Menopause

Question 1

Define natural menopause

Answer 1

The permanent cessation of menses of 1 year’s duration secondary to lack of estrogen production by the ovaries

Question 2

Define perimenopause (menopause transition)

Answer 2

The time period prior to menopause which is characterized by menstrual cycle irregularity, increased frequency of anovulatory cycles, & symptoms similar to menopause

Question 3

What age is early menopause?

Answer 3

Early menopause = before age 45

Question 4

What age is premature menopause?

Answer 4

Premature = before age 40

Question 5

What age is primary ovarian insufficiency (POI)?

Answer 5

POI = before 40, but can still have irregular or transient menstruation

Question 6

True or False? If menopause is premature/early then it is not recommended to try to restore estrogen levels.

Answer 6

False - restoring estrogen levels until natural age of menopause is recommended to help prevent some complications - may require higher doses of estrogen (also Ca, Vit D, exercise, follow-ups)

Question 7

What are some factors which MAY precipitate earlier onset of menopause? (4)

Answer 7

1. Smoking
2. Exposure to toxins
3. Chemotherapy
4. Hysterectomy

Question 8

Go through the hormonal changes seen throughout the years that leads to menopause.

Answer 8

1. During the reproductive years, E and P levels rise & fall with cycles, as FSH promotes follicle development and ovum release.
2. There is an age related decrease in # and quality of ovarian follicles; by menopause few/none remain.
3. As a result, ovarian secretion of estradiol ceases & ovulation does not occur, so P concentrations also remain low.
4. The pituitary increases FSH and LH in an attempt to initiate follicle development, but the ovaries cannot respond.
5. End result: the ovaries cease to secrete estradiol & progesterone.
6. This can be a slow, progressive decline over years, or a dramatic drop at once.

Question 9

How is estrogen produced pre-menopause?

Answer 9

Mainly by the ovaries (as 17 beta-estradiol). However, other sites can produce smaller amounts of estrogen through the conversion of androgens.

Question 10

How is estrogen produced post-menopause?

Answer 10

• Estrogen production decreases to ~10% of premenopausal levels.
• The primary estrogen is estrone, which has ~ 1/3 estrogenic potency of estradiol.
• It is produced in adipose tissue via conversion of androstenedione.
  – Androstenedione –> estrone –> estradiol

Question 11

What are the main symptoms/groups of symptoms of menopause? (5)

Answer 11

1. Vasomotor symptoms
2. Sleep pattern changes
3. Mood and cognition changes
4. Genitourinary changes
5. Bleeding changes

Question 12

How do vasomotor symptoms mainly present? When and how long?

Answer 12

• Hot flashes and night sweats.
• Begin pre-menopause, max prevalence in 1st 2 years post-menopause.
• On average, VMS persist for 7-8 years.

Question 13

How are hot flashes characterized?

Answer 13

1. The sudden onset of intense warmth that begins in the chest and may progress to the neck and face.
2. Often accompanied by visible red flushing.
3. May also be accompanied by anxiety, palpitations, and profuse sweating.
4. Are typically episodic and last, on average, for 4 minutes.

Question 14

What (might) be some causes for hot flashes?

Answer 14

1. Appears to be due to a narrowing of the thermoregulatory system caused by changes in estrogen levels.
2. Postmenopausal women are thought to have narrowing of their “thermoneutral zone” - small changes in temp can stimulate the regulatory response of sweating or shivering.

Question 15

What are some risk factors for hot flashes?

Answer 15

1. Less physical activity
2. Family history/genetics
3. Age of onset
4. Induced menopause

Question 16

What are the 3 groups of treatment options for vasomotor symptoms (VMS)?

Answer 16

1. CBT
2. Menopausal Hormonal Therapy (MHT)
   - Estrogen
   - Estrogen + progestogen
   - Estrogen + bazedoxifene
   - Tibolone
3. Nonhormonal therapy (Lifestyle management in there too)

Question 17

While lifestyle modifications don’t have a whole lot of evidence for VMS, they are still okay to try. What are some examples to try/suggest?

Answer 17

1. Cooling techniques - Fans, A/C, cool drinks
2. Avoidance of triggers - Caffeine, alcohol, spicy foods
3. Exercise, yoga, relaxation training - May improve overall well-being
4. Weight loss in those who have extra weight
5. Smoking cessation

Question 18

When is estrogen therapy (ET) used alone for VMS? When is ET used in combination with a progestogen (EPT)?

Answer 18

1. Estrogen therapy (ET) is used alone for VMS if women have had a hysterectomy.
2. In those who have a uterus, it is used in combination with a progestogen (EPT).

Question 19

The most effective treatment options for VMS are?

Answer 19

Estrogen therapy and EPT

Question 20

Why must estrogen be combined with progestogen in women with a uterus? How should P be dosed?

Answer 20

1. Unopposed ET for 3 years is associated with a 5-fold increased risk of endometrial hyperplasia or cancer.
2. Use P for a minimum of 12-14 days/month, & match the dose of the P to the dose of the E.

Question 21

What are the 2 main estrogen (and combo products) dosage forms for VMS?

Answer 21

1. Oral
2. Transdermal - patch or gel

Question 22

How long is onset of symptom control of VMS when on ET/EPT?

Answer 22

• As little as 2 weeks for some, up to 8 weeks for others.
• Assess for response at 4 weeks at standard dose and 6-12 weeks for lower doses.

Question 23

Estrogen: transdermal vs. oral. What are the differences to be aware of in terms of efficacy and ADEs/benefits (if any)?

Answer 23

• Are similarly effective for vasomotor sx’s.
• Appear to provide same protection on BMD.
• There are some potential benefits to use of a transdermal estrogen:
  – Avoids first pass effect, so less nausea, less headache, less of an effect on TGs.

Question 24

What is the potential ADE of micronized progesterone?

Answer 24

May cause drowsiness, especially when taken with food

Question 25

What are the advantages of micronized progesterone vs. medroxyprogesterone acetate (MPA)?

Answer 25

Observational data shows it has a lower risk of VTE and breast cancer

Question 26

What is tibolone?

Answer 26

A synthetic steroid analogue of norethynodrel (a progestogen), which is metabolized in the body to make 3 substances that act like E, P, and A (androgen) – it has weak activity (DOES NOT CONTAIN ACTUAL HORMONES)

Question 27

When is tibolone indicated?

Answer 27

Indicated for short-term tx of VMS in menopausal women with an intact uterus

Question 28

What if contraception is desired in women experiencing VMS?

Answer 28

1. Low dose CHC (pill, patch, or ring) 2. Estrogen + LNG-IUS 3. MHT + barrier 4. Nonhormonal treatment option + progestogen-only contraceptive

Question 29

When can hormonal contraceptives be used in menopause?

Answer 29

Safe to use in the perimenopausal period when contraception is required, but do not use once in menopause as the daily dose of ethinyl estradiol (e.g. 20 μg) is 4-5x times higher than the low-standard dose required for symptom relief and bone benefit (e.g. 1mg estradiol)

Question 30

What are bioidentical hormones?

Answer 30

1. Plant-derived hormones structurally identical to what is naturally produced in the body. Examples: - Oral and transdermal 17 B-estradiol & micronized progesterone (commercially available pharma products) - Biest (20% estradiol/80% estriol) – compounded product 2. Compounded products may contain a mix of estradiol, estrone, estriol, DHEA, testosterone, progesterone. 3. Neither is more ‘natural’ than the other – they still need to be converted through a synthetic process to mimic body’s hormones. 4. Bioidentical hormones – whether from pharma or compounded pharmacist – contain the same ingredients.

Question 31

What do those in favour of compounded BHT say?

Answer 31

1. ‘Safe and natural’ (generally a marketing advantage) 2. ‘Custom-made’ based on salivary, serum, urine hormone level testing 3. Can compound in many different delivery routes (e.g. troches, subdermal implants) 4. Still require a written Rx.

Question 32

What do the detractors of compounded BHT say?

Answer 32

1. Individualized testing not necessary as not narrow TI meds. Hormone testing is unreliable. 2. The desired levels of hormones have not been established and may not correlate with symptoms. 3. Products have variable potency which could result in under/over-dosing – don’t adhere to strict FDA-mandated potency tests that Rx products do (PK/PD testing). 4. Lack safety / efficacy data.

Question 33

What are the EPT dosing regimens?

Answer 33

1. Estrogen is taken continuously every day. 2. Progestogens can be taken: - Continuously every day, or... - Cyclically for 12-14 days per month

Question 34

What are the main advantages of continuous combined EPT?

Answer 34

1. Easy to remember 2. Avoids the withdrawal bleeding 3. Decreases risk the most for endometrial hyperplasia

Question 35

What are the potential side effects of continuous combined EPT?

Answer 35

Unpredictable bleeding may occur; 40% have irregular breakthrough bleeding in 1st 6 months; 20% by 1 year

Question 36

In what situation might continuous E + cyclic P be preferred?

Answer 36

1. Prefer fewer pills 2. Recent menopausal who do not want breakthrough bleeding

Question 37

What are the common ADEs of estrogen?

Answer 37

1. Nausea 2. Breast tenderness 3. Headache 4. Bloating 5. Vaginal bleeding is common in 1st 3-6 months

Question 38

What are the common ADEs of progestins?

Answer 38

1. Irritability 2. Breast tenderness 3. Bloating 4. Headache 5. 'PMS-like symptoms': mood swings, bloating, fluid retention, sleep disturbance, decreased libido, weight gain 6. Vaginal bleeding is common in 1st 3-6 months

Question 39

How to manage common ADEs of estrogen and/or progestins?

Answer 39

1. Often dose-related 2. Change products

Question 40

What are the contraindications of MHT?

Answer 40

1. Unexplained vaginal bleeding 2. Active liver dx 3. Estrogen-dependent cancer 4. Pregnancy 5. Active thromboembolic dx (e.g. DVT, PE, stroke, MI) 6. Untreated / uncontrolled CVD

Question 41

What is the caution for using MHT?

Answer 41

High cancer risk

Question 42

When to consider non-oral estrogen?

Answer 42

1. Hypertriglyceridemia 2. Hepatobiliary disease 3. Migraine 4. Established CVD 5. Past VTE 6. Diabetes 7. Advanced age and no previous MHT

Question 43

What are the SSRIs and SNRIs that can be used for VMS symptoms?

Answer 43

1. Paroxetine 2. Citalopram 3. Escitalopram 4. Venlafaxine 5. Desvenlafaxine

Question 44

True or False? SSRIs/SNRIs used for VMSs act quicker than they would for depression.

Answer 44

True (2-4 weeks)

Question 45

Veozah (fezolinetant) is a new non-hormonal drug for VMS. What is the MOA?

Answer 45

Nonhormonal selective neurokinin 3 receptor antagonist

Question 46

What are some 'other' nonhormonal drugs that can be used for VMS?

Answer 46

1. Clonidine 2. Oxybutynin 3. Gabapentin 4. Pregabalin

Question 47

What are 2 herbal products that might have some decent evidence for VMS?

Answer 47

1. Black cohosh 2. Isoflavones

Question 48

What to know about osteoporosis and menopause?

Answer 48

Post-menopause, estrogen deficiency causes accelerated bone loss by increasing bone turnover & resorption

Question 49

Estrogen therapy, menopause, and osteoporosis. When should hormone therapy be used if at all?

Answer 49

1. Estrogen therapy can reduce fracture risk at various sites by 24% to 39% in postmenopausal women. 2. Indicated for prevention of osteoporosis only – not treatment. 3. Effects on bone protection are dose-related BUT IF NO VMS THEN SHOULD NOT BE ON HORMONE THERAPY FOR OSTEOPOROSIS ONLY.

Question 50

What effects on LDL, HDL, and triglycerides do the following have: 1. Estrogen oral 2. Estrogen topical 3. MPA daily or cyclical 4. Micronized progesterone daily or cyclical

Answer 50

Estrogen Oral: - Decrease LDL - Increase HDL - Increase TG Estrogen Topical - Decrease LDL - Increase HDL - Neutral TG MPA daily or cyclical - Blunt good lipid effects of estrogen Micronized - Lipid friendly

Question 51

What effects on LDL, HDL, and triglycerides do the following have: Estrogen topical?

Answer 51

Estrogen Topical: - Decrease LDL - Increase HDL - Neutral TG

Question 52

What effects on LDL, HDL, and triglycerides do the following have: MPA daily or cyclical?

Answer 52

MPA daily or cyclical: - Blunt good lipid effects of estrogen

Question 53

What effects on LDL, HDL, and triglycerides do the following have: Micronized progesterone daily or cyclical?

Answer 53

Micronized: - Lipid friendly

Question 54

What are the effects of estrogen on the CV system with short-term use?

Answer 54

Causes vasodilation

Question 55

What are the effects of estrogen on the CV system with long-term use?

Answer 55

1. Decreases LDL, increases HDL 2. Lowers fibrinogen 3. Lowers plasminogen-activator inhibitor type 1 Countering this is its effect on inflammation (measured by CRP) and on markers of thrombosis

Question 56

What to know about hormone therapy and CVD/CHD risk?

Answer 56

Multiple observational studies, meta-analysis suggest that the use of HT in younger women (<60yo) within 10 years since menopause has a beneficial effect on reducing CVD, or at very least does not increase.

Question 57

What are the effects of long-term hormone therapy?

Answer 57

1. Decreases LDL, increases HDL 2. Lowers fibrinogen 3. Lowers plasminogen-activator inhibitor type 1 Countering this is its effect on inflammation (measured by CRP) and on markers of thrombosis.

Question 58

What do multiple studies suggest about hormone therapy (HT) in younger women?

Answer 58

HT in younger women (<60yo) within 10 years since menopause has a beneficial effect on reducing CVD, or at very least does not increase CHD risk.

Question 59

What is the timing hypothesis of HT and CHD risk?

Answer 59

In younger (<60yo) healthy women & <10yrs since menopause transition, there is no increased CHD risk. If ≥10yrs post menopause or >60yo: increased risk of CHD, VTE, and stroke vs. earlier initiation.

Question 60

Is there a link between MHT and stroke?

Answer 60

- No increased risk with MHT if initiated <10 years and <60yo. - Higher incidence if initiated later.

Question 61

What is the link between MHT and VTE?

Answer 61

1. Increased risk regardless of <10 years or >10 years (although higher in older starters). 2. Address risk factors for stroke and DVT before deciding to initiate HT.

Question 62

What is the relationship between HT and breast cancer?

Answer 62

Risk increases with longer duration. Studies are lacking with regard to breast cancer risk with long term use. In women with prior breast cancer history, systemic HT is not generally advised.

Question 63

What is the duration of treatment of HT in VMS?

Answer 63

No clear answer, it is highly individualized. Reassess ~yearly to see if the person still requires treatment.

Question 64

How to manage insomnia/sleep disorders due to menopause?

Answer 64

1. General insomnia recommendations: CBT, valerian, hypnotics, antidepressants. 2. MHT may help in those also experiencing VMS.

Question 65

What effects on brain function does estrogen have?

Answer 65

1. Positive effect on serotonergic activity. 2. Increases the activity of NA. 3. E receptors located in regions of brain responsible for learning and memory. 4. Increases cerebral blood flow.

Question 66

How does estrogen therapy affect mood?

Answer 66

1. Some studies show ET improving depressive symptoms in perimenopausal women (but not late menopausal), and it may augment the clinical response to SSRIs. 2. The use of antidepressants and psychotherapy (CBT) remains the mainstay of treatment for mood disorders and anxiety.

Question 67

Is hormone therapy recommended for cognition and dementia?

Answer 67

HT is not recommended to preserve cognitive function or prevent/treat dementia. Further, initiation >65 years may increase the risk.

Question 68

What changes occur due to decreased estrogen in the vagina, vulva, urethra, and bladder?

Answer 68

1. Tissue atrophy. 2. Reduced secretions. 3. Reduced blood flow. 4. Vaginal pH increases to 6-8 (premenopause 4.5 - 5). 5. A decrease in E in addition to normal tissue aging can result in vaginal symptoms.

Question 69

What is genitourinary syndrome of menopause (GSM)?

Answer 69

GSM refers to the signs/symptoms resulting from E deficiency on the genitourinary tract.

Question 70

What are the common symptoms of GSM?

Answer 70

1. Vaginal dryness. 2. Vaginal itching / irritation. 3. Burning. 4. Painful intercourse. 5. Lower urinary tract symptoms: (urinary frequency, urgency, UTIs). 6. Nocturia, dysuria.

Question 71

What are the first-line treatments for GSM?

Answer 71

1st-Line: Non-hormonal lubricants (OTC). A. Lubricants: Use with intercourse. - Water-based: Astroglide, K-Y Jelly. - Silicone-based: Astroglide X, K-Y Intrigue. - Oil-based: Olive oil. B. Moisturizers: Use regularly (2-3 times weekly). - Goal is to reduce daily symptoms and make intercourse comfortable. - Replens (polycarbophil gel), Gynatrof, RepaGyn (hyaluronic acid), K-Y SILK-E.

Question 72

What is the next option if OTC agents are ineffective for GSM?

Answer 72

Vaginal estrogen preparations - Minimal systemic absorption so less concerns with use. Don't need accompanying progestogen.

Question 73

What are the types of local vaginal estrogen products?

Answer 73

1. Vaginal creams. 2. Vaginal ring. 3. Vaginal tablets. 4. Vaginal softgel inserts.

Question 74

What are the common side effects for all of the local vaginal products?

Answer 74

1. Local burning/irritation. 2. Leakage.

Question 75

Is there a difference in efficacy between the local vaginal products?

Answer 75

Similar for all.

Question 76

When might improvement be seen when using a local vaginal product?

Answer 76

See improvement in a few weeks - up to 12 weeks for max benefit. Assessed at 3-6 months, then yearly typically.

Question 77

Might we use systemic estrogen therapy for GSM?

Answer 77

1. If someone is also experiencing VMS, then oral MHT would be trialed as in addition to helping the VMS symptoms, it will also help with the GSM symptoms as well. 2. ~10-15% of women will still experience GSM symptoms while on systemic MHT, so systemic and intravaginal ET may be used together.

Question 78

What is a non-hormonal agent to treat GSM?

Answer 78

Prasterone - Is a synthetic form of DHEA (dehydroepiandrosterone) that has no estrogenic (E) or androgenic (A) activities. However, when administered intravaginally, the cells in the vagina convert it into E and A where they act locally, thus avoiding exposure of other tissues to these hormones.

Question 79

What is the potential oral treatment for GSM and how does it work?

Answer 79

Ospemifene - Is a nonhormonal SERM. Has weak agonist effects in the endometrium, activates estrogenic pathways in vulvar and vaginal tissues and bone, and blocks pathways in breast (antagonist). Is not co-administered with a progesterone.

Question 80

What to know about weight gain and menopause and MHT?

Answer 80

During menopause transition: avg. weight gain of 1.5lbs/yr – this is due to a decreased resting metabolic rate that occurs with aging (change in fat-to-lean body mass ratio) – not MHT.

Question 81

What to know about skin changes in menopause?

Answer 81

Soon after menopause, skin collagen content, thickness, and elasticity decline.

Question 82

What is abnormal uterine bleeding (AUB)?

Answer 82

1. AUB (irregular menstrual cycles) is common during the menopause transition period. 2. Prolonged cycle intervals as well as variable bleeding patterns precede eventual amenorrhea and menopause.

Question 83

What are some potential causes of abnormal uterine bleeding (AUB)?

Answer 83

1. Dysfunctional uterine bleeding (DUB) which results from anovulation. 2. Endometrial hyperplasia and cancer. 3. Benign lesions (endometrial polyps).

Question 84

How is AUB treated?

Answer 84

1. Treatment is aimed at regulating bleeding patterns. 2. Low dose OCPs (20ug EE). 3. Progestin therapy - Can be given intermittently or continuously.