PCOS Treatment

Question 1

How is IR different to Type 2 diabetes (aka pre-diabetes)? (2)

Answer 1

circulating insulin levels increase to compensate = hyper-insulinaemia for IR (basically tolerance for IR) - so glucose levels low at first but as IR inc. so does glucose (hyperglycaemia)

T2D has prog. so no response to insulin or no insulin made

Question 2

IR in PCOS driven by adiposity-facts (5)

Answer 2

• USA – obesity affects 80% of women with PCOS & in rest of world
  50%
• Women with PCOS have central adiposity, which is linked to IR
• May NOT due to higher relative percentage of visceral fat
• In animals exposure to androgens is associated with increased fat
  accumulation
• Treatment with high androgens in female-to-male transsexuals inc. visceral fat accumulation

Question 3

Insulin sensitivity in relation to weight compared to normal (2)

Answer 3

Although everyone becomes more IR w/ increasing weight »
insulin sensitivity declines at a faster rate in women with PCOS than in
women with normal ovaries with increasing weight

However, in some PCOS women IR is inherent and not driven by obesity

Question 4

Molecular mechanism of IR in PCOS (5)

Answer 4

• insulin resistance is familial
  – No mutations in insulin receptor gene found in PCOS
  – Post-receptor binding defect somewhere in downstream signalling pathway/cascade
  i.e. insulin binds to receptor = phosph. + triggers GLUT4 to send transporters vesicle = bind and allow entry of glucose into cell out of blood (something messed up in this pathway)

-inflammation + markers as result of obesity can interact + inhib. thsi pathway

Question 5

Using OGTT to determine IGT (4)

Answer 5

• Oral glucose tolerance test to determine IGT
  – Fasting 8-12h before test → glucose given as a solution → blood samples taken (0-2h) to determine how quickly cleared from blood

Normal: Fasting value (before test): <5.6 mM;
At 2 hours: between 6-7.8 mM

Impaired: Fasting value (before test): 6.0 -7.0 mM;
At 2 hours: 7.9-11.0 mM

Diabetic: Fasting value (before test): >7.0 mM;
At 2 hours: >11.0 mM

Question 6

PCOS, IR, T2DM & GDM (5)

Answer 6

• Obesity exacerbates many aspects of PCOS clinical, hormonal and metabolic features in women
  – If patient has oligomenorrhea & hyper-androgenism in adolescence then increased risk of developing obesity & MetS by 24y
• 30-40% women with PCOS have impaired glucose tolerance (IGT) and 10% develop T2DM by age 40yrs
• Higher incidence of T2DM in women with family history i.e. Indian sub-continent Asians
• Obesity & insulin resistance results in – increased incidence of GDM

Question 7

Why would Gestational Diabetes Mellitus (GDM) present first in pregnancy? (6)

Answer 7

1)Placenta produces E, cortisol & human placental lactogen
↓
2)HPl interferes with insulin receptors
↓
3)Maternal Hyperglycemia
↓
4)Increased glucose in maternal circulation crosses to foetal circulation
↓
5)Increase in fetal insulin
↓
6)Excess fetal growth – large for gestational age

Question 8

Complications of GDM for mother & fetus (4)

Answer 8

• probelms in labour + delivery: shoulders get stuck
  -premature delivery
  -preeclampsia
  -birth weight > 90 percentile

Question 9

IR also linked to anovulation - graph

Answer 9

increase in Insulin = decrease in no. of menstrual cycles

not obese women get IR - so despite IR + weight being linked, it is not causal

Question 10

Other manifestations of metabolic defect in PCO - outcomes of longterm studies (risks) (5)

Answer 10

• tendency to obesity with increase in truncal-abdominal fat
• increased hypertension
• Altered lipid profile
  – higher levels of LDL cholesterol – regardless of BMI
  – low levels of HDL cholesterol and elevated triglycerides
• apparent increased risk for atherosclerotic disease
  – Increased coronary artery calcification (independent of age & BMI)
  – Increased carotid artery intima-media thickness (predictor of stroke & MI)
  compared to age-matched controls
  – Limited longitudinal studies → PCOS diagnosed during reproductive lifespan
  (20-30 years old) but CVD manifests 30 to 40 years later.
  – Also majority of conducted research on CVD on male →concept that women
  present differently
• Recent study showed that women with PCOS at ↑risk of osteosarcopenia

Question 11

Why do women with PCOS gain weight? (5)

Answer 11

-increased food production + availability
- androgens
- Constant tendency to gain weight:
– Normal-weight women with PCOS consistently maintain a lower-calorie diet than their over-weight counterparts
– HRQoL study in women with PCOS → normal-weight women experienced as many problems with their weight as obese women.

Question 12

Are women with PCOS more inclined to put on weight or is it parallel to growing obesity epidemic? (2)

Answer 12

PCO is associated with reduced energy expenditure equivalent to over 17,000 kcal/pa - extra storing compared to others

+ due to Post- Prandial Thermogenesis (PPT)

Question 13

PCOS and PPT (3)

Answer 13

PCOS is associated with reduced energy expenditure - by 1700 calories
* this is due to reduced post -prandial thermogenesis (PPT)
* it is amplified by obesity in PCOS
* Insulin sensitivity is reduced in both obese & lean women with PCOS compared to normal

Question 14

PCOS and weight (3)

Answer 14

constant increase
1) young: look at skin
2) mid 20’s put on a lot of weight
3) want children - cannot and struggle to conceive

Question 15

Sex Hormone Binding Globulin (SHBG) levels in PCO (6)

Answer 15

• Vast majority of testosterone is bound to SHBG.
• Small change in SHBG causes large change in free testosterone
• SHBG dependent on BMI ie obesity ↓SHBG & ↑free T
• SHBG production by liver is also inhibited by insulin
• # Insulin also stimulates ovarian androgen production (synergises with LH)Increase T

Question 16

Summary - Long-term outcomes for women with PCOS

Answer 16

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Question 17

Endocrine Society Clinical Guidelines for Treatment of PCOS

Answer 17

No “cure” – treatment is symptomatic

• Lifestyle intervention and weight loss improves overall PCOS status in overweight/obese patients along with other health benefits eg insulin resistance, CVD
• 1st line management for menstrual abnormalities and hirsutism/acne in PCOS are hormonal contraceptives (HC)
• 1st line therapy for infertility is Clomiphene
• Metformin is beneficial for metabolic/glycaemic abnormalities & for improving menstrual irregularities, but of limited benefit in treating hirsutism, acne or infertility

Question 18

Lifestyle Interventions & Weight Loss

Answer 18

• First line treatment to improve insulin resistance
  – diet and exercise
• Kiddy: 24 women on very calorie-restricted diet (1000 calories)
• Target was to loose 5% of body weight
  – Of the 13 who succeeded → 5/7 conceived
  – 11 who didn’t → 1/8 conceived
• Subsequent trials shown that if overweight/obese women with PCOS have 5-15% weight loss then significant improvement in following parameters
  – Serum lipids
  – Serum T and SHBG
  – Glucose tolerance and fasting insulin
  – Hirsutism
  – Ovulation and menstrual cycle regularity

Question 19

How would diet and exercise help?

Answer 19

Studies from Australia show diet is as successful as medical intervention
(Anne Clarke) but drop-out rate high » requires support system and frequent
attendance and exercise programme

Question 20

Use weight loss drugs?

Answer 20

Orlistat (lipase inhibitors)…reduces uptake of fat from bowel and
increases it in stools – side effects of anal leakage

Question 21

For morbidly obese (BMI>40) bariatric surgery (4)

Answer 21

Meta-analysis of 2130 women who had bariatric surgery:
» 46% identified as having PCOS pre-op → dropped to 7% one year post-op (p<0.001)
» Incidence of hirsutism pre-op was 67% & dropped to 39% one year post-op (p=0.03)
» Menstrual irregularity was 56% pre-op and dropped to 8% one year post-op
» Pre-op fertility was 18% and post-op was 43%

Question 22

metformin MoA- Good for PCOS? (5)

Answer 22

Diabetes drugs
* Metformin is a biguanide (insulin sensitiser)
* Decreases hepatic glucose production therefore less in serum
* Enhances glucose uptake into muscle
* Increases oxidation by adipose tissue

for IR not PCOS - so need PCOS w/IR

Question 23

Treatment of PCO…metformin (6)

Answer 23

Recent recommendations for use of metformin in women with
PCOS who have T2DM or IGT who fail lifestyle interventions
* Improvement in ovulation rates on metformin (Tang et al, Cochrane
Review (2012); Endocrine Society Clinical Practise Guideline for PCOS)
* Metformin is 2nd-line treatment for women with PCOS who have
menstrual irregularities and cannot tolerate HC
* Adjust dose for different body weights
* Metformin maybe of use to treat gestational diabetes
* Recommended for use in adolescents with PCOS

Question 24

HC Treatment – Menstrual Irregularity- to limit endometrial hyperplasia (+cancers) (8)

Answer 24

irregular cycles i.e. oligo/amenorrhoea
– unlike many women with amenorrhoea, women with PCO are well-oestrogenised
– Aim for minimum of 4 ovulations per year to avoid
endometrial hyperplasia

– HC pill first line treatment for menstrual abnormalities:
* Important to limit endometrial hyperplasia and menorrhagia
* Increased risk of endometrial CA with prolonged amenorrhoea in
PCOS as well-oestrogenised
* Progestins in HCs suppress LH levels and hence ovarian androgen
production
* Avoid androgenic progestogens
* Risk…appetite stimulant so need advice regarding weight gain

Question 25

unlike many women with amenorrhoea, women with PCO are well-oestrogenised …why?

Answer 25

Still have antral follicles = they’re still producing oestrogen

Question 26

PCOS & Endometrial Cancer- studies (7)

Answer 26

Even when amenorrhoeic, women with PCOS are well- oestrogenised
* Unopposed oestrogen on endometrium → risk factor for hyperplasia
* Probably exacerbated by obesity
* Recent meta-analysis showed 3 fold increased risk of endometrial CA…even under 50
* Another study found an increase only in obese women with PCOS
* Recommendation to have bleed at least every 3 months, more often if very heavy

Question 27

PCOS & Cutaneous Manifestations (2)

Answer 27

• Hyperinsulinemia from IR acts at dermis to induce acanthosis nigricans (velvety, light-brown-to-black markings) on neck, under arms, in groin & skin tags)
• Treatment to just improve the appearance includes tretinoin (derivative of
  Vitamin A), 20% urea, alpha hydroxyacids and lactic or salicylic acid.

Question 28

hirsutism/acne (6)

Answer 28

• 75% women with hirsutism/acne have PCO
• even higher in women with h/a and oligomenorrhoea
• consistently reported as most distressing symptom
• cause of significant reduction in quality of life by questionnaire, cause of low- self esteem
• Hirsutism assessed by modfied Ferriman-Galway score (ethnic differences)
• > 80% of patients presenting to dermatology clinic for acne had PCOS

Question 29

Spectrum of Presentation (3)

Answer 29

Sophia Vergara , Harnaam Kaur

Androgenic alopecia – less frequent and presents later, but very distressing with significant psychological comorbidities.

Poor association with biochemical hyper-androgenism, maybe associated
with IR and metabolic syndrome

Question 30

hirsutism/acne treatment -Medical Management (5)

Answer 30

COCP with non-androgenic progesterone eg deogestrel*

COCP with androgen blocking diuretic effect eg drospirenone*

Anti-androgens eg cyproterone acetate, ethinyloestradiol,spironolactone (monitor renal function),finasteride (post-menopausal), flutamide

GnRH therapy – very severe acne only

BSO – bilateral saplingo-oophorectomy (after had children)

*higher risk of thrombosis
** not for pregnant women or those trying to conceive

Question 31

hirsutism/acne treatment- Other Therapies (6)

Answer 31

Weight reduction

Physical therapies – electrolysis, laser hair removal, waxing, shaving, plucking

Topical treatments: eg eflornithine 11% for facial hair**

Isotretinoin (popular drug used to treat acne) but not recommended in PCOS

Psychological intervention

Androgenetic alopecia – 2% solution minoxidil used 2x/day for 6 months

*higher risk of thrombosis
** not for pregnant women or those trying to conceive

Question 32

hirsutism/acne treatment-Mechanical treatments (2)

Answer 32

• Electrolysis
  – Electrical current causes high temperature in hair shaft
  – Must destroy dermal papillae to prevent regrowth
  – Not really practical for large areas
  – Often worth removing hair by another means a short while before, then growing hairs can be focussed on.
  – May be best combined with medical treatment
• Laser..
  – heat destroys the hair follicle. Need dark pigment to absorb the heat of the light/laser
  – Needs dark hair on light skin
  – Not often available on NHS
  – Hair follicle cycle is long → many sessions

Question 33

hirsutism/acne treatment-Vaniqa. Eflornithine HCl (3)

Answer 33

Topical cream inhibits enzyme Ornithin Decarboxylase
– that is needed for hair shaft growth.

Now, up close is up to you

Must be applied 2x day every day Grows back as soon as stop use

Question 34

Infertility treatment - Weight reduction is primary goal in the overweight (6)

Answer 34

– Increased chance of spontaneous ovulation
– Reduced chance of miscarriage
– Need less drugs for induction of ovulation
– Reduction in GDM
– Improved outcome for baby
– Improved long term outcome for patient

Question 35

Infertility treatment – Induction of Ovulation (6)

Answer 35

– Clomiphene Citrate i.e. anti-oestrogen (1st line)
* raised acyclical oestrogen results in disordered pituitary LH and more
importantly FSH
* given for 5 days to mimic inter-cycle rise in FSH
– CC is a SERM (selective oestrogen receptor modulator) and binds to ER in
hypoth/pit & removes negative feedback, allowing for GnRH & FSH release
* 70-90% responders in the best hands
* Multiple pregnancy around 10%
* high miscarriage rate……up to 40% → blocks ER on endometrium
* risk of multiple follicles/ovulation & OHSS…ultrasound monitoring 1st
cycle

– Metformin + CC
* Improves clinical pregnancy rates but not live birth rates

– Aromatase inhibitors (eg Letrozole)
* Same effects as the anti-oestrogen but inhibits production of oestrogen

– FSH treatment (low dose)
* Daily injections of FSH: aim for single follicle

Question 36

AMH and induction of ovulation (5)

Answer 36

• 748 women with PCOS and anovulation (18-40 years)
  – AMH measured at baseline
  – Treated with clomiphene citrate or letrozole for 5 days per cycle & for 5 cycles
  – AMH levels significantly lower in women who achieved ovulation vs women who did not overall and also within each treatment group

High serum AMH associated with a reduced response to ovulation induction among women with PCOS

Question 37

Infertility treatment– Ovarian laser diathermy/ovarian
puncture or wedge resection (6)

Answer 37

• ovary “drilled” laparoscopically with laser
• mechanism of action unknown → may act
  by destroying stroma, reducing size of
  matrix and lowering endogenous androgen
  production → disrupts hippo signalling to
  allow for follicle activation
• Return of cycles for up to 6 months in high percentage of women
• no risk of hyper-stimulation but ↑ risk peritoneal adhesions
• should be used only as a last resort as long term damage
  unknown…..although recent study suggested better outcome than
  those not receiving it
• Reduced response rate to subsequent IVF

Question 38

Infertility treatment – IVF

Answer 38

Recommended use of metformin as adjuvant to prevent OHSS
which is very common in women with PCOS

Question 39

Infertility Treatment - Alternative therapies (3)

Answer 39

• Some publications on acupuncture

– Cochrane review (2011) found no randomized trials to investigate effect of
acupuncture treatment for PCOS
* Herbal preps also suggested
– Agnus castus
– Saw palmetto etc

No known micronutrient deficiency has been identified as relevant to PCOS

Question 40

Digital resource for women with PCOS- AskPCOS (5)

Answer 40

• New development of evidence- based free AskPCOS app
• Co-developed with women and health professionals
• Many apps available but for PCOS, but commercially developed and
  lack quality and evidence-based information
• Used in over 100 countries
• Helps to meet women’s information needs and enhance self-management.
  https://www.askpcos.org/

Question 41

PCOS - summary

Answer 41

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