Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex hormonal condition that primarily involves:

1.         Menstrual dysfunction / anovulation

And

2.         Signs of hyperandrogenism.

The exact aetiology PCOS is essentially unknown but it does have familial and genetic associations.

The Rotterdam criteria are used for diagnosis.

Many women are not diagnosed or have long delays before the condition is recognised.

Of relevance to the ED setting, patients may present with: 

1.         Ovarian cyst complications

2.         Pregnancy related complications:

            Although fertility is reduced, PCOS does not exclude the possibility of pregnancy

            For those who do become pregnant there is a greater incidence of

            ●          Preterm birth

            ●          Pre-eclampsia

            ●          Miscarriage

            ●          Gestational diabetes

3.         Diabetes

4.         Psychological / psychiatric conditions  

5.         PV bleeding – consider possibility of endometrial malignancy. 

6.         Increased risk of VTE (from obesity / oral contraceptive pill).

History

PCOS was first described in 1935 by the American gynecologists Irving F. Stein, and Michael L. Leventhal

The original name of the condition was Stein – Leventhal syndrome.

Epidemiology

Polycystic ovary syndrome (PCOS) is one of the most common hormonal conditions in women of reproductive age and often presents in adolescence with further manifestations in later reproductive life.

In Australia Polycystic ovary syndrome (PCOS) affects 8 – 13% of reproductive age women, with a higher incidence of up to 21% of Indigenous women affected.

Pathophysiology

The exact aetiology PCOS is essentially unknown but it does have familial and genetic associations.

Genomic markers have been identified but these have a low predictive value.

Intrauterine events may predispose to this condition, including:

1.         Hyperandrogenemia

2.         Excess maternal hormones, such as anti-Müllerian hormone, acting directly and indirectly on the developing endocrine system.

During infancy and childhood, excess weight gain is a significant predisposition to PCOS.

Metabolic abnormalities include:

1.         Androgen excess

Women with PCOS have abnormalities in the metabolism of androgens and estrogen and in the control of androgen production.

High serum concentrations of androgenic hormones are seen including:

●          Testosterone

●          Androstenedione

●          Dehydroepiandrosterone sulfate (DHEA-S)

2.         Diabetes:

            PCOS is associated with: 

            ●          Peripheral insulin resistance

            ●          Hyperinsulinemia

3.         Dyslipidaemia

            ●          Hyperinsulinemia is thought to be responsible for the dyslipidaemia

Clinical features

Obtaining a timely formal diagnosis of PCOS diagnosis is challenging. Many women consult multiple different doctors.

Many are not diagnosed or have long delays before the condition is recognised.

In adults where menstrual abnormalities occur with hyperandrogenism, ultrasound is not required for diagnosis.

In adolescents (within 8 years of menarche), both menstrual abnormalities and hyperandrogenism are necessary for diagnosis, and ultrasound is not recommended owing to inaccuracy and risk of over-diagnosis at this life stage.

Diagnostic criteria:

Adult women:

Rotterdam diagnostic criteria require two of:

1.         Oligo or anovulation

2.         Clinical and/or biochemical hyperandrogenism

3.         Polycystic ovaries, (as defined on ultrasonography):

●          However, when the combination of hyperandrogenism and ovulatory          dysfunction is present, ultrasound examination of the ovaries is not            necessary for diagnosis of PCOS in adult women.

After exclusion of other aetiologies

Adolescents:

Diagnostic criteria require:

1.         Oligo – or anovulation

And

2.         Clinical and/or biochemical hyperandrogenism

After exclusion of other aetiologies

Note that Ultrasound is not recommended in diagnosis for those < 8 years post menarche.

Oligoovulation is infrequent or irregular ovulation:

Irregular menstrual cycles are defined as:

Age	Pattern
First year post menarche	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
Age 15 or > 3 years post thelarche (breast development)	Primary amenorrhea

Phenotypes:

4 specific phenotypes are recognized:

The natural history and clinical implications of the phenotypes however remain unclear.

The phenotypes are:

Phenotype	Features
Phenotype A	Androgen excess + ovulatory dysfunction + polycystic ovarian morphology.
Phenotype B	Androgen excess + ovulatory dysfunction
Phenotype C	Androgen excess + polycystic ovarian morphology
Phenotype D	Ovulatory dysfunction + polycystic ovarian morphology

Ethnic variation in PCOS:

In general terms ethnic variations may occur in PCOS including:

●          Relatively milder phenotypes in Caucasians, but higher BMIs are seen,      especially in North America and Australia.

●          Greater hirsutism in Middle Eastern, Hispanic and Mediterranean women.

●          Increased central adiposity, insulin resistance, diabetes, metabolic risks and           acanthosis nigricans in South East Asians and Indigenous Australians.

●          Lower BMI and milder hirsutism in East Asians.

●          Higher BMI and metabolic features in Africans.

Complications:

These include:

1.         Menstrual abnormalities / reduced fertility

            ●          Anovulation

            ●          Oligoovulation (reduced and/ or irregular ovulation) 

2.         Obstetric complications:

Although fertility os reduced, PCOS does not exclude the possibility of pregnancy

            For those who do become pregnant there is a greater incidence of

            ●          Preterm birth

            ●          Pre-eclampsia

            ●          Miscarriage

            ●          Gestational diabetes

3.         Hyperandrogenism / virilizing signs 

            These include:

            ●          Hirsutism

            ●          Acne

            ●          Male-pattern hair loss (androgenic alopecia).

4.         Weight gain:

Weight gain and obesity is common in PCOS

This increases the severity of the condition, and can cause considerable concern for those affected and mandates attention to healthy lifestyle.

5.         Endocrine 

            Diabetes

●          PCOS is an insulin resistant (regardless of BMI) and metabolic disorder

●          Gestational diabetes and type 2 diabetes, which is at least four times more common and appears at a younger age than in women without PCOS.

6.         Metabolic:

            ●          Dyslipidaemia 

            ●          Association with the metabolic syndrome:

Metabolic syndrome is not a disease in itself, but a collection of risk factors that often occur together.

A person is diagnosed as having metabolic syndrome when they have any three or more of:

♥          Central (abdominal) obesity

 ♥         Hypertension

♥          High blood triglycerides

♥          Low levels of high-density lipoproteins (HDL) – the “good”            cholesterol

♥          Impaired fasting glucose or diabetes.

♥♥       Impaired fasting glucose occurs when blood glucose levels are higher than normal, but not high enough to be      diagnosed as type 2 diabetes.

7.         CVS disease:

Risk factors for cardiovascular disease are also more prevalent in women with PCOS, including:

            ●          Dyslipidaemia

            ●          Hypertension 

8.         Respiratory:

            Sleep apnoea

●          Many women with PCOS have obstructive sleep apnoea which is an           independent risk factor for cardiovascular disease

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.

9.         Endometrial malignancy:

Endometrial hyperplasia and carcinoma, may occur as a result of chronic anovulation.

●          PCOS has a 2 – 6-fold increased risk of endometrial cancer, which often     presents before menopause; however absolute risk still remains relatively    low.

There should be 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.

10.       Dermatological:

            Acanthosis nigricans

●          Acanthosis nigricans is a diffuse thickening and hyperpigmentation of the skin.

It may be present at the nape of the neck, axillae, area beneath the breasts, intertriginous areas, and exposed areas.

In patients with PCOS, acanthosis nigricans is thought to be the result of insulin resistance, although syndromic and familial variants are described. Acanthosis nigricans can also be a cutaneous marker of malignancy.

11.       Non-alcoholic steatohepatitis:

The prevalence of non-alcoholic steatohepatitis (NASH) appears to be increased in women with PCOS.

Both weight loss and metformin use appear to improve metabolic and hepatic function in these women

12.       Increased risk of venous thromboembolism (VTE):

This is due to obesity and use of the oral contraceptive pill.

There have been concerns that the presence of PCOS per se may also represent an additional independent risk factor for VTE, but there is no current evidence to support this concept.

13.       Psychological / psychiatric disorders:

There is a high prevalence of moderate to severe anxiety and depressive symptoms in adults; and a likely increased prevalence in adolescents.

There is high potential for significant psychosocial impact due to infertility and /or clinical hyperandrogenism.

Perception of unwanted face and body hair and/or alopecia are important, regardless of apparent clinical severity.

Manifestations can include:

            ●          Anxiety

            ●          Depression

            ●          Eating disorders

Investigation

Blood tests:

Blood tests used in the diagnosis of, or the evaluation of complications of, PCOS include:

1.         FBE

2.         U&Es/ glucose

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 people with PCOS and thereafter, every 1 – 3 years, based on presence of other diabetes risk factors.

In high risk women with PCOS (including a BMI > 25kg/m2 or in Asians > 23kg/m2, history of abnormal glucose tolerance or family history of diabetes, hypertension or high risk ethnicity) an oral glucose tolerance test (OGTT) is recommended. Otherwise a fasting glucose or HbA1c should be performed.

An OGTT should be offered in all with PCOS when planning pregnancy or seeking fertility treatment, given increased hyperglycaemia and comorbidities in pregnancy.

If not performed preconception, an OGTT should be offered at < 20 weeks gestation, and all women with PCOS should be offered the test at 24-28 weeks gestation.

3.         Beta HCG:

●          Most of the drugs used to treat the complications of PCOS are         contraindicated in pregnancy.

4.         LFTs

5.         Thyroid function tests

            ●          To help exclude other causes of menstrual irregularities.

6.         Serum prolactin level

            ●          To exclude hyperproplactinemia.

7.         Biochemical hyperandrogenism:

For diagnosis use:

●          Calculated free testosterone

●          Free androgen index

●          Calculated bioavailable testosterone

Androstenedione and dehydroepiandrosterone sulfate (DHEAS) have only a limited role in PCOS diagnosis.

Interpretation of androgen levels should be guided by the reference ranges of the laboratory used.

Reliable assessment of biochemical hyperandrogenism is not possible on hormonal contraception. Consider withdrawal for ≥ 3 months before testing, advising non-hormonal contraception during this time.

In diagnosis, biochemical hyperandrogenism is most useful when clinical hyperandrogenism is unclear.

Where levels are well above laboratory reference ranges, other causes should also be considered.

The history of symptom onset and progression is critical in assessing for the possibility of neoplasia, however, some androgen-secreting neoplasms may only induce mild to moderate increases in biochemical hyperandrogenism.

8.         Sex hormones:

●          Androstenedione level

●          FSH and LH levels

●          GnRH stimulation testing

9.         Blood lipid screen.

Overweight and obese women with PCOS, regardless of age, should have a fasting lipid profile a diagnosis:

●          Total cholesterol

●          Low density lipoprotein cholesterol

●          High density lipoprotein cholesterol

●          Triglyceride level

Thereafter, measurement should be guided by the results and the global (i.e overall) CVD risk.

Ultrasound:

There is potential for over diagnosis, when isolated polycystic ovarian morphology on ultrasound is incorrectly equated with PCOS.

Ultrasound should not be used for the diagnosis of PCOS in those with a gynaecological age of < 8 years (i.e < 8 years after menarche) due to the high incidence of multi-follicular ovaries in this life stage.

The transvaginal ultrasound approach is preferred in the diagnosis of PCOS, if sexually active and if acceptable to the individual being assessed.

Using endovaginal ultrasound transducers with a frequency bandwidth that includes 8MHz, the threshold for PCOM should be:

●          A follicle number per ovary of ≥ 20

And / or

●          An ovarian volume ≥ 10 ml

on either ovary, ensuring no corpora lutea, cysts or dominant follicles are present.

If using older technology, the threshold for PCOM could be an ovarian volume ≥ 10ml on either ovary.

In patients with irregular menstrual cycles and hyperandrogenism, an ovarian ultrasound is not necessary for PCOS diagnosis; however ultrasound will identify the complete PCOS phenotype.

Transabdominal ultrasound should primarily report ovarian volume with a threshold of ≥ 10 ml, given the difficulty of reliably assessing follicle number with this approach.

Management

In general terms:

1.         Lifestyle modifications are important:

●          Healthy diet

●          Exercise

●          Weight loss:

            Weight loss should be considered a first line management strategy.

Weight loss, can help restore ovulatory cycles and improve metabolic risk.

Achievable goals such as 5 – 10% weight loss in those with excess weight yields significant clinical improvements and is considered successful weight reduction within 6 months.

Ongoing monitoring is important in weight loss and maintenance.

There is no good evidence that one particular type of diet is superior to another for women with PCOS.

Consider referral to a professional to assist with healthy lifestyle.

2.         Virilizing complications: 

            Oral contraception:

●          Combined estrogen-progestin oral contraceptives are the mainstay of    pharmacologic therapy for women with PCOS for managing:

            ♥          Hyperandrogenism

            ♥          Menstrual dysfunction

            ♥          Contraception.

            Additional strategies for virilizing complications include:

            Anti-androgens:

            ●          Spironolactone

            ●          Leuprolide

            ●          Finasteride

            Physical treatments:

            ●          Bleaching

            ●          Laser therapies

3          Menstrual abnormalities are managed with:

            ●          Oral contraceptive pill

            ●          Progestins.

4.         Metformin:

For diabetes:

●          Metformin is an insulin sensitizer 

            It can prevent or delay diabetes in individuals with impaired glucose         tolerance.

            Metformin is not a specific weight loss agent.   

            For menstrual regulation:

●          Metformin can also help restore menstrual cyclicity as it restores   ovulatory menses in approximately 30 – 50 % of women with PCOS

It is thought to reduce ovarian androgen production (and serum free testosterone concentrations) and so restore normal menstrual cyclicity.

The action of metformin is synergistic with clomiphene in restoring ovulation.  

Thiazolidinediones (or “Glitazones” e.g.pioglitazone, rosiglitazone) have been less well studied than metformin, but they also appear to improve insulin sensitivity and hyperandrogenemia. However, because of limited clinical data, potential weight gain, and a possible association with cardiovascular adverse events, \ the use of thiazolidinediones in women with PCOS is not routinely recommended.   

5.         Infertility:

Infertility may be managed in the first instance by:

●          Oral agents to induce ovulation

Letrozole is now considered first line treatment for infertility as it improves live birth rates while reducing the incidence of multiple pregnancies compared with the older agent clomiphene.

Letrozole works by inhibiting aromatase thereby suppressing estrogen production. Clomiphene citrate, on the other hand, blocks estrogen receptors. In both cases, the result is that the pituitary gland produces more of the hormones needed to stimulate the ovaries

●          Gonadotrophins if the above fail.

Gonadotropin-releasing hormone (GnRH) agonists are sometimes used to suppress ovarian androgen production.

●          The use of in vitro fertilisation is generally only necessary where there is             another factor contributing to infertility.

            ●          Surgery – “Ovarian Laser Drilling”: ³

For women who do not respond to ovulation induction with either letrozole or clomiphene, laparoscopic ovarian laser drilling (also referred to as laparoscopic ovarian diathermy or electrocoagulation) is a surgical option.

When compared with gonadotropin therapy, ovarian drilling has similar efficacy

Disadvantages of ovarian drilling include surgical risk and potential adhesion formation.

Although laparoscopic ovarian drilling has been utilized for decades, the technique has never been standardized regarding the energy source, number of punctures, dose and duration per puncture, or whether one or both ovaries should be treated.

Ovarian drilling likely reduces ovarian secretion of androgens, resulting in an increase in LH and FSH secretion. In turn the ovary is more responsive to stimulation by endogenous gonadotropins favoring the growth of a dominant ovarian follicle and ovulation.

6.         Metabolic abnormalities:

Metabolic abnormalities require adequate investigation, with treatment based around lifestyle management and/or the appropriate medication for impaired glucose or lipid metabolism.

The approach to treatment of dyslipidemia in women with PCOS is the same as for other patients with dyslipidemia. Exercise and weight loss are the first-line approach, followed by pharmacotherapy, if needed. Statins are effective for dyslipidemia in women with PCOS but do not appear to have other clinically important metabolic or endocrine effects.

7.         Sleep apnea:

For women with PCOS and obstructive sleep apnea, continuous positive airway pressure (CPAP) can improve insulin sensitivity and reduce diastolic blood pressure.

8.         Psychological support:

Emotional issues require awareness, screening and management, including controlling common and often-distressing features of PCOS such as anxiety, depression and eating disorders, which are partly dependent on cosmetic and body image issues.

Disposition:

Doctors often focus on individual features of PCOS in line with their particular specialty (such as infertility by Gynaecologists), rather than taking a broader holistic approach to care.

The management of PCOS must be a multidisciplinary, and will/ may involve:  

1.         General Practitioner:

●          It is vital for patients to have a GP, who will take a holistic approach to      management and its coordination.

All patient interactions should be patient-centred and value women’s individualised healthy lifestyle preferences and cultural, socioeconomic and ethnic differences.

2.         Paediatrics

3.         Dietetics

4.         Endocrinology

5.         Gynaecology / Obstetrics / Infertility specialists.

6.         Psychology

7.         Psychiatry

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References

FOAMed

Publications

• Teede HJ, Misso ML, Boyle JA, Garad RM, McAllister V, Downes L, Gibson M, Hart RJ, Rombauts L, Moran L, Dokras A, Laven J, Piltonen T, Rodgers RJ, Thondan M, Costello MF, Norman RJ; International PCOS Network. Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Med J Aust. 2018 Oct 1;209(S7):S3-S8.