Endo 9: Endocrine Infertility Flashcards
Outline the hypothalamo-pituitary-gonadal axis for men
GnRH –> FSH and LH –> Testosterone. Leydig cells release testosterone, which negatively feeds back to hypo. and pit. Sertoli cells, responsive to FSH, release inhibin negatively feedback on pit. and hypothalamus
Outline the hypothalamo-pituitary-gonadal axis for females
GnRH –> FSH/LH –> oestreogen. Negative feedback on hypothalamus and pituitary…. however at high concentration, the OESTRADIOL actually has positive feedback ON THE HYPOTHALAMUS –> INCREASED GnRH–> (FSH) and LH surge and ovulation!
3 stages of 28 day menstrual cycle
Follicular phase, ovulation and luteal phase
Define infertlity
Infertility: inability to conceive after 1 year of regular unprotected sex.
How many couples affected by infertlilty
1:6
What proportion caused by males, females, or unknown
in males (30%) or females (45%) or unknown (25%)
Outline primary gonadal failure
Ovary/testes not working.
Outline secondary hypo/pituitary disease
Low LH/FSH and thus low testosterone and oestradiol
Male hypogonadism clinical featrures
Loss of libido, impotence, small testes, decrease muscle bulk, osteoporosis
Cause of male hypogonadism
HYPOTHALAMC-PITUITARY DISEASE:
- Hypopituitarism
- Kallmans syndrome (low GnRH as neurones havent developed properly)
- Illness/underweight
PRIMARY GONADAL DISEASE
- Congenital: Klinefelters syndrome (XXY)
- Acquired: Testicular torsion, Chemotherapy
SECONDARY: HYPERPROLACTINAEMIA
OTHER: ANDROGEN RECEPTOR DEFICIENCY (congenital- testosterone can’t act on the receptor)
Clinical features of Kallman’s syndrome
small penis (micropenis) and undescended testes (cryptorchidism), lack of sense of smell (anosmia)
Investigations for male hypogonadism
LH, FSH, testosterone (if all low –> MRI pitutary )
Prolactin (in case prolactinoma means that GnRH is suppressed)
Sperm count
Azoospermia = absence of sperm in ejaculate
Oligospermia = reduced numbers of sperm in ejaculate
Chromosomal analysis (Klinefelters XXY)
Treatment for male hypogonadism
Replacement testosterone for all patients (for symptoms, not fertility)
For fertility: if hypo / pit disease sc gonadotrophins (LH & FSH) (as testosterone won't stimulate spermatogenesis)
Hyperprolactinaemia – dopamine agonist
Where are androgens produced
- interstitial Leydig cells of the testes
- adrenal cortex (males and females)
- ovaries
- placenta
- tumours
Main actions of testosterone
- development of the male genital tract
- Maintains fertility in adulthood
- Control of secondary sexual characteristics
- Anabolic effects (muscle, bone)
How does testosterone travel in the circulation
98% protein bound)
In what forms does testosterone act on receptors
Where are ER receptors found
Androgen receptor (if testosterone converted by 5a-reductase to DHT)
Estrogen receptor (if testosterone converted to 17b-oestradiol (E2) by aromatase)
ER and AR are nuclear receptors
ER (oestrogen receptor) in brain and adipose tissue
Clinical use of testosterone
lean body mass
muscle size and strength
bone formation and bone mass (in young men)
libido and potency
WILL NOT RESTORE FERTILITY WHICH REQUIRES TREATMENT WITH GONADOTROPHINS
State the 3 categories of fertility disorders in females
- Amenorrhoea
- Polycystic Ovarian Syndrome (PCOS)
- Hyperprolactinaemia
Differentiate Primary amenorrhoea and Secondary amenorrhoea and what is oligoenorroea
P: failure to begin spontaneous menstruation by age 16 years
S:absence of menstruation for 3 months in a woman who has previously had cycles
Oligomenorrhoea = irregular long cycles
Causes of amenorrhoea
Pregnancy / Lactation (due to high prolactin which inhibits GnRH)
Ovarian failure:
- premature ovarian failure
- Ovariectomy / chemotherapy
- ovarian dysgenesis (Turners 45 XO) – lacking one chromosome
Gonatrophin failure:
- Hypo / pit disease
- Kallmann’s syndrome (anosmia, Low GnRH)
- Low BMI
- Post pill amenorrhoea
Hyperprolactinaemia
Androgen excess: gonadal tumour
Turners clinical effects
short stature cubitus valgus (wide carrying angle) gonadal dysgenesis
Investigation of amenorrhoea
Pregnancy test
LH, FSH, oestradiol
Day 21 progesterone (will be high if ovulating-as corpus luteum will produce, if low then there isn’t ovulation)- NOTE THIS IS ONE OF TWO WAYS OF TESTING IF THERE HAS BEEN OVULATION (the other is ultrasound scan for corpus luteum)
Prolactin, thyroid function tests
Androgens (testosterone, androstenedione, DHEAS)
Chromosomal analysis (Turners 45 XO)
Ultrasound scan ovaries / uterus
Treatment of amenorrhoea
Treat the cause (eg low weight)
Primary ovarian failure – infertile so don’t give gonadotropns, give HRT for symptoms due to lack of oestrogen and progesterone (not good in terms of bones)
Hypothalamic / pituitary disease
- HRT for oestrogen replacement
- Fertility: Gonadotrophins (LH & FSH) – part of IVF treatment
Incidence of PCOS
1 in 12 women of reproductive age
What is PCOS associated with
increased cardiovascular risk and insulin resistance (>diabetes) ? why
How is a PCOS diagnosis made
2 from:
- polycystic ovaries on USS
- oligo- / anovulation
- clinical / biochemical androgen excess
Clinical features of PCOS
Hirsuitism
Menstrual cycle disturbance
Increased BMI
How to treat PCOS for fertility
Metformin (for insulin resistance and diabetes)
Clomiphene
Gonadotrophin therapy as part of IVF treatment
Mechanism of action of clomiphene
anti-oestrogenic in the hypothalamo-pituitary axis
Bind to oestrogen receptors in the hypothalamus thereby blocking the normal negative feedback, resulting in an increase in the secretion of GnRH and gonadotrophins
(SERM!)
Outline control of prolactin secretion
Dopamine inhibits prolactin, TRH stimuates it
Suckling suppresses dopamien release increasing prolactin release
How does prolactin affect other hormones
GnRH pulsatlity (-)
LH actions on ovary / testis (-)
Causes of hyperprolactinaemia
Dopamine antagonist drugs
Anti-emetics (metoclopramide)
Anti-psychotics (phenothiazines)
Prolactinoma
Stalk compression due to pituitary adenoma (i.e. dopamine from hypothalamus can’t reach the pituitary)
PCOS
Hypothyroidism
Oestrogens (OCP), pregnancy, lactation,
Idiopathic
Why is prolactin preventing pregnancy
To stop immediate pregnancy after breastfeeding etc.
Clinical features of Hyperprolactinaemia
Galactorrhoea
Reduced GnRH secretion / LH action»_space; hypogonadism
Prolactinoma
- Headache
- Visual field defect
Treatment of Hyperprolactinaemia
Treat the cause – stop drugs
Dopamine agonist
- Bromocriptine
- Cabergoline
Prolactinoma
- Dopamine agonist therapy
- Pituitary surgery rarely needed
Levels of GnRH, FSH/LH and oestrogen/testosterone in primary gonadal failure
High GnRH and high LH and FSH because of lack of negative feedback,
Low testosterone and oestradiol
Testosterone supports spermatogenesis, why can it not be given alone to treat infertility in males
pharmacological testosterone replacement this will downregulate their LH & Fsh and switch off spermatogenesis. Hence need gonadotropins which will also downstream more physiologically stimulate testosterone release
T/f treatment with testosterone will restore fertility in male
It will not restore fertility, which requires treatment with gonadotrophins to restore normal spermatogenesis
How is GnRH released
In pulses, every 90 minutes or so
This is switched off by prolactin
T/f prolactin increases following pregnancy to stimulate milk production. Because this inhibits GnRH, periods stop after pregnancy
F….. periods do not stop…. it’s weakly contraceptive
