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Horm Metab Res 2014; 46(06): 433-439
DOI: 10.1055/s-0034-1371891
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Circulating Gonadal and Adrenal Steroids in Amyotrophic Lateral Sclerosis: Possible Markers of Susceptibility and Outcome

G. M. Gargiulo-Monachelli
1   Department of Neurology, Ramos Mejia Hospital, School of Medicine, ­Buenos Aires University, Buenos Aires, Argentina
2   Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y ­Medicina Experimental-CONICET, Buenos Aires, Argentina
,
M. Sivori
3   Department of Pneumonology, Ramos Mejia Hospital, School of Medicine, Buenos Aires University, Buenos Aires, Argentina
,
M. Meyer
2   Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y ­Medicina Experimental-CONICET, Buenos Aires, Argentina
,
R. E. P. Sica
4   Department of Science and Technology, School of Medicine, Buenos Aires University, Buenos Aires, Argentina
,
A. F. De Nicola
2   Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y ­Medicina Experimental-CONICET, Buenos Aires, Argentina
5   Department of Human Biochemistry, School of Medicine, Buenos Aires University, Buenos Aires, Argentina
,
M. C. Gonzalez-Deniselle
2   Laboratory of Neuroendocrine Biochemistry, Instituto de Biología y ­Medicina Experimental-CONICET, Buenos Aires, Argentina
6   Department of Physiology and Biophysics, School of Medicine, Buenos Aires University, Buenos Aires, Argentina
› Author Affiliations
Further Information

Publication History

received 15 October 2013

accepted 11 March 2014

Publication Date:
07 May 2014 (online)

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Abstract

Although changes of circulating steroids have been reported in patients with sporadic amyotrophic lateral sclerosis (ALS), a full comparison of the adrenal and gonadal steroid profile between control subjects and ALS patients is lacking. Considering that respiratory failure is the most frequent cause of death in ALS, we looked into whether a relationship emerged between circulating steroids and respiratory parameters. Serum levels of adrenal and gonadal steroids were measured in 52 age- and gender-matched subjects (28 ALS and 24 controls) using radioimmunoassay techniques. We also evaluated respiratory parameters in ALS patients, including forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP). We found increased levels of testosterone in female ALS patients compared to healthy female subjects. Furthermore, control subjects showed a significant decline of testosterone, dehydroepiandrosterone and its sulfate, and a borderline decline of progesterone with increasing age. Instead, testosterone did not decline with increasing age in ALS patients. We also found that the dehydroepiandrosterone sulfate/cortisol ratio was positively associated with FVC, MIP, and MEP. Moreover, ALS patients showing higher testosterone levels and lower progesterone/free testosterone ratio presented a more rapid worsening of the monthly FVC. In conclusion, first our study revealed a differential steroid profile with age and gender in ALS patients relative to controls. Second, we demonstrated an association between some steroids and their ratios with respiratory function and disease progression. Thus, we hypothesize that the endogenous steroid profile could be a marker of susceptibility and prognosis in ALS patients.

Key words

gonadal steroids - adrenal steroids - motor neuron disease - amyotrophic lateral sclerosis - respiratory function - hormones
 

  • References

  • 1 Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet 2007; 369: 2031-2041
    CrossrefPubMedGoogle Scholar
  • 2 Haverkamp LJ, Appel V, Appel SH. Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain 1995; 118 (Pt 3) 707-719
    CrossrefPubMedGoogle Scholar
  • 3 Baumann F, Henderson RD, Morrison SC, Brown M, Hutchinson N, Douglas JA, Robinson PJ, McCombe PA. Use of respiratory function tests to predict survival in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2010; 11: 194-202
    CrossrefPubMedGoogle Scholar
  • 4 Blasco H, Guennoc AM, Veyrat-Durebex C, Gordon PH, Andres CR, Camu W, Corcia P. Amyotrophic lateral sclerosis: A hormonal condition?. Amyotroph Lateral Scler 2012; 13: 585-588
    CrossrefPubMedGoogle Scholar
  • 5 Patacchioli FR, Monnazzi P, Scontrini A, Tremante E, Caridi I, Brunetti E, Buttarelli FR, Pontieri FE. Adrenal dysregulation in amyotrophic lateral sclerosis. J Endocrinol Invest 2003; 26: RC23-RC25
    CrossrefPubMedGoogle Scholar
  • 6 Gargiulo MG, Meyer M, Rodriguez GE, Garay LI, Sica RE, De Nicola AF, Gonzalez Deniselle MC. Endogenous progesterone is associated to amyotrophic lateral sclerosis prognostic factors. Acta Neurol Scand 2011; 123: 60-67
    CrossrefPubMedGoogle Scholar
  • 7 Armanini D, Vecchio F, Basso A, Milone FF, Simoncini M, Fiore C, Mattarello MJ, Sartorato P, Karbowiak I. Alzheimer’s disease: pathophysiological implications of measurement of plasma cortisol, plasma dehydroepiandrosterone sulfate, and lymphocytic corticosteroid receptors. Endocrine 2003; 22: 113-118
    CrossrefPubMedGoogle Scholar
  • 8 Blum CA, Mueller C, Schuetz P, Fluri F, Trummler M, Mueller B, Katan M, Christ-Crain M. Prognostic value of dehydroepiandrosterone-sulfate and other parameters of adrenal function in acute ischemic stroke. PLoS One 2013; 8: e63224
    CrossrefPubMedGoogle Scholar
  • 9 D’Astous M, Morissette M, Tanguay B, Callier S, Di Paolo T. Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced dopamine depletion in mice. Synapse 2003; 47: 10-14
    CrossrefPubMedGoogle Scholar
  • 10 Militello A, Vitello G, Lunetta C, Toscano A, Maiorana G, Piccoli T, La Bella V. The serum level of free testosterone is reduced in amyotrophic lateral sclerosis. J Neurol Sci 2002; 195: 67-70
    CrossrefPubMedGoogle Scholar
  • 11 Vivekananda U, Manjalay ZR, Ganesalingam J, Simms J, Shaw CE, Leigh PN, Turner MR, Al Chalabi A. Low index-to-ring finger length ratio in sporadic ALS supports prenatally defined motor neuronal vulnerability. J Neurol Neurosurg Psychiatry 2011; 82: 635-637
    PubMedGoogle Scholar
  • 12 Wicks P. Hypothesis: higher prenatal testosterone predisposes ALS patients to improved athletic performance and manual professions. Amyotroph Lateral Scler 2012; 13: 251-253
    CrossrefPubMedGoogle Scholar
  • 13 Groeneveld GJ, Van Muiswinkel FL, Sturkenboom JM, Wokke JH, Bar PR, Van den Berg LH. Ovariectomy and 17beta-estradiol modulate disease progression of a mouse model of ALS. Brain Res 2004; 1021: 128-131
    CrossrefPubMedGoogle Scholar
  • 14 Mitsumoto H, Ulug AM, Pullman SL, Gooch CL, Chan S, Tang MX, Mao X, Hays AP, Floyd AG, Battista V, Montes J, Hayes S, Dashnaw S, Kaufmann P, Gordon PH, Hirsch J, Levin B, Rowland LP, Shungu DC. Quantitative objective markers for upper and lower motor neuron dysfunction in ALS. Neurology 2007; 68: 1402-1410
    CrossrefPubMedGoogle Scholar
  • 15 Nagata T, Nagano I, Shiote M, Narai H, Murakami T, Hayashi T, Shoji M, Abe K. Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients. Neurol Res 2007; 29: 772-776
    CrossrefPubMedGoogle Scholar
  • 16 Ranganathan S, Nicholl GC, Henry S, Lutka F, Sathanoori R, Lacomis D, Bowser R. Comparative proteomic profiling of cerebrospinal fluid between living and post mortem ALS and control subjects. Amyotroph Lateral Scler 2007; 8: 373-379
    CrossrefPubMedGoogle Scholar
  • 17 Singh M, Su C. Progesterone-induced neuroprotection: Factors that may predict therapeutic efficacy. Brain Res 2013; 1514: 98-106
    CrossrefPubMedGoogle Scholar
  • 18 Schumacher M, Sitruk-Ware R, De Nicola AF. Progesterone and progestins: neuroprotection and myelin repair. Curr Opin Pharmacol 2008; 8: 740-746
    CrossrefPubMedGoogle Scholar
  • 19 Behan M, Wenninger JM. Sex steroidal hormones and respiratory control. Respir Physiol Neurobiol 2008; 164: 213-221
    CrossrefPubMedGoogle Scholar
  • 20 Joseph V, Behan M, Kinkead R. Sex, hormones, and stress: how they impact development and function of the carotid bodies and related reflexes. Respir Physiol Neurobiol 2013; 185: 75-86
    CrossrefPubMedGoogle Scholar
  • 21 Jackson CE, Rosenfeld J, Moore DH, Bryan WW, Barohn RJ, Wrench M, Myers D, Heberlin L, King R, Smith J, Gelinas D, Miller RG. A preliminary evaluation of a prospective study of pulmonary function studies and symptoms of hypoventilation in ALS/MND patients. J Neurol Sci 2001; 191: 75-78
    CrossrefPubMedGoogle Scholar
  • 22 Tatsumi K, Pickett CK, Jacoby CR, Weil JV, Moore LG. Role of endogenous female hormones in hypoxic chemosensitivity. J Appl Physiol (1985) 1997; 83: 1706-1710
    PubMedGoogle Scholar
  • 23 Gargiulo-Monachelli G, Campos Melo D, Droppelmann C, Keller B, Leystra Lantz Ch, De Nicola AF, Gonzalez Deniselle MC, Volkening K, Strong MJ. Expression and cellular localization of the classical progesterone receptor in healthy and amyotrophic lateral sclerosis affected spinal cord. Eur J Neurol 2014; 21: 273-280
    CrossrefPubMedGoogle Scholar
  • 24 Schumacher M, Mattern C, Ghoumari A, Oudinet JP, Liere P, Labombarda F, Sitruk-Ware R, De Nicola AF, Guennoun R. Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors. Prog Neurobiol 2014; 113: 6-39
    CrossrefPubMedGoogle Scholar
  • 25 Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; 1: 293-299
    CrossrefPubMedGoogle Scholar
  • 26 Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 1999; 169: 13-21
    CrossrefPubMedGoogle Scholar
  • 27 Nicolau GY, Lakatua D, Sackett-Lundeen L, Haus E. Circadian and circannual rhythms of hormonal variables in elderly men and women. Chronobiol Int 1984; 1: 301-319
    CrossrefPubMedGoogle Scholar
  • 28 Melmed S, Polonsky KS, Larsen PR, Kronenberg HM. (eds.) Williams Textbook of Endocrinology. 12th ed. Philadelphia, Pa: Saunders Elsevier; 2011
  • 29 Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999; 84: 3666-3672
    CrossrefPubMedGoogle Scholar
  • 30 Maggio M, Colizzi E, Fisichella A, Valenti G, Ceresini G, Dall’Aglio E, Ruffini L, Lauretani F, Parrino L, Ceda GP. Stress hormones, sleep deprivation and cognition in older adults. Maturitas 2013; 76: 22-44
    CrossrefPubMedGoogle Scholar
  • 31 Standardization of Spirometry, 1994 Update . American Thoracic Society. Am J Respir Crit Care Med 1995; 152: 1107-1136
    CrossrefPubMedGoogle Scholar
  • 32 Black LF, Hyatt RE. Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis 1969; 99: 696-702
    PubMedGoogle Scholar
  • 33 McKim DA, Katz SL, Barrowman N, Ni A, LeBlanc C. Lung volume recruitment slows pulmonary function decline in Duchenne muscular dystrophy. Arch Phys Med Rehabil 2012; 93: 1117-1122
    CrossrefPubMedGoogle Scholar
  • 34 Ikeda K, Hirayama T, Takazawa T, Kawabe K, Iwasaki Y. Relationships between disease progression and serum levels of lipid, urate, creatinine and ferritin in Japanese patients with amyotrophic lateral sclerosis: a cross-sectional study. Intern Med 2012; 51: 1501-1508
    CrossrefPubMedGoogle Scholar
  • 35 R Development Core Team . R: A Language and Environment for Statistical Computing. Vienna, Austria: the R Foundation for Statistical Computing; ISBN: 3-900051-07-0, 2011. Available online at http://www.R-project.org/
    Google Scholar
  • 36 Mahendroo MS, Mendelson CR, Simpson ER. Tissue-specific and hormonally controlled alternative promoters regulate aromatase cytochrome P450 gene expression in human adipose tissue. J Biol Chem 1993; 268: 19463-19470
    PubMedGoogle Scholar
  • 37 Ishunina TA, van Beurden D, van der MG, Unmehopa UA, Hol EM, Huitinga I, Swaab DF. Diminished aromatase immunoreactivity in the hypothalamus, but not in the basal forebrain nuclei in Alzheimer’s disease. Neurobiol Aging 2005; 26: 173-194
    CrossrefPubMedGoogle Scholar
  • 38 Ishunina TA, Fischer DF, Swaab DF. Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer’s disease. Neurobiol Aging 2007; 28: 1670-1681
    CrossrefPubMedGoogle Scholar
  • 39 Costa J, Gomes C, de Carvalho M. Diagnosis, pathogenesis and therapeutic targets in amyotrophic lateral sclerosis. CNS Neurol Disord Drug Targets 2010; 9: 764-778
    CrossrefPubMedGoogle Scholar
  • 40 Markopoulou K, Papadopoulos A, Juruena MF, Poon L, Pariante CM, Cleare AJ. The ratio of cortisol/DHEA in treatment resistant depression. Psychoneuroendocrinology 2009; 34: 19-26
    CrossrefPubMedGoogle Scholar
  • 41 Ren J, Greer JJ. Neurosteroid modulation of respiratory rhythm in rats during the perinatal period. J Physiol 2006; 574: 535-546
    CrossrefPubMedGoogle Scholar
  • 42 Makino S, Fujiwara M, Handa H, Fujie T, Aoki Y, Hashimoto K, Terada Y, Sugimoto T. Plasma dehydroepiandrosterone sulphate and insulin-like growth factor I levels in obstructive sleep apnoea syndrome. Clin Endocrinol (Oxf) 2012; 76: 593-601
    CrossrefPubMedGoogle Scholar
  • 43 Rasmuson S, Andrew R, Nasman B, Seckl JR, Walker BR, Olsson T. Increased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer’s disease. Biol Psychiatry 2001; 49: 547-552
    CrossrefPubMedGoogle Scholar
  • 44 González Deniselle MC, Gonzalez S, Piroli G, Ferrini M, Lima AE, De Nicola AF. Glucocorticoid receptors and actions in the spinal cord of the Wobbler mouse, a model for neurodegenerative diseases. J Steroid Biochem Mol Biol 1997; 60: 205-213
    CrossrefPubMedGoogle Scholar
  • 45 Fidler JA, Treleaven CM, Frakes A, Tamsett TJ, McCrate M, Cheng SH, Shihabuddin LS, Kaspar BK, Dodge JC. Disease progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone. FASEB J 2011; 25: 4369-4377
    CrossrefPubMedGoogle Scholar
  • 46 Driver HS, McLean H, Kumar DV, Farr N, Day AG, Fitzpatrick MF. The influence of the menstrual cycle on upper airway resistance and breathing during sleep. Sleep 2005; 28: 449-456
    PubMedGoogle Scholar
  • 47 Slatkovska L, Jensen D, Davies GA, Wolfe LA. Phasic menstrual cycle effects on the control of breathing in healthy women. Respir Physiol Neurobiol 2006; 154: 379-388
    CrossrefPubMedGoogle Scholar
  • 48 McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral sclerosis. Gend Med 2010; 7: 557-570
    CrossrefPubMedGoogle Scholar