Revision Checklist Topics Flashcards
Outline the hypothalamic-pituitary-gonadal axis for both males and females
GnRH is released from the hypothalamus, which acts on the pituitary to release LH and FSH
In the male, LH and FSH go on to cause release of Testosterone from the testes
In the female, LH and FSH go on to cause the release of Oestrogen and Progesterone from the ovaries
Testosterone, oestrogen and progesterone then negatively feedback on the pituitary and hypothalamus

Where does glandular synthesis of oestrogen occur?
Granulosa and the theca cells of the ovaries, and the corpus luteum
Define the following terms
- Oligomenorrhoea
- Primary amenorrhoea
- Secondary amenorrhoea
Oligomenorrhea - irregular periods/reduction in frequency to less than 9 a year
Primary amenorrhoea - failure of menarche by age 16
Secondary amenorrhoea - cessation of periods for >6months in an individual who has previously menstruated
Give some causes of primary and secondary amenorrhea
Physiological causes - pregnancy, menopause
Primary amenorrhoea - consider congenital disorders (Turner’s Syndrome - female is partially or completely missing an X chromosome, Kallman’s syndrome - delayed/asbent puberty and anosmia)
Secondary amenorrhoea - Ovarian problems (PCOS, premature ovarian failure), Uterine problems, Hypothalamic disorders (weight loss, stress, extreme exercise, infiltrative), Pituitary disorders (high PRL, hypopituitarism)
What investigations would you perform in someone presenting with oligo/amenorrhoea?
All patients:
- LH, FSH, Oestradiol (to determine if primary or secondary)
- Thyroid function, Prolactin
Additional investigations
- ovarian USS +/- endometrium thickness
- if hirsutism, test testosterone levels
- Pituitary function tests
- Karyotyping if suspecting a primary cause
How is hypogonadism identified in females?
How can you tell between primary and secondary?
Identified by low levels of oestrogen
Primary
- problem is with the ovaries themselves
- High LH/FSH - termed ‘hypergonadotrophic hypogonadism’
- example - premature ovarian failure
Secondary
- problem is with the hypothalamus or pituitary
- Low LH/FSH - termed ‘hypogonadotrophic hypogonadism’
- example - high PRL, hypopituitarism
Primary Ovarian Failure (POF) - how is it defined and what are some of the possible causes?
Definition
- amenorrhoea, oestrogen deficiency and elevated gonadotrophins occuring <40 years of age
- FSH >30 on two separate occasions and >1 month apart from each other
Causes
- chromosomal abnormalities - e.g. Turner’s syndrome, fragile X syndrome
- gene mutations
- autoimmune disease - e.g. associated with Addison’s, Thyroid disease etc.
- iatrogenic - e.g. due to radiotherapy/chemotherapy
Give some causes of secondary hypogonadism in females
Hypothalamic
- functional hypothalamic disorders
- Kallman’s syndrome
- idiopathic hypogonadotrophic hypogonadism (IHH)
Pituitary problems
Miscellaneous
- Prader-Willi
- Haemachromatosis
What are some causes of functional hypothalamic amenorrhoea? (loss of the pulsatile release of GnRH from the hypothalamus)
Extreme exercise
Stress
Weight change
Anabolic steroids
Systemic illness
Iatrogenic
Recreational drug use
Head trauma
Infiltrative disorders e.g. sarcoidosis
Give a brief description of Idiopathic Hypogonadotrophic Hypogonadism (IHH)
Absent/delayed sexual development associated with low levels of gonadotrophin and sex hormone levels, in the absence of anatomical/functional abnormalities in the HPG axis
The major defect is an inability to activate pulsatile GnRH secretion during puberty
Associates with a large number of genetic defects
What ligand has been identified as being important in the development of IHH? What does it do?
The ligand for KISS1R - Kisspeptin - stimulates GnRH secretion and has an influence on both positive and negative feedback of oestrogen secretion
Encoded for by the G-protein coupled receptor KISS1R, mutations in which are associated with IHH
Kallman’s syndrome is a cause of secondary hypogonadism. What is missing in this condition and how does this present?
Loss of GnRH secretion but normal pituitary function elsewhere.
MRI of pituitary will appear normal but there will be an absence of olfactory bulbs
Presents more commonly in males than females (4:1) and is characterised by anosmia
What drugs might cause hyperprolactinaemia?
Dopamine antagonists - metoclopramide, domperidone
What criteria is used to diagnose PCOS?
Rotterdam criteria
2 of the following…
- menstrual irregularity e.g. oligo/amenorrhoea
- clinical/biochemical signs of hyperandrogenism (hirsutism, acne, infertility, elevated free testosterone etc.)
- polycystic ovaries seen in USS
What is Congenital Adrenal Hyperplasia (CAH)? What are 90% of CAH due to?
What are the two forms of CAH?
CAH is an inherited group of disorders characterised by a defiency in one of the enzymes necessary for cortisol synthesis
In 90% of cases, the deficient enzyme is 21-alpha hydroxylase
Two forms of CAH are Classic (presents in childhood) and Non-classic (presents in adolescene/adulthood and is characterised by partial 21-alpha hydroxylase deficiency, resulting in hirsutism, virilism, menstrual disturbance and infertility)

How is PCOS treated?
Oral contraceptive pill - regulates menstrual cycle and decreases ovarian androgens
Anti-androgens - cyproterone acetate. Also local anti-androgens
Cosmesis e.g. electrolysis, laser therapy
What’s the diagnosis?
How might this present clinically?

Turner Syndrome (45 XO) - only affects women
Clinical features
- short stature
- webbed neck
- ‘shield chest’
- shortened IV metacarpal
- lack of menstruation
Clinical scenario - 18 year old male presents with delayed puberty and symptoms of hypogonadism
What do you need to investigate?
Cause - primary or secondary?
Primary
- Low testosterone with high LH/FSH
- causes can be both acquired and genetic
Secondary
- Low testosterone with inappropriately low LH/FSH
- Hypothalamic/Pituitary disorders
Give some causes of primary and secondary male hypogonadism
Primary
- Klinefelter’s Syndrome
- Y-chromosome microdeletions
- mutations in LH and FSH receptors
- myotonic dystrophy
Secondary
- isolated hypogonadotrophic hypogonadism (Kallman’s syndrome)
- Prader-willi syndrome
- mutations in beta subunit of LH and FSH
What’s the diagnosis?
How might this condition present?

Klinefelter’s syndrome
Most common form of congenital hypogonadism, affecting 1:500 men
Low testosterone, high LH/FSH
Clinical features
- reduced testicular volume
- gynaecomastia
- eunuchoidism
- intellectual dysfunction in 40%
- azoospermia
Describe the menstrual cycle - how long does it take on average, what is the range, how long does menses last and at what point does ovulation typically occur?
On average, duration is 28 days
Range of duration between 21-35 days
Menses typically lasts 3-7 days
Ovulation typically occurs around day 14
What are the two phases of the menstrual cycle, and what separates them?
Follicular and Luteal phases - separated by ovulation
In what manner is GnRH released from the Hypothalamus?
How is stimulation of LH and FSH triggered by GnRH?
GnRH is released in a pulsatile manner
FSH release is stimulated by low frequency pulses
LH release is stimulated by high frequency pulses
What is the main function of FSH?
Stimulates follicular development and thickens the endometrium
What is the main function in LH?
LH peak stimulates ovulation
Also stimulates corpus luteum development, and like FSH also causes thickening of the endometrium
Describe progesterone - where and when is it produced, and what does it do?
Produced and secreted by the corpus luteum to support and maintain the early pregnancy (becomes the placenta)
Inhibits LH secretion
Levels peak after ovulation (unlike LH), and their decline triggers the start of the next menstrual cycle
Maintains thickness of the endometrium and is also responsible for thick, infertile cervical mucous
Describe oestrogen - where and when is it produced, and what does it do?
What effect does oestrogen level have on LH, Prolactin and FSH?
Secreted primarily by the ovaries, but small amounts are also produced in the adrenal cortex and by the placenta during pregnancy
Stimulates thickening of the endometrium and is responsible for fertile cervical mucous
High oestrogen levels inhibit secretion of FSH and Prolactin (-ve feedback), but stimulate secretion of LH (+ve feedback)
How can regular menstruation be confirmed?
Regular cycles are very suggestive of normal ovulation
Can be confirmed with serum progesterone measurements (x2) samples at the midluteal phase
What are the 3 groups of HPG axis disorders, according to the WHO?
Group I - Hypothalamic Pituitary failure (10% of ovulatory disorders)
Group II - Hypothalamic Pituitary dysfunction (85% of ovulatory disorders)
Group III - Ovarian failure (5% of ovulatory disorders)
Group I HPG axis disorders - presentation, causes and treatment
Presentation
- Absence of GnRH = low/no LH or FSH
- Result is oestrogen deficiency, Prolactin levels normal - hypogonadotrophic hypogonadism
- Amenorrhoea - no progesterone present therefore no menstruation
Causes
- Stress
- Excessive exercise
- Anorexia/low BMI
- Brain/Pituitary disorders and head trauma
- Kallman’s syndrome
- Drugs (steroids, opiates)
Treatment
- Stabilisation of weight
- Hormonal therapy - pulsatile administration of GnRH every 90 mins or daily gonadotrophin injections (LH and FSH, harder to control and higher risk of multiple pregnancy)
- Both forms of hormone therapy require USS monitoring of follicles to track response
What Class of HPG axis disorder accounts for 85% of ovulatory disorders? Give an example of one of these conditions
Class II (hypothalamic pituitary dysfunction)
Normal gonadotrophins/excessive LH
Normal oestrogen levels
Oligo/amenorrhea
PCOS is an example - affects 5-15% of women of reproductive age
What other endocrine feature is commonly seen in patients with PCOS?
How does this result in hyperandrogenism?
Insulin resistance - seen in 50-80% of PCOS cases
Normal pancreatic reserve of insulin, but diminished biological response = hyperinsulinaemia
Insulin acts as a co-gonadotrophin to LH and lowers levels of sex hormone binding globulin (SHBG) = increased free testosterone levels
How is PCOS managed?
Dependent on symptoms/patient needs:
Weight loss/lifestyle modifcation
Subfertility - ovulation induction
-
Clomifene citrate - FIRST LINE TREATMENT, stimulates LH and FSH, driving ovulation
- 70% ovulate, 40-60% conceive
-
Gonadotrophin injection therapy - daily injections with recombinant FSH
- 80% ovulate, 60-70% conceive, but risk of multiple pregnancy
-
Laproscopic ovarian diathermy - drilling into ovaries
- 80% ovulate, but risk of ovarian destruction
What other endocrine drug has a role in ovulation induction? How does it work?
Metformin
Improves insulin resistance and causes a reduction in androgen production, aiding in the restoration of menstruation and ovulation
May also improve sensitivty to clomifene?
What are the 3 main concerns associated with ovulation induction?
Multiple pregnancy
Overstimulation
Ovarian cancer
What are the medical treatments for Hyperprolactinaemia?
Dopamine Agonists
- Longer-acting preparation - cabergoline twice a week, takes 6-12 months to take effect
- Conventional treatment - bromocriptine
Treatments should be stopped once pregnancy occurs
What is the classic hormone level picture of menopause (ovarian failure)?
High LH/FSH but low oestrogen
What are the clinical and endocrine features of Anorexia Nervosa?
Clinical
- Low BMI, under 18.5
- Loss of hair
- Increased lanugo
- Low pulse and BP
- Anaemia
Endocrine
- Low LH, FSH and oestradiol
What are the clinical and endocrine features of PCOS?
Clinical
- Obesity
- Hirsutism or acne
- Cycle abnormalities
- Infertility
Endocrine
- High free androgens
- High LH
- Impaired glucose tolerance
What are the clinical and endocrine features of premature ovarian failure?
Clinical
- Hot flushes
- Night Sweats
- Atrophic vaginitis
Endocrine
- High FSH and LH
- Low oestradiol
What are the clinical and endocrine features of non-obstructive fertility problems in men?
Clinical
- Low testicular volume
- Reduced secondary sexual characteristics
- Vas deferens are present
Endocrine
- High LH and FSH
- Low testosterone
What are the clinical and endocrine features of obstructive fertility problems in men?
Clinical
- Normal testicular volume
- Normal secondary sex characteristics
- Vas deferens may be absent
Endocrine
- Normal LH, FSH and testosterone
What 3 hormones does the thyroid gland produce?
Tri-idothyronine (T3)
Thyroxine (T4)
Calcitonin
Pretibial myxoedema is seen in (hypothyroidism/hyperthyroidism)
What else might be seen on clinical examination?
Hyperthyroidism
General - irritability, anxiousness, weight loss, warm moist skin
Hands - onycholysis (painless detachment of the nail from the nail bed)
Face - hair loss, Graves ophthalmology
CVS - sinus tachycardia, AF, congestive heart failure
Diffuse goitre
Name some other conditions associated with Grave’s Disease
T1DM
Addison’s Disease
Pernicious anaemia (lack of RBCs e.g. due to Vitamin B12 deficiency)
Myasthenia Gravis
Coeliac disease
Vitiligo
Patient presents with symptoms of hyperthyroidism - what are the possible causes
Grave’s
Toxic Multinodular Goitre
Toxic adenoma
Thyroiditis (either painful or painless - De Quervian’s is painful)
Very generally, how do the following conditions differ…
- Addison’s
- Cushing’s
- Conn’s
Addison’s - primary adrenal insufficiency, independent of pituitary dysfunction. Most commonly autoimmune and is characterised by damage to the various layers of the adrenal cortex
Cushing’s - excessive cortisol due to an ACTH-producing tumour in the pituitary
Conn’s - primary hyperaldosteronism, excessive production of aldosterone by the adrenal glands resulting in low renin
Addison’s - clinical presentation
Anorexia/weight loss
Tiredness
Weakness
Pigmentation
Dizziness
GI symptoms
Arthralgia/myalgia
Adrenal (Addisonian) crisis - life-threatening
Addison’s - what investigations would you perform, and what would you expect to see?
U&Es - hyponatraemia, hyperkalaemia, raised urea
Serum cortisol - undetectable = adrenal insufficiency
Serum ACTH - elevated
Synacthen test - cortisol levels double in healthy individuals over 30-60 mins, but in someone with Addison’s this will not be seen
Addison’s - how is this condition managed?
Patient education
Glucocorticoid replacement - hydrocortisone (replacement cortisol)
Mineralocorticoid replacement - fludrocortisone (replacement aldosterone)
What’s the difference between Cushing’s Disease and Cushing’s Syndrome?
Disease - hypercortisolaemia due to an ACTH-secreting tumour in the pituitary
Syndrome - disease complex resulting from chronic hypercortisolaemia of any cause
Cushing’s - what is the Gold Standard investigation?
24-hour urinary free cortisol - at least 2 measurements
In practice however, an overnight dexamethasone suppression test is done where a high-dose steroid (dexameth.) is given at bed time which should suppress cortisol levels
In normal individuals cortisol will be under 50nmol/L
In someone with Cushing’s, their cortisol will be over 100nmol/L