Urogenital atrophy is a common result of the menopause. Between 10 to 40% of postmenopausal women experience the problem.¹ It may present for the first time more than 10 years after the last menstrual period (LMP). Symptoms include:

• Vaginal dryness, itching or burning
• Vaginal discharge
• Superficial dyspareunia
• Urinary symptoms and recurrent urinary tract infections (UTIs)

The vulva and vagina typically appear thin, dry and pale

Preparations containing oestrogen (topical or vaginal HRT) are often used to alleviate this condition. They include:

• Vaginal creams
• Pessaries
• Slow-release vaginal tablets
• Vaginal rings

The advantage of this route of administration is that oestrogen is delivered directly to oestrogen-depleted tissues with similar efficacy to oral oestrogen, with the hope of avoiding significant systemic absorption and consequent side-effects. Given recent concerns surrounding the safety of systemic HRT, particularly on breast tissue and the coagulation cascade, topical HRT offers a more targeted approach.

As drug absorption across the vaginal epithelium avoids the first pass effect, lower doses are required vaginally compared to orally to achieve equivalent plasma concentrations.¹ In practice, systemic absorption is low but not negligible and increases with the dose of oestrogen. There is little evidence of accumulation over short-term use.²

Unlike other forms of HRT, progestogen opposition for women with a uterus is not routinely used with topical oestrogens. Concerns have been expressed that the continuous use of low-dose vaginal oestrogens could result in sufficient systemic absorption to stimulate endometrial hyperplasia. The majority of preparations are only licensed for 3-6 months of continuous use in the UK and, whilst observational studies suggest the safety of longer-term use, there is a lack of randomised prospective studies confirming this.¹

Indications

• There is good evidence for the efficacy of topical HRT in the short-term treatment of menopausal atrophic vaginitis. Vaginal symptoms are improved, vaginal atrophy and pH decrease and there is improved epithelial maturation with topical oestrogen preparations compared to placebo or non-hormonal gels. The different preparations of topical HRT (creams, pessaries, tablets and the estradiol vaginal ring) all appear equally effective for treating vaginal atrophy.³
• Topical HRT is sometimes used prior to prolapse repair surgery in postmenopausal women with evidence of epithelial atrophy.
• There is some evidence that recurrent UTIs in postmenopausal women can be prevented by oestrogen replacement but no trial data is available as to suitable dosing and duration of treatment. Similarly, urge incontinence may be improved by low-dose vaginal oestrogens.⁴
• Topical oestrogens are used to treat labial adhesions in girls.⁵

Contra-indications^6,7,8,9

These include:

• Oestrogen-dependent cancers
• Past history of breast cancer – evidence is conflicting but seek specialist advice^10,1
• Patients on aromatase inhibitors¹¹
• Active or recent cardiovascular disease
• Idiopathic or current venous thromboembolic disease
• Liver disease with abnormal liver function tests
• Untreated endometrial hyperplasia or undiagnosed abnormal vaginal bleeding
• Porphyria

Cautions^6,7,8,9

• Migraine
• Diabetes and other risk factors for heart disease
• Risk factors for oestrogen-dependent tumours, e.g. breast cancer in first degree relatives
• Uterine fibroids (may increase in size)
• Endometriosis
• Risk factors predisposing to thromboembolism, e.g. antiphospholipid syndrome

Side-effects^6,7,8,9

• Systemic absorption may cause oestrogen-related side-effects such as breast tenderness.
• Endometrial hyperplasia (see below).
• There is limited data looking at the risk of breast cancer or venous thromboembolism specifically associated with vaginal oestrogen delivery. It is generally assumed that local preparations are safer because of the very low systemic oestrogen levels associated with their use.¹
• Some women experience local irritation with the use of topical oestrogens.

Endometrial hyperplasia

To date, studies have found no significant association between the use of low-potency unopposed vaginal oestrogens and the risk of endometrial cancer. In the UK, vaginal creams, tablets and pessaries are only licensed for 3-6 months of continuous use, with the exception of Estring® which can be used for up to 2 years. Conjugated equine oestrogen cream may have a more pronounced effect on oestrogen levels and endometrial stimulation than other oestrogen preparations.³

Initiating and monitoring treatment⁴

• Establish no contra-indications to oestrogen therapy – if present, avoid prescribing topical oestrogens or seek specialist advice as some systemic absorption will occur.
• Breast and pelvic examination are required if indicated by current personal history or family history.
• Use the lowest effective dose to minimise systemic absorption, e.g. pessaries or creams daily for the first two weeks reducing to twice weekly.
• Use preparations that have low systemic bioavailability. Efficacy of creams, pessaries, tablets and vaginal rings appears equal but, as a treatment choice, women appear to favour the estradiol-releasing vaginal ring.³
• Maximal benefit usually occurs after 1-3 months but may take up to a year.
• Treatment should be reviewed regularly with efforts to reduce or discontinue at 3-6 month intervals with re-examination. Where used over a longer term (>3-6 months), addition of a progestogen for those with an intact uterus should be considered (but see above).
• If bleeding or spotting occurs at any time, refer to a gynaecologist for exclusion of endometrial malignancy.

Alternatives

• Vaginal lubricants if main symptoms are pain on intercourse due to dryness.
• Bioadhesive, non-hormonal preparations, such as Replens®.
• Systemic HRT if flushing and night sweats are also present.

Patient advice

• Report any vaginal bleeding. This will require referral and investigation with ultrasound and endometrial biopsy.
• The longer-term safety of these drugs is uncertain at the moment. It is safest to limit treatment to lowest doses and shortest durations to control symptoms and regularly review the situation. However, treatment is often required on an intermittent or ongoing basis, as symptoms frequently recur with treatment cessation.⁴

Document references

1. Kalentzi T, Panay N; Safety of vaginal oestrogen in postmenopausal women, The Obstetrician and Gynaecologist 2005; 7:241-144.
2. Notelovitz M, Funk S, Nanavati N, et al; Estradiol absorption from vaginal tablets in postmenopausal women.; Obstet Gynecol. 2002 Apr;99(4):556-62. [abstract]
3. Suckling J, Lethaby A, Kennedy R; Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD001500. [abstract]
4. Menopause, Clinical Knowledge Summaries (January 2008)
5. British National Formulary for Children; British Medical Association and Royal Pharmaceutical Society of Great Britain. London.
6. Summary of Product Characteristics Ortho-Gynest®pessaries, Janssen-Cilag Ltd. Last updated June 2009.
7. Summary of Product Characteristics Vagifem®, Novo Nordisk Ltd. Last updated March 2009.
8. Summary of Product Characteristics Premarin® cream, Wyeth Pharmaceuticals. Last updated December 2005.
9. Summary of Product Characteristics Estring®, Pharmacia Ltd. Last updated February 2009.
10. Ponzone R, Biglia N, Jacomuzzi ME, et al; Vaginal oestrogen therapy after breast cancer: is it safe?; Eur J Cancer. 2005 Nov;41(17):2673-81. Epub 2005 Oct 18. [abstract]
11. Kendall A, Dowsett M, Folkerd E, et al; Caution: Vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol. 2006 Apr;17(4):584-7. Epub 2006 Jan 27. [abstract]
12. Current problems in pharmacovigilance, CSM Vol 29, Sept 2003.

Internet and further reading

• Roberts H; Managing the menopause. BMJ. 2007 Apr 7;334(7596):736-41.

Acknowledgements