4GHM Lecture 11 - Endocrinopathies
Endocrinopathy Classification
Primary:
Problem with downstream glands.
Secondary:
Problem with the pituitary gland.
Tertiary:
Problem with the hypothalamus.
Other:
Damage to receptor mechanisms in target tissues.
Panhypopituitarism
Decreased production:
Most or all pituitary hormones.
Causes:
Tumors:
Including pituitary adenomas and tumors compressing the stalk.
Infections:
Meningitis, autoimmune.
Vascular disease:
Pituitary apoplexy, Sheehan syndrome.
Congenital hypoplasia:
Of the gland.
Other:
Surgery, radiation.
Deficiencies and Symptoms:
Hypoglycaemia:
Cortisol induces gluconeogenesis, lipolysis, and glucagon secretion, and decreases insulin secretion.
Fatigue.
Bradycardia.
Depression.
Constipation:
Thyroid hormones increase the BMR, affect protein synthesis, regulate growth, and increase catecholamine sensitivity.
Delayed puberty:
Micropenis, lack of male muscle distribution in males.
Delayed puberty:
Amenorrhoea in females.
Dwarfism.
Dehydration.
Polyuria.
Polydipsia.
Pickhardt-Fahlbusch Syndrome
Disruption:
Of portal veins between the hypothalamus and pituitary.
Results:
In hypothyroidism due to reduced TSH.
Hypophyseal portal system:
Connects the hypothalamus and pituitary.
Portal venous system:
Two capillary beds connected by veins.
May be caused:
By a tumor squashing the pituitary stalk.
Disrupts transfer:
Of hormones/releasing factors from the hypothalamus to the anterior pituitary.
Treatment:
Remove tumor, hormone-replacement.
Sheehan Syndrome
A hypopituitarism.
Cause:
Ischemic necrosis due to blood loss, hypovolemic shock at childbirth.
Ischemia: restriction of blood supply to tissues.
Hypovolemia: decreased blood volume (plasma).
Symptoms:
Absence of lactation or symptomless, secondary symptoms of hypopituitarism years later.
Treatment:
Hormone-replacement therapy, e.g., GH, corticosteroids.
Adrenal Insufficiency
Primary adrenal insufficiency:
Example: Addison’s disease.
Secondary adrenal insufficiency:
Example: Sheehan syndrome.
Tertiary adrenal insufficiency:
Example: brain tumors stopping CRH release.
Diabetes Mellitus (DM)
DM affects:
About 2% of the Western population.
Diabetes mellitus:
Literally means ‘copious amounts of sweet urine’.
DM is caused:
By insulin deficiency or complete lack of insulin or a lowered response of cells to insulin.
Type I DM
Type I:
Insulin-dependent diabetes mellitus (IDDM) affects about 15% of diabetics.
Cause:
Destruction of pancreatic beta cells – e.g., autoimmune reaction, possibly following virus infection.
Hyperglycaemia results.
Treatment:
Insulin administered by injection.
Type II DM
Type II:
Non-insulin-dependent diabetes mellitus (NIDDM) occurs when cells fail to respond to insulin, even though insulin levels are normal or elevated (insulin resistance).
Cause:
Disruption to the insulin receptor or part of the insulin-signaling pathway.
Treatment:
Consists of diet control and exercise.
Gestational Diabetes
In pregnant women:
With no prior diabetes.
Natural interference:
With insulin receptors, insulin resistance.
Recovery:
Usually follows delivery.
4%:
Of pregnant women.
Persistent hyperglycemia:
\uparrow risk of intrauterine foetal death and macrosomia (big baby syndrome).
Type A1: abnormal OGTT, normal blood glucose levels during fasting; diet modification sufficient to control.
Type A2: abnormal OGTT, abnormal glucose levels during fasting; additional therapy with either insulin or other medications.
Risk factors:
Previous GDM.
Obesity:
(2-9x depending on extend).
PCOS.
Ethnicity:
(black African, black Caribbean or South Asian heritage).
Mother >35, father >50.
GDM patients:
Are recommended to have a 75g OGTT done 6 weeks to 6 months post partum to detect diabetes.
Other rare causes:
Of beta cell dysfunction in GDM are due to autoimmune destruction of pancreatic beta cells or mutations in autosomes (commonly referred to as MODY).
Women with GDM:
May be at a 50-70% risk for developing Type 2 DM in the next 10-30 years depending on diet & lifestyle.
Diabetes Insipidus
Symptoms:
Polydipsia.
Polyuria.
Causes:
Central (neurogenic):
Lack of vasopressin synthesis (Antidiuretic Hormone, ADH).
Nephrogenic:
Kidney does not respond (receptors impaired?).
Dipsogenic:
Damage of thirst mechanism in hypothalamus.
Hyperinsulinism
Rare.
Cause:
Often a benign tumor of the islets of Langerhans (rarely a malignant tumor).
Excess insulin produced:
In an uncontrolled way.
Symptoms:
Nervous system deprived of glucose → anxious, nervous, sweats, trembles, coma.
Treatment:
Administer vast quantities of glucose; administer glucagon.
Graves Disease
The most common cause:
Of hyperthyroidism.
Graves disease:
Is an autoimmune disorder – antibodies (thyroid-stimulating immunoglobulin) bind to and activate TSH receptor.
Radioiodine, surgery, antithyroid drugs.
Hashimoto’s Thyroiditis
From thyroid destruction:
(autoimmune disorder).
Autoimmune antibodies:
Against thyroperoxidase (TPO).
May have:
Other autoimmune disorders (DM I destruction of pancreatic beta-cells).
Goitre, gland inflamed.
Symptoms:
Fatigue.
Muscle weakness.
Weight gain.
TSH high.
T3/T4 low.
Polycystic Ovary Syndrome (PCOS)
Most common cause:
Of ovulation disorders.
Graffian follicles:
Fail to develop properly → cysts.
Usually present:
In teens or twenties (5% - 10% of 12-45 yr olds).
Possibly the most common endocrinopathy:
In women of reproductive age.
Metabolic syndrome:
Tendency towards central obesity and insulin resistance.
Cause:
Uncertain, thought to be genetic.
Symptoms:
Infertility, obesity, and hirsutism (excessive hairiness).
Treatment:
Clomiphene (fertility), diet and lifestyle.
Alcoholic Fatty Liver Disease
Ethanol upregulates:
Hepatic cell fatty acid transporters such as fatty acid transport protein 1 and 5 (FATP1,5).
Excessive alcohol consumed:
The liver cannot process ethanol and its metabolites quickly enough → ethanol, acetaldehyde, and NADH accumulate in the liver and may enter the bloodstream.
Acetaldehyde activates HSC:
HSC release tumor necrosis factor alpha (TNF-\alpha), an inflammatory marker → \uparrow liver inflammation.
TNF-\alpha stimulates:
Fat production in liver cells.
Damaged mitochondria:
Can no longer efficiently perform metabolic tasks.
NAFLD and PCOS
Obesity and adipose tissue dysfunction.
\uparrow Pro-oxidant, pro-apoptotic and pro-inflammatory factors.
Altered expression levels:
Of inflammatory and fat mass genes, LDLR, protein ninein, SHBG, 5 \alpha -reductase.
Disturbed insulin-related pathways.
NAFLD causes hyperandrogenism.
Endocrinopathies and Male Reproduction
HPG axis:
GnRH (hypothalamus), LH and FSH (pituitary).
GnIH inhibits:
Gonadotropin synthesis.
LH:
Steroidogenesis.
FSH:
Spermatogenesis.
Disruption of male reproductive functions:
Upregulation of aromatase CYP19 (cyt P450 Family 19):
higher conversion rate of testosterone to estrogen
estrogen excess inhibits the HPG axis.
Hyperprolactinemia: prolactin inhibits GnRH release.
Endocrinopathies causing this:
obesity
thyroid pathologies
DM
metabolic hormones and inflammatory mediators
induce oxidative stress
all affect the normal endocrine crosstalk regulating male reproductive functions.
Thyroid Disease Leading to Diabetes
Normal thyroid state:
Maintains normal brain function by glucose uptake lipid metabolism
regulates neurotransmitter synthesis and synaptic transmission.
Hypothyroid state:
Impairs brain functions by impaired glucose uptake and lipid metabolism
impaired neurogenesis
altered neurotransmitter synthesis
poor synaptic plasticity
leading to cognitive decline.
Impaired the glucose and lipid metabolism:
Increased hepatic gluconeogenesis and Lipogenesis
impaired insulin sensitivity,
leading to Hyperglycemia