The HPG axis

Question 1

What does HPG stand for? (3)

Answer 1

• Hypothalamus
• Pituitary
• Gonads

Question 2

Which system is the HPG axis part of?

Answer 2

Endocrine system

Question 3

What is an axis?

Answer 3

Multiple endocrine glands working together as a system to regulate development, reproduction and aging in animals

Question 4

What do endocrine glands do?

Answer 4

Secrete hormones into the bloodstream which travel to and act on other organs/tissues

Question 5

What is the HPG axis?

Answer 5

Hypothalamic-pituitary-gonadal axis

Question 6

What is the hypothalamus? (3)

Answer 6

• 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

Question 7

What is the function of the hypothalamus in the HPG axis?

Answer 7

Secretes GnRH which travels down the infundibulum and acts on the anterior pituitary

Question 8

What is GnRH? (2)

Answer 8

• Gonadotrophin releasing hormone
• Peptide hormone

Question 9

What is the pituitary gland?

Answer 9

Made up of posterior and anterior pituitary which are derived from separate cell types during embryogenesis and have different functions

Question 10

Which part of the pituitary is relevant to the HPG axis?

Answer 10

Anterior pituitary

Question 11

What is the anterior pituitary made up of? (5)

Answer 11

• Thyrotropes
• Somatotropes
• Gonadotrophs
• Corticotropes
• Lactotropes

Question 12

What is the function of thyrotropes?

Answer 12

Make thyroid stimulating hormone (TSH)

Question 13

What is the function of somatotropes?

Answer 13

Make growth hormones

Question 14

What is the function of gonadotrophs? (2)

Answer 14

• Make follicle stimulating hormone (FSH)
• Make luteinising hormone (LH)

Question 15

What is the function of corticotropes?

Answer 15

Make adrenocorticotrophic hormone (ACTH) which acts on the adrenal cortex in the stress response

Question 16

What is the function of lactotropes?

Answer 16

Make prolactin (PRL)

Question 17

What is the function of the anterior pituitary in the HPG axis? (2)

Answer 17

• 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

Question 18

What are the gonadotrophins? (2)

Answer 18

• Hormones produced by the gonadotrophs in the anterior pituitary and act on the gonads
• FSH and LH

Question 19

How do gonadotrophs respond to hypothalamic signals? (4)

Answer 19

• 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

Question 20

What are the sex steroids? (3)

Answer 20

• Oestrogens
• Androgens
• Progestogens

Question 21

Where are the sex steroids released from?

Answer 21

Gonads

Question 22

How do cells in the gonads (male and female) respond to stimulation by FSH and LH from the anterior pituitary? (2)

Answer 22

• Release sex steroids
• Release inhibins and activins which are important for feedback control

Question 23

What are examples of sex steroids? (3)

Answer 23

• Progestogens: progesterone
• Androgens: testosterone, dihydrotestosterone, androstenedione
• Oestrogens: oestradiol, oestrone

Question 24

How are sex steroids made? (2)

Answer 24

• All derived from common precursor: cholesterol
• Interconversion occurs via a biosynthetic network

Question 25

What is the function of the sex steroids? (3)

Answer 25

- 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

Question 26

How do the sex steroids secreted by the gonads feedback onto the anterior pituitary? (3)

Answer 26

- 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

Question 27

How do inhibin and activin secreted by the gonads feedback onto the anterior pituitary? (3)

Answer 27

- Bind to specific cell-surface receptors on the gonadotrophs - Exert opposing actions on FSH expression (inhibin inhibits, activin activates) - Inhibin also inhibits activin activity

Question 28

What is the function of inhibin and activin? (2)

Answer 28

- 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

Question 29

How is GnRH released? (3)

Answer 29

- 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

Question 30

What is GnRH essential for? (2)

Answer 30

- Gonadal function - Gonadal atrophy observed in the absence of GnRH

Question 31

How can alterations in FSH and LH output be achieved? (2)

Answer 31

- 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

Question 32

How is GnRH secretion regulated? (2)

Answer 32

- Positive regulation by kisspeptin - Negative regulation by RFRP-3

Question 33

What is Kisspeptin? (5)

Answer 33

- 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

Question 34

What is RFRP-3? (3)

Answer 34

- 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

Question 35

What is the feedback action of the sex steroids produced by the gonads? (2)

Answer 35

- Pituitary: internalised by the gonadotrophs and negatively regulate FSH, LH and GnRHr - Hypothalamus: negatively regulate KiSS1 neurons so less kisspeptin and less GnRH production

Question 36

How is energy balance involved in regulation of the HPG axis? (5)

Answer 36

- 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

Question 37

How do the sex steroids differ between males and females?

Answer 37

Both males and females have all of the sex steroids but the balances differ (males have higher testosterone, females have higher oestrogen)