(a) (i) Describe the role of SRY (Sex-determining region on Y gene) transcription factors in testicular development. 10 (ii)…

(a)(i) Role of SRY in testicular development

SRY (Sex-determining Region of the Y chromosome, on Yp11.2) is a single-exon gene whose product is a transcription factor with a high-mobility-group (HMG) DNA-binding domain. It is expressed briefly in pre-Sertoli cells of the bipotential gonad around the 6th to 7th week of development, and its action runs as follows: SRY, together with steroidogenic factor 1 (SF1), binds the testis-specific enhancer of SOX9 and switches it on. SOX9 maintains its own expression (with FGF9 as a positive feedback loop) and drives differentiation of supporting cells into Sertoli cells, which organise into testis cords. SOX9 and SRY suppress the ovarian pathway (WNT4, RSPO1 and β-catenin signalling). Sertoli cells secrete anti-Müllerian hormone, causing regression of the paramesonephric ducts, and induce Leydig cells, whose testosterone maintains the mesonephric (Wolffian) duct derivatives, and whose dihydrotestosterone virilises the external genitalia. Clinical correlates: SRY mutation or deletion causes XY gonadal dysgenesis (Swyer syndrome); translocation of SRY to the X chromosome gives XX males.

(a)(ii) Vitelline duct abnormalities

The vitelline (omphalomesenteric) duct joins the midgut to the yolk sac and normally disappears by the 6th to 7th week. Persistence of any part gives: Meckel's diverticulum, the commonest, is the persistent proximal part on the antimesenteric border of the ileum. By the rule of twos: about 2% of people, about 2 feet from the ileocaecal valve, about 2 inches long, two types of ectopic mucosa (gastric and pancreatic), usually presenting by age 2. It may bleed (ectopic gastric mucosa), perforate, become inflamed like appendicitis, or cause intussusception or obstruction. Vitelline fistula: the whole duct stays patent and faeces discharge from the umbilicus. Umbilical sinus: only the distal part persists, discharging mucus at the umbilicus. Vitelline cyst (enterocystoma): the middle part persists as a cyst, joined by fibrous cords. Vitelline (fibrous) band: a fibrous cord from ileum to umbilicus, which can cause strangulation or volvulus of small bowel.

(b)(i) Iodine in thyroid hormone synthesis, and Hashimoto's thyroiditis

Role of iodine. Iodine (daily requirement about 150 μg) is the essential component of T3 and T4. Steps in follicular cells: Trapping: iodide is actively taken up at the basolateral membrane by the sodium-iodide symporter (NIS), driven by the Na⁺/K⁺-ATPase gradient; it is stimulated by TSH. Oxidation: iodide moves across the apical membrane (pendrin) and is oxidised to reactive iodine by thyroid peroxidase (TPO) with hydrogen peroxide. Organification: TPO iodinates tyrosine residues of thyroglobulin to give monoiodotyrosine (MIT) and diiodotyrosine (DIT). Coupling: MIT with DIT gives T3 and two DIT give T4, still within thyroglobulin. Release: thyroglobulin is endocytosed, digested in lysosomes and free T3 and T4 are secreted; peripheral deiodinases convert T4 to active T3. Excess iodide briefly blocks organification (Wolff-Chaikoff effect); lack of iodine causes goitre and hypothyroidism.

Hashimoto's thyroiditis is the commonest cause of hypothyroidism in iodine-sufficient areas: an autoimmune disease in which T-cell and antibody-mediated attack destroy follicles. The gland is firm, diffusely enlarged and shows lymphocytic infiltration with germinal centres and Hürthle (oxyphil) cells. It is more common in women, is linked with HLA-DR3 and DR5, and occurs with other autoimmune diseases. It may start with a brief hyperthyroid phase (hashitoxicosis) and carries a small risk of thyroid lymphoma.

Biochemical investigations: Serum TSH raised, free T4 and T3 low (overt) or normal (subclinical). Anti-thyroid peroxidase antibodies, positive in over 90% of patients, and anti-thyroglobulin antibodies, which establish the autoimmune basis. Fine-needle aspiration showing lymphocytes and Hürthle cells is used if a nodule is present. Anti-TSH-receptor antibodies distinguish Graves' disease.

(b)(ii) Vitamin K and the basis of warfarin therapy

Biochemical role. Vitamin K (K1 phylloquinone from vegetables, K2 menaquinone from gut bacteria) is the cofactor of γ-glutamyl carboxylase, which converts glutamate residues to γ-carboxyglutamate (Gla) in factors II, VII, IX and X and in proteins C and S. Gla residues bind Ca²⁺ and so let these factors attach to platelet phospholipid surfaces. The enzyme uses reduced vitamin K (hydroquinone), which becomes vitamin K epoxide and is recycled by vitamin K epoxide reductase (VKORC1). Vitamin K is also needed for osteocalcin and matrix Gla protein.

Warfarin. It inhibits VKORC1, so the epoxide is not recycled, the vitamin K supply runs out, and the liver releases under-carboxylated, inactive factors II, VII, IX and X. The effect starts only after 2 to 3 days, because already circulating factors must decay first (factor VII first, prothrombin last), and it is monitored by the INR. Protein C falls first, so heparin cover is needed at the start. Vitamin K reverses it.

(c)(i) Functions and regulation of vasopressin

Vasopressin (ADH) is a nonapeptide made in the supraoptic and paraventricular nuclei, transported in axons and stored in the posterior pituitary.

Functions: V2 receptors (collecting duct principal cells, Gs-cAMP-PKA) insert aquaporin-2 water channels into the apical membrane, so water is reabsorbed and urine is concentrated; it also raises urea permeability in the medullary collecting duct. V1a receptors (Gq-IP3-calcium) cause vasoconstriction, important in haemorrhage, and glycogenolysis. V1b (V3) receptors in the anterior pituitary raise ACTH secretion; it also releases factor VIII and von Willebrand factor through V2.

Regulation of secretion: Osmolality is the main control. Hypothalamic osmoreceptors respond to a rise of 1 to 2% above a threshold of about 280 mOsm/kg, and secretion rises steeply. Volume and pressure: a fall of about 10% in blood volume or pressure, through atrial stretch receptors and carotid and aortic baroreceptors, raises ADH. Other stimuli: pain, nausea, stress, angiotensin II and nicotine increase it. Inhibition: low osmolality, a rise in blood volume (atrial natriuretic peptide), alcohol and cold reduce secretion. Deficiency causes diabetes insipidus and excess causes SIADH.

(c)(ii) Physiological effects of glucagon

Glucagon is a 29-amino-acid peptide from pancreatic α cells, secreted in fasting, hypoglycaemia, high amino acids and sympathetic stimulation, and inhibited by glucose and insulin. Through hepatic receptors (Gs-cAMP-PKA) it: Raises blood glucose by glycogenolysis (activation of glycogen phosphorylase) and inhibits glycogen synthesis; it has no effect on muscle glycogen. Stimulates gluconeogenesis from amino acids, lactate and glycerol (PEPCK and fructose-1,6-bisphosphatase induced) and inhibits glycolysis. Stimulates lipolysis in adipose tissue and hepatic fatty acid oxidation and ketogenesis, as inhibition of acetyl-CoA carboxylase lowers malonyl-CoA and releases CPT-1. Increases amino acid uptake for gluconeogenesis and urea formation; at high doses it has a positive inotropic effect on the heart. It is the main counter-regulatory hormone to insulin; excess glucagon contributes to hyperglycaemia and ketoacidosis in uncontrolled diabetes.