madman
Super Moderator
Individual Benefits and Risks of Intravaginal Estrogen and Systemic Testosterone in the Management of Women in the Menopause, With a Discussion of Any Associated Risks for Cancer Development (2022)
Abbie J. Laing, MBChB, BSc, RCGP, DFSRH,* Louise Newson, MBChB(Hons), BSc(Hons), MRCP, FRCGP,*†‡ and James A. Simon, MD, CCD, NCMP, IF, FACOG§||
Abstract
Several formulations of intravaginal estrogen are available for the treatment of genitourinary syndrome of menopause (GSM). These are safe and effective treatments for the symptoms of GSM. Licensed doses of intravaginal estrogen do not elevate systemic estradiol levels above the normal postmenopausal range with long-term use and there is no evidence of an increased risk of coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, breast cancer or breast cancer recurrence with their use. This should reassure both women and their healthcare professionals and should lead to more women receiving these localized, vaginally administered hormonal treatments. Available evidence also suggests a positive safety profile for transdermal testosterone treatment when delivered at physiological concentrations.
PART 1: INTRAVAGINAL ESTROGEN
Introduction
In the United Kingdom, intravaginal estrogen includes estradiol and estriol preparations available in various formulations including pessaries, rings, creams, or gels. A newer pessary has also been licensed in the United Kingdom containing dehydroepiandrosterone, which is converted intracellularly into both androgens and estrogens. In the United States, estriol preparations are not available, and Premarin cream is mostly prescribed. Premarin contains conjugated estrogens. Although not available at the moment, in the future there may be a role for estrogen receptor β analogs. The benefits pertained by using these treatments are multiple and include alleviation of symptoms caused by the genitourinary syndrome of menopause (GSM), for example, vaginal dryness, itching, pain, sexual concerns, and urinary problems; restoration of urogenital physiology including a reduction in risk of urinary tract infections (UTIs); improved quality of life; and increased likelihood of obtaining satisfactory cervical smears.1 Transvaginal estrogen all have documented efficacy and safety profiles and do not elevate systemic estradiol levels above the normal postmenopausal reference range at licensed doses.2 They can be considered for women with a history of any estrogen receptor-positive cancer after an informed decision-making process, and for many well-informed women, the benefits of their use outweigh any theoretical or unproven risks.
Alleviation of GSM Symptoms Genitourinary syndrome of menopause describes hypestrogenic changes to the vulvovaginal and bladder-urethral areas that occur following menopause.3 For some women, these changes can start in the perimenopause, and by the mid to late 1950s, symptoms can become severe enough that women seek care specifically for them. Symptoms are very common, affecting approximately 70% of all menopausal women.4 Symptoms include genital changes (dryness, itching, burning, pain, and irritation), sexual concerns (dyspareunia, decreased arousal, reduced lubrication, postcoital bleeding, reduced or absent orgasm), and urinary problems (urgency, nocturia, dysuria, recurrent UTIs, and urinary incontinence).4,5 Women who have not had a vaginal birth in the past appear to present with more severe sexual symptoms and at an earlier age compared with multiparous women. Collectively, these symptoms can cause significant distress, reduced quality of life, depression, anxiety, and other mood disorders6 and unlike vasomotor symptoms do not usually improve with time; instead, they are chronic and progressive. A response to hormonal treatments is usually rapid and sustained with most women obtaining substantial relief even after 3 weeks.5 Although GSM symptoms are primarily treated with vaginal estrogens, the vestibule, and the vulva cannot be ignored as they also undergo atrophy and may require focused treatment here too. If treatment is discontinued, symptoms will usually return, and so maintenance regimens are required.5 An improvement in urinary symptoms, particularly recurrent UTIs, deserves particular attention. Many postmenopausal women are treated with antibiotics for their recurrent UTIs when the underlying cause is GSM. This can lead to a perennial cycle of antibiotic prescribing with resulting antibiotic resistance. Reductions in UTIs with improvements in urinary continence and overactive bladder symptoms all usually occur with transvaginal estrogen use.7–12 One study demonstrated the estradiol ring releasing 7.5 μg per 24 hours and oral oxybutynin to have comparable efficacy for the treatment of overactive bladder.13
*Restoration of Urogenital Physiology
Estrogen receptors, both α, and β are ubiquitous in the vagina, urethra, bladder trigone, and pelvic floor.4 This is because these structures share the same embryological origin, the primitive urogenital sinus tissue.14 When estrogen levels decline during perimenopause and menopause, the effect is a progressive dominance of parabasal cells, and the multilayered squamous vaginal epithelium becomes thinner.15 The vagina loses its pink color, the introitus retracts, and the epithelium becomes friable with petechiae, ulceration, and fragility. The density of sensory nociceptor neurons in the vagina increases, which is likely to contribute to some of the symptoms of discomfort.16 As there is a loss of glycogen-rich superficial cells, there is a reduction in the colonization of the vagina by Lactobacillus, and the vaginal pH increases.5,17 When Lactobacillus levels reduce, colonization by other unwanted pathogens increases, and this can be the cause of urinary infections and vaginal odor. The most common cause of these pathogens is fecal flora. This means the postmenopausal vagina is at risk of infection and inflammation.5 Elastin becomes fragmented, and collagen is subject to hyalinization.5,17 This causes a loss of vaginal rugae, and the vagina becomes shorter and narrower, contributing to pain with penetrative sexual activity. The altered collagen turnover may also contribute to vaginal prolapse.18 Smooth muscle in the superficial layers of the bladder trigone and proximal and distal urethra atrophies,19 the urethral mucosa becomes thinner,20 and there is decreased activity of the α-adrenergic system innervating the bladder neck and urethral sphincter.21 The same pH changes in the vagina can also affect the lower urinary tract, increasing the risk of urethritis and cystitis.5 Use of vaginal estrogen restores urogenital physiology. It lowers vaginal pH, increases subepithelial capillary growth, thickens the epithelium, raises the level of vaginal secretions, and reduces the density of autonomic and sensory vaginal innervations.22 These changes lead to a reversal of atrophy.
*Improving Cervical Smears
Severe symptoms of GSM can often be a barrier for women to achieve satisfactory cervical cancer screening or colposcopy.23 Because the squamous epithelium becomes very thin, insertion of the speculum can cause extreme discomfort and even traumatic hemorrhages.23 The transformation zone is also less likely to be fully visualized or sampled in women with GSM because of inversion of the endocervical canal,1,23 and there is some evidence that the hypoestrogenic state seen after the menopause produces reactive cytological atypia, which can be misinterpreted as atypical squamous cell of undetermined significance.1 Short-term treatment with intravaginal estrogen for as little as 6 weeks has been shown to improve the ability to distinguish between benign atrophic inflammatory changes and true preinvasive disease.1 It also can often reduce discomfort during the examination and increases the likelihood of satisfactory smear results by causing enough ectropion of endocervical cells to visualize or sample the full transformational zone.1
*Maintaining Quality of Life and Emotional Well-being
Recognizing the positive impact intravaginal estrogen can have on emotional well-being and quality of life cannot be overemphasized. Several large surveys demonstrate the negative effects of inadequate symptom control on lifestyle measures.24–27 In the REVIVE Survey, which involved 3046 postmenopausal women from the United States, GSM symptoms negatively affected the enjoyment of sex (59%), intimacy (85%), relationships with their partner (47%), sleep (29%), overall enjoyment of life (27%), and temperament (23%).27 In the VIVA survey, which included 3520 postmenopausal women in 6 countries, GSM symptoms negatively impacted sexual intimacy (64%), loving relationships with a partner (32%), overall quality of life (32%), feeling healthy (21%), and feeling attractive (21%).24 In the international CLOSER survey, which included 4100 women and 4100 men, vaginal discomfort had a negative impact on the intimacy of both partners.26 It is not surprising therefore that a recent case-control study, which included half a million women, found a significantly increased risk for depression and anxiety in women with symptomatic GSM compared with women without GSM.6 Thus, it remains very concerning that only 7% of women with GSM receive treatment.4
*Systemic Absorption of Vaginally Administered Hormonal Therapy
Licensed doses of transvaginal estrogen do not elevate systemic estradiol levels above the normal postmenopausal range (which is likely to be <10 pg/mL), with long-term use.2 At treatment initiation, there may be a small peak in absorption; however, this is transient and declines as the vaginal epithelium thickens, which in general occurs after 2 to 4 weeks (but is slower in women on aromatase inhibitors).2,28 Low-dose estrogen preparations include the estradiol vaginal ring, which has a typical serum level of 8.0 pg/mL and a maximum annual delivered systemic dose of 2.74 mg29,30 and 10 μg estradiol vaginal tablets, which result in a typical serum level of 4.6 pg/mL and a maximal annual delivery dose of 1.14 mg. To put this into perspective, this means the total administered vaginal dose per year of a preparation containing 10 μg of estradiol used twice weekly is comparable to the single dose of a 1 mg estradiol oral tablet.31 Lower doses can be given if desired, and the lowest documented doses with proven efficacy are estriol 30 μg and estradiol 4 μg, both administered twice weekly.32,33 It is important to mention that considerable absorption of estriol occurs with vaginal cream and tablets. However, this is a weak estrogen, and there is no conversion to the more potent estrogens, estradiol, or estrone.5,34 Intravaginal dehydroepiandrosterone has also not been shown to cause significant changes in serum estradiol or androgen levels.35
*Risks
The Women's Health Initiative Observational Study examined the risks of transvaginal estrogen use, and the findings were very reassuring.36 This was a prospective cohort study of approximately 45,000 women that assessed coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, and invasive breast cancer. The study showed no increased risks for any condition with vaginal estrogen use. Because absorption of vaginal estradiol remains below the reference range in postmenopausal women, it is reasonable to conclude that any concerning risks following treatment use would be rare and unlikely.2 All preparations, however, could cause minor problems, such as vaginal irritation, discharge, or breast tenderness, and there has been a link with a greater frequency of mycotic infections.31
*Primary Breast or Endometrial Cancer
There is no increased risk of primary breast cancer development with the use of transvaginal estrogen.36–39 In fact, an advantage of transvaginal estrogen is that a progestogen is not required, and an increase in breast cancer risk seems to be related to the addition of a progestogen.40 There is also no increased risk of endometrial cancer or hyperplasia with low-dose vaginal estrogen use; occurrences are rare and consistent with rates in the general population.15,36 Systemic reviews have shown endometrial safety for both topical estradiol and estriol for up to 52 weeks.41–43 Large observational follow-up studies evaluating longer exposure to vaginal estrogens also confirm this,36,38 and a Cochrane review of randomized controlled trials (RCTs) reported no significant differences among transvaginal estrogens formulations in terms of endometrial thickness or hyperplasia.44
*Women Considered at High Risk for Cancer Development
The use of systemic estrogen-only hormone therapy appears to not increase the risk of breast cancer in women with increased risk because of family history.29,45 Similarly, evidence suggests estrogen therapy does not increase breast cancer risk in carriers of the BRCA1 or BRCA2 mutation with intact breasts,46–49 although the relatively small sample sizes of the BRCA trials could miss a rare finding. Given these findings were obtained from high-risk women using systemic estrogen therapy, it is likely that lower doses used in vaginal therapy do not elevate a high baseline risk. The BRCA1 and BRCA2 genes increase the risk of invasive epithelial ovarian cancer, and risk-reducing salpingo-oophorectomy is often recommended. Data on estrogen replacement in this group demonstrate it is safe.50 There are no studies available for women with Lynch syndrome.51
*Women With a History of Cancer
Management of GSM in women with a history of cancer that was not estrogen receptor-positive is similar to that for women without a cancer history. For those women with a history of estrogen-receptor-positive cancer, namely, breast cancer, endometrial cancer, ovarian cancer, adenocarcinoma of the cervix, and some uterine sarcomas, the use of intravaginal estrogen can be considered after an informed decision making and consent process.
*History of Hormone Receptor-Positive Breast Cancer
Many women with a history of the breast cancer experience severe and early symptoms of GSM as an iatrogenic consequence of chemotherapy, radiotherapy, surgery, or use of adjuvant endocrine therapies such as tamoxifen or aromatase inhibitors.29 Hormone receptor-positive breast cancer makes up 75% of cases, and this subset of women understandably often feels particularly cautious about using vaginal estrogens.29 Most of their treatment strategies will have focused on lowering systemic estrogen concentrations, for example, by blocking estrogen at the level of the receptor with tamoxifen or reducing estrogen production with aromatase inhibitors, or by suppressing ovarian production with gonadotropin-releasing hormone agonists.29 However, the assumption that less systemic absorption of vaginally administered estrogens equates with less breast stimulation has not been established. Several lines of evidence suggest that estrogens may, in fact, cause breast cancer cell apoptosis after a period of estrogen deprivation.52–54 This has been termed the estrogen-deprivation hypothesis.53 Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone receptor-positive breast cancer tumor cells to low-dose estradiol therapy.55 A randomized trial in women with advanced breast cancer and acquired resistance to aromatase inhibitors reports that an estradiol dose of 6 mg daily helped prevent recurrence and improve breast cancer sensitivity to treatment.55 Of all the data, there is currently only 1 study that describes an increased risk of recurrence in women taking hormone replacement therapy after a history of breast cancer,56 whereas 3 studies demonstrate a decreased risk,57–59 and most studies demonstrate no difference whatsoever.60
Nonhormonal options are often given as the first-line treatment option for managing symptoms of GSM in women with prior estrogen receptor-positive breast cancer.37 These non-hormonal options include emollients, vaginal moisturizers, and vaginal lubricants. These options moisturize and lubricate, which for some women may be enough, but they do not significantly alter the vaginal biome or modify tissue change. An individualized approach is needed, and for many well-informed breast cancer patients, the use of low-dose vaginal estrogen is acceptable after a careful discussion about any theoretical and unproven risks.4 An individualized discussion involves balancing the risk of recurrence, which is influenced by the stage, grade of cancer, presence of lymphovascular invasion, hormone receptor status, use of endocrine therapy, time since diagnosis with the efficacy of conservative therapies, the severity of GSM symptoms, and associated quality of life.29
Tamoxifen binds with a high affinity for the estrogen receptor, and there is little concern that the use of local estrogen may compromise its effects. It is more likely that tamoxifen will compromise the vaginal estrogen.5 Ospemifene is a selective estrogen receptor modulator approved for the treatment of GSM in postmenopausal women who are not candidates for intravaginal estrogen. It evolved from a tamoxifen metabolite and has weak antiestrogen activity on the breast tissue. Clinical studies since its approval have indicated no increased risk for breast cancer among patients receiving it.61
In contrast, for women taking aromatase inhibitors, the use of vaginal estrogen has been more controversial. Because aromatase inhibitors reduce estrogen production, for some it seems counterintuitive to prescribe concomitant estrogen. Furthermore, some data show increased absorption of vaginal estradiol in women using aromatase inhibitors.15 Switching an aromatase inhibitor to tamoxifen could be an appropriate option, and this decision would need to be made in conjunction with a breast specialist. However, the use of add-back vaginal estrogen in women using aromatase inhibitors should not be an absolute contraindication.4 The profound estrogen depletion caused by aromatase inhibitors can cause such substantial distress that it can trigger treatment discontinuation62 due not only to the impact of this treatment on vulvovaginal health but mood, and cognition. and osteoporosis as well, and for some, this might be avoidable. A recent meta-analysis, which included 11 high-quality studies, provided indirect evidence for the safety of intravaginal estrogens in women taking aromatase inhibitors.4,63 Furthermore, the BLISSAFE study in women taking aromatase inhibitors randomized to either vaginal estriol or placebo for 12 weeks showed symptom benefit and no effect on gonadotropins, serum estradiol, or estrone.64 The concept of measuring serum estradiol levels in women taking aromatase inhibitors to access systemic absorption of vaginally administered estrogen has been asked. This is not recommended; very small changes in pharmacokinetics are hard to assess accurately in postmenopausal women unless very sensitive mass spectrometry methods are used.65 An assay needs to measure estradiol down to at least 0.3 pg/mL to be used to determine the degree of suppression of estradiol in women with breast cancer treated with aromatase inhibitors.2 In addition, there is a lack of clarity regarding whether higher levels within a narrow postmenopausal range are associated with an increased risk of breast cancer recurrence and similarly whether lower levels are reassuring.66
Although there is a paucity of data, current evidence does not show an increased risk of breast cancer recurrence among women using low-dose vaginal estrogen who have a history of estrogen receptor-positive breast cancer.4,67–70 One nested case-control study showed that, after 3.5 years of follow-up, local vaginally administered estrogen was not associated with breast cancer recurrence among women taking either aromatase inhibitors or tamoxifen.67 Several organizations, including the American College of Obstetricians and Gynecologists, have endorsed the use of specific low-dose vaginal estrogen products and therapies acting in the vagina such as estrogens in women with breast cancer, including estrogen receptor-positive disease.68 Furthermore, a large study looking at ospemifene also indicates no increased risk for breast cancer recurrence with its use.61
*History of Endometrial Cancer
The majority of endometrial cancers are diagnosed at an early stage and have a good overall prognosis, with a 5-year survival rate of greater than 85%.51 Treatment usually involves hysterectomy and bilateral oophorectomy.51 The most common type is a lowgrade endometrioid adenocarcinoma, which is considered an estrogen receptor-positive neoplasm.71 Because of this, there have been concerns about disease recurrence with exogenous estrogen use. However, in an RCT, women treated with oral estrogen after a history of grade 1 or 2 endometrial adenocarcinomas had low absolute recurrence rates.72 In addition, a systematic review concluded that although there is insufficient high-quality evidence to make firm conclusions, from the available evidence, if hormone replacement is used after surgical treatment for early-stage endometrial cancer, it is unlikely to cause harm.73 By extrapolation, it is likely that low-dose intravaginal estrogen is also safe for these women. More recently, a retrospective cohort study concluded that intravaginal estrogen does not appear to increase recurrence risk beyond the baseline for women with both early and advanced disease.71 These findings provide some reassurance about intravaginal low-dose estrogen use in women with either early-stage or even higher-stage endometrial cancers suffering from GSM.
*History of Ovarian Cancer
The 3 major types of ovarian cancer include epithelial (90% of cases), sex cord-stromal, and germ cell tumors. Epithelial ovarian cancers are divided into 5 histological types: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous.51 Of the epithelial ovarian tumors, there is no evidence of any estrogen receptors in women with clear cell or mucinous tumors.51 In contrast, endometrioid and serous epithelial ovarian tumors can be hormone receptor-positive.51 Following treatment for an early endometrioid disease, the use of exogenous hormone therapy appears to be safe.51 However, there have been concerns that this might not be the case in women with more advanced endometrioid tumor disease, where residual hormone-responsive disease could theoretically remain after surgery.51 Nonetheless, any suggested effect of intravaginal estrogen on residual disease is unproven and theoretical only. In addition, a recent retrospective cohort study demonstrated no increased recurrence risk in women using intravaginal estrogens with a history of ovarian cancer, and in this study, high-grade serous and endometrioid histologies were the most prevalent.71 The most common sex cord-stromal tumor is a granulosa cell tumor. These tumors secrete estrogens as well as other hormones.51 For this reason, women with these tumors are typically denied exogenous estrogens.51 However, no study has demonstrated any deleterious effects on these tumors with exogenous estrogen use.51 Ovarian germ cell tumors are a category that affects girls and young women. There is no evidence of any adverse effects from estrogen treatments in these tumor types.51 In the absence of definitive data, shared decision-making involves a comprehensive discussion of off-label use, as well as benefits, and is justified.
*History of Adenocarcinoma of the Cervix
Estrogen and progesterone receptors are expressed in approximately one-third of cervical adenocarcinomas.51,74 A recent retrospective cohort study of 244 women who received vaginal estrogen found no increased risk of cervical cancer recurrence, and in this study, 40.3% of the cervical cancer cohort had prior adenocarcinoma.71 Furthermore, in a very recent small retrospective study of women younger than 50 years with stage 1B–2B cervical adenocarcinomas, there was a trend toward improved survival rates with hormone replacement therapy.75
Conclusion
Low-dose intravaginal estrogens appear to be a safe and effective treatment for symptoms of GSM with the benefits of restoring urogenital physiology, improving quality of life and mental well-being, and increasing the likelihood of obtaining satisfactory cervical smears. Women without GSM symptoms are also candidates for treatment, as such symptoms and the underlying cellular and anatomic changes are progressive, meaning treatment should be started early to prevent such effects and taken long-term to avoid recurrence. The absorption of low-dose vaginal estradiol results in very low, even immeasurable systemic estradiol levels above the normal postmenopausal range. The total administered vaginal dose per year of a preparation containing 10 μg of estradiol used twice weekly is comparable to the single dose of a 1- mg oral estradiol tablet. Because of this, any concerning risks following treatment use would be rare and unlikely, and there is no evidence of an increased risk of coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, breast cancer, or breast cancer recurrence. This should reassure both women and their health care professionals and should lead to more women receiving these localized, vaginally administered hormonal treatments.
Abbie J. Laing, MBChB, BSc, RCGP, DFSRH,* Louise Newson, MBChB(Hons), BSc(Hons), MRCP, FRCGP,*†‡ and James A. Simon, MD, CCD, NCMP, IF, FACOG§||
Abstract
Several formulations of intravaginal estrogen are available for the treatment of genitourinary syndrome of menopause (GSM). These are safe and effective treatments for the symptoms of GSM. Licensed doses of intravaginal estrogen do not elevate systemic estradiol levels above the normal postmenopausal range with long-term use and there is no evidence of an increased risk of coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, breast cancer or breast cancer recurrence with their use. This should reassure both women and their healthcare professionals and should lead to more women receiving these localized, vaginally administered hormonal treatments. Available evidence also suggests a positive safety profile for transdermal testosterone treatment when delivered at physiological concentrations.
PART 1: INTRAVAGINAL ESTROGEN
Introduction
In the United Kingdom, intravaginal estrogen includes estradiol and estriol preparations available in various formulations including pessaries, rings, creams, or gels. A newer pessary has also been licensed in the United Kingdom containing dehydroepiandrosterone, which is converted intracellularly into both androgens and estrogens. In the United States, estriol preparations are not available, and Premarin cream is mostly prescribed. Premarin contains conjugated estrogens. Although not available at the moment, in the future there may be a role for estrogen receptor β analogs. The benefits pertained by using these treatments are multiple and include alleviation of symptoms caused by the genitourinary syndrome of menopause (GSM), for example, vaginal dryness, itching, pain, sexual concerns, and urinary problems; restoration of urogenital physiology including a reduction in risk of urinary tract infections (UTIs); improved quality of life; and increased likelihood of obtaining satisfactory cervical smears.1 Transvaginal estrogen all have documented efficacy and safety profiles and do not elevate systemic estradiol levels above the normal postmenopausal reference range at licensed doses.2 They can be considered for women with a history of any estrogen receptor-positive cancer after an informed decision-making process, and for many well-informed women, the benefits of their use outweigh any theoretical or unproven risks.
Alleviation of GSM Symptoms Genitourinary syndrome of menopause describes hypestrogenic changes to the vulvovaginal and bladder-urethral areas that occur following menopause.3 For some women, these changes can start in the perimenopause, and by the mid to late 1950s, symptoms can become severe enough that women seek care specifically for them. Symptoms are very common, affecting approximately 70% of all menopausal women.4 Symptoms include genital changes (dryness, itching, burning, pain, and irritation), sexual concerns (dyspareunia, decreased arousal, reduced lubrication, postcoital bleeding, reduced or absent orgasm), and urinary problems (urgency, nocturia, dysuria, recurrent UTIs, and urinary incontinence).4,5 Women who have not had a vaginal birth in the past appear to present with more severe sexual symptoms and at an earlier age compared with multiparous women. Collectively, these symptoms can cause significant distress, reduced quality of life, depression, anxiety, and other mood disorders6 and unlike vasomotor symptoms do not usually improve with time; instead, they are chronic and progressive. A response to hormonal treatments is usually rapid and sustained with most women obtaining substantial relief even after 3 weeks.5 Although GSM symptoms are primarily treated with vaginal estrogens, the vestibule, and the vulva cannot be ignored as they also undergo atrophy and may require focused treatment here too. If treatment is discontinued, symptoms will usually return, and so maintenance regimens are required.5 An improvement in urinary symptoms, particularly recurrent UTIs, deserves particular attention. Many postmenopausal women are treated with antibiotics for their recurrent UTIs when the underlying cause is GSM. This can lead to a perennial cycle of antibiotic prescribing with resulting antibiotic resistance. Reductions in UTIs with improvements in urinary continence and overactive bladder symptoms all usually occur with transvaginal estrogen use.7–12 One study demonstrated the estradiol ring releasing 7.5 μg per 24 hours and oral oxybutynin to have comparable efficacy for the treatment of overactive bladder.13
*Restoration of Urogenital Physiology
Estrogen receptors, both α, and β are ubiquitous in the vagina, urethra, bladder trigone, and pelvic floor.4 This is because these structures share the same embryological origin, the primitive urogenital sinus tissue.14 When estrogen levels decline during perimenopause and menopause, the effect is a progressive dominance of parabasal cells, and the multilayered squamous vaginal epithelium becomes thinner.15 The vagina loses its pink color, the introitus retracts, and the epithelium becomes friable with petechiae, ulceration, and fragility. The density of sensory nociceptor neurons in the vagina increases, which is likely to contribute to some of the symptoms of discomfort.16 As there is a loss of glycogen-rich superficial cells, there is a reduction in the colonization of the vagina by Lactobacillus, and the vaginal pH increases.5,17 When Lactobacillus levels reduce, colonization by other unwanted pathogens increases, and this can be the cause of urinary infections and vaginal odor. The most common cause of these pathogens is fecal flora. This means the postmenopausal vagina is at risk of infection and inflammation.5 Elastin becomes fragmented, and collagen is subject to hyalinization.5,17 This causes a loss of vaginal rugae, and the vagina becomes shorter and narrower, contributing to pain with penetrative sexual activity. The altered collagen turnover may also contribute to vaginal prolapse.18 Smooth muscle in the superficial layers of the bladder trigone and proximal and distal urethra atrophies,19 the urethral mucosa becomes thinner,20 and there is decreased activity of the α-adrenergic system innervating the bladder neck and urethral sphincter.21 The same pH changes in the vagina can also affect the lower urinary tract, increasing the risk of urethritis and cystitis.5 Use of vaginal estrogen restores urogenital physiology. It lowers vaginal pH, increases subepithelial capillary growth, thickens the epithelium, raises the level of vaginal secretions, and reduces the density of autonomic and sensory vaginal innervations.22 These changes lead to a reversal of atrophy.
*Improving Cervical Smears
Severe symptoms of GSM can often be a barrier for women to achieve satisfactory cervical cancer screening or colposcopy.23 Because the squamous epithelium becomes very thin, insertion of the speculum can cause extreme discomfort and even traumatic hemorrhages.23 The transformation zone is also less likely to be fully visualized or sampled in women with GSM because of inversion of the endocervical canal,1,23 and there is some evidence that the hypoestrogenic state seen after the menopause produces reactive cytological atypia, which can be misinterpreted as atypical squamous cell of undetermined significance.1 Short-term treatment with intravaginal estrogen for as little as 6 weeks has been shown to improve the ability to distinguish between benign atrophic inflammatory changes and true preinvasive disease.1 It also can often reduce discomfort during the examination and increases the likelihood of satisfactory smear results by causing enough ectropion of endocervical cells to visualize or sample the full transformational zone.1
*Maintaining Quality of Life and Emotional Well-being
Recognizing the positive impact intravaginal estrogen can have on emotional well-being and quality of life cannot be overemphasized. Several large surveys demonstrate the negative effects of inadequate symptom control on lifestyle measures.24–27 In the REVIVE Survey, which involved 3046 postmenopausal women from the United States, GSM symptoms negatively affected the enjoyment of sex (59%), intimacy (85%), relationships with their partner (47%), sleep (29%), overall enjoyment of life (27%), and temperament (23%).27 In the VIVA survey, which included 3520 postmenopausal women in 6 countries, GSM symptoms negatively impacted sexual intimacy (64%), loving relationships with a partner (32%), overall quality of life (32%), feeling healthy (21%), and feeling attractive (21%).24 In the international CLOSER survey, which included 4100 women and 4100 men, vaginal discomfort had a negative impact on the intimacy of both partners.26 It is not surprising therefore that a recent case-control study, which included half a million women, found a significantly increased risk for depression and anxiety in women with symptomatic GSM compared with women without GSM.6 Thus, it remains very concerning that only 7% of women with GSM receive treatment.4
*Systemic Absorption of Vaginally Administered Hormonal Therapy
Licensed doses of transvaginal estrogen do not elevate systemic estradiol levels above the normal postmenopausal range (which is likely to be <10 pg/mL), with long-term use.2 At treatment initiation, there may be a small peak in absorption; however, this is transient and declines as the vaginal epithelium thickens, which in general occurs after 2 to 4 weeks (but is slower in women on aromatase inhibitors).2,28 Low-dose estrogen preparations include the estradiol vaginal ring, which has a typical serum level of 8.0 pg/mL and a maximum annual delivered systemic dose of 2.74 mg29,30 and 10 μg estradiol vaginal tablets, which result in a typical serum level of 4.6 pg/mL and a maximal annual delivery dose of 1.14 mg. To put this into perspective, this means the total administered vaginal dose per year of a preparation containing 10 μg of estradiol used twice weekly is comparable to the single dose of a 1 mg estradiol oral tablet.31 Lower doses can be given if desired, and the lowest documented doses with proven efficacy are estriol 30 μg and estradiol 4 μg, both administered twice weekly.32,33 It is important to mention that considerable absorption of estriol occurs with vaginal cream and tablets. However, this is a weak estrogen, and there is no conversion to the more potent estrogens, estradiol, or estrone.5,34 Intravaginal dehydroepiandrosterone has also not been shown to cause significant changes in serum estradiol or androgen levels.35
*Risks
The Women's Health Initiative Observational Study examined the risks of transvaginal estrogen use, and the findings were very reassuring.36 This was a prospective cohort study of approximately 45,000 women that assessed coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, and invasive breast cancer. The study showed no increased risks for any condition with vaginal estrogen use. Because absorption of vaginal estradiol remains below the reference range in postmenopausal women, it is reasonable to conclude that any concerning risks following treatment use would be rare and unlikely.2 All preparations, however, could cause minor problems, such as vaginal irritation, discharge, or breast tenderness, and there has been a link with a greater frequency of mycotic infections.31
*Primary Breast or Endometrial Cancer
There is no increased risk of primary breast cancer development with the use of transvaginal estrogen.36–39 In fact, an advantage of transvaginal estrogen is that a progestogen is not required, and an increase in breast cancer risk seems to be related to the addition of a progestogen.40 There is also no increased risk of endometrial cancer or hyperplasia with low-dose vaginal estrogen use; occurrences are rare and consistent with rates in the general population.15,36 Systemic reviews have shown endometrial safety for both topical estradiol and estriol for up to 52 weeks.41–43 Large observational follow-up studies evaluating longer exposure to vaginal estrogens also confirm this,36,38 and a Cochrane review of randomized controlled trials (RCTs) reported no significant differences among transvaginal estrogens formulations in terms of endometrial thickness or hyperplasia.44
*Women Considered at High Risk for Cancer Development
The use of systemic estrogen-only hormone therapy appears to not increase the risk of breast cancer in women with increased risk because of family history.29,45 Similarly, evidence suggests estrogen therapy does not increase breast cancer risk in carriers of the BRCA1 or BRCA2 mutation with intact breasts,46–49 although the relatively small sample sizes of the BRCA trials could miss a rare finding. Given these findings were obtained from high-risk women using systemic estrogen therapy, it is likely that lower doses used in vaginal therapy do not elevate a high baseline risk. The BRCA1 and BRCA2 genes increase the risk of invasive epithelial ovarian cancer, and risk-reducing salpingo-oophorectomy is often recommended. Data on estrogen replacement in this group demonstrate it is safe.50 There are no studies available for women with Lynch syndrome.51
*Women With a History of Cancer
Management of GSM in women with a history of cancer that was not estrogen receptor-positive is similar to that for women without a cancer history. For those women with a history of estrogen-receptor-positive cancer, namely, breast cancer, endometrial cancer, ovarian cancer, adenocarcinoma of the cervix, and some uterine sarcomas, the use of intravaginal estrogen can be considered after an informed decision making and consent process.
*History of Hormone Receptor-Positive Breast Cancer
Many women with a history of the breast cancer experience severe and early symptoms of GSM as an iatrogenic consequence of chemotherapy, radiotherapy, surgery, or use of adjuvant endocrine therapies such as tamoxifen or aromatase inhibitors.29 Hormone receptor-positive breast cancer makes up 75% of cases, and this subset of women understandably often feels particularly cautious about using vaginal estrogens.29 Most of their treatment strategies will have focused on lowering systemic estrogen concentrations, for example, by blocking estrogen at the level of the receptor with tamoxifen or reducing estrogen production with aromatase inhibitors, or by suppressing ovarian production with gonadotropin-releasing hormone agonists.29 However, the assumption that less systemic absorption of vaginally administered estrogens equates with less breast stimulation has not been established. Several lines of evidence suggest that estrogens may, in fact, cause breast cancer cell apoptosis after a period of estrogen deprivation.52–54 This has been termed the estrogen-deprivation hypothesis.53 Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone receptor-positive breast cancer tumor cells to low-dose estradiol therapy.55 A randomized trial in women with advanced breast cancer and acquired resistance to aromatase inhibitors reports that an estradiol dose of 6 mg daily helped prevent recurrence and improve breast cancer sensitivity to treatment.55 Of all the data, there is currently only 1 study that describes an increased risk of recurrence in women taking hormone replacement therapy after a history of breast cancer,56 whereas 3 studies demonstrate a decreased risk,57–59 and most studies demonstrate no difference whatsoever.60
Nonhormonal options are often given as the first-line treatment option for managing symptoms of GSM in women with prior estrogen receptor-positive breast cancer.37 These non-hormonal options include emollients, vaginal moisturizers, and vaginal lubricants. These options moisturize and lubricate, which for some women may be enough, but they do not significantly alter the vaginal biome or modify tissue change. An individualized approach is needed, and for many well-informed breast cancer patients, the use of low-dose vaginal estrogen is acceptable after a careful discussion about any theoretical and unproven risks.4 An individualized discussion involves balancing the risk of recurrence, which is influenced by the stage, grade of cancer, presence of lymphovascular invasion, hormone receptor status, use of endocrine therapy, time since diagnosis with the efficacy of conservative therapies, the severity of GSM symptoms, and associated quality of life.29
Tamoxifen binds with a high affinity for the estrogen receptor, and there is little concern that the use of local estrogen may compromise its effects. It is more likely that tamoxifen will compromise the vaginal estrogen.5 Ospemifene is a selective estrogen receptor modulator approved for the treatment of GSM in postmenopausal women who are not candidates for intravaginal estrogen. It evolved from a tamoxifen metabolite and has weak antiestrogen activity on the breast tissue. Clinical studies since its approval have indicated no increased risk for breast cancer among patients receiving it.61
In contrast, for women taking aromatase inhibitors, the use of vaginal estrogen has been more controversial. Because aromatase inhibitors reduce estrogen production, for some it seems counterintuitive to prescribe concomitant estrogen. Furthermore, some data show increased absorption of vaginal estradiol in women using aromatase inhibitors.15 Switching an aromatase inhibitor to tamoxifen could be an appropriate option, and this decision would need to be made in conjunction with a breast specialist. However, the use of add-back vaginal estrogen in women using aromatase inhibitors should not be an absolute contraindication.4 The profound estrogen depletion caused by aromatase inhibitors can cause such substantial distress that it can trigger treatment discontinuation62 due not only to the impact of this treatment on vulvovaginal health but mood, and cognition. and osteoporosis as well, and for some, this might be avoidable. A recent meta-analysis, which included 11 high-quality studies, provided indirect evidence for the safety of intravaginal estrogens in women taking aromatase inhibitors.4,63 Furthermore, the BLISSAFE study in women taking aromatase inhibitors randomized to either vaginal estriol or placebo for 12 weeks showed symptom benefit and no effect on gonadotropins, serum estradiol, or estrone.64 The concept of measuring serum estradiol levels in women taking aromatase inhibitors to access systemic absorption of vaginally administered estrogen has been asked. This is not recommended; very small changes in pharmacokinetics are hard to assess accurately in postmenopausal women unless very sensitive mass spectrometry methods are used.65 An assay needs to measure estradiol down to at least 0.3 pg/mL to be used to determine the degree of suppression of estradiol in women with breast cancer treated with aromatase inhibitors.2 In addition, there is a lack of clarity regarding whether higher levels within a narrow postmenopausal range are associated with an increased risk of breast cancer recurrence and similarly whether lower levels are reassuring.66
Although there is a paucity of data, current evidence does not show an increased risk of breast cancer recurrence among women using low-dose vaginal estrogen who have a history of estrogen receptor-positive breast cancer.4,67–70 One nested case-control study showed that, after 3.5 years of follow-up, local vaginally administered estrogen was not associated with breast cancer recurrence among women taking either aromatase inhibitors or tamoxifen.67 Several organizations, including the American College of Obstetricians and Gynecologists, have endorsed the use of specific low-dose vaginal estrogen products and therapies acting in the vagina such as estrogens in women with breast cancer, including estrogen receptor-positive disease.68 Furthermore, a large study looking at ospemifene also indicates no increased risk for breast cancer recurrence with its use.61
*History of Endometrial Cancer
The majority of endometrial cancers are diagnosed at an early stage and have a good overall prognosis, with a 5-year survival rate of greater than 85%.51 Treatment usually involves hysterectomy and bilateral oophorectomy.51 The most common type is a lowgrade endometrioid adenocarcinoma, which is considered an estrogen receptor-positive neoplasm.71 Because of this, there have been concerns about disease recurrence with exogenous estrogen use. However, in an RCT, women treated with oral estrogen after a history of grade 1 or 2 endometrial adenocarcinomas had low absolute recurrence rates.72 In addition, a systematic review concluded that although there is insufficient high-quality evidence to make firm conclusions, from the available evidence, if hormone replacement is used after surgical treatment for early-stage endometrial cancer, it is unlikely to cause harm.73 By extrapolation, it is likely that low-dose intravaginal estrogen is also safe for these women. More recently, a retrospective cohort study concluded that intravaginal estrogen does not appear to increase recurrence risk beyond the baseline for women with both early and advanced disease.71 These findings provide some reassurance about intravaginal low-dose estrogen use in women with either early-stage or even higher-stage endometrial cancers suffering from GSM.
*History of Ovarian Cancer
The 3 major types of ovarian cancer include epithelial (90% of cases), sex cord-stromal, and germ cell tumors. Epithelial ovarian cancers are divided into 5 histological types: high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous.51 Of the epithelial ovarian tumors, there is no evidence of any estrogen receptors in women with clear cell or mucinous tumors.51 In contrast, endometrioid and serous epithelial ovarian tumors can be hormone receptor-positive.51 Following treatment for an early endometrioid disease, the use of exogenous hormone therapy appears to be safe.51 However, there have been concerns that this might not be the case in women with more advanced endometrioid tumor disease, where residual hormone-responsive disease could theoretically remain after surgery.51 Nonetheless, any suggested effect of intravaginal estrogen on residual disease is unproven and theoretical only. In addition, a recent retrospective cohort study demonstrated no increased recurrence risk in women using intravaginal estrogens with a history of ovarian cancer, and in this study, high-grade serous and endometrioid histologies were the most prevalent.71 The most common sex cord-stromal tumor is a granulosa cell tumor. These tumors secrete estrogens as well as other hormones.51 For this reason, women with these tumors are typically denied exogenous estrogens.51 However, no study has demonstrated any deleterious effects on these tumors with exogenous estrogen use.51 Ovarian germ cell tumors are a category that affects girls and young women. There is no evidence of any adverse effects from estrogen treatments in these tumor types.51 In the absence of definitive data, shared decision-making involves a comprehensive discussion of off-label use, as well as benefits, and is justified.
*History of Adenocarcinoma of the Cervix
Estrogen and progesterone receptors are expressed in approximately one-third of cervical adenocarcinomas.51,74 A recent retrospective cohort study of 244 women who received vaginal estrogen found no increased risk of cervical cancer recurrence, and in this study, 40.3% of the cervical cancer cohort had prior adenocarcinoma.71 Furthermore, in a very recent small retrospective study of women younger than 50 years with stage 1B–2B cervical adenocarcinomas, there was a trend toward improved survival rates with hormone replacement therapy.75
Conclusion
Low-dose intravaginal estrogens appear to be a safe and effective treatment for symptoms of GSM with the benefits of restoring urogenital physiology, improving quality of life and mental well-being, and increasing the likelihood of obtaining satisfactory cervical smears. Women without GSM symptoms are also candidates for treatment, as such symptoms and the underlying cellular and anatomic changes are progressive, meaning treatment should be started early to prevent such effects and taken long-term to avoid recurrence. The absorption of low-dose vaginal estradiol results in very low, even immeasurable systemic estradiol levels above the normal postmenopausal range. The total administered vaginal dose per year of a preparation containing 10 μg of estradiol used twice weekly is comparable to the single dose of a 1- mg oral estradiol tablet. Because of this, any concerning risks following treatment use would be rare and unlikely, and there is no evidence of an increased risk of coronary heart disease, stroke, thromboembolism, colorectal cancer, endometrial cancer, breast cancer, or breast cancer recurrence. This should reassure both women and their health care professionals and should lead to more women receiving these localized, vaginally administered hormonal treatments.
