Endocrine Flashcards
Definition and causes of micropenis
Micropenis is defined as a normally formed penis that is at least 2.5 standard deviations below the mean in size. Stretched penile length of the newborn is typically 3.5cm (+/- 0.7), diagnosis is made on a length of <1.9cm. Micropenis results from a hormonal abnormality that occurs after 14wks of gestation, commonly:
1) Hypogonadothropic gonadism = secondary hypogonadism (most commonly GRH deficiency e.g. Kallmann synd, Prader Willi or Lawrence Moon-Biedl)
2) Hypergonadotrophic gonadism (primary testicular failure)
3) Idiopathic micropenis
Congenitalpanhypopituitarism is characterised by:
1) Micropenis – FSH/LH def – usually small but normal appearing penis, small testes
2) Optic atrophy
3) Midline defects
4) Poor growth
5) Hypoglycaemia – due to severe GH and/or ACTH def – jitteriness, irritability, seizures
Presentation depends on severity of deficiency. Some come to attention because of low thyroid levels on Guthrie screen, others may present with hypernatraemic diabetes insipidus, and older children most commonly present with growth failure at any age.
Presentation of classic CAH
Commonest is 21-hydroxylase deficiency, ‘classic’ CAH, 50% of these have salt wasting form. Usually presents with an adrenal crisis at 2-3 weeks of age (FTT, vomiting, hypotension, dehydration, hyponatraemia, hyperkalemia, hypoglycaemia, shock).
Females have ambiguous genitalia at birth due to virilizing effects of excess androgens inutero
Males not identified early in neonatal period because normal genitalia
5 alpha-reductase deficiency
Autosomal recessive ‘intersex’ condition -5AR converts testosterone to the more physiologically active dihydrotestosterone (DHT). DHT is required for masculinisation of male external genitalia in-utero. Genotypicaly male, phenotypically variable – from mildly undervirilised male genitalia with isolated micropenis or hypospadias to marked undervirilisation with female genitalia with clitoral enlargement. Have internal testes, wolffian organs. No uterus, fallopian tubes, may have pseuodovagina. May be misdiagnosed for androgen insensitivity syndrome, until puberty when start to virilise instead of feminise
primary amenorrhoea, sterility, short 4th metatarsal, wide spaced nipple, webbed neck, short stature, lack of development of primary and secondary sexual characteristics, pigmented naevi, increased urinary gonadotrophins.
Turner syndrome – a gonadal dysgenesis syndrome.Female phenotype -45X (also written as 45XO) is commonest genotype. Mosaicism is 45X/46XY – a non-dysjunction event in the zygote creates a cell line that is missing an X. If happens early -Turner syndrome; if happens late - normal male.
Signs - primary amenorrhoea, sterility, short 4th metatarsal, wide spaced nipple, webbed neck, short stature, lack of development of primary and secondary sexual characteristics, pigmented naevi, increased urinary gonadotrophins.
Action of 1,25-dihydroxycholecalciferol to increase plasma Ca
Promotes activation of osteocalcin and alkaline phosphatase production by osteoblasts, and the differentiation of osteoclasts precursors, having a net effect in mobilising calcium and phosphate from bone.
In the kidney, 1,25-dihydroxycholecalciferol facilitates the action of PTH on distal tubule calcium absorption.
The growth promoting effects of Growth Hormone (GH) are mostly mediated by?
Specific effects of GH
GH acts by binding to a specific receptor, located mostly in the liver, and inducing intracellular signaling by a phosphorylation cascade. Its predominant action is to stimulate hepatic synthesis and secretion of IGF-I, a potent growth and differentiation factor.
As a differentiating and growth factor, IGF-I is a critical protein induced by GH, and is likely responsible for most of the growth-promoting activities of GH.
Furthermore, IGF-I also directly inhibits GH secretion and GH receptor function by a negative feedback loop.
Specific effects
GH stimulates linear growth in children by acting directly and indirectly (via the synthesis of IGF-I) on the epiphyseal plates of long bones.
GH also has specific metabolic actions including:
Increased lipolysis and lipid oxidation, which leads to mobilization of stored triglyceride
Stimulation of protein synthesis
Antagonism of insulin action
Phosphate, water, and sodium retention
Insulin requirements in diabetes
Pre/Mid/end puberty
Pre-pubertal children require about 0.7U/kg/day
1U/kg/day mid puberty
1.2U/kg/day by end of puberty.
Mechanism of thiazolidinediones
The thiazolidinediones, also known as glitazones, are a class of medications used in the treatment of Type 2 diabetes mellitus. They were introduced in the late 1990s.
They increase insulin sensitivity by acting on adipose, muscle, and liver to increase glucose utilisation and decrease glucose production.
The mechanism by which the thiazolidinediones exert their effect is not fully understood. They bind to and activate one or more peroxisome proliferator-activated receptors, which regulate gene expression in response to ligand binding.
Rosiglitazone and pioglitazone are registered for use in monotherapy, and in combination with sulfonylureas and metformin. Pioglitazone is also licensed for use in combination with insulin.
Central precocious puberty
Bloods
When is it pathological
Most common causes
Rx
Elevated LH and FSH is suggestive of central precocious puberty.
CPP in girls is only pathological in 10-20% of cases, but is more likely to be pathological if onset is at <6 years of age and/or is rapidly progressive.
Hypothalamic hamartomas are the most common CNS cause of precocious puberty; in some cases puberty is preceded by gelastic seizures. Puberty in these instances is always isosexual.
In NF1, optic gliomas interrupting the HPG axis are the most common cause of CPP.
Regardless of the causative lesion, treatment with a GnRH-agonist is the treatment of choice for halting pubertal development.
Most common cause of death in DKA
60% mortality due to cerebral oedema
0.3 to 0.9 percent of cases of diabetic ketoacidosis (DKA)
Among children with DKA who develop cerebral injury, the mortality rate is 20 to 25 percent, and 21 to 26 percent of survivors have permanent neurologic sequelae.
What is leptin
Leptin is a 16 kDA protein hormonethat plays a key role in regulating energy intake and energy expenditure (appetite and metabolism).Leptin is released by fat cells in amounts mirroring overall body fat stores. Thus, circulating leptin levels give the brain a reading of energy storage for the purposes of regulating appetite and metabolism.
most commonly deficient hormones following craniopharyngioma surgery.
Vasopressin, also known as ADH
The second most common is growth hormone.
5a-reductase deficiency
Deficiency in which hormone
5a-Reductase is an enzyme required for the conversion of testosterone to dihydrotestosterone, a potent androgen particularly important in the fetal development of male external genitalia. 5a-reductase deficiency thus results in an increased ratio of testosterone: DHT, and ambiguous genitalia in XY individuals. Testosterone production at puberty results in male secondary sex characteristics.
GH in hypoglycemia
Hypoglycaemia usually stimulates GH release as part of the physiological counter-regulatory response. GH and cortisol both increase lipolysis and gluconeogenesis and inhibit the effects of insulin. Severe GH deficiency may cause hypoglycaemia, particularly if it occurs in conjunction with panhypopituitarism. It is thus investigated routinely in the setting of severe, unexplained hypoglycaemia.
Hormonal regulation of calcium
A complex hormonal system regulates the serum calcium concentration
Acutely: large reservoir of calcium that is present in bone
Chronically: balance between calcium intake from the GIT and renal losses
In growing children, a net +ve calcium balance is required for growth and skeletal mineralization.
Calcium absorption occurs in theduodenum and jejunum
Calcium binding proteins and activation of calcium pump
1,25-dihydroxyvit D stimulates transport of calcium
Breast milk (300mg/L), formula (530mg/L), and cow’s milk (1,200mg/L)
Parathyroid hormone (PTH), released by the parathyroid gland in response to low serum calcium levels:
Stimulates bone osteoclasts to dissolve bone, also increases number of osteoclasts
Stimulates 1α-hydroxylase
Also affects intestinal absorption
Increases calcium reabsorption in distal nephron
Active vit D suppresses PTH production
Parathyroid hormone (PTH) acutely increases serum calcium predominantly by:
Stimulating release from bone
Stimulates bone osteoclasts to dissolve bone, also increases number of osteoclasts
It also….
Stimulates 1α-hydroxylase
Also affects intestinal absorption
Increases calcium reabsorption in distal nephron
Active vit D suppresses PTH production
What is inappropriate ketosis in hypoglycemia and what does it mean
Inappropriate ketosis — The presence of only mild or moderate ketosis (beta-hydroxybutyrate of <2.5 mmol/L) at the time of hypoglycemia in a child indicates that FFAs are not being mobilized appropriately or cannot be used for ketone body formation. These findings suggest hyperinsulinism or fatty acid oxidation defects, respectively.
Hypoglycemia with Appropriate ketosis
The presence of ketonemia indicates that the child is able to mobilize FFAs and use them for ketone body formation. Diagnostic considerations in these children include a normal fasting response, ketotic hypoglycemia, growth hormone and/or cortisol deficiency, some disorders of fatty acid oxidation, and disorders of amino and organic acids. The measurement of qualitative urine organic acids and the presence or absence of hepatomegaly can help to distinguish among these possibilities.
Biochemical findings during the hypoglycemic episode that are consistent with ketotic hypoglycemia include:
Appropriately decreased insulin levels (≤2 microM/mL [15 pmol/L])
Normal lactate and pyruvate
Elevated GH, cortisol, FFA, and associated ketonuria and ketonemia
Decreased alanine on quantitative plasma amino acids
Normal thyroxine (excludes hypopituitarism)
Normal free and total carnitine, normal distribution of the fatty acid length in the acylcarnitines
No response to administration of glucagon at time of hypoglycemia, but normal response after an overnight fast
Negative urine reducing substances
Presentation of Growth hormone deficiency.
Patients with congenital, severe GHD have a low birth size. There is a higher frequency of breech presentation and perinatal asphyxia. Neonatal morbidity may include hypoglycemia (can be severe if combined with deficiency of ACTH or TSH) and prolonged jaundice. However, acquired (later onset) GHD would be unlikely to present with hypoglycaemia.
MCAD presentation
Abnormalities in fatty acid oxidation and ketone body formation are rare, but severe, metabolic disorders that result in hypoglycemia and hypoketonemia. Fatty acid oxidation disorders include carnitine deficiency, fatty acid transportation defects, and defects of beta-oxidation enzymes. The generation of ketone bodies by the liver (which is the only organ with the enzymatic capacity to generate acetoacetate and beta-hydroxybutyrate) involves mobilization of FFA, activation of fatty acids by acyl-CoA synthetase, transport into the hepatic mitochondrial matrix, and mitochondrial beta-oxidation of the fatty acids and transport of the ketone bodies into the circulation. Medium-chain-acyl-CoA dehydrogenase (MCAD) deficiency is the most common fatty acid oxidation defect.Children who have disorders of fatty acid oxidation may present with profound hypoglycaemia, decreased plasma concentration of free and total carnitine, relatively low plasma ketone concentrations, and elevated concentrations of free fatty acids. Their urine may contain dicarboxylic acids or acylglycine.
Presentation of Type IV glycogen storage disease
. Glycogen branching enzyme (GBE) deficiency (GSD IV) is also known as Andersen disease, and is an autosomal recessive disorder. GBE catalyzes the attachment of short glucosyl chains to a naked peripheral chain of nascent glycogen. Deficiency results in abnormal structure of glycogen. Affected patients typically present in early infancy with hepatosplenomegaly and failure to thrive. Hypoglycemia is not a feature until late in the course of the disease, when it is associated with cirrhosis, esophageal varices, and ascites.Therefore, youwould expect features of liver disease in this child
Presentation of 21-hydroxylase deficiency
21-hydroxylase deficiency is the most common form of CAH, accounting for >90% of cases. Females are often recognised at birth due to clitoromegaly or ambiguous genitalia. Postnatal virilisation occurs in both genders.The classic form involves a complete or near-complete deficiency of 21-hydroxylase, resulting in adrenal insufficiency and androgen excess. 70% of those with the classic form are also ‘salt-wasting’ due to mineralocorticoid deficiency. The non-classic form results from a partial deficiency of 21-hydroxylase and may present as precocious adrenarche, hirsuitism, acne, or infertility. 17-hydroxypreogesterone is elevated.
Presentation of 11 beta hydroxylase definitely
11-beta hydroxylase deficiency is the second most common subtype of CAH, accounting for 5% of cases.Corticosterone is produced therefore adrenal insufficiency is rare. Aldosterone synthesis is normal, however excessive deoxycorticosterone causes hypertension with decreased renin. Androgen excess can cause ambiguous genitalia in females and increased height, skeletal age, virilisation and pubic hair development in both genders. Penile enlargement with pre-pubertal testes is classical in boys. 17-hydroxyprogesterone is elevated.
Presentation of 17-alpha hydroxylase deficiency
17-alpha hydroxylase deficiency is an uncommon subtype of CAH which manifests as ambiguous genitalia in males due to androgen insufficiency, and excess deoxycortisosterone causing hypertension, hypokalaemia, and suppression of the RAA-System. Females often present with failure of sexual development at puberty. Corticosterone is produced and is an active glucocorticoid, therefore cortisol is low but adrenal insufficiency is not manifested.Hydrocortisone is given to suppress deoxycorticosterone and manage hypertension.
Most common hormone deficiency post craniopharyngioma surgery
Vasopressin, also known as ADH
.The second most common is growth hormone.
Hormones of the posterior pituitary
Oxytocin
ADH/Vasopressin
Both secreted by hypothalamus
Insulin requirements in diabetic children
Pre pubertal 0.7 units/kg/day
Mid pubertal 1unit/kg/day
End of puberty 1.2units/kg/day
How is PTH regulated
Serum ionised calcium via a sensitive calcium sensing receptor on the surface of parathyroid cells
A small increase in iCa causes inhibition of PTH secretion
Commonest autoantibody in newly diagnosed Type 1 DM
Glutamic acid decarboxylase (antibody against beta cell antigens)
GAD
Hypothalamic hormones acting on anterior and posterior pituitary
Hypothalamic hormones - anterior pituitary:
GnRH (LH, FSH)
GHRH (GH)
Dopamine (prolactin)
TRH (TSH)
CRH (ACTH)
Hypothalamic hormones - posterior pituitary:
ADH
Oxytocin
Pressure on the hypothalamic centres affects?
appetite, thirst, somnolence/wakefulness, precociouspuberty.Mamillary bodies in the posterior pituitary are involved in memory.
acanthosis nigricans associations
Commonest association is familial/common obesity
Most patients with acanthosis nigricans have higher insulin levels cf. pts of the same weight and no AN, and usually some degree of insulin resistance
It is thought that high insulin levels or ILGF-1 causes AN
Other (rare) causes – tumour, congenital, medications
The bioavailability of sex hormones depends on
Testosterone and oestradiol circulate in blood stream bound to sex hormone binding globulin and to a lesser extent, albumin. Only a small amount is unbound -therefore free and biologically active. The bioavailability of sex hormones depends on level of SHBG
What role do Sertoli cells play in embryonic development
Produce AMH which is responsible for the regression of the Mullerian ducts (which would go on to form the uterus, fallopion tubes and cervix)
What role do leydig cells play in embryonic development
Leydig cells produce testosterone
- which acts locally to form the Wolffian structures such as the epididymis, Vas deferans, seminiferous tubules
- circulating testosterone is also converted into the more potent dihydrotestosterone which is required for fusion of the genital folds and complete masculisation of the fetus
Later in life adult type leydig cells (LH responsive) is required for pubertal development and fertility
Pseudo parathyroidism
Hypocalcemia
Hyperphosphatamie
Raised PTH
Order of puberty events in boys
Growth of the testes (>3 mL in volume or 2.5 cm in longest diameter) and thinning of the scrotum are the first signs of puberty
Followed by pigmentation of the scrotum and growth of the penis
Pubic hair then appears, axillary hair usually occurs in midpuberty
Acceleration of growth maximal at genital stage IV–V (typically between 13 and 14 yr of age
Order of puberty events in girls
Breast development (thelarche) is usually the first sign of puberty (10–11 years)
Appearance of pubic hair (adrenarche) 6–12 months later
Peak height velocity occurs early (at breast stage II–III, typically between 11 and 12 years of age) in girls and always precedes menarche
The interval to menarche is usually 2–2.5 years but may be as long as 6 years
The mean age of menarche is about 12.75 years
