TMP - Endocrine Physio Flashcards

Question

Cortisol exerts its effects by which mechanism?

Answer 1

Binding to two GRs before translocating to the nucleus

Answer 2

Cortisol levels are detected by the hypothalamus and anterior pituitary, which decrease CRH and

Answer 3

endocrine disorder 1,2,3

Answer 4

The pituitary gland consists of two lobes – the anterior and posterior pituitary. They have separate embryological origins, are histologically different, and effectively function as two separate endocrine glands.

Answer 5

Anterior Pituitary Growth Hormone (GH) Thyroid stimulating Hormone TSH) Follicle Stimulating Hormone (FSH) Luteinising Hormone (LH) Adrenocorticotrophic Hormone (ACTH) Prolactin (PRL) Melanocyte stimulating hormone (MSH) Posterior Pituitary Antidiuretic Hormone Oxytocin

Answer 6

1. The hypothalamus releases a releasing hormone 2. pituitary hormone 1. ADH -> ADH (stored in pituitary) 2. /3. GnRH -> LH/FSH 4. TRH -> TSH 5. PRH (inhibited by PIH) -> Prolactin (PRL) 6. GHRH (inhibited by GHIH) -> GH 7. CRH -> ACTH

Answer 7

3. Target 4. Effects 1. (ADH) kidneys, sweat glands, circulatory system -> water balance 2. (LH) reproductive system -> stimulates production of sex hormones by gonads 3. (FSH) -> reproductive system -> stimulates production of sperm and eggs 4. (TSH) -> Thyroid gland -> stimulates release of thyroid hormone (TH) which regulates metabolism 5. (PRL) -> mammary glands -> promotes milk production 6. (GH) -> liver, bone, muscles -> induces targets to produce insulin like growth factors (IGF) - stimulates body growth and higher metabolic rate 7. (ACTH) -> adrenal -> induces targets to produce glucocorticoids which regulate metabolism and the stress response

Answer 8

The anterior pituitary releases hormones in response to hormones secreted from the hypothalamus. In response to the hypothalamus, the anterior pituitary releases hormones into the blood. They have a tropic (“turning on”) effect on another endocrine organ in the body. This means they stimulate another endocrine organ to release a third hormone in the pathway, known as a peripheral hormone. This peripheral hormone travels in the bloodstream to exert metabolic actions at different tissues in the body. Note that in some cases, the hormone secreted by the anterior pituitary hormone may itself be the peripheral hormone in the pathway. Or, it may have dual actions to act directly on tissues, in addition to stimulating a target endocrine gland to release a peripheral hormone.

Answer 9

The hypothalamus releases hormones into its surrounding interstitial fluid, which permeate into nearby fenestrated capillaries. These capillaries form the hypophyseal portal system that extends into the anterior pituitary. They are histologically similar to veins. However, they connect to each other, rather than to arteries and veins, and provide a rich supply to the pituitary endocrine cells.

Answer 10

The hormones released by the hypothalamus into the anterior pituitary are either releasing hormones (RH) that stimulate the secretion/synthesis of hormones, or inhibiting hormones (IH) that inhibit the synthesis/secretion of hormones.

Answer 11

The peripheral hormone will usually have a positive and/or negative feedback effect on the pituitary and hypothalamus. In other words, it will stimulate or inhibit further release of hypothalamic and/or pituitary hormones. This circuit between the hypothalamus, anterior pituitary and third endocrine gland is known as an axis.

Answer 12

1. Hypothalamic-Pituitary-Adrenal Axis - Involving Adrenocorticotrophic Hormone (ACTH) 2. Growth Hormone Axis - Involving Growth Hormone (GH) 3. Hypothalamic-Pituitary-Thyroid Axis - Involving Thyroid Stimulating Hormone (TSH) 4. Hypothalamic-Pituitary-Gonadal Axis - Involving Follicle Stimulating Hormone (FSH) and Luteinising Hormone (LH) 5. Prolactin Axis Involving Prolactin (PRL)

Answer 13

Endocrine disorders are commonly referred to as being primary, secondary or tertiary diseases. This relates to which organ in the axis is affected. A primary endocrine disease refers to a disease that affects hormone secretion in the organ that produces the hormone. An example of this would be Addison’s disease, which is where the disease affects the adrenal gland directly and cortisol production. This is sometimes referred to as primary hypoadrenalism. A secondary endocrine disease affects the endocrine organ that releases tropic hormones, which indirectly affects peripheral hormone secretion. An example here would be Cushing’s disease – a tumour in the pituitary secreting ACTH, resulting in increased adrenal gland activity and raised cortisol production. This would be known as secondary hyperadrenalism. A tertiary endocrine disease affects the initial endocrine organ in an axis. This is usually a disease of the hypothalamus. Indirectly, it affects a second endocrine organ and then a third endocrine organ, ultimately affecting peripheral hormone levels. Tertiary adrenal insufficiency is a disease of low cortisol caused by a dysfunctional hypothalamus and decreased CRH production.

Answer 14

Prostate cancer

Answer 15

The hypothalamic-pituitary-gonadal (HPG) axis includes the hypothalamus, pituitary gland and gonads. Gonadotropins are the hormones produced to control the reproductive system.

Answer 16

The hormones involved are gonadotropin-releasing hormone (GnRH) secreted from the hypothalamus, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) produced by the anterior pituitary gland and oestrogen and testosterone produced by the gonads. LH and FSH are known as gonadotropins.

Answer 17

It is essential for the control of the reproductive system and regulates the production of gametes and sex steroids.

Answer 18

LH stimulates the Leydig cells in the testes to produce testosterone, the main male sex steroid hormone.

Answer 19

Testosterone has numerous effects, including: - Stimulates formation of sperm (spermatogenesis) in the testes - Maintenance of libido (sexual drive) - Development of secondary sexual characteristics (pubic, axillary and facial hair) - Growth of external genitalia - Deepening of voice - Muscle growth - Bone growth - Promotion of anabolic reactions

Answer 20

n some tissues, testosterone is converted to dihydrotestosterone (DHT), making up 10% of total circulating testosterone levels. DHT binds to the same receptors as testosterone. Some tissues only respond to DHT, while others such as the prostate are more sensitive to DHT than testosterone. High levels of testosterone have a negative feedback effect on the hypothalamus to inhibit GnRH production, as well on gonadotrophs in the pituitary to inhibit LH secretion, thereby decreasing testosterone levels.

Answer 21

FSH drives sperm production in the Sertoli cells of the testes (spermatogenesis), as well as synthesis of proteins important for the production and action of steroid hormones. They include: Androgen binding protein (ABP) which maintains high levels of testosterone locally in the luminal space of the seminiferous tubules. P450 aromatase, an enzyme that converts testosterone into oestradiol. Growth factors that support sperm cells and spermatogenesis, that result in increasing the number of sperm cells, as well as promote motility and the fertility potential of sperm. Inhibins, which have a selective negative feedback effect on FSH only and not LH (i.e., inhibits FSH production, but does not inhibit LH production). They also act as growth factors on Leydig cells.

Answer 22

LH binds to theca cells on developing follicles as well as granulosa cells. After ovulation, LH binds to cells of the. corpus luteum. It acts on theca cells to produce progestins and androgens. Androgens enter granulosa cells and are then converted to oestrogens.

Answer 23

FSH binds to granulosa cells to: Increase production of enzymes that catalyse the production of steroid hormones, stimulating follicle growth Increase production of activins, which have a positive feedback effect on the anterior pituitary Increase production of inhibins, which have a selective negative feedback effect on the pituitary Help convert androgens to oestrogen

Answer 24

Oestrogens and progestins act on the anterior pituitary and the hypothalamus to exert negative and positive feedback effects. Moderate oestrogen levels exert negative feedback on LH and FSH secretion High oestrogen levels (in the absence of progesterone) positively feedback on LH and FSH secretion Oestrogen in the presence of progesterone exerts negative feedback on the HPG axis

Answer 25

Progesterone is a sex steroid released by the corpus luteum, which is what the follicle turns into after the egg has been released during ovulation. Progesterone increases the inhibitory effect of moderate oestrogen concentration levels on LH and FSH secretion. However, progesterone prevents the positive feedback effect of high oestrogen concentrations on the pituitary.

Answer 26

Gonadotropin-Releasing Hormone (GnRH) is released in a pulsatile fashion from neurons in the hypothalamus. These neurons form an interconnected network with other neural circuits of the brain, allowing for integration of various signals, including light-dark cycles, body fat levels and stress.

Answer 27

GnRH acts on GnRH receptors found on gonadotroph cells of the anterior pituitary

Answer 28

stimulating the production of two hormones: Luteinising Hormone (LH) Follicle Stimulating Hormone (FSH) LH and FSH are released in an episodic fashion, reflecting the pulsatile release of GnRH. LH and FSH then act on the gonads (testes/ovaries), with differential effects.

Answer 29

Desensitisation to GnRH can be induced for clinical benefit. In prostate cancer, long-acting GnRH analogues are administered to suppress LH and FSH release, thereby reducing testosterone production. This is effectively medical/chemical castration. This is useful in the treatment of prostate cancer because testosterone production can cause the cancer to grow, so by removing this signal the tumour will shrink.

Answer 30

When GnRH binds to gonadotrophs in the pituitary, the GnRH receptor becomes internalised and degraded by lysosomes. As a result, prolonged and continuous exposure of gonadotrophs to GnRH causes a diminished response and suppresses the release of LH and FSH.

Answer 31

Deficiency/acromegaly (excess)

Answer 32

Growth hormone, also known as somatotrophin, is one of the hormones produced by the anterior pituitary gland.

Answer 33

GH has direct metabolic effects on tissues by binding to cells, and has indirect effects by stimulating cells in the liver to produce insulin-like growth factors (IGFs or somatomedins).

Answer 34

The main IGF is IGF-1.

Answer 35

Growth hormone, either directly or indirectly, affects almost every tissue in the body, especially skeletal muscle and cartilage cells (chondrocytes). The overall effects, arising from an interplay between GH and IGF-1, are important for the following: Skeletal growth Muscle strength Bone density Cardiac function

Answer 36

Increased lipolysis – cells use the resultant fatty acids to generate ATP, sparing glucose Glycogenolysis in the liver (breakdown of glycogen to glucose), which is a diabetogenic effect, due to the significant increase in blood glucose levels Stimulation of stem cell division and differentiation of daughter cells in epithelia and connective tissues

Answer 37

The effects of GH via IGF-1 can be thought of as “anabolic” (compound building) like insulin and include: Increased protein synthesis and cell growth Increased carbohydrate oxidation

Answer 38

IGF-1 is important especially after a meal when glucose and amino acids are available in the blood. Glucose is taken up into cells through the action of insulin for ATP synthesis. At the same time, IGF-1 binds to plasma membrane receptors to increase their uptake of amino acids for protein synthesis, which uses up energy.

Answer 39

The hypothalamus secretes growth hormone releasing-hormone (GHRH). GHRH stimulates somatotroph cells of the anterior pituitary to release growth hormone (GH), also known as somatotropin.

Answer 40

Several factors including stress, exercise, nutrition, hormones such as ghrelin (synthesised by the stomach) and sleep modulate the production of growth hormone.

Answer 41

The growth hormone axis is different to the typical endocrine axis. Whilst GHRH promotes GH release, the hypothalamus also produces growth hormone inhibiting hormone, also known as somatostatin, which inhibits GH.

Answer 42

IGFs directly suppress GH secretion by somatotrophs. IGFs also indirectly suppress GH secretion by inhibiting GHRH release and stimulating GHIH release. ????

Answer 43

In children, a deficiency of GH could result in short stature due to slow bone and muscle maturation and delayed puberty. In adults, changes are more subtle and include: Depression Reduced muscle mass and strength Reduced bone mass Reduced energy Possible cardiac dysfunction

Answer 44

In adults, excess GH is called acromegaly and is mostly caused by a pituitary tumour secreting GH. Clinical features include: Large extremities with growth of hands, feet and jaw Paraesthesia in the extremities Amenorrhoea Coarse facial features, wide nose and rounded face Hypertension Cardiomegaly (enlarged heart)

Answer 45

In children, hypersecretion of GH before the bony epiphyses have fused results in gigantism, whereby the child grows very tall. Treatment involves surgery to remove the pituitary tumour, via the sphenoid bone (“transsphenoidal”) if the tumour is large enough, or medically by using somatostatin analogues.

Answer 46

Hyperprolactinaemia

Answer 47

It has a variety of roles but is particularly important in breast development and production of breast milk in females.

Answer 48

Prolactin (PRL) is produced by the lactotroph cells of the anterior pituitary gland. There is no stimulatory hormone produced by the hypothalamus.

Answer 49

Prolactin has well known physiological functions in females only. Gradual increases in PRL during pregnancy, along with high oestrogen and progesterone levels result in full breast development. The main actions of prolactin are listed below: Initiate milk production by alveolar cells (lactogenic) Maintain milk production once it has been established (galactopoietic) Proliferation of alveolar and duct cells (mammogenic)

Answer 50

Prolactin has primarily lactogenic and galactopoietic effects.

Answer 51

Prolactin release is inhibited by dopamine (DA), known in this context as a PRL-inhibitory factor (PIF).

Answer 52

Suckling is the most powerful stimulus for PRL release. Stimulation of the nipple sends signals via afferent neural pathways up through the spinal cord. This inhibits dopaminergic neurons in the hypothalamus. Thus, there is inhibition of an inhibitory neurotransmitter. This is known as disinhibition. Thyrotropin releasing hormone (TRH), released from the hypothalamus, also stimulates the release of prolactin. Furthermore, oestrogens increase the sensitivity of lactotrophs to TRH, as well as decreasing their sensitivity to dopamine inhibition.

Answer 53

the prolactin axis does not technically have a negative feedback system. Without inhibition by dopamine, prolactin would be secreted indefinitely.

Answer 54

Lactation generally inhibits normal ovarian cycles. It decreases the release of GnRH by neurons in the hypothalamus. This causes decreased FSH and LH release, which are responsible for normal ovarian function. Nursing the infant will not indefinitely cease ovarian cycles, and eventually they will resume regardless of whether the infant is nursed or not. If the mother does not nurse the infant, ovulatory cycles will generally resume 8-10 weeks after delivery.

Answer 55

Hyperprolactinaemia is a state of raised prolactin levels.

Answer 56

It can cause: Menstrual disturbances – amenorrhoea or oligomenorrhoea Galactorrhoea (leaking of milk through the nipples) Hypogonadism causing infertility and erectile dysfunction, as well as osteoporosis

Answer 57

The causes can be remembered as the 5 Ps: Physiological – breastfeeding, stress, acute rises post-intercourse Pregnancy Pharmacological e.g. dopamine antagonists, antipsychotics (due to dopamine antagonist effects) Prolactinoma (a prolactin producing tumour in the pituitary) Polycystic Ovarian Syndrome (PCOS). The mechanism is not exactly known but is thought to be due to raised oestrogen levels having a stimulatory effect on prolactin production Diagnosis is based on finding the underlying cause and treatment will be tailored accordingly.

Answer 58

The hypothalamic-pituitary-thyroid (HPT) axis consists of the hypothalamus, the pituitary gland, and the thyroid gland. The hormones involved are thyrotropin-releasing hormone (TRH) secreted by the hypothalamus, thyroid-stimulating hormone (TSH) released by the anterior pituitary, and T3 and T4 produced by the thyroid gland.

Answer 59

The actions of T3 and T4 are widespread. Some important functions include: Metabolic – increasing basal metabolic rate and promoting catabolism e.g. lipolysis, glycogenolysis, glycolysis and proteolysis Nervous system – important for speed of reflexes and mental activity Cardiovascular system – increases synthesis of cardiac muscle protein, increases cardiac output Bone – increases bone mineralisation

Answer 60

The hypothalamus produces thyrotrophin-releasing hormone (TRH). TRH binds to TRH receptors on thyrotropic cell membranes in the anterior pituitary, stimulating the production of thyroid-stimulating hormone (TSH), also known as thyrotropin.

Answer 61

TSH enters the blood and binds to receptors on follicular cells of the thyroid gland, stimulating the production of thyroid hormones: triiodothyronine (T3) and tetraiodothyronine (T4), also known as thyroxine.

Answer 62

Control of this system is via negative feedback: high levels of T3 and T4 inhibit TRH and TSH production by the hypothalamus and anterior pituitary gland, respectively.

Answer 63

T3 is found in thyrotropes either as a result of the deiodination of T4 or by entering from the bloodstream. This intracellular T3 decreases the number of TRH receptors of thyrotrope cells, leading to indirect inhibition of downstream T4/T3 synthesis. T3 also binds directly to response elements in TSH promotor elements of thyrotrophic cell DNA, inhibiting TSH synthesis

Answer 64

A common presentation for a malfunctioning HPT axis is cardiac-related symptoms. The patient may complain of palpitations. This is because an overactive thyroid gland can cause sinus tachycardia or atrial fibrillation. Patients may also present with acute heart failure. Take the example of a patient who has compensated heart failure secondary to a past myocardial infarction. Excess circulating thyroxine in this context can put extra strain on the heart, causing it to decompensate. Other common presentations of an under or over-active thyroid gland include: Menorrhagia (heavy periods) Confusion Weight loss/gain Tremor

Answer 65

The function of the thyroid gland is measured using a blood test called thyroid function tests (TFTs).

Answer 66

Treatment for an overactive thyroid gland is by blocking the production of thyroxine, usually with a medication called carbimazole. Similarly, if a patient presents with proptosis and eye symptoms, corticosteroids can also help. It is important to treat symptoms, so palpitations may be treated using beta-blockers such as propanolol which slow down the heart.

Answer 67

Treatment for an underactive thyroid gland is by replacing inadequate thyroxine with levothyroxine tablets.

Answer 68

Oxytocin is a hormone released from the posterior pituitary gland. The main functions of oxytocin include the regulation of lactation and the control of uterine contractions in labour. However, oxytocin also influences anxiety, interpersonal bonding and stress responses.

Answer 69

Oxytocin is a neuropeptide that is synthesised by hypothalamic magnocellular neurons. Within the hypothalamus, neurons from the paraventricular and supraoptic nuclei extend into the posterior pituitary. From here, the hormone is secreted into the extracellular space. The blood supply to the posterior pituitary then carries it into the bloodstream.

Answer 70

The oxytocin receptor is a Gq coupled G-protein coupled receptor (GPCR). In brief, activation of this receptor leads to a cascade that results in a significant influx of calcium ions into the cell. These calcium ions then act on targets, including myosin light-chain kinase, which facilitates smooth muscle contraction.

Answer 71

During the last few months of pregnancy, the number of oxytocin receptors in the uterine muscle increases, and the receptors become more sensitised. This helps to prepare for labour. Uterine production of oxytocin is largely responsible for triggering normal labour and delivery.

Answer 72

During labour, the baby’s head exerts pressure on the cervix, which stimulates oxytocin production. This acts on receptors in the uterus which causes an increase in intracellular calcium ions. Calcium activates myosin light chain kinase which induces uterine contraction. Contractions release further oxytocin, forming a positive feedback loop. Following birth, oxytocin maintains uterine contractions and reduces the risk of postpartum bleeding.

Answer 73

When an infant suckles on the nipple, it stimulates oxytocin release from the posterior pituitary into the blood. This occurs via afferent sensory nerves from the breast to the hypothalamus. Oxytocin reaches the myoepithelial cells lining the alveoli in the breast, causing these cells to contract. Milk is thus expressed from the alveoli and into the ducts. Accordingly, this is known as the milk ejection reflex or milk let-down reflex.

Answer 74

Oxytocin released during ejaculation stimulates contraction of the vas deferens and prostate gland for the emission of sperm and prostatic secretions. Similarly in females, oxytocin during intercourse may cause contractions of the uterus and vagina. This helps to transport sperm towards the fallopian tubes.

Answer 75

Synthetic oxytocin, also known as syntocinon, is also used in the medical management of several conditions.

Answer 76

These include: Cervical ripening to reduce the length of induction during labour Active management to remove the placenta during the third stage of labour Management of: Retained placenta as a cause of primary postpartum haemorrhage Uterine atony as a cause of primary postpartum haemorrhage Uterine inversion, when traction on the cord has inadvertently caused the uterus to descend through the cervix before the placenta has separated

Answer 77

SIADH/Diabetes insipidus

Answer 78

It is found within the sella turcica of the sphenoid bone. The posterior lobe arises from a down growth of the diencephalon – a division of the forebrain – and is essentially an extension of the hypothalamus. This lobe consists of axons of the hypothalamic neurons and neuroglial cells, which support these axons.

Answer 79

There are two posterior pituitary hormones, oxytocin and antidiuretic hormone (ADH), which are released by periventricular and supraoptic nuclei.

Answer 80

These peptide hormones are derived from precursor molecules produced by hypothalamic neurons. The precursor molecules are transported along the axons of the hypothalamic neurons to the posterior pituitary. Cleavage of the precursor molecules occurs during this transport along the axons and are stored in axon terminal swellings known as Herring Bodies. Upon appropriate stimulation, the neurosecretory neurones generate an action potential, causing the release of hormones from the nerve terminals into a rich plexus of vessels.

Answer 81

The primary stimulus for the release of oxytocin occurs as the cervix distends, an effect known as the Ferguson reflex. Oxytocin is an essential stimulator of myometrial contraction during labour, and uterine contraction perpetrates a positive feedback loop on oxytocin release to help maintain labour. The release of oxytocin is also triggered by the suckling of a baby on the breast. Afferent input from the nipple triggers oxytocin production and release from the posterior pituitary into the bloodstream.

Answer 82

Oxytocin then travels to the myoepithelial cells of the breast to induce contraction, leading to milk expression. This is known as the milk ejection reflex or milk let-down reflex.

Answer 83

Maternal oxytocin plasma levels gradually increase during pregnancy, and oestrogen increases the number of oxytocin receptors present in the myometrium and decidua during this time.

Answer 84

ADH (also called arginine vasopressin, AVP) is a neuropeptide hormone that acts on the kidney’s collecting ducts to increase water reabsorption. Various factors control ADH release, but its most important factors are changes in plasma osmotic pressure and volume status.

Answer 85

Osmoreceptors in the hypothalamus regulate ADH release by detecting and responding to changes in plasma osmotic pressure: If osmolarity increases, i.e. following a fall in plasma volume, this stimulates osmoreceptor cells to contract. This sends afferent signals from the hypothalamus to the posterior pituitary to increase the release of ADH. If osmolarity is decreased, i.e. following an increase in total body volume, osmoreceptors will expand. This sends afferent signals to the posterior pituitary to decrease the release of ADH.

Answer 86

Stimulus: Labour, Suckling Target tissues: Uterus, Breast Response: Uterine contraction, Milk ejection

Answer 87

Stimulus: Increased plasma osmolarity Target Tissues: Renal collecting ducts, Blood vessels Response: Increases water permeability and absorption in collecting ducts, Increases total peripheral resistance

Answer 88

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) SIADH is characterised by excessive ADH secretion. This excessive secretion can come from the posterior pituitary or another source, such as a small cell lung carcinoma. Continual ADH production occurs independent of serum osmolality, leading to abnormally low serum sodium levels, highly osmolar urine and high urinary sodium levels. SIADH has a variety of causes, including brain injury, malignancy, drugs, infection, and hypothyroidism. Treatment involves identifying the underlying cause and fluid restriction.

Answer 89

Diabetes insipidus is characterised by the passage of vast volumes of dilute urine. In some cases, as much as 20 litres of urine can be produced in 24 hours, leading to rapid dehydration and potentially death.

Answer 90

Neurogenic diabetes insipidus occurs due to decreased circulating levels of ADH due to impaired production/release within the central nervous system.

Answer 91

Causes of neurogenic diabetes insipidus include: Mutations in vasopressin gene Malignancy: pituitary adenomas, craniopharyngiomas/metastases Trauma Infection: Meningitis Vascular: Sheehan’s Syndrome Sarcoidosis (formation of granulomas in the pituitary gland) Haemochromatosis (deposition of iron in the hypothalamus and pituitary gland)

Answer 92

Neurogenic diabetes insipidus can be treated with replacement therapy, such as desmopressin.

Answer 93

Nephrogenic diabetes insipidus occurs when ADH cannot bind to their receptors in the kidney.

Answer 94

Causes of nephrogenic diabetes insipidus include: Mutations in ADH receptor gene or aquaporin-2 gene Metabolic: hypercalcaemia, hyperglycaemia, hypokalaemia Drugs Chronic renal disease Amyloidosis

Answer 95

cranial diabetes insipidus/Prader-Willi syndrome

Answer 96

The hypothalamus is made up of three units. Anterior (Supraoptic) Nuclei Middle (Tuberal) Nuclei Posterior (Mammillary) Nuclei

Answer 97

The hypothalamus is highly interconnected with other parts of the central nervous system and has a close relationship with the pituitary gland. This is known as the hypothalamic-adenohypophyseal axis (hypophysis = pituitary, adenohypophysis = anterior pituitary).

Answer 98

Two categories of hormones are produced in the hypothalamus: Hypophysiotropic hormones (affecting the pituitary gland) Tropic hormones (targeting other endocrine glands) Both types are released from the median eminence (a part of the hypothalamus that extends outwards) into the hypophyseal portal system. This carries them to the anterior pituitary. Depending on the hormone, the pituitary will either begin secreting or stop secreting hormones into the circulation.

Answer 99

Cranial diabetes insipidus describes a scenario whereby the hypothalamic production of ADH is inadequate. ADH normally acts on the kidneys to help retain fluid. A relative lack of ADH results in the kidneys excreting excess free water

Answer 100

Patients present with polyuria (increased urination) and polydipsia (increased thirst). Unlike people with diabetes mellitus, patients with this condition have stable blood sugar levels

Answer 101

Prader-Willi syndrome occurs spontaneously in most instances, and direct inheritance is comparatively rare. The hyperphagia (excess eating) that occurs in this condition is caused by abnormal hypothalamic activity, resulting in a lack of satiety.

Answer 102

Signs and symptoms include: Obesity caused by food-seeking behaviours: hoarding or foraging for food, eating inedible items, and stealing money to buy food Constant urge to eat Slower metabolism Decreased muscle mass

Answer 103

Neuroectoderm

Answer 104

A chemical messenger which has other endocrine glands as their target

Answer 105

Glucagonoma

Answer 106

Glucagon is the hormone that opposes insulin, so it acts to raise blood glucose levels. It is a peptide hormone produced by the alpha cells of the pancreas.

Answer 107

Glucagon is a single chain polypeptide and has no disulfide bridges, making it incredibly flexible.

Answer 108

A precursor molecule, proglucagon, undergoes post-translational processing to become a biologically active glucagon.

Answer 109

Glucagon is secreted by alpha cells in the islets of Langerhans in the tail of the pancreas. Low glucose levels in the blood are detected by alpha cells, stimulating the release of glucagon. Like insulin, this undergoes margination and exocytosis to be released.

Answer 110

Glucagon binds to a specific glucagon receptor in the cell membrane, a G-protein coupled receptor (GPCR). This activates the enzyme adenylate cyclase which increases cAMP intracellularly. This activates protein kinase A which phosphorylates and activates a number of important enzymes in target cells.

Answer 111

The overall metabolic effects of glucagon are typically exerted on the liver: Increased glycogenolysis Decreased glycogenesis Increased gluconeogenesis Increased ketogenesis It also increases lipolysis in adipose tissue.

Answer 112

Adrenaline noradrenaline

Answer 113

GI tract hormones Acetylcholine

Answer 114

A glucagonoma is a tumour of the alpha cells of the pancreas. These tumours lead to the overproduction of glucagon

Answer 115

Hyperglycaemia Weight loss Anaemia Diarrhoea Diabetes mellitus

Answer 116

The presenting problem in most cases however, is necrolytic migratory erythema (NME), a red, blistering rash that spreads across the skin. It particularly affects the skin around the mouth and extremities, but can also be found on the lower abdomen, perineum and groin.

Answer 117

A blood serum glucagon of more than 1000pg/mL is indicative of a glucagonoma and the tumour can be localised using radiography such as CT or MRI scans.

Answer 118

Medication that inhibits glucagon release or damages alpha cells in the pancreas can be used to help minimize symptom progression, however the only curative treatment is surgical resection of the tumour.

Answer 119

Glucagon is a single chain polypeptide molecule, and contains zero disulphide bridges. This allows it to be flexible. Insulin, by contrast, has 3 disulphide bridges.

Answer 120

Type 2 diabetes mellitus

Answer 121

Insulin is a peptide hormone produced by beta cells within the pancreas. It is responsible for regulating the movement of glucose from the blood into cells. It is released in an endocrine fashion into the bloodstream.

Answer 122

Insulin consists of two polypeptide chains, an A chain and a B chain, covalently linked by two inter-chain disulfide bridges. There is a third, intra-chain disulfide bridge.

Answer 123

Insulin is synthesised in the beta cells of the islets of Langerhans.

Answer 124

Firstly, the insulin mRNA is translated as a single chain precursor called preproinsulin. There is then removal of its signal peptide at the N-terminus during insertion at the endoplasmic reticulum. This generates proinsulin. In the endoplasmic reticulum, endopeptidases excise a connecting peptide (c-peptide) between the A and B chains. This breaks the single-chain into two strands (A and B) that are held together by disulfide bridges – i.e. this generates the mature form of insulin.

Answer 125

Equimolar amounts of insulin and free c-peptide are packaged in the golgi apparatus into storage vesicles which accumulate in the cytoplasm.

Answer 126

A rise in glucose levels in extra-cellular fluid (ECF) is the stimulus for insulin release.

Answer 127

Glucose is transported into the beta cell by facilitated diffusion through GLUT2 channels. Therefore, a rise in glucose concentration in the ECF causes a rise in glucose concentration in beta cells. This leads to membrane depolarisation of ATP-sensitive K+ channels, opening Ca2+ channels, triggering an influx of calcium. An increase in intracellular Ca2+ triggers insulin release by a two stage process

Answer 128

Margination – the process by which insulin storage vesicles move to the cell surface Exocytosis – fusion of the vesicle membrane with the plasma membrane, with release of the vesicle’s entire contents

Answer 129

Secretion of insulin follows a biphasic pattern – i.e. occurs in two phases: Pulsatile release (rapid onset) – short-term blood glucose control: clearing absorbed nutrients from the blood following a meal. Protracted release (longer) – long-term insulin release for glucose uptake e.g. for cell growth, cell division, stimulating protein synthesis and DNA replication.

Answer 130

Insulin binds to a highly specific insulin receptor on cell surfaces. The receptor is a dimer – 2 identical sub-units spanning the cell membrane. The 2 subunits are made of: One alpha chain (on the exterior of the cell membrane) One beta chain (spans cell membrane in a single segment) These are connected by a single disulfide bond.

Answer 131

When insulin is detected, the alpha chains move together and fold around the insulin. This moves the beta chains together making them an active tyrosine kinase. This initiates a phosphorylation cascade which results in an increase of GLUT4 expression – a protein channel to allow glucose uptake. The result is an increase of glucose uptake by cells.

Answer 132

Overall, insulin can be considered the “anabolic” or building hormone – it assists processes that build compounds for storage and decrease processes that break down those storage reserves.

Answer 133

In muscle and liver, insulin increases glycogenesis and decreases glycogenolysis. Decreased gluconeogenesis in the liver Increased glycolysis in liver and adipose tissue. Decreased breakdown of amino acids in the liver. Increased amino acid uptake and protein synthesis in muscle, liver, and adipose tissue. Decreased lipolysis Increased lipogenesis and esterification of fatty acids in the liver and adipose tissue.

Answer 134

GI Tract hormones Acetylcholine

Answer 135

Adrenaline Noradrenaline

Answer 136

Type 2 diabetes mellitus involves a dual pathology: there is insulin resistance, i.e. there is normal insulin secretion but tissue become insensitive, losing their receptiveness to insulin. In a compensatory effort, beta cells work harder to produce insulin. This cannot be sustained and eventually, there is also relative insulin deficiency in type 2 diabetes mellitus.

Answer 137

This can present with the classic triad of symptoms; polyuria, polydipsia, and weight loss, although it is likely to be less noticeable than those with type 1 diabetes as it is a more gradual process.

Answer 138

It is an important diagnosis as it can lead to macrovascular complications such as strokes and heart attacks. Therefore, early recognition and treatment are vital to reduce these serious complications.

Answer 139

The first intervention should always be lifestyle modifications, such as diet changes and an increase in exercise. Next, metformin is the mainstay of initial pharmacological intervention. If hyperglycemia is still present, a range of pharmacological managements can be trialled, such as SGLT2 inhibitors.

Answer 140

The pancreas is a dual-functional gland with both exocrine (digestive) and endocrine (hormonal) functions.

Answer 141

The pancreas is a partially retroperitoneal, abdominal organ found posterior and inferior to the stomach.

Answer 142

There are a variety of cell groups within the pancreas. Firstly, there are clusters of cells known as Islets of Langerhans. These islets contain the cell types that produce the hormones relating to the endocrine functions of the pancreas. There are also acini and duct systems within the pancreas, which are responsible for producing enzymes relating to the exocrine functions of the pancreas.

Answer 143

Islets are thought to make up 5% of the overall volume of the pancreas, although they receive around 15% of its blood flow.

Answer 144

The Islets of Langerhans contain the following cell types: Alpha cells – these make up roughly 15-20% of Islet cells and are responsible for producing glucagon Beta cells – these make up 65-80% of Islet cells and produce insulin and amylin Delta cells – these make up 3-10% of Islet cells and produce somatostatin Gamma cells – these make up 3-5% of Islet cells and are responsible for production of pancreatic polypeptide Epsilon cells – these make up less than 1% of Islet cells and produce ghrelin

Answer 145

Pancreatic hormones are produced in the Islets of Langerhans. Scattered throughout exocrine tissue in the tail of the pancreas, these are spherical groups of different cell types producing different polypeptide hormones.

Answer 146

There are 6 key polypeptide hormones secreted by the endocrine pancreas.

Answer 147

These hormones can also regulate the action of other cell types within the Islets. Insulin stimulates action of beta cells and inhibits alpha cells. Glucagon stimulates action of alpha cells, which in turn then leads to activation of beta and delta cells Somatostatin leads to inhibition of both alpha and beta cells.

Answer 148

Diabetes mellitus is an endocrine disorder characterised by chronic hyperglycaemia due to either insulin resistance and/or insulin deficiency. Type 1 diabetes mellitus mainly affects younger people <30 years There is absolute insulin deficiency due to autoimmune destruction of pancreatic beta cells. This means that the beta cells are recognised as “foreign” or “non-self” by the body and so are attacked and destroyed by the body’s immune system.

Answer 149

Viral infection in a young person with pre-disposing factors, e.g. family history, is a common trigger. In some cases there is relative insulin deficiency due to defective beta cells and inadequate insulin secretion or rate of secretion.

Answer 150

Commonly, type 1 diabetes mellitus presents with a classic triad of symptoms: polyuria, polydipsia and weight loss. Due to the lack of insulin being produced by the body in type 1 diabetes, patients must be treated with injectable insulin regime.

Answer 151

The average age of diagnosis in the UK is between 10 and 14 years, therefore effective patient education forms an important part of treatment for this disease. It is a lifelong disease which needs tight control of glucose levels and explaining the importance to children and young adults can be challenging.

Answer 152

Phaeochromocytoma

Answer 153

The adrenal medulla is the central part of the adrenal gland, surrounded by the cortex. It plays a very important role in homeostasis: it secretes the essential circulating hormones adrenaline and noradrenaline.

Answer 154

The adrenal glands, also known as supra-renal glands, are found immediately superior to the kidneys. They are retroperitoneal structures and composed of two major regions: the outer adrenal cortex and the inner adrenal medulla.

Answer 155

The main secreting cells of the adrenal medulla are called chromaffin cells, which are neuroendocrine cells that are modified sympathetic ganglia. The chromaffin cells are neural crest cell derivatives.

Answer 156

Adrenaline is released in response to activation of the sympathetic nervous system, fibres of which are carried to the adrenal medulla by the thoracic splanchnic nerves.

Answer 157

The adrenal medulla is mainly responsible for the synthesis of the catecholamines, adrenaline and noradrenaline, but also has other secretory functions such as the production of dopamine.

Answer 158

Both adrenaline and noradrenaline are produced from the amino acid tyrosine, through multiple reactions.

Answer 159

The synthesised adrenaline is stored in vesicles before being released into the blood stream. Adrenaline is mainly associated with the “fight or flight response“, and noradrenaline also plays a role in the activation of the sympathetic nervous system as a neurotransmitter in post-ganglionic synapses. It exhibits its actions through α and β adrenoreceptors (G protein coupled receptors), both in the central nervous system and in the periphery. The “fight or flight response” is a key survival mechanism, and causes a number of physiological changes, such as increased cardiac output and increased glycogenolysis in liver and muscle tissue.

Answer 160

A phaeochromocytoma is a neuroendocrine tumour of the adrenal medulla, specifically the chromaffin cells which secrete adrenaline. This leads to an excess of adrenaline, and constant activation of the “flight or fight response”.

Answer 161

Hence, this can lead to symptoms such as: Tachycardia Hypertension Anxiety Palpitations Weight loss Hyperglycaemia

Answer 162

In some situations it can lead to a hypertensive crisis. Whilst the above symptoms are all possible, the most typical presentation is intermittent attacks of headaches, excessive sweating and tachycardia.

Answer 163

These patients present with extremely high blood pressures, typically greater than 180/120 mmHg. Hypertension can lead to increased pressure in vital circulations, such as in the brain and in the kidney, which can be lethal.

Answer 164

Typically, treatment involves surgical resection of the tumour, however alpha adrenoceptor blockers often need to be given prior to surgery to minimize complications.

Answer 165

Cushings syndrome/ enzyme deficiencies

Answer 166

The zona fasciculata is the middle zone of the adrenal cortex, deep to the zona glomerulosa and superficial to the zona reticularis. It is the thickest of the three adrenal layers, measuring approximately 0.9mm and making up 50% of the mass of the adrenal gland.

Answer 167

The zona fasciculata is made up of parenchymal cells known as spongiocytes, arranged into columns (sometimes called fascicles) with venous sinuses in between.

Answer 168

Blood flows into the adrenal gland from the adrenal arteries, which are branches of the phrenic and renal arteries as well as the aorta. From here, blood flows through the adrenal tissue from superficial to deep, draining into sinusoids in the adrenal medulla and eventually into the central adrenal vein.

Answer 169

The cells of the zona fasciculata secrete the glucocorticoids cortisol and corticosterone. These hormones regulate carbohydrate metabolism, particularly when an individual is in a time of stress (as part of the “fight-or-flight” response).

Answer 170

In an adult human, approximately 10mg of cortisol and 3mg of corticosterone are secreted over a 24-hour period.

Answer 171

The synthesis pathway of the steroids secreted by the zonas of the adrenal gland is complex. Cholesterol is the major precursor for all steroids secreted.

Answer 172

The first step is initiated by the actions of ACTH and angiotensin II activating adenylyl cyclase and phospholipase C respectively. Cholesterol can then be converted to a steroid called pregnenolone via an enzyme of the cytochrome P450 superfamily called cholesterol desmolase. From pregnenolone, all the major secreted mineralocorticoids, glucocorticoids and androgens can be synthesised in a multi-step enzyme-assisted pathway. The metabolites of the synthesis pathway are moved in and out of the mitochondria, the smooth endoplasmic reticulum and the cytoplasm.

Answer 173

It is the presence or lack of specific enzymes in each zona that determines which hormones are secreted. In the zona fasciculata, the enzyme 11β-hydroxylase catalyses the final step of the reaction that forms cortisol and corticosterone. Additionally the secretion of cortisol follows a diurnal pattern with more being secreted in the mornings.

Answer 174

In a steroid-producing adrenal tumour (or anterior pituitary adenoma), large concentrations of glucocorticoids are secreted in the body. When in high concentrations, glucocorticoid steroids activate mineralacorticoid receptors due to the similarity in shape of the receptors. Therefore, a patient with Cushing’s Syndrome will have symptoms of high glucocorticoid secretion (fat build-up on back of neck and around face, wasting of limb muscles with central obesity, purple striae, hyperpigmentation) as well as effects of high mineralocorticoid concentrations (hypertension, hypokalaemia).

Answer 175

Treatment of Cushing’s depends on the underlying cause, for example a pituitary adenoma may be surgically removed, as can a metastatic lung tumour secreting ACTH.

Answer 176

A deficiency in the enzyme 3β-hydroxysteroid dehydrogenase causes an increased secretion of DHEA – a weak androgen that causes masculinisation in females but is not strong enough to drive male genital development alone. As such, male neonates with this deficiency are likely to have hypospadias, where the opening of the urethra is found on the underside of the penis rather than at the tip.

Answer 177

The most common adrenal enzyme deficiency is 21β-hydroxylase deficiency, making up 90% of the deficiency cases. Production of Cortisol and Aldosterone are reduced, causing a raised ACTH secretion. Precursor steroids are converted to androgens which then drive masculinisation, although this may not become apparent until later life. The lack of aldosterone results in massive loss of Na+ which manifests as severe hypovolaemia.

Answer 178

Conn's syndrome

Answer 179

The zona glomerulosa is the outermost layer of the adrenal cortex and is responsible for secreting the mineralocorticoid hormones (i.e., aldosterone), which are important in regulating fluid balance.

Answer 180

The zona glomerulosa is the outermost layer of the adrenal cortex, lying just below the fibrous adrenal capsule. It accounts for around 15% of the thickness of the cortex.

Answer 181

The secretory cells of the zona glomerulosa are arranged in oval-shaped clusters – its name comes from the Latin word glomus, meaning ball. These clusters are divided by connective tissue bands called trabeculae which extend down into the cortex from the adrenal capsule. The blood supply to the secretory cells travels within these trabeculae.

Answer 182

The primary function of the zona glomerulosa is the synthesis of mineralocorticoid hormones, which play an important role in the maintenance of electrolyte and water balance in the body. Mineralocorticoids are steroid hormones, and so are synthesised from cholesterol.

Answer 183

The most important mineralocorticoid is aldosterone, which is responsible for controlling the uptake of Na+ and secretion of K+ in the collecting duct of the renal tubule. Aldosterone acts within the tubule cell to increase the transcription of Na+/K+-ATPase and ENaC (epithelial sodium channels), promoting re-absorption of Na+ and excretion of K+.

Answer 184

The following factors increase the rate of aldosterone production within the zona glomerulosa: Increase in plasma concentration of angiotensin-II Increase in plasma K+ concentration Decrease in plasma pH (acidosis) Decreased blood pressure, as detected by atrial stretch receptors

Answer 185

It is also worth noting that aldosterone secretion follows a diurnal rhythm, with higher levels typically being released during sleep.

Answer 186

Whilst all the above factors are important in the production and secretion of aldosterone, one of the most important is the plasma concentration of angiotensin-II. The release of aldosterone is therefore an important part of the renin-angiotensin-aldosterone system (RAAS) which is fundamental in the long-term regulation of blood pressure.

Answer 187

Conn’s syndrome occurs when patients develop an adenoma (benign tumour) of the zona glomerulosa which secretes excess aldosterone, leading to primary hyperaldosteronism.

Answer 188

This condition is usually asymptomatic, however, some patients will experience muscle cramps, headaches, and lethargy due to electrolyte disturbances.

Answer 189

Most importantly, the increased reabsorption of sodium and water by the kidneys leads to hypertension, which increases the patient’s risk of diseases such as strokes and ischaemic heart disease.

Answer 190

Conn’s syndrome is usually treated by surgical removal of the tumour. The patient may also be given spironolactone (an aldosterone antagonist) to reduce their blood pressure and relieve any symptoms prior to surgery.

Answer 191

Cogenital adrenal hyperplasia

Answer 192

They are composed of an inner medulla and an outer cortex, which is, in turn, divided into three zones. The zona reticularis is the innermost layer of the adrenal cortex. It is responsible for the production and secretion of androgens.

Answer 193

The zona reticularis is the innermost layer of the adrenal cortex, lying just above the adrenal medulla. It comprises of cylindrical masses of epithelia arranged in an irregular, net-like pattern. In comparison to the zona fasciculata, the cells contain fewer vacuoles as well as appearing more irregular and smaller in size.

Answer 194

Adrenal androgens are regulated by ACTH (adrenocorticotropic hormone) secreted from the anterior pituitary gland which is stimulated by the release of CRH (corticotrophin-releasing hormone) from the hypothalamus.

Answer 195

The zona reticularis is the site of biosynthesis of androgen precursors such as dehydroepiandrosterone (DHEA) and androstenedione from cholesterol. These androgens are released into the bloodstream and transported to gonads where they are converted into testosterone or oestrogen. These are largely responsible for the normal development of sexual characteristics during puberty. Further information on the effects of adrenal androgens during puberty can be found here. In postmenopausal women, the conversion of adrenal androgens to oestrogen is the only source of oestrogen synthesis and hence is a significant source.

Answer 196

However, the adrenal androgens along with their potent metabolites such as testosterone do not negatively feedback to ACTH or CRH. Therefore, in cases where there is a dramatic increase in ACTH, this leads to excess production of androgens which cannot be regulated.

Answer 197

Congenital adrenal hyperplasia (CAH) can result from one of several autosomal recessive diseases. There is typically a mutation in an enzyme mediating one of the steps necessary in the production of mineralocorticoids or glucocorticoids from cholesterol. This results in a lack of mineralocorticoids and glucocorticoids, as well as an excess of testosterone and its derivatives.

Answer 198

Clinical features can include: Virilisation of female babies Neonatal salt-losing crisis Hypotension Hypoglycaemia Hyponatraemia

Answer 199

It may present as a milder form in later life, however, in an acute situation, urgent confirmation is needed. Babies born with CAH will show high levels of testosterone, androstenedione and ACTH.

Answer 200

Treatment requires the replacement of the missing glucocorticoids and mineralocorticoids, as well as suppression of ACTH. This allows normalisation of the androgen levels. Finally, long-term follow-up is necessary and eventually genetic counselling, as these conditions are inherited.

Answer 201

Hyper/Hypoparathyroidism

Answer 202

The parathyroid glands are small endocrine glands located in the anterior neck. They are responsible for the production of parathyroid hormone (PTH).

Answer 203

The parathyroid glands are located on the posterior, medial aspect of each lobe of the thyroid gland.

Answer 204

Anatomically, the glands can be divided into two pairs: Superior parathyroid glands – Derived embryologically from the fourth pharyngeal pouch. They are usually located at the level of the inferior border of the cricoid cartilage. Inferior parathyroid glands – Derived embryologically from the third pharyngeal pouch. They are usually located near the inferior poles of the thyroid gland. However in 1-5% of people they can be found deep in the superior mediastinum.

Answer 205

There are two types of cells within the parathyroid gland, the chief cells and the oxyphil cells. Note that histologically fat cells (adipose cells) are also seen within the parathyroid gland.

Answer 206

Chief cells – The role of this cell type is to secrete parathyroid hormone. They contain prominent golgi apparatus and endoplasmic reticulum to allow for the synthesis and secretion of PTH. The chief cells are the smaller of the two cell types, however, they are more abundant.

Answer 207

Oxyphil cells – These cells are much larger but less abundant than chief cells. Their purpose is unknown. It is interesting to note however that the number of oxyphil cells increases with age and few are seen before puberty.

Answer 208

The synthesis of PTH begins within the rough endoplasmic reticulum, where pre-pro-PTH is produced. Pre-pro-PTH is 115 amino acids long and consists of a biologically active sequence, a C terminal fragment sequence, a pro sequence and a signal sequence. The signal sequence is cleaved within the lumen of the endoplasmic reticulum, leaving pro-PTH. After transfer to the golgi apparatus the pro sequence is also cleaved, resulting in the production of mature PTH, which can then be stored in secretory granules for release.

Answer 209

PTH has three main actions, all of which act to increase calcium levels in the body; Increased bone resorption Increased reabsorption in the kidney Vitamin D synthesis

Answer 210

– PTH acts directly on bone to increase bone resorption. It induces cytokine secretion from osteoblasts that act on osteoclast cells to increase their activity. Osteoclasts are responsible for the breakdown of bone and thus an increase in their activity leads to increased bone breakdown. This leads to an increase in calcium in the extracellular fluid.

Answer 211

– PTH increases the amount of calcium absorbed from the loop of Henle and distal tubules, however, the mechanism is not fully understood. Additionally, PTH increases the rate of phosphate excretion which is very important to prevent to formation of calcium phosphate kidney stones.

Answer 212

– Although PTH does not actively increase the absorption of calcium from the gut it stimulates the formation of vitamin D, which subsequently increases absorption from the gut.

Answer 213

Like most endocrine organs, the parathyroid gland is controlled by a negative feedback loop. Chief cells have a unique G-protein calcium receptor (CaR) on their surface, which regulates this.

Answer 214

When calcium levels in the blood are elevated, PTH production must be stopped in order to prevent further elevation of calcium which could lead to hypercalcaemia. Calcium binds to the G protein CaR which subsequently leads to the production of a molecule called phosphoinositide. The activation of this molecule prevents PTH secretion thus calcium is deposited back into the bones. Furthermore, as mentioned above, PTH stimulates vitamin D synthesis. Vitamin D also acts directly on the parathyroid gland to decrease the transcription of the PTH gene hence less PTH is synthesised. When calcium is reduced, the reverse occurs. Lowered calcium means reduced stimulation of CaR and decreased phosphoinositide. Subsequently, PTH secretion is not inhibited. Decreased vitamin D results in upregulation of PTH gene transcription thus more PTH is synthesised. Note: Elevated phosphate lowers free calcium in the blood and inhibits the formation of vitamin D.

Answer 215

Hyperparathyroidism is the over-activity of the parathyroid glands and can be classed as primary, secondary, tertiary or malignant depending on the underlying cause.

Answer 216

Primary hyperparathyroidism is a result of direct alterations to the parathyroid gland such as a benign tumour, hyperplasia or very rarely parathyroid cancer. The excess secretion of PTH leads to elevated calcium in the blood which can cause signs of hypercalcaemia, osteoporosis, osteitis fibrosa cystica and hypertension.

Answer 217

Secondary hyperparathyroidism is a physiologically elevated PTH due to reduced calcium levels. This could be caused by chronic renal failure or decreased vitamin D intake.

Answer 218

Tertiary hyperparathyroidism occurs after prolonged secondary hyperparathyroidism. This is due to structural changes seen within the gland. To distinguish between secondary and tertiary hyperparathyroidism, a blood test will be carried out. Elevated calcium levels indicate tertiary hyperparathyroidism.

Answer 219

Malignant hyperparathyroidism can be caused by some tumours, such as bronchial squamous cell carcinomas, as they produce a protein called parathyroid hormone related protein (PTHrP). PTHrP can mimic PTH due to the similarity in their structure which ultimately results in elevated calcium in the blood. However, PTH will be reduced due to negative feedback to the parathyroid gland itself.

Answer 220

Hypoparathyroidism is the underactivity of the parathyroid gland and can be classed as primary or secondary depending on the cause.

Answer 221

Primary hypoparathyroidism is a result of decreased PTH secretion due to gland failure. This results in symptoms of hypocalcaemia and patients will often need calcium supplementation.

Answer 222

Secondary hypoparathyroidism is commonly caused by surgical removal of the parathyroid glands. This is often accidental due to the fact that the inferior parathyroid glands are difficult to locate.

Answer 223

Hyper/Hypothyroidism

Answer 224

The thyroid gland is an endocrine organ found in the neck, it is responsible for regulating the body’s metabolic rate via hormones it produces. I

Answer 225

The thyroid gland is a ductless alveolar gland found in the anterior neck, just below the laryngeal prominence (Adam’s apple). It is roughly butterfly-shaped, with two lobes wrapping around the trachea and connected in the middle by an isthmus. The thyroid gland is not usually palpable. It is supplied by superior and inferior thyroid arteries, drained via superior, middle and inferior thyroid veins and has a rich lymphatic system.

Answer 226

The function of the Thyroid gland is to produce and store thyroid hormones.

Answer 227

Thyroid epithelia form follicles filled with colloid – a protein-rich reservoir of the materials needed for thyroid hormone production. These follicles range in size from 0.02-0.3mm and the epithelium may be simple cuboidal or simple columnar. In the spaces between the follicles, parafollicular cells can be found. These cells secrete calcitonin, which is involved in the regulation of calcium metabolism in the body.

Answer 228

The thyroid gland is one of the main regulators of metabolism. T3 and T4 typically act via nuclear receptors in target tissues and initiate a variety of metabolic pathways. High levels of them typically cause these processes to occur faster or more frequently.

Answer 229

Basal Metabolic Rate Gluconeogenesis Glycogenolysis Protein synthesis Lipogenesis Thermogenesis This is achieved in a number of ways, such as increasing the size and number of mitochondria within cells, increasing Na-K pump activity and increasing the presence of β-adrenergic receptors in tissues such as cardiac muscle.

Answer 230

There are six steps in the synthesis of thyroid hormone, and you can remember them using the mnemonic ATE ICE: 1. Active transport of iodide into the follicular cell via the sodium-iodide symporter (NIS). This is actually secondary active transport, and the sodium gradient driving it is maintained by a sodium-potassium ATPase. 2.Thyroglobulin (Tg), a large protein rich in tyrosine, is formed in follicular ribosomes and placed into secretory vesicles. 3. Exocytosis of thyroglobulin into the follicle lumen, where it is stored as colloid. Thyroglobulin is the scaffold upon which thyroid hormone is synthesised. 4. Iodination of the thyroglobulin. Iodide is made reactive by the enzyme thyroid peroxidase. Iodide binds to the benzene ring on tyrosine residues of thyroglobulin, forming monoiodotyrosine (MIT) then diiodotyrosine (DIT). 5. Coupling of MIT and DIT gives the triiodothyronine (T3) hormone and coupling of DIT and DIT gives the tetraiodothyronine (T4) hormone, also known as thyroxine. 6. Endocytosis of iodinated thyroglobulin back into the follicular cell. Thyroglobulin undergoes proteolysis in lysosomes to cleave the iodinated tyrosine residues from the larger protein. Free T3 or T4 is then released, and the thyroglobulin scaffold is recycled

Answer 231

T3 and T4 are the active thyroid hormones. They are fat soluble and mostly carried by plasma proteins – thyronine binding globulin (TBG) and albumin. While T3 is the more potent form, it also has a shorter half-life due to its lower affinity for the binding proteins. Less than 1% of T3 and T4 is unbound free hormone. At the peripheries, T4 is deiodinated to the more active T3. T3 and T4 are deactivated by removing iodine. This happens in the liver and kidney. As T4 has a longer half-life, it is used in the treatment of hypothyroidism over T3 as its plasma concentrations are easier to manage.

Answer 232

Thyroid hormones are released as part of the hypothalamic-pituitary-thyroid axis. The hypothalamus detects a low plasma concentration of thyroid hormone and releases thyrotropin-releasing hormone (TRH) into the hypophyseal portal system. TRH binds to receptors found on thyrotrophic cells of the anterior pituitary gland, causing them to release thyroid stimulating hormone (TSH) into the systemic circulation. TSH binds to TSH receptors on the basolateral membrane of thyroid follicular cells and induces the synthesis and release of thyroid hormone.

Answer 233

Hyperthyroidism is the medical term for an overactive thyroid gland. One common cause of hyperthyroidism is Grave’s Disease – an autoimmune condition where antibodies are produced that stimulate the TSH receptors on follicular cells. It affects roughly 1% of the population and is 10 times more common in women than in men.

Answer 234

Patients may present with heat intolerance, weight loss, tachycardia, nervousness, increased sweating, exophthalmos and increased bowel movements. Hyperthyroidism can be treated with carbimazole which inhibits iodine binding to thyroglobulin.

Answer 235

Hypothyroidism is an underactive thyroid gland. One common cause of hypothyroidism is Hashimoto’s disease – an autoimmune condition where thyroid follicles are destroyed or antibodies are produced that block the TSH receptor on follicle cells.

Answer 236

Like hyperthyroidism, roughly 1% of the population is affected with it being 10 times more common in women than in men. In the developing world, the most common cause of hypothyroidism is iodine deficiency.

Answer 237

Patients can present with cold intolerance, weight gain, bradycardia, poor concentration, myxoedema, dry skin, some hair loss and constipation. Hypothyroidism can be treated with oral T4 tablets (100-200 µg/day), to replace the hormone that is not being produced by the body.

Answer 238

One way to remember the associated diseases with hyperthyroidism and hypothyroidism is to look at the prominent vowels in each: hypErthyroidism is caused by gravE‘s disease, whereas hypOthyroidism is caused by hashimOtO‘s disease.