S4: Menopause

Question 1

Common clinical questions patients ask about menopause

Answer 1

I am tired, is this the menopause?
I’m 42 and my periods have stopped why is this?
Can I predict when my menopause will be?
Can I take HRT to boost my energy?
Is HRT safe?
What can I take for symptoms of the menopause?

Question 2

Define menopausal transition

Answer 2

The menopausal transition is the period of time from changes in menstrual pattern to the menopause. it is usually around 4 years although it can be more or can even be zero (menstruation can just stop suddenly).

Question 3

Define menopause

Answer 3

Menopause is the permanent cessation of menstruation due to loss of ovarian follicular function and it is a retrospective diagnosis so one must have amenorrhoea (menstruation stops) for 12 months to be diagnosed.

Question 4

Define perimenopause

Answer 4

No agreed upon definition, generally defined as a period of changing ovarian function that precedes the menopause by 2-8 years.

Question 5

Define premature ovarian failure

Answer 5

Premature ovarian failure is having the menopause under the age of 40 (average age is 51). The first issue associated with this is fertility, the second is osteoporosis at an early age.

Question 6

Describe symptoms of menopausal transition

Answer 6

• Initially there is a reduced menstrual cycle length due to a reduced follicular phase.
• On average, around 4 years before the final menstrual period some women experience irregular periods with episodes of amenorrhoea.
• Common that a year before menopause, women experience hot flushes due to declining oestrogen levels (and sweat a lot as a result) and disturbed sleep caused by the flushes. Hot flushes are a very common feature of menopausal transition, SSRIs do appear to help with them. They are thought to be due to reduced tolerance to ranges in body temperature, so you trigger vasodilation and sweating at temperatures normally experienced.
• Dry vagina is common due to lack of oestrogen which can lead to difficulty with sex.
• More infrequent periods or being amenorrhoeic will impair fertility and even if someone is having regular periods they will also have impaired fertility due to changes in the quality of the eggs.
• Some women will have no symptoms.

Question 7

Why do some individuals experience amenorrhoea during menopause transition?

Answer 7

The individual is amennorrhoeic because of the lack of the corpus luteum. In order to bleed, there must be a built up endometrium, once the progesterone declines the endometrium is shed as prostaglandins cause it to become necrotic. But if there is a thin endometrium and it isn’t vascularised yet, it won’t shed as no progesterone and low oestrogen.

Question 8

Are urinary symptoms and mood changes related to menopause?

Answer 8

• Historically other symptoms have been linked to the menopause such as mood changes. However there is not much evidence they are causative to the menopause rather it may be caused by other life events going on at that age e.g. parents dying.
• Urinary symptoms are not causally related to the menopause, as they have similar prevalence in pre and post menopausal women.

Question 9

Describe the pathological/physiological observations seen at menopause that can explain why it occurs

Answer 9

• By the time a women reaches menopause, she had very few follicles if any at all (reduced follicle count). The reason is not that she had ovulated all of them, rather most of them die. Follicles that are not recruited into the menstrual cycle will die and with those that are recruited, all will die except one very month.
• The granulosa cells also decline in number and function. This has implications on the oocyte in the follicle and the menstrual cycle itself.
• Increased chromosomal abnormality of the oocyte is also seen at this age and there is a decline in occyte function and development.
• Around 14yrs before the menopause there is a very rapid decline in oocytes in the ovaries. The oocyte also depends on various growth factors and at menopausal transition the secretion of growth factors can be impaired and other signalling pathways, survival factors, oestrogen and progesterone.

Question 10

Describe how follicle depletion occurs

Answer 10

• Follicular depletion due to increased follicular death by apoptosis and there is accelerated death in that period 14 years prior to menopause thought to be defects in DNA repair. The ovarian environment is also a factor, smoking reduces the age of menopause on average by 2 years and there is a shorter menopausal transition.
• There is also an accelerated follicular loss by increasing the rate at which follicles are recruited (more recruited, more will die as only one is selected). During uterine life, only male sertoli cells express AMH so mullerian ducts regress. However in an adult women, granulosa cells on preantral follicles also express AMH which inhibits FSH. Granulosa cells ability to produce AMH decreases in menopausal transition and so increased FSH increases follicular recruitment.

Question 11

Describe how decline in granulosa cells is the biggest contributor to menopause

Answer 11

• Older women have 30% less granulosa cells than younger women.
• Decreased AMH produced.
• Inhibin B is another hormone produced by the granulosa cells and in older women approaching menopause there is less Inhibin B produced in the follicular phase. This results in much higher FSH levels (as inhibin b usually inhibits FSH release).
• Not enough oestrogen being produced by granulosa can cause anovulatory cycles which decreases inhibin A (normally in luteal phase) which then allows higher FSH.
• FSH receptors also decrease in number and their sensitivity decreases this can lead to the dominant follicle not being selected.

Question 12

Describe consequence of granulosa cell dysfunction: how it affects the start of menopausal transition

Answer 12

At the start of the menopausal transition, most women will have a shortened cycle this is because:

1. There is a decline in inhibin B production from the granulosa cells (that usually inhibits FSH).
2. This leads to elevated FSH in the follicular phase, causing earlier elevated oestrogen and earlier LH surge.

Question 13

Describe consequence of granulosa cell dysfunction: how it affects the start of menopausal transition

Answer 13

Later on in the menopausal transition, this can change to having delayed ovulation or absent ovulation due to:

1. Oestrogen is stimulated to be released from granulosa by the elevated FSH.
2. However as granulosa cell function is impaired, oestrogen levels although they do rise are not high enough to induce the LH surge. Therefore ovulation is delayed or doesn’t occur as the LH surge is what stimulates ovulation initiation.
3. This often results in heavier periods because there is longer oestrogen stimulation of the endometrium causing it to proliferate. The dominant follicle isn’t recruited so the woman will have consistent heavy bleeding (no progesterone).
4. Also note there is relative FSH insensitivity due to fewer FSH receptors on the granulosa cells, consequently fewer follicles will get recruited and as there is no inhibin A and so FSH rises!

Question 14

What symptoms does mechanism of granulosa cell dysfunction in menopausal transition explain?

Answer 14

• Breast tenderness is also common due to the transient increases in oestrogen.
• Nearing menopause, hot flushes are very common due to a steep decline in oestrogen levels that causes disturbances with serotonin levels. As a result of this, there is resetting of the thermoregulatory nucleus (in the brain stem) and this leads to excess heat loss.
• Heavier periods: Longer oestrogen stimulation of endometrium and oestrogen levels may be higher than in women aged under 35.

Question 15

Describe hormonal profile of a women in menstrual transition and menopause

Answer 15

• AMH declining is generally the first sign of declining ovarian function, but not usually used clinically.
• Inhibin B starts to decline about 2 years before the FMP (final menstrual period).
• FSH levels are quite variable during this time with each cycle, but tend to increase towards the menopause (post menopause FSH will be very high).
• LH also increases but later on in the menopausal transition.
• Oestrogen also starts to fall closer to the menopause and around this time the hot flushes will be experienced.
• Adrenal and ovarian androgens do decline with age (from 20s) but this is not related to the menopause.
• No progesterone is produced after the menopause.

Question 16

Describe decline in oocyte function and development in menopausal transition to menopause

Answer 16

• As well as the problems with the follicles and granulosa cells, there is a decline in function of the oocyte. This is the consequence of impaired production of growth factors/survival factors from the granulosa cells.
• Due to a decreased ability to repair DNA, there is increased aneuploidy so increased Down’s syndrome, Turners, Patau etc. occur in older women.
  Increased oocyte abnormality impairs follicle recruitment, even with clomiphene ( a medication to help).
• Result: in anovulatory cycles and an increased miscarriage rate.

Question 17

List determinants in the large variability in the age of onset of menopause amongst women

Answer 17

• Smoking status.
• Ethnicity.
• Maternal age (onset of menopause by mother and daughter will be similar).
• Several candidate genes (genetic).
• Having gynecological surgery or chemotherapy thought to reduce age of menopause.

Question 18

What are the clinical markers for declining fertility (how women tell when their menopause will be)?

Answer 18

• An easy way is to find out when woman’s mother had her menopause.
• Commonly in clinic, ovarian volume is used to estimate no. of follicles.
• Looking at the ovarian response to stimulation, to see the antral follicles that respond is another way.
• May measure AMH levels, but not usually used. However is useful for planning in IVF.

Question 19

How are hot flushes managed?

Answer 19

• The most unpleasant menopausal symptom is the hot flushes!
• We have used meta-analysis to help work out the best treatments for hot flushes. These generally suggest that oestrogen is the best at reducing hot flushes, however not everyone can take oestrogen due to contraindications. The SSRIs also show good evidence of helping with hot flushes, but they are not recommended as first line treatment by NICE.
• In terms of herbal medicines, black cohosh is an option that is licensed but it is associated with liver problems in rats.

Question 20

Describe when to prescribe HRT (hormone replacement therapy) during menopausal symptoms

Answer 20

Oestrogen is the primary treatment for hot flushes (and vaginal dryness) and has a very high efficacy (80%). Oestrogen replacement = HRT. You should start with a low dose (60% efficacy) and be very patient centred about it.
The woman should be clear about the risks and benefits and a plan should be made for review.

Question 21

Risks of HRT and contraindications

Answer 21

• Individual risks must be considered (e.g. obesity, family history of breast cancer would be a caution to not prescribe HRT).
• The main risks of HRT are breast cancer and thrombosis.
• For women with a uterus, progesterone must be used for 13 days of the month, otherwise just using oestrogen causes endometrial hyperplasia that can turn into endometrial carcinoma. Giving progesterone prevents this and allows shedding (stabilise endometrium to stop over proliferation). Best protection obtained by continuous combined oestrogen and progesterone, though may get break through bleeding and not good for women whose periods have not stopped.
• If a woman has not gone a year with amenorrhoea, the woman should still use contraception as HRT doesn’t guarantee anovulation. Start with low doses to minimise unwanted effects such as mastalgia (breast pain), nausea.
  The risks are very low for short term use of HRT!

Question 22

Describe different methods of administration of HRT for menopausal symptoms

Answer 22

• Clinicians can prescribe oestrogen tablets, patches, subcutaneous implants and gel (patches best at preventing risk of thrombosis).
• Progesterone can be prescribed as tablets, intrauterine devices or patches (combined with oestrogen) or gel.
• The combined oestrogen and progesterone HRT can be given continuously or give cyclical progesterone.
• Tibolone is a synthetic derivative of norethynodrel, which has oestrogenic, androgenic and progestagenic properties.
• In a woman without a uterus (has had hysterectomy), continuous oestrogen can be given on its own.
• If a woman’s only symptom is vaginal dryness, there are vaginal oestrogen creams or rings that can be used.

Question 23

List other uses of HRT in the 1980s. Issues?

Answer 23

In the 1980’s HRT was used to treat hot flushes, but was also used to treat a wide variety of other pathologies such as osteoporosis, prevention of heart disease, improve sex, prevent dementing disorders, prevent feeling tired and irritability.
- HRT use was widespread and used it for a long time. It was encouraged by pharma to prescribe it for unlicensed use. But there wasn’t evidence for it.

Question 24

What is long term use of HRT associated with?

Answer 24

Randomised control trials (2002 - The women’s health initiative study) suggested that long term use was associated with:

• Increased risk of breast cancer.
• Increased risk of pulmonary embolus and venous thrombosis and stroke (thrombotic disease).
• Decreased risk of hip fracture.
• Decreased risk of colorectal cancer.

Question 25

Describe whether HRT can treat Alzheimer, urinary incontinence, ovarian carcinoma.

Answer 25

• No evidence that HRT helps treat Alzheimers.
• Combined HRT increases risk of urinary incontinence and worsens existing problems.
• Small increase in risk of ovarian carcinoma in combined HRT use.

Question 26

Describe HRT use for osteroporosis

Answer 26

To prevent osteoporosis HRT needs to be used continuously without stopping so not a good treatment for osteoporosis (instead use bisphosphonates, calcium etc.). If HRT stopped, bone strength decreases within a couple of years to original pre-HRT state. Alternatives to oestrogen for osteoporosis:

• Biphosphonates
• ? raloxifene (SERM)
• calcium and vitamin D
• Strontium
• Other agents currently being investigated: teriparatide (a peptide fragment of parathormone), simvastatin, leptin, phyto-oestrogens and manipulation of RANKL gene, anti-oxidants.

Question 27

Describe chronic management of menopausal women

Answer 27

• Treat hot flushes.
• Address the smoking.
• Increase physical activity, monitor BMI and nutrition.
• Cardiovascular risk management.
• Do mammography and cervical cytology.

Question 28

Why no randomized control trial of long term use of HRT for so long?

Answer 28

• Flakey understanding of menopause, lack of clarity about symptoms of menopause.
• Flaky science: simple conceptualisation of menopause as a single hormone ‘deficiency’ disease.
• Flaky methodologies: over-reliance on cohort studies.
• Flakey skills: Most doctors didn’t know about methodology of investigation and not trained in critical appraisal.
• Flakey licensing, no long term data required for licensing, HRT was widely used outside its licensed use.
• Flakey education where pharmaceutical companies provided professional education and marketing.

Question 29

Describe horizontal scanning (for HRT in future_

Answer 29

• Micronised progesterone vs synthetic progesterones.
• Interest in bioidentical hormone for future.
• Problem is there is no data around to prove safety, efficacy etc.
• Investigation of genetic loci for age of menopause.
• RCTs looking at ischaemic heart disease in women around the menopause to see if there a reduction in cholesterol.
• ‘Critical period’ theories for IHD and Alzheimers……but…could we ever precisely predict risks for individual women?
• Will another RCT looking at long term outcomes be mounted?

Question 30

Is there treatment for women with premature ovarian failure (premature menopause)?

Answer 30

There is hope, some scientists implanted fragments of ovary near fallopian tube and stimulated follicular development. Then removed eggs and fertilised using IVF. In 27 women there was 1 live birth.