Polycystic ovary syndrome

Presentation by:
Marzeih Saei
PhD of Reproductive Health
Reproductive Endocrinology Research Center, Research institute for
Endocrine Sciences, Shahid Beheshti University of Medical Sciences

September 2020
Outlines

BACKGROUND 1

DEFINITION / PREVALENCE
2

ISSUES RELATED TO PCOS

3

APPROACH TO MANAGEMENT
4
 Background

• Ovarian Theca Cells >> Under the control of LH/IGF-1 >>

Produces Testosterone >> Granulosa cells convert (Aromatase
enzyme) to active Oestradiol

• Increased androgen production

• Increased free androgens

Background
Pathophysiology of polycystic ovary syndrome
Background

 1935 : Stein IF and Leventhal ML designated PCO

as a syndrome

 ’80s/’90s : Addition of ultrasound criteria

 2003 : Rotterdam Consensus Conference

 2018 : International evidence-based guideline for the

assessment and management of polycystic ovary syndrome
2018
The heterogeneous nature of PCOS
Diagnostic Criteria
 Irregular menstrual cycles

 Clinical hyperandrogenism

 Biochemical hyperandrogenism

 Ultrasound and polycystic ovarian morphology (PCOM)

Criteria for Diagnosis of PCOS
 polycystic ovary
 A polycystic ovary is defined as an ovary containing 12
 or more follicles (or 25 or more follicles using new ultrasound
technology) measuring 2 to 9 mm in diameter
 or an ovary that has a volume of greater than 10 mL on
 ultrasonography. A single ovary meeting either or both
 polycystic ovary
 Ultrasound should not be used for the diagnosis of PCOS in those with a
gynaecological age of < 8 years (< 8 years after menarche), due to the high
incidence of multi-follicular ovaries in this life stage.
 polycystic ovary
 Distribution of follicles
 Subcapsular cysts, produce a ‘string of pearls’ sign
Description of stroma
  stromal echogenicity &/or stromal volume

 Pathogenesis
  circulating insulin level   Ovarian size
 Exaggerated LH pulsatile messages
 multifollicularity, stroma,  androgen production
Hyperandrogenism: clinical
 Hyperandrogenism: clinical
 A comprehensive history and physical examination should be completed for
symptoms and signs of clinical hyperandrogenism, including acne, alopecia
and hirsutism and, in adolescents, severe acne and hirsutism

 Health professionals should be aware of the potential negative psychosocial

impact of clinical hyperandrogenism. Reported unwanted excess hair
growth and/or alopecia should be considered important, regardless of
apparent clinical severity.

 Standardised visual scales are preferred when assessing hirsutism, such as

the modified Ferriman Gallwey score (mFG) with a level ≥ 4 - 6
indicating hirsutism, depending on ethnicity, acknowledging that self-
treatment is common and can limit clinical assessment.
 Hyperandrogenism: clinical
The Ludwig visual score is preferred for assessing the degree and distribution
of alopecia.

There are no universally accepted visual assessments for evaluating acne.

As ethnic variation in vellus hair density is notable, over-estimation of

hirsutism may occur if vellus hair is confused with terminal hair; only terminal
hairs need to be considered in pathological hirsutism, with terminal hairs
clinically growing > 5mm in length if untreated, varying in shape and texture
and generally being pigmented.
Hyperandrogenism: clinical
 Biochemical

 Calculated free testosterone, free androgen index or calculated bioavailable testosterone

should be used to assess biochemical hyperandrogenism in the diagnosis of PCOS.

 Androstenedione and dehydroepiandrosterone sulfate (DHEAS) could be considered if

total or free testosterone are not elevated; however, these provide limited additional
information in the diagnosis of PCOS.

 Where assessment of biochemical hyperandrogenism is important in women on hormonal

contraception, drug withdrawal is recommended for three months or longer before
measurement, and contraception management with a non-hormonal alternative is needed
during this time.
 Irregular cycles and ovulatory dysfunction

 Irregular menstrual cycles are defined as:

 ● normal in the first year post menarche as part of the
pubertal transition
 ● > 1 to < 3 years post menarche: < 21 or > 45 days
 ● > 3 years post menarche to perimenopause:
 < 21 or > 35 days or < 8 cycles per year
 ● > 1 year post menarche > 90 days for any one cycle
 ● Primary amenorrhea by age 15 or > 3 years post
thelarche (breast development)
 When irregular menstrual cycles are present a diagnosis of
PCOS should be considered and assessed according to the
guidelines.
 Biochemical


Assessment of biochemical hyperandrogenism is most useful in establishing the diagnosis of PCOS
and/or phenotype where clinical signs of hyperandrogenism (in particular hirsutism) are unclear or
absent.

 Interpretation of androgen levels needs to be guided by the reference ranges of the laboratory used,
acknowledging that ranges for different methods and laboratories vary widely.

 Where androgen levels are markedly above laboratory reference ranges, other causes of biochemical
hyperandrogenism need to be considered. History of symptom onset and progression is critical in
assessing for neoplasia, however, some androgen-secreting neoplasms may only induce mild to
moderate increases in biochemical hyperandrogenism.
Screening, diagnostic assessment
Polycystic ovary syndrome phenotypes
Factors contributing to PCOS phenotype
 digit length ratio (2D:4D) and polycystic ovarian
syndrome (PCOS)

we can say that those with a lower ratio than the determined cut off values have
high probability of developing PCOS in adult life.
Prevalence
 Polycystic ovary syndrome: a
complex condition with
psychological, reproductive and
metabolic manifestations that
impacts on health across the
lifespan
 PCOS long term consequences
o Impaired glucose tolerance and diabetes
It is well known that obesity is observed in about 60% of women with PCOS.
o Cardiovascular disease and hypertension
Hyperinsulinemia appears to be the main reason for the increased
cardiovascular risk of women with PCOS.
o Endometrial cancer
Recent interest in the long term risks of PCOS has also focused on its
possible associations with endometrial cancer.
o Ovarian cancer
There has been much debate and concerns about the risk of ovarian cancer in
women with anovulation, particularly because of the extend use of drugs for
induction of ovulation to these patients
o Breast cancer
Obesity, hyperandrogenism and infertility are features known to be
associated with the development of breast cancer.
Infertility and PCOS:

 PCOS is reported as the cause of anovulatory

infertility in 70% of women, making it the
most common cause of ovulatory dysfunction
PCOS consequences
 PCOS and reactive hypoglycemia

Reactive hypoglycemia (RH) is defined as a drop in blood glucose (BG) levels 1½–5 h
after food consumption without indication of hypoglycemia due to other causes.

Two studies performed 5 h oral glucose tolerance test (5 h OGTT) and reported a
prevalence of RH of 50% (Altuntas et al., 2005) and 64% (Kasim-Karakas et al., 2007)
in PCOS. These studies, however, included only lean and young (Altuntas et al., 2005)
or obese (Kasim-Karakas et al., 2007) subgroups of patients with PCOS.
 PCOS and weight

Women with PCOS had increased prevalence of overweight [RR (95% CI): 1.95 (1.52,
2.50)], obesity [2.77 (1.88, 4.10)] and central obesity [1.73 (1.31, 2.30)] compared
with women without PCOS.

Clinical management of PCOS should include the prevention and

management of overweight and obesity.
 PCOS and Insulin Resistance

Acanthosis Nigricans.

Skin Tags.

Abdominal Obesity.
 PCOS and Obstructive sleep apnoea

Obstructive sleep apnea (OSA) is characterised by repetitive occlusions of the upper

airway during sleep with futile ventilatory efforts, oxygen desaturations, sleep arousal
and the resumption of ventilation, fragmenting sleep and causing daytime sleepiness.
OSA appears more common in PCOS and in obesity, a common corollary of PCOS.
 PCOS and Obstructive sleep apnoea

Screening should only be considered for OSA in PCOS to identify and alleviate related
symptoms, such as snoring, waking unrefreshed from sleep, daytime sleepiness, and
the potential for fatigue to contribute to mood disorders.
Screening should not be considered with the intention of improving cardiometabolic
risk, with inadequate evidence for metabolic benefits of OSA treatment in PCOS and
in general populations.
 Treatment

o PCOS treatment: What does the patient want?

o Fertility?
o Hirsutism?
o Acne?
o Obesity?
o Irregular periods?
o All off the above!!?
9/1/20 39
 lifestyle interventions

Healthy lifestyle behaviours encompassing healthy eating and regular physical

activity should be recommended in all those with PCOS to achieve and/or maintain
healthy weight and to optimize hormonal outcomes, general health, and quality of
life across the life course.

Lifestyle intervention (preferably multicomponent including diet, exercise and

behavioural strategies) should be recommended in all those with PCOS and excess
weight, for reductions in weight, central obesity and insulin resistance.
 lifestyle interventions
Physical activity includes leisure time physical activity, transportation such
as walking or cycling, occupational work, household chores, games, sports
or planned exercise, in the context of daily, family and community activities.
Daily, 10000 steps is ideal, including activities of daily living and 30 minutes
of structured physical activity or around 3000 steps. Structuring of
recommended activities need to consider women’s and family routines as
well as cultural preferences.

Achievable goals such as 5% to 10% weight loss in those with excess weight
yields significant clinical improvements and is considered successful weight
reduction within six months. Ongoing assessment and monitoring is
important during weight loss and maintenance in all women with PCOS.
Behavioral and Psychological Correlates of Weight
Management Success
Herbal medicine for the management of polycystic
ovary syndrome
 Herbal medicine for the management of polycystic
ovary syndrome

• Cinnamomum cassia
• Vitex agnus-castus
• Trigonella foenum-graecum

impact on menstrual and ovulatory dysfunctions, obesity, insulin

resistance, lipid-metabolism dysfunction, and androgen excess-related
conditions.
Pharmacological treatment for non-fertility indications

• COCPs, metformin and other pharmacological treatments are

generally off label in PCOS, as pharmaceutical companies have not
applied for approval in PCOS. However, off label use is
predominantly evidence-based and is allowed in many countries.
Where it is allowed, health professionals should inform women and
discuss the evidence, possible concerns and side effects of treatment.
Comprehensive Assessment Before Prescription of an
OC in PCOS
Contraindications to the Use of Low-Dose Combined OC Pills
Noncontraceptive benefits of hormonal contraception in
women with PCOS

Management of hyperandrogenism symptoms

Impact On Risk Of Endometrial Cancer

Second line pharmacological therapies

COCP + lifestyle + metformin

COCP + anti-androgens

Metformin + lifestyle
Metformin
Metformin
 COCP + lifestyle + metformin
 Should be considered in women with PCOS for management of
metabolic features, where COCP + lifestyle does not achieve goals.

 Could be considered in adolescents with PCOS and BMI ≥ 25kg/m2

where COCP and lifestyle changes do not achieve desired goals.

 Most beneficial in high metabolic risk groups including those with

diabetes risk factors, impaired glucose tolerance or high-risk ethnic
groups.
 COCP + anti-androgens
 Evidence in PCOS relatively limited.

 Anti-androgens must be used with contraception to prevent male fetal

virilisation.

 Can be considered after 6/12 cosmetic treatment + COCP if they fail to

reach hirsutism goals.

 Can be considered with androgenic alopecia.

 Side effects of SP in PCOS
The most frequent side effects are reduced blood pressure, hyperkalemia, and
polyuria

intermenstrual bleeding
 Metformin + lifestyle
 With lifestyle, in adults should be considered for weight, hormonal and
metabolic outcomes and could be considered in adolescents.

 Most useful with BMI ≥ 25kg/m2 and in high risk ethnic groups. Side-
effects, including GI effects, are dose related and self-limiting. Consider
starting low dose, with 500mg increments 1-2 weekly.

 Metformin appears safe long-term. Ongoing monitoring required and has

been associated with low vitamin B12.
 Effectiveness of lifestyle interventions

Achievable goals such as 5% to 10% weight loss in those with excess weight
yields significant clinical improvements and is considered successful weight
reduction within six months.

Ongoing monitoring is important in weight loss and maintenance. Consider

referral to a professional to assist with healthy lifestyle.

To achieve weight loss in those with excess weight, an energy deficit of 30% or
500 - 750 kcal/day (1,200 - 1,500 kcal/day) could be prescribed

for women, also considering individual energy requirements, body weight, food
preferences and physical activity levels and an individualised approach.
 Effectiveness of lifestyle interventions
Health professionals should encourage and advise the following for prevention
of weight gain and maintenance of health:

● in adults from 18-64 years, a minimum of 150 min/week of moderate

intensity physical activity or 75 min/week of vigorous intensities

● in adolescents, at least 60 minutes of moderate to vigorous intensity physical

activity/day including those that strengthen muscle and bone at least 3 times
weekly.

● activity be performed in at least 10 minute bouts or around 1000 steps,

aiming to achieve at least 30 minutes daily on most days.
 Effectiveness of lifestyle interventions
Health professionals should encourage and advise the following for modest
weight-loss, prevention of weight-regain and greater health benefits including:

● a minimum of 250 min/week of moderate intensity activities or 150

min/week of vigorous intensity or an equivalent combination of both, and
muscle strengthening activities involving major muscle groups and minimised
sedentary, screen or sitting time.
 Cardiovascular disease risk and weight
management
All with PCOS should be offered regular monitoring for weight change and
excess weight, in consultation with and where acceptable to the individual.
Monitoring could be at each visit or at a minimum 6-12 monthly, with
frequency planned and agreed between the health professional and the
individual.
 Gestational diabetes, impaired glucose tolerance and
type 2 diabetes

Regardless of age, gestational diabetes, impaired glucose tolerance and type 2

diabetes (5 fold in Asia, 4 fold in the Americas and 3 fold in Europe) are
increased in PCOS, with risk independent of, yet exacerbated by obesity.

Glycaemic status should be assessed at baseline in all with PCOS and

thereafter, every one to three years, based on presence of other diabetes risk
factors.

An OGTT should be offered in all with PCOS when planning pregnancy or

seeking fertility treatment, given increased hyperglycaemia and comorbidities
in pregnancy.
 Endometrial cancer
Health professionals and women with PCOS should be aware of a two to six
fold increased risk of endometrial cancer, which often presents before
menopause; however absolute risk remains relatively low.

Health professionals should have a low threshold for investigation of

endometrial cancer in PCOS, with transvaginal ultrasound and/or endometrial
biopsy recommended with persistent thickened endometrium and/or risk factors
including prolonged amenorrhea, abnormal vaginal bleeding or excess weight.
Routine ultrasound screening of endometrial thickness in PCOS is not
recommended.

Optimal prevention for endometrial hyperplasia and endometrial cancer is not

known. A pragmatic approach could include COCP or progestin therapy in
those with cycles longer than 90 days.
 Assement and teratment of infertility
.
 Summary of treatment options in polycystic ovary
syndrome (PCOS)

Oligomenorrhoea/amenorrhoea

• Lifestyle change (5% to 10% weight loss and structured exercise).

• Oral contraceptive pill (OCP; low oestrogen doses, for example 20 μg may be
preferable).

• Cyclic progestins (for example, 10 mg medroxyprogesterone acetate for 14

days every 2 to 3 months).

• Metformin (improves ovulation and menstrual cyclicity).

 Summary of treatment options in polycystic ovary
syndrome (PCOS)

Hirsutism treatment recommendations

• Cosmetic therapy.

• Laser treatment.

• Eflornithine cream can be added and may induce a more rapid response.
 Summary of treatment options in polycystic ovary
syndrome (PCOS)
Pharmacological therapy

• Medical therapy if patient concerned about hirsutism and cosmetic therapy

ineffective, inaccessible or unaffordable.

• Primary therapy is the OCP (monitor glucose tolerance in those at risk of

diabetes).

• Antiandrogen monotherapy should not be used without adequate

contraception.

• Combination therapy: if ≥ 6 months of OCP is ineffective, add antiandrogen

to OCP (daily spironolactone 50 mg twice a day or cyproterone acetate 25 mg/
day for days 1 to 10 of the active OCP tablets).
 Summary of treatment options in polycystic ovary
syndrome (PCOS)

Infertility

• Obesity independently exacerbates infertility and reduces effectiveness of

interventions. Maternal and foetal pregnancy risks are greater and long-term
metabolic outcomes in the child are related to maternal weight at conception.
Consistent with international guidelines, women who are overweight prior to
conception should be advised on folate, smoking cessation, weight loss and
optimal exercise, prior to additional interventions.
 Emotional wellbeing

Health professionals should capture and consider perceptions of symptoms,

impact on quality of life and personal priorities for care to improve patient
outcomes.

Anxiety and depressive symptoms should be routinely screened in all

adolescents and women with PCOS at diagnosis. If the screen for these
symptoms and/or other aspects of emotional wellbeing is positive, further
assessment and/or referral for assessment and treatment should be completed
by suitably qualified health professionals, informed by regional guidelines
 Psychosexual function

All health professionals should be aware of the increased prevalence of

psychosexual dysfunction and should consider exploring how features of
PCOS, including hirsutism and body image, impact on sex life and
relationships in PCOS.
Significant small effect sizes were found on sexual function subscales (total
score: P = 0.006; arousal: P = 0.019; lubrication: P = 0.023; satisfaction: P =
0.015; orgasm: P = 0.028), indicating impaired sexual function in women with
PCOS. Large effect sizes for the effect of body hair on sex were shown on VAS
(P = 0.006); social effect of appearance (P = 0.007); sexual attractiveness (P <
0.001).
PCOS in Epilepsy
 Menstrual disturbances are said to occur more frequently in
women with epilepsy, especially those with complex partial
seizures originating in the temporal lobe.
 Prevalence of PCOS is generally regarded in western WWE
to be about 3–4 times of that in the general population.

 The etiology of PCOS in WWE is complex and includes

epilepsy itself as well as the administration of antiepileptic
drugs (AEDs). It has been proposed that epileptic electrical
discharges alter secretion of pituitary and gonadal hormones,
thus resulting in reproductive dysfunction.
Potential causes of the increased
risk in pregnancy complications
Pregnancy and PCOS:

 Multiple pregnancy
 Multiple pregnancies are the most important cause of the increased
.
perinatal morbidity observed following fertility treatments

 Miscarriage
 It is still debated whether women with PCOS have an increased
risk of miscarriage
 Pregnancy-induced hypertension and pre-eclampsia
 3–4-fold increased risk
 Gestational diabetes mellitus
Neonatal Outcome and PCOS:

 neonatal hypoglycemia
 SGA
 LGA
 Preterm
 low Apgar score (<7) at five minutes
 meconium aspiration
breastfeeding and PCOS:

 It is important to know that many mothers with PCOS

have no problem with milk supply and breastfeed
successfully.

 Androgens such as testosterone inhibit lactation

 Women with PCOS appear to have a reduced

breastfeeding rate in the early postpartum period.
Possibly, gestational dehydroepiandrosterone-sulphate
might negatively influence breastfeeding rate in
women with the
 syndrome
long-term impacts on health and development:

 Maternal PCOS status may negatively influence

offspring infant and childhood growth,
cardiometabolic health, reproductive health, and
neurodevelopment.
Polycystic ovary syndrome (PCOS) and COVID-19:
 References

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1573.
• Polycystic Ovary Syndrome, ACOG Practice Bulletin, Number 194
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of-polycystic-ovary-syndrome/
• Long term health consequences of polycystic ovarian syndrome: a review
analysis. Hippokratia. 2009 Apr-Jun; 13(2): 90–92.
• Pregnancy complications in women with polycystic ovary syndrome. Human
Reproduction Update, Volume 21, Issue 5, September/October 2015, Pages
575–592, https://doi.org/10.1093/humupd/dmv029
• Lifestyle and Behavioral Management of Polycystic Ovary Syndrome.
• JOURNAL OF WOMEN’S HEALTH. Volume 00, Number 00, 2017

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