Abstract
Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice (Fshr−/−). We found that Fshr−/− mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg−1 · d−1, i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr−/− mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.
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References
Malhi GS, Mann JJ. Depression. Lancet. 2018;392:2299–312.
Soares CN. Depression and menopause: an update on current knowledge and clinical management for this critical window. Med Clin North Am. 2019;103:651–67.
Frokjaer VG, Pinborg A, Holst KK, Overgaard A, Henningsson S, Heede M, et al. Role of serotonin transporter changes in depressive responses to sex-steroid hormone manipulation: a positron emission tomography study. Biol Psychiatry. 2015;78:534–43.
Jovanovic H, Kocoska-Maras L, Radestad AF, Halldin C, Borg J, Hirschberg AL, et al. Effects of estrogen and testosterone treatment on serotonin transporter binding in the brain of surgically postmenopausal women-a PET study. Neuroimage. 2015;106:47–54.
Joffe H, Petrillo LF, Koukopoulos A, Viguera AC, Hirschberg A, Nonacs R, et al. Increased estradiol and improved sleep, but not hot flashes, predict enhanced mood during the menopausal transition. J Clin Endocrinol Metab. 2011;96:E1044–54.
Morrison MF, Kallan MJ, Ten Have T, Katz I, Tweedy K, Battistini M. Lack of efficacy of estradiol for depression in postmenopausal women: a randomized, controlled trial. Biol Psychiatry. 2004;55:406–12.
Resnick SM, Coker LH, Maki PM, Rapp SR, Espeland MA, Shumaker SA. The Women’s Health Initiative Study of Cognitive Aging (WHISCA): a randomized clinical trial of the effects of hormone therapy on age-associated cognitive decline. Clin Trials. 2004;1:440–50.
Welton AJ, Vickers MR, Kim J, Ford D, Lawton BA, MacLennan AH, et al. Health related quality of life after combined hormone replacement therapy: randomised controlled trial. BMJ. 2008;337:a1190.
Qi X, Guo Y, Song Y, Yu C, Zhao L, Fang L, et al. Follicle-stimulating hormone enhances hepatic gluconeogenesis by GRK2-mediated AMPK hyperphosphorylation at Ser485 in mice. Diabetologia. 2018;61:1180–92.
Liu XM, Chan HC, Ding GL, Cai J, Song Y, Wang TT, et al. FSH regulates fat accumulation and redistribution in aging through the Galphai/Ca(2+)/CREB pathway. Aging Cell. 2015;14:409–20.
Slopien R, Wichniak A, Pawlak M, Slopien A, Warenik-Szymankiewicz A, Sajdak S. Disturbances of sleep continuity in women during the menopausal transition. Psychiatr Pol. 2015;49:615–23.
Berent-Spillson A, Marsh C, Persad C, Randolph J, Zubieta JK, Smith Y. Metabolic and hormone influences on emotion processing during menopause. Psychoneuroendocrinology. 2017;76:218–25.
Brambilla F, Maggioni M, Ferrari E, Scarone S, Catalano M. Tonic and dynamic gonadotropin secretion in depressive and normothymic phases of affective disorders. Psychiatry Res. 1990;32:229–39.
Bromberger JT, Kravitz HM. Mood and menopause: findings from the Study of Women’s Health Across the Nation (SWAN) over 10 years. Obstet Gynecol Clin North Am. 2011;38:609–25.
Hoang YD, Nakamura BN, Luderer U. Follicle-stimulating hormone and estradiol interact to stimulate glutathione synthesis in rat ovarian follicles and granulosa cells. Biol Reprod. 2009;81:636–46.
Shen M, Jiang Y, Guan Z, Cao Y, Sun SC, Liu H. FSH protects mouse granulosa cells from oxidative damage by repressing mitophagy. Sci Rep. 2016;6:38090.
Tsai-Turton M, Luderer U. Opposing effects of glutathione depletion and follicle-stimulating hormone on reactive oxygen species and apoptosis in cultured preovulatory rat follicles. Endocrinology. 2006;147:1224–36.
Farias JG, Herrera EA, Carrasco-Pozo C, Sotomayor-Zarate R, Cruz G, Morales P, et al. Pharmacological models and approaches for pathophysiological conditions associated with hypoxia and oxidative stress. Pharmacol Ther. 2016;158:1–23.
Michel TM, Pulschen D, Thome J. The role of oxidative stress in depressive disorders. Curr Pharm Des. 2012;18:5890–9.
Zhang HT, Huang Y, Jin SL, Frith SA, Suvarna N, Conti M, et al. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology. 2002;27:587–95.
Gong MF, Wen RT, Xu Y, Pan JC, Fei N, Zhou YM, et al. Attenuation of ethanol abstinence-induced anxiety- and depressive-like behavior by the phosphodiesterase-4 inhibitor rolipram in rodents. Psychopharmacology. 2017;234:3143–51.
Liu MY, Yin CY, Zhu LJ, Zhu XH, Xu C, Luo CX, et al. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat Protoc. 2018;13:1686–98.
Bay-Richter C, Janelidze S, Sauro A, Bucala R, Lipton J, Deierborg T, et al. Behavioural and neurobiological consequences of macrophage migration inhibitory factor gene deletion in mice. J Neuroinflammation. 2015;12:163.
Kremer PM, Torres DJ, Hashimoto AC, Berry MJ. Disruption of selenium handling during puberty causes sex-specific neurological impairments in mice. Antioxidants. 2019;8:110. https://doi.org/10.3390/antiox8040110.
Kucharczyk M, Kurek A, Pomierny B, Detka J, Papp M, Tota K, et al. The reduced level of growth factors in an animal model of depression is accompanied by regulated necrosis in the frontal cortex but not in the hippocampus. Psychoneuroendocrinology. 2018;94:121–33.
Hodes A, Rosen H, Cohen-Ben Ami H, Lichtstein D. Na+, K+-ATPase alpha3 isoform in frontal cortex GABAergic neurons in psychiatric diseases. J Psychiatr Res. 2019;115:21–8.
Lee AL, Ogle WO, Sapolsky RM. Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord. 2002;4:117–28.
Birkhauser M. Depression, menopause and estrogens: is there a correlation? Maturitas. 2002;41(Suppl 1):S3–8.
Bromberger JT, Schott LL, Kravitz HM, Sowers M, Avis NE, Gold EB, et al. Longitudinal change in reproductive hormones and depressive symptoms across the menopausal transition: results from the Study of Women’s Health Across the Nation (SWAN). Arch Gen Psychiatry. 2010;67:598–607.
Reus GZ, Dos Santos MA, Abelaira HM, Titus SE, Carlessi AS, Matias BI, et al. Antioxidant treatment ameliorates experimental diabetes-induced depressive-like behaviour and reduces oxidative stress in brain and pancreas. Diabetes Metab Res Rev. 2016;32:278–88.
Fernandes J, Gupta GL. N-acetylcysteine attenuates neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat. Behav Brain Res. 2019;364:356–65.
Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019;20:148–60.
Amsterdam JD, Winokur A, Lucki I, Snyder P. Neuroendocrine regulation in depressed postmenopausal women and healthy subjects. Acta Psychiatr Scand. 1983;67:43–9.
Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S. Symptoms in the menopausal transition: hormone and behavioral correlates. Obstet Gynecol. 2008;111:127–36.
Gu S, Jing L, Li Y, Huang JH, Wang F. Stress induced hormone and neuromodulator changes in menopausal depressive rats. Front Psychiatry. 2018;9:253.
Dzemaili S, Tiemensma J, Quinton R, Pitteloud N, Morin D, Dwyer AA. Beyond hormone replacement: quality of life in women with congenital hypogonadotropic hypogonadism. Endocr Connect. 2017;6:404–12.
Aydogan U, Aydogdu A, Akbulut H, Sonmez A, Yuksel S, Basaran Y, et al. Increased frequency of anxiety, depression, quality of life and sexual life in young hypogonadotropic hypogonadal males and impacts of testosterone replacement therapy on these conditions. Endocr J. 2012;59:1099–105.
Liu P, Ji Y, Yuen T, Rendina-Ruedy E, DeMambro VE, Dhawan S, et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature. 2017;546:107–12.
Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z, Papachristou DJ, et al. FSH directly regulates bone mass. Cell. 2006;125:247–60.
Guo Y, Zhao M, Bo T, Ma S, Yuan Z, Chen W, et al. Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol. Cell Res. 2019;29:151–66.
Saher G, Stumpf SK. Cholesterol in myelin biogenesis and hypomyelinating disorders. Biochim Biophys Acta. 2015;1851:1083–94.
Ma T, Li B, Le Y, Xu Y, Wang F, Tian Y, et al. Demyelination contributes to depression comorbidity in a rat model of chronic epilepsy via dysregulation of Olig2/LINGO-1 and disturbance of calcium homeostasis. Exp Neurol. 2019;321:113034.
Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol. 2011;14:123–30.
Pal SN, Dandiya PC. Glutathione as a cerebral substrate in depressive behavior. Pharmacol Biochem Behav. 1994;48:845–51.
Acknowledgements
This work was supported by the National Key Research and Development Program of China (2017YFC1309800), National Natural Science Foundation of China (81430020, 81670796, 31471321, and 81900716), Key Research and Development Plan of Shandong province (2017G006006), and Shandong Provincial Natural Science Foundation (ZR2019BH023). We acknowledge the support of Yan-Meng Zhou for the behavior tests.
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WKB performed the experiments and analyzed the data; SSS, ZWL, YWR, SSL, and TG performed the experiments; WKB wrote the paper; ZH, JJZ, and LG conceived the idea; and ZHD, JW, SSW, and SZM assisted with animal studies. All authors read and approved the final paper.
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Bi, Wk., Shao, Ss., Li, Zw. et al. FSHR ablation induces depression-like behaviors. Acta Pharmacol Sin 41, 1033–1040 (2020). https://doi.org/10.1038/s41401-020-0384-8
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DOI: https://doi.org/10.1038/s41401-020-0384-8
