Comparisons of effectiveness and safety of intra-vaginal hormone therapy vs. low dose intra-vaginal hormone therapy

Around 25-50% of women experience a range of symptoms 4-5 years after the menopause due to atrophic vaginitis (also known as vaginal or urogenital atrophy). It is an inflammation of the vagina and the outer urinary tract as a result of the thinning and shrinking of tissues and decreased lubrication. This happens as a result of a lack of the reproductive hormone oestrogen. It is estimated that only around 25% of women with symptoms as a result of the disease will seek medical attention for the condition (1).

Symptoms of atrophic vaginitis

The symptoms Symptoms of atrophic vaginitis include vaginal dryness, itching or burning, superficial dyspareunia (difficult or painful sexual intercourse), increased incidence of recurrent urinary tract infections (UTIs), and vaginal discharge (2).

Treatment options for atrophic vaginitis

Topical or vaginal hormone replacement therapy (HRT), containing oestrogen, are most frequently used to alleviate the condition. The role of oestrogen in treatment is to restore normal pH levels and thicken and revascularise the epithelium (3), with the current available treatment options including vaginal creams, vaginal rings, slow-release vaginal tablets and pessaries.

Benefits of intra-vaginal HRT

The advantage of using intra-vaginal HRT is that oestrogen is delivered directly to depleted tissues with a similar efficacy to oral oestrogen, yet with less chance of significant systemic absorption and some of the associated health risks such as such as excessive breast tenderness and endometriosis (4).

In this instance, the application of topical HRT offers a more targeted approach. Whilst drugs applied vaginally can be given at a much lower dose than their oral counterparts and achieve the equivalent plasma concentration, there has also been some concern expressed in the pharmaceutical research community regarding systemic absorption for higher doses of topical HRT. In response to these concerns, a number of pharmaceutical companies have begun offering intra-vaginal therapies at a new, low-dose as opposed to the previously prescribed dose. 

Low-dose intra-vaginal therapies

In practice, systemic absorption from drugs that have been administered intra-vaginally is low but not negligible, and increases with the dose of the oestrogen. This information has been known and well researched for some time, but has not historically resulted in amendments to drug dosage as the risk it posed to the large majority of the population was considered to be relatively low.

There is some research available on low dose pessaries (30mcg) in postmenopausal women with breast cancer, showing that the drug of choice yielded excellent clinical safety and effectiveness results when used to treat women with severe dyspareunia (5). However, there remains little long-term evidence of low dose drug treatments for women affected by cancer and the menopause, or other groups, highlighting gaps in research regarding the long term effectiveness of low dose treatment.

Long term use of all HRT 

What is already known, and is clear in the evidence regarding the longer term use of all HRT, is the heightened risk of developing endometrial carcinoma and hyperplasia as a result of prolonged HRT intake (6). The risk increases when oestrogen-only HRT tablets or patches are used for a prolonged time, so all women, irrespective of the level of HRT dosage, are advised to have regular a medical and gynaecological check up at least once a year.

The cumulative effect of taking HRT medication over a period of time is more than likely the driving factor that has resulted in the recommended dosage of HRT being reduced. Whilst there is little evidence to suggest dosage is a clear risk factor in the development of adverse outcomes or unwanted side effects, there is enough evidence to suggest that an increased dosage of HRT treatment is no more effective at treating atrophic vaginitis than the same drug administered in a smaller dose for the majority of patients.

However, it is also observed that lower doses of oestrogen replacement therapy will not be sufficient to eliminate the symptoms of atrophic vaginitis in an estimated 10-25% of all women who have the condition, and as such systemic oestrogen in higher doses is sometimes required to alleviate discomfort and suffering (7). As such, low dose alternative products may not be beneficial for all women affected by HRT, and for this reason higher dose should continue to be made available, although it may not be.

As different dosage levels will continue to be required for a relatively large number of individuals affected by atrophic vaginitis, it is important that all treatment dosage and delivery methods are individualised as appropriate to best meet the needs of patients. The length of time for which certain patients must take intra-vaginal medication also needs to be carefully managed, as although the efficacy of drugs tends to increase over time (due to the enhanced vascularity of the treated epithelium), so do the risks associated with treatment.

Prolonged use, although sometimes clinically beneficial, can also expose women to a number of other risks. There remains little evidence that long term misuse is associated with further harm specifically in the use of low-dose topical oestrogen, although with most cases experiencing the maximum benefit of treatment within 1-3 months, there are relatively few cases where treatment lasts for a significant period of time.

Conclusions

It is clear from the evidence that the optimal dose of intra-vaginal topical hormone therapy varies from woman to woman. Low-dose formulations have been evidenced to be very effective in the treatment of some cases of atrophic vaginitis, yet the need for higher dose formulations due to a lack of low dose clinical effectiveness in a number of people affected by the condition means that both should continue to be available to patients as required. Both doses are shown to be safe and clinically effective in the short term, although longer term use requires careful monitoring and review in order to mitigate some of the known risk factors and disadvantages associated with HRT.

References

1. Sturdee DW, Panay N (2010) Recommendations for the management of postmenopausal vaginal atrophy Climacteric 13(6):509-22
2. Bachmann GA, Nevadunsky NS (2000) Diagnosis and Treatment of Atrophic Vaginitis Am Fam Physician 61(10):3090-96
3. Pandit L, Ouslander JG (1997) Postmenopausal vaginal atrophy and atrophic vaginitis Am J Med Sci. 314:228–31
4. Archer DF (2010) Efficacy and tolerability of local oestrogen therapy for urogenital atrophy Menopause 17(1):194-203
5. Donders G, Bellen G, Neven P, Grob P et al (2015) Effect of ultra-low-dose estriol and lactobacilli vaginal tablets (Gynoflor®) on inflammatory and infectious markers of the vaginal ecosystem in postmenopausal women with breast cancer on aromatase inhibitors Eur J Clin Micro Inf Dis Jul 30 [Epub ahead of print]
6. Lupulescu A (1995) Estrogen use and cancer incidence: a review Cancer Invest 13:287–95
7. Smith RN, Studd JW. Recent advances in hormone replacement therapy (1993) Br J Hosp Med 49:799–808