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Prolonged Inhibition of Presynaptic Catecholamine Synthesis With α-Methyl-Para-Tyrosine Attenuates the Circadian Rhythm of Human TSH Secretion

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Abstract

Objective

Originating from the pituitary gland, TSH secretion is regulated predominantly by thyroid-releasing hormone (TRH) neurons located in the hypothalamus. Norepinephrine and dopamine have important effects in modulation of TSH secretion. An inhibitor of catecholamine synthesis, α-methyl-para-tyrosine (AMPT) has been used in several studies of the regulation of human TSH secretion. The short-term effects (<8 hours) of low doses of AMPT include stimulation of pituitary TSH secretion by selective lowering of brain dopamine levels. After prolonged administration of AMPT (>24 hours), theoretically both dopamine and norepinephrine levels are lowered significantly in the brain, although this has not been reported previously.

Methods

Nine subjects (five women and four men) received a total of five 1-g doses of AMPT or five 50-mg doses of promethazine (active placebo) over 28 hours in a randomized, double-blind, placebo-controlled crossover design in which the active and control tests were separated by 4–6 weeks. Blood samples were obtained over 24 hours (18 time points) on day 2 of each condition.

Results

Changes in prolactin secretion and 6-hydroxymelatonin sulfate excretion indirectly showed the effects of AMPT on dopamine and norepinephrine. The typical circadian rhythm of TSH secretion was blunted by AMPT throughout the night; at ten time points, the difference between the two groups was statistically significant (P <. 01). The long-term effects of repeated doses of AMPT were inhibition of TSH secretion and significant attenuation of the circadian rhythm of TSH. Additionally, AMPT induced low norepinephrine levels, which counteracted the stimulatory effect of low dopamine levels on TSH.

Conclusions

Through its inhibitory effect on TRH, norepinephrine appeared to be involved in the regulation of TSH.

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Authors and Affiliations

  1. Departments of Obstetrics and Gynecology, Division of Reproductive Endocrinology, and Psychiatry, Columbia University, 630 West 168th Street, 10032, New York, New York, USA

    Ralf C. Zimmermann MD, Lois E. Krahn MD, George G. Klee MD, Edward C. Ditkoff MD, Steven J. Ory MD & Mark V. Sauer MD

  2. Division of Adult Psychiatry and Sleep Disorders Center, Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota, USA

    Ralf C. Zimmermann MD, Lois E. Krahn MD, George G. Klee MD, Edward C. Ditkoff MD, Steven J. Ory MD & Mark V. Sauer MD

  3. Margate, Florida, USA

    Ralf C. Zimmermann MD, Lois E. Krahn MD, George G. Klee MD, Edward C. Ditkoff MD, Steven J. Ory MD & Mark V. Sauer MD

Authors
  1. Ralf C. Zimmermann MD
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  2. Lois E. Krahn MD
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  3. George G. Klee MD
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  4. Edward C. Ditkoff MD
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  5. Steven J. Ory MD
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  6. Mark V. Sauer MD
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Additional information

Supported by a NARSAD (National Alliance for Research on Schizophrenia and Depression) Young Investigator Award (to RCZ).

The authors thank the clinical research staff of the Mayo General Clinical Research Center (NIH M01 00585), especially Jean M. Feehan, provided expert assistance. We thank Darlene L. Lucas, who performed the 6-hydroxymelatonin sulfate assay.

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Zimmermann, R.C., Krahn, L.E., Klee, G.G. et al. Prolonged Inhibition of Presynaptic Catecholamine Synthesis With α-Methyl-Para-Tyrosine Attenuates the Circadian Rhythm of Human TSH Secretion. Reprod. Sci. 8, 174–178 (2001). https://doi.org/10.1177/107155760100800309

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