Atrophic vaginitis: symptoms, diagnosis and treatment

Throughout the last few decades, improvement of living conditions and advances in medicine have led to prolonged life expectancy. A small or even nega- tive population growth rate observed in the majority of developed countries means that the share of elderly people in the ageing general population significantly increases with a high prevalence of postmenopausal women. They are often fully physically and mentally fit and wish to lead an active lifestyle. Inevitable physiological processes of ageing unfortu- nately cause burdensome changes responsible for wors- ening of the quality of life. Many of them are linked to the loss of ovarian hormonal activity. Main complaints in postmenopausal women are vasomotor symptoms and urogenital atrophy resulting from a decline in the estro- gen level. Whereas vasomotor symptoms tend to resolve with age, urogenital atrophy typically develops later in life and is often progressive. The lack of estradiol pro- proliferative effect on the epithelium of the vagina, ure- thra as well as the lower part of the cervix is noticeable in every third female in perimenopause and over 50% of postmenopausal women [1]. Influence of estrogens on vaginal milieu In the premenopausal state, vaginal epithelium is influenced by high estradiol levels, stimulating cell mat- uration up to the superficial layer. Superficial epithelial cells continuously exfoliate and die, releasing glycogen, that breaks down to glucose. Glucose is metabolised by species of Lactobacillus to lactic acid and H 2O2, which allows for maintaining of normal vaginal microflora. The coexistence of estrogenic activity and Lactobacilli leads to acidic vaginal pH 3.5-4.5, which mechanism in a healthy female of reproductive age prevents urogeni- tal infections [2-4]. Postmenopausal decline in the estrogen level leads to impairment of blood flow in the lower genitourinary tract, decrease in vaginal discharge as well as deteriora- tion of connective tissue metabolism which negatively influences vaginal elasticity. The vaginal exam reveals smooth, pale, thinned mucosa prone to injuries and bleeding with minimal trauma. Lack of maturation of epithelial cells and thinning of the superficial layer rich in glycogen disturbs the normal vaginal microflora. The loss of Lactobacilli suppresses production of lac- tic acid which results in the increase in vaginal pH and development of abnormal microflora. In consequence, increased susceptibility to infections with bacteria mi- grating from the vulvar and perianal region is observed. Clinical symptoms constellation connected with post- menopausal decreased estrogenization of vulvovaginal mucosa may be described as atrophic vaginitis, vaginal atrophy or urogenital atrophy. Diagnosis of atrophic vaginitis The most common complaints and symptoms in pa- tients with atrophic vaginitis according to Lynch et al. are [3]: • vaginal dryness (in 3-5% of females of reproductive age and in 30-50% of postmenopausal women), • vulvovaginal irritation: pruritus, burning; redness and petechiae in the case of accompanying inflammation, • dyspareunia: pain and burning on sexual intercourse, • yellow or purulent discharge, • malodor, which is a bacterial vaginosis (BV) symp- tom. The development of BV is caused by the decre- ase in Lactobacilli and colonisation of the lower ge- nitourinary tract by anaerobes: Gardnerella vaginalis, Prevotella spp., Mobiluncus spp., Atopobium vaginae. The above-mentioned symptoms may be accompa- nied by lower urinary tract complaints. Atrophic changes of structures derived from embryonic urogenital sinus

in dysuric symptoms, bladder overactivity, stress incontinence and recurrent urinary tract infections. Clinical findings include sparse pubic hair, atrophy of labia majora and minora, narrowing of vaginal in- troitus and decrease in length and width of the vagina. Other symptoms include decreased or abnormal vaginal discharge, thinning and paleness of vaginal epithelium, smoothing and reduced elasticity of the vulvovaginal mucosa, rectocele, uterine prolapse, reddened inflamed vulvar skin with fissures. Laboratory tests reveal a low serum estradiol level (< 30 pg/l) and cytological smear shows a lower percent- age of superficial cells with the dominance of parabasal cells. Objective tests evaluating the effect of estrogen on vaginal tissue are: vaginal pH measurement and cell maturation index assessed in smear taken from the lat- eral vaginal wall. Vaginal pH > 4.6 with no signs of BV indicates vaginal atrophy. Vaginal maturation index evaluates the percentage of superficial, intermediate and parabasal epithelial cell types. In premenopausal women, there is over 15% of superficial cells, whereas in postmenopause the percentage is less than 5%. In clinical practice, the vaginal maturation index is rarely performed, mainly because of lack of necessary labora- tory devices and experienced staff [2]. Microbiological evaluation of vaginal discharge often reveals presence of bacterial infection [5, 6]. Atrophic vaginitis is more commonly encountered in obese and diabetic females. It should be noted that loss of endogenous estrogen production may result from immunologic disorders, radio- and chemotherapy as well as surgical castration. Besides, low estrogen levels are encountered typically in the postpartum and breast- feeding period as well as in the case of pharmacological therapy of endometriosis and uterine fibroids [7]. Atrophic vaginitis is a chronic condition and symp- toms worsen with time since menopause. It leads to de- Przegl¥d menoP auzalny 5/2013 436 terioration of quality of life resulting from physical dis- comfort, sexual disorders and severe emotional distress. Treatment options Non-hormonal preparations In females who choose the non-hormonal treatment option or have contraindications to estrogen use, vagi- nal moisturizers and lubricants are helpful in sympto- matic atrophic vaginitis. They relieve vaginal symptoms such as itching and irritation by means of restoring vag- inal pH and moisture. They allow for regular sexual ac- tivity which maintains proper elasticity and pliability of the vagina. There are also reports on vaginal moisture improvement with use of vitamin E or D preparations. Systemic hormone therapy Exogenous estrogen used in systemic HT restores vaginal epithelium and vascularization, improves its moistness and sinks pH level. According to published reports, it relieves vaginal symptoms in 75% of wom- en with atrophic vaginitis. It was noted that hormonal therapy with an addition of topical estrogen improves vaginal symptoms more efficiently than HT itself [1]. Systemic hormone therapy is not recommended in fe- males with isolated vaginal symptoms. Local estrogen therapy [8] In the absence of systemic menopausal complaints, local estrogen therapy is a preferable and efficacious

of chronic atrophic vaginitis treatment. Vaginal symptoms quickly resolve on local estrogen therapy. The superficial epithelium layer thickens, vagi- nal blood flow improves and so does vaginal pH. Similar processes are observed in the lower urinary tract. Inter- national societies published EBM guidelines suggesting that in females with urogenital atrophy without con- traindications to estrogen use, the local therapy with low dose estrogen is a treatment of choice. Tissues of the lower genitourinary tract are highly responsive to the pro-proliferative effect of low dose estrogen prep- arations because of greater, in comparison to uterus, sensitivity of estrogen receptors. Typically, no systemic effects of local estrogen therapy are observed. Preparations used in local estrogen therapy are available in several forms (tablets, pessaries, cream, vaginal rings) containing conjugated estrogens, estra- diol, estriol or estrone. Local estrogen therapy effect is observed after 4-6 weeks in 80-90% of patients. The treatment is well tolerated even in the case of pro- longed use, although there are sparse data on safety of long-term therapy [9]. Available preparations in topical estrogen therapy: • vaginal rings: placed vaginally every 3 months, deliv- ering 17β-estradiol or estradiol acetate. Not available in Poland, • vaginal estrogen tablets: containing 25 µg of 17β-estradiol or 0.5 mg of estriol. According to published data, they not only relieve vag- inal atrophy but also improve vasomotor symptoms. • Conjugated estrogens (CEE) vaginal creams contain 0.3-0.625 mg of conjugated estrogens: estrone and 17β-estradiol in a single dose. Highest systemic ab- sorption of those preparations, with a higher estra- diol and lower FSH serum level, was observed. There were cases of endometrial proliferation and uterine bleeding on CEE therapy, so it is less acceptable in vaginal atrophy treatment. • Preparations of estriol with Lactobacillus cultures. According to the majority of international societies, estriol is the most preferable and effective estrogen in vaginal symptoms treatment. It is produced in the liver as 17β-estradiol metabolite and has relatively low sys- temic estrogenic activity. However, it exerts a specific cytotropic effect on tissues developing from embryonic genitourinary sinus. As estriol derives from estradiol and estrone metabolism, therapy with this hormone does not affect serum estradiol and estrone levels. Ex- cretion of estriol occurs via urine in inactive forms of glucuronates and sulphates. Especially favorable out- comes of atrophic vaginitis treatment are observed with the use of estriol combined with Lactobacilli cultures. Lactobacilli, prevailing in healthy vaginal microflora, have a significant impact on vaginal ecosystem through lactic acid and H 2O2 production. Estriol with Lactoba- cilli combination optimizes immunologic mechanisms responsible for detection and fighting infections of the urogenital tract. Mucosal secretion of secretoglobin 1D and 2A increases thanks to higher activity of respec- tive genes transcription. Similarly, the rise of lactofer - rin gene activity is observed. Lactoferrin is a protein playing an important role in regulation of immunologic response of mucosae to bacterial infection. Another fa- vorable mechanism is activation of interleukin-1 gene. Interleukin-1 regulates immunologic response in vaginal mucosa (leukocyte migration, gene expression, inflam- mation) that inhibits pathogenic bacteria proliferation. Lactobacilli in vaginal milieu, in the presence of estriol, reinitiate their metabolism and lower vaginal pH within few hours. It leads to quick re-establishment of normal vaginal milieu and recline of abnormal microflora symp- toms (most frequently bacterial vaginosis). Estriol administered in the ultra-low dose prevents a typical side effect of estrogen therapy such as en- dometrial proliferation. Numerous studies proved that the ultra-low dose of estriol (0.03 mg) combined with Lactobacilli administered vaginally relieved vaginal at- rophy symptoms and re-established normal vaginal Przegl¥d menoP auzalny 5/2013 437 microflora with the same efficacy as 0.05 mg of estra- diol. At the same time, there are no reports of endo- metrial proliferation or increased risk of endometrial hyperplasia. The expected effect is achieved in 80-90% of females after 3 weeks’ therapy, in some cases after 4-6 weeks. To maintain the effect of treatment and avoid frequent recurrence, typically in 6 months after termination of therapy, it is suggested to administer a maintenance dose 1-2 times a week [10-12]. Local therapy was also proven effective in overac- tive bladder in postmenopausal women and after uro- gynecological incontinence surgeries. The treatment is recommended for urogynecological complaints, al- though not only estrogen deficiency is responsible for their occurrence. It has a favourable effect in women with recurrent urinary tract infections after meno- pause. In the Cochrane meta-analysis published in 2008 (9 clinical studies including 3345 women), it was demonstrated that vaginal therapy with estriol decreas- es frequency of lower urinary tract infections more ef- ficiently than oral estrogen therapy. Better outcomes of surgical incontinence/prolapse treatment have been reported by many authors after local vaginal estrogen therapy [5, 6, 13]. The Polish Menopause and Andropause Society in 2011 published recommendations on local estrogen therapy in postmenopausal women, listing indications to therapy [14]: • dyspareunia resulting from vaginal dryness, • urge incontinence in patients with vaginal atrophy, • perioperative therapy in patients undergoing surgery because of genital prolapse, • additional therapy to pelvic floor exercises. The safety of local estrogen therapy Local estrogen therapy led for 12-24 months is rela- tively safe. It is believed that it does not require endo- metrial protection by addition of gestagens. The pos- sibility of overdose leading to systemic side effects and endometrial proliferation and hyperplasia should nevertheless be remembered. Currently, the exact in- fluence of local estrogen therapy on development or recurrence of breast cancer is not known. There are study results suggesting that estriol administered in high doses may stimulate estrogen receptors in breast and endometrial tissue. So far there are no guidelines regarding duration of local estrogen therapy and ultra- low dose of estrogen is recommended. There are only sparse data regarding safety of local estrogen therapy in atrophic vaginitis in females with endometrial cancer and therefore use of topical estrogens is advisable only in individual cases after weighing up risks and benefits of the therapy and after consultation with the oncolo- gists [1, 13, 15].

Local estrogen therapy of atrophic vaginitis is a sim- ple and safe treatment leading to improvement of the quality of life. The treatment should be commenced early, before irreversible atrophic changes develop. Early local therapy may prevent urogynecological complaints occurrence. It should be continued as maintenance therapy in order to maintain healthy vaginal ecosys- tem. Release of symptoms may be achieved by means of vaginal moisturizers and lubricants. Recently there have been trials analyzing use of progestagens, andro- gens (dehydroepiandrosterone – DHAES) and agonists and antagonists of estrogen receptors [16]. The authors declare no conflict of interests.

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