Block 2 Lecture 4 -- Menopause and HRT Flashcards
What is the definition of menopause?
12 consecutive months of amenorrhea via cessation of ovarian follicular activity
What is the median age of menopause in the US?
51 (2 years earlier if smoker or hysterectomy)
What are the hormonal changes in menopause?
1) estrogen, progesterone decrease
2) FSH and LH increase
3) ovaries primarily produce androgens
4) SHBG decreases, generating increased free T, but overall less total T
What is perimenopause?
the period preceding menopause by 2-4 years and the year following menopause
What are the symptoms of menopause?
1) vasomotor
2) mood changes, anxiety
3) sleep disturbances
4) vaginal dryness
When do menopausal symptoms begin?
perimenopause
Describe the enrollment in the WHI ‘91 study.
160k post-menopausal women aged 50-79
How long was the WHI study run?
15 years
What are the interventions in the WHI study?
1) HRT
2) d-mod
3) D + Ca
Describe the drugs given as HRT in the WHI study.
CEE 0.625mg/day
+ MPA 2.5 mg/day if uterus intact
Why was the HRT arm halted?
increased stroke risk with no effect on CHD
combo increased risk of breast cancer
When was the HRT arm halted?
combo after 5 years
e only after 7 years
Describe the interventions in the d-mod arm of WHI?
1 g/day Ca + 400 IU/day Vit. D
What were the expectations in the Ca/D arm of the WHI study?
1) decreased bone fx
2) decreased colorectal cancer risk
3) increase kidney stones
Describe the interventions in the d-mod arm of WHI.
low-fat diet (less than 20% of calories) resulting in a 10% fat reduction vs. control
What were the criticisms of the WHI study?
1) low adherence, high attrition
2) under-reported benefits
3) average as was 63
What did sub-group analysis of the WHI study conclude?
HRT not harmful if initiated early
What were the under-reported benefits of the WHI study?
- decreased total mortality
- decreased colorectal/endometrial cancer
- decreased hip and total fx
- decreased t2dm and PAD
What did outside analysis of the WHI study conclude?
window of opportunity for max effect of HRT on total mortality and CHD:
- within 6 years of menopause and/or before age 60
- continue for 5+ years
Describe the enrollment in the Danish Osteoporosis Prevention Study
1006 peri-menopausal women (u-60 yo) randomized to combined HRT (or estrogen only)
How long was the Danish Osteoporosis Prevention study conducted?
treated for 10 years
followed for 16
What was the conclusion of the Danish Osteoporosis Prevention Study?
significantly reduced risk of: -- mortality, -- heart failure -- MI without increased risk of: -- cancer -- thromboembolism -- stroke
What are the goals of menopause treatment?
1) relieve vasomotor symptoms in the short term (5-years)
2) prevent osteoporosis in the long term
What is the standard dose of CEE?
0.625 mg/day
Describe the content of CEE
50-60% estrone sulfate
– remainder = other equine estrogens
What is the most popular oral estrogen in the US?
premarin (CEE)
How much of the oral estrogen forms reach circulation as free estradiol?
less than 10%
– estrones are converted back to estradiol over time
Describe the absorption of estradiol?
during absorption, intestinal mucosa and liver convert to estrones
What estrogen form gives the most physiologic (pre-menopause) E2:E1 ratio?
transdermal estrogen patch
How is the IN estrogen spray dosed?
1-2 x/day
What are the forms of parenteral estrogen?
1) patch/gels/creams
2) sq implant
3) intranasal spray
4) vaginal rings
How often do estrogen-containing vaginal rings last?
3 months
Which parenteral estrogens are effective (increase BMD and relieve vasomotor sxs) at low doses?
transdermal, vaginal ring
Which parenteral estrogen is least likely to have ADRs?
transdermal
What are the drug interactions for estrogens?
1) anticonvulsants (induce 3A4)
2) may increase THBG, CBG, SHBG
What are the forms of progesterone used in menopause?
1) micronized (prometrium)
2) levonorgestrel IUD (mirena, skyla)
3) drosperinone
Why are progestogens always included with estrogens?
to prevent endometrial hyperplasia and cancer
What are the effects of progesterone on estrogens?
1) decrease nuclear ER concentration
2) promote conversion of estradiol to estrone
What are the estrogen-progestogen regimens used in menopause?
1) continuous cyclic
2) continuous combined
3) continuous long-cycle
4) intermittent combined
others
- lo-dose
- quarterly progestogen
Describe the continuous cyclic regimen.
E daily + P last 12-14 days
- results in withdrawal bleed 90% of patients
- oral or TD
Describe the continuous combined regimen.
E + P continuously
- oral or TD
- endometrial atrophy and amenorrhea
- unpredictable spotting/bleeding initially, resolved within 6-12 months
- usually reserved for recent menopause (2 years past)
How may spotting be stopped in the continuous combined regimen?
increase P or decrease E
Describe the continuous long-cycle regimen.
E daily + P q other month x 12-14 days
– longer heavier bleeding than continuous cycling
Describe the intermittent combined regimen.
– 3 days E
– then 3 days E+P
– repeat
results in decreased incidence of bleeding
lower P dose = fewer ADRs
Describe low-dose HRT
- 45 mg CEE + 1.5 mg MPA
- - maintains sx relief and BMD
Describe quarterly progestogen regimen in HRT.
MPA x 14 days q 3 months
– higher incidence of endometrial hyperplasia
What are the ADRs of progesterone?
1) irritability
2) depression
3) HA
4) sleep disturbance
5) bloating
What is drosperinone?
anti-androgenic P with anti-MR effects
- decreased hyperplasia
- no hyperkalemia
What are the results of levonorgestrel IUD therapy?
off-label HRT use:
- atrophic endometrium
- low systemic P levels
What are the effects of micronized progesterone therapy?
- less bleeding
- - does not improve lipids
