madman
Super Moderator
ABSTRACT
Vulvovaginal atrophy (VVA) is a chronic disease that mostly occurs in postmenopausal women. After menopause, insufficient sex hormones affect the anatomy of the vagina and cause drastic physiological changes. The main histopathological studies of VVA show that postmenopausal estrogen deficiency can lead to the increase of intermediate/parabasal cells, resulting in the loss of lactobacillus, elasticity, and lubricity, vaginal epithelial atrophy, pain, dryness. Although the role of estrogen hormones in the treatment of VVA has always been in the past, it is now widely accepted that it also depends on androgens. Estrogen drugs have many side effects. So, Dehydroepiandrosterone（DHEA）is promising for the treatment of VVA, especially when women with contraindications to estrogen have symptoms. This review is expected to understand the latest developments in VVA and the efficacy of DHEA.
1. Introduction
Perimenopausal and postmenopausal vulvovaginal atrophy (VVA) are primarily associated with symptoms and signs of estrogen loss [1]. About 50% of postmenopausal women suffer from VVA symptoms [2]. Genitourinary syndrome of menopause (GSM) includes vaginal dryness, burning, lack of lubrication, discomfort and pain, urgency, urination, and repeated urinary tract infections [3]. Major obstacles to the treatment of VVA include a lack of understanding of VVA and insufficient relief of existing symptoms. Experts believe that the term VVA is included in GSM, but more specifically, applies to the above symptoms and conditions related to genitals, except for urological symptoms [4].
Decreased ovarian estrogen production leads to decreased glycogen content in vaginal epithelial cells, estrogen levels and glycogen, lactobacillus counts, and increased vaginal pH [5]. Lack of estrogen stimulation results in pale and dry vaginal labia and reduced the volume of vaginal exudate and other glands. If the estrogen is low, the vaginal epithelium becomes thin, the function of the barrier is lost, and vaginal folds are reduced. Otherwise, the lack of estrogen leads to the fusion of collagen fibers and the breakage of elastin fibers, resulting in a loss of tissue elasticity [6].
Androgens have a regulatory effect on nerve fiber networks because testosterone is related to the nerve relaxation of these non-vascular smooth muscles. Administration of testosterone can produce DHEA-derived androgenic effects in ovariectomized animals because testosterone is related to the nerve relaxation of these non-vascular smooth muscles [7]. Estrogen therapy may be absorbed in the circulation and increase the unhealthy dependence on systemic estrogen. Dehydroepiandrosterone (DHEA)/ dehydroepiandrosterone sulfate (DHEA-S) and its local metabolites are useful for maintaining the normal structure and functional strength of the tissues around the vagina and genitourinary organs [8]. The topical effect of DHEA on the vagina is promising, especially in women with contraindications to estrogen [9].
2. Clinical definition and diagnosis of VVA
3. Pathology of VVA
3.1. Role of estrogen deficiency in VVA
3.2. Androgen and vaginal function
The four main androgens in the systemic circulation of premenopausal women are DHEA, androstenedione, testosterone, and 5a-dihydrotestosterone (5a-DHT). The synthesis of androgen mainly occurs in the ovaries and adrenal glands, but it can be synthesized in peripheral tissues [32]. The lack of androgen in the vaginal tissue can lead to VVA and urogenital syndrome during menopause, resulting in decreased lubrication and difficulty in sexual intercourse [33]. Androgen has a regulatory effect on the nerve fiber network because testosterone is related to the nerve relaxation of these non-vascular smooth muscles. Even androgen receptors (AR) are also expressed at various levels (mucosa, submucosa, interstitium, smooth muscle, and vascular endothelial), affecting neurovascular and neuromuscular functions under different endocrine conditions [34].ARs are transcription regulators activated by ligands. The binding of testosterone or 5a-DHT to AR in target cells leads to the dissociation of Heat shock protein (HSP), conformational changes of AR, and receptor dimerization [35]. The ligand-bound receptor dimer binds to AREs (androgen-response elements, AREs) on the DNA (Figure 2). Such specific binding androgen-response elements recruit transcription factors and co-activators or co-inhibitors, resulting in an increase or decrease in androgen, mRNA expression of hormone-responsive genes, and subsequent changes in protein synthesis and cell metabolism [36]. The administration of testosterone induces protein gene products in ovariectomized animals. It increases the protein gene product 9.5 (PGP 9.5), which makes these fibers thicker and produces DHEA-derived androgenic effects [37]. Androgen is very important for the differentiation of the vagina. Testosterone is responsible for the structural integrity of vaginal tissues (including the thickness and contractility of vascular smooth muscle and the firmness of collagen fibers) and the relaxation of vascular smooth muscle through the NO/cGMP/PDE5 pathway, nerve fiber density, and neurotransmission regulating arousal, and lubrication complex neurovascular [38]. Testosterone regulates nociception, inflammation, and mucin secretion in the vagina. In the ovaries, adrenal glands, and peripheral tissues, DHEA and androgen can be converted into testosterone, and testosterone can be converted into a stronger androgen 5a-DHT by the action of 5a-reductase, and it can also be converted into estradiol by aromatase. Aromatase also converts androstenedione into estrogen, which is a weaker estrogen. The reversible reaction mediated by multiple isomers of 17b-hydroxysteroid dehydrogenase can mutually convert estrone and estradiol, but estrogen (18-carbon steroid compound) generally does not convert back to androgen [39]. In postmenopausal women, circulating DHEA and androstenedione are important precursors for the local synthesis of testosterone and estradiol in extra-gonadal tissues.
4. Current treatment options and their limitations
4.1. DHEA is promising in VVA women with contraindications to estrogen
4.2. How does DHEA really work?
4.3. The clinical application of DHEA
5. Conclusion and future perspective
In this comprehensive review, different opinions summarize the possibility that DHEA can treat VVA. This article briefly introduces the latest research on potential applications. VVA is defined as a variety of genitourinary complications. Although a lot of research work has been conducted in the past two decades, there is still a big gap between academic research and clinical trials. The gap may be due to the lack of sufficiently effective in vitro and in vivo animal models to simulate the pathophysiological conditions involved in the overall pathogens of VVA. In addition, because the onset of clinical symptoms of VVA is long (possibly as long as decades), it has research value for preventing or delaying the onset of VVA. Finally, the identification of VVA-related biomarkers may supplement the therapeutic significance of VVA.
For the current treatment of VVA/GSM, the biggest obstacle to vaginal estrogen therapy is the fear of potential side effects, including the increased risk of endometrial and breast cancer, stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction (Table 2). Although DHEA targeted treatment, there is a lack of research on absorbed or metabolite blood level changes and how the drug is passed vaginal absorption. Due to the mechanism of the disease, the administration of estrogen can increase vaginal blood flow, and improve vaginal elasticity and lubrication. It remains the gold standard for the treatment of the disease and can be used systemically and locally [57]. However, high levels of estrogen can have a negative effect and may increase the risk of breast cancer, endometrial cancer, and uterine cancer, which may lead to the fact that most women would rather suffer pain than seek treatment [58]. Androgen is also a common clinical drug for the treatment of this disease. When exogenous testosterone is absorbed into the blood, androgen produced in vaginal target cells promotes the production of lower vaginal epithelial cells and improves the maturity index of vaginal cells. Androgen can be partially transferred to estrogen to play a role. However, long-term use of androgens can also cause some adverse effects, such as abnormal liver function, hyperlipidemia, weight gain, hair, and virilization [59]. Current data have confirmed that the local administration of DHEA can rapidly obtain beneficial effects on vaginal atrophy through its intracellular transformation, without systemic exposure to sex steroids, thereby avoiding the increased risk of breast cancer.
DHEA has shown great potential in the treatment of postmenopausal diseases. Women using topical, minimally absorbed topical treatments will not increase the risk of these diseases, but this still needs to be verified.
Vulvovaginal atrophy (VVA) is a chronic disease that mostly occurs in postmenopausal women. After menopause, insufficient sex hormones affect the anatomy of the vagina and cause drastic physiological changes. The main histopathological studies of VVA show that postmenopausal estrogen deficiency can lead to the increase of intermediate/parabasal cells, resulting in the loss of lactobacillus, elasticity, and lubricity, vaginal epithelial atrophy, pain, dryness. Although the role of estrogen hormones in the treatment of VVA has always been in the past, it is now widely accepted that it also depends on androgens. Estrogen drugs have many side effects. So, Dehydroepiandrosterone（DHEA）is promising for the treatment of VVA, especially when women with contraindications to estrogen have symptoms. This review is expected to understand the latest developments in VVA and the efficacy of DHEA.
1. Introduction
Perimenopausal and postmenopausal vulvovaginal atrophy (VVA) are primarily associated with symptoms and signs of estrogen loss [1]. About 50% of postmenopausal women suffer from VVA symptoms [2]. Genitourinary syndrome of menopause (GSM) includes vaginal dryness, burning, lack of lubrication, discomfort and pain, urgency, urination, and repeated urinary tract infections [3]. Major obstacles to the treatment of VVA include a lack of understanding of VVA and insufficient relief of existing symptoms. Experts believe that the term VVA is included in GSM, but more specifically, applies to the above symptoms and conditions related to genitals, except for urological symptoms [4].
Decreased ovarian estrogen production leads to decreased glycogen content in vaginal epithelial cells, estrogen levels and glycogen, lactobacillus counts, and increased vaginal pH [5]. Lack of estrogen stimulation results in pale and dry vaginal labia and reduced the volume of vaginal exudate and other glands. If the estrogen is low, the vaginal epithelium becomes thin, the function of the barrier is lost, and vaginal folds are reduced. Otherwise, the lack of estrogen leads to the fusion of collagen fibers and the breakage of elastin fibers, resulting in a loss of tissue elasticity [6].
Androgens have a regulatory effect on nerve fiber networks because testosterone is related to the nerve relaxation of these non-vascular smooth muscles. Administration of testosterone can produce DHEA-derived androgenic effects in ovariectomized animals because testosterone is related to the nerve relaxation of these non-vascular smooth muscles [7]. Estrogen therapy may be absorbed in the circulation and increase the unhealthy dependence on systemic estrogen. Dehydroepiandrosterone (DHEA)/ dehydroepiandrosterone sulfate (DHEA-S) and its local metabolites are useful for maintaining the normal structure and functional strength of the tissues around the vagina and genitourinary organs [8]. The topical effect of DHEA on the vagina is promising, especially in women with contraindications to estrogen [9].
2. Clinical definition and diagnosis of VVA
3. Pathology of VVA
3.1. Role of estrogen deficiency in VVA
3.2. Androgen and vaginal function
The four main androgens in the systemic circulation of premenopausal women are DHEA, androstenedione, testosterone, and 5a-dihydrotestosterone (5a-DHT). The synthesis of androgen mainly occurs in the ovaries and adrenal glands, but it can be synthesized in peripheral tissues [32]. The lack of androgen in the vaginal tissue can lead to VVA and urogenital syndrome during menopause, resulting in decreased lubrication and difficulty in sexual intercourse [33]. Androgen has a regulatory effect on the nerve fiber network because testosterone is related to the nerve relaxation of these non-vascular smooth muscles. Even androgen receptors (AR) are also expressed at various levels (mucosa, submucosa, interstitium, smooth muscle, and vascular endothelial), affecting neurovascular and neuromuscular functions under different endocrine conditions [34].ARs are transcription regulators activated by ligands. The binding of testosterone or 5a-DHT to AR in target cells leads to the dissociation of Heat shock protein (HSP), conformational changes of AR, and receptor dimerization [35]. The ligand-bound receptor dimer binds to AREs (androgen-response elements, AREs) on the DNA (Figure 2). Such specific binding androgen-response elements recruit transcription factors and co-activators or co-inhibitors, resulting in an increase or decrease in androgen, mRNA expression of hormone-responsive genes, and subsequent changes in protein synthesis and cell metabolism [36]. The administration of testosterone induces protein gene products in ovariectomized animals. It increases the protein gene product 9.5 (PGP 9.5), which makes these fibers thicker and produces DHEA-derived androgenic effects [37]. Androgen is very important for the differentiation of the vagina. Testosterone is responsible for the structural integrity of vaginal tissues (including the thickness and contractility of vascular smooth muscle and the firmness of collagen fibers) and the relaxation of vascular smooth muscle through the NO/cGMP/PDE5 pathway, nerve fiber density, and neurotransmission regulating arousal, and lubrication complex neurovascular [38]. Testosterone regulates nociception, inflammation, and mucin secretion in the vagina. In the ovaries, adrenal glands, and peripheral tissues, DHEA and androgen can be converted into testosterone, and testosterone can be converted into a stronger androgen 5a-DHT by the action of 5a-reductase, and it can also be converted into estradiol by aromatase. Aromatase also converts androstenedione into estrogen, which is a weaker estrogen. The reversible reaction mediated by multiple isomers of 17b-hydroxysteroid dehydrogenase can mutually convert estrone and estradiol, but estrogen (18-carbon steroid compound) generally does not convert back to androgen [39]. In postmenopausal women, circulating DHEA and androstenedione are important precursors for the local synthesis of testosterone and estradiol in extra-gonadal tissues.
4. Current treatment options and their limitations
4.1. DHEA is promising in VVA women with contraindications to estrogen
4.2. How does DHEA really work?
4.3. The clinical application of DHEA
5. Conclusion and future perspective
In this comprehensive review, different opinions summarize the possibility that DHEA can treat VVA. This article briefly introduces the latest research on potential applications. VVA is defined as a variety of genitourinary complications. Although a lot of research work has been conducted in the past two decades, there is still a big gap between academic research and clinical trials. The gap may be due to the lack of sufficiently effective in vitro and in vivo animal models to simulate the pathophysiological conditions involved in the overall pathogens of VVA. In addition, because the onset of clinical symptoms of VVA is long (possibly as long as decades), it has research value for preventing or delaying the onset of VVA. Finally, the identification of VVA-related biomarkers may supplement the therapeutic significance of VVA.
For the current treatment of VVA/GSM, the biggest obstacle to vaginal estrogen therapy is the fear of potential side effects, including the increased risk of endometrial and breast cancer, stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction (Table 2). Although DHEA targeted treatment, there is a lack of research on absorbed or metabolite blood level changes and how the drug is passed vaginal absorption. Due to the mechanism of the disease, the administration of estrogen can increase vaginal blood flow, and improve vaginal elasticity and lubrication. It remains the gold standard for the treatment of the disease and can be used systemically and locally [57]. However, high levels of estrogen can have a negative effect and may increase the risk of breast cancer, endometrial cancer, and uterine cancer, which may lead to the fact that most women would rather suffer pain than seek treatment [58]. Androgen is also a common clinical drug for the treatment of this disease. When exogenous testosterone is absorbed into the blood, androgen produced in vaginal target cells promotes the production of lower vaginal epithelial cells and improves the maturity index of vaginal cells. Androgen can be partially transferred to estrogen to play a role. However, long-term use of androgens can also cause some adverse effects, such as abnormal liver function, hyperlipidemia, weight gain, hair, and virilization [59]. Current data have confirmed that the local administration of DHEA can rapidly obtain beneficial effects on vaginal atrophy through its intracellular transformation, without systemic exposure to sex steroids, thereby avoiding the increased risk of breast cancer.
DHEA has shown great potential in the treatment of postmenopausal diseases. Women using topical, minimally absorbed topical treatments will not increase the risk of these diseases, but this still needs to be verified.
