Resident Editor: Joseph R. Cartwright, MD, MEd

Faculty Editor: Alison Huang, MD

Background

• Menopause is defined as amenorrhea for at least 12 months.
• The median age of menopause in the US is 51 years. 

Signs and Symptoms

• Peri-menopause symptoms start on average 4 years before the final period. 
• Symptoms may include irregular menstrual cycles, hot flashes, night sweats, sleep disturbance, depressed mood, dyspareunia, vaginal dryness, decreased concentration, joint aches, change in libido.
• Hot flashes are the most common menopause symptom of US women, occur in 75% of postmenopausal US women, and usually last 2-5 years. 30% of women have symptoms after 5 years; 10% of women have persistent symptoms >10 years after menopause. African-American women most likely to be bothered by hot flashes & night sweats. 
• Breast pain, skin changes, impaired balance, and menstrual migraines may also occur. 
• Changes in lipids and bone loss may accelerate during menopause. 

Work-up

• In the late transition (intervals of amenorrhea of 60 days or more) FSH >25 IU/L suggestive of menopausal transition. However, FSH measurement is NOT required for diagnosis in a women age >45 years. 
• If age >45 yrs, check prolactin & TSH for amenorrhea only if suggestive features e.g. galactorrhea, goiter, tachycardia, proptosis.
• If age 40-45 yr with irregular cycles, check serum hCG, prolactin, and TSH for amenorrhea before assuming menopause.
• If age <40 yr, have concern for premature ovarian failure and pursue work-up with cycle day 3 FSH and estradiol. Referral to fertility clinic is appropriate. Measurement of serum antimullerian hormone and an antral follicle count on transvaginal ultrasound can also aide in diagnosis
• Other rare clinical conditions that can have some symptomatic overlap with menopause, and which should be evaluated for if there are strongly suggestive features, include the following: carcinoid syndrome, pheochromocytoma, opioid withdrawal, niacin use, chronic infection, dumping syndrome, mast cell disorders, some cancers (medullary thyroid, pancreatic islet-cell, renal cell carcinoma, and lymphoma), and anxiety disorders

Treatment

A. Non-hormonal symptom management

Vasomotor symptoms (hot flashes & night sweats)

• Counseling re: smoking cessation, alcohol use in moderation, and weight loss (if overweight/obese). 
• Additional lifestyle modifications include turning down the thermostat, dressing in layers, avoiding spicy foods, and reducing stress.
• Potential benefit with clinical hypnosis, cognitive behavioral therapy, mindfulness-based stress reduction.
• SSRIs are modestly efficacious in RCTs (reduction in frequency of hot flashes by 25-69%). Benefits usually appreciated within a week.
  • Paroxetine 7.5 mg FDA-approved; 12.5-25 mg/day shown to be efficacious, and other formulations may be appropriate if the 7.5mg brand version is not covered
    • Note: greatest association with SSRI withdrawal symptoms with missed doses (due to short half-life); weight gain is common; interferes with tamoxifen metabolism. 
  • Other SSRIs include fluoxetine 20 mg (most activating SSRI), escitalopram 10-20 mg/day (fewest drug-drug interactions), or citalopram (risk of QT prolongation).
  • Common SSRI effects include nausea, headache, insomnia (typically resolve within 1-2 weeks). 
• Venlafaxine, an SNRI, is also modestly beneficial at 37.5, 75, or 150 mg/day 
  • Side effects include nausea, mouth dryness, anorexia (usually all transient).
  • Desvenlafaxine may be better tolerated.
• Gabapentin 900 mg/day is modestly effective. May be especially helpful for night sweats and poor sleep. 
  • Side effects include dizziness, unsteadiness, drowsiness (typically resolve within 1-2 weeks). 
• Pregabalin (Lyrica®) 75-150mg BID has been shown to be modestly effective and well tolerated. 
  • Side effects similar to gabapentin.
• Clonidine 0.1-0.3mg daily (transdermal preferred) may be suggested if above trials fail. 
• Soy products, herbal remedies (black cohosh, red clover), omega-3 fatty acids, and vitamin E have not been shown to be effective. Use caution with soy or other phytoestrogens in women with ER+ breast cancer.

Vaginal dryness / dyspareunia

• Over-the-counter lubricants & moisturizers may be as effective in improving symptoms as low-dose vaginal estrogen, but cannot reverse physical signs of vaginal atrophy.
• Locally administered estrogen as a cream, gel, or pill can be effective. 
  • Any abnormal vaginal bleeding should be investigated immediately. 
  • Endometrial safety data beyond 1 year is lacking. 
• Ospemifene is a non-steroidal, non-hormonal estrogen receptor agonist/antagonist FDA approved for dyspareunia due to menopausal vulvovaginal atrophy
  • 60 mg/day effective
  • Side effects include hot flashes (6.6% of women), UTI, vaginal discharge, nasopharyngitis, headache
• Also see separate chapter on vaginitis

B. Menopausal Hormone Therapy

• USPSTF recommends against use of combined estrogen and progestin for the prevention of chronic conditions in post-menopausal women, so the main indication is menopause symptom relief
• Symptom relief is largely due to estrogen. Progestin is added to avoid risk of endometrial cancer with unopposed estrogen; and should be given to all women with an intact uterus on systemic estrogen therapy. 
• Systemic estrogen is effective for both vasomotor symptoms and symptoms of vulvovaginal atrophy
  • Vaginal estrogen is more effective than oral/transdermal estrogen for symptoms of vulvovaginal atrophy
  • Adverse effects include breast tenderness, uterine bleeding, nausea, vomiting, headaches, weight change, rash, pruritis, cholecystitis, which may be dose dependent 
  • Transdermal estrogen may be preferred over oral (transdermal avoids first-pass hepatic metabolism that promotes pro-thrombotic changes)
  • Associated with increased risks of stroke, VTE
  • Decreased risk of postmenopausal bone loss and hip fractures
• Progestins continuous or cyclic based on pt preference; given orally, transdermally, or vaginally
  • Cyclic regimens more likely to cause withdrawal bleeding
  • Medroxyprogesterone acetate given continuously is associated with breast cancer risk, unclear if other types of progestin pose less risk of breast cancer. Increased risk of breast cancer detectable by 3-5 years of use. 
  • Estrogen plus progestin is also associated with increased risk of coronary events, dementia, urinary incontinence
• Adverse effects of estrogen plus progestin appear concentrated in women ≥5 years past menopause, so may be safe to use within first 5 years after menopause

* Conjugated estrogens 0.625 mg or equivalent (1 mg oral estradiol, 50 mcg transdermal 17-beta estradiol) are considered standard or full-dose, while conjugated estrogens of 0.3 mg or equivalent (0.5 mg oral estradiol, 25 mcg transdermal estradiol) are considered low-dose. Transdermal estriol of 14 mcg is considered very/ultra low-dose.

• Bioidentical hormones refer to custom-made hormone therapy formulations, not tested for efficacy, safety, standardization, or purity. 
• Absolute Contraindications to use of menopausal hormone therapy: 
  • hx of breast cancer or endometrial cancer
  • hx of thromboembolic disease (stroke, TIA, MI, PE, VTE, thrombophilic disorders)
  • unexplained vaginal bleeding
  • active liver disease
  • clinically significant CAD
  • porphyria
  • prolonged immobilization
• Relative Contraindications to use of menopausal hormone therapy:
  • hypertriglyceridemia (>400mg/dL)
  • uncontrolled HTN
  • intermediate or high risk of breast cancer
  • high risk of CAD
  • active gallbladder disease
  • migraine with aura
  • meningioma
  • hypoparathyroidism (risk of hypocalcemia)
  • diabetes (as a CAD equivalent)
• Duration of menopausal hormone therapyselected based on symptoms, preferences and benefit-risk profile
  • Some guidelines recommend treatment for <5 years for combined menopausal hormone therapy and <7 years for estrogen therapy
• In general, prescribe lowest dose of menopausal hormone therapy for shortest duration to minimize adverse health effects.
• Annual to biannual weaning recommended to allow for re-assessment of symptoms and re-titration to the lowest effective dose.
• With cessation of menopausal hormone therapy, 50% chance of recurrent vasomotor symptoms. Menopausal hormone therapy discontinuation associated with resumption of bone resorption, recurrent vulvovaginal atrophy. Risk of breast cancer persists for a few years after discontinuation of menopausal hormone therapy. 

References:

The 2012 Hormone Therapy Position Statement of The North American Menopause Society. Menopause. Mar 2012:19(3): 257-271.

Caroll DG. Nonhormonal therapies for hot flashes in menopause. Am Fam Physician. 2006 Feb 1;73(3):457-464.

Freeman EW et al. Efficacy of Escitalopram for Hot Flashes in Healthy Menopausal Women: A Randomized Controlled Trial. JAMA. 2011;305(3):267-274.

Nelson HD et al.  Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA;2006 May 3;295(17):2057-71.

Tice JA, Grady D. Alternatives to estrogen for treatment of hot flashes: are they effective and safe? JAMA. May 3 2006;295(17):2076-2078.

Al-Safi ZA and Santoro N. Menopausal hormone therapy and menopausal symptoms. Fertility and Sterility. April 2014; 101(4): 905-915. 

Manson JE. Current recommendations: what is the clinician to do? Fertility and Sterility. April 2014; 101(4): 916-921. 

Marjoribanks J, Farquhar C, Roberts H, and Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. The Cochrane Collaboration. 2012; 7. 

Moyer VA. Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine. January 1, 2013; 158(1): 47-54.

Manson JE et al. Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials. JAMA. October 2, 2013; 310(13): 1353-1368. 

Nelson LM. Clinical manifestations and evaluation of spontaneous primary ovarian insufficiency (premature ovarian failure). UpToDate. 

Stuenkel CA, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, November 2015, 100(11):3975–4011.