2. Reproductive endocrinology Flashcards
What are the different groups of hormones used in fertility regulation?
- Water-soluble (hydrophilic): peptides, proteins - ex: GnRH, FSH, LH, prolactin, oxytocin, AMH, inhibins/activins
- Water-insoluble (hydrophobic): steroid hormones - ex: androgens, oestrogens, progesterone
Group depends on structure - if water-soluble or not
What are the main reproductive hormones involved in regulating fertility?
- Gonadotropin releasing hormone (GnRH)
- Follicle stimulating hormone (FSH)
- Luteinising hormone (LH)
- Anti-mullerian hormone (AMH)
- Prolactin
- Oxytocin
- Inhibins/activins
- Androgens
- Oestrogens
- Progesterones
How are hydrophilic hormones transported in the body?
Freely in the blood:
1. Float in the blood - bind to their receptor on target cell surface (first messenger)
2. Receptor binding activates G proteins -> activates adenylate cyclase - (hydrophilic - can’t go through hydrophobic membrane)
3. ATP kinase -> cAMP (second messenger) - activates a signalling cascade inside the cell
4. Further phosphorylation - enzyme activation => effect
How are hydrophobic hormones transported in the body?
Bind to transport proteins:
1. Hydrophilic hormone binds to hydrophilic proteins - transported in hydrophilic blood environment
2. When reaches target cell - hormone diffuses into the cell (hydrophobic - through hydrophobic membrane)
3. Hormone nuclear import - intranuclear receptor - when bind to hormone dimerize into receptor-hormone complex-> activated
4. Receptor-hormone complex acts as TF - alters gene expression
5. New mRNA -> new protein -> hormone effect in target cell
What are gonadotropins?
Gonadotropins - peptide hormones that regulate ovarian / testicular function + essential for normal growth, sexual development and reproduction - ex: LH, FSH
What are gonadotropin functions in males?
In males gonadotropins:
- FSH supports spermatogenesis via Sertoli cells
- LH supports testosterone production in Leydig cells
What are gonadotropin functions in females?
In females gonadotropins:
- LH in theca cells supports estradiol production
- FSH in granulosa cells supports estradiol production
Explain the anatomy of a follicle
Follicle - oocyte nurturing structure
What are the functions of testosterone?
Testosterone, 5α-dihydrotestosterone:
- spermatogenesis
- prostate secretions
- secondary male characteristics (males+females)
- male sex determination and genital development
What are the functions of oestradiol?
Oestradiol:
- endometrial proliferation
- secondary female characteristics
- female genital development (female sex determination - default)
- HPG axis feedback: low level - negative, high level - positive -> influences GnRH -> influences LH, FSH
What are the functions of progesterone?
Progesterone:
- endometrial secretion and vascularisation in menstrual cycle
- mainatain pregnancy, support embryo
What are the effects of hormonal contraception in males and females?
Hormonal contraception manipulates steroid gonadal hormones - disturbs HPG axis (pos/neg feedback loops)
In females:
- suppress ovulation (neg feedback of progesterone)
- promote progesterone receptor secretion (oestrogen feedback)
- secondary effects - thickens mucus in genital tract - sperm can’t get through
In males:
- supress spermatogenesis (neg feedback of testosterone + progesterone)
When hormonal contraception stopped - own HPG axis re-awakened
What is the HPG axis?
Reproduction and fertility are regulated via hormones of the hypothalamic-pituitary-gonadal (HPG) axis
What is the pos feedback in HPG axis?
Pos feedback in HPG axis:
activins produced by Sertoli / granulosa cells stimulates FSH secretion from anterior pituitary
What hormones are involved in lactation?
Prolactin and oxytocin
Suckling - nerve inmpulses to brain - release of:
- prolactin (anterior pituitary): alveoli swell - secrete milk (prior to birth placenta secretes steroids to block) + neg feedback on FSH/LH (lactational ammenorrhea)
- oxytocin (posterior pituitary): affects myoepithelial cell (smooth muscle) contractions around alveoli - milk ejection reflex + used to induce labour - effects on uterine smooth muscle
What is the only reproductive hormone which is released form posterior pituitary?
Oxytocin
All others form anterior pituitary
What is the function of AMH?
Anti-Mullerian hormone (AMH):
- critical for male sex determination in embryos - SOX9 activates AMH in Sertoli cells - inhibits Mullerian duct development (female development - default)
- released by granulosa cells from primary stage - inhibits other follicle development
AMH levels can be used to determine the # of maturing follicles - indicates number but not quality + can fluctuate month to month - not very reliable
Explain what is GnRH and its function
Gonadotropin releasing hormone (GnRH):
- synthesised by hypothalamic GnRH neurons
- pulsatile release - prevents receptor desensitisation and downregulation
- surges prior to ovulation
- important for timing of puberty and menstrual cycle
- GnRH different effects on LH and FSH secretion - LH pulsatile release / FSH stable level release
Explain kisspeptin-GnRH signalling pathway
Kisspeptin-GnRH signalling pathway - essential for GnRH secretion:
1. Kisspeptin - neuropeptide encoded by KiSS1 gene - produced by hypothalamus - released into blood
2. Kisspeptin travels to GnRH neurons - binds to GnRH expressed KiSS1 receptors - triggers a signalling cascade
3. GnRH neurons activated - release GnRH into bloodstream - travels to pituitary gland
4. GnRH stimulates release of LH and FSH in pituitary - travel to gonads -> stimulate :
- testosterone production
- menstrual cycle
- follicle development
5. Testosterone / oestrogen produced from gonads feedback on hypothalamus + pituitary -> regulates secretion of kisspeptin, GnRH, LH, FSH
How do GnRH neurons respond to ERα if they lack ERα receptors?
Kisspeptin indirect signalling pathway - kisspeptin and KNDY neurons regulate GnRH neuron activity: ERα receptors on kisspeptin + KNDY neurons - once ERα binds initiates intracelullar signalling + gene expression to signal GnRH neurons via:
- Kisspeptin neurons: release of Kiss1 for which GnRH has receptors
- KNDY neurons: release of 3 neuropeptides (kisspeptin, neurokinin B (NKB), dynorphin
Do kisspeptin neurons only respond to gonad released hormones?
No, kisspeptin neurons also respond to:
- adrenal gland - cortisol
- body fat - leptin
- immune cell responses to infections
- changes in environment - melatonin
=> KiSS neurons receive signals - affect fertility - fertility affected by many health factors
What are ER?
Estrogen receptor (ERα and ERβ) - main estrogen receptors found **inside cells **
ERα nuclear receptor (mainly found as a chromatin-binding protein) - activated by the sex hormone estrogen
How can KISS signalling be manipulated?
Current therapies can manipulate HPG axis at GnRH receptors to supress gonadal function
Explain hypogonadotropic hypogonadism
Hypogonadotropic hypogonadism:
- gonads producing too little hormones because of pituitary/hypothalamus problems
Explain polycystic ovarian syndrome
PCOS - cystic ovaries - pores filled with fluid
Explain premature ovarian insufficiency
Premature ovarian insufficiency (POI):
- depletion of follicles before 40
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