The main therapeutic goal in managing VVA is to relieve symptoms and restore the vaginal environment to a healthy premenopausal state.
However, despite the high prevalence and negative impact on the quality of life, VVA is under-reported by patients, under-diagnosed by healthcare professionals, and under-treated. Healthcare professionals should proactively start an open discussion with patients on urogenital symptoms. Treatment should be started as early as VVA occurs and should be maintained over time. As there are many treatment options, therapy should be individualised.1

The choice of a therapy depends on symptom severity, treatment effectiveness and safety, and patient preference.2 According to the generally accepted international standards, the first-line recommendation for the treatment of mild and moderate manifestations of VVA are nonhormonal vaginal lubricants that should be used before intercourse and vaginal moisturisers with a long-term effect that are used regularly (several times a week). This treatment option is also recommended for women for whom the use of vaginal estrogen preparations is unacceptable.1

Why and when to use intravaginal estrogens.
To relieve the symptoms of menopausal urogenital atrophy it is recommended that women should be offered vaginal estrogen and continue treatment for as long as needed to relieve symptoms. Women should be advised that symptoms often come back when treatment is stopped and that adverse effects from vaginal estrogens are very rare.3

The vaginal route of administration has the advantage of delivering hormone therapy (HT)
directly to the affected tissues in post-menopausal women with symptoms caused by urogenital atrophy. It is becoming increasingly clear that even in women who are estrogen replete systemically, there may still be intractable local symptoms that will only respond to local application. Local application of HT also avoids first pass metabolic effects, allowing a lower dosage to be used with the same effect. Patient choice, and therefore likelihood of continuation of therapy, has been improved with the advent of vaginal formulations.4

Of note, following the publication of a study of some 100,000 women with breast cancer (Lancet 2019) the Medicines and Healthcare Products Regulatory Agency (MHRA) has confirmed the risk of breast cancer increases during use of all types of hormone replacement therapy (HRT), except vaginal estrogens, and that an excess risk of breast cancer persists for longer after stopping HRT than previously thought.5

What differentiates intravaginal estrogen preparations?
Estrogens are steroids whose immediate precursors are either androstenedione or testosterone. These precursors are synthesised primarily in the ovaries, adrenals, and testes. Estradiol, produced by androgenic precursors, is the principal estrogen secreted by the ovaries premenopausally. Secreted estradiol is oxidised reversibly to estrone, and both can be converted irreversibly to estriol6 – see Figure 3.

Estriol also has a lower estrogenic potency than estradiol (ranging from 1/10 to 1/100, 1/80 most often cited) and a greater relative affinity for β than α estrogenic receptors (approximately 3:1).7 Additionally, estriol has a high affinity for estrogen receptors in the bladder and vaginal tissue and a relatively low binding affinity to endometrial and breast estrogen receptors.8

There are a number of vaginal estrogen preparations available as creams (estriol 0.1% and estriol 0.01%) and pessaries (estradiol 10 micrograms and estriol 30 micrograms). A gel preparation (Blissel - estriol 0.005%) is also now
available.9

Whilst vaginal preparations containing estriol are as effective as those containing estradiol,10 the lower potency of estriol (recognised as 80x less potent) confers an additional benefit in minimising the estrogenic exposure. The formulation containing estriol 50mcg/ g (Blissel) allows a low dose of estriol to be delivered in a strongly hydrating, clear, aqueous mucoadhesive gel.7

Figure 3. Interconversion of the three naturally occurring estrogens11
In clinical trials, Blissel proved to be an efficacious therapy for the treatment of post-menopausal vaginal atrophy.
Blissel is a local treatment for vaginal dryness in postmenopausal women with vaginal atrophy.

It is important to note the highly favourable opinion of women regarding the formulation itself and the ease of administration, which may contribute to improved satisfaction and compliance with therapy. Leakage from the vagina is considered an important drawback of certain vaginal products, some of which are perceived as messy, and is a common complaint among post-menopausal women treated with these therapies.

Blissel is administered using a single reusable dose-marked applicator; a feature well received by patients and health care professionals. Finally, the product’s formulation as a highly hydrating gel provides a supplementary effect that may potentially be an advantage in the initial phase of the treatment of this condition.

References
  1. Naumova, I. and Castelo-Branco, C. 2018 ‘Current treatment options for postmenopausal vaginal atrophy’, International Journal of Women’s Health. Volume 10, 387-395.
  2. Palma, F. et. al. 2016 ‘Vaginal atrophy of women in post menopause. Results from a multicentric observational study: The AGATA study’, Maturitas. Volume 83, 40-44
  3. National Institute for Health and Care Excellence (NICE) 2015 Menopause: diagnosis and management. NG23
    Available at: www.nice.org.uk/guidance/ng23 (Accessed February 2022)
  4. Kalentzi, T. and Panay, N. 2005 ‘Safety of vaginal oestrogen in postmenopausal women’, The Obstetrician and Gynaecologist. Volume 7, 241-244
  5. https://www.gov.uk/drug-safety-update/hormone-replacement-therapy-hrt-further-information-on-the-known-increased-risk-of-breast-cancerwith-hrt-and-its-persistence-after-stopping (Accessed February 2022)
  6. Head, K.A. 1998. ‘Estriol: Safety and Efficacy’, Alternative Medicine Review: A Journal of Clinical Therapeutic, Volume 3, No. 2, 101-113
  7. Cano, A. et. al. 2012 ‘The therapeutic effect of a new ultra-low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: results from a pivotal phase Ⅲ study’, The North American Menopause Society, Volume 19, No.10, 1130-9
  8. Blissel SmPC (Accessed February 2022)
  9. https://services.nhsbsa.nhs.uk/dmd-browser/search (Accessed February 2022)
  10. Delgado, J.L. et. al. 2016 ‘Pharmacokinetics and preliminary efficacy of two vaginal gel formulations of ultra-low-dose estriol in postmenopausal women’, Climacteric. Volume 9, issue 2, 172-180
  11. Lonmen, E. and Mead, J.H. 2013 ‘Estriol; the ‘Good’ Estrogen. Advances and Updates in its Clinical Uses’, Journal of Restorative Medicine. Volume 2, 45-52