Menopause

Menopause is the time at which a woman permanently stops menstruating, usually between 45 and 55 years of age, and is diagnosed after 12 months of amenorrhea. It is preceded by the climacteric period, sometimes referred to as perimenopause or menopausal transition, which is the transition period in a woman's life from the time of full sexual maturity to the onset of menopause. The physical manifestations are caused by hormonal changes (primarily a drop in progesterone and estrogen levels) that occur during the climacteric period. Clinical features leading up to menopause include irregular menses, autonomic symptoms (e.g., hot flashes), mental symptoms (e.g., mood swings), and atrophic features (e.g., reduced breast size, vaginal atrophy). Menopausal transition is a natural phase of the aging process in females, and as such does not usually warrant treatment. However, treatment is warranted in the case of severe symptoms or early onset menopause. The choice of treatment is decided on a case-by-case basis and includes conservative methods, hormone replacement therapy, and non-hormonal therapy. Menopause occurring before the age of 40 is considered premature. A common cause of premature menopause is ovarian insufficiency. The diagnosis is confirmed by increased FSH levels occurring after more than three months of amenorrhea in a woman under the age of 40. Treatment involves hormone replacement therapy.

• Perimenopause
  • Definition: the time period from the first instance of climacteric symptoms caused by fluctuating hormonal levels to one year after menopause
  • Duration: The average length of perimenopause is 4 years.
• Premenopause
  • Definition: the time period from the first occurrence of climacteric irregular menstruation cycles to the last menstrual period
  • Onset: usually 45–55 years of age
  • Characterized by increasingly infrequent menstruation
• Menopause ^[1][2]
  • Definition: time at which menstruation ceases permanently and confirmed after 12 months of amenorrhea in the absence of hormone contraceptives
  • Average age at menopause: ∼ 49–52 years (earlier in smokers)
• Postmenopause: : the time period beginning 12 months after the last menstrual period

Numerical depletion of ovarian follicles with age → ↓ ovarian function → ↓ estrogen and progesterone levels → loss of negative feedback to the gonadotropic hormones → ↑ GnRH levels → ↑ levels of FSH and LH in blood (hypergonadotropic hypogonadism) → ↑ frequency of anovulatory cycles → ovarian function eventually stops permanently ^[2]

In menopausal women, estrogens are mainly produced by peripheral aromatase conversion of adrenal androgens in adipose tissue. Therefore, onset of menopause might be delayed and symptoms might be milder in obese women.

The onset and intensity of symptoms is dependent on the phase of menopausal transition. ^[2]

• Menstruation: irregular menses (which gradually decrease in frequency) to complete amenorrhea
• Autonomic symptoms
  • Increased sweating, hot flashes, and heat intolerance
  • Vertigo
  • Headache
• Mental symptoms
  • Impaired sleep (insomnia and/or night sweats)
  • Depressed mood or mood swings
  • Anxiety/irritability
  • Loss of libido
• Atrophic features: result from an age-related drop in estrogen levels
  • Breast tissue atrophy: breast tenderness and reduced breast size
  • Vulvovaginal atrophy: atrophy of the vulva, cervix, vagina; leading to vaginal dryness, pruritus, and dyspareunia (See “Atrophic vaginitis.”)
  • Urinary atrophy: atrophy of the urinary tract leading to urinary incontinence, dysuria, urinary frequency, urgency, and increased urinary tract infections
  • Osteoporosis
• Others
  • Weight gain and bloating
  • Hirsutism (due to a relative increase in androgens)
  • Increased risk of coronary artery disease

Menopausal HAVOCS: Hot flashes/Heat intolerance, Atrophy of Vagina, Osteoporosis, Coronary artery disease, Sleep impairment.

The onset and duration of these symptoms is widely variable. Symptoms may begin up to 6 years before menopause and continue for a number of years after the last menstrual period

• Surgical menopause: due to removal of ovaries (commonly after hysterectomy with bilateral salpingo-oophorectomy) ^[3]

Women ≥ 45 years of age

• Diagnosis is usually clinical.
• However, certain laboratory tests may help confirm the onset/presence of perimenopause ^[4][5]
  • ↓ Estrogen, ↓ progesterone, ↓ inhibin B, ↑↑ FSH
  • Testosterone and prolactin levels are within normal ranges.
  • Vaginal pH > 4.5
  • Lipid profile: ↑ total cholesterol, ↓ HDL

Special circumstances

• Underlying menstrual cycle disorders or posthysterectomy
  • Diagnosis cannot be established using menstrual bleeding criteria.
  • Confirmation: serum FSH-level measurements
• Oral contraceptive use
  • Oral contraceptives can mask the signs and symptoms of menopause.
  • To accurately determine whether menopause has been reached:
    • Patients should discontinue oral contraceptives.
    • Assess whether amenorrhea persists following the discontinuation of oral contraceptives.
  • Confirmation: serum FSH-level measurements at least 4 weeks after discontinuation of oral contraceptives.

FSH levels can fluctuate widely in perimenopause.

All postmenopausal women above the age of 65 should be screened for osteoporosis (i.e., using the DEXA scan to measure bone mineral density).

Hyperthyroidism and menopause present similarly. Serum TSH should be checked in all suspected perimenopausal cases with heat intolerance and disturbed sleep to determine the cause.

Indications ^[5]

• Treatment is not warranted for all women approaching or undergoing menopause, as it is a normal aging process. Treatment may be considered in the following cases:
  • Symptoms are severe; enough to infringe significantly on functional capacity, and hence affect quality of life.
  • Premature menopause
  • Surgical menopause (e.g., post-oophorectomy)

Lifestyle modifications and local medical therapy ^[5]

• For hot flashes
  • Avoidance of triggers (e.g., bright lights, predictable emotional triggers)
  • Environmental temperature regulation (e.g., using fans)
• For atrophic vaginal symptoms: vaginal estrogen creams, rings, or tablets (Estrogen therapy may reduce the incidence of UTIs and features of overactive bladder.)
• For impaired sleep and/or hot flashes: exercise, acupuncture, and relaxation techniques
• Prevention of osteoporosis
  • Smoking cessation, adequate vitamin D intake, and regular weight-bearing exercise
  • See “Osteoporosis.”
• Alternative medicine therapies (like black cohosh/Cimicifuga racemosa, a phytotherapeutic with estrogen-like effects) are widely used, but the efficacy of most of these therapeutic modalities has been debated or is not yet proven. ^[6]

Hormone replacement therapy (HRT) ^[5]

• Indication: short-term treatment of menopausal symptoms
• Types
  • Estrogen therapy: for women who have had a hysterectomy
  • Estrogen plus progestin therapy: for women with a uterus
• Routes: oral, transdermal
• Risks
  • Cancer
    • Unopposed estrogen can result in endometrial hyperplasia → increased risk of endometrial cancer
    • Estrogen plus progestin therapy → increased risk of breast cancer
  • Cardiovascular disease: coronary heart disease, deep vein thrombosis, pulmonary embolism, stroke
  • Gallbladder disease
  • Stress urinary incontinence
• Contraindications
  • Undiagnosed vaginal bleeding
  • Pregnancy
  • Breast cancer/endometrial cancer
  • Chronic liver disease
  • Hyperlipidemia
  • Recent DVT/stroke
  • Coronary artery disease

Non-hormonal therapy

Non-hormonal therapy is used to treat menopausal vasomotor symptoms in women who do not want to use hormonal medications or who have contraindications for HRT. ^[7]

• Selective estrogen receptor modulators: tamoxifen, ospemifene , and raloxifene
• Paroxetine: for vasomotor symptoms (i.e., hot flashes)
• Clonidine and/or gabapentin

Premature menopause

• Definition: permanent cessation of menses before the age of 40
• Etiology
  • Idiopathic
  • Primary ovarian insufficiency
  • Bilateral oophorectomy ^[8]

Smoking is associated with premature menopause.

Ovarian insufficiency

• Definition: failure of adequate ovarian function (endocrine as well as reproductive) before the age of 40, which often leads to premature menopause

Primary ovarian insufficiency (POI) ^[9]

• Definition: ovarian insufficiency despite adequate gonadotropin stimulation (previously called premature ovarian failure)
• Etiology ^[10]
  • Idiopathic (90% of cases)
  • Genetic disorders associated with ovarian hypoplasia, especially in women < 30 years; (e.g., Turner syndrome; , Swyer syndrome, androgen insensitivity syndrome, adrenogenital syndrome, fragile X syndrome)
  • Autoimmune diseases; (e.g., autoimmune lymphocytic oophoritis, Hashimoto thyroiditis, Addison disease, type I diabetes mellitus, pernicious anemia)
  • Toxins: Smoking is a major risk factor.
  • Iatrogenic: radiation and/or chemotherapy, prolonged GnRH agonist therapy, induction of multiple ovulation in infertility treatment
  • Infectious diseases (e.g., measles, mumps, tuberculosis of the genital tract)
• Pathophysiology: follicular dysfunction or depletion → ↓ estrogen levels → reduced feedback inhibition of estrogen on FSH and LH → ↑ FSH and LH (usually FSH > LH)
• Clinical features ^[11]
  • Climacteric symptoms such as vaginal dryness, night sweats, hot flashes, dyspareunia, and irritability
  • Abnormal/irregular bleeding pattern that can progress to secondary amenorrhea or permanent cessation of menstruation
  • Infertility or reduced fertility (Pregnancy is possible via in vitro fertilization.)
• Diagnostics
  • Confirmed by two ↑ FSH levels (> 30–40 mIU/mL) and two ↓ estradiol levels (< 50 pg/mL) at least 1 month apart after > 3 months of menstrual irregularities in a woman under age 40
  • Further tests help determine the underlying cause (e.g, karyotyping, thyroid function).
• Treatment
  • See “Hormone replacement therapy.”
  • Treatment of underlying causes

Secondary ovarian insufficiency

• Definition: ovarian insufficiency due to inadequate stimulation of the ovaries by the hypothalamus and/or pituitary
• See “Secondary hypogonadism.”

Postmenopausal bleeding ^[12]

• Definition: any vaginal bleeding that occurs after menopause in women who are not taking HRT or any unscheduled bleeding in women who are taking HRT
• Etiology
  • See “Overview of causes of vaginal bleeding in different age groups" and “Etiology” in “Abnormal uterine bleeding” for a comprehensive list of causes.
  • Endometrial or vulvovaginal atrophy, submucous leiomyomas, and endometrial polyps are among the most common causes of postmenopausal bleeding. ^[13]
  • Approx. 10% of cases of postmenopausal bleeding are due to endometrial cancer
• Symptoms: vaginal bleeding
• Diagnostics and management: See “Abnormal uterine bleeding.”