Menopause and Related Conditions

• Menopause is defined as one year after the last menstrual period
• The average age of menopause is 51
• Hormone changes during menopause affect the hypothalamic–pituitary–ovarian (HPO) axis.
• Estradiol and progesterone levels decrease.
• Follicle-stimulating hormone (FSH) levels increase.
• Symptoms of menopause can include vasomotor symptoms (hot flushes), night sweats, genitourinary syndrome of menopause (GSM), weight gain, and insomnia

Vasomotor Symptoms

• 50-82% of women experience vasomotor symptoms.
• 87% experience them on a daily basis.
• 33% experience more than 10 hot flashes per day.
• The median duration of vasomotor symptoms is 7 years
• Pathophysiology involves changing hormones and a narrowed thermoregulatory zone
• African Americans are more likely to report vasomotor symptoms, while Asians report them least.
• Obesity is a risk factor for experiencing vasomotor symptoms

Genitourinary Syndrome of Menopause (GSM)

• GSM is related to estrogen deficiency, affecting the labia, vagina, urethra, and bladder
• 10-40% of patients experience GSM
• Symptoms of GSM include genital dryness, burning, and irritation.
• Sexual and urinary symptoms are also associated with GSM

History of Hormone Therapy

• 1941: Premarin introduced by Wyeth Ayerst for treatment of menopausal symptoms
• 1960: Observations indicated women experience fewer heart attacks before age 50.
• 1966: The Coronary Drug Project took place.
• 1975: NEJM publishes information that indicated an increased risk of endometrial carcinoma among users of conjugated estrogens.
• 1980: The Harvard Nurses Health Study took place.
• 1990: Estrogen was brought to the FDA for approval for prevention of heart disease

Women's Health Initiative (WHI)

• RCT was conducted using Premarin 0.625mg/MPA 2.5mg (Prempro) vs. placebo
• The plan was for 8.5 years, with enrollment from 1993-1998.
• The study involved 16,809 postmenopausal women, aged 50-79 with a uterus, across 40 centers in the US.
• The primary outcome was coronary heart disease (CHD), measured as myocardial infarction (MI) or congestive heart failure (CHF)
• Primary adverse outcomes included invasive breast cancer, stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, endometrial cancer, and death due to other causes
• The study was stopped after 5.2 years on May 31, 2002
• The test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect.

WHI: Estrogen Only Arm

• RCT included 10,739 women who had been administered 0.625mg conjugated equine estrogen (Premarin) versus placebo
• The primary outcome was CHD
• The primary safety adverse outcome was breast cancer.
• Inclusion criteria: Age 50-79 and prior hysterectomy
• Exclusion criteria: Previous cancer in the last 10 years, dementia, alcoholism

Flaws of the WHI

• Average age of particpants was 63
• The WHI included asymptomatic patients
• Elevated BMI

What the WHI Learned

• Hormone therapy not recommended for CHD prevention
• The timing hypothesis was developed
• Progesterone does affect breast cancer risk
• Estrogen used alone does not show an increased risk of breast cancer
• Type of hormone, dosage, and route does matter

Breast Cancer Risks

• CEE + MPA arm of WHI had 9 additional cases out of 10,000 women
• Observed one additional case of breast cancer diagnosed per 1,000 users annually
• This risk is less than the increased risk of breast cancer seen with 2 daily glasses of wine, obesity and/or low physical activity

Cardiovascular Disease

• Newer observational data and reanalysis of older studies by age and time since menopause suggest that for healthy recently menopausal women, the benefits of HT outweigh its risks with fewer CVD events in younger vs older women

Summary of the Literature

• For healthy symptomatic women aged younger than 60 years who are within 10 years of menopause onset, the more favorable effects of HT on CHD and all cause mortality should be considered against potential rare increases in risks of breast cancer, VTE and stroke
• HT is a safe and effective option for treatment of menopause symptoms when initiated in healthy postmenopausal women aged younger than 60 or are within 10 years of menopause onset

HT Indications

• FDA Approved Indications:
• Vasomotor symptoms (VMS)
• Prevention of bone loss
• Hypoestrogenism caused by hypogonadism (surgical or POF)
• Genitourinary Syndrome of Menopause
• Additional Benefits:
• Improved wellbeing and QOL
• Decreased insomnia
• Improved skin moisture and fewer wrinkles
• Less joint pain or stiffness
• Prevention of loss of muscle mass
• Reduction in T2DM
• Weight loss, decreased abdominal adiposity

When Considering HT

• Appropriate dose, duration, regimen, and route of administration matter
• Must consider:
• Contraindication to Estrogen use
• Do they have a uterus?
• Age and time since menopause
• Symptoms treating
• Other issues, medical problems, complaints

Contraindications to HT

• Unexplained vaginal bleeding
• Severe active liver disease
• Prior estrogen-sensitive breast or endometrial cancer
• Coronary Heart Disease
• Stroke
• Dementia
• History of VTE or known inherited thrombophilia
• Hypertriglyceridemia

Side Effects of HT

• Common adverse effects:
• Nausea
• Bloating
• Mood swings (Progesterone related)
• Breakthrough bleeding
• Headaches
• Breast tenderness
• Could potentially cause:
• Migraine headaches may worsen
• Growth of fibroids
• Reactivate endometriosis
• More dense breast tissue – difficult to read mammograms

Routes of Estrogen

• PO

• Transdermal

• Sprays/Gels

• Vaginal Rings or Tablets

• Non-oral routes bypass first-pass hepatic effect

• Shown to have a theoretic decreased risk of VTE

• Won't decrease Testosterone levels (LIBIDO)

• Decrease effect on liver and biliary tract

• The BEERS criteria to routinely stop systemic HT in women aged 65 and older is not supported by existing data

• Discussion with patient regarding risks & benefits, QOL, and symptoms is recommended

• Transdermal approach and lowering doses as tolerated is recommended

Treatment of Vasomotor Symptoms

• Hormone therapy remains the gold standard for relief of VMS
• Estrogen alone therapy can be used in symptomatic women after hysterectomy
• Symptomatic women with a uterus should be administered:
• Estrogen plus progesterone combination
• Estrogen plus Bazedoxifene (Duavee)
• Estrogen plus Mirena IUD
• Micronized progesterone

Nonhormonal Treatments for VMS

• Lifestyle modifications
• Venlafaxine (Effexor) 50-100mg daily
• Paxil 7.5mg
• FDA Approved for this indication
• Be careful if on Tamoxifen
• Oxybutynin 5mg PO BID
• Gabapentin 300-900mg qhs
• Veozah (Fezolinetant) 45mg daily!!!

Treatments for GSM

• Low dose systemic estrogen formulations beneficial for atrophy
• Premarin 0.3mg PO daily
• Climara 0.0125 weekly patch
• Vaginal Formulations: ring, cream or tablet
• Daily x 1-2 weeks, then 2 times per week indefinitely
• Premarin cream
• Vagifem tablet (10mcg)
• Estring – vaginal ring placed for 90 days
• Estrace (Estradiol) cream
• Non-hormonal Treatment for vaginal dryness include lubricants and moisturizers
• Use of Ospemifene 60mg can be beneficial
• SERM
• FDA approved for this indication

Postmenopausal Bleeding

• Differential Diagnosis:
• Atrophy
• Endometrial Polyp
• EIN or endometrial cancer
• Evaluation:
• SSE: look for cervical polyp, atrophy
• TVUS: endometrial stripe
• Consider endometrial biopsy if endometrial stripe is > 4mm
• If THIN endometrial stripe on US (under 4mm): reassurance that bleeding is likely atrophy
• If THICK endometrial stripe on US (over 4mm): endometrial biopsy required.

Premature Menopause

• Menopause before age 40 years
• Change in menstrual function (oligomenorrhea and/or amenorrhea)
• Elevated serum FSH and low serum estradiol
• After exclusion of pregnancy, thyroid and prolactin disorders
• Typically associated with menopausal symptoms: hot flashes and vaginal dryness

POI Evaluation

• If POI diagnosed, evaluate for underlying cause
• Hx of ovarian surgery, chemo, RT
• Underlying autoimmune disorders, Adrenal autoantibodies, and/or Thyroid peroxidase antibodies
• Karyotype (Turner syndrome)
• FMR1 premutation (fragile X pre-mutation)
• Evaluate bone mineral density
• Treat with hormone therapy if no contraindication

Key Takeaways

• Average age of menopause is 51 years and it is diagnosed by lack of menses for 12 months
• Hormone therapy is the first-line treatment for menopause symptoms.
• It is safe to start HT if < 60 years of age and within 10 years of menopause
• Topical estrogen is a first-line therapy for genitourinary syndrome of menopause (GUSM)
• Postmenopausal bleeding should be evaluated with TVUS to assess endometrial stripe
• Premature menopause is < age 40 and requires evaluation