Reproductive Endocrinology (12-14) Flashcards
What is puberty marked by?
Maturation of the genital organs
Development of secondary sexual characteristics → great tissue, pubic hair
Accelerated growth → height and weight (2in:6lb/year to 3in:17.4lb/year)
Occurrence of menarche → first menstruation in females
What is gonadarche?
Growth and maturation of the gonads → ovaries and testes
→ leading to production of sex hormones
What is adrenarche?
Maturation of the adrenal cortex
→ produce increased amounts of androgens
→ contributes to the development of secondary sexual characteristics
What are the Tanner stages?
5 stages that describe the physical development of children during puberty
→ different characteristics at each stage
→ ages variable
(developed by James Tanner in the 1960s)
What hormones are involved in the gonadal-hypothalamic-pituitary axis?
Hormone → location released
Gonadotropin releasing hormone (GnRH) → hypothalamus
Follicle stimulating hormone (FSH) → anterior pituitary
Luteinising hormone (LH) → anterior pituitary
Prolactin → anterior pituitary
Oxytocin → posterior pituitary
Oestradiol → ovary (granulosa cells)
Testosterone → ovary (theca cells)
Progesterone → ovary corpus luteum
Inhibin B → ovary (granulosa cells)
What are primordial follicles?
Primary oocytes that are arrested in prophase I of meiosis
→ each one surrounded by a layer of undefined granulosa cells
→ born with lots of primordial follicles
→ don’t go any further until after puberty
Follicle = oocyte + surrounding layers of specialised cells
How does a primordial follicle reach the early antral stages?
A small number of primordial follicles are activated each menstrual cycle
→ primary oocyte resumes meiosis and the granulosa cells proliferate forming more uniform layers - primary follicle
→ further expansion - secondary follicle
→ secondary layer made up of theca cells forms - early astral follicle
→ fluid filled cavities start to form - early antral stage
What is an antral follicle?
The follicle that becomes dominant and continues to grow
→ enlargement via fluid filled cavities not cell division
→ second layer of theca cells wrapping egg - lots of vascularisation
→ granulosa cells produce increasing amounts of oestrogen
→ in response to LH mature egg is released into fallopian tube - ovulation
What is a corpus luteum?
After ovulation the remaining follicular cells regress forming the corpus luteum
→ secretes progesterone
What are theca cells?
Found in mammalian ovaries surrounding granulosa cells
→ mainly responsible for the production of androgens
→ combined action of LH and FSH drive theca cells to make testosterone
→ testosterone passes over granulosa cells - converts it to oestrogen
What is the role of LH and FSH?
GnRH is released in bursts - causes pituitary to release LH and FSH
FSH → stimulates the development of follicles
LH → stimulates the development of the corpus luteum
Both → stimulate the secretion of oestradiol
What is the hypothalamic maturation hypothesis for puberty?
Theory explaining the onset of puberty
→ triggered by maturation within the hypothalamus
→ HPG axis relatively quiet in children, but as age there’s an increase in GnRH activity
Most supported → puberty only requires hypothalamic GnRH
→ there is a direct link between CNS:pituitary:hypothalamic GnRH neurones
→ supports other experimental studies using animals models
What is the menstrual cycle?
Monthly rhythmical changes in hormones resulting in secondary changes to ovarian function, the lining of the uterus and breasts
→ typically 28 days long
What is the follicular stage of the menstrual cycle?
Development of ovarian follicles (14 days)
→ increase in oestrogen and gonadotropins
→ FSH secreted by the pituitary gland stimulates the growth and development of ovarian follicles
What is ovulation?
Midpoint of the menstrual cycle (day 14)
→ surge in LH triggered by rise in oestrogen levels
→ mature follicle ruptures releasing mature egg into fallopian tubes
→ here most fertile - sperm can live in uterus for 2 days
What is the luteal phase in the menstrual cycle?
Occurs after ovulation (day 15-28)
→ follicle tissue left becomes corpus luteam - takes over secretion of sex hormones
→ produces progesterone - inhibits LH and FSH
→ progesterone promotes expansion of uterine lining and development of spiral arteries to prepare the lining for implantation
If fertilisation doesn’t occur
→ corpus luteum regresses
→ decline in progesterone and oestrogen levels
→ shedding of uterus lining
How does the feedback of gonadal steroid and peptide change during the menstrual cycle?
Pulsatile secretion of GnRH from hypothalamus stimulates the synthesis and secretion of LH and FSH from the pituitary
→ stimulate development and secretion of gonadal steroids and peptides that feedback to the hypothalamus
Following the middle FSH:LH surge and ovulation, the feedback becomes inhibitory
Why do the changes during the menstrual cycle happen with specific timing?
Facilitating support for the next stage
→ ovulation occurs at time when uterus is primes - increase chance of implantation
What is involved in the biosynthesis of oestrogen?
Sex hormones are made from cholesterol as a starting point - enzyme controlled biosynthetic processes
Biosynthesis of oestrogen is dependant of cooperation between 2 cells
Theca cells → LH receptors - cholesterol to testosterone involving CYP17
→ testosterone passes through membrane into neighbouring granulosa cells
Granulosa cells → last stage of development (hormone can be secreted) involving CYP19
How does the number of follicles change as you age?
Number of follicles decreases as you age
→ less than ~1000 results in menopause
What is the role of the placenta during pregnancy?
Produces steroid and peptide hormones regulating hormonogenesis in both pregnant individual and foetus
→ metabolises hormones from pregnant person to protect the foetus
→ major role in coordinating development of pituitary-adrenocortical axis
What occurs after fertilisation?
The fertilised egg is pushed down the fallopian tube by microvilli and starts to divide
Tries to embed in uterine wall
→ wall has to be prepared
→ before follicle can implant egg cell has to break ‘hatch’ out of zone pellucida
What hormones changes happen to the menstrual cycle upon pregnancy?
Typically after ovulation if the egg isn’t fertilised oestrogen and progesterone levels drop
If implantation occurs there is a change hormones
→ hCG hormones is produced by the placenta (pregnancy tests detect) - triggers body to make more oestrogen/progesterone
→ progesterone levels stay high - to support extra tissue growth in uterus
What are the roles of oestrogens?
Steroid hormones primarily produced by the ovaries that play many roles in the body and have a variety of effects dependant on the receptors
→ 2 forms of oestrogen receptors - alpha and beta - expressed widely throughout the body
→ different oestrogens are produced at different times, with different affinities for ERs giving different effects
→ slight change in structure of oestrogen produces - different effect on target tissue
Estradiol E2 → main oestrogen, central role in regulating menstrual cycle, responsible for development of secondary sexual characteristics
Estriol E3 → least potent form, produced during pregnancy by placenta, promotes growth and development of uterus/placenta
Estrone E1 → an intermediate form of oestrogen, converted from androstenedione, predominant form in postmenopausal women
What are the two main types of oestrogen receptors?
Oestrogen receptors are intracellular receptors → steroid hormones can pass through membrane
→ they translocate to nucleus and act as a transcription factor
Two main types → alpha and beta - very similar but differ in aa length
A/B → amino terminal domain
C → central region DNA binding domain, recognise the response lemon on the gene it acts on, important for transcription factor function
D → flexible hinge region - conformational shape, contains nuclear localisation signal
E → ligan binding domain - links to carbody-terminal F domain
Exist as dimers without ligand → upon binding have a conformational shift
How does oestrogen lead to proliferation?
Oestrogen binding to its receptor increases interaction with growth factor
→ growth factor binds receptor, which via signalling cascade inactivated FOXO - usually keeps cells in rest
→ causes cell proliferation to support thickening of uterus lining
PTEN → mechanism to switch off - stops tissue becoming overly proliferative
What are the physiological actions of progesterone (P4)?
Ovary → ovulation, luteinisation
Uterus/endometrium → proliferation, differentiation, implantation, myometrium quiescence (stops its being contractile until birth)
Bone → increases process of bone formation
Brain/CNS → HPA axis, sexual behavioural
Pregnancy → correct development of mammary glands, milk ducts
What are the two forms of progesterone receptor?
Alpha → role in mammary ductal morphorgenesis
Beta → role in ovulation, implantation, decidualisation
→ KO mice shoe infertility
Intracellular receptors
What is endometrial decidualisation?
Change in endometrium cell morphology during the luteal phase
→ thickening of tissue
→ development of spiral arteries - increased blood supply
→ immunomodulation - suppression of immune system - doesn’t reject foreign tissue
→ when blastocyst does implant its got good supply
→ mostly driven by progesterone
What drives decidualisation?
Convergence of cAMP and progesterone (P4) signalling
→ prostaglandins, relaxing bind GPCRs - activates cAMP
How does the uterine develop in a fertilised cycle?
After implantation of a fertilised egg
→ production of hCG supports corpus luteum - can keep producing steroid hormones
→ at the end of first trimester placenta takes over role of corpus luteum in hormone production
How is blood transported between maternal and foetal tissues?
Oxygenated blood comes to foetus via umbilical veins
→ enters foetus vena cava, bypasses liver, goes mainly to right atrium
→ blood travels to head and body and back to placenta via the aorta
What is the foramen ovale?
An opening between the right and left atria of a foetus heart
→ normal blood circulation goes right atrium - right ventricle - pulmonary circuit
→ but no gas exchange occurs in foetus so foramen ovale allows blood to be circulated around foetal body directly
How does cortico-releasing hormone aid in keeping uterus quiescent?
CRH from foetus drives release of cortisol and androgens - go into placenta
→ androgens (like DHEAS) drive production of oestrogens in placenta and break down of cholesterol into progesterone - keeps uterus quiescent
What is the role of placenta progesterone?
Suppress myometrial contractions through out pregnancy
Promotes formation of mucous plug in cervical canal → prevents further fertilisation events, keeps clean/separate
Prepares mammary glands for lactation
What is the role of placental oestrogens?
Proliferative effect on → uterus and breasts
Preparation of uterus and cervix for labour
Induction of pro-labour genes
Where do placental progesterone and oestrogens start from?
Cholesterol from maternal blood
What is the progesterone paradox?
Humans are different to other mammals
→ in humans progesterone is kept high until the end of pregnancy
→ usually progesterone drops off in mammals to remove quiescence - allow for contractility
→ at point of birth humans really underdeveloped so babies can still get out - mediated by reproductive strategy and anatomy
→ birthing heavily coordinated - have to do it while progesterone around
→ humans use other hormones to overcome quiescent nature created by progesterone
How is the human progesterone paradox resolved?
Uterine levels of progesterone receptors drop
→ uterus less responsive - allows contractility
→ parturition involves oxytocin and prostaglandins - essential to overcome quiescence
What are the four phases of human parturition?
Phase 0 → quiescence - progesterone and prostacyclin
Phase 1 → preparation for labour (activation) - prostaglandins, oxytocin receptor, relaxin
Phase 2 → active labour (stimulation) - oxytocin, prostaglandins
Phase 3 → involution - oxytocin, prostaglandins
What is the signal transduction involved in mouse parturition?
Membrane phospholipids (cPLA2) → arachidonic acid (COX-1, PGR synthase) → PGF2alpha → corpus luteum (progesterone decrease) → increased uterine contractility → labour
no cPLA2, no COX-1, no FP receptor (receives signals from PGF2alpha) → no labour
→ non labour phenotypes rescues with pharmacological administration of PGF2alpha - for labour to start you need to produce prostaglandins
→ prostaglandins importation for initiation of progesterone withdrawal and onset of labour
What is the role of oxytocin in mouse parturition?
Focuses the timing
→ doesn’t drive labour - in oxytocin KO labour successful but no oxytocin affects milk production
→ big increases in oxytocin receptors at end of term - oxytocin and prostaglandins work together to drive labour
High levels initiate parturition
→ OT has opposing luteotropic and luteolytic actions - switch in roles controlled by temporal and spatial OTR expression
→ OT initiates PGF2alpha accelerates
OTR expression can compensate for low expression of PGF2alpha
How is the pregnant human uterus structured?
Active segment → upper uterine segment
→ during labor undergoes strong, rhythmic contractions, primarily facilitated by the myometrium (the muscular layer of the uterus).
→ these contractions help to push the fetus downward through the birth canal (vagina) and eventually expel it from the mother’s body during delivery
→ the active segment is the part of the uterus directly involved in the process of labor and delivery
Passive segment → lower uterine segment - particularly the area surrounding the cervix.
→during labor remains relatively quiescent compared to the active segment
→ provides support to the active segment and allow for the passage of the fetus through the cervix and into the birth canal.
→ passive segment gradually thins out and stretches to accommodate the descending fetus
→ crucial role in allowing for the safe passage of the fetus from the uterus into the vagina during childbirth
What is the Ferguson reflex?
Process of starting birth increasing pressure of cervix increasing stimulation of afferent fibres going into brain stem
→ stimulates NTS - signals to hypothalamus to increase oxytocin production - positive feedback
- Baby’s head stretches cervix
- Cervical stretch excites funds contractions
- Pushes baby further increasing stretch
- Cycle repeats
What is involution of the uterus?
Following delivery the uterus will continue to contract, shearing the placenta (PGs and OT)
→ uterus 1/2 size by 1 week and after 4 weeks back tp pre-pregnancy size
Oxytocin release for breastfeeding → aids healing
Uterus weight increases from ~50g to 1100g (pregnant)
