4.12 - Sex Hormones During Life Flashcards
What is the definition of puberty?
- maturation of reproductive organs
- production of sex steroids e.g. oestradiol/testosterone
- develop secondary sexual characteristics
- attain capability to reproduce
How do we assess puberty development in boys and girls?
- Tanner staging (has 5 stages)
- in girls - thelarche (breast development)
- in boys - genitalia (testicular volume)
- we also assess pubarche (pubic hair development) in both
What is the Tanner staging for thelarche (breast development)?
- 1 (prepubertal) - elevation of papilla only
- 2 - breast bud with elevation of breast and papilla and enlargement of areola
- 3 - further enlargement of breast and papilla with no separation of their contours
- 4 - projection of areola and papilla to form a secondary mound
- 5 (adult) - mature breast, projection of papilla only as areola conforms to breast contour
What is the Tanner staging for genitalia (testicular volume)?
- 1 (prepubertal) - testes, penis and scrotum same size as early childhood
- 2 - early enlargement of testes 2-6cm3; scrotal skin reddens and changes in texture
- 3 - penis lengthens; testes enlarge 6-12cm3; growth of scrotum
- 4 - further penile and scrotal growth; testes 12-15cm3
- 5 - genitalia adult in size and shape; testes >15cm3
What is the Tanner staging for pubarche (pubic hair development)?
- 1 (prepubertal) - vellus hair no different form abdominal hair
- 2 - slightly pigmented, downy hair
- 3 - darker, coarser, more curled hair
- 4 - adult pubic hair that does not reach thighs (axillary hair)
- 5 - adult hair now on thighs
What does ‘-arche’ mean and what types are there?
- -arche = onset of
- gonadarche - activation of gonads by HPG axis
- thelarche - breast development
- menarche - menstrual cycles
- spermarche - spermatogenesis
- adrenarche - adrenal androgen production e.g. DHEAS and DHEA (starts two years before gonadarche) - more important in girls as androgens are produced from adrenal gland so is more responsible for pubarche, whereas in boys they are produced in the testes
- pubarche - pubic hair
What are secondary sexual characteristics in girls?
- effects of oestradiol
- breast development
- hair growth - pubic, axillary
- sweat gland composition - skin oiliness/acne
- changes to external genitalia
What are secondary sexual characteristics in boys?
- effects of testosterone
- deepening voice
- hair growth - pubic then axillary, facial
- sweat gland composition - skin oiliness/acne
- changes to external genitalia
What are the first and late signs of puberty in girls?
- first - thelarche
- late - menarche
- onset 8-13 years
- breast bud –> onset pubic hair –> peak height velocity –> menarche –> adult pubic hair –> adult breast
- adrenarche: 6-9 years
What are the prepubertal and adult testicle sizes?
- prepubertal < 4 mls
- adult size > 15mls
- testicular volume measured using a Prader orchidometer
- testicular volume >2ml –> onset pubic hair –> onset penis growth –> peak height velocity –> adult genitals –> adult pubic hair
When does adrenarche happen in boys?
7-10 years
What is the term for starting puberty below 8 years?
- precocious
- more common in girls
What is the term for starting puberty after 14 years?
- delayed
- more common in boys
How do DHEAS/DHEA levels change during adrenarche in boys and girls?
DHEAS/DHEA increases in both boys and girls
How do LH, FSH, testosterone and oestradiol levels change during gonadarche in boys and girls?
- LH and FSH go up in both
- testosterone increases a lot in boys, and a little in girls
- oestradiol increases a tiny bit in boys and a lot in girls
What is normal GnRH secretion like in HPG axis?
- pulsatile
- if secretion was continuous non-pulsatile, rather than stimulation of pituitary you would get decrease in LH+FSH production and therefore hypogonadism
- useful in treating prostate cancer - we give non-pulsatile GnRH which causes castration by reducing FSH+LH, which reduces testosterone levels
How does GnRH pulsatility change during the menstrual cycle?
- in follicular phase, there are pulses every 2 hours
- in luteal phase this goes up to 4 hours
How does GnRH secretion change from foetus to adult?
- increases foetal
- peaks and decreases to infant
- smaller peak at infant
- decreases during childhood until puberty - quiescence of HPG axis
- increases during puberty - increased nocturnal GnRH pulsatility
- stable during adult - normal pulsatile GnRH secretion
When does menarche start?
- 2.3 years after thelarche
- soon after peak height velocity (PHV) when girl grows most
- mean age is 12.7 years (range 10.7-16.1)
How long are menstrual cycles?
- 28 day cycle (24-35 days range)
- +/- 2 days each month
What is amenorrhoea?
- no periods for at least 3-6 months
- or up to three periods a year
What is primary amenorrhoea?
Starting periods later than 16 years is regarded as abnormal
What is secondary amenorrhoea?
- common for periods to be irregular/anovulatory for first 18 months
- periods start then stop for at least 3-6 months
- commonest physiological cause is pregnancy
What is oligomenorrhoea?
- irregular or infrequent periods >35 day cycles
- or 4-9 cycles per year
What are the main phases of the ovarian cycle?
- follicular phase
- ovulation
- luteal phase
What are the steps of the follicular (pre-ovulatory) phase of the ovarian cycle?
- FSH rises
- 2-3 follicles start to grow
- produce E2 (oestradiol) and inhibin B, which reduce FSH by negative feedback on pituitary
- these restrict ‘FSH window’ and non-dominant follicles undergo atresia (as there are more FSH dependent than dominant ones)
- a dominant ‘Graafian’ follicle emerges
- E2 continues to rise
- there is a switch to positive feedback on hypothalamus and pituitary by high E2 (from -ve feedback at low E2)
- induces a mid-cycle LH surge
- causes ovulation
What happens during the ovulation phase of the ovarian cycle?
The positive feedback from release of oestradiol induces a mid-cycle LH surge which causes ovulation
What happens during the luteal phase of the ovarian cycle?
- empty follicle becomes corpus luteum, which releases progesterone and oestradiol
- progesterone highest in midluteal (day 21, 3/4 through cycle) phase - gives evidence of ovulation
Describe the steps of the uterine cycle?
- menstrual phase (shedding of endometrium)
- proliferative phase (action of oestradiol) - endometrial lining regrows with growth of new epithelial cells, gland proliferation and increase in stroma/arterioles
- secretory phase (action of progesterone from corpus luteum) - changes endometrium to be receptive for implantation by: increasing volume of stromal cells leading to thick spongy lining, cork-screw shaped glands secreting glycogen, coiling and lengthening of spiral arteries
What happens if sperm meets egg and embryo implants in endometrium?
- embryo starts producing beta-hCG which acts on LH receptors on corpus luteum which maintains production of progesterone and oestradiol through first part of pregnancy
- if there is no fertilisation, no embryo formed = no hCG = no stimulation of corpus luteum = it dies = no more progesterone and oestradiol to maintain endometrium lining
What is hypogonadism?
- decreased oestrogen in a woman
- decreased testosterone in a man
What is primary hypogonadism?
- something directly affecting gonads leading to low E2 and testosterone
- but high LH and FSH due to reduced negative feedback
- causes in men are infection / trauma / cancer of testes
- causes in women is menopause - also causes low inhibin which partly leads to high FSH
What is secondary (or hypogonadotrophic) hypogonadism?
- problem in pituitary gland or hypothalamus leading to low (or normal) FSH/LH and low E2/testosterone
- causes include pituitary tumour, high prolactin
What are the symptoms of menopause? (Due to a lack of oestradiol)
- skin dryness / hair thinning
- hot flushes / sweating / sleep disturbance
- mood disturbance
- osteoporosis - decreased bone mineral density (BMD) as E2 stimulates osteoblasts, joint pain
- sexual dysfunction - vaginal dryness, decreased libido
- genito-urinary disturbance
- weight gain
- amenorrhoea - perimenopausal if you are within one year of last menstrual period and postmenopausal if you are after one year of last menstrual period
- cessation of fertility
- climacteric - irregular periods in years close to menopause
What are the treatments for menopause?
- oestrogen replacement through MHT (menopausal hormone therapy), previously known as HRT (hormone replacement therapy)
- oestrogen stimulates endometrium to proliferate
- add progesterone too to prevent risk of endometrial hyperplasia/cancer if endometrium is intact
What is ovarian reserve and give an example of a marker and how it changes throughout a woman’s life?
- ovarian reserve is how many eggs are in the ovaries before you reach menopause
- Anti-Mullerian Hormone (AMH) produced by granulosa cells in ovaries is an ovarian reserve marker that peaks in early adult life and is very low at menopause
What is the range and median age of menopause, and what is premature menopause?
- range 45-55 years
- median 51 years
- only 1% of women undergo menopause below 40 years old and they are premature
What is premature ovarian insufficiency (POI)?
- same symptoms as menopause
- previously called ‘premature ovarian failure (POF)’
- difference is that conception can still happen in 20% of cases
- diagnosis: high FSH > 25 iU/L on at least two occasions, four weeks apart
- early menopause
What causes premature ovarian insufficiency (POI)?
- autoimmune
- genetic e.g. fragile X syndrome / Turner’s syndrome (XO)
- previous cancer therapy e.g. radio/chemotherapy
Is there an andropause?
- after age 40, male testosterone decreases by 1% every year
- however free testosterone decreases more steeply which can be associated with hypogonadism symptoms like erectile dysfunction, low libido - late onset hypogonadism (age-related decreased testosterone)
What is the ‘free hormone’ hypothesis with testosterone?
- this is the binding of total testosterone in circulation
- 60% strongly bound to SHBG (sex hormone binding globulin) = unavailable for tissues
- 38% weakly bound to albumin = still bioactive
- 2% free testosterone = active
With age, how do SHBG and free testosterone levels change?
Total testosterone is unchanged, but SHBG is increased and free testosterone is reduced
What kind of rhythm does testosterone have and under what conditions should it be measured?
- diurnal rhythm
- testosterone is higher in the morning = measure before 11am
- can fall around 20% with sugar = ideally measure it fasting
What are symptoms of testosterone deficiency?
- sexual dysfunction - reduced libido
- erectile dysfunction + loss of early morning erections
- hair growth - frequency of shaving decreases
- energy levels decrease - fatigue
- mood disturbance
- body composition - increased fat and reduced muscle mass
- gynaecomastia - breast enlargement in men
- spermatogenesis - decreases as high levels of intratesticular testosterone needed
- bone health - can lead to osteoporosis as testosterone usually converted to oestrogen which is needed for good bone health
How is testosterone converted into DHT and what is DHT?
- through 5-alpha-reductase to di-hydro-testosterone (DHT)
- 5-alpha-reductase found in testes (seminal vesicle, epididymis), prostate, skin of scalp, liver
- DHT is a more potent ligand for androgen receptor (AR) than testosterone - binds to receptors more effectively
How can 5-alpha-reductase activity be reduced?
- using 5-alpha-reductase inhibitors
- e.g. finasteride to treat prostate cancer as we want less of the potent DHT in them
How is testosterone converted to oestrogens?
- through aromatase
- e.g. androstenedione converted to oestrone, testosterone converted to 17B-oestradiol
- aromatase found in adipose tissue, adrenal glands, ovaries (granulosa cells), testes (Sertoli cells), brain, bone, skin
What factors increase aromatase function?
- age
- obesity
- insulin
- gonadotrophins
- alcohol
How can aromatase activity be reduced and when is this needed?
- by aromatase inhibitors
- e.g. anastrozole used in breast cancer to reduce testosterone being converted to oestrogens as we want less oestrogen in them
