The effects of the menopause and hormone levels in women have been associated with cognitive decline (Tsolaki M et al. 2005).
The fact that women are more likely to have cognitive deficits than men is an important factor (Laws KR, 2018). Considering the reproductive endocrinology of both males and females, where women experience an increase in follicle stimulating hormone (FSH) in response to low levels oestrogen in the hypothalamic-pituitary-adrenal (HPA) axis feedback loop. Most men continue to produce testosterone throughout life and do not experience this increase in FHS to the same extent as females. However, when low levels of testosterone do occur FSH must be increased due to the HPA axis feedback and low testosterone is associated with dementia in men (Yeap BB, 2011).
Some studies reveal that FSH levels and dementia show that there is an association between increased level of the hormone and loss of cognitive function, in animal studies. Interestingly, FSH blockers have been shown to reduce cognitive decline in one study (Xiong J et al 2022).
A recent study reported that men who use Sildenafil for erectile dysfunction have been associated with a decrease in susceptibility to Alzheimer’s disease (Huo X, 2023). Sildenafil (Viagra) increases testosterone levels in men, thus the FSH should also be reduced (Spitzer M, 2013). Has this aspect of FSH levels and susceptibility to dementia been investigated?
A systemic review investigated the use of sildenafil for Alzheimer's patients and recommends a repurposing of the drug for patients with dementia (Sanders O, 2020).
Could the above discussion of endocrinology be a partial explanation for the effects of Sildenafil and reduced incidence of dementia in men who take the drug and should further investigation take place into this aspect of endocrinology and dementia?
- Laws KR, Irvine K, Gale TM. Sex differences in Alzheimer's disease. Curr Opin Psychiatry. 2018 Mar;31(2):133-139. doi: 10.1097/YCO.0000000000000401. PMID: 29324460.
- Tsolaki M, Grammaticos P, Karanasou C, Balaris V, Kapoukranidou D, Kalpidis I, Petsanis K, Dedousi E. Serum estradiol, progesterone, testosterone, FSH and LH levels in postmenopausal women with Alzheimer's dementia. Hell J Nucl Med. 2005 Jan-Apr;8(1):39-42. PMID: 15886752.
- Yeap BB, Flicker L. Testosterone, cognitive decline and dementia in ageing men. Rev Endocr Metab Disord. 2022 Dec;23(6):1243-1257. doi: 10.1007/s11154-022-09728-7. Epub 2022 May 28. PMID: 35633431; PMCID: PMC9789006.
- Xiong J, Kang SS, Wang Z, Liu X, Kuo TC, Korkmaz F, Padilla A, Miyashita S, Chan P, Zhang Z, Katsel P, Burgess J, Gumerova A, Ievleva K, Sant D, Yu SP, Muradova V, Frolinger T, Lizneva D, Iqbal J, Goosens KA, Gera S, Rosen CJ, Haroutunian V, Ryu V, Yuen T, Zaidi M, Ye K. FSH blockade improves cognition in mice with Alzheimer's disease. Nature. 2022 Mar;603(7901):470-476. doi: 10.1038/s41586-022-04463-0. Epub 2022 Mar 2. PMID: 35236988; PMCID: PMC9940301.
- Huo X, Finkelstein J. Using Big Data to Uncover Association Between Sildenafil Use and Reduced Risk of Alzheimer's Disease. Stud Health Technol Inform. 2023 May 18;302:866-870. doi: 10.3233/SHTI230291. PMID: 37203519.
- Spitzer M, Bhasin S, Travison TG, Davda MN, Stroh H, Basaria S. Sildenafil increases serum testosterone levels by a direct action on the testes. Andrology. 2013 Nov;1(6):913-8. doi: 10.1111/j.2047-2927.2013.00131.x. Epub 2013 Sep 18. PMID: 24106072; PMCID: PMC6036338.
- Sanders O. Sildenafil for the Treatment of Alzheimer's Disease: A Systematic Review. J Alzheimers Dis Rep. 2020 Apr 22;4(1):91-106. doi: 10.3233/ADR-200166. PMID: 32467879; PMCID: PMC7242821.
https://www.bbc.co.uk/news/health-68232649 (Radio 4 Today programme report 8.2.24)
Further to this line of thinking about the relationship between hormone levels and dementia, could the GnRH increases associated with FSH increased levels also be an important factor? When considering the chicken or the egg in this pathogenesis, could GnRH have a hormesis effect on neurone where low levels are functional but high levels have a pathogenic effect when levels cross a certain threshold of expression?
A recent study reported an association in midlife women where elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease.
One study in mice indicated an association with the HPG axis and cognitive senescence with a suggestion that pharmaceutical intervention reducing GnRH could reduce the pathophysiological processes underlying AD and plaque formation.
- Nuruddin S, Syverstad GH, Lillehaug S, Leergaard TB, Nilsson LN, Ropstad E, Krogenæs A, Haraldsen IR, Torp R. Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice. PLoS One. 2014 Aug 4;9(8):e103607. doi: 10.1371/journal.pone.0103607. PMID: 25089901; PMCID: PMC4121068.
- Nerattini Matilde, Rubino Federica, Jett Steven, Andy Caroline, Boneu Camila, Zarate Camila, Carlton Caroline, Loeb-Zeitlin Susan, Havryliuk Yelena, Pahlajani Silky, Williams Schantel, Berti Valentina, Christos Paul, Fink Matthew, Dyke Jonathan P., Brinton Roberta Diaz, Mosconi Lisa, Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women, Frontiers in Dementia, 2, 2023 https://www.frontiersin.org/articles/10.3389/frdem.2023.1303256 DOI:10.3389/frdem.2023.1303256
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