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
How is testosterone modified to bind to ERα?
Testosterone is aromatised before binding to ERα on KiSS neurons - but only female AVPV neurons can cause LH surge - exposure to sex steroids in utero involved in establishing neuron ‘sex’
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
What are the main reproductive endocrine disorders?
Main reproductive endocrine disorders:
- Hypogonadotropic hypogonadism
- Polycystic ovarian syndrome (PCOS)
- Premature ovarian insufficiency (POI)
-> importance of HPG axis
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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