Menstrual Cycle (Normal Physiology,Menopause and Pre-menstrual dysphoric syndrome)) Flashcards
Name the two phases in the menstrual cycle
Follicular phase
Luteal phase
Average length of menstrual cycle?
28 days.
What pituitary axis controls the menstrual cycle?
Hypothalamus-pituitary-gonadal axis
Describe how the female HPG axis works
- Hypothalamus secretes GnRH
- GnRH travels down anterior pituitary gland and bind to receptor on gland
- This promotes release of LH and FSH from the anterior pit
- LH and FSH travel in blood stream to the ovaries
- LH and FSH bind to the ovaries, stimulating production of oestrogen and inhibin.
- Increasing levels of oestrogen and inhibin have negative feedback effect on hypothalamus and anterior pit
- This leads to decreased production of GnRH, LH< FSH.
- This results in decreased production of oestrogen and inhibin.
Name hormones involved in menstrual cycle
GnRH, LH, FSH, Oestrogen, Progesterone, Inhibin, activin
Describe release of hormones in female HPO axis
Pulsatile manner
Why is HPO axis in females pulsatile?
- Persistent presence of GnRH would lead to desensitisation of its receptors on gonadotrophs (in ant pit gland).
- So FSH and LH production would cease
- Gonadal steriod production would cease
What type of feedback do oestrogen, progesterone and inhibin have on pituitary and hypothalamus?
NEGATIVE
Describe the early follicular phase (days 0-5 of the menstrual cycle)
No ovarian hormone production (i.e no oestrogen and inhibin made)
Granulosa cells (endocrine cells in ovary) secrete activin
* This incerases FSH production, and have increase FSH receptors on granulosa cells
* Reduced production of androgens by theca cells at this point (so less oestrogen is made).
Collectively, this increases FSH levels, so:
* to stimulate follicle growth
* theca interna appears
* enhanced aromatase function –> so the follicle is now capable of enhanced oestrogen production
The follicle with the most FSH = the dominant follicle - sometimes called Graafian follicle.
Dominant Follicle/Graafian follicle’s granulosa cells switch from producing activin to producing inhibin
Describe the late follicular phase (days 5-14 of the menstrual cycle)
Dominant follicle/Graafian follicle granulosa cells** produce oestrogen and inhibin **
Oestrogen:
* Increases FSH receptors on the follicle (so the dominant follicle continues to grow)
* Initially exert negative feedback to reduce FSH production
* Increases LH receptors on granulosa cells to prep for ovulation
Inhibin:
* **Reduces FSH **production
* Helps LH to increase theca cells androgen production (androgens are converted to oestrogen)
Oestrogen and inhibin continue to rise.
How is FSH important in the production of oestrogen?
FSH enhances the function of aromatase.
Aromatase converts androgen –> oestrogen
Describe what happens in the ovulatory phase (day 14)
Oestrogen rises (independent of FSH)
High levels of oestrogen exert positive feedback on the hypothalamus and anterior pituitary
Results in a surge in LH production
There is no rise in FSH, due to presence of inhibin
Granulosa cells start secreting **progesterone **
How do high levels of LH change the membrane of the Graafian follicle?
Membrane becomes thinner.
Follicle ruptures releasing oocyte
What happens after follicle rupture? (but before luteal phase begins)
Secondary oocyte matures into mature ovum
Mature ovum is released into peritoneal space
It is taken into the fallopian tube via the fimbriae.
Describe the luteal phase of the menstrual cycle
Starts once ovulation has occured.
LH and FSH now stimulate remaining Graffian follicle to develop into corpus luteum (i.e. follicle is luteinised)
Corpus luteum produces progesterone (also secretes oestrogen and inhibin but that’s not as important)
Oestrogen and progesterone exert **negative feedback on LH **
Levels of FSH and LH fall, so corpeus luteum dedgenerates.
Degeneration of corpus luteum results in loss of progesterone production.
Falling progesterine levels** trigger mensturation** - then we are back to start of early follicular phase!
In the luteal phase, progesterone levels increase. What does this result in?
- Endometrium becoming receptive to implantation of blastocyst
- negative feedback causing decreased LH and FSH
- increase in woman’s basal body temperature
Which hormones are needed to maintain corpeus luteum?
FSH and LH
(That’s why when they fall in the luteal phase, the C.L degenerates)
What happens if an ovum is fertilised?
ie. what hormones, what happens to corpeus luteum
Fertilised ovum produced hCG, which has similar function to LH
hCG prevents degeneration of corpus luteum = get continued production of progesterone
Continued production of progesterone = prevent menstruation
What takes over role of corpus luteum from ~8 weeks gestation
Placenta
What are the three phases of the uterine cycle?
Menstrual
Proliferative
Secretory
Name for inside lining of uterus?
Endometrium
What are two layers of endometrium?
Functional layer
basal layer
Describe the growth of the functional layer of the endometrium
Grows thicker in response to oestrogen
Is shed in menstruation
Describe the basal layer of the endometrium
Forms the foundation from which the functional layer develops
(is not shed!)
What happens during the proliferative phase of the uterine cycle?
a) think about the hormones involved
b) how do those hormones affect the endometrium
Endometrium is exposed to increases levels of oestrogen (as LH and FSH have stimulated its production)
Oestrogen stimulates repair and growth of the functional layer
This allows recovery from recent menstruation
What is endometrium made up of?
Epithelium + stroma
When does the secretory phase of the uterine cycle begin?
Once ovulation has occured
Describe what happens in he secretory phase
a) name hormone(s) involved
b) what happens as a result?
Driven by progesterone produced by the corpus luteum
Results in secretion of substances from endometrial glands - so uterus becomes ready for embryo implantation
Describe the menstrual phase of the uterine cycle (i.e how the period comes about)
At the end of the luteal phase the corpus luteum degenerates.
Loss of corpus luteum results in decreased progesterone production
Reduced progesterone levels cause the spiral arteries in he functional layer of the endometrium to contract
This causes a loss of blood supply to this layer, so the functional endometrium becomes ischaemic and necrotic.
As a result, the functional endometrium is shed and exits through the vagina as menstruation.
In what phase of the menstrual cycle is oestrogen highest?
Follicular phase
In what phase of the menstrual cycle is progesterone highest?
Luteal phase
What are the actions of oestrogen in a woman’s health?
Both in menstrual / uterine cycle and other effects on the body
- Thickens endometrium
- fallopian tube function (increases function of cilia of epithelial cells to waft oocyte along tube)
- growth and motility of myometrium (middle layer of uterus, endometrium is innermost, perimetrium is outermost)
- Thin alkaline cervical mucus
- Vaginal changes
- Changes in skin, hair and metabolism
What are actions of progesterone in a woman’s health?
Both in menstrual / uterine cycle and other effects on the body
- further thickening of the endometrium
- thickening of mymoetrium and reduction of motility
- Thick, acidic cervical mucus
- Development of breast tissue
- increased body temp
- metabolic changes
- electrolyte changes
What factors can cause disruption to the menstrual cycle?
Physiological - pregnancy, lactation
Emotional stress
Body weight
Infertility
What should be asked in a menstrual history? (not gynaecological history)
Duration of periods
* average 5 days
Frequency
* how often?
* are they regular?
* predictable
Menstrual blood flow
* Ask about volume
* are they heavier than usual?
* are you flooding sanitary towels
* are you passing blood clots larger than 10p coin?
* do heavy periods impact on day to day life?
* any abnormal bleeding patterns? intermenstrual, post-coital
Menstrual pain/ dysmenorrhoea
* Painful periods interfere w/ day to day life?
* more painful than usual?
Date of LMP
* if late, consider preg test
Age at menarche
* how old when they started periods
* early? increased risk od breast cancer and cardiovascular disease.
Menopause (if relevant)
* age of onset
* ask about perimenopausal sx - hot flushes, vaginal dryness
Define premenstrual syndrome
NICE cks:
a condition characterized by psychological, physical, and behavioural symptoms occurring in the luteal phase of the normal menstrual cycle (that is, the time between ovulation and onset of menstruation)
Define premesntrual dysphoric disorder
NICE cks:
A severe form of PMS occuring when a woman sufferes from at least 5 out of 11 distinct psychological premenstrual symptoms, one of which must include mood
The symptoms must strictly occur in the luteal phase of the menstrual cycyel and must be severe enough to disrut daily functioning
What psychological symptoms are experienced in PMS?
- mood swings
- irritability
- depressed mood
- anxiety
- feeling out of control
- poor concentration
- change in libido
- food cravings.
What physical symptoms are experienced in PMS?
- breast tenderness
- bloating
- headaches
- backache
- weight gain
- acne
- gastrointestinal disturbance
What behavioural symptoms are experienced in PMS?
- reduced visio-spatial and cognitive ability
- aggression
- increase in accidents
Differenetial Diagnosis for PMS?
- Depression
- Anxiety and panic disorders
- Hypothyroidism
- Anaemia
- Dysmenorrhoea
- IBS
- Interstitial cystitis
- Endometriosis
- Chronic fatigue syndrome
- Fibromyalgia
- SLE
What lifestyle advice should you give women presenting with PMS?
(regardless of severity)
- Regular, frequent, small, balanced meals rich in complex carbs
- regular exercise
- regular sleep
- stress reduction
- smoking cessaton
- alcohol restriction
How to manage pain symptoms of PMS?
Prescribe simple analgesic - paracetamol or NSAID
How to manage PMS when the main symptom is breast pain (cyclical)?
- reassure there is no serious underlying pathology
- offer written info on cyclical breast pain - on NHS website
- Conservative - well fitted bra, keep pain diary
- Oral paracetamol/ NSAID or topical NSAID as required
- Consider referral to breast specialist if pain is severe enough to affect QofL or sleep and does not respond to 1st line treatment after 3 m (breast specialist is likely to offer danazol and tamoxifen)
How to manage moderate PMS?
Consider COC
* more evidence to support use of Yasmin
* Current data suggest using continuously rather than cyclically
Arrange referral for CBT
How to manage severe PMS?
Consider SSRI
* take continuously or just during luteal phase
* initial trial of 3 months
* monitor closely
* inform ADRs of SSRIs
Arrange referral for CBT
Review at 2 months in to assess effectiveness of treatment
Describe social burden of PMS dysphoric syndrome
- disrupt parenting
- disrupt partner relationships
- decreased productivity in work roles - fail to meet professional standards
- time off work
- isolating - as takes over social life
- impact on sex life
- changes to diet and alcohol intake
Define menopause
Menopause is a biological stage in a woman’s life when menstruation stops permanently due to the loss of ovarian follicular activity.
It occurs with the final menstrual period and is usually diagnosed clinically after 12 months of amenorrhoea [NICE, 2019].
Define perimenopause
Perimenopause, also called the ‘menopausal transition’ or ‘climacteric’, is the period before the menopause when the endocrinological, biological, and clinical features of approaching menopause start.
It is characterized by irregular cycles of ovulation and menstruation and ends 12 months after the last menstrual period [NICE, 2019].
Repro slides Year 2:
Climacteric = phyisiological period in a woman’s life during which there is regression of ovarian function.
Menopausal transition = time between onset of irregular menses and permanent cessation of menstruation; averga dutation is about 4 years
Define postmenopause
Time agter a woman has not had a menstrual period for 12 consectutive months
Define early menopause
The cessation of ovarian function occurring between the ages of 40 and 45 years, in the absence of other causes of secondary amenorrhoea
Define premature menopause
Premature menopause describes definitive loss of ovarian function before the age of 40 years, for example following bilateral oophorectomy
Define premature ovarian insufficiency
Premature ovarian insufficiency (POI, also known as premature ovarian failure) is a clinical syndrome defined as the transient or permanent loss of ovarian function before the age of 40 years, characterized by menstrual disturbance (amenorrhoea or oligomenorrhoea), and potential spontaneous resumption of ovulation, menstruation, and spontaneous pregnancy
What are the 4 categories of the menopausal phase?
- pre-menopause
- peri-menopause
- menopause
- post menopause
Using understanding of endocrinology, describe the changes that occur in the perimenopause
- ovarian follicular activity begins to fall (follicular phase shortens and ovulation occurs early or is absent)
- oestrogen and inhibin levels decrease
- get reduced negative feedback to anterior pituitary
- This causes FSH and LH to rise
- Decreasing oestrogen levels disrupt menstrual cycle.
How long do symptoms last for menopause (on average)?
typically last for 5–7 years, but some women continue to experience symptoms for at least 10–15 years
Regarding the menopause, what are persistent vasomotor symptoms associated with?
- Ethnicity.
- Younger age at menopause.
- Current smoking.
- Weight gain.
- Lower educational level.
Main symptom to suspect perimenopause?
- initial change to menstrual pattern
- menstrual cycle length may shorten to 2-3 weeks or lengthen to many months
- Amount of menstrual blood loss may change, and commonly increases slightly.
Symptoms associated to menopause? (think of them in categories)
Vasomotor symptoms:
* hot flushes/night sweats
* anxiety, palpatations
Cognitive impairment and mood disorders:
* mood swings
* irritability
* cognitive impairment - e.g. brain fog
* mood disorders - low mood, mild depressive symptoms.
* poor concentration
* difficulty in multi-tasking
Urogenital symptoms and altered sexual function:
* vulvovaginal irritation
* discomfort
* burning
* itching
* dryness
* dyspareunia
* dysuria
* urianry frequency + urgency
* recurrent UTIs
* vaginal dryness
* loss of sexual desire and libido
Sleep disturbance:
* hot flushes and night sweats
* mood disorder affecting sleep
* insomina
Other:
* joint and muscle pains
* headaches
* fatigue
Describe characteristics of hot flushes that would be suggestive of menopause
- sudden feeling of heat in upper body - face, neck and chest
- Spreads upwards and downwards
- can become generalised
- lasts 2-4 mins
- excessive sweating
- palpatations and anxiety alongside it
Potential triggers for hot flushes?
Spicy food
Alcohol
How can hot flushes affect QofL?
Disturb day to day
embarrasing
distressing
How can you distinguish between low mood in menopause and depression?
low mood in the menopause is mild depressive symptoms that impair quality of life but are usually **intermittent **and often **associated with hormonal fluctuations **in the perimenopause).
Depression - during the last month, have been bothered by feeling down, depressed, or hopeless
During the last month, have been bothered by having little interest or pleasure in doing things?
Regardless of changes with hormones
How is perimenopause diagnosed?
Woman has vasomotor symptoms
AND
irregular periods
How to diagnose menopause in a healthy woman?
if the woman has not had a period for at least 12 months (and is not using hormonal contraception)
Serum FSH measurenments are not routinely used to diagnose menopause. What patient factor(s) need to be present to do a serum FSH test?
- Aged over 45 years with atypical symptoms.
- Aged between 40–45 years with menopausal symptoms, including a change in menstrual cycle.
- Younger than 40 years with a suspected diagnosis of premature ovarian insufficiency (POI).
- Over 50 years of age using progestogen-only contraception, including depot medroxyprogesterone acetate (DMPA).
If FSH level is in premenopausal range:
1. when should FSH levels be rechecked?
2. what should woman do if sexually active?
- in one year
- contine using contraception
Features in Hx that would lead you to suspect premature ovarian insufficiency?
- younger than 40yrs
- not taking COC
- has menopausal symptoms, including no or infrequent periods
AND - elevated serum FSH levels on TWO blood samples taken 4-6 weeks apart
Braindump:
What questions would you ask in Hx for lady who’s PC is ‘i think i am going through the menopause’?
Symptoms of menopause
* nature of them
* frequency
* duration
* time of day
* severity
* impact on QofL
Other causes of amenorrhea:
* pregnant?
Lifestyle:
* smoking
* alcohol
* exercise
* nutrition
Contraception:
* is she on it?
* Does she still need it
Smear:
* when was it last done?
* What was outcome?
FHx:
* premature menopause
* POI
* VTW
* hormone -dependent cancers - breast cancer
Treatment:
* what does she want?
* what has she tried? what was effective? What symptoms can she tolerate?
PMH
DHx
BOne health and risk of osteoporosis.
DDx for PC of irregular vaginal bleeding?
endometrial polyps; uterine fibroids; adenomyosis; endometrial hyperplasia or cancer; and vulval, vaginal, or cervical lesions.
DDx for PC of hot flushes?
Endocrine causes:
* hyperthyroidism
* Phaeochromocytoma
Tumors:
* carcinoid tumour
* pancreatic cancer
* medullary thyroid cancer
* RCC kidney
* lymphoma
* mastocytoma
* mast cell disroders
* paraneoplastic syndrome
Lifestyle:
* excess alcohol
* spicy food in diet
Psychiatry causes:
* anxiety
* panic disorder
Respiratory:
* Tb
Pharmacological causes:
* opiods
* nitrates
* SSRIs
* CCBs
* Levodopa
* GnRH agonists
* anti-oestrogens or selective esotrogen receptor modulators
DDx for vaginal atrophy?
Trauma
Infection
Lichen sclerosis
DDx for urinary incontinence (other than menopause)?
Obesity
Previous gynae surgery complications
multiparity - weak pelvic floor
DDx for loss of libido (other than menopause)?
Endocrine - androgen insufficency, thyroid disorders
Insomina
Inadequate sexual stimulation
Life stresses
Depression
What are postmenopausal women at increased risk of?
- Osteoporosis and fractures
- CVD
- Stroke disease
- Genitourinary syndrome of menopause
What does premature / early menopause put pts at risk of?
All-cause mortality
CVD
T2DM
Depression
Osteoporosis and fractures
What does premature / early menopause put pts at risk of?
All-cause mortality
CVD
T2DM
Depression
Osteoporosis and fractures
What conservative management should you discuss for menopause and prevention of complications?
- seek occi health support in workplace if needed
- Manage CVD RF - smoking cessation, weight loss, diet changes - reduce sugar and salt, increase exercise
- encourage engagement with screening programes - e.g. for bowel cancer
- advise on bone health
For hot flushes:
* regular exercise
* weight loss
* wear lighter clothing
* turn down central heating / sleep in cooler room
* avoid triggers - spicy food, caffeiene, smoking, alcohol
Sleep disturbances:
* avoid exercise late in day
* maintain bed routine
Low mood and anxiety:
* adequate sleep
* regular physical activity
* relaxation exercises
Cognitive symptoms:
* exercise
* good sleep hygiene
HRT formulations available for menopause?
- Tablets
- skin patches
- oestrogen gel
- implants
- vaginal oestrogen
- testosterone
What type of HRT to offer woman with a uterus?
Oral or transdermal combined preparation (of oestradiol plus progestogen)
What options are available for urogenital symptoms of menopause?
- 1st line = low dose vaginal oestrogen
- if not tolerated or contraindicated = trial of oral ospemifene (selective oestrogen receptor modulator)
- vaginal moisturizer and lubricant can be used alone or in addition to the oestrogen prep
What type of HRT to offer woman without a uterus?
Oral or transdermal oestrogen-only preparation
When to arrange 2ww appt for woman over 40-50?
- Sudden change in menstrual pattern
- Intermenstrual bleeding
- Postcoital bleeding
- Postmenopausal bleeding
How long should HRT be used?
As long as benefits of symptom control and improved QofL outweigh any risks, and there is no limit arbitary limit for duration of HRT use.
Risks of HRT?
- VTE
- CHD and stroke
- T2DM
- Dementia
- Breast cancer
Benefits of HRT?
Benefits outweigh risks for most symptomatic women who are under 60 or less than 10 years before they start menopause
- risk of fragility fractures is decreased as it prevents osteoporosis
- improves muscle mass and strength
- most effective treatment for hot flushes and low mood
- can improve sexual desire and reduces vaginal dryness and pain with sex
- reduces urinary symptoms and risk of urine infections (esp when used with topical vaginal preparations)
If a woman does not want to take hormonal therapies, what can be given for vasomotor symptoms? (hot flashes and night sweats)
- Selective serotonin reuptake inhibitors (SSRIs, off-label) or serotonin and norepinephrine reuptake inhibitors (SNRIs, off-label) for 2 weeks initially
* fluoxetine 20mg OD
* citalopram 20mg OD
* Paroxetine 10mg OD
* Venladaxine mod-release - Clonidine - 50micrograms BD for 2 weeks then increased to 75mincrograms BD if needed
- Gabapentin 300mg TDS
- CBT
When should referral to specialist be done for woman with menopausal symtpoms?
- ongoing symptoms and treatments are ineffective
- Persistant troublesome ADRs
- Uncertainity about treatments due to comorbidities or contraindictations
- Persistant altered sexual function and treatments are ineffective
- Sudden changes in menstrual pattern - needs 2ww for specialist.
By describing the difference in the HPO axis in the menstrual cycle and the menopause, explain why there are increased levels of FSH and LH in menopausal women
In menopause, ant pit releases FSH and LH to stimulate the ovary.
However, the ovaries can not produce enough oestrogen and progesterone
This feedsback to the hypothalmus and the ant pit, causing increase in FSH and LH -to try and stimulate the ovaries.
At what age (or age range) can blood tests for diagnosing menopause be done?
can be done at 40-45
Should be done before 40
No blood test needed after 45, just go off symptoms
If a 42year old woman has a blood test done to diagnose menopause:
a) what hormone are we looking at?
b) how many times should this test be done?
c) how many weeks apart should tests be?
a) FSH at more than 40 miu/ml
b) 2 tests need to be done
c) at least 4-6 weeks between the two tests
Natural management of menopausal symtpoms (added as was in BB lec)
- exercises
- running, swimming and yoga are highly recommended
- smoking cessation
- reduced alcohol and coffee intake helps w/ hot flushes and night sweats
- mediterranean style diet
Side effects of hormone therapy for menopause?
BB slides
headaches
breast tenderness
bloating
muscle cramps
irregular bleeding
Which form of HRT has highest risk of VTE developing?
Oral
It is not increased if using patch or gel
A lady does not ant to take HRT as she has read it can cause breast cancer. What would you tell her?
from BB
- HRT with oestrogen alone (if she has no uterus) is associated with little or no increased risk of breast cancer
- Combined HRT with O + P can increase the risk of breast cancer BUT the risk is higher the longer she stays on it. The risk reduces when HRT is stopped - especially after 5 years of stopping HRT
- Risk of breast cancer depends on individual risk factors.
- being overweight
- over 50
- driking 2+ units of alcohol per day
^ these increase breast cancer risk just as much as HRT.
- driking 2+ units of alcohol per day
Types of hormone therapy for menopause?
- Sequential HRT - start within 12m of last period to minimise risk of irregular bleeding patterns
- Continuous combined HRT - not had period for 12m, can get irregular bleed for first 3m
- Tibolone
- Vaginal oestrogen - pessaries or creams to help with vaginal or urinary sx
What are non-hormonal treatment options for women going through menopause?
Bio-identical hormones - from soy and plant extracts –> these are not regulated or licenced in the UK
Herbal medicien - not regulated by medcine authority and safety is unkown.
Vaginal lubricants and moisturiser
Alternative - acupressure, acupuncture, reflexology, homeopathy
Psychological treatment - CBT
Apart from HRT, what other medical treatments are available on prescription for hot flushes?
Clonidine
Gabapentin
SSRIs
Why might androgen therapy be given to a woman in the menopause (note: currently not available on NHS for menopausal Sx!)
From bb
Testosterone producton from ovaries reduces with menopause
This leads to low blood testosterone levels and might be associated with reduced libido and sex drive
