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Endocrinology 

Endocrinology
Chapter:
Endocrinology
Author(s):

Arisudhan Anantharachagan

, Ippokratis Sarris

, and Austin Ugwumadu

DOI:
10.1093/med/9780199592333.003.0006
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Contents

Sex hormones

  1. 1. The ovary secretes 11 hormones (by definition a ‘hormone’ is a substance produced and secreted by a gland or from cell(s)/tissues) into the blood stream that circulates and acts at a target site remote from the source. Thus ovarian prostaglandins are strictly paracrine substances (Fig. 6.1)

  2. 2. Androgens in females are produced by

    • Ovary = 25%

    • Adrenal glands = 25%

    • Peripheral conversion of androstenedione = 50%

  3. 3. Markers of corpus luteum function are

    • 17-hydroxyprogesterone (not secreted by placenta)

    • Relaxin

  4. 4. Oestrogen

    • 3 naturally occurring oestrogens

      1. i. Oestrone (E1) – produced in menopause

      2. ii. Oestradiol (E2) – primary oestrogen in non-pregnant women

      3. iii. Oestriol (E3) – primary oestrogen in pregnancy

    • Oestradiol is the most active of the natural oestrogens

    • Produced by

      1. i. Developing follicles in ovary

      2. ii. Corpus luteum

      3. iii. Placenta

      4. iv. Liver

      5. v. Adrenal glands

      6. vi. Breast

      7. vii. Adipocytes

    • In plasma binds to

      1. i. Sex hormone-binding globulin (SHBG)

      2. ii. Albumin

    • Metabolized in the liver to oestrone and oestriol (Fig. 6.2)

    • Excreted in the kidney as oestriol glucuronide

    • Has 2 main receptors subtypes (other receptor subtypes exist)

      1. i. α‎ (found in endothelial cells)

      2. ii. β‎

    • Work by genomic expression

  5. 5. Oestrogen functions

    • Cardiovascular

      1. i. Vasodilator (via an increase of NOS leading to an increase in NO)

      2. ii. Prevents atherosclerosis

    • Bone

      1. i. Maintenance of bone density – decreases resorption of bone by antagonizing PTH

      2. ii. Fusion of epiphyseal plates

    • Increases clotting by

      1. i. Increasing levels of factors II, VII, IX, X, and plasminogen

      2. ii. Decreasing anti-thrombin 3

      3. iii. Increase platelet adhesiveness

    • Gastrointestinal

      1. i. Decrease motility of bowel

      2. ii. Increases bile production

    • Metabolic changes

      1. i. Increases high-density lipoprotein (HDL) levels

      2. ii. Decreases low-density lipoprotein (LDL) levels

      3. iii. Decreases cholesterol levels

      4. iv. Increases TAG synthesis

    • Stimulates pigmentation of skin by increasing phaeomelanin

      1. i. Nipple

      2. ii. Areola

      3. iii. Genital regions

    • Proliferation of endometrium

    • Causes Na+ and H2O retention by kidney

  6. 6. Progesterone

    • Sources

      1. i. Dioscorea mexicana (a type of plant)

      2. ii. Corpus luteum

      3. iii. Adrenal glands

      4. iv. Placenta

    • Stored in adipose tissue

    • In plasma binds to

      1. i. Corticosteroid-binding globulin (CBG)

      2. ii. Albumin

    • Metabolized in liver to pregnanediol

    • Excreted by kidney as pregnanediol glucuronide

    • Levels

      1. i. Pre-ovulation = <2 ng/mL

      2. ii. Post-ovulation = 5 ng/mL

      3. iii. At term = 100–200 ng/mL

    • At term placenta produces 250 mg/day progesterone

  7. 7. Progesterone functions

    • Uterus, cervix, and vagina

      1. i. Converts proliferative to secretory endometrium

      2. ii. Withdrawal of progesterone causes menstruation

      3. iii. Thickens cervical mucus

      4. iv. Inhibits uterine contraction until term

    • Increases core temperature following ovulation

    • Smooth muscle relaxant

    • Catabolic (thus causes an increase in appetite)

    • Increases aldosterone production (leading to Na+ and H2O retention)

    • Reduces pressor responsiveness to angiotensin-2

    • Respiration

      1. i. Increased ventilator response to CO2

      2. ii. Decreased arterial and alveolar pCO2

    • Inhibits lactation during pregnancy

    • Neuroprotective (is being investigated in treatment of multiple sclerosis; demyelination halts during pregnancy)

  8. 8. Inhibins

    • Are peptide members of transforming growth factor (TGF)-β‎ family

    • There are 2 forms of inhibin

      1. i. Inhibin A

      2. ii. Inhibin B

    • Are secreted by ovarian granulosa cells

    • Selectively inhibit FSH secretion but not LH secretion

    • Produced in

      1. i. Gonads

      2. ii. Pituitary gland

      3. iii. Placenta

    • Inhibin A is part of the quad screen test in the first trimester of pregnancy – elevated levels of inhibin A, elevated β‎-hCG, decreased α‎-fetoprotein (AFP), and decreased oestriol are suggestive of Down's syndrome

  9. 9. Activins

    • Are peptide members of TGF-β‎ family

    • Are derived from

      1. i. Ovarian granulosa cells

      2. ii. Pituitary gonadotropes

    • Functions

      1. i. Augment FSH action in the ovary

      2. ii. Stimulate FSH secretion in the pituitary

      3. iii. Inhibit prolactin, growth hormone, and ACTH responses

  10. 10. Relaxin

    • Produced by

      1. i. Corpus luteum

      2. ii. Placenta

      3. iii. Breast

      4. iv. Prostate

    • Relaxes pelvic ligaments in pregnancy

    • Plays a role in cervical dilatation

    • Inhibit contractility of myometrium

  11. 11. Testes secretes

    • 3 main hormones

      1. i. Testosterone

      2. ii. DHT – strictly it is a paracrine hormone

      3. iii. Oestradiol

    • Minor hormones

      1. i. DHEA

      2. ii. Androstenedione

      3. iii. Oestrone

      4. iv. Pregnenolone

      5. v. Progesterone

      6. vi. 17α‎-hydroxypregnenolone

      7. vii. 17α‎-hydroxyprogesterone

  12. 12. Testosterone

    • Is an anabolic steroid

    • Secreted by

      1. i. Testis (Leydig cells)

      2. ii. Ovary (theca cells)

      3. iii. Adrenals (zona reticularis)

      4. iv. Placenta (cyto or syncytiotrophoblastic cells)

    • In serum exists

      1. i. Freely (2% of testosterone)

      2. ii. Bound to

        • SHBG (60% of testosterone)

        • Albumin (38% of testosterone)

    • Effects of testosterone on tissue are via 2 mechanisms

      1. i. By activation of nuclear androgen receptors

      2. ii. By aromatization of testosterone to oestradiol (occurs in bone and brain)

    • Is converted to DHT by 5α‎-reductase

    • Excreted in urine as 17-ketosteroid

  13. 13. 5α‎-reductase

    • Consist of 2 isoforms

    • Is produced in

      1. i. Skin

      2. ii. Seminal vesicles

      3. iii. Prostate

      4. iv. Epididymis

      5. v. Brain

    • Deficiency results in

      1. i. Low DHT levels

      2. ii. Increased testosterone levels

      3. iii. Gynaecomastia

      4. iv. Ambiguous genitalia at birth (DHT is necessary for development of male genitalia in utero)

  14. 14. SHBG

    • Is a glycosylated dimer protein

    • Synthesized by liver

    • Gene located on chromosome 17

    • Levels are higher in females

    • SHBG levels are influenced by the following (Box 6.1):

Hypothalamic hormones

  1. 1. Hypothalamic hormones (Box 6.2)

  2. 2. Paraventricular nucleus (PVN)

    • Adjacent to 3rd ventricle

    • Within blood–brain barrier

    • Has 2 types of neurones

      1. i. Magnocellular

      2. ii. Parvocellular

    • Magnocellular neurones produce

      1. i. Oxytocin

      2. ii. ADH

    • Parvocellular neurones produce

      1. i. CRH

      2. ii. ADH

      3. iii. TRH

  3. 3. Dopamine

    • Is a prolactin-inhibitory hormone

    • Has 5 receptor types

    • Produced in

      1. i. Substantia nigra

      2. ii. Arcuate nucleus

      3. iii. Medulla of adrenal glands

    • Functions

      1. i. Plays an important role in behaviour, cognition, and voluntary movements

      2. ii. Inhibits prolactin

      3. iii. Inotropic

      4. iv. Chronotropic

      5. v. Induces vomiting via chemoreceptor trigger zone (metoclopramide is a dopamine receptor antagonist)

    • Does not cross blood–brain barrier

    • Is metabolized by

      1. i. Catechol-O-methyl transferase (COMT)

      2. ii. Monoamine oxidase (MAO)

  4. 4. GnRH

    • Release is pulsatile

      1. i. GnRH pulsatile frequency is high in follicular phase

      2. ii. GnRH pulsatile frequency slows in late luteal phase

    • Half life = 2–4 min

    • Gene is located on chromosome 8

    • Activity is low in childhood

    • Insulin increases GnRH activity

    • Prolactin decreases GnRH activity

  5. 5. Somatostatin

    • Is a GHRH inhibitor

    • Secreted by

      1. i. Stomach

      2. ii. Intestines

      3. iii. Pancreatic cells (D-cells)

      4. iv. Thyroid (parafollicular cells)

      5. v. Periventricular nucleus

    • Functions are inhibitory

      1. i. Inhibits growth hormone (GH)

      2. ii. Inhibits TSH

      3. iii. Suppresses release of gastrointestinal hormones

        • Gastrin

        • CCK

        • Secretin

        • Vasoactive intestinal peptide (VIP)

        • Motilin

        • Insulin

        • Glucagon

      4. iv. Decreases gastric emptying, blood flow, and intestinal contractions

      5. v. Suppresses release of pancreatic hormones

  6. 6. Thyrotrophin-releasing hormone (TRH)

    • Stimulates release of

      1. i. Prolactin

      2. ii. TSH

    • Secreted by paraventricular nuclei

  7. 7. Melatonin

    • Is synthesized from serotonin

    • Is associated with biorhythms

    • Inhibits gonadotrophins

    • Diurnal

    • Produced in

      1. i. Pineal gland

      2. ii. Retina

      3. iii. Lens of eye

      4. iv. GIT

      5. v. Suprachiasmatic nucleus

    • Melatonin secretion increases in response to

      1. i. Hypoglycaemia

      2. ii. Darkness

Pituitary gland hormones

  1. 1. The 6 anterior pituitary hormones can be classified into 3 groups (Box 6.3)

  2. 2. FSH

    • Is a glycoprotein

    • Released in response to GnRH

    • Structure has 2 subunits

      1. i. α‎ (gene located on chromosome 6)

      2. ii. β‎ (gene located on chromosome 11)

    • Functions

      1. i. Stimulates maturation of germ cells

      2. ii. In females – stimulates ovary to produce Graafian follicle

      3. iii. In males – induces Sertoli cells to synthesize and secrete inhibin

    • High levels of FSH are due to

      1. i. Premature menopause

      2. ii. Reduced ovarian reserve

      3. iii. Gonadal dysgenesis

      4. iv. Castration

      5. v. Swyer's syndrome

      6. vi. CAH

    • Half life = 3–4 hours

    • Receptors are only in granulosa cells

  3. 3. LH

    • Is a heterodimeric glycoprotein

    • Structure has 2 subunits

      1. i. α‎ (gene located on chromosome 6)

      2. ii. β‎ (gene located on chromosome 19)

    • α‎-subunit has 92 amino acids and is identical to the α‎-subunit of

      1. i. TSH

      2. ii. FSH

      3. iii. hCG

    • In females

      1. i. Triggers ovulation

      2. ii. Prevents apoptosis of corpus luteum

      3. iii. Stimulates oestrogen and progesterone production

    • In males – stimulates Leydig cells to produce testosterone

    • Low LH levels are due to

      1. i. Kallmann's syndrome

      2. ii. Hypothalamic suppression

      3. iii. Hypopituitarism

      4. iv. Hyperprolactinaemia

    • High levels of LH are due to

      1. i. Premature menopause

      2. ii. Gonadal dysgenesis

      3. iii. Castration

      4. iv. Polycystic ovary syndrome (PCOS)

      5. v. Swyer's syndrome

      6. vi. CAH

    • Surge

      1. i. Is biphasic

      2. ii. Ovulation occurs

        • 36 h after LH surge

        • 16–26 h after peak of LH

      3. iii. Causes

        • Prostaglandin production

        • Progesterone secretion from corpus luteum

        • Resumption of meiosis by oocyte

    • Half life = 20 min

    • Gonadotrophins reach 2 peaks at

      1. i. 20 weeks in fetal life

      2. ii. 1–2 months in infancy

    • LH and testosterone increases in the first 3–6 months of life

    • Receptors are found in

      1. i. Granulosa cells

      2. ii. Theca cells

  4. 4. Prolactin

    • Is a peptide hormone

    • Has a molecular weight of 24 000 Daltons

    • Consists of 199 amino acids

    • Structure is similar to

      1. i. GH

      2. ii. Placental lactogen

    • Gene located on chromosome 6

    • Cycle is

      1. i. Diurnal

      2. ii. Ovulatory

    • Functions

      1. i. Lactogenesis

      2. ii. Promotes breast development

    • Is also responsible for decreasing serum levels of

      1. i. Oestrogen

      2. ii. Testosterone

    • Also produced by

      1. i. Decidua

      2. ii. Breast

      3. iii. Brain

      4. iv. Immune system

    • Factors affecting prolactin secretion (Table 6.1)

  5. 5. GH

    • Most of GH effects are mediated by IGF

    • Gene located on chromosome 17

    • Consists of 191 amino acids

    • Functions are

      1. i. Mainly anabolic

        • Increases protein synthesis

        • Decreases protein catabolism

      2. ii. Lipolysis

      3. iii. Anti-insulin actions

    • Factors affecting GH secretion (Table 6.2)

  6. 6. ACTH

    • Released in response to CRH from hypothalamus

    • Can be produced by cells of the immune system

      1. i. T-cell

      2. ii. B-cell

      3. iii. Macrophage

    • Stimulates production of steroids from the adrenals

    • Released in circadian rhythm – highest in the morning

    • Derived from pro-opiomelanocortin (POMC)

    • By-products are

      1. i. melanocyte-stimulating hormone (MSH)

      2. ii. Endorphins

  7. 7. Oxytocin

    • Is a nanopeptide (consists of 9 amino acids)

    • Produced in supra-optic and paraventricular nucleus of hypothalamus

    • Stored in posterior pituitary

    • Involved in smooth muscle contraction of

      1. i. Uterine muscle

      2. ii. Myoepithelial cells surrounding breast alveoli (letdown reflex)

    • Oxytocin receptor

      1. i. Is a G-protein-coupled receptor which requires Mg2+ and cholesterol

      2. ii. Also found in brain and spinal cord

  8. 8. ADH

    • Is a nanopeptide

    • Also known as vasopressin

    • Is derived from pre-pro-hormone precursors synthesized in the hypothalamus

    • Released when body fluid volume decreases

    • Functions

      1. i. Vasoconstrictor

      2. ii. Increases urine osmolarity

      3. iii. Increases reabsorption of H2O at DCT and collecting duct

      4. iv. Na+ reabsorption in ascending loop of Henle

      5. v. Implicated in memory formation

Table 6.1 Factors affecting prolactin secretion

Hyperprolactinaemia

Physiological

Pharmacological

Pathological

Pregnancy

TRH

Pituitary tumour

Lactation

Oestrogen

Chest wall lesions

Exercise

Dopamine antagonists

Spinal cord lesions

Stress

MAOI

Hypothyroidism

Sleep

Cimetidine

Chronic renal failure

Hypoglycaemia

Verapamil

Liver failure

Stalk syndrome

Hypoprolactinaemia

Pharmacological

Pathological

Dopamine agonists

Sheehan's syndrome

Hypopituitarism

Bulimia

Table 6.2 Factors affecting GH secretion

Raised serum GH

Physiological

Pharmacological

Pathological

Sleep

GHRH

Chronic renal failure

Stress

Oestrogen

Anorexia nervosa

Exercise

Adrenergic agonist

Hypoglycaemia

Dopamine agonist

Decreased serum GH

Physiological

Pharmacological

Pathological

Hyperglycaemia

Somatostatin

Obesity

Elevated free fatty acids

Progesterone

Glucocorticoids

Thyroid gland hormones

  1. 1. Action of thyroid hormone

    • Increases activity of Na+-K+ ATPase (in all tissue except brain, spleen, and testis) causing

      1. i. Increased O2 consumption

      2. ii. Heat production

    • Decreases superoxide dismutase levels

    • Increases β‎-adrenergic receptors in

      1. i. Myocardium (leading to positive ionotropic and chronotropic effects)

      2. ii. Skeletal muscles

      3. iii. Adipose tissue

      4. iv. Lymphocytes

    • Blood

      1. i. Increases EPO

      2. ii. Increases erythropoiesis

      3. iii. Increases DPG content of erythrocyte

    • Bone

      1. i. Increases bone turnover

      2. ii. Increases bone resorption, leading to osteopenia

    • Metabolism

      1. i. Increases hepatic gluconeogenesis

      2. ii. Increases glycogenolysis

      3. iii. Increases lipolysis

  2. 2. Thyroid hormone production

    • I2 absorbed from bloodstream via iodide trapping

    • Thyroglobulin synthesis

    • Iodination (I2 binds to tyrosine contained in thyroglobulin)

      1. i. I2 + tyrosine = monoiodotyrosine (MIT)

      2. ii. I2 + MIT = diiodotyrosine (DIT)

    • Coupling of iodinated residues

      1. i. MIT + DIT = T3

      2. ii. DIT + DIT = T4

    • Stored in colloid of the follicular cells

  3. 3. Thyroid hormones

    • Bound to

      1. i. Thyroid-binding globulin (TBG) = 70%

      2. ii. Albumin = 15%

      3. iii. Pre-albumin (transthyretin) = 15%

    • T4

      1. i. Amount is approximately 20 times more than T3

      2. ii. Half-life = 7 days

    • T3 is

      1. i. The active component

      2. ii. Half-life = 1 day

    • rT3

      1. i. Is inactive

      2. ii. Half life = 4 h

  4. 4. Changes in pregnancy (Fig. 6.3)

Figure 6.3 Thyroid changes in pregnancy

Figure 6.3
Thyroid changes in pregnancy

Adrenal hormones

  1. 1. Adrenal hormones are derived from the

    • Adrenal cortex and

    • Adrenal medulla

Adrenal cortex

  1. 1. Mediates the stress response via the production of

    • Mineralocorticoids

    • Glucocorticoids

  2. 2. Consists of 3 layers

    • Zona glomerulosa (produces mineralocorticoids)

    • Zona fasciculata (produces glucocorticoids)

    • Zona reticularis (produces weak androgens)

  3. 3. All adrenocortical hormones are synthesized from cholesterol

  4. 4. Glucocorticoids include

    • Cortisol

    • Corticosterone

  5. 5. Glucocorticoid actions

    • Protein catabolism

      1. i. Inhibit DNA synthesis

      2. ii. Inhibit RNA and protein synthesis (except in the liver)

    • Formation of ATP

    • Metabolism

      1. i. Increases gluconeogenesis

      2. ii. Inhibits peripheral glucose usage

      3. iii. Increases lipolysis

    • Connective tissue and bone

      1. i. Inhibits fibroblasts

      2. ii. Loss of collagen

      3. iii. Increases bone resorption

    • Renal

      1. i. Increases excretion of Na+ and water

      2. ii. Increases GFR

    • Increases secretion of stomach acid

    • Blood

      1. i. Increases neutrophil count

      2. ii. Decreases lymphocyte count

  6. 6. Aldosterone

    • Is a mineralocorticoid

    • Has 21 carbon atoms

    • Is part of the renin–angiotensin system

    • Functions

      1. i. Reabsorption of Na+ from DCT and collecting ducts

      2. ii. Excretion of H+ and K+ via kidneys

      3. iii. Acts on posterior pituitary to release ADH

    • Secretion is regulated by

      1. i. Renin–angiotensin system

      2. ii. Sympathetic nerves

      3. iii. Juxtaglomerular apparatus

      4. iv. Carotid artery baroreceptors

      5. v. Plasma concentration of K+

      6. vi. Plasma concentration of Na+

  7. 7. During adrenarche

    • Adrenal androgen production starts at

      1. i. Males = 7–9 years old

      2. ii. Females = 6–7 years old

    • The adrenal cortex secretes weak androgens

      1. i. DHEA

      2. ii. Dehydroepiandrosterone sulphate (DHEAS)

      3. iii. Androstenedione

Adrenal medulla

  1. 1. Is composed mainly of chromaffin cells

  2. 2. Adrenal medulla cells are modified neural crest cells which did not complete their development to postganglionic neurones, but retain the same functions

  3. 3. Synthesizes

    • Adrenaline

    • Noradrenaline

    • Dopamine

  4. 4. Adrenaline

    • Synthesis: Tyrosine → L-DOPA → dopamine → noradrenaline → adrenaline

    • Actions

      1. i. Lipolysis

      2. ii. Glycogenolysis

      3. iii. Salt and water balance

      4. iv. Vasoconstriction

      5. v. GIT – relaxes smooth muscle

      6. vi. Increases plasma levels of

        • Insulin

        • Renin–angiotensin system

    • Adrenaline acts on α‎ and β‎ receptors

    • Noradrenaline acts only on α‎ receptors

    • The dominant fetal catecholamine is l-DOPA

    • Metabolized by

      1. i. MAO

      2. ii. COMT

Renin–angiotensin system

  1. 1. Juxtaglomerular apparatus in kidney

    • Composed of

      1. i. Juxtaglomerular cells of afferent arterioles

      2. ii. Macula densa (cells on ascending loop of Henle)

    • Regulates renin secretion

  2. 2. Renin

    • Also known as angiotensinogenase

    • Secreted by juxtaglomerular cells in response to

      1. i. Decreased arterial blood pressure

      2. ii. Decrease Na+ levels in plasma

    • Renin cleaves angiotensinogen to form angiotensin 1

    • Renin inhibitors are used to treat hypertension

    • Synthesis (Fig. 6.4)

  3. 3. Angiotensinogen

    • Secreted by liver

    • Production is increased by

      1. i. Oestrogen

      2. ii. Glucocorticoids

  4. 4. Angiotensin

    • Synthesis

      1. i. Angiotensinogen → angiotensin 1 (catalyst = renin)

      2. ii. Angiotensin 1 → angiotensin 2 (catalyst = ACE)

    • Function

      1. i. Vasoconstriction

      2. ii. Stimulates aldosterone secretion

  5. 5. ACE

    • Found in

      1. i. Endothelial cells of the pulmonary capillaries

      2. ii. Brain

      3. iii. Glomeruli

    • Also catalyses

      1. i. Bradykinin breakdown

      2. ii. Enkephalin breakdown

      3. iii. Substance P breakdown

Pancreatic hormones

  1. 1. Insulin actions

    • Anabolic effects

      1. i. Glycogen synthesis

      2. ii. TAG synthesis

    • Inhibits catabolism

      1. i. Inhibits glycogenolysis

      2. ii. Inhibits ketogenesis

      3. iii. Inhibits gluconeogenesis

    • Stimulates glucose uptake into

      1. i. Muscle

      2. ii. Adipose tissue

  2. 2. Insulin antagonists

    • Glucagon

    • Cortisol

    • Growth hormone

    • Adrenaline

    • Oestrogen

    • Thyroid hormone

    • Prolactin

    • Human placental lactogen (responsible for the insulin resistance of pregnancy)

  3. 3. Glucagon

    • Main target tissue = liver

    • Actions

      1. i. Glycogenolysis

      2. ii. Inhibits glycogen synthesis

      3. iii. Gluconeogenesis

      4. iv. Lipolysis

      5. v. Ionotropic

      6. vi. Causes release of

        • Insulin

        • Catecholamines

Endocrine diseases

  1. 1. Syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH)

    • Clinical features

      1. i. Hyponatraemia

      2. ii. Hypo-osmolality of plasma (<280 mOsm/kg)

      3. iii. Excessive renal excretion of Na+ (>20 mEq/L)

      4. iv. Hypervolaemia

      5. v. Absence of oedema

      6. vi. Normal renal function

      7. vii. Normal adrenal function

    • Aetiology

      1. i. Tumour – oat cell carcinoma

      2. ii. CNS disease

      3. iii. Respiratory disease

      4. iv. Myxoedema

      5. v. Porphyria

      6. vi. Drugs

        • Vinblastine

        • SSRIs

        • Thiazide

        • Carbamazepine

      7. vii. Trauma

      8. viii. Infection

      9. ix. Surgery

    • Treatment

      1. i. Fluid restriction (1 L/day)

      2. ii. Diuretics

      3. iii. Demeclocycline (is a tetracycline which induces nephrogenic diabetes insipidus)

      4. iv. Conivaptan (is an ADH inhibitor)

      5. v. Hyponatraemia can be corrected by using hypertonic saline 5% (rapid rise in sodium levels may cause central pontine myelinolysis; aim for maximum increase of 12 mEq/L/day of Na+)

  2. 2. Diabetes insipidus (DI)

    • Is a disorder resulting from deficient ADH action

    • Treatment = desmopressin

    • Classification of DI (Box 6.4)

    • Also associated with pregnancy-related diseases such as

      1. i. Pre-eclampsia

      2. ii. HELLP syndrome

      3. iii. Acute fatty liver of pregnancy (due to activation of hepatic vasopressinase)

  3. 3. Hypothyroidism

    • Can result in congenital hypothyroidism in the fetus, known as cretinism

    • Aetiology (Box 6.5)

    • Associated with

      1. i. Pernicious anaemia

      2. ii. Sjogren's syndrome

      3. iii. Rheumatoid arthritis

      4. iv. Systemic lupus erythematosus (SLE)

      5. v. Diabetes

    • Clinical features

      1. i. Cardiomegaly

      2. ii. Decreased intestinal peristalsis

      3. iii. Renal

        • Decreased GFR

        • Myxoedematous facies

      4. iv. Anaemia

      5. v. Amenorrhoea/menorrhagia

      6. vi. Overweight

      7. vii. Hands

        • Dry

        • Cool

        • Rough

        • Inelastic skin

        • Non-pitting oedema

        • Carpal tunnel syndrome

      8. viii. Face

        • Thin, dry and brittle hair

        • Loss of outer 1/3 of eyebrow

        • Yellowish complexion

      9. ix. Reflex – slow relaxing reflex

    • Complication = myxoedema coma

    • Tested for by Guthrie's test

  4. 4. Hyperthyroidism

    • Aetiology (Fig. 6.5)

    • Treatment

      1. i. Carbimazole and propylthiouracil (PTU)

      2. ii. Surgery

      3. iii. Radioactive iodine

    • Clinical features

      1. i. Hands

        • Pulse suggestive of atrial fibrillation

        • Excessive sweating

        • Tremor

      2. ii. Weight loss

      3. iii. Muscular weakness

      4. iv. Heat intolerance

      5. v. Insomnia

      6. vi. Eyelid retraction

      7. vii. Lid-lag

      8. viii. Exophthalmos

      9. ix. Thyroid acropachy

    • Complication = thyroid crisis

  5. 5. Exophthalmos

    • Is due to

      1. i. Cross-reaction of autoimmune antibodies to intraorbital muscle

      2. ii. Increased retro-orbital fat

      3. iii. Intraorbital muscle infiltrated with lymphocytes

    • Complications of exophthalmos include

      1. i. Chemosis

      2. ii. Ophthalmoplegia

      3. iii. Diplopia

  6. 6. Addison's disease

    • Is due to decreased levels of cortisol

    • Is primary adrenocortical insufficiency

    • Clinical features

      1. i. Hypotension

      2. ii. Hyponatraemia

      3. iii. Hypoglycaemia

      4. iv. Hyperkalaemia

      5. v. Hyperpigmentation (due to increased ACTH)

    • Aetiology

      1. i. CAH

      2. ii. Infection

        • TB

        • CMV

      3. iii. Autoimmune

      4. iv. Adrenal haemorrhage

      5. v. Infiltrative disorder

        • Amyloidosis

        • Haemochromatosis

      6. vi. Rapid removal of exogenous hormone

      7. vii. Drugs

        • Ketoconazole

        • Etomidate

  7. 7. Cushing's syndrome

    • Is chronic glucocorticoid excess

    • Aetiology (Box 6.6)

    • Clinical features

      1. i. Hypertension

      2. ii. Hyperglycaemia

      3. iii. Hyperlipidaemia

      4. iv. Hypokalaemia

      5. v. Amenorrhoea

      6. vi. Osteoporosis

      7. vii. Obesity

    • Tumours causing ectopic ACTH secretion

      1. i. Small cell carcinoma of lung

      2. ii. Pancreatic cancer

      3. iii. Carcinoid

      4. iv. Medullary carcinoma of thyroid

      5. v. Phaeochromocytoma

  8. 8. Conn's disease

    • Is primary hyperaldosteronism

    • Aetiology = adrenal adenoma

    • Shows low renin: aldosterone ratio

    • Clinical features

      1. i. Hypokalaemia

      2. ii. Hypernatraemia

      3. iii. Hypertension

    • Treatment = spironolactone

  9. 9. Phaeochromocytoma

    • Are tumours arising from chromaffin cells

    • Secretes

      1. i. Adrenaline

      2. ii. Noradrenaline

      3. iii. Dopamine

    • Associated with

      1. i. MEN type 2 syndrome

      2. ii. Neurofibromatosis

    • Can be caused by RET proto-oncogene mutations

    • Clinical features

      1. i. Hypertension

      2. ii. Hyperglycaemia

      3. iii. Headache

      4. iv. Sweating

    • Diagnosis is achieved by measuring urinary levels of vanillylmandelic acid (VMA) and metanephrine

    • Untreated phaeochromocytoma leads to inhibition of renin–angiotensin system

    • Treatment

      1. i. Surgery

      2. ii. Preoperative salt loading

      3. iii. Intraoperative α‎-blocker (e.g. phenoxybenzamine)

      4. iv. Avoid pure β‎-blockers (e.g. atenolol)

  10. 10. Prolactinoma

    • Is a benign tumour of the pituitary gland

    • Results in hyperprolactinaemia

    • Classification

      1. i. Macroprolactinoma (i.e. tumour size >10 mm)

      2. ii. Microprolactinoma (i.e. tumour size <10 mm)

    • Features

      1. i. Headache

      2. ii. Bitemporal hemianopia (due to pressure on optic chiasm)

      3. iii. Galactorrhoea

      4. iv. Hypogonadism (resulting in amenorrhoea)

      5. v. Erectile dysfunction

    • Treatment

      1. i. Dopamine agonist (shrinks tumour in 80% of patients)

      2. ii. Trans-sphenoidal surgery

      3. iii. Radiotherapy

    • May result in osteoporosis due to reduced oestrogen and testosterone

Figure 6.5 Aetiology of hyperthyroidism

Figure 6.5
Aetiology of hyperthyroidism

Puberty

  1. 1. Sex determination

    • Default phenotype in utero = female

    • Male phenotype determined by

      1. i. SRY

      2. ii. Testosterone (promotes Wolffian ducts)

      3. iii. Mullerian inhibiting substance (MIS) – secreted by Sertoli cells

  2. 2. Physical changes in puberty

    • Stages of development described by Tanner (5 stages in total) (Fig. 6.6)

    • Male development

      1. i. Chronologically: testes → scrotum → penis → pubic hair

      2. ii. Seminiferous tubule is solid until the age of 5

    • Female development

      1. i. Chronologically: increased growth velocity → breast (thelarche) → pubic hair (adrenarche) → axillary hair → menarche

      2. ii. Breast development is determined by ovarian oestrogen

      3. iii. Pubic hair development is determined by adrenal and ovarian androgens

      4. iv. Average age of menarche is 12.3 years in African girls and 12.8 in Western Caucasians

  3. 3. Growth spurt in puberty

    • Is under endocrine control

      1. i. GH

      2. ii. IGF

    • Oestrogen is important for epiphyseal fusion

    • Begins in males 2 years later than females

    • Bone mineralization peak

      1. i. Girls at the age of 14–16 years old

      2. ii. Boys at the age of 17.5 years old

  4. 4. GnRH and gonadotropin changes up to puberty

    • GnRH

      1. i. Is secreted in a pulsatile manner (every 90–120 min)

      2. ii. Increased GnRH pulse frequency increases LH: FSH ratio

      3. iii. Continuous GnRH secretion causes suppression of gonadotrophins

      4. iv. Increased LH: FSH ratio is characteristic of midcycle dynamics

    • Fetal life

      1. i. Fetal LH and FSH peak at mid-gestation then decline until term

      2. ii. Fetal GnRH increases until mid-gestation

    • Age 2–9

      1. i. Gonadotrophin level is low (juvenile pause)

    • Peripubertal

      1. i. Gonadotrophin release is circadian

      2. ii. GnRH secretions increase in frequency and amplitude during early sleep

    • Early puberty

      1. i. The peak of LH and FSH occurs during the day

    • Late puberty

      1. i. The peak of LH and FSH occurs all the time

      2. ii. Gonadotrophin diurnal rhythm is eliminated

Figure 6.6 Tanner's stages for male (circled numbers represent testicular volume in ml, numbers next to arrows represent testicular length in cm) and female

Figure 6.6
Tanner's stages for male (circled numbers represent testicular volume in ml, numbers next to arrows represent testicular length in cm) and female

Reproduced from the Oxford Handbook of Reproductive Medicine and Family Planning, by McVeigh, Homburg and Guillebaud, © Oxford University Press (2008). Original data from Marshall WA and Tanner JM. Archives of Disease in Childhood 1969; 44:291–303.

Endocrine changes in pregnancy

  1. 1. Maternal hormonal changes in pregnancy include (Fig. 6.7)

    • LH and FSH levels are minimal

    • Cortisol and corticosteroids – increase in 2nd trimester

    • T3 and T4 – peak at 10–15 weeks gestation

    • Relaxin – highest in the first trimester

  2. 2. Proteins associated with pregnancy (Box 6.7)

Figure 6.7 Maternal endocrine changes in pregnancy

Figure 6.7
Maternal endocrine changes in pregnancy

Placental hormones

  1. 1. Placenta produces 9 hormones during pregnancy (Fig. 6.8)

  2. 2. hCG

    • Is a peptide hormone (glycoprotein)

    • Is composed of 244 amino acids

    • Is secreted by the syncytiotrophoblast

    • Functions

      1. i. Prevents degradation of corpus luteum

      2. ii. Induces ovulation

      3. iii. Stimulates Leydig cells to produce testosterone

    • Is heterodimeric

    • Structure has 2 subunits

      1. i. α‎ – identical to LH/FSH/TSH

      2. ii. β‎ – unique to hCG

    • Peaks at 9–12 weeks to 290 000 mIU/mL

    • Secreted by some types of tumour

      1. i. Choriocarcinoma

      2. ii. Germ cell tumour

      3. iii. Hydatidiform mole

  3. 3. hPL

    • Consists of 190 amino acids linked by disulphide bonds

    • Is an anti-insulin (i.e. is diabetogenic)

    • Is secreted by the syncytiotrophoblast

    • Gene located on chromosome 17

    • Belongs to the same family as

      1. i. GH

      2. ii. Prolactin

    • Peaks at 35 weeks gestation (5–7 mg/mL)

    • Half-life = 15 min

    • Functions

      1. i. Induces lipolysis – raises maternal free fatty acids (FFAs)

      2. ii. Decreases maternal insulin sensitivity

Labour

  1. 1. Initiation of labour involves 2 endocrine systems

    • Fetal

    • Maternal

  2. 2. Labour is characterized by

    • Uterine contractions

    • Cervical effacement and dilatation

  3. 3. Cervical ripening (obvious in the last 5 weeks of pregnancy) has much in common with an inflammatory process involving

    • Prostaglandin E2

    • Cytokines (especially interleukin (IL)-8)

    • Recruitment of neutrophils

    • Synthesis of metalloproteinases (including collagenases and elastase)

    • Increased cervical tissue water content

    • Reduction in cervical tissue collagen concentration, and rearrangement and realignment of collagen

  4. 4. The fetus is thought to trigger parturition

    • Fetal pituitary releases corticotrophin, which acts on the fetal adrenals

    • Fetal adrenals release

      1. i. Cortisol

      2. ii. DHEAS

  5. 5. Hormonal changes leading to labour

    • Fetal adrenal cortisol rises towards the end of term causing

      1. i. Increased oestrogen production

      2. ii. Formation of oxytocin receptors

    • Fetal adrenal DHEAS is metabolized in the placenta leading to increased oestrogen levels, which provoke the release of prostaglandin F2α‎ from the decidua, causing myometrial contractions

    • Rise in placental CRH, causing augmentation of levels of

      1. i. Oxytocin

      2. ii. Prostaglandin F2α‎

  6. 6. Other factors initiating labour

    • NO withdrawal

    • Progesterone

      1. i. Withdrawal

      2. ii. Switch from type 1 to type 2 progesterone receptors

    • Increased placental release of

      1. i. CRH

      2. ii. Oestrogen

    • Upregulation of oxytocin receptors

    • Increased prostaglandin synthesis in

      1. i. Uterus

      2. ii. Fetal membranes

    • Increased IL

      1. i. IL-1

      2. ii. IL-8

    • Fetal release of

      1. i. Cortisol

      2. ii. Platelet-activating factor

    • Catecholamines

      1. i. β‎2-adrenergic receptor agonists inhibit labour

      2. ii. α‎2-adrenergic receptor agonists cause uterine contractions

    • Fetal posterior pituitary (umbilical artery oxytocin > umbilical vein oxytocin)

    • Increased myometrial gap junctions during labour

  7. 7. Ferguson reflex

    • Is a neuronal reflex triggered by pressure application to the

      1. i. Cervix

      2. ii. Vagina

    • Causes spurts of oxytocin release

    • Occurs during the following labour phases

      1. i. Active

      2. ii. Expulsive

Puerperium and lactation

Puerperium

  1. 1. Most hormone levels drop dramatically except for the rise in

    • Prolactin (only in breast-feeding women)

    • Oxytocin

  2. 2. The following hormone levels decline in the puerperium

    • Oestrogen

    • Progesterone

    • Thyroid

    • Most hormones takes 6 weeks to return to normal

  3. 3. Menses returns in

    • Breastfeeding women at 28 weeks post partum

    • Non-breast feeding women at 9 weeks post partum

  4. 4. Prolactin levels drop 2 weeks post partum in non-breast feeding women, resulting in cessation of lactation

Breastfeeding

  1. 1. Lactation

    • Maternal breast changes occur from 7 weeks gestation onwards

    • Influenced by

      1. i. Oestrogen

      2. ii. hPL

      3. iii. Prolactin

      4. iv. Decreased serum progesterone levels

      5. v. Oxytocin

      6. vi. LH

      7. vii. FSH

  2. 2. Lactational amenorrhoea is a reliable form of contraception (98% effective according to the World Health Organization (WHO)) if the following criteria are met

    • The baby is exclusively breastfed (intervals between breastfeeding are no longer than 5 h)

    • Amenorrhoea (less than 6 months postpartum)

  3. 3. Breast milk

    • Composition (Box 6.8)

    • Also contains

      1. i. 2-arachidonoyl glycerol (a type of endocannabinoid)

      2. ii. Growth factors (e.g. epidermal growth factor (EGF), IGF)

      3. iii. Digestive enzymes (e.g. bile acid-stimulating lipase, amylase)

      4. iv. Hormones (e.g. feedback inhibitor of lactation (FIL), prolactin, insulin, ACTH)

    • Benefits (Box 6.9)

    • Typical breast milk volume at day 5 post partum is 500 mL/day

    • Colostrum

      1. i. Secreted for the first 3–5 days after delivery

      2. ii. Typical volume = 100 mL/day

      3. iii. Rich in the following (compared with mature breast milk)

        • Vitamin A

        • Lactoferrin

        • Ig A

        • Sodium

Fetal and neonatal endocrine system

  1. 1. Fetal endocrine system is largely functional by term

  2. 2. Surfactant production is controlled by

    • Cortisol

    • Oestrogen

    • Adrenaline

    • Thyroid hormone

  3. 3. Development of gonads and adrenals in the 1st trimester is directed by hCG

  4. 4. Fetal endocrine development (Box 6.10)