Menopausal transition period is a "critical window" for cardiovascular prevention in women

A healthy lifestyle during the perimenopausal and menopausal years reduces the risk of cardiovascular events in later life report the result of a prospective, cohort study published in in the December 4 issue the Journal of the American Heart Association.

The study is a secondary analysis of data from the ongoing, multicentric, multiethnic, prospective Study of Women's Health Across the Nation (SWAN) initiated in 1996 to know more about transition across menopause.  The researchers looked at data from 1143 women to create a composite 10-year average Healthy Lifestyle Score (HLS) involving smoking, diet quality, and physical activity. All three are modifiable behavioral risk factors for CVD and earlier studies have shown an inverse association between healthy lifestyle and various CV outcomes.

The study participants were followed for an average of 15 years with the last follow-up in the year 2015-2016. Carotid ultrasound scans were performed after 14 years to measure the markers of subclinical atherosclerosis which include common carotid artery intima‐media thickness (CCA‐IMT), adventitial diameter (CCA‐AD), and carotid plaque.

Information about the diet was collected at baseline, visit 5, and visit 9 using a modified version of the Block Food Frequency Questionnaire (FFQ) and the amount was quantified using the Alternate Healthy Eating Index (AHEI).

To assess whether the recommended physical activity (≥150 minutes/week of moderate-intensity physical activity) is met or not, the participants were asked to fill the sports and exercise questions on the Kaiser Physical Activity Survey.

Data on smoking were collected using the standardized questions from the American Thoracic Association.

The HLS was calculated based on the sum of individual scores on all the three parameters at baseline, visit 5 and visit 9 and averaged to get the final score. Other covariates included in the study at baseline were age, race/ethnicity, education, financial status, marital status, depression, self-reported health status, and menopausal status.

Physiological risk factors, including BMI, high blood pressure, impaired fasting glucose, serum triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, use of antilipidemic medications, and use of antihypertensive medications were adjusted in a separate model.

The association between the individual component of HLS and the three markers of subclinical atherosclerosis were also looked at.

At 10 years follow-up, average HLS was found to be inversely and statistically significantly associated with CCA-IMT and CCA-AD — an association that persisted, even after "extensive" adjustment for confounders (P = .0031) and physiological risk factors (P < .001 for both CCA-IMT and CCA-AD).

Compared with participants with the lowest range of HLS, those with highest HLS had a 0.024 mm smaller CCA-IMT and a 0.16 mm smaller CCA-AD.

After adjusting for various physiological risk factors, the researchers did not find a statistically significant association between carotid plaque and average HLS.

Analyzing individual component of HLS, smoking conferred the highest risk for a CV event and those who never smoked had a 0.047 mm smaller CCA-IMT, a 0.24 mm smaller CCA-AD, and 49% lower odds of having a higher carotid plaque index.

The investigators message for the physicians “the menopausal transition represents a crucial, yet understudied, window of increased cardiovascular risk in women. For the prevention of future cardiovascular disease among women undergoing the menopausal transition, the physician should focus on modifiable health behaviors including smoking, diet, and physical activity."

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New International Menopause Society (IMS) guidelines affirms the safety of menopausal HT.

The International Menopause Society (IMS) recently released 2016 Global Consensus Statement on Menopausal Hormone Therapy (MHT).[1]  The IMS brought together 7 international societies, including European Menopause and Andropause Society and the North American Menopause Society to formulate comprehensive, evidence based guidelines with practice essentials to help and guide physicians across the globe in managing women through menopause transition and beyond.

The guidelines are aimed at helping women across the globe to prevent chronic diseases due to aging along with treatment of troublesome menopausal symptoms. 

The term Menopausal Hormone Therapy (MHT) includes estrogen, progesterone and combined therapies.

The recommendations simply provide an overview of basic principles of hormone therapy which can be modified and adapted according to the geographical region, country specific belief and practices, basic infrastructure of healthcare and the variation and availability of the hormones. It also simply provides consensus and is not a replacement for the detailed guidelines issued by each individual societies.

Professor Rod Baber, IMS President, commented “I believe the new Global Consensus is a major step forward in the management of menopausal women as it provides women and their doctors with internationally endorsed guidance”.[2]

General principles that governs the use of MHT

The option of starting MHT should be decided according to the need of each patient depending upon age, time elapsed since menopause, the symptoms, risk of VTE, breast and gynecological malignancies and CVD.

It should be a part of overall life style change and management including diet, exercise and smoking cessation for prevention of postmenopausal osteoporosis.

MHT include a range of hormonal products that can be administered by various routes. It includes Tibolone or CE/BZA too when available. Each product has its own side effects, and risk/benefit rations.

MHT should always begin with the lowest possible dose that alleviates the symptoms with minimum side effects. The route of administration should be tailored to individual need, preference and side effects. 

The benefit/risk ratio should be assessed annually for each patient. The duration of the treatment should be planned accordingly with the lowest possible dose schedule. Some women may require longer duration of treatment for relief of Vaso Motor symptoms (VMS).

Use of estrogen as single systemic agent is only advocated in case of patients who have undergone hysterectomy, concomitant use of progesterone is always advocated with intact uterus unless CE is combined with BZA for uterine protection. 

Testosterone only therapy or in combination with MHT is only indicated in selective postmenopausal women with sexual interest/arousal disorder.

Use of custom compound hormone therapy is not recommended because of batch to batch variability, lack of regulation standards for safety, efficacy and purity.  

Safety data on use of MHT for breast cancer survivor is limited currently. It’s use in such patients can only be undertaken after discussing it with patient’s oncologist when complementary options have exhausted.   

Benefit/risk profile for MHT

Quality of life, sexual satisfaction, mood changes, joint pain and sleep disturbances may improve with MHT.

MHT with Tibolone and combination of Conjugated Equine estrogen and bazedoxifene (CE/BZA) is effective in treatment of osteoporosis. It has consistently seen to be effective in reducing the risk of vertebral, hip and other osteoporosis-related fractures in post-menopausal women.

MHT is the only therapy that is effective in preventing fractures in postmenopausal women with mean T-score in normal or osteopenic range. It should be initiated before the age of 60 or 10 years within menopause for at risk women for osteoporosis. 

If started after the age of 60 years, it is considered the second line of therapy and risk/ benefit ratio should be compared with other first line drugs.

The most effective treatment of VMS at any age is Tibolone and combination of Conjugated Equine estrogen and bazedoxifene (CE/BZA). Symptomatic women derive maximum benefits if treatment is started within 10 years of menopause or before the age of 60 years.

Vulvovaginal atrophy(VVA) is now considered a component of genitourinary syndrome of menopause (GSM). MHT including Tibolone relieves the symptoms of VVA. Topical estrogen preparations are first line of treatment in patients with only local vaginal dryness, dyspareunia or recurrent UTI. Ospemifene, a selective estrogen receptor modulator (SERM) is also licensed in some countries for treatment of dyspareunia due to VVA.

Many observational studies, RCTs and meta-analysis provides data that shows consistent benefits in standard dose estrogen alone group as compared to estrogen plus progestogen MHT in decreasing myocardial infarction and all-cause mortality when initiated before age of 60 or within 10 years of menopause.

The risk of VTE and ischemic stroke increases with oral MHT as compared with transdermal therapy (0.05 mg twice weekly or lower) when started before the age of 60 years.

The risk of breast cancer with MHT in women over the age of 50 years is a complex issue. Estrogen only MHT in women with hysterectomy shows a lower risk as compared to combine therapy the medroxyprogesterone acetate in the women’s health initiative study (WHI). However, the risk of < 1.0 per 1000 women per year is less than that associated with sedentary life style, alcohol consumption and obesity.

Women who experience a natural or iatrogenic menopause before the age of 45, particularly before the age of 40 face a consistent high risk for cardiovascular disease, osteoporosis, mood disorders and dementia. Results of observational studies have shown that these women benefit from MHT, but they have to be confirmed by RCTs. MHT can be prescribed till the age of natural menopause. 

In women with major depressive disorders, antidepressant therapy remains the first line of treatment, although MHT can be used to improve mood in women with anxiety/depressive symptoms.  MHT initiated in early menopause and after the age of 65 years also does not have significant effect on cognition and increase the risk of dementia.  Although some observational studies have shown that early initiation may prevent Alzheimer’s disease in later life.

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[1] http://www.imsociety.org/manage/images/pdf/fd28270c02bdca95a58a471e1719e9b4.pdf

[2] http://www.imsociety.org/manage/images/pdf/d9cfd8c2b902d63b0c1bb0ada805240d.pdf