Authors

• Dubravka Mihaljević — Medicinski fakultet Osijek Sveučilišta Josipa Jurja Strossmayera u Osijeku, Osijek, Hrvatska — ORCID: 0000-0002-0051-4154

Abstract

The risk of cardiovascular disease increases significantly in menopause, which is associated with faster development of vascular disease and osteoporosis. Elevated blood pressure, dyslipidemia, pre-diabetes and diabetes, and chronic kidney disease contribute to cardiovascular disease development. Impaired kidney function increases total mortality and cardiovascular mortality independently of the traditional risk factors.

Keywords

women, menopausis, cardiovascular disease

DOI

Full Text

Chronic kidney disease (CKD) is a major public health issue with a prevalence of 10.5%-13.1% (1). Generally, many risk factors for CKD onset have been identified, such as advanced age, male sex and diabetes mellitus, as well as the risk factors favoring CKD development, such as arterial hypertension, proteinuria and hyperuricemia (2). The multitude of risk factors makes the prevention and treatment of CKD highly challenging. Younger female CKD patients experience premature menopause due to estrogenic hormone deficiency, leading to a number of structural and functional changes in all organ systems. Hormone replacement therapy is an important treatment option for menopausal discomforts, which can successfully improve the patient quality of life. The Women’s Health Initiative study has resulted in designing the so-called timing hypothesis, according to which hormone therapy benefits can only be expected if introduced in women below 60 years of age and within 10 years of the menopause onset. ## Menopause Menopause is defined by the cessation of menstruation for a one-year period. Menopause is associated with faster development of vascular disease and osteoporosis, thus considerably increasing the risk of cardiovascular disease (2). Arterial hypertension, diabetes mellitus and dyslipidemia, as well as CKD itself, contribute to the development of cardiovascular disease (2). Impaired renal function increases the overall and cardiovascular mortality independently of the traditional risk factors (3). Menopause is frequently associated with the occurrence of vasomotor symptoms that persist for about seven years in most women (4). International guidelines recommend postmenopausal hormone therapy to treat vasomotor symptoms (4, 5). Estrogen therapy is the gold standard of postmenopausal hormone therapy; in women with intact uterus, it can be combined with progesterone, as well as with selective estrogen receptor modulators. ## Chronic kidney disease and premature menopause Impairment of kidney function, along with disorders in other body systems leads to menstrual impairments, infertility and premature menopause in women (6). The prevalence of CKD and the proportion of postmenopausal women with CKD increase with the general population aging (4% per year) (6). Premature menopause associated with hypoestrogenism is common in CKD women. The onset of menopause occurs four years earlier in CKD women than in women from the general population (6). Current guidelines include administration of postmenopausal hormone therapy in the general population but there are no clear instructions on the treatment of high-risk women including those with CKD. Kidney has a major role in the regulation of sex hormones (5). During the course of CKD, ovarian function disorder occurs due to impairment in the hypothalamic-pituitary-ovarian axis, which leads to anovulatory cycles, premature menopause, and an increased risk of malignant endometrium disease (5). Cyclic release of the gonadotropin-releasing hormone (GnRH) is reduced in CKD patients, which leads to decreased estrogen secretion and anovulatory cycles via luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Hyperprolactinemia in CKD is the result of increased prolactin production due to resistance to the inhibitory effect of dopamine and reduced renal excretion. Elevated prolactin level leads to reduced cyclic GnRH secretion and consequential reduction in LH and FSH pulse secretion, which in turn results in a reduced estrogen release that clinically manifests by menstruation cycle irregularities, infertility, and functional menopause (5). Hypothalamic dysfunction can be partially recovered with intensified hemodialysis or following kidney transplantation. The onset of menopause may accelerate CKD progression, and postmenopausal hormone therapy is inefficient in reducing this effect. Hormone therapy has favorable impact on the patient quality of life, sexual desire, and prevention of bone mass loss in postmenopausal women on dialysis (7, 8). ## Effect of sex hormones on kidney function The effect of sex hormones on kidney function has not yet been fully clarified. There is no direct evidence for the renoprotective effect of female sex hormones. Studies on experimental animals have shown differences in estrogen receptors on renal cells, as well as the effect of sex hormones on the synthesis and activity of some cytokines, growth factors and vasoactive substances. It has been demonstrated that estrogen plays a major role in the activation of the renin-angiotensin-aldosterone system and that hormone replacement therapy can influence the progression of CKD in laboratory animals. Unlike the general population, there are no guidelines on the use of postmenopausal hormone therapy in female CKD patients. The effect of postmenopausal hormone therapy is assessed through cardiovascular and fracture risk reduction, whereas the effect of postmenopausal hormone therapy on kidney function has not been completely elucidated (8). Studies have shown variable results, depending on the mode of postmenopausal hormone therapy administration, other components added to therapy, and timing of treatment initiation. Prospective studies of the kidney function and menopause relationship and of the impact of postmenopausal hormone therapy on the outcome of female CKD patients are lacking. Effects of the potential risk factors exclusively associated with female patients manifest most intensively in menopause; in the future, studies should also tackle the effects of hormone therapy administered in low doses and in the transgender population (9, 10). The side effects of postmenopausal hormone therapy in the general population include venous thromboembolism, and malignant diseases of the breast, ovary and endometrium, thus requiring careful risk assessment in the population of women with CKD, as they fall in the group at an increased cardiovascular risk in case of premature menopause (before age 45) (11, 12). ## Conclusion Internists and other specialists relatively rarely talk to their female patients about menstruation problems, fertility and menopause. In female CKD patients, these problems and their treatment require additional research and development of strict therapeutic guidelines for this group of patients at a high risk of undesired cardiac and/or cerebrovascular event.

Literature

1. Tsai WC, Wu HY, Peng YS, Ko MJ, Wu MS, Hung KY, et al. Risk Factors for Development and Progression of Chronic Kidney Disease: A Systematic Review and Exploratory Meta-Analysis. Medicine (Baltimore). 2016 Mar;95(11):e3013. https://doi.org/10.1097/MD.0000000000003013
2. Yang W, Xie D, Anderson AH, Joffe MM, Greene T, Teal V, et al. Association of kidney disease outcomes with risk factors for CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) study. Am J Kidney Dis. 2014 Feb;63(2):236–43. https://doi.org/10.1053/j.ajkd.2013.08.028
3. Nitsch D, Grams M, Sang Y, Black C, Cirillo M, Djurdjev O, et al. Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: a meta-analysis. BMJ. 2013 Jan 29;346:f324. https://doi.org/10.1136/bmj.f324
4. Ahmed SB. Menopause and Chronic Kidney Disease. Semin Nephrol. 2017 Jul;37(4):404–11. https://doi.org/10.1016/j.semnephrol.2017.05.013
5. Ahmed SB, Ramesh S. Sex hormones in women with kidney disease. Nephrol Dial Transplant. 2016 Nov;31(11):1787–95. https://doi.org/10.1093/ndt/gfw084
6. Suzuki H, Kondo K. Chronic kidney disease in postmenopausal women. Hypertens Res. 2012 Feb;35(2):142–7. https://doi.org/10.1038/hr.2011.155
7. Dumanski SM, Ramesh S, James MT, Metcalfe A, Nerenberg K, Seely EW, et al. The effect and safety of postmenopausal hormone therapy and selective estrogen receptor modulators on kidney outcomes in women: a protocol for systematic review and meta-analysis. Syst Rev. 2017 Jul 7;6(1):134. https://doi.org/10.1186/s13643-017-0519-2
8. Ramesh S, James MT, Holroyd-Leduc JM, Wilton SB, Seely EW, Wheeler DC, et al. Sex Hormone Status in Women With Chronic Kidney Disease: Survey of Nephrologists’ and Renal Allied Health Care Providers’ Perceptions. Can J Kidney Health Dis. 2017 Oct 27;4:2054358117734534. https://doi.org/10.1177/2054358117734534
9. Demel SL, Kittner S, Ley SH, McDermott M, Rexrode KM. Stroke Risk Factors Unique to Women. Stroke. 2018 Mar;49(3):518–23. https://doi.org/10.1161/STROKEAHA.117.018415
10. Sheikh HU, Pavlovic J, Loder E, Burch R. Risk of Stroke Associated With Use of Estrogen Containing Contraceptives in Women With Migraine: A Systematic Review. Headache. 2018 Jan;58(1):5–21. https://doi.org/10.1111/head.13229
11. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008 May 31;336(7655):1227–31. https://doi.org/10.1136/bmj.39555.441944.BE
12. Muka T, Oliver-Williams C, Kunutsor S, Laven JS, Fauser BC, Chowdhury R, et al. Association of age at onset of menopause and time since onset of menopause with cardiovascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol. 2016 Oct 1;1(7):767–76. https://doi.org/10.1001/jamacardio.2016.2415