Local vaginal estrogen treatment should be considered if nonhormonal strategies fail to address symptoms of dyspareunia and vaginal dryness or concomitant with them. Systemic estrogen therapy does not have a place in the management of GSM alone, without concomitant systemic symptoms of estrogen deprivation (i.e., hot flushes, night sweats, and poor sleep) as low-dose vaginal estrogen should be more than adequate for focal symptom relief with minimal adverse effects [43]. Therefore, systemic estrogen will not be a topic of therapeutic discussion. Vaginal estrogens are available in a variety of formulations including tablet, vaginal rings, and creams (Table 7.2). Each of these methods has its own benefits and drawbacks in terms of localization of estrogen, ease of dosing, and modulation of dosing.

Delivery of estrogen directly to the vulvovaginal tissue targets hormone delivery to the affected area while minimizing risk for systemic absorption. This targeting of focal tissue with “local” hormone application however can still contribute to systemic hormone levels as the absorption of estrogen is dependent on dosage of estrogen applied as well as the degree of vaginal atrophy [9]. Thus systemic absorption is not completely eliminated with low-dose local estrogen treatment, particularly in the early stages of treatment when the vaginal epithelium is still atrophic [4, 44]. As the integrity of the vaginal epithelium improves, and the tissue thickens, estrogen absorption decreases, and with regular use, lower estrogen dose regimens can sustain the positive tissue effects of local hormone therapy with minimal systemic absorption [4]. While all local vaginal estrogen therapies available on the market have similar efficacy and labeling, tablets, creams, and rings vary in terms of ease of administration resulting in differing adherence to treatment [45] with users favoring the ring, followed by tablet, above vaginal creams as a method of hormone delivery, thereby resulting in a statistically significant increase in adherence to treatment [45]. Compliance with recommended treatment is critical to effectiveness as GSM is a chronic and progressive condition. Regardless of the convenience, modulation of dosing and ability to provide focal treatment to the vulva is not available for the ring and tablet, formulations, except to the degree that estrogenized vaginal secretions can secondarily act upon the vulva. Creams allow for variable dosing options to meet the patient’s individual needs. In addition to vaginal administration with an applicator, treatment directly to the vulvar tissue is also possible from direct application or from vaginal leakage as the available cream warms to physiological temperature and its viscosity changes from cream to liquid. The increased therapeutic coverage helps target the introital and urethral tissue, which can benefit from increased direct exposure. While for some patients this messier dosing method is not preferred, others may benefit from the additional lubrication provided by the cream base that helps to facilitate sexual intercourse and alleviate dyspareunia. Individualized approaches may require a combination strategy (estrogen cream to the vulva and an insert [ring or tablet] for vaginal symptoms) to best achieve results.

Unfortunately, obstacles for woman seeking local vaginal estrogen therapy exist in the form of estrogen class labeling, insurance coverage, and lack of generic options. Despite the safety of low-dose vaginal estrogen formulations, the boxed warnings (“class labeling”) on these products and their package inserts continue to erroneously convey risk profiles that are seen only with systemic administration of estrogen in much higher doses than used in vaginal products [43]. The erroneous estrogen class labeling of adverse events results in a large number of women with GSM not seeking or utilizing treatment due to perceived risk [43]. The perceived risk can also result in primary care physicians advising patients to discontinue local vaginal estrogen therapy without assessing need by consulting with the patient’s gynecologist. There is an ongoing and concerted effort by experts in the field of menopause to highlight this misperceived risk escalation of low-dose vaginal estrogen products based on a drug class labeling [43]. Estrogen use-related risks of endometrial cancer [43], breast cancer [46, 47], cardiovascular disorders [48], and of dementia [43] that are displayed in the boxed warnings of vaginal formulations are far removed from the adverse event profile observed during clinical trials of low-dose vaginal estrogen therapy. In fact, the current opinion of The American College of Obstetricians and Gynecologists advocates that low-dose vaginal estrogens (ring or tablet) can be safely used not only for women with a personal history of breast cancer but also for women who are currently experiencing GSM symptoms as a result of current breast cancer treatment [46].

Among factors that impact real-life use of efficacious therapies for GSM, financial considerations loom high. Insurance coverage and out-of-pocket payments can result in a cost barrier restricting access to treatment entirely or necessitating the patient stretch the limits of a single vaginal estrogen prescription by reducing the amount used per dose or the frequency of dosing. Conversely, some patients require more than the recommended dose to alleviate symptoms and are denied additional doses prescribed by their physician based on medical need. The overall absence of generic substitutes for vaginal estrogen formulations in the US market results from the erroneously escalated risk perception as discussed earlier, fueled to some degree by the absence of a former guidance from the Food and Drug Administration (FDA). Only in 2014 were guidance documents revised for conducting generic bioequivalence and pharmacokinetic studies for estradiol creams and tablets [49].

A relatively new and novel addition to the treatment options available to address symptoms of moderate to severe dyspareunia of menopause is a SERM, ospemifene. Relative to other investigational selective estrogen receptor modulators, ospemifene was identified as a viable option to treat dyspareunia related to VVA due to its estrogen agonist effects on both vulvar and vaginal tissues yet weak action on the endometrium [50]. Data on long-term effects of ospemifene are limited, and longitudinal studies are needed in light of the increased risk of uterine cancer that became apparent after 5 years of tamoxifen (another SERM) use [51]. Meanwhile, the quest for the ideal SERM formulation (one which would provide protection against breast and endometrial cancers, mitigate bone loss, and address both vasomotor symptoms and symptoms of GSM) continues; in the interim, the combination of oral conjugated estrogen and BZA holds promise as the ideal formulation for women with systemic symptoms and without contraindications for use of systemic hormone therapy.

Future pharmacological considerations include vaginal DHEA. DHEA is the precursor to all sex hormones in postmenopausal women [52] and is inactive in serum until it undergoes intracrine processing within target tissues. Vaginally administered DHEA would result in active sex steroids exclusively within the vaginal tissue without systemic involvement [53], which would be highly desirable for the treatment of VVA. Daily vaginal DHEA has shown to improve both physiological and patient-reported outcomes of VVA [54].

GSM effects at least 50 % of postmenopausal women and has adverse implications for health, sexual, psychological, and social well-being of the affected population [1]. Despite the high prevalence, there remains a general lack of information, among both patients and healthcare providers, about the spectrum of symptoms of GSM, the variety and efficacy of available strategies, and the safety of treatment options [2]. GSM is a chronic condition and, once manifest, will not improve without intervention and adherence to treatment. A number of factors including aesthetics, convenience, dosing regimen, access, and cost may influence patient’s choice and therapeutic preference. Once an intervention is initiated, consistent reassessment of symptom burden and management strategies is important to patient satisfaction and treatment success. Moderate to severe GSM is easily, effectively, and safely treated with low-dose local vaginal estrogen products. Hopefully, the advent of generics to the market will lower the cost and expand access to a more diverse variety of vaginal estrogen formulation options for more women whose quality of life is affected not only by the burden of GSM but also by the barriers to pharmaceutical access.