Endocrine Flashcards
MEN 1
Pancreatic (gastrinoma, insulinoma) pituitary tumours hyperparathyroid. Werner syndrome ; 3ps
MEN 2A + MEN 2B
- 2A: (RET gene) medullary thyroid cancer parathyroid tumours pheochromocytoma. Sippley syndrome
- 2B; thyroid, pheochromocytoma, Marfinoid habitus, mucosal neuromas, skeletal abnormalities. Wagenmann-Froboese syndrom
Autoimmune polyglandular syndrome type 1 consists of?
- Addison’s disease (early adolescence) - Chronic mucocutaneous candidiasis (1st manifestation) - Hypoparathyroidism - Other associations: Primary hypogonadism, malabsorption, chronic active hepatitis, keratopathy, enamel hypoplasia, nail dystrophy, vitiligo, alopecia, juvenile gastritis +/-pernicious anaemia. AIRE gene mutation ; APECED
Autoimmune polyglandular syndrome type 2 consists of?
- Addison’s disease & - Primary hypothyroidism (Chronic Lymphocytic Thyroiditis) OR - Type 1 diabetes - Other associations: vitiligo, primary hypogonadism, alopecia, adult gastritis +/-pernicious anaemia AKA Schmidt syndrome, more common than APS1
Precocious and delayed puberty timings
- Girls precocious <8, delayed > 13 - Boys precocious <9, delayed > 14
Where do LH and FSH act?
Males: - LH - leydig cells - testosterone - FSH - sertoli cells - spermatogenesis Females: - LH - lutein cells - progesterone + androgens - FSH - granulosa cells - oestrogen
What is the difference between 11-beta hydroxylase and 21-hydroxylase deficiency?
In 11-beta hydroxylase deficiency you don’t get salt wasting. Get hypertension due to salt retention due to inc deoxycorticosterone. Also deoxycortisol has reasonable cortisol function
Describe the hormone production in the adrenal glands
- Cortex: - Glomerulosa - aldosterone - Fasciculata - cortisol - Reticularis - Androgens - (GFR - salt, sugar/stress, sex - the deeper you go the sweeter it gets) Other Mnemonic - go find rex make good sex - Medulla - Epinephrine, norepinephrine
Causes of pheochromocytoma?
- Sporadic, SDHx mutation (succate dehydrogenase mutation) or SDHB gene - risk of paragangliomas - MEN 2 - NF1 - Von Hippel Lindau 10% bilateral, 10% malignant, 10% familial, 10% present children, 10% extra-adrenal, 10% recur
The enzyme 21 hydroxylase is required for which biochemical step?
- Progesterone to 11 deoxycorticosterone (aldosterone pathway) - 17alpha-hydroxyprogesterone to 11-deoxycortisol (cortisol pathway)
What mutation causes 21 hydroxylase deficiency?
- Mutations in the CYP21A2 gene - Causes >90% of CAH
What are the 3 different causes of CAH?
- 21 hydroxylase deficiency (90%) - 11 hydroxylase deficiency - 3-beta-hydroxysteroid dehydrogenase type 2 deficiency
Hypothyroidism can cause…?
Umbilical hernia Large anterior fontanelle Poor feeding and weight gain Small stature or poor growth Jaundice Decreased stooling or constipation Hypotonia Hoarse cry Macroglossia Coarse facial features
Most common CNS cause of precocious puberty?
Hypothalamic hamartoma, may be preceded by gelastic seizures
What causes delayed puberty and anosmia?
Kallman syndrome - hypogonadotrophic hypogonadism
Describe the features of Cushing’s syndrome
Short stature, obesity, hypertension, easy bruising, striae, acne, menstrual abnormalities, proximal muscle weakness (10%)
What are the causes of Cushing’s syndrome?
Exogenous steroid therapy is most common cause. Those not on steroids: - In young children 50% due to a ACTH-secreting pituitary adenoma and 50% due to adrenal tumours - After the age of 7 pituitary adenomas account for around 75% of cases
Describe autoimmune polyendocrinopathy (APECED)
- AR disorder - Chronic mucocutaneous candidiasis before progressing to hypoparathyroidism and Addison’s disease - Can present with hypocalcaemia
What are the risk factors for developing cystic fibrosis-related diabetes (CFRD)?
- Advancing age (25% by 20y), pancreatic insufficiency, delta F508 mutation, and female gender. - Symptoms will include: failure to gain weight; pubertal delay; poor growth; and an unexplained decline in respiratory function. - Screen with glucose tolerance test (fasting plasma glucose and HbA1C have low sensitivity )
What is the main cause of congenital hypothyroidism?
- Thyroid dysgenesis (ectopia, aplasia, or hypoplasia) is the underlying aetiology in 85% of cases - Primary hypothyroidism
Why should you treat glucocorticoid deficiency before thyroid deficiency?
- Hypothyroid state reduces cortisol clearance and reduces the metabolic rate - Therefore, giving thyroxine prior to treating glucocorticoid deficiency may precipitate an adrenal crisis
What is the mutation in MODY-1 and how do you treat it?
- MODY-1 is due to a transcription factor mutation in HNF4a - Treated with sulfonylureas (act by stimulating the production of insulin from the beta cells in the pancreas) - Adolescent/early adult onset, progressive - Progressive insulin secretory defect - May have fetal macrosomia, transient neonatal hypoglycaemia
Describe MODY-2
- AD - Present since birth - Stable mild fasting hyperglycaemia, max 11-13 - Mutation in glucokinase (B-cell “sensor”) - reset sensor - Usually asymptomatic, usually no treatment required, not progressive, likely underdiagnosed - Can have low birth weight is mother doesn’t carry mutation
How do you treat MODY-3?
- Sulfonylureas - HNF-1A transcription factor mutation - Most common, progressive B cell failure - Onset adolescent/early adult, progressive - Progressive insulin secretory defect - Often normal BSL but high glucose in urine
How to distinguish between central and peripheral causes of precocious puberty?
- Peripheral (e.g. CAH and McCune-Albright) are GnRH independent, therefore have a flat GnRH stimulation test (pre-pubertal range) - Central (e.g. hypothalamic hamartomas and severe untreated hypothyroidism) are GnRH dependant, therefore have a positive GnRH stimulation test, with inc LH and FSH
What are the causes of cafe-au-lait spots?
- NF1 and NF2 - McCune Albright syndrome - Russell-Silver syndrome - Bloom syndrome - LEOPARD syndrome - Fanconi anaemia
What are the findings in Vitamin D resistant rickets?
- Normal or slightly low Ca, mod reduced PO4, no evidence of secondary hyperparathyroidism
Effect of maternal hyperparathyroidism on neonatal Ca/ALP/PTH/phos?
- Neonate: low PTH (supressed due to Mum’s high PTH), low Ca, high/normal phos, normal ALP, low Vit D - Transient neonatal hypocalcaemia due to maternal hyperparathyroidism - Often symptomatic - irritability, poor feeding, seizures, cardiac conduction defects, tetany
Effects of parathyroid hormone
- Mobilises calcium from bones - Acts on distal renal tubule to increase calcium reabsorption - Stimulates 1-a-hydroxylase in kidney to activate Vit D - Inhibits renal phosphate reabsorption -> inc Ca, decr phos, inc Vit D
What is the role of Vitamin D?
- Promotes calcium and phosphate absorption from gut and reabsorption from renal tubules - Also causes inc resorption calcium from bones
What is the role of calcitonin?
- Released by parafollicular cells of thyroid gland in response to calcium levels - Lowers serum calcium by decreasing resorption from bone and increasing renal excretion
Most common cause of neonatal hypocalcaemia?
- Maternal diabetes (decr PTH, increased calcitonin, decr maternal Ca+ transfer) - However, we don’t actively screen or treat
Calcium-sensing receptor defects
- Activating defect shift curve to L - PTH release not triggered at low Ca levels - hypocalcaemia - Inactivating defects shift curve to R - PTH inappropriately released at high Ca levels - hypercalcaemia (e.g. familial hypocalciuric hypercalcaemia, AD, usually asymptomatic, low Ca:Creat urinary clearance ratio)
Discuss Albright’s Hereditary Osteodystrophy
- Pseudohypoparathyroidism type 1a - PTH resistance due to inactivating mutation in GNAS1 - Short stature, obesity - Shortened 3-5th metacarpals, 2-3 toe syndactyly - Round face, flat nasal bridge, subcutaneous calcifications, cataracts - Paternally imprinted, therefore only inherited from mother - Multi-hormone resistance - TSH - <2y - PTH - infancy or later - GHrH - leads to short stature - FSH and LH - menstrual irreg in older girls -> same mutation inherited from father (maternally imprinted) causes pseudopseudohypoparathyroidism (AHO phenotype but no endocrine dysfunction)
Discuss Vitamin D-dependant rickets type 1 and 2
- Type 1: alpha hydroxylase deficiency - cannot produce active form of Vit D - Type 2: hereditary vitamin D resistant rickets - mutations in vitamin D receptor - end organ resistance to activated Vit D
Discuss X-linked hypophosphatemic rickets
- X-linked dominant, PHEX mutation, FGF23 inhibits phos resorption in kidney, and activation Vit D - Most common cause inherited phosphate wasting - Low serum phosphate, low active Vit D - low phosphate resorption from gut - Osteoarthritis, pseudofractures - Rickets, lower limb deformities with short stature, poor growth, poor mineralisation of teeth - Ix: high renal phosphate, low serum phos and active VitD, inc ALP, normal PTH and Ca - Tx: phos supplements in regular doses to avoid peaks - causes hyperparathyroid, calcitriol supp, risk hypercalciuria and nephrocalcinosis, new = burosumab (targets FGF23)
Causes of primary hyperparathyroidism?
- Rare in childhood - Sporadic due to adenoma - Men1 and Men2 - McCune Albright syndrome -> fatigue, abdo pain, nausea, polyuria and polydipsia, depression, renal calculi, pathological fractures
Treatment of hypercalcaemia?
- ECG monitoring - Hyperhydration, NaCl, loop diuretics - maximise urinary calcium excretion - Bisphosphonates, calcitonin - inhibit bone resorption - Glucocorticoids - decrease intestinal absorption calcium - Dialysis
What is the structure of the thyroid?
- Closed follicles which contain central colloid (thyroglobulin - involved in thyroxine synthesis and storage) and surrounded by follicular cells (cuboidal epithelial cells) and C-cells (secrete calcitonin) - T3 and T4 stored in colloid, secreted as needed
Discuss transient neonatal hypothyroidism
- TFTs normalise within months-years, 40% of CH - Still important to start treatment, then stop at age 3-4yrs and recheck TFTs after 1 month to see if still stable
Causes:
- Maternal antithyroid meds
- Prenatal or postnatal iodine
- Maternal TSH receptor blocking antibodies (no uptake on radioisotope scan) - resolves by 3-6m
- Prenatal exposure to maternal hyperthyroid
- Prematurity esp <27/40
- Drugs: steroids, dopamine
Discuss Grave’s disease
- Stimulating antibodies to the thyrotropin receptor (TSHR-Ab) - High T3 and T4, low TSH - Usually early puberty - ADHD like symptoms, goitre, exophthalmos, acceleration of growth - Tx: antithyroid drug 1st line (carbimazole > PTU as more side effects with PTU. Inhibits thyroid peroxidase). Remission rates 35-65%. 2nd line = surgery or radioactive iodine (no inc risk malignancy).
Neonatal hyperthyroidism
- 2% of maternal Grave’s disease - TSH receptor stimulating antibodies (still present even if maternal thyroidectomy) - Baby restless, tachy, irritable, anxious, alert, exophthalmos - Remits by age 3-4m but need treatment in meantime to dec risk microcephaly and ID, heart failure - Tx: carbimazole
Discuss subacute thyroiditis
- Quervain Disease - Painful swelling of thyroid gland, follows URTI - High fever, unilateral swelling of gland, suppurative thyroiditis - Due to release or preformed thyroid hormones - High ESR, low TSH, thyroid antibodies -ve, absent radioactive uptake - Acute phase 2-6/52, pain, mild hyperthyroidism -> hypothyroid phase, permanent in 10%, recovery wks-mths
Discuss Pendred Syndrome
- AR, sensorineural deafness, 50% have hypothyroidism Mutation SLC26A4 - Mutations in pendrin which is needed for transport of iodide across apical membrane of follicular cell into colloid space ( DYSHORMOGENESIS) - Show only a partial discharge of iodide with thiocyanate or perchlorate
Discuss sick euthyroid
- Change in serum thyroid function associated with acute illness - Protective: prevents catabolism - Stages: 1 - decr T3, 2 - decr TSH, 3 - decr T4, 4 - resolution with modest inc TSH, normal T3 and T4 - No benefit in treating as resolves
What are the lab findings for 5-alpha reductase deficiency?
- low DHT - high Testosterone
What causes short stature in Turner Syndrome?
SHOX gene problem (not enough)
What percentage of beta cells need to be destroyed for T1DM?
80%
What blood findings might there be in primary adrenal insufficiency?
- “Salt losing” i.e. low Na/high K - High ACTH/low cortisol - Short synacthen test - no response
What hormone inhibits prolactin?
Dopamine
What does ketoconazole do to hormone secretion?
Inhibits C-17,20-lyase and testosterone synthesis
Anterior pituitary hormones:
- Follicle Stimulating Hormone - Lutenising Hormone - Adrenocorticotropic hormone - Thyroid stimulating hormone - Growth hormone - Prolactin
Posterior pituitary hormones:
- Oxytocin - ADH
What factors stimulate and suppress growth hormone?
Suppressed by: glucose, bromocriptine, somatostatin Stimulated by: insulin, glucagon, exercise, arginine, clonidine, l-dopa
McCune Albright clinically (triad and other)
Classic triad: Precocious puberty (peripheral) endo gain of function (ovarian enlargement and follicles, secrete oestrogen) Polyostotic Fibrous dysplasia Cafe au lait (Coast of Maine, rarely cross midline) Other: – Phosphate wasting (hypophosphataemic rickets) – Growth hormone excess (gigantism) – Cushing’s syndrome – Thyrotoxicosis (toxic multinodular goitre) – Cardiac arrhythmias – Cholestasis etc - Ovarian cysts secreting oestrogen Activating mutation of the alpha unit of G protein that activates adenylyl cyclase (GNAS)
Mesomelia =
Shortening of the intermediate segment of limbs
Rhizomelia =
Shortening of proximal segment of limbs
Acromelia
Shortening of distal segments of limbs
Madelung deformity is
Dinner fork deformity of wrist
Hypogonadotrophic hypogonadism causes
Genetic (KAL1, FGFR1, zgnHT, DAX1, Kallman (anosmia) tumours, post head trauma, pituitary infarction CHARGE (60-80% defect in CdH7 gene), prader-Willi, Kallman (anosmia) Bardet-Biedl (obesity, polydactyly) Chronic disorders, anorexia Prolactinoma Galactosaemia (75-96%) defect GaLT (galactose-1-phosphate uridyltrsnsferase
Most common cause for hypothyroidism and investigation of choice
The most common cause of acquired overt hypothyroidism in both children and adults is autoimmune thyroiditis (Hashimoto disease). An elevated thyroid peroxidase (TPO) antibody concentration would be most consistent with this diagnosis.
Turners percent which have puberty spontaneously
30
Autosomal recessive. Prenatal and postnatal growth retardation. Microcephaly, ptosis, anteverted nares, broad alveolar ridges, syndactyly of the 2nd-3rd toes, severe mental retardation. 70% male. Genital ambiguity or complete sex reversal. Low cholesterol and elevated 7-dehydrocholesterol.
Smith-lemli-opitz Mutations in Δ7-reductase gene on chromosome 11q12-q13.
GH stimulated by
GHRH Ghrelin (stomach and hypothalamus) Sleep Exercise Stress Fasting Amino acids Puberty Hypoglycaemia (Inhibited by insulin)
Secreted pulsatile fashion under regulation hypothalamus.
Somatostatin inhibits GH release (also hypothyroid, high BSL, steroids, high carbs)
Effect: Increase linear growth, bone thickness, soft tissue growth, protein synthesis, FA release from adipose tissue Normal insulin and nutrition needed for hepatic production IGF-1 (malnutrition and poorly controlled T1DM inhibit IGF-1)
What is CAH?
Mutation in CYP21A2 gene = deficiency in 21 hydroxylase 21 hydroxylase converts 17-OH progesterone to 11 deoxycortisol Lack of 21 hydroxylase = raised 17-OH progesterone (this is what we test to confirm CAH 2 types -salt losing form with virilisation - simple virilisation Girls present with ambiguous genitalia Boys present either at birth with salt losing adrenal crisis (low Na, high K, FTT) or as toddlers in precocious puberty
What is MELAS?
Mitochondrial myopathy Encephalopathy Lactic acidosis and stroke - mitochondrial -short, deaf, developmental delay - Fhx death -associated with diabetes (type 2 like picture) - can have pyroxidine anaemia –> treat with pyroxidine and resolves
What is transient neonatal diabetes?
-Low insulin levels antenatally, IUGR, poor fat layers. Normal placental function. Initial hypoglycemia (low BW, no glycogen stores) Super sensitive to insulin. Then recovers well with sky rocketing growth. -At increased risk of insulin deficient (abnormal beta cells) diabetes later on in life (around age 10years) -70% chromo 6q24, paternal imprinted genes -Overexpression of ZAC and HYMAI genes (methylation defect- one of two copies should be silenced but this doesn’t happen)
What is the most common MODY?
MODY type 3 - 65% Progressive B cell failure Presents with symptomatic hyperglycemia in adolescence or in 20’s Later develops secondary insulin resistance
What is DEND syndrome? (developmental delay, epilepsy, and neonatal diabetes)
Defect in K ATP channel (controls release of insulin from B cells)- reduced sensitivity to ATP. K ATP channels are present in brain, muscle and pancreas In neonatal period develops weight loss, diabetes. Developmental delay Epilepsy Severe muscle weakness Can prevent morbidity if detect early Treatment is with Sulphonylurea! (Glibenclamide) which resolves diabetes and prevents/treats all the sequelae!
Congenital hypothyroidism
The Guthrie test is a measure of TSH.
An elevated level is abnormal and indicates hypothyroidism (misses central/ secondary hypothyroidism, approx 5-10%)
Congenital hypothyroidism:
- most cases from thyroid dysgenesis - 85%
- some cases familial, inborn error of thyroid hormone synthesis – 10%
- transplacental maternal thyrotropin receptor blocking antibody – 5%
- most infants asymptomatic at birth (some maternal T4 crosses placenta)
Clinical features: lethargy, slow movement, hoarse cry, feeding problems, constipation, macroglossia, umbilical hernia, large fontanels, hypotonia, dry skin, hypothermia, prolonged jaundice
Associated congenital malformations: affecting heart, kidneys, urinary tract, GI, skeletal
In dyshormonogensis – goitre is present
Thyroid dysgenesis:
-Unknown cause in most cases
2/3 ectopic
1/3 thyroid Aplasia
Dyshormogenesis - AR inheritance
- PENDRED- AR, goitre and SNHL (SLC26A4 gene) Inx TFTs Thyroids US Radionuclear scintigraphy scan
Causes of ambiguous genitalia
Either: virilised female or an undervirilised male
CAH if female
In males- Causes of an undervirilised XY - see below
CAH – the less common forms (non-classical) only. CAH caused by 21-hydroxylase deficiency is also seen in 46,XY children but does not result in genital ambiguity.
Abnormal testicular activity
◾Gonadal dysgenesis
◾Testicular regression syndrome
◾Vanishing testes syndrome
◾Persistent Mullerian duct syndrome
Abnormal androgen synthesis: have abnormal response to hCG stimulation.
◾17-beta-hydroxysteroid dehydrogenase type 3 deficiency ◾Steroid 5-alpha-reductase deficiency (SRD)
◾LH receptor defects Abnormal response to androgen ◾Androgen insensitivity
◾ MIS receptor defect
◾Endocrine disrupter
True hermaphroditism
– Ovotesticular DSD (previously termed true hermaphroditism), is characterised by the presence of both functional ovary and testis. It is most often associated with an XX karyotype. However, it can be seen with an XY karyotype, a mixed XX/XY karyotype, or various other sex chromosome patterns
Adrenoleukodystrophy
Adrenoleukodystrophy (ALD) is a peroxisomal disorder of beta-oxidation that results in accumulation of very long chain fatty acids (VLCFA) in all tissues. ALD is an X-linked disorder. Therefore a female is unlikely to be severely affected. Female carriers may be symptomatic depending upon the pattern of X-chromosome inactivation. Affected individuals typically present with mild spastic paraparesis in mid-adulthood. An AMN-like (adrenomyeloneuropathy) syndrome affects up to 50% of female heterozygotes in middle age or later, although cerebral disturbance is uncommon. Adrenal insufficiency is rare in females.
Wolfram Syndrome
DIDMOAD Diabetes insipidus Diabetes mellitus Optic atrophy Deafness Autosomal recessive , Type 1 ( WFS1 gene)
Pituitary
Located base of skull in sella turcica, connected to hypothalamus by pituitary stalk Anterior pituitary (80%) - adenohypophysis ; originates from Rathkes pouch Vascular supply is internal carotid (hypophyseal arteries) Anterior pituitary - Somatotropes produce GH - Lactotropes produce Prolactin - Thyrotropes produce TSH -Corticotropes express precursor to ACTH - Gonadotropes express LH and FSH Posterior pituitary (Neurohypophysis) consists of neutrons from supraoptic and paraventricular nuclei of hypothalamus - ADH - Oxytocin
McCune Albright syndrome
missense mutation in GNAS1 (post zygotic mutation in G protein coupled receptors) Peripheral Precocious puberty (mostly girls) - GNRH stimulations testing flat/no response (LH+FSH<5) - Oestrogen producing ovarian cysts - Advanced bone age CAL (coast Maine) Polyostotic fibrous dysplasia Other pituitary hormone issues - hyperthyroidism, cushings, GH excess Phosphate wasting causing Rickets Cholestasis, arrhythmia Rx - Tamoxifen (Oestrogen receptor inhib) - slows bone age - Anastrazole (aromatase inhibitor)
Neonatal diabetes (<6months)
Transient (50%), onset first week life, more common in SGA females, can persist for weeks before spontaneous resolution.
Normal basal insulin but low response to high BSL.
70% due to paternal imprinting disorder 6q24 (increased risk with IVF), over expression of ZAC
Permanent in 50%
Test for KCNJ11 mutation (K ATP channel) and ABCC8
Others MODY 4, IPEX 20% neurological features (devel delay, epilepsy)
30% present DKA, ( typical at 3-4 weeks age)
DEND = defect in sulphonylurea channel - DM, devel delay, aggressive behaviour (low CSF glucose), muscle weakness, epilepsy Rx Sulphonylureas, insulin
Monogenic diabetes
suspect in patient with elevated BSL but Atypical Type 1 - no insulin autoantibodies in Type 1 (GAD negative within 5 years diagnosis) - still some prandial C-peptide >5 years post diagnosis Atypical type 2 - FHx suggestive Monogenic diabetes Absence obesity, HTN, PCOS, Acanthosis MODY 3 most common (HNF1a mutation) - High BSL, Glycosuria with normal BSL - High HDL. ++ sensitive sulphonylurea(gliclazide) MODY 2 (GCK defect, no treatment, mild, no macrovasc comp) MODY1 - macrosomia, neonatal hypo (HNF4a) MODY5 - assoc renal cysts (HNF1B) MIDD - maternally inherited diabetes and deafness (Hx SNHL). Rx Coenzyme Q, thiamine Do not present with DKA
Diabetes inheritance risk
Mum has it 1-4% Dad has it 6-9% Sibling 5-6% (16% if HLA identical) Monozygotic twins 50%
CFTR diabetes
Don’t get DKA Screen from 10 years with OGTT (HBA1c less reliable) RF - female, increasing age, delta 508 Affects 50% adults with CF No macrovascular disease
Mauriac syndrome
Rare complication T1DM with persistent high BSL Growth failure Large hepatomegaly (Glycogen deposition) Delayed puberty
% patients with T1DM get coeliac
5%
Elevated FSH and low testosterone
Sertoli cell failure - reduced fertility, often seen in Klinefelters
GNRH stimulation test
LH dominant in central precocious puberty FSH dominant in thelarche
Metformin (Biguanide)
Increase insulin sensitivity Decrease production glucose by liver(inhibit gluconeogensis) SE: GI SE ; CI if metabolic acidosis or conditions such as renal F, Liver F that predispose to it Can reduce folate and B12
46XY undervirisilised male DSD
Male Sex development
- Testes: Y chromosome specifically intact SRY gene, and other genes such as SOX9, SF1, WT1
- Mullerian inhibiting substance (aka Anti-mullerian hormone) from testis – causes regression of mullerian ducts (6-7 weeks gestation)
- Testosterone (from testicular Leydig cells) stimulated by placental hCG then later by LH – initiates virilisation of wolffian duct to epididymis, vas deferns, and seminal vesicle. Also needs dihydrotestosterone (active metabolite of testosterone), and functional androgen receptor.
- Testicular differentiation defect (deletion of SRY gene on short arm Y chromosome) – results in female phenotype, mullerian structures, streak gonads
o Denys-Drash synd – nephropathy (proteinuria to ESRF by 3y), atypical genitals, bilateral Wilms tumors
o WAGR synd – Wilms tumor, aniridia, GUT malform, retardation
o Camptomelic synd – short limb dysplasia (anterior bowing of femur, tibia, small scapulae, 11 ribs…lethal)
o XY pure gonadal dysgenesis – NOT chromosomal. Normal stature and full female phenotype, but puberty fails
o XY gonadal agenesis – due to testicular degeneration during fetal life, resulting in external female-ish, and internal no mullerian structures and no testes (though perhaps a streak of testicular tissue somewhere)
• Testicular hormone defects – inadequate masculinisation due to fetal testis not producing testosterone properly
o Leydig cell aplasia – female phenotypes, but mild virilisation, no pubertal change, doesn’t respond to hCG stimulation test.
o Lipoid adrenal hyperplasia – severest form of congenital adrenal hypERplasia, serum steroids absent, female external, o 3B-hydroxysteroid dehydrogenase def – congenital adrenal hypERplasia – hypospadias +/- bifid scrotum
o 17-hydroxylase def – complete female phenotype, or less, pubery failure o 17-ketosteroid reductase def – mostly female phenotype, with absent mullerian ducts
o Persistent mullerian ducty synd – persistence of mullerian duct but otherwise completely virilised male. Normal testicular function
- Androgen action defect – normal testosterone production, but defect in its action o 5A-reductase def – decreased production of dihydrotestosterone, with severe ambiguity, small phallus, bifid scrotum, urogenital sinus with perineal hypospadias, blid vaginal pouch, testes in inguinal canals. No mullerian structures, normal wolffian structures. At puberty virilisation occurs, phallus enlarges, testes descend and grow normally, spermatogenses occurs. Normal testosterone but low dihydrotestosterone. Identify as female until puberty, then male.
- Androgen insensitivity synd – MOST COMMON, 1/20,000. If complete are phenotypic females, but all ranges with partial AIS. Normal testes, normal/elevated testosterone.
o CAIS – female external, blind vagina, no uterus, intra-abdominal testes (may present with inguinal hernia). No puberty (present with amenorrhoea). Normal response to hCG stimulation test.
o PAIS - variety of phenotypes.
46XX DSD, overvirisilised female
Female Sex development
- Ovaries: 46 XX, genetic factors such as DAX1 and signalling molecule WNT-4 • Absence of SRY gene, MIS and testosterone – persistence of mullerian duct into uterus, vagina, ovaries.
- CAH (commonest) – usually due to 21-hydroxylase or 11-hydroxylase defects.
- Aromatase deficiency – hypergonadotrophic hypergonadism
- Glucocorticoid receptor gene mutation
- Virilising maternal tumour
- Maternal ingestion of androgens during pregnancy
Ovotesticular DSD – ovarian and testicular tissue present
• 70% 46 XX karyotype
Control of insulin release
CAH with ambiguous genitalia or female genitalia XY (undervirilised)
17 alpha hydroxylse/17,20 lyase def
- HTN, Hypokalemia and xy pseudohermaphrodism
- Excess mineralocorticoids
3 beta hydroxysteroid dehydrogenase deficiency
- reduction in all adrenal hormones - salt wasting
- XY and XX can have ambiguous genitalia
17beta hydroxysteroid dehydrogenase deficiency (phenotypically similar to 5 alpha reductase deficiency ; can get virilisation at puberty)
STAR deficiency (moves cholesterol to mitochondria to allow steroid production) - affect all steroids
Determinants of growth
birth-3 years, mostly nutritional 3years - puberty - growth hormone, thyroid hormone Puberty - sex hormones, growth hormone - growth spurt in girls occurs earlier in puberty, approx 1 year before menses (mean 12 yrs) - growth spurt later in boys (14yrs)
Genetic short stature
Turners (45XO, webbed neck, shield chest, wide carrying angle, hypogonadism, Cardiac - CoA, BAV ; renal (horseshoe kidney), short stature due to defect SHOX Noonans Russel silver PW Achondroplasia / skeletal dysplasia T21 Familial (calculate MPH)
What do sertoli and leydig cells secrete?
- Sertoli - AMH, inhibin, androgen binding protein - Leydig - testosterone
IPEX Syndrome
- immunodysregulation polyendocrinopathy enteropathy X-linked -FOXP3 gene immune dysfunction enteropathy - diarrhoea Endocrine - early diabetes, hypothyroidism
What is the defect in osteogenesis imperfecta?
Type I collagen
What is the likelihood of spontaneous puberty in Turner Syndrome?
-70% of Turner Syndrome patients will not go through puberty themselves -30% spontaneous puberty - FSH should be measured prior to pubertal induction to confirm that it is elevated
What are some common endocrinological changes in anorexia nervosa?
- hypothalamic suppression, low normal to low gonadotropin and sex hormone levels - Decelerated linear growth, pubertal delay/regression, menstrual dysfunction - Low IGF-1 and T4 levels - Sick euthyroid if severely malnourished - Reduced bone mineral density
Mechanism action GNRH agonist
Physiological puberty requires the pulsatile secretion of gonadotrophin releasing hormone (GnRH). • GnRH agonists are analogues of native GnRH. • GnRH agonists are now used to suppress puberty in adolescents with gender dysphoria and contemplating cross-hormone treatment and later gender-affirming surgery. The rationale of continuous GnRH secretion for the suppression of pubertal development is that the pituitary gonadotrophs are subject to prolonged rather than intermittent (pulsatile) exposure to the RH. • Following an initial ‘flare’ in LH and FSH secretion, the pituitary gonadotroph receptors become desensitized and LH and FSH secretion is subsequently suppressed.
Causes of heavy menstrual bleeding
The most common cause of heavy menstrual bleeding is anovulatory cycles. 40% of adolescent women report heavy menstrual bleeding. Causes of heavy menstrual bleeding can be divided into the PALM-COEIN acronym. • PALM = structural causes = polyp, adenomyosis, leiomyoma, malignancy and hyperplasia. • Structural causes are rare in adolescent women with heavy menstrual bleeding. • COEIN = non-structural causes = coagulopathy, ovulatory dysfunction, endometrial, iatrogenic (medications), not yet classified. • Screen for a personal and family history of heavy or unusual or prolonged bleeding. • Of women with heavy menstrual bleeding, 10 – 20% have an underlying clotting disorder (e.g. von willebrand disease, thrombocytopaenia, platelet defects, clotting factor deficiencies). • Polycystic ovarian syndrome and thyroid disease can also cause ovulatory dysfunction.
