NAMS video series 2019: Understanding the etiology and mechanism of vasomotor symptoms

The North American Menopause Society (NAMS) regularly posts comprehensive videos for clinicians about important midlife health topics. All interviews in the series are hosted by NAMS Board of Trustees Member and Past-President Dr. Marla Shapiro, a Canadian physician who led this exciting initiative. Dr. Shapiro is also a medical consultant for CTV News.

In this first video of 2019, Dr. Rebecca Thurston, Director of the Women’s Biobehavioral Health Laboratory and Professor of Psychiatry, Psychology, Epidemiology, and Clinical and Translational Science at the University of Pittsburgh throws some light on the why and how about vasomotor symptoms (VMS).

The natural history of vasomotor symptoms is still evolving. It is estimated that about 75% of women experiencing menopause will have hot flashes. A substantial number of women seen in everyday gynecological practice or specialty menopause clinic report VMS well past the age of 60 and some well into the 80s.

Hot flashes considerably reduce the quality of life and hamper the day to day activities. Prevalence of VMS is generally associated with increased risk of CVD due to endothelial dysfunction. Hence, women with VMS could be screened for CVD risk factor and offered lifestyle modifications and frequent screening for early diagnosis and prevention.

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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

New natural (bioidentical) 17ß-estradiol-progesterone combination available as single soft gel capsules effective in treating postmenopausal symptoms: News from ENDO17

Courtesy: TherapeuticsMD

An innovative, investigational combination of 17ß-estradiol and progesterone in a single, oral softgel, was found effective for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause. The results of the study were presented at the ENDO 2017, the annual meeting of the Endocrine Society in Orlando, Florida, April 1-4.

TherapeuticsMD, Inc which specializes in developing women’s health products has developed this combination drug named as TX-001HR. TherapeuticsMD is using the unique technology called ‘SYMBODA’ in manufacturing the softgel capsules. SYMBODA, meaning “similar to the body,” is a solubilized female hormone technology for formulation of estradiol and progesterone identical in chemical structure to the estradiol and progesterone that women naturally produce.

Robert G. Finizio, Chief Executive Officer of TherapeuticsMD. "There are currently no FDA-approved oral bio-identical estradiol and progesterone combination products for women experiencing hot flushes and night sweats. Approximately 1 million to 2.5 million women are currently estimated to use non-FDA-approved compounded menopausal hormone therapy (CBHT) in the U.S. 

TherapeuticsMD seeks to address the unmet needs of post-menopausal women as we develop potentially the first FDA-approved 17β-estradiol plus progesterone combination softgel capsule in the United States."

If the drug gets approved by FDA, it represents first single combined bioidentical estradiol and progesterone formulation in the market. Till now bioidentical hormones are custom made at compounding pharmacies which are ‘not regulated by FDA.’ Many women choose these because they think they are natural, plant based, safer and do not have any side effects.

Many Societies like The Endocrine Society, the North American Menopause Society, the American College of Obstetricians and Gynecologists (ACOG) and the British Menopause Society have all raised concern regarding the hazards of using custom-compounded hormones to treat menopausal symptoms.

The positive results of Replenish Trial, a phase 3 study that evaluated the safety and efficacy of four doses of TX-001HR were presented at the conference by Rogerio Lobo, M.D., professor of Obstetrics and Gynecology and Director of the Reproductive Endocrinology Program at Columbia University.

Replenish trial is a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating four doses of TX-001HR with an objective of evaluating the drug’s effectiveness in relieving hot flashes in post-menopausal women.

The study enrolled 1835 healthy women between 40−65 years with intact uterus having ≥7/day or ≥50/week hot flushes. They were randomized to 5 groups receiving either of this 4-dose combination of TX-001HR:  E2/P 1.0 mg/100 mg; E2/P 0.5 mg/100 mg; E2/P 0.5/50; E2/P 0.25/50 or a placebo.

The efficacy of the drug was assessed by changes in number and intensity of hot flushes while on drug at end of 1 and 3 months.

Another subset of women who did not fit the criteria for VMS were randomized to receive either of the 4-dose combination of the drug to evaluate endometrial hyperplasia. All women underwent biopsy at the start of therapy and at the end of1 year. The safety end point was ≤1% incidence of endometrial hyperplasia at end of 12 months.

The results showed that TX-001HR combinations of E2/P 1.0 mg/100 mg or 0.5 mg/100 mg was most effective in controlling VMS without any unacceptable side effects.

Incidence of endometrial hyperplasia was 0%, with no reported case of endometrial cancer with any of the dose combination at the end of 12 months which is unlike reported cases of endometrial hyperplasia with compounded bio-identical hormone therapy (CBHT).

Dr Lobo concluded his talk saying “TX-001HR, "if approved," would be a new oral hormone-therapy option for postmenopausal women with moderate to severe vasomotor symptoms who have an intact uterus.

It may be a new option for the estimated millions of women currently using less regulated and unapproved compounded bioidentical hormone therapy."

The combination hormone pill Replenish Trial is the second clinical trial completed by TherapeuticsMD, which last December announced results from its Rejoice trial where it tested its softgel successfully in relieving vaginal dryness associated with menopause.

The 2 abstracts from the ENDO 17 conference can be accessed here: Abstract 1 and Abstract 2.

North American Menopause Society (NAMS) video series about important midlife health topics: February 2017.

The North American Menopause Society (NAMS) has started comprehensive video series for clinicians about important midlife health topics. All the interviews in the series are hosted by NAMS Board of Trustees Member and President Dr. Marla Shapiro, a Canadian physician, who led this exciting initiative.

In this monthly series, the  latest video is ‘ Sleep Disorders in Midlife’, Dr. Shapiro interviews Dr. Hadine Joffe, Professor of Psychiatry at Harvard Medical School, Director, Division of Women's Mental Health at Brigham and Women's Hospital and Director Psycho-Oncology Research at the Dana Farber Institute in Boston, Massachusetts. Dr. Joffe discusses how to diagnose and treat common sleep disorders in midlife women.

                                          Dr Hadine Joffe discusses sleep disorders