Consensus statement – Urogenital atrophy

Introduction

Vasomotor symptoms start during the peri-menopause, a time of transition from reproductive to post reproductive life. Long-term estrogen deficiency can be associated with an increase in cardiovascular disease and osteoporosis. The effect of lack of estrogen on urogenital tissue quality is an intermediate effect, often taking three to 5 years to become apparent. Exact prevalence rates are unknown,^1-4 but most women are likely to be affected by some degree of urogenital atrophy and the number of affected women will increase with time from menopause if untreated. Women using systemic HRT may still experience symptoms of urogenital atrophy and can use vaginally delivered estrogen in addition to systemic HRT.

Terminology

Changing terminology has failed to improve recognition and treatment of urogenital atrophy. Other commonly used terms include genitourinary syndrome of menopause and vulvovaginal atrophy. Urogenital atrophy is a term which accurately describes the condition and is the term preferred by the British Menopause Society.

Aetiology

In a healthy vagina, the superficial mucosal cells shed approximately every 4 hours, releasing large amounts of glycogen, which support lactobacilli (healthy vaginal bacteria). Estrogen deficiency causes the mucosa to become thin, with a significant reduction in superficial cells (less than 10%). Consequently, there is a reduction in glycogen and lactobacilli, allowing vaginal commensal organisms such as E. Coli to become more predominant, with a rise in the pH of vaginal secretions (>5) and an increased likelihood of vaginal discharge. Below the mucosa, the lamina propria consists of connective tissue arranged in papillae. Fibroblasts, which produce collagen are the predominant cell type in the connective tissue. Post menopause, these cells become dormant (fibrocytes), and the collagen fibres in the dermal layer hyalinize and fuse. Mucosal thinning and an alteration in connective tissue quality along with fragmentation of elastin fibres results in a reduction in vaginal elasticity, which is linked to pain with penetration.

Symptoms

The most common symptoms experienced include vaginal dryness, itching, burning and pain with sexual intercourse, all of which are likely to impact on desire. Neuronal function is adversely influenced by a reduction in blood flow and this in association with a decrease in normal vaginal secretions can affect sensation and sexual pleasure. Consequent loss of sexual intimacy has a negative effect on the quality of life of women and their partners. ⁵ However, urogenital atrophy is not a condition which exclusively affects sexually active women; vulvovaginal discomfort and urinary symptoms can affect any woman who is estrogen deficient. It is important to ask about potential symptoms as this information may not be volunteered, with women mistakenly believing the symptoms experienced to be an inevitable consequence of aging. Urinary symptoms include frequency, nocturia, urgency and dysuria, which can lead to misdiagnosis of urinary tract infection, and some women develop culture positive urinary tract infection. Urinalysis is important and depending on the results, it may be pertinent to send a midstream sample to microbiology for microscopy and culture. Overactive bladder may be misdiagnosed or may coexist in women with urogenital atrophy.

Signs

Examination is essential, both to confirm the diagnosis and to rule out other conditions including vulval dermatoses, Lichen Planus, Lichen Sclerosis et Atrophicus (LSA), pre-cancer and cancer. It is important to note that there may be minimal signs of disease despite marked symptoms. ⁶

The clinical signs to look for include changes in tissue colour ranging from pallor to inflammation. The vaginal mucosa becomes thinner and more prone to trauma. This can lead to bleeding when inserting a speculum (or during attempts at penetrative sex). There is loss of tissue elasticity, loss of vaginal rugae and shortening of the vagina and it may be very difficult to open the blades of the speculum. There may be a reduction in normal vaginal secretions, but in some women vaginal discharge can be observed due to an alteration in the vaginal microbiome as described above. The urethra can become more prominent and, in some women, prolapsed, facilitating ascending infection, leading to urinary tract infection. Narrow range pH paper is a very useful adjunct to assist diagnosis, with a pH of 5–7 supporting the diagnosis in association with symptoms and other clinical signs. The fat content of the labia majora reduces in some women and the labia minora can become resorbed or fused, which can lead to either loss of the clitoris from view or exposure due to a reduction in mobility of the clitoral hood.

Treatment

Diagnosis is key and this depends upon being aware of the condition and how common it is. Both estrogen and androgen deficiency play a part in the aetiology of urogenital atrophy and in women with no contraindication to hormone therapy, replacing the deficient hormone(s) is the logical approach. Treatment should be started early, as the time to respond to therapy will depend on the degree of atrophy at the time of presentation. It may take three to 4 months for an improvement to become apparent, and the most severely affected women may require longer to respond (vaginal estrogen is best provided indefinitely with annual review).

Non-hormonal lubricants and moisturisers

Vaginal lubricants and moisturisers, which are available with or without a prescription, can be used in conjunction with vaginal estrogen therapy. Lubricants, primarily used for short term relief of vaginal dryness, may be water, oil or silicone based and should be used at the time of sexual activity to reduce discomfort. Choice is based on individual preference, but it is important to remember that oil-based lubricants can weaken condoms in women dependent on barrier contraception. It can be useful to combine water and oil-based lubricants, producing a ‘double glide’ effect. Moisturisers are recommended to be used at least twice weekly, irrespective of sexual activity. They affect the fluid content of the epithelium, replace normal vaginal secretions and reduce the pH of the vaginal secretions. This relieves dryness and efficacy has been demonstrated to match that of local vaginal estrogen therapy. ⁷ To minimise any adverse effect on the vaginal microbiome, the pH and osmolality of lubricants and moisturisers should be similar to that of naturally occurring vaginal secretions. ⁸ Lubricants and moisturisers are particularly relevant in women for whom estrogen is contraindicated. This group includes women diagnosed with breast cancer who are taking aromatase inhibitors.

Vaginal estrogen

Guidance from the National Institute for Health and Care Excellence (NICE), published in November 2015, ⁹ stated that vaginal (local) estrogen can be used for as long as needed. It also made clear that there is no need for endometrial surveillance or the addition of a progestogen for endometrial protection with the current low dose vaginal estrogen preparations in use. A Cochrane Database Review has drawn similar conclusions. ¹⁰ Vaginally delivered estrogen enhances blood flow which restores cell maturation, healthy bacterial flora and a pH below 5. Vaginal secretions and peripheral nerve function are improved with optimal symptom relief and low systemic absorption. ¹¹ Vaginal estrogen therapy has also been found to be superior to placebo for urinary symptoms including urge incontinence, urinary frequency, nocturia and urinary urgency and should be considered in conjunction with anti-cholinergic drugs for women with symptoms of overactive bladder. Treatment choices include natural estrogens, such as estradiol (E2) delivered as a small vaginal tablet or ring, or the weaker estrogen, estriol (E3) delivered as a cream (either 0.1% or 0.01%), a waxy pessary or an oily gel.

Absorption is greatest following initiation of treatment when the vaginal epithelium is most atrophic. Once the tissue quality has recovered, absorption of local estrogen decreases with minimal systemic effects and therefore smaller doses can be used to maintain the benefits achieved, hence a loading dose followed by a maintenance dose for most preparations. ¹²

It is important to inform women that although symptom control is usually seen within the first few weeks of treatment, a beneficial effect may take longer to become apparent, and treatment needs to be continued in order to achieve and maintain this. It is also important to ascertain the individual patient’s preference as to the choice of product used or compliance will be poor. There would appear to be a low appreciation of available treatment choices and a lower uptake in the United Kingdom compared to Scandinavia and North America. ¹³

Vaginal dehydroepiandrosterone (DHEA)

The adrenal glands (80%) and ovaries (20%) secrete dehydroepiandrosterone (DHEA), a neurosteroid and precursor to sex steroid hormones and the exclusive source of estrogens and androgens post menopause. ¹⁴ Prasterone ®, 6.5 mg a pessary containing DHEA delivered vaginally on a daily basis, is licensed in the UK to treat urogenital atrophy. When DHEA is delivered vaginally, it is converted into estrogens and androgens by enzymes within the epithelial cells of the vagina, but not the endometrium, as a result of a process known as intracrinology. ¹⁵ This results in maturation of the parabasal cells into superficial cells, with an associated increase in mucosal thickness and secretions. There is also an increase in collagen density in the lamina propria and stimulation of the muscle in the layer below, most likely due to the influence of the androgens, produced by DHEA, on fibroblasts. Ninety-five per cent of the active hormones made in the vaginal mucosa are inactivated at the site of synthesis preventing any increase in systemic hormone levels or a stimulatory effect on the endometrium. A phase 3 randomised placebo controlled, double blind, prospective study demonstrated a highly statistically significant beneficial effect in women with urogenital atrophy receiving DHEA in a dose of 6.5 mg, delivered daily vaginally for 12 weeks. Androgens can influence structural changes, due to loss of collagen and muscle, including a reduction in rugae and shortening of the vagina. ¹⁶ There are no topical androgen products available and use of vaginal DHEA is the only means of provision.