Swiss consensus on the role of DHEA in the management of genitourinary syndrome of menopause

Abstract

Genitourinary syndrome of menopause (GSM) has a significantly negative impact on affected women’s lives. However, despite the increasing number of GSM treatment options (e.g. non-hormonal vaginal products, vaginal hormones [estrogens], dehydroepiandrosterone [DHEA; prasterone], vaginal laser therapy, oral ospemifene), many women remain untreated. The goal of the Swiss interdisciplinary GSM consensus meeting was to develop tools for GSM management in daily practice: a GSM management algorithm (personalized medicine); a communication tool for vaginal DHEA (drug facts box); and a communication tool for understanding regulatory authorities and the discrepancy between scientific data and package inserts. The acceptance and applicability of such tools will be further investigated.

摘要

更年期泌尿生殖系统综合征（GSM）对受影响女性的生活有显著的负面影响。然而, 尽管GSM治疗选择越来越多（例如非激素性阴道产品、阴道激素[雌激素]、脱氢表雄酮[DHEA；普拉睾酮]、阴道激光治疗、口服奥培米芬）, 许多女性仍然没有得到治疗。瑞士跨学科GSM共识会议的目标是在日常实践中开发GSM管理工具：GSM管理算法（个性化医疗）；阴道DHEA通讯工具（药物事实箱）；以及一种沟通工具, 用于了解监管机构以及科学数据和包装说明书之间的差异。将进一步调查此类工具的可接受性和适用性。

Keywords:

• Genitourinary syndrome of menopause
• prasterone
• vaginal estrogen
• personalized treatment
• drug facts box
• interdisciplinary consensus

Introduction

The term genitourinary syndrome of menopause (GSM) describes the hypoestrogenic changes to the vulvovaginal and bladder–urethral areas that occur in menopausal women [1]. GSM symptoms may comprise genital symptoms (dryness, burning, irritation), sexual symptoms (lack of lubrication, discomfort or pain, impaired sexual function) and urinary symptoms (urgency, dysuria, recurrent urinary tract infections) [2]. Symptoms associated with GSM are highly prevalent, affecting up to 84% of postmenopausal women [3]. An international survey including more than 4000 menopausal women reported a decreased quality of life in 52% of women with symptomatic GSM [4]. A recent case–control study comprising half a million women found a significantly increased risk for depression and anxiety in women with symptomatic GSM compared to women without GSM [5]. In contrast to vasomotor symptoms, which will decrease with time, GSM symptoms, if untreated, will remain or even become worse with lasting hypoestrogenic state. However, despite the negative impact GSM may have on women’s lives, many women remain untreated.

Therefore, the goals of the Swiss interdisciplinary consensus meeting were to update scientific evidence for GSM treatment, and to provide tools to support daily clinical practice. These tools include: a GSM management algorithm (personalized medicine); a communication tool for vaginal dehydroepiandrosterone (DHEA); and a communication tool for explaining the discrepancy between regulatory labeling and current scientific data.

In order to gather different points of view, experts and stakeholders from various (medical) fields were invited; for example, gynecological endocrinology (P.S., A.R., S.S.), sexual medicine (J.B., A.R., A.G.), psychiatry (A.G.), internal medicine endocrinology (M.B.), Swiss Menopause Society (P.S., A.R.), Swiss Society of Obstetrics and Gynecology (S.S.), health-care research (S.B.), and risk communication and statistics (V.S.).

Estrogens for GSM treatment

According to international guidelines [3], first-line therapy for women with symptomatic vaginal atrophy/GSM includes non-hormonal lubricants with sexual intercourse and, if indicated, regular use of long-acting vaginal moisturizers. For symptomatic women with moderate to severe vaginal atrophy and for those with milder vaginal atrophy who do not respond to lubricants and moisturizers, vaginal DHEA (prasterone) (see next section), the oral selective estrogen receptor modulator ospemifene [6] (not available in Switzerland) and estrogen therapy either vaginally at low dose or systemically are recommended. Low-dose vaginal estrogen is preferred when vaginal atrophy is the only menopausal symptom. For women receiving systemic estrogen therapy for other menopausal symptoms, such as hot flushes, low-dose vaginal estrogen therapy may be added if relief of atrophic symptoms is insufficient.

Internationally, there are various vaginal estrogen preparations containing either estradiol, estriol or conjugated equine estrogens, respectively. Table 1 presents an overview of vaginal estrogen products approved by the Swiss Agency for Therapeutic Products (Swissmedic). A progestogen for endometrium protection is generally not indicated when low-dose vaginal estrogen is administered for symptomatic GSM. However, endometrial safety data are not available for use longer than 1 year. However, based on observational safety data, vaginal estrogens may be used as long as needed [3]. Vaginal estrogens may be applied as cream, gel, suppositories and tablets daily within the first 2–3 weeks, and then twice weekly, whereas the vaginal ring is applied once every 3 months. They all have a good efficacy and safety profile [7]. However, about 12–15% of women will still have GSM symptoms despite vaginal estrogen treatment [7].

Table 1. Vaginal estrogen products approved by the Swiss Agency for Therapeutic Products (Swissmedic).

Estrogen type	Trade name	Application form
Estriol	Oestro-Gynaedron^®	Cream
Estriol	BLISSEL^®	Gel
Estriol	Gynoflor^®	Tablet
Estriol	Kadefemin^® Estriol Ovula 0.03 mg	Suppository
Estriol	Ovestin^® Ovula	Suppository
Estradiol	Vagifem^® 10 μg	Tablet
Estradiol	Estring^®	Ring

Treatments have been organized, first, by estrogen type (all estriol, all estradiol) and then, second, by application form (cream, gel, ring) within type.

Vaginal DHEA for GSM treatment

In recent years, additional GSM treatment options have become available including vaginal laser therapy [8] (available in Switzerland but not covered by Swiss health insurances) and vaginal prasterone (DHEA, approved by Swissmedic in 2020).

DHEA is a prohormone produced by the adrenal glands. DHEA is metabolized to androgens (androstenedione, testosterone) and then aromatized to estrogens (estrone, estradiol). During the reproductive life stage, serum DHEA(-sulfate) levels are much higher than serum testosterone and estradiol levels. During reproductive aging DHEA and testosterone formation decrease, resulting in 50% lower serum levels around menopause compared to young adulthood [9]. Development of vaginal DHEA for GSM treatment started almost 20 years ago. Table 2 presents an overview of relevant clinical studies performed with vaginal DHEA ovules (suppositories/pessaries) [10–31]. In 2016, vaginal DHEA at 6.5 mg/day was approved by the US Food and Drug Administration (FDA) (trade name Intrarosa^®). In 2020, vaginal DHEA at 6.5 mg/day was also approved by Swissmedic.

Table 2. Overview of clinical studies performed with vaginal DHEA ovules.

Study identifier and study type	Primary study objective and inclusion criteria	Daily dosage regimen of DHEA vaginal ovules (number of patients enrolled)	Study duration	Main results	Papers based on study data
ERC-213^a Bioavailability Phase I	Evaluation of the systemic bioavailability of DHEA and its metabolites and the pharmacokinetics of vaginal suppositories at three different DHEA concentrations and a placebo Postmenopausal women with vaginal atrophy	0% (0 mg DHEA), n = 10 0.50% (6.5 mg DHEA), n = 10 1.0% (13 mg DHEA), n = 10 1.8% (23.4 mg DHEA), n = 10	7 days	DHEA vaginal ovules are well tolerated At the low 6.5 mg dose of DHEA, serum levels of DHEA and its metabolite remained within the range of values found in normal postmenopausal women At the three tested DHEA doses, vaginal maturation value was significantly increased, and vaginal pH was significantly decreased from day 1 to day 7	Labrie, Cusan et al. 2008; Labrie, Martel et al. 2013; Labrie and Martel, 2017
ERC-210^a Efficacy/safety Phase III	To determine the dose–response of vaginal mucosa parameters to the local action of DHEA Postmenopausal women suffering from at least one moderate to severe symptom of vaginal atrophy	0.0% (0 mg DHEA), n = 54 0.25% (3.25 mg DHEA), n = 54 0.50% (6.5 mg DHEA), n = 56 1.0% (13 mg DHEA), n = 54	12 weeks	Rapid and efficient reversal of all symptoms and signs of vaginal atrophy Significant beneficial change after 2 weeks in the percentage of vaginal parabasal and superficial cells and pH as well as in the most bothersome symptom of VVA Circulating estrogens and androgens as well as the total metabolites of androgens reflecting the total androgen pool and estrone sulfate, a parameter of total estrogens, all remained within the range observed in normal postmenopausal women Major positive effects on libido and sexual dysfunction	Labrie, Archer et al. 2009; Labrie, Archer et al. 2009; Labrie, Archer et al. 2009; Labrie, Archer et al. 2010; Labrie 2010; Labrie, Archer et al. 2011; Labrie, Archer et al. 2014; Portman, Labrie et al. 2015; Martel, Labrie et al. 2016; Archer, Labrie et al. 2017; Labrie, Archer et al. 2017
ERC-231^a Efficacy/safety Phase III Pivotal	To confirm the efficacy of intravaginal DHEA on the symptoms and signs of VVA Postmenopausal women with moderate to severe dyspareunia as their most bothersome symptom of VVA	0.0% (0 mg DHEA), n = 81 0.25% (3.25 mg DHEA), n = 87 0.5% (6.5 mg DHEA), n = 87	12 weeks	Clinically and statistically significant beneficial effects of treatment with daily intravaginal 0.50% (6.5 mg) prasterone on the four co-primary objectives (dyspareunia, percentage of parabasal cells, percentage of superficial cells and vaginal pH) Highly significant beneficial effects observed at examination of the vaginal mucosa (vaginal secretions, color, epithelial integrity and epithelial thickness) No clinically or biologically meaningful change in serum steroid levels	Archer, Labrie et al. 2015; Portman, Labrie et al. 2015; Martel, Labrie et al. 2016; Archer, Labrie et al. 2017; Labrie, Archer et al. 2017
ERC-238^a Efficacy/safety Phase III Pivotal	To confirm the efficacy of intravaginal DHEA on moderate to severe pain at sexual activity (dyspareunia) as MBS of VVA due to menopause and to collect further data on subjects exposed to intravaginal DHEA Postmenopausal women with moderate to severe dyspareunia as their MBS VVA	0.0% (0 mg DHEA), n = 182 0.5% (6.5 mg DHEA), n = 376	12 weeks	DHEA significantly improved vaginal pH, superficial and basal/parabasal epithelial cell counts, and relieved the MBS dyspareunia. Significant improvement was also seen on moderate to severe vaginal dryness, vaginal secretions, epithelial integrity, epithelium thickness and vaginal color as well as on the six domains of the FSFI All serum sex steroids related to DHEA remained well within the normal postmenopausal values	Labrie, DeRogatis et al. 2015; Ke, Labrie et al. 2015; Labrie, Montesino et al. 2015; Labrie, Archer et al. 2016; Montesino, Labrie et al. 2016; Martel, Labrie et al. 2016; Archer, Labrie et al. 2017; Labrie, Archer et al. 2017
ERC-234^a Efficacy/safety Phase III	To confirm the efficacy of intravaginal (DHEA) on vaginal dryness, a symptom of vaginal atrophy, in postmenopausal women suffering from vaginal dryness Postmenopausal women with moderate to severe vaginal dryness as their most bothersome symptom of VVA	0.0% (0 mg DHEA), n = 152 0.25% (3.25 mg DHEA), n = 148 0.5% (6.5 mg DHEA), n = 150 Daily for 2 weeks followed by twice weekly for 10 weeks	12 weeks	Statistically significant effects on the decrease in the percentage of parabasal cells, the increase in the percentage of superficial cells and the decrease in vaginal pH The improvement of MBS vaginal dryness did not reach statistical significance (over placebo) at 12 weeks following 10 weeks of biweekly treatment after 2 weeks of daily administration (loss in efficacy when the dosing regimen was changed from daily to twice weekly at 2 weeks) No biologically meaningful change in serum DHEA and its most relevant metabolites, including estradiol and testosterone	Bouchard, Labrie et al. 2015; Portman, Labrie et al. 2015
ERC-230^a Safety Phase III	To assess the long-term safety of intravaginal prasterone Postmenopausal women (non-hysterectomized), between 40 and 75 years of age	0.5% (6.5 mg DHEA), n = 530	52 weeks	Prasterone was well tolerated following intravaginal administration at a dose of 0.50% (6.5 mg) per day for up to 52 weeks. The only drug-related adverse event was application site discharge (sponsor assessment) All endometrial biopsies samples have shown atrophic or inactive endometrium and, in women with no biopsy specimen, no clinically significant change in endometrial thickness (evaluated by TVUS) Absence of meaningful systemic exposure to prasterone and its metabolites	Labrie, Archer et al. 2015; Ke, Gonthier et al. 2015; Portman, Labrie et al. 2015; Bouchard, Labrie et al. 2016; Martel, Labrie et al. 2016

^aRandomized, double-blind, placebo-controlled studies (except ERC-230: open-label).

DHEA, dehydroepiandrosterone (prasterone); FSFI, Female Sexual Function Index; MBS, most bothersome symptom; TVUS, transvaginal ultrasound; VVA, vulvovaginal atrophy.

Vaginal DHEA is different from vaginal estrogens in some aspects. Based on the concept of intracrinology [32], an inactive prohormone enters cells of peripheral target organs where it is transformed into an active hormone by intracellularly localized enzymes (Figure 1). Thus, the active hormone exerts its effects within the cell only, but not systemically since they are inactivated within the same cells. This minimizes changes in serum sex steroid levels after daily vaginal DHEA application [13,29]. Similarly, there were no endometrial changes reported after 1 year of daily application of vaginal DHEA at 6.5 mg [31]. The most frequent adverse reaction reported in clinical trials with vaginal DHEA was vaginal discharge (9.9% of patients [31]). The efficacy of vaginal DHEA on the symptoms of dyspareunia and vaginal dryness, as well as on three indicators of vaginal health (vaginal pH and percentage of parabasal and superficial cells), was shown in two pivotal 12-week placebo-controlled clinical trials [31]. Furthermore, in women suffering from GSM, sexual function has been shown to improve in all Female Sexual Function Index (FSFI) domains with vaginal DHEA application [25]. At first sight, this may be a surprising finding as serum sex steroid levels remain within the normal range for postmenopausal women and thus the brain is not exposed to, for example, supraphysiological levels of androgens for that population. Most likely, it is not mediated by endocrine mechanisms. In contrast to vaginal estrogens, vaginal DHEA does not only have a beneficial effect on the vaginal epithelium but also on the cell layers below. Accordingly, in oophorectomized rats, vaginal DHEA has been found to increase the density of nerve fibers within the lamina propria and the density of sympathetic fibers within the muscularis [34]. Sympathetic fibers induce rhythmic contractions of the vaginal wall (orgasm), as well as an elongation and widening of the vagina.

Figure 1. Fundamentals of intracrinology: mechanism of action of DHEA (reprinted with permission from Labrie and Labrie [33]). DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone.

Of course, as for all GSM treatment options, there are conditions in which vaginal DHEA will not be the first choice for a patient. For example, if other menopausal symptoms are present requiring systemic menopausal hormone therapy (MHT), additional vaginal therapy might not be necessary. In women with a focus on urological GSM symptoms, vaginal estrogen therapy that has been specifically studied in, for example, urinary incontinence, overactive bladder or recurrent urinary tract infection, respectively, should be chosen. Also, other choices might be preferred based on patient’s preference on formulation and posology. For example, some women are happy to use a product daily (better to remember) while others do not like the idea of ‘putting something into the vagina’ every single day. In breast cancer survivors, international recommendations differ. For example, in Europe and Switzerland, vaginal DHEA is contraindicated in breast cancer survivors. In contrast, the American Society of Clinical Oncology Clinical Practice Guideline states that vaginal DHEA can be recommended for women with current or a history of breast cancer who are on aromatase inhibitors and have not responded to previous treatment [35]. Furthermore, a retrospective cohort study has shown that vaginal DHEA was not associated with an increased risk of breast cancer recurrence [36]. Similarly, a pilot study demonstrated that in breast cancer survivors treated with aromatase inhibitors, serum estrogen levels did not increase when using vaginal prasterone [37]. Finally, there is no contraindication for breast cancer survivors in the Intrarosa^® package labeling in Canada and the USA.

Approval process for new products for GSM treatment

Internationally, the regulatory process for new drug approval differs, resulting in slightly different indications for vaginal (pro)hormones for GSM treatment. Table 3 presents an overview of vaginal DHEA regulation for GSM treatment in selected markets. Vaginal DHEA at 6.5 mg is administered daily with the use of the provided applicator or with fingers. In contrast to vaginal estrogens (tablet, cream, gel, suppository) where there is an initiation period followed by a maintenance therapy period, vaginal DHEA is always applied on a daily basis regardless of treatment duration. As all regulatory authorities require safety data (including endometrial biopsies) for at least 1 year, all studies investigating new (pro)hormones for GSM treatment fulfill these criteria – but not more. Thus, in general, endometrial safety data are usually limited to 1 year of treatment.

Table 3. Overview of vaginal DHEA regulation for GSM treatment in selected markets (status: March 2021).

	Switzerland	Europe	USA	Canada
Regulatory authority	Swissmedic	EMA	FDA	Health Canada
Year of approval	2020	2018	2016	2019
Pharmaceutical company (MAH)	Labatec Pharma SA	Endoceutics SA	Endoceutics, Inc. (at approval) Millicent Pharma US (current)	Endoceutics, Inc.
Indication	Local treatment of vulvovaginal atrophy in postmenopausal women	Vulvar and vaginal atrophy in postmenopausal women having moderate to severe symptoms	Moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause	Postmenopausal vulvovaginal atrophy
Contraindication	Breast cancer, endometrial hyperplasia/cancer, undiagnosed abnormal bleeding, history of VTE/ATE, thrombophilia, history of liver disease with abnormal serum liver enzymes, porphyria, pregnancy/lactation, hypersensitivity to the drug	Hypersensitivity to the active substance or to the excipient Undiagnosed genital bleeding Known, past or suspected breast cancer Known or suspected estrogen-dependent malignant tumors (e.g. endometrial cancer) Untreated endometrial hyperplasia Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal Previous or current VTE (deep vein thrombosis, pulmonary embolism) Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency) Active or recent ATE disease (e.g. angina, myocardial infarction) Porphyria	Undiagnosed abnormal genital bleeding	Undiagnosed abnormal genital bleeding Hypersensitivity to the active substance or to the excipient
Safety (precautions and warnings) (selection)	The metabolization of prasterone leads to the formation of estrogens in particular. The following risks have been associated with systemic MHT and apply to a lesser extent to Intrarosa^® where systemic estrogen exposure remains within normal postmenopausal values. However, these risks must be taken into account in case of prolonged or repeated use of the product: Endometrial hyperplasia and carcinoma Breast cancer Ovarian cancer Abnormal Pap smear VTE Coronary artery disease Ischemic stroke	Prasterone is metabolized into estrogenic compounds. The following risks have been associated with systemic HRT and apply to a lesser extent for estrogen products for vaginal application of which the systemic exposure to the estrogen remains within the normal postmenopausal range. However, they should be considered in case of long-term or repeated use of this product: Endometrial hyperplasia and carcinoma Breast cancer Ovarian cancer Abnormal Pap smear VTE Coronary artery disease/hypertension Ischemic stroke	Estrogen is a metabolite of prasterone. Use of exogenous estrogen is contraindicated in women with a known or suspected history of breast cancer. Intrarosa^® has not been studied in women with a history of breast cancer	Estrogen is a metabolite of prasterone. Use of exogenous estrogen is contraindicated in women with a known history of breast cancer. Intrarosa^® has not been studied in women with a history of breast cancer
Interaction	Since Intrarosa^® is administered locally and at low doses, clinically relevant interactions are unlikely As DHEA is metabolized to estrogens, potential interactions with drugs that affect enzymes (CYP450) are highlighted	x	x	No drug interaction with Intrarosa^® has been established
Reimbursement by health insurances	Reimbursed by complementary insurances	Reimbursed in parts of the UK	Reimbursed (private)	TBD
Others	Combination therapy of vaginal DHEA with systemic MHT or vaginal estrogens is not recommended (as there are no such studies)	Concomitant use with systemic MHT (estrogen-only or estrogen–progestogen combination or androgen treatment) or vaginal estrogens has not been investigated and is therefore not recommended

ATE, arterial thromboembolism; CYP450, cytochrome P450; DHEA, dehydroepiandrosterone; EMA, European Medicines Agency; FDA, US Food and Drug Administration; GSM, genitourinary syndrome of menopause; HRT, hormone replacement therapy; MAH, Marketing Authorisation Holder; MHT, menopausal hormone therapy; TBD, to be done; VTE, venous thromboembolism.

The biggest challenge for communication, however, is the discrepancy between regulatory authorities’ demands (Table 3) and scientific data (Table 2). For example, in European countries, as DHEA is metabolized to estrogens and was thus approved under guidelines used for estrogens. Product labeling is based on standard templates used for all hormonal products: all potential risks associated with long-term (!), systemic (!), oral (!), combined (!) estrogen–progestogen MHT had to be mentioned in the package insert, although vaginal DHEA does not increase serum estrogens levels (no systemic effect) [13,29] and has scientifically neither been associated with increased risks for cardiovascular events, cancer and dementia (no known safety issues) in clinical trials performed (n = 1196 patients exposed to 6.5 mg of prasterone from 12 to 52 weeks) [23] nor from postmarketing experience since launch in 2017. Similarly, from a medical-scientific point of view there is no known reason not to combine vaginal (pro)hormones with systemic MHT – just the contrary applies: as many women still suffer from GSM despite being treated with systemic (ultra)low-dose MHT, additional vaginal (pro)hormones should be offered. However, there are no studies to document the combination is safe, and neither are there long-term studies on the safety of DHEA.

Practical recommendations

Taking the information already mentioned together, three main questions remain for patient consultation in practice. First, to whom should be offered which GSM treatment (personalized medicine)? Second, how to communicate real (scientific) benefits and risks of vaginal DHEA (drug facts box)? Third, how to communicate the discrepancy between scientific data and package inserts?

Personalized GSM treatment

Today in Switzerland, approved GSM treatment options comprise non-hormonal vaginal products (lubricant, moisturizer, cream), vaginal estrogens (tablet, gel, cream, suppository, ring), vaginal DHEA (suppository) and vaginal laser therapy, respectively. Some of the vaginal products come with an applicator, some do not. Vaginal DHEA is a suitable solution for all postmenopausal women suffering from dyspareunia, vaginal dryness and irritation/itching due to estrogen deficiency. Vaginal DHEA brings all benefits that can be expected from local estrogenic treatments with the added benefit to genitourinary health attributed to androgens [38,39]. Thus, vaginal DHEA is currently the only approved physiological treatment addressing both estrogen and androgen deficiencies causing GSM [3].

Figure 2a provides an algorithm for choosing the ‘right’ GSM treatment for the individual woman which, however, still needs testing and implementation in daily practice. This algorithm comprises four steps:

Figure 2. (a) Algorithm for choosing the ‘right’ GSM treatment for the individual woman. (b) Example algorithm for choosing the ‘right’ GSM treatment for the individual woman. DHEA, dehydroepiandrosterone; GSM, genitourinary syndrome of menopause; ICF, International Classification of Functioning, Disability and Health.

1. Taking the personal history (comorbidities, co-medication)

   Taking the personal history helps to rule out other potential reasons for GSM-like symptoms and to evaluate potential contraindications (Table 3) approved by the Health Authority for vaginal (pro)hormone products.

2. Evaluating prior GSM treatment experiences (number of products, treatment duration, treatment adherence, efficacy, adverse events)

   Many women have tried other GSM treatments before. For consultation it is helpful to know which product a woman has used before (how many?), for how long she has used it/them (long enough?), whether she adhered to the treatment regimen according to the package insert (if not, why?), how effective the treatment(s) was/were (symptom reduction on a scale 0–100%) and whether she experienced any side-effects (if yes, which?).

3. Quantifying the individual need for treatment

   Although it seems obvious that reported GSM symptoms should improve with the GSM treatment to be chosen, it is helpful to quantify symptom intensity as well as urgency and expected degree of symptom relief prior to treatment start. To do so, a so-called ‘ICF categorical profile’ has been developed by linking the Menopause Rating Scale (MRS-II) to the International Classification of Functioning, Disability and Health (ICF) [40]. First, a woman defines her global goal (>12 months), mid-term goal (<12 months) and short-term goal (3 months). Then the intensity of 11 MRS-II items including ‘sexual problems’, ‘bladder problems’ and ‘dryness of vagina’ can be rated on a 5-point Likert scale (no symptom [0 points], mild symptom [1 point], moderate symptom [2 points], severe symptom [3 points], very severe symptom [4 points]). Each symptom is then linked to the goal category (global, mid-term, short-term). Finally, the expected extent of symptom reduction is defined on the MRS-II 5-point Likert scale (0–4 points). Obviously, if the patient’s focus is not on GSM symptoms or also involves other menopausal symptoms, the treatment options to be discussed need to be broader (not part of this algorithm).

4. Prioritizing preferences of the GSM treatment to be chosen (mode of application, frequency of application, willingness to eventually experience minor side-effects, cost)

   Knowing and prioritizing the woman’s preferences of a treatment to be chosen are essential as this will increase her acceptance of and adherence to the treatment, improve the patient–physician communication and is thus the basis for shared decision-making.

For example, a 57-year-old healthy postmenopausal woman presents with menopausal symptoms, especially GSM (Figure 2b):

• Step 1: Taking the personal history

  No other potential reasons for GSM-like symptoms, no co-medication, no contraindications for vaginal (pro)hormone products.

• Step 2: Assessing prior GSM treatment experiences

  For GSM, she has tried two non-hormonal vaginal products before, a moisturizer and a cream. Both treatments were applied on demand only (prior to sexual intercourse) as she did not like the vaginal discharge and burning sensation upon application (for being able to have sexual intercourse these side-effects were acceptable). So far, we can summarize: number of products used before consultation, two; treatment duration, too short for evaluation; adherence to treatment according to package insert, not given; treatment effectiveness, 50% reduction of dyspareunia, other GSM symptoms not evaluable; side-effects, vaginal discharge and burning (only short-term use).

• Step 3: Quantifying the individual need for GSM treatment

  Her statements in the ‘Categorical ICF profile’ are as follows (Table 4): global goal (>12 months), feeling like the woman she used to be again; mid-term goal (<12 months), regain overall sexual function; short-term goal (3 months), reduce vaginal dryness and dyspareunia. The intensity of ‘sexual problems’ is rated as severe (3 points), the intensity of vaginal dryness and dyspareunia as very severe (4 points each). Her treatment goal for ‘sexual problems’ is to reduce symptom intensity to mild (1 point) within 12 months (mid-term goal). Her treatment goal for vaginal dryness and dyspareunia is to reduce symptom intensity to none to mild (0–1 point) within 3 months (short-term goal).

• Step 4: Prioritizing preferences of the GSM treatment to be chosen

  Finally, after providing an overview of treatment options, her GSM treatment preferences are prioritized as follows: applicator preferred (does not like to touch herself in the vagina), daily application (better to remember), initial vaginal irritation is ok (but not forever), low/moderate cost. Taking all information together, the following GSM treatment options emerge: vaginal (pro)hormone product > only products with applicators; estriol cream/gel, estradiol tablet, DHEA suppository > only product applied daily; DHEA suppository becomes the chosen treatment. Initial vaginal irritation may occur with all vaginal products. The first follow-up consultation will be scheduled after 3 months (short-term goal) for treatment evaluation and adjustment if needed.

Table 4. Example of an ICF categorical profile (modified according to Zangger et al. [40]).

Assessment
Global goal (GG) (>12 months): Feeling like the woman she used to be again						x			1
Mid-term goal (MG) (<12 months): Regain overall sexual function						x			1
Short-term goal (SG) (3 months): Reduce vaginal dryness and dyspareunia							x		0–1
MRS item	ICF category		Problem					Goal relation	Goal v alue
			0	1	2	3	4
Hot flushes, sweating	b550	Thermoregulatory functions	x						0
	b830	Other functions of the skin	x						0
Heart discomfort	b460	Sensations associated with cardiovascular and respiratory functions	x						0
Sleep problems	b134	Sleep function	x						0
	b1340	Amount of sleep	x						0
	b1341	Onset of sleep	x						0
	b1342	Maintenance of sleep	x						0
Depressive mood	b152	Emotional functions (feeling down, sad, on verge of tears, mood swings)	x						0
	b130	Energy and drive function	x						0
Irritability	b126	Temperament and personality function	x						0
	b152	Emotional functions (feeling nervous, inner tension)	x						0
Anxiety	b152	Emotional functions (inner restlessness, feeling panicky)	x						0
Physical and mental exhaustion	b4550	General physical endurance	x						0
	b1300	Energy level	x						0
	b140	Attention function	x						0
	b144	Memory function	x						0
Sexual problems	b640	Sexual function				x		Mid-term goal	1
Bladder problems	b620	Urination function	x						0
	b6202	Urinary continence	x						0
	b630	Sensations associated with urinary functions	x						0
	b6200	Urination	x						0
Dryness of vagina	b670	Sensations associated with genital and reproductive functions					x	Short-term goal	0–1
	b6700	Discomfort associated with sexual intercourse					x	Short-term goal	0–1
Joint and muscular discomfort	b280	Sensation of pain (muscle)	x						0
	b28016	Pain in joints	x						0
	b710	Mobility of joint function	x						0

ICF, International Classification of Functioning, Disability and Health; MRS, Menopause Rating Scale.

Drug facts box for vaginal DHEA

A drug facts box helps to communicate benefits and risks of vaginal DHEA (Figure 3).

Figure 3. Drug facts box for vaginal DHEA. DHEA, dehydroepiandrosterone; FSFI, Female Sexual Function Index; GSM, genitourinary syndrome of menopause.

Question: How many women are affected by vaginal dryness and dyspareunia?

Answer: Four out of five women aged 40 years and above complain of vaginal dryness. Of those, three out of five complain of dyspareunia [41,42].

Question: Does vaginal DHEA at 6.5 mg/day reduce vaginal dryness?

Answer: If five women with moderate/severe vaginal dryness are treated with vaginal DHEA at 6.5 mg/day for 12 weeks, four out of five will have less vaginal dryness (84% responders, reduction in the severity score of 1 or more). Of those responders, three women (89%; 75% of total patients treated) will have their vaginal dryness relieved (only mild or no more symptom), including two women (48%; 40% of total patients treated) who will be symptom-free [23].

Question: Does vaginal DHEA at 6.5 mg/day reduce dyspareunia?

Answer: If five women with moderate/severe dyspareunia are treated with vaginal DHEA at 6.5 mg/day for 12 weeks, four out of five will have less dyspareunia (79% responders). Of those responders, three women (80%; 63% of total patients treated) will have their dyspareunia relieved (only mild or no more symptom), including two women (36%; 28% of total patients treated) who will be symptom-free [23].

Question: Does vaginal DHEA at 6.5 mg/day improve sexual function (based on FSFI domains [desire, arousal, orgasm and pain])?

Answer: If five women with moderate/severe dyspareunia are treated with vaginal DHEA at 6.5 mg/day for 1 year, four out of five will experience improvement of at least one (out of six) FSFI domain (p = 0.0124 versus women using a placebo) [19].

Question: Is vaginal DHEA at 6.5 mg/day associated with vaginal discharge?

Answer: If five women with GSM symptoms are treated with vaginal DHEA at 6.5 mg/day for 12 weeks, less than one woman (10%) will experience vaginal discharge as a side-effect [23].

Communication tool for understanding regulatory authorities

Sometimes there is a huge discrepancy between the scientific data and the package insert of a certain drug. Not surprisingly, patients may then distrust her/his physician’s advice when reading the package insert. Similarly, also for physicians this discrepancy is hard to understand and they may start distrusting what they are told by so-called ‘key opinion leaders’. Therefore, this section aims to clarify some obscurities.

According to the authorities’ guidelines the category ‘adverse events’ within the package insert has to list all adverse events that have been observed in clinical trials and that may have a causal relationship to the drug (although this may be a subjective attribution). In contrast, criteria are less clear for the category ‘precautions’. In general, potential severe adverse events should be mentioned herein. Internationally, the approval processes differ. Thus, although the underlying scientific data are the same, the resulting decisions are not. For example, there is no internationally consented algorithm to evaluate safety issues. Thus, as there is no standard on the regulatory level there is also no internationally accepted algorithm for pharmaceutical companies to assess all safety aspects to support the approval process.

Furthermore, in some countries, history of a product class and ‘equal rights’ are important. If, for example, a vaginal estrogen product (in much higher and potentially systemically acting dosage) was approved 30 years ago and a certain adverse event was reported and included in the package insert, then a new vaginal estrogen product (in much lower dosage) has to report the same adverse events even if the causal relationship for the new product is questionable. In respect to vaginal DHEA this discrepancy in international approval processes becomes obvious. In the USA and Canada, the regulatory authorities accepted to have a labeling based on the scientific data (adverse events) obtained during the clinical studies, whereas in Europe the European Medicines Agency (EMA) preferred to keep the same CMDh HRT core labeling template [43] of (old-fashioned) vaginal estrogens as there is no head-to-head trial showing another safety profile for vaginal DHEA compared to (old-fashioned) vaginal estrogens. Furthermore, this labeling is not based on evidence obtained with these vaginal preparations, but on deductions from oral systemic MHT. As DHEA is a prohormone, it has been evaluated according to hormone standards. Switzerland mainly follows the EMA decision.

Conclusion

GSM has a significantly negative impact on affected women’s lives. The Swiss GSM consensus group identified three major challenges in GSM management and developed the following tools: a GSM management algorithm (personalized medicine); a communication tool for vaginal DHEA (drug facts box); and a communication tool for understanding regulatory authorities. Yet both of the tools need testing and implementation in daily practice.

Potential conflict of interest

The authors have been part of an interdisciplinary expert board funded by Labatec Pharma SA. The authors alone are responsible for the content and writing of the article.

Acknowledgements

The authors are grateful to Ms Hostettler, secretary, for formatting support.

Additional information

Funding

This publication was developed by an interdisciplinary expert board in Switzerland. The meeting (travel expenses, compensation for loss of salary) was funded by Labatec Pharma SA without influence on the content.