Vaginal estrogen deficiency

Transcription

1 DOI: /tog The Obstetrician & Gynaecologist ;21:37 42 Reviews Shirin Khanjani MD PhD MRCOG, a, * Nick Panay BSc FRCOG MFSRH b,c,d a Clinical Lecturer and Subspecialist Trainee in Reproductive Medicine, Institute of Reproductive and Developmental Biology, Hammersmith Hospital, London W12 0NN, UK b Consultant Gynaecologist, Specialist in Reproductive Medicine, Imperial College NHS Healthcare Trust, London W12 0HS, UK c Consultant Gynaecologist, Specialist in Reproductive Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London SW10 9NH, UK d Honorary Senior Lecturer, Imperial College London, London SW10 9NH, UK *Correspondence: Shirin Khanjani. s.khanjani@imperial.ac.uk Accepted on 2 July Key content occurs with declining serum estradiol levels in menopause and premature ovarian insufficiency. The symptoms most commonly involve vulval and vaginal dryness, pruritis, dyspareunia and discharge. Treatment is simple and easily accessible and can be hormonal and nonhormonal. Nonhormonal treatments are particularly helpful for women who cannot take estrogen. They include simple treatments such as local lubricants and moisturisers, and newer modalities of treatment, including laser. Vaginal estrogen is the most commonly used form of hormonal treatment. However, selective estrogen receptor modulators, tissue-selective estrogen complexes, androgens and dehydroepiandrosterone have recently been introduced and are effective and safe. Learning objectives To understand the pathogenesis, symptoms and diagnosis of vulvovaginal atrophy. To appreciate attitudes and stances towards vulvovaginal atrophy. To understand management options for vaginal estrogen deficiency. Ethical issues The impact of vulvovaginal atrophy on the quality of life of many women is profound but underestimated. Vulvovaginal atrophy is underdiagnosed and undertreated. Considering that more women are spending a significant proportion of their lives in the postmenopausal period, understanding the diagnosis and treatment of vulvovaginal atrophy must develop in synchrony with this growing unmet need. Keywords: hormone replacement therapy / menopause / vaginal atrophy Please cite this paper as: Khanjani S, Panay N.. The Obstetrician & Gynaecologist. 2019;21: Introduction Pathophysiology The female genital tract (vulva, vestibule, cervix and uterus) and the bladder and urethra are rich in estrogen receptors. 1 Vaginal estrogen deficiency occurs with declining serum estradiol levels, i.e. in menopause and premature ovarian insufficiency. The decline in estrogen levels results in reduced blood flow to the epithelium of the vulva, vestibule, vagina and cervix. Moreover, the superficial to parabasal cell proportion decreases with the loss of glycogen and lactobacilli, causing the skin in the area to become thin and vulnerable. Vaginal ph can increase to 6 8 (from 4 5 in the premenopausal status), making the vagina more susceptible to infection. Vaginal dryness follows as a result of decreased secretions. 2 4 Menopause can influence and alter expression of genes involved in extracellular matrix metabolism in the vagina. 5 Additionally, changes occurring in the bacterial population of the vagina in postmenopausal women may have a profound effect on vulvovaginal atrophy (VVA), vaginal dryness and sexual health. 6,7 Together, these changes result in a pale appearance, which may contain small petechiae and/or other signs of inflammation. 8 Symptoms Symptoms of vaginal estrogen deficiency most commonly include vaginal dryness (75%), dyspareunia (40%), vulval and vaginal pruritis and discharge. The urinary tract is also commonly affected, leading to urinary frequency and urgency, nocturia, dysuria and incontinence. Recurrent urinary tract infections occur in up to 20% of postmenopausal women because of atrophy of the urothelium in response to estrogen deficiency can have a profound effect on quality of life. The impact of VVA on the quality of life of many women continues to be underestimated. In a recent European survey, 54% of respondents said they discussed their sexual health concerns only when the healthcare professional asked, and 33% said they were too shy to discuss them. 11,12 Treatment is usually safe and effective, and, therefore, suffering in silence is not justified. Diagnosis Assessment tools have been developed to facilitate the formal diagnosis and classification of the severity of VVA. The ª 2019 Royal College of Obstetricians and Gynaecologists 37

2 Vaginal Health Index is commonly used: clinicians rate both the appearance of the vaginal mucosa and production of secretions on a scale of In 2014, the North American Menopause Society/International Society for the Study of Women s Sexual Health Consensus Panel introduced the Genitourinary Syndrome of Menopause (GSM), an overarching terminology that describes various menopausal symptoms and signs including genital, sexual and urinary symptoms. 14 The GSM assessment tool considers three categories of elasticity, lubrication and tissue integrity; an anatomical section that includes vulval, vaginal and urethal anatomy; and two objective measures, vaginal ph and vaginal maturation. These seven components each receive a score from 0 3 based on severity of the condition. A total score is then calculated by adding each of the scores together to give a total out of 21. A score of 0 7 is considered to be mild atrophy, 7 14 moderate atrophy and >14 severe atrophy. The score system refers to the degree of atrophy rather than the syndrome itself. This tool has not yet been validated and is therefore not in routine use. 11 Publication of outcomes from clinical trials will provide further insight into improving existing and developing diagnostic tools. Attitudes and stances In 2015, the English Longitudinal Study of Ageing reported that 53.7% of women between the ages of 50 and 90 years are sexually active. 15 In 2016, the results of the REVIVE (REal Women s VIews of Treatment Options for Menopausal Vaginal ChangEs) survey were reported. This study was conducted in four European countries (Italy, Germany, Spain and the UK) and considered the perceptions, experiences and needs of postmenopausal women with regard to sexual and vaginal health. 12 The opportunity for treatment varied among different countries. The UK participants were significantly older, with almost one-quarter being over 65 years of age, and had the highest proportion of women experiencing recent vulval and vaginal atrophy (52.8%). Most Italian and Spanish participants were receiving VVA treatment, compared with just 28% of postmenopausal UK women. The most common menopausal symptom was vaginal/vulval dryness, with almost 80% of participants reporting this in all countries except the UK (48%). The percentage of participants with a partner was lower in the UK (71%), as was the monthly rate of sexual activity (49%). In the UK, the proportion of participants who had seen a healthcare professional for gynaecological reasons in the last year was lower than in other countries (27% versus 50%), as was the proportion who had discussed their VVA symptoms with a healthcare professional (45% versus 67%). UK postmenopausal women therefore waited longer before seeking help. In 2017, the Women s EMPOWER survey concluded that despite efforts VVA continues to be underrecognised and undertreated. Furthermore, it showed that minimal progress has been made with regard to increasing women s awareness, knowledge or understanding of VVA. 16,17 Treatment Vaginal lubricants and moisturisers Vaginal lubricants and moisturisers are used to reduce vaginal dryness and pain during intercourse in women with mild to moderate VVA. Lubricants and moisturisers work in different ways and are particularly helpful for women who are not medically suitable to take estrogen. 18 Lubricants do not have long-lasting effects and mainly provide short-term relief during intercourse. A variety of vaginal lubricants are commercially available and can be water-based, plant oilbased, mineral oil-based or silicone-based products. Vaginal moisturisers imitate natural secretions by rehydrating the mucosal layer and adhering to the vaginal lining. The effect of moisturisers is longer lasting compared with lubricants, if used regularly. Therefore, moisturisers are not only used by women with VVA who have painful intercourse, but also by symptomatic women who are not sexually active. Most vaginal moisturisers contain water, polymers and a variety of other excipients to provide viscosity, ph buffering and preservation. It is generally perceived that oil-based and silicone-based lubricants are thicker in composition and longer lasting compared with water-based lubricants. It is important that lubricants and moisturisers match vaginal ph and osmolality as closely as possible to maximise effectiveness and avoid side effects such as irritation and infections. 19 It should be noted that oil-based preparations can break down latex condoms, and therefore these products could interfere with protection against sexually transmitted infections and unplanned pregnancies. Phytoestrogens There are limited data showing that phytoestrogens can be beneficial in alleviating symptoms of VVA. Intravaginal application, as opposed to oral usage, has shown some positive effects on the vaginal epithelium. 20 In a randomised placebo-controlled study, the efficacy of an isoflavone vaginal gel for the treatment of VVA was compared with conjugated equine estrogen and placebo. 21 Women treated with isoflavone gel and women treated with estrogen showed similar improvements in vaginal dryness and dyspareunia. This was significantly different to the placebo group and, reassuringly, no changes in estradiol levels or endometrial thickness were seen in any of the patient groups. However, products containing phytoestrogens should be used with caution in women who have contraindications to estrogen. 20 Vaginal laser treatment Vaginal erbium and CO 2 lasers have been used to treat VVA. The procedure is performed using a vaginal speculum and a 38 ª 2019 Royal College of Obstetricians and Gynaecologists

3 Khanjani et al. hand piece laser beam delivery system. It is hypothesised that the vaginal laser stimulates cellular proliferation and viability of the vaginal epithelium. A small study suggested a significant improvement in symptoms, including vaginal dryness and dyspareunia. 22 This was followed by a recent pilot study, which showed that erbium laser is an effective treatment for VVA in breast cancer survivors. 23 Several prospective observational trials with both CO 2 and erbium lasers have yielded encouraging findings; however, the results of randomised controlled trials with a sham laser control are still awaited. 24,25 Local and systemic hormone replacement therapy Treatment is indicated in menopausal women and women with premature ovarian insufficiency who are symptomatic of VVA. Systemic hormone replacement therapy (HRT) can alleviate vaginal symptoms. The rise in serum estradiol levels stimulates revascularisation and regeneration of the collagen of vaginal and lower urinary tract epithelium. However, the British Menopause Society recommends that when the symptoms are predominantly vaginal or urogenital, topical treatment should be used. Systemic HRT is best used in the presence of vasomotor symptoms or osteoporosis. Addition of vaginal estrogen to systematic HRT may be required, particularly if lower doses of HRT have been used. Several vaginal estrogen preparations are available, including estradiol and estriol creams, tablets and rings. Controlling the dosage is easiest with tablet or ring preparations. Currently, it is advised that the lowest possible dose that provides effective relief of symptoms should be used as maintenance therapy. Numerous clinical trials have shown that monitoring endometrial thickness and/or progesterone treatment in asymptomatic, low-risk women receiving lowdose vaginal estrogen is not indicated. 26,27 A recent Cochrane review of 30 randomised controlled trials, representing 6235 postmenopausal women, compared intravaginal estrogenic preparations to one another or with placebo. The review concluded that there was no difference in efficacy between the various intravaginal estrogenic preparations when compared to each other. 28 The estradiol ring was found to be most acceptable to the participants after comparing comfort of products, ease of use and overall product satisfaction. 29 Vaginal estrogen therapy improves sexual function in postmenopausal women with VVA. The REJOICE trial concluded that vaginal estradiol soft gel capsules were safe and effective for the treatment of moderate to severe dyspareunia in women suffering from vaginal atrophy. 30 Clinical trials do not support a role for systemic estrogen therapy for the treatment of female sexual dysfunction. Vaginal atrophy is common in women who receive treatment for breast and most gynaecological cancers. Detailed counselling of the patient, as well as liaison with the oncology team, is essential before considering estrogen therapy in women with a history of breast or gynaecological cancers. Nonhormonal options are usually the first line of treatment in this population. Data regarding the safety of vaginal estrogen therapy in breast cancer survivors are limited. A case control study of 271 women with breast cancer on tamoxifen or aromatase inhibitors concluded that there is no increased risk of recurrence in women on vaginal estrogen therapy, with a mean follow-up of 3.5 years. 31 In a retrospective cohort study, 60 women with early-stage breast cancer were treated with an estradiol tablet or estriol cream for a median of 1 year. There was no increase in the risk of recurrence at a median of 5.5-years follow-up. 32 A more recent study showed that in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors, treatment with a vaginal ring or vaginal testosterone over 12 weeks met the primary safety points. 33 In 2014, a metaanalysis concluded that there is no increased risk of recurrence in women who are taking HRT following treatment of endometrial cancer. 34 Following ovarian cancer, although some concerns have been expressed about systemic treatment, there are no data to suggest an increased risk of recurrence with either systemic or local estrogen therapy. 35 Treatment with selective estrogen receptor modulators and tissue-selective estrogen complexes Selective estrogen receptor modulators (SERMs) act as estrogen agonists/antagonists. Although raloxifene and tamoxifen are well-known SERMs, they are not effective in the treatment of VVA. Ospemifene and lasofoxifene, which were originally used to treat postmenopausal osteoporosis, have positive effects on vaginal epithelium and can therefore reduce the symptoms of VVA The Postmenopausal Evaluation and Risk Reduction with Lasofoxifene (PEARL) study concluded that lasofoxifene significantly reduced symptoms of moderate to severe VVA over the course of 12 weeks. Additional studies have supported these findings and have also shown reduced dyspareunia in postmenopausal women treated with lasofoxifene. 39,40 Tissue-selective estrogen complexes (TSECs) combine conjugated estrogens with an SERM. This combination treats VVA, alleviates hot flushes and prevents bone loss, while also protecting the breast and endometrium. 41,42 The first TSEC to be studied was conjugated estrogens with bazedoxifene (CE/BZA). The Selective Estrogens Menopause and Response to Therapy 1 (SMART-1) study found that CE/BZA improved vaginal atrophy with reduced incidence of dyspareunia at 2 years compared with placebo. CE/BZA treatment was associated with less than a 1% rate of endometrial hyperplasia over 2 years. 43 Androgens and dehydroepiandrosterone Androgens play an essential role in female sexual function. 44 Studies have shown that androgen receptors (ARs) are ª 2019 Royal College of Obstetricians and Gynaecologists 39

4 Table 1. A summary of different treatment options for vaginal estrogen deficiency Intervention Route Advantages Cautions Moisturisers and lubricants Vaginal - Can alleviate symptoms of mild to moderate VVA - Can alleviate dyspareunia caused by VVA - Can be used in women who have contraindications to estrogen - Lubricants only provide short-term relief during intercourse - Not effective in cases of severe VVA - Need to be ph and osmolality balanced otherwise irritation/discharge can occur Vaginal estrogen Vaginal - Improves symptoms without the need for progesterone opposing treatment - Reverses physiological changes of menopause - Minimal systemic absorption - Should be used with caution in women who have contraindications to estrogen - Benefits only last for as long as treatment is continued Systemic HRT Transdermal/ oral - Can alleviate symptoms of VVA as well as vasomotor symptoms and osteoporosis - Is best used in the presence of vasomotor symptoms or osteoporosis - Not recommended in women who have contraindications to estrogen Phytoestrogens Vaginal and oral - Some vaginal (not oral) preparations have shown similar effects as vaginal estrogen - Should be used with caution in women who have contraindications to estrogen Laser treatment Vaginal - Preliminary prospective observational data are showing benefit - Can be used in women who have contraindications to estrogen Selective ER modulator Oral - Ospemifene and lasofoxifene are the most effective - Are effective in treatment of VVA as well as osteoporosis (ospemifene license is for dyspareunia) - Can be used in women who have contraindications to estrogen - More long-term/sham laser randomised data needed to prove efficacy - More studies are needed to assess safety for the endometrium with lasofoxifene Tissue-selective estrogen complex treatment Oral - Can alleviate symptoms of vulvovaginal atrophy, hot flushes and bone loss - Has potential protective effects for breast and endometrium - Relatively new treatment, longer term data regarding safety would be desirable - No product range only one dose, which may not be sufficiently estrogenic for some women Androgens and DHEA Oral and vaginal - Vaginal administration appears safe and effective in treatment of VVA (licence is for dyspareunia) - Can improve libido - Minimal systemic absorption - Relatively new treatment, more safety data regarding systemic effect would be desirable Key: VVA = vulvovaginal atrophy; HRT = hormone replacement therapy; ER = estrogen receptor; DHEA=dehydroepiandrosterone expressed in the vagina. The expression levels of ARs decrease with age, suggesting a role for androgens in treating VVA. 45 A pilot study of women with breast cancer, who were on aromatase inhibitors and suffering from vaginal atrophy, showed promising results. The authors concluded that a 4-week course of vaginal testosterone improved signs and symptoms of vaginal atrophy without an increase in systemic estradiol levels. 46 Since then, multiple studies have compared the use of vaginal testosterone to other treatments and found it to be safe and effective. 47 Dehydroepiandrosterone (DHEA) is a precursor steroid in the biosynthesis of sex steroids. Like estrogen and ARs, levels of DHEA decrease with age. 48 Recent trials have suggested that oral and vaginal preparations of DHEA can improve symptoms of VVA. 49 A recent study compared the effect of intravaginal DHEA (prasterone), conjugated equine estrogens and estradiol on moderate to severe dyspareunia and/or vaginal dryness. The authors concluded that 6.5 mg prasterone used daily appears to be as efficacious as 0.3 mg conjugated equine estrogens or 10 lg estradiol for the treatment of VVA. 50 Reassuringly, intravaginal DHEA does not seem to increase the levels of sex steroids beyond those normally found in menopause. 51 Prasterone is now licensed in the USA for the treatment of moderate to severe dyspareunia. Table 1 summarises the various treatment options for vaginal estrogen deficiency. Conclusion occurs with declining serum estradiol levels and can have extreme effects on womens quality of life and sexual health. It can result in VVA, pelvic floor disorders and sexual dysfunction. Many treatment modalities are now available; treatment should be tailored to 40 ª 2019 Royal College of Obstetricians and Gynaecologists

5 Khanjani et al. individual women. Recent efforts notwithstanding, VVA continues to be suboptimally managed. With women living longer and spending nearly half of their lives in a postmenopausal state, education and management of VVA must be improved. Disclosure of interests SK has no conflicts of interest. NP has lectured and acted in an advisory capacity for a number of pharmaceutical companies. Contribution to authorship NP instigated and edited the article. SK researched and wrote the article. Both authors read and approved the final version of the manuscript. References 1 Press MF, Nousek-Goebl NA, Bur M, Greene GL. Estrogen receptor localization in the female genital tract. Am J Pathol 1986;123: Semmens JP, Wagner G. Estrogen deprivation and vaginal function in postmenopausal women. JAMA 1982;248: Brown KH, Hammond CB. Urogenital atrophy. Obstet Gynecol Clin North Am 1987;14: Garcia-Closas M, Herrero R, Bratti C, Hildesheim A, Sherman ME, Morera LA, Schiffman M. 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