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What is the first step to take if TSH is measured at > 40 mU/L?
What is the first step to take if TSH is measured at > 40 mU/L?
Delayed bone age is considered a definitive indicator of hypothyroidism.
Delayed bone age is considered a definitive indicator of hypothyroidism.
False
What is the goal of administering oral Thyroxine (T4) in treating hypothyroidism?
What is the goal of administering oral Thyroxine (T4) in treating hypothyroidism?
Normalize serum free T4
Endemic cretinism is primarily found in countries with severe ______ deficiency.
Endemic cretinism is primarily found in countries with severe ______ deficiency.
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Match the diagnostic studies to their purposes:
Match the diagnostic studies to their purposes:
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What is a clinical feature associated with 21-hydroxylase deficiency in females?
What is a clinical feature associated with 21-hydroxylase deficiency in females?
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In 11-β-hydroxylase deficiency, aldosterone levels are typically high.
In 11-β-hydroxylase deficiency, aldosterone levels are typically high.
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What is the primary management for lifelong replacement in patients with 21-hydroxylase deficiency?
What is the primary management for lifelong replacement in patients with 21-hydroxylase deficiency?
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In 11-β-hydroxylase deficiency, patients may exhibit _________ due to high levels of ACTH.
In 11-β-hydroxylase deficiency, patients may exhibit _________ due to high levels of ACTH.
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Match the following conditions with their associated clinical features:
Match the following conditions with their associated clinical features:
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What is the mode of inheritance for 5-α-reductase deficiency?
What is the mode of inheritance for 5-α-reductase deficiency?
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Individuals with 5-α-reductase deficiency typically do not develop male external genitalia.
Individuals with 5-α-reductase deficiency typically do not develop male external genitalia.
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What is the karyotype associated with 5-α-reductase deficiency?
What is the karyotype associated with 5-α-reductase deficiency?
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In females with 5-α-reductase deficiency, breast development occurs due to the conversion of testosterone to _____ by aromatase.
In females with 5-α-reductase deficiency, breast development occurs due to the conversion of testosterone to _____ by aromatase.
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Match the following management treatments with their corresponding age and sex:
Match the following management treatments with their corresponding age and sex:
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What is the main regulator of glucocorticoid synthesis?
What is the main regulator of glucocorticoid synthesis?
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Cushing's Syndrome can be caused by both endogenous and exogenous sources of glucocorticoids.
Cushing's Syndrome can be caused by both endogenous and exogenous sources of glucocorticoids.
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What is the common exogenous cause of Cushing's Syndrome?
What is the common exogenous cause of Cushing's Syndrome?
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In Cushing's Syndrome, increased glucocorticoids lead to ______ of fat deposition.
In Cushing's Syndrome, increased glucocorticoids lead to ______ of fat deposition.
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Match the following conditions with their respective causes:
Match the following conditions with their respective causes:
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What clinical feature is associated with 17 α-Hydroxylase Deficiency in males?
What clinical feature is associated with 17 α-Hydroxylase Deficiency in males?
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In 3β-Hydroxysteroid Deficiency, aldosterone levels are high.
In 3β-Hydroxysteroid Deficiency, aldosterone levels are high.
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Name one feature associated with high ACTH levels in 3β-Hydroxysteroid Deficiency.
Name one feature associated with high ACTH levels in 3β-Hydroxysteroid Deficiency.
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In 11β OH Deficiency, patients experience _____ levels of serum androgens.
In 11β OH Deficiency, patients experience _____ levels of serum androgens.
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Match the adrenal disorder with its related clinical feature:
Match the adrenal disorder with its related clinical feature:
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Which of the following is a characteristic feature of neurological hypothyroidism?
Which of the following is a characteristic feature of neurological hypothyroidism?
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Weight gain in hypothyroidism occurs despite an increased appetite.
Weight gain in hypothyroidism occurs despite an increased appetite.
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What is the common cause of acquired hypothyroidism?
What is the common cause of acquired hypothyroidism?
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The recommended dose of oral thyroxine (T4) for treating hypothyroidism is _____ µg/kg/day.
The recommended dose of oral thyroxine (T4) for treating hypothyroidism is _____ µg/kg/day.
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Match the following symptoms with the type of hypothyroidism:
Match the following symptoms with the type of hypothyroidism:
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What is the most common cause of delayed puberty?
What is the most common cause of delayed puberty?
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Absence of menarche by age 16 indicates delayed puberty in females.
Absence of menarche by age 16 indicates delayed puberty in females.
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Name one syndrome associated with delayed puberty that is characterized by loss of smell.
Name one syndrome associated with delayed puberty that is characterized by loss of smell.
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Obesity and almond-shaped eyes are characteristics of __________ syndrome.
Obesity and almond-shaped eyes are characteristics of __________ syndrome.
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Match the syndrome with its characteristic feature:
Match the syndrome with its characteristic feature:
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What is the most common cause of central gonadotropin-dependent precocious puberty in females?
What is the most common cause of central gonadotropin-dependent precocious puberty in females?
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Cafe-au-lait spots are a clinical feature of McCune-Albright syndrome.
Cafe-au-lait spots are a clinical feature of McCune-Albright syndrome.
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What genetic defect is associated with McCune-Albright syndrome?
What genetic defect is associated with McCune-Albright syndrome?
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Autonomous functioning ovarian cysts in girls may lead to increased ______ production.
Autonomous functioning ovarian cysts in girls may lead to increased ______ production.
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Match the following conditions with their associated features:
Match the following conditions with their associated features:
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Which of the following is a surgical treatment for Cushing's disease?
Which of the following is a surgical treatment for Cushing's disease?
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Congenital adrenal hyperplasia (CAH) is inherited in an autosomal dominant pattern.
Congenital adrenal hyperplasia (CAH) is inherited in an autosomal dominant pattern.
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What is the most common adrenal disorder in childhood?
What is the most common adrenal disorder in childhood?
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The enzyme responsible for converting progesterone to 11-deoxycorticosterone is called ______.
The enzyme responsible for converting progesterone to 11-deoxycorticosterone is called ______.
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Match the following adrenal disorders with their associated enzyme deficiencies:
Match the following adrenal disorders with their associated enzyme deficiencies:
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Which of the following manifestations is commonly associated with Cushing's syndrome?
Which of the following manifestations is commonly associated with Cushing's syndrome?
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Proximal muscle weakness is a symptom associated with excess cortisol production.
Proximal muscle weakness is a symptom associated with excess cortisol production.
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What is the primary screening test for assessing Cushing's syndrome?
What is the primary screening test for assessing Cushing's syndrome?
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The presence of striae is often observed in patients with __________.
The presence of striae is often observed in patients with __________.
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Match the following testing methods with their purpose:
Match the following testing methods with their purpose:
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Study Notes
TSH Assessment
- TSH is measured 2-4 days after birth.
- If TSH is greater than 40 mU/L, TFT (Thyroid Function Tests) should be performed, and treatment should be initiated.
Radiological Assessment
- Delayed bone age is a sign of possible hypothyroidism.
- Epiphyseal stippling/dysgenesis, dot-like structures at the epiphysis, can be observed but are not diagnostic of hypothyroidism.
Confirmatory Tests
- Ultrasound of the Thyroid: Confirms the presence, absence, or ectopic location of the thyroid gland.
- Radionuclide Study: Uses radioactive isotopes, primarily 131^{131}131I or to a lesser extent 99m^{99m}99mTc, to assess thyroid function.
Treatment
- Oral Thyroxine (T4) is the primary treatment for hypothyroidism.
- Treatment should begin as early as possible to promote brain growth.
- The initial dose is typically 10-15 µg/kg/day, with adjustments made to normalize serum free T4 levels.
- Treatment is lifelong.
Endemic Cretinism
- Endemic cretinism is prevalent in regions experiencing severe iodine deficiency.
21-Hydroxylase Deficiency: Clinical Features
- Low aldosterone levels result in decreased blood pressure, hyponatremia (salt wasting), hyperkalemia (potassium reabsorption), and potentially shock.
- High androgen levels lead to precocious puberty in males and ambiguous genitalia (clitoromegaly) in females.
21-Hydroxylase Deficiency: Management
- Newborn screening for 17-hydroxyprogesterone (17-OHP) levels is essential for early diagnosis.
- Lifelong replacement therapy with fludrocortisone (for aldosterone) and hydrocortisone (for cortisol) is required.
- Dosage adjustments are necessary during periods of stress, with increased requirements for minor stress (infections) and major stress (surgeries).
- Surgical correction of ambiguous genitalia should be performed within 2-6 months (clitoroplasty).
11β-Hydroxylase Deficiency: Clinical Features
- Low aldosterone levels are present.
- Low cortisol levels are present.
- High androgen levels lead to precocious puberty in males and ambiguous genitalia in females.
- High ACTH (Adrenocorticotrophic hormone) levels contribute to hyperpigmentation.
- High 11-deoxycorticosterone levels have mineralocorticoid activity, leading to hypertension despite low aldosterone.
5 α-Reductase Deficiency: Mode of Inheritance and Karyotype
- X-linked recessive inheritance pattern.
- Karyotype: 46 + XY (male).
5 α-Reductase Deficiency: Phenotypic Appearance (Classical Form)
- Variable features depending on the severity of resistance.
- Females with 5 α-reductase deficiency can have breast development due to increased testosterone conversion to estrogen via aromatase.
- These individuals lack a uterus, pubic, and axillary hair, and have palpable inguinal masses due to undescended testes.
5 α-Reductase Deficiency: Pathophysiology
- Testosterone is converted into 5-dihydrotestosterone (5-DHT) by 5-α-reductase.
- Deficiency in 5-α-reductase impairs the development of male external genitalia, specifically the fusion of the scrotum and the lengthening of the penis.
5 α-Reductase Deficiency: Clinical Features
- Female-like features in childhood, potentially leading to being raised as a girl.
- Puberty brings increased testosterone levels, resulting in spontaneous virilization (development of male characteristics).
- Apparent change of gender can occur.
5 α-Reductase Deficiency: Management
- Sex steroid replacement is essential.
- For females, ethinylestradiol is prescribed after the age of 12, while males receive testosterone after the age of 14.
- Oral progesterone can be added two years later in females to induce breakthrough bleeding.
- Early administration of replacement therapy can lead to premature epiphysis fusion and short stature.
17 α-Hydroxylase Deficiency: Enzyme Pathway
- Deficiency in 17α-hydroxylase enzyme leads to decreased cortisol and testosterone production, while aldosterone is unaffected.
- The decreased cortisol triggers an increase in ACTH.
17 α-Hydroxylase Deficiency: Clinical Features
- High aldosterone levels result in hypertension.
- Low androgen levels cause undervirilization (reduced male sexual development) in males, including hypospadias, bifid scrotum, and delayed puberty. Ambiguous genitalia can occur in severe cases. Females usually have asymptomatic delayed puberty.
3β-Hydroxysteroid Deficiency: Enzyme Pathway
- Deficiency in 3β-hydroxysteroid dehydrogenase enzyme leads to decreased production of cortisol, aldosterone, and androgens.
- ACTH levels are elevated.
3β-Hydroxysteroid Deficiency: Clinical Features
- Low aldosterone levels lead to low blood pressure, hyponatremia, and hyperkalemia.
- High ACTH causes hyperpigmentation.
- Low androgen levels cause undervirilization in males, while females experience mild virilization in older children.
- Additional features include acne, hirsutism, and menstrual irregularities.
Pointers for Diagnosis of Adrenal Deficiencies
Feature21 OH Deficiency11β OH Deficiency3β HSD Deficiency17 α OH DeficiencySalt Wasting+---Serum Androgen↑↑↓↓
Steroidogenesis: Physiology
- Steroidogenesis refers to the synthesis of glucocorticoids, androgen steroids, and mineralocorticoids.
- Glucocorticoids are regulated by ACTH.
- Mineralocorticoids (specifically aldosterone) are regulated by intravascular volume, plasma K+, and the Renin Angiotensin-Aldosterone System (RAAS).
Cholesterol in Steroidogenesis
- Cholesterol is the precursor molecule for steroid hormone synthesis.
STAR (Steroidogenic Acute Regulatory Protein) in Steroidogenesis
- STAR is a protein essential for the transport of cholesterol into mitochondria, the site of steroid synthesis.
ACTH (Adrenocorticotrophic Hormone) in Steroidogenesis
- ACTH stimulates the production of cortisol, a glucocorticoid, from the adrenal cortex.
Cushing's Syndrome: Etiology
- Cushing's syndrome is characterized by high glucocorticoid levels.
- The cause can be endogenous, meaning increased production within the body, or exogenous, due to external steroid sources.
Cushing's Syndrome: Endogenous Causes
- ACTH-independent: Usually occurs in young children.
- Adrenal adenoma (benign tumor)
- Adrenal carcinoma (malignant tumor)
- ACTH-dependent:
- Pituitary source: Usually occurs in older children or adolescents.
- Microadenoma (small tumor in the pituitary gland): Cushing's disease
- Ectopic source (from tumor): Rare.
- Neuroblastoma (most common ectopic tumor)
- Wilms tumor
- Carcinoid
- Pituitary source: Usually occurs in older children or adolescents.
Cushing's Syndrome: Exogenous Cause
- Most common cause: External source of steroids (e.g., medications).
Cushing's Syndrome: Clinical Features
- Increased fat deposition: Glucocorticoids promote lipolysis (breakdown of fat), leading to fat deposition in specific areas.
Acquired Hypothyroidism: Cause
- Less common than congenital hypothyroidism.
- Autoimmune disease, Hashimoto's thyroiditis, is the primary cause, involving autoimmune antibody-mediated damage to the thyroid gland.
- Hashimoto's thyroiditis is more prevalent in adolescent females.
Acquired Hypothyroidism: Features
- Growth retardation/short stature is the first sign.
- Constipation, dry skin, and uncontrollable weight gain despite poor appetite are common.
- Goiter (firm, nodular swelling) is often present.
- Delayed puberty is frequently observed.
Acquired Hypothyroidism: Management
- TFT: T3, T4, and TSH levels need to be assessed.
- Detection of autoantibodies: Anti-TPO (thyroid peroxidase) and anti-thyroglobulin antibodies are indicative of autoimmune thyroiditis.
Acquired Hypothyroidism: Treatment
- Oral thyroxine (T4) is the primary treatment.
- The dose, typically 3-5 µg/kg/day, is adjusted based on TSH levels.
- Treatment is lifelong.
Puberty: Definition
- Puberty entails the development of secondary sexual characteristics.
- In females, thelarche (breast development) is the first sign, occurring earlier than males.
- In males, testicular enlargement marks the onset of puberty.
Delayed Puberty: Definition
- Male: Pubertal changes do not occur after 14 years of age.
- Female:
- No breast development (thelarche) after 13 years of age.
- Menarche (first menstruation) does not occur by 16 years of age or more than 5 years after thelarche.
Delayed Puberty: Etiology
- Most common cause: Constitutional delay in growth and puberty.
- Central/Hypogonadotropic Hypogonadism: Caused by pituitary or hypothalamic disorders, leading to low LH and FSH levels and consequently low sex steroid levels.
Syndromes Associated With Delayed Puberty
- Kallmann syndrome: Characterized by anosmia (loss of smell) in addition to delayed puberty.
- Prader-Willi syndrome: A genomic imprinting disorder with features including obesity, almond-shaped eyes, and small hands.
- Laurence-Moon-Biedl-Bardet syndrome: Includes obesity, polydactyly (extra fingers or toes), and retinitis pigmentosa (eye disorder).
Peripheral/Hypergonadotropic Hypogonadism
- Occurs when low sex steroid levels stimulate an increase in LH and FSH.
Causes of Peripheral/Hypergonadotropic Hypogonadism
- Chromosomal anomalies:
- Turner syndrome: Characterized by streak ovaries.
- Klinefelter syndrome: A chromosomal disorder affecting males.
- Cryptorchidism: Undescended testes leading to reduced testosterone production.
- Congenital adrenal hyperplasia (CAH): Impairment of 17-α-hydroxylase can cause delayed puberty in males.
- Insufficient androgen action:
- Androgen Insensitivity Syndrome (AIS): Resistance to androgen due to mutations in the AR gene.
- 5-α-reductase deficiency: Impaired conversion of testosterone to 5-DHT.
Other Potential Causes of Delayed Puberty
- CNS injury: Trauma or infiltrative disorders of the pituitary gland (e.g., histiocytosis, sarcoidosis).
Precocious Puberty: Definition
- Pubertal changes occurring before the expected age.
Precocious Puberty: Etiology
- Central/gonadotropin-dependent: Disorders in the hypothalamus and pituitary gland are the root causes.
- Idiopathic: Most common in females.
- CNS pathology: Most common in males.
- Hypothalamic hamartomas (most common)
- Other factors: Gelastic seizures.
- Peripheral/gonadotropin-independent:
- Functioning tumors: More common in the testes, leading to increased testosterone production.
- Leydig cell tumors
- Sertoli cell tumors
- Autonomously functioning ovarian cysts:
- Albright syndrome: Increased estrogen production.
- Congenital adrenal hyperplasia: Deficiency of 21-hydroxylase or 11-β-hydroxylase.
- Functioning tumors: More common in the testes, leading to increased testosterone production.
McCune-Albright Syndrome
- A genetic disorder characterized by autonomous endocrine hyperfunction of multiple glands, including the thyroid, pituitary, adrenal gland, and ovaries.
- Genetic defect: GNAS1 gene mutation (gain of function) affects the α-subunit of Gs receptors, leading to uncontrolled receptor activation.
McCune-Albright Syndrome: Clinical Features
- Cafe-au-lait spots: Irregularly shaped, light brown spots on the skin with "Coast of Maine" appearance.
- Polyostotic fibrous dysplasia: Multiple lytic bone lesions.
- Sites affected: Base of skull, proximal femur (bowing), and Shepherd's crook deformity (deformation of the proximal humerus).
Manifestations of Cushing's Syndrome
- Moon facies (round, full face).
- Abdominal obesity.
- Striae (stretch marks).
- Buffalo hump (fat accumulation between the shoulders).
Mechanisms of Cushing's Syndrome
- Hypertension: Intrinsic mineralocorticoid activity of some glucocorticoids.
- Hirsutism (excessive hair growth): Overstimulation of the adrenal gland leads to increased androgen production in ACTH-dependent cases.
- Delayed puberty: Cortisol inhibits gonadotropin production.
- Proximal muscle weakness: Affects shoulders and hips.
- Short stature: Slows down growth.
Cushing's Syndrome: Investigations
- Screening: 24-hour urine free cortisol levels.
- Tests:
- Overnight dexamethasone suppression test: Single dose of dexamethasone given at night.
- Normal: Decreased cortisol levels in the morning due to suppression by dexamethasone.
- Cushing's syndrome: Increased cortisol levels next morning, indicating inability to suppress.
- Low-dose dexamethasone suppression test: 0.5 mg/kg of dexamethasone every 6 hours for 2 days.
- Decreased feedback: ACTH should be estimated.
- High-dose dexamethasone suppression test:
- Suppression: If the test shows suppression of cortisol.
- No suppression: If the test does not show suppression of cortisol.
- Overnight dexamethasone suppression test: Single dose of dexamethasone given at night.
ACTH Estimation (pg/mL)
- Low (ACTH-independent): <15 pg/mL.
- Very high (Ectopic tumor releasing ACTH): >100 pg/mL.
Cushing's Syndrome: Treatment
- Surgical:
- Resection of the identified tumor.
- Cushing's disease: Trans-sphenoidal resection (surgical removal of the pituitary tumor through the nose).
- Medical:
- AKA medical adrenalectomy.
- Medical inhibition of adrenal steroidogenesis using antifungals:
- Ketoconazole
- Metirapone
- Metotane
Congenital Adrenal Hyperplasia (CAH)
- Most common adrenal disorder in childhood.
- Mode of inheritance: Autosomal recessive.
Pathophysiology of CAH
- Enzyme deficiencies:
- 21-hydroxylase (21-OH)
- 11β-hydroxylase (11β-OH)
- 17α-hydroxylase (17α-OH)
- 3β-hydroxysteroid dehydrogenase (3β-HSD)
Feedback to Pituitary Gland in CAH
- Deficiencies in enzymes lead to a buildup of precursor steroids, which trigger an increase in ACTH.
- Increased ACTH stimulates adrenal gland hyperplasia (enlargement).
Adrenal Zones in CAH
- Zona glomerulosa: Secretes mineralocorticoids (aldosterone).
- Zona fasciculata: Secretes glucocorticoids (cortisol).
- Zona reticularis: Secretes androgen steroids.
- Peripheral tissues: Target tissues for steroid hormones.
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Description
Test your knowledge on hypothyroidism, disorders related to adrenal hormone deficiencies, and the associated clinical features. This quiz covers key topics such as TSH levels, Thyroxine treatment, and genetic inheritance patterns in endocrine diseases.
