Adrenocortical Function Disorders

Disorders of Adrenocortical Function

• Abnormal adrenal cortex function leads to clinical problems.

Hypoactivity

• Decreased adrenal cortex activity, known as Addison's disease, can stem from diseases such as autoimmune destruction, reducing glucocorticoids and mineralocorticoids.
• Issues in the pituitary or hypothalamus can decrease ACTH or corticotrophin releasing hormone (CRF) secretion, mainly affecting glucocorticoids.

Hyperactivity

• Increased glucocorticoid secretion, or Cushing's syndrome, may arise from adrenal cortex tumors (adenomas).
• Disorders affecting ACTH secretion, such as pituitary adenomas (Cushing's disease) or ectopic ACTH secretion, increase glucocorticoid secretion.

Congenital Adrenal Hyperplasia

• Genetic defects in enzymes crucial for cortisol synthesis can lead to clinical conditions.
• A lack of cortisol means the pituitary isn't controlled by negative feedback, leading to high ACTH levels, causing adrenal cortex enlargement (hyperplasia).
• The severity depends on the enzyme affected.

Clinical Effects of Excess Cortisol Secretion (Cushing's Syndrome)

• Increased muscle protein breakdown and enhanced liver gluconeogenesis, potentially leading to hyperglycemia, polyuria, and polydipsia.
• Increased muscle protein breakdown causes wasting of proximal muscles, producing thin arms and legs, and muscle weakness.
• Increased lipogenesis in adipose tissue leads to fat deposition in the abdomen, neck, and face, creating a moon-shaped face and weight gain.
• Purple striae appear on the lower abdomen, upper arms, and thighs because of catabolic effects on skin protein structures, which makes skin thin and causes easy bruising.
• Immunosuppressive, anti-inflammatory, and anti-allergic cortisol functions increase vulnerability to bacterial infections and acne.
• Osteoporosis may result from disturbances in calcium metabolism and bone matrix protein loss, causing back pain and rib collapse.
• Mineralocorticoid effects from excess cortisol can cause hypertension due to sodium and fluid retention.

Clinical Effects of Too Little Cortisol Secretion

• Insufficient cortisol secretion, due to autoimmune adrenal gland destruction causes Addison's disease, which can manifest as an acute emergency (Addisonian Crisis) or a chronic debilitating disorder.
• Symptoms include insidious onset of tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss, and occasional dizziness.
• Hyperpigmentation is a key sign, especially in exposed areas, friction points, buccal mucosa, scars, and palmar creases, due to ACTH-mediated melanocyte stimulation.
• Other symptoms: decreased blood pressure, postural hypotension, and hypoglycemic episodes, especially when fasting.
• Stress (trauma, infection) can worsen these effects, leading to nausea, vomiting, extreme dehydration, hypotension, confusion, fever, and even coma (Addisonian crisis).
• Treatment involves intravenous cortisol and fluid replacement to prevent death.

Clinical Tests of Adrenocortical Function

• Plasma cortisol and ACTH levels, 24-hour urinary cortisol excretion, and 17-hydroxysteroid measurements are important in evaluating adrenocortical disease.
• Dexamethasone suppression tests and ACTH stimulation tests can aid in differential diagnosis.
• Dexamethasone, a potent synthetic steroid, typically suppresses ACTH and cortisol secretion.
• Dexamethasone suppresses plasma cortisol by >50% is a sign of Cushing's disease
• Synacthen, a synthetic ACTH analogue, increases plasma cortisol to >200 nmol/L and rules excludes Addison's disease.

Steroid Hormone Receptor Homology

• Steroid receptors include thyroid and vitamin D receptors.
• The receptors have a hormone-binding, DNA-binding and variable region.
• Glucocorticoid receptors share sequence homology with mineralocorticoid (~64%), androgen (~62%), oestrogen (~31%), and thyroid (~24%) receptors.
• Cortisol binds mineralocorticoid and androgen receptors with low affinity.

Actions of Other Adrenal Steroids

• Aldosterone promotes sodium reabsorption in the kidney, exchanging it for potassium or hydrogen ions.
• Oversecretion of aldosterone causes sodium and water retention, potassium loss, hypertension, and muscle weakness.
• Lack of aldosterone can lead to hypotension.
• Androgens stimulate male genital tract and secondary sexual characteristic development like height, body shape, facial and body hair, and lower voice pitch.
• Androgens also have anabolic effects on muscle protein.
• Overproduction of adrenal androgens in females can lead to hair growth (hirsutism), acne, menstrual issues, increased muscle mass, virilization, and a deeper voice.
• Oestrogens encourage female genital tract, breasts, and secondary characteristic development like broad hips and fat accumulation in breasts and buttocks.
• They are weakly anabolic and lower cholesterol.

Metabolic Response to Pregnancy

• After fertilization and implantation, fetal growth and development begin and persist.
• Typical weight gain by the end of pregnancy is ~8 kg.
• About ~3.5 kg is the fetus.
• The placenta is ~0.6 kg.
• Amniotic fluid is ~0.8 kg.
• Maternal fuel stores are ~3 kg.
• The mother supplies the fetus everything for growth including (nutrients, vitamins, minerals, oxygen and water).
• An environment in which the fetus develops is controlled by maternal metabolism.
• The fetus is supplied with necessary nutrients.
• Those nutrients are supplied at the correct rate for the stage of development.
• The maternal nutrient homeostasis experiences minimal disturbances.
• The fetus is buffered from major disturbances in nutrient supply.
• The metabolism of the major maternal nutrients is impacted during pregnancy.
• The hormones that regulate it are maternal insulin and those from the foetal-placental unit (oestrogens, progesterone, and placental lactogen).
• Insulin regulates changes in maternal metabolism during pregnancy and increases in concentration in the maternal circulation as pregnancy continues.
• Insulin promotes uptake and storage of nutrients, largely as fat in maternal adipose tissue.
• Foetal-placental hormones become increasingly important during pregnancy, largely opposing insulin's actions.
• During the first 20 weeks of pregnancy, changes in homeostasis are related to the preparation for increased maternal nutrient stores, especially adipose.

Metabolic Changes During the Second Half of Pregnancy

• The second half of pregnancy is the point where the placenta and fetus grow immensely.
• Maternal metabolism adapts to increasing demand by the foetal-placental unit to meet the need for nutrients.
• Maternal metabolism is achieved by keeping nutrients in concentration.
• The maternal utilization of glucose is reduced.
• Maternal disposal of nutrients after meals is limited.
• Releasing fatty acids from the built up stores increases.
• Metabolic changes are controlled by insulin to anti-insulin ratios.
• Maternal insulin increases, but fetal placental units increase faster.

Gestational Diabetes

• Gestational Diabetes is a type of diabetes that develops during pregnancy for women who did not previously have diabetes.
• Gestational Diabetes affects how your cells use sugar (glucose).
• Gestational Diabetes causes high blood sugar levels.
• High blood sugar negatively affects both the mother and baby.
• The Placenta, the connection of the baby to the supply of blood produces high levels of hormones.
• The high levels of hormones impair insulin function.
• This elevates blood sugar levels.
• The Pancreas will respond by producing more insulin to counteract the elevated blood sugar level.
• If the Pancreas cannot keep up with increasing demands for insulin production, blood sugar levels rise too high.
• You may have Gestational Diabetes if blood sugar levels peak too high.
• Women with Gestational Diabetes do not usually have any symptoms.
• If not managed properly, Gestational can lead to complications to the Mother and Baby.
• These Complications include a higher risk of preeclampsia, preterm birth and cesarean delivery
• The baby may experience the risks of developing obesity and type 2 diabetes later in life.

Diagnosis of Gestational Diabetes

• Initial Screening for Pregnant Women is between weeks 24 and 28 of pregnancy.
• If there are risk factors present, screening may be done sooner.
• A glucose challenge test (GCT) may be required.
• In the glucose challenge test, the pregnant woman drinks a sugary solution.
• Blood sugar levels are tested after one hour.
• If the blood sugar levels are higher than normal at this stage, this does not necessarily dictate that you have diabetes.
• If blood sugar levels are high, you will need further testing.

Metabolic Response to Exercise

• The body needs to meet the demands of cardiac and skeletal structure during exercise.
• The body needs to ensure that waste products are removed.
• Short lived adaptations to metabolism, temperature, regulation and cardiovascular systems needs to be achieved.
• The body will be able to increase energy demand of skeletal and cardiac structure.
• By keeping the mobilization equal to rate of utilization, the body will have minimal disturbances to homeostasis.
• The body maintains the glucose supply to the brain in an attempt to prevent hypoglycaemia.
• The waste products of metabolism needs to be removed as quickly as possible.

Energy Requirements for Exercise

• The energy requirements of exercise largely reflect the increased activity of skeletal and cardiac muscles.
• The increased activity of respiratory muscles are less significant.
• In the normal resting state (BMR) the body uses ~4 kJ/min of energy.
• During a marathon a body uses ~80 kJ/min of energy.
• During a 100m sprint a body uses ~200 kJ/min of energy.
• The energy for muscle contraction comes from ATP hydrolysis.
• ATP + H2O >>>> ADP + Pi + energy.
• At rest the rate of ATP in skeletal structure is ~0.06 mmol/sec/kg muscle.
• During a marathon the rate of ATP in skeletal structure increases to ~1.2 mmol/sec/kg muscle.
• During a the 100m sprint the rate of ATP in skeletal structure increases to ~3 mmol/sec/kg muscle.
• The ATP concentration in muscle is ~5 mmol/kg muscle and could only last for ~2 sec.
• ATP concentration does not fall by more than 20% because it is regenerated from ADP by a variety of mechanism.
• The body can increase glycogen stores for muscle with enough glucose for ~18 minutes of low intensity exercise (marathon running).
• Liver cannot provide enough glucose needed to prevent hypoglycaemia (impairment of CNS may occur).
• Muscle glycogen cannot be affected by a blood supply issue.
• Muscle glycogen needs the membrane to transport it into muscle.
• Muscle glycogen produces G-6-P without using ATP.
• Mobilisation can be very rapid(highly branched structure;many sites of enzyme attack, and glycogen phosphorylase activity can be changed rapidly by covalent modification and allosteric activation).