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."

Full text 

Ob/Gyn Updated Facebook page

News from NAMS 2018: Estetrol, the next generation hormone therapy linked to significant improvement in menopausal VMS

Estetrol (E4) (Donesta®) in daily oral dose of 15 mg appears to be the most effective dose for the treatment of menopausal VMS reports the results of Phase IIb (E4 Relief) clinical trial presented at the 29th Annual Meeting of the North American Menopause Society (NAMS), being held on 3-6 October 2018 in San Diego, CA.  

Estetrol (E4) is the first promising NEST™ or Native Estrogen with Selectively action in Tissues produced by the human fetal liver, crossing the placenta and excreted in maternal urine at relatively high levels during pregnancy. It has a half-life of 28 hours and exhibits a unique mode of action.

It acts as an estrogen agonist in the vagina, endometrium, bone, and cardiovascular system and shows a mixed agonist and antagonist estrogenic property in liver and breast tissue. This results in lower level of breast stimulation with no effect on hemostasis parameters and triglycerides levels.

This multicentric, randomized, placebo-controlled, double-blinded, dose-finding study Phase IIb clinical trial recruited post-menopausal women, aged 40-65years across many European countries. Women qualified to participate in the trial if they had ≥7 moderate to severe hot flushes (HF) per day, or ≥50 moderate to severe HF in the week and Transvaginal Ultrasound (TVUS) showed a bi-layer endometrial thickness ≤5 mm.

Women were randomized to receive 2.5; 5; 10; or 15 mg E4, or placebo, once-daily, for 12 weeks. The primary endpoints were decreased in frequency and severity of hot flashes (VMS), while effects on genitourinary symptoms, lipid and glucose metabolism, hemostatic and bone markers were secondary endpoints of interest. Menopause Rating Scale (MRS) assessed the health-related quality of life. Safety of the drug was assessed by measuring the endometrial thickness and bleeding episodes while on therapy. 

As a protective measure against endometrial hyperplasia, the patients receive 2 weeks of progestin therapy (Dydrogesterone 10 mg) after the cycle of E4 is complete.

Of the 257 women selected, 200 women completed the study. At the end of the study period, there was an 80% improvement in frequency and severity of hot flashes, vaginal dryness, and dyspareunia in the E4 15mg group as compared to placebo. The improvement in VMS started as early as the end of 2 weeks with a trend reaching significance at the end of 4 weeks.

All the 11 dimensions of MRS also showed improvement with a near 50% reduction in the total score. The drug was completely safe with no effect on total triglycerides and cholesterol panel, hemostatic parameters and endometrial hyperplasia.

Estetrol (E4) (Donesta®) could be the next breakthrough for treatment of the full spectrum of menopausal symptoms. It is wholly natural and safety profile differs from that of estrogen. It could be the next oral alternative for transdermal estrogen preparations because of more breast safety.

Maud Jost, E4 Program Director, commented: “The presentation of data from the E4 Relief trial provides further evidence of the potential of Estetrol in the treatment of menopausal symptoms. This is the second-high profile conference where our compelling data from our promising Donesta program is presented. Preparations are already underway to progress Donesta into Phase III trials, which if approved could provide an innovative alternative to the millions of women seeking treatment with an improved benefit and risk profile.” 

Mithra (Euronext Brussels: MITRA), is a company specialized in Women’s Health is headquartered in Liège, Belgium.

Press release

Abstract S-16

Product page

Ob/Gyn Updated Facebook page

Media Courtesy: www.Mithra.com

NAMS 2018 annual meeting kicks off in San Diego, California

The North American Menopause Society Annual Scientific Meeting kicks off today in San Diego, California. The agenda is packed with symposiums, lectures, research presentations, and debates over many challenging topics related to health and quality of life of women at midlife and beyond.

The conference theme is Innovation, Evidence, and Individualization: Moving Menopause Management Forward and begins Wednesday, October 3, from 8:00 AM to 1:00 PM with pre-Meeting organized by the 2018 Pre-Meeting Co-Chair, Sheryl Kingsberg, Ph.D. on female sexuality.

The presentation will address various aspects of the critical topics including the epidemiology and classification of hypoactive sexual desire disorder (HSDD).

The focus is to make the gynecologist comfortable about talking on the topic with patients.   The six speakers from different discipline of medicine will cover biopsychosocial approach to treating hypoactive sexual desire disorder (HSDD) in postmenopausal women, pharmacologic and nonpharmacologic options for arousal and orgasm issues, the role of the physical therapist in female sexual function and dysfunction, treatment options for sexual problems resulting from genitourinary syndrome of menopause, and testosterone for HSDD: clinical perspectives from sexual medicine and gynecology.

Elissa Epel, Ph.D., from the University of California, San Francisco will talk about Telomere lengths, their role in aging process and psychological aspects of aging in her keynote address “Healthy Longevity and Telomeres: what does sex have to do with it.”

Symposiums are scheduled throughout the conference to discuss critical midlife topics like the role of stress in cardiovascular health of women, breast health, bone health, osteoporosis and increasing rate of hip fractures, and obesity and weight loss.

The Friday morning breakfast is reserved for ‘Trauma-informed care’ including the #MeToo discussion to help physician deal effectively with women who have suffered adverse sexual event, rape or abuse.

Looking forward to some very interesting abstracts presented at the conference.

Meeting page
Scientific Program
Ob/Gyn Updated Facebook page

North American Menopause Society (NAMS) video series about important midlife health topics: What women need to know about stress?

The North American Menopause Society (NAMS) provides practical information on important midlife health topics for women. All the interviews in the series are hosted by NAM Board of Trustees Member and Immediate Past-President Dr. Marla Shapiro, a Canadian physician who led this exciting initiative. Dr. Shapiro is also the medical consultant for CTV News.

In this informative video, Dr. Thurston discusses current research regarding the effects of stress on health.

Ob/Gyn Updated Facebook page

North American Menopause Society (NAMS) video series about important midlife health topics: Nonhormone Prescription Options for Hot Flashes

The North American Menopause Society (NAMS) provides practical information on important midlife health topics for women. All the interviews in the series are hosted by NAM Board of Trustees Member and Immediate Past-President Dr. Marla Shapiro, a Canadian physician who led this exciting initiative. Dr. Shapiro is also the medical consultant for CTV News.

HRT remains the most effective solution for the relief of menopausal hot flashes but not all women want to use hormones, or it may be contraindicated in some as women with breast cancer. Fortunately, there are some non-hormonal therapy that provide some relief, although they may not be as effective as estrogen.

In this informative video of 2018 series, Dr. Shapiro interviews Dr. James Simon, Clinical Professor, Department of Obstetrics and Gynecology, the George Washington University School of Medicine. Dr. Simon explains the efficacy of nonhormone options for hot flashes.

Ob/Gyn Updated Facebook page

Vaginal dryness— why no one is talking or doing anything about it?

A new study published in the North American Menopause Society's Journal Menopause identifies the factors associated with the taboo of not talking about vaginal dryness. According to the study results, more than 50% of women do not report vaginal dryness and less than 4% of those affected ever use any of the proven therapies.  

It is no secret that as the estradiol level plummets during the transition through menopause, most women experience vaginal dryness and dyspareunia. The Study of Women Across the Nation (SWAN) recruited a multiracial/ethnic cohort of 2,435 women at baseline and followed them over 17 years, with each woman clocking in approximately 13 visits.

This prospective cohort study identifies the incidence of vaginal dryness and its role in the causation of dyspareunia and frequency of sexual intercourse.

When the women were enrolled in the study, 19.4% of women (aged 42-53 years) reported vaginal dryness. At the completion of the study, 34% of women reported dryness (aged 57 to 69 years).

Advancing menopausal stage, anxiety, surgical menopause, and being married all contributed positively towards vaginal dryness.

Higher endogenous estradiol level was inversely associated with vaginal dryness in women not taking hormone replacement therapy. Whereas concurrent testosterone levels, concurrent dehydroepiandrosterone sulfate levels were not associated with developing vaginal dryness.

The study also highlighted the fact that the frequency of sexual intercourse was not related to the degree of vaginal dryness or pain during sexual intimacy. So, women who were thinking that having more or less frequency of sex is a remedy for vaginal dryness have to look for some other proven therapy.

Besides, HRT was more effective in managing vaginal dryness in women who transitioned into menopause naturally as opposed to those who had surgical menopause.

Dr. JoAnn Pinkerton, NAMS executive director, says in a press release, “Studies have confirmed that although more than half of women develop vaginal dryness as they become more postmenopausal, most do not report symptoms. Some will try lubricants as they begin to develop pain with sex. However, if lubricants and vaginal moisturizers are not enough, there are highly effective vaginal therapies such as vaginal estrogen tablets, creams, the low-dose ring, and the new intravaginal dehydroandrosterone. It is shocking that less than 4% of women in the SWAN study were using these effective therapies by the end of the study period.”

She urged women to please report symptoms, and healthcare providers to please offer safe, effective therapies.

Abstract

NAMS press release 

Ob/Gyn Updated Facebook page

What should midlife women know about preventive cardiology?

We are all aware that sex and gender differences are important in the diagnosis and management of cardiovascular diseases. A woman’s risk of a cardiac event and stroke sharply increases after the onset of menopause. Here is an informative video regarding preventing and managing the increased risk of a cardiac event after menopause.

Dr. Beth Abramson is a preventive cardiologist and helps women manage the risk of heart disease.  In this video by North American Menopause Society (NAMS), she answers many vital questions about menopausal hormone therapy, midlife weight gain, smoking, alcohol, and aspirin therapy.  

FDA approves Imvexxy to treat moderate to severe dyspareunia due to menopause

The United States Food and Drug Administration (FDA) has approved TX-004HR: IMVEXXY (estradiol vaginal inserts) for the treatment of moderate-to-severe dyspareunia due to vulvar and vaginal atrophy (VVA) of menopause.

Imvexxy is the only product in its therapeutic class to offer a 4 mcg and 10 mcg dose, the 4 mcg representing the lowest approved dose of vaginal estradiol currently available in the market. The product will be available to the consumers in July.

Imvexxy should be administered intravaginally as follows: one vaginal insert daily for 2 weeks, followed by one insert twice weekly.

Brian Bernick, MD, Chief Clinical Officer of TherapeuticsMD, said in a press release, “Imvexxy is a bio-identical vaginal estrogen product that offers a fraction of the estrogen contained in the average doses of many existing products currently on the market.”

“Imvexxy is the only product specifically designed to be applicator-free. It dissolves completely without mess or additional cleanup and can be used any time of day. It allows women the freedom to immediately return to their normal daily activities. Studies showed that, in patients who used Imvexxy, systemic absorption of estradiol remained within postmenopausal range," he further added.

The product was approved following the results of Phase 3, randomized, double-blind, placebo-controlled study (REJOICE, NCT02253173), published in April 2017 issue of Journal Menopause. The study results showed that Imvexxy was safe and well tolerated in all three doses (4, 10, and 25 μg).

In 2 weeks there was considerable improvement in dyspareunia, even with the lowest dose of 4 μg and vaginal dryness as early as 6 weeks as compared to women who received placebo.

A substudy of the REJOICE trial evaluated the pharmacokinetics of the 4-μg and 10-μg inserts and placebo.

There was negligible or very low systemic absorption as evident by the serum levels with no accumulation of the drug as seen by the low endogenous values observed at day 84.

Other products like vaginal estradiol tablet, vaginal creams, and vaginal estrogen ring used for the treatment of VVA limit systemic estrogen absorption but does not completely eliminate it.

The Pharmacokinetics profile for Imvexxy (ie, negligible to very low systemic absorption) could allow clinicians to follow the recommendation of The North American Menopause Society (NAMS) to use low-dose vaginal estrogens without a concomitant progestin.

It could also be used for the treatment of vaginal symptoms in survivors of estrogen-dependent breast cancer as recommended by the American Congress of Obstetricians and Gynecologists (ACOG).

The most commonly reported side effect by the users of vaginal inserts was a headache but it was not statistically significant when compared to placebo users.

VVA affects an estimated 32 million postmenopausal women in the United States. Approximately 7% (2.3 million) of these women receive prescription treatment. In addition, nearly 1 out of 2 women will experience pain during intercourse due to VVA at some point during their lives.

Dr. Sheryl Kingsberg, President, North American Menopause Society, said in a statement issued by TherapeuticsMD, “Studies have shown that many women are not seeking treatment for VVA, and 81% are unaware that VVA is a treatable medical condition and part of a constellation of symptoms associated with loss of estrogens."

 "I am delighted that our patients will now have a convenient treatment option with IMVEXXY and hope that the excitement generated by this new option will encourage women to talk to their healthcare provider and get relief from their pain and discomfort due to VVA,” she further added.

The product comes with a boxed warning about the increased risk of endometrial cancer, stroke, deep vein thrombosis (DVT), and dementia when used as estrogen-alone therapy without progesterone therapy.

Imvexxy is contraindicated in women with any of the following conditions: undiagnosed abnormal genital bleeding; known, suspected, or history of breast cancer; known or suspected estrogen-dependent neoplasia; active DVT, PE, or history of these conditions; active arterial thromboembolic disease or a history of these conditions; known anaphylactic reaction or angioedema to Imvexxy; known liver impairment or disease; known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.

REJOICE Trial

TherapeuticsMD Press Release

Ob/Gyn Updated Facebook page

New oral drug treatment found highly effective in reducing menopausal hot flashes

A neurokinin 3 receptor (NK3R) antagonist (MLE4901) rapidly reduced hot flashes for short and long-term in postmenopausal women; thus, eliminating the need for estrogen therapy report researchers from Imperial College London. The study was published on March 12, ahead of print in North American Menopause Society Journal Menopause.

The neurokinin 3 receptor (NK3R) antagonist (MLE4901) is manufactured by Millendo Therapeutics Inc, based at Ann Arbor, Michigan.

Nearly 73% of postmenopausal women experience hot flashes with disruptive effects on activities of daily life along with increased use of hormonal medications. Although estrogen is crucial for the maintenance of bone and cardiovascular health during menopausal years, the maximum efficacy takes weeks to develop and women often discontinue the estrogen therapy for fear of side effects. 

In this phase 2, randomized, double-blind, placebo-controlled, single-center, crossover trial (NCT02668185) the researchers recruited 37 women between the age of 40 to 62 years, experiencing ≥7 HF/24 hours to receive either NK3R antagonist MLE4901 40mg bd for 4 weeks or placebo 40 mg bd in random order.

After a gap of 2 weeks, the women received another drug which they didn’t receive first time for4weeks.

The oral NK3R antagonist MLE4901 not only reduced the frequency of hot flashes by 72% by day 3 of treatment but also reduced the severity of HF by 38% (44% by end of 4 weeks) as compared to baseline symptoms (all P < 0.0001).

The interference due to HF was also reduced by 61% (70% by end of 4 weeks) and level of bother by 39% (50% by end of 4 weeks) at the end of 3 weeks of treatment as compared to a placebo.

Professor Waljit Dhillo, the lead author of the study said: “If a woman is having more than seven flushes a day and the drug is getting rid of three-quarters of them, that’s pretty life-changing.

“For day to day living and work, that’s a significant impact on quality of life. If we can reduce flushing by 73 percent it’s a game-changer for those patients,” he further added.

JoAnn Pinkerton, MD, executive director of The North American Menopause Society opined that further large-scale trials to bring the drug into clinical practice would be game-changing for women with a history of estrogen-dependent cancers like breast and uterine cancers.

"Relief of hot flashes is an important, unmet need for these women, as other nonhormonal therapies such as low dose antidepressants or gabapentin have not been as effective as hormone therapy at relieving severe hot flashes," she further added.

She also suggested looking at the long-term effect of this drug, specifically after continued use for 3-5 years as some women continue to experience HF for 15-20 years past menopause.

Abstract

Media courtesy: Getty Images

Younger age at hysterectomy linked to increased risk of heart disease later in life

Ovarian conservation at hysterectomy does not reduce the risk of future cardiometabolic diseases reports the results of large prospective cohort study published in Menopause, the journal of The North American Menopause Society (NAMS).

This is one of the few studies that focuses on long term effect of hysterectomy with ovarian conservation. Earlier studies have documented strong evidence between increased incidence of cardiovascular diseases(CVD) and other chronic diseases after hysterectomy with bilateral oophorectomy.

The risk was especially increased if the hysterectomy was carried out before the age of 35.

Using Epidemiological project record, the researchers identified 2094 women who underwent hysterectomy with ovarian conservation between 1980 and 2002. Each woman was age matched with a control residing in the same county and who have neither undergone hysterectomy nor bilateral oophorectomy.

Cox proportional hazard models and Kaplan-Meier analysis was used to calculate hazards ratios and absolute risk after taking into consideration 20 risks factors and other potential confounders.

The two cohort were followed up for a period of 22 years, and women who have undergone hysterectomy were at increased risk of obesity, hyperlipidemia, hypertension, cardiac arrhythmias and coronary artery diseases.

Women who had hysterectomy under the age of 35 years were at nearly 5 times increased risk of congestive heart failure and 2.5 times increased risks of coronary artery disease.

Dr. JoAnn Pinkerton, NAMS executive director said in a NAMS press release, “These study results suggest that alternative uterine-preserving treatments may need to be considered more often in lieu of hysterectomies, especially in benign situations. For those women having hysterectomy, hormone therapy should be considered for added protection, because ovarian function appears to be impaired by the surgery.”

Abstract

NAMS press release

Media courtesy: Detroit Free Press

A practical guide to count ovarian antral follicles by ultrasound

A consensus opinion highlighting the main techniques of ovarian antral follicle count (AFC), and providing recommendations for future research is published in special issue on Reproductive Medicine of the journal Ultrasound in Obstetrics and Gynecology.

The consensus makes several recommendations for varied methods used in counting the antral follicles, but no single method is superior over others and the choice should make best use of resources available in a particular setting.

Ultrasound imaging of ovary with several follicles: (a) two-dimensional (2D) ultrasound (US) without harmonics; (b) 2D-US with harmonics; (c) multiplanar view without volume contrast imaging (VCI); (d) three-dimensional inversion mode; (e) multiplanar view with VCI; (f) sonography-based automated volume calculation (SonoAVC).
courtesy: Ultrasound in Obstetrics and Gynecology

In the absence of a single reliable test for predicting ovarian reserve, ovarian antral follicle count serves as a good surrogate marker for it.

AFC is most often carried out in women more than 35yrs of age and already tried to become pregnant since last 6 months, diminished ovarian reserve, ovarian surgery for endometrioma, prediction of risk of fetal aneuploidy and to predict age at menopause.

AFC count is used most often in obstetric practice while ‘follicle number per ovary’ (FNPO), is often more useful in gynecological clinical practice.

The main recommendations in the consensus include:

The AFC usually include follicles with a mean diameter between 2 to 10 mm. AFC less than 5-7 indicates small oocytes will be retrieved and AFC more than 20, predicts a higher risk of ovarian hyperstimulation syndrome. AFC less than 4 indicates an increased risk of menopause in next 7 years.

The sonography for performing AFC can be carried out anytime during menstrual cycle and is not limited to menstrual period.

AFC should be performed using a transvaginal ultrasound (US) probe with frequency ≥ 7 MHz. Transabdominal route should only be employed when ovaries are situated cranially and anteriorly in pelvic cavity or transvaginal procedure is not possible.

The sonographer should undergo 20-40 supervised examination to get trained in the technique.

AFC can be performed using real-time two-dimensional (2D) US, stored 2D-US cine-loops and stored three-dimensional (3D) US datasets. The most common method using 2D-US either in real-time or stored cine-loops.

Using 3D-US, requires special machines and software and follicles are counted manually in multiplaner mode, however, rendered mode can be used particularly inversion mode or semi-automatically, using sonography-based automated volume calculation (SonoAVC™).

Standardized report consists of:

The technique used for evaluation of the follicles.

Day of the cycle and use of hormones, especially hormonal contraception.

Mention the number of follicles between 2 to 10 mm in each ovary and the total number of follicles.

Presence of dominant follicles and cysts or tumor.

It is always good to mention the accessibility of the ovaries for egg collection.

The future research might focus on reproducibility of studies that consists of storage and later evaluation of 3D datasets.

The consensus is based on expert opinions as there are very few studies focusing on AFC. There are limitations and scarcity of studies about semi-automated techniques, and an inattentive observer may report a totally different AFC. Hence, the consensus recommends manual counting of follicles in clinical practice, using any of the following techniques: real-time 2D-US, pre-acquired 2D-US cine-loops or 3D-US datasets.

Full Text

NAMS updates position statement about Hormone Therapy at the 2017 annual meeting

courtesy: dailytimes.com

The North American Menopause Society(NAMS) executive director, JoAnn Pinkerton, MD, from the University of Virginia in Charlottesville, issued the updated Hormone Therapy(HT) Position statement at the ongoing annual meeting at Philadelphia October 11-14, 2017.

This update’s the 2012 statement from NAMS, and includes special needs population like women who had early menopause or breast cancer.

The recent findings from Women’s Health Initiative(WHI) follow-up study, published recently reinforced the development of this position statement. The results of follow-up study showed no increase in all-cause or disease specific mortality in women taking hormone therapy.

The advisory panel reviewed WHI data along with 13 years of follow -up, plus newer randomized trial and other observational data and studied the effect of HT on a wide range of diseases.

Recommendations:

NAMS urges the health practitioners to assess each individual woman based on her unique health risk and co-morbidities, and make a shared, informed decision about staring the HT. The women should be revaluated and her risk reassessed periodically.

The practitioners should choose the best dose, combination, route and duration of therapy for each individual patient.

HT is most effective in treating hot flashes, night sweats, and sleep disruption caused by menopause in addition to preventing bone loss and fractures.

Risk of HT differ according to the duration, timing of starting the therapy, type and route of administration and formulation. Risks vary according to the addition of progesterone.

Always use the lowest and safest dose that brings about relief of symptoms.

HT is safe for most menopausal women age less than 60 years or when started within 10 years of menopause.

The benefits of starting HT decreases and the risk increases (Increased benefit/risk ratio) if started 10-20 years after menopause or after the age of 60 years. In these women low dose vaginal estrogen is recommended for relief of Genitourinary syndrome(GSM).

Special populations:

Breast cancer: The WHI study data analysis did not show any increased risks with conjugated estrogen alone during the study period (7 years), but some studies have suggested increased risk after 15-20 years. The rare risk of <1/1000 for breast cancer appears to be due to combination of estrogen and progesterone or extended duration of estrogen alone.

CVD: HT reduces the risk of CHD when started at younger age or within 10 years of menopause and no effect of risk reduction was observed when it was initiated 10-20 years after menopause or after the age of 60 years.

Early menopause: Unless contraindicated, women who have had premature ovarian failure or surgically induced menopause should receive HT till median age of 52 years as benefits outweigh the risks. (Level II).

Family history of breast cancer: Evidence shows that HT does not alter the risk of breast cancer in women with FH of the disease, however she should undergo counselling about it. (Level II).

BRCA-positive women without breast cancer: These group of women are at high risk of primarily estrogen-receptor negative breast cancer. To mitigate the health risk caused by oophorectomy, systematic HT can be started after shared decision making until the median age of natural menopause. (Level II).

Extended use of HT: The recent data does not support the routine discontinuation of HT after the age of 65 years as per Beers criteria. Each woman should be individually assessed to continue HT beyond the age of 60 years. Her risk should be reassessed and close follow-up is needed. (Level III).

On World Contraceptive day: Review of contraception during perimenopausal years.

September 26^th is World Contraceptive day, it is annual worldwide campaign to improve global awareness about contraception, with the dream that every pregnancy is intentional.

RCOG has released a review paper about contraceptive methods around menopause, published today in RCOG journal The Obstetrician and Gynecologists. The WHO defines the menopause as permanent cessation of menstruation caused by the loss of ovarian follicular activity, which is essentially a retrospective diagnosis.

There exists no accurate biological marker that defines the moment when the woman ceases to be fertile.  During the perimenopausal years menstrual irregularities are very common with irregular scanty or heavy blood loss.

Although after 30’s natural fertility is on decline, effective contraception should still be used till menopause to avoid unintended pregnancies.

Some important key contents of this review paper on perimenopausal contraception are:

No method of contraception is contraindicated based on age alone, up to the age of 50 years, HRT does not provide adequate contraception as it inhibits ovulation in only 40% of women.

Some hormonal contraceptive also helps in relieving common perimenopausal gynecological problem.  Contraception must be used alongside HRT to avoid unplanned conception. Progestogen-only methods and intrauterine contraception (IUC) are suitable.

During the perimenopausal years, in women over the age of 50 years not using hormonal methods, contraception can be stopped after 1 year of amenorrhea as fertility is unlikely to return, while in women under 50 years of age, contraception should be continued for 2 years, as the return of fertile ovulation is more likely to occur.

The Faculty of Sexual and Reproductive Healthcare (FSRH) recommends that contraception should be continued for 1 year after recording two FSH levels at >30 IU/l, taken at least 6 weeks apart.

Alternatively, women can consider stopping their method of contraception at the age of 55 years when most will have reached natural infertility.

Women must be advised on all available methods of contraception, including long-acting reversible methods (LARC), so they can make an informed choice.

Combined oral contraception have the advantage of regular bleeding pattern and relief in hot flushes, but increased risk of thrombosis, and breast and cervical cancer. Some women prefer progesterone only pills because it is contraindicated in few medical conditions but irregular bleeding is a problem.

Progesterone only injectables are long acting but they often mask menopause, causes loss of BMD and once injected cannot be removed.

Copper intrauterine device and Levonorgestrel-releasing device are unsuitable if women have irregular uterine cavity.

Barrier methods are best, without any side effects and can be safely used till menopause.

Women can also avail emergency contraception in the perimenopausal age group. Levonorgestrel an oral progestogen; ulipristalacetate (UPA) an oral selective progestogen receptor modulator; and the copper IUD can be used in emergency.

Contraceptives of future: Frameless IUDs and Intrauterine ball has recently been licensed in Austria and will likely be marketed elsewhere in Europe and North America. It is a frameless IUD consisting of a shaped memory alloy (Nitinol^®) thread that holds 20 tiny copper spheres. The device becomes spherical once delivered into the uterus and might have greater potential for use in non-uniform endometrial cavities. As a hormone-free method, there will be no contraindications to its use in perimenopausal women.

http://newatlas.com/intra-uterine-ball-iub/23534/

Microchip drug-release technology is currently under development and will allow a progestogen-releasing microchip to be implanted for up to 16 years of use, which can be switched on and off with a remote control.

http://news.mit.edu/2015/implantable-drug-delivery-microchip-device-0629

Researchers are working on vaginal ring releasing UPA, a selective progesterone receptor modulator that will provide estrogen free contraception.

Not much progress has been made in areas of male contraception and condoms and sterilization are only current methods available.

Full Text

NAMS updates its position statement on HRT, clearing five critical areas of confusion.

courtesy: www.renewedvitalitymd.com

The North American Menopause Society has updated its position statement regarding menopausal and post-menopausal hormone therapy, replacing the earlier statement issued in 2012.

Instead of prescribing, “lowest dose for the shortest period of time” which may be harmful for some women, the new emphasis is on “appropriate dose, duration, regimen, and route of administration that provides the most benefit with the minimal amount of risk.”

The new position statement was published online June 21 in NAMS’s Journal Menopause.

Hormone Replacement Therapy remains the most effective treatment for vasomotor symptoms (VMS) and Genitourinary symptoms of menopause (GSM) and helps prevent osteoporosis and fractures.

The US FDA approved indications for starting HRT are bothersome vasomotor symptoms and genitourinary symptoms, Estrogen deficient states caused by premature ovarian insufficiency (POI), hypogonadism and castration and prevention of bone loss.

Women who are seeking relief for bothersome vasomotor symptoms are offered conjugated equine estrogen (CEE) if they already had hysterectomy or it is paired with a progestogen or with bazedoxifene, a selective estrogen-receptor modulator (SERM), to protect users against endometrial cancer.

The statement authors also suggest that micronized progesterone at a dose of 300 mg at bedtime can be an effective treatment to reduce hot flashes and night sweats and improves sleep.

Low dose, intravaginal estrogen preparation is the treatment of choice for women with vulvovaginal atrophy (VVA), because of minimum systemic absorption. For women who are intolerant to estrogen, ospemifene or intravaginal DHEA is equally effective in relieving the symptoms of atrophy. This preparation also bring relief from urinary symptoms.

Systemic Hormonal therapy is not effective in improving urinary incontinence and on the other hand may exacerbate stress incontinence.

HRT in women who have undergone surgical menopause or POI should be started early and at least continued till the age of 52 years.

An important update in this statement was about starting HRT in women with BRCA 1/2 mutation. Dr. JoAnn V. Pinkerton, NAMS executive director said, "For BRCA-positive women without breast cancer who have undergone risk-reducing bilateral salpingoophorectomy, observational data suggest that systemic HRT to the median age of menopause may decrease health risks associated with premature loss of estrogen without increasing breast-cancer risk. "

Physician should be cautious in starting HRT in women who are 10 years past menopause or 60 years old at the time of initiating HRT. In these group of women, the benefit/risk ration is less favorable than for younger women because of increased risk of stroke, CVD, venous thromboembolism and dementia.

If the women are already on HRT, the therapy need not be discontinued abruptly at age 60 or 65 years. It may be continued past 65 years of age for persistent hot flashes, prevention of osteoporosis, and quality-of-life issues, with an open dialogue with the patients about the risk and benefits of HRT at this age.

Once HRT is stopped, in 50% of women, vasomotor symptoms will recur, irrespective of age of starting the therapy or duration of therapy quoted the authors of the statement.

And, nearly all women, will lose [bone-mineral density], with increased risk of bone fractures and excess mortality from hip fracture," they also point out.

Dr Pinkerton added "And the risks of longer use of HRT may be minimized with the use of lower doses of both estrogen and progestogens, the use of transdermal therapies to avoid hepatic first-pass effect, or the combination of conjugated estrogen paired with the SERM bazedoxifene, which provides endometrial protection without the need for a progestogen."

NAMS has also released a patient information sheet called ‘MenoNote’ that simplify the facts and help women to decide using HRT. The ‘MenoNote’ is available on NAMS website. It can be accessed here.

New class of drug effective in targeting menopausal symptoms: News from Endocrine Conference 2017.

courtesy: Getty images

A new class of drug Neurokinin 3 (NK3) receptor antagonists is highly effective and low risk alternative to hormone replacement therapy(HRT) for treatment of menopausal hot flashes according to a study presented at the ENDO 2017, The endocrine society annual meeting from April 1–4, 2017, in Orlando, FL.

NK3 receptor blockers fezolinetant (Ogeda) and MLE4901 (Millendo Therapeutics) were found useful in reducing moderate to severe hot flashes in postmenopausal women.  

The study results of MLE4901 trial were also simultaneously published in Lancet.

About two-third of women are affected by hot flashes that reduce the quality of life and overall well-being. Approximately 20 million women in the United States currently experiencing VMS. HRT is effective alternative, but it is not without any side effects and cannot be used in patients with malignancies.

In this phase2, randomized, double-blind, placebo-controlled, single-center, crossover trial 37 women aged 40–62 years were assigned to take either 40 mg BD of the drug/placebo for 4 weeks and then received other treatment for 4 weeks after a 2 weeks’ gap in between.

The primary end point of study was number of hot flashes, the secondary endpoints were hot flush severity, bother, and interference with daily activities, gonadotrophins and LH concentrations.  

MLE4901 reduced the number and severity of hot flashes considerably as compared to placebo (p<0·0001 for both). 

The women also reported increased sleep, decreased fatigue and irritability. The drug was well tolerated except a small increase in transaminase without rise in serum bilirubin.

Studies during the last 2 decades have increasingly shown the role of NKB–NK3R signaling in the etiology of menopausal hot flushes.

Dr Julia K Prague, of Imperial College London, United Kingdom, said of MLE4901 in her presentation"Treatment with the NK3 receptor antagonist could be practice-changing, as it significantly relieves hot-flash symptoms without the need for estrogen exposure. Larger-scale studies of longer duration are now indicated and planned."

The other study presented at the conference evaluated the effect of fezolinetant, which was a 12-week double-blind, placebo-controlled, multicenter study involving 80, healthy postmenopausal women between 40-65 years.

The women were randomized to receive either fezolinetant (90 mg, BID) or placebo. Women receiving the NK3 antagonist experienced 50% less frequent hot flashes that were half as severe as women in the placebo group. (P < .001)

At a biochemical level these women showed a 50% decrease in LH levels. LH levels are biomarkers for reduction in hot flashes. Quality of life, sleep and irritability also improved, that continued after stopping the drug.

Both the drugs did not have any significant effect on libido, "That is to be expected, because after all this isn't estrogen replacement," said the lead author Dr Fraser.  He further added that the safety profile is extremely good and only two patients experienced mild side effects and the patients were able to reach the end of study.

Ogeda chief scientific officer Dr Graeme L Fraser, who presented the fezolinetant data, said that the company plans to further test the drug in women who have had breast, uterine, and ovarian cancer, for whom hormone-replacement therapy is contraindicated. "This really is a perfect fit for this population, where there is an important unmet need."

Pr. Herman Depypere (UZ Ghent), principal investigator said: "More than 80% of menopausal women develop hot flashes and 20% to 30% of this population seek treatment because their symptoms are severe and debilitating and negatively affect their quality-of-life. The Women's Health Initiative Study advises against the chronic use of HRT due to important safety concerns including the increased risks of cancer and cardiovascular events. The degree of relief demonstrated with fezolinetant (a non-HRT) in this study could represent an important breakthrough in the way we can manage menopause."

The results of both these studies call for larger studies for long period of time.

The conference abstract can be accessed here.

The article in Lancet can be accessed here.