Class 2 anovulation - Hormone disturbance - Investigations for underlying cause

Class 2: normogonadotrophic anovulation Normal FSH, LH, Estradiol Investigations: - Provera withdrawal test positive - pelvic ultrasound to exclude PCOS - Provera withdrawal test negative - endometrial/ outflow tract problems/ anatomical anomalies: i) 3D USG/ MRI pelvis ii) USG renal tract (common embryonic origin) iii) laparoscopy/ hysteroscopy

JC 106 (O&G) - Climacteric symptoms Flashcards by Max Kam

Define primary and secondary amenorrhea

Primary - Absence of menstruation by age 16

Secondary - Absence of menstruation for 6 months in a woman with previous menstruation

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6 major groups of causes of amenorrhea

Physiological

Disorders of hypothalamus/ CNS

Disorders of pituitary

Disorders of ovary

Disorders of outflow tract and/ or uterus

Androgen insensitivity syndrome (AIS)

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List physiological causes of amenorrhea

Pre-pubertal
Pregnancy & lactation
Postmenopausal

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List CNS/ hypothalamic causes of Amenorrhea

CNS effect, e.g. weight loss, over-exercise, stress, eating disorders (e.g. anorexia nervosa)

Kallmann’s syndrome (X-linked/autosomal recessive hypogonadotrphic hypogonadism)

Idiopathic hypogonadotrophic hypogonadism

Tumours, e.g. craniopharyngioma causing growth hormone deficiency

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List pituitary causes of amenorrhea

Sheehan’s syndrome (severe postpartum hemorrhage causing hypopituitarism)

Prolactinomas (suppress GnRH secretion, inhibit gonadotrophins (FSH, LH)

Non-functioning adenoma

Iatrogenic: surgery, radiotherapy

Other endocrinopathies:
 Hyperprolactinaemia (e.g. prolactinoma)
 Thyroid dysfunction (TRH also regulates the synthesis and release of prolactin)
 Congenital adrenal hyperplasia

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List ovary causes of amenorrhea

Premature ovarian insufficiency
 Gonadal agenesis/ dysgenesis: chromosomal/ non-chromosomal
 Iatrogenic: surgery (bilateral oophorectomy), radiotherapy to pelvis, chemotherapy
 Autoimmune

Polycystic ovary syndrome (ovaries are working but hormonal disturbance)

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Clinical diagnostic criteria for PCOS

Rotterdam consensus: 2 out of the 3 criteria

1) Oligo-anovulation
2) Clinical/ biochemical hyperandrogenism

3) Sonographic features of polycystic ovaries:
 Follicle number per ovary of >20; and/or
 An ovarian volume >=10ml

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List outflow tract/ uterus causes of amenorrhea

Outflow tract obstruction
 Cervical/ vaginal atresia
 Transverse vaginal septum
 Imperforate hymen

Absence of vagina/ uterus

Endometrial destruction:
 TB endometritis
 Asherman’s syndrome (severe intrauterine adhesions, usually following surgery, e.g. suction, evacuation)

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Features of Androgen insensitivity syndrome (AIS)

Androgen receptor mutation in 46XY:
 Non-virilisation of genitalia - female phenotype
 Undescended gonads
 No axillary/pubic hair
 Some breast development (peripheral conversion of androgen into oestrogen)

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Clinical presentation of outflow tract/ uterine obstruction

primary amenorrhea with cyclical abdominal pain (due to distension)
pelvic mass, endometriosis (due to backflow of period)

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Approach to primary amenorrhea

Indication for investigation
Which conditions to rule out

Investigate by age 14 if no secondary sexual characteristics (low estrogen levels)

Must rule out:
 Outflow tract obstruction
 Absence of uterus
 Disorder of sex development:
 AIS
 Swyer syndrome (46,XY but mutant SRY)
 All causes of secondary amenorrhoea occuring before first period

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Outline history taking questions for amenorrhea

 Onset, duration

Menstrual history:
 Previous menstruation (1o or 2o)
 Pubertal development (growth spurt, age, pubic/axillary hair, breast)

Ddx:
 Menopausal symptoms (hot flushes, vaginal dryness, premature ovarian insufficiency)
 Nutrition, stress, weight change (hypothalamic)
 Galactorrhoea, headache, visual disturbance (pituitary)
 Thyroid symptoms (hyper or hypo)
 Hyperandrogenic symptom (acnes, hirsutism, male-pattern balding)
 Family history of genetic diseases

Iatrogenic causes:
 Past medical history (chemotherapy, radiotherapy, surgery)
 Drug history (long-term medications)

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Outline P/E for amenorrhea

General:
 Body height/ weight, calculate BMI - PCOS risk
 Stigmata of chromosomal abnormalities

Sexual characteristics:
 Hirsutism/ virilisation
 Secondary sexual characteristics
 Genital tract development (observe introitus, external genitalia; imaging if needed)

Associated endocrine dysfunction:
 Goitre
 Galactorrhoea, visual field

Abdominal mass (pregnancy, PCOS, undescended testes)

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First-line investigations for amenorrhea

Pregnancy test (always rule out pregnancy)

Hormonal profile: FSH, LH, E2, PRL, TFT, testosterone

Progestogen (Provera) challenge test (give a course of progestogen for a week then stop):

Positive result (i.e. gets period after): estrogen production is normal in the body giving endometrial thickness
Negative result (i.e. no period after progestogen): endometrial lining quite thin, hence low estrogen

USG pelvis

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WHO classification of anovulation

Define the hormonal disturbance in each class

Class 1 hypogonadotrophic hypogonadism - Hypothalamic/ pituitary causes

Low FSH, LH
Low Estradiol
or high prolactin

Class 2: normogonadotrophic anovulation - Uterine outflow obstruction
- Normal FSH, LH and Estradiol

Class 3: hypergonadotrophic hypogonadism - Ovarian dysfunction

High FSH, LH
LOW Estradiol

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Class 1 anovulation

Hormone disturbance
Investigations for underlying cause

Class 1: hypogonadotrophic hypogonadism

Low FSH, LH, Estradiol
Or high prolactin

Investigations:
- Visual field perimetry
- MRI to exclude tumour in hypothalamus/ pituitary stalk lesion
- +/- dynamic test: GnRH stimulation test for pituitary function

Thyroid function (hypothyroidism, High TSH induce Prolactin)
Renal function test (Renal failure = decrease PRL clearance, increase dopamine excretion)
Pelvic USG - PCOS
Genetic test: PRLR mutation

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Class 2 anovulation

Hormone disturbance
Investigations for underlying cause

Class 2: normogonadotrophic anovulation
Normal FSH, LH, Estradiol

Investigations:
- Provera withdrawal test positive - pelvic ultrasound to exclude PCOS

Provera withdrawal test negative - endometrial/ outflow tract problems/ anatomical anomalies:
i) 3D USG/ MRI pelvis
ii) USG renal tract (common embryonic origin)
iii) laparoscopy/ hysteroscopy

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Class 3 anovulation

Hormone disturbance
Investigations for underlying cause

Class 3: hypergonadotrophic hypogonadism
High FSH, LH but low estradiol

Suspect premature ovarian insufficiency (POI)

Confirm diagnosis: FSH >25 IU/L twice over 4 weeks apart

Genetic tests:
i) Karyotype (primary amenorrhoea): Turner syndrome, disorders of sex differentiation (ambiguous genitalia, absent uterus)
ii) Fragile X premutation

Autoimmune screening: anti-thyroid Ab, anti- adrenal Ab vs ovaries

MRI pelvis: Structural lesions (Ovarian cancer, Iatrogenic damage…etc)

DXA scan (risk of osteoporosis)

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Investigations for significant virilization/ hirsutism/ raised testosterone

Test for androgens:
 SHBG/ sex hormone binding globulin
 17-OH progesterone (if raised = congenital adrenal hyperplasia)

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Test for low estrogen levels

Negative progestogen challenge/ Estrogen and progesterone withdrawal test

Withdrawal with no bleeding = low endogenous estrogen level

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Treatment of amenorrhea: Hypogonadotrophic hypogonadism

Hypothalamic functional causes: lifestyle (stress, eating disorder, excessive exercise), reassurance and observe, psychological treatment
Neurosurgery for hypothalamic-pituitary lesions
Estrogen therapy for primary amenorrhea and induce puberty
Maintenance HRT (E+P) against osteoporosis
Exogenous gonadotrophins for fertility issue (e.g. Follitropin, Lutropin a)

Treatment of PCOS

Weight reduction (restore ovulation + prevent metabolic disorder in long term)

Menstrual regulation to prevent endometrial hyperplasia/CA due to unopposed estrogen:

Periodic progestogen for withdrawal bleeding
Combined OC pills

Hirsutism:

Combined OC pills
cosmetic measures (laser, shaving)
anti- oestrogens (spironolactone)

Fertility:
 Letrozole (1st line)
 Gonadotrophin
 Laparoscopic ovarian drilling

Treatment for premature ovarian insufficiency

Primary amenorrhea: estrogen to induce puberty

Maintenance HRT (E+P) against osteoporosis until age 51

Fertility:
Oocyte donation
Adopt children

Treatment for hyperprolactinaemia

 Dopaminergic drugs e.g. bromocriptine, cabergoline

 Neurosurgery (rarely)

Treatment for outflow tract/ uterine obstruction causing amenorrhea

Surgical correction of congenital anomalies/ outflow tract obstruction (e.g. vaginal dilation for vaginal atresia)

Define climacteric and menopause

Climacteric: - the years of waning ovarian function - Marks the transition from the reproductive to the non-reproductive state Menopause: - a specific event (the final menstrual period) - diagnosed retrospectively after cessation of menses for 12 months in previously cyclical women - permanent cessation of ovarian function and fertility

Define the time period for perimenopause

 Begins with the first clinical, biological and endocrinological features of the approaching menopause  Ends 12 months after the final menstrual period  Can last for several years post-menopause = after perimenopause

Define 3 clinical types of menopause

Natural menopause - Clinically diagnosed in retrospect following spontaneous amenorrhoea for 12 months - without other obvious pathological/ physiological cause (mean age 51 years) Artificial/ induced menopause - Sudden termination of menstrual life due to surgery/ radiotherapy/ chemotherapy Premature ovarian insufficiency - Loss of ovarian function before age 40 yrs

Hormonal changes at menopause

Decline in number of ovarian follicles - Decrease Estradiol - Decrease inhibins and loss of negative feedback >> Increase FSH and LH >> stimulates ovarian stroma to produce androgens >> peripheral conversion to estrone

List 4 major categories of climacteric symptoms

Vasomotor symptoms Psychological symptoms Sexual dysfunction Urogenital atrophy

List vasomotor symptoms due to menopause

 Hot flushes  Sweating  Palpitation  Dizziness

List psychological symptoms due to menopause

```  Loss of energy and drive  Loss of concentration  Irritability  Anxiety  Depression  Mood fluctuations  Sleep disturbances ```

List sexual dysfunctions due to menopause

 Dyspareunia (atrophic change) |  Decreased libido (Can be multifactorial)

List urogenital atrophy symptoms due to menopause

``` Vagina:  Dryness  Burning  Pruritus  Dyspareunia  Prolapse ``` ``` Urinary:  Urgency  Frequency  Dysuria  Urinary tract infection  Incontinence  Voiding difficulties ```

Long-term health problems in menopause

Cardiovascular disease: loss of estrogen protective effect on vasculature and lipid profile Postmenopausal osteoporosis: loss of estrogen causing compromised bone strength, fractures Musculoskeletal degeneration: Laxity of soft tissue, poor muscular strength, Backache, joint pains Dementia, cognitive decline

WHO criteria for osteoporosis severity Name 1 clinical tool for fracture risk assessment

BMC or BMD below the young adult mean for women by: Normal <1 SD Low bone mass 1-2.5 SD Osteoporosis >2.5 SD Severe osteoporosis >2.5 SD And the presence of >1 fragility fractures FRAX tool – takes other risk factors of fracture into account in clinical management

Clinical definition for diagnosis of menopause Any tests for onset of menopause?

Clinical diagnosis in healthy women >45 years who have amenorrhoea for 12 months Tests: No biological marker High FSH for some years before menopause

General lifestyle management for menopause

``` Lifestyle modification  Smoking cessation  Air conditioning  Dress in layers  Avoid alcohol and spicy food  Reduce obesity  Reduce stress (counseling) ```

Outline management plan for menopause

``` A. Lifestyle modification B. Cardiovascular risk assessment and management C. Cancer screening and prevention D. Hormone replacement therapy (HRT) E. Non-hormonal treatments for symptoms ```

Hormone replacement therapy (HRT) for menopause - Benefits - Risks

Benefits  Effective for severe climacteric symptoms  Slow progression of atrophic symptoms (topical oestrogen)  Prevent/ delay bone loss, lower risk of vertebral & non-vertebral fractures ``` Risks:  Carcinoma of breast  Venous thromboembolism  Stroke  Gallbladder disease ```

Hormone replacement therapy (HRT) for menopause - Dosage - Contraindications

Use lowest possible dose for shortest possible duration for symptom relief ``` Contraindications:  Severe liver disease  Oestrogen-dependent tumours e.g. breast, uterus  Deep vein thrombosis, embolism  Cerebrovascular disease  Undiagnosed uterine bleeding ```

Regimens of Hormone replacement therapy (HRT) for menopause

With uterus: Oestrogen and progestogen (prevent endometrial hyperplasia/CA) - Sequential (cyclical) – add Progestogen for 12-14 days/cycle for scheduled bleeding - Continuous = non-bleeding regimen (suitable for >2 years post-menopause Without uterus/ hysterectomy: - Estrogen only

HRT for menopausal women - Drug options

Oestrogen types: 1) Natural oestrogens (preferred): - E.g. 17β-oestradiol (Estrofem®), conjugated equine estrogens (Premarin®) - Preparation: oral, transdermal patch, gel Implant, vaginal ring 2) Phytoestrogens Progestogen types: 1) Oral progestogen 2) Mirena® - levonorgestrel-releasing intrauterine system (IUCD) Tibolone - synthetic compound: converted to metabolites with oestrogenic, progestogenic actions

Definite benefit, risks of estrogen only HRT

Benefit - reduce hip fracture Risk - Stroke Neutral/ conflicting: - Venous thromboembolism - CRC - CHD - Invasive breast cancer

Definite benefit, risks of combination E+P HRT

Benefit: - Reduce hip fracture - Reduce CRC Neutral - Endometrial cancer Risks: - Invasive breast cancer - Venous thromboembolism (VTE) - Stroke - Coronary heart disease (CHD) if administered after age 60-70

HRT for menopausal women - Withdrawal method - SIde effects

Withdrawal: Tapering vs. abrupt stop (no proven difference in clinical outcome) Side effects: breast tenderness, fluid retention, bloating, nausea, headache, irregular bleeding

Outline non-hormonal treatments for vasomotor climacteric symptoms

 Clonidine, gabapentin  Relaxation  Lifestyle modifications

non-hormonal treatments for psychological climacteric symptoms

 Psychological counselling/ therapy  Anti-depressants

non-hormonal treatments for vaginal atrophy in climacteric symptoms

 Lubricants, moisturisers

non-hormonal treatments for cardiovascular climacteric symptoms

Lifestyle:  Exercise  Avoid smoking Control predisposing factors: HT, DM, hyperlipidaemia, obesity

non-hormonal treatments for osteroporosis after menopause

Lifestyle:  Calcium, vit D  Weight-bearing exercise  Avoid smoking/ excessive alcohol/ caffeine Selective estrogen receptor modulator e.g. raloxifene Bisphosphonates RANK ligand (denosumab)