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Update on management of genitourinary syndrome of menopause: A practical guide
Accepted Manuscript Title: Update on management of genitourinary syndrome of menopause: a practical guide Author: Santiago Palacios Camil Castelo-Branco Heather Currie Velja Mijatovic Rossella E. Nappi James Simon Margaret Rees PII: DOI: Reference:
S0378-5122(15)00752-5 http://dx.doi.org/doi:10.1016/j.maturitas.2015.07.020 MAT 6455
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Maturitas
Please cite this article as: Palacios Santiago, Castelo-Branco Camil, Currie Heather, Mijatovic Velja, Nappi Rossella E, Simon James, Rees Margaret.Update on management of genitourinary syndrome of menopause: a practical guide.Maturitas http://dx.doi.org/10.1016/j.maturitas.2015.07.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Update on management of genitourinary syndrome of menopause: a practical guide. Santiago Palacios, Director of Palacios Institute of Women´s Health. Madrid. Spain Camil Castelo-Branco, Institut Clínic of Gynecology, Obstetrics and Neonatology, Hospital ClínicInstitut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine-University of Barcelona, Barcelona, Spain Heather Currie, Associate Specialist Gynaecologist, Dumfries and Galloway Royal Infirmary, Dumfries, UK. Velja Mijatovic, Department of Reproductive Medicine, VU University Hospital, Amsterdam, The Netherlands Rossella E Nappi, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy James Simon, Clinical Professor of Obstetrics and Gynecology, George Washington University School of Medicine, Medical Director, Women’s Health & Research Consultants®, Washington, DC, USA Margaret Rees, Women's Centre, John Radcliffe Hospital, Oxford, UK Corresponding author: Margaret Rees, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK [email protected] [email protected] Abstract The term Genitourinary Syndrome of Menopause (GSM) emerged following a consensus conference held in May 2013. GSM is a more descriptive term than vulvovaginal atrophy (VVA) and does not imply pathology. However there are concerns that GSM is all encompassing and includes not only symptoms resulting from estrogen deficiency, but also those arising from the effects of ageing and other processes on the bladder and pelvic floor. Focusing on symptoms related to estrogen deficiency, the update provides a practical guide for health and allied health professionals on the impact of GSM on women and their partners, assessment, management and areas for future research. As GSM is a chronic condition, long term therapy is required. Hormonal, nonhormonal, laser and alternative and complementary therapies are described. Key words: Genitourinary syndrome of menopause, vulvovaginal atrophy, menopausal hormone therapy, nonhormonal vaginal therapy, sexuality
1. Introduction The term Genitourinary Syndrome of Menopause (GSM) emerged following a consensus conference held in May 2013 in Chicago USA. The boards of the International Society for the Study of Women's Sexual Health (ISSWSH) and the North American Menopause Society (NAMS) then endorsed the term in 2014 [1]. The aims of the new terminology were to describe the condition appropriately for medical care, teaching, and research. It was also hoped that it would reduce the stigma associated
with genital symptoms after menopause, while helping to make patients aware of the urinary component of the syndrome, and make it easier for women to seek medical help. The purpose of the current update is to provide a practical guide for health and allied health professionals on the impact of GSM on women and their partners, assessment, management and areas for future research. The update will focus on symptoms related to estrogen deficiency. 2. What is Genitourinary Syndrome of Menopause? GSM is a more descriptive term than vulvovaginal atrophy (VVA) and does not imply pathology. Thus it is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra and bladder [1]. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria and recurrent urinary tract infections. However there are concerns that GSM is an all encompassing term and includes not only symptoms resulting from estrogen deficiency, but also those arising from the effects of ageing and other processes on the bladder and pelvic floor. Further, regulatory authorities around the world have focused on the vulvar and vaginal symptoms of the syndrome with little or any recognition of the urinary symptoms. They have not provided a regulatory pathway for therapeutic development for these urinary symptoms. This situation has therapeutic implications. For example urinary urgency can result from overactive bladder, whose etiology is often multifactorial and where antimuscarinic drugs are the most common treatment [2]. On the other hand, estrogens are useful in the prevention of recurrent urinary tract infections and vaginal dryness [3-7]. 3. What is the impact on couple’s lives? The negative impact of vaginal atrophy and the positive impact of its treatment on a woman’s general and sexual quality of life cannot be underestimated. Up to 50% of women will develop urogenital signs and symptoms at some time in their postmenopausal life; the incidence is probably under-reported and therefore underestimated [8]. Recent publications [9,10], based on many international surveys in postmenopausal women with VVA, suggest health-care providers (HCPs) should be proactive in order to help their patients to disclose the symptoms related to VVA and seek adequate treatment when vaginal discomfort is clinically relevant. Women are generally unaware that VVA is a chronic condition with a significant impact on sexual health and quality of life, and that effective and safe treatments may be available. Indeed, the Vaginal Health: Insights, Views & Attitudes (VIVA) international survey [11] found that almost half (46%) of postmenopausal women lacked knowledge about local estrogen therapy and outlined the need for a country-specific approach in dealing with a sensitive topic such as VVA. The effect on couple’s lives can be significant. Evidence from a US sample shows that sexual dysfunction was present almost 4 times more frequently in women reporting VVA symptoms than in those who did not [12]. The CLOSER (Clarifying Vaginal Atrophy's Impact on Sex and Relationships) survey was conducted to better understand VVA in a socio-cultural perspective and in the context of the couple [13]. The European arm [14,] including over 5,000 women and men, found that ‘worry that vaginal discomfort would never go away’ was expressed by 28% and 38% of women in Northern and Southern Europe respectively; and 21% and 27% were worried that vaginal discomfort would ruin their future sex life. Half of the women who avoided intimacy worried about painful sex. Men with partners who avoided intimacy recognised that worry about painful sex was the main reason. Vaginal discomfort impaired self-esteem and emotional wellbeing among women, whereas local estrogen treatment improved relationships. In the US CLOSER arm [15], which included 2000 responders, approximately 30% of women and men cited vaginal discomfort as the reason they ceased having sex altogether. A significant effect of VVA symptoms on enjoyment of sex was also reported by 59% of 3,046 women in the US REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey [16]. The impact of postmenopausal vulvovaginal symptoms on relationships is greater in women from countries where symptoms are more prevalent [17].
Furthermore, two consecutive cross-sectional studies conducted in Europe [18] outlined the importance of identifying personality traits to develop interventions to help overcome ‘patientspecific’ barriers to the diagnosis, management and treatment of VVA.
4. Assessment While many postmenopausal women have features of GSM, the prevalence of symptoms is consistently reported at around 50%. Many of those with symptoms do not seek help, with a significant difference being demonstrated between incidence of symptoms and rate of treatment [10, 11, 13,14,15]. Assessment is symptom-driven. Thus it relies on women being aware of the condition and availability of treatments to be able to report symptoms and seek help, and healthcare professionals knowing about GSM and its management. To improve identification of GSM, healthcare professionals should increasingly ask appropriate non-judgemental questions about symptoms both during menopause consultations and opportunistically at other times such as annual visits and routine cervical screening. When the presence of vulval, vaginal and/or urinary symptoms has been identified, the history should take account of: •
severity and duration of symptoms,
•
impact on patient and relationship,
•
menopausal status,
•
past medical history,
•
contributory factors, particularly bladder symptoms
•
previously used treatments if any,
•
patient’s views on treatments
•
ability to use treatments, eg due to reduced mobility and dexterity or cognitive impairment
Examination aims to confirm diagnosis and exclude other conditions such as dermatoses. While use of vaginal pH testing to demonstrate raised pH associated with GSM is used in some countries, this is not universally employed and is not essential for diagnosis or assessment.
5. Management GSM is a chronic condition and therefore requires long term therapy as symptoms will return when treatment is stopped. The principles of treatment in women with established vaginal atrophy are the restoration of normal urogenital physiology and the alleviation of symptoms. Hormonal, nonhormonal, laser and alternative and complementary therapies will be discussed. 5.1 Hormonal therapies 5.1.1 Topical and systemic hormone therapy Estrogen, either topical or systemic, is an effective treatment for women with moderate to severe symptoms of vaginal atrophy and both can be used together. As well as increasing the Vaginal Maturation Index, estrogen lowers vaginal pH, increases subepithelial capillary growth, improves epithelial integrity and differentiation, raises the level of vaginal secretions and restores the normal vaginal flora [19,20]. Given their proven efficacy and safety, this section will focus on topical
estrogens [21]. A Cochrane review examined the literature on topical estrogens in 2006 [22] and the European Menopause and Andropause Society published a clinical guide in 2012 on the low dose preparations which had since become available [5]. The literature supports the efficacy of lower doses to minimize adverse effects [23]. Topical preparations include estradiol-containing tablets and rings; estriol pessaries, creams and ovules; promestriene and conjugated estrogens. The 2006 Cochrane review found them to be equally effective [22]. Availability of individual preparations varies worldwide. Absorption depends on the dose used and the degree of vaginal atrophy. Thus plasma estrogen levels do not exceed the normal postmenopausal range of ≤ 20 pg/ml with long term use of 10mcg estradiol tablets and does not increase the risk of endometrial hyperplasia and carcinoma [5, 21, 24]. On the other hand, absorption may be higher when treatment is initiated as the vaginal epithelium is thin and atrophic. Absorption subsequently decreases with continued use [25]. Progestogen opposition is therefore not necessary to protect against endometrial hyperplasia with low dose topical estrogens if used in the recommended doses [ see for example 26,27]. However the 2006 Cochrane systematic review found significant endometrial stimulation with conjugated equine estrogen cream [22]. 5.1.2 Tibolone Tibolone is a synthetic steroid that has estrogenic effects on the vagina but not on the endometrium [28]. This drug has been associated with significant improvements in sexual function in postmenopausal women, reflecting both its estrogenic and androgenic properties. It increases the Vaginal Maturation Index and vaginal blood flow. Furthermore it also reduces nocturia and urinary urgency [29]. 5.1.3 Ospemifene Approved in the USA and Europe, oral ospemifene adds new flexibility for women with urogenital symptoms. In Europe, it is indicated for the treatment of moderate to severe symptomatic VVA in post-menopausal women who are not candidates for local vaginal estrogen therapy [30]. Ospemifene is a selective estrogen receptor modulator (SERM) [31]. Several studies have shown efficacy [ 32-38]. A pivotal 12 week randomized trial showed that ospemifene was shown to be effective and well tolerated for the treatment of the symptoms of vaginal dryness and dyspareunia associated with vulvovaginal atrophy over and above the use of provided lubricants [32].Subsequent studies have confirmed efficacy and safety over 12 months. Hot flushes are the most common reported treatment related adverse events in about 7% of patients [34,37]. Endometrial safety was evaluated in six randomized, double-blind, placebo controlled, parallel-group studies lasting up to 52 weeks [33]. In these trials, 1,242 women who received ospemifene 60 mg/day and 924 women who received placebo were evaluable for safety. Endometrial hyperplasia occurred in less than 1% of women treated with ospemifene; no endometrial cancer was reported. The mean (SD) increase in endometrial thickness among women treated with ospemifene was 0.51 (1.54) mm at 12 weeks, 0.56 (1.61) mm at 6 months, and 0.81 (1.54) mm at 12 months. Women who received placebo had a mean (SD) increase of 0.07 (1.23) mm at 12 months. Thus the authors concluded that the clinical trial data indicated that up to 52 weeks of treatment with oral ospemifene 60 mg/day was safe for the endometrium. As with other SERMs the risk of VTE (venous thromboembolism) is increased. Thus its use is contraindicated in women with an active or past history of VTEs, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis [30]. Other SERMs may become available in the future for the treatment of VVA [39]. 5.1.4 Vaginal dehydroepiandrosterone Vaginal DHEA has been proposed as a treatment for VVA [40]. A recent study open-label phase III of daily intravaginal administration of 0.5% (6.5mg) DHEA for 52 weeks found improvement of dyspareunia, vaginal dryness and irritation/itching[41]. Furthermore no endometrial stimulation has been found [42] 5.2 Non hormonal therapies
The North American Menopause Society [NAMS] recommends that nonhormonal vaginal lubricants and moisturizers should be first-line therapies for women with vaginal atrophy [43]. A combination of vaginal moisturizing agents used on a regular basis and lubricants during intercourse can alleviate symptoms of vaginal dryness. These compounds do not reverse the atrophic vaginal changes but improve coital comfort and maintain vaginal secretions. Lubricants are typically used episodically to correspond to sexual activity. There are different types of lubricants which may be water, oil, silicone or hyaluronic acid based. The qualities of these different lubricants can serve different purposes, and hybrids from different categories attempt to provide more than one characteristic to broaden appeal. Lubricants, in general, give only temporary relief of symptoms and must be applied frequently for more continuous relief and require reapplication before intercourse. Lubricants such as petroleum-based products and baby oil can compromise the integrity of condoms [44]. This is important when condoms are used for contraception and/or to prevent sexually transmitted infections. Several plant oils such olive oil have demonstrated efficacy without adverse events [45]. The use of lubricants, even when not required, may improve sexual pleasure [see for example 46]. Moisturisers are typically used on a regular basis, rather than episodically associated with sexual activity. They may contain a bioadhesive polycarbophil-based polymer, which attaches to mucin and epithelial cells on the vaginal wall and retains water. Comparative studies of a vaginal polycarbophil moisturizer (Replens®) and estrogens have shown the same degree of efficacy in reducing symptoms such as itching, irritation and dyspareunia[47]. Vitamin D is a promoter of keratinocyte differentiation and a modulator of keratinocyte proliferation. The vagina is surrounded by a stratified squamous epithelium and thus, vitamin D can enhance proliferation and differentiation of the epithelium [48]. 5.3 Laser Recent short-term studies with limited numbers of subjects have suggested that laser therapy may result in remodelling of vaginal connective tissue and thickening and improved glycogen storage of the vaginal epithelium in women with vaginal atrophy [49, 50]. Improvement in VVA symptoms (vaginal dryness, burning, itching and dyspareunia) and vaginal health index scores [51, 52], have been reported but long term studies are required. 5.4 Alternative and complementary therapies Alternative and complementary therapies have been proposed for the treatment of GSM, but the data do not document evidence of efficacy. For example, a soy-rich diet was not found to relieve urogenital symptoms or restore the vaginal epithelium or improve vaginal health in perimenopausal and postmenopausal women [53]. Administration of genistein (54 mg/day) for 12 months did not improve the maturation index compared with placebo [54]. Similarly black cohosh, used alone or as part of a multibotanical product with or without soy dietary changes, had no effects on the vaginal epithelium, the endometrium or reproductive hormones [55]. Other herbal alternatives (red clover, dong quai, wild yam, chasteberry, cat's claw, chamomile, calendula flower, gingko biloba, green tea), alone or with plant oils, have been proposed but evidence of efficacy is lacking [56]. Although an inverse correlation between Lactobacillus ratio and dryness and an increased bacterial diversity in women experiencing moderate to severe vaginal dryness has been found, there is no conclusive evidence that administration of lactobacilli alone into the vagina are effective[ 57,58]. 6. Follow-up Recommendations with regard to duration of use and follow-up vary between preparations. However GSM is a chronic condition and will recur upon cessation of treatment. It is probably prudent to review women’s needs annually to assess efficacy and acceptability while updating on any new advice, information or treatment options [5].
7. Research agenda Even though VVA is a well-known condition associated with menopause and aging, more needs to be done so that treatment options can be tailored to women’s individual needs leading to a more personalised approach. Taking into account the concept of GSM, areas of further investigation should include the following: 1. Use of standardized scales to quantify objective symptoms and signs of VVA and to measure the subjective distress associated with GSM, 2. Consider GSM in the context of the couple taking into account frequency of sexual activity and partner’s general and sexual health in designing research studies and clinical trials, 3. Address comorbidities and their treatments which can potentially contribute to the severity of GSM in research studies and clinical trials, 4. Management of women at higher risk of GSM such as early menopause, breast cancer and pelvic irradiation, 5. Designing interventions to overcome barriers to effective treatments and to improve longterm adherence.
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Competing interests: S Palacios has been a symposium speaker or advisory board member for Servier, Pfizer, GSK, Abbott, Ferrer, Bioiberica, Shionogi, Amgen, Bayer, Healthcare, Gedeon Richter, Teva Women’s Health and has received research grants and/or consulting fees from Pfizer, Servier, Amgen, MSD, Preglem, Leon Farma, Gynea and Procare.
C Castelo-Branco has received educational grants, lecture fees and advisory board fees from different pharmaceutical companies including: Pfizer, Pierre-Fabre, Isdin, Grunenthal, Shionogi and TEVA and from educational institutions. H Currie has received educational grants, lecture fees and advisory board fees from several pharmaceutical companies and is MD of Menopause Matters Ltd R Nappi has had financial relationships (lecturer, member of advisory boards and/or consultant) with Bayer HealthCare AG, Boehringer Ingelheim, Ely Lilly, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc, Procter & Gamble Co, Shionogi Limited, TEVA Women’s Health Inc. J Simon has served (within the last year) or is currently serving as a consultant to or on the advisory boards of: AbbVie, Inc., Actavis, PLC., Amgen Inc., Amneal Pharmaceuticals, Apotex, Inc., Ascend Therapeutics, Dr. Reddy Laboratories, Ltd., Everett Laboratories, Inc., Merck & Co., Inc., Noven Pharmaceuticals, Inc., Novo Nordisk, Nuelle, Inc., Radius Health, Inc., Regeneron Pharmaceuticals, Inc., Sanofi S.A., Sermonix Pharmaceuticals, Inc., Shionogi Inc., Sprout Pharmaceuticals, TherapeuticsMD. In the last year he has received or is currently receiving grant/research support from AbbVie, Inc., Actavis PLC., Agile Therapeutics, Bayer Healthcare LLC., New England Research Institute, Inc., Novo Nordisk, Palatin Technologies and TherapeuticsMD. He has also served or is currently serving on the speaker’s bureaus of Amgen Inc., Eisai, Inc., Merck, Noven Pharmaceuticals, Inc., Novo Nordisk, and Shionogi Inc. V Mijatovic and M Rees have no conflicts of interest to declare. Funding: production of the update and round table discussion, held on May 21, 2015 in Madrid, Spain during the 10th European Menopause and Andropause Society (EMAS) Congress, was supported by an unrestricted educational grant from Shionogi, Spain to EMAS. Shionogi, Spain had no involvement in the writing of the update. Provenance and peer review: not commissioned; not externally peer reviewed.
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Please cite this article as: Palacios Santiago, Castelo-Branco Camil, Currie Heather, Mijatovic Velja, Nappi Rossella E, Simon James, Rees Margaret.Update on management of genitourinary syndrome of menopause: a practical guide.Maturitas http://dx.doi.org/10.1016/j.maturitas.2015.07.020 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Update on management of genitourinary syndrome of menopause: a practical guide. Santiago Palacios, Director of Palacios Institute of Women´s Health. Madrid. Spain Camil Castelo-Branco, Institut Clínic of Gynecology, Obstetrics and Neonatology, Hospital ClínicInstitut d´Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine-University of Barcelona, Barcelona, Spain Heather Currie, Associate Specialist Gynaecologist, Dumfries and Galloway Royal Infirmary, Dumfries, UK. Velja Mijatovic, Department of Reproductive Medicine, VU University Hospital, Amsterdam, The Netherlands Rossella E Nappi, Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy James Simon, Clinical Professor of Obstetrics and Gynecology, George Washington University School of Medicine, Medical Director, Women’s Health & Research Consultants®, Washington, DC, USA Margaret Rees, Women's Centre, John Radcliffe Hospital, Oxford, UK Corresponding author: Margaret Rees, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK [email protected] [email protected] Abstract The term Genitourinary Syndrome of Menopause (GSM) emerged following a consensus conference held in May 2013. GSM is a more descriptive term than vulvovaginal atrophy (VVA) and does not imply pathology. However there are concerns that GSM is all encompassing and includes not only symptoms resulting from estrogen deficiency, but also those arising from the effects of ageing and other processes on the bladder and pelvic floor. Focusing on symptoms related to estrogen deficiency, the update provides a practical guide for health and allied health professionals on the impact of GSM on women and their partners, assessment, management and areas for future research. As GSM is a chronic condition, long term therapy is required. Hormonal, nonhormonal, laser and alternative and complementary therapies are described. Key words: Genitourinary syndrome of menopause, vulvovaginal atrophy, menopausal hormone therapy, nonhormonal vaginal therapy, sexuality
1. Introduction The term Genitourinary Syndrome of Menopause (GSM) emerged following a consensus conference held in May 2013 in Chicago USA. The boards of the International Society for the Study of Women's Sexual Health (ISSWSH) and the North American Menopause Society (NAMS) then endorsed the term in 2014 [1]. The aims of the new terminology were to describe the condition appropriately for medical care, teaching, and research. It was also hoped that it would reduce the stigma associated
with genital symptoms after menopause, while helping to make patients aware of the urinary component of the syndrome, and make it easier for women to seek medical help. The purpose of the current update is to provide a practical guide for health and allied health professionals on the impact of GSM on women and their partners, assessment, management and areas for future research. The update will focus on symptoms related to estrogen deficiency. 2. What is Genitourinary Syndrome of Menopause? GSM is a more descriptive term than vulvovaginal atrophy (VVA) and does not imply pathology. Thus it is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra and bladder [1]. The syndrome may include but is not limited to genital symptoms of dryness, burning, and irritation; sexual symptoms of lack of lubrication, discomfort or pain, and impaired function; and urinary symptoms of urgency, dysuria and recurrent urinary tract infections. However there are concerns that GSM is an all encompassing term and includes not only symptoms resulting from estrogen deficiency, but also those arising from the effects of ageing and other processes on the bladder and pelvic floor. Further, regulatory authorities around the world have focused on the vulvar and vaginal symptoms of the syndrome with little or any recognition of the urinary symptoms. They have not provided a regulatory pathway for therapeutic development for these urinary symptoms. This situation has therapeutic implications. For example urinary urgency can result from overactive bladder, whose etiology is often multifactorial and where antimuscarinic drugs are the most common treatment [2]. On the other hand, estrogens are useful in the prevention of recurrent urinary tract infections and vaginal dryness [3-7]. 3. What is the impact on couple’s lives? The negative impact of vaginal atrophy and the positive impact of its treatment on a woman’s general and sexual quality of life cannot be underestimated. Up to 50% of women will develop urogenital signs and symptoms at some time in their postmenopausal life; the incidence is probably under-reported and therefore underestimated [8]. Recent publications [9,10], based on many international surveys in postmenopausal women with VVA, suggest health-care providers (HCPs) should be proactive in order to help their patients to disclose the symptoms related to VVA and seek adequate treatment when vaginal discomfort is clinically relevant. Women are generally unaware that VVA is a chronic condition with a significant impact on sexual health and quality of life, and that effective and safe treatments may be available. Indeed, the Vaginal Health: Insights, Views & Attitudes (VIVA) international survey [11] found that almost half (46%) of postmenopausal women lacked knowledge about local estrogen therapy and outlined the need for a country-specific approach in dealing with a sensitive topic such as VVA. The effect on couple’s lives can be significant. Evidence from a US sample shows that sexual dysfunction was present almost 4 times more frequently in women reporting VVA symptoms than in those who did not [12]. The CLOSER (Clarifying Vaginal Atrophy's Impact on Sex and Relationships) survey was conducted to better understand VVA in a socio-cultural perspective and in the context of the couple [13]. The European arm [14,] including over 5,000 women and men, found that ‘worry that vaginal discomfort would never go away’ was expressed by 28% and 38% of women in Northern and Southern Europe respectively; and 21% and 27% were worried that vaginal discomfort would ruin their future sex life. Half of the women who avoided intimacy worried about painful sex. Men with partners who avoided intimacy recognised that worry about painful sex was the main reason. Vaginal discomfort impaired self-esteem and emotional wellbeing among women, whereas local estrogen treatment improved relationships. In the US CLOSER arm [15], which included 2000 responders, approximately 30% of women and men cited vaginal discomfort as the reason they ceased having sex altogether. A significant effect of VVA symptoms on enjoyment of sex was also reported by 59% of 3,046 women in the US REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey [16]. The impact of postmenopausal vulvovaginal symptoms on relationships is greater in women from countries where symptoms are more prevalent [17].
Furthermore, two consecutive cross-sectional studies conducted in Europe [18] outlined the importance of identifying personality traits to develop interventions to help overcome ‘patientspecific’ barriers to the diagnosis, management and treatment of VVA.
4. Assessment While many postmenopausal women have features of GSM, the prevalence of symptoms is consistently reported at around 50%. Many of those with symptoms do not seek help, with a significant difference being demonstrated between incidence of symptoms and rate of treatment [10, 11, 13,14,15]. Assessment is symptom-driven. Thus it relies on women being aware of the condition and availability of treatments to be able to report symptoms and seek help, and healthcare professionals knowing about GSM and its management. To improve identification of GSM, healthcare professionals should increasingly ask appropriate non-judgemental questions about symptoms both during menopause consultations and opportunistically at other times such as annual visits and routine cervical screening. When the presence of vulval, vaginal and/or urinary symptoms has been identified, the history should take account of: •
severity and duration of symptoms,
•
impact on patient and relationship,
•
menopausal status,
•
past medical history,
•
contributory factors, particularly bladder symptoms
•
previously used treatments if any,
•
patient’s views on treatments
•
ability to use treatments, eg due to reduced mobility and dexterity or cognitive impairment
Examination aims to confirm diagnosis and exclude other conditions such as dermatoses. While use of vaginal pH testing to demonstrate raised pH associated with GSM is used in some countries, this is not universally employed and is not essential for diagnosis or assessment.
5. Management GSM is a chronic condition and therefore requires long term therapy as symptoms will return when treatment is stopped. The principles of treatment in women with established vaginal atrophy are the restoration of normal urogenital physiology and the alleviation of symptoms. Hormonal, nonhormonal, laser and alternative and complementary therapies will be discussed. 5.1 Hormonal therapies 5.1.1 Topical and systemic hormone therapy Estrogen, either topical or systemic, is an effective treatment for women with moderate to severe symptoms of vaginal atrophy and both can be used together. As well as increasing the Vaginal Maturation Index, estrogen lowers vaginal pH, increases subepithelial capillary growth, improves epithelial integrity and differentiation, raises the level of vaginal secretions and restores the normal vaginal flora [19,20]. Given their proven efficacy and safety, this section will focus on topical
estrogens [21]. A Cochrane review examined the literature on topical estrogens in 2006 [22] and the European Menopause and Andropause Society published a clinical guide in 2012 on the low dose preparations which had since become available [5]. The literature supports the efficacy of lower doses to minimize adverse effects [23]. Topical preparations include estradiol-containing tablets and rings; estriol pessaries, creams and ovules; promestriene and conjugated estrogens. The 2006 Cochrane review found them to be equally effective [22]. Availability of individual preparations varies worldwide. Absorption depends on the dose used and the degree of vaginal atrophy. Thus plasma estrogen levels do not exceed the normal postmenopausal range of ≤ 20 pg/ml with long term use of 10mcg estradiol tablets and does not increase the risk of endometrial hyperplasia and carcinoma [5, 21, 24]. On the other hand, absorption may be higher when treatment is initiated as the vaginal epithelium is thin and atrophic. Absorption subsequently decreases with continued use [25]. Progestogen opposition is therefore not necessary to protect against endometrial hyperplasia with low dose topical estrogens if used in the recommended doses [ see for example 26,27]. However the 2006 Cochrane systematic review found significant endometrial stimulation with conjugated equine estrogen cream [22]. 5.1.2 Tibolone Tibolone is a synthetic steroid that has estrogenic effects on the vagina but not on the endometrium [28]. This drug has been associated with significant improvements in sexual function in postmenopausal women, reflecting both its estrogenic and androgenic properties. It increases the Vaginal Maturation Index and vaginal blood flow. Furthermore it also reduces nocturia and urinary urgency [29]. 5.1.3 Ospemifene Approved in the USA and Europe, oral ospemifene adds new flexibility for women with urogenital symptoms. In Europe, it is indicated for the treatment of moderate to severe symptomatic VVA in post-menopausal women who are not candidates for local vaginal estrogen therapy [30]. Ospemifene is a selective estrogen receptor modulator (SERM) [31]. Several studies have shown efficacy [ 32-38]. A pivotal 12 week randomized trial showed that ospemifene was shown to be effective and well tolerated for the treatment of the symptoms of vaginal dryness and dyspareunia associated with vulvovaginal atrophy over and above the use of provided lubricants [32].Subsequent studies have confirmed efficacy and safety over 12 months. Hot flushes are the most common reported treatment related adverse events in about 7% of patients [34,37]. Endometrial safety was evaluated in six randomized, double-blind, placebo controlled, parallel-group studies lasting up to 52 weeks [33]. In these trials, 1,242 women who received ospemifene 60 mg/day and 924 women who received placebo were evaluable for safety. Endometrial hyperplasia occurred in less than 1% of women treated with ospemifene; no endometrial cancer was reported. The mean (SD) increase in endometrial thickness among women treated with ospemifene was 0.51 (1.54) mm at 12 weeks, 0.56 (1.61) mm at 6 months, and 0.81 (1.54) mm at 12 months. Women who received placebo had a mean (SD) increase of 0.07 (1.23) mm at 12 months. Thus the authors concluded that the clinical trial data indicated that up to 52 weeks of treatment with oral ospemifene 60 mg/day was safe for the endometrium. As with other SERMs the risk of VTE (venous thromboembolism) is increased. Thus its use is contraindicated in women with an active or past history of VTEs, including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis [30]. Other SERMs may become available in the future for the treatment of VVA [39]. 5.1.4 Vaginal dehydroepiandrosterone Vaginal DHEA has been proposed as a treatment for VVA [40]. A recent study open-label phase III of daily intravaginal administration of 0.5% (6.5mg) DHEA for 52 weeks found improvement of dyspareunia, vaginal dryness and irritation/itching[41]. Furthermore no endometrial stimulation has been found [42] 5.2 Non hormonal therapies
The North American Menopause Society [NAMS] recommends that nonhormonal vaginal lubricants and moisturizers should be first-line therapies for women with vaginal atrophy [43]. A combination of vaginal moisturizing agents used on a regular basis and lubricants during intercourse can alleviate symptoms of vaginal dryness. These compounds do not reverse the atrophic vaginal changes but improve coital comfort and maintain vaginal secretions. Lubricants are typically used episodically to correspond to sexual activity. There are different types of lubricants which may be water, oil, silicone or hyaluronic acid based. The qualities of these different lubricants can serve different purposes, and hybrids from different categories attempt to provide more than one characteristic to broaden appeal. Lubricants, in general, give only temporary relief of symptoms and must be applied frequently for more continuous relief and require reapplication before intercourse. Lubricants such as petroleum-based products and baby oil can compromise the integrity of condoms [44]. This is important when condoms are used for contraception and/or to prevent sexually transmitted infections. Several plant oils such olive oil have demonstrated efficacy without adverse events [45]. The use of lubricants, even when not required, may improve sexual pleasure [see for example 46]. Moisturisers are typically used on a regular basis, rather than episodically associated with sexual activity. They may contain a bioadhesive polycarbophil-based polymer, which attaches to mucin and epithelial cells on the vaginal wall and retains water. Comparative studies of a vaginal polycarbophil moisturizer (Replens®) and estrogens have shown the same degree of efficacy in reducing symptoms such as itching, irritation and dyspareunia[47]. Vitamin D is a promoter of keratinocyte differentiation and a modulator of keratinocyte proliferation. The vagina is surrounded by a stratified squamous epithelium and thus, vitamin D can enhance proliferation and differentiation of the epithelium [48]. 5.3 Laser Recent short-term studies with limited numbers of subjects have suggested that laser therapy may result in remodelling of vaginal connective tissue and thickening and improved glycogen storage of the vaginal epithelium in women with vaginal atrophy [49, 50]. Improvement in VVA symptoms (vaginal dryness, burning, itching and dyspareunia) and vaginal health index scores [51, 52], have been reported but long term studies are required. 5.4 Alternative and complementary therapies Alternative and complementary therapies have been proposed for the treatment of GSM, but the data do not document evidence of efficacy. For example, a soy-rich diet was not found to relieve urogenital symptoms or restore the vaginal epithelium or improve vaginal health in perimenopausal and postmenopausal women [53]. Administration of genistein (54 mg/day) for 12 months did not improve the maturation index compared with placebo [54]. Similarly black cohosh, used alone or as part of a multibotanical product with or without soy dietary changes, had no effects on the vaginal epithelium, the endometrium or reproductive hormones [55]. Other herbal alternatives (red clover, dong quai, wild yam, chasteberry, cat's claw, chamomile, calendula flower, gingko biloba, green tea), alone or with plant oils, have been proposed but evidence of efficacy is lacking [56]. Although an inverse correlation between Lactobacillus ratio and dryness and an increased bacterial diversity in women experiencing moderate to severe vaginal dryness has been found, there is no conclusive evidence that administration of lactobacilli alone into the vagina are effective[ 57,58]. 6. Follow-up Recommendations with regard to duration of use and follow-up vary between preparations. However GSM is a chronic condition and will recur upon cessation of treatment. It is probably prudent to review women’s needs annually to assess efficacy and acceptability while updating on any new advice, information or treatment options [5].
7. Research agenda Even though VVA is a well-known condition associated with menopause and aging, more needs to be done so that treatment options can be tailored to women’s individual needs leading to a more personalised approach. Taking into account the concept of GSM, areas of further investigation should include the following: 1. Use of standardized scales to quantify objective symptoms and signs of VVA and to measure the subjective distress associated with GSM, 2. Consider GSM in the context of the couple taking into account frequency of sexual activity and partner’s general and sexual health in designing research studies and clinical trials, 3. Address comorbidities and their treatments which can potentially contribute to the severity of GSM in research studies and clinical trials, 4. Management of women at higher risk of GSM such as early menopause, breast cancer and pelvic irradiation, 5. Designing interventions to overcome barriers to effective treatments and to improve longterm adherence.
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Competing interests: S Palacios has been a symposium speaker or advisory board member for Servier, Pfizer, GSK, Abbott, Ferrer, Bioiberica, Shionogi, Amgen, Bayer, Healthcare, Gedeon Richter, Teva Women’s Health and has received research grants and/or consulting fees from Pfizer, Servier, Amgen, MSD, Preglem, Leon Farma, Gynea and Procare.
C Castelo-Branco has received educational grants, lecture fees and advisory board fees from different pharmaceutical companies including: Pfizer, Pierre-Fabre, Isdin, Grunenthal, Shionogi and TEVA and from educational institutions. H Currie has received educational grants, lecture fees and advisory board fees from several pharmaceutical companies and is MD of Menopause Matters Ltd R Nappi has had financial relationships (lecturer, member of advisory boards and/or consultant) with Bayer HealthCare AG, Boehringer Ingelheim, Ely Lilly, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc, Procter & Gamble Co, Shionogi Limited, TEVA Women’s Health Inc. J Simon has served (within the last year) or is currently serving as a consultant to or on the advisory boards of: AbbVie, Inc., Actavis, PLC., Amgen Inc., Amneal Pharmaceuticals, Apotex, Inc., Ascend Therapeutics, Dr. Reddy Laboratories, Ltd., Everett Laboratories, Inc., Merck & Co., Inc., Noven Pharmaceuticals, Inc., Novo Nordisk, Nuelle, Inc., Radius Health, Inc., Regeneron Pharmaceuticals, Inc., Sanofi S.A., Sermonix Pharmaceuticals, Inc., Shionogi Inc., Sprout Pharmaceuticals, TherapeuticsMD. In the last year he has received or is currently receiving grant/research support from AbbVie, Inc., Actavis PLC., Agile Therapeutics, Bayer Healthcare LLC., New England Research Institute, Inc., Novo Nordisk, Palatin Technologies and TherapeuticsMD. He has also served or is currently serving on the speaker’s bureaus of Amgen Inc., Eisai, Inc., Merck, Noven Pharmaceuticals, Inc., Novo Nordisk, and Shionogi Inc. V Mijatovic and M Rees have no conflicts of interest to declare. Funding: production of the update and round table discussion, held on May 21, 2015 in Madrid, Spain during the 10th European Menopause and Andropause Society (EMAS) Congress, was supported by an unrestricted educational grant from Shionogi, Spain to EMAS. Shionogi, Spain had no involvement in the writing of the update. Provenance and peer review: not commissioned; not externally peer reviewed.