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Women’s Health - Menopause - Fast Facts | NEJM Resident 360

Diagnosis

Menopause is a clinical diagnosis that can only be made in retrospect one year after the last menstrual period. No laboratory evaluation is required to confirm a menopausal transition. Workup is indicated if other causes of symptoms or irregular menses are suspected (e.g., thyroid disease, other endocrine abnormalities, medication side effects, or drug intoxication or withdrawal).

Perimenopause: Perimenopause can begin at age 40 to 50 and can last for 10 years. It is characterized by irregular menstrual cycles and vasomotor and vaginal symptoms.

Menopausal symptoms are caused by fluctuating hormone levels, notably a decrease in estrogen. Most common symptoms include:

• vasomotor symptoms: hot flushes, night sweats

• vaginal symptoms: dryness, discharge, dyspareunia

• other: change in sleeping patterns, urinary incontinence, depression, anxiety, fatigue, headaches

Treatment of Vasomotor Symptoms

Treatment algorithm: See an algorithm (Figure 1) for hormone therapy in menopausal patients with vasomotor symptoms.

• First-line therapy for symptomatic women is typically transdermal or transvaginal estrogen or low-dose paroxetine.

• Systemic hormone therapy with estrogen, either transdermally or orally, is the most effective therapy for severe vasomotor symptoms; women with a uterus require use of a progestin in combination with estrogen therapy to avoid endometrial proliferation.

• • Initial research on menopausal hormone therapy suggested possible reduction in overall mortality, cardiovascular events, and osteoporotic fractures. Data from the Women’s Health Initiative in the United States and the Million Women Study suggested that postmenopausal estrogen and progestin administration is associated with an increased risk of coronary disease and invasive breast cancer. However, more recent evidence has shown no association between hormonal therapy and risk of all-cause, cardiovascular, or cancer mortality. 

  • Other research indicates that the benefits of hormone therapy may outweigh the risk for symptomatic younger women (<60 years old) and those who are <10 years from the onset of menopause.

• Nonhormonal options: Paroxetine (7.5 mg once daily) is FDA approved for treatment of systemic menopause symptoms. Other selective serotonin-reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are also used. Evidence for additional treatment is summarized below in a table from the American Congress of Obstetricians and Gynecologists (ACOG) 2014 Practice Bulletin and in guidelines from the North American Menopause Society.

• Alternative therapies: Many therapies such as gabapentin, acupuncture, yoga, Chinese herbs, ginseng, soy, and other alternative medicine have been studied, none of which have convincing evidence to support their use.

Guidelines for Management of Menopausal Symptoms

• ACOG recommends that postmenopausal hormone therapy be used at the lowest dose for the shortest possible time for the treatment of menopausal symptoms. Data from observational studies suggest that transdermal estrogen is associated with a lower risk of venous thromboembolism than oral regimens.

• Current guidelines do not support the use of hormone therapy for reduction of cardiovascular risk or osteoporotic fracture risk.

• USPSTF recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women, but they do not address use for treatment of menopausal symptoms.

• Endocrine Society guidelines recommend an individualized patient approach, weighing the risks of cardiovascular disease with the benefits of symptom reduction.

The following table summarizes existing guidelines for hormonal treatment of menopausal symptoms across a number of professional societies.

(Source: Hormonal Therapy for Postmenopausal Women. N Engl J Med 2020.)

The following tables provide a treatment approach for addressing menopausal vasomotor symptoms:

Hormonal Treatment Options for Menopausal Vasomotor Symptoms

Treatment	Dosage/Regimen	Evidence of Benefit*
Estrogen, alone or combined with progestin

• Standard dose

| Conjugated estrogen, 0.625 mg/day | Yes | | Micronized estradiol-17β, 1 mg/day | Yes | | Transdermal estradiol-17β, 0.0375–0.05 mg/day | Yes | |

• Low dose

| Conjugated estrogen, 0.3–0.45 mg/day | Yes | | Micronized estradiol-17β, 0.5 mg/day | Yes | | Transdermal estradiol-17β, 0.025 mg/day | Yes | |

• Ultra-low dose

| Micronized estradiol-17β, 0.25 mg/day | Mixed | | Transdermal estradiol-17β, 0.014 mg/day | Mixed | | Estrogen combined with estrogen agonist/antagonist | Conjugated estrogen, 0.45 mg/day and
bazedoxifene, 20 mg/day | Yes | | Progestin | Depot medroxyprogesterone acetate | Yes | | Testosterone | | No | | Tibolone | 2.5 mg/day | Yes | | Compounded bioidentical hormones | | No |

*Evidence of benefit as compared with placebo

(Adapted from: Practice Bulletin No 141: Management of Menopausal Symptoms. Obstet Gyneccol 2014.)

Nonhormonal Treatment Options for Vasomotor Symptoms

Treatment	Dosage	Evidence of Benefit*
Pharmacologic
Overall		Yes
SSRIs		Yes

• Paroxetine

| 10–25 mg/day | Yes | |

• Paroxetine salt

| 7.5 mg/day | Yes | |

• Escitalopram

| 10–20 mg/day | Yes | |

• Citalopram

| 10–20 mg/day | Yes | |

• Fluoxetine

| 20 mg/day | Yes | | SNRIs | |

• Venlafaxine

| 37.5–75 mg/day | Yes | |

• Desvenlafaxine

| 75 mg once or twice daily | Yes | | Gabapentinoids | |

• Pregabalin

| 75–150 mg twice per day | Yes | |

• Gabapentin

| 300 mg nightly up to 900 mg divided doses | Yes | | Clonidine patch | 0.1 mg, 0.2 mg, or 0.3 mg weekly | Mixed results | | Nonpharmacologic | | Overall | | No | | Phytoestrogens | | No | | Black cohosh | | No | | Cognitive behavior therapy | | Reduced distress but not frequency of
hot flashes | | Mindfulness-based stress reduction | | Reduced distress from hot flashes | | Hypnosis | | Yes | | Acupuncture | | Inconsistent effects | | Yoga | | Improved mood, reduced distress; no apparent effect on hot-flash frequency | | Exercise | | Inconsistent effects |

Abbreviations: SSRIs, selective serotonin-reuptake inhibitors; SNRIs, serotonin–norepinephrine reuptake inhibitors

*Evidence of benefit when compared with placebo
(Adapted from: Hormonal Therapy for Postmenopausal Women. N Engl J Med 2020.)

Treatment of Vaginal Symptoms

• Vaginal estrogens (creams, tablets, and rings) may be effective for vaginal dryness and dyspareunia, but there are concerns about their use in patients with estrogen-sensitive cancers and because they can be associated with vaginal bleeding.

• Nonhormonal vaginal moisturizers provide a reasonable alternative and can be beneficial in some women for symptom relief. Local preparations have minimal effect on serum estrogen levels and are therefore thought to be a safer option.

The following table provides treatment options for menopausal vaginal symptoms:

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