Ovulation disorders and male hypogonadism Flashcards
Briefly describe the hypothalamic-pituitary-gonadal axis
Hypothalamus secretes gonadotrophin releasing hormone >
GnRH acts upon the anterior pituitary >
Anterior pituitary secretes LH and FSH >
LH and FSH stimulate gamete formation (FSH only in males) directly and via the production of steroid and peptide hormones within the gonads
What type of hormones are oestrogens?
Steroid
Where and by which cells does glandular oesteogen synthesis occur?
Ovaries - theca and granulosa cells
Corpus luteum
Which type of cells does LH stimulate? Which hormone production does it induce?
Granulosa
Pregnenolone
Describe the process of oestradiol production
Pregnenolone diffuses form the granulosa cells to theca cells >
Theca cells convert pregnenolone to androstenedione using 17,20-lyase and 3beta-HSD >
Androstenedione returns to the granulosa cells where it is converted to oestrone by aromatase >
Oestrone is further converted to oestradiol by 17beta-HSD
What does FSH do? How does it do this?
Stimulates the conversion of androstenedione to oestrone via aromatase
Stimulates the conversion of oestrone to oestradiol via 17beta-HSD
Where and how does extra-glandular oestrogen synthesis occur?
Aromatase expression in fat and bone allows conversion of androstenedione to oestrone
Explain progesterone synthesis
3beta-HSD converts pregnenolone to progesterone in the corpus luteum, placenta (during pregnancy) and adrenals (pathway to androgen and mineralocorticoid synthesis)
What receptors numbers increase in the presence of oestrogen?
Intracellular progesterone receptor
How do the products of hormone synthesis vary with the menstrual cycle?
Follicular phase - oestradiol
Luteal phase - progesterone
When are LH and FSH highest?
Just before and during ovulation
What does oligomenorrhea mean?
Less than 9 periods a year
What does primary amenorrhea mean?
Failure of menarche before age 16
What does secondary amenorrhea mean?
Cessation of periods for over 6 months in an individual who has previously menstruated
What categories do the causes of amenorrhea fall under?
Physiological
Primary (genetic)
Secondary (ovarian, uterine, hypothalamic, pituitary)
How should amenorrhea be investigated?
LH/FSH
Oestradiol
Thyroid function
Prolactin
Ovarian ultrasound Testosterone Pituitary function MRI Karyotype
What is female hypogonadism?
Low levels of oestrogen
Where does the problem lie with primary and secondary hypogonadism respectively?
Primary - ovaries
Secondary - hypothalamic or pituitary
What is hypergonadotrophic hypogonadism?
Low oestradiol
High FSH/LH
What is hypogonadotrophic hypogonadism
Low oestradiol
Low FSH/LH
What is premature ovarian failure?
Amenorrhea, oestrogen deficiency and elevated gonadotrophs occurring before the age of forty
What is the diagnostic criteria for premature ovarian failure?
FSH > 30 on two separate occasions at least 1 month apart
What are the causes of premature ovarian failure?
Chromosomal
Genetic mutation (FSH/LH receptor)
Iatrogenic
Autoimmune
What are the chromosomal causes of premature ovarian failure?
Turner’s
Fragile X
What are the iatrogenic causes of premature ovarian failure?
Surgery
Radiation
What are the autoimmune causes of premature ovarian failure?
Addison’s
Thyroid disease
What is kallman’s syndrome a problem with?
Hypothalamus
Wilson’s syndrome can cause hypogonadism. T/F
False - haemochromatosis
What is idiopathic hypogonadotrophic hypogonadism?
Absent/delayed sexual maturation with low gonadotrophs in the absence of anatomical or functional problem with the hypothalamic-pituitary-gonadal axis
Where is the problem with idiopathic hypogonadotrophic hypogonadism?
Hypothalamus - inability to activate GnRH secretion
There are a number of genetic defects associated with idiopathic hypogonadotrophic hypogonadism. T/F
True - GnRH secretion is pretty complex
What is the role of kisspeptin in the regulation of GnRH production?
Kisspeptin binds to the KISS1P gene to induce GnRH secretion
What are the effects of kisspeptin?
Gatekeeper of puberty
Regulator of male and female fertility
Involved in feedback control of oestrogen and therefore menstruation and ovulation
What is Kallman’s syndrome?
A genetic disorder causing the loss of GnRH secretion and anosmia/hyposmia due to failure of hypothalamic migration
How is the pituitary affected in Kallman’s syndrome?
Normal apart from reduced LH/FSH due to lack of stimulation from GnRH
What does a brain MRI show in Kallman’s syndrome?
Normal pituitary
No olfactory bulbs
Which sex is affected by Kallman’s most often?
Male
Is Kallman’s associated with a family history or nah?
Sometimes
How can you differentiate between Kallman’s syndrome and idiopathic hypogonadotrophic hypogonadism?
Presence or absence of anosmia
How are the hormone levels affected in pituitary dysfunction?
Low/normal LH/FSH
Low oestradiol
What causes of pituitary dysfunction can cause hypogonadism?
Non-functioning adenoma
Pituitary infarction
Prolactinoma
Dopamine antagonists
What are the causes of hyperprolactinemia?
Prolactinoma Pituitary pathology Anti-psychotics Dopamine antagonists Hypothyroidism Idiopathic
What are the ovarian causes of amenorrhea?
PCOS
Ovarian failure
Congenital problem
What is the rotterdam criteria for PCOS?
Menstrual irregularity
Hyperandrogenism
Polycystic ovaries
(>2/3)
What are the signs of hyperandrogenism?
Hirsutism
Elevated free testosterone
What types of congenital problems can cause amenorrhea?
Absent uterus Vaginal atresia Turner's Testicular feminisation Congenital adrenal hyperplasia
Describe the pathophysiology of polycystic ovarian syndrome?
Genetic predisposition to excess androgen secretion >
Increased testosterone >
Hirsutism ; increased LH ; insulin resistance + hyperinsulinaemia >
Increased LH & hyperinsulinaemia further increase testosterone and cause anovulation ; hyperinsulinaemia causes the liver to secrete less sex hormone binding globulin propagating hirsutism
What is hirsutism?
Excess hair in the male pattern distribution in females
What causes hirsutism?
Excess androgen at hair follicles caused by increased circulating androgen and increased peripheral conversion at the hair follicle
Where is androgen synthesised?
Ovaries and adrenals
What are the causes of hirsutism?
PCOS Familial Idiopathic Non-classical adrenal hyperplasia Adrenal tumour Ovarian tumour
How can adrenal/ovarian tumours causing hirustism be differentiated from other causes?
Tumours - short history, virilisation
Other causes - long history, testosterone not crazy high, no virilisation
What is virilisation?
Deep voice
Clitomegaly
What is congenital adrenal hyperplasia?
Group of genetic disorders causing a deficiency in an enzyme essential for cortisol synthesis
What is the most common enzyme responsible for congenital adrenal hyperplasia?
21 alpha hydroxylase
Is congenital adrenal hyperplasia dominant or recessive?
Recessive
When is classical CAH diagnosed?
Infancy
When is non-classical CAH diagnosed?
Adolescence or adulthood
How does classical and non-classical CAH present respectively?
Classical - virilisation, salt-wasting
Non-classical - hirsutism, menstrual disturbance, infertility
What should be particularly elevated in CAH after synacthen?
Progesterone (ACTH drives androgen production)
How do androgen secreting tumours present?
Short history
Virilisation
Testosterone >5mmol/l
What can be done to investigate a suspected androgen secreting tumour?
MRI adrenals and ovaries
How is PCOS treated?
Oral contraceptive pill
Anti androgens (cyproterone acetate)
Local anti-androgens (efflornithine cream)
Cosmesis (laser, electrolysis)
How is non-classical CAH treated?
Low dose glucocorticoid
What is the chromosomal abnormality in Turner’s syndrome?
Only one X chromosome
Which sex is affected by turner’s syndrome?
Females
How does turner’s syndrome present?
Short stature
Webbed neck
Shield chest w/ wide spaced nipples
Cubitus valgus
What is XX gonadal dysgenesis?
Absent ovaries with no chromosomal abnormality
What is testicular feminisation/androgen insensitivity syndrome?
Genetically XY but phenotypically female (pseudohaemaphrodite)
What is primary male hypogonadism?
Low testosterone
High LH/FSH
What is secondary male hypogonadism?
Low testosterone
Low LH/FSH
What are some causes of primary hypogonadism?
Congenital
Acquired (cirrhosis, testicular trauma, radiation, mumps, etc)
What aspects of a history are important to cover in male hypogonadism?
Sexual function (libido, erections & ejaculation) Age of puberty Fertility Symptoms of pituitary disease Duration of symptoms
What signs may be found in male hypogonadism?
Lower than expected stage of puberty
Small testicular volume
Features of pituitary disease (e.g visual field defects)
How should male hypogonadism be investigated?
Testosterone (free and total)
LH & FSH
What is klinefelter’s syndrome?
Congenital form of primary hypogonadism caused by chromosomal abnormality XXY
Which sex is affected by klinefelter’s syndrome?
Male
What are the features of klinefelter’s?
Reduced testicular volume Gynecomastia Eunuchoidism Intellectual dysfunction Azoospermia
How should klinefelter’s syndrome present biochemically?
Low testosterone
High LH/FSH
High sex hormone binding globulin
High oestradiol
What are the causes of secondary male hypogonadism?
Hypothalamic
Pituitary
When should testosterone level be measured?
9am
What are the congenital causes of secondary male hypogonadism?
Idiopathic hypogonadotrophic hypogonadism
Kallman’s
Congenital adrenal hyperplasia
When is testosterone therapy indicated?
Hypogonadism in young men (>50 seek specialist advice)
Does testosterone therapy restore fertility?
No. May even act as a contraceptive
What are the benefits of testosterone therapy?
Improved sexual function (young > old)
Improved bone health (IM > transdermal)
Improved muscle strength and decreased fat
Minimal affect on diabetes
How does gynecomastia result?
Increase oestrogen effect on breast tissue
What are the causes of gynecomastia?
Physiological Spironolactone Digoxin Hypogonadism Adrenal tumours Testicular tumours Endocrine pathology (thyrotoxicosis, cushing's) Systemic illness Hereditory disorders
Which aspects of a history are important in gynecomastia?
Duration Pain Hypogonadism Systemic illness Drugs Alcohol
Which aspects of an examination are important in gynecomastia?
Breast tissue vs fat Unilateral vs symmetrical Lumps Testicular examination General examination (liver disease)
How should gynecomastia be investigated?
Testosterone LH/FSH Oestradiol Prolactin AFP/HCG LFT SHBG Breast imaging Adrenal imaging Testicular imaging
How is gynecomastia treated?
Underlying cause
Reassurance
Cosmetic surgery
Medication (anti-oestrogens)
