Modern approach to the management of genitourinary syndrome in women with gynecological malignancies

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 endometrial cancer (FIGO stage I–II), but is not recommended 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 ovarian cancer subtype. In clear cell carcinoma HT has generally been considered appropriate, but this hystological ovarian subtype itself has been associated 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 malignancy are shown in Table 3.

In women with moderate to severe GSM symptoms, 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 appropriate to treatment goals should be used. Estrogens and progestogens are the main hormonal preparations used in HT. Although both classes of hormones may have symptomatic benefits, progestogen is specifically added to estrogen regimens, unless the uterus has been removed to avoid endometrial hyperplasia and the increased risk of endometrial 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 estrogens 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 administered either locally or systemically. Systemic oral, transdermal (patch and spray), intranasal, sublingual, buccal, vaginal, subcutaneous, and intramuscular routes of administration of estrogen are possible, as are oral, vaginal, transdermal, intranasal, 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 concentrations 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 improvement 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 systemic recurrences in endometrial, ovarian, and cervical cancer, respectively, and a low incidence of other adverse outcomes, treatment was considered 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 endometrial cancer and treated with estrogen replacement therapy versus placebo for GSM, 70.1% of estrogen-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 vaginal dryness (28% vs. 18%), less vaginal shortening (27% vs. 17%), and less pain during intercourse (23% vs. 12%).¹¹

Ospemifene is a selective estrogen receptor modulator (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 vaginal cells, and decrease in vaginal pH. The differences in endometrial thickness at weeks 12 and 52 were significant and reflected greater thickening associated with ospemifene. Endometrial thickness was also assessed, and biopsies did not show endometrial hyperplasia or carcinoma with either short- or long-term use.^38,39,40 However, ospemifene is not recommended for estrogen-dependent malignancies.¹⁷

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 estrogens in vaginal mucosal cells and improves symptoms of vaginal irritation.²⁸ Studies showed that DHEA administered intravaginally for 12 weeks improves vaginal cytological environment, lowers vaginal pH, and promotes cell maturation, resulting in symptom relief. Vaginal DHEA affects serum androgen and estradiol concentrations, which increase as a result, making the safety of DHEA use in hormone-dependent cancers an issue.^27,41,42

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 disorder is the only evidence-based indication for the use of testosterone in postmenopausal women.⁴²

If women suffer from penetrational dyspareunia, topical lidocaine can be used on the vaginal vestibule. In a randomized study, women who applied liquid lidocaine to the vaginal vestibule 3 minutes before intercourse reported less pain during intercourse and more comfortable penetration compared with the use of saline.⁴³

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 vaginal 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 every 2–3 days. They lower vaginal pH and hydrate vaginal mucosa. They alter vaginal epithelium by absorbing and adhering to it and mimicking vaginal secretion. The effect lasts up to a few days.⁵ Moisturizers are also recommended for women who are not sexually active and experience symptoms 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 commercially available products exceed this value, so an osmolarity of up to 1200 mOsm/kg is generally accepted. In healthy women, normal vaginal pH is between 3.8 and 4.5, and lubricants or moisturizers 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 moisturizers 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.

With regard to a conservative approach, smoking 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 lubrication during arousal.¹⁸ Regular exercise for pelvic muscle strengthening and relaxation are also advised. If available, psychosexual support should be offered.¹⁰ Consumption of nutrients containing equol, which is produced by equol-producing bacteria from isoflavonoids, showed a beneficial effect on alleviating vaginal symptoms in GSM.^46,47

In the last 5 years, laser use has gained popularity and has become an innovative treatment method for GSM. It is used as a minimally invasive technique that generates pulses that act on the vaginal mucosa. Epithelial cellularity and proliferation are increased, resulting in neoangiogenesis and neocolagenesis 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 common energy setting for CO₂ lasers is 30–40 W and 3–10 J/cm² 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 cancer and in general population of postmenopausal women has been demonstrated in several retrospective 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 treatment may be considered, but they need to be informed 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.

Due to surgery and/or radiation therapy, the elasticity 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 stages.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 effects on vaginal stenosis.⁵⁰ It is important to educate women on how to relax the pelvic muscles and provide them with guidelines and instructions on dilators and their use.¹⁹ In a randomized trial the women who regularly used vaginal dilators after radiotherapy had less frequent and less severe vaginal stenosis.⁵¹