29 April, 2013: 

Looking at the cardiovascular system, it is clear that the heart has been extensively investigated and discussed in regard to the effects of menopause on the one hand, and hormone therapy (HT) on the other hand. But the area of peripheral arterial disease (PAD) in this respect has received much less attention. In a new cross-sectional study on 887 women aged 52–81 years, reproductive parameters were obtained by standardized interviews, and PAD was assessed by measuring non-invasively the ankle-brachial index (using a cut-off value of 0.9) and by assessing the presence of claudication using the Edinburgh questionnaire [1]. The only significant associations with the presence of PAD were later age at menarche (> 15 years) compared to age at menarche between 12 and 15 years (odds ratio (OR) 0.48; 95% confidence interval (CI) 0.24–0.98), and the presence of hot flushes (OR 2.09; 95% CI 1.11–3.92). Other reproductive parameters, such as parity, age at menopause, time since menopause, duration of fertility, ever use or current use of HT, ever use of oral contraceptives, history of hysterectomy, bilateral oophorectomy and depressive mood in relation to menopausal transition showed no significant association with PAD.

Comment

Despite the importance of obtaining more data on any association between PAD and menopause-related parameters, the study of Stöckl and colleagues [1] has many defaults in my eyes. First, too many parameters were evaluated, making the necessary statistical adjustments more problematic. Second, it is not quite clear what the definition of hot flushes actually was. The Methods section reads as follows: ‘women were asked about the presence of two symptoms of the menopausal transition: hot flushes and depressive mood.’ Since the mean age of the cohort was around 65 years, and the percentage of women reporting on flushes was 44–50%, I guess that any frequency/severity of flushes in the past or present was graded just as one category, comparing those with any to those with no history of flushes or current flushes. This may be faulty in view of relevant data on coronary artery disease (CAD). There is a clear association between CAD and hot flushes, although results from various studies were not uniform. As an example, data from the WHI observational study showed that total cardiovascular events and mortality due to myocardial infarction were lower in women reporting early vasomotor symptoms, but higher in those with late vasomotor symptoms [2]. The WHI clinical trial reached similar conclusions: ‘Risk factors for CAD tended to be more adverse in the women with vasomotor symptoms in each age group. The higher risks for CAD events in women more distant from menopause appeared to be concentrated in the small subset of women with moderate or severe vasomotor symptoms’ [3]. In contrast, in the subset of the WHI clinical study (50–59 years old, estrogen-alone arm), it was found that a history of any vasomotor symptom was significantly associated with reduced odds for coronary artery calcifications independent of traditional cardiovascular disease risk factors and other relevant covariates [4].

What do we know of PAD in postmenopausal women? Age is probably the most powerful risk factor, with a prevalence of 3% in women less than 60 years old, but mounting to 15–20% in women older than 70 years [5]. Whether or not males have a higher risk than females is questionable. Data are also inconsistent because of the multifactorial pathophysiological mechanisms, and the various inclusion criteria and definitions of PAD (affected carotid arteries? lower extremity arteries? abdominal aneurysm? all?). Several major studies have addressed the potential contribution of postmenopausal HT. Rockman and colleagues analyzed a prospective database of 847,982 women (half reported on hormone use, mean age 64 years) who underwent voluntary vascular screening [6]. Despite the increased prevalence of several atherosclerotic risk factors among women who used hormones, they were significantly less likely to have PAD than non-users of HT (3.3% vs. 4.1%, p < 0.001). Multivariate analysis adjusting for age, race, and medical co-morbidities that predispose toward the development of atherosclerosis confirmed HT was independently associated with a decreased risk of PAD (OR 0.8, 95% CI 0.78–0.82). In the three large US randomized, placebo-controlled trials on HT, results were not statistically significant and not uniform in direction [5,7]. In the HERS study (women with established CAD, mean age 64 years, 4-year follow-up), those who used a continuous combined conjugated equine estrogen–medroxyprogesterone (CEE–MPA) regimen demonstrated a relative hazard for all types of PAD (aortic, carotid, and lower extremity) of 0.87 (95% CI 0.66–1.44); In the WHI CEE–MPA arm (healthy women, mean age 63 years, 5.6-year follow-up), the hazard ratio for all peripheral arterial events (including aortic and carotid disease) was 0.89 (95% CI 0.63–1.25). However, in the CEE-alone arm of the WHI trial (healthy women, mean age 64 years, 7-year follow-up), the corresponding values for hazard ratio were opposite and almost reached significance: 1.32, 95% CI 0.99–1.77. Overall, it seems that, unlike the case with the heart, postmenopausal HT provides no protection against peripheral arterial events.

Amos Pines Department of Medicine ‘T’, Ichilov Hospital, Tel-Aviv, Israel

References

1. Stöckl D, Döring A, Thorand B, et al. Reproductive factors and its association with peripheral arterial disease in women aged 52–81 years: The KORA F4 study. Atherosclerosis 2013 Feb 5. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/23466069

2. Szmuilowicz ED, Manson JE, Rossouw JE, et al. Vasomotor symptoms and cardiovascular events in postmenopausal women. Menopause 2011;18:603–10.
http://www.ncbi.nlm.nih.gov/pubmed/21358352

3. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-77.
http://www.ncbi.nlm.nih.gov/pubmed/17405972

4. Allison MA, Manson JE, Aragaki A, et al. Vasomotor symptoms and coronary artery calcium in postmenopausal women. Menopause 2010;17:1136-45.
http://www.ncbi.nlm.nih.gov/pubmed/20651617

5. Vavra AK, Kibbe MR. Women and peripheral arterial disease. Womens Health (Lond Engl) 2009;5:669-83.
http://www.ncbi.nlm.nih.gov/pubmed/19863470

6. Rockman CB, Maldonado TS, Jacobowitz GR, Adelman MA, Riles TS. Hormone replacement therapy is associated with a decreased prevalence of peripheral arterial disease in postmenopausal women. Ann Vasc Surg 2012;26:411-18.
http://www.ncbi.nlm.nih.gov/pubmed/22285341

7. Mazhari R, Hsia J. Prevalence, clinical significance, and management of peripheral arterial disease in women: is there a role for postmenopausal hormone therapy? Vasc Health Risk Manag 2005;1:111-17.
http://www.ncbi.nlm.nih.gov/pubmed/17315397