More Research Needed on Menopause and the Kidneys

Physiological paths

Menopause and kidney diseases have some commonalities, but it is unclear whether there are physiological linkages. Both come with a higher risk of CV disease and bone disease. In addition, females with CKD can develop early menopause because there is a disruption of the physiological process that results in a normal menstrual cycle. The hypothalamic-pituitary-gonadotropin axis is disrupted due to loss of a pulsatile gonadotropin-releasing hormone, but this loss is not fully understood, said nephrologist Sofia B. Ahmed, MD, MS, MSc, professor in the Faculty of Medicine and Dentistry and research chair in sex and gender at the University of Alberta, Edmonton, Canada.

Most knowledge about perimenopause and menopause and the kidneys comes from studies examining only people with kidney failure, often undergoing conventional hemodialysis, Dumanski said. What is known: CKD is more prevalent in females than in males, and kidney diseases are diseases of accelerated aging, said nephrologist Katharine L. Cheung, MD, MS, PhD, FASN, assistant professor and interim director of the Center on Aging at The University of Vermont Medical Center, Burlington. A 2015 study of 17,891 postmenopausal females in the Women's Health Initiative cohort showed that females with mild CKD went through menopause but had fewer vasomotor symptoms when compared with females without CKD (4). The study compared those with an estimated glomerular filtration rate >60 versus <60 mL/min/1.73 m²; the mean estimated glomerular filtration rate in the cohort was 50, which is not low for kidney diseases, Cheung said. “I think it's interesting that even in modestly reduced kidney function, you’re seeing signs that CKD is impacting menopause,” she added.

That females with CKD reported fewer vasomotor symptoms contradicted Cheung's original hypothesis that people with CKD would have more vasomotor symptoms and that they would be more severe. She wonders if the pathophysiology behind the finding could be related to people with kidney diseases having preexisting vascular disease. “Vasomotor symptoms occur because of peripheral vasodilation of the blood vessels that allows heat to be expelled, and then you have that flushing feeling,” she explained. But in kidney diseases, the blood vessels are not normal. “Often, there's vascular disease. The blood vessels have calcification, the arteries are stiffer, and there's endothelial dysfunction.”

Research findings

One condition that menopause and kidney diseases have in common is weaker bones. But is there any connection? In natural menopause, lower levels of estrogen decrease bone density and can lead to osteoporosis, while people living with kidney diseases can have renal bone disease because of an imbalance in phosphorus and calcium. Furthermore, the use of bisphosphonates to treat osteoporosis in the general population is generally contraindicated in advanced kidney diseases, said Vesna D. Garovic, MD, PhD, FASN, professor of medicine and chair in the Division of Nephrology and Hypertension at the Mayo Clinic, Rochester, MN. “Thus, safer alternatives are needed for treatment of postmenopausal osteoporosis in [females] with kidney disease[s],” she said.

A recent study among postmenopausal females in Korea showed an association between CKD and tooth loss (5). The study evaluated a survey of nearly 65,000 participants, ages 40 to 79 years. They were divided into two groups based on their number of teeth. Adults should have 32 teeth, but the results showed that females with kidney diseases had a higher risk of having fewer than 20 teeth, particularly among postmenopausal females, ages 66 to 79 years.

But what about individuals with healthy kidneys who are going through menopause? “The short answer is we don't know much about menopause in general, let alone what happens in the setting of kidney disease[s] or in a completely healthy individual,” Ahmed said. Kidney disease clinics often see older individuals, she continued. “A lot of these individuals are menopausal through normal physiological processes, and then they develop kidney disease[s] later on—and some of the other people in clinic have developed menopause presumably because of kidney disease[s]. But we don't know who is who.”

For many individuals with CKD who are experiencing menopause and who undergo a successful kidney transplant, their menstrual cycles may return. This demonstrates that they did not undergo a “normal” state of menopause, so maybe their kidney-related menopause should be called “functional menopause,” Ahmed said.

In a 2020 study, Ahmed's laboratory hypothesized that a lower level of estrogen over many years might contribute to the higher mortality rates of females with kidney failure compared with males. However, the results were the opposite. They measured estradiol levels of 482 females over 2.9 years. There were 237 deaths, with 31% caused by CV disease. When stratified by age, higher levels of estradiol were associated with greater all-cause mortality and non-CV mortality but not CV mortality in older females.

Another area that calls for more research is hormone therapy (HT). Guidelines from the American College of Obstetricians and Gynecologists and other leading medical societies recommend HT for the management of menopausal symptoms (6). HT (sometimes called “hormone replacement therapy”) is typically a combination of estrogen and progestin; those without a uterus can take estrogen alone.

Dumanski said that more research is needed on the different formulations and types of HT for menopausal individuals, which include pills, patches, skin gels, vaginal creams, and more. Clinicians do not have concrete evidence-based guidelines stating which types are safer and more effective in females with certain health characteristics, such as kidney diseases. “Saying you’re taking hormone replacement therapy is akin to saying, ‘I’m taking antibiotics,’” Ahmed said. “The type of estrogen, the route of delivery—meaning as a tablet, a patch, or vaginally—concomitant progestin use, and the type of progestin all matter. Other factors to consider are the indication for and duration of HT use and age [at] menopause relative to HT initiation, as well as the cause of menopause.”

The studies on HT and kidney function have been conflicting. HT use is associated with less albumin in the urine, but oral HT, at least in older populations, may not be as good for kidney function compared with the other routes of HT delivery, Ahmed continued. She added that HT requires more research in general, including any effects on the kidneys with gender-affirming HT, hormonal contraception, androgen deprivation therapy for prostate cancer, or antiestrogen therapy for breast cancer.

A path forward

Women's health has been getting increasingly more attention in recent years. Earlier this year, the federal government's Advanced Research Projects Agency for Health announced the Sprint for Women's Health, a $100 million investment to close the gap in federal funding for research and development into women's health. The program is the first major project of the new White House Initiative on Women's Health Research.

In February 2023, Kidney Disease: Improving Global Outcomes (KDIGO) held its Controversies Conference on Women and Kidney Health, which convened a global, multidisciplinary clinical panel and patients to identify key gender and sex issues in kidney care (7). (At press time, the conference report was not yet available.)

There are many questions and so much research yet to do. “The course of chronic [kidney] disease in postmenopausal [individuals] needs to be better characterized in order to optimize the treatment of these [individuals],” Garovic said. For instance, is there a potential therapeutic role of estrogen in kidney diseases? “At present, due to the lack of specific data [on] the [population with CKD], guidelines for the general population are being followed with recommendation for dose reduction,” she said. “Future efforts should focus on developing compounds that mimic the protective role of this hormone but [that] do not have adverse cardiovascular effects.”

Dumanski points to several other areas that need more attention: large, well-designed studies that examine how menopause affects CKD and vice versa, studies that ask females about their menopausal symptoms and experiences, and whether—and how—to prescribe HT to females of menopausal age with kidney diseases.

“I think there is a movement within nephrology and an increased recognition that these are important factors,” Ahmed said. “Is there work to do? Absolutely. Can we do better? Yes. This is an important area that we can't ignore any longer.”