PCOS treatment Flashcards
What is the central metabolic defect associated with PCO?
-insulin resistance
how is insulin resistance in PCOS different to type 2 diabetes?
- type 2 diabetes insulin production eventually stops when cells dont respond.
- whereas in insulin resistance(pre-diabetes) in PCOS circulating insulin levels increase to compensate = hyper- insulinaemia
What is the role of insulin in maintaining glucose levels?
-when glucose levels are low, insulin is released by pancreatic cells (converts glycogen => glucose) allowing glucose to enter cells for energy.
What happens to glucose levels if you’re in insulin resistance state in PCOS?
- initially insulin levels increase converting glycogen => glucose so levels are maintained, but as you become more insulin resistant, you get glucose levels rising in the blood (hyperglycaemic) bc it cant enter the cells for energy and remains in the blood circulation.
What is the difference between PCO and PCOS?
PCO = polycystic ovary - variant in the normal ovary, not the disease
PCOS= polycystic ovarian syndrome - metabolic disorder associated with unbalanced hormones.
PCOS, IR, adiposity and androgen levels
- women with PCOS have central adiposity, which is linked to IR
- May NOT be due to higher relative percentage of visceral fat
- in animals exposure to androgen is associated with increased fat (women with PCOS have higher levels of androgen so put on weight easier)
Insulin sensitivity in relation to weight
- Everyone becomes less insulin resistant as they put on weight
-as you put on weight insulin sensitivity decreases even more in women with PCO than women with normal ovary.
-PCOS are more likely to put on weight so even more likely to be insulin resistant - high insulin due to IR is inherent in PCOS affecting 75-90% of women with PCOS.
-increased inflammatory substances come in as a result of obesity come and increase insulin resistance
Is insulin resistance caused by inherited insulin receptor gene mutation or by defect in the molecular mechanism pathway(familial)?
-IR is familial/inherited bc no mutation in the insulin receptor gene found in PCOS which cause less binding and resistance but it is a defect in the post- receptor binding somewhere in the signalling pathway
outline the basic mechanism of IR
1 insulin binds to insulin receptor on the cell membrane
2. phosphorylates receptor and initiates downstream signalling
3. This triggers the release of GLUT4 receptors contained int the vesicle which migrate to the cells surface allowing glucose to enter from blood stream into the cell.
=> defect somewhere along this pathway leads to insulin resistance so glucose cant enter cell and accumulates in blood stream (hyperglacemic)
How does obesity make it worse?
-macrophages/inflammatory markers (come in as a result of obesity) can cause IR.
OGTT - oral glucose tolerance test
- determine impaired tolerance
- Fasting 8-12hrs before test -> glucose given as a solution -> blood samples taken (0-2h) to determine how quickly cleared (insulin resistance cant clear it quickly, high levels persist)
What are normal values for fasting glucose and values after 2hrs in IGT?
- fasting value= <5.6 mM
- at 2h = 6-7.8mM
anything above shows impaired glucose tolerance:
1. impaired - fasting= 6-7
- at 2h =7.9-11mM
2. Diabetic
-Fasting value = >7 mM
-At 2hrs = > 11mM
Women with PCOS and prevalence of IR, T2D and GDM
- 30-40% women with PCOS have impaired glucose tolerance (IGT) and 10% develop TDM by age 40 y/o
-higher incidence of T2DM in women with family history i.e Indian sub continent Asians. - obesity exacerbates many aspects of PCOS clinical hormonal and metabolic features in women
Why does obesity and insulin resistance result in gestational diabetes (GDM) in pregnant women?
Placenta produces E, cortisol & human
placental lactogen(HPL)
↓
HPL interferes with insulin receptors
↓
Maternal Hyperglycemia
↓
Increased glucose in maternal
circulation crosses to foetal circulation
↓
Increase in fetal insulin
↓
Excess fetal growth – large for
gestational age
=> after pregnancy HPL decreases and goes back to normal
Complications if GDM for mothers
- birth weight (38%)
- shoulder dystocia/birth injury (22%)
- premature delivery (16%)
- Preclampsia (28%)
What are other manifestations of metabolic defect in PCOS?
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 (Kazemi M et al (2020) JCEM 105:e3400-e3414)
Why do women with PCOS gain weight?
Constant tendency to gain weight:
– Normal-weight women with PCO consistently maintain a lower-calorie diet than their counterparts with normal ovaries.
– HRQoL study in women with PCOS → normal-weight
women experienced as many problems with their
weight as obese women.
Why are women with PCOS more inclined to gaining weight?
PCOS is associated with reduced energy
expenditure equivalent to over 17,000 kcal/pa, compared to their normal counterparts who can burn these calories easily.
What is post -prandial thermogenesis(PPT)?
- energy used by body to digest your food
PCOS and PPT
-women with PCOS have reduced PPT
-levels of PPT in women with normal ovaries > lean PCOS women > obese PCOS women (so less energy/calories burnt)
- insulin sensitivity is reduced in both obese and lean women with PCOS compared to normal.
- so PCOS women more inclined to gain weight
SHBG levels in PCO
- sex hormone binding globulin - binds to androgens
- 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 (more androgen) - SHBG production by liver is
also inhibited by insulin (so IR in PCOS = more insulin in serum = less SHBG = increased T) - Insulin also stimulates ovarian
androgen production (synergises with LH)
Summary
- PCOS more inclined to weight gain
- weight gain -> TMD2 -> insulin resistance
- IR drives Androgen secretion
- IR decreases SHBG -> increased free T (makes hirsutism and acne worse and adds to follicular problems)
- increased T -> anovulation
- if you do get pregnant ->GDM
- women who go through all this get DM2 and CVD in later life.
What is guidelines from endocrine society for treatment of PCOS?
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
* First line management for menstrual abnormalities
and hirsutism/acne in PCOS are hormonal
contraceptives (HC)
* First 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
Lifestyle intervention and weight loss- first line treatment to improved IR?
diet and exercise
Study : lifestyle intervention and weight loss
Kiddy: 24 women on very calorie-restricted diet (1000 calories)
* Target was to loose 5% of body weight (Kiddy et al, 1992, Clin.
Endocrinol. (Oxf) 36:105-11)
– 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 regularityLifestyle
(Harrison CL et al, 2011, Hum. Reprod. Update 17:171-83)
Diet and PCOS
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.
Reducing obesity in PCOS
Weight loss notoriously hard to achieve
* Use weight loss drugs?
* Orlistat (lipase inhibitors)…reduces uptake of fat from bowel and
increases it in stools – side effects of anal leakage
* For morbidly obese
(BMI>40) bariatric surgery
Study : reducing obesity by bariatric surgery in PCOS
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%
What is the second line of treatment in PCO?
Metformin
How does metformin work?
- Diabetes drugs such as metformin
- Metformin is a biguanide (insulin sensitiser)
- Decreases hepatic glucose production therefore less in serum
- Enhances glucose uptake into muscle
- Increases oxidation by adipose tissue
- Good for PCOS?
What are results of using metformin?
- improvement in ovulation rates
-may be used to treat gestational diabetes - can be used in women who cant tolerate hormonal contraception to regulate periods
- adolescents with PCOS are put on
Why are women with PCO still well oestrogenised?
- Even when amenorrhoeic( absence of period), women with PCOS are well-oestrogenised -antral follicles are still there which release oestrogen.
- 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 (Fuberg & Thune (2003) Int. J. Cancer) - Recommendation to have bleed at least every 3
months, more often if very heavy
=> contraceptive pills are first line of treatment for menstrual abnormalities
How do HC pills work?
- Important to limit endometrial hyperplasia and menorrhagia
- Increased risk of endometrial cancer 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
PCOS and cutaneous manifestations
- 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.
PCOS and Hirustism/acne
- 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
androgen 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
Medical management and other therapies for hirsutism and acne treatment
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What are mechanical treatments for hirsutism?
- 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
What are chemical treatment for hirsustism?
Vaniqa. Eflornithine Hcl
topical cream inhibits enzyme - Ornithin Decarboxylase
– that is needed for hair shaft growth.
Treatment - PCOS and infertility
- Weight reduction is primary goal in the overweight
– 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 - Which diets are best?
– Hard to say……but low calorie of any kind seems to work
What is the first line of treatment for infertility?
– Clomiphene Citrate
- 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
What are other drugs for infertility treatment?
– 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 (Legro et al, NEJM (2014) 371:119-129)
– FSH treatment (low dose)
* Daily injections of FSH: aim for single follicle
Study : AMH and induction of ovulation
- 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
How is serum levels of AMH linked to ovulation?
High serum AMH associated
with a reduced response to
ovulation induction among
women with PCOS
Ovarian laser diathermy/ovarian puncture or wedge resection as infertility treatment:
– Ovarian laser diathermy/ovarian
puncture or wedge resection* 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
– IVF* Recommended use of metformin as adjuvant to prevent OHSS
which is very common in women with PCOS
What are alternative therapies?
- 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
Digital resource for women with PCOS
- 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
