Premature or early onset menopause is associated with increased risk of CVD and all-cause mortality.

Clinical pearls:

• Women who had premature menopause are at high risk for CHD, CVD and all-cause mortality.
• With every 1 in 3 women dying due to CVD, identifying those who are high risks for it is important from public health perspective.
• Women with premature menopause can be benefited by pharmacological and life style interventions to prevent the increased all-cause mortality and CVD risk they are put at due to accelerated reproductive aging.

Majority of women around the world undergo menopause between 45 to 55 years of age with the average age being 51 years.[1] According to recent estimates about 5% of women attain natural menopause between the age of 41-45 years and additional 1% of have the last period before the age of 40.  Another 5% have premature menopause due to surgical removal of the ovaries, radiation and chemotherapy for malignancies or smoking.  The age at final menstrual period is of great public health significance and is considered as an important marker for predicting future cardiovascular, bone and overall health of the women. [2]

Women who attain menopause before 45 years of age have shorter total duration of estrogen exposure as compared to women who have menopause in 50s.

Multiple observational and cross sectional studies in the past have tried to assess the effect of loss of ovarian function and increased risk of cardiovascular diseases (CVD) and all-cause mortality in women undergoing premature menopause.

A recent meta-analysis published in JAMA cardiology by Muka et al [3] tried to systemically review and meta-analyze the relationship between age and duration of menopause and increased risk of cardiovascular diseases.

The analysis included 32 studies consisting of 310,329 non-overlapping women in their analysis.

The investigators compared the outcomes between women who entered menopause before 45 years of age to those women who were 45 or older at the onset. It was seen that women in the early menopause group had 1.5 times the risk of overall coronary heart disease, 1.11 times the risk of fatal coronary heart disease,1.23 times the risk for overall stroke, 0.99 for stroke mortality, 1.19 times the risk for CVD mortality, and 1.12 for all-cause mortality as compared to women who had menopause after the age of 45 years.

Women who had menopause between age of 50-54 have decreased risk (.87 times) of suffering from fatal CHD as compared to women who had menopause before 50 years of age. The risk for stroke was comparable in both the groups.

With every 1 in 3 women dying due to CVD, identifying those who are high risks for it might be important from public health perspective. Menopause might be a crucial period in women’s life to evaluate her future risk for CVD and introduce interventions to reduce the risk.

In an invited commentary about the article by Dr JoAnn E Manson (Harvard Medical School, Boston, MA) and D. Teresa K Woodruff (Northwestern University), the authors stress upon the complicated relationship between menopause and CVD. They discuss the findings of the Framingham Heart Study which states that increase in systolic, diastolic blood pressure, cholesterol and other vascular risk factors around pre and peri menopausal years led to an accelerated menopause at a younger age. The data from the study provides an important clue about cardiovascular health being responsible for menopausal timing, but it does not exclude a bidirectional relationship. [4]

An earlier Meta-analysis of observational study showed that bilateral surgical oophorectomy was associated with more than double the risk of CVD (risk ratio=2.62). Women who are put on HRT after the surgery nullify their increased risk for CVD as compared to women with intact ovaries.

A detailed analysis of Women’s Health Initiative study also stressed the beneficial effects of HRT in relation to cardiovascular health when initiated between the ages of 50 to 59 years as compared to older women. [5]

The ELITE: Early Versus Late Intervention Trial With Estradiol also affirms the timing hypothesis in relation to timing of estradiol administration, when a beneficial cardiovascular effect is only seen in women with early, but not later menopause. [6]

To conclude, the findings of the review indicates that women who had premature menopause are at high risk for CHD, CVD and all-cause mortality.

Complex relationship exists between cardiovascular health and accelerated reproductive aging and further research is needed to clarify the issue, but currently women with premature menopause can be benefited by pharmacological and life style interventions to prevent the increased all-cause mortality and CVD risk they are put at due to accelerated reproductive aging.

---

[1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285482/

[2] http://www.cdc.gov/reproductivehealth/infertility/

[3] http://cardiology.jamanetwork.com/article.aspx?articleid=2551981

[4] http://amaprod.silverchaircdn.com/data/Journals/CARDIOLOGY/0/hic160023.pdf.gif

[5] https://www.nhlbi.nih.gov/whi/

[6] https://clinicaltrials.gov/ct2/show/NCT00114517

First Zika virus vaccine enters phase 1 trials in US.

A healthy volunteer receives the NIAID Zika virus investigational DNA vaccine as part of an early-stage trial to test the vaccine’s safety and immunogenicity. This is the first administration of this vaccine in a human.
Credit: NIAID

The National Institute of Allergy and Infectious Diseases (NIAID) made a press announcement on August 3,2016 about its recent launch of phase I clinical trials for its newly developed DNA Zika vaccine.

Zika is rife in Puerto Rico, American Samoa, the US Virgin Islands, and Florida and United States department of defense(DoD) recently confirmed about 30 cases of Zika virus infection among troops. As per Florida Department of Health recent update there are 15 total number of non-travel related infections and 55 pregnant patients have been infected due to either local transmission, sex with an infected partner or travel.[1] A total of more than 6,400 Zika cases have been reported in the US and its territories.[2]  

The NIAID Zika virus vaccine is investigational and was developed in the beginning of this year. The vaccine contains bio-engineered, non-infective Zika virus plasmid that contains genetic code for protein of the Zika virus. When injected into our body by intramuscular route, the DNA quickly assemble into a virus like particle, that has lost its infecting capabilities. It incites an immune response in the host by making antibodies and T cells.

The DNA vaccine, is delivered on the site on skin via a short electrical pulse that propels the DNA, which seeks  human cells through a process called electroporation.

It is also known from the animal experiment that despite being genetically different, all strains of the Zika virus have identical surface antigen, thereby vaccine developed against one will be effective against others too. [3]

According to John Mascola, MD, director of NIAID’s Vaccine Research Center (VRC), “DNA or gene-based vaccines include antibodies, but they also can activate the cell-mediated immune response, which ultimately could yield strong and durable protection against disease.”

DNA vaccines are new in the vaccine armament and no other DNA vaccine has been approved by US.[4] But since they do not need to grow live virus, DNA vaccines have short development time.[5]

The vaccine will be tested in 80 healthy volunteer in Maryland and Atlanta. The volunteers will receive the first shot at the same time and then they are divided into 4 groups of 20 each receiving the subsequent shots at varying intervals to study which dosing schedule works best. All the participants will be closely monitored for 44 weeks of initial vaccine administration.[6]They will be tested to measure the immune response to the vaccine at 18 and 24 months after the initial dose.

Researchers have already tested the vaccines in animal studies and found them to be effective and safe. When monkeys were exposed to Zika virus 4 weeks after the second dose, they showed no clinical signs of infection nor the virus was found in the blood.[7]

Meanwhile, a similar vaccine developed by The Infectious Disease Research Centre (IDRC) and the Centre de recherche du CHU (Centre hospitalier de l’Université) at Laval University in Canada has also begin its phase 1 clinical trials.

The vaccine is temporarily named GLS-5700, and is manufactured by Inovio, based in Plymouth Meeting, Pennsylvania, and GeneOne Life Science, of Seoul, South Korea.

At this point of time around 18 countries around the world are competing each other to develop Zika virus vaccines including French pharmaceutical giant Sanofi SA and GlaxoSmithKline.

According to CDC Zika virus infection is a public health emergency because of its causation of congenital birth defects. Currently 61 countries and territories are infected with Zika virus and 12 countries have reported birth defects due to Zika.

If the phase 1 trial is successful, the vaccine will enter phase 2 trial in early part of 2017. But, even at this pace it will be another 2 years before it is commercially available.

---

[1] http://www.floridahealth.gov/newsroom/2016/08/080316-zika-update.html

[2] https://www.niaid.nih.gov/news/newsreleases/2016/Pages/Zika-Investigational-Vaccine.aspx

[3] https://www.niaid.nih.gov/news/newsreleases/2016/Pages/Zika-serotype.aspx#

[4] https://www.statnews.com/2016/08/03/nih-zika-vaccine-trial/?trendmd-shared=0

[5] http://fortune.com/2016/01/28/zika-virus-vaccine/

[6] http://www.contagionlive.com/news/niaid-zika-vaccine-enters-clinical-trial

[7] https://www.niaid.nih.gov/news/newsreleases/2016/Pages/3-Zika-Vaccine-Approaches.aspx#

Douching doubles the risk of developing ovarian cancer.

Clinical pearls:

• Douching and not talc was associated with increased risk of ovarian cancer in the sister study. 
• ACOG and NHS both does not support douching and other vaginal washing practices that do more harm than good by eliminating the healthy vaginal flora. 

A National Health study in US linked the age old ritual of douching to subsequent development of ovarian cancer. Women who douche have nearly twice the risk as compared to women who do not practice it.

According to Department of Health and Human services(HHS) one quarter of women between the ages of 15 and 44 practice douching. [1] Studies have linked douching to Bacterial Vaginosis, Pelvic Inflammatory Disease(PID), STIs, including HIV, preterm birth, ectopic pregnancy and vaginal irritation or dryness. [2] A meta-analysis of more than 10,000 HIV-negative women in sub-Saharan Africa found that intravaginal use of drying agents was associated with an increased risk of BV and HIV.[3] 

American College of Obstetricians and Gynecologists (ACOG) and most practitioners strongly advice against douching and ACOG list it as one of the cause of vaginitis, women continue to practice it because of they see it as a cleaning ritual leading to positive health benefits.[4] The NHS also advise against douching and use of scented wipes and vaginal deodorants.

The new National Institute of Environmental Health Sciences study published online on 20 June,2016 in the Epidemiology Journal recruited 50,884 participants of the “Sister study” and followed them to see the link between douching and ovarian cancer. [5]The sister study is conducted by the National Institute of Environmental Health Sciences of the US Department of Health and Human Services. The study enrolled 50,884 women between ages 35–74 whose sister have breast cancer and followed them from 2003 to 2009, across all 50 US states and Puerto Rico.  Due to the shared environment and genetics, this landmark study provides a great chance of identifying risk factors for breast cancer.

All the women were free of breast or ovarian cancer at baseline. The women were asked about douching and use of talc during the previous 12 months before enrolment.

At the end of the follow up period (median 6.6 years) 154 women were diagnosed with ovarian cancer. Women practicing douching has nearly twice the odds of developing malignancy as compared to women who did not douche. The association looked even stronger when only women without the breast cancer gene in the family were analyzed.

Contrary to previous studies, this particular study did not find any association between talc use and ovarian cancer. (HR=0.73) although talc users were twice as likely to practice douching. (OR=2.1)

This is the first study to trying to find a link between douching and ovarian cancer.

Senior author Clarice Weinberg commented: “There are a number of health reasons not to douche, and I can’t think of any reason to do it.”

Vagina cleans itself naturally and douching cause more harm by cleaning away the healthy bacterial flora. The Office on Women's Health at the U.S. Department of Health and Human Services (HHS) says that due to squirting of the douching solution the bacteria are pushed inside uterus, fallopian tube causing PID.

A study conducted by Brown, J et al in 2016 shows women practice intravaginal washing due to personal hygiene and sexuality. It is common to get cleaned up after or before sex. Majority of these women learn the practices from their mothers or electronic or print media. Many women believe that since departmental stores aisles are packed with these products of personal hygiene, they must be safe to use.

But douching products do not fall under FDA regulation, as they are considered cosmetics. Hence, these products do not have to undergo safety tests like drugs.

The pilot study does not prove causation and larger studies are needed in the area. Perhaps women who douche frequently might have other pathologies going on which may be the cause for the behavior. We need to see more studies in the future. 

---

[1]Centers for Disease Control and Prevention. (2013). Key Statistics from the National Survey of Family Growth, 2006–2010.

[2] http://womenshealth.gov/publications/our-publications/fact-sheet/douching.html#

[3] Low N, Chersich MF, Schmidlin K, Egger M, Francis SC, van de Wijgert JH, et al. Intravaginal practices, bacterial vaginosis, and HIV infection in women: individual participant data meta-analysis. PLoS medicine. 2011;8(2):e1000416. 

[4] http://www.acog.org/Patients/FAQs/Vaginitis

[5] http://journals.lww.com/epidem/Abstract/publishahead/Douching,_Talc_Use,_and_Risk_of_Ovarian_Cancer_.98997.aspx