All vessels are not created equal. When it comes to the topic of males and females, cardiovascular physiology has entered an era of studying how sex differences in function and form influence disease risk across the lifespan.
We have known for some time that these differences exist, but this is still a relatively new area of research. Our lab, for instance, has shown that older men and women respond differently to an a single bout of exercise. Exercise physiology has some explaining to do.
Until about age 60, the risk of cardiovascular disease (CVD) is lower in women than it is in men. However, from about age 20–60, the increase in prevalence of CVD is greater in women — owing an explanation. There must be something happening inside women that accelerates the risk of developing CVD and other risk factors.
That explanation could very well have to do with hormones, menopause, and their interaction with vascular aging. The changes in sex hormones that occur during the menopause transition may put women at a greater risk of developing certain risk factors that predispose them to CVD.
With “normal” aging, vascular function, the ability to relax blood vessels declines due to various factors. In particular, a loss of the relaxing molecule nitric oxide (NO) is to blame. NO is also an antioxidant with anti-inflammatory and anti-coagulative (blood clotting) properties. We lose the ability to synthesize (make) and utilize NO with age and along with it, we lose the cardioprotective benefits.
Vascular function may take a double hit in aging women. During the menopause transition, estradiol (estrogen) declines. This has devastating cardiovascular effects.
What’s so special about estrogen? Besides its role in reproductive function, estrogen is a well-known vasodilator and blood-pressure lowering hormone. Estrogen can induce the release of vasorelaxing nitric oxide (NO) and has potent anti-inflammatory properties throughout the cardiovascular system.
Evidence for a widening gap of CVD prevalence between men and women comes from studies in which vascular function is shown to be greater in age-matched premenopausal women vs. age-matched men, but that no sex differences are observed after menopause (~50–60 yrs of age). This suggests that whatever was “protecting” the women before menopause was lost after the transition. This cardiovascular bodyguard might be estrogen.
Lower endothelial function is correlated with reduced estradiol and a higher follicle stimulating hormone (FSH, high levels of which indicate menopause). A transition from pre- to early peri- to late peri- to postmenopause neatly correlates with a progressive loss in endothelial function. Hormones appear to mediate this pattern of decline.
Another cardiovascular risk mediator, stiffening of the large arteries (aorta and carotid) occurs with aging. While the evidence for arterial stiffening in women is not as salient as that for endothelial dysfunction, hormone changes with aging may still play a role. Post-menopausal women on hormone replacement therapy (HRT) with estrogen have more elastic arteries vs. their age-matched peers no on therapy.
Experiments in Function
Since it’s difficult to draw conclusions from associations and correlations, many studies have been done to elucidate the mechanisms by which declining endothelial function/enhanced arterial stiffening occur in women with aging.
A straightforward way to do this is hormone withdrawal and add-back —where women can be given certain doses (or deprived of) various hormones to test how they influence vascular function.
Short and long term treatment with estradiol improves endothelial function in estrogen deficient (postmenopausal) women. The same treatment also reduces arterial stiffening in this population to levels near, but not identical to, premenopausal females.
And a loss of estrogen? To elucidate just how estrogen (or a lack thereof) influences vascular function, researchers can prevent the release of sex hormones via gonadotropin-releasing hormone antagonists (GnHRHant) — which block the release of estrogen and other hormones.
Using this method, it has been shown that blocking sex hormones leads to a decline in endothelial function in premenopausal women to levels observed in perimenopausal women (who are older and at a later menopause stage). Blocking sex hormones in perimenopausal women? This caused a decline in endothelial function to levels observed in postmenopausal women.
Most mechanisms of vascular (dys)function and arterial stiffening with age in men and women overlap. However, understanding the additional risk due to hormonal changes in women requires further explanation.
Oxidative stress and inflammation are the main mechanisms owing to the decline in cardiovascular structure and function with age. During the menopause transition, a loss of estrogen and its anti-inflammatory properties could perhaps exacerbate the inflammatory environment and further potentiate women’s risk.
Where estrogen once leveled the redox balance of anti-inflammatory and pro-inflammatory factors, a decline in estrogen during the menopause transition likely leads to a greater oxidative. An oxidative environment is “bad” because oxygen free radicals are highly reactive — they react with proteins, lipids, and even DNA to cause damage, breakdown of certain structures, and neutralize the benefits of cardioprotective molecules.
What is the evidence that greater oxidative stress in women may exacerbate vascular decline? Animal models of menopause (tiny little postmenopausal rats) have shown that reactive oxygen species (ROS) are elevated in rats who have had their ovaries removed (they don’t produce estrogen). These animals exhibit lower endothelial function compared to the same animals given estradiol replacement.
More evidence for a role of oxidative stress comes from studies using a. anti-oxidants, in particular vitamin C; which sops up the pesky free radicals. Infusing vitamin C into estrogen-deficient women improves endothelial function and compliance of the carotid artery while it had zero benefits in premenopausal women. This is likely due to the fact that premenopausal women have sufficient estrogen to protect against ROS. Vitamin C had no job to do.
Inflammation is usually seen as bad. In the case of vascular function, it is. Molecules like tumor necrosis factor (TNF) and other inflammatory cytokines counteract the beneficial effects of nitric oxide (NO) on the vascular system, leading to dysfunction. Estrogen is known to antagonize pro-inflammatory effects of various signaling molecules and inhibit ROS formation. A change (or loss) in estrogen with aging in women likely has pro-inflammatory effects; a loss of protection. “Postmenopausal” rats have higher pro-inflammatory TNF levels, higher ROS, and reduced levels of nitric oxide synthase (NOS) in their blood vessels.
In women (and men), CVD remains the leading cause of death, and will for some time without proper intervention (more like a lifestyle overhaul). Studies by many groups investigating the sex differences in vascular function with age have concluded that the additional insult that women incur to their aging vascular system is probably a result of changing sex hormones, among other factors.
The transition from peri to postmenopause is accompanied by a drastic decline in estradiol, and shift in the anti/pro-inflammatory balance. This subects the blood vessels to ROS, leads to changes in structure, and ultimately a decline in function.
Interventions such as exercise and nutrition can help. However, some recent evidence suggests that along with an increased CVD risk during the menopause transition, women might become less responsive to certain interventions like aerobic exercise.
The research is ongoing , but these data point to the fact that in physiology, no longer can we assume that findings from any one study can be generalized to the whole population, no less to the opposite sex. This is why separating study results by sex is becoming “mainstream”, as is doing studies solely on women.
The future of this area of research is bright…and perhaps female.
When I think about the history of physiology research, I can only chuckle. It used to be a non-issue, even “taboo” to study women. Most exercise training studies were done solely in men. The reason for this is simply due to the fact that men were thought to be “simpler” (perhaps we are just “simple” creatures) — the “default” physiology without complications of menstrual fluctuations, etc.
This is no longer an excuse, and it’s moving the field forward. Think about all of the knowledge we’ve assumed, all of the knowledge we have that we use as a physiological blanket to make conclusions about women, drawn from studies on men. I’m excited to see the progress in this area.
Kerrie L. Moreau, Kerry L. Hildreth, Amie L. Meditz, Kevin D. Deane, Wendy M. Kohrt; Endothelial Function Is Impaired across the Stages of the Menopause Transition in Healthy Women, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 12, 1 December 2012, Pages 4692–4700,
David S. Celermajer, Keld E. Sorensen, David J. Spiegelhalter, Dimitri Georgakopoulos, Jacqui Robinson, John E. Deanfield. Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. Journal of the American College of Cardiology,Volume 24, Issue 2,1994,Pages 471–476,
Kerrie L. Moreau. Intersection between gonadal function and vascular aging in women. Journal of Applied Physiology Volume 125, Issue 6, 2018 Pages 1881–1887
Moreau, Kerrie L., Ozemek, Cemal. Vascular Adaptations to Habitual Exercise in Older Adults: Time for the Sex Talk. Exercise and Sport Sciences Reviews. Volume 45, Issue 2, 2017, Pages 116–123
Jeung-KiYoo, Michelle M.Pintoa, Han-KyulKim, Chueh-LungHwang, JisokLimaEileen M.Handberg, Demetra D.Christou. Sex impacts the flow-mediated dilation response to acute aerobic exercise in older adults. Experimental Gerontology. Volume 91, 2017, Pages 57–63