Disorders of Ovalution

Question 1

Review the phases of ovulation

Answer 1

Question 2

What is the role of Kisspeptin in the regulation of Ovulation?

Answer 2

• it’s a GnRH secretagogue found at the apex of the reproductive axis in the hypothalamus
• KISS1 neurons are highly responsive on oestrogen
• it is implicated in +ve and -ve central feedback of sex steroids on GnRH production
• there are also metabolic influences via
  
  • leptin
  • has permissive effects on puberty & reproduction

Question 3

How would you diagnose/ identify ovulation?

Answer 3

• via Biochemistry:
  
  • 7 days before start of next menstrual period a progesterone blood test is taken
  • LH detection kits: urine sample (over the counter)
• via Transvaginal pelvic ultrasound:
  
  • done form day 10 of ovulation cycle, to look at the developing follicle size of the corpus luteum

Question 4

Define the following terms

• Amenorrhoea
• Primary Amenorrhoea
• Secondary Amenorrhoea
• Oligomenorrhoea
• Polymenorrhoea

Answer 4

• Amenorrhoea - lack of a period for more than 6 months
  
  • Primary Amenorrhoea - never had a period (never went through menarche)
  • Secondary Amenorrhoea -has menstruated before
• Oligomenorrhoea - irregular periods
  
  • usually occurring more than 6 weeks apart
• Polymenorrhoea - periods occurring less than 3 weeks apart

Question 5

What are the Pituitary causes of ovulation problems?

Answer 5

• Pituitary (lack of FSH and LH)
  
  • pituitary tumours (prolactinoma/other tumours)
  • post pituitary surgery /radiotherapy

Question 6

What are the Hypothalamic causes of ovulation problems?

Answer 6

• Hypothalamus (lack of GnRH)
  
  • GnRH deficiency (Kallmann’s syndrome)
    
    • may be associated with anosmia (lack of sense of smell)
  • ‘Functional’ hypothalamic amenorrhoea
    
    • weight loss/stress-related/excessive exercise
    • anorexia nervosa/bulimia

Question 7

What are Ovarian causes of ovulation problems?

Answer 7

• Premature ovarian insufficiency
  
  • Chromosomal abnormalities eg Turner syndrome
  • Autoimmune (endocrine conditions, familial link)
  • Iatrogenic
    
    • Surgery/chemotherapy/radiotherapy

Question 8

What is Hyperandrogenism?

Answer 8

• excessively high male sex hormones e.g
  
  • PCOS: polycystic ovarian syndrome
  • Cogenital adrenal hyperplasia

Question 9

What is Hirsutism?

Answer 9

• Androgen-dependent excess body hair in a male distribution
• there is androgen-independent hair growth: Hypertrichosis
• their a familial and racial links to the pattern of hair growth

Question 10

What is a differential diagnosis for hirsutism?

Answer 10

• 95% - PCOS or ‘idiopathic hirsutism’
  
  • occurs in 5-10% of women
• 1% - Non-classical congenital adrenal hyperplasia (CAH)
• <1% - Cushing’s syndrome
• <1% - Adrenal / ovarian tumour

Question 11

When would presentation of Hirsutism symptoms be problematic/ worrying?

Answer 11

• Sudden onset of severe symptoms compared to a life long PCOS diagnosis
• if it was associated with Virilisation (more sever impact of male hormones)
  
  • Frontal balding
  • Deepening of voice
  • Male-type muscle mass
  • Clitoromegaly
• Possible Cushing’s syndrome requires more investigation

Question 12

What are the clinical features of PCOS?

Answer 12

• Hyperandrogenism
  
  • causing hirsutism and acne
• Chronic oligomenorrhoea/amenorrhoea
  
  • nine or fewer periods a year
  • subfertility
• Obesity (25% of women with PCOS are “lean”), obesity can make it worse

Question 13

What is this an image of and what is it showing?

Answer 13

• Polycystic ovaries- via a transvaginal USS
• the dark spaces are multiple premature follicles that have sprung up instead of the usual one follicle becoming dominant before ovulation
• not all women with PCOS with have USS appearance

Question 14

What hormonal abnormalities are seen in PCOS?

Answer 14

• Raised baseline LH and normal FSH levels. Ratio LH:FSH 3:1
• Raised androgens and free testosterone (due to less SHBG)
• Reduced Sex Hormone Binding Globin (SHBG)
  
  • binds testosterone and oestradiol
  • produced in the liver
  • increased by oestrogen and decreased by testosterone
• Oestrogen usually normal

Question 15

What potential consequences does insulin resistance/obesity present in women with PCOS?

• Reproductive
• Metabolic

Answer 15

• Endocrine manifestations
  
  • increased insulin –> decreased liver production of SHBG
  • increased ovary and adrenal activity
    
    • increased androgen activity
      
      • Infertility/ menstrual disturbance, hirsutism
      • increased risk of Gestational Diabetes
• Metabolic manifestations
  
  • Glucose intolerance
  • Dyslipidemia
  • vascular dysfunction
    
    • Vascular disease

Question 16

What is the link between PCOS and Endometrial Cancer?

Answer 16

• irregular periods coupled with high oestrogen levels can lead to endometrial hyperplasia –> increased risk of cancer
• endometrial cancer is associated with type 2 diabetes and obesity

Question 17

What lifestyle modifications can be made to improve PCOS symptoms?

Answer 17

• Diet & exercise
  
  • high risk of eating disorders so approach with sensitivity
• Stop smoking (increases androgen levels in women)
• RESULTS:
  
  • decreased insulin resistance
  • ­ increased [SHBG]
  • decreased [free testo]
  • Improved fertility/pregnancy outcomes
  • Improve metabolic syndrome risk factors

Question 18

What’s the effect of Combined Oral Contraceptives on PCOS?

Answer 18

• increases SHBG and thus decreases free testosterone
• decreases FSH & LH and therefore ovarian stimulation
• regulates cycle & decreases endometrial hyperplasia
• BUT may cause weight gain, venous thrombosis, adverse effects on metabolic risk factors

Question 19

What is the role of Anti-androgens in PCOS?

Answer 19

• can be used with COCP / other forms of secure contraception (have a teratogenic effect)
• Cyproterone Acetate (oral tablet)
  
  • inhibits binding of testosterone & 5 alpha dihydrotestosterone to androgen receptors
• Spironolactone (oral tablet)
  
  • anti mineralocorticoid and anti-androgen properties

Question 20

Explain targeting insulin resistance in PCOS

Answer 20

Metformin

• decreased insulin resistance decreased insulin levels –> decreased ovarian androgen production
• may help with weight loss/ diabetes prevention
• may increase ovulation frequency (with clomifene) (safe in pregnancy)
• less helpful for hirsutism & oligomenorrhoea but may be an option in obese women

Question 21

What treatment can be given to women with Hirsutism?

Answer 21

• mechanical hair removal is usually required
  
  • Photepialtion/ electrolysis
• Eflornithine cream (non-NHS, cost, lack of efficacy)
  
  • inhibits ornithine decarboxylase enzyme in hair follicles

Question 22

What is the treatment of ovulation for women with PCOS?

Answer 22

Clomifene

Question 23

How would Primary Ovarian Insufficiency present?

Answer 23

• Primary or secondary amenorrhoea
  
  • Secondary amenorrhoea may be associated with hot flushes & sweats
• Other terms used:
  
  • Premature ovarian failure
  • Premature menopause

Question 24

What is the aetiology of Primary Ovarian Insufficiency?

Answer 24

• Autoimmunity
  
  • May be associated with other autoimmune endocrine conditions
• X chromosomal abnormalities
  
  • Turner syndrome
  • Fragile X associated
• Genetic predisposition
  
  • Premature menopause
• Iatrogenic
  
  • Surgery, radiotherapy or chemotherapy

Question 25

What investigations can be done in Premature Ovarian Failure?

Answer 25

* history / examination * ­increased LH and FSH, repeat at least once not at 14 days intervals * ? Karyotype * Consider pelvic USS * Consider screening for other autoimmune endocrine diseases * Thyroid function tests, glucose, cortisol

Question 26

What is the management for Premature Ovarian Failure

Answer 26

* Psychological support: daisy network * Hormone Replacement Therapy (HRT) * Continue till ± 52 * reduces hot flushes and other symptoms, can maintain bone health * Monitor bone density * DEXA scan * Fertility tx * IVF with donor egg

Question 27

What is Turner Syndrome? - genetic presentation - general presentation/ diagnosis?

Answer 27

* Complete / partial X monosomy in some / all cells * 50% of cases will be XO * Rest: partial absence of X or mosaicism * occurs in 1:2000 – 1:2500 live-born girls * Presentation * May be diagnosed in the neonate/ various stages * May present with short stature in childhood * May present with primary / secondary amenorrhoea

Question 28

What are associated problems with Turner Syndrome?

Answer 28

* **Short stature** * Consider GH treatment (high dose in childhood, benefits in adulthood) * **CV system** * Coarctation of aorta * Bicuspid aortic valve * Aortic dissection * Hypertension (adults) * **Renal** * Congenital abnormalities * single horseshoe kidney * **Metabolic syndrome** * **Hypothyroidism** * **Ears/hearing problems** * usually **​**high-frequency hearing loss * **Osteoporosis (lack HRT)**

Question 29

What is Congenital adrenal hyperplasia (CAH)?

Answer 29

* disorders of cortisol biosynthesis * high Carrier frequency of 1 : 60 * Most patients are compound heterozygotes * Different mutations on two alleles * 95% CAH cases caused by 21-hydroxylase deficiency * Cortisol deficiency * May have aldosterone deficiency * Androgen excess * Depends on degree of enzyme deficiency

Question 30

Give an overview of how CAH presents in - childhood - adulthood

Answer 30

* Childhood * classic/severe * salt-losing (in 2/3rd of patients) * non-salt losing (1/3rd of patients) * simple virilisng occurs * Adulthood * non-classic/ mild * late-onset

Question 31

How does CAH (Congenital adrenal hyperplasia) present in childhood?

Answer 31

* Salt wasting present early in life * Hypovolaemia, shock * Virilisation * Ambiguous genitalia in girls * Early virilisation in boys (unable to determine sex) * Precocious puberty * Abnormal growth * Accelerated early * Premature fusion

Question 32

How does CAH (Congenital adrenal hyperplasia) present in adulthood?

Answer 32

* Hirsutism * Oligo / amenorrhoea * Acne * Subfertility * Similar to ‘PCOS’ presentation

Question 33

What is the treatment for CAH (Congenital Adrenal Hyperplasia) treatment?

Answer 33

* Glucorticoid & mineralocorticoid replacement * *Hydrocortisone & fludrocortisone* * Additional salt in infancy * _Glucocorticoids suppress CRH / ACTH (which itself drives the system to produce too many androgens_ * Supraphysiological glucocorticoid doses may be needed to suppress adrenal androgen production * Monitor [17-OH-P] / androstenedione * Monitor growth in childhood * Excess glucocorticoid treatment may inhibit growth * Surgical management for ambiguous genitalia (done later in life in orderfor female to have more involvement in tx) * Non-classical CAH in adult women (mild) * Can treat as for PCOS with COCP ± anti-androgen