Week 5 Flashcards
Where does glandular synthesis of oestrogen occur?
Granulosa and theca cells of the ovaries as well as the corpus luteum
Where does extra-glandular synthesis of oestrogen occur?
Aromatase is expressed in non-gonadal sites and facilitates peripheral aromatisation of androgens to estrone (e.g. in fat and bone)
This is why overweight men can develop breast tissue
Briefly describe the sequence of steps that results in oestrogen synthesis
LH stimulates the granulosa cells in the ovaries to release pregnenolone, which then passes into the theca cells
Pregnenolone is converted in the theca cells to androstenedione via DHEA
Most androstenedione returns to the granulosa cells and is converted to oestrone by aromatase, and then converted to oestradiol by 17beta-HSD
What is progesterone synthesised from?
Pregnenolone by 3beta-HSD in the corpus luteum, by the placenta during pregnancy and by the adrenals
What are the two phases of the menstrual cycle?
What is the main hormonal product of each phase?
Follicular phase - oestradiol
Luteal phase - progesterone
Define the following terms
- oligomenorrhoea
- primary amenorrhoea
- secondary amenorrhoea
Oligomenorrhoea - reduction in the frequency of periods to less than 9 in a year
Primary amenorrhoea - failure of menarche by the age of 16
Secondary amenorrhoea - cessation of periods for >6 months in someone who has previously menstruated
What are some physiological causes of amenorrhoea?
Pregnancy
Menopause
Primary amenorrhoea - causes
Consider congenital causes e.g. Turner’s syndrome, Kallman’s syndrome
Secondary amenorrhoea - causes
Ovarian problem - PCOS, Premature Ovarian Failure
Uterine problem - uterine adhesions
Hypothalamic dysfunction - stress, excessive exercise, weight loss
Pituitary - high PRL, hypopituitarism
What investigations do all patients presenting with amenorrhoea have done?
(hCG if age-appropriate)
LH, FSH and Oestradiol
Thyroid function and PRL
How is female hypogonadism identified?
What is the difference between primary and secondary hypogonadism?
Hypogonadism in females = low levels of oestrogen
Primary
- problem is with the ovaries
- High LH/FSH but low oestradiol - “hypergonadotrophic hypogonadism”
- e.g. Premature Ovarian Failure
Secondary
- problem is with the hypothalamus or the pituitary
- Low LH/FSH and low oestradiol - “hypogonadotrophic hypogonadism”
- e.g. high PRL, hypopituitarism
How is Premature Ovarian Failure defined?
How is it diagnosed?
Amenorrhoea, low oestrogen and elevated LH/FSH before the age of 40
Measure FSH >30 on two separate occasions, more than a month apart
What would be lost if the cause of amenorrhoea was due to the hypothalamus?
There would be no pulsatile release of GnRH, meaning no release of LH/FSH
Mutations in what receptor have recently been identified as a cause of idiopathic hypogonadotrophic hypogonadism (IHH)?
What is the ligand for this receptor? How does it affect GnRH secretion?
The G-Protein Coupled Receptor KISS1R
Kisspeptin is the ligand for KISS1R and has been noted to be a potent stimulator of GnRH secretion - treatments with kisspeptin may be able to help restore menstruation
What genetic disorder can cause hypothalamic hypogonadism?
What are the symptoms?
Kallman’s syndrome - loss of GnRH secretion
Presents with infertility and anosmia (loss of olfactory bulbs)
What drugs can cause hyperprolactinaemia?
Dopamine antagonists e.g. metoclopramide, domperidone
What criteria is used to determine if a patient has Polycystic Ovary Syndrome?
What does this criteria consist of?
The Rotterdam Criteria
2/3 to diagnose PCOS…
- Menstrual irregularities
- Hyperandrogenism (hirsutism, acne, elevated free testosterone)
- Polycystic ovaries
PCOS is an ovarian cause of amenorrhoea. What other ovarian causes are there?
Ovarian failure (POF)
Congenital problems - absence of uterus/vaginal atresia, Turner syndrome, CAH etc.
If a woman presented with signs of hirsutism that developed over a short period of time, is this cause for concern?
Potentially - could indicate adrenal or ovarian tumour
PCOS and other causes of hirsutism in women typically occur over a longer period of time
How is Congenital Adrenal Hyperplasia inherited?
What is the difference between Classical and Non-Classical CAH?
Autosomal recessive
Classical CAH - typically diagnosed in infancy with virilism and salt-wasting
Non-Classical CAH - partial deficieny in 21alpha-hydroxylase and presents in adolescence/adulthood with hirsutism, menstrual disturbances and infertility
How is Non-Classical CAH tested for clinically? What is used as a marker?
Synacthen test is used
Following ACTH stimulation, an increase in 17-OH progesterone is seen
PCOS - treatment
Oral contraceptive pill - regulates cycle and decreases androgens
Can also use anti-androgens - cyproterone acetat
Cosmesis to treat virilism
Late-onset (i.e. Non-Classical) CAH - treatment
Low dose glucocorticoids to suppress ACTH (hydrocortisone)
Turner’s Syndrome only affects women - true or false
What are the clinical features?
True, patients are 45 XO
Clinical features
- short stature
- webbed neck
- “shield-like chest” with wide-spaced nipples
- failure to progress through puberty
What is the biochemical difference between primary and secondary hypogonadism in males?
Primary - low testosterone, high LH/FSH (congenital and acquired)
Secondary - low testosterone, low LH/FSH (hypothalamic/pituitary disease)
Congenital and acquired causes of primary hypogonadism in males
Congenital
- Kleinfelter’s
- Y-chromosome microdeletions
- LH/FSH receptor mutations
- Myotonic dystrophy
Acquired
- Trauma/torsion/radiation to testicles
- Orchitis
- Chemotherapy
- Infiltrative disease
- Varicocele
- Cirrhosis/excessive alcohol intake
Congenital and acquired causes of secondary hypogonadism in males
Congenital
- Kallman’s
- Prader-Willi
Acquired
- Hyperprolactinaemia
- Damage to pituitary
- Excessive exercise
- Acute illness
- Medications etc. etc.
Klinefelter’s - clinical presentation
Reduced testicular volume
Gynaecomastia
Eunuchoidism
Intellectual dysfunction in 40%
Karyotype is XXY
Low testosterone, high LH/FSH
What is the mean duration of the menstrual cycle?
What is the range?
Mean duration = 28 days
Range = 21-35 days
What is the range of duration of menses (period)?
What day does ovulation typically occur?
Range of menses = 3-8 days
Ovulation typically occurs around day 14
In the follicular stage of the menstrual cycle, at what point is the oocyte released?
Approx 24-36 hours after the LH surge
At what point in the mestrual cycle are progesterone levels at their peak?
1 week after ovulation
Which part of the hypothalamus produces GnRH?
The arcuate nucleus
LH acts on ____ cells
FSH acts on ____ cells
LH acts on theca cells
FSH acts on granulosa cells
What are the actions of…
- Inhibin
- Activin
Inhibin - negative feedback on pituitary FSH secretion and locally enhances LH-induced androstenedione production
Activin - stimulates FSH-induced oestrogen production
In the male, LH acts on ____ cells and FSH acts on ____ cells
LH - Leydig cells
FSH - Sertoli cells
What process must occur for the sperm to be able to fertilise the egg?
What occurs after this proces?
Capacitation
2 parts to the process, 1) the acrosomal head membrane of the sperm destabilises and 2) chemical changes occur in the tail of the sperm giving it a greater degree of motility
Occurs in the female genital tract
Following capacitation, an acrosome reaction occurs that allows the sperm to penetrate the egg (triggered by zona pellucida ZP3)
Low frequency pulses of GnRH cause release of _____
High frequency pulses of GnRH cause release of _____
Low frequency pulses = FSH release
High frequency pulses = LH release
What are the main actions of FSH?
Stimulates follicular development
Thickens endometrium
What are the main actions of LH?
Stimulates ovulation and corpus luteum development
Also thickens endometrium (like FSH)
What triggers the beginning of the next menstrual cycle?
Fall in progesterone
What feedback mechanisms is oestrogen involved in regarding ovulation?
What type of mucus is oestrogen responsible for?
High oestrogen concentrations inhibit secretion of FSH and prolactin (negative feedback) and stimulate secretion of LH (positive feedback)
Responsible for fertile cervical mucus
What effects does progesterone have?
What type of mucus is it responsible for?
Inhibits LH secretion
Maintains thickness of endometrium (as does oestrogen)
Increases basal body temp and relaxes smooth muscle
Responsible for thick, infertile cervical mucus
How is ovulation assessed?
If regular cycles, highly likely that ovulation is normal
Assess by measuring progesterone at mid-luteal phase (day 21)
What other endocrine sign is seen in 50-80% of women with PCOS?
Insulin resistance
However, they have a normal pancreatic reserve, resulting in hyperinsulinaemia
What are the 3 approaches that could be taken in inducing ovulation in someone with PCOS (after pre-treatment interventions i.e. weight loss, smoking cessation etc.)?
- Give clomifene citrate - stimulates LH and FSH to drive ovulation, 70% ovulate and 40-60% conceive
- Daily gonadotrophin injections with recombinant FSH, 80% ovulate and 60-70% conceive
- Laparoscopic ovarian diathermy, 80% ovulate
What other drug can be given alongside lifestyle modifcations that restores menstruation and ovulation, and may improve chances of conception in PCOS?
Metformin
Improves insulin resistance and reduces the amount of androgen produced
What medication can be given in hyperprolactinaemia?
Dopamine agonists e.g. cabergoline
Woman presents with dysmenorrhoea, dysparenuia, menorrhagia, painful defaecation, chronic pelvic pain, infertility and “chocolate cysts” are seen on ovary.
What’s the diagnosis?
Endometriosis (presence of endometrial glands outside of uterine cavity)
