GU: menopause and hormone therapy

menopause

• permanent cessation of menses secondary to the loss of ovarian follicular activity

• defined as occurring after 12 months of amenorrhea

• typical age → 40-55 years

  • after around 35 years old, there becomes a decline the follicle stores, leading to less and less estrogen production (the aging ovaries)

• symptoms have impacts on quality of life

• the ovaries are responsible for the release of estrogen, progesterone, and androgens

  • role of FSH → FSH levels gradually increase as we age, with peaks during menopause

hormone cycle

1. hypothalamus releases GnRH, which stimulates the anterior pituitary

2. anterior pituitary releases LH and FSH, which stimulates the ovaries

   • LH stimulates the corpus luteum as well as the follicles

   • FSH stimulates the follicles!

   • the follicles (and subsequently the corpus luteum) are found in the ovaries

3. the corpus luteum releases progesterone, and the follicle releases both estradiol and inhibin

   • progesterone and estradiol act as a negative stimulus to both the anterior pituitary and the hypothalamus

   • inhibin acts a negative stimulus to the anterior pituitary!

risk factors for early-onset menopause

• smoking

• poor nutrition

• ovarian failure

• history of hysterectomy

factors that have NO effect on menopause

• age of menarche

• number of ovulations or pregnancies

• use of oral contraceptives

• race or socioeconomic status

clinical presentation of menopause

• menstrual cycle alterations

• vasomotor symptoms → hot flashes

• sleep disturbances

• genitourinary syndrome of menopause (GSM) → vaginal atrophy

  • can lead to sexual dysfunction

• mood changes

• skin, hair, and nail changes

• osteoporosis

• cardiovascular changes

• miscellaneous

vasomotor symptoms (hot flashes)

• the first physical manifestation of ovarian failure

  • affects > 95% of individuals

• characteristics:

  • rapid onset and resolution → lasts approximately 3 minutes

  • skin, face, and chest become flushed, followed by a cooling feeling (“cold sweat”)

  • diaphoresis or sweating

  • can lead to sleep disturbances

  • can have significant consequences on a patient’s quality of life → “how often are they experiencing this?”

  • can be accompanied by feelings or aura or pressure in the head (headache)

• triggers may include hot weather, spicy foods, stress, caffeine, alcohol, etc

genitourinary syndrome of menopause (GSM) or vaginal atrophy

• the vaginal mucosa, vulvar epithelium, cervix, endocervix and endometrium are all estrogen-dependent tissues

• decreases in estrogen (menopause) can cause:

  • diminished and thinner VAGINAL epithelium

  • dyspareunia, aka difficult/painful sexual intercourse, as well as atrophic vaginitis

  • less resilience to friction → less elastic and less lubricated

  • dryness

  • increases in pH

  • recurrent UTIs

  • urgency

• so, this term refers to thinning of the vaginal and vulvar epithelium, NOT the endometrium

  • therefore, patients with a hysterectomy can still experience these symptoms (because they still have these estrogen-dependent tissues)

diagnosis of menopause

• evaluating patients…

  • clinical presentation

  • history and physical exam

  • labs

WHI combination estrogen-progestin study

• prior to, hormone therapy was recommended to (aka benefits):

  • reduce post-menopausal symptoms

  • reduce the risks of CHD

  • reduce the risk of osteoporosis fractures

  • prevent colorectal cancer

  • improve QOL

• included menopausal patients (50-79 years old) with an intact uterus to see if these recommendations were valid (did it ↓ stroke, CHD, fractures, etc?)

  • combination hormone therapy vs placebo

• the research was stopped prematurely due to increases in the…

  • incidence of breast cancer when used after menopause and for > 5 years

  • incidence in the risk of CHD, stroke, DVT, and PE

• demonstrated that the risks >> benefits of combination hormone therapy

  • it does NOT provide cardioprotection

  • however, potential benefits include prevention of colorectal cancer, prevention of fractures, as well as improvement in vasomotor symptoms and preventing vaginal atrophy

WHI estrogen alone study

• included menopausal patients (50-79 years old) with a history of a hysterectomy with the primary objective of evaluating the risks vs benefits of hormone therapy vs placebo

• the research was stopped prematurely due to increases in the…

  • risk of stroke and VTE

  • endometrial cancer in patients without a hysterectomy

  • risk of ovarian cancer when used for > 10 years

• demonstrated that the risks >> benefits of estrogen hormone therapy

  • it does NOT provide cardioprotection, nor colorectal cancer prevention

  • however, potential benefits include prevention of fractures, as well as improvement in vasomotor symptoms and preventing vaginal atrophy

timing hypothesis

• when initiating hormone therapy, focus on…

  • the age of the patient (< 60 years old)

  • risk factors (eg. patients with higher CVD risk)

  • the time since menopausal onset → within 10 years of menopause onset

• somewhat relevant to the WHI coronary artery calcium study (as well as the KEEPS trial), which demonstrated that in relatively younger patients (50-59 years old), there was no increased risk of CHD

  • however, estrogen therapy should still NOT be used for cardiovascular disease prevention

treatment algorithm for menopause

1. menopausal patient present to clinic

2. if the patient is experiencing vasomotor symptoms only:

   1. mild symptoms? → non-pharmacologic approaches

   2. moderate-severe symptoms? → determine if menopausal hormone therapy (MHT) os contraindicated

      1. if no CI to MHT, consider if they have a hysterectomy

         1. if the patient has a hysterectomy,

non-pharmacologic treatment options for vasomotor symptoms (hot flashes)

• avoiding hot places

• wearing lighter clothing

• avoiding spicy foods

• trying to avoid stress

non-pharmacologic treatment options for vaginal atrophy

• vaginal lubricants

• enjoying other activities

• seek counseling

pharmacological treatment options for vasomotor symptoms (hot flashes)

• hormonal therapy (estrogen, progestin)

• antidepressants

• clonidine

• gabapentin

• Duavee (bazedoxifene and conjugated estrogen 20/0.45 mg)

• Bijuva capsules (estradiol/progesterone 1/100mg)

considerations for estrogen alone products

• used for replacement therapy → relief of vasomotor symptoms

• beneficial ONLY in patients with a hysterectomy → less risk of endometrial cancer

• dosage forms:

  • oral

  • transdermal

  • vaginal

• side effects

  • fluid retention

  • breast tenderness

  • N/V

  • headache

  • weight gain

black box warning for estrogen MHT

• increased risk of endometrial cancer → monitor for abnormal vaginal bleeding

• products with or without progestins should not be used for the prevention of cardiovascular disease

• increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) have been reported

• an increased risk of developing probable dementia in postmenopausal women 65 years of age or older has also been reported

• risks should be assumed to be similar for other doses, combinations, and dosage forms of estrogens and progestins

• products with or without progestins should be prescribed at the lowest effective doses and for the shortest duration possible

contraindications/precautions for estrogen

• thromboembolic disease

• CAD

• pregnancy

• breast cancer

• liver disease

considerations for progesterone

• used as replacement therapy

• added to estrogen therapies (combination) to reduce the risk of endometrial cancer

  • counteracts estrogen’s endometrial stimulation

  • stabilizes the endometrium

  • however, it is NOT required for intravaginal estrogen products (eg. creams) because these formulations do not raise systemic estrogen levels enough to stimulate the endometrium

• used for 12-14 days per cycle

• same BBW

• dosage forms:

  • oral

  • patch

  • IUD

• side effects:

  • breast tenderness

  • bloating

  • edema

  • weight gain

  • vaginal bleeding

  • mood changes

contraindications/precautions for progesterone

• breast cancer

• liver disease

• pregnancy

• undiagnosed vaginal bleeding

• CVD disease

methods of administration for estrogen and progesterone

1. continuous cycling

   • daily estrogen + cyclic progestin

2. continuous-combined

   • daily combined estrogen and progestin

3. continuous long-cycle

   • daily estrogen/progestin every other month

4. intermittent-combined

   • 3 days of estrogen alone then 3 days combined

considerations for androgens

• controversial…

  • may be effective in treating decreased libido

• dosage forms:

  • oral (methyltestosterone + esterified estrogen)

  • IM

• side effects

  • virilization

  • fluid retention

  • lipid changes

• contraindications/precautions:

  • moderate-severe acne

  • hirsutism

  • androgenic alopecia

custom compound bioidentical hormones

• these are hormones that are chemically similar or structurally similar to those produced in the body

• pros!

  • customized dosing

• cons…

  • lack of FDA oversight to ensure safety or appropriate efficacy or standardization with custom compounding practices

  • lack of evidence showing that they’re any safer than synthetic hormonal therapy

• indications:

  • patients that have an allergy to any of the variety of commercially provided hormonal options

  • no best-fit dosing option that is commercially available

antidepressants used to treat vasomotor symptoms → drugs

• venlafaxine (Effexor) 75-150 mg daily

• paroxetine (Brisdelle) 7.5 mg daily

• escitalopram (Lexapro) 10-20 mg daily

brand name for paroxetine mesylate

• brand name

  • Brisdelle

considerations for clonidine

• 50 mcg every 12 hours initially

  • may increase up to 400 mcg every 12 hrs

considerations for gabapentin

• dose dependent relationship

• 200-1600 mg daily

considerations for Duavee

• bazedoxifene and conjugated estrogen 20/0.45 mg

  • contains conjugated estrogen with a selective estrogen receptor modulator (SERM)

  • the SERM serves as an antagonist on uterine tissue, preventing the risk of endometrial cancer

  • alternative to MHT therapy with progestin add-on

• used for treatment of moderate-severe vasomotor symptoms associated with menopause in patients WITH a uterus

• 1 tablet once daily

considerations for Bijuva

• estradiol and progesterone capsules (1/100 mg)

• used for treatment of moderate-severe vasomotor symptoms associated with menopause in patients WITH a uterus

• 1 capsule by mouth once daily in the evening with food

• an example of a commercially available bioidentical hormone product

  • estradiol and progesterone are both commercial bioidentical hormones

alternative options for treating vasomotor symptoms

• overall, efficacy = 30% reduction in symptoms… (pretty similar to placebo effects)

  • black cohosh

  • soy

  • vitamin E

  • red clover

  • evening primrose

  • acupuncture

pharmacological treatment options for vaginal atrophy (GSM)

• vaginal moisturizers

• vaginal estrogen cream or estrogen ring

• Ospemifene 60 mg (Osphena)

• Estradiol 4mcg or 10mcg vaginal inserts (Imvexxy)

• Prasterone 6.5 mg vaginal inserts (Intrarosa)

considerations for Ospemifene (Osphena)

• 60 mg once daily

• FDA approved for the treatment of dyspareunia (painful intercourse)

• a SERM

  • acts as an estrogen agonist on vaginal/vulvar tissue, with antagonistic activity on endometrial tissue

  • great for patients with an intact uterus (but patients without can still benefit from use)

considerations for Imvexxy

• used to treat moderate-severe vaginal pain with sexual activity

• use 1 vaginal insert daily for 2 weeks, then 1 insert twice weekly

considerations for Intrarosa

• used to treat moderate-severe vaginal pain with sexual activity

  • prasterone is converted to estrogen locally → comes with minimal systemic absorption of estrogen

• use 1 vaginal insert daily at bedtime