The Effects of Intensive Blood Pressure Lowering on Markers of Mineral Metabolism in Persons with CKD in SPRINT
Charles GinsbergRonit KatzMichel B. ChoncholAlexander L. BullenKalani L. RaphaelWilliam R. ZhangWalter T. AmbrosiusJeffrey T. BatesJavier A. NeyraAnthony A. KilleenHenry PunziMichael G. ShlipakJoachim H. Ix
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Serum concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are elevated in patients with CKD, and higher concentrations are well established as risk factors for cardiovascular disease and death (1). In the Systolic Blood Pressure Intervention Trial (SPRINT), intensive systolic BP lowering led to lower rates of cardiovascular events and mortality despite a more rapid decline in eGFR (2). Given that FGF23 and PTH would be expected to increase in the setting of declining eGFR, the effects of intensive systolic BP control on these key potential intermediates are of considerable interest. The SPRINT, described in detail elsewhere (2,3), was a randomized, controlled trial among nondiabetic persons with hypertension evaluating the effects of intensive systolic BP lowering (<120 mm Hg) versus standard systolic BP target (<140 mm Hg). Of the 9361 participants enrolled in the SPRINT, 1000 participants with an eGFR<60 ml/min per 1.73 m2 were randomly chosen to have repeated serum measurements of intact FGF23 (Kainos), intact PTH, calcium, phosphate, and urine creatinine and phosphate (4). Using these data, we calculated fractional excretion of phosphate (FePhos) and fractional excretion of calcium. We evaluated the changes in each parameter from baseline to year 1 stratified by intervention status. We used linear mixed models to evaluate the effect of randomization to the intensive BP lowering arm on longitudinal changes in serum FGF23, PTH, calcium, phosphate, FePhos, and fractional excretion of calcium. Of the 1000 participants with CKD randomly sampled for this study, 987 had specimens available at year 1. Baseline characteristics stratified by intervention arm are reported elsewhere (5). The mean age was 72±9 years old, 42% were women, and the mean eGFR was 46±10 ml/min per 1.73 m2. Baseline intact FGF23 concentrations were 65 and 66 pg/ml in the standard and intensive arms, respectively. The mean eGFR changes were +1.58 and −2.12 ml/min per 1.73 m2 in the standard and intensive arms, respectively. Compared with participants in the standard arm, participants in the intensive arm experienced an 11.5% (95% confidence interval, 6.0 to 17.0) increase in FGF23 over the year (Table 1). This relative difference in FGF23 was unchanged by adjustment for concurrent changes in eGFR and albuminuria. There were no relative differences in serum PTH, calcium, or phosphate across treatment arms. In parallel with the increase in FGF23 in the intensive arm, FePhos rose by 4.2% in the intensive arm relative to the standard arm, although this association was not statistically significant (P=0.15). Table 1. - Effect of intensive BP therapy on markers of mineral metabolism Outcome Intensive Arm, a % Change/yr (95% CI) Standard Arm, % Change/yr (95% CI) Difference between Arms, b % Change/yr (95% CI) P Value ΔIntact FGF23 −0.6 (−4.4 to 3.2) −12.1 (−16.1 to −8.0) 11.5 (6.0 to 17.0) 0.01 ΔIntact PTH −4.6 (−7.7 to −1.4) −3.0 (−6.1 to 0.1) −1.6 (−6.1 to 2.9) 0.33 ΔPhosphate 1.19 (0.08 to 2.31) −0.06 (−1.24 to 1.13) 1.25 (−0.38 to 2.88) 0.13 ΔCalcium 0.26 (−0.23 to 0.74) 0.13 (−0.39 to 0.65) 0.13 (−0.59 to 0.84) 0.73 ΔFractional excretion of phosphate 2.69 (−1.17 to 6.56) −1.49 (−5.56 to 2.60) 4.18 (−1.45 to 9.80) 0.15 ΔFractional excretion of calcium −13.46 (−21.17 to −5.78) −7.83 (−15.89 to 0.32) −5.63 (−16.85 to 5.56) 0.33 95% CI, 95% confidence interval; FGF23, fibroblast growth factor 23; PTH, parathyroid hormone.aValues adjusted for baseline concentrations.bStandard arm serves as reference. In this analysis of randomized, controlled trial participants with hypertension and CKD, we demonstrate that randomization to the intensive BP arm resulted in a relative increase in FGF23 over 1 year and was accompanied with a nonsignificant increase in FePhos. Moreover, the change in FGF23 did not seem to be explained by the observed concurrent decrease in eGFR. The clinical implications of these findings are uncertain. Although longitudinal increases in FGF23 levels have been associated with greater cardiovascular risk in patients with CKD (6), the intensive arm of the SPRINT experienced lower cardiovascular events and mortality risk despite the concurrent rise in FGF23 (2). Thus, mechanisms leading from intensive BP lowering to cardiovascular protection are likely via pathways distinct from FGF23. A priori, we hypothesized that reductions in eGFR due to intensive BP lowering would lead to increases in FGF23 and PTH. However, we found that the increases in FGF23 persisted despite accounting for concurrent changes in eGFR, and PTH did not change. These findings suggest that mechanisms beyond changes in eGFR may be driving increases in FGF23. Responsible mechanisms and the examination of other markers of mineral metabolism (e.g., Klotho) require additional investigation. The observed rise in FePhos in the intensive arm suggests that the changes in FGF23 may be biologically meaningful. This study has important limitations. Implicit in the evaluation of 1-year changes in FGF23, participants had to survive to year 1, and some participants had cardiovascular events prior to the year 1 measurement. It would be optimal to examine the association of changes in FGF23 with subsequent cardiovascular risk. However, this inherent survival bias to year 1, the small sample size with repeated measurement, and the short-term follow-up after year 1 in the SPRINT preclude us from evaluating the clinical consequences of these increases in FGF23. We previously found that baseline FGF23 concentrations in the SPRINT had no independent associations with cardiovascular events or mortality after adjustment for eGFR (4). In addition, among SPRINT participants with CKD, randomization to the intensive arm was associated with a statistically significant reduction in mortality risk (2). Thus, although a longitudinal rise in FGF23 is of high interest and warrants future study, we do not believe that these findings should dissuade clinicians from pursuing aggressive systolic BP lowering in their patients with CKD. In conclusion, among SPRINT participants with CKD, those randomized to the intensive BP arm experienced a 12% relative increase in serum FGF23 over 1 year compared with participants in the standard arm. Further investigation is needed to understand the clinical consequences of changes in FGF23 that occur during intensive BP lowering. Disclosures Dr. Chonchol reports grants from Otsuka, grants from Sanofi, and grants from Kadmon outside the submitted work. Dr. Shlipak is a scientific advisor for TAI Diagnostics. All remaining authors have nothing to disclose. Funding This work was supported by the National Institutes of Health (NIH) and the National Research Service Award through the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) grants RO1DK098234 and K24DK110427 to J.H.I. and T32DK104717, F32DK116476, and K23DK118197 to C.G., the NIH Loan Repayment Program to C.G., and the American Heart Association grant 14EIA18560026 to J.H.I.. SPRINT is funded with federal funds from the NIH, including the National Heart, Lung, and Blood Institute, the NIDDK, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200900049C, and interagency agreement A-HL-13-002- 001. It was also supported in part with resources and use of facilities through the Department of Veterans Affairs. We also acknowledge the support from the following Clinical and Translation Science Awards funded by National Center for Advancing Translational Sciences, Case Western Reserve University, UL1TR000439; Ohio State University, UL1RR025755; University of Pennsylvania, UL1RR024134 and UL1TR000003; Boston University, UL1RR025771; Stanford University, UL1TR000093; Tufts University, UL1RR025752, UL1TR000073, and UL1TR001064; University of Illinois, UL1TR000050; University of Pittsburgh, UL1TR000005; University of Texas, Southwestern, 9U54TR000017-06; University of Utah, UL1TR000105-05; Vanderbilt University, UL1 TR000445; George Washington University, UL1TR000075; University of CA, Davis, UL1 TR000002; University of Florida, UL1 TR000064; University of Michigan, UL1TR000433; Tulane University, P30GM103337 Centers of Biomedical Research Excellence Award National Institute of General Medical Sciences; and Wake Forest University, UL1TR001420.Keywords:
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To study the influence of different blood glucose (BG) concentrations on the release of pituitary hormones, the effect of the simultaneous iv administration of LRH (200 micrograms), TRH (400 micrograms), and arginine (30 g/30 min) upon the serum concentrations of LH, FSH, TSH, PRL, and GH was determined in six male insulin-dependent diabetics. BG concentration was clamped by feedback control and an automated glucose-controlled insulin infusion system at euglycemic (BG 4-5 mmol/liter) or hyperglycemic (BG, 14-18 mmol/liter) levels. Increments in serum concentrations of LH, FSH, TSH, and PRL were similar in the euglycemic and hyperglycemic steady states, whereas the GH response to arginine was suppressed during the hyperglycemic clamp (P less than 0.01). Omission of exogenous insulin during hyperglycemia did not modify the observed hormonal responses. Thus, the release of LH, FSH, TSH, and PRL in response to adequate acute stimuli at the pituitary level is not modulated by hyperglycemia in insulin-dependent diabetes, while arginine-induced GH release is suppressed. Since the effect of arginine on GH is most likely mediated by an action on the hypothalamus, the data suggest that elevated glucose concentrations may exert their modulatory influence on GH secretion at the hypothalamic rather than at the pituitary level.
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Corticosterone (CORT) and other glucocorticoids cause peripheral insulin resistance and compensatory increases in β-cell mass. A prolonged high-fat diet (HFD) induces insulin resistance and impairs β-cell insulin secretion. This study examined islet adaptive capacity in rats treated with CORT and a HFD. Male Sprague-Dawley rats (age ∼6 weeks) were given exogenous CORT (400 mg/rat) or wax (placebo) implants and placed on a HFD (60% calories from fat) or standard diet (SD) for 2 weeks (N = 10 per group). CORT-HFD rats developed fasting hyperglycemia (>11 mM) and hyperinsulinemia (∼5-fold higher than controls) and were 15-fold more insulin resistant than placebo-SD rats by the end of ∼2 weeks (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR] levels, 15.08 ± 1.64 vs 1.0 ± 0.12, P < .05). Pancreatic β-cell function, as measured by HOMA-β, was lower in the CORT-HFD group as compared to the CORT-SD group (1.64 ± 0.22 vs 3.72 ± 0.64, P < .001) as well as acute insulin response (0.25 ± 0.22 vs 1.68 ± 0.41, P < .05). Moreover, β- and α-cell mass were 2.6- and 1.6-fold higher, respectively, in CORT-HFD animals compared to controls (both P < .05). CORT treatment increased p-protein kinase C-α content in SD but not HFD-fed rats, suggesting that a HFD may lower insulin secretory capacity via impaired glucose sensing. Isolated islets from CORT-HFD animals secreted more insulin in both low and high glucose conditions; however, total insulin content was relatively depleted after glucose challenge. Thus, CORT and HFD, synergistically not independently, act to promote severe insulin resistance, which overwhelms islet adaptive capacity, thereby resulting in overt hyperglycemia.
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The effect of 48 h of fasting in C57B1/6J-ob/ob and +/+ mice on body weight (BW), blood glucose (BG), serum immunreactive insulin (IRI), plasma immunoreactive glucagon (IRG) and on tissue levels of cyclic adenosine monophosphate (cAMP) were studied. Both groups of mice lost weight and demonstrated a decrease in BG and IRI with fasting. However, the BG and IRI of the ob/ob animals were initially highter and remained higher than those of the 2% of their initial weight while the +/+ lost 14 %. The +/+ mice exhibited an increase in cAMP levels in skeletal muscle, fat and liver with fasting, while the ob/ob mice had increased levels of cAMP in fat, but not in muscle. They also had a paradoxical decrease in liver cAMP levels with fasting, and associated with this was the lack of stimulation of glycogenolysis. Glycogenolysis was significant in the livers of fasted +/+ mice. The plasma IRG levels of the fed ob/ob mice were significantly higher (1.8) times) than those of the fed +/+ mice. Islet cAMP levels were decreased with fasting in ob/ob mice. However, the levels were significantly higher in 48-h faster ob/ob mice compared to the fasted +/+ group. The apparent paradoxical response to fasting observed in the livers of the ob/ob mice remains unexplained.
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Diabetes mellitus is frequently associated with reduced levels of TSH, PRL, GH, and gonadotropins. In this study we have wanted to determine whether chemically induced diabetes mellitus is associated with a decreased hypothalamic release of TRH. Male rats were made diabetic with streptozotocin (STZ; 65 mg/kg), whereas controls received vehicle. After 2 weeks, STZ diabetic rats had 25% lower body weights, 3.5-fold higher blood glucose, and 40-60% lower plasma TSH, T3, and T4 levels than controls. The plasma T4 dialyzable fraction had increased 2.5-fold in STZ diabetic rats, and the plasma free T4 concentration was similar to that in controls. Thus, treatment with STZ results in decreased plasma TSH and T4 levels, but does not reduce free T4 concentrations. The content of TRH in hypothalami of 2-week STZ diabetic rats was similar to that in controls, but in vitro these hypothalami released less TRH than those of control rats. In 2-week STZ diabetic rats, TRH in hypophysial stalk blood was 30% lower than that in control rats. The in vitro TRH secretion from hypothalami of untreated rats was dependent on the glucose concentrations in the incubation medium; increasing the glucose concentration from 10 to 30 mM did not alter TRH secretion, but basal TRH release increased in the absence of glucose. In conclusion, STZ-induced diabetes in the rat is associated with reduced hypothalamic secretion of TRH, which, in turn, may be responsible for the reduced plasma TSH and thyroid hormone levels. Furthermore, it is suggested that the inhibitory effect of STZ-induced diabetes on TRH secretion is probably not due to hyperglycemia.
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Bilateral destruction of the hypothalamic paraventricular nuclei (PVN) produced a profound depression of plasma TSH and the median eminence TRH concentration in hypothyroid rats. Anterior pituitary type II iodothyronine 5′- deiodinase (5′-D) activity was consistently lower but not significantly different in sham- and PVN-lesioned rats. Treatment with suboptimal replacement doses of 0.15 and 0.75 ng T4/100 g BW-day produced a graded depression of plasma TSH in the PVN (P < 0.02), but not in the sham (P > 0.8) groups. Adenohypophyseal 5′-D was depressed in both sham and PVN groups by the highest T4 dose. Plasma T4 was much lower in PVN than in sham rats given comparable doses of T4 (P < 0.001), but plasma T3 was not significantly different. This suggests that an increase in peripheral T4 metabolism was produced by PVN lesions. Our data indicate that changes in adenohypophyseal 5′- D activity are not responsible for the decrease in plasma TSH in PVN-lesioned rats and that neither the PVN nor endogenous TRH plays a significant role in the regulation of anterior pituitary 5′-D activity. (Endocrinology123: 1676–1681, 1988)
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Abstract Dysregulation of the adipoinsular axis in male obese Zucker diabetic fatty (ZDF; fa/fa) rats, a model of type 2 diabetes, results in chronic hyperinsulinemia and increased de novo lipogenesis in islets, leading to β-cell failure and diabetes. Diazoxide (DZ; 150 mg/kg·d), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 wk as a strategy for prevention of diabetes. DZ reduced food intake (P < 0.02) and rate of weight gain only in ZDF rats (P < 0.01). Plasma insulin response to glucose load was attenuated in DZ-Zucker lean rats (ZL; P < 0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P < 0.001). DZ improved hemoglobin A1c (P < 0.001) and glucose tolerance in ZDF (P < 0.001), but deteriorated hemoglobin A1c in ZL rats (P < 0.02) despite normal tolerance in the fasted state. DZ lowered plasma leptin (P < 0.001), free fatty acid, and triglyceride (P < 0.001) levels, but increased adiponectin levels (P < 0.02) only in ZDF rats. DZ enhanced β3-adrenoreceptor mRNA (P < 0.005) and adenylate cyclase activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet β3- adrenergic receptor mRNA (P < 0.005) but paradoxically decreased islet adenylate cyclase activity (P < 0.005) in these animals. Islet fatty acid synthase mRNA (P < 0.03), acyl coenzyme A carboxylase mRNA (P < 0.01), uncoupling protein-2 mRNA (P < 0.01), and triglyceride content (P < 0.005) were only decreased in DZ-ZDF rats, whereas islet insulin mRNA and insulin content were increased in DZ-ZDF (P < 0.01) and DZ-ZL rats (P < 0.03). DZ-induced β-cell rest improved the lipid profile, enhanced the metabolic efficiency of insulin, and prevented β-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing β-cell failure and progression to diabetes in humans.
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In normal rats, females have higher circulating GH-binding protein (GHBP) levels than males, whereas in the GH-deficient dwarf (Dw) rat, there is no sexual dimorphism in plasma GHBP, suggesting that GH secretion may be involved in this difference. In order to study the relationship between gonadal steroids and GH on GHBP and GH receptor regulation, the levels of plasma GHBP, hepatic bovine GH, and human GH (hGH) binding as well as GHBP and GH receptor messenger RNA (mRNA) have now been studied in normal, Dw, hypophysectomized (Hx), or ovariectomized (Ovx) rats, subjected to different GH and gonadal steroid exposure. In normal male rats, estradiol (E2, 12.5-25 micrograms/day for 1 or 2 weeks) markedly increased plasma GHBP and hepatic hGH, and bGH binding. These effects of E2 were diminished in Dw rats, absent in Hx rats, but restored in Hx rats given exogenous hGH. Plasma GHBP rose in female rats given E2, and fell in females given the anti-estrogen tamoxifen. Ovx animals had lower plasma GHBP and hepatic GH binding which was reversed by E2, but not testosterone treatment. Continuous hGH infusions in Ovx rats restored hepatic GH binding, and increased plasma GHBP. In Dw males, hGH increased plasma GHBP and hepatic GH binding, whereas testosterone had no effect on GHBP or GH receptors and did not affect their up-regulation by hGH. Hepatic levels of GHBP-, and GH receptor mRNA transcripts showed the same trends in response to steroid or GH treatment, but the differences were rarely significant, except in Ovx animals which had higher GHBP mRNA transcripts after GH or E2 treatment. Thus E2 and GH increase both plasma GHBP and hepatic GH receptor binding. GH up-regulates GHBP in the absence of E2, whereas E2 treatment does not raise GHBP in the absence of GH. Whereas some of the effects of estrogen could be mediated via alterations in GH secretion, estrogen may also directly influence GHBP production at the liver, but only in the presence of GH.
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GH secretion is markedly blunted in obesity; however, the mechanism(s) mediating this response remains to be elucidated. In the present study we examined the involvement of the two hypothalamic GH-regulatory hormones, GH-releasing factor (GRF) and somatostatin (SRIF), using the genetically obese male Zucker rat. Spontaneous GH, insulin, and glucose secretory profiles obtained from free moving, chronically cannulated rats revealed a marked suppression in amplitude and duration of GH pulses in obese Zucker rats compared to their lean littermates (mean 6-h plasma GH level, 3.9 ± 0.4 us. 21.5 ± 3.8 ng/ml; P < 0.001). Obese rats also exhibited significant hyperinsulinemia in the presence of normoglycemia. The plasma GH response to an iv bolus of 1 ng rat GRF-(1-29) NH2, administered during peak and trough periods of the GH rhythm, was significantly attenuated in obese rats at peak (137.4 ± 26.1 vs. 266.9 ± 40.7 ng/ml; P < 0.02), although not at trough, times. Passive immunization of obese rats with a specific antiserum to SRIF failed to restore the amplitude of GH pulses to normal values; the mean 6-h plasma GH level of obese rats given SRIF antiserum was not significantly different from that of obese rats administered normal sheep serum. Both pituitary wet weight and pituitary GH content and concentration were reduced in the obese group. Measurement of hypothalamic GRF immunoreactivity revealed a significant (P < 0.05) reduction in the mediobasal hypothalamic GRF content in obese rats (503.2 ± 60.1 pg/fragment) compared to that in lean controls (678.1 ± 50.2 pg/fragment), although no significant difference was observed in hypothalamic SRIF concentration. Peripheral SRIF immunoreactive levels were significantly (P < 0.01) elevated in both the pancreas and stomach of obese rats. These results demonstrate that the genetically obese Zucker rat exhibits 1) marked impairment in both spontaneous and GRF-induced GH release, which cannot be reversed by SRIF immunoneutralization, 2) significant reduction in pituitary GH concentration, 3) depressed hypothalamic GRF content, and 4) elevated gastric and pancreatic, but not hypothalamic, SRIF levels. The findings suggest that the defect in pituitary GH secretion observed in the genetically obese Zucker rat is due, at least partially, to insufficient stimulation by hypothalamic GRF, and that SRIF does not play a significant role. (Endocrinology127: 3087–3095, 1990)
Somatropin
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The role of the hypothalamic paraventricular nucleus (PVN) in thyroid hormone regulation of TSH synthesis during hypothyroidism was studied in adult male rats that were normal (n = 10), had primary hypothyroidism with sham lesions in the hypothalamus (n = 17), and had primary hypothyroidism with PVN lesions (n = 14). Two and 4 weeks after initiation of treatment, plasma levels of thyroid hormones (TSH, corticosterone and PRL) and pituitary content of TSH beta and alpha-subunit mRNA were measured. TRH mRNA levels in the PVN were determined by in situ hybridization histochemistry. At 2 weeks, despite a decrease in plasma free T4 in both hypothyroid groups, plasma TSH levels increased, but to a lesser degree, in the hypothyroid PVN lesioned compared to hypothyroid sham-lesioned group (7.8 +/- 1.3 vs. 20.5 +/- 1.1 ng/dl; P less than 0.05). Similarly, at 4 weeks, the hypothyroid PVN-lesioned group demonstrated a blunted TSH response compared to the hypothyroid sham-lesioned group (6.8 +/- 0.7 vs. 24.0 +/- 1.3 ng/dl; P less than 0.05). Plasma corticosterone and PRL did not significantly differ between sham-lesioned and PVN-lesioned groups. TSH beta mRNA levels markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls at 2 weeks (476 +/- 21% vs. 100 +/- 39%; P less than 0.05) and 4 weeks (1680 +/- 270% vs. 100 +/- 35%; P less than 0.05). In contrast, TSH beta mRNA levels did not increase with hypothyroidism in the PVN-lesioned group compared to those in euthyroid controls at 2 weeks (140 +/- 16%, P = NS) and only partially increased at 4 weeks (507 +/- 135; P less than 0.05). alpha mRNA levels at 4 weeks markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls (1121 +/- 226% vs. 100 +/- 48%; P less than 0.05), but did not increase in the hypothyroid PVN-lesioned rats (61 +/- 15%; P = NS). TRH mRNA in the PVN increased in the hypothyroid sham-lesioned rats compared to those in euthyroid controls (16.6 +/- 1.3 vs. 4.8 +/- 1.2 arbitrary densitometric units; P less than 0.05), and TRH mRNA was not detectable in the PVN of hypothyroid-lesioned rats at 2 weeks. In summary, lesions in rat PVN prevented the full increase in plasma TSH, pituitary TSH beta mRNA, and alpha mRNA levels in response to hypothyroidism. Thus, factors in the PVN are important in thyroid hormone feedback regulation of both TSH synthesis and secretion.
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