Endocrine Infertility Flashcards
Outline the hypothalamo-pituitary-gonadal axis, including negative feedback influences in
1) Men
2) Women
1)
- Hypothalamus secretes GnRH
- GnRH stimulates LH / FSH secretion from pituitary
- LH / FSH stimulates testosterone secretion from the testes
- Testosterone and inhibin have negative feedback inhibition on the secretion of LH / FSH from the pituitary
- Testosterone has negative feedback inhibition on the secretion of GnRH
2)
- Hypothalamus secretes GnRH
- GnRH stimulates LH / FSH secretion from pituitary
- LH / FSH stimulates oestrogen secretion from the ovaries
- Oestrogen and inhibin have negative feedback inhibition on the secretion of LH / FSH from the pituitary
- Oestrogen has negative feedback inhibition effect on the secretion of GnRH from the hypothalamus
Name the 3 phases of the menstrual cycle
- Follicular phase
- Ovulation
- Luteal phase
Outline the hypothalamo-pituitary-gonadal (HPG) axis hormonal changes (i.e. excluding progesterone) in the phases of the menstrual cycle - don’t need to go into the detail like graaffian follicles, corpus luteum etc
Follicular
- Normal HPG axis - i.e. hypothalamic GnRH stimulates LH / FSH which stimulates oestrogen secretion from the ovaries and the oestrogen has negative feedback on the hypothalamus and the pituitary
- However, as the follicle enlarges, oestrogen no has a positive feedback on GnRH and LH / FSH
Ovulation
- This positive feedback that oestrogen exerts causes an LH surge - which causes the egg to be released in ovulation
Luteal phase
- If implantation does not occur - there is breakdown of the endometrium
- If it does, there is endometrial proliferation
Why is unhindered endometrial proliferation not alright, in the event there is no implantation that occurs?
- Predisposes to cancer
Define infertility in terms of at what point is there considered to be infertility problems in one of either the male or the female (or both) in a couple?
- Infertility = Inability to conceive after 1 year of unprotected sex
What would a blood test indicate in the event of primary hypogonadism…
1) In males?
2) In females?
1)
- Low testosterone
- High LH / FSH due to less negative feedback by testosterone
2)
- Low oestradiol
- High LH / FSH due to less negative feedback by testosterone
What would a blood test indicate in the event of secondary hypogonadism…
1) In males?
2) In females?
1)
- Low LH / FSH
- Low testosterone as a result of the low LH / FSH
2)
- Low LH / FSH
- Low oestradiol as a result of the low LH / FSH
What is defective in…
1) Primary hypogonadism?
2) Secondary hypogonadism?
1)
- The gonads’ (testes / ovaries) production of testosterone / oestradiol
2)
- The hypothalamus / pituitary’s production of GnRH or LH / FSH respectively which therefore loweres production of testosterone / oestradiol
Give 5 clinical features of male hypogonadism
- Loss of libido
- Impotence
- Small testes
- Decreasd muscle bulk
- Osteoporosis
Give the 4 main cause categories for male hypogonadism and then, where applicable, give the subcategories of these hypogonadism causes
- Hypothalamic-pituitary disease
- Hypopituitarism
- Kallman’s disease (inappropriate migration and development of GnRH neurones in hypothalamic development)
- Illness / underweight - appropriate nutrition is required for appropriate hypothalamo-pituitary function in regards to sex hormones
- Primary gonadal disease
- Congenital e.g. Klinefelter’s (XXY)
- Acquired e.g. Testicular torsion → necrosis
- Hyperprolactinaemia
- Androgen receptor deficiency
5.
1) What is the pathophysiology of Kallman’s syndrome and how it causes male hypogonadism?
2) What are the clinical signs?
1)
- Inappropriate migration and development of GnRH neurones in hypothalamic development - so is a hypothalo-pituitary disease causing male hypogonadism due to the resulting lack in testosterone production
2)
- Anosmia - lack of smell sense (as GnRH neurones and olfactory neurones migrate together in embryonic development)
- Pre-pubertal phenotype
- Testes originally undescended
- Stature low-normal
4 ways to investigate male hypogonadism and what findings may show?
- Check LH / FSH + Testosterone levels - if all low this indicates secondary hypogonadism and if testosterone is low but LH / FSH is high, this indicates primary hypogonadism
- Check Prolactin level - high prolactin indicates hypogonadism as a result of hyperprolactinaemia
- Check sperm count and motility - either azoospermia (absence of sperm in ejaculate) or oligospermia (reduced number of sperm in the ejaculate)
- Chromosomal analysis - e.g. if you see 47 XXY this is Klinefelter’s causing hypogonadism
3 treatments for male hypogonadism?
- Testosterone replacement therapy to preserve muscle bulk and prevent osteoporosis
- Subcutaneous gonadotrophin injections to stimulate spermatogenesis if male hypogonadism caused by hypothalamo-pituitary disease
- Dopamine agonist if male hypogonadism caused by hyperprolactinaemia because dopamine suppresses prolactin secretion
5 possible endogenous sites for androgen production?
- Interstitial Leydig cells of the testes
- Adrenal cortex
- Ovaries
- Placenta
- Tumours
Give 4 main actions of testosterone
- Development of male genital tract
- Secondary sexual characteristics
- Anabolic effects (muscle, bone)
- Maintains fertility in adulthood
1) What are the 2 things that testosterone can be converted into and outline the reaction, and the enzyme involved in each reaction. Basically express it in terms of the reaction with formula: ‘testosterone (+enzyme) → product’
2) What receptors do these products act on?
3) What type of receptors do both of them act on?
1)
- Testosterone (+5α-reductase) → DHT (dihydrotestosterone)
- Testosterone (+aromatase) → 17ß-oestradiol (E2)
2)
- DHT acts on androgen receptors
- 17ß-oestradiol (E2) acts on oestrogen receptors
3)
- Nuclear receptors
What will testosterone do in adulthood?
- Lean body mass (due to anabolic activity)
- Muscle size and strength
- Bone formation and bone mass (in young men)
- Libido and potency
Define primary amenorrhoeas
Failure to develop spontaneous menstruation by the age of 16 years
Define secondary amenorrhoeas
Absence of menstruation for 3 months in a woman who previously had cycles
Define oligomenorrhoeas
Irregular long cycles
Give 4 causes of amenorrhoea and the subcategories of the causes where applicable
- Pregnancy
- Lactation - high prolactin stops menstruation
- Ovarian failure:
- Premature ovarian failure (early menopause)
- Ovariectomy / chemotherapy
- Ovarian dysgenesis due to Turner’s syndrome (45X)
- Gonadotrophin failure:
- Hypothalo-pituitary disease
- Kallman’s syndrome (failure of GnRH secretion)
- Low BMI (leptin deficiency)
- Post-pill amenorrhoea (downregulates the hypothalamus and pituitary)
- Hyperprolactinaemia
- Androgen excess - gonadal tumour
1) How do you represent Turner’s syndrome symbolically and what is the pathophysiology?
2) What are the signs of Turner’s?
1) 45 X (missing one X chromosome)
2)
- Short stature
- Ovarian dysgenesis
- Cubitus Valgus
8 investigations into amenorrhoea?
- Pregnancy test
- Day-21 progesterone - if low then ovulation did not occur
- LH / FSH and oestrogen levels - test for hypothalamic-pituitary disease
- Androgen levels (testosterone, androstenedione, DHEAS)
- Prolactin measurement - test for hyperprolactinaemia
- Chromosomal analysis (check for Turner’s)
- U/s scan of ovaries / uterus
- Thyroid function tests (hyper- and hypothyroidism can impact menstruation)
3 ways to treat amenorrhoea?
- Treat the cause e.g. low weight
- Primary ovarian failure - HRT, infertile
- Hypothalamic / pituitary disease - HRT for oestrogen replacement (won’t improve fertility) and gonadotrophins for fertility
2 things that PCOS (polycystic ovary syndrome) is associated with?
- Increased CVS risk (dunno why)
- Insulin resistance - diabetes
What are the criteria for diagnosis of PCOS?
- You need 2 of the following:
- Polycystic ovaries on the u/s scan
- Oligoovulation / anovulation - irregular ovulation
- Clinical / biochemical androgen excess - hirsutism is a visible sign
3 clinical features of PCOS (polycystic ovary syndrome)
- Hirsutism - XS hair growth in male pattern
- Menstrual cycle disturbance
- Increased BMI
3 treatments for PCOS, and one potential complication of one of these therapies?
- Metformin:
* Increases insulin sensitivity - combats insulin resistance leading to diabetes associated with PCOS - Clomiphene:
- Short-term use (5 days-ish)
- Antagonist of oestrogen receptor in hypothalamus, thereby blocking the negative inhibition effect of oestrogen on GnRH release in hypothalamus
- So increase in GnRH and thus increase in oestrogen
- Gonadotrophin therapy as part of IVF
- People with PCOS have lots of follicles but can’t get them out
- You super-stimulate the follicles with IVF
- Over-stimulation may result in ovarian hyper-stimulation syndrome which is potentially life-threatening
Outline the hypothalic-pituitary axis in prolactin secretion, and what is the effect of prolactin on the body,
- Hypothalamus secretes dopamine and TRH. Dopamine is the dominant hypothalamic hormone in this axis. Dopamine inhibits prolactin secretion at the pituitary whereas TRH stimulates prolactin secretion. Therefore there is overall more suppression of prolactin, but its still secreted
- Pituitary secretes prolactin
- Prolactin stimulates lactation in mammary glands
Outline the effects of prolactin on other hypothalamic-pituitary hormone secretion (outside of its own hypothalamic-pituitary axis), which explains why it causes hypogonadism in females and males
- Inhibits GnRH pulsatile secretion from the hypothalamus
- Inhibits LH action on ovaries and testes
Give 8 causes of hyperprolactinaemia
- Dopamine antagonist drugs
- Anti-emetics (metoclopramide) - anti-sickness
- Anti-psychotics (phenothiazides)
- Prolactinoma (pituitary tumour secreting prolactin)
- Stalk compression due to pitiutary adenoma
- PCOS
- Hyperthyroidism - increased TRH so prolactin stimulation
- Oestrogens (OCP)
- Pregnancy - lactation
- Idiopathic
What are the clinical features of hyperprolactinaemia, including the 2 extra ones caused by prolactinoma?
- Galactorrhoea - increased breast milk expression
- Hypogonadism - due to reduced GnRH and LH
- Prolactinoma - headaches and visual field defect
3 treatment methods for hyperprolactinaemia?
- Treat the cause e.g. stop taking dopamine antagonist drugs
- Dopamine agonist drug e.g. Bromocriptine, Cabergoline
- Pituitary surgery very rarely if caused by prolactinoma
