The HPG axis Flashcards
What does HPG stand for? (3)
- Hypothalamus
- Pituitary
- Gonads
Which system is the HPG axis part of?
Endocrine system
What is an axis?
Multiple endocrine glands working together as a system to regulate development, reproduction and aging in animals
What do endocrine glands do?
Secrete hormones into the bloodstream which travel to and act on other organs/tissues
What is the HPG axis?
Hypothalamic-pituitary-gonadal axis
What is the hypothalamus? (3)
- Part of the diencephalon in the forebrain
- Regulates many core body functions e.g. metabolism, growth, reproduction and stress
- In contact with the anterior pituitary gland via the infundibulum
What is the function of the hypothalamus in the HPG axis?
Secretes GnRH which travels down the infundibulum and acts on the anterior pituitary
What is GnRH? (2)
- Gonadotrophin releasing hormone
- Peptide hormone
What is the pituitary gland?
Made up of posterior and anterior pituitary which are derived from separate cell types during embryogenesis and have different functions
Which part of the pituitary is relevant to the HPG axis?
Anterior pituitary
What is the anterior pituitary made up of? (5)
- Thyrotropes
- Somatotropes
- Gonadotrophs
- Corticotropes
- Lactotropes
What is the function of thyrotropes?
Make thyroid stimulating hormone (TSH)
What is the function of somatotropes?
Make growth hormones
What is the function of gonadotrophs? (2)
- Make follicle stimulating hormone (FSH)
- Make luteinising hormone (LH)
What is the function of corticotropes?
Make adrenocorticotrophic hormone (ACTH) which acts on the adrenal cortex in the stress response
What is the function of lactotropes?
Make prolactin (PRL)
What is the function of the anterior pituitary in the HPG axis? (2)
- GnRH from the hypothalamus travels in the portal blood to the anterior pituitary
- Gonadotrophs in the anterior pituitary respond to GnRH from the hypothalamus by secreting FSH and LH which travel to the gonads
What are the gonadotrophins? (2)
- Hormones produced by the gonadotrophs in the anterior pituitary and act on the gonads
- FSH and LH
How do gonadotrophs respond to hypothalamic signals? (4)
- GnRH binds to GnRH receptors (GnRHr) on the gonadotroph membrane and stimulates proliferation and triggers signalling cascades resulting in upregulation of FSH, LH and GnRHr genes
- Causes expression of FSH and LH, both heterodimeric glycoprotein hormones
- Increased intracellular calcium stimulates gonadotrophin release
- FSH and LH travel to the ovaries and testes in the bloodstream
What are the sex steroids? (3)
- Oestrogens
- Androgens
- Progestogens
Where are the sex steroids released from?
Gonads
How do cells in the gonads (male and female) respond to stimulation by FSH and LH from the anterior pituitary? (2)
- Release sex steroids
- Release inhibins and activins which are important for feedback control
What are examples of sex steroids? (3)
- Progestogens: progesterone
- Androgens: testosterone, dihydrotestosterone, androstenedione
- Oestrogens: oestradiol, oestrone
How are sex steroids made? (2)
- All derived from common precursor: cholesterol
- Interconversion occurs via a biosynthetic network
What is the function of the sex steroids? (3)
- Action of the sex steroids is dictated by tissue-specific receptors so not only about hormone levels but which cells are expressing the receptors at a given time and the level of receptor expression
- Essential for normal reproductive development, gametogenesis and the maintenance of secondary sex characteristics
- Feedback mechanisms onto the pituitary and hypothalamus in the HPG axis are an additional aspect
How do the sex steroids secreted by the gonads feedback onto the anterior pituitary? (3)
- Progesterone/oestrogen/testosterone are internalised by the gonadotrophs and bind to intracellular receptors
- Hormone-receptor complexes enter the nucleus and mediate negative transcriptional control of target genes
- Therefore negative feedback onto FSH, LH and GnRHr which also reduces gonadotroph stimulation by the hypothalamus
How do inhibin and activin secreted by the gonads feedback onto the anterior pituitary? (3)
- Bind to specific cell-surface receptors on the gonadotrophs
- Exert opposing actions on FSH expression (inhibin inhibits, activin activates)
- Inhibin also inhibits activin activity
What is the function of inhibin and activin? (2)
- Members of the TGF-beta family which regulate FSH expression from the gonadotrophs
- Have additional diverse biological roles e.g. sperm development, tumour suppression, erythropoiesis
How is GnRH released? (3)
- GnRH release is pulsatile (~1 per hour)
- Pulses begin at puberty and pulse generator resides in the hypothalamus
- Therefore anterior pituitary hormones FSH and LH are also released in a pulsatile manner
What is GnRH essential for? (2)
- Gonadal function
- Gonadal atrophy observed in the absence of GnRH
How can alterations in FSH and LH output be achieved? (2)
- Increasing/decreasing the amplitude or frequency of GnRH pulses
- Modulating the response of the gonadotrophs to the pulses by changing their levels of cellular receptors
How is GnRH secretion regulated? (2)
- Positive regulation by kisspeptin
- Negative regulation by RFRP-3
What is Kisspeptin? (5)
- Master regulator of reproduction
- Neuropeptide encoded by the KiSS1 gene
- Produced by neurons in the hypothalamus and binds to KiSS1 receptors (KiSS1R/GPR54) on the GnRH neurons, causing GnRH secretion (positive regulator)
- KiSS1R found in many tissues in the body so this isn’t its only role
- Sex steroids also negatively regulate KiSS1 neurons resulting in less GnRH production
What is RFRP-3? (3)
- RFamide-related peptide 3 is a mammalian orthologue of gonadotropin-inhibitory hormone (GnIH)
- Acts on the gonadotrophs, KiSS1 neurons and GnRH neurons in the hypothalamus, and the gonads
- Results in reduced GnRH output and suppresses the signalling cascade in the gonadotrophs which causes FSH and LH expression
What is the feedback action of the sex steroids produced by the gonads? (2)
- Pituitary: internalised by the gonadotrophs and negatively regulate FSH, LH and GnRHr
- Hypothalamus: negatively regulate KiSS1 neurons so less kisspeptin and less GnRH production
How is energy balance involved in regulation of the HPG axis? (5)
- Kisspeptin-GnRH axis becomes fully activated at puberty
- Pulse generator mechanism causes regulator production of kisspeptin and then pulsatile release of GnRH
- Puberty is metabolically gated and energy balance is sensed by many peripheral hormones and central transmitters e.g. leptin, insulin and grehlin
- Leptin is necessary for puberty but isn’t the sole requirement and acts on GnRH neurons indirectly via other neurons including KiSS1 neurons
- Leptin levels correlate with fat levels so females with low fat content are likely to go through puberty later than those with higher fat content
How do the sex steroids differ between males and females?
Both males and females have all of the sex steroids but the balances differ (males have higher testosterone, females have higher oestrogen)
