Benign gynae Flashcards
Secondary amenorrhoea
Absence of menses for >6 months in girls or women who previously had regular menstrual cycles
Or 12 months if irregular cycles / oligomenorrhoea (bleeds less frequently than 6 weekly)
Categories (WHO) of ovulatory disorders
Group 1 - 10% Hypothalamic-pituitary failure - Hypothalamic amenorrhoea - Hypogonadotrophic hypogonadism - Low oestrogen, low FSH
Group 2 - 85%
Hypothalamic-pituitary-ovarian dysfunction
- Predominantly PCOS
- Normal oestrogen, Normal FSH, Normal prolactin
Group 3 - 5% Ovarian failure - Hypergonadotrophic hypogonadism - Ovarian insufficiency - Low oestrogen, High FSH
Progestogen / gestogen challenge test
Give progesterone (e.g. provera 10mg / day for 5 days)
- Negative - nothing happens
- Positive - if period happens (usually heavy period) - Got to have oestrogen to have a positive test
More accurate way to assess oestradiol than oestradiol blood test
Positive in anovulation
Hypothalamic-pituitary amenorrhoea
causes
HYPOTHALAMIC
- Low body weight / weight change, stress or exercise-related amenorrhoea
- Craniopharyngioma or other tumours affecting the hypothalamus
- Kallmann’s syndrome
- Idiopathic
- Congenital GnRH deficiency
PITUITARY
Sheehan’s syndrome
Hyperprolactinaemia
Functioning tumours of the pituitary (prolactinoma)
Non-functioning tumours of the pituitary or affecting the pituitary
Brain radiotherapy
Post-pituitary surgery
Work up for type 1 amenorrhoea
Prolactin and TSH
Evidence of oestrogen deficiency?
GnRH challenge test
- To discriminate between hypothalamic and pituitary cause of HH
- If FSH + LH levels increase after GnRH administration, then hypothalamic cause
- Limited benefit as gonadotrophin OI is successful regardless of exact site of dysfunction
Unless apparent cause in history, MRI to exclude tumour
Correct any weight / exercise imbalance
Correction of amenorrhoea is not necessary unless conception desired
Responds very well to GnRH or gonadotrophins if conception needed
- High rate of achieving ovulation (>95%)
Interpreting prolactin results
<500 mu/l -Normal
<1000 mu/l - Consistent with stress or recent breast exam –> repeat
Threshold for imaging: >1500 mu/l on 2 occasions
- MRI or CT
Check TSH, T4, FSH/LH, testosterone, SHBG
- can be raised in hypothyroid and PCOS
Clinical features
of hyperprolactinaemia
Galactorrhoea (up to 30%)
- No correlation with prolactin levels or the presence of a tumour
Headaches
Visual field defects (5%)
- bitemporal hemoanopia due to compression of the optic nerve
Variety of menstrual cycle disturbances (e.g. anovulatory cycles, amenorrhoea)
Pathophysiology of high prolactin
Prolactin is secreted solely by the lactotroph cells of the pituitary gland
Hyperprolactinaemia can be caused:
- Decreased dopamine inhibition of prolactin release
- Increased prolactin production
- Decreased prolactin clearance
Pathological causes of high prolactin
Prolactin-secreting pituitary adenomas
- Microadenomas <10mm
- Macroadenomas >10mm
- Almost all are benign
Idiopathic Hypothyroidism - Raised TSH stimulates lactotrophs Drugs - estrogens, metoclopramide, SSRI, methyldopa, TCA, other psychotropic drugs (haloperidol, risperidone) Renal failure - decreased metabolic clearance Liver cirrhosis - Reduction in estrogen metabolism increases the estrogen concentration - depletion of dopamine
Any disease in or near the hypothalamus or pituitary that interferes with the secretion of dopamine or its delivery
- Tumours of the hypothalamus or pituitary
- Infiltrative diseases (e.g. sarcoidosis)
Physiological causes of high prolactin
Pregnancy Lactation Sleep Stress Chest wall stimulation
Treatment of prolactinomas
Don’t always treat hyperprolactinaemia
Indications for treatment:
- Anovulatory and wishing conception
- Significant tumour
- Symptomatic (e.g. galactorrhoea, headaches)
As hypo-estrogenic state, may affect bone health if untreated in the long term
Once prolactin levels <1000 IU/L, periods usually return
Surgery reserved for large marcoprolactinomas with compression-related symptoms (visual defects) which may not respond to medication
- Complication: pan-hypopituitarism
Meds: dopamine agonists
Medications for hyperprolactinaemia
Cabergoline (Dostinex)
- Initial dose 0.25mg twice weekly, up to 1mg daily.
- side effects: headaches, psych adverse effects (aggression)
- Not licensed for use in pregnancy
- Better than bromocriptine (lower side effect profile and longer acting)
Bromocriptine
- 1.25mg nocte for 5 nights, and gradually up titrate to 7.5mg daily in 2-3 divided doses over about 3 weeks
ommon adverse effects:
- N/v, headache, postural hypotension, vertigo, GI disturbance, psych changes
- 10% of patients have unacceptable adverse effects
Management of prolactinoma in sub fertility
~80% achieve pregnancy on dopamine agonist treatment
No increase in risks of pregnancy complications
- Neither cabergoline or bromocriptine has been a/w an increased risk of miscarriage, congenital malformations
Usually stop dopamine agonist once pregnant
Very low risk of tumour growth with microadenomas (<2%) in pregnancy
Risk if higher with macroadenomas (15-30% if unmedicated)
Review regularly during pregnancy - ask about headaches and changes in vision
- Microadenomas - every 3 months
- Macroadenomas - 2-3 monthly visual field check
Breastfeeding may be undertaken normally
Unless women have visual field impairment - should be treated with dopamine agonist
Incidence of PCOS
6-7% of the population
Conservative estimate - recent data suggests higher, particularly in Aboriginal population
Rotterdam criteria
Clinical and/or biochemical signs of hyperandrogenism
- Calculated free testosterone, free androgen index or calculated bioavailable testosterone
- Consider androstenedione an DHEAS if total or free testosterone are not elevated
- Reliable assessment not possible if on hormonal contraception
- Clinical - Acne, alopecia, hirsutism
Oligo and/or anovulation
- Cycle <21 or >35 days
The appearances on ultrasound of polycystic ovaries
- 20 or more follicles measuring 2-9mm in diameter
- Increased ovarian volume (>10cm3)
Other aetiologies must be excluded
Adolescents and PCOS
In adolescence women (<18y), after 2y of irregular cycles following the onset of menarche, PCOS should be considered and appropriate assessment should be undertaken
- Irregular periods are common in adolescence so don’t do anything until >2y of issues
- Need hyperandrogenism and irregular cycles to make diagnosis
PCO almost normal in this age group
- Don’t scan women <8y post menarche - 68% of women aged 19-21 will have US morphology similar to PCO
- If can’t make diagnosis but suspicious, say “at risk of PCOS”
Delay definitive diagnosis until 21y (RANZCOG revision tutorial)
Clinical features of PCOS
PSYCHOLOGICAL
Anxiety
Depression
Body image
REPRODUCTIVE Irregular cycles Hirsutism Infertility Pregnancy complications
METABOLIC (ESP IF BMI >30) Insulin resistance Metabolic syndrome Prediabetes T2DM Cardiovascular risk factors OSA
Investigations to exclude differentials in PCOS
Lab findings in PCOS
- Normal or high oestrogen
- elevated free testosterone, total and FAI
- reduced SHBG
- increased LH/FSH ratio
- prolactin - usually normal, but can be elevated
If total testosterone levels (>2x normal), virilisation Sx - consider androgen secreting tumours of adrenals or ovaries
–> imaging
If Cushing’s features –> cortisol, DHEAS - dexamethasone suppression test
17-OH progesterone elevated in late onset CAH
Pathophysiology of PCOS
NORMAL: cholesterol converted to androgens in the theca cells under influence of LH and insulin
- Some androgens released into circulation
- Remainder are aromatised to oestrogen in the granulosa cells under the influence of FSH
- This system is regulated by circulating androgens and insulin growth factor
PCOS: Insulin resistance –> insulin augments LH-stimulated androgen production in theca cells
Low SHBG from insulin resistance –> high levels of free testosterone
Uncoupling of the normal mechanism that controls normal androgen flow onward to the granulosa cells
- Mature dominant follicles don’t develop
- Lots of small follicles develop –> Make more testosterone
- Get low progesterone as produce oestradiol only
LH thickens thecal cells in ovaries –> more testosterone
Unopposed oestradiol speeds up GnRH pulses –> make LH increase more than FSH
Implications of PCOS
Insulin resistance Metabolic syndrome Endometrial cancer Anxiety and depression Eating disorders Pregnancy risks Obstructive sleep apnoea - Remains significant even when controlling for BMI - Independent risk factor for CVD Cardiovascular disease
Insulin resistance in PCOS
Increased risk of GDM, T2DM and impaired glucose tolerance, with risk independent of, yet exacerbated by obesity
Lean women with PCOS has a 2-fold increase in incidence of T2DM compared to controls
Australian cohort with PCOS
- Impaired glucose tolerance 15%
- T2DM 4%
RANZCOG - 2h OGTT for screen
- Some authorities recommend screening all women diagnosed with PCOS
- Others recommend if fasting BSL >5.6 mmol/l, BMI >30, strong FHx of GDM, lean women >40y
By age 40, up to 40% of women with PCOS will have T2DM or impaired glucose tolerance
What is metabolic syndrome
Metabolic syndrome:
- Elevated BP >130/85 - Increased waist circumference >88cm - Elevated fasting blood glucose levels - Reduced high density lipoprotein cholesterol levels - Elevated triglyceride levels
Risk for development of CVD
Prevalence in PCOS up to 45%
Endometrial cancer
and PCOS
2-6 fold increased risk
Women with infrequent cycles (no natural period for >3 months) are at risk of endometrial hyperplasia
RANZCOG: if PCOS and oligo or amenorrhoea
- Induction of regular withdrawal bleeds (at least every 3-4 months) is advised using cyclic progestagens for at least 12 days or the COCP
- Mirena is an option
Treatment of PCOS
Lifestyle management
- 5-10% weight loss in those with excess weight yields significant clinical improvements (restore menstrual cycle and lower long term risks)
- Use of bariatric surgery should be considered where obesity is not controlled by lifestyle modifications (BMI >40, or >35 with high-risk obesity related condition)
COCP - limited evidence
- For hyperandrogenism, irregular cycles
- 35 mcg ethinyloestradiol + cyproterone acetate should not be considered first line in PCOS as per general population guidelines - due to adverse effects, including VTE
Metformin
- Routine use not recommended (RANZCOG)
- Role with increased glucose tolerance or T2DM has been diagnosed
- 20-40% get significant GI upset
Anti-androgens
- consider adding to COCP - if after >6 months failed to adequately improve hirsutism
Regular monitoring and assessment of CVD risk
Check HbA1c at diagnosis and then every 1-3y (RANZCOG - 2h OGTT)
Cushing syndrome
- causes
Results from chronic exposure to excess glucocorticoids
CAUSES
ACTH dependent
- Cushing’s disease - ACTH-producing pituitary tumour
- Ectopic ACTH syndrome - E.g. small cell lung cancer
ACTH independent
- Adrenal tumours
- Adrenal hyperplasia
Iatrogenic
- Exogenous steroids
Cushing syndrome
- Clinical presentation
Moon face Bufalo hump Wide purplish striae Proximal muscle weakness Hirsutism HTN
Diagnosis of Cushing syndrome
Exclude exogenous
High testosterone and DHEA
Diagnosis is established when 2+ different first-line tests are unequivocally abnormal
- Late night salivary cortisol - 24h urinary free cortisol excretion - Overnight 1mg dexamethasone suppression test
Effects of Cushing syndrome on pregnancy
Very high rate of pregnancy complications
- Pregnancy loss (40%)
- FGR
- Premature delivery (>50%)
- Neonatal adrenal insufficiency
Maternal morbidity high if untreated
- HTN (up to 70%)
- Diabetes (up to 25%)
- Heart failure
- Severe PET is common (15%)
- Maternal mortality is increased (2-4%)
If previous treated, or treated <20/40, then do well
Late onset adrenal hyperplasia
Unlikely classic CAH, not picked up by newborn screening
Increase in cortisol precursors, which are forced along the androgen pathway
- 17-OH progesterone
ACTH stimulation test to confirm diagnosis
- Response to ACTH is exaggerated in NCCAH
Causes of ovarian failure
Chromosomal
- Most common is Turner syndrome 45X0
- Offer karyotype if amenorrhoea before age 30
- Fragile X
Autoimmune
- Linked to other autoimmune issues, therefore screen
Resistant ovary syndrome
- On biopsy there are oocytes but they don’t respond, but not required because doesn’t change prognosis
Pure gonadal dysgenesis
Androgen-insensitivity syndrome
- Absent ovaries and uterus with a 46XY karyotype
Galactosaemia (carbohydrate metabolism, autosomal recessive)
Premature menopause
Surgical removal
Chemotherapy
Radiotherapy in proximity to the pelvic area
Idiopathic
Investigations of premature ovarian failure
Serum FSH Serum estradiol Serum free testosterone (to rule out PCOS) HCG - rule out pregnancy Serum prolactin TSH +/- thyroid antibodies Autoimmune screen Karyotype - chromosomal analysis should be performed in all women with non-iatrogenic POI - Test for Y chromosome - Fragile X
Fragile X
X-linked disorder
Decreased or absent levels of fragile X mental retardation protein (FMR 1 gene)
Full mutation
- In males causes classical FXS phenotype - developmental delay, intellectual disability, learning disabilities , ADHD, anxiety, autism, Seizures
- Full mutation in girls is much more variable
Premutation
- Spectrum of clinical findings
- Females: 1 in 250-300 in women
- Premature ovarian insufficiency
- Fragile X-associated tremor-ataxia syndrome later in life
- Neurocognitive deficits
Diagnosis
of POI
Spectrum disorder
Menstrual irregularity associated with diminishing ovarian reserve in women <40y
Characterised by menstrual disturbance (amenorrhoea or oligomenorrhoea for >4 months) with FSH levels in the post menopausal range (dependent on lab, >20 IU/l) on two occasions >4 weeks apart
Prevalence 1%
Modifiable factors to reduce POI
Gynaecological surgical practice
Lifestyle - smoking
- No causal r/ship for smoking and POI, but there is in relation to early menopause
Modified treatment regimens for malignant and chronic diseases
Sequelae of POI
Untreated POI –> reduced life expectancy, mainly due to CVD
Fertility
- Small chance of spontaneous pregnancy (5-10%), as varying and unpredictable ovarian function
- Donor oocyte and IVF if required
Reduced BMD
- Estrogen replacement is recommended - e.g. COCP
- Measure BMD at diagnosis of POI
Continue HRT until the age of natural menopause
Annual BP, weight and smoking status
Psychological wellbeing
Sexual and GU function - Topical oestrogen
Cognitive impairment
Hirsutism definition and prevalence
Presence of terminal (coarse) hairs in females in a male-like pattern
Affects 5-15% of women
Usually associated with an underlying endocrine disorder
Three types of hair
Lanugo - soft hair densely covering fetus, shed in first 4/12 PP
- Can be seen in women with disorders that include anorexia nervosa
Vellus hair - soft, longer than lanugo hair (<2cm), non-pigmented, covers the body
Terminal hair - longest, pigmented, makes up hair of eyebrows, scalp, axillary and pubic areas
Phases of hair growth
Impact of hormones
Three phases of hair growth
○ Anagen - active growing phase
○ Catagen - involuting phase
○ Telogen - resting phase, hair is shed
Androgens are the most important hormones regulating hair type, growth and distribution
Causes of hirsutism
Androgen excess
- PCOS (70-80% of women with hirsutism )
- Androgen-secreting tumours
- Late onset CAH
- Cushing’s syndrome
- Drugs - Testosterone, danazol, anabolic steroids
Drugs - Non-androgen factors
- Phenytoin
- Minoxidil - for baldness
- High-dose corticosteroids
Idiopathic hirsutism (6-7%)
Ferriman and Gallwey score
0 = absence of terminal hair 4 = extensive terminal hair growth
Modified score (current one) uses 9 sites - Upper lip, chin, chest, arm, upper abdomen, upper back, lower back, thighs
- Mild 8-15
- 16-25 moderate
- > 25 severe
Issues with Ferriman and Gallwey score
Impact for women doesn’t correlate with scores
- Scoring systems used for research rather than clinical settings typically
Ethnic variation - derived from population study of white women
Most women have been using cosmetic measures by the time they see a clinician, so scores may not be accurate
Intra-observer agreement appears to be relatively good, but inter-observer agreement appears poor
Management of hirsutism
COCP
- reduces free plasma testosterone levels
Cyproterone acetate - strong progestogen, reduces LH
- Wide variation, but expect to lower Ferriman-Gallwey score by 15-40% within 6 months
Spironolactone (androgen inhibitor)
- When used with COCP overall effectiveness improved
- Cochrane review: superior to finasteride and low dose cyproterone acetate for up to 12 months after end of treatment
Finasteride - inhibitor of 5 alpha-reductase enzyme
Definition of PMS
When symptoms cause impairment of daily activities and interpersonal relationships in cyclical fashion usually following ovulation and resolved by menstruation
- Must demonstrate during the luteal phase of the menstrual cycle
Symptoms are not an exacerbation of an underlying psychological or physical disorder
PMS vs. PMDD
The affective and/or somatic symptoms in physiological PMS are bothersome but are not disabling to the woman, whereas they would cause significant impairment of occupational or social function in PMDD
Premenstrual dysphoric disorder (PMDD) diagnosis
Most severe form
Must have 5 / 11 symptoms, one of which must include mood
- Mood swings
- Anger, irritability
Sense of hopelessness,
- Tension, anxiety
- Difficulty concentrating
- Change in appetite
- Diminished interest in usual activities
- decreased energy
- Feeling overwhelmed
- Breast tenderness, bloating, weight gain, joint / muscle aches
- Sleeping too much or not sleeping enough
Luteal phase symptoms
By definition, affective symptoms predominate but most women also have physical symptoms
Must disrupt daily functioning
Pathophysiology of PMS
Revolves around the ovarian hormone cycle
- Reinforced by absence prior to puberty, in pregnancy and after menopause
Two theories
1. Some women are ‘sensitive’ to progesterone
- Abnormalities in neurotransmitters (serotonin and GABA) –> progesterone hypersensitivity
○ Serotonin receptors are responsive to oestrogen and progesterone
No evidence of hormone imbalance
Diagnosis of PMS
Symptoms should be recorded prospectively, over two cycles, using a symptom diary
- Useful comparison for effectiveness of treatment in future
Symptom diary should be completed prior to commencing treatment
GnRH analogues may be used for 3 months for a definitive diagnosis if the completed symptom diary alone is inconclusive
Complementary treatments for PMS
CBT
- Consider routinely
- Better maintenance of treatment effects compared with fluoxetine in one study
- May avoid pharmacotherapy and potential adverse effects
Benefit in trials for
- Calcium, vitamin D
- Vitex agnus castus (herbal supplement)
Some benefit
- Exercise
- Evening primrose
- Acupuncture
Mixed results
- vitamin B6
- Mg
- St John’s wort
Medications for PMS
SSRI - consider 1st line - luteal or continuous dosing - fluoxetine works within 24h Spironolactone - Can treat physical Sx
COCP
- Drospirenone-containing COCP (Yasmin)
- Caution about type of progestogen in pill
- Continuous rather than cyclical use recommended
Hormonal medical management
- Percutaneous estradiol + cyclical progesterone has been shown to be effective
- Consider LNG-IUS for endometrial protection
Danazol
- is effective in luteal phase for breast symptoms
- Potential irreversible virilising effects
- effect on lipid profile
- must be on contraception
Progesterone - good evidence that it is not appropriate
- No evidence to support LNG-IUS use alone
Hysterectomy + BSO
- Trial GnRH analogues pre-op as a test of cure and to ensure HRT is tolerated
- Use HRT post-op, especially if <45y
Menstrual cycle
- Follicular phase
First half = follicular phase (of ovary)
- Menstrual phase at the start, then proliferative phase of endometrium
With menses, progesterone from previous luteal phase falls (as CL involutes), lifting the negative feedback on hypothalamic GnRH
Rise in FSH –> maturation of follicles
Increasing oestrogen produced by the follicles - at low levels cause negative feedback suppressing FSH
Smaller follicles undergo atresia as they rely on FSH for development
larger follicle continues to grow independently of FSH
Dominant follicle makes large amount of oestradiol
When certain oestrogen threshold is reached, leads to LH (and smaller FSH) surge (positive feedback)
LH surge –> ovulation
- Ovulation occurs approx 36h from the onset of surge
Define menopause
The permanent cessation of menstruation
Defined retrospectively, 12 months after the final menstrual period
Average age 51.5y
Define
- Early menopause
- Premature menopause
Early menopause
-Before age 45, but after the age of 40
Premature menopause
- Before age 40
- Primary ovarian insufficiency
- POI affects ~1% of women
Perimenopause or menopause transition
Time from the onset of menstrual cycle changes until one year after the final menstrual period
Early menopause transition - marked by persistent difference of 7+ days in length of consecutive cycles
Late - periods of amenorrhoea of 60 days or more, frequent anovulation, onset of perimenopausal symptoms
Usually starts ~47y
Can last 4-8y
factors a/w early and late menopause
Factors a/w earlier menopause
- Hysterectomy
- Smoking
- Lower level of education
- Living at an altitude >2000m
- Being single
Factors a/w later menopause:
- Parity
- Higher BMI
- Oral contraceptive use
Numbers of vasomotor symptoms of menopause
70-80% of women
Most common reason for women to seek advice / treatment
Usually start during the menopause transition
Average duration = 4-5y
10% have symptoms for >10y
Midlife women health assessment
- Smear
- Mammogram
- Lipids
- FBC
- TSH
- Renal and liver function
- Ferritin
- HbA1c
- Vit D in at risk women
Screen for anxiety and depression
Offer lifestyle advice
Dual x-ray Absorptiometry (DXA) - if high risk
- Used to measure bone density in those with increased fracture risk
Contraceptive needs for perimenopause
Use for 2y after the LMP in women <50y
Use for 1y after LMP in women >50y
Lifestyle changes for menopause to recommend
Stress reduction Regular exercise Optimal weight management Appropriate diet Smoking cessation Weight bearing exercise Calcium / vitamin D intake Avoid excessive alcohol and caffeine
