IPFC 1 - Menopause

Menopause

is the last spontaneous episode of physiologic uterine bleeding (the last period)

Menopause is identified retrospectively 12 months after amenorrhea and marks the end of menstrual cycling

Amenorrhea

the absence of menstruation

Menstrual cycle transition

is the time from the cycle irregularity to the final period

Perimenopause

(aka climacteric phase) is the 4-5 year period between the transition and the months after the last period

Premature ovarian failure

happens when you reach menopause before age 40.

Average age of menopause

51 (range is 40-58)

Menopausal age depends on...

It’s about genes not race, physical characteristics, age at menarche, age at last pregnancy, socioeconomic status or oral contraceptive use

What causes menopause to happen early?

- Smoking (1-2 years earlier)

- Chemotherapy

- Radiotherapy

- Bilateral oophorectomy

When do females have the highest number of follicles

20 weeks gestation in utero

COME BACK TO SLIDES 9-11

YES SIR

If you had a hysterectomy and don't have a period, how would you know when you are menopausal?

Can monitor FSH and LH levels

very high levels demonstrate that the body is working overtime to try to produce more

particularly helpful in women with hysterectomy

What hormones drop around menopause

estradiol (and Inhibin A and B)

What happens during the EARLY menopausal transition period

- Menstrual cycles vary in length (by ≥7 days)

- FSH levels start to increase

- low follicle count

What happens during the LATE menopausal transition period

- Intervals of amenorrhea of >60 days

- high FSH levels

- low follicle count

- Vasomotor symptoms likely begin

What happens during the early postmenopausal period (first 2-6 years after menopause)

- FSH levels stabilize

- AMH and inhibin are very low

- Follicle count very low

- Vasomotor symptoms most likely in first 2 years after menopause

What symptoms occur in latte menopause (remaining lifespan)

increasing urogenital atrophy

Vasomotor symptoms

• Hot flashes, night sweats

• Spontaneous sensation of warmth, often with perspiration, palpitations, anxiety

• Most common concern of menopause

– ~80% of perimenopausal women and ~40% of

post menopausal have >3 hot flashes per day

What causes vasomotor symptoms

Associated with the decline in estrogen

when do vasomotor symptoms (VMS) occur

Starts 2 years before menopause

- Worst 2 years after last menstrual period

- Often lasts ~5 years after last period

- Can last for 7- 8 years

In which population do VMS tend to last longer

- Start menopause earlier

- Higher BMI

- Smoke

- Low socioeconomic status

- Depressive symptoms, stress, anxiety at start of symptoms

Menopausal Symptoms

Vasomotor symptoms

Mood

Vulvovaginal atrophy

Aches & pains

Genitourinary syndrome

Aches & Pains

• Joint pain common during menopause

transition

• Unlike arthritis, aches and pains respond to hormone therapy

Mood symptoms of menopause

• Irritability, tearfulness, anxiety

• Depression, lack of motivation or energy

• Poor concentration and sleep

• More common in women with a history of depression, poor physical health, stressors

Possible causes:

– Declining estrogen levels

– Vasomotor symptoms resulting in poor sleep

Vulvovaginal Atrophy

• Vulva and vagina appear thin, pale and dry

• Vagina can shorten, narrow, constrict, especially in the absence of sex

• Vaginal lining may be thin, lose elasticity, lose the rugal folds and have petechiae

• Decrease in sebaceous gland secretions and in lubrication during sexual stimulation

- treatment becomes harder the longer we waitAtrophic vaginitis refers to vaginal inflammation

When does Vulvovaginal Atrophy occur

• Starts a few years after LMP

• Does not improve over time (unlike other symptoms)

• Symptoms include dryness, itchiness, dyspareunia (painful intercourse)

• Lower libido

*Key to treat this before it perpetuates a cycle of poor sexual health

Atrophic vaginitis

Refers to vaginal inflammation

Genitourinary Syndrome

• Genitourinary syndrome of menopause (GSM) is a more comprehensive term (includes genital, sexual, urinary)

• Frequent UTIs, dysuria, increased frequency and urgency

• Late postmenopause stage

Hormone therapy

• Estrogen Therapy (ET)

• Routes: systemic (oral, transdermal), local (vaginal)

Estrogen HT drug interactions

Carbamazepine increased hepatic metabolism of estrogen

Smoking also increases hepatic metabolism of oral therapy (smoking cessation is key)

Systemic estrogen therapy contraindications (not for local therapy)

• Unexplained vaginal bleeding (after 1y of amenorrhea)

• Acute liver disease

• Active or history of thromboembolic disease

• Estrogen-dependent cancer (breast/endometrial cancer)

• Current or history of breast cancer

• Pregnancy

• Coronary heart disease

• Previous stroke

• Gallstones

Estrogen common adverse effects

Fluid retention, headache, stomach upset, breast tenderness, gallbladder disease, urinary incontinence (w/ systemic therapy)

Estrogen rare but serious ADRs

Myocardial infarction, ischemic stroke, venous thromboembolism (clotting), breast cancer

natural forms of estrogen

Estradiol (more potent) > Estrone

– Oral estradiol and estrone are not well absorbed

– Estradiol is converted to estrone in intestines

– Estradiol must be micronized (made really small) to be absorbed but only 5% gets through first pass

Synthetic estrogen

Conjugated Estrogen is a combo of

10 estrogens

Estrogen first pass

First pass effect increases HDL cholesterol, triglycerides, coagulation factors

Also increases bad cholesterol though :(

- make sure to check triglyceride and cholesterol levels to make sure they are controlled before beginning HT

Preparations of oral estrogen

Conjugated equine estrogen (CEE)

17β- estradiol (micronized)

Estropipate (discontinued)

Conjugated equine estrogen (CEE) dosing

Premarin

- Oral

- 0.3, 0.625, 1.25mg dosing qd

(1.25mg dosing very uncommon)

17β- estradiol (micronized) dosing

Estrace, Lupin-estradiol

- oral

- 0.5, 1 and 2mg tabs qd

- preferred because its more natural with less CV risk

T/F: doses of estrogen for VM symptoms are higher than contraceptive doses

false, they are lower

So there is some overlap in years where a woman may have VM symptoms almost starting menopause and can get pregnant - so we can actually use this as both contraception and for VM symptoms and use the higher dose

T/F Transdermal estradiol does not go through first pass metabolism

True

Transdermal estrogen

- Does not go through first pass metabolism

• Patches are changed 1-2x/wk

• Gel is applied daily and is absorbed in 1-2 min

- More expensive

When should women use transdermal estrogen > oral

Used for women at risk (clotting)

• Hypertriglyceridemia

• High risk of VTE

• Malabsorption

• Obese women with metabolic syndrome

• History of gallstones or pancreatitis

17β- estradiol - Transdermal patch (Applied twice weekly)

Sandoz-Estradiol Derm® (matrix)

50, 75, 100 mcg/24 hr patches

Oesclim® (matrix)

25, 50 mcg/24 hr patches

Estradot® (matrix)

25, 37.5, 50, 75, 100 mcg/24 hr patches

17β- estradiol - Transdermal patch (Applied once weekly)

Climara® (matrix) 25, 50, 75, 100 mcg/24 hr patches

17β- estradiol - Transdermal gel (Applied once daily)

Estrogel® 0.06% Divigel® 0.1%

0.75mg, 1.5mg 0.25mg, 0.5mg, 1mg

lower strength gives more flexibility in how to treat and dose. start low, go slow

Sex-hormone binding globulin (SHBG)

If SHBG is increased, testosterone is decreased which can further lower libido

Non-oral route has less effect on SHBG

Estrogen efficacy

VERY effective!

• 18 fewer episodes/week of hot flashes compared to placebo

• At does of 17-beta estradiol 1mg/day or equivalent

• Eliminated VMS in ~80% of women

• Reduced severity and frequency in the rest

Why might we add on progestogen HT on top of the estrogen

estrogen will promote endometrial hyperplasia which can increase risk of cancer, so we HAVE to take progestogen in some form along with estrogen therapy

Progestogen HT

• Progestogen includes natural progesterone

and synthetic progestins

• In women with an intact uterus taking systemic ET, oral progesterone must be taken to prevent endometrial hyperplasia and cancer

• Hyperplasia can occur within 6 months of ET

• Occasionally used alone for vasomotor symptoms if CI to estrogen

Progestogen Contraindications

• Unexplained vaginal bleeding

• Current or history of breast cancer

• Pregnancy

• Peanut allergy (generic uses micronized progesterone; Prometrium® uses sunflower oil now)

• Soy allergy

Progestogen ADRs

• Menstrual irregularities

• Weight gain (38% gain >10lbs over 2y)

• Irritability

• Fatigue

• Breast tenderness

• Decrease in libido

Progestogen IUD

- Levonorgestrel-released IUDs with Estrogen-Therapy (ET) for endometrial protection

- Acts locally to protect the endometrium

- Benefits also includes contraception, ease of use, amenorrhea

- Good option for patients with s/e to oral progesterone

- As effective, or perhaps more effective, than oral progesterone regimens for endometrial protection

- Off-label, but viable option as per SOGC

Progestogen preparations used for endometrial protection

Medroxy- progesterone (MPA)

Micronized progesterone

Medroxy- progesterone (MPA) dosing

Oral (synthetic progestogen)

Provera® + generics

5-10mg/day x 12-14days/mth or 2.5mg continuous daily

Micronized progesterone dosing

Oral

Prometrium® + generics

200-300mg/dy for 12-14 days/mth or 100mg continuous daily

Better! more commonly used, closer to what is found in the body

Continuous vs cyclical progestogen dosing

The daily dosing is what prevents withdrawal bleed, while the cyclical dosing will have the bleed

- But using continuous dosing for someone who just hit menopause may actually increase random spotting/BTB, so better to do cyclical for them and have predictable WBs

Combination HT products

17β-estradiol / Norethindrone acetate (Oral, TD)

17β-estradiol/ drospirenone (Oral)

17β-estradiol / Norethindrone acetate (Oral) dosing

Oral

Activelle®, Activelle LD®

0.5mg/0.1mg QD

1mg/0.5mg QD

17β-estradiol/ drospirenone (Oral) dosing

Oral

Angeliq®

1mg/1mg QD

17β-estradiol / Norethindrone acetate (transdermal) dosing

Trans- dermal Patch (matrix)

Estalis®

0.05mg/140ug per 24 hrs;

0.05mg/250ug per 24 hrs

1 patch twice weekly

When can we use hormonal contraceptives for menopausal symptoms

Hormonal contraceptives can be used in perimenopausal women

• Useful when need to control irregular or heavy bleeding

Ethinyl estradiol (EE)/levonorgesterol Oral (Alesse®) If needed for contraception

Ethinyl estradiol (EE)/levonorgesterol Oral (Alesse®) dose

0.02mg/0.1mg

Ethinyl estradiol (EE)/levonorgesterol

Oral

(Alesse®) If needed for contraception

0.02mg/0.1mg

Vaginal estrogen indications

• Symptoms of vulvovaginal atrophy (including dyspareunia)

• Urinary urge incontinence (not stress incontinence)

• Recurrent UTIs

Benefit seen within weeks, f/u appt monitoring in 4-6 weeks

Vaginal estrogen mechanism

Improves blood supply to urogenital tissues, induces normal mucous proliferation/lubrication, restores normal flora, makes acidic pH

T/F Very little vaginal estrogen is absorbed systemically

True

T/F Concurrent progesterone is required with vaginal estrogen

False - not required

Vaginal estrogen contraindications

Not contraindicated in women with contraindications to systemic estrogen (e.g. recent stroke, VTE) but avoid in women with breast cancer who are taking aromatase inhibitors

- May consider for patients on tamoxifen after consultation with oncologist

Vaginal Estrogen preparations

Conjugated estrogens - Premarin® Vag. Cream

Estrone - Estragyn® Vag. Cream

17β-estradiol - Estring®, Vaginal ring

17β-estradiol - Vagifem® Vaginal Tablet

Conjugated estrogens - Premarin® Vag. Cream DOSING

0.625mg/g

0.5g QD x 14 days, then 0.5g 2-3x weekly

Estrone - Estragyn® Vag. Cream DOSING

1mg/g

0.5-4g QD cyclic (3 weeks on, 1 week off)

OR 2-3x weekly

17β-estradiol - Estring®, Vaginal ring DOSING

2mg/ring Releases 0.0075mg/d

Insert & replace q3m

17β-estradiol - Vagifem® Vaginal Tablet DOSING

0.010 mg

1 vaginal tab QD x 2wks then 2/week

Bioidentical hormones

By definition are identical to the hormones we

produce in our body

• Do not naturally occur outside of humans, so must be produced in labs

• Promoted as “natural” and “safe”

• Estradiol, estrone, estriol, progesterone, testosterone

• Providers usually target a specific hormone level, despite lack of evidence to do so

"Compounded bioidentical HT should be avoided, given concerns about safety, including the possibility of overdosing or underdosing, lack of efficacy"

Commercially available bioidentical hormones

Estrace®, Estrogel®, Prometrium®

When should compounded HT be used (bioidentical hormones)

Compounded HT should only be used by women allergic to approved products

HERS/HERS II trials

Showed that ET caused more CV events, more DVTs, more PEs, more strokes, more breast cancer, heart attacks

Less colorectal cancer, less hip and vertebral fractures

WHI - ET Outcomes

• HT is not for chronic disease management

• Greatest benefit is in symptom management

• For long-term therapy, risks generally outweigh benefits, even in younger women

Menopause & HT - when is CVD & Stroke risk minimized

• Low risk of CVD & stroke if started right after

menopause and used for

Menopause & HT - when is CVD & Stroke risk incrceased

Increased risk if started >10y postmenopause

EPT riskier than ET

Oral riskier than transdermal

When does HT have the most risk for VTE (blood clots)

Risk increases with age

EPT riskier than ET

Oral riskier than transdermal

- Use TD if older (>65), obese, or with DVT history

HT risk of breast cancer

Risk persists after stopping (for 3 -13 years)

• Can prescribe when a woman has increased risk of breast cancer, but with counselling and surveillance

• Increased breast cancer risk first seen 3-4 years after

starting EPT (so

Hormone therapy benefits

• Vasomotor symptoms

• Vaginal irritation or dryness

• Sleep disturbances/ mood disorders

• Aches, pains

• Osteoporosis

• GSM (vaginal ET)

Hormone therapy risks

• VTE

• Stroke

• Breast cancer (after ~4 years on EPT)

• CHD if >60y, or >10 years after menopause

• Endometrial hyperplasia, cancer (when unopposed systemic ET in a woman with a uterus)

Unknown risks:

• CHD if

HRT associated with _______________ surrogate markers of atherosclerosis

improved

• Reduced carotid intima-media thickness (KEEPS, ELITE)

• Reduced coronary artery calcium (KEEPS)

HRT associated with a(n) ____________ risk of a

composite outcome of mortality, heart failure, or myocardial infarction (DOPS)

reduced

In someone with moderate - severe hot flashes and/or night sweats and no CIs, how should they be treated?

Can use estrogen and progesterone (or if they have had hysterectomy, then only estrogen)

If someone has GSM and no CIs, how should they be treated?

Vaginal lubricants and/or moisturizer

consider low-dose vaginal estrogen

If someone has GSM and has CIs (breast cancer, endometrial cancer etc.), how should they be treated?

Vaginal lubricants and/or moisturizers

In someone with moderate - severe hot flashes and/or night sweats and has a contraindication (hormone dependent cancer, VTE, CHD, stroke etc.), how should they be treated?

treat with a low dose SSRI (paroxetine

if still not controlled or SSRI contraindicated, try gabapentin/pregabalin

When to avoid HT in women for CVD risk

if they are at high risk, or moderate risk with >10 years since menopause onset

If moderate risk

Alternatives to traditional HT for vasomotor symptoms

Tibolone

Bazedoxifene (SERM)

Antidepressants (SSRIs, SSNRIs)

NHPs, lifestyle changes

Tibolone

• Synthetic steroid (“prohormone”) that metabolizes to 3 metabolites with estrogenic, progestogenic and androgenic activity

• Start at least 12 months after LMP due to the risk of breakthrough vaginal bleeding

Who is tibolone indicated for

Only indicated in patients with intact uterus

Tibolone dosing

Typical dosage: 2.5mg PO once daily

Tibolone efficacy

• Less effective than EPT in reducing vasomotor

symptoms

• More effective than EPT at improving sexual dysfunction

Other benefits: Reduced vertebral fractures, improved BMD, improved vaginal dryness, improved mood

Tibolone short-term safety

Side effect profile similar to EPT, with

additional acne and hirsutism (male pattern hair growth)

• Substrate of CYP3A4, possible fibrinolytic activity

• Less unscheduled bleeding compared to EPT

Tibolone long-term safety

• Increased risk of stroke vs. placebo in women

> 60 years old

• Increased risk of breast cancer recurrence vs. placebo

Tibolone adherence

• More expensive and not on ODB

• Lower pill burden (single daily pill)

• Classified as a controlled drug, similar to

testosterone

- not first line for most patients. consider for those who do not tolerate EPT

Bazedoxifene (SERM)

• Does not require a progestogen (no endometrial hyperplasia)

• Works for vasomotor symptoms, vulvovaginal symptoms, osteoporosis

• Less vaginal bleeding, less breast tenderness