9. Endocrine Infertility Flashcards
Outline the male hypothalamo-pituitary-gonadal axis
- GnRH pulses from hypothalamus
- Stimulation of LH + FSH release from pituitary
- LH stimulates leydig cells to produce testosterone
- FSH stimulates sertoli cells in seminiferous tubules to produce sperm and inhibin A + B
- Inhibin has negative feedback on pituitary FSH secretion
What are the phases of the menstrual cycle?
- Follicular phase
- Ovulation
- Luteal phase
Describe the follicular phase
- GnRH pulses stimulate LH + FSH
- LH stimulates production of oestradiol and progesterone in the ovaries
- FSH stimulates follicular development and inhibin
- Around day 10, leading follicle => Graffian Follicle
- Oestrogen initially has negative feedback on LH + FSH secretion
Describe ovulation and the luteal phase
- Once oestrogen reaches a certain level, it switches from negative to positive feedback
- Increases GnRH release and LH sensitivity to GnRH
- Mid-cycle LH surge
- Triggers ovulation from the leading follicle
- Progestrone rises
- If no implantation - endometrium is shed
Define infertility, and the proportion of couples it can affect
- Inability to conceive after 1 year of regular unprotected sex
- 1/6 couples can be affected
- Abnormalities - 30% males, 45% females, 25% unknown
What does primary gonadal failure lead to?
- Testes/ovaries not producing testosterone/oestrogen
- No negative feedback on HPG axis
- High GnRH and high LH + FSH
What is hypothalamic/pituitary disease?
- Secondary gonadal failure/hypopituitarism
- Inability of pituitary to produce FSH + LH - low levels
- Therefore, low oestradiol/testosterone
What are the clinical features of male hypogonadism?
- Loss of libido
- Impotence
- Small testes
- Decreased muscle bulk
- Osteoporosis (testosterone has anabolic action in the bone)
What are the causes of hypothalamic-pituitary disease?
- Hypopituitarism - secondary gonadal failure
- Kallmann Syndrome - anosmia and low GnRH, due to failure of GnRH and olfactory neurones to migrate from back of brain in development
- Illness/underweight - low levels of leptin
Give congenital and acquired causes of primary gonadal disease
- Congenital: Klinefelters Syndrome (XXY)
* Acquired: Testicular torsion, chemotherapy
What effect can hyperprolactinaemia have on the gonads?
Inhibit gonadal function
How else can low testosterone levels/insensitivity be referred to and why?
- Hypoandrogenism
- Testosterone = androgen
- Androgen receptor deficiency is a rare congenital cause of hypogonadism
How do you investigate male hypogonadism?
- LH, FSH and testosterone - if low, MRI of pituitary
- Prolactin
- Sperm count: azoospermia = absence, oligospermia = reduced numbers
- Chromosomal analysis
What is an ICSI?
- Intracytoplasmic sperm injections
* Combats infertility in someone with oligospermia
How can male hypogonadism be treated?
- All patients: replacement testosterone for all patients
- Hypothalamic/pituitary disease: subcutaneous gonadotrophin injections, inducing spermatogenesis for fertility
- Hyperprolactinaemia: dopamine agonist, (main influence) negative effect on prolactin release
What are the endogenous sites of androgen production?
- Adrenal cortex
- Interstitial Leydig cells
- Ovaries
- Placenta
- Tumours
What are the main actions of testosterone?
- Development of male genital tract
- Maintains fertility in adulthood
- Control of secondary sexual characteristics
- Anabolic effects
How much of testosterone is protein bound
98%
How is testosterone altered to act on androgen receptors?
- 5 α-reductase converts it into dihydrotestosterone (DHT)
* Goes into nucleus - nuclear receptors
How is testosterone altered to act on oestrogen receptors?
- Aromatase converts it into 17β-oestradiol (E2)
* Goes into nucleus - nuclear receptors
What are the clinical uses of testosterone?
• Lean body mass • Muscle size and strength • Bone formation and bone mass • Libido and potency (• will not restore fertility)
What is primary amenorrhoea?
Failure to develop spontaneous menstruation by age 16
What is secondary amenorrhoea?
- Absence of menstruation for 3 months in a woman who has previously had cycles
- Probably not congenital
What is oligomenorrhoea?
Irregular long cycles
What are the causes of amenorrhoea?
• Pregnancy • Lactation • Ovarian failure - premature ovarian insufficiency - oophorectomy/ovariectomy - chemotherapy - ovarian dysgenesis - Turner's syndrome • Gonadotrophin failure (can also be caused by the pill)
What are some of the features of Turner’s syndrome?
- Short stature
- Cubitus Valgus (angled forearm)
- Gonadal dysgenesis
How can amenorrhoea be investigated?
- Pregnancy test
- LH, FSH and oestradiol
- Day 21 progesterone - rises in second half of menstrual cycle
- Prolactin
- Thyroid function test - hyper/hypothyroidism can cause problems
- Androgens
- Chromosomal analysis
- Ultrasound
How can amenorrhoea be treated?
• Treat the cause • Primary ovarian failure - hormone replacement therapy (HRT) • Hypothalamic/pituitary disease - HRT for oestrogen replacements - Gonadotrophins for fertility
Who gets polycystic ovarian syndrome (PCOS) and what is it associated with?
- 1/12 women of reproductive age
* Associated with increased cardiovascular risk and insulin resistance (diabetes)
What are the criteria to diagnose PCOS?
• 2 of the following:
- polycystic ovaries on ultrasound
- oligoovulation/anovulation
- androgen excess
What are the clinical features of PCOS?
- Hirsuitism
- Menstrual cycle disturbance
- Increased BMI
How is PCOS treated (fertility)?
• Metformin - insulin sensitiser
• Clomiphene
- anti-oestrogenic effect in hypothalamo-pituitary axis
- Binds to oestrogen receptors in hypothalamus, blocking negative feedback
- Increase in GnRH and gonadotrophin secretion
• Gonadotrophin therapy
What happens if prolactin secretion is dysregulated?
- Gonadal function switched off via LH actions on the ovaries and testes
- Reduced GnRH pulsatility - released all the time rather than in pulses
What are the causes of hyperprolactinaemia?
- Dopamine antagonists: anti-emetics and anti-psychotics (more likely as it’s used long term)
- Prolactinoma
- Stalk compression due to adenoma - dopamine can’t get through
- PCOS
- Hypothydroidism
- Oestrogens (pill), pregnancy, lactation
- Idiopathic
What are the clinical features of hyperprolactinaemia?
- Galactorrhoea
- Hypogonadism - due to reduced GnRH secretion/LH action
- Prolactinoma - headache, visual field defect
How can hyperprolactinaemia be treated?
- Treat the cause e.g. stop taking drugs causing the problem if possible, surgery
- Dopamine agonists - bromocriptine, cabergoline (also decreases tumour if prolactinoma)
