Reproductive Endocrinology (12-14)

Question 1

What is puberty marked by?

Answer 1

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

Question 2

What is gonadarche?

Answer 2

Growth and maturation of the gonads → ovaries and testes
→ leading to production of sex hormones

Question 3

What is adrenarche?

Answer 3

Maturation of the adrenal cortex
→ produce increased amounts of androgens
→ contributes to the development of secondary sexual characteristics

Question 4

What are the Tanner stages?

Answer 4

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)

Question 5

What hormones are involved in the gonadal-hypothalamic-pituitary axis?

Answer 5

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)

Question 6

What are primordial follicles?

Answer 6

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

Question 7

How does a primordial follicle reach the early antral stages?

Answer 7

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

Question 8

What is an antral follicle?

Answer 8

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

Question 9

What is a corpus luteum?

Answer 9

After ovulation the remaining follicular cells regress forming the corpus luteum
→ secretes progesterone

Question 10

What are theca cells?

Answer 10

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

Question 11

What is the role of LH and FSH?

Answer 11

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

Question 12

What is the hypothalamic maturation hypothesis for puberty?

Answer 12

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

Question 13

What is the menstrual cycle?

Answer 13

Monthly rhythmical changes in hormones resulting in secondary changes to ovarian function, the lining of the uterus and breasts
→ typically 28 days long

Question 14

What is the follicular stage of the menstrual cycle?

Answer 14

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

Question 15

What is ovulation?

Answer 15

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

Question 16

What is the luteal phase in the menstrual cycle?

Answer 16

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

Question 17

How does the feedback of gonadal steroid and peptide change during the menstrual cycle?

Answer 17

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

Question 18

Why do the changes during the menstrual cycle happen with specific timing?

Answer 18

Facilitating support for the next stage
→ ovulation occurs at time when uterus is primes - increase chance of implantation

Question 19

What is involved in the biosynthesis of oestrogen?

Answer 19

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

Question 20

How does the number of follicles change as you age?

Answer 20

Number of follicles decreases as you age
→ less than ~1000 results in menopause

Question 21

What is the role of the placenta during pregnancy?

Answer 21

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

Question 22

What occurs after fertilisation?

Answer 22

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

Question 23

What hormones changes happen to the menstrual cycle upon pregnancy?

Answer 23

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

Question 24

What are the roles of oestrogens?

Answer 24

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

Question 25

What are the two main types of oestrogen receptors?

Answer 25

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

Question 26

How does oestrogen lead to proliferation?

Answer 26

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

Question 27

What are the physiological actions of progesterone (P4)?

Answer 27

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

Question 28

What are the two forms of progesterone receptor?

Answer 28

Alpha → role in mammary ductal morphorgenesis
Beta → role in ovulation, implantation, decidualisation
→ KO mice shoe infertility

Intracellular receptors

Question 29

What is endometrial decidualisation?

Answer 29

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

Question 30

What drives decidualisation?

Answer 30

Convergence of cAMP and progesterone (P4) signalling
→ prostaglandins, relaxing bind GPCRs - activates cAMP

Question 31

How does the uterine develop in a fertilised cycle?

Answer 31

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

Question 32

How is blood transported between maternal and foetal tissues?

Answer 32

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

Question 33

What is the foramen ovale?

Answer 33

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

Question 34

How does cortico-releasing hormone aid in keeping uterus quiescent?

Answer 34

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

Question 35

What is the role of placenta progesterone?

Answer 35

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

Question 36

What is the role of placental oestrogens?

Answer 36

Proliferative effect on → uterus and breasts
Preparation of uterus and cervix for labour
Induction of pro-labour genes

Question 37

Where do placental progesterone and oestrogens start from?

Answer 37

Cholesterol from maternal blood

Question 38

What is the progesterone paradox?

Answer 38

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

Question 39

How is the human progesterone paradox resolved?

Answer 39

Uterine levels of progesterone receptors drop
→ uterus less responsive - allows contractility
→ parturition involves oxytocin and prostaglandins - essential to overcome quiescence

Question 40

What are the four phases of human parturition?

Answer 40

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

Question 41

What is the signal transduction involved in mouse parturition?

Answer 41

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

Question 42

What is the role of oxytocin in mouse parturition?

Answer 42

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

Question 43

How is the pregnant human uterus structured?

Answer 43

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

Question 44

What is the Ferguson reflex?

Answer 44

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

1. Baby’s head stretches cervix
2. Cervical stretch excites funds contractions
3. Pushes baby further increasing stretch
4. Cycle repeats

Question 45

What is involution of the uterus?

Answer 45

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)