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Polycystic ovarian syndrome (PCOS)

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OLIGOMENORRHOEA  (< 9 menstrual cycles/ year)

DIFFERENTIALS:

  • Pregnancy
  • PCOS
  • Obesity
  • Hypothyroidism
  • Cushing’s
  • Late onset congenital adrenal hyperplasia (CAH)
  • Androgen secreting tumours
  • Hyperprolactinaemia
  • Menopause
  • Hormonal contraception
  • Exogenous androgens
  • Asherman syndrome (adhesions and fibrosis of the endometrium related  to previous uterine surgical interventions)

Polycystic ovary syndrome

  • Spectrum of reproductive and metabolic problems
    • Reproductive morbidities
      • Anovulation
        • oligomenorrhea or amenorrhea (1o or 2o)
        • infertility
        • DUB
        • endometrial hyperplasia/Ca
      • Androgen excess
        • Hirsutism
  • Acne 
  • androgen alopecia (infrequent)
  • polycystic ovaries
    • on ultrasound
  • Metabolic morbidities
    • Hypertension
    • Dyslipidaemia (increased TC, LDL-C, TG;s & decreased HDL-C)
    • hyperinsulinemia
    • Abnormal glucose metabolism- IGT, NIDDM, GDM
    • ? CVD (coronary disease, myocardial infarction)
  1. increases CVD risk factors (obesity, diabetes, IR, hypertension, dyslipidaemia etc)
  2. no direct evidence of an increased risk of coronary events.

Incidence prevalence

  • polycystic ovaries common on ultrasound but most are asymptomatic
  • 33% had polycystic ovaries on ultrasound

Causes ‘- may be insulin resistance with resultant hyperinsulinemia stimulating excess ovarian androgen production

Non-Invasive Pregnancy Analysis – Arbor Assays

Diagnosis (Rotterdam consensus group criteria)

  • If 2 out of 3 criteria present
    • Oligo and/or anovulation
    • Hyperandrogenism
      • clinical (hirsutism or less commonly male pattern alopecia) or
      • biochemical (raised total testosterone /or free testosterone /or free androgen index (FAI) /or  dehydroepiandrosteronesulphate (DHEAS))
    • PCO on ultrasound
      • At least 1 ovary with 12+ follicles 2-9 mm &/or 
      • increase in ovarian volume > 10mls
  • With the exclusion of other hyperandrogenic disorders including
    • LOCAH(late onset congenital adrenal hyperplasia)
    • hyper Prl (prolactin)
    • androgen secreting ovarian tumour
    • Cushings syndrome. 

Assessment

  • History
    • Anovulation – Irregular menstrual bleeding, oligomenorrhoea, infertiliy
    • Menstrual disturbance
    • Androgen excess
      • Hirsutism
      • Acne
      • androgenic alopecia
      • Virilization (clitoromegaly, deep voice, breast atrophy, significant hirsutism, muscularity, male body habitus, increased libido) is rarely seen in PCOS and is suspicious of an androgen secreting tumour.
    • Infertility, recurrent miscarriages
    • Psychological symptoms
      • anxiety, depression, psychosexual dysfunction, eating disorders
  • +/- insulin resistance associated with:
  • metabolic syndrome –  obesity, dyslipidaemia, diabetes
  • nonalcoholic fatty liver disease (NAFLD)
  • sleep apnea
  • diabetes mellitus type 2/prediabetes
  • cardiovascular disease
  • FHx (PCOS, T2DM, obesity)

Examination

  • BMI
  • BP
  • Hirsutism
  • PVE- usually unhelpful and only necessary to exclude other causes of bleeding and miscarriage.
  • Acanthosis nigracans- a hyperpigmented hyperplasia of the skin typically seen in the axillae, skin flexures, under the breasts, and nape of the neck – is a marker associated with IR (insulin resistance).

Investigations 

  • Pelvic Ultrasound +/- Endometrial sampling
    • Ovaries
    • Endometrial thickness – exclude endometrial hyperplasia
    • Ultrasound is not reliable in the diagnosis of polycystic ovaries in adolescent and young women. 
    • Up to 70% of young women may have polycystic ovaries on ultrasound
  • Hormones  – done On Day 2-5 cycle if regular cycles or oligomenorrhoea
    • BHCG if amenorrhea
      • Exclude pregnancy
    • gonadotropin levels – FSH/LH, E2
      • Raised LH in 50% of patients
      • Exclude other causes of anovulation such as Hypogonadotropic hypogonadism, Premature Ovarian Failure
    • Thyroid
      • Hypothyroidism – cause anovulation
    • Prolactin
      • exclude hyperprolactinaemia, another cause of anovulation, with the caveat that some PCOS patients may have prolactin levels slightly above normal 
    • 17OHP
      • Exclude congenital adrenal hyperplasia 
    • Androgens – help confirm PCOS and exclude androgen producing tumours
      • DHEAS
        • Measures adrenal activity
        • normal 250-300 ng/dl
        • DHEAS <700 ng/dl: Hyperandrogenic chronic Anovulation
        • DHEAS >700 ng/dl: Adrenal tumor Secreting androgens
      • free testosterone/free androgen index/bioavailable testosterone
        • Hormonal contraceptive use will affect free testosterone measures.
        • If appropriate, assess after 3 months cessation
        • alternative contraception should be discussed for this time
        • If free testosterone is significantly raised or there is evidence of rapid virilisation, further investigations are required to exclude late onset congenital adrenal hyperplasia and virilising tumours
  • Metabolic screen
    • oGTT, insulin – markers of insulin resistance/hyperinsulineamia
    • fasting lipids 
    • Dexamethasone Suppression Test (AM Serum Cortisol)
      • Assess for Cushing’s Syndrome

Management:

  • Counselling- about PCOS (reproductive and metabolic)
  • Weight loss 
    • if BMI>25 is the best first line treatment for PCOS
    • Even a small amount of weight loss (5%) can help restore menstrual cycle regularity and ovulation, assist mental wellbeing, halve the risk of diabetes in high risk groups and help prevent future cardiometabolic risk
      • healthy diet with caloric restriction
      • behaviour change support 
      • exercise – 150 minutes of exercise weekly with 90 minutes of this exercise being aerobic activity at moderate to high intensity
  • Endometrial protection or cycle control 
    • Combined oral contraceptive pill
      • (low oestrogen doses, eg. 20 µg may have less impact on insulin resistance)
    • Cyclic progestins
      • (eg. 10 mg medroxyprogesterone acetate 10–14 days every 2–3 months) – to induce a withdrawal bleed and protect the endometrium from hyperplasia.
    • Metformin (improves ovulation and menstrual cyclicity)
    • combined oral contraceptive pill (COCP) 
  • Specific Treatments (symptom Mx, as aetiology unknown)
    • Infertility
      • Advise smoking cessation, optimal weight, exercise and folate supplementation
      • Advise regarding the age-related decline in fertility to allow optimal timing of family planning
      • Ovulation induction
        • Weight loss if BMI>25
        • Medical
          • Clomiphene citrate (CC)
            • has a pregnancy rate of 30–50% after six ovulatory cycles
          • gonadotrophins /FSH
          • Metformin
            • in women with a BMI <30–32 kg/m2, metformin may have a similar efficacy to clomiphene citrate
          • Metformin and CC
        • Surgical
          • Laparoscopy with ovarian surgery/drilling (LOS) is a suitable second line treatment if clomiphene citrate with metformin has failed.
          • IVF
    • Hirsutism
      • Weight loss if BMI>25
      • Cosmetic (mechanical/physical hair removal)
        • Temporary: shaving, plucking, bleaching, depilating creams
        • Permanent: electrolysis, laser
      • Medical
        • Androgen suppressive therapies
          • OCP
          • Insulin sensitizers such as metformin
          • GnRH agonists
        • Anti-androgen monotherapy
          • eg. Spironolactone, Aldactone or Cyproterone acetate
          • should not be used without adequate contraception
          • Combination therapy
            • if 36 months of COCP is ineffective, add anti-androgen to COCP
              • spironolactone >50 mg twice daily or
              • cyproterone acetate 25 mg/day, days 1–10 of COCP
              • spironolactone 50-100 mg/day may reduce hair growth  and may be more effective than metformin laser treatment may improve facial hair, depression, anxiety, and quality of life in women with facial hirsutism and PCOS 
      • Cardiometabolic risk
        • Lifestyle change with a >5% weight loss in those who are overweight reduces diabetes risk by ~50–60% in high risk groups
        • Metformin* reduces the risk of diabetes by ~50% in adherent high risk group

Indications for specialist consultation 

  • Abnormal unexplained per vaginal bleeding or very heavy bleeding 
  • Anovulatory dysfunctional uterine bleeding not responding to pharmacological treatment 
  • Infertility management, especially if there are other infertility factors involved such as a poor semen analysis 
  • High suspicion of other hyperandrogenic disorders needing exclusion or advice on the exclusion of such disorders 
  • Diagnosis of T2DM 
  • Severe hypercholesterolaemia 
  • Recurrent miscarriage 
  • Patient not tolerant of usual treatments 
  • Treatment failures
  • Follow up
    • diabetes screening every 1-3 years
    • Monitor MH concerns
    • Cycle regularion
    • Discuss family planning
    • Assessment cardiovascular disease/ BP/lipids
    • Hirsutism management
    • Weight loss 5-10%
    • Regular exercise
    • Monitor sleep apnoea

Hirsutism

  • Excessive terminal hair growth in androgen-dependent skin areas which is socially unacceptable to the patient
  • Affects 5-15% of women

Causes

Androgen dependent

  1. Androgen excess disorders
    1. Ovary (PCOS, tumour)
    2. Adrenal (LOCAH, Cushings, tumour)
    3. HyperPrl
    4. Drugs (androgens)
  2. Idiopathic hirsutism
    1. Increased peripheral sensitivity to androgens

Androgen Independent (hypertrichosis)

  1. Familial hypertrichosis
  2. Medications (cyclosporine, diazoxide, minoxidil)

Investigation

  • Pelvic Ultrasound 
  • Hormones
    • On Day 2-5 cycle if regular cycles or oligomenorrhoea
    • BHCG (amenorrhea)
    • FSH/LH, E2, TFT, Prl
    • Androgens, (170HP, DHEAS, T, SHBG, FAI)
Polycystic ovary syndrome and the differential diagnosis of hyperandrogenism - Meek - 2013 - The Obstetrician & Gynaecologist - Wiley Online Library

Hyperandrogenism

  • Hyperandrogenism describes excessive circulating male sex hormone (testosterone) in females and its effects on the body caused by high levels of circulating male sex hormones in females may arise from:
    • Disease of the ovaries
      • Polycystic ovary syndrome
      • Benign (non-invasive) or malignant (cancerous) ovarian tumours
    • Disease of the adrenal gland
      • Partial deficiency of the adrenal enzyme 21-hydroxylase (late onset CYP21A2 deficiency) and other forms of congenital adrenal hyperplasia
      • Benign or malignant adrenal tumours
    • Disease of the pituitary gland
      • Cushing syndrome due to excessive adrenocorticotrophic hormone (ACTH)
      • Acromegaly (gigantism) due to excessive growth hormone and insulin-like growth factor (IFG-1)
      • Prolactinoma, a tumour that produces prolactin, as prolactin stimulates the adrenal gland
    • Obesity and the metabolic syndrome
      • more androgens are made by the adrenals and in body fat in response to release of insulin and IFG-1, and less vitamin-D is produced in the skin
    • Medications
      • anabolic steroids
      • recombinant human IGF-1
  • The mechanisms that result in hyperandrogenism may involve:
    • High overall levels of circulating testosterone
    • Normal overall testosterone but increased free testosterone, due to low levels of circulating sex-hormone-binding-globulin (SHBG, the protein that carries testosterone in the blood). Normally there is little free testosterone circulating in the blood as testosterone is tightly bound by SHBG
    • More active conversion of weaker androgens to stronger androgens such as dihydroxytestosterone (DHT) by the enzyme Type 1 5-alpha-reductase within the sebaceous gland
    • Adrenal steroids converted first to androstenedione by 3-beta-hydroxysteroid dehydrogenase then to testosterone by 17-beta hydroxysteroid dehydrogenase.
    • The higher sensitivity of the skin to DHT
    • Effects of insulin and IGF-1
  • effects of hyperandrogenism
    • Seborrhoea (oily skin)
    • Acne
    • Hidradenitis suppurativa
    • Hirsutism
    • Female pattern balding (alopecia)
    • Male pattern balding in females
    • Irregular menstruation
    • Masculine appearance with increased muscle mass and decreased breast size
    • Deepening of voice with prominent larynx (voice box)
    • Clitoral enlargement associated with increased libido (virilisation)
    • Infertility
    • Associated type 2 diabetes due to insulin resistance
    • Obesity

Signs of hyperandrogenism

  • baseline laboratory investigations may be useful to identify the exact cause.
    • FSH (follicle stimulating hormone)
    • LH (luteinising hormone)
    • Oestradiol
    • Prolactin
    • Testosterone
    • SHBG (sex hormone binding globulin)
    • 17-hydroxyprogesterone
    • DHEAS
    • Thyroid function.
    • Pelvic ultrasound scan to evaluate ovarian cysts
Mildly decreasedMildly increasedSignificantly increased
Serum ProlactinFunctional Hypothalamic AmenorrheaPolycystic Ovary Syndrome (PCOS)Pituitary Adenoma
Hypothyroidism
LH) FSHFunctional Hypothalamic Amenorrhea
Constitutional delay of Puberty
Congenital Adrenal Hyperplasia (CAH)		Normal
Outflow tract obstruction
Non-endocrine causes of Amenorrhea
Polycystic Ovary Syndrome (PCOS) – may also be low normal		Primary Ovarian Insufficiency
Menopause
Turner Syndrome
Serum TestosteroneFunctional Hypothalamic Amenorrhea
Menopause
Primary Ovarian Insufficiency		Polycystic Ovary Syndrome (PCOS)Congenital Adrenal Hyperplasia
Adrenal or ovarian tumor
Cushing Syndrome
Genetic male
Androgen insensitivity syndrome
5a-Reductase Deficiency
17-OHPCongenital Adrenal Hyperplasia (late onset)
DHEA-SCongenital Adrenal Hyperplasia
Hyperprolactinemia
Polycystic Ovary Syndrome (PCOS)
Anti-Mullerian Hormone Primary Ovarian InsufficiencyMenopausePolycystic Ovary Syndrome (PCOS)Functional Hypothalamic Amenorrhea
Estradiolpoor ovarian function low in most Amenorrhea except for outflow obstruction

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