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Hormone Therapy

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The healthyher.life team supports a holistic approach to managing women’s hormonal healthcare. Our goal is to help our members be well-informed about their hormonal health, by providing them with evidence-based integrated health information that includes the current standard of medical care advised by qualified physicians, clinical insights from licensed allied health professionals (naturopathic doctors, nurse-practitioners, nutritionists, psychotherapists) and new health innovations that will be soon coming to market. Always consult with your doctor regarding your medical condition, diagnosis, treatment, or to seek personalized medical advice. 

Introduction of Hormone Therapy for Menopause
 

Reviewed by Rina Carlini, Ph.D and Joanne Tejeda, Ph.D
July 20, 2023

Hormone therapy (HT) is the general term used to describe the various hormonal treatments commonly used to manage and relieve menopause-related symptoms such as hot flashes, night sweats, headaches, sleep disturbance, vaginal dryness, mood swings and irritability, among others [1–6].   During the menopause transition (a.k.a. perimenopause), these symptoms occur as a result of low estrogen and progesterone levels in the body [1–6]. Hormone therapy may be described as MHT (menopausal hormone therapy) when it is prescribed as a supplemental form of estrogen and/or progesterone hormones for women experienceing a normal perimenopause transition, or during the post-menopause year. Hormone Replacement Therapy (HRT) is the medical term for when hormone therapy is prescribed as a replacement of the natural hormone levels of estrogen and/or progesterone that decreased to very low or insufficient levels for women in the pre-menopause stage (below age 40), or early perimenopause stage (below age 45), or for women who have had a hysterectomy or oophorectomy (removal of one or both ovaries, but not the uterus). 

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HT is often prescribed as the first line treatment of vasomotor symptoms such as hot flashes and night sweats in menopausal women who have no history of other medical conditions [1,2,7].  However HT might not be recommended if you have had one or more of the following health conditions [1,2,7]:

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  • Breast cancer

  • Coronary artery disease

  • Thromboembolic disease (Deep vein thrombosis)

  • Stroke

  • Undiagnosed vaginal bleeding

  • Endometrial cancer

  • Endometriosis

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Estrogen deficiency due to menopause can cause significant loss of bone mass, resulting in osteoporosis [1,8,9]. Osteoporosis is a systemic skeletal condition seen by low bone density, deterioration of the bone tissue and decreased bone strength which leads to bone fragility and increased risk of fractures [1,8,9]. HT is normally used as a secondary line of treatment for the prevention of osteoporosis in menopaused women [1,8,9]. However a recent article published in the Canadian Medical Association Journal reported that HT is the treatment of choice for peri-menopausal women who are in their 40s and 50s experiencing vasomotor symptoms (i.e., hot flashes and night sweats) within 10 years of their final menstrual period [1]. The duration and dosage of treatment is dependent on the individual's needs and is no longer recommended to be limited to the first 5 years of taking HT [1].

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How does Hormone  Therapy (HT) Work?

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The main purpose of HT during menopause is to restore estrogen and progesterone hormones in females to normal levels [10]. Usually, HT treatments are delivered as a combination of estrogen and a progestin – which is the term used for the synthetic version of the natural hormone progesterone [1,6,11]. Estrogen is prescribed to manage menopause symptoms, while progestins work primarily to protect the tissue lining of the uterus from becoming enlarged or inflamed, or to prevent endometrial cancer, and also in managing menopause symptoms [1,6,11]. The types of estrogen hormone used in HT can include estradiol (most prescribed), ethinylestradiol, mestranol, esterified estrogens (estradiol valerate), estropipate, and conjugated equine estrogens (CEE) [11]. The types of progesterone hormone used in HT can include a progestin (synthetic progesterone) such as medroxyprogesterone acetate (MPA), levonorgestrel, norethindrone, desogestrel, micronized progesterone and others [13,14]. 

 

For those who are scientifically curious, here is a visual representation of the structural differences between naturally occurring estrogens and progesterone and their synthetic counterparts. 

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Please consult with your medical doctor or naturopathic doctor to discuss the benefits and risks of taking Hormone Therapy for managing your menopause hormonal health.

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Types of Hormone Therapy and Delivery Formats [1,3,15]: 

  1. Estrogen-Progestin Combination – for individuals that have a uterus

    • Oral pills

    • Transdermal patch (applied outside of upper arm, lower stomach, or top of the buttocks)

  2. Estrogen Only – for individuals who have had a total hysterectomy [1]​

    • Transdermal patch (applied to outside upper arm, lower stomach, or top of the buttocks)

    • Transdermal gel (applied to the forearm)

    • Transdermal spray (applied to the forearm)

    • Vaginal creams, tablets, or rings

  3. Oral pills

  4. Progestin Only – for individuals with an adverse reaction to estrogen [16]

    • Oral pills

    • Intrauterine device (IUD) (e.g., Levonorgestrel , commercially sold as Mirena®) [1,17,18]

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For individuals that are recommended to take progesterone but are not interested in taking synthetically made progestin, there is the option of taking oral micronized progesterone that is extracted from a species of yams (Prometrium®) [19].

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Benefits of Hormone Therapy [1,2,6]

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  • Improves up to 90% of vasomotor symptoms in patients with moderate to severe hot flashes [1].

  • Improves sleep quality by lowering mood disturbances and reducing night sweats

  • Relieves vaginal dryness (a.k.a. vaginal atrophy) and increases libido (sexual drive)

  • Lowers the risk of osteoporosis-related fractures such as hip fractures (up to 34% decreased risk), vertebral fractures (up to 23% decreased risk) [1]

  • Improves insulin sensitivity and reduces the risk of type II diabetes

  • Reduces the risk of coronary artery disease in women who start HRT before their 60’s.

  • Improves overall quality of life, sleep, and relationships with family, spouse/partners, friends [1,2,20]

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Risks of Hormone Therapy

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Over the past two decades, HT has been the subject of many medical debates and controversies because of the flawed conclusions that were reported as outcomes from a large USA population health research study published in 2002 known as the Women’s Health Initiative (WHI) study [1,21–23].  The authors of the WHI study reported that HT could lead to detrimental health risks, and specifically higher risk of breast cancer, than health benefits for women aged 65 years or older, who were the subject of the study [1,21–23]. These negative results were widely publicized among the medical community and popular media, which ensued panic among women patients, and triggered lawsuits [1–3,7,11,22]. 

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However, by 2006 the conclusions of the WHI study had been debunked because of new clinical studies which proved that the use of HT by younger women entering perimenopause or in the early post-menopause years, led to a reduced risk of coronary disease, osteoporosis, endometrial cancer, and a lowered risk of poor cognitive health [1–3,7,11,22]. Unfortunately a huge generation of ‘babyboom’ and ‘GenX’ women, many of whom are currently in their 50s to 80s, were negatively impacted by the false outcomes originally reported from the WHI study, since many physicians in the Western medicine fields were advised by their professional medical associations to avoid prescribing HT to women who could have greatly benefited from this therapy during their menopausal journey [1–3,7,11,22]. In the 10-15 years subsequent to the poorly-studied conclusions of the WHI trial, a generation of physicians and obstetrician-gynecologists had unfortunately received an inadequate level of training about hormone therapies for treating pre-menopause, perimenopause and post-menopause symptoms.

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It is important to note that from both the 2002 WHI study and new clinical studies, it remains true that for women over the age of 60, HT can present a greater risk of health complications rather than benefit, so it is usually not recommended to women in this older age group [1–3,6,7,11,20,22,24]. 

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There has also been research that has associated estrogen-progestin combination HT with an increased risk of dementia and Alzheimer’s disease even in women aged 55 and younger although more research needs to be done in order to determine if the increased risk comes from HT or from a natural predisposition to these diseases [25]. 

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Hormone Therapy and Cancer

 

A review of all clinical studies looking at HT and cancer patients and survivors published in the Cancer Journal in 2022, found that out of 25 studies published between 1980 and 2013, only 1 study (the hormonal replacement therapy after breast cancer (HABITS) trial) demonstrated an increased risk of cancer recurrence (colorectal and local cancer but not breast cancer) [24,26].  However, that study was prematurely stopped in 2003 and so its results were misinterpreted and misrepresented to mean that HT should not be recommended to cancer survivors [24].

 

Despite the above stated research, according to the North American Menopause Society (NAMS), for breast cancer survivors, the use of systemic estrogen HT (i.e., estrogen that is delivered orally or transdermally and which circulates in the bloodstream) is not recommended for relief of vasomotor symptoms [27]. 

 

However, both the NAMS and the Canadian Menopause Society acknowledge that estrogen HT is associated with little impact on breast cancer risk and that with prolonged use, there is a slight increase in risk [28,29]. In order to minimize risk, the NAMS recommends starting with the lowest effective dose of estrogen for the shortest time period possible [28]. 

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Side effects of Hormone Therapy

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Common side effects of HT may include, but are not limited to [1,2,6]:

  • Headache

  • Vaginal bleeding (or breakthrough bleeding)

  • Premenstrual-like symptoms such as breast-tenderness, bloating, mood swings can persist within the first few months of starting HRT [13]

  • Breast pain (Mastalgia)

  • Weight change

  • Cholecystitis (inflammation of the gallbladder)

  • Blood clots in the legs and lungs [20]

 

The duration of hormone therapy as well as the format will vary depending on the symptoms and personal preferences, along with the risk profile of the woman [6].

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If you are interested in learning more about the impact of the 2002 WHI study, please see the following resources that feature Dr. Avrum Bluming, a USA gynecologist, hematologist, medical oncologist who has written extensively and was interviewed on many podcasts about the negative fallout of the study.

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  • Podcast – “Avrum Bluming, M.D. and Carol Tavris, Ph.D.: Controversial topic affecting all women—the role of hormone replacement therapy through menopause and beyond—the compelling case for long-term HRT and dispelling the myth that it causes breast cancer” available at https://peterattiamd.com/caroltavris-avrumbluming/​​​

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Please consult with your doctor to determine if any form of Hormone Therapy is right for you.

 

Tags

Menopause, hormone therapy, vasomotor symptoms, hot flashes, estrogen, progestin, progesterone, hot flashes, night sweats, vaginal bleeding, cancer, women’s health, hormonal health

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HRT.png

Figure 1. Chemical structures of natural and synthetic estrogens and progesterone.

References

​To view the list of references, click on the plus symbol 

HRT Article 2

​Depression & Menopause Coinciding for Midlife Women: Know the Symptoms and Treatment Options

By Susan Johnson
Reviewed by Rina Carlini, PhD
November 19, 2024

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Image Source: Shutterstock (ID: 12208279959)

Depression is a significant mental health concern, affecting around 280 million people in the world–most of them women. [1] In most women, the risk of experiencing depression spikes in midlife (ages 45 to 54), with about 20-30% facing first or recurrent episodes of major clinical depression during this time. [2] While concerns about aging, dealing with workplace issues, and challenges in intimate relationships are a few reasons to blame, menopause is another crucial factor.

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The transition to menopause is accompanied by notable psychological changes, such as mood swings and anxiety, in nearly one in three women. Even women with no prior history of depression are two to four times more likely to experience depressive symptoms during perimenopause than their younger or older counterparts. [3]

The Menopausal Transition

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According to the American College of Obstetricians and Gynecologists (ACOG), menopause is the time when a woman’s menstrual periods stop permanently following 12 consecutive months of no periods.[4]

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The period leading up to menopause is called perimenopause, which can span a period of 3-7 years on average. During this time, the hormone levels, particularly estrogen, begin to decline, causing irregular menstrual cycles and symptoms like hot flashes, insomnia, anxiety, mood swings, and depressive feelings.

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Depressive symptoms during the menopause transition can manifest in several ways:

  • Fatigue or low-energy

  • Irritability, restlessness, or agitation

  • Difficulty concentrating or making decisions

  • Persistent sadness or feeling of emptiness

  • Sleep disorders, such as insomnia or oversleeping

  • Loss of interest in activities once enjoyed

  • Feelings of worthlessness or guilt

  • Changes in appetite or weight

  • Suicidal thoughts

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Most women get relief from depressive symptoms in the post-menopause years, but some may continue to experience mood disturbances. This could be due to poor social support, unaddressed mental health concerns, substance abuse, and others.

 

Are Hormones The Only Thing To Blame?

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In the past, researchers have studied the association between mood changes and hormones like follicle-stimulating hormone (FSH) and estradiol. The results were inconsistent, with some studies linking higher levels of these hormones to increased depressive symptoms while others not confirming this connection.

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During perimenopause, the estrogen and progesterone levels start to fall. Since estrogen acts as a protective agent in the brain, a decline in estrogen levels plays a crucial role in increasing the risk of developing depression, particularly in those who have suffered major depression in the past. Estrogen also impacts serotonin transmission (a neurotransmitter that promotes feelings of happiness) by influencing serotonin receptor expression. When the estrogen levels fall, it disrupts serotonin balance, potentially destabilizing moods and leading to irritability, anxiety, and sadness. [5]

​

Changes in the transmission of other neuropeptides, such as dehydroepiandrosterone sulfate (DHEAS) and gamma-aminobutyric acid (GABA), may also happen during perimenopause and can cause depressive symptoms. Lower levels of DHEAS and GABA in older women have been associated with increased symptoms of depression, similar to those seen in major depressive disorders. [6] [7]

​

Beyond hormonal changes, studies have also shown two major risk factors–biological and psychological–that shape a woman’s experience during menopause. Biological risk factors include hot flashes, night sweats, sleep disturbances, and unrelated chronic medical conditions. For instance, hot flashes occur as a result of the dysregulation in the brain’s thermoregulatory center due to ovarian failure and estrogen loss. It can lead to poor sleep quality, making women feel low and anxious and, ultimately, depressed. [8] Sleep disturbances and chronic health conditions can also add stress, which increases the likelihood of experiencing mood changes.

A history of depression/ postpartum depression, an adverse perception of menopause, and higher levels of neuroticism—a personality trait associated with negative emotions–are psychological factors that are strongly related to depressive symptoms during the menopause transition. [9]

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Lastly, additional life challenges such as relationship conflicts, caregiver responsibilities, career transitions or job demands, financial stress, retirement planning, or even kids moving out can contribute to feeling depressed and anxious during menopause.

​

How Is Menopausal Depression Managed/ Treated?​

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Current guidelines recommend treating menopausal depression with a combination of antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), psychological therapy, and lifestyle changes. [10] However, antidepressants may not work for everyone and can cause side effects like serotonin syndrome, emotional numbness, diarrhea, agitation, nausea, anorexia, excessive sweating, insomnia, headache, decreased libido, etc. [11] For example, some menopausal women with

significant insomnia, irritability, or anxiety may not respond well to common SSRIs like escitalopram, or they might experience an exacerbation of symptoms with fluoxetine. For this reason, the choice of antidepressants should be tailored for each woman.

Newer medications, like desvenlafaxine (an SNRI) and agomelatine, have shown promise for perimenopausal women, with agomelatine proving to help treat insomnia. [12] [13] [14]

When it comes to psychosocial treatment, it is effective in women with perimenopausal depression that stems from work or relationship stresses common in midlife. In addition, exercise, mindfulness techniques, yoga, and dietary adjustments are also helpful in managing symptoms of depression to some extent.

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According to the data so far, menopausal hormone therapy (MHT) has shown promise in treating mild perimenopausal depression linked to hormonal fluctuations, but its effectiveness for postmenopausal depression remains unclear. [15] Recently, newer MHT regimens like low-dose hormones and transdermal estradiol, which can cross the blood-brain barrier, are also being explored. [16]

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However, MHT is not suitable for women with a history of hormone-dependent cancers or venous thromboembolism. The Australasian Menopause Society (AMS) has evidence-based guidelines that healthcare providers should follow when prescribing MHT. [17] [18]​

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How effective are lifestyle changes such as meditation, exercise and choice of diet?

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Hormonal treatments are not generally prescribed for women who smoke, have high blood pressure, have a history of blood clotting, have heart or liver diseases, have conditions like diabetes or epilepsy or are already postmenopausal.

​

For these patients, lifestyle adjustments are recommended, such as adopting a balanced diet [19], practicing meditation, exercising regularly, and limiting caffeine and alcohol intake. These strategies can promote mental well-being and significantly ease perimenopausal symptoms. While these adjustments may alleviate symptoms, they cannot fully resolve the major depressive disorder and should be combined with medication and/or psychological therapy for the best outcomes.

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References:

[1] World Health Organization: WHO & World Health Organization: WHO. (n.d.). Depressive disorder (depression). https://www.who.int/news-room/fact-sheets/detail/depression

[2] Colvin A, Richardson GA, Cyranowski JM, Youk A, Bromberger JT. Does family history of depression predict major depression in midlife women? Study of Women's Health Across the Nation Mental Health Study (SWAN MHS). Arch Womens Ment Health. 2014 Aug;17(4):269-78. doi: 10.1007/s00737-014-0433-8. Epub 2014 Jun 21. PMID: 24952069; PMCID: PMC4120816.

[3] Bromberger JT, Kravitz HM, Chang YF, Cyranowski JM, Brown C, Matthews KA. Major depression during and after the menopausal transition: Study of Women's Health Across the Nation (SWAN). Psychol Med. 2011 Sep;41(9):1879-88. doi: 10.1017/S003329171100016X. Epub 2011 Feb 9. Erratum in: Psychol Med.2011 Oct;41(10):2238. PMID: 21306662; PMCID: PMC3584692.

[4] The menopause years. (n.d.). ACOG. https://www.acog.org/womens-health/faqs/the-menopause-years

[5] Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of Hormones and Menopausal Status With Depressed Mood in Women With No History of Depression. Arch Gen Psychiatry. 2006;63(4):375–382. doi:10.1001/archpsyc.63.4.375

[6] Morrison MF, Ten Have T, Freeman EW, Sammel MD, Grisso JA. DHEA-S levels and depressive symptoms in a cohort of African American and Caucasian women in the late reproductive years. Biol Psychiatry. 2001 Nov 1;50(9):705-11. doi: 10.1016/s0006-3223(01)01169-6. PMID: 11704078.

[7] Wang Z, Zhang A, Zhao B, Gan J, Wang G, Gao F, Liu B, Gong T, Liu W, Edden RA. GABA+ levels in postmenopausal women with mild-to-moderate depression: A preliminary study. Medicine (Baltimore). 2016 Sep;95(39):e4918. doi: 10.1097/MD.0000000000004918. PMID: 27684829; PMCID: PMC5265922.

[8] Freeman EW, Sammel MD, Lin H. Temporal associations of hot flashes and depression in the transition to menopause. Menopause. 2009 Jul-Aug;16(4):728-34. doi: 10.1097/gme.0b013e3181967e16. PMID: 19188849; PMCID: PMC2860597.

[9] Ormel J, Jeronimus BF, Kotov R, Riese H, Bos EH, Hankin B, Rosmalen JGM, Oldehinkel AJ. Neuroticism and common mental disorders: meaning and utility of a complex relationship. Clin Psychol Rev. 2013 Jul;33(5):686-697. doi: 10.1016/j.cpr.2013.04.003. Epub 2013 Apr 29. PMID: 23702592; PMCID: PMC4382368.

[10] Managing menopausal symptoms. (n.d.). https://ranzcog.edu.au/wp-content/uploads/Managing-Menopausal-Symptoms.pdf

[11] Ma H, Cai M, Wang H. Emotional Blunting in Patients With Major Depressive Disorder: A Brief Non-systematic Review of Current Research. Front Psychiatry. 2021 Dec 14;12:792960. doi: 10.3389/fpsyt.2021.792960. PMID: 34970173; PMCID: PMC8712545.

[12] Soares CN, Thase ME, Clayton A, Guico-Pabia CJ, Focht K, Jiang Q, Kornstein SG, Ninan PT, Kane CP. Open-label treatment with desvenlafaxine in postmenopausal women with major depressive disorder not responding to acute treatment with desvenlafaxine or escitalopram. CNS Drugs. 2011 Mar;25(3):227-38. doi: 10.2165/11586460-000000000-00000. PMID: 21323394.

[13] Kornstein SG, Jiang Q, Reddy S, Musgnung JJ, Guico-Pabia CJ. Short-term efficacy and safety of desvenlafaxine in a randomized, placebo-controlled study of perimenopausal and

postmenopausal women with major depressive disorder. J Clin Psychiatry. 2010 Aug;71(8):1088-96. doi: 10.4088/JCP.10m06018blu. PMID: 20797382.

[14] S. Krüger, T. Tran, EPA-1061 – Agomelatine in the treatment of perimenopausal depression - a pilot study, European Psychiatry, Volume 29, Supplement 1, 2014, Page 1, ISSN 0924-9338, https://doi.org/10.1016/S0924-9338(14)78345-2. (https://www.sciencedirect.com/science/article/pii/S0924933814783452)

[15] Gnanasegar R, Wolfman W, Galan LH, Cullimore A, Shea AK. Does menopause hormone therapy improve symptoms of depression? Findings from a specialized menopause clinic. Menopause. 2024 Apr 1;31(4):320-325. doi: 10.1097/GME.0000000000002325. Epub 2024 Feb 19. PMID: 38377443.

[16] Goldštajn MŠ, Mikuš M, Ferrari FA, Bosco M, Uccella S, Noventa M, Török P, Terzic S, Laganà AS, Garzon S. Effects of transdermal versus oral hormone replacement therapy in postmenopause: a systematic review. Arch Gynecol Obstet. 2023 Jun;307(6):1727-1745. doi: 10.1007/s00404-022-06647-5. Epub 2022 Jun 17. PMID: 35713694; PMCID: PMC10147786.

[17] Grainger, S. (n.d.). AMS Guide to MHT/HRT Doses Australia only - Australasian Menopause Society. https://www.menopause.org.au/hp/information-sheets/ams-guide-to-mht-hrt-doses

[18] Grainger, S. (n.d.-b). Treatment Options - Australasian Menopause Society. https://www.menopause.org.au/hp/management/treatment-options

[19] Samuthpongtorn C, Nguyen LH, Okereke OI, et al. Consumption of Ultraprocessed Food and Risk of Depression. JAMA Netw Open. 2023;6(9):e2334770. doi:10.1001/jamanetworkopen.2023.34770

Fezolinetant And Elizanetant: What Should You Know About These New Non-Hormonal Therapies For Menopause

By Susan Johnson
Reviewed by Rina Carlini, PhD
October 30, 2024

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For decades, hormone replacement therapy (HRT) has been the standard for treating menopausal symptoms, especially vasomotor symptoms (VMS) like hot flashes and night sweats, which affect nearly 80% of women during menopause.[1] However, HRT isn’t suitable for everyone. Women with a history of breast cancer and blood clots are not typically prescribed hormonal therapies since they can increase the risk of recurrence.

​

Until recently, there were only a few non-hormonal treatment options available for treating the disruptive symptoms of menopause, and they are mostly naturopathic treatments. However, that is changing with the development of new non-hormonal pharmaceutical drugs like fezolinetant (available under the commercial name VEOZAH™) and elinzanetant–the latest therapies and the first significant advances in more than two generations for managing vasomotor symptoms (VMS) associated with perimenopause and menopause.

What Is Fezolinetant And Elinzanetant?

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Fezolinetant (developed by Astellas Pharma) and elinzanetant (developed by Bayer) are both non-hormonal oral medications that are indicated to specifically treat the VMS associated with menopause. In May 2023, fezolinetant made history as the first of its kind to be approved by the US Food and Drug Administration (FDA) for treating severe VMS.[2] Although Bayer’s elinzanetant hasn’t been commercialized yet, it was recently submitted for FDA approval in August 2024.[3]

 

How Do These Drugs Work?

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Fezolinetant and elizanetant are not synthetic hormone drugs like conventional HRT drugs. Instead, these are a new class of drugs that act on the neural activity that causes flushing and sweating spells in women who are experiencing the perimenopause transition.

Recently, researchers identified a new pathway in the brain that could potentially be responsible for the VMS experienced by menopausal women. This pathway involves the kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which contain neurokinin 3 (NK3) receptors on their surface. When estrogen binds to the NK3 receptors, it inhibits the KNDy neurons that cause VMS. On the other hand, neurokinin B (NKB) stimulates the receptors and signals the induction of hot flashes.[4]

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Before menopause, a balance exists between estrogen and NKB in the body. This balance helps women regulate their body temperature based on their surroundings. However, during menopause, when estrogen levels drop significantly, the balance gets disrupted. More NKB binds to the NK3 receptors, causing increased KNDy neuronal activity, which in the long term leads to the hypertrophy (or enlargement) of KNDy neurons. This affects the woman’s ability to regulate core body temperature and triggers hot flashes. [4]

Fezolinetant is a selective NK3 receptor antagonist. It binds to NK3 receptors, making them unavailable for NKB to bind to, which in turn blocks neuronal activity and supports thermoregulation, thereby reducing the frequency and severity of menopausal VSM. [5]

Elizanetant works similar to fezolinetant. However, it is a dual receptor antagonist drug that targets two receptors in the brain: NK3, which regulates body temperature, and NK1, which affects mood and sleep. [6]

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"Oftentimes, the focus on a lot of these drugs is hot flashes, hot flashes, hot flashes, but we know hot flashes do not occur in isolation,” said Chrisandra Shufelt, MD, professor and chair of general internal medicine and associate director of the Women's Health Research Center at Mayo Clinic. “Elinzanetant is an interesting compound because it actually works on sleep, and that was critical because sleep disturbance precedes many other menopausal symptoms,” she shared with Medscape Medical News

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Who Should Consider Taking Non-Hormonal Therapies?​

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During the perimenopause transition phase, as a woman’s estrogen and progesterone levels start to drop significantly, menopausal hormone therapy (MHT) is considered one of the fastest and most effective ways to treat the bothersome VSM that can occur since MHT works to replenish the body’s estrogen and progesterone levels.

Some women should not be administered MHT even if they are requesting it to be prescribed by their doctors. Menopausal women with a history of breast or endometrial cancer, especially hormone receptor-positive (HR+) cancers, should not take MHT because these types of cancer cells have receptors for estrogen, progesterone, or both, which can significantly increase the risk that these tumors can grow, metastasize and cause more serious complications. For this reason, women who have had breast or endometrial cancer, any family members who had these cancers, or those women who are considered high risk for developing these cancers should not be prescribed MHT. [7]

In addition, women with a history of venous thromboembolic events or stroke, gallbladder problems, and coronary heart diseases should avoid MHT. However, they can instead consider non-hormonal treatments like fezolinetant or elinzanetant.

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How Effective Are Non-Hormonal Therapies For Treating VMS?​

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SKYLIGHT 1

SKYLIGHT 1, a Phase III randomized controlled clinical study, was performed to assess the effectiveness of fezolinetant in treating moderate-to-severe vasomotor symptoms associated with menopause. The clinical study included over 500 women between 40 and 65 years of age, who were selected from around the world and who had experienced at least seven hot flashes a day. [8]

The study participants were split into three groups, one receiving a placebo intervention and the other two receiving 35 mg and 45 mg of fezolinetant, respectively. After 4 weeks, the women who were administered fezolinetant reported a reduction in the frequency and severity of hot flashes. After 12 weeks, 45% of women taking 30 mg of fezolinetant, 57% of women taking 45 mg of fezolinetant, and 30% of the placebo group reported a reduction in the frequency of hot flashes. [8]

The study's authors also wrote that the participants reported better quality of life and fewer night-time awakenings. [8]

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OASIS 1 and 2

Bayer conducted three Phase III clinical studies–OASIS 1, 2, and 3–to analyze the effectiveness of elinzanetant. OASIS 1 and 2 were specifically conducted to analyze the impact of elinzanetant on moderate to severe VMS, its effects on sleep disturbances, and overall menopause-related quality of life. These trials followed a double-blind, placebo-controlled design to ensure accurate results.

Both OASIS 1 and 2 studies met all primary endpoints. Compared to the placebo, there was a 50% reduction in the frequency and severity of hot flashes in 80% of participants taking elinzanetant by the fourth and twelfth weeks. In addition, the participants also said they slept better while taking elinzanetant. Improvement in these areas was seen as early as week one, indicating a rapid onset of action. The drug’s safety was consistent with prior studies, with no unexpected adverse effects.

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According to Dr Michelle Jacobson, a Canadian OB/GYN physician and certified menopause specialist based in Toronto, Canada, these findings mark a significant milestone for managing menopausal symptoms. She said, “As a menopause specialist, I am truly excited to see the results of the Phase III trials on elinzanetant. For so long, we have been treating those suffering from menopausal symptoms with second-line, non-indicated therapies. Now, we are one step closer to having effective, indicated, and safe treatments for our patients. I look forward to being able to offer women a novel treatment that has such positive outcomes once it is approved by Health Canada. The more options we have, the better we can individualize therapies for our patients to help them live their best and healthiest lives possible."

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Claudio N Soares, MD, PhD, who is a Professor of Psychiatry at Queen’s University in Canada, an experienced clinical researcher in menopause and women’s mental health, and President-elect of The Menopause Society, also expressed similar views.

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“These results are really encouraging. For too long, we have underestimated, sometimes even overlooked, the negative impact that menopausal symptoms–hot flashes, sleep disturbances, mood changes–may have on a woman’s health and quality of life. It is reassuring to see that this is no longer the case and that women may soon have access to novel, non-hormonal options to alleviate these symptoms and improve their quality of life”.

​

While the findings of OASIS 3 have not yet been published, the study was performed with a large sample size of participants to confirm the findings of OASIS 1 and 2. [9][10]

​

Are There Any Side Effects?

​

In the SKYLIGHT 1 study, a significant number of participants had experienced side effects or adverse reactions (listed below), which were 37% of women taking 30 mg and 43% of women taking 45 mg Fezolinetant. Interestingly, 45% of women in the placebo group (who were not taking any drug) also reported similar side effects. So, the difference in side effects between the drug medication group and placebo groups was minimal. [8]

The most commonly reported side effects included:

  • Headache

  • Abdominal pain

  • Diarrhea

  • Insomnia

  • Back pain

  • Elevated  hepatic transaminase levels (potential risk of liver damage)

The study also included a warning for potential liver damage or elevated hepatic transaminase levels. Therefore, women considering Fezolinetant are advised to have their baseline bloodwork done to evaluate liver function and injury before starting the medication. While on the drug, follow-up blood tests should be performed every three months for the first nine months of treatment to monitor liver health.

Additionally, patients should watch for symptoms and signs of liver damage, such as nausea, vomiting, or jaundice (yellowing of the skin and eyes), and contact their physician if these signs appear.

With elinzanetant, no participant showed signs of hepatotoxicity or possible drug-induced liver injury. Safety assessments were performed to look for adverse effects in participants and included endometrial biopsies, bone mineral density, weight, and blood tests. It was found that 30.4% of participants taking elinzanetant and 14.6% of participants taking the placebo pill reported adverse effects, which were, most commonly, headache, fatigue, and sleepiness. [9]

​

Final Thoughts

​

Over 75% of menopausal women experience VMS, with 25% describing their symptoms as severe. In one-third of women, these symptoms can persist for seven years or more.[11] A pooled analysis of individual-level data revealed that women experiencing both persistent and severe hot flashes and night sweats had a significantly higher risk of cardiovascular disease (CVD). [12]

In such cases, having access to medications like fezolinetant and elinzanetant will not only expand treatment options for women but also prove to be an effective alternative for women who should not take HRT.

It should be noted that both fezolinentant and elinzanetant are very new classes of drugs that do not have a long clinical history, and as such, the clinical practice guidelines on how to incorporate them into the treatment regimen are currently unclear. While both these drugs will prove to be exciting options for women, whether they can be used in combination with other treatments for menopausal symptoms still needs further study.

​

References:

[1] Gold EB, Colvin A, Avis N, Bromberger J, Greendale GA, Powell L, Sternfeld B, Matthews K. Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women's health across the nation. Am J Public Health. 2006 Jul;96(7):1226-35. doi: 10.2105/AJPH.2005.066936. Epub 2006 May 30. PMID: 16735636; PMCID: PMC1483882.

[2] https://www.fda.gov/news-events/press-announcements/fda-approves-novel-drug-treat-moderate-severe-hot-flashes-caused-menopause

[3] https://www.bayer.com/en/us/news-stories/new-drug-application-to-us-fda-for-elinzanetant

[4] Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Mohideen P, Lin VH, Stern TP, Panay N, Hunter MS, Webber LC, Dhillo WS. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause. 2018 Aug;25(8):862-869. doi: 10.1097/GME.0000000000001090. PMID: 29533369; PMCID: PMC6092106.

[5] Santoro N, Waldbaum A, Lederman S, Kroll R, Fraser GL, Lademacher C, Skillern L, Young J, Ramael S. Effect of the neurokinin 3 receptor antagonist fezolinetant on patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA). Menopause. 2020 Dec;27(12):1350-1356. doi: 10.1097/GME.0000000000001621. PMID: 32769757; PMCID: PMC7709922.

[6] Pawsey S, Mills EG, Ballantyne E, Donaldson K, Kerr M, Trower M, Dhillo WS. Elinzanetant (NT-814), a Neurokinin 1,3 Receptor Antagonist, Reduces Estradiol and Progesterone in Healthy Women. J Clin Endocrinol Metab. 2021 Jul 13;106(8):e3221-e3234. doi: 10.1210/clinem/dgab108. PMID: 33624806; PMCID: PMC8277204.

[7] Clusan L, Ferrière F, Flouriot G, Pakdel F. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int J Mol Sci. 2023 Apr 6;24(7):6834. doi: 10.3390/ijms24076834. PMID: 37047814; PMCID: PMC10095386.

[8] Lederman S, Ottery FD, Cano A, Santoro N, Shapiro M, Stute P, Thurston RC, English M, Franklin C, Lee M, Neal-Perry G. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomized controlled study. Lancet. 2023 Apr 1;401(10382):1091-1102. doi: 10.1016/S0140-6736(23)00085-5. Epub 2023 Mar 13. PMID: 36924778.

[9] Pinkerton JV, Simon JA, Joffe H, et al. Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause: OASIS 1 and 2 Randomized Clinical Trials. JAMA. 2024;332(16):1343–1354. doi:10.1001/jama.2024.14618

[10] https://www.bayer.com/en/ca/bayers-elinzanetant-meets-all-primary-and-key-secondary-endpoints-in-oasis-1-and-2-phase-iii

[11] https://thebms.org.uk/2023/12/new-treatment-for-vasomotor-symptoms-hot-flushes-and-night-sweats-licensed-by-the-mhra/

[12] Zhu, Dongshan et al.Vasomotor menopausal symptoms and risk of cardiovascular disease: a pooled analysis of six prospective studies; American Journal of Obstetrics & Gynecology, Volume 223, Issue 6, 898.e1 - 898.e16

Evaluating the safety of estrogen route of administration when using hormone therapy for relieving menopause symptoms

Reviewed by Rina Carlini, PhD, Joanne Tejeda, PhD and Azi Nia, PhD
October 18, 2023

The majority of women worldwide struggle with menopausal symptoms, which can include hot flashes and/or night sweats (vasomotor symptoms), mood changes (anxiety, depression), vaginal dryness (genitourinary symptoms), irregular and/or heavy menstruation, weight gain, thyroid disorders (metabolic symptoms), anemia (low iron stores), fatigue and hair loss, joint pain (musculoskeletal symptoms), irritable bowel (gastrointestinal symptoms), dry skin, dry eyes, insomnia and others [1]. Unfortunately, only a quarter of women in the USA actually seek treatment options to manage their symptoms, which indicates that the conversion about how to get qualified menopause care should be amplified in every family household and workplace setting.

​

The Menopause Society (formerly known as the North American Menopause Foundation) and also the Canadian Menopause Society have advocated that a first line of treatment for relief of menopausal symptoms and complications is Hormone Therapy, or HT [2]. HT can be administered as either estrogen-progesterone combination therapy, progesterone-only therapy, or estrogen-only therapy.

Recently, a large population health clinical study was conducted in Alberta, Canada involving more than 112,000 women aged 45 years or older to examine the safety of the various formats and routes of administration for estrogen-only hormone therapies, which included oral pills, transdermal patches, and vaginal creams [3]. The clinical study enrolled women who had used at least two consecutive treatments of estrogen-only HT during the period of 2008 to 2019, and the primary outcome of the study was to evaluate the risk of developing high blood pressure (incident hypertension) [3]. The effect of the source of estrogen being taken – where the majority of study participants were taking either conjugated equine estrogen (CEE; 40%) or synthetic estradiol (55%), and a minority of participants were taking synthetic estrone (5%) –  was also investigated.

The key findings learned from the study:

  • Women taking oral estrogen had a 14% higher likelihood of developing hypertension than those using transdermal estrogen.

 

  • Women taking oral estrogen had a 19% elevated risk of developing hypertension compared to women using vaginal estrogen creams. This association was more notable in women below the age of 70 years.

 

  • No differences in the risk of hypertension were observed for the study participants taking either transdermal or vaginal estrogen across all age groups.

 

  • When comparing the two different sources of estrogen, conjugated equine estrogen was linked to an 8% heightened risk of high blood pressure.

 

  • Higher daily estrogen dose in oral form, compared with the same dose in transdermal and vaginal forms, was associated with a significantly greater risk of hypertension.

 

  • Long-term administration of any form of estrogen-only HT may increase the risk of developing hypertension.

To reduce the risk of developing hypertension while managing menopausal symptoms, a physician may prefer to prescribe estrogen HT treatment delivered as a transdermal patch or vaginal cream rather than the oral pill. The study also emphasized that HT treatment is  prescribed by a physician based on the specific needs and health profiles of each individual. Most women who are already taking oral estrogen – and are at low risk of developing hypertension – can continue their estrogen-only HT safely based on the recommendations and health monitoring by their physician.

Interested to know more about menopause?

Visit our Knowledge Centre here :

Download Clinical Study article

References

[1] Santoro, N., Roeca, C., Peters, B. A., & Neal-Perry, G. (2021). The Menopause Transition: Signs, Symptoms, and Management Options. In Journal of Clinical Endocrinology and Metabolism, 2020, 106, 1-15. https://doi.org/10.1210/clinem/dgaa764

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[2] The 2022 hormone therapy position statement of The North American Menopause Society. Menopause: The Journal of The North American Menopause Society, 2022, 29, 767-794. DOI: 10.1097/GME.0000000000002028

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[3] Kalenga, C. Z., Metcalfe, A., Robert, M., Nerenberg, K. A., Macrae, J. M., & Ahmed, S. B. (2023). Association between the Route of Administration and Formulation of Estrogen Therapy and Hypertension Risk in Postmenopausal Women: A Prospective Population-Based Study. Hypertension, 2023, 80, 1463-1473. https://doi.org/10.1161/HYPERTENSIONAHA.122.19938

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Mithra and Searchlight Pharma announce Donesta® licensing agreement for Canada

Source: Mithra Women's Health
June 28, 2023

Mithra, a Belgian biotech company specializing in women's hormonal health therapeutics, has licensed their natural estrogen therapy, Donesta (estetrol), to Montreal-based Searchlight Pharma Inc. for the Canadian market. Donesta is an investigational medicine for menopause symptoms based on Estetrol (E4), a unique estrogen with distinctive biological mechanisms. Clinical trials of Donesta have shown encouraging efficacy results, including a significant reduction in menopause symptoms, and phase 3 trials have supported regulatory submissions in the US and Canada. The partnership aims to provide Canadian women with an improved treatment option for managing menopause symptoms effectively. 

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