ENDOCRINOLOGY WK 6 Flashcards
definition of infertility and subfertility
Infertility defined as inability to conceive after 1 yr of unprotected sex
Subfertility defined after 6 months
what has lead to a rise of infertility
On rise due to…
- STIs
- Obesity
o Hormones important become off-balanced in obesity
o If underweight hormones inbalanced
- Tobacco
o Worse for men > dec. blood flow in penis
formation of the ovarian reserve - stage of arrest of germ cells, and how this relates to chromosome instability in later life
Formation of ovarian reserve
- Primordial germ cells colonise the gonad
- Numbers expand by mitosis
- Germ cell enter, and then arrest in meiosis (form oogonial cycts)
o In these structures they begin meiosis
o This is when women is still a foetus (men only begin meiosis at puberty)
o Cysts breakdown and eggs get wrapped up by granulosa cell to form…
- Primordial follicles form
o Arrested at diplotene of meiosis 1
o Don’t resume meiosis til ovulation
o Vv important for connections between chromosomes to be stable for 30-40 yrs
o This is why old women have higher prevelance of down syndrome
o Bc/ connections between chromosomes are worse
- Folliculogenesis
the follicle stages
WHAT IS A FOLLICLE
- Reproductive unit of the ovary
- Comprised of egg(oocyte) and surrounded by granulosa cells
o Primordial follicle
egg and single layer of squamous granulosa cells
o Primary follicle
squamous granulosa cells become cuboidal and form layers around oocyte
oocyte secretes a glycoprotein layer – zona pellucida
zona pellucida is a barrier between oocyte and granulosa cells
o secondary follicle
inc. number of granulosa cells
extra layer called theca
theca comes from surrounding stroma that differentiate
o early antral follicle
theca differentiates into 2 parts
• theca interna – glands, blood vessels (important for getting nutrients and hormones)
• theca externa – big fibrous capsule to proect whole follicle
fluid filled gaps secreted by granulosa cells
• folicular fluid/ antral fluid
• starts to build the antrum (fluid-filled space)
o ovulatory/ antral/ graafian follicle
all the fluid form a big follicular antrum
this pushes the oocyte out so it’s dnagling by granulosa cells in the antrum
one layer of grnaulosa cells become attached to oocyte – corona radiata
other granulosa cells more loosely associated – cumulus cells
HPG axis - what hormones involved etc
- hypothalamus releases Gonadotrophin-releasing hormone
- anterior pituitary gonadotroph cells makes FSH and LH
- FSH and LH work on the ovary
- The follicle makes oestrogen, progesterone, inhibin etc
o These hormone signal back to pituitary and hypothalamus to regulate hormones
posterior pituitary (HPG axis)- what hormones and what are there roles
Posterior pituitary - Paraventricular and supraoptic neurone from hypothalamus to posterior pituitary - 2 hormones made here o ADH o Oxytocin
OXYTOCIN
- Has major effects on smooth muscle contraction
o Milk ejection
o Contraction of uterus during childbirth
- Secretion is stimulated in response to stimulation of nipples or uterine distention
- Oxytocin is used to induce labour
- Released during female orgasm
anterior pituitary (HPG axis) - what hormones involved
Neurones run from hypothalamus to the hypophyseal capillary network
In the hypothalamus GnRH is made….
- GnRH has a pulsatile release
o Prevents receptor desensitisiation and downregulation
o Responds to ovarian hormonal feedback
kisspeptin
- Small neuropeptide hormone
- Feedback onto GnRH neurone
- And regulate secretion of GnRH
- Although it can receive signals from gonads can also integrate other hormones eg cortisol, leptin, environmental cues
o May be why shift workers have fertility problems
water soluble hormone transport - what hormones and how
WATER SOLUBLE HORMONE TRANSPORT
- GnRH
- FSH
- LH
So can travel through blood freely
- At target site diffuse out
- Cell membranes are hydrophobic so can’t diffuse through this
- Need to bind to cell receptor to trigger and signalling cascade
- Involves CAMP to phosphorylate protein kinases > reaction in the cell itself
lipid soluble hormone transport - what hormones and how
LIPID SOLUBLE HOMRONE TRANSPORT
- Oestrogen
- Progesterone
Travel in blood on a transport protein
- When get to cell they can freely diffues through the cell membrane
- Travel into nucleus and bind to a nucelus receptor to change gene expression
what causes follicle activation
No one realy knows from primordial to primary follicle
- Doesn’t involve signals from brain
- Maybe due to changes in the ovary itself
At preantral stage gonadotrophins become vv important
- FSH and LH
- Granulosa cells have FSH recptors
o Then undergoe massive proliferation and start producing oestrogen
- Thecal cells have LH receptors
o LH important for antral expansion ond ovulation
anti-mullerian hormone
- Made by granulosa cells
- Absent in primordial follicles but present at later stages
- Inhibitory effect on follicle development
- Unaffected by gonaotrophins/ steroid hormones
o Reliable reflection of growing follicles - AMH is seen as brown staining to the right
follicle secretion/ ovulation
- To do with the LH receptor
- Oestrogen and FSH induce the expression of the LH receptor on the thecal cells
- Whatever follicle has the most number of LH receptors will receive all the LH hormone from pituitary > aka is ovulated
- Humans developed mechanism to ovulate one follicle every month (or maybe 2) – nobody knows why
o But does have something to do with LH recptor
the menstrual cycle - from menstruation up to the LH surge
THE MENSTRUAL CYCLE - Between 24-32 days - Most women ~28 days - 14-20 follicles grow every month o 1 is ovulated o The rest die Day 1 – menstruation - Due to dropping oestrogen and progesterone levles - Uterus lining begins to be shed - Pituitary gland then releases FSH which signals to follicles - Follicles are starting to grow - Granulosa cell proliferate and start to make oestrogen
- Oestrogen continues to rise
- Oestrogen cause endometrium to thicken – produce nutrient
- Oestrigen feedsback on pituitary causing FSH levels to drop slightly
- Oestrogen levels continue to rise
- As follicle grows it cont. secrete oestrogen but once it reaches threshold level becomes positive feedback instead of neg.
- Oestrogen pos. signals to pituitary leading to release of LH
- Causing LH SURGE
- Together FSH and oestrogen stimulate LH binding sited on outer layers of granulosa cells
- LH surge at day 14 > ovulation
- Oocyte begins meiosis up to metaphase of second meiotic division then stops
- Meiosis doen’t complete until it reaches the sperm
- In response to these hormones there’s a sudden drop off of FSH and LH
- Oestrogen drops as follicle is gone – corpus lutem produces some
- Begin secretory phase of uterine cycle
menstrual cycle follicular rupture and corpus luteum and luteinisation
FOLLICULAR RUPTURE
- Release follicular fluid taking egg
- Egg is spilt into cavity and fimbriae sweep it up into oviduct
- Then transported down into uterus
- 30-40% of women can feel follicular rupture
- After egg release there’s a corpus luteum that secretes progesterone
- In reponse to this we have a fall in FSH and LH
- Progesterone prepares the endometrium for pregnancy
CORPUS LUTEUM AND LUTEINISATION
- Ruptured follicle develops into corpus luteum
o Granulosa and theca cells
- Lutein cells – mitochondria, smooth ER, Golgi, lipid droplets, pigment lutein
- Luteinisation = progesterone secretion
hormonal contraception
- Supresses ovulation via negative feedback of progesterone
o Secondary effects on female genital tract - Combined pill
o Oestrogen provides additional feedback and promotes progesterone recepotor expression - During ‘off period’ own HPG axis is awakened
hormones and breast development - prolactin
- Released from pituitary in response to placental hormones
- Important for breast feeding – breast makes milk
- Breast can’t officially make milk until placental is delivered at birth
Prolactin levles maintained afterbirth for a few weeks
- But needs suckling for it to be continuously signalled
- This stimulates anterior pituitary to make prolactin
- Alveoli swell and secrete milk
how/ why do the breasts release milk
Releasing milk
- Need suckling > nerve impulse sent to the brain
- Boosts oxytocin synthesis and secretion from posterior pituitary
- Myoepithelial cell contraction around alveoli = milk expulsion
- Milk ejection reflex can be conditioned
fertility during lactation
Fertility is reduced during lactation
- Lactation can continue for months
- Menstruation and ovulation re-established by 3-6 months
- ~50% of unprotected nursing mothers fall pregnant during 9 months of lactation
- Neg. feedback of prolactin of FSH/LH
how is oestrogen made in the follicle - granulosa an dthecal cell roles
Granulosa cells have lots of aromatase to convert andorgens into oestrogen when signalled to by FSH
- But granulosa cell don’t have
o P450sce
o 3B-HSD
o 17a-hydroxylase
- Granuslosa cells get androgens from elsewehere…
AKA FROM THECAL CELLS
- These are signalled by LH to make androgens
what tests to do for irregular periods
- Meausre oestrogen
- FSH and LH
- Prolactin
- Androgens
hypogonadotrophic hypogonadism - what, history, examination, ,management
what
- LH low, FSH low, E2 low, PRL normal
- Womens not having period because of low oestrogen > nothing to thicken endometrium
- Low oestrogen because of low FSH and LH
- Not an ovary problem
- Pituitary isn’t affected because prolactin is normal
- So problem is the hypothalamus
o If meausred GnRH in hypothalamus it would be low
o Would have low GnRH when you’re a child > this women has childlike hormones
o When body decides when to start puberty it does this by deciding if you have the capacity to nourish a child > looking at body fat
o Over weight girls go through puberty quicker
o If you don’t have enough fat – body swtiches off reproduction
- May be due to eating disorder or over-exercise, or stress
History
- Weight loss, low body fat, low BMI, stress, illness
Examination
- Scales – low weight
Management
- Encourage to gain weight, and stop exercise
- Hormone replacement therapy – oestrogen and progesterone (To help bones)
- If wanst to get pregnant – LH and FSH injections, or pulsatile GnRH
