Lecture 19 - Menopause & HRT Flashcards
Mechanisms of Menopause
Menopause = ‘pause of the menses’
An absence of menses > 12 months
Not the same as amenorrhea
Termination of ovulation means termination of menstrual cycle
Preceded by ‘Perimenopause’ (aka menopause transition)
Up to six years before Menopause irregular menstrual cycles
At birth human female has 500,000-1,000,000
At begin of puberty, that number is significantly lower (25-75 thousand)
At onset of menopause, that number is <0.1% from puberty levels (less than 5000)
LH / FSH fail to induce follicle growth no E2 or P means no more menstrual cycle
Without follicle growth, no estrogen release to inhibit LH / FSH
FSH/LH levels remain high
Estrogen levels remain low (shift in ratio of estradiol to estrone)
Progesterone levels remain low
No follicle development / dominance / ovulation
Ovulation stops, cycling stops, chances for subsequent menstrual cycle reduced
As these add up, eventually it stops altogether
In comparison: Mechanisms of oral contraceptives
COMBINED:
Progestogen negative feedback on the Hypothalamus
Inhibit GnRH, reduce LH / FSH
Estrogens additional negative feedback on the anterior pituitary
Further reduce LH
Low LH / FSH = limited follicle development, no dominance or ovulation
Endometrium from estrogens and progestogens (less if only P)
Switch to placebo after day 21 (the last 7 days) so menses occur
Age and menopause (plus risks)
Hormone levels fluctuate causing disturbances similar to adolescence
Mean age of menopause is 51 (range [±2 SD] is 45 - 57)
Before 45 considered premature
Younger natural menopause linked with adverse health cardiovascular disease osteoporosis overall increased mortality vaginal atrophy and decreased libido Alzheimer’s Disease
These risks actually inversely correlate with the number of years of ovarian hormones’ you have had
Late menopause risk of breast and endometrial cancer
Hormone Replacement Therapy
Substitution of estrogen and sometimes progesterone after menopause
will it induce ovulation? no, only of cyclical and you have ovas
will it induce menstrual cycle? if you did this cyclically yes but you do not
will it cure side effects of hormonal imbalance?
will it have the effects that estrogen normally has?
Cancer and HRT
HUGE multicenter study
Included McGill’s Dr Barbara Sherwin
Experiment (random assignment, double blind)
Effects of hormone replacement on health outcomes internationally
Many things a worsened following menopause Osteoporosis Cardiovascular disease Alzheimer’s disease Thermal regulation Sleep Sexual functioning
Can HRT help?
HRT conclusions from big study
E+P oral hormone replacement therapy:
Increased incidence of heart disease, stroke, pulmonary embolism
Increased risk of breast cancer and death by breast cancer
Suggests that HRT is in fact a VERY bad idea
Some drawbacks to the study:
Avg screening age is 63
75% over 60yrs
A long way out from menopause have not menstruated for over 10 years
More women in E+P group were prone to breast cancer
More women in the E+P group had falls increasing risk of thrombosis
Consequences of the WHI trial?
60% drop in women on HRT
Study that disagrees
WHI results can be prevented
HRT not effective after longterm estrogen deprivation
Remains unclear why – permanent receptor downregulation?
Cancer risk increased ONLY when P administered with E
Also they used equine E and a bad type of P (Sweden and Canada no longer use equine E, the USA does)
Mode of administration might matter
Hepatic first pass mechanism because of being in an oral pill, possible with transdermal to avoid this
Suggests that HRT might not be so negative
E+P does increase bone density (E alone too)
Multiple areas of concern
The E+P increase in breast cancer most common in thin ppl - so can screen them out maybe
E only = no increase in cancer risk until more than 15yrs HRT
Overview of HRT effects:
E+P increases the # of breast cancer, thrombolism, gallbladder inflammation, stroke
E alone negatively effects gallbladder
Gallbladder inflammation easily treated
Minimal increased in # with thrombosis and stroke
THIS WAS THE ONLY REALLY BIG RISK WITH E ALONE
Decreases a number of menopause related physiological concerns (E and E+P)
Massive benefit thermoregulation and sexual functioning
Limited risk but many benefits with E alone HRT
Progesterone instead of medroxyprogesterone lower risk
Still a cancer risk but much less and maybe with screening, manageable
Recent paper with large international sample in respected journal
E+P treatment is related to an increase in breast cancer risk
E alone is too, but much lower risk
Unclear what forms of estrogen and progesterone are used
Although clear risk, the message is weigh the benefits vs risks
Hormone Replacement Therapy:
A role in cognition too??
When estrogen levels are HIGH women perform better on:
tests on verbal fluency
speeded articulation
manual coordination
Women using HRT show superior performance on verbal learning and memory tasks (Maki et al., 2001)
More clustering of words into semantic categories
Better encoding and retrieval
Better retention after interference task
Estrogen and the hippocampus
Woolley & McEwen, 1992:
32% decrease in hippocampal synaptic density detectable 24 h following onset of rat estrus (low E2)
Observe hippocampal changes across menstrual cycle with MRI - just the cycle in women changes the hipp synaptic density within the same cycle indicating hormones may support this structure
Pruessneur and colleagues, 2008
HC volume higher with E only HRT
HRT supports the physical structure of the hippocampus and therefore could be a good thing
Dementia and sex
1 in 6 women get alzh
only 1 in 11 men
Also, less time with ovulating hormones means a greater risk
Prof’s research
Dr Gillian Einstein (my former supervisor)
Cognitive and neurobiological changes following surgical menopause
Eliminate the age confound!
Clarify the role of estrogens in cognition, brain structure, and brain function
Declines associated with loss of estrogen in population at risk of Alzheimer’s?
Women with the BAC gene will et breast/ovarian cancer so these re removed at 40, called a BSO
BSO women – poorer working and verbal memory
Protective effect of E2 for working memory
Having done a Manual segmentation of the hippocampus
You see:
Lower volume following BSO
Protective effect of E2
Cortical thickness reduced in BSO
Reduced thickness in the right frontal cortex following BSO
E2 protects against this. It was not as good as controls but was better than the BSO and no E2 group (somewhere in the middle)
Working and verbal memory require the hippocampus and frontal cortices
Brain changes mediate cognitive changes?
