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Abstract

Thanks to advanced treatments, many breast cancer (BC) patients become long-term survivors, yet suffer a diminished quality of life (QOL) due to estrogen deprivation. This affects adherence to endocrine treatments, potentially compromising outcomes. While there is increasing recognition of genitourinary side effects, vulvovaginal health remains under-addressed. Many clinicians overlook the impact of endocrine therapy on the genitourinary system and lack knowledge about safe and effective treatments, leading to undertreatment and aggravated symptoms. Proper treatments not only boost the QOL but also enhance endocrine therapy adherence, directly influencing long-term outcomes. We offer an updated review and guidelines on vulvovaginal health for BC survivors. Our review details the genitourinary hypoestrogenic state, its effects on the genitourinary system, its diagnosis, as well as the safety, effectiveness, and available treatment options for BC patients. Furthermore, we offer practical recommendations for managing vulvovaginal symptoms, considering underlying mechanisms and the safe use of topical estrogen, with attention to receptor and cancer status.

Plain language summary

Practical care for vaginal health in women after breast cancer

Many breast cancer survivors experience a lower quality of life due to the lack of estrogen caused by their treatments. This can lead to uncomfortable symptoms, especially in the genital and urinary areas, and make it harder for them to adhere to their hormone therapy, potentially compromising their outcomes. Unfortunately, these issues are often overlooked by doctors, who may not feel confident that they have effective and safe tools to minimize and improve these complaints. This article reviews the effects of low estrogen on the genital and urinary systems and offers updated guidelines on how to diagnose and treat these problems in breast cancer patients. It includes practical recommendations for managing symptoms and discusses the safe use of treatments like topical estrogen, considering the patient’s cancer type and hormone status. Proper treatment can improve the quality of life and help patients stay on track with their cancer therapy, ultimately improving outcomes.

Keywords

aromatase inhibitors breast cancer genitourinary syndrome of menopause (GSM)hypoestrogenism tamoxifen vaginal atrophy

Introduction

Breast cancer (BC) is the most commonly diagnosed cancer among women¹ with a decreasing mortality rate thanks to the progress in widespread early screening and improvements in systemic therapies.² In the United States, the 5-year survival rates are as high as 90%³ (reaching as high as 99% for women free of lymph node metastases).⁴ Moreover, although most women with BC are postmenopausal with a median age at diagnosis of 62 years, 20%–30% of cases will be diagnosed in women younger than 50 years of age, and 7% will be diagnosed in those younger than 40 years of age.⁵ Thus, addressing survivors’ unique post-treatment needs is critical to providing quality healthcare and ensuring treatment adherence.⁶

Many BC survivors of all ages suffer from menopausal symptoms of varying severities at some point during their cancer journey due to an estrogen deficiency state resulting from ongoing anti-estrogenic treatment, chemotherapy-induced amenorrhea, premature ovarian insufficiency (POI), or spontaneous menopause. As conventional estrogen replacement therapy is usually contraindicated, and many healthcare providers are unaware of other effective treatment modalities, many BC survivors remain undertreated.^7–9 Unlike vasomotor symptoms, such as hot flashes that usually improve over time, genitourinary symptoms, including vaginal dryness, burning, dysuria, and dyspareunia, are generally progressive without effective therapy.^10–12 Unfortunately, these conditions are underdiagnosed and undertreated as many clinicians often overlook and misdiagnose vulvovaginal symptoms that worsen with time, and a detrimental effect on the quality of life (QOL) is seen.^13–17 Consequently, there is an increased risk of compromising BC treatment compliance, with a reported discontinuation rate of 20%–40% of BC survivors receiving endocrine treatment due to hypoestrogenism-related side effects.^18–20 In the SOFT and TEXT studies examining endocrine therapies for pre-menopausal patients at diagnosis, 21%–25% discontinued their prescribed oral therapies by the 4-year mark. Among those on ovarian function suppression and exemestane, there was no observed improvement in vaginal dryness over time.²¹ Thus, healthcare professionals (HCPs) treating BC survivors must understand and mitigate endocrine therapy (ET) side effects to improve patient QOL and treatment adherence. Thorough knowledge of hormonal and non-hormonal treatment options is crucial for HCPs to address potential therapy-induced complications.^8,12,22

This review outlines strategies for managing genitourinary health in BC patients, emphasizing the roles of endocrine therapies and chemotherapy in hypoestrogenic states and their genitourinary effects. We present an updated approach to diagnose and treat estrogen-deficiency-related vulvovaginal symptoms in these survivors.

Adjuvant therapy in BC survivors and hypoestrogenism

Beyond local breast and lymph node interventions (surgery, with potential radiation), most women receive (neo)-adjuvant treatments, such as hormonal therapy, chemotherapy, biological agents, and immunotherapy, based on tumor type to reduce recurrence risk.⁴ About 70%–80% of BCs are estrogen receptor (ER)-positive, with racial and ethnic variations.^5,23 Tamoxifen or an aromatase inhibitor (AI) is typically prescribed as adjuvant ET for these cases.^24,25 Tamoxifen, a selective estrogen receptor modulator (SERM), blocks ER in normal and BC cells. Its interaction with vaginal ER may vary based on hormonal state: in premenopausal women, it tends to exhibit antiestrogenic effects, while in postmenopausal women, it can occasionally mimic estrogen, enhancing vaginal secretions.^26–29 AIs inhibit aromatase, the enzyme converting androgens to estrogens peripherally, suppressing plasma estrogen levels by blocking 95% of its synthesis and reducing concentrations from 20 to 3 pmol/L or lower.^28,30 AIs are effective only in patients without functional ovaries. For premenopausal women on AIs, ovarian suppression is typically induced^24,25 either with a gonadotropin-releasing hormone agonist (GnRH-a), less frequently surgical oophorectomy, or rarely, in metastatic cases, ovarian irradiation.^31,32 Incorporation of AIs as part of adjuvant ET is the preferred approach in post-menopausal women and is recommended along with ovarian suppression in pre-menopausal patients at high risk of recurrence.³³ Fulvestrant, another adjuvant ET, is a competitive ER antagonist that acts as an ER down regulator and is used in patients with advanced or metastatic disease.³⁴

Adjuvant chemotherapy, frequently combined with ET, depends on factors like lymph node status and tumor size. Gonadotoxic drugs, for example, cyclophosphamide, can induce POI by damaging follicles, notably in women over 40, within a year post-BC treatment. Over half of BC patients in their 40s and 15%–30% under 35 face complete ovarian failure depending on the treatment.^35,36 The ovarian impact of newer agents like immunotherapy remains unclear.

While these therapies significantly improve clinical outcomes and survival rates,^8,37 they also induce both acute and chronic estrogen deprivation effects in multiple organs and tissues.^38,39

Hypoestrogenism effect on the genitourinary tract—physiology

The vulvar vestibule, vagina, urethra, and bladder trigone derive from the estrogen-responsive urogenital sinus. ER are also found in pelvic muscles, endopelvic fascia, and vaginal and vulvar neurons, highlighting estrogen’s pivotal role in influencing genitourinary functions, pain modulation, and muscle composition and function. Estrogen withdrawal can lead to significant anatomic and physiological changes attributed to reduced collagen content and hyalinization, decreased elastin and adipose tissue, altered appearance and function of smooth muscle cells, increased density of connective tissue, loss of water-retaining ability, fewer blood vessels, and reduced blood flow. Regarding the vaginal microbiome, diminished estrogen leads to fewer glycogenated superficial cells, a shift from lactobacillus bacterial dominance to anaerobic Gram-negative rods and Gram-positive cocci, consequently raising vaginal pH.¹¹ Table 1 summarizes the physiologic effect of hypoestrogenism on the genitourinary tissues.^11,28,40

Table 1.

The physiologic effect of hypoestrogenism on the urogenital tract.

Urogenital site	Effect of hypoestrogenism
	Loss of labial and vulvar fullness, turgor, and elasticity
	Loss of pubic hair
	Labia minora thinning and regression
	Constriction of introitus
Vagina	Thin, pale, and smooth vaginal epithelium
	Short and narrow vaginal vault
	Decreased flexibility and elasticity
	Friable tissue with petechiae, ulcerations, and tears in severe cases
Vaginal microbiota	Anaerobic Gram-negative rods and Gram-positive cocci microbiota, loss of lactobacilli dominance
Vaginal secretions	Diminish secretions
Vaginal secretions	Elevated pH
Pelvic floor muscles	Weakness and mobility limitation
Urinary tract	Reduced urethral closure pressure due to weakening of the surrounding tissue
	Decreased urethral smooth muscle sensitivity
	Reduced bladder sensory threshold

Clinical consequences of hypoestrogenism on the genitourinary tract

Reduced estrogen levels in genitourinary tissues give rise to genitourinary syndrome of menopause (GSM), also termed vulvovaginal atrophy or genitourinary atrophy.⁴¹ GSM affects the vulva, vagina, urethra, bladder, and pelvic floor, manifesting as genital, sexual, and urinary symptoms. Genital concerns include vulvar irritation, altered skin barrier sensitivity, dryness, and discharge. Sexual issues arise from inadequate arousal, lubrication, epithelial thinning, and potential anatomic constriction (narrowing and stenosis), causing discomfort or pain during intercourse. Reduced vaginal capillary blood flow can impair engorgement during arousal, exacerbating dyspareunia, and diminished sexual function.^28,40 Urinary symptoms result from the atrophic epithelium and weakening of the surrounding tissue that can be expressed as urgency, frequency, nocturia, incontinence, dysuria, and recurrent urinary tract infections (UTIs).^28,40

GSM in BC survivors

Symptoms of GSM are frequent in BC survivors for several reasons. Many patients are menopausal at diagnosis, with symptoms intensified either by cessation of estrogen replacement therapy or the effects of chemotherapy on residual post-menopausal ovarian estrogen synthesis.¹⁷ Younger patients may face POI from chemotherapy or ovary removal.^42,43 Additionally, in women with ER-positive tumors, the use of GnRH-a and AIs for estrogen suppression has increased over time,⁴⁴ with treatment periods sometimes lasting up to 10 years.^8,4,45 Consequently, BC survivors exhibit GSM symptoms at a higher rate compared to the general population (74% vs 50%),^{15,29,39,46,47} and these symptoms are often more severe.²⁹ In young women, the rapid estrogen drop further amplifies these symptoms and increases distress from changes in sexual function.^48,49 Moreover, GSM that develops in the cancer treatment setting has been associated with more significant sexual dysfunction, distress, and poorer QOL outcomes.^15,48–50 Data also suggest that although long-term survivors of BC often report normalization of physical and emotional functioning, they experience continued difficulty with sexual functioning and satisfaction for five or more years after treatment.^12,41

GSM diagnosis

GSM diagnosis involves a comprehensive clinical evaluation, which includes symptom assessment and physical examination. For a confirmed diagnosis, at least one bothersome sign or symptom unrelated to other conditions, such as vulvovaginal dermatoses or infection, is necessary.¹¹

History

The goal of history-taking is to ascertain the presence, severity, and impact of GSM symptoms on sexual health, intimacy, and QOL. Since women might withhold details due to embarrassment or seeing GSM as a natural aging consequence, proactive inquiry by HCPs is crucial, especially in BC survivors.^{11,16,43,51–56}

This process should consider menstrual patterns, past treatments, and other potential causative factors. It is essential to differentiate symptoms tied to estrogen loss from other factors like inflammation, infection, or prior surgeries. A sexual history can help determine if symptoms relate to sexual activity. A detailed sexual history can correlate symptoms to sexual activity. Given the profound impact of GSM on QOL in BC survivors,^30,48,50,57 understanding its daily and intimate implications is vital.²⁸

Physical examination

The gynecologic examination should identify signs consistent with GSM and eliminate other pathologic conditions that may cause similar symptoms, such as vaginitis, lichen sclerosus, or other dermatopathology.^11,12

The external genitalia may display diminished mons pubis and labia majora, reduced hair, elasticity, and moisture, as well as constricted introitus. The labia minora might show fusion or resorption, with a more noticeable clitoral and urethral meatus. A caruncle might appear at the urethral meatus, and the vestibular tissue may become pale. Vaginal atrophy typically presents as a pale, dry, smooth epithelium with decreased rugation. Underlying blood vessels may be visible through the thinned epithelium. A thin yellow discharge is common. Inflammation might show as erythema, petechiae, friability, bleeding, or purulent discharge. The vagina may lose elasticity, shorten, narrow, and have obliterated fornices, aligning the cervix with the vault.^11,28 When the main complaint is dyspareunia, a targeted physical examination should also be done to identify the specific pain component. This algorithm was recently described in our previous work⁵⁸ and should include an evaluation of vestibular tenderness, vestibular atrophy, pelvic muscle hypertonicity, and tender annular hymenal ring or scar tissue.

Complimentary examination to support GSM diagnosis

Wet-mount microscopy and vaginal pH assist in GSM diagnosis. A pH over 5.0, excluding factors like infections or semen, signifies estrogen-deficient vaginal atrophy.^59,60 Microscopy shows immature vaginal cells with pronounced nuclei (parabasal cells), more than one white blood cell per epithelial cell, and few or no lactobacilli. A shift to a diverse microbiota, including enteric organisms commonly associated with UTIs, may be observed.¹²

Assessment tools for evaluating GSM symptoms

For assessing GSM and sexual function, standardized tools like the visual analog scale (VAS), vaginal health index (VHI), and female sexual function index (FSFI) are employed to monitor outcomes.^12,61

VAS records patient disturbances on a 10-point scale, and the FSFI, validated for female cancer survivors, assesses sexual function through self-reports.^62,63 Both provide insights into subjective symptom severity.⁶⁴ The Vaginal and Vulvar Assessment Scales, recently validated, also evaluate GSM symptom severity in cancer survivors.⁶⁵

GSM physical signs are often assessed using pH level, VHI, and the vaginal maturation index (VMI).⁶⁴ The VHI, introduced by Bachmann⁶⁶ in the 1990s, is widely used as an objective tool, although mainly relying on subjective parameters. Of its five parameters assessed during a speculum exam, only vaginal pH is objective; the others—vaginal elasticity, fluid volume, epithelial integrity, and moisture—are subjective, introducing potential variability between and within observers.⁶¹ A score below 15 suggests atrophy. The absence of clear instructions makes VHI evaluations susceptible to examiner interpretation.^61,67,68 The VMI is a cytologic score assessing atrophy, based on the evaluation of the ratio between parabasal, intermediate, and superficial cells in a vaginal microscopic smear, aiding in both diagnosis and treatment effectiveness.⁶⁹

The “modified Schirmer test” employs calibrated filter paper and is validated for objective assessment of vaginal dryness treatment efficacy. Contrary to pH, VMI, and VHI, which are influenced by estrogen, this test evaluates outcomes of non-estrogen-dependent treatments as well.⁷⁰

Several subjective questionnaires exist to assess QOL parameters. These include the Most Bothersome Symptoms, the Day-to-Day Impact on Vaginal Aging Questionnaire, the Vulvovaginal Symptoms Questionnaire, and the Vulvar Pain Assessment Questionnaire.⁶⁴

Treatment

In addressing GSM in BC survivors, the primary objective is QOL enhancement. Educating patients on GSM and BC treatment effects is vital. Treatment decisions should factor in patients’ therapeutic needs and BC recurrence concerns, with discussions covering known mechanisms of action, efficacy, potential side effects, safety data, and any knowledge gaps regarding specific risks^{8,12,17,21,71,72} (Table 2). Embracing a shared decision-making approach based on informed consent⁷³ is paramount, emphasizing that multiple treatment trials might be needed to attain individual patient’s efficacy and tolerance.⁸ In relevant cases, consultation with the woman’s oncology team is advised.^12,22 Upon initiating therapy, subsequent follow-ups should evaluate symptom improvement, treatment adherence, and potential barriers.¹²

Table 2.

Available treatment options for GSM in BC survivors.

Treatment	Mechanism of action	Indication and instruction	Efficacy	Safety
Non-hormonal interventions
Vaginal lubricants(water, silicone, and oil-based products)	Form a short-term physical barrier that reduces friction between surfaces and diminishes discomfort.	- Use during sexual activity- applied to both partners’ genitals prior to vaginal penetration- Lubricants with an osmolality of <380 mOsm/kg and pH in the normal range (3.8–4.5) are recommended	Short-duration efficacy in reducing dyspareunia resulting from mild dryness, irritation, and friction	- Possible genital irritation with additives such as parabens, glycerin, warming properties, flavors, perfumes, and spermicides- Oil-based lubricants can erode condoms
Vaginal moisturizers(Gel, cream)	Maintaining prolonged tissue integrity and elasticity as well as replacing normal vaginal secretions by:- Attracting and retaining moisture- Forming a protective barrier to prevent water loss- Often maintain the vagina’s optimal acidic pH	- Recommended when daily symptoms are present- Use regularly to be effective- 3–5 times a week before bedtime	- Effective in reducing daily mild-moderated vulvovaginal irritation, itching, and burning sensations- Not suitable for severe GSM	- Possible genital irritation with additives such as parabens, glycerin, warming properties, flavors, perfumes, and spermicides
Hyaluronic acid vaginal preparations	- Stimulates the tissue’s water-retention capabilities.- Releases water molecules into the tissue → providing lubricating and moisturizing effects to maintain a proper level of hydration and viscoelasticity	- 3–5 times a week before bedtime- Insert into the vagina- Apply manually on the vulvar skin	- Improving vaginal and vulvar dryness, discomfort, irritation- Decreasing vestibular irritation	Possible genital irritation with additives
Vitamin Dand E suppositories	- Vitamin D is involved in regulating cell development and differentiation, especially in the stratified epithelium tissue of the vagina- Vitamin E has an anti-inflammatory, antioxidant role, and healing properties	- Vitamin E 30–200 IU- Vitamin D 1000 IU- Use every night	Efficient in:- Lowering pH,- increased VMI,- Improved subjective GSM symptoms	-
Lidocaine	Topical anesthesia for tender vulvar vestibule	- Topical aqueous 4% lidocaine- Fully saturated cotton ball applied to the vulvar vestibule a few minutes before sexual activity	- Reduction in dyspareunia due to vestibular tenderness- Reversing vestibular sensitivity	- Considered a safe option for painful intercourse in BC survivors- Male partners may report penile numbness
Vaginal dilators+/−PFPT+/−vibratory stimulation	Dilators provide mechanical stretching of the tissue and maintain vaginal elasticityVibratory stimulation increases blood flow to the tissuePFPT relaxing pelvic floor muscles can aid with both dilators and vibratory stimulation	- Recommended to use several times per week, although the ideal duration and frequency are unknown- vaginal dilators should be used in graduated sizes- Adjunctive work with a pelvic floor physical therapist has a beneficial outcome	- Reduce dyspareunia resulting from loss of vaginal capacity and narrowed introitus- Improve elasticity- Give women confidence that they can insert an object into the vagina without pain	Not supported by clinical trials on BC survivors
Energy-based treatments (CO₂ laser, Er-YAG laser, RF)	Laser:The thermal effect of fractional beams of CO₂ causes:- Minor wounds in the epithelium and lamina propria- Activation of fibroblasts- Increasing collagen production- Neovascularization and increased blood flow- Vaginal tissue regenerationRF: controlledelectromagnetic waves to produce heat within the tissue:- Synthesis of collagen- Reorganization of collagen fibers- Tissue remodeling	Data inconclusive regarding efficacyThere is an undefined optimal number of treatment cycles and a need for retreatment for persistence efficacy	Not yet clear if the reported improvement in GSM symptoms (dryness, itching, dyspareunia, dysuria, bleeding, and sexual function) is due to laser treatment or a placebo effect.	Long-term follow-up is needed to evaluate scar tissue formation and the overall safety of this intervention
Hormonal interventions
Vaginal estrogen	Reverse the hypo-estrogenic state in the genitourinary system	- Second-line option for symptomatic BC survivors who failed non-hormonal treatments- Individualizing each case with oncologists- If indicated, short-term local hormonal therapy may be considered- The lowest effective dose should be used- First 2 weeks—once a day- Maintenance dose—twice a week	Local estrogen is the most effective way to treat GSMAll forms of vaginal estrogens have a similar effectiveness but different levels of systemic absorptionProven efficacy in most bothersome symptoms (dyspareunia, dryness, irritation, soreness, dysuria, or bleeding associated with sexual activity)	Possible systemic absorption → Unknown association between systemic absorption and recurrence risk or stimulation of occult BC cells is unknownSafer on tamoxifen treatment rather than AIsAdverse events:- vaginal discharge,- vulvovaginal candidiasis,- vaginal bleeding- breast pain.
Intravaginal DHEA	DHEA is transformed within the vaginal mucosal cells to androstenedione, which, in turn, can be converted to testosterone and estrogens through aromatization	- A daily use low-dose DHEA vaginal insert- It is indicated for moderate to severe dyspareunia caused by vulvovaginal atrophy.	Improvement in vaginal cell maturation, pH, dyspareunia, and FSFI scoreno studies directly comparing vaginal DHEA to vaginal estrogen in efficacy or hormone levels	Its use raises concern as DHEA metabolizes into estrogenIncreases DHEA-S and testosterone levels (within the lower quartile of the postmenopausal range)Vaginal discharge
Vaginal testosterone	Testosterone can induce the proliferation of the vaginal epithelium	Daily use of 150–300 µg of testosterone propionate	Efficient in improving signs and symptoms of vulvovaginal atrophy, dyspareunia, and sexual dysfunction	The safety of vaginal testosterone could not be concluded as longer follow-ups are needed
Oral Ospemifene	Ospemifene is a SERM with an estrogen agonist effect on vaginal tissues and bone and a probable antagonist effect in breast tissue.	- can be considered in high-risk women who are not concurrently taking another SERM for BC risk reduction- 60 mg/day	- Improvement in GSM symptoms- Higher patient satisfaction and adherence compared to other local therapies	Clinical studies have indicated no increased risk for BC incidence, recurrence, or breast-related safety concerns among patients receiving ospemifene

AIs, aromatase inhibitors; BC, breast cancer; DHEA, dehydroepiandrosterone; FSFI, female sexual function index; GSM, genitourinary syndrome of menopause; PFPT, pelvic floor physiotherapy; RF, radiofrequency; SERM, selective estrogen receptor modulator; VMI, vaginal maturation index.

Vulvar skincare

Throughout life, the vulva is highly sensitive to various irritants compared to other skin areas. Age and estrogen deficiency amplify this vulnerability. Elevated skin pH and reduced lipid production diminish its antimicrobial action and healing speed, posing to trauma and infection. Frequent vulvar damage can occur from clothing abrasion or panty liners. Additionally, its proximity to the rectum and exposure to ammonia in those with urinary incontinence further heighten vulnerability. Hence, patients with vulvovaginal symptoms should adopt vulval care, using regular emollients and avoiding irritants (Box 1).^13,58,74,75

Box 1.

Counseling patient on vulvar skin care.

1. Identify and avoid common irritants and allergens a. Sweat, urine, and feces b. Adult or baby wipes c. Colored or scented toilet paper d. Laundry detergents, fabric softeners, dryer sheets e. Sanitary pads and panty liners f. Soaps, bubble baths and salts, shampoos, conditioners g. Tea tree oil h. Vaginal hygiene products, including perfumes and deodorants i. Vaginal douching j. Contraceptive creams, jell, spermicide-containing condoms k. Over the counter and prescribed topical medication: i. Anesthetics—mostly those containing benzocaine ii. Antibacterial—mostly those containing neomycin iii. Antimycotics iv. Corticosteroids v. Hormonal creams vi. Preservatives found in cream bases—parabens, chlorcresol, benzyl alcohol.2. Correction of skin barrier function a. Sitz baths—plain tepid water b. Pat dry the vulva after bathing (do not rub) c. Apply preservative-free emollient to hold moisture in the skin d. Add estrogen if indicated after consultation with the oncologist e. Treat superimposed infection when present (oral fluconazole, oral antibiotics).3. Stop scratching a. Nonspecific: Sitz baths or cool packs b. Specific: i. Hydroxyzine or doxepin 10–75 mg for night itch. ii. Cetirizine 5–10 mg bid or Citalopram 20–40 mg for day itch.

Lifestyle modification and control of underlying medical conditions

Women with multiple health conditions often experience urinary incontinence, genitourinary atrophy, and sexual issues. Beyond estrogen deficiency, contributors to GSM include smoking, infrequent coitus, vaginal nulliparity, and prior vaginal surgeries.²⁸ Smoking, linked to urgency, frequency, and rapid vaginal atrophy, reduces genitourinary blood flow.^76–78 Quitting smoking and weight management can counter these effects by increasing capillary refill.^79,80 A 5%–10% weight drop improves urinary incontinence.⁸¹ Managing diabetes, obesity (BMI >30), and hypertension can also improve genitourinary and sexual health.⁸² Additionally, addressing underlying emotional challenges can enhance sexual function and QOL in BC patients.⁸³

Non-hormonal regimens

Decreased estrogen levels can reduce genitourinary blood flow, causing atrophy, reduced lubrication, and elasticity, leading to vaginal dryness, dyspareunia, and possible introital lacerations during intercourse. First-line therapy for vulvar and vaginal dryness in women with BC are non-hormonal moisturizers and lubricants,^12,14 sometimes combined with pelvic floor physical therapy (PFPT) and dilators for tissue elasticity enhancement.^{11,29,84–88}

Other non-hormonal treatments found to be safe and effective in clinical studies include vitamin D and E suppositories,^89–91 hyaluronic acid,^92,93 as well as 4% topical lidocaine.^94,95 Table 2 describes the mechanism of action, indication, efficacy, and safety of the available treatment options for GSM in BC survivors.

Moisturizers and lubricants

Both are over-the-counter products, effective in relieving discomfort and pain in women with mild to moderate vaginal dryness and are differentiated in their intended use.^96,97

Lubricants alleviate friction and discomfort during penetrative and external sexual activity by providing lubrication with direct application to the external genitalia, vaginal introitus, and vagina. Lubricant formulations are water, silicone, or oil-based products, short-acting, and do not affect vaginal pH or underlying moisture content.^14,96–99

It is recommended to choose lubricants with an osmolality of <380 mOsm/kg and a pH of 3.8–4.5¹² and to avoid products with irritants like parabens, glycerin, flavors, or perfumes as they may irritate the delicate genital tissues.^87,96 Notably, parabens, weakly estrogenic compounds, can disrupt endocrine function, making paraben-free options crucial for at-risk populations.⁹⁶

Vaginal moisturizers aim to replicate natural secretions, enhancing vaginal health by retaining water and rehydrating tissues.^100,101 Intended for regular use, their application frequency depends on atrophy severity, from daily to twice weekly.^87,102 Certain moisturizers, made of acidic polymers, aid in vaginal pH regulation. Data demonstrate that polycarbophil-based non-hormonal moisturizers are superior to lubricants in temporarily mitigating vaginal dryness and genitourinary atrophy, enhancing vaginal moisture, fluid volume, pH, and elasticity while decreasing dryness, itching, and dyspareunia.^103–105 In the broader general postmenopausal population, studies demonstrate moisturizers are equally effective as vaginal estrogen creams in addressing GSM symptoms.^106–108 Yet, their efficacy is often transient and less pronounced for severe symptoms.

Intercourse and mechanical measures (physical therapy and dilator use)

Estrogen deficiency can decrease tissue elasticity, causing pain or reduced vaginal capacity. Non-hormonal interventions like vaginal dilators and PFPT aim to enhance this elasticity.¹⁷ Regular vaginal penetration, via intercourse, lubricated fingers, or dilators, may prevent fibrotic changes, provide mechanical tissue stretching, and preserve vaginal elasticity. Maintaining sexual activities increases pelvic blood flow, promoting tissue health.^28,79

Dilators, available in multiple sizes, benefit women abstaining from intercourse due to pain, emotional concerns, or lack of a partner. Consistent use, several times weekly, is crucial for effectiveness.^17,109 Another significant benefit of using dilators is that they give women confidence that they can insert an object into the vagina without pain.⁸⁷

For symptomatic vaginal atrophy, combining vaginal moisturizers and lubricants with dilators is advised. Research has shown that vibratory stimulation applied to the vagina or directly to the clitoris can effectively reduce pain during vaginal penetration.⁸⁶

Vaginal pain often prompts women to involuntarily tighten their pelvic floor muscles during penetration, intensifying the discomfort in a continuous cycle. Therefore, guided PFPT by a skilled pelvic floor therapist is advised to mitigate this pain. Alongside, integrating PFPT with vaginal dilator training offers women insights into controlling pelvic muscle tension, enhancing dilator efficacy and outcomes.^17,87,88,110

Mechanical therapy can be time-intensive, potentially leading to non-compliance. However, explaining the underlying pathophysiology of GSM and the rationale behind treatments can boost adherence. Emphasizing the benefits of regular vibratory stimulation for improving pelvic blood flow and the significance of dilator use can be motivational. Pelvic floor therapists play a crucial role in educating patients about pelvic muscle awareness and control, especially the importance of muscle relaxation. This education not only helps reduce pain from vaginal atrophy and during sexual activities but is also central to therapeutic success.⁸⁷

Energy-based treatment: fractional CO₂ laser, erbium-YAG, and radiofrequency

Recent studies on intravaginal energy-based treatments for GSM emphasize laser and radiofrequency (RF) modalities. It is suggested that these approaches promote tissue regeneration and collagen production via controlled vaginal tissue injury, eliminating the need for hormonal interventions.^111,112

Fractional CO₂ and Er:YAG lasers employ fractionated light beams to induce minor epithelial and lamina propria injuries. This thermal action stimulates fibroblasts, boosting collagen output, neovascularization, and vaginal tissue repair.^113,114 Conversely, RF utilizes electromagnetic waves for controlled heating, fostering collagen synthesis, fiber reorganization, and tissue remodeling.¹¹²

No randomized studies have shown that CO₂ and erbium-YAG lasers usage is associated with improvements in vulvovaginal symptoms, like dryness, itching, dyspareunia, dysuria, and bleeding, along with improved sexual function and better VHI scores.^115–120 However, recent randomized controlled trials (RCTs) found no significant benefit of intravaginal lasers over placebo in menopausal women¹²¹ and BC survivors.¹²²

Concerns regarding energy-based GSM treatments include the absence of long-term data, unclear guidelines, and high costs not typically covered by insurance. RF treatments are less studied than lasers.¹¹² Comprehensive RCTs are essential before recommending lasers for BC survivors. Until more evidence emerges, their use should be reserved for clinical trials, ensuring informed discussions with patients about potential risks and benefits.¹²

Hormonal therapy

Estrogen promotes breast epithelial and cancer cell growth, whereas reduced estrogen levels or tissue responsiveness decreases BC or cancer recurrence. Consequently, many BC prevention and treatment approaches target reducing or countering existing estrogen levels.^123–125 Reasonably, systemic and local estrogen treatments are debated or advised against for women with a BC history or at elevated BC risk. Nevertheless, if non-hormonal treatments are ineffective for vulvovaginal symptoms, low-dose local hormonal therapy, with proper counseling and risk-benefit analysis, might be an option. Women with lower recurrence risk, influenced by stage, grade, and lymphovascular invasion; with receptor-negative diseases, on tamoxifen over AIs; and with significant symptoms prioritizing QOL may be more suitable for local hormone therapy.¹²

Systemic estrogen

Current consensus advises against systemic estrogens for women with a BC history or elevated risk,¹¹ given their association with increased BC onset or recurrence, especially in those with hormone receptor-positive (HR+) disease.¹²⁶ International guidelines advise against systemic hormonal therapy. Yet, for severe vasomotor symptoms not alleviated by non-hormonal methods, systemic estrogen could be considered, providing that decisions are made collaboratively with oncologists.¹²⁷

Topical estrogen

Topical estrogen therapy is highly effective for GSM, but its use in BC patients is debated due to potential systemic estrogen absorption, which could increase the risk of BC recurrence.⁸ Low-dose vaginal estrogens alleviate genitourinary symptoms^11,128 and enhance vaginal health metrics, including VMI and pH in BC survivors.^105,129,130 They also improve sexual function per the FSFI.¹³⁰ Local estrogen treatments, while similarly effective, vary in systemic absorption rate,¹⁴ generally staying within postmenopausal ranges.¹³¹ Absorption depends on the estrogen type (Conjugated equine estrogen (CEE) > estradiol > estrone > estriol),^79,131 product form, application area, and mucosa state. For example, creams, covering more vaginal area, absorb more than tablets or rings. Due to high systemic absorption, CEE cream is not recommended for BC patients.^79,131 Estrogen absorption differs by application site: vulvar skin, vestibule, or the highly absorptive vaginal epithelium. Applying in the proximal third of the vagina is advised to avoid enhanced absorption.¹³² The vaginal mucosa state (atrophic vs estrogenic) and assessment timing post-application also impact absorption rates. A thin, atrophic vagina is highly absorptive, and this diminishes when the epithelium thickens in response to estrogenization.¹³³

The safety of local estrogen therapy in BC survivors remains a topic of debate, with multiple prospective studies reporting increased blood hormone levels when used in conjunction with adjuvant endocrine treatment.^134–136 The biological implications of systemic estrogen absorption differ depending on the type of adjuvant ET, which aims to lower estrogen levels. Tamoxifen functions as a SERM, competitively binding to ERs and blocking estrogen-driven tumor growth. Consequently, minor increases in systemic estrogen levels are unlikely to meaningfully stimulate tumor cells in tamoxifen-treated patients.¹³⁷ In contrast, AIs profoundly suppress systemic estrogen biosynthesis by halting androgen-to-estrogen conversion, leading to nearly absent estradiol levels. Therefore, in AI-treated patients with HR-positive BC, even small systemic increases in estradiol levels could theoretically restore sufficient estrogenic stimulation to impact residual tumor cells.^8,12,102,127

This mechanistic distinction suggests that vaginal estrogen therapy may be safer in women treated with tamoxifen than in those receiving AIs.

Limited clinical data exist on the long-term safety of vaginal estrogen in BC patients and on the impact of concurrent low-dose vaginal estrogen on ET efficacy. As a result, many oncologists are hesitant to prescribe local estrogen therapy for BC survivors; a study indicates that approximately 70% abstain from such treatments, largely due to interference and recurrence concerns.⁴³ Presently, because of recurrence worries, a minority of BC survivors with GSM are prescribed vaginal estrogen, leading to GSM undertreatment in this population.^138,139

Several studies have evaluated the systemic absorption of vaginal estrogen. While some research found that intravaginal estrogen did not significantly elevate serum estradiol levels, others detected brief transient increases.^{128,130,135,136,140,141} Despite these observations, serum estradiol concentrations generally remained within postmenopausal ranges.¹³¹ Similarly, a year of vaginal estrogen use in menopausal women did not result in alterations of breast density or Breast Imaging Reporting and Data System (Bi-RADS) scores, surrogate markers associated with BC risk.¹⁴²

Clinical outcomes data further clarify the safety profile. A nationwide target trial emulation¹⁴³ demonstrated that vaginal estrogen therapy was not associated with an increased risk of BC recurrence or mortality among survivors with HR-negative tumors or those treated with tamoxifen. However, a modestly increased risk of recurrence was observed among HR-positive survivors receiving AIs.¹⁴³ These findings are consistent with several observational and case-control studies spanning up to a decade, which similarly found no heightened BC recurrence risk overall, except in a subset of women using vaginal estrogen concurrently with adjuvant AI therapy.^144,145 Most importantly, there was no elevated risk for BC mortality in patients using concurrent adjuvant AIs or tamoxifen.^145,146

Taken together, the available evidence suggests that low-dose vaginal estrogen therapy may be considered relatively safe for BC survivors, particularly those treated with tamoxifen or those with HR-negative tumors. Greater caution is warranted for HR-positive survivors receiving AIs.

Although definitive RCT data on the long-term safety of vaginal hormone therapy in BC survivors are lacking, many guidelines and societies support low-dose vaginal estrogen for persistent GSM symptoms, even in patients on AIs, especially when non-hormonal treatments are insufficient.^{8,12,102,127,147}

The use of vaginal estrogen is advised to be approached with caution, following shared decision-making between the patient, gynecologist, and oncologist, or by contemplating a switch from AIs adjuvant treatment to tamoxifen.^8,12

Vaginal androgens

Androgen receptors have been identified in the vaginal mucosa, therefore, are gaining attention as a potential treatment for GSM in BC survivors.¹⁴⁸ Vaginal androgens can be an effective and safe alternative to estrogens in resolving vulvovaginal symptoms related to AIs therapy in BC survivors.^12,56,128

Dehydroepiandrosterone

The FDA has approved intravaginal 0.5% (6.5 mg) dehydroepiandrosterone (DHEA) ovules (prasterone, Intrarosa) for treating dyspareunia due to vulvovaginal atrophy. DHEA may be converted to estrogen through aromatization, posing concerns for individuals with a history of BC.^8,12 In two 12-week RCTs, 6.5-mg DHEA nightly improved vaginal cell maturation, pH, and dyspareunia secondary to atrophy relative to placebo. Adverse effects included vaginal discharge (5.71%) and abnormal pap tests (2.1%).^149,150 A 52-week study found intravaginal DHEA enhanced all FSFI score sexual function domains.¹⁵¹

In an RCT of 464 women with gynecologic cancer and BC survivors with moderate vaginal symptoms, 3.25- and 6.5-mg compounded vaginal DHEA were assessed against moisturizer over 12 weeks. Both treatments reduced symptoms, with 6.5-mg DHEA showing quicker relief by week 8 and improved sexual health per the FSFI.¹⁵² Adverse effects were consistent across groups. Serum estradiol increases were observed in the 6.5 mg group not on AI therapy. Moreover, DHEA also raised DHEA-S and testosterone, remaining within postmenopausal ranges, correlating with improved vaginal cytology.¹⁵³ Without direct comparisons between vaginal DHEA and estrogen, a recommendation for BC survivors remains inconclusive.

Testosterone

Testosterone promotes vaginal epithelial proliferation and ameliorates vaginal atrophy symptoms in postmenopausal women.¹⁵⁴ In individuals on AIs, testosterone-to-estrogen conversion is inhibited, potentially allowing testosterone to alleviate atrophy without affecting AIs’ efficacy. Preliminary data suggest that vaginal testosterone can improve vulvovaginal atrophy, dyspareunia, and sexual dysfunction in AIs users.^{128,155–157}

In a safety study using 150–300 µg daily testosterone propionate for genitourinary atrophy in 21 BC patients on AIs, no significant estrogen increase was observed after 4 weeks.¹³⁵ Conversely, in a trial with 69 postmenopausal women using a higher intravaginal testosterone dose (5000 µg, thrice weekly), 12% exhibited a sustained estrogen rise, implying that reduced testosterone dosing may be more optimal.¹²⁸

Longer-term studies on testosterone use are required, as most research spans only 4 weeks. Currently, using testosterone in women for this purpose is off-label.⁸

SERMs—ospemifene

A newer medication for systemic use—the SERM Ospemifene—was recently reported to have a promising safety and efficacy profile in physiological menopause. In an RCT with over 1000 postmenopausal women, 12-week to 1-year Ospemifene use improved vaginal pH, tissue health, and reduced dyspareunia reports.^158,159 Notable, while ospemifene has estrogenic effects on vaginal tissues and bone, it appears to act as an antagonist in breast tissue.^160,161

Clinical studies suggest no elevated risk for BC incidence, recurrence, or breast-related safety concerns with Ospemifene use.^{158,161–165} However, due to limited study durations, its long-term effects remain unclear, leading to its debated use among healthcare providers. The FDA warns against its use in women with a history of BC, but in Europe, Ospemifene is approved for women with moderate to severe vulvovaginal atrophy with a history of BC who have completed all anti-estrogenic adjuvant treatments.^8,12,166

Treatment guidelines

For BC survivors experiencing GSM symptoms, a personalized treatment approach is essential, taking into consideration aspects such as HR status, type of adjuvant therapy, disease stage, time since diagnosis, risk of relapse, symptom severity, impact on QOL, and patient preferences.¹² Navigating treatment choices for GSM in BC survivors presents complexities. A one-size-fits-all approach is not suitable for managing vulvovaginal symptoms associated with GSM. Instead, treatments should be tailored based on the underlying cause. For instance, if dyspareunia results from reduced lubrication or vaginal friction, the primary intervention should involve the use of lubricants during sexual activity, possibly complemented by daily moisturizers.^12,100 Alternatively, if dyspareunia results from vestibular atrophy, local anesthesia gel before sexual intimacy should be offered first.^94,95 PFPT with dilators should be offered as a first-line treatment option for dyspareunia due to narrowed introitus and/or loss of vaginal capacity.¹⁷ Table 3 outlines the common GSM symptoms in BC survivors and our suggested treatment strategies based on the underlying mechanism in accordance with society’s guidelines.^{8,12,102,127,147}

Table 3.

Targeted treatment recommendations for vulvovaginal symptoms in BC survivors.

Main symptom	Mechanism/etiology	First-line treatment options	Second line
Vulva dryness/itching/burning	Atrophic changes and decreased blood flow	- Vulvar hygiene measures (Box 1)- Moisturizers/lubricants- PFPT and vibratory stimulation to enhance blood flow- Local anesthesia cream	Topical hormonal therapy
Vaginal dryness/itching/burning	Atrophic changes:- Decreased blood flow- Thin, smooth, less elastic vaginal epithelium- Cervical atrophy and decreased secretions	- Moisturizers/lubricants- PFPT and vibratory stimulation to enhance blood flow	- Topical hormonal therapy- Laser treatment
Dyspareunia	Loss of vaginal elasticity:- Vaginal vault thinning,- Vaginal narrowing and shortening	- PFPT- Dilators- Vibratory stimulation to enhance blood flow	Topical hormonal therapy
	Narrowing of vaginal introitus (including rigid hymenal ring)	- Manual therapy, PFPT- Dilators- Vibratory stimulation to enhance blood flow	Perineoplasty
	Tender scar tissue (past vulvovaginal operations, episiotomy, etc.)	- Manual therapy for scar tissue- PFPT and vibratory stimulation to enhance blood flow- Local anesthesia	Topical hormonal therapyand/orPerineoplasty
	Vestibular atrophy + circumferential vestibular pain	- PFPT- Moisturizers/lubricants- Local anesthesia	Topical hormonal therapy
	Hypertonic, tender pelvic floor muscles	- PFPT + local anesthesia- Dilator use- Vibratory stimulation to enhance blood flow	Diazepam suppositories (10 mg)Botox injections (pelvic floor muscles)
	Vaginal atrophy:- Decreased lubrication- Fragile vaginal walls- Friction induced vaginal discomfort	- Moisturizers/lubricants- PFPT and vibratory stimulation to enhance blood flow	Topical hormonal therapy

BC, breast cancer; PFPT, pelvic floor physical therapy.

Furthermore, utilizing a systematic approach that takes into account the receptor status, type of adjuvant ET (AIs vs Tamoxifen), and its current or past usage can guide clinicians toward more effective treatment care. Our proposed therapeutic approach for GSM in BC survivors is depicted in Figure 1, reflecting societies recommendations.^8,12,102,127 Briefly, data on the safety and efficacy of local hormone therapy for ER-negative BC survivors are limited. While reducing estrogen levels is not a primary adjuvant treatment for this group, local hormone therapy for GSM symptoms could be considered. However, the diverse nature of tumors means that some apparent receptor-negative cases might still possess ER-positive elements.^167,168 Nevertheless, considering local topical low-dose hormone therapy is reasonable when the risk of recurrence is low and symptoms are troubling.¹²

Figure 1.

General guidelines for GSM treatment in BC survivors.

Conversely, for patients with ER-positive BC, estrogen suppression is a vital aspect of treatment and prevention.¹² In this group, local hormone therapy should be considered only after non-hormonal treatments prove ineffective, and after consultation with oncologists. This decision must weigh potential risks, the likelihood of disease recurrence, and the intensity of vaginal symptoms. Using intravaginal estrogens in women taking tamoxifen, with blocked ERs, poses fewer concerns compared to women on AIs. In the latter, significantly reduced estrogen levels mean that any systemic uptake might counteract the therapeutic effectiveness of the AIs.¹²

In women with metastatic BC, aspects like sexual health and GSM management are frequently overlooked by HCPs. Data to guide GSM treatment decisions for this group are lacking. However, considering local low-dose hormone therapy may be reasonable for those with severe symptoms and compromised QOL after evaluating the risks and benefits. The healthcare team should not underestimate the significance of QOL, comfort, and enhanced sexual function for these patients. As the lifespan of women with metastatic BC extends, further research into their needs becomes imperative.¹²

Considerations for systemic therapy adjustment

For patients experiencing persistent and severe vulvovaginal symptoms despite optimal local therapy, adjusting systemic endocrine treatment may be a reasonable option. In postmenopausal women receiving AIs, which are associated with profound estrogen depletion, switching to tamoxifen may be considered if medically appropriate, as its partial estrogen agonist effects can be less detrimental to vulvovaginal health.^26–29 Shared decision making with a frank discussion of the limitations and benefits of switching endocrine treatment is imperative, and flexibility with choice of ET may ultimately result in improved patient adherence and compliance. Additionally, emerging endocrine therapies, such as Lasofoxifene, a next-generation SERM, may have a more favorable impact on vulvovaginal symptoms, though data remain limited.^169–171

Similarly, oral selective estrogen receptor degraders, such as elacestrant, are under investigation in early-stage HR+ BC, including in the adjuvant setting.^172,173 These agents have demonstrated favorable overall tolerability, with nausea and hot flashes being the most common side effects, but their specific effects on vulvovaginal tissues have not yet been studied. In addition, novel endocrine therapies such as proteolysis-targeting chimeras and selective estrogen receptor covalent antagonists are being developed, although their impact on mucosal health remains unknown.^174–177

Future research should prospectively evaluate the effects of novel endocrine therapies on vulvovaginal health to guide treatment decisions and improve QOL in patients with ER-positive BC.

Summary

Advancements in BC treatments have reduced mortality but can compromise QOL due to estrogen deprivation. It is crucial for clinicians managing BC survivors to understand the local and systemic side effects of ET that might hinder its use and adherence. A proactive approach is essential: clinicians should inform BC survivors about potential vulvar and vaginal changes tied to low estrogen and share information on safe, effective treatments. Emphasizing multi-disciplinary care is of utmost importance. Limited information exists on how new biological therapies, such as CDK4/6 inhibitors and immunotherapy, influence GSM. This highlights the need for more research on these patients. It is imperative to explore further GSM management, especially among women with metastatic disease. This review offers valuable insights and actionable guidelines to assist clinicians in addressing vulvovaginal health for BC survivors. By doing so, they can mitigate physical changes, alleviate GSM symptoms, enhance QOL, and ultimately encourage continued commitment to vital adjuvant treatment.

Footnotes

Acknowledgements

None.

Declarations

ORCID iD

Maya Ram-Weiner

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Vaginal health in breast cancer survivors: a practical clinical approach

Abstract

Plain language summary

Keywords

Introduction

Adjuvant therapy in BC survivors and hypoestrogenism

Hypoestrogenism effect on the genitourinary tract—physiology

Clinical consequences of hypoestrogenism on the genitourinary tract

GSM in BC survivors

GSM diagnosis

History

Physical examination

Complimentary examination to support GSM diagnosis

Assessment tools for evaluating GSM symptoms

Treatment

Vulvar skincare

Lifestyle modification and control of underlying medical conditions

Non-hormonal regimens

Moisturizers and lubricants

Intercourse and mechanical measures (physical therapy and dilator use)

Energy-based treatment: fractional CO2 laser, erbium-YAG, and radiofrequency

Hormonal therapy

Systemic estrogen

Topical estrogen

Vaginal androgens

Dehydroepiandrosterone

Testosterone

SERMs—ospemifene

Treatment guidelines

Considerations for systemic therapy adjustment

Summary

Footnotes

Acknowledgements

Declarations

ORCID iD

References

Energy-based treatment: fractional CO₂ laser, erbium-YAG, and radiofrequency