Vaginal impact of menopause-related estrogen deficiency

Professor, Department of Obstetrics and Gynecology, Director, The Women’s Place Midlife Health Center, University of Virginia Health System, Charlottesville, Va

DISCLOSURE
The author has received research grants from, and served as a consultant to, Wyeth, Eli Lilly, Amgen, Novo Nordisk, Pfizer (fees to University of Virginia), DSMB, Boehringer Ingelheim, and Depomed.

Vaginal atrophy associated with postmenopausal estrogen deficiency is a common but under-recognized and undertreated disorder. Because the vagina and surrounding tissues require estrogen stimulation to maintain normal structure and function,¹ declines in estrogen levels—regardless of the cause—can result in vaginal atrophy and its associated symptoms, such as vaginal dryness, itching, burning, and inadequate lubrication during sexual activity. Together, these symptoms can lead to dyspareunia, vaginitis, and vaginismus. Urinary symptoms associated with vaginal atrophy include increased frequency, urgency, and recurrent urinary tract infections, as well as urinary incontinence resulting from pelvic floor relaxation.

The urogenital system is exquisitely sensitive to estrogen loss because of the presence of estrogen receptors in the vagina, vulva, musculature of the pelvic floor, endopelvic fascia, urethra, and bladder.² Declines in estrogen concentrations associated with menopause can result in significant cytologic and structural changes in the vulva, vagina, and lower urinary tract; can prompt the development of vulvo-vaginal and urinary symptoms; and may contribute to symptoms of sexual dysfunction.^3,4

Other causes of vaginal atrophy related to estrogen deficiency include lactation, various treatments for breast cancer (e.g., aromatase inhibitors) and other gynecologic cancers, and the use of certain medications. However, vaginal atrophy and its symptoms may resolve with use of systemic or topical estrogen.

Symptoms of vaginal atrophy—which can range from annoying to very bothersome—can cause significant emotional distress, sexual dysfunction, and reductions in quality of life.^5-8 Because these symptoms are often progressive and do not typically resolve without treatment, and women are living longer, untreated women may experience these symptoms for more than one third of their lives.⁵ Therefore, there is a clear need to reevaluate the symptoms of vaginal atrophy and its causes, and for a greater clinical focus on this disorder.

PREVALENCE OF VAGINAL ATROPHY AND ITS SYMPTOMS

VAGINAL ATROPHY. The prevalence of vaginal atrophy has been evaluated in numerous studies with varying results.⁹ Generally, the prevalence of vaginal atrophy has been reported to range from 7% to 57% in healthy peri- and postmenopausal women.^9-11 In observational studies, 27% to 55% of postmenopausal women reported vaginal dryness,^5,11-13 and 19% reported irritation or itching.¹⁴

The prevalence of vaginal atrophy in certain populations, such as breast cancer survivors, is even higher. For example, in a 2004 study, 62% of postmenopausal breast cancer survivors reported vaginal dryness.¹⁵ More recent studies have demonstrated that current endocrine therapy for breast cancer has an even more profound impact on vaginal dryness during intercourse (73%).¹⁶ More than 20% of premenopausal breast cancer survivors also experienced these symptoms. Nearly one half of women who have breast cancer and are receiving endocrine therapy experience vaginal dryness, and one half of these patients have moderate or severe symptoms.¹⁶

SEXUAL DYSFUNCTION. According to a recent study, as many as 55% of sexually active postmenopausal women experience sexual dysfunction.¹⁰ Symptoms associated with vaginal atrophy have an adverse effect on sexual function and interest in sexual activity. For example, vaginal dryness has been associated with reduced sexual enjoyment in midlife women.¹⁷ Another study found that 39% of postmenopausal women experience difficulty with vaginal lubrication during sex.¹⁸

In women who have vaginal atrophy and who are sexually active, dyspareunia is frequently reported.¹⁸ Recent population-based prevalence studies of postmenopausal women not using hormone therapy have estimated that approximately 22% to 29% suffer from dyspareunia.^19-21 In a 2009 study of women receiving endocrine therapy for breast cancer, 56% of sexually active women reported dyspareunia, and a very high percentage of patients also have vaginal dryness during intercourse, as stated earlier.¹⁶

URINARY SYMPTOMS. Urinary symptoms associated with vaginal atrophy include urinary tract infection and urinary urgency and incontinence.^22,23 About 20% of elderly women not institutionalized show evidence of bacteriuria and up to 17% experience recurrent urinary tract infection (UTI).^24,25 Among women aged 60 years or older still living in the community, urinary incontinence affects approximately 15% to 35%.^24,26 In women receiving endocrine therapy for breast cancer, 41% reported urinary urgency, 36% reported urinary incontinence, and 11% reported an increased frequency of urinary tract infection.¹⁶

ROLE OF ESTROGEN IN UROGENITAL HEALTH

Estrogen has numerous effects on urogenital tissues. In a recent study of RNA profiling of vaginal biopsies in women with postmenopausal vaginal atrophy after estrogen treatment, investigators reported that more than 3,000 genes are regulated by estrogen, including those involved in regulating cell growth, proliferation, and defense against infection.²⁷ Estrogen receptors are found not only in the vagina and vulva but also in the urethra and neck of the bladder.

In the vagina, estrogen causes a thickening of the vaginal epithelium, creating a redundant tissue layer. During sexual arousal, this redundancy allows the vaginal surface area to expand. The thickened vaginal epithelium, along with cervical mucous secretions and local bacterial flora, also act as physical barriers, preventing infection.

In addition, estrogen stimulation increases the glycogen content of vaginal epithelial cells. Glycogen is metabolized by organisms in the vagina to lactic acid, which acts to maintain the vaginal pH at about 3.5 to 4.5.^28,29 This acidic pH is an important component of a woman’s nonspecific defense against pathogens.^28-30

In premenopausal women, estradiol levels typically fluctuate from 10 to 800 pg/mL, whereas circulating estradiol levels after menopause are typically less than 30 pg/mL.³¹

Evidence suggests that the incidence of symptoms related to vaginal atrophy is associated with estrogen levels.³² In one study, women with lower serum estradiol levels (<50 pg/mL) had higher rates of vaginal dryness and dyspareunia compared with those with higher levels (>50 pg/mL).³²

PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS
OF VAGINAL ATROPHY

VAGINAL ATROPHY. In premenopausal women, intermediate and superficial cells predominate and few parabasal cells are observed in the vaginal epithelium.^28,33 After menopause, cytologic changes in the vagina associated with estrogen deficiency are readily observed, including an increase in parabasal and intermediate cells and a large decrease in superficial cells.²⁸

Clinically, vaginal atrophy is characterized by thin, pale, dry, and possibly inflamed vaginal walls (TABLE 1).^28,34,35 The vaginal walls may exhibit petechiae, or non-raised, round, purple or red spots caused by intradermal or submucous hemorrhage.

Genital and urethral signs of vaginal atrophy^34,35

Vaginal walls may become thinner, less elastic, and progressively smoother as vaginal rugation decreases. In addition, the vagina may shorten and narrow and become paler in color. If untreated, vaginal atrophy can result in a friable, ulcerated surface that may tear and bleed, often after the minimal trauma associated with intercourse or speculum insertion.

Similar changes in the vulva are observed. Losses in vulvar collagen, adipose tissue, and the ability to retain water are common and may cause the epithelial surface of the vulva to thin.^5,36 In addition, the clitoral glans may lose its protective covering and be easily irritated from contact. Clitoral blood flow has been shown to be reduced in the presence of estrogen deficiency. Estrogen and androgen deficiency have been shown to be associated with reduced expression of sex steroid receptors and, most importantly, with attenuated genital blood flow and lubrication in response to stimulation.³⁷

SEXUAL DYSFUNCTION. Estrogen deficiency can impair vaginal function and impede the physiologic responses that characterize sexual arousal, such as smooth muscle relaxation, vasocongestion, and vaginal lubrication.^1,5 Decreased blood flow, reduced vaginal secretions, and delayed onset of lubrication during sexual stimulation due to estrogen deficiency may contribute to sexual dysfunction observed in some postmenopausal women.^1,11,28

These changes, in addition to the structural and epithelial changes described above, increase the likelihood of trauma and pain during sex and can result in dyspareunia. The fear of pain caused by vaginal atrophy can reduce a woman’s genital and subjective sexual response or desire to have sex.³³ Spasm of the levator muscles may further increase pain with penetration leading to dyspareunia.³⁸

URINARY SYMPTOMS. After menopause, estrogen deficiency may result in disorders of the lower urinary tract. For example, a reduction in superficial epithelial cells in the vagina results in less exfoliation of cells, reduced release of glycogen, and reduced conversion into lactic acid by the vaginal flora.⁹ These changes may increase the vaginal pH to 5 or greater (compared to 3.5 to 4.5) and may result in the cultivation of bacteria and the colonization of vagina by fecal flora. These bacteria can not only cause symptomatic vaginal changes and inflammation but also increase the risk of recurrent UTIs.

Postmenopausal estrogen-deficient atrophic changes within the urinary tract include atrophy in the urethral epithelium and decreased periurethral collagen,^39,40 which may result in introitus narrowing and prolapse of the urethra (urethral caruncle) in advanced stages. Estrogen loss is also associated with a reduction in collagen content with atrophic changes in pelvic floor tissues. Therefore, postmenopausal estrogen deficiency may play a role in the development or progression of pelvic floor relaxation, stress incontinence, and pelvic organ prolapse.

EVALUATION

MEDICAL HISTORY. Although most cases of vaginal atrophy result from reductions in estrogen production, postmenopausal estrogen deficiency is not the only cause of atrophy-related symptoms.

One goal of taking the medical history in patients with these symptoms is to rule out other or additional causes of vaginal atrophy, such as other conditions associated with estrogen deficiency, the use of certain endocrine therapies, and medically induced menopause.

A second goal is to determine the patient’s current sexual activity, status of the relationship with partner(s), history of treatments used, therapeutic goals, and the level of distress associated with the complaints.²⁸

Because patients may be reluctant to volunteer information about their vulvovaginal symptoms, clinicians should specifically ask postmenopausal patients about the presence and severity of these symptoms. For example, clinicians should ask patients if they are having vaginal dryness, pain with penetration, or pain either during or after intercourse.

COMPONENTS OF THE PHYSICAL EXAM. Clinicians should evaluate vaginal atrophy during the pelvic examination of postmenopausal patients, even in women who have not complained of vulvovaginal symptoms. Vaginal atrophy associated with estrogen deficiency can start during the perimenopausal years.

In women with early stages of vaginal atrophy, the vaginal epithelium may be thin, dry, and mildly erythematous.²⁸ As atrophy progresses, the tissues of the vulva become progressively pale, dry, and thin, and the vagina loses elasticity, shortens, and narrows. A thin, watery, yellow vaginal discharge may also be observed. There also may be tenderness to palpation in the vestibule, and the vagina can be easily traumatized and irritated.

To decrease pain and irritation associated with vaginal atrophy during the physical examination, clinicians should use adequate lubricant and consider using a smaller speculum.

See “Clinical pearls for evaluating vaginal atrophy,”.

LABORATORY TESTS. Although vaginal atrophy is typically a clinical diagnosis, an evaluation of vaginal pH may be used to support the diagnosis. Vaginal pH can be assessed by placing a piece of litmus paper on the lateral vaginal wall.⁹ Patients with vaginal atrophy typically have a vaginal pH of 5 or higher.²⁸

Although laboratory assessments of vaginal maturation using vaginal cytology are common in clinical trials, they are generally not needed in clinical practice. One such laboratory test is the vaginal maturation test, which evaluates the relative proportion of parabasal, intermediate, and superficial vaginal epithelial cells in a sample. Premenopausal women typically have more than 15% super!cial cells, whereas postmenopausal women with vulvo-vaginal atrophy usually have less than 5%.⁹

If a wet mount evaluation is performed, immature epithelial cells and white blood cells will be apparent if vaginal atrophy is present.

While vaginal cultures are generally of limited utility in patients with postmenopausal estrogen deficiency, they may be useful to help clinicians pinpoint the presence of a specific organism involved in vaginal atrophy.

DIFFERENTIAL DIAGNOSIS

Other disorders that can cause symptoms similar to those of vaginal atrophy include infection, trauma, presence of a foreign body, lichen sclerosis, benign and malignant tumors, other medical disorders (e.g., diabetes and lupus), and, potentially, psychological problems (TABLE 2).^9,28,33 Bacterial vaginosis, one of the most common vaginal infections, can occur from vaginal atrophy.⁹ Irritants such as perfumes, lubricants or moisturizers, and soaps can cause similar symptoms.

In addition, the presence of vulvovaginal dermatoses, such as lichen sclerosis, lichen planus, and lichen simplex chronicus, may cause similar vulvovaginal symptoms.^9,42 Cancer and precancerous lesions, including vulvar and vaginal intraepithelial neoplasm and vulvar cancer, should also be considered. If any of these disorders are suspected, a biopsy should be performed to obtain diagnosis and suggest treatment options.⁹

Differential diagnosis for symptoms of vaginal atrophy^9,33

CONSIDERATIONS

Despite the frequency and impact of symptoms of vaginal atrophy, they are often underreported and, consequently, undertreated. A recent Web-based survey of postmenopausal women found that only 40% of women are likely to discuss their vaginal symptoms with their physician.⁴³

Even fewer women receive treatment for their symptoms. Estimates suggest that only 20% to 25% of postmenopausal women su$ering from symptoms of vaginal atrophy will seek medical attention.^5,28,34 Consequently, the care of the menopausal woman should include both a physical assessment of vaginal atrophy and dialogue exploring possible existence of symptoms and their effect on vulvovaginal symptoms, sexuality, and quality of life issues.

SUMMARY

Postmenopausal estrogen deficiency can lead to vaginal dryness and discomfort, dyspareunia, vaginitis, and even recurrent urinary tract infections or symptoms of urinary incontinence, all of which result from atrophic changes in the vagina, vulva, and lower urinary tract. Symptoms of vaginal atrophy in postmenopausal women are commonly prevalent, may be highly distressing, and are often overlooked until problems occur.

Due to the progressive nature of vaginal atrophy, the significant impact of its symptoms on quality of life, and the persistence of its symptoms in the absence of treatment, it is critical that clinicians evaluate the presence and severity of vaginal atrophy in their postmenopausal patients and other patients with prolonged estrogen deficiency.

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