Postmenopausal Syndrome

Etiology

Postmenopausal symptoms are primarily attributed to the decreased level of circulating estrogen. Hot flashes, vulvovaginal atrophy, and sexual dysfunction result from the complex changes that occur around menopause. At the level of the ovary, there is a depletion of ovarian follicles, especially the granulosa cells. The ovary, therefore, is no longer able to respond to the pituitary hormones. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) level increases due to lack of feedback inhibition, and ovarian estrogen, progesterone, and inhibin production cease. However, the androgen production continues in the remaining ovarian theca cells and adrenal gland, which gets converted to estrogen through peripheral aromatization.

Hot Flashes

The etiology of hot flashes is complex. There is thought to be resetting and narrowing of the thermoregulatory system secondary to the fluctuations or loss of estrogen production. Hot flashes have also been thought to be due to alteration in both estrogen and FSH levels. It may also be related to the up-regulation of the 5-hydroxytryptamine receptor (5-HT2A) in the hypothalamus in response to the reduced serotonin level. The reduction is thought to be due to decreased estrogen levels.[1]

Vulvovaginal Atrophy

Urogenital tissues are highly sensitive to estrogen, and lack of estrogen causes atrophy and shortening of the vagina, uterine prolapse, and dyspareunia. Decreased estrogen levels affect the urinary tract, including the bladder and urethra, and many develop urinary incontinence. Unlike vasomotor symptoms, vulvovaginal atrophy does not improve over time without treatment.

Sexual Dysfunction

Unlike hot flashes and vulvovaginal atrophy, the etiology of sexual dysfunction does not correlate with hormonal changes. The decreased libido could also be attributed to the vasomotor symptoms, sleep disturbance, and mood changes in postmenopausal women.

Epidemiology

Around 1.5 million women experience the menopause transition each year. Although 70 to 80% of women experience vasomotor symptoms, only 15 to 20% of women have significant interference with quality of life and seek help. The average duration of hot flashes is about 5.2 years, with symptom onset one year before the final menstrual period and declining thereafter. About 27 to 60% of women report vaginal dryness or dyspareunia in association with menopause. Around 50% of women report sleep disturbance. There is a reported 3-fold risk for the development of a major depressive episode during perimenopause.[2]

Pathophysiology

There is progressively dwindling of ovarian follicles as a woman ages. The ovarian estrogen and inhibin production decreases because of the loss of granulosa cells. The FSH and LH level remains high because of the lack of negative feedback from the ovary. Androgen production from the ovary continues beyond the menopausal transition because of the sparing of the stromal compartment. Menopausal women continue to have low levels of circulating estrogens, principally from peripheral aromatization of ovarian and adrenal androgens. Adipose tissue is a major site of aromatization, so obesity affects many of the sequelae of menopause. The hot flash is thought to be due to the resetting and narrowing of the thermoregulatory system in response to the variability of estrogen and FSH levels.[3] The decreased levels of serotonin and elevated norepinephrine levels are also thought to play a part in the development of these symptoms.[4][1]

History and Physical

The significant symptoms of postmenopausal syndrome are vasomotor (hot flashes), vaginal and urinary (termed as GSM-genitourinary syndrome of menopause), insomnia, and mood. Hot flashes are a sudden sensation of heat centered on the upper chest and face that rapidly becomes generalized and lasts two to four minutes with associated perspiration. Palpitations, chills, shivering, and a feeling of anxiety may be present. This frequency of symptoms ranges from one to several times per day. It is also reported most commonly at night. The average duration of hot flashes is about 5.2 years but can also persist as long as 20 years.[2][5]

Clinical manifestations of GSM are usually mild. The symptoms are vaginal dryness, burning, itching, dyspareunia, loss of libido, and lower urinary tract symptoms (urinary frequency, urgency, and nocturia, urgency, and urge incontinence (28%) recurrent urinary tract infections, stress incontinence). Signs of GSM include decreased moisture, lack of vaginal rugae, vaginal pallor, and decreased pubic hair, loss of elasticity, and narrowing of introitus. They may also have uterine prolapse, cystocele, and rectocele.[6]

Irregular menstrual cycles, hot flashes, and night sweats are predominant during the perimenopausal state. After menopause, genitourinary symptoms like vulvovaginal atrophy and dryness predominate. Most of the symptoms have been difficult to establish a true relationship with menopause and response to treatment with estrogen, but vasomotor and genitourinary symptoms show a good response to hormone replacement therapy. Postmenopausal women also have symptoms of sexual dysfunction, including decreased libido, reduced frequency of sexual thoughts, and fantasies.

Sleep disturbance is prevalent in almost 50% of patients by menopause. There is increased sleep-onset insomnia and an increased prevalence of obstructive sleep apnea (OSA).[7] Hormonal changes alone are not likely to provide a complete explanation for the relationship between sleep difficulty and menopause. Insomnia in these women can be secondary to hot flashes, mood disorders, psychosocial factors, obstructive sleep apnea (OSA), restless legs syndrome (RLS), or other medical comorbidities.

Evaluation

The diagnosis of postmenopausal syndrome is primarily based on symptoms. In otherwise healthy women older than 45 years, no diagnostic workup is required. The follicle-stimulating hormone levels do not help as the hormone levels fluctuate during this period. Work up, including blood count or thyroid function tests, are done if non-menopausal causes of symptoms are suspected. In women younger than 40, persistently elevated FSH levels are needed to confirm the diagnosis. In this age group, differential diagnoses like pregnancy or polycystic ovarian syndrome should be considered.

Treatment / Management

Vasomotor Symptoms

The severity of symptoms, presence of other coexistent medical problems, other menopausal symptoms, age, and the personal choice of the patient should guide the management plan.

1. Mild hot flashes-Behavioral measures are usually effective in mild symptoms. This includes lowering room temperature, using fans, heat-friendly clothing, dress in layers, and avoiding triggers (stress, spicy foods).[4] Other unproven benefits include weight loss, mindfulness-based stress reduction, cognitive-behavioral therapy (CBT), acupuncture, hypnosis, yoga, and vitamin E.[8][5]
2. Moderate to severe hot flashes-Most patients will need pharmacologic therapy apart for behavioral and lifestyle changes. This includes hormonal and nonhormonal treatments. Hormonal therapy is the treatment of choice in women with no contraindications. 
(B3)

Hormonal Therapy

Women younger than 60 years or within ten years of menopause are candidates for hormone therapy as the risk of the adverse effect is minimal in this group. Women with an intact uterus need combination therapy with both estrogen and progestin to protect against uterine cancer, while those who have undergone hysterectomy can receive estrogen only. Transdermal therapy is the treatment of choice in women with diabetes, hypertriglyceridemia, and migraine without aura, those with increased risk for venous thrombosis, gallbladder disease, and liver disease. Studies have reported a decrease in the frequency of hot flashes by 75% and the severity by 87% with either estrogen alone or with progesterone. The response is usually noted by two weeks with good symptom relief by six weeks—no difference in efficacy between oral or transdermal treatment. Progestogens are added in women with an intact uterus to protect against uterine cancer. Hormonal treatment is also indicated and safe in women with primary ovarian insufficiency or early menopause. 

Typically the treatment can be safely used for up to 3 to 5 years and up to 60 years of age, after which it is discontinued. Typically they are tapered and stopped over six months to 1 year, especially in those with frequent bothersome symptoms. Symptoms may recur in 50%. In women with early menopause or primary ovarian failure, hormone therapy is recommended until the expected age of natural menopause. This is to reduce cardiovascular, osteoporosis, and fracture risk. In a small percentage who continues to have significant symptoms impacting the quality of life beyond 60 years of age, hormonal therapy can be continued at a lower dose and preferably by the transdermal route.

Dosing, Formulation, and Route of Administration

Estrogen preparations are available as oral tablets, transdermal patches, topical gels, emulsions, and lotions. The intravaginal creams and tablets and vaginal rings and are usually used for vulvovaginal atrophy at lower doses, but vaginal rings at higher doses are available for hormone replacement therapy (HRT).[5]Transdermal estrogen has a better risk profile for venous thrombosis and stroke and has less of an effect on serum lipid concentrations. The most common oral estrogen preparations are conjugated equine estrogen, oral micronized 17-beta estradiol, esterified estrogen, and ethinylestradiol. Ethinyl-estradiol is the most potent among the estrogens.[2] Transdermal preparations include 17 beta-estradiol transdermal gel and topical emulsion.

Nonhormonal Therapy

This includes lifestyle changes, nonprescription therapies, and prescription medicines. Nonhormonal treatment is preferred in women above 60 years of age or if more than ten years postmenopausal. Other categories of patients are symptomatic women with a history of MI, stroke, venous thromboembolic disease, estrogen-sensitive cancers, those with increased risk of breast cancer, heart diseases, or venous thromboembolism (VTE). Black cohosh, ginseng, vitamin E, flaxseed, etc., are not shown any benefits. Some data suggest possible improvement in symptoms with activities that involve reduced stress like cognitive behavioral therapy, hypnosis, and mindfulness-based stress reduction. Yoga, acupuncture, and exercise have not shown any benefit.[5][9] 

Nonhormonal pharmacologic therapies that are effective include SSRIs (paroxetine, escitalopram, fluoxetine, citalopram), SNRIs (venlafaxine, desvenlafaxine), clonidine (patch), and gabapentinoids (pregabalin, gabapentin). These have been shown to decrease the severity and frequency of hot flashes. The onset of relief is noticed in 2 to 3 weeks. SSRIs and SNRIs reduce the frequency and severity of menopause-associated vasomotor symptoms by 10% to 64%. Among these, escitalopram and paroxetine ER and venlafaxine XR were the most effective.[10] SSRIs should be avoided in patients on tamoxifen as it decreases the efficacy of tamoxifen. Venlafaxine and desvenlafaxine is the treatment of choice in these patients. However, paroxetine is the only FDA-approved treatment for vasomotor symptoms. The adverse effects are mild nausea, constipation, and dry mouth, which are relatively mild and subside within the first week.[11] The drawbacks of paroxetine and venlafaxine are that some patients have withdrawal syndrome.

Genitourinary Syndrome

1. Hormonal therapy - Low dose topical estrogen is the treatment of choice for moderate to severe symptoms. It increases the thickness of the epithelium, secretion, moisture, and vaginal flora. The effect wears off when use is discontinued. But it is interesting to note here that it does not improve urinary incontinence.[12] Higher doses estrogen does not show an increase in effectiveness and also places the patient at increased risk of breast cancer, heart disease, VTE, and cerebrovascular event. Currently, there is no evidence of low-dose vaginal estrogen causing these risks. Progesterone is not needed for endometrial protection with vaginal estrogen, but any postmenopausal bleeding needs to be evaluated by endometrial biopsy and ultrasonography. Oncologists should be involved when determining whether to prescribe vaginal hormones in breast cancer patients because of concerns of vaginal estrogen, lowering the effect of aromatase inhibitors.

Conjugated equine estrogens daily (for 2 to 3 weeks followed by one week off, repeat as needed), estradiol vaginal cream 0.01% (1 gm. every two weeks or every three weeks), estradiol ring (one every three months) are used.

2. Lubricant and moisturizers - These can be used in milder symptoms and as first-line treatment in general, especially for women with estrogen-sensitive cancer. These are available over the counter as vaginal lubricants and moisturizers, such as globules, creams, and liquids. The active component is hyaluronic acid that improves the moistening of the extracellular matrix. Studies have shown subjective and objective improvement in symptoms, including vaginal dryness, itching, burning, and dyspareunia. The therapeutic effects are limited to the duration of treatment.

3. Selective estrogen receptor modulator with affinity to vaginal mucosa - Ospemifene is the first SERM approved for moderate to severe VVA symptoms in patients, not candidates for estrogen. It increases the risk of vein thromboembolism (1.45/1000 women in the ospemifene group and 1.04/1000 women in the placebo group), hence it is contraindicated in women with current or past thromboembolic disease. Ospemifene is given orally at a dose of 60 mg daily. 

4. Vaginal dehydroepiandrosterone (DHEA) (prasterone) - It is a treatment option for dyspareunia. The dose is 6.5 mg (0.5% formulation) as a daily vaginal suppository.

5. Laser therapy - Has been used recently in the treatment of vulvovaginal atrophy. The goal is to stimulate collagen remodeling and new collagen synthesis. More studies are needed to assess the long-term efficacy and safety of these procedures before recommending them for common use.

Sexual Dysfunction

Sexual dysfunction is multifactorial. Treating hot flashes, vaginal dryness, and mood changes have been found to improve sexual dysfunction. Some of the symptoms, especially post-surgical menopause, are attributed to a decreased level of androgen. Low-dose vaginal estrogen and DHEA can be used in dyspareunia. Several randomized, placebo-controlled clinical trials suggest that testosterone therapy improves sexual function like desire and frequency in postmenopausal women. The potential benefit and harm and the limited data on long-term use need to be discussed. Also, all safer options like relationship intervention, sex therapy sessions, optimizing treatment of depression, and treatment of another postmenopausal problem should be done before the trial of testosterone therapy. Transdermal and oral preparations are preferred in women. 

Androgen should be used with caution in patients with a high risk of breast cancer, endometrial hyperplasia or cancer, cardiovascular disease, and hepatic disease. It can cause hirsutism and decreased HDL levels. Since testosterone is converted to estrogen in the body, a close watch on all potential complications of estrogen treatment can occur. It also needs monitoring of lipid levels and liver function at regular intervals.[13](A1)

Sleep Disturbance

The nature of the sleep disturbance can help guide the clinician to appropriate treatment. The specific cause needs to be identified, and appropriate treatment needs to be initiated. Insomnia related to vasomotor symptoms (VMS) should be treated with HRT. Primary insomnia shows a good response to cognitive behavioral therapy. Non-benzodiazepine hypnotics and melatonin also can be tried. Sleep disturbance associated with depression may respond to antidepressants. Women with persistent sleep complaints need to be referred to sleep specialists for comprehensive sleep management to diagnose and treat unrecognized and untreated sleep disorders.[14]

Differential Diagnosis

The differential diagnosis depends on the presentation. The symptoms of hot flashes mimic thyroid disease, malignancies, hypoglycemia carcinoid, and pheochromocytoma.[15]

Prognosis

Vasomotor symptoms improve over time but rarely the symptoms last to up to 20 years post-menopause. The duration is affected by race with the minimum in Asian women and longer in African American women (10 years). Hormonal therapy reduces the frequency and severity of hot flashes by 75% and 87 % respectively. It also improves the risk of bone loss and risk of fractures and improves genitourinary syndrome of menopause. The genitourinary symptoms typically do not improve over time and the symptoms return once the treatment is stopped.[5]

Complications

The women’s health initiative (WHI) trial reported increased risks of cardiovascular disease (0.6/1000), stroke (0.9/1000), venous thromboembolism (VTE), and breast cancer with the use of hormone replacement therapy. The increased risk of breast cancer was noted at four years with combination therapy and increased risk of endometrial neoplasia with estrogen therapy. All doses and routes of administration for estrogen and progestogen products have a boxed warning to use the lowest dose, and the shortest duration possible was based on the above trial.[5]