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Effect of Altered Thyroid Hormone Levels on Hypothalamic-Pituitary-Adrenal Function^*

THEMIS C. KAMILARIS, C. ROWAN DEBOLD, SPYROS N. PAVLOU, DONALD P. ISLAND, ANESTIS HOURSANIDIS and DAVID N. ORTH

Department of Medicine, Vanderbilt University School of Medicine (T.C.K., C.R.D., S.N.P., D.P.I., D.N.O.) Nashville, Tennessee 37232
the Department of Endocrinology and Metabolism, Agia Marina Hospital, Institute of Social Security (A.H.) Athens, Greece

Address all correspondence and requests for reprints to: Dr. David N. Orth, Division of Endocrinology, AA-4206, Medical Center North, Nashville, Tennessee 37232.

To determine whether alterations in serum thyroid hormone levels affect hypothalamic-pituitary-adrenal function, we measured the plasma immunoreactive (IR) ACTH and IR-cortisol responses to 1 µg/kg BW ovine CRH (oCRH) given iv in the late afternoon and the plasma IR-ACTH, IR-cortisol, and IR-11-deoxycortisol responses to 2 g metyrapone given orally at midnight in 10 athyreotic patients during T₄ treatment and 1 month after stopping T₄ when they were biochemically, but not clinically, hypothyroid. Mean serum TSH increased from 0.7 ± 0.9 (±SD) mU/L (normal range 0.5–4.9 mU/L) during T₄ therapy to 107 ± 82 mU/L after stopping T₄. The serum total T₄ level and free T₄ index fell from 165 ± 37 nmol/L and 1.9 ± 0.4, respectively (normal range, 59–154 nmol/L and 0.9–2.5, respectively), to 19 ± 9 and 0.2 ± 0.1, respectively, after stopping T₄. Basal plasma IR-ACTH and IR-cortisol levels at 0800 and 1630 h were similar during and after stopping T₄ therapy. Peak plasma IR-ACTH and IR-cortisol levels after oCRH were significantly greater after stopping T₄ (20 ± 9.2 pmol/L and 880 ± 260 nmol/L, respectively) than during T₄ therapy (9.7 ± 4.7 pmol/L and 720 ± 190 nmol/L; P < 0.01 and P < 0.05, respectively). The mean integrated plasma IR-ACTH and IR-cortisol responses to oCRH were also significantly greater P < 0.01 and P < 0.05, respectively) after stopping T₄ than during T₄ therapy.

Plasma IR-ACTH the morning after metyrapone was slightly (1.6-fold) but not significantly greater during therapy than after stopping T₄ therapy (100 ± 86 vs. 65 ± 54 pmol/L, respectively). The plasma IR-11-deoxycortisol responses to metyrapone during and after stopping T₄ therapy were similar (720 ± 250 and 750 ± 330 nmol/L, respectively), presumably because plasma IRACTH concentrations were maximally stimulating in both instances.

These results indicate that thyroid hormone deficiency of short duration 1) increases corticotroph sensitivity to oCRH, 2) may diminish the plasma ACTH response to metyrapone-induced hypocortisolemia, and 3) has no apparent effect on the acute adrenal response to ACTH. These data together with those of previous studies that have shown reduced responses of the hypothalamic-pituitary-adrenal axis to metyrapone and hypoglycemia in hypothyroid patients suggest that the release of hypothalamic CRH and/or other ACTH secretagogues may be decreased in hypothyroidism.

^* This work was supported in part by USPHS Grants 1-R01-DK-33334 from the NIDDK, 5-R01-CA-11685 from the NCI, and 5-M01-RR-00095 from the General Clinical Research Centers Branch of the NIH.

Recipient of National Research Fellowship Award 1-F32-CA-06939 from the NCI. Clinical Associate Physician of the Vanderbilt General Research Center (RR-00095). Currently the recipient of a John A. and George L. Hartford Fellowship.

Clinical Associate Physician of the Vanderbilt General Clinical Research Center (RR-00095).

Received March 18, 1987.

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