increased (p < 0.05) between day 10 (2.9 ± 0.3) and 30 (4.3 ± 0.7) in C animals. This puberal rise did not occur in 30-day Trats, whose IR-GRF was lower (2.6 ± 0.3; p < 0.01) than in C. It can thus be concluded that a decrease in pituitary GH availability is not the only factor implicated in the abnormal GH secretion found in hypothyroidism. An enhanced GH response to TRH was found to coexist with a 94% reduction in pituitary GH content on days 20 and 30 of hypothyroidism. In the normal rat, hypothalamic IR-SRIF and IR-GRF content increased to adult values in the puberal period. The influence of hypothyroidism on the hypothalamic IR-SRIF content is closely related to its duration, occurring only in long-term thyroid deprivation. Hypothyroidism also prevents the puberal rise of IR-GRF, but does not affect the concomitant increase of IR-SRIF. The blunting of the puberal rise in IR-GRF occurs despite the normal testosterone increase in hypothyroid rats, suggesting that the diminished concentration of thyroid hormone impairs the testosterone-mediated IR-GRF rise.

Primary hypothyroidism in dogs is associated with elevated GH release

“…It is likely that the low thyroid hormone levels of hypothyroidism will result in a low expression of pituitary GH in species with a positive TRE in the GH gene. Indeed, in hypothyroid rats both decreased pituitary content of GH mRNA (Martinoli & Pelletier 1989, Lloyd et al 1990, Tam et al 1996 and reduced pituitary GH content (Szabo et al 1985, Katakami et al 1986, Wood et al 1987, Lloyd et al 1990, Varela et al 1991 have been reported. The lack of a decrease in GH biosynthesis and release in dogs with primary hypothyroidism may be explained by the absence of a positive TRE within the canine GH gene.…”

“…In contrast to observations in other mammals, in dogs both basal and integrated GH levels were significantly higher in hypothyroidism than in euthyroidism. In some mammals, such as sheep and steers, primary hypothyroidism does not seem to affect GH secretion (Elsasser et al 1992, Fletcher & Clarke 1994, whereas in rats (Varela et al 1991, Santini et al 1993, Mizobuchi et al 1996, Tam et al 1996, Osorio et al 1998) and pigs (Morovat & Dauncey 1998) primary hypothyroidism is associated with low circulating GH levels.…”

“…In healthy humans administration of TRH does not result in appreciable changes in plasma GH levels (Faggiano et al 1985, Coiro et al 1994, Hanew et al 1995, whereas in euthyroid rats stimulation with TRH elicits no (Varela et al 1991) or only a small transient (Szabo et al 1985) rise in plasma GH levels. In contrast, in humans and rats with primary hypothyroidism TRH administration results in significantly increased plasma GH levels (Faggiano et al 1985, Varela et al 1991, Coiro et al 1994, Hanew et al 1995. In line with these observations, Konaka et al (1997) have demonstrated the expression of TRH receptor mRNA in rat somatotrophs.…”

“…Severe hypothyroidism in rats is associated with markedly reduced circulating GH levels (Varela et al 1991, Santini et al 1993, Mizobuchi et al 1996, Tam et al 1996, Osorio et al 1998, abolished GH bursts (Takeuchi et al 1978, Katakami et al 1986, blunted GH response to GHRH (Williams et al 1985, Tam et al 1996 and decreased pituitary content of mRNA encoding for GH (Martinoli & Pelletier 1989, Lloyd et al 1990, Tam et al 1996. In addition, hypothyroidism in rats causes a reduction in pituitary GH content (Szabo et al 1985, Katakami et al 1986, Wood et al 1987, Lloyd et al 1990, Varela et al 1991, pituitary GHRH receptor mRNA (Tam et al 1996, Korytko & Cuttler 1997, hypothalamic SS content (Tam et al 1996) and hypothalamic SS mRNA (Tam et al 1996).…”

Use of basal and TRH‐stimulated plasma growth hormone concentrations to differentiate between primary hypothyroidism and nonthyroidal illness in dogs

“…18,22 In contrast, in some mammals, such as sheep, primary hypothyroidism does not seem to affect GH secretion, 23 whereas in humans, rats and pigs primary hypothyroidism is associated with low circulating GH concentrations. [24][25][26][27][28] The human and rat pituitary GH gene contains a positive thyroid hormone response element (TRE), 29 and as a consequence the low thyroid hormone concentrations of hypothyroidism will result in low expression of pituitary GH in these species. Indeed, in hypothyroid rats decreased pituitary content of both GH mRNA and GH protein have been reported.…”