Resident Editor: Joseph R. Cartwright, MD, MEd
Faculty Editor: Alison Huang, MD
BOTTOM LINE ✔ For women >45 years of age, no lab testing required for menopause diagnosis unless unusual symptoms. ✔ Consider short-term menopausal hormone therapy or non-hormonal options for symptoms. ✔ Menopausal hormone therapy not recommended for prevention of chronic conditions in postmenopausal women. |
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).
- 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
- 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
Estrogen preparations, starting doses* |
|
---|---|
Oral |
Micronized 17 β-estradiol 0.5 mg/day Ethinyl estradiol 2.5 mcg/day Conjugated estrogen 0.3-0.45 mg/day |
Intramuscular |
Estradiol valerate 10mg q4wk |
Transdermal |
17 β-estradiol patch 0.014-0.0375 mg/day 17 β-estradiol gel 0.25-0.75 mg/day 17 β-estradiol spray 1.5 mg/day 17 β-estradiol emulsion 8.7 mg/day |
Vaginal |
17 β-estradiol vaginal cream 0.2 mg/day Conjugated estrogen vaginal cream 0.3125 mg/day 17 β-estradiol vaginal tablet 10 mcg/day 17 β-estradiol vaginal ring 7.5 |
Progestogen preparations, starting doses |
|
Oral |
Medroxyprogesterone acetate 1.5-2.5 mg/day Norethindrone acetate 0.1 mg/day Drospirenone 0.25 mg/day Micronized progesterone 100-200 mg/day |
Transdermal |
Norethindrone acetate 0.14 mg/day Levonorgestril 0.015 mg/day |
* 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.