关键词: 绝经期, 女（雌）性泌尿生殖系统疾病, 绝经泌尿生殖综合征, 药物疗法, 物理治疗方法, 早期干预（教育）

Abstract: Advances in the Treatment of Genitourinary Syndrome of Menopause
LIU Shuangxue1, LI Yanhua2*
1. Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China
2.Department of General Medicine, the Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310005, China
*Corresponding author: LI Yanhua, Chief physician, Master supervisor; E-mail:liyanhua330@163.com
Abstract: Genitourinary syndrome of menopause (GSM) is a symptom that may occur in the vast majority of women, which gradually aggravates with age and time from the menopausal transition, and may seriously affect the daily life and intimacy in marriage in middle-aged and elderly women. However, due to a variety of personal and external factors, the consultation rate of GSM women is low, resulting in a low rate of obtaining effective counseling, appropriate diagnosis and treatment, and lifelong management in this population. We reviewed the advances in the treatment for GSM in peri-menopausal or postmenopausal women, aiming to raise public awareness of GSM and to offer theoretical guidance for related treatment, thereby promoting the physical and mental health of middle-aged and elderly women.
Keywords:Menopause; Female urogenital diseases; Genitourinary syndrome of menopause; Drug therapy; Physical therapy modalities; Early intervention (education)
1. Introduction
Genitourinarysyndromeofmenopause (GSM) refers to the collection of symptoms and signs related to the decrease of estrogen and other sex hormones, involving the changes of the vulva, vagina, urethra, and bladder. The main clinical manifestations include external genitalia, urinary system, and sex, such as vaginal dryness, itching, urinary tract infection, sexual difficulty, and so on[1]. Studies have shown that more than 50% of women develop GSM symptoms at some point in their lives[2]and considering that some people do not see a doctor because of sexual embarrassment or lack of awareness of them, the prevalence of GSM is likely to be underestimated. This paper analyzes the treatment of GSM in peri-menopausal or postmenopausal women, providing a theoretical basis for general practitioners' early intervention, diagnosis and treatment, and health management of GSM, as well as new ideas for specialists to study the disease in the futureto improve the quality of life and happiness of women.
2 Drug therapy
2.1 Menopause Hormone Therapy (MHT)
Menopause Societies at home and abroad have pointed out that the time window of hormone therapy is before the age of 60 or within 10 years after menopause, and its risk depends on the type of drug, dose, time of use, route of administration, start-up time and whether to use progesterone, and the benefits and risks of treatment regimens need to be reassessed regularly[3-4]. Based on some clinical trials and observational studies, this paper summarizes the safety and efficacy of different hormone therapy regimens.
2.1.1 Vaginal estrogen preparation
For GSM symptoms can not be relieved by over-the-counter drug therapy, and there is no indication of systemic hormone therapy, it is recommended to use low-dose vaginal estrogen treatment[3-4]. At present, there are many dosage forms, such as cream, ring, implant, or tablet.
Several clinical trials have confirmed that the use of vaginal estradiol or estriol vaginal preparation (15~50 μg/d) which is much lower than the conventional dose approved by the Food and Drug Administration (FDA) can also significantly reduce vaginal pH and improve sexual function, and there are no adverse reactions[5-7]. The results of the meta-analysis carried out by BIEHL et al.[8] showed that the effective dose of 17 β-estradiol soft capsules (TX-004HR) was as low as 4 μg. The above results support the use of vaginal estrogens with the lowest possible dose to alleviate the symptoms of GSM, and also provide a reference for patients who are concerned aboutthe safety of estrogen exposure or have contraindications for estrogen use.
2.1.2 Systematic MHT
Systemic MHT is recommended for patients with GSM complicated with obvious systemic symptoms. Transdermal and oral administration are two common methods[3-4]. Butthe latest research suggests that lower doses of transdermal estrogen may be a better form of administration, reducing coronary heart disease, stroke, and cardiovascular mortality[10]. In addition, combined estrogen and progesterone therapy (estrogen-progestogen therapy, EPT) is recommended forwomen with uteri[3], and the E3N cohort study found that compared with synthetic progesterone, micronized progesterone had a lower effect on breast proliferation and did not increase the prevalence of breast cancer[11]. Women with a hysterectomy can be treated with estrogen alone[3-4]. Furthermore, in a previous clinical controlled study, GENG et al.[12] demonstrated that MHT could reshape the composition of vaginal microorganisms and significantly increase the abundance of lactic acid bacteria, which was of great significance for the clinical treatment of GSM.
2.1.3 Compound hormone
At present, there is a bioequivalent compound hormone therapy, which can combine a variety of hormones (such as estradiol, estriol, dehydroepiandrosterone, progesterone, etc.), but clinicians consider using compound hormone only if the patient is allergic or unable to tolerate the treatment approved by FDA. There is evidence that compound hormones can increase the prevalence of endometrial cancer[13]. Therefore, there are some safety problems in compound hormone therapy, and further research is still needed.
2.2 Tissue-selective estrogen complex
The tissue-selective estrogen complex is composed of conjugated equine estrogens (CEE) and selective estrogen receptor modulator Bazedoxifene (BZA) and does not contain progesterone. A 12-week multicenter clinical trial of CEE/BZA in postmenopausal women with one or more moderate to severe vulvovaginal atrophy (VVA) symptoms, and vaginal pH > 5.0 found that CEE/BZA significantly improved vaginal cytology, decreased vaginal pH, and effectively relieved VVA symptoms[14]. In addition, according to the analysis of this trial data, several studies have shown that there is an approximately linear relationship between VVA symptoms and sexual function so that CEE/BZA can significantly improve sexual function while relieving VVA symptoms[15], and there is no significant difference in efficacy and safety among different ethnic groups[16]. Therefore, women who cannot tolerate adverse reactions to progesterone can benefit from the combination of CEE/BZA.
2.3 Selective estrogen receptor modulator (SERM)
SERMsare tissue-specific and can showexcitatory or antagonistic effects. Currently, ospemifene has been approved by the FDA and the European Medicines Agency for the treatment of postmenopausal women with moderate to severe sexual dysfunction caused by GSM or with VVA symptoms but not suitable for local hormone therapy[17]. Pharmacodynamics showed that
ospemifene had an estrogenic effect on the vaginal epithelium, significantly improved the morphology of vaginal mucosa, relieved dyspareunia[18], and could prevent postmenopausal urinary tract infection[19]. It may also be a potential treatment for VVA complicated with overactive bladder[20] and did not produce an estrogenic effect in breast tissue, and the stimulating effect on endometrium was neutral or minimal[18]. It has good tolerance and safety. However, it is still necessary to conduct long-term randomized controlled trials with large samples, including high-risk patients, in order to better clarify the safety of ospemifene.
2.4 Intravaginal dehydroepiandrosterone
According to the mechanism of human endocrinology, dehydroepiandrosterone (DHEA) produced by the adrenal gland is the only source of sex hormones in postmenopausal women[21]. At present, intravaginal DHEA (prasterone, 6.5mg/d) has been approved by FDA for the treatment of moderate to severe dyspareunia due to GSM[22]. A phase Ⅲclinical trial showed that daily intravaginal administration of DHEA for 12 weeks significantly reduced vaginal pH, improved vaginal cytology, and alleviated vaginal dryness and dyspareunia[23]. And SAUER et al.[24] analyzed that the curative effect of DHEA was similar to that of vaginal estrogen preparations. In addition, because DHEA transformation is cell-specific and tissue-specific and does not cause significant changes in serum hormone levels[21], it can be speculated that its potential risk is relatively smaller than that of local estrogen preparations. According to statistics, only 6% of women reported one adverse reaction reasonably related to treatment, vaginal discharge, which was caused by the melting of drugs at body temperature[23], indicating that this treatment has a high benefit-risk ratio.
2.5 Intravaginal oxytocin gel
GHORBANI et al.[25] pointed out that intravaginal oxytocin gel can improve vaginal cytology and subjective symptoms, and does not significantly change the thickness of the endometriumin the latest meta-analysis. The main mechanism of intravaginal oxytocin gel is that oxytocin stimulates vaginal cell proliferation in a time-and dose-dependent manner[26]. But its long-term effectiveness and safety remain to be verified.
2.6 Vaginal lubricants and moisturizers
The North American Menopause Societyrecommends vaginal lubricants and moisturizers as first-line therapy for GSM to reduce daily discomfort and improve sexual comfort[9]. Some studies have found that some common vaginal lubricants and moisturizers can inhibit the growth of pathogenic Escherichia coli while having a weak inhibitory effect on the growth of potential protective Lactobacillus crispatus[27]. This mechanism may improve vaginal health to some extent.
In addition, a study has found that hyperosmolar lubricantshave cytotoxic effects on vaginal epithelial cells, induce abnormal secretion of inflammatory mediators and destroy barriers[28]. Therefore, Potter et al.[29] have clearly proposed that when using vaginal lubricants and moisturizers, products with pH (about 3.5, range 3 ~ 5) and osmotic pressure (about 380 mOsmol/kg, range 200 ~ 600 mOsmol/kg) as close as possible to vaginal secretion should be selected to reduce endothelial stimulation and adverse reactions, and products should not contain paraben, chlorhexidine, and polyquaternium-15. Because such preservatives may cause vaginal flora imbalance.
2.7 Phytoestrogens (PEs)
PEsare compounds with estrogenic activity, which can be derived from soy, Pueraria mirifica, flaxseed, fennel, and other plants. They can be divided into three classes: isoflavones, lignans,
andcoumestans. Currently, isoflavones have the most clinical trial data, but whether isoflavones can improve the symptoms of GSM has been controversial. CARMIGNANI et al.[30] found that oral isoflavones could effectively relievevaginal dryness, but could not improve vaginal atrophy. SUWANVESH et al.[31] found that 6% Pueraria mirifica gel could also increase the vaginal maturity index when applied to the vagina, suggesting that local use of isoflavones may have an estrogenic effect on the vagina. However, SRITONCHAI et al.[32] found that isoflavones only showed a significant estrogenic effect in restoring normal vaginal flora, but did not relieve symptoms when using 5% Pueraria mirifica gel for topical use. Therefore, according to these randomized controlled trials, it can be inferred that the efficacy of PE on GSM may be produced in a dose-effect manner, and the effect on vaginal atrophy varies with different types and modes of administration. Additionally, taking into account the different methods of each trial, different sample sizes and other factors, and the degree of symptom relief is a subjective result, which is greatly affected by individual factors, a clear conclusion on the efficacy and mechanism of PE can not be obtained at present.
3 Physical therapy modalities
3.1 Transvaginal therapies based on energy
In recent years, three kinds of energy-based transvaginal therapies have been proposed for the treatment of GSM, which are microablative fractional CO2 laser, non-ablative vaginal Erbium: YAG laser (Er: YAG), and radiofrequency. At present, a number of clinical trials have revealed the benefits of these treatments in different female populations, including women who have contraindications to hormone therapy or have a history of gynecological tumors[33-38].
In randomized controlled trials of laser therapy and vaginal estrogen therapy, it was found that the efficacy of laser was comparable to that of local estrogen and produced a more lasting effect than hormone therapy (lasting at least 6-12 months)[39-41]. This is because a certain degree of thermal energy is deposited on the vaginal wall, which can stimulate epithelial cell proliferation, neovascularization, and collagen formation, and vaginal histology is improved, which is the immediate repair response of heat to mucosal tissue[42-43]. In addition, ATHANASIOU et al.[44] found that laser therapy could also improve the vaginal microecosystem and restore vaginal health, while BECORPI et al[45] found that the relief of GSM symptoms was mainly related to the significant changes in the expression of vaginal inflammatory and regulatory cytokines, which made the vaginal epithelium in a highly remodeled state without significant changes in vaginal flora. Therefore, there is no clear conclusion on the mechanism of laser therapyat present, and further research is needed. Furthermore, some experiments have proved that the efficacy of CO2 laser treatment may be produced in a dose-effect manner[46], and there is no significant correlation with power[47-48]. According to different types of energy therapies, after receiving 3-6 regular courses of treatment, the curative effect can last for 12 months[36-49-50], and the additional course of treatment can further improve the asymptomatic rate[46].
At present, energy-based transvaginal therapies show excellent prospects in the treatment of GSM, but 4 clinical trials have reported related complications, such as fibrosis, scar formation, adhesion, and penetrating injury[51]. According to the existing research, there seems to be the most
evidence to support CO2 laser, followed by Erbium laser, and the least is radiofrequency, but it is not clear which is good or bad. It is necessary to design a more careful comparative study to compare the advantages and disadvantages of various treatment methods, and further investigate the potential benefits, harm, and effectiveness of laser or radiofrequency to GSM.
3.2 Pelvic floor muscle training (PFMT)
Menopause and aging will directly or indirectly affect the pelvic floor muscle (pelvic floor muscle, PFM), and the increase of PFM dysfunction may also lead to an increase in the prevalence of GSM[52]. PFMT is a kind of training designed to increase the strength, endurance, and flexibility of pelvic floor muscles[53]. There is already a single-arm feasibility study and a case study has been reported that the symptoms of GSM and its effect on the quality of daily life and sexual function can be significantly reduced after PFMT treatment, which proves that PFMT is a potential intervention to improve GSM[54-55].
3.3 Lifestyle modifications
Lifestyle modifications refer to the application of interventions in the management of related health problems, such as choosing a healthy diet, participating in physical activities regularly, and quitting smoking. The above lifestyle changes can be used to treat pelvic floor dysfunction, either in combination with other treatments or as a separate therapy[53]. This is a relatively low-cost, non-invasive, and harmless intervention, and general practitioners can individually develop targeted lifestyle adjustment plans for every woman with GSM.
4 New direction
4.1 Vitamin E vaginal suppository
The result of a randomized, single-blind clinical trial shows that vitamin E vaginal suppository can replace estrogen cream to alleviate the symptoms of vaginal atrophy of GSM[56]. However, due to the limited data, it is not recommended for clinical use, but it can become a new research direction.
4.2 ZP-025 vaginal gel— Monurelle Biogel (ZP-025)
Monurelle Biological vaginal gel is a kind of gel containing 2.3% purified bovine colostrum. It has been found in animal experiments that it can significantly improve vaginal hemodynamics, increase the thickness of the vaginal epithelium, and lubricate vaginal mucosa[57]. At present, some clinical trials have proved that ZP-025 is an effective method for the treatment of postmenopausal women with VVA, which can improve sexual life and urinary symptoms[58-59]. However, a large number of studies are still needed to verify this result in the future.
4.3 Micro-fat and nano-fat transplantation
In recent years, a micro-fat and nano-fat transplantation technique has been proposed to regenerate the vulvovaginal area and restore the appearance and function of the labia majoris, in order to increase the vaginal health index (VHI) and improve vaginal atrophy and sex-related problems. Clinical results have shown that after transplantation, the scores of VHI andFemale Sexual Distress Scale-Revisedwere significantly higher than those at baseline, and patients still benefited during the 18-month follow-up after treatment, and no adverse events occurred[60]. At present, this method shows a good prospect in the treatment of GSM, but more studies are needed to verify its safety and effectiveness.
5. Conclusion
GSM is a chronic progressive disease that requires lifelong management. General practitioners should pay attention to the physiological changes of women at this stage, actively inquire about
relevant symptoms in the process of consultation, GSM screening, and popularization of related knowledge for peri-menopausal and postmenopausal women, so as to increase their awareness of this aspect and improve their self-management ability. In addition, in terms of treatment, each of the above methods has its own advantages and disadvantages, and it is necessary to comprehensively consider the overall health status and personal wishes of the patients before making a choice.
Nowadays, combining the vast majority of the current guidelines and the treatment methods retrieved in this article, it is suggested that in daily diagnosis and treatment, general practitioners can tell women who do not have obvious symptoms of GSM before menopause what changes will happen to their pelvic floor muscles in the next stage and point out what controllable risks they have in their lives, and then they can first choose conservative treatments to carry out early intervention on the risk factors. Encourage women to maintain a healthy lifestyle and PFMT, which may reduce the incidence or severity of GSM. For women who have mild GSM symptoms, it is recommended to use non-hormonal vaginal lubricants and moisturizers to alleviate the symptoms. When women use over-the-counter drugs that are ineffective or have moderate to severe GSM symptoms, a very small dose of vaginal estrogen can be preferred.When women combined with other complications, such as vasomotor symptoms, then choose systemic MHT, and for women withuteri, EPT or CEE/BZA is more recommended. In addition, for women with hormone contraindications, we can also try to use ospemifene and vaginal DHEA, which will not cause changes in serum hormone levels, and have no significant stimulating effect on breast or endometrium.
For some emerging treatments, such as energy-based transvaginal therapies, micro-fat, and nano-fat transplantation, compared with the traditional hormone therapies, they have a longer curative effect and are more widely applicable to the population, and have good prospects. However, for PEs, vaginal oxytocin gel, vitamin E vaginal suppository, Monurelle Biological vaginal gel, and other treatment regimens, there are still many blind spots, which are not recommended for routine clinical treatment.
Author contribution:LIU Shuangxue is responsible for the conception and design of the article, the collection and arrangement of documents/materials, the writing, revision, and English translation of the paper. LIU Shuangxue and LIYanhua are responsible for the quality control and revision of the article.LIYanhua is responsible for the article as a whole, supervising and managing it.
Conflicts of Interest: The authors declare no conflict of interest.
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Key words: Menopause, Female urogenital diseases, Genitourinary syndrome of menopause, Drug therapy, Physical therapy modalities, Early intervention（education）