Endocrine Infertility Flashcards
Which cells within the testes does LH stimulate and what does it make these cells produce?
Leydig Cells –> they are stimulated to produce testosterone
Which cells within the testes does FSH stimulate and what does it makes these cells produce?
Sertoli cells (in the seminiferous tuules) –> they are stimulated to produce sperm and inhibin A and B
What does inhibin inhibit?
Pituitary FSH secretion
Summarise the male gonadal axis.
- GnRH pulses from hypothalamus –> LH and FSH release from pituitary
- LH–> testosterone production by Leydig cells –> secondary sexual characteristic and spermatogenesis
- FSH –> sperm and Inhibin A&B production by Sertoli cells
- Testosterone negatively feeds back on pituitary and hypothalamus
- Inhibin sends negative feeback to pituitary to stop FSH secretion
What are the three phases of the menstrual cycle?
Follicular Phase
Ovulation
Luteal Phase
What does LH stimulate in the ovaries?
Oestradiol and progesterone production
What does FSH stimulate in the ovaries?
Follicular development and inhibin production
What effect does oestrogen have on the HPG axis in the follicular phase of the menstrual cycle?
It has a negative feedback effect – inhibits FSH and LH
What does the leading follicle develop into by around day 10?
Graffian Follicle
Describe the female gonadal axis in the ovulation phase.
- Oestrogens initially send negative feedback to stop LH and FSH release
- Later in the cycle oestrogen levels rise because as the follicles grow the oestradiol levels increase
- This leads to positive feedback –> increased GnRH release & increased LH sensitivity to GnRH
- This causes a mid-cycle LH surge
- This leads to ovulation from the leading follicle
Summarise the female gonadal axis in the follicular phase.
- GnRH pulses –> LH and FSH from pituitary
- LH–> ovarian oestrogen and progesterone
- FSH—> follicular development & inhibin production
- By day 10 Graafian follicle matures and inhibin inhibits FSH release
- Oestrogen also (initially) send negative feedback to stop LH and FSH secretion
Once oestrogen reaches a certain level it switches to positive feedback. How does it do this?
It increases the GnRH secretion
It increases LH sensitivity to GnRH
Briefly summarise what happens in the luteal phase.
If implantation does not occur –> endometrium is shed (menstruation)
If implantation does occur –> pregnancy
Define infertility.
How many couples are affected?
Inability to conceive after 1 year of regular unprotected sex
1:6 couples affected
What is primary gonadal failure and what effects does it have on the HPG axis?
It is a problem with the gonads(primary)
The testes/ovaries don’t produce enough testosterone/oestrogen so there is no negative feedback on the HPG axis meaning that you get high GnRH, high LH and high FSH.
Describe the levels of the different hormones in the HPG axis in the case of hypothalamic/pituitary disease causing infertility.
Low GnRH
Low FSH
Low LH
–> low testosterone and low oestradiol because the hypothalamus and pituitary are not sending signals to make sex hormones.
State some of the clinical features of male hypogonadism.
- Loss of libido
- Impotence
- Small testes
- Decreased muscle bulk
- Osteoporosis (testosterone has anabolic action in the bone)
State 4 main causes of male hypogonadism. Give some examples.
- Hypothalamis-pituitary disease
- Hypopituitarism
- Kallmann’s Syndrome (anosmia + low GnRH)
- Illness/underweight
- Primary gonadal disease
- Congenital: Kleinfelter’s syndrome (XXY)
- Acquired: Testicular tortion, chemotherapy
- Hyperprolactinaemia
- Androgen receptor deficiency (RARE)
State some congenital and acquired causes of primary gonadal disease.
Congenital: Klinefelter’s Syndrome (XXY)
Acquired: Testicular torsion, chemotherapy
Describe the features of Kallman’s syndrome.
- A hypogonadism disorder affecting the hypothalamo-pituitary axis
- Anosmia and low GnRH
- Testes are undescended and stature is low
What are the main investigations for male hypogonadism?
- LH, FSH and testosterone (if all are low –> MRI to check pituitary problem)
- Prolactin
- Sperm count (azoospermia – absence of sperm in ejaculate; oligospermia – reduced number of sperm in ejaculate)
- Chromosomal analysis (check for Klinefelter’s)
Define azoospermia and oligospermia.
azoospermia – absence of sperm in ejaculate;
oligospermia – reduced number of sperm in ejaculate
What is given to all patients with hypogonadism?
Testosterone to increase muscle bulk and protect against osteoporosis
How do you restore fertility in someone with hypothalamic/pituitary disease?
Subcutaneous gonadotrophin injections – stimulates testosterone release
What is the treatment for hyperprolactinaemia(causing hypogonadism)?
- Dopamine agonists – bromocriptine and cabergoline
- Pituitary surgery (though this is rarely used because medicine normally works well)
State some endogenous sites of production of androgens.
Interstitial leydig cells in the testes
Adrenal cortex
Ovaries
Placenta
Tumours
What are the main actions of testosterone?
- Development of the male genital tract
- Maintains fertility in adulthood
- Control of secondary sexual characteristics
- Anabolic effects (muscle, bone)
Testosterone is heavily plasma protein bound and it can be converted to other hormones in various tissues. State two products that testosterone can be converted to and the enzymes responsible for these conversions.
98% of testosterone is plasma protein bound.
- Converted by 5-alpha-reductase to dihydrotestosterone (DHT), which acts on androgen receptors
- Converted by aromatase to 17-beta-oestradiol, which acts on oestrogen receptors
What type of receptors does DHT and E2 act on?
Nuclear receptors
DHT: acts via androgens receptors (AR)
E2: acts via osetrogen receptors (ER) e.g. brain and adipose tissue
What are the clinical uses of testosterone?
- Lean body mass
- Muscle size and strength
- Bone formation and bone mass
- Libido and potency
NOTE: it does NOT restore fertility - this requires treatment with gonadotrophins to restore normal spermatogenesis
List some common reproductive system disorders in the female.
- Amenorrhoea
- Polycystic ovarian syndrome (PCOS)
- Hyperprolactinaemia
What is the difference between primary and secondary amenorrhoea?
Primary Amenorrhoea = failure to develop spontaneous menstruationby the age of 16 years
Secondary Amenorrhoea = absence of menstruation for 3 months in a woman who has previously had cycles
What is oligomenorrhoea? What is amenorrhoea?
Irregularly long cycles
Amenorrhoea=absence of periods
List some causes of amenorrhoea.
- Pregnancy+ Lactation
- Ovarian failure:
- Premature ovarian insufficiency
- Ovariectomy/Chemotherapy
- Ovarian dysgenesis (Turner’s Syndrome (45 X))
- Gonadotrophin failure:
- Hypothalamic/pituitary disease
- Kallmann’s syndrome
- Low BMI
- Post-pill amenorrhoea
- Hyperprolactinaemia
- Androgen excess (gonadal tumour)
State some features of Turner’s syndrome.
- Short statue
- Cubitus valgus (wide carrying angle - forearm is angled away from the body to a greater degree than normal when fully extended)
- Gonadal dysgenesis
State some investigations for amenorrhoea.
- Pregnancy test
- LH, FSH and Oestradiol
- Day 21 Progesterone (this should be high (showing that you’re ovulating) because progesterone rises in the second half of the menstrual cycle)
- Prolactin
- Thyroid function test (both hyper- and hypothyroidism can cause problems with the menstrual cycle)
- Androgens (testosterone, androstenedione, DHEAS)
- Chromosomal analysis
- Ultrasound to scan ovaries/uterus
How do you treat amenorrhoea?
- Treat the cause e.g. low birth weight
- If primary ovarian failure - give HRT
- If hypothalamic/pituitary disease - give HRT to replace the oestrogen and give gonadotrophins if trying to conceive (as part of IVF treatment)
What are the implications on health of polycystic ovarian syndrome (PCOS)?
- Increased cardiovascular risk
- Insulin resistance (diabetes)
What are the criteria for diagnosing PCOS?
They must have at least 2 of the following:
- Polycystic ovaries on ultrasound scan
- Clinical/biochemical signs of androgen excess
- Oligoovulation/anovulation
What are the clinical features of PCOS?
- Hirsuitism
- Menstrual irregularities
- Increased BMI
Describe the treatment for PCOS.
METFORMIN – insulin sensitiser
CLOMIFENE – a fertility drug - blocks negative feedback to the hypothalamu.
Gonadotrophin therapy as part of IVF treatment
Describe the mechanism of action of clomiphene.
It is anti-oestrogenic in the hypothalamo-pituitary axis
Binds to oestrogen receptors in the hypothalamus –> blocking the normal negative feedback –> increase in the secretion of GnRH and gonadotrophins
What hypothalamic hormone has a stimulatory effect on prolactin release?
Thyrotrophin releasing hormone (TRH)
What effect does hyperprolactinaemia have on the HPG axis?
- It reduces GnRH pulsatility- so that it is released basally all the time rather than in regular pulses
- It will switch off gonadal function via LH actions on the ovaries and testes
State some causes of hyperprolactinaemia.
- Dopamine antagonists (anti-emetics and anti-psychotics)
- Prolactinoma
- Stalk compression due to pituitary adenoma (so dopamine can’t get to adenohypophysis)
- PCOS
- Hypothyroidism
- Oestrogens (OCP), pregnancy, lactation
- Idiopathic
What are the clinical features of hyperprolactinaemia?
Galactorrhoea
Reduced GnRH and gonadotrophin secretion –> HYPOGONADISM
Prolactinoma:
- Visual field defect
- Headache
How is hyperprolactinaemia treated?
- Dopamine agonists - bromocriptine/cabergolin
- Pituitary surgery - rarely needed
A male presents to endocrine clinic who has had bilateral orchidectomy (removal of testes). What would you expect his blood results to show:
- Low LH, Low FSH, Low Testosterone
- Low LH, high FSH, Low Testosterone
- high LH, high FSH, Low Testosterone
- high LH, high FSH, high Testosterone
3
A young woman presents to endocrine clinic who complains of secondary amenorrhea and galactorrhea. Her GP measured her prolactin at 4500 (high). What would you expect her blood results to show:
- Low LH, Low FSH, Low oestradiol
- Low LH, high FSH, Low oestradiol
- high LH, high FSH, Low oestradiol
- high LH, high FSH, high oestradiol
1
Testosterone:
- Can induce fertility in patients with secondary hypogonadism
- Possesses some aldosterone-like activity
- Is 38% bound in the circulation
- Can be converted to estradiol by the enzyme 5alpha reductase
- As an oral presentation is the best replacement therapy to restore physiological testosterone levels in patients with hypogonadism
False
False
False
False
False
Secondary amenorrhoea:
- Is the condition in which no menstruation has ever occurred
- Is associated with Turner’s syndrome
- May be linked to anorexia
- May be due to a prolactinoma
- Is associated with low serum oestrogen levels
False
False
True
True
True
Polycystic ovary syndrome:
- Is associated with raised serum androgen levels
- Is commonly associated with anorexia
- Often involves raised peripheral insulin sensitivity
- Often involves hirsutism
- Can be confirmed with ultrasound imaging of the ovaries
True
False
False
True
True
