The influence of hyperthyroidism on the hypothalamic-pituitary-gonadal axis

Summary:

We have investigated the function of the hypothalamic-pituitary-gonadal (H-P-G)-axis in patients with severe, untreated Graves' disease. We studied 7 male and 6 female healthy volunteers, and 7 male and 7 female patients with Graves' disease. Hormone profiles were developed by blood sampling every 10 min for an 8 hour period. In women this was done in the early follicular phase of menstrual cycle. LH-, FSH-, and PRL levels were measured using immunoradiometric assays and testosterone (T), estradiol (E2), sex-hormone binding globulin (SHBG), and progesterone (P) were measured with standard assays. The pulsatility of LH, FSH and PRL was calculated using the programmes Pulsar, Cluster and Desade. The temporal relationship of plasma LH, FSH, and PRL pulses was also investigated using specific concordance analysis. Data were evaluated by means of non-parametric statistics. LH-secretion was increased in all hyperthyroid patients, while FSH-secretion was increased in hyperthyroid men only. Pulsatile characteristics of LH- and FSH-secretion (frequency, peak shape) in patients were not different from controls. No change in PRL-secretion was shown. Significant copulsatility occurred between LH and FSH, and LH and PRL. This was more pronounced in hyperthyroid than in healthy study subjects. Plasma levels of steroid hormones and sex-hormone-binding globulin were significantly (p < 0.005) increased in hyperthyroid men. Free Androgen Index was significantly (p < 0.005) decreased in hyperthyroid males. No other auto immune diseases were noticed. Our results indicate that the function of the H-P-G axis is not impaired in hyperthyroid patients, but gonadotropin levels are increased. Hyperthyroid men show relative primary gonadal insufficiency that may be due to exaggerated SHBG levels. The copulsatility of LH and FSH, and of LH and PRL was confirmed both in patients and controls.

References

• 1 Bals-Pratsch M, Schober O, Hanker J P, de Geyter C, Schneider H P. Disorders of thyroid function and sterility in the woman.  Zentralbl Gynäkol. 115 18-23 1993; 
• 2 Batrinos M L. The ovaries. In: Batrinos ML (eds) Up to date endocrinology. Medical Publications, Paschalidis, P. H. 1982
• 3 Castel M A, Willey K P, Hunt N, Leidenberger F. The antibodies causing thyroid stimulating hormone-binding inhibition (TSH-BI) are not responsible for the specific inhibition of gonadal steroidogenesis by Graves' sera.  J Reprod Immunol. 30 1-15 1996; 
• 4 Crowley W F Jr, Filicori M, Spratt D I, Santoro N F. The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women.  Recent Prog Horm Res. 41 473-531 1985; 
• 5 Distiller L A, Sagel J, Morley J E, Oxenham E. Assessment of pituitary gonadotropin reserve using luteinizing hormone-releasing hormone (LRH) in states of altered thyroid function.  J Clin Endocrinol Metab. 40 512-515 1975; 
• 6 Dunger D B, Matthews D R, Edge J A, Jones J, Preece M A. Evidence for temporal coupling of growth hormone, prolactin, LH and FSH pulsatility overnight during normal puberty.  J Endocrinol. 130 141-149 1991; 
• 7 Dunn J F, Nisula B C, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma.  J Clin Endocrinol Metab. 53 58-68 1981; 
• 8 Genazzani A D, Petraglia F, Volpogni C, D'Ambrogio G, Facchinetti F, Genazzani A R. FSH secretory pattern and degree of concordance with LH in amenorrheic, fertile, and postmenopausal women.  Am J Physiol. 264(5 Pt 1) E776-E781 1993a; 
• 9 Genazzani A D, Petraglia F, Volpogni D, Pianazzi F, Montanini V, D'Ambrogio G, Genazzani A R. Growth hormone treatment affects plasma LH pulsatile release in women with secondary amenorrhoea.  Clin Endocrinol Oxford. 39 607-611 1993b; 
• 10 Genazzani A D, Rodbard D. Use of the receiver operating characteristic curve to evaluate sensitivity, specificity, and accuracy of methods for detection of peaks in hormone time series.  Acta Endocrinol Copenh. 124 295-306 1991; 
• 11 Guardabasso V, Genazzani A D, Veldhuis J D, Rodbard D. Objective assessment of concordance of secretory events in two endocrine time series.  Acta Endocrinol Copenh. 124 208-218 1991; 
• 12 Hakamata M, Itoh M, Sudo Y, Katada E, Miyata N. Decreased secretion of gonadotropins in a patient with Graves' disease.  Exp Clin Endocrinol Diabetes. 104 85-88 1996; 
• 13 Horn K, Kubiczek T, Pickardt C R, Scriba P C. Thyroxin-bindendes Globulin (TBG): Präparation, radioimmunologische Bestimmung und klinisch-diagnostische Bedeutung.  Klin Wochenschr. 55 881-894 1977; 
• 14 Knobil E. The neuroendocrine control of the menstrual cycle.  Recent Prog Horm Res. 36 53-88 1980; 
• 15 Luthold W W, Borges M F, Marcondes J A, Hakohyama M, Wajchenberg B L, Kirschner M A. Serum testosterone fractions in women: normal and abnormal clinical states.  Metabolism. 42 638-643 1993; 
• 16 Merriam G R, Ma N, Liu L, Wachter K W, Libre E. Methods for assessing the linkage between pulsatile hormone profiles.  Acta Paediatr Scand Suppl. 349 167-172 1989; 
• 17 Merriam G R, Wachter K W. Algorithms for the study of episodic hormone secretion.  Am J Physiol. 243 E310-E318 1982; 
• 18 Merriam G R, Wachter K W. How to use the pulsar program on a pc. Growth & Metabolic Service, Kabi Pharmacia, Stockholm 1992
• 19 Peluso J J, Gruenberg M L, Steger R W. Regulation of ovarian follicular growth and steroidogenesis by low-amplitude LH pulses.  Am J Physiol. 246(2 Pt 2) R184-R189 1984; 
• 20 Prank K, Brabant G. Estimating thyrotropin secretory activity by a deconvolution procedure. In: Levine JE (eds) Methods in Neurosciences Academic Press 377-390 1994
• 21 Reame N E, Sauder S E, Case G D, Kelch R P, Marshall J C. Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation.  J Clin Endocrinol Metab. 61 851-858 1985; 
• 22 Reiser F, Scherbaum W A, Rossmanith W G. Gonadotropin and prolactin secretion during hyperthyroidism in women.  Acta Endocrinol Copenh 126 ((Suppl 4)) 152 1992; 
• 23 Rosner W. Errors in the measurement of plasma free testosterone [letter; comment].  J Clin Endocrinol Metab. 82 2014-2015 1997; 
• 24 Russell P MG, Dean E M. Reduced menstrual flow in thyreotoxicosis.  Lancet II. 243 66-68 1942; 
• 25 Samuels M H, Veldhuis J D, Hendry P, Ridgway E C. Pathophysiology of pulsatile and copulsatile release of thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and alpha-subunit.  J Clin Endocrinol Metab. 71 425-432 1990; 
• 26 Schopohl J, Mojto J, Losa M, Mehltretter G, Müller O A, von Werder K. Changes in anterior pituitary response in patients with idiopathic hypothalamic hypogonadism caused by pulsatile GnRH therapy and testosterone replacement.  Exp Clin Endocrinol Diabetes. 103 184-190 1995; 
• 27 Sheckter C B, Matsumoto A M, Bremner W J. Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary.  J Clin Endocrinol Metab. 68 397-401 1989; 
• 28 Talbot J A, Rodger R S, Shalet S M, Littley M D, Robertson W R. The pulsatile secretion of bioactive luteinising hormone in normal adult men.  Acta Endocrinol Copenh. 122 643-650 1990; 
• 29 Thomas R, Reid R L. Thyroid disease and reproductive dysfunction: a review.  Obstet Gynecol. 70 789-798 1987; 
• 30 Toscano V, Balducci R, Bianchi P, Guglielmi R, Mangiantini A, Sciarra F. Steroidal and non-steroidal factors in plasma sex hormone binding globulin regulation.  J Steroid Biochem Mol Biol. 43 431-437 1992; 
• 31 Velazquez E M, Bellabarba Arata G. Effects of thyroid status on pituitary gonadotropin and testicular reserve in men.  Arch Androl. 38 85-92 1997; 
• 32 Veldhuis J D, Johnson M L. Cluster analysis: a simple, versatile, and robust algorithm for endocrine pulse detection.  Am J Physiol. 250(4 Pt 1) E486-E493 1986; 
• 33 Veldhuis J D, Johnson M L. Instructions summary for use of “cluster analysis”. 1993
• 34 Veldhuis J D, Johnson M L, Seneta E. Analysis of the copulsatility of anterior pituitary hormones.  J Clin Endocrinol Metab. 73 569-576 1991; 
• 35 Weltman J Y, Veldhuis J D, Weltman A, Kerrigan J R, Evans W S, Rogol A D. Reliability of estimates of pulsatile characteristics of luteinizing hormone and growth hormone release in women.  J Clin Endocrinol Metab. 71 1646-1652 1990; 

1 * Supported by DAAD grant (II, 314)