PCOS

Question 1

Describe the pathophysiology of PCOS

Answer 1

• Unclear exactly why PCOS occurs, thought to be related to insulin resistance –> increases insuin —> insulin receptors on theca cells –>cause theca cells to grow and divide —> increase in LH receptors —> GnRH increases secretion of LH
• excess LH in comparison to FSH
• LH->Theca cells-> androstenedione ++++ (androgen)
• Low FSH–>can’t convert all of androstenedione to oestrogen via aromatase
• Excess estrone converted instead
• Estrone negatively feeds back to ant pit to decrease FSH
• No LH surge therefore no ovulation - amenorrhoea or oligomenorrhoea
• Remaining follicles either become cysts (hence polycystic) or degenerate
• Relative hyperoestrogenic with low levels of progesterone due to anovulation

Question 2

What is the prevalence of PCOS?

Answer 2

8-13% of reproductive age women depending on diagnostic criteria used

(MONASH)

Question 3

Define the Rotterdam criteria for diagnosing PCOS

Answer 3

Need two out of three of the following:

• Oligo- or amenorrhoea
• Polycystic ovaries on ultrasound (increased ovarian volume >10 mL (without corpus luteum) or >20 follicles per ovary)
• Clinical or biochemical androgen excess

Question 4

List the clinical features of hyperandrogenism associated with PCOS?

What are some other clinical features associated with PCOS?

Answer 4

• Hirsuitism
• Acne
• Alopecia

Other features:

• Heavy periods
• Obesity
• Infertility

Question 5

What tests would you order to make a diagnosis of biochemical hyperandrogenism?

Answer 5

Serum free testosterone, SHBG, free androgen index on day 2-5 of cycle.

Women should be off hormonal contraception for >1 month as affects SHBG and androgen levels.

Free T increased
SHBG decreased
FAI increased

Question 6

How might concurrent use of the combined oral contraceptive pill affect testing for androgen excess?

Answer 6

The COCP inhibits ovarian and adrenal production of androgens and increases the level of SHBG, leading to falsely low levels of androgen.

Question 7

Why might you organise serum LH and FSH levels in a woman being investigated for PCOS?

Answer 7

To exclude primary ovarian insufficiency (characterised by elevated FSH >30-40 mIU/L measured twice at least 4 weeks apart).

Question 8

List the differential diagnoses for PCOS and appropriate investigations you would order to differentiate these

Answer 8

• Pregnancy: BhCG
• Thyroid dysfunction: TSH
• Hyperprolactinaemia: prolactin level
• Late onset Congenital adrenal hyperplasia: 8 am 17-OHP
• Androgen-secreting tumour: DHEA and DHEA-S; if elevated consider abdominal CT.
• Primary ovarian insufficiency: FSH/LH on two occasions at least 4 weeks apart, consider estrogen level
• Cushing’s disease: 1 mg overnight dexamethasone suppression test; a low / suppressed cortisol level excludes Cushing’s disease. If not suppressed, perform high dose dexamethasone suppression test to delineate between pituitary tumour vs ectopic production of ACTH.
• Intracranial pathology (e.g. tumour, sheehans syndrome, etc); low FSH/LH and oestrogen - arrange CT or MRI head
• Functional hypothalamic amenorrhoea: diagnosis of exclusion based on Hx and exam
• Previous uterine surgery and concern for Ashermans; saline infused sonohysterogram or hysteroscopy

Question 9

Outline the long term sequelae for untreated PCOS

Answer 9

• Increased risk of endometrial hyperplasia and malignancy
• Increased risk of infertility
• Increased risk of cardiovascular disease/metabolic syndrome
• Increased risk of diabetes
• Increased risk of OSA
• Increased risk of depression
• Increased risk poor body image
• Increased risk of eating disorders (notably bullimia)

Question 10

Outline your approach to managing a woman with PCOS

Answer 10

• Weight loss
• Endometrial protection / contraception if desired
• Regulation of cycles
• Fertility
• Cardiometabolic risk
• Hirsuitism and acne
• Mental health
• OSA

Question 11

Describe what advice you would give regarding weight loss

Answer 11

• Weight loss target 5-10%; improves ovulation rates, hirsuitism and insulin sensitivity.
• Diet, exercise
• Referral for bariatric surgery if appropriate (BMI > 40 or BMI > 35 with an obesity related condition)
• Orlistat (lipase inhibitor that reduces dietary fat absoprtion)

Question 12

Describe what advice would you give regarding endometrial protection and contraception

Answer 12

• Unopposed oestrogen long term increases risk of endometrial hyperplasia and malignancy.
• Options: COCP, Mirena, cyclical (12 days) oral progesterone
• Offer endometrial sampling if abnormally thickened endometrium + other risk factors (HMB, high BMI, diabetes etc).
• Should have a cycle at least every 3-4 months - can be induced with progesterone for 12/7

Question 13

Describe what advice you would give regarding fertility

Answer 13

• Even 5-10% weight loss will lead to resumption of ovulatory cycles.
• 1st line: Ovulation induction: letrozole (first), clomiphene citrate, clomiphene citrate plus metformin (for women resistant to clomiphene)
• 2nd line: gonadotrophin injections OR laparoscopic ovarian drilling
• 3rd line: IVF

Question 14

Describe the mechanism of action of letrozole for ovulation induction

Answer 14

Aromatase inhibitor that inhibits ovarian and adrenal conversion of androstenedione and testosterone to oestrone and oestradiol.

Lower circulating oestrogen results in reduced negative feedback on hypothalamus and anterior pituitary leading to more FSH secretion and follicular development.

Question 15

Describe a commonly used ovulation induction protocol with letrozole and risks associated with its use.

Answer 15

After period or induced bleeding, commence letrozole 2.5 mg po daily on days 3 to 7 of cycle. If anovulatory can increase dose in 2.5 mg increments (i.e. 2.5, 5 and 7.5 mg) up to max dose of 7.5 mg daily.

Risks associated with letrozole use: multiple pregnancies; hot flushes, nausea, fatigue, dizziness.

Question 16

Describe the mechanism of action of clomiphene citrate for ovulation induction

Answer 16

A selective oestrogen receptor modulator (competitively inhibits oestrogen binding to its receptor.)

Primary site of action is at hypothalamus; it blocks the negative feedback of circulating endogenous oestradiol leading to increased GnRH pulse frequency and increased serum concentrations of FSH and LH.

This in turn increases ovarian follicular development

Question 17

Describe a commonly used ovulation induction protocol with clomiphene citrate and risks associated with its use.

Answer 17

Rule of 5s
The starting dose of clomiphene citrate is 50 mg per day for 5 days, commencing between day 2 and 5 of menses.

Menses may be induced with a progestin if required.

If this dose produces multiple follicular development, the dose can be lowered to 25 mg.

If ovulation is not achieved using 50 mg per day, the dose can be increased to maximum 150 mg per day. Maximum 6 months therapy.

Advise couple to start having sexual intercourse every second day 5 days after the last dose of clomiphene.

Risks associated with letrozole use: multiple pregnancies; hot flushes, nausea, fatigue, dizziness. Increased risk of borderline ovarian tumours if >12cycles

Success rates: 60% to 85% of patients will ovulate on CC, only about one half will conceive

Question 18

What management options are there for acne and hirsuitism associated with PCOS?

Answer 18

1st line: COCP
2nd line: cyproterone acetate OCP (Ginet)
3rd line:
- conventional acne treatments e.g. antibiotics, topical retinoids, isotretinoin
- Vaniqa – eflornithine hydrocholride a cream applied twice daily to prevent new hair growth.

If unsuitable for COCP or persistence on COCP trial anti androgens :

1. Spirinolactone 100–200mg/day. Renal function and potassium should be monitored if using with a drosperidone COCP.
2. Cyproterone acetate 50–100mg ten days/month. Liver function tests should be monitored.
3. Flutamide 250mg oral dosing. Liver function tests must be monitored – liver failure has been reported.
4. Finasteride 2.5mg oral dosing may be helpful for androgenic alopecia.

Question 19

What metabolic screening should be performed?

What cardiovascular screening should be performed?

Answer 19

Metabolic:

• OGTT and HbA1c
• Screening every 1-3 years depending on risk factors
• early OGTT in pregnancy and repeat at 24-28 weeks

Cardiovascular:

• Annual: BP, BMI, waist circumference, OGTT, smoking status
• If elevated BMI >25: fasting lipid profile

Question 20

With PCOS, what is the RR of getting GDM?

Answer 20

3

Question 21

With PCOS, what is the RR of getting T2DM?

Answer 21

2

Question 22

With PCOS, what is the RR of getting endometrial cancer?

Answer 22

2-6

Question 23

What five components make up metabolic syndrome?

Answer 23

Elevated BP
Increased waist circumference
Elevated fasting BSLs
Reduced high density lipoprotein cholesterol levels
Elevated triglyceride levels

Question 24

Ongoing management of cardiovascular risk factors for PCOS?

Answer 24

• Monitor for conversion to T2DM (fasting levels not as helpful for diabetes in women wit PCOS, should have OGTT)
• Measure cholesterol/lipid profile
• Manage BP
• Encourage lifestyle factors/weight loss
• Ask about sx of OSA- increased risk even when controlled for BMI with link. OSA a risk factor for CVD.

Question 25

What is the role of metformin in PCOS for reducing CVD risk?

Answer 25

Insulin sensitising agents such as metformin have a role when IGT or T2D has been diagnosed. However, there is no current evidence indicating that these drugs lower cardiovascular risk, and their routine use in PCOS is not recommended. Trials suggest that metformin is not superior to lifestyle intervention in improving cardio-metabolic risk or progression to T2D.

Question 26

When should bariatric surgery be considered?

Answer 26

where obesity is not controlled by lifestyle modifications.

Question 27

Risks of bariatric surgery?

Answer 27

0.1-1% mortality, risk of bowel obstruction, infection, oesophagitis nutritional abnormalities. ● perinatal risks such as small for gestational age, premature delivery, possibly increased infant mortality ● recommendations for pregnancy avoidance during periods of rapid weight loss and for at least 12 months after bariatric surgery with appropriate contraception. Bariatric surgery should be performed only when standard weight loss regimes have failed in PCOS women with a BMI greater than 40 or greater then 35 with a high-risk obesity related condition

Question 28

How to differentiate CAH from PCOS?

Answer 28

- 17-hydroxyprogesterone should be measured in the follicular phase and will be raised in CAH - If 17- hydroxyprogesterone is borderline, it will have to be confirmed by an ACTH stimulation test to diagnose CAH

Question 29

Which women with PCOS should be screened for diabetes?

Answer 29

All women should have glycemic status assessed by one of: OGTT, fasting plasma glucose or HbA1c OGTT is recommended in high-risk women with PCOS including: - BMI > 25kg/m2 or in Asians > 23kg/m2, - history of impaired fasting glucose, - impaired glucose tolerance or gestational diabetes, - family history of diabetes mellitus type 2, - hypertension - high-risk ethnicity.

Question 30

An endometrial thickness of less than ___mm is unlikely to be endometrial hyperplasia in women with PCOS?

Answer 30

7mm for every 1 mm increase in endometrial thickness, the odds ratio of hyperplasia increases by 1.48

Question 31

What lifestyle intervention techniques have been shown to be effective for weight loss?

Answer 31

motivational interviewing and established behaviour techniques appear more effective than traditional advice giving for changes in weight, diet and/or exercise. Suggesting ways to access support to help with weight loss and exercise, establishing self-monitoring (including pedometer use), time management techniques, relapse prevention techniques, individual tailoring, engaging social support and setting goals have all been shown to be useful. Individual, group and mixed interventions have been shown to be effective

Question 32

Role of weight loss and fertility in PCOS

Answer 32

Obese women with PCOS are more likely than thin women with PCOS to suffer from anovulation In obese, anovulatory women with PCOS, weight loss of even 5% to 10% of body weight often restores ovulatory cycles overweight women are also less likely to respond to pharmacologic ovulation induction methods Exercise increases insulin sensitivity

Question 33

Mechanism of action of metformin?

Answer 33

A biguanide insulin-sensitizing agent. Metformin works by decreasing gluconeogenesis, lipogenesis and enhancing glucose uptake in the liver, skeletal muscle, adipose tissue and ovaries. It is known in other populations to assist with weight loss, to prevent and manage DM2, gestational diabetes (GDM), and to reduce microvascular and cardiovascular disease in DM2 Side effects are not uncommon, yet these are primarily gastrointestinal, appear mild and self-limiting It does not stimulate secretion of insulin or cause hypoglycemia

Question 34

Metformin and fertility in PCOS?

Answer 34

Metformin combined with clomiphene citrate may increase ovulation rates and pregnancy rates but does not significantly improve the live birth rate over that of clomiphene citrate alone. Metformin may be added to clomiphene citrate in women with clomiphene resistance who are older and who have visceral obesity

Question 35

Ovulation induction with gonadotrophins in PCOS?

Answer 35

Second line treatment Higher risk of hyperstimulation Method: - Daily injections of gonadotropins combined with concurrent blood and ultrasound monitoring - Aim is monofollicular growth and development. However, multifollicular development is not uncommon, despite careful dose adjustment and monitoring. - Once the dominant follicle has reached the appropriate size, hCG is administered to trigger ovulation. Pregnancy rates with gonadotropins are 20% to 25% per cycle. Gonadotrophin induced ovulation is only triggered when ≤ 2 mature follicles, if 3 or more the patient advised to avoid unprotected intercourse due to risk OHSS and multiple pregnancy.

Question 36

What should be recommended to reduce risk of OHSS during IVF?

Answer 36

- GnRH antagonist short protocol; reduce the length of exposure/stimulation - lowest dose HCG trigger - Consider using metformin before and during follicle stimulation - Consider electively freezing all embryos

Question 37

Compare letrozole, clomiphene and clomiphene +metformin for ovulation induction

Answer 37

Letrozole has higher ovulation, pregnancy and live birth rates than CC. Reduced rate multiple pregnancies. Letrozole outcomes comparable to CC + metformin for women who are CC resistant.

Question 38

What is the increase in live birth rate when using letrozole vs clomiphene?

Answer 38

40-60% increased live birth rate.

Question 39

What are the risks of multiple pregnancy and OHSS with clomiphene?

Answer 39

multiple pregnancy 5-7% | OHSS <1%

Question 40

Evidence for laparoscopic ovarian surgery for ovulation induction.

Answer 40

A 15-25 year follow-up of nearly 150 women after ovarian wedge resection shows that regular menstrual patterns lasting up to 25 years after surgery were restored in 88% of patients with a cumulative pregnancy/live birth rate of 78% (MONASH)

Question 41

Why is USS not included in diagnostic criteria within 8 years of menarche?

Answer 41

Normal to have PCOM during this timeframe, leading to false diagnosis of PCOS. If high suspicion of PCOS - testing can be repeated after this time frame to confirm.

Question 42

What are the diagnostic values for HbA1c and OGTT for IR and diabetes mellitus?

Answer 42

insulin resistance - HbA1c 42-47 - OGTT fasting = 6.0-7.0, 2hr = 7.0 - 11.1 diabetes mellitus - Hba1c ≥ 48 - OGTT fasting > 7.0 and 2 hour after 75g glucose challenge >11.1