Radiol Oncol 2023; 57(3): 292-298. doi: 10.2478/raon-2023-0038 292 review Modern approach to the management of genitourinary syndrome in women with gynecological malignancies Nina Kovacevic 1,2,3 , Ines Cilensek 4 , Sebastjan Merlo 1,2 , Barbara Segedin 2,5 1 Department of Gynecological Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Faculty of Health Care Angela Boškin, Jesenice, Slovenia 4 Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 5 Department of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia Radiol Oncol 2023; 57(3): 292-298. Received 15 May 2023 Accepted 25 June 2023 Correspondence to: Assist. Prof. Barbara Šegedin, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: bsegedin@onko-i.si and Assist. Prof. Sebastjan Merlo, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: smerlo@onko-i.si Disclosure: No potential conflicts of interest were disclosed. This is an open access article distributed under the terms of the CC-BY license (https://creativecommons.org/licenses/by/4.0/). Background. The term genitourinary syndrome of menopause was first used in 2014 by the North American Menopause Society and the International Society for the Study of Women’s Sexual Health to describe conditions previously known as atrophic vaginitis, urogenital atrophy, or vulvovaginal atrophy. It is a complex, chronic, progres- sive condition characterized by a wide range of signs and symptoms affecting sexual function and the tissues of the urinary and genital tracts. The main cause of genitourinary syndrome of menopause is estrogen deficiency caused by ovarian removal or dysfunction. The most bothersome symptoms are vaginal dryness, decreased vaginal lubrication, and pain during penetration and intercourse. They all have a negative impact on the quality of life. Conclusions. The main goal of treatment is to relieve the symptoms. Treatment modalities are pharmacological or non-pharmacological. The first-line treatment for mild to moderate symptoms is the use of personal lubricants and moisturizers, but the gold standard is estrogen replacement therapy. Hormone therapy may not be an option for women with hormone-dependent cancer. Key words: genitourinary syndrome; gynecological malignancies, therapy Introduction Gynecological malignancies account for approxi- mately 10% of all cancers in women, and 40% of patients are premenopausal at the time of diagno- sis. 1,2 Treatment of gynecological malignancies is often multimodal with surgery (hysterectomy with bilateral salpingo-oophorectomy), systemic therapy, and radiation leading to induced menopause. This hypoestrogenic state can lead to menopausal symp- toms and can negatively affect sexual quality of life. 3 Genitourinary syndrome of menopause (GSM) is a new term that describes conditions formerly known as vulvovaginal atrophy, atrophic vagini- tis, or urogenital atrophy, all of which result from estrogen deficiency. 4 GSM is a chronic, progressive condition that causes multiple changes in the vul- var and vaginal area, pelvic floor tissues, bladder, and urethra, and impairs sexual function and li- bido. These changes occur in response to hypoes- trogenism and do not improve with time. 5 GSM affects 27 to 84% of menopausal women. 6 Women Radiol Oncol 2023; 57(3): 292-298. Kovacevic N et al. / Genitourinary syndrome in women with gynecological malignancies 293 treated for gynecological malignancy may enter menopause earlier than healthy women. Many survivors of gynecologic malignancies experience GSM symptoms, which impair their quality of life. Compared to healthy controls, women after surgery for early cervical cancer and endometrial cancer report sexual desire dysfunc- tion, arousal dysfunction, entry dyspareunia and reduced intensity orgasm more often. 7,8 Fertility- sparing procedures may preserve childbearing po- tential, but they do not have the impact on sexual satisfaction. 9,10 The addition of radiotherapy can additionally impair vaginal function, resulting in loss of elas- ticity and fibrosis of vaginal walls. After curative radiotherapy for cervical cancer, less women are sexually active compared to the time before treat- ment. Women report vaginal functioning prob- lems, such as vaginal dryness, shortening and/or tightening of the vagina, which in turn correlate with diminished sexual enjoyment. 11 45% of pa- tients are not capable of full intercourse after cura- tive radiotherapy for cervical cancer. 10 Given high prevalence of GSM, it is impor- tant for physicians to address this issue. Women are often hesitant to address sexual and vaginal health issues, which are still considered taboo and are relieved when physicians bring up the topic. Because GSM is a chronic, complex condition, life- long treatment is required to prevent recurrence of symptoms. 12 We must keep in mind that up to 18% of endo- metrial carcinomas occur in women younger than 40 years. A multidisciplinary approach should be taken whether bilateral salpingo-oophorectomy is required as part of the staging procedure and when we can avoid problems with menopause. 13 Similarly, ovarian transposition should be recom- mended for cervical cancer in premenopausal pa- tients undergoing pelvic irradiation to avoid pre- mature menopause and menopausal symptoms. 14 We will discuss treatment modalities for GSM in women with gynecological cancer, considering both hormonal and non-hormonal options. Assessment The clinical manifestations of GSM can be mild and nonspecific, so diagnosis may prove difficult. A careful assessment and identification of the most bothersome symptoms and their impact on quality of life should be performed before choos- ing a therapeutic approach. Simple and effec- tive questionnaires are available, including the Vulvovaginal Symptoms Questionnaire (VSQ), the Sexual Symptom Checklist for Women After Cancer and EORTC QLQ CX-24, to assess symp- toms, emotions, impact on life, and sexuality. 15,16 In addition, a complete medical and gynecologi- cal history and a gynecological examination are required. The examination should include inspec- tion of the external genitalia, vaginal inspection with a speculum, and bimanual palpation to rule out other conditions that may mimic GMS, such as urinary tract infections, vulvovaginal infections, allergic reactions, and urinary incontinence. 5,17 Symptoms and clinical manifestation Hypoestrogenism due to bilateral oophorectomy or ovarian failure and pelvic irradiation results in anatomic and functional changes in urogenital tis- sue. There is loss of collagen and elastin in the vag- inal epithelium, smooth muscle function is altered, and the number of small blood vessels is reduced, resulting in local tissue hypoxia. The increase in connective tissue leads to decreased elasticity, thinning of the epithelium and weakening of the vaginal mucosa. 6,18,19 GSM presents as a wide range of signs and symptoms, the most common are summarized in Table 1. Dyspareunia and vaginal bleeding due to vaginal dryness are the most common symptoms of GSM. 12 Vaginal dryness affects up to 93% of women, and burning, itching, and pruritus affect up to 63% of women. The most common sexual complaints are decreased vaginal lubrication and dyspareunia, affecting 90% and 80% of women, re- spectively. Urinary symptoms, dysuria, and incon- tinence are less common, affecting 29% and 25% of women, respectively. 5,20 Treatment approach The main goal of GSM management is to relieve symptoms. The approach varies depending on the severity of symptoms. For severe and moderate symptoms, pharmacological treatment with hor- mone therapy (HT) is the gold standard. For mild symptoms nonhormonal therapies are subjective- ly effective. Nonhormonal therapies may also be used if gynecologic cancer is responsive to estro- gen. 6,12 Available treatment modalities are listed in Table 2. Radiol Oncol 2023; 57(3): 292-298. Kovacevic N et al. / Genitourinary syndrome in women with gynecological malignancies 294 Pharmacological treatment Hormone therapy HT is the most effective therapy for GSM, but it is underutilized in women with gynecologic cancer. 6 Systemic HT is acceptable for early stage endo- metrial cancer (FIGO stage I–II), but is not recom- mended for late stage endometrial cancer (FIGO stage III–IV). Systemic HT is also not recommended for uterine sarcomas, especially leiomyosarcomas and endometrial stromal sarcomas that express estrogen and progesterone receptors. 21 According to the data, HT can be prescribed to women with epithelial ovarian cancer, but low-grade serous cancer may respond to anti-estrogen treatment, so systemic HT is not recommended in this ovar- ian cancer subtype. In clear cell carcinoma HT has generally been considered appropriate, but this hystological ovarian subtype itself has been asso- ciated with higher rate of venous thrombembolic events. 22 HT is also safe and acceptable in women with cervical cancer. 2,13 Recommendation for HT use in women with different gynecologic malig- nancy are shown in Table 3. In women with moderate to severe GSM symp- toms, the use of local estrogen might be suggested. Up to 45% of women find systemic HT insufficient to control GSM symptoms, whereas local HT is highly effective and provides symptomatic relief. The lowest dose for the shortest duration appropri- ate to treatment goals should be used. Estrogens and progestogens are the main hormonal prepa- rations used in HT. Although both classes of hor- mones may have symptomatic benefits, progesto- gen is specifically added to estrogen regimens, unless the uterus has been removed to avoid endo- metrial hyperplasia and the increased risk of en- dometrial cancer. Premenopausal patients treated with curative radiotherapy with a dose of 80 Gy or more, may have symptoms of residual functional endometrium and should be advised to use estro- gens in combination with a progestogen, instead of unopposed estrogens, to prevent stimulation of residual functional endometrium. 23,24 HT is available through a variety of different routes of administration. 25 Estrogen can be ad- ministered either locally or systemically. Systemic oral, transdermal (patch and spray), intranasal, sublingual, buccal, vaginal, subcutaneous, and in- TABLE 1. Genital, urinary, and sexual signs and symptoms of genitourinary syndrome of menopause Genital Urinary Sexual Vaginal dryness Dysuria Dyspareunia Vaginal irritation Urgency Decreased lubrication Vaginal burning Frequency Postcoital bleeding and spotting Vaginal itching Reccurent urinary tract infections Decreased arousal Vulvar pruritus Cystocele Dysorgasmia Thinning and graying pubic hair Stress urinary incontinence Loss of libido Vaginal/pelvic pain and pressure Urge urinary incontinence Loss of arousal Vaginal vault prolapse Hematuria Pelvic pain Vaginal and introital stenosis Nocturia Palor of vaginal mucosa Fewer vaginal rugae Petechiae in vaginal and cervical mucosa Labial shrinking and atrophia TABLE 2. Pharmacological and non-pharmacological treatment modalities for the genitourinary syndrome of menopause Pharmacological treatment Non-pharmacological treatment Hormone therapy Lifestyle changes SERM Vaginal lubricants DHEA Vaginal moisturizers Testosteron Laser therapy Lidocain Vaginal dilatators DHEA = dehydroepiandosterone; SERM = selective estrogen receptor modulator Radiol Oncol 2023; 57(3): 292-298. Kovacevic N et al. / Genitourinary syndrome in women with gynecological malignancies 295 tramuscular routes of administration of estrogen are possible, as are oral, vaginal, transdermal, in- tranasal, buccal, intramuscular, and intrauterine applications of progestogens. 26 Vaginal estrogen is administered locally as a cream, gel, ring, or vaginal tablet, with minimal systemic absorption. 27,28 With vaginal application of 10 mcg of estrogen, systemic estrogen concen- trations remain in the postmenopausal range. 29 There is no good evidence to support the use of a specific local estrogen product. In a retrospective cohort study of 244 women, treated for cervical, endometrial or ovarian cancer, symptom improve- ment was documented in one third of patients, unfortunately data on treatment efficacy is lacking for almost 60% of patients. With an incidence of 7.1%, 21.7%, and 9.7% of combined local and sys- temic recurrences in endometrial, ovarian, and cervical cancer, respectively, and a low incidence of other adverse outcomes, treatment was consid- ered safe. 30 Local vaginal estrogen therapy may be considered in women with hormone-dependent cancer if symptoms persist and nonhormonal treatment has failed. This should be an informed shared decision between physician and patient. 17,27 In a randomized double-blind trial of 1236 women surgically treated for early-stage endome- trial cancer and treated with estrogen replacement therapy versus placebo for GSM, 70.1% of estro- gen-treated women experienced improvement in symptoms. The recurrence rate was low at 2.1%. 31 In a prospective cohort study of 1045 patients treated for locally advanced cervical cancer with chemoradiotherapy and brachytherapy, hormone replacement therapy was associated with less vag- inal dryness (28% vs. 18%), less vaginal shortening (27% vs. 17%), and less pain during intercourse (23% vs. 12%). 11 Selective estrogen receptor modulator Ospemifene is a selective estrogen receptor modu- lator (SERM) and is approved for the treatment of moderate to severe dyspareunia, a symptom of vulvovaginal atrophy. It acts as an estrogen agonist on vaginal tissue and the endometrium, with no systemic effects on bone, breast, or cardiovascular health. 37 A meta-analysis conducted by Cui et al. showed that daily use of 60 mg ospemifene per os improved vaginal structure in terms of decrease in vaginal parabasal cells, increase in superficial vagi- TABLE 3. Recommendations for hormone therapy in women treated for gynecological malignancies Gynecological malignancy Recommendation Selected articles Level of evidence Note Uterine cancer Early stage endometrial cancer HT acceptable Barakat et al. 2006 31 randomized control trial 1236 patients, no difference in recurrence rate with the use of HT Shim et al. 2014 32 meta-analysis no increased risk of recurrence Advanced stage endometrial cancer HT not recommended Sinno et al. 2020 2 NAMS clinical practice statement no data supporting use of HT Uterine sarcoma HT not recommended George et al. 2014 21 phase 2 trial 27 patients, a potential response to anti- estrogen therapy (Letrozole) Sinno et al. 2020 2 NAMS clinical practice statement lack of data regarding HT safety Ovarian cancer High grade serous HT acceptable Li et al. 2015 33 meta-analysis HT is not associated with poorer clinical outcome, epithelial ovarian cancers Low grade serous HT not recommended Gershenson et al. 2012 34 retrospective study 64 patients, high rate of hormone receptor expression and maintenance anti-endocrine therapy Sinno et al. 2020 2 NAMS clinical practice statement not sufficient safety data available Endometrioid HT acceptable Power et al. 2016 35 retrospective cohort data 391 patients, HT is not associated with decreased disease-free or overall survival Clear cell HT not recommended Didar et al. 2023 22 meta-analysis increased risk of venous thromboembolism events Mucinous HT acceptable Li et al. 2015 33 meta-analysis HT is not associated with poorer clinical outcome, epithelial ovarian cancers Cervical cancer HT acceptable Ploch et al. 1987 36 prospective study 120 patients, no difference in recurrence rate with the use of HT HT = hormone therapy; NAMS = North American Menopause Society Radiol Oncol 2023; 57(3): 292-298. Kovacevic N et al. / Genitourinary syndrome in women with gynecological malignancies 296 nal cells, and decrease in vaginal pH. The differenc- es in endometrial thickness at weeks 12 and 52 were significant and reflected greater thickening associ- ated with ospemifene. Endometrial thickness was also assessed, and biopsies did not show endome- trial hyperplasia or carcinoma with either short- or long-term use. 38-40 However, ospemifene is not rec- ommended for estrogen-dependent malignancies. 17 Dehydroepiandosterone Dehydroepiandosterone (DHEA) is a source of sex steroid hormones produced by the adrenal gland, and it is useful in treatment of vaginal dryness and dyspareunia. DHEA is metabolized to estro- gens in vaginal mucosal cells and improves symp- toms of vaginal irritation. 28 Studies showed that DHEA administered intravaginally for 12 weeks improves vaginal cytological environment, lowers vaginal pH, and promotes cell maturation, result- ing in symptom relief. Vaginal DHEA affects se- rum androgen and estradiol concentrations, which increase as a result, making the safety of DHEA use in hormone-dependent cancers an issue. 27,41,42 Testosteron Vaginal tissue is rich in testosterone receptors, so intravaginal testosterone is sometimes used off- label for GSM treatment. The enzyme aromatase converts testosterone to estradiol, so there are legitimate concerns about the safety of elevated serum estradiol levels in response to testosterone treatment in patients with hormone-dependent cancers. 17,27 To date, hypoactive sexual desire dis- order is the only evidence-based indication for the use of testosterone in postmenopausal women. 42 Lidocain If women suffer from penetrational dyspareunia, topical lidocaine can be used on the vaginal vesti- bule. In a randomized study, women who applied liquid lidocaine to the vaginal vestibule 3 minutes before intercourse reported less pain during in- tercourse and more comfortable penetration com- pared with the use of saline. 43 Nonpharmacological treatment Vaginal lubricants and moisturizers Lubricants and moisturizers should be used as first-line treatment for immediate discomfort and pain relive during intercourse, especially in women with hormone-dependent cancers. Lubricants are water-, oil-, mineral oil-, plant- or silicone-based and are not absorbed by the vagi- nal mucosa. 27 They are applied before intercourse and have a temporary effect to reduce vaginal wall friction and relieve pain and discomfort during penetration and intercourse. 18 Moisturizers are used regularly, from daily application to once eve- ry 2–3 days. They lower vaginal pH and hydrate vaginal mucosa. They alter vaginal epithelium by absorbing and adhering to it and mimicking vag- inal secretion. The effect lasts up to a few days. 5 Moisturizers are also recommended for women who are not sexually active and experience symp- toms of vaginal dryness. There is a wide variety of over-the-counter lubricants and moisturizers, but women should be counseled regarding pH and osmolarity. The WHO recommends an osmolarity of no more than 380 mOsm/kg to avoid damage to the vaginal epithelium. However, most commer- cially available products exceed this value, so an osmolarity of up to 1200 mOsm/kg is generally ac- cepted. In healthy women, normal vaginal pH is between 3.8 and 4.5, and lubricants or moisturiz- ers should adhere to this range and not have a pH below 3. Additives such as parabens, microbicides and glycols should also be avoided, because they can irritate the vaginal tissue and mucosa. 44 The main limitation of using lubricants and moistur- izers is short-term relief of symptoms and the fact that they do not reverse atrophy. They are suitable for mild to moderate GSM symptoms and daily wellbeing. 3 Women should be advised on which products are suitable, to avoid further damage to the vaginal epithelium. Lifestyle changes With regard to a conservative approach, smok- ing cessation is recommended as one of the GSM treatment modalities. Cigarette smoking has a negative effect on the vaginal epithelium, leading to a lack of vaginal cell maturation and increasing vaginal cell atrophy. 45 Regular sexual activity with or without a partner is recommended to maintain vaginal elasticity, blood circulation, and lubrica- tion during arousal. 18 Regular exercise for pelvic muscle strengthening and relaxation are also ad- vised. If available, psychosexual support should be offered. 10 Consumption of nutrients containing equol, which is produced by equol-producing bac- teria from isoflavonoids, showed a beneficial effect on alleviating vaginal symptoms in GSM. 46,47 Laser therapy In the last 5 years, laser use has gained popularity and has become an innovative treatment method Radiol Oncol 2023; 57(3): 292-298. Kovacevic N et al. / Genitourinary syndrome in women with gynecological malignancies 297 for GSM. It is used as a minimally invasive tech- nique that generates pulses that act on the vaginal mucosa. Epithelial cellularity and proliferation are increased, resulting in neoangiogenesis and neo- colagenesis in the lamina propria of the vaginal mucosa. 48 When using lasers for GSM treatment, microablative CO2 lasers or nonablative vaginal erbium Yag lasers are an option. 17 The most com- mon energy setting for CO2 lasers is 30–40 W and 3–10 J/cm 2 for erbium Yag lasers. In a phase I–II study, progressive increase in vaginal length and improvement in vaginal health index was achieved with laser treatment, however, this did not transfer into improvement of female sexual function index. 49 The efficacy of laser treatment for GSM caused by hormone therapy for breast can- cer and in general population of postmenopausal women has been demonstrated in several retro- spective series. 48 In general, laser treatment appears to be safe and effective for GSM treatment, and no serious adverse events have been reported. 48 In women who prefer nonhormonal treatment, laser treat- ment may be considered, but they need to be in- formed about the lack of data on long-term safety and efficacy of various laser therapies for GSM symptoms. 12,17,48 In Slovenia laser treatment is not reimbursed by health insurance. Vaginal dilators Due to surgery and/or radiation therapy, the elas- ticity or length of the vagina may be compromised. In such cases, vaginal dilators can be helpful. In the early stages, dilators prevent or minimize the formation of adhesions between vaginal walls and promote elasticity and reduce fibrosis in later stag- es. 37 The use of vaginal dilators should begin no later than 3 months after the end of radiotherapy and should be performed at least 2 to 3 times per week for 10 to 15 minutes to achieve positive ef- fects on vaginal stenosis. 50 It is important to edu- cate women on how to relax the pelvic muscles and provide them with guidelines and instruc- tions on dilators and their use. 19 In a randomized trial the women who regularly used vaginal dila- tors after radiotherapy had less frequent and less severe vaginal stenosis. 51 Conclusions Anatomic, physiologic, and sexual changes after treatment of gynecological malignancies are com- mon and negatively impact quality of life and re- covery from cancer. 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