Selective estrogen receptor modulators SERMs aim to elicit specific positive effects on targeted tissues with neutral or minimal negative effects on other tissues. This review compares the vaginal effects of currently available and investigational SERMs. Both authors reviewed all articles, which formed the basis of this narrative literature review. Tamoxifen and arzoxifene have no specific positive vaginal effects but have reported variable or adverse gynecologic effects. Raloxifene does not improve VVA but can be used safely in combination with vaginal estrogen.
Absorption of low-dose vaginal estrogen preparations into the systemic blood stream is minimal and serum estradiol level does not exceed SSerm physiological value for the postmenopausal period. Background therapy was a nonhormonal vaginal lubricant to be used as needed during the treatment period. Abbreviation: VVA, vulvovaginal atrophy. Lubricants provide Serm vaginal atrophy short-term relief from vaginal dryness and discomfort during sexual intercourse. The main therapeutic goal in managing VVA is to relieve symptoms and restore the vaginal environment to a healthy premenopausal state. Management of post-menopausal vaginal atrophy and atrophic vaginitis. Clinical effects of selective estrogen receptor modulators on vulvar and vaginal atrophy. Apolihina I, Gorbunova E. Serm vaginal atrophy Today.
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Local estrogen therapy allows to quickly eliminate the symptoms of VVA, but it does not alleviate the vasomotor symptoms and reduce the risk of osteoporosis. These tests check several factors, including your estrogen levels. As a single agent, bazedoxifene is approved in Europe for postmenopausal osteoporosis. The advantage Shed bondage raloxifene over the triphenylethylene tamoxifen is Serm vaginal atrophy effect on the uterus. Constantine et al, in their double-blind, placebo-controlled study, found the efficacy and safety within 1 year of using ospemifene. Tamoxifen is selectively antiestrogenic in the breast but estrogen-like in bones and endometrial cancer. Not every woman will be able to use this treatment option, however. Categories : Hormonal antineoplastic drugs Progonadotropins Selective estrogen receptor modulators. It has a high affinity for the ER with potent Serm vaginal atrophy activity and tissue-specific effects Cliques in teen schools from estradiol. Currently, estrogen replacement is the best way to reverse vaginal atrophy and GSM.
An investigational selective estrogen receptor modulator SERM effectively reduced symptoms of postmenopausal vulvovaginal atrophy in phase III studies, according to topline results released by QuatRx Pharmaceuticals of Ann Arbor.
- SERMs are used for various estrogen-related diseases, including treatment of ovulatory dysfunction in the management of infertility, treatment and prevention of postmenopausal osteoporosis, treatment and reduction in risk of breast cancer  and treatment of dyspareunia due to menopause.
- Many women experience vaginal atrophy during and after menopause.
- Ospemifene is the first and only nonestrogen compound approved for this indication.
- Postmenopausal atrophic vaginitis, or vaginal atrophy, is the thinning of the walls of the vagina caused by decreased estrogen levels.
Editor who approved publication: Professor Everett Magann. Hormonal changes, especially hypoestrogenism inherent in menopause, are characterized by a variety of symptoms. More than half of menopausal women are concerned about the symptoms of VVA, such as dryness, burning, itching, vaginal discomfort, pain and burning when urinating, dyspareunia, and spotting during intercourse.
All these manifestations significantly reduce the quality of life and cause discomfort in the sexual sphere. Modern medicine has in the arsenal various options for treating this pathological condition, including systemic and topical hormone replacement therapy, the use of selective estrogen receptor modulators, vaginal dehydroepiandrosterone, use of lubricants and moisturizers, as well as non-drug therapies.
Timely diagnosis and adequately selected therapy for the main symptoms of VVA lead to restoration and maintenance of the vaginal function and vaginal health. Keywords: vulvovaginal atrophy, vaginal dryness, dyspareunia, menopause, hormonal replacement therapy, local estrogen, selective estrogen receptor modulator, vaginal dehydroepiandrosterone. Menopause is a phenomenon that inevitably occurs in the life of every woman.
The mean age of menopause in European countries is between With increased life expectancy, the impact of vulvovaginal atrophy VVA on the quality of life, sexual function, and pelvic floor health is becoming more evident in the present practice of medicine. Clinical manifestations of the menopausal syndrome are diverse and determined by the duration of hypoestrogenism.
Genitourinary syndrome of menopause is one of the most frequent complaints referred by postmenopausal women. Genitourinary syndrome of menopause is a recent terminology that describes an assortment of exam findings and bothersome symptoms related to estrogen deficiency that involves changes in the labia, introitus, clitoris, vagina, urethra, and bladder.
VVA is just a component of this general condition. Characterized by a chronic progressive course, VVA significantly impairs the quality of life and sexual health of women. Women affected by this condition may present a variety of symptoms including vaginal and vulvar pain and irritation. Vaginal dryness due to hypoestrogenism can be accompanied by itching, burning, discharge, and dyspareunia.
Frequency of occurrence of VVA, severity of pathological changes, and clinical course of the disease depend on the duration of postmenopause. As the estrogen deficiency grows, dystrophic and atrophic changes develop in the vaginal mucosa, vulva, and other structures of the urogenital tract. According to the results of the survey, the quality of life in this group of women was significantly lower in comparison to that of women of postmenopausal age without symptoms of VVA.
The mucus membrane of the lower sections of the urogenital tract is very sensitive to the effects of estrogens. A sufficient level of these hormones ensures a good blood supply to the vaginal mucosa and the optimal level of lubrication is maintained. Vaginal microbiota is a dynamic variable system, represented by a variety of bacteria, the vital activity and balance of which provides vaginal homeostasis.
The importance of microbiota in the formation of vaginal health cannot be underestimated. The dominant constituent of the vaginal microbiota is lactobacillus. Production of lactic acid, as a result of the vital activity of these bacteria, ensures the maintenance of the optimum low pH of the vaginal fluid, thus protecting from infections of the urogenital tract. The low pH of the vaginal fluid is also maintained by the active proton transport by the vaginal epithelium formed because of anaerobic glucose metabolism.
Under hypoestrogenic conditions, the vaginal epithelium becomes thinner, its barrier function is lost, the vaginal folding decreases, the elasticity of the tissues decreases, and the secretory activity of the Bartholin glands decreases, which lead to traumatization of the vaginal mucosa and painful sensations Figure 1.
Figure 1 Cascade effects of the mechanism of VVA. Abbreviation: VVA, vulvovaginal atrophy. In addition, under conditions of estrogen deficiency, the balance of the vaginal microbiota is disrupted, the pathogenic gram-negative fecal flora and other bacteria prevail in its composition, and the vagina develops a less acidic pH, that is, from 5. The data obtained by the authors demonstrate differences in the vaginal microbiota of pre-, peri-, and postmenopausal women.
In the proposed hypothesis, the predominance of anaerobic flora in the vaginal environment plays a role in the development of VVA symptoms. Clinically, VVA is manifested by dryness in the vagina, dyspareunia, vaginal discharge, itching, and pain.
Dyspareunia leads to a decrease in sex drive and fear of sexual intercourse. As the frequency of coitus diminishes, vaginal lubrication declines further. Some women may already have narrowing of the vagina or manifestations of vaginismus, limiting the penetration into the vagina. However, in some women with mild-to-moderate severity, VVA occurs asymptomatically and verification of diagnosis is possible only with vaginal examination.
In terms of the survey, a detailed history of the patient with a suspicion of VVA should be conducted to identify the possible causes, including effects of irritants lubricants, hygienic gels, soaps, spermicides , the use of antiestrogen drugs, advanced oophorectomy, or chemotherapy.
The diagnosis is confirmed by vaginal examination and colposcopy, wherein atrophic epithelium and thin, pale, and easily traumatized petechial hemorrhages can be detected. It is necessary to carry out bacteriological studies, determine the acidity of the vaginal contents, perform cytological examination of the vaginal smears, and count the karyopicnotic index.
Differential diagnosis has to be performed with the conditions summarized in Table 1. The main therapeutic goal in managing VVA is to relieve symptoms and restore the vaginal environment to a healthy premenopausal state. However, despite the high prevalence and negative impact on the quality of life, VVA is underreported by patients, undiagnosed by health care providers, and undertreated. Gynecologists should proactively start an open discussion with patients on urogenital symptoms. Treatment should be started as early as VVA occurs and should be maintained over time.
As there are many treatment options, therapy should be individualized. Treatment of VVA depends on the severity of the symptoms of the disease and on the preferences and expectations of women. According to the generally accepted international standards, the first-line recommendations for the treatment of mild and moderate manifestations of VVA are nonhormonal vaginal lubricants that should be used before intercourse and vaginal moisturizers with a long-term effect that are used regularly several times a week ; in such cases, regular sexual activity is of importance.
This treatment option is also recommended for women for whom the use of vaginal estrogen preparations is unacceptable. Lubricants provide a short-term relief from vaginal dryness and discomfort during sexual intercourse.
They may be water, silicone, or oil based and are applied to the vulva, vagina, or penis before sexual activity. Lubricants with a water base have fewer side effects, which is an advantage compared to lubricants based on silicone.
There is also evidence of an increased risk of developing bacterial vaginosis and vaginal candidiasis with the use of these medications. Vaginal moisturizers have a long-lasting effect in relieving the symptoms of VVA, enhancing moisturizing of the vaginal mucosa, and reducing the pH. These drugs are prescribed on a regular basis: daily or every 2—3 days, depending on the extent of the symptoms.
When choosing lubricants and moisturizers, it is important that the product is similar to vaginal secretion in terms of osmolality, pH, and composition.
Vaginal lubricants and moisturizers can be used as needed in combination with other VVA treatments. Considering the cause hypoestrogenism , and the pathogenesis of the development of VVA, the most logical choice for the treatment of this condition would be estrogen therapy.
However, for most physicians and scientific societies, it is a second-line treatment after moisturizers and lubricants.
Replenishment of estrogen deficiency can be carried out with hormonal preparations with systemic and local action, as well as with preparations of plant origin. According to the latest clinical guidelines for the management of patients with VVA, systemic or topical application of pharmacological estrogen preparations sufficiently and quickly improves the index of maturation and thickness of the vaginal mucosa, reduces the pH of the vagina, increases vaginal maturation index, and eliminates the symptoms of VVA.
Systemic hormone replacement therapy HRT includes all preparations containing estradiol, estradiol valerate, or conjugated estrogens. Systemic HRT is prescribed in the case of a combination of symptoms of urogenital atrophy with other symptoms of climacteric syndrome, as well as for the prevention and treatment of late-onset manifestations of the syndrome and its complications.
The local HRT includes preparations containing estradiol, as well as estriol. Local estrogen therapy is preferred in the presence of isolated urogenital disorders; the patients should be informed that the effect is achieved after 1—3 months of local estrogen therapy, and that they should be able to choose the drug that they consider most appropriate for them.
Estrogen therapy is prescribed after a clinical examination, identifying the risk factors for possible complications, and explaining the information to the patient.
Low doses of estrogens are preferred for use, since the use of high doses of estrogen in menopausal age is associated with a high risk of hyperproliferative endometrial and adenocarcinoma.
Absorption of low-dose vaginal estrogen preparations into the systemic blood stream is minimal and serum estradiol level does not exceed the physiological value for the postmenopausal period. Local estrogen therapy allows to quickly eliminate the symptoms of VVA, but it does not alleviate the vasomotor symptoms and reduce the risk of osteoporosis. According to the North American menopausal community, when taking low-dose vaginal estrogen preparations, the following ones occur: a decrease in the rugae of the vagina, an increase in the number of lactobacilli, and an improvement in the state of the vaginal epithelium and the epithelium of the urethra.
Pharmaceutical estrogen-containing preparations for topical use are available in the form of a cream, tablets, and a vaginal estrogen-releasing ring which may contain estriol, conjugated equine estrogens, estradiol, or estrone Table 2.
Table 2 Hormonal therapy for management of vulvovaginal atrophy Abbreviation: SERM, selective estrogen receptor modulator. According to the Cochrane review, all forms of drug administration are equally effective in providing relief from vaginal dryness, dyspareunia, and pruritus. As well, there are no significant differences in the thickness of the endometrium, the incidence of endometrial hyperplasia, and side effects. However, an insignificant risk of vaginal bleeding has been described in all studies in which various methods of topical estrogen therapy have been used.
The most commonly used form of local estrogen therapy is vaginal creams based on conjugated equine estrogens and 17b estradiol; they provide a good moisturizing effect. However, the amount of cream administered can vary, exceeding the recommended daily dosage, which is particularly undesirable for patients at high risk. According to data of Kingsberg et al, several women experience discomfort when using vaginal cream, finding it messy.
If more controlled dosing of estrogen is required, the drug of choice may be vaginal tablets containing 10 mg of estradiol. During the first 2 weeks of use, the daily use of the above-mentioned drug groups is recommended, followed by a transition to maintenance therapy with a dose of two to three times a week. Sustained-release estradiol vaginal rings are preferred for women for whom daily use of drugs is unacceptable.
Vaginal rings are inserted for up to 90 days and can be independently installed and removed by the patient. However, depending on the daily dose of estrogens, such systems can facilitate not only urogenital symptoms, but also vasomotor manifestations of the climacteric syndrome. The use of vaginal rings is not recommended in women with prolapse of the genitals. It is also necessary to warn a woman about the possible expulsion of the vaginal ring.
At the same time, the absorption of the drug into the systemic circulation and the maximum concentration of estradiol in the serum were significantly lower in comparison with the use of vaginal tablets.
However, clinical observations of the use of this group of low-dose estrogens are limited to 1 year. Several clinical studies have also noted improvements in urinary symptoms, such as urgency, frequency, nocturia, and stress and urgency urinary incontinence. Very interesting are the data published by Santen, where various variants of local estrogen therapy low-, intermediate-, and high-dose and their adsorption into the systemic circulation are considered.
The intermediate- and high-dose vaginal estradiol preparations are well absorbed, and they maintain the concentration of estrogens in the plasma corresponding to the period of premenopause. When administering local and systemic estrogen preparations, it is necessary to remember the side effects of drugs associated with systemic adsorption and carefully assess the risks of complications.
Excess estrogen levels in postmenopausal women are associated with an increased risk of heart disease, breast cancer, thromboembolic complications, and cerebrovascular diseases.
Results from preclinical studies suggested that ospemifene has potential for the treatment and prevention of osteoporosis. Recently introduced in the treatment of VVA, laser vaginal therapy has demonstrated effectiveness as well as high satisfaction among patients and health care providers. Smokers are also less responsive to estrogen therapy in pill form. These mice produce stable lines of transplantable MIN-O tissues. Raloxifene [6-hydroxy 4-hydroxyphenyl -benzothiophenyl]-[4-[2- 1-piperidyl ethoxy]phenyl]-methanone; see figure 9 belongs to the second-generation benzothiophene SERM drugs.
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