Menopause Flashcards
1
Q
What does menopause mean for women?
A
- WHO defines natural menopause as at least 12 consecutive months of amenorrhea (no periods) not due to any physiological/ pathological causes. Natural event reached upon exhaustion of primordial follicles. Pool of primordial follicles is formed in utero (as the foetus develops). This defines their fertility and menopause. Once depleted, the woman enters menopause (there is no male equivalent).
- The global age at menopause is on average 51 years (range 40-60 years) suggesting a distinct genetic control; strong correlation exists between mothers and daughters
- Menopause affects many aspects of health. Menopausal health aspects include bone density, breast, the cardiovascular system, mood/cognitive function and sexual well being
- Common symptoms include = Hot flushes, night sweats, vaginal dryness (urogenitoury system is affected) and discomfort during sex, difficulty sleeping, low mood/anxiety, reduced libido
- Physical and emotional changes strongly affect women
- 1:10 women experience suicidal thoughts due to the perimenopause (the years leading up to menopause; this time period can vary).
- The perimenopausal period can vary from 3 to 10 years. Suicidal thoughts are relatively serious to take into account. Women may not realise why they are feeling this way, especially because they aren’t aware they are in the perimenopausal period (approaching menopause). It is put down to other things, so it is often treated incorrectly; treatment should be tailored to each individual woman’s symptoms (doesn’t happen much in reality).
- Effective health care support should be individually tailored to all aspects of the menopause when women feel particularly vulnerable
2
Q
What are the associations of menopause in society?
A
- Psychosexual and social implications; menopause is often associated with ageing and loss of status. This time coincides with other changes, e.g. children leaving home (empty nest syndrome).
- Ageing is often associated by women with a loss of status – feeling of becoming invisible
- Closely associated with psychosocial events in midlife and ageing i.e. health issues, family and marital relations, sociocultural background and attitudes toward a sex life determine women’s experience of the menopause.
3
Q
How does the number of eggs in the ovary change from conception with age postnatally?
A
- Ovarian reserve is formed during foetal life. There is massive loss; huge numbers of primordial follicles are formed (around 6.5-7 million), but foetus is born with half a million to a million.
- There is continual decline throughout reproductive life. Once the pool of primordial follicles has been depleted, menopause is reached (around 50 years old).
4
Q
What is the correlation between ovarian reserve and age of menopause?
A
- The initial ovarian pool of non growing follicles (NGFs) will determine how quickly they become depleted in continued life (The ovarian reserve will determine the rate of decline of NGF & age of the menopause).
- Follicles can’t be seen without taking ovarian tissue out and dissecting the primordial follicles under the microscope or fixing a bit of ovary and sectioning it to count all the primordial follicles. It is very difficult to assess how many primordial follicles there are and, hence, the ovarian reserve.
- This paper used data from various histological studies and follicles that were counted. They counted as many follicles as possible, then created various mathematical modelling to fit the data. These human samples were from all ages, even before birth (e.g. foetuses that dies in utero late in gestation so foetuses had to be delivered in labour or natural abortions due to abnormalities). Other ovaries that were taken out from women at different stages were for different reasons; in very young girls and young women, it was likely due to certain cancers etc. Tissues extracted from foetuses or adults can be fixed and stored for research/teaching purposes.
- About 20 different mathematical models were created and this is the one that fitted the data best. Model demonstrating the individual variation of the initial size of the non growing follicle (NGF) pool and subsequent decline in NGFs until ovarian depletion - when NGF count <1000. At birth the ovary contains about 500,000-1million primordial follicles. Can see the confidence intervals of the actual data and then for the model. This is looking at non-growing follicles. When there are less than 1000 primordial follicles in the pool, it is classified as entering menopause.
- Women who begin with a smaller pool before birth menopause quicker than women at the upper end who started off with more follicles pre-birth. (menopause a bit later coming up to about 60 years old).
- Estimated that for 95% of women by 30yrs only 12% of max. pre-birth NGF population is present and by 40yrs only 3% remains.
- For the majority of women, by the time they hit 30 years old, extrapolating the data shows they are left with about 12 to 15% of the non-growing follicles than what they had at birth (losing a lot of follicles all the time and this accelerates). This is unfortunate for women that physiologically there is unfortunately a right time to have a baby biologically that doesn’t always fit in to the way society is. This biology cannot be shifted too much but in today’s society, women prolong having children or the age they want to have children with huge pressures on women to have children at different stages in their life, fit in careers and husbands etc.
5
Q
How does reproductive ageing affect fertility?
A
- Due to decreasing ovarian reserve, subfertility will progress to infertility. Around ten year intervals between subfertility, sterility and the menopause. The ovarian reserve will determine the onset of subfertility to sterility and to complete loss of menstrual cycles – the menopause.
- Even before menopause, a period of 10 years can be looked at as to when some women will start having fertility issues. At around 30 years old, women will start to have fertility issues (depends on where you are on this cumulative graph); at the top end (in terms of ovarian reserve), it won’t be much of an issue in comparison to the bottom end. Often, the onset of fertility issues due to a diminishing ovarian reserve can start well before the age of menopause.
- Even if you can stimulate the ovaries at 50+ to produce a few oocytes that may be present, the quality will be poor. It is a combination of quality and quantity. As mentioned in meiosis and follicles being in meiotic arrest for decades (the implication of that on the quality of the egg), e.g. chromosomal errors and increased risk of having miscarriage due to chromosome abnormality etc.
6
Q
What are the various factors affecting ovarian reserve?
A
- Various factors will affect the ovarian reserve as listed here. There is not a huge amount of evidence, but these have been implicated.
1) In utero environment = as the foetus is developing and as the ovarian reserve is being established (primordial follicles are forming)
2) Some people think that androgens/PCOS slightly delays menopause (pushes it the other way) because there is stockpiling of follicles
3) It is known that women with certain autoimmune conditions can menopause early and can affect ovarian reserve.
4) Nutrition (overweight/ underweight)
5) Genetic abnormalities, some medications, injury
6) Ethnicity/geography
7) Genetics - Part of the problem is how to assess ovarian reserve. - Women want to know when they are approaching menopause, their fertile window, when to consider assisted reproductive techniques etc. There is modelling and predictive data, but many fertility clinics are beginning to look at the link between AMH and ovarian reserve.
7
Q
What are the trends in AMH levels with age in boys, men and women?
A
- AMH is produced in both males and females, but it varies depending on what stage and how old.
- In utero, boys have high levels of AMH since it has a renowned role in sexual differentiation. Women have no AMH before birth. After birth, it declines in boys coming up into teenage years.
- Boys have high AMH levels in utero as it is important in sexual differentiation. It then declines with age (measured in nM in boys and pM in men; pM is 1000 times smaller than nM).
- The levels of AMH in the human circulation vary during the life cycle, with a sexually dimorphic pattern. Females produce virtually no AMH in utero.
- In women, it is in pM but a distinct increase and then decline can be seen over the reproductive years.
AMH is produced by the granulosa cells of the follicles. Therefore, levels decrease with age in women corresponding with follicle depletion. Results in reduced AMH and then no AMH.
8
Q
What happens to levels of Inhibin B and FSH as approach peri-menopause?
What is the link between AFC, AMH, Inhibin B and FSH?
A
- AMH is secreted by growing follicles (preantral to small antral stages) and it is related to declining levels of AMH as the ovarian reserve becomes depleted.
- AMH clearly declines with age. The age-related decline has been banded with the red band showing women with low ovarian reserve. The orange band is considered normal, but it is quite a big spread. It depends where you are within this category. - Those in the green band thought to have PCOS. There is high AMH in PCOS as there are more arrested antral follicles, so more granulosa cells. It is also thought that women with PCOS produce more AMH per follicle per granulosa cell. These two abnormalities (increased antral follicles and more AMH production per follicle) = high AMH.
- AMH is secreted from the growing follicle (rather than primordial or small preantral follicles); typically comes from the bigger preantral follicles into the early antral follicles. Inhibin B is also created once the follicles becomes antral follicles and when the antral follicles reach a certain size, they also become responsive to FSH (have to combine them all together).
- Inhibin is produced by the granulosa cells (like AMH). In the perimenopausal period (approaching menopause), as there are less follicles and less granulosa cells, inhibin levels will decrease. As follicles number decline, oestrogen levels also decline, and negative feedback is removed. Therefore, FSH levels will increase. Also, inhibin inhibits FSH so as inhibin levels decrease, FSH will increase.
- These factors are all used in conjunction to assess menopause and fertility. Fertility is the opposite of menopause in a way; declining fertility due to ovarian reserve = approaching menopause. It is this link between antral follicle count, AMH, inhibin and FSH.
9
Q
Can AMH predict ovarian reserve? Is it a good predictor?
A
- Relation between age-specific anti-Müllerian hormone (AMH) concentrations and the distribution of age at menopause. The left nomogram depicts the baseline AMH levels of 185 normoovulatory women and percentile declines. The right nomogram depicts the variation of age at menopause during approximately 11 years of follow up for different AMH percentiles.
- The decline in AMH is related to timing of the menopause – i.e. those with the highest percentile range of AMH (eg >P90) had the highest age at menopause (purple graphs).
- Each line on the left model shows lines of best fit to fit the AMH values. AMH values were measured in a range of women and these women were then followed for another 10 years to see at what age they underwent menopause (lots of numbers are required to fit mathematical models and use equations). The lilac line shows women with high AMH. The graph on the right shows that these women menopause later (comparing the peaks) compared to women with very low AMH (red line). The problem is that there is a lot of overlap between them and it depends where you are on the line.
- Can’t rely only on AMH to predict when a woman will enter menopause, because AMH technically measures growing follicles (produced by them), whereas ovarian reserve is the number of primordial (non-growing) follicles. In some ways, AMH is a reflection of the growing follicle pool, but it is the best thing we have currently. People are extrapolating back, saying the growing follicle pool emerges from the non-growing follicle pool, so it can still be used as a marker.
10
Q
Are AMH levels are becoming the gold-standard biomarker to evaluate ovarian reserve and predict ovarian response to hormonal stimulation?
A
- Measurements of AMH and AFC are used to diagnosed premature ovarian failure/insufficiency
- This age-related decline in fecundity is characterized by a decrease in both egg quality and number, and a population-based change in the expression of markers of ovarian activity, such as a gradual increase in circulating FSH and decreases in circulating anti-Müllerian hormone (AMH) and inhibin B concentrations (Broekmans et al, 2006, Faddy et al, 1992, American College of Obstetricians, Gynecologists Committee on Gynecologic Practice and Practice Committee, 2014). It should be noted that a wide variation exists in the number of eggs between women of any age, and that a 30-year-old woman with high ovarian reserve typically demonstrates a total follicle count as much as 100-fold higher than that of a 30-year-old woman with low ovarian reserve (Wallace and Kelsey, 2010).
- Often, it is used clinically to assess fertility as a biomarker to evaluate ovarian reserve, response to hormonal stimulation in IVF or in fertility treatment. Really, it is the interplay between it all.
- There is the primordial pool of follicles which are present from birth (non growing). Cohorts start growing, very slowly, until they reach the late preantral stage (secondary). This is where there is no antrum, very slow over three months. They start to produce AMH. This AMH acts to inhibit FSH action and will then reduce that active over recruitment of those early antral follicles. Eventually, those early antral follicles will prevail FSH and will be responsive to FSH. It is not known what signal switches off AMH completely, but they become responsive to FSH and start growing. As they grow, they produce inhibin B. All AMH, FSH and inhibin B act to keep things in balance to prevent quick depletion of the pool. This is in normal follicles in the normal ovary. There is then production of oestrogen. Selection into the early follicular phase of the menstrual cycle and dominance within 14 days.
- There is utility in using AMH and antral follicle counts, but other factors should be taken into account. A clinic should not only use AMH without antral follicle counts (and ideally inhibin B and FSH). They should not really rely on AMH, particularly without assessing if the woman has PCOS (AMH can’t really be used if a woman has PCOS).
11
Q
What are the hormonal changes that occur during menopause?
A
1) Ovarian senescence begins around 35 years ends with menopause ~51 years = decline in ovarian function from around 35 years of age with the declining ovarian pool, though this can vary between women.
2) Decline in ovarian oestrogen largely related to number of primordial follicles, number of recruitable follicles in each ovarian cycle and proportion of follicles that reach adequate maturity. Majority of the effects are because of declining oestrogen = less number of primordial follicles, less follicles growing, less follicles recruited and so there won’t be enough reaching maturity. Therefore, the decline in oestrogen is what drives a lot of the symptoms and changes in menopause.
3) Rise in FSH – loss of negative feed back
4) Decline in inhibin B and AMH (decline in follicle numbers). Androgens are associated with sexual libido, even in women. This decline in androgens causes the loss in sexual libido when approaching menopause.
5) Decline in androgen synthesis in adrenal glands and ovaries
6) Marked decline in fertility after age of 35 although this depends on ovarian reserve . It is often said that women’s fertility drops by the age of 35, but it is not necessarily an abrupt event; really depends on ovarian reserve (some women can reach 40 before it begins to decline). AMH would have utility especially in predicting this if you had normal ovaries with all the other measurements mentioned.
12
Q
What are the trends in approximate average serum concentrations of estradiol, estrone, FSH, LH, and total testosterone during the menopausal transition and post-menopause?
A
- FSH starts to rise as negative feedback from oestradiol has been removed (decline in oestradiol is associated with the real increase in FSH).
- When a woman comes in with perimenopausal symptoms, FSH and LH levels are often measured first. If FSH levels are rising, depending on which part of the cycle they are in, it is clear they are reaching perimenopause.
- LH levels increase (not as significantly as FSH).
- Testosterone levels are NEVER as high in women compared to males, but even the slight decline in total testosterone levels is enough to cause the changes mentioned.
- Linking this to the ovarian reserve. There is a steep decline in the number of follicles and the perimenopausal period can be anywhere from about five or six years preceding actual menopause. There is this depletion of the ovarian reserve that will increase dramatically at a certain point (coincides with significant increase in FSH). It is about thinking about all of these factors in combination together.
13
Q
What are menopausal symptoms?
A
- The most common form of climacteric complaints is hot flushes. There are also psychological aspects and can be related to social circumstances, e.g. empty nest syndrome.
- Women start to have a lot of symptoms which are associated with menopause, but they don’t all just come on abruptly. They will present at different stages. This graph suggests when the complaints manifest themselves. Often, the initial complaint and the one that women feel most is called climacteric complaints, i.e. changes in hot flushes and the feeling of night sweats etc. Atrophy of the vagina wall, urge continents or skin atrophy can present at different stages much later, probably after progressing through menopause when they are older. Really, all of it starts because of the menopause and the lack of oestrogen; the onset of many menopausal symptoms is after the steep oestrogen decrease. Often, also the genitourinary problems will be because of lack of oestrogen. Oestrogen is needed for bone health = osteoporosis.
- Studies looking at the prevalence of menopausal symptoms are difficult to conduct. Most of these studies are carried out as diary studies (women keep diaries of their symptoms, self-report or fill in questionnaires), so they can be a bit unreliable or more difficult to analyse statistically (compared to measuring levels of hormones, for example). Very large ranges can be seen when comparing studies. These kind of studies are important to know how women are feeling or how these things are affecting them. Symptoms include hot flashes and night sweats (most common), vaginal dryness, sleep disturbance, mood symptoms, urinary symptoms.
14
Q
What are hot flushes and night sweats?
A
- Experienced by approximately 80% menopausal women, can last up to 5-13 years though number of episodes decrease with time. Even if women have completely passed through a lot of their menopausal symptoms (completing menopause), they will still occasionally have these hot flashes and night sweats.
- Measuring frequency most objective way of assessing severity of menopausal symptoms (rather than how hot did you feel which is subjective and can’t be assessed etc.)
- Typically occurs on the face but can occur in other body areas such as arms and the torso
- Aetiology unknown but oestrogen interacts with the noradrenergic system in the brain which plays a major role in thermogenesis. Other neural systems have also been implicated such as the endorphin pathways. Comes down to the decline in oestrogen again, but it is not all oestrogen. There are even women on hormone replacement therapy (where oestrogen has been replaced) who get these hot flashes. There are other systems in play; the whole endorphin system in the brain is quite complex.
- ‘Wet’ flushing occurs through inappropriate vasodilation and activation of sweat glands through both central and peripheral mechanisms. Hormone withdrawal and emotions are both causes
- ‘Dry’ flushing (no sweat!) can be caused by several drugs, the carcinoid syndrome, phaeochromocytomas amd mastocytosis (accumulation of mast cells in tissues including the skin)
- With both dry and wet flushing, there are many potential causes that need to be considered when making a differential diagnosis. Symptoms should not just be dismissed as menopause clinically (there can be other reasons), e.g. many things can cause dry flushing with no sweat, like pheochromocytoma (rare tumour found in the adrenal medulla). Have to make this judgement; woman is having these flashes, whether they are wet or dry, due to menopause only in conjunction with measuring FSH and carrying out other tests before reaching diagnosis.
- Needs to be measured in conjunction with hormone levels, e.g. FSH.
15
Q
What causes osteoporosis in menopause?
A
- This often happens much later on in menopause because it is again related to oestrogen. Women can lose up to 20% of their bone density in the 5 to 7 years after the menopause.
- The drop in bone density is caused by falling levels oestrogen, which impairs the normal cycle of bone remodelling, i.e. increases amount of bone resorbed (osteoclastic activity) over the amount deposited (osteoblastic activity), leading to net loss of bone.
- Although bone density decreases at the menopause, the risk of osteoporosis and fractures stays relatively low until women get much older, because bone density is only one of the things that affects bone strength.
- There are lots of factors involved, e.g. weight-bearing exercise, how active women are etc. Sometimes, it doesn’t manifest until they retire (when they slow down).
- Weight-bearing exercise does not necessarily include lifting weight; it can be using body strength against yourself, e.g. active yoga can be good for bones.
- Treatment option include the use of bisphosphonate compounds, maintaining calcium and Vit.D levels, weight bearing exercises
