Expert Opinion on Pharmacotherapy ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: https://www.tandfonline.com/loi/ieop20 Pharmacotherapy for the treatment of vaginal atrophy Gilbert G. G. Donders, Kateryna Ruban, Gert Bellen & Svitrigaile Grinceviciene To cite this article: Gilbert G. G. Donders, Kateryna Ruban, Gert Bellen & Svitrigaile Grinceviciene (2019): Pharmacotherapy for the treatment of vaginal atrophy, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2019.1574752 To link to this article: https://doi.org/10.1080/14656566.2019.1574752 Published online: 21 Mar 2019. Submit your article to this journal View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ieop20 EXPERT OPINION ON PHARMACOTHERAPY https://doi.org/10.1080/14656566.2019.1574752 REVIEW Pharmacotherapy for the treatment of vaginal atrophy Gilbert G. G. Donders a,b, Kateryna Rubana, Gert Bellena,c and Svitrigaile Grinceviciened aDepartment of Clinical Research for Women, Femicare vzw, Tienen, Belgium; bDepartment of OB/Gyn, Antwerp University, Edegem, Belgium; cSpine Society of Belgium, Leuven University, Belgium; dDepartment of Biothermodynamics and Drug Design, Vilnius University Institute of Biotechnology, Vilnius, Lithuania ABSTRACT ARTICLE HISTORY Introduction: Despite its frequency, recognition and therapy of vulvovaginal atrophy (VVA) remain Received 18 September 2018 suboptimal. Wet mount microscopy, or vaginal pH as a proxy, allows VVA diagnosis in menopause, but Accepted 22 January 2019 also in young contraception users, after breast cancer, or postpartum. Intravaginal low dose estrogen KEYWORDS product is the main therapy. Ultra-low-dose vaginal estriol is safe and sufficient in most cases, even in Genito-urinary syndrome of breast cancer patients, while hyaluronic acid can help women who cannot or do not want to use menopause; steroid hormones. hormones; estrogen; Areas covered: The authors provide an overview of the current pharmaceutical treatment for vulvo- therapy; lactobacillary vaginal atrophy and provide their expert opinions on its future treatment. grades; vaginal cell maturity Expert opinion: The basis of good treatment is a correct and complete diagnosis, using a microscope to study the maturity index of the vaginal fluid. Minimal dose of estriol intravaginally with or without lactobacilli is elegant, cheap and can safely be used after breast cancer and history of thromboembolic disease. Laser therapy requires validation and safety data, as is can potentially cause vaginal fibrosis and stenosis, and safer and cheaper alternatives are available. 1. Introduction layers have receptors for ovarian sex steroid hormones. Shortage of sex hormones in the postmenopausal period Vulvovaginal atrophy (VVA) is a chronic condition that com- affects all layers of the vagina and leads to dramatic anatomi- monly occurs mostly in postmenopausal women, but some- cal and physiological changes, such as shortening and narrow- times in reproductive age patients under the influence of ing of the vagina, loss of rugae, and flattening and natural or induced decrease or activity of female sex hor- keratinization of the surface [9]. mones. External factors like smoking or alcohol abuse can also trigger this condition [1,2]. Taking into consideration that hypoestrogenic condition, 2.1. Changes in the epithelium combined with a decrease of other sex hormones, results in 2.1.1. Estrogen receptor stimulation a broad array of both urinary tract and vulvovaginal symptoms The epithelium is a superficial non-keratinized layer of vagina. [3,4], it was suggested by International Society for the Study of Stimulated estrogen receptors (ER) increase epithelial prolif- Women’s Sexual Health and The North American Society to eration and stratification. Supra(Para)basal cells undergo dif- change ‘vulvovaginal atrophy’ into ‘genitourinary syndrome of ferentiation, move up through to the superficial layers of the menopause’ (GSM) [5–8]. epithelium, while undergoing cornification [10]. Nuclear αER Although we agree that the term ‘atrophic vaginitis’ is not stimulation occurs in both the epithelial and stromal layers, as always accurate in describing all aspects of the clinical condi- stimulation of only epithelial or stroma is insufficient to tion (e.g. due to the fact that there is not always observe expression of cytokeratin. Alfa-ER stimulation differ- a concomitant inflammation present) we also have to admit entiates the vaginal epithelium through Wisp2 (WNT1 induci- the newly proposed syndrome might make the diagnosis ble signaling pathway protein 2), inducing stratification of vague and increase the risk to underdiagnose important spe- vaginal stoma cells [11]. Due to the decrease of estrogen, cific vulvar and vaginal diseases such as lichen sclerosus, epithelial cells became smaller, with less cytoplasmic content. lichen ruber, vulvar dysplasia, aerobic vaginitis, etc. Hence, The vaginal epithelium loses intermediate epithelial cells, lead- for the purpose of clarity in this chapter, we will use the ing to a severely reduced intermediate cell layer [12]. term ‘vulvovaginal atrophy (VVA)’ in the following paragraphs. 2.1.2. Progesterone 2. Pathogenesis Except if administered together with estrogen, progesterone did not restore the morphological changes of the vagina in The vagina is composed of four layers – the epithelium, the oophorectomized mice, although the epithelial proliferation lamina propria, the muscular layer, and the adventitia. All CONTACT Gilbert G. G. Donders [email protected] Femicare vzw, Gasthuismolenstraat 31, Tienen B- 3300, Belgium © 2019 Informa UK Limited, trading as Taylor & Francis Group 2 G. G. DONDERS ET AL. the only source of estrogens and androgens, converted in Article highlights peripheral tissues. There is also no feedback control mechan- ● Despite its frequency, vulvovaginal atrophy (VVA, part of Genito- ism which allows to increase the level of DHEA when its serum Urinary Syndrome of Menopause) is underdiagnosed and under- level decreases [19], making supply of exogenous DHEA the treated, but a proper and complete diagnosis is essential for design- only way to correct for this deficiency. ing a good therapy and follow-up. ● Although vaginal pH measurement can be used as a proxy, wet mount microscopy of vaginal fluid is superior to diagnose VVA by calculating the vaginal epithelial cell maturity index, but also to 2.1.5. Vitamin D and E influence on vaginal epithelium exclude infections and inflammation. Vitamin D [1,25-dihydroxyvitamin D3 1,25(OH) 2D3] is ● Local estrogens are the cornerstone of treatment, while systemic a promoter of keratinocyte differentiation and proliferation in estrogens are reserved for patients with more menopausal symp- toms. Although any type of locally applied estrogen is efficient, the epidermis [20]. It stimulates the proliferation of the vaginal synthetic as well as biological, the safest and lowest dose should epithelium by activating the vitamin D receptor (VDR)/p-RhoA/ be used. p-Ezrin pathway, upregulating cell-to-cell junction. This opens ● Novel hormonal therapies, such as dehydroepiandrosterone sulfate, ospemifene, estretol, are efficient, but their risks on complications an interesting nonhormonal alternative for the treatment of like breast cancer and thromboembolism require further studies. VVA, but clinical studies are necessary to support this theory. ● Women with contraindications for hormonal use such as breast Being a fat-soluble vitamin with strong antioxidant proper- cancer or previous thromboembolism should be tried on nonhormo- nal therapies, such as hyaluronic acid but if insufficient, use of ultra- ties, vitamin E is involved in the metabolism of all cells and low-dose of locally applied estriol with our without lactobacilli can be prevents the tissue damage caused by oxidants. It keeps the a safe alternative. arteries flexible and facilitates blood circulation, which conse- ● Mechanical therapies like applying radiofrequency or laser waves to the vagina lack proper randomized studies comparing their efficacy quently increases the metabolism of vaginal connective tis- to standard estrogen therapy, and to prove their safety to prevent sues and enhances the moisture and flexibility of vaginal later scarring and stenosis of the vagina. walls [21] This box summarizes key points contained in the article. 2.1.6. Oxytocin Oxytocin stimulates oxytocin receptors co-located with caveo- lin enriched micro-domains (a subset of lipid rafts containing was less pronounced than after estrogen-only stimulation [12]. the scaffolding protein caveolin-1) [22]. This stimulation is So progesterone may be less important for epithelial restora- important for epithelial proliferation [23]. The effect is dose tion, but helps to maintain epithelial integrity after restora- and time dependent, and increases the number of layers in tion [12]. the epithelium [24]. As not all cells have oxytocine receptors, the effect is moderate [23]. 2.1.3. Androgens Androgen receptors, located at the proximal ends of the nerves, are present in both the epithelial layer, lamina propria 2.2. The lamina propria changes and muscular layer [13]. Data about the androgenic effect on the epithelial layer are conflicting. Collagen and elastan are two important players in the Systemic estrogen replacement, followed by higher levels dynamic structural changes of the lamina propria: the first of circulating sex hormone