Week 4

• Adrenal Glands


  Small, triangular-shaped (cone-shaped) glands located at the top of the kidneys
• Adrenal Glands


  • There is more than one adrenal gland in the body - we have two, one on top of each kidney
  • Each adrenal gland measures about 3.5 to 4cm in height and 7 to 8cm in length
  • Each adrenal gland is made up of two distinct parts: the adrenal cortex and adrenal medulla
• Adrenal Cortex


  The outer part of the adrenal gland which produces hormones that are vital to life
• Adrenal Medulla


  The inner part of the adrenal gland which produces non-essential hormones
• The adrenal glands produce hormones that help regulate metabolism, immune system, blood pressure, response to stress and other essential functions
• Hormones produced by the adrenal cortex


  • Hormones that controls sex (androgens and estrogens)
  • Hormones that control salt balance in the blood (aldosterone)
  • Hormones that control sugar balance (cortisol)
• Hormones produced by the adrenal medulla


  • Hormones involved in the fight or flight response (catecholamines, or adrenaline type hormones such as epinephrine and norepinephrine)
• Adrenal Cortex


  • Comprises about 80% of the adrenal gland
  • Can be subdivided into three layers: zona glomerulosa, zona fasciculata and the zona reticularis
  • Each of the 3 cortical layers synthesize and secrete steroid hormones
• The outermost layer of the adrenal gland is comprised of thick connective tissue and does not produce hormones
• The fibrous capsule is supplied with many small arteries, which branch into numerous capillaries within the cortical layers
• Groups of steroid hormones

  • Gonadal or sex steroids
  • Glucocorticoids
  • Mineralocorticoids
• Gonadal or sex steroids


  Steroid hormones produced mainly in the ovaries and testes, but they are also produced by the adrenal cortex
• Glucocorticoids


  Steroids named in relation to their effect on blood glucose, but they have more diverse actions than just effects on glucose
• Mineralocorticoids


  Steroids named in relation to their effect on mineral or electrolyte concentrations
• Cholesterol is the precursor of all steroid hormones
• Steroid biosynthesis


  1. Cholesterol can be synthesised within cells (adrenal or gonad) from acetate, or more usually is obtained from low density lipoprotein (LDL) uptake from blood, via LDL receptor-mediated endocytosis

  2. The first step is the conversion of cholesterol to pregnenolone catalysed by the "side chain cleavage enzyme" (cytochrome P-450scc or CYP11A1)

  3. Pregnenolone is converted to progestogens, then on to either androgens or glucocorticoids

  4. Androgens can also be converted into oestrogens

  5. The enzymes that drive these reactions are located in the smooth ER or the mitochondria in adrenal cortical cells (and the gonads)
• Aldosterone


  Only produced in the zona glomerulosa of the adrenal cortex
• Aldosterone is produced by the enzyme aldosterone synthase which converts corticosterone to aldosterone
• Corticosterone, cortisol and aldosterone differ only slightly in structure, but at physiological concentrations, aldosterone has virtually no glucocorticoid activity
• Cortisol can bind weakly to mineralocorticoid receptors
• Main steroid hormones secreted by the adrenal cortex

  • Mineralocorticoids (aldosterone)
  • Glucocorticoids (cortisol and corticosterone)
  • Androgens (DHEA and androstenedione)
• Mineralocorticoids and glucocorticoids are exclusively secreted by the adrenal cortex, meaning its not produced elsewhere in the body
• Mineralocorticoids and glucocorticoids are produced by the zona fasciculata and zona reticular layers
• Aldosterone is only produced in the zona glomerulosa
• Progesterone, corticosterone and cholesterol can be converted to aldosterone
• Cortisol is the most common glucocorticoid in humans
• Sex steroids include oestrogens
• Hypothalamus-pituitary-adrenal (HPA) Axis


  1. The hypothalamus produces corticotropin releasing hormone (CRH), which stimulates Adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary gland

  2. ACTH then circulates to the adrenal gland where it acts to increase hormone synthesis and secretion by the adrenal cortex

  3. Cortisol exerts long-loop negative feedback effects on both the hypothalamus (CRH neurons) and the anterior pituitary (corticotroph cells) to regulate the HPA axis

  4. Stressors, like low blood glucose levels, activate the axis and increase the hormones CRH, ACTH and cortisol

  5. Cortisol acts to bring about metabolic changes, like an increase in blood glucose
• The hypothalamus is an integrator centre and activation of the HPA axis is in response to many inputs, and that stress is a key activator of the HPA axis
• With starvation, low blood glucose will activate the HPA axis and result in increased secretion of cortisol, which as a glucocorticoid increases blood glucose concentrations, which acts to alleviate the initial signal in the brain of low blood glucose
• ACTH


  • Adrenocorticotrophic hormone synthesised and secreted by the corticotroph cells in the anterior pituitary gland
  • Binds to plasma membrane receptors on adrenal cortical cells (the "melanocortin type 2 receptors" or MC2-R)
  • Stimulates steroidogenesis by increasing cholesterol uptake and trafficking, increasing pregnenolone production, and increasing expression of key enzymes
  • Also acts to promote growth of the adrenal cortex, increasing the size and number of cells
• ACTH primarily stimulates glucocorticoid production by the adrenal cortex, much more than affect androgen production, whilst ACTH has no effect on the mineralocorticoid aldosterone
• Cortisol 24h profile


  • Plasma cortisol concentrations change during the day
  • Cortisol increases markedly when you wake up (cortisol awakening response)
  • Cortisol declines during the day, from morning to evening (diurnal "cortisol slope")
  • These responses are normal physiology, and can change if you work at nights and sleep at different times of the day
• The structures responsible for controlling the circulating cortisol concentrations are the central endogenous clock, the hypothalamic suprachiasmatic nucleus and the hypothalamus
• Stress response


  1. Stress stimulates the release of corticotropin releasing hormones (CRH) from the hypothalamus

  2. The anterior pituitary increases synthesis and secretion of adrenocorticotropic hormone (ACTH)

  3. The adrenal glands release cortisol in response

  4. Cortisol induces metabolic changes which influence how the body responds to stress
• Steroid hormones (like thyroid hormones) are ligands that activate gene expression by binding to intracellular receptors
• Structures responsible for controlling circulating cortisol concentrations

  • Central endogenous clock
  • Hypothalamic suprachiasmatic nucleus
  • Hypothalamus
• Events that allow the hypothalamus to induce the metabolic effects associated with stress


  1. Stress stimulates the release of corticotropin releasing hormones (CRH) from the hypothalamus

  2. The anterior pituitary increases synthesis and secretion of adrenocorticotropic hormone (ACTH) due to hormonal activation

  3. The adrenal glands on the kidneys release cortisol in response to hormonal activation

  4. Cortisol induces metabolic changes which influence how the body responds to stress
• Glucocorticoids


  Cortisol (corticosterone)
• Glucocorticoid signalling


  1. Steroid hormones (like thyroid hormones) are ligands that activate gene expression by binding to intracellular receptors

  2. The hormone-receptor complex ends up binding to specific regulatory elements on DNA called hormone response elements to regulate gene transcription

  3. Cortisol enters cells via diffusion as it is lipophilic. It binds to the glucocorticoid hormone receptor in the cytoplasm, forming a hormone-receptor complex

  4. Binding of cortisol causes the receptor to dissociate from a chaperone hsp-90 (90 kDa heat shock protein). The heat shock protein acts to stabilise the glucocorticoid receptor when it is not bound to cortisol

  5. The hormone-receptor complex translocates to the nucleus, where it binds to what is known as a glucocorticoid response element (GRE), a nucleotide sequence in the DNA upstream of the gene transcription start site in the promotor region

  6. The outcome of binding of the hormone receptor complex on genes may be positive or negative, either activating or repressing transcription (depending on gene and cell)