O&G JC106: Climacteric Symptoms: Menopause And Related Illness, Amenorrhoea Flashcards
Hypothalamic-Pituitary-Ovarian axis (HPO axis)
Hypothalamus –> GnRH
–> Pituitary –> FSH, LH
–> Ovary –> Estrogen (-ve feedback)
–>
1. Growth of dominant follicle in the beginning of Follicular phase
2. Thickening of endometrial lining
LH surge
–> Ovulation
–> ↑ Progesterone level
Amenorrhoea
Definition:
- Absence of menstrual period in a woman of reproductive age
- A symptom, NOT diagnosis (∵ many causes)
- Primary vs Secondary
Primary amenorrhoea:
- Absence of menstruation by age **16 (if presence of normal secondary sexual characteristics)
(Investigate by age **14 if no secondary sexual characteristics: indicate low Estrogen level)
—> Congenital / Genetic abnormalities
—> Disturbance of normal endocrinological events of puberty
—> ALL causes of Secondary amenorrhoea can also present as primary amenorrhoea if occur early enough
Secondary amenorrhoea:
- Absence of menstruation for ***6 months in a woman who has menstruated before
(Oligomenorrhoea:
- Have period but Cycle length >35 days
- Investigations / Management similar to Secondary amenorrhoea ∵ lots of overlap)
Causes of Amenorrhoea
- Physiological
- Pre-pubertal
- Pregnancy + Lactation
- Post-menopausal
- Contraceptives - Pathological (in HPO axis)
Endocrine:
- Hypothalamus / CNS disorders
- Pituitary disorders
- Ovary disorders
- Thyroid disorders (Hyper / Hypo)
- Adrenal disorders (Tumour, Cushing’s, CAH)
Anatomical:
- Outflow tract obstruction
- Uterus disorders (e.g. absence of uterus)
- Endometrial damage (e.g. Asherman’s syndrome)
Hypothalamus / CNS disorders
Not enough GnRH secreted
1. Functional hypothalamic amenorrhoea (CNS effect)
- weight loss
- over exercise
- stress
- eating disorders (e.g. anorexia nervosa)
- systemic illness
- ***Kallmann syndrome
- congenital hypogonadotrophic hypogonadism (isolated GnRH deficiency) associated with anosmia - Idiopathic hypogonadotrophic hypogonadism
- Tumours e.g. ***Craniopharyngioma
- Cranial irradiation
Pituitary disorders
Hyperprolactinaemia:
1. ***Prolactinoma
2. Non-functioning adenoma (stalk effect)
3. Other causes of Hyperprolactinaemia (prolactinoma may be a cause)
Hypopituitarism:
1. ***Sheehan’s syndrome
- follow severe post-partum haemorrhage (∵ severe hypotension –> severe hypovolaemia –> ischaemia + necrosis of pituitary –> hypopituitarism following delivery)
2. Iatrogenic: Surgery / RT
Other endocrinopathies:
1. Thyroid dysfunction (Hyper / Hypo)
***Causes of Hyperprolactinaemia (SpC O&G)
- ***Pregnancy, Lactation
- Stress (transient)
- ***Prolactinoma
- Other pituitary tumours, non-functioning “disconnection” tumour —> disrupt inhibitory influence of Dopamine on Prolactin
- ***Primary hypothyroidism
- Drug inhibiting Dopamine secretion
- **Dopaminergic antagonist
- Phenothiazine (+ Other Typical antipsychotics)
- **Domperidone
- ***Metoclopramide
- Cimetidine
- Methyldopa
Ovary disorders
- Primary ovarian insufficiency (POI) (loss of function of ovaries ~ menopause; In contrast to PCOS (ovaries are actually working))
- **Gonadal agenesis / dysgenesis
—> ∵ chromosomal / non-chromosomal problems (e.g. **Turner syndrome / variant, **Fragile X premutation (but not full blown Fragile X))
- **Iatrogenic
—> Surgery: Bilateral oophorectomy for ovarian tumours
—> RT to pelvis
—> Chemotherapy
- ***Autoimmune
- Idiopathic - Polycystic ovary syndrome (PCOS)
- Androgen-secreting ovarian tumour (rare)
Polycystic ovary syndrome (PCOS) (多囊卵巢綜合症)
- Disorders of ovary (but ovaries are working vs Ovarian insufficiency)
- Endocrine disturbance –> Oligo / Anovulation
Diagnosis (**Rotterdam criteria, 2 out of 3):
1. Oligo-anovulation
2. Clinical / Biochemical hyperandrogenism (e.g. hirsutism, ↑ acnes)
3. Sonographic features of polycystic ovaries (Follicle number per ovary **>=20, each 2-9mm / Ovarian volume ***>=10ml, String of pearls sign) (ONE ovary is sufficient for definition)
Exclusion of other etiologies with similar clinical features:
- Thyroid disorders
- Hyperprolactinaemia
- POI
- Hypogonadotrophic hypogonadism
- **Non-classic CAH
- **Cushing’s syndrome
- ***Adrenal tumours (androgen-secreting (self notes))
- etc.
Long-term health sequalae of PCOS:
1. **Metabolic syndrome (HT, DM, HL, CVS disease)
2. **Infertility (∵ anovulation)
3. ***Endometrial hyperplasia / cancer (∵ unopposed estrogen)
Outflow tract / Uterus disorders
End organs in which hypothalamic, pituitary, ovarian hormones act on
1. Outflow tract obstruction (at different levels, generally congenital –> primary amenorrhoea usually)
- **Cervical / Vaginal atresia
- **Transverse vaginal septum
- **Imperforate hymen
S/S:
- **Cyclical abdominal pain (∵ trapped period –> distension)
- **Pelvic mass
- **Endometriosis (∵ backflow of period)
- Vagina / Uterus absence
- Endometrial destruction leading to obstruction
- **TB endometritis
- **Asherman’s syndrome (intrauterine adhesions following surgery e.g. suction, evacuation, myomectomy) –> causes problems e.g. infertility, amenorrhoea, recurrent miscarriage
(Congenital abnormality in Mullerian development (i.e. uterus):
- Isolated defect (absence / hypoplasia of uterus)
- Androgen insensitivity syndrome
- 5α-reductase deficiency
Congenital defect of Urogenital sinus development (i.e. outflow tract):
- Agenesis of lower vagina
- Imperforate hymen
Damage to endometrium:
- Asherman syndrome
- TB endometritis)
Androgen insensitivity syndrome (AIS)
Androgen receptor mutation
- ***46XY (in a girl) (I.e. born a male, but phenotype girl)
- Androgen receptors resistant to androgens
- Testosterone: High-Normal / Slightly elevated male range
- Estradiol: Upper normal male range
S/S:
1. Primary amenorrhoea
2. Female external genitalia (∵ Non-virilisation of genitalia –> Female phenotype)
3. Undescended gonads
4. No axillary / pubic hair
5. Some breast development (∵ peripheral conversion of androgen –> estrogen)
6. Inguinal masses / hernia
7. Absent uterus (AMH: Anti-mullerian hormone)
8. Short vagina
Associated health problems:
1. Testicular malignancy
2. Hypoestrogenism (after gonadectomy)
Treatment:
1. HRT (after gonadectomy (remove testes))
2. Fertility: Child adoption
3. Sexuality: Vaginal dilation / reconstruction (let the male live as a female instead)
Summary of causes of Amenorrhoea
Primary amenorrhoea:
- MUST rule out:
1. Absence of uterus / outflow tract obstruction / disorders of sex development (AIS, Swyer syndrome)
2. All causes of secondary amenorrhoea (∵ can cause primary amenorrhoea if occurs before they have first ever period)
Secondary amenorrhoea:
- Women MUST have had:
1. Patent lower genital tract
2. Endometrium that is responsive to ovarian hormone stimulation
3. Ovaries that have responded to pituitary gonadotrophins
–> ∴ can rule out congenital causes
***History taking of Amenorrhoea
- Onset + Duration
- Previous menstruation (determine primary / secondary amenorrhoea)
- ***Pubertal development
- growth spurt and age it occurred
- development of pubic / axillary hair / breast - ***Nutrition, Stress, Weight change, Excessive exercise
- indicate hypothalamic cause - ***Galactorrhoea, headache, visual disturbance
- indicate hyperprolactinaemia / prolactinoma - ***Menopausal symptoms
- e.g. hot flushes / dryness –> indicate POI - ***Thyroid symptoms
- hyper / hypothyroidism - ***Hyperandrogenic symptoms (e.g. Adrenal tumour, Androgen-secreting ovarian tumour, Cushing’s, PCOS)
- e.g. ↑ acne, hirsutism, male pattern baldness - Congenital symptoms
- ***Anosmia (Kallmann syndrome) - ***Anatomical symptoms
- Cyclical abdominal pain
- Urinary retention - Past medical, surgical
- previous OG history, cervical smear, fertility wish
- previous chemo, RT, surgery (POI)
- previous **ovarian surgery, dilatation, curettage (Asherman’s syndrome)
- previous *PPH (Sheehan’s syndrome) - Sexual history
- ***pregnancy - Drug history
- long-term medications
- ***contraceptives - Social history
- Family history
Rmb: ALWAYS rule out ***pregnancy! (∵ commonest cause of amenorrhoea in reproductive age women!)
***Physical examination of Amenorrhoea
- Body height, weight, BMI (compare with previous BMI)
- ***Stigmata of chromosomal abnormality (Turner syndrome)
- ***Galactorrhoea, visual field
- ***Goitre, Thyroid signs
- **Cushingoid features / **Hirsutism / Virilisation (Ferriman-Gallwey hirsutism scoring system: 9 body areas most sensitive to androgen (score 0-4))
- ***Secondary sexual characteristics
- Abdominal mass
- Genital tract development / PR exam
- clitoromegaly (sign of hyperandrogenism)
- pubic hair distribution + maturity (Tanner stage for pubic hair)
- swelling of introitus (outflow tract obstruction)
- hymen
- vaginal length
- presence of cervix / uterus / ovaries
- may be difficult to assess in patients not been sexually active –> inspect introitus, genitalia, imaging
Rmb: ALWAYS rule out ***pregnancy! (∵ commonest cause of amenorrhoea in reproductive age women!)
***Investigations of Amenorrhoea
1st line:
1. ***Pregnancy test (exclude pregnancy!!!)
-
**Hormonal profile
- **FSH, LH —> check HPO axis
- **Estradiol —> check HPO axis
- **Prolactin —> exclude hyperprolactinaemia
- ***Testosterone —> (<5: PCOS, >5 more likely androgen-secreting tumour)
- TFT —> exclude thyroid disorders -
**Progestogen challenge test (Provera withdrawal test) (通經藥)
- give progestogen for 1 week
–> withdrawal bleeding (+ve test) –> sufficient Estrogen in body resulting in sufficient endometrial thickness –> when progestogen withdrawn –> shedding of endometrium –> amenorrhoea is due to **Anovulation
–> no withdrawal bleeding (-ve test) –> insufficient Estrogen in body (∴ thin lining) or Anatomical problems - ***USG pelvis
- Uterus / Ovarian morphology (e.g. PCOS) / presence / absence
Other investigations (depending on cause)
5. Hormonal
- **Androgens (SHBG, 17-OH progesterone –> CAH) (if significant virilisation / hirsutism)
- **E+P withdrawal test (when -ve progestogen challenge test –> if now +ve (有翻bleeding) –> indicate low endogenous Estrogen level rather than Anatomical problems)
- Dynamic tests: e.g. GnRH test for pituitary function
- Genetic
- ***Karyotype (Primary amenorrhoea, POI) (e.g. Turner syndrome)
(if suspect primary amenorrhoea / disorders of sex differentiation ∵ ambiguous genitalia, absent uterus)
- Fragile X premutation (POI) - Radiological
- 3D USG pelvis / MRI / USG renal tract (∵ common embryonal origin as pelvic organ –> examine whether there is co-existing congenital urinary tract problem) –> examine congenital uterine abnormality
- **Pituitary imaging
- **CT adrenal glands - Visual field by perimetry
- Laparoscopy / Hysteroscopy
- if suspect congenital uterine problem - Autoimmune screening (for POI)
- Anti-thyroid Ab (Anti-TPO)
- Anti-adrenal Ab
***Diagnostic approach to Amenorrhoea
Presented with amenorrhoea
–> History + P/E + **Pregnancy test
–> Negative
–> **Hormonal profile (FSH, Estrogen, Prolactin, TFT, **Provera (Progestogen) withdrawal test)
–>
1. FSH ↑ –> **POI –> Karyotype / Fragile X / Autoimmune functions
- FSH ↓ –> ***hypogonadotrophic hypogonadism –> MRI to exclude hypothalamic / pituitary tumour
- FSH normal
–> Withdrawal +ve –> Pelvic USG to rule out **PCOS
–> Withdrawal -ve –> **Endometrial / Outflow tract problems - Prolactin ↑ –> MRI to exclude ***pituitary tumour
- TFT abnormal –> Refer physician
Anovulation
WHO classification:
Class 1: Hypogonadotrophic hypogonadism (hypothalamic / pituitary problems)
- ↓ FSH / LH
- ↓ E2
Class 2: Normogonadotrophic anovulation (e.g. ***PCOS)
- Normal FSH / LH
- Normal E2
Class 3: Hypergonadotrophic hypogonadism (e.g. ***POI)
- ↑ FSH / LH
- ↓ E2
Principles of treatment of Amenorrhoea
Rmb: Amenorrhoea is a symptom! (NOT diagnosis)
1. Need to look for underlying cause + treat accordingly
2. Rmb **physiological causes e.g. Pregnancy
3. **Hormone replacement?
4. Treat **sexuality issues?
5. Treat **fertility issues?
6. Prevent + treat associated ***health problems
Treatment of Hypogonadotrophic hypogonadism
- Environmental causes
- lifestyle (avoid stress, eating disorder, significant weight loss, over exercise)
- reassurance + observe
- psychological treatment - Primary / Secondary amenorrhoea without obvious external cause
- **Pituitary imaging
- **GnRH stimulation test - Visual field perimetry
- for hypothalamic / pituitary lesions - ***Neurosurgical treatment
- for hypothalamic / pituitary lesions - Induction of puberty in Primary amenorrhoea
- Estrogen (start slow, go slow) - Protect bone if after puberty / induction of puberty
- Maintenance ***HRT (Estrogen + Progestogen) (except for transient secondary causes) - Fertility treatment
- ***Gonadotrophin injections to induce ovulation
***Management of Polycystic Ovary Syndrome (PCOS)
- Weight reduction (Diet control + Exercise)
- ∵ Often obesity associated
- Beneficial in help restoring ovulation + improve metabolic disorder - Menstrual regulation (∵ Oligo/Anovulation –> No corpus luteum –> ↓ Progesterone –> unopposed Estrogen –> ↑ risk of endometrial hyperplasia / CA)
- **Cyclical progestogen (given for 1 week every 2-3 months) –> induce **withdrawal bleeding + **endometrial protection
- **COC pills -> induce **normal menstruation + **contraceptive effect + ***endometrial protection - Hirsutism
- COC pills (risk of thromboembolism esp. overweight women)
- Cosmetic measures (e.g. laser therapy, shaving)
- **Anti-estrogens (*Anti-androgen?? (self notes)) (Spironolactone) - Fertility
- Ovulation induction
—> 1st line: **Letrozole (Aromatase inhibitor) / **Clomiphene citrate
—> 2nd line: **Gonadotrophin / **Surgical (e.g. laparoscopic ovarian **drilling)
—> 3rd line: **IVF
- Weight reduction - Metabolic disorder in the long-term
- Healthy lifestyle
- Monitor BMI, BP, **OGTT, **Lipid profile
(From JC111:
- Letrozole: Aromatase inhibitor —> ↓ Estrogen from Testosterone conversion —> ↓ suppression of FSH —> allow maturation of follicle)
- Clomiphene: Anti-estrogen acting at Hypothalamus —> ↓ -ve feedback (self notes) —> ↑ GnRH pulse frequency (wiki) —> ↑ FSH, LH —> ↑ Ovulation
- Gonadotrophin: FSH+LH / Recombinant FSH injections, Acts directly on ovaries + very effective, High risk of ***OHSS)
Premature Ovarian Insufficiency (POI)
Diagnosis:
- ***↑ FSH >25 twice (>=4 weeks apart in age <40)
Investigations:
1. Karyotype (Turner syndrome)
2. Fragile X premutation
3. Autoimmune tests
- Anti-thyroid Ab (Anti-TPO)
- Anti-adrenal Ab
4. DXA scan
- look for osteoporosis (∵ higher risk)
Treatment:
1. Induction of puberty if Primary amenorrhoea
- ***Estrogen
- Maintenance **HRT (Estrogen + Progesterone) for bone protection (till **51)
- Fertility treatment
- ***Oocyte donation
- Adoption
Other endocrinopathies
- ***Thyroid disorder
- ***Hyperprolactinaemia
- Dopamine agonists e.g. Bromocriptine, Cabergoline
- Neurosurgery (rarely) - ***Congenital adrenal hyperplasia (CAH)
Anatomical anomalies
Diagnosis:
- 3D USG
- MRI pelvis
- ***Laparoscopy / Hysteroscopy
–> Identify location / types of anomaly –> treat accordingly
Investigations:
1. Assess associated renal tract anomalies by imaging
Treatment:
1. **Surgical correction of congenital anomalies / outflow tract obstruction
- Hymenotomy / Cruciate incision for imperforate hymen
2. Treat fertility / sexual issues depending on cause
3. **Vaginal dilation (if vaginal atresia) for sexual life
Climacteric and Menopause
Climacteric:
- years of waning ovarian function
- a period of time which marks transition from reproductive to non-reproductive state
Menopause:
- a specific time-point / event (**final menstrual period)
- permanent cessation of ovarian function and fertility
- diagnosed retrospectively after cessation of menses for **12 months in a previously cycling woman
Perimenopause:
- period beginning with the first clinical, biological, endocrinological features of approaching menopause
- ends 12 months after final menstrual period
- may last for several years
Clinical types of menopause
- Natural menopause
- clinically diagnosed in retrospect following spontaneous amenorrhoea for 12 months
- without other obvious pathological / physiological causes
- mean age 51 yo - Artificial / Induced menopause
- sudden termination of menstrual life due to surgery / RT / chemo - Premature ovarian insufficiency
- loss of ovarian function before 40 yo
Endocrine changes at menopause
↓ Ovarian follicle number
1. ***↓ Estradiol
- ↓ Inhibins
–> Loss of -ve feedback
–> ↑ FSH + LH
–> ↑ LH stimulates ovarian stroma to produce **androgens
–> peripheral conversion to **estrone
Climacteric symptoms
Associated with low estradiol level
- Vasomotor symptoms
- **hot flushes
- **sweating
- palpitation
- dizziness - Psychological symptoms
- **loss of energy and drive
- loss of concentration
- **irritability
- anxiety
- depression
- mood fluctuations
- ***sleep disturbances - Sexual dysfunction
- **Dyspareunia (∵ low estrogen –> atrophic changes)
- **↓ Libido
Can also be multi-factorial (apart from menopause) –> Bio-psycho-social factors
- Urogenital atrophy
Vaginal
- ***dryness
- burning
- pruritus
- dyspareunia
- prolapse
Urinary
- urgency
- ***frequency
- dysuria
- UTI
- incontinence
- voiding difficulties
Long-term health conditions in Post-menopause
- ***CVS disease
- incidence ↑ after menopause
- ∵ estrogen probably protective to vasculature + favourable effect on lipid profile - ***Osteoporosis
- estrogen deficiency –> bone loss
- postmenopausal osteoporosis an important risk factor for fracture (+ loss in muscle mass –> weakness –> instability) - Musculoskeletal
- laxity of soft tissues + ↓ muscle strength
- backache + joint pain - Dementia + cognitive decline
Osteoporosis
Skeletal disorder characterised by compromised bone strength predisposing a person to ↑ risk of fracture
Bone strength determined by:
1. Bone density
2. Bone quality
WHO criteria:
Normal: BMD <1 SD (below young adult mean for women)
Low bone mass: 1-2.5 SD
Osteoporosis: ***>2.5 SD
Severe osteoporosis: >2.5 SD + presence of >=1 fragility fractures
Fracture risk assessment + clinical management:
- FRAX tool: take into account other risk factors
Diagnosis of menopause
- ***Clinical diagnosis
- Retrospective diagnosis
- Healthy women >45 yo with amenorrhoea for ***12 months
- No adequate biological markers
–> **FSH ↑ some years before menopause
–> High FSH may be **supportive in special circumstances (2 FSH test 6-8 weeks apart, persistently high confirm menopause (SpC FM))
Management principles of Menopause
- Holistic bio-psycho-social approach for the general health of a post-menopausal woman
- Management of menopausal symptoms
- Prevention of chronic health conditions
Health considerations:
1. **Bone health
2. **CVS risk assessment + management
3. Smoking cessation
4. Alcohol use moderation
5. Cancer screening + prevention
Management of Menopause
- Lifestyle modification (to reduce hot flushes)
- **air conditioning
- dressing in layers
- **avoid alcohol / spicy food
- reducing obesity
- ***reducing stress -
**HRT
- effective for treatment of severe climacteric symptoms + improve QOL
- notes other psychosocial issues
- prevent / delay **bone loss, ↓ both vertebral + non-vertebral fractures
- **topical estrogen for **atrophic symptoms - Non-hormonal treatments
Vasomotor symptoms: - ***Clonidine
- ***Gabapentin
- Relaxation / lifestyle modifications
Mood symptoms:
1. ***Psychological therapy
2. Anti-depressants
Vaginal atrophy:
1. Lubricants for intercourse
2. ***Moisturisers
Osteoporosis:
1. Lifestyle e.g. Ca, Vit D, weight bearing exercise, avoid smoking / excessive alcohol + caffeine
2. SERM e.g. Raloxifene
3. ***Bisphosphonates
4. RANK-L inhibitor e.g. Denosumab
CVS health:
1. Lifestyle e.g. exercise, avoid smoking
2. ***Control of predisposing factors e.g. HT, HL, DM, obesity
HRT regimens
Without uterus: Estrogen alone
With uterus: Estrogen + **Progesterone
- prevent endometrial hyperplasia / CA from unopposed estrogen
1. **Cyclical
- Estrogen daily –> add Progesterone for 12-14 days per cycle for scheduled withdrawal bleeding
- Novofem, Femoston (SpC FM)
-
**Continuous
- Daily administration of Estrogen + Progestin (web)
- Non-bleeding regimen
- more suitable for women **>2 years of menopause
- Premique, Activella, Kliogest (SpC FM) - Tibolone
- synthetic compound
- converted to metabolites with estrogenic + progestogenic + some androgenic properties
Types of HRT
- Estrogen type
- Natural estrogen preferred e.g. ***17β-estradiol (Estrofem), conjugated equine estrogens (Premarin)
Preparations:
- **Oral
- **Gel
- Transdermal patch (not available in HK)
- Implant (not available in HK)
- Vaginal ring (not available in HK)
- Progestogen type (**still need to take estrogen as well!!!)
- **Oral
- ***Mirena IUCD (levonogestrel-releasing intrauterine system) - Phytoestrogens
- Evidence conflicting
- Limited data on role + safety in long-term post-menopausal health
- Beware of unregulated preparations
Principles of prescribing HRT
- **Lowest possible dose for **shortest possible duration for symptom relief
- No universal rule, tailored to individual’s condition and needs
- Special situation: POI
- HRT till ***51
- no ↑ CA breast risk than general population
Risks of HRT
- ***CA breast
- ***Venous thromboembolism
- ***Stroke
- Gallbladder disease
(5. CHD (some data suggestive benefits in CHD prevention if administered before 60 / within 10 years of menopause))
but no ↑ long-term risks (except stroke) on women without uterus on estrogen-only HRT
CI:
1. **Severe liver disease
2. **Cerebral vascular disease
3. **DVT, embolism
4. **Estrogen-dependent tumours e.g. breast, uterus
5. Undiagnosed uterine bleeding
Monitoring of HRT
- Annual monitoring for continued need
- Well-women check-up as usual
- SE: breast tenderness, fluid retention, bloating, nausea, headache, irregular bleeding –> usually transient
- Bleeding pattern
- report ***unscheduled bleeding promptly if occur after 3 months - Cessation
- tapering vs abrupt stop –> no proven difference
- ***symptom recurrence
HRT vs COC (SpC OG)
Both suitable for replacement of hormone
HRT:
- Dosage of estrogen, progesterone mimic endogenous level —> No contraceptive effect
COC:
- Dosage of estrogen, progesterone higher than endogenous level —> Contraceptive effect
