Definition and Epidemiology
Menopause is the permanent physiologic cessation of menses due to loss of ovarian activity determined retrospectively after 12 consecutive months of no menstrual bleeding and low estrogen levels.
- Average age: 51 years
- Typical range: 44–55 years of age (95% of women)
- Abnormal < 40 years of age: primary ovarian insufficiency
- Factors affecting age:
- Reproductive history
- Chemotherapy or pelvic radiation
- Hysterectomy with ovarian conservation → post-surgical impairment in blood supply
- Bilateral oophorectomy → surgical menopause
Menopause is characterized by a physiologic ↓ in oocytes due to progressive atresia, ultimately leading to a chronic hypoestrogenic state in postmenopause. During the menopause transition, hormone levels fluctuate significantly.
Physiology of menopause transition
Normal oocyte counts:
- At birth: 1–2 million oocytes
- At puberty: 400,000 oocytes
- At age 30–35: 100,000 oocytes
- At menopause: < 1,000 oocytes
Effects of estrogen:
- Inhibits release of FSH
- Endometrial stimulation
- Vaginal lubrication
- Breast growth
- Bone growth
- Modulating effects on thermoregulation and mood
Late reproductive years/early menopause transition:
- Transitional period from reproductive to non-reproductive stage
- Begins on average 4 years prior to last menstrual period
- Usually lasts 2–8 years
- Characterized by increasing menstrual irregularity and fluctuating hormone levels
- ↓ Oocytes → ↓ estrogens → ↓ inhibition of FSH → ↑ FSH → ↑ follicular response → ↑ estrogen (mid-cycle)
- Significant fluctuations in estrogen throughout cycle
Late menopause transition:
- Accelerated oocyte atresia
- Severely depleted follicle supply → more anovulatory cycles
- ↓ Oocytes → ↓ estrogens → ↓ inhibition of FSH → ↑ FSH → ↓ quality of oocytes are unable to respond → estrogen stays ↓
Primary estrogen switches from estradiol (E2) to estrone (E1):
- Primary estrogen in premenopausal women
- Produced in ovaries
- ↓ Significantly at menopause
- Primary estrogen in postmenopausal women
- Produced primarily in adipose tissue
Other hormonal changes in perimenopause
|Anti-Müllerian hormone (AMH)||↓|
|LH and FSH||↑||Inhibin B has an inhibitory effect on LH and FSH, so during menopause their levels increase.|
The clinical symptoms of perimenopause are caused by fluctuating hormone levels in the menopause transition period. The presentation of postmenopause results from the low estrogen levels that ensue after cessation of ovarian function, which persist for the remainder of a woman’s life.
Symptoms associated with perimenopause
- Menstrual changes:
- Late reproductive years: Menstrual cycles shorten (cycles get closer).
- Menopausal transition: shorter cycles → longer cycles → very irregular/sporadic cycles → final menstrual period
- Vasomotor symptoms:
- Hot flushes
- Occur in 50%–90% of women
- Usually last 1–5 minutes, but may last up to 45 minutes
- Night sweats: can significantly disrupt sleep → chronic fatigue
- Emotional symptoms:
- Mood swings and irritability
- Stress and anxiety
- Symptoms related to sexual function :
- Genitourinary syndrome of menopause (GSM): vulvovaginal atrophy (the physical changes of vulva, vagina, and lower urinary tract due to estrogen deficiency)
- Vaginal dryness and itching
Symptoms and conditions associated with postmenopause
These symptoms are a result of long-term estrogen deficiency:
- Bone loss:
- Fragility fractures
- Cardiovascular disease:
- Lipid profiles worsen (↑ cholesterol).
- Weight gain
- ↑ Risk for myocardial infarction and thromboembolic events
- Hair, muscle, and skin changes:
- Hair thins.
- Skin becomes drier and rougher.
- ↓ Lean mass and muscle tone
- ↑ Fat mass
- Symptoms of GSM:
- ↑ Risk of pelvic organ prolapse
- Incontinence issues
- ↑ Urinary tract infections (UTIs)
- Hot flashes
- Atrophy of the Vagina
- Coronary artery disease
- Sleep disturbances
- Primarily clinical
- Pelvic exam: Assess vaginal atrophy in context of sexual complaints.
- Routine lab evaluation not indicated:
- FSH, LH, and estrogen levels fluctuate significantly and are not clinically useful in most cases.
- Exception: if patient is around age of menopause with abnormal bleeding, ↑ FSH may be helpful in clarifying menopausal status
- Abnormal uterine bleeding should be evaluated:
- Endometrial biopsy
- Pelvic ultrasound
- Hysteroscopy if diagnosis still uncertain
- Possible pathologic findings:
- Endometrial hyperplasia/cancer
- Ovulatory dysfunction from other causes
A majority of women in perimenopause and postmenopause do not require treatment. The primary goals of management are relief of bothersome symptoms and ensuring health through appropriate screening.
Hormone replacement therapy (HRT)
Hormone replacement therapy is also referred to as menopausal hormone therapy (MHT).
Estrogen therapy (ET):
- Effective at treating:
- Vasomotor symptoms: hot flushes, night sweats → sleep disturbances
- Mood symptoms in peri- (but not post-) menopause
- GSM: vaginal dryness, dyspareunia
- Routes of therapy:
- Systemic therapy: oral, transdermal patches, topical gels
- Vaginal therapy: creams, vaginal tablets, ring
- Selection of route and dosing:
- Give continuously.
- Transdermal is usually preferred for vasomotor symptoms.
- Vaginal ET is preferred when treating GSM only.
- Estrogen stimulates endometrium → progestin required if patient has uterus
- Higher risk of adverse events than estrogen therapy
- Required for endometrial protection in patients with uterus
- Selection of route and dosing:
- Usually oral
- Give cyclically if still menstruating regularly.
- Give continuously if post-menopausal.
Candidates for therapy:
- Patients within 10 years of menopause
- Patients < 60–65 years of age
- Symptoms severe enough to affect quality of life
- No contraindications
Contraindications to HRT include history of:
- Hormone-sensitive breast cancer
- High-risk endometrial cancer
- Unexplained vaginal bleeding
- Cardiovascular disease
- Venous thromboembolism
- Stroke or transient ischemic attack (TIA)
- Acute liver disease
- Use lowest dose for shortest duration required to treat symptoms.
- Should not be used for prevention of chronic disease
Risks and benefits beyond symptom relief:
- HRT/MHT ↑ risk of:
- Breast cancer
- Cardiovascular disease
- Deep venous thrombosis and stroke
- Gallbladder disease
- HRT/MHT ↓ risk of:
- Colorectal cancer
- All-cause mortality
Other management options for vasomotor symptoms
- Selective estrogen receptor modulators (SERMs):
- Modulate effects of estrogen
- Different effects (agonist vs. antagonist) in different tissue types
- Common examples:
- Raloxifene (agonist in bone, antagonist in breast and uterus)
- Ospemifene (specifically for GSM)
- Non-hormonal medications:
- Selective serotonin reuptake inhibitors (SSRIs): Paroxetine is the only FDA-approved SSRI.
- Serotonin-norepinepherine reuptake inhibitors (SNRIs)
- Botanical and herbal remedies: not shown to be effective in clinical trials
- Lifestyle changes:
- Layer clothing.
- Maintain lower ambient temperature at home.
- Avoid alcohol and caffeine.
- Stress management
Management options for GSM
- Low-dose vaginal estrogen:
- Most effective treatment
- Doses are low enough that progestins are not required for endometrial protection.
- Vaginal lubricants
- Vaginal moisturizers
- Regular sexual activity or use of dilators
Recommended health screening for menopausal women
|Cervical cytology||Up to age 65/every 3 years|
|Diabetes testing||At age 45/every 3 years|
|Colonoscopy||At age 50 (45 if at high risk)/every 10 years|
|Mammography||At age 40/annually|
|Bone mineral density||At age 65/every 2 years if risk factors are present|
- Primary ovarian insufficiency (POI): a condition characterized by impaired ovarian function in women < 40 years of age. Symptoms are identical to menopause, including amenorrhea, vasomotor symptoms, and vaginal dryness. The key difference is patient age. Menopause is a natural physiologic process, while POI is pathologic, and may be caused by genetic or chromosomal anomalies, an autoimmune process, or ovarian toxins. Management is with HRT, addressing fertility concerns, and counseling.
- Abnormal uterine bleeding (AUB): preferred term for uterine bleeding outside normal parameters, and includes heavy and irregular bleeding. Common causes include leiomyomas, polyps, endometrial hyperplasia or malignancy, coagulopathy (especially in younger women), and ovulatory dysfunction. Diagnosis usually requires endometrial biopsy and pelvic ultrasound. Management depends on underlying etiology. Important to exclude pathologic causes of AUB in perimenopausal women.
- Anxiety disorders: can cause hot flushes, palpitations, and mood symptoms, similar to menopause. Often, these conditions may co-exist with menopause. Management may include SSRIs, SNRIs, other anxiolytics, and psychotherapy.
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