W11 - FEMALE REPRODUCTIVE PATHOPHYSIOLOGY

Question 1

Define polycystic ovary syndrome?

Answer 1

• A heterogeneous disorder of unexplained hyperandrogenic chronic anovulation in which secondary causes (Androgen secreting neoplasms) have been excluded
  
  • It is a multi-system reproductive-metabolic disorder
  • Most common endocrine disturbance affecting women (5-10% prevalence in reproductive-age women)

Question 2

What are some symptoms associated with polycystic ovary syndrome?

Answer 2

• Principle clinical manifestations
  
  • Hyperandrogenism - excessive androgen production
  • Irregular menstruation or infertility
  • Ovaries can be polycystic
  • Associated metabolic dysfunction - insulin resistance, dyslipidaemia and increase prevalence of obesity

Question 3

Describe the hormone profile in polycystic ovary syndrome

Answer 3

• Chronically static not cyclic
  
  • Increased LH or increase LH:FSH ratio
  • FSH low to normal
  • Increased inhibin
  • Increased testosterone, androstenedione
  • Normal to increased oestrogens - extraovarian conversion
• Decreased sex hormone-binding globulin (SHBG)
• Increased adrenal dehydroepiandrosterone sulphate (DHEAS)
• Increased insulin
• Increased IGF I and IGF II

Question 4

Describe the physical examination of an individual with polycystic ovary syndrome

Answer 4

• Balding
• Acne
• Clitoromegaly - enlargement of the clitoris
• Body hair distribution
• Signs of insulin resistance - obesity, central fat disposition, acanthosis nigricans
• Bimanual examination may suggest enlarged ovaries

Question 5

What criteria are to be met for the diagnosis of polycystic ovary syndrome?

Answer 5

• Polycystic ovary syndrome if 2/3 are met
  
  • Oligoovulation and/or anovulation
  • Excess androgen activity
  • Polycystic ovaries by sonogram

Question 6

Describe the clinical significance of polycystic ovary syndrome

Answer 6

• Menstrual irregularities (80%)
  
  • Irregular, infrequent or absent bleeding - begin soon after menarche and regularity never established
• Infertility (75%)
  
  • Chronic anovulation and/or recurrent miscarriage - enlarged ovaries with multiple peripheral cystic follicles
• Hirsutism (70%)
  
  • Mild to severe male-pattern hair growth - upper lip, chin, chest, and back
  • Acne
• Obesity (50%)
  
  • Major contribution to metabolic disorders
  • Often associated with hyperinsulinemia or insulin resistance (20-40%)

Question 7

Describe some ovarian changes in an individual with polycystic ovarian syndrome

Answer 7

• Ultrasound examination
  
  • Enlarged ovaries
    
    • 2-5 times normal size
  • Multiple, 2-15mm cystic follicles peripherally distributed
  • Hyperplasia of theca and central stroma
    
    • >25% ovarian area
• Follicle dynamics
  
  • Normal development to mild-antral stage than arrest
  • Majority undergo atresia but many retain functional capacity
  • Granulosa layer thins as follicles enlarge
  • Corpora lutea are usually absent

Question 8

Explain insulin resistance in relation to polycystic ovary syndrome

Answer 8

• Well-documented association between polycystic ovary syndrome and insulin resistance or impaired glucose tolerance
  
  • Insulin resistance generally mild
  • Glucose intolerance (31%) and subsequent diabetes (7.5%) significantly prevalent
• Acanthosis nigricans is a marker for insulin resistance
  
  • Grey-brown velvety discolouration and thickness of skin - neck, groin, axillae and under breasts

Question 9

Explain how polycystic ovary syndrome leads to infertility

Answer 9

• Chronic anovulation
  
  • Do not go any further than mid-antral follicles
• Other considerations
  
  • Higher incidence of spontaneous pregnancy loss
    
    • Possible insulin resistance or poorly prepared endometrium
    • High androgens, no progesterone, continual stimulation by oestrogens - unsuitable environment for implantation

Question 10

Describe the pathophysiology of polycystic ovarian syndrome

Answer 10

• Disturbance in central nervous system upregulates GnRH and high insulin in the blood
• Leads to high LH and low FSH (High inhibin suppresses FSH) - disequilibrium of LH:FSH
• FSH - required for normal growth of granulosa and the development of follicles
• Low FSH - not enough development of follicles to ovulate
• LH - act on thecal cells to stimulate overproduction of androgens, however, the granulosa cells cannot convert these into oestrogens (Due to low FSH)
• Causes a net output of androgens instead of oestrogens
• Adrenal gland increases weak androgen output due to central nervous system - elevated androgen profile in the blood and male type hair pattern growth
• Conversion in adipose tissues to oestrogens (Aromatisation) - elevated oestrogens - stimulation of endometrium constantly (no cycle)
• Metabolic disturbances - obesity and high insulin - upregulate LH secretion, and act with androgens to supress sex hormone binding globin (SHBG) in the liver
• Less SHBG makes the high effect of steroids worse as they are not bound
• Persistent maintenance of disequilibrium between FSH and LH keeps the disorder going

Question 11

What are the causes of polycystic ovary syndrome?

Answer 11

• Fundamental defect in PCOS appears to be inappropriate signalling to hypothalamus and pituitary
• Primary causes are largely unknown but possibly due to
  
  • Ovarian defect
  • Hypothalamus defect
  • Insulin resistance - insulin enhances LH-beta gene transcription
  • Genetic factors

Question 12

Explain the genetic basis of polycystic ovary syndrome

Answer 12

• PCOS tends to aggregate within families
• Up to 50% of first-degree relatives may be affected by PCOS (or hyperandrogenemia)
• Hyperinsulinism may be a familial characteristic in daughters of women with PCOS
• Circulating DHEAS in first-degree male relatives higher than unrelated BMI-matched controls
• Several candidate genes
  
  • InPsulin gene (CY₁₁A₁)
  • Follistatin gene
• PCOS phenotype consequence of genes and environment
  
  • E.g. Poor lifestyle-induced obesity may aggravate PCOS in genetically susceptible women

Question 13

What are the immediate and long-term consequences of polycystic ovary syndrome?

Answer 13

• Immediate concerns
  
  • Hirsutism and acne
  • Irregular menstruation
  • Anovulatory infertility
  • Obesity
• Long-term concerns
  
  • Develop endometrial cancer
    
    • Persistent oestrogen stimulation
  • Become diabetic
    
    • 20-40% of patients develop glucose intolerance or type 2 diabetes
  • Develop cardiovascular disease
    
    • Dyslipidaemia - significant increase in total cholesterol, LDL, triglycerides and decrease in HDL
    • Increased risk of plague generation in coronary vessels
  • Become hypertensive
    
    • High blood pressure

Question 14

What are the goals of treatment of polycystic ovary syndrome? Describe the treatment options

Answer 14

• Treatment goals
  
  • Reversing signs and symptoms of androgen excess
  • Establish cyclic menstruation and prevent endometrial cancer
  • Restore fertility
  • Ameliorate metabolic and endocrine disturbances
    
    • E.g. Lower insulin levels
• General treatment measures
  
  • Weight loss
    
    • Balanced diet
    • Moderate exercise
      
      • Can help reduce hyperandrogenemia, blood pressure and insulin resistance
    • Reduce fat tissue for conversion to oestrogens
    • Reduce insulin
      
      • Less LH, less androgen output from ovaries
  • Screen for cardiovascular risk factors
  • If not trying to conceive, use an oral contraceptive
• Medical therapy
  
  • Oral contraceptives
    
    • Combined oral contraceptives - suppresses circulating LH (reduce circulating androgen levels), reduces ovarian androgen production (ameliorates hirsutism) and increases SHBG
      
      • Overall - lower androgen levels, provides contraception
      • Treatment for anovulation and hyperinsulinemia in women with androgen excess; does not increase cardiovascular risk
    • Single progesterone - patient does not complain of hirsutism but is anovulatory and has irregular bleeding
      
      • Interrupts chronic exposure of endometrium to unopposed effects of oestrogens
      • Ensure withdrawal bleeding and prevent endometrial hyperplasia
      • Does not decrease androgen excess, does not provide contraception
  • Anti-androgens
    
    • Often used in conjunction with oral contraceptives
    • Spironolactone, cyproterone acetate (Diane), flutamide
  • Clomiphene citrate
    
    • Induces ovulation where fertility desired (Blocks hypothalamic E₂ receptor to normalise LH and FSH release)
      
      • No feedback - follicles can develop unregulated
      • FSH levels are increased
      • Displaces endogenous oestrogens from hypothalamus, thereby removing the negative feedback effect exerted by endogenous estrogens
    • Need 4-6 weeks pre-treatment with oral contraceptives (suppresses LH)
      
      • Firstly, to lower LH and then afterwards negative feedback can be taken away for those who desire pregnancy
• Metformin (Insulin-sensitiser)
  
  • Inhibits output of glucose from liver = Decrease insulin secretion (Improved glucose tolerance), decreases androgen levels, increases ovulation rates
  • Enhances ovulatory response to clomiphene

Question 15

Describe the surgical therapies for polycystic ovary syndrome

Answer 15

• Ovarian drilling with laser or diathermy
  
  • Few advantages over medicinal therapy for infertility
  • Does not appear to have a significant long-term benefit for improving metabolic abnormalities
• Mechanical hair removal
  
  • Laser
  • Electrolysis
  • Depilatory creams