Ovulation disorders and male hypogonadism Flashcards by Robyn Baxter

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

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What type of hormones are oestrogens?

Steroid

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Where and by which cells does glandular oesteogen synthesis occur?

Ovaries - theca and granulosa cells

Corpus luteum

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Which type of cells does LH stimulate? Which hormone production does it induce?

Granulosa

Pregnenolone

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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

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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

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Where and how does extra-glandular oestrogen synthesis occur?

Aromatase expression in fat and bone allows conversion of androstenedione to oestrone

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Explain progesterone synthesis

3beta-HSD converts pregnenolone to progesterone in the corpus luteum, placenta (during pregnancy) and adrenals (pathway to androgen and mineralocorticoid synthesis)

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What receptors numbers increase in the presence of oestrogen?

Intracellular progesterone receptor

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How do the products of hormone synthesis vary with the menstrual cycle?

Follicular phase - oestradiol

Luteal phase - progesterone

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When are LH and FSH highest?

Just before and during ovulation

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What does oligomenorrhea mean?

Less than 9 periods a year

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What does primary amenorrhea mean?

Failure of menarche before age 16

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What does secondary amenorrhea mean?

Cessation of periods for over 6 months in an individual who has previously menstruated

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What categories do the causes of amenorrhea fall under?

Physiological
Primary (genetic)
Secondary (ovarian, uterine, hypothalamic, pituitary)

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How should amenorrhea be investigated?

LH/FSH
Oestradiol
Thyroid function
Prolactin

Ovarian ultrasound
Testosterone
Pituitary function
MRI
Karyotype

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What is female hypogonadism?

Low levels of oestrogen

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Where does the problem lie with primary and secondary hypogonadism respectively?

Primary - ovaries

Secondary - hypothalamic or pituitary

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What is hypergonadotrophic hypogonadism?

Low oestradiol

High FSH/LH

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What is hypogonadotrophic hypogonadism

Low oestradiol

Low FSH/LH

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What is premature ovarian failure?

Amenorrhea, oestrogen deficiency and elevated gonadotrophs occurring before the age of forty

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What is the diagnostic criteria for premature ovarian failure?

FSH > 30 on two separate occasions at least 1 month apart

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What are the causes of premature ovarian failure?

Chromosomal
Genetic mutation (FSH/LH receptor)
Iatrogenic
Autoimmune

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What are the chromosomal causes of premature ovarian failure?

Turner’s

Fragile X

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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)

Ovulation disorders and male hypogonadism Flashcards

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