Treatment of Menopausal Symptoms

Menopause is the permanent cessation of menstruation and loss of reproductive capacity, and is caused by loss of ovarian follicular function. Natural menopause occurs at an average age of 52 years and is diagnosed by amenorrhea for 12 months from the last menstrual period.¹ By 2025, the number of postmenopausal women is expected to rise to 1.1 billion worldwide.¹ Common clinical issues associated with menopause include mood changes; sexual issues; sleep disturbances; urogenital atrophy, also known as genitourinary syndrome of menopause (GSM); and vasomotor symptoms. Some women transition through menopause without symptoms. However, up to 75% experience vasomotor symptoms, specifically hot flashes. Although most hot flashes last 6 months to 2 years, some women experience them for more than 10 years.² GSM refers to the symptoms of urogenital atrophy, such as burning, decreased lubrication, dyspareunia, urinary symptoms, and vaginal dryness caused by estrogen deficiency. GSM affects up to 50% of women during menopause.³ Let’s look at the pharmacologic treatment of GSM and vasomotor symptoms.

VASOMOTOR SYMPTOMS

The most effective treatment for vasomotor symptoms is hormone therapy (HT), with either systemic estrogen or combination systemic estrogen and progestogens for women with an intact uterus. Progestin should be added to the HT regimen in women who have not had a hysterectomy to reduce the risk of endometrial cancer and hyperplasia.⁴ HT is an FDA-approved first- line therapy for relief of vasomotor symptoms in appropriate patients. HT is also approved for prevention of bone loss, hypoestrogenism caused by hypogonadism, castration, and premature ovarian insufficiency and genitourinary symptoms. The benefit and safety of HT seems to be best for young menopausal women (younger than 60 years and within 10 years of menopause) with moderate to severe vasomotor symptoms and no contraindications to HT.⁴

HT PREPARATIONS

FDA-approved systemic HT is available as estrogen alone, progestogens alone, and estrogen-plus-progestogen combinations, in different doses. Some systemic estrogens include conjugated equine estrogens (CEEs) and oral estradiol in varying doses taken daily. Transdermal estrogen as estradiol is available as a daily gel, a patch worn once to twice weekly, a spray, and a 3-month intravaginal ring. Combination HT includes oral estrogen—progestin combinations administered continuously or cyclic regimens (estrogen daily and progestin on days 1 to 13 or 14 of each calendar month). There are 2 combination transdermal estrogen-plus-progestin patches applied either once or twice weekly. Progestin-only options are oral medroxyprogesterone and oral micronized progesterone. In women with an intact uterus, progestins must be added to estrogen therapy in a cyclic (12 days per month) or continuous manner.

HT is associated with adverse effects and contraindications. Contraindications include active liver disease, advanced-stage or high-risk endometrial cancer, breast cancer, coronary heart disease, a previous venous thromboembolic event (VTE)or stroke, transient ischemic attack, and unexplained vaginal bleeding.⁵ There are transdermal and oral HT options with either estrogen alone, progestogen, or a combination. Transdermal and other nonoral systemic HT options avoid first-pass metabolism, which may decrease negative effects on clotting factors and lipids such as triglycerides. Common adverse effects are dose related, classic for HT, and include bloating, breakthrough bleeding, breast tenderness, fluid retention, headaches, mood swings, nausea, and weight gain.⁴

Another hormonal option, bazedoxifene, is a selective estrogen receptor modulator, estrogen agonist or antagonist, combined with CEE, a daily oral medication approved for hot flashes in postmenopausal women with a uterus.⁶ This option may be an alternative for patients with progestin-associated effects, such as breast tenderness, or in women who cannot take bisphosphonates for osteoporosis.

RISKS OF HT

Meta-analysis of recent studies suggests that initiation of HT less than 10 years after menopause onset does not increase the risk of coronary heart disease or stroke but slightly increases the risk of VTE, especially in the first 1 to 2 years of HT.⁴

Breast cancer is also a potential concern with HT. Data from the largest placebo-controlled trial using oral CEE alone or in combination with oral medroxyprogesterone (MPA) suggest an increased risk of breast cancer in users of CEE plus MPA.⁷ Women using CEE alone did not have an increased risk of breast cancer. Longer duration of therapy with oral CEE plus MPA may increase breast cancer risk. The use of transdermal estrogens and oral micronized progestins may not be associated with the same risks as those of oral CEE and MPA.

NONHORMONAL MEDICATIONS

For patients who are not candidates or do not want to use HT, there are nonhormonal options for vasomotor symptoms. Nonhormonal prescriptive treatments for vasomotor symptoms include antidepressants, specifically paroxetine mesylate capsules (Brisdelle), the only nonhormonal medication approved by the FDA to treat moderate to severe hot flashes and night sweats.⁸ Clonidine, gabapentin, and other serotonin—norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, such as desvenlafaxine and venlafaxine, have been used with variable efficacy. Although paroxetine and venlafaxine are more effective than the placebo for improving vasomotor symptoms, they do not improve GSM or bone mineral density. Paroxetine is also associated with potential drug interactions with other CYP2D6 substrates.⁸

GENITOURINARY SYNDROME OF MENOPAUSE

GSM refers to changes in the lower genital tract, the vagina, and the vulva because of decreasing estrogen. This condition affects up to 50% of women during menopause.⁹ Thinning of the vulvar mucosa may cause symptoms, such as burning and irritation, which can lead to dyspareunia. Other symptoms of GSM may include recurrent urinary tract infections, and urinary urgency.¹⁰ Estrogen therapy is the most effective therapy for GSM.¹¹ All estrogen products for GSM have similar effectiveness, regardless of administration route.¹² Low-dose vaginal estrogen preparations include creams, rings, and tablets containing CEE or estradiol and have minimal absorption.⁹ Women using low-dose estrogen for less than a year should not require progesterone to decrease the risk of endometrial cancer.⁹ Clinicians can tell patients that there is no evidence that low-dose local estrogen increases breast cancer risk.¹³

Other treatment options include intravaginal dehydroepiandrosterone (DHEA),¹⁴ the oral systemic estrogen agonist—antagonist ospemifene (Osphena),¹⁴ and vaginal mois- turizers. Although not as effective as estrogen, it is acceptable to try as first-line therapy. Vaginal moisturizers are effective for symptoms such as dyspareunia and mild vaginal dryness. FDA- approved nonhormonal ospemifene can be used for dyspareunia but should not be used by women with a history of breast cancer or thromboembolic disease.¹⁵

CONCLUSION

In young menopausal women with a uterus, clinicians should prescribe combination HT to treat vasomotor symptoms using the smallest therapeutic dose for the shortest time. Although HT is the most effective treatment for vasomotor symptoms, nonhormonal alternatives can be used. Patients with GSM may benefit from intravaginal DHEA, nonhormonal vaginal moisturizers, ospemifene, or vaginal estrogen.

Jennifer L. Hofmann, MS, PA-C, is a clinical associate professor and full-time faculty and pharmacology courses instructor at Pace University-Lenox Hill Hospital PA Program in New York, New York. She is also a Touro PA Program adjunct professor for Bayshore, New York, and Nassau University Medical Center in East Meadow, New York. In addition, she is a Stony Brook University PA Program postprofessional PA program clinical pharmacology seminar adjunct professor in Stony Brook, New York.

Jean Covino, DHSc, MPA, PA-C, is the director of didactic education at Pace University-Lenox Hill Hospital and works clinically at Medemerge Family Practice/Urgent Center in Green Brook, New Jersey.

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