Endocrine infertility Flashcards
21.10.2019
How long is the female menstrual cycle?
- textbook: 28d
- reality: 25-35d
Normal hypothalamo-pituitary-gonadal axis in males
GnRH ++ LH, FSH ++Testosterone
negative feedback on H and AP by inhibin
What are the phases of the menstrual cycle?
- follicular phase
- ovulation
- luteal phase
Describe, in detail, how the menstrual cycle works
LAST YEARS FLASHCARD
What are the possible outcomes in the luteal phase?
- if implantation occurs -> pregnancy
- if implantation does not occur - endometrium I shed (menstruation)
What is infertility?
- inability to concieve after 1 year of regular unprotected sex
How common is infertility?
1:6 couples
What abnormalities cause infertility?
- in males (30%)
- or females (45%)
- or unknown (25%)
Primary gonadal failure
- there is stimulation by the hypothalamus / AP
- gonads themselves don’t make oestradiol / testosterone
Secondary gonadal failure
- due to hypothalamus / pituitary disease
- low LH and FSH
- not enough stimulation of the gonads -> low estradiol / testosterone
Clinical features of male hypogonadism
- Loss of libido = sexual interest / desire
- Impotence
- Small testes
- Decrease muscle bulk
- osteoporosis
Why does male hypogonadism cause osteoporosis?
- is it because Testosterone is aromatised to oestrogen and oestrogen has bone preserving qualities?
- is it because of the anabolic effects that testosterone has on muscle and bone?
What are causes of male hypogonadism?
- hypothalamic-pituitary disease (hypopituitarism, Kallmans syndrome, Illness/underwight (linked to leptin))
- primary gonadal disease (congenital: Klinefelters syndrome XXY; acquired: testicular torsion, chemotherapy)
- Hyperprolactinaemia
- androgen receptor deficiency
Kallmanns syndrome
- anosmia
- low GnRH
=> delayed or absent puberty, impaired sense of smell
Why is anosmia common with low GnRH?
This is due to the fact that during embryonal development GnRH neurones and the olfactory nerves travel together
Investigations in male hypogonadism
- LH, FSH, testosterone -> if all low do a pituitary MRI
- Prolactin
- Sperm count
- chromosomal analysis (Klinefelters XXY)
Azoospermia
absence of sperm in ejaculate
Oligospermia
reduced numbers of sperm in ejaculate
How can you treat male hypogonadism?
- replacement testosterone for all patients
- For fertility: if hypo / pit disease -> s.c. gonadotrophins (LH & FSH)
- Hyperprolactinaemia - dopamine agonist
Endogenous sites of production of androgens
- interstitial Leydig cells of the testes
- adrenal cortex (males and females)
- 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)
How much of circulating testosterone is protein bound?
98%
What can testosterone be turned into?
- reduction: Dihydrotestosterone (DHT), more potent, acts via the androgen receptor
- aromatisation: 17-beta-oestradiol (E2), acts via the oestrogen Receptor (ER) e.g. brain and adipose tissue
Enzyme: Testosterone -> DHT
5-alpha reductase
Enzyme: Testosterone -> 17-beta-oestradiol
aromatase
Mechanism of action of DHT / E2
via nuclear receptors
Clinical uses of testosterone
- in adulthood will increase
- lean body mass
- muscle size and strength
- bone formation and bone mass (in young men)
- libido and potency
It will not restore fertility, which requires treatment with gonadotrophins to restore normal spermatogenesis!!
What are 3 common disorders in females that cause infertility?
- Amenorrhea
- PCOS
- Hyperprolactinaemia
Amenorrhoea
= absence of periods
Primary amenorrhoea
failure to begin spontaneous menstruation by age 16 years
Secondary Amenorrhoea
absence of menstruation for 3 months in a woman who has previously had cycles
Oligomenorrhoea
irregular long cycles
Causes of Amenorrhoea
- pregnancy / lactation
- ovarian failure (premature ovarian failure, ovariectomy, chemotherapy, ovarian dysgenesis in Turners Syndrome 45X
- Gonadotrophin failure (hypo/pit disease, kallmann’s syndrome, low BMI, post pill amenorrhoea)
- hyperprolactinaemia
- androgen excess: gonadal tumor
How common is Turners syndrome?
1:5000 live female births
Investigations for Amenorrhoea
- Pregnancy test
- LH, FSH, oestradiol
- Day 21 progesterone (18,21,24 due to variation)
- Prolactin
- thyroid function tests
- androgens (testosterone, androstenedione, DHEAS)
- chromosomal analysis (Turners 45X)
- Ultrasound scan of ovaries/uterus
Treatment of amenorrhoea
- Treat the cause (eg low weight)
- Primary ovarian failure – infertile, HRT
- Hypothalamic / pituitary disease
HRT for oestrogen replacement
Fertility: Gonadotrophins
PCOS
= polycystic ovarian syndrome
- Associated with increased cardiovascular risk and insulin resistance (>diabetes)
How common is PCOS?
1 in 12 women of reproductive age have it.
What are the criteria needed to diagnose PCOS?
- polycystic ovaries on USS
- oligo-/anovulation
- clinical / biochemical androgen excess
Clinical feature of PCOS
- Hirsutism
- Menstrual cycle disturbance
- Increased BMI
Treatment of PCOS
- metformin (insulin sensitiser)
- clomiphene (anti-oestrogen in the hypo-pit axis)
- gonadotrophin as part of IVF
Clomiphene
- anti-oestrogenic in the hypothalamo-pituitary axis
- Bind to oestrogen receptors in the hypothalamus -> block normal negative feedback -> increase in the secretion of GnRH and gonadotrophins
Hyperprolactinaemia
- prolactin secreted from the AP has a negative effect on GnRH pulsatility and decreases LH actions on gonads
What are causes of Hyperprolactinaemia?
- Dopamine antagonist drugs (Anti-emetics (metoclopramide); Anti-psychotics(phenothiazines))
- Prolactinoma
- Stalk compression due to pituitary adenoma
- PCOS
- Hypothyroidism
- oestrogens (OCP, pregnancy, lactation)
- idiopathic
Clinical features if Hyperprolactinaemia
- galactorrhoea
- reduced GnRH secretion / LH action -> hypogonadism
- prolactinoma (headache, visual field defect)
How do you treat hyperprolactinaemia?
- Treat the cause – stop drugs
- Dopamine agonist
- Bromocriptine
- Cabergoline
- Bromocriptine
- Prolactinoma
- Dopamine agonist therapy
- 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:
1. Low LH, Low FSH, Low oestradiol 2. Low LH, high FSH, Low oestradiol 3. high LH, high FSH, Low oestradiol 4. high LH, high FSH, high oestradiol
1
(this is secondary hypogonadism)
Clinically: however you could also have a normal LH and FSH but on the low end. (inappropriately normal in the context of a low oestradiol)
Phenothiazine
- antipsychotic
- dopamine antagonist
- can cause hyperprolactinaemia
Which drugs can cause hyperprolactinaemia?
Dopamine antagonist drugs
- Anti-emetics (metoclopramide)
- Anti-psychotics (phenothiazines)
Oestrogen (OCP)
