Obesity, PCOS, amenorrhoea Flashcards
Why do we want rapid weight loss before bariatric surgery?
Ideally 8 weeks of VLCD
Shrinks the liver and makes the procedure safer
List potential weight loss drugs
Phentermine
Locaserin
Natrexone/bupropion
Topiramate
Liraglutide (GLP1 agonist)
In T2DM, metformin, SGLT2i and GLP1 agonist have weight benefits
What’s the gold standard for bariatric surgery?
Gastric bypass
Benefits and downfalls of gastric bypass
Gold standard
Benefits
Completely reversible
Good at reversing diabetes if done within 8 years of diagnosis
40% reduction in all cause mortality (CAD, diabetes, cancer)
Downfalls Need to take lifelong iron and vitamins Lifelong monitoring Rapid absorption with ETOH Rapid bone loss in the first 2 years --> OP (ensure calcium and vitamin D are adequate)
Downfalls of gastric banding
Lots of reflux
Permanent damage to the proximal portion of stomach and oesophagus
Not very good at reversing OSA or T2DM
Benefits and downfalls of gastric sleeve
Benefits
Easier to do in obese people, laparoscopic procedure
Downfalls
Permanent
Tubular stomach that remains can dilate and lead to weight gain again
Reflux
Nutritional insufficiency (but not as bad as gastric bypass)
Rapid absorption of ETOH
Bone loss (not a bad as gastric bypass)
Less effective at reversing T2DM compared to bypass
Which bariatric surgery is best at reversing diabtes?
Roux-en-Y gastric bypass
Exam findings in PCOS
High BMI
High BP
Hyperandrogenism - hirsutism, acne, alopecia
Acanthosis nigricans (Hyperpigmented areas at the nape of neck and axillae)
Pathogenesis of PCOS
Poorly understood
Insulin-resistant hyperinsulinemia
LH excess
Both contribute to dysregulation of ovarian steroidogenesis –> hyperandrogenism
Diagnostic criteria of PCOS
Diagnosis of exclusion - exclude thyroid disorder, hyperprolactinaemia, Cushing’s, non-classic CAH, androgen secreting tumour, acromegaly
Rotterdam criteria 2 out of 3 of the following: - Oligo- and/or anovulation - Clinical and/or biochemical hyperandrogenism - Polycystic ovaries
Investigations to do in suspected PCOS
LH, FSH
- LH/FSH ratio is raised in PCOS
- Rule out ovarian failure (high FSH)
Free serum testosterone (high), SHBG (low), free androgen index (testosterone to SHBG ratio)
TSH, prolactin, 17-hydroxyprogesterone, B-HCG, gonadotropin, midnight salivary cortisol (rule out other causes)
Metabolic panel - HbA1c, fasting lipids
+/- pelvic US (will also see if there is outflow obstruction)
Does polycystic ovaries on USS equal PCOS?
No
USS features cannot diagnose PCOS alone
Clinical features of PCOS
1) Irregular menstrual cycle
- Oligomenorrhoea (menstrual interval >35 days or <8 cycles/year)
- Cycles are usually anovulatory –> heavy bleeding + increased risk of endometrial hyperplasia/ca
2) Hyperandrogenism
- Hirsutism, acne, male-pattern hair loss
How does PCOS increase risk of endometrial hyperplasia/carcinoma?
Anovulatory –> unopposed estrogen stimulation –> endometrial hyperplasia/carcinoma
Management of PCOS
Specifically, management for Hirsutism Menstrual dysfunction Infertility Risk assessment
1) Lose weight - 5-10% weight loss can restore ovulation and increase insulin sensitivity in obese anovulatory women
2) Quit smoking
3) Hirsutism
- Combined OCP - suppresses ovarian androgen production, increases SHBG to reduce free androgen
- Spironolactone, cyproterone acetate (block androgen; teratogenic)
- Metformin - insulin-sensitiser, weight loss
- Eflornithine - topical drug that inhibits hair growth
4) Menstrual dysfunction
- COCP or progestin only pill/Mirena (endometrial protection) or cyc`lical progestin (aim 4 bleeds/year for endometrial protection)
5) Infertility
- Lifestyle modifications
- Letrozole (1st line for anovulatory infertility)
- Clomiphene
- Metformin
- Gonadotropin therapy
- IVF
Also
Risk assessment for T2DM, lipids, endometrial ca
What’s primary and secondary amenorrhoea?
Primary amenorrhoea
- Absence of menses, in the presence of normal development of secondary sexual characteristics by age 16
- Failure of onset of puberty by age 13
Secondary amenorrhoea
- Absence of menstruation for 6 months or more in women with past menses
What’s thelarche?
Breast development
Requires estrogen
What’s pubarche?
Pubic hair development
Requires androgens
What’s menarche?
First period Requires GnRH (hypothalamus), FSH+LH (pituitary), E2+progesterone (ovary), normal outflow tract
How is GnRH released?
Pulsatile manner from the hypothalamus
Anosmia and amenorrhoea. What’s the dx?
Turner’s
Headache or visual changes and amenorrhoea. What’s the dx?
Pituitary mass
Vasomotor symptoms and amenorrhoea. What’s the dx?
Primary ovarian failure
What dysmorphic features do you expect in Turner’s?
Webbed neck
Short stature
Widely spaced nipples
Causes of amenorrhoea
Hypothalamus
- Gonadotropin deficiency
- Neoplasm
- Exercise, weight or nutrition related, chronic illness
Pituitary
- Pituitary adenoma -
macroadenoma, prolactinoma
- Hypopituitarism - post treatment, Sheehan’s
Endocrine
- Hypothyroidism
- Hyperprolactinoma including drug induced
Ovarian
- Gonadal dysgenesis (Turner’s syndrome)
- Ovarian failure (idiopathic, treatment failure)
- PCOS
Outflow tract
- Mullerian agenesis
- Vaginal atresia
- Imperforate hymen
- Asherman syndrome (adhesions within the uterus)
45 XO is…
Turner syndrome
List 7 associated conditions in Turner syndrome
Coarctation of the aorta
Horseshoe kidney
Autoimmune hypothyroidism
Hearing loss
Metabolic syndrome
Neurocognitive and behavioural issues
Amenorrhoea
What’s primary ovarian insufficiency?
Hypergonadotropic hypogonadism <40 years
Causes primary ovarian insufficiency
Surgery, chemo, radiotherapy
Autoimmune e.g. autoimmune thyroiditis, Addison’s disease, T1DM, MG, hypoparathyroidism
Genetic e.g. fragile X syndrome
Idiopathic
How to diagnose primary ovarian insufficiency?
BHCG - rule out pregnancy
FSH >40U/L in a two sittings at least 1 month apart OR reduced estradiol and elevated FSH, in the context of amenorrhea and menopausal symptoms
Amenorrhoea and FHx of primary ovarian insufficiency, mental retardation, or a tremor/ataxia syndrome.
What is the diagnosis? How do you test for it?
Fragile X syndrome
Test for FMR1 premutation -
Management primary ovarian insufficiency
Counselling
Hormone therapy with cyclical estrogen and progestin to relieve symptoms of estrogen deficiency, maintain bone density, sexual health and QOL. Continue until age of natural menopause (age 50-51).
No therapy to improve fertility
Monitoring for primary ovarian insufficiency
Annual TSH because of increased risk of developing autoimmune hypothyroidism
Those with positive adrenal ab but normal adrenal function at the initial evaluation (corticotropin stimulation test) should be retested annually
What are the cases of hypothalamic amenorrhoea?
Stress –> high cortisol
Weight loss –> low leptin
Exercise related
Alters normal pulsatile release of GnRH
Initial investigations in amenorrhoea
BHCG LH FSH TSH E2 Prolactin Pelvic US
Amenorrhoea normal FSH, low E2
DDx
?Hyperandrogenism
- Do androgen profile, DHEAS (high in congenital adrenal hyperplasia), 17OHP, Cushing’s screen. Consider adrenal/ovarian imaging
PCOS
Late onset CAH
Cushing’s syndrome
Androgen secreting tumour
Leptin
What does it do?
Secreted by adipocytes
Acts on the hypothalamus
Long-term control
Leptin deficiency = hyperphagia + impaired satiety = weight gain
What if we replace leptin in obesity?
As we gain weight, leptin levels go up
Hence leptin replacement doesn’t work for most obesity people = become leptin resistant
MC4R
What is it? What does it do?
Leptin works on leptin receptor in hypothalamus (arcuate nucleus) –> signals through to MC4R –> reduces appetite
MC4R mutation = obesity
Cholecystokinin
What does it do?
Satiety factor that regulates meal size
Short-term control
Eat –> stomach stretches –> increased vagal afferents –> brain
Receptors in small intestine –> signal through CCK to the brain
Ghrelin
What does it do?
Effects of bypass surgery?
Appetite trigger
Produced in small intestine, triggered with food intake
Suppressed after gastric bypass –> less trigger to appetite –> weight loss
Brown adipose tissue is defined by
Contains uncoupling protein 1 - uncoupling proteins in mitochondria allows expenditure as heat, rather than stored fat.
Amount of brown adipose tissue inversely correlates with BMI, glucose levels
More frequent in women
VLCD is ..
When do you do it?
<800 calories/day
E.g. optifast
Do this when weight loss is medically urgent
E.g. before surgery
Poor adherence due to hunger after 3-6/12
Low calorie diet is …
800-1500 calories/day
E.g. Lite n’ easy
Better tolerated for longer than VLCD
Weight loss is slower
Moderate calorie reduction is
How much weight loss?
About 500 cal less than atypical daily intake
Results in 0.5kg loss /week
Orlistat
MOA
Efficacy
Blocks gastrointestinal lipase
Blocks absorption of fat
Get fatty diarrhoea if you eat fat
Powerful behavioural tool
But not very effective. Average weight loss 2-3kg over 12 months.
Phentermine and topiramate
As a combination
Topiramate use is currently off label
Can achieve 12% weight loss in 1 year
But beware of side effects
What is the most successful approach to morbid obesity?
Bariatric surgery
Most successful weight loss over long term
Mean body weight loss is 25kg
Who is eligible for bariatric surgery?
BMI>35 and comorbidities T2DM HTN OSA Dyslipidaemia MAFLD PCOS
Note that TG and HDL may improve but hypercholesterolaemia does not
Biliary pancreatic diversion risk of …
Cirrhosis
Not done much anymore
Risk of bariatric surgery
Mortality Dehiscence of wound PE HAP Adhesions Recurrent hypoglycaemia due to hyperplasia of beta cells (nesidioblastosis)
In general, the safety of gastric bypass is equivalent to knee replacement, and safety of sleeve gastrectomy or banding is same as cholecystectomy
There are issues with safety but properly informed, its extremely useful for morbid obesity
However if you survive short post op period, there is improved mortality long-term
Advantages of bariatric surgery
Remission of T2DM
Reduced incidence of T2DM
Higher remission and lower incidence rate of HTN and dyslipidaemia
Sustained weight loss
Recurrent hypoglycaemia post bariatric surgery
Why?
May be mediated by incretin secreted by distal ileum
Increased incretin release –> stimulate beta cells –> beta cell hyperplasia (nesidioblastosis) –> hypoglycaemia
Much higher risk in RYGB
GLP1 and PYY … after gastric bypass
How do they work?
Increase
GLP1/incretin: secreted upon ingestion of food; reduces glucose by enhancing beta cell insulin secretion, promoting satiety and reducing gastric emptying
Peptide YY: acts within arcuate nucleus to inhibit release of NPY and thereby reduce food intake
Dual gastric inhibitory peptide (GIP)/GLP1 receptor agonists = “Twincretins”
What is it?
GIP differs from GLP1 in its role of stimulating glucagon secretion during hypoglycaemia; GIP might also promote weight loss by signaling satiety through its receptors present in the hypothalamus
Tirzepatide is a novel once a week dual GIP/GLP1 receptor agonist
How is estradiol made in women?
Which 2 cells are involved?
2 cells involved
Theca cell
LH binds theca cell
Within theca cell, changes cholesterol to androstenedione –> shuffles to granulosa cells and becomes aromatase
Within granulosa cell
FSH binds to granulosa cells –> aromatase becomes estradiol
How is tesosterone and sperm made in men?
Which 2 cells are involved?
2 cells involved
Leydig cell
LH binds to leydig cell, changes cholesterol to testosterone
Sertoli cell
FSH binds to sertoli cell –> makes sperm
Amenorrhoea
High FSH, low E2
DDx
Hypergonadotropic hypogonadism
Do karyotype to look for Turner syndrome (45 XO). If not, then its premature ovarian failure.
Amenorrhoea
Low FSH, LH, E2
DDx
Hypogonadotropic hypogonadism
Structural
E.g. craniopharyngioma, Kallmann’s syndrome, panhypopituiarism, pituitary adenoma
Functional
E.g. weight loss, exercise, psychological stress
Amenorrhoea
Normal FSH, LH, E2
DDx
PCOS
Turner’s syndrome
Clinical features
45XO Streak gonads Dysmorphic features Short stature CV abnormalities: coarctation, bicuspid AV, aortic dissection Renal abnormalities
Amenorrhoea and high prolactin
DDx
Pituitary tumour (do MRI)
Rarely, hypothyroidism (do TSH)
Premature ovarian failure
Menopause before age 40
Can have sex chromosome abn e.g. 45X, 47XXY mosaic
Autoimmune polyendocrinopathies
Can be after chemo or radiotherapy
How do you estimate ovarian reserve?
AMH
Low AMH may indicate low egg reserve
High AMH can occur in PCOS
Can be used as a predictor for IVF success
Pathophysiology of PCOS
What’s the role of insulin?
Increased pulsed frequency of GnRH –> Increased LH compared to FSH release from anterior pituitary –> increased stimulation of theca cells to produce testosterone, and less oestradiol formation from granulosa cell
Elevated insulin –> promotes androgen formation in theca cell, and hepatic synthesis of SHBG –> increases free testosterone
Testosterone deficiency in men
Clinical features
Birth: ambiguous genitalia
Puberty: delayed secondary sexual characteristics
Adult: Low libido Erectile dysfunction Osteoporosis Infertility
What’s primary vs secondary testosterone deficiency in men
Primary: inadequate leydig cell function (high LH)
Secondary: pituitary dysfunction (low LH)
Klinefelter syndrome
1) Chromosome abn
2) How common?
3) Clinical features
XXY
1 in 500 males
Small firm testes Azoospermia Increased LH, FSH Gynaecomastia Impaired sexual maturation
