Menopause

Question 1

What is the Menopausal transition?

Answer 1

Menopausal transition: Period of time from changes in menstrual pattern to menopause

Question 2

What is Menopause?

Answer 2

Menopause: The permanent cessation of menstruation due to loss of ovarian follicular function (amenorrhoea for 12 months)

Question 3

What is Perimenopause and premature ovarian failure?

Answer 3

Perimenopause: No consistent definition. A period of changing ovarian function which precedes the menopause by 2-8 years
Premature ovarian failure: menopause <40

Question 4

What does Menopause mean for women?

Answer 4

WHO defines natural menopause as at least 12 consecutive
months of amenorrhea not due to physiological/pathological causes.
Natural event reached upon exhaustion of primordial follicles
 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
 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 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
Effective health care support should be individually tailored to
all aspects of the menopause when women feel particularly
vulnerable

Question 5

What is fertility determined by?

Answer 5

Fertility is determined by ovarian reserve. The ovarian reserve will determine the rate of decline
of NGF & age of the menopause

Estimated that
for 95% of
women by 30yrs
only 12% of
max. pre-birth
NGF population
is present and
by 40yrs only
3% remains.

Question 6

Life of eggs

Answer 6

Changes in the number of germ cells in the
human ovary during fetal development and
throughout postnatal life.

Question 7

Perimenopausal period:

Answer 7

The ovarian reserve will determine the onset of
subfertility to sterility and to complete loss of menstrual
cycles – the menopause

Question 8

Factors affecting ovarian reserve:

Answer 8

Nutrition (uw/ow)
In utero environment
Genetic abnormalities, some medications, injury
androgens/pcos
ethnicity/geography
autoimmunity
genetics

SMOKING: IF MOTHER SMOKES SHE CAN AFFECT OVARIAN RESERVE OF BABY GIRL

Question 9

Factors affecting ovarian reserve:

Answer 9

Nutrition (uw/ow)
In utero environment
Genetic abnormalities, some medications, injury
androgens/pcos
ethnicity/geography
autoimmunity
genetics

SMOKING: IF MOTHER SMOKES SHE CAN AFFECT OVARIAN RESERVE OF BABY GIRL

Question 10

AMH & Ovarian reserve

Answer 10

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

Levels of AMH decreases in boys and men as they age

IN women, AMH is detect in post-menopause women, declines with age becuase of a decline in follicles

Question 11

AMH come from?

Answer 11

Small preantral to antral follicle
- produced from granulosa cells

> 45pmol/L: PCOS
<15pmol/L: low ovarian reserve

Question 12

Declining levels of AMH with age. AMH secretion from
growing follicles. What happens to levels of Inhibin B and FSH as
approach peri-menopause? Link between AFC, AMH, Inhibin B and FSH.

Answer 12

Rise in FSH (due to loss of negative feedback)
Decline in Inhibin B (inhibin is produced by growing follicles/ grnaulosa cells, follicles decrease so inhibin B also decreases)

Question 13

Can AMH predict ovarian
reserve?

Answer 13

Women with higher AMH, menopause at an older age than women with low AMH

Question 14

Are AMH levels are becoming the gold-standard biomarker to evaluate
ovarian reserve and predict ovarian response to hormonal stimulation?

Answer 14

Measurements of AMH and AFC are used to diagnosed premature ovarian failure/insufficiency

used in IVF to predict ovarian response to hormonal stimulation

Question 15

Homronal changes during menopause

Answer 15

Ovarian senescence begins near 35 years, ends with menopause ~51 years

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

Rise in FSH – loss of negative feed back
Decline in inhibin B and AMH

Decline in androgen synthesis in adrenal glands and
ovaries (substrate is lost)

Marked decline in fertility after age of 35 although
this depends on ovarian reserve

Question 16

Age vs Hormonal Levels

Answer 16

Approximate average serum concentrations
of estradiol, estrone, FSH, LH, and total
testosterone during the menopausal
transition and post-menopause.

Drop in ____

Question 17

Dynamics of Perimenopause

Question 18

Ovary reserve depleted <1000 follicles

Answer 18

Begin Menopause

Question 19

Menopausal symptoms and their onset

Answer 19

Steep oestrogen decrease causes:

Climateric complaints
Vaginal wall atrophy
Urge incontinence
skin atrophy
Stress incontinence
Osteoporosis
Atherosclerosis
Complaint manifest
Latent Period

Question 20

Estimated prevalence of menopausal symptoms: Pre-Menopause, Peri-menopause and post menopause

Answer 20

Hot flashes and night sweats: 14 – 51% 35 – 50% 30 – 80%
Vaginal dryness: 4 – 22% 7 – 39% 17 – 30%
Sleep disturbance:16 – 42% 39 – 47% 35 – 60%
Mood symptoms: 8 – 37% 11 – 21% 8 – 38%
Urinary symptoms: 10 – 36% 11 – 21% 8 – 38%

Question 21

Hot flushes and night sweats

Answer 21

Experienced by approximately 80% menopausal women, can
last up to 5-13 years though number of episodes decrease with
time

Measuring frequency most objective way of assessing severity
of menopausal symptoms

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

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 (rare cancer of adrenal medulla) & mastocytosis (accumulation of mast cells in tissues including the skin)

Question 22

Osteoporosis in Menopause

Answer 22

Women can lose up to 20% of their bone density in
the 5 to 7 years after the menopause (www.nhs.uk).
 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.
 Treatment option include the use of bisphosphonate
compounds, maintaining calcium and Vit.D levels, weight
bearing exercises

Question 23

Genitourinary Syndrome of Menopause (GSM)

Answer 23

GSM – relatively new term for the condition.
Previously known as vulvovaginal atrophy,
atrophic vaginitis or urogenital atrophy.

Chronic, progressive, vulvovaginal, sexual and
lower urinary tract condition characterised by
a broad spectrum of signs and symptoms

GSM more accurately describes the post-
menopausal hypoestrogenic state of the
genitourinary tract.

Can have a significant impact on quality of life
Treatment aimed at symptomatic relief.
GSM for BSSM

Question 24

POI

Answer 24

Premature ovarian failure
(POF)/insufficiency (POI)
Defined as cessation of ovarian function
before 40 years
Affects 1:100 women before 40 years of age and
1:1000 women before 30 years of age

Question 25

Various causes of premature ovarian
failure/insufficiency

Answer 25

Gonadal dysgenesis
Automimmune (Anti-ovaria antibodieS)
Oncologic treatment
Viral infections e.g. mumps
Vaccination
Congenital enzymatic deficiencies (e.g. galactosemia)
UNKNOWN (idiopathic)Up to 50% of all
cases
Genetic

Question 26

Investigating POF

Answer 26

Hypergonadotrophic-hypogonadism
Low estradiol (<20 IU/l)
Elevated FSH (>20 IU/l)
Low AMH levels (< 0.5 ng/ml)
Low inhibin B levels
Assessed day 3 of the menstrual cycle

Question 27

Symptoms and treatment of POF (premature ovarian failure)

Answer 27

Symptoms are those similar to those observed at
a normal menopause. Loss of oestrogen
e.g. oligomenorrrhea, hot flushes, sweating, nervousness, skin
changes, mucous membrane dryness  decreased bone mineral
density (osteoporosis), metabolic changes, CVD, urogenital atrophy
and early mortality
Treatment: HRT
 Combined oral contraceptive pill (but contain
higher doses of steroids)

Question 28

Long term consequences and treatment of premature menopause

Answer 28

Adverse effects on health and mortality

HRT can lessen some of these risks but not all

Provide HRT at least until natural age of
menopause

Psychological aspects of early menopause

Individualising treatment both in terms of HRT
and the psychological impact

Question 29

Treatment of menopausal symptoms

Answer 29

Menopausal hormone therapy (MHT/HRT)

Plant-based, bioidentical hormones

CBT plus relaxation techniques

Neurokinin B (NKB) antagonists in Phase 2 clinical trials (Menopause 2020 27(5):498-
505; also 27(12):1350-1356)

Non-Hormonal prescription medications (but not as useful as MHT)

Bisphosphonates for bone density

Regular exercise and good diet
To maintain bone strength and reduce weight and hence risk of various pathologies

Question 30

MHT/HRT

Answer 30

Tablets, skin patches, gels and implants to
replace oestrogen

Vaginal oestrogen creams/lubricants/moisturisers

Question 31

Plant based, bioidentical hormones

Answer 31

unregulated & no evidence of effectiveness

https://thebms.org.uk/publications/consensus-
statements/bioidentical-hrt/

Question 32

CBT plus relaxation techniques

Answer 32

To help with low mood and anxiety

Question 33

Non-Hormonal prescription meictaion (not as useful as MHT)

Answer 33

e.g SSRI (selective serotonin reuptake inhibitors)

Question 34

Neurokinin B (NKB) antagonists in Phase 2 clinical trials

Answer 34

 For treatment of hot flushes
 NKB hypothalamic neuropeptide involved in GnRH secretion and thought to stimulate activity of the vasomotor centre, resulting in hot flushes

Question 35

Regular exercise and good diet

Answer 35

To maintain bone strength and reduce weight and hence risk of various pathologies

Question 36

HRT/ MHT tretaments (slide 28)

Question 37

Three large studies – 1990’s to early 2000’s

Answer 37

1. Heart and Estrogen/Progestin Replacement Study (HERS)
   (CCEPT in postmenopausal women with CHD):
   HERS ended after 4.1 years due to risks
2. Women’s Health Initiative (WHI) (healthy postmenopausal
   women):

Prospective, randomised, double-blind, placebo-controlled studies of continuous-
combined estrogen progestin therapy (CCEPT) or CEE only

Evaluated only one hormone combination; no perimenopausal women

WHI was stopped at 5.2 years –increased risk of breast cancer

3. Million women study – started recruiting participants in 1996 to
   investigate effect of use of HRT amongst other things.

Study includes 1 in 4 women in UK born between 1935 and 1950

Participants sent postal resurvey questionnaires every 3-5 years.
http://www.millionwomenstudy.org/introduction/

Question 38

Impact of clinical trials

Answer 38

The press had a field day
and the prescribing of HRT
fell dramatically after
publication of these results
But the press always use
the most alarmist statistics
Absolute versus relative

Question 39

WHI: risks and benefirs of CCEP compared to placebo relative vs absolute risks

Answer 39

(get info from slide 31)

Question 40

The tides began to change again when data from
the studies were re-evaluated and analysed

Answer 40

Subsequent re-examination of the data from the WHI and
Million Women study showed certain flaws in interpretation and study designs and that risks of the

WHI study were not statistically significant apart from
venous thrombosis and ischaemic stroke

The follow up from the WHI trials showed benefits for the
use of MHT in younger women (50-59 years) have
decreased coronary disease and all causes of mortality

• Have we come full circle?
• Should MHT become part of a prevention strategy at the onset of the menopause?

The tides began to change again when data from the studies were re-evaluated and analysed

NICE recommends its use for menopausal symptoms!

Question 41

BENEFITS OF HRT

Answer 41

Symptom control
Skeletal benefit
Decreased CHD ( recently menopausal women)
Breast Cancer (E alone)

Question 42

Risks of HRT

Answer 42

Venous thrombosis
Stroke
Breast Cancer (E+P)
Gallstones
Dementia (E+P)

Question 43

Menopause and Society

Answer 43

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 back ground and attitudes
toward a sex life determine women’s experience of
the menopause

Campaigning by women resulted in recent publication
(Oct.2022) of all-party parliamentary group on menopause report. Five key recommendations:
1. Funding research into benefits of HRT
2. Ensuring doctors are trained
3. Scrapping prescription charges for HRT in England
4. National drug formulary for HRT
5. Summoning all women aged 45 to GP to discuss menopause