Endocrinology Flashcards
1
Q
Growth hormone
- ____ stimulates GH release
- ____ Inhibits GH release
A
Growth hormone
- Growth hormone-releasing hormone (GHRH) stimulates GH release
- Somatostatin inhibits GH release
2
Q
LH and FSH
- ____, released primarily from the gonad, inhibits only FSH secretion.
A
LH and FSH
- Inhibin, released primarily from the gonad, inhibits only FSH secretion.
3
Q
Prolactin
- Different in that it is under tonic hypothalamic inhibition by _____ sent down the pituitary stalk.
- ____ drugs (such as metoclopramide and phenothiazines) also increase prolactin, as does ____. Thus, prolactin elevates with primary ____ and with any inhibition in the production of dopamine from the hypothalamus (most commonly, medications).
A
Prolactin
- Different in that it is under tonic hypothalamic inhibition by dopamine sent down the pituitary stalk.
- Antidopaminergic drugs (such as metoclopramide and phenothiazines) also increase prolactin, as does TRH. Thus, prolactin elevates with primary hypothyroidism and with any inhibition in the production of dopamine from the hypothalamus (most commonly, medications).
4
Q
Congenital hypopituitarism:
- Generally includes ____ deficiency along with >1 of the 5 hormones produced in the anterior pituitary
- Pt:
- Predominant presenting symptom: _____
- Small penis, undescended testes- microphallus is a clue in males to GH deficiency
- _____ suggests septa-optic dysplasia
- Low free thyroxine, TSH deficiency
- Neonatal cholestasis with direct hyperbilirubinemia
A
Congenital hypopituitarism:
- Generally includes GH deficiency along with >1 of the 5 hormones produced in the anterior pituitary
- Pt:
- Predominant presenting symptom: Hypoglycemia
- Small penis, undescended testes- microphallus is a clue in males to GH deficiency
- Wandering nystagmus suggests septa-optic dysplasia
- Low free thyroxine, TSH deficiency
- Neonatal cholestasis with direct hyperbilirubinemia
5
Q
Congenital defects that can present with hypopituitarism Septooptic dysplasia (Morsier syndrome) - Involves abnormality of the optic nerve (absence of the optic chiasm, optic nerve hypoplasia, or both), agenesis or hypoplasia of the septum pellucidum or corpus callosum or both; and often variable degrees of hypothalamic insufficiency
Any lesion that destroys the hypothalamus, pituitary, or pituitary stalk can cause pituitary hormone deficiencies.
- Due to its location in the suprasellar region, craniopharyngioma is the most common tumor to cause acquired pituitary hormone deficiencies in children. Tumor calcifications are often noted on imaging studies
A
Congenital defects that can present with hypopituitarism Septooptic dysplasia (Morsier syndrome) - Involves abnormality of the optic nerve (absence of the optic chiasm, optic nerve hypoplasia, or both), agenesis or hypoplasia of the septum pellucidum or corpus callosum or both; and often variable degrees of hypothalamic insufficiency
Any lesion that destroys the hypothalamus, pituitary, or pituitary stalk can cause pituitary hormone deficiencies.
- Due to its location in the suprasellar region, craniopharyngioma is the most common tumor to cause acquired pituitary hormone deficiencies in children. Tumor calcifications are often noted on imaging studies
6
Q
GROWTH HORMONE DEFICIENCY
- Pt:
- Normal length and weight at birth.
- Severe defects in GH production: Drop lower than 4 SDs below the mean by 1yo
- Less severe defects have a variable effect on growth
- Microphallus (or micropenis) is a clue in males
- Hypoglycemia and prolonged direct hyperbilirubinemia in the neonatal period
- Know: ______ anomalies, such as a solitary ______, indicate a high likelihood of GH deficiency. Pts with cleft lip or cleft palate have about a 4% chance of having GH deficiency. Bilateral or unilateral ______ hypoplasia is also associated with hypopituitarism.
- Normal length and weight at birth.
- Dx:
- Suspect GH deficiency with postnatal _______ (heights or lengths >3 SD below the mean) and even more importantly, a slow growth velocity.
- Falling off the growth curve after 3 yo is a huge red flag and deserves evaluation.
- CBC with diff, ESR or CRP, CMP, celiac disease screen, Free T4/TSH, IGF-1, IGF-BP3, urinalysis, karyotype (in girls)
- Serum level of ________ and the GH-dependent _________ that are in the upper part of the normal range pretty much rule out GH deficiency.
- Definitive: Lack of response to ____________ in the clinical setting of growth failure
- GH levels that do not rise >10ug/L after stimulation using 2 different agents are consistent with GH deficiency.
- Bone age must be >2 SD from the mean to be considered delayed or advanced.
- Suspect GH deficiency with postnatal _______ (heights or lengths >3 SD below the mean) and even more importantly, a slow growth velocity.
- Treatment of GH Deficiency
- Begin tx as soon as you make the diagnosis
- Give recombinant ______ at a dose of 0.18-0.30mg/kg/week subcutaneously in 6-7 divided doses/week.
- Side effects of GH therapy:
- ____, ______, transient carbohydrate intolerance, transient hypothyroidism, and scoliosis
- Must monitor for hypothyroidism as it occasionally occur transient during therapy
- From careful analysis of existing databases, there appears to be no increased risk of leukemia for children with no other risk factors
- Side effects of GH therapy:
A
GROWTH HORMONE DEFICIENCY
- Pt:
- Normal length and weight at birth.
- Severe defects in GH production: Drop lower than 4 SDs below the mean by 1yo
- Less severe defects have a variable effect on growth
- Microphallus (or micropenis) is a clue in males
- Hypoglycemia and prolonged direct hyperbilirubinemia in the neonatal period
- Know: Midfacial anomalies, such as a solitary maxillary central incisor, indicate a high likelihood of GH deficiency. Pts with cleft lip or cleft palate have about a 4% chance of having GH deficiency. Bilateral or unilateral optic nerve hypoplasia is also associated with hypopituitarism.
- Normal length and weight at birth.
- Dx:
- Suspect GH deficiency with postnatal growth failure (heights or lengths >3 SD below the mean) and even more importantly, a slow growth velocity.
- Falling off the growth curve after 3 yo is a huge red flag and deserves evaluation.
- CBC with diff, ESR or CRP, CMP, celiac disease screen, Free T4/TSH, IGF-1, IGF-BP3, urinalysis, karyotype (in girls)
- Serum level of insulin-like growth factor-1 (IGF-1) and the GH-dependent IGF-binding protein-3 (IGF-BP3) that are in the upper part of the normal range pretty much rule out GH deficiency.
- Definitive: Lack of response to stimulation of GH production (GH-stimulation testing) in the clinical setting of growth failure
- GH levels that do not rise >10ug/L after stimulation using 2 different agents are consistent with GH deficiency.
- Bone age must be >2 SD from the mean to be considered delayed or advanced.
- Suspect GH deficiency with postnatal growth failure (heights or lengths >3 SD below the mean) and even more importantly, a slow growth velocity.
- Treatment of GH Deficiency
- Begin tx as soon as you make the diagnosis
- Give recombinant human growth hormone (hGH) at a dose of 0.18-0.30mg/kg/week subcutaneously in 6-7 divided doses/week.
- Side effects of GH therapy:
- SCFE, pseudotumor cerebri, transient carbohydrate intolerance, transient hypothyroidism, and scoliosis
- Must monitor for hypothyroidism as it occasionally occur transient during therapy
- From careful analysis of existing databases, there appears to be no increased risk of leukemia for children with no other risk factors
- Side effects of GH therapy:
7
Q
Congenital growth hormone deficiency
- Pt:
- Linear growth deceleration after the first 6-12mo of life
A
Congenital growth hormone deficiency
- Pt:
- Linear growth deceleration after the first 6-12mo of life
8
Q
Acquired growth hormone deficiency
- Path:
- Pituitary hormone deficiencies are common after cranial irradiation. GH axis is the most sensitive and the first to be affected.
- Pt: Linear growth deceleration after a period of normal growth
A
Acquired growth hormone deficiency
- Path:
- Pituitary hormone deficiencies are common after cranial irradiation. GH axis is the most sensitive and the first to be affected.
- Pt: Linear growth deceleration after a period of normal growth
9
Q
SHORT STATURE
Short stature is ___ STD below mean height for children of same sex and age OR height less than ____rd%ile
A
SHORT STATURE
Short stature is 2 STD below mean height for children of same sex and age OR height <2.3rd%ile
10
Q
Evaluation for child with short stature
- For children with short stature, normal growth rate, and no other symptoms
- Bone age indicates a pt’s potential growth
- A delayed bone age gives a pt more growth potential whereas an advanced bone age gives less potential growth, and a normal bone age does not allow for any additional growth when compared to age-matched peers.
- Bone age must be >2 SD from the mean to be considered delayed or advanced.
- Turner’s syndrome would have a concordant bone age. A declining growth velocity can be consistent with an endocrine disorder such as GH deficiency or hypothyroidism. Bone age, however, would be delayed in these endocrine disorders.
- For children with severe short stature (height less than -2.5 SD / 0.6th%ile) or growth failure
- Falling off the growth curve after 3 yo is a huge red flag and deserves evaluation.
- CBC with diff, ESR or CRP, CMP, celiac disease screen (tTG, IgA), Free T4/TSH, IGF-1, IGF-BP3, urinalysis, karyotype (in girls)
- Karyotype to rule out Turner syndrome
A
Evaluation for child with short stature
- For children with short stature, normal growth rate, and no other symptoms
- Bone age indicates a pt’s potential growth
- A delayed bone age gives a pt more growth potential whereas an advanced bone age gives less potential growth, and a normal bone age does not allow for any additional growth when compared to age-matched peers.
- Bone age must be >2 SD from the mean to be considered delayed or advanced.
- Turner’s syndrome would have a concordant bone age. A declining growth velocity can be consistent with an endocrine disorder such as GH deficiency or hypothyroidism. Bone age, however, would be delayed in these endocrine disorders.
- For children with severe short stature (height
11
Q
Familial/ Genetic short stature (Normal growth velocity, normal bone age, family hx of short stature)
- CA __ BA ___ HA.
A
Familial/ Genetic short stature (Normal growth velocity, normal bone age, family hx of short stature)
- CA = BA > HA.
12
Q
Constitutional delay of growth and puberty (Normal growth velocity, delayed bone age, typically family hx of delayed puberty)
- Pt:
- Birth weight and height are normal with normal growth during initial 4-12mo.
- Followed by decreased linear growth at 4-6 months and continuing until 2-3 years old.
- By 2-3yo, linear growth resumes at a normal growth velocity at >5cm/year
- Puberty is delayed
- Family hx of “late bloomers”
- Dx
- Diagnosis of exclusion
- ___ bone age radiography.
- CA __ BA __ HA
- If height is plotted for bone age, it falls within the target height range percentiles
- ___ bone age radiography.
- Diagnosis of exclusion
- Tx:
- Providing reassurance regarding final height with follow-up in 6-12 months
A
Constitutional delay of growth and puberty (Normal growth velocity, delayed bone age, typically family hx of delayed puberty)
- Pt:
- Birth weight and height are normal with normal growth during initial 4-12mo.
- Followed by decreased linear growth at 4-6 months and continuing until 2-3 years old.
- By 2-3yo, linear growth resumes at a normal growth velocity at >5cm/year
- Puberty is delayed
- Family hx of “late bloomers”
- Dx
- Diagnosis of exclusion
- Delayed bone age radiography.
- CA > BA = HA
- If height is plotted for bone age, it falls within the target height range percentiles
- Delayed bone age radiography.
- Diagnosis of exclusion
- Tx:
- Providing reassurance regarding final height with follow-up in 6-12 months
13
Q
Arrest/slow in height and increasing/maintained weight, think endocrine causes.
A
Arrest/slow in height and increasing/maintained weight, think endocrine causes.
14
Q
Growth Hormone Deficiency (decrease in growth velocity, delayed bone age, family hx of hormone deficiency is sometimes seen in these pts)
A
Growth Hormone Deficiency (decrease in growth velocity, delayed bone age, family hx of hormone deficiency is sometimes seen in these pts)
15
Q
Russell-Silver syndrome
- Short stature, frontal bossing, triangular facies, shortened and incurved 5th fingers (clinodactyly), and asymmetry. With NORMAL head circumference
- Low birth weights (SGA) and FTT
- Hemihypertrophy. Cafe au lait spots. Delayed bone age. Reflux is major issue.
A
Russell-Silver syndrome
- Short stature, frontal bossing, triangular facies, shortened and incurved 5th fingers (clinodactyly), and asymmetry. With NORMAL head circumference
- Low birth weights (SGA) and FTT
- Hemihypertrophy. Cafe au lait spots. Delayed bone age. Reflux is major issue.
16
Q
Growth hormone is approved for the following indications
- Idiopathic short stature
- Children with idiopathic short stature whose height is >___ STDs below the mean (less than __%) and who are unlikely to catch up in height.
- Children born SGA who have not achieved a height >2 SDs below the mean (about __%) by age 2yo
- ____ deficiency
- ____ syndrome
- ___ syndrome
- ____ syndrome
- SHOX gene haploinsufficiency (short stature homeobox)
- Chronic renal insufficiency (pretransplantation only)
A
Growth hormone is approved for the following indications
- Idiopathic short stature
- Children with idiopathic short stature whose height is >2.25 STDs below the mean (<1.2%) and who are unlikely to catch up in height.
- Children born SGA who have not achieved a height >2 SDs below the mean (about 2%) by age 2yo
- Growth hormone deficiency
- Turner syndrome
- Noonan syndrome
- Prader-Willi syndrome
- SHOX gene haploinsufficiency (short stature homeobox)
- Chronic renal insufficiency (pretransplantation only)
17
Q
DIABETES INSIPIDUS
- Classifications:
- Think of Central DI (inadequate ADH production) in the pt with high Na and high urine volume who also has a hx of recent neurosurgery, head trauma, or brain cancer/metastasis. Some pts have idiopathic central DI, but most endocrinologists would still rule-out pituitary etiologies, esp adenomas, with appropriate imaging.
- A pt with nephrogenic DI has renal ADH insensitivity.
- Pt: Polyuria and polydipsia are the classic symptoms (but these sx may be discounted or not noticed), in which case chronic dehydration is likely to be the presenting finding.
- New-onset enuresis may be the 1st sign seen in older children.
- Dx:
- Serum osmolality >___mOsm/kg with urine osmolality less than __ mOsm/kg is pathognomonic for DI.
- Extremely low or absent serum ADH strongly supports the dx of central DI.
- Administer _______ to determine whether the pt can respond to ADH.
- Central DI: Giving desmopressin increases urine osmolality and therefore decreases plasma osmolality back toward normal values (~280mOsm/kg)
- Nephrogenic DI, giving desmopressin does not increase urine osmolality
- Water restriction test distinguishes primary polydipsia from central DI.
- Uosm increases = ______
- No change in Uosm, Dilute urine - give ADH
- Uosm increases =_____
- No change in Uosm = _____
- A 2015 study found that a ______ level >21.4 pmol/L has a 100% sensitivity and 100% specificity for nephrogenic DI! If this test is available, do it when nephrogenic DI is a possibility to immediately rule it out.
A
DIABETES INSIPIDUS
- Classifications:
- Think of Central DI (inadequate ADH production) in the pt with high Na and high urine volume who also has a hx of recent neurosurgery, head trauma, or brain cancer/metastasis. Some pts have idiopathic central DI, but most endocrinologists would still rule-out pituitary etiologies, esp adenomas, with appropriate imaging.
- A pt with nephrogenic DI has renal ADH insensitivity.
- Pt: Polyuria and polydipsia are the classic symptoms (but these sx may be discounted or not noticed), in which case chronic dehydration is likely to be the presenting finding.
- New-onset enuresis may be the 1st sign seen in older children.
- Dx:
- Serum osmolality >300mOsm/kg with urine osmolality <300 mOsm/kg is pathognomonic for DI.
- Extremely low or absent serum ADH strongly supports the dx of central DI.
- Administer 1-desamino-8-D-arginine vasopressin (aka desmopressin or DDAVP) to determine whether the pt can respond to ADH.
- Central DI: Giving desmopressin increases urine osmolality and therefore decreases plasma osmolality back toward normal values (~280mOsm/kg)
- Nephrogenic DI, giving desmopressin does not increase urine osmolality
- Water restriction test distinguishes primary polydipsia from central DI.
- Uosm increases = psychogenic polydipsia.
- No change in Uosm, Dilute urine - give ADH
- Uosm increases = central diabetes insipidus
- No change in Uosm = nephrogenic diabetes insipidus
- A 2015 study found that a copeptin level >21.4 pmol/L has a 100% sensitivity and 100% specificity for nephrogenic DI! If this test is available, do it when nephrogenic DI is a possibility to immediately rule it out.
18
Q
Nephrogenic Diabetes Insipidus
- Lack of response to ADH by the kidney collecting tubules.
- _____ is the most widely known drug to induce nephrogenic DI.
- Tx: _______
- Requires sufficient intake of water.
- If applicable, discontinue any drug that is the cause of DI.
- Low-sodium (specifically, low-solute-load) diets
- ____
- _____
A
Nephrogenic Diabetes Insipidus
- Lack of response to ADH by the kidney collecting tubules.
- Lithium is the most widely known drug to induce nephrogenic DI.
- Tx: Gentle diuresis
- Requires sufficient intake of water.
- If applicable, discontinue any drug that is the cause of DI.
- Low-sodium (specifically, low-solute-load) diets
- Thiazides
- Amiloride
19
Q
Central (Neurogenic) Diabetes Insipidus
- Decreased antidiuretic hormone
- Path:
- Idiopathic (most common)
- Primary/inherited forms are very rare
- Second/acquired forms are much more common. Injury to the hypothalamus and posterior pituitary gland:
- CNS tumors (most common cause)
- Craniopharyngioma
- Infiltrative lesions (histiocytosis)
- Head trauma (surgical or nonsurgical)
- CNS tumors (most common cause)
- Tx: Responds well to ______
A
Central (Neurogenic) Diabetes Insipidus
- Decreased antidiuretic hormone
- Path:
- Idiopathic (most common)
- Primary/inherited forms are very rare
- Second/acquired forms are much more common. Injury to the hypothalamus and posterior pituitary gland:
- CNS tumors (most common cause)
- Craniopharyngioma
- Infiltrative lesions (histiocytosis)
- Head trauma (surgical or nonsurgical)
- CNS tumors (most common cause)
- Tx: Responds well to desmopressin
20
Q
Syndrome of Inappropriate Antidiuretic Hormone Secretion
- Causes: SIADH results from either excess secretion of ADH or the production of ADH-like molecules by tumors or other tissues.
- Ex: Brain lesion (tumor close to posterior pituitary results in transient SIADH)
- Pt: Dilutional hyponatremia due to water retention
- Dx:
- ____ serum sodium, ____ serum osmolality due to water retention
- High Urine osmolality (UOsm), high urine specific gravity due to water retention in kidney
- High urine sodium (UNa) due to sodium excretion in the kidney from hypervolemia suppressing aldosterone
- Rule out ____ or ____ before making diagnosis of SIADH as both can have low serum osmolalities and high urine osmolalities
- Tx:
- _____
- Severe symptoms/hyponatremia require immediate tx with hypertonic 3% NaCl
- Antibiotic _____ has been shown to interfere with ADH receptor and can be used to tx pts with chronic low Na concentrations due to SIADH.
A
Syndrome of Inappropriate Antidiuretic Hormone Secretion
- Causes: SIADH results from either excess secretion of ADH or the production of ADH-like molecules by tumors or other tissues.
- Ex: Brain lesion (tumor close to posterior pituitary results in transient SIADH)
- Pt: Dilutional hyponatremia due to water retention
- Dx:
- Low serum sodium, low serum osmolality due to water retention
- High Urine osmolality (UOsm), high urine specific gravity due to water retention in kidney
- High urine sodium (UNa) due to sodium excretion in the kidney from hypervolemia suppressing aldosterone
- Rule out hypothyroidism or glucocorticoid deficiency before making diagnosis of SIADH as both can have low serum osmolalities and high urine osmolalities
- Tx:
- Fluid restriction.
- Severe symptoms/hyponatremia require immediate tx with hypertonic 3% NaCl
- Antibiotic demeclocycline has been shown to interfere with ADH receptor and can be used to tx pts with chronic low Na concentrations due to SIADH.
21
Q
Cerebral Salt Wasting
- Path: Due to oversecretion of ______ that is normally released in response to hypervolemia states and promotes ___ and ___ excretion and lowers BP.
- Pt:
- Increased UOP with resultant hypovolemia
- Labs:
- Low plasma sodium
- High urinary sodium excretion (>150 mEq/L)
- Low ___
- High ___ concentrations
- (vs SIADH with low UOP, low plasma sodium, high vasopressin, normal ANP concentrations)
- Tx:
- Replacement of UOP with IV solutions - NS Isotonic fluid hydration to 3% sodium, depending on the clinical situation
A
Cerebral Salt Wasting
- Path: Due to oversecretion of atrial natriuretic peptide (ANP) that is normally released in response to hypervolemia states and promotes salt and water excretion and lowers BP.
- Pt:
- Increased UOP with resultant hypovolemia
- Labs:
- Low plasma sodium
- High urinary sodium excretion (>150 mEq/L)
- Low vasopressin
- High ANP concentrations
- (vs SIADH with low UOP, low plasma sodium, high vasopressin, normal ANP concentrations)
- Tx:
- Replacement of UOP with IV solutions - NS Isotonic fluid hydration to 3% sodium, depending on the clinical situation
22
Q
ACTH-Adrenal-Cortisol Axis Deficiency
- Different from SIADH in that, with cortisol deficiency, there is dilute urine with low urine osmolality (vs decreased UOP and high urine osmolality with SIADH).
- In addition, cortisol deficiency causes hypoglycemia.
A
ACTH-Adrenal-Cortisol Axis Deficiency
- Different from SIADH in that, with cortisol deficiency, there is dilute urine with low urine osmolality (vs decreased UOP and high urine osmolality with SIADH).
- In addition, cortisol deficiency causes hypoglycemia.
23
Q
Tall stature = >__SD above the mean height for age
A
Tall stature = >2SD above the mean height for age
24
Q
3 genetic causes of tall stature include ___ syndrome (XXY; 1/600 males), ___ syndrome (AD; 1/5000), and ___ (AR; 1/200,000)
A
3 genetic causes of tall stature include Klinefelter syndrome (XXY; 1/600 males), Marfan syndrome (AD; 1/5000), and homocystinuria (AR; 1/200,000)
25
Q
Evaluation of tall stature
- Lab and further testing should be directed by history and physical exam findings.
- If hx is suggestive of a genetic disorder or the physical exam is abnormal, screen for GH excess with a random ___ level and serum ___ and ____ concentrations.
- If there is increased GH, order a brain/sella MRI
- An oral glucose tolerance test can also be useful, bc a large glucose load should suppress GH levels but typically does not in the setting of excess GH production.
- Chromosomal analysis is helpful in males if Klinefelter syndrome is suspected.
- If hx is suggestive of a genetic disorder or the physical exam is abnormal, screen for GH excess with a random ___ level and serum ___ and ____ concentrations.
- Tx:
- Can give height-limiting therapy if predicted adult height is >77” for boys and >72” for girls or if significant psychosocial impairment exists bc of the height. However, this is highly controversial.
- Sex steroids (estrogens for girls, testosterone for boys) can be helpful but only if given early enough in puberty to accelerate epiphyseal fusion and limit further growth.
- Remember estrogen fuses the growth plates.
- Can give height-limiting therapy if predicted adult height is >77” for boys and >72” for girls or if significant psychosocial impairment exists bc of the height. However, this is highly controversial.
A
Evaluation of tall stature
- Lab and further testing should be directed by history and physical exam findings.
- If hx is suggestive of a genetic disorder or the physical exam is abnormal, screen for GH excess with a random GH level and serum IGF-1 and IGF-BP3 concentrations.
- If there is increased GH, order a brain/sella MRI
- An oral glucose tolerance test can also be useful, bc a large glucose load should suppress GH levels but typically does not in the setting of excess GH production.
- Chromosomal analysis is helpful in males if Klinefelter syndrome is suspected.
- If hx is suggestive of a genetic disorder or the physical exam is abnormal, screen for GH excess with a random GH level and serum IGF-1 and IGF-BP3 concentrations.
- Tx:
- Can give height-limiting therapy if predicted adult height is >77” for boys and >72” for girls or if significant psychosocial impairment exists bc of the height. However, this is highly controversial.
- Sex steroids (estrogens for girls, testosterone for boys) can be helpful but only if given early enough in puberty to accelerate epiphyseal fusion and limit further growth.
- Remember estrogen fuses the growth plates.
- Can give height-limiting therapy if predicted adult height is >77” for boys and >72” for girls or if significant psychosocial impairment exists bc of the height. However, this is highly controversial.
26
Q
PUBERTY
- Normally, about 1-3 years before puberty is clinically evidence, LH levels become detectable during sleep.
- ____ is pulsatile in nature and increases as clinical puberty approaches.
- ____ is the most useful gonadotropin to assess for the onset of puberty
- ____ secretion is responsible for the onset and progression of puberty.
___ - and not androgens - lead to epiphyseal fusion and cessation of growth.
A
PUBERTY
- Normally, about 1-3 years before puberty is clinically evidence, LH levels become detectable during sleep.
- LH is pulsatile in nature and increases as clinical puberty approaches.
- LH is the most useful gonadotropin to assess for the onset of puberty
- GnRH secretion is responsible for the onset and progression of puberty.
Estrogens - and not androgens - lead to epiphyseal fusion and cessation of growth.
27
Q
Female:
No SRY gene - causes gonads to develop into ovaries
Testosterone → ( aromatase) → Estrogen → _____
Adrenal gland → Androgen (DHEA) → ____
A
Female:
No SRY gene - causes gonads to develop into ovaries
Testosterone → ( aromatase) → Estrogen → breast development (gonadal)
Adrenal gland → Androgen (DHEA) → pubic/axillary/odor
28
Q
Male:
SRY gene - causes formation of testes
FSH → ___ cells → ___ & ____ → Inhibit mullerian duct formation
LH → ____ cells → ____
→ Wolffian duct virilize into epididymis, vas deferens, seminal vesicle
→ Secondary sex characteristics (hair/voice)
→ Estrogen
– (5a-reductase) → DHT → _____ (gonadal)
Adrenal gland → Androgen (DHEA) → _____
A
Male:
SRY gene - causes formation of testes
FSH → Sertoli cells → Estrogens & MIS → Inhibit mullerian duct formation
LH → Leydig cells → Testosterone
→ Wolffian duct virilize into epididymis, vas deferens, seminal vesicle
→ Secondary sex characteristics (hair/voice)
→ Estrogen
– (5a-reductase) → DHT → external genitalia (gonadal)
Adrenal gland → Androgen (DHEA) → hair/acne/odor
29
Q
PUBERTY STAGES
Female
- Stage I (0-15yo)
- Stage 2 (8-15yo)
- Height increases at accelerated rate 7-8cm/year
- Stage 3 (10-15yo)
- P3: Adult type pubic hair (coarse, dark, curly) with distribution limited to symphysis pubis and labia majora
- Peak growth velocity occurs 8cm/year
- Menarche occurs in 2% of girls in late stage 3
- Stage 4 (10-17yo)
- B4: Projection of areola from secondary breast mound at a different angle
- Menarche occurs in most girls 1-3 years after thelarche in Tanner stage 3 or 4
- Stage 5 (12.5-15yo)
A
PUBERTY STAGES
Female
- Stage I (0-15yo)
- Stage 2 (8-15yo)
- Height increases at accelerated rate 7-8cm/year
- Stage 3 (10-15yo)
- P3: Adult type pubic hair (coarse, dark, curly) with distribution limited to symphysis pubis and labia majora
- Peak growth velocity occurs 8cm/year
- Menarche occurs in 2% of girls in late stage 3
- Stage 4 (10-17yo)
- B4: Projection of areola from secondary breast mound at a different angle
- Menarche occurs in most girls 1-3 years after thelarche in Tanner stage 3 or 4
- Stage 5 (12.5-15yo)
30
Q
Male
- Stage 1 (0-15yo)
- Stage 2 (10-15yo)
- Enlargement and reddening of testes - Stage 3 (11.5-16.5yo)
- Lengthening of phallus begins in SMR 3.
- Height increases at accelerated rate: 7-8 cm/year
- Gynecomastia may occur (age 13.2yo)
- Voice breaks (age 13.5yo)
- Ejaculation and spermarche - SMR 3. Occurs one year after testes enlarge
- Change of voice at SMR 3-4 pubic
- Stage 4 (12-17yo)
- Pubic hair adult in type but not in distribution (extends across the pubis but spares the medial surface of the thighs)- Darker scrotal skin
- Axillary hair, acne, and deepening of voice
- Height increases at peak rate 10cm/year (13.8yo)
- Stage 5 (13-18yo)
- Facial hair
- Testes >__mL, >___cm
A
Male
- Stage 1 (0-15yo)
- Stage 2 (10-15yo)
- Enlargement and reddening of testes - Stage 3 (11.5-16.5yo)
- Lengthening of phallus begins in SMR 3.
- Height increases at accelerated rate: 7-8 cm/year
- Gynecomastia may occur (age 13.2yo)
- Voice breaks (age 13.5yo)
- Ejaculation and spermarche - SMR 3. Occurs one year after testes enlarge
- Change of voice at SMR 3-4 pubic
- Stage 4 (12-17yo)
- Pubic hair adult in type but not in distribution (extends across the pubis but spares the medial surface of the thighs)- Darker scrotal skin
- Axillary hair, acne, and deepening of voice
- Height increases at peak rate 10cm/year (13.8yo)
- Stage 5 (13-18yo)
- Facial hair
- Testes >25mL, >4.5cm
31
Q
Tanner 1 less than __cm, Tanner 2: __-___cm length of testes, Tanner 3: ___-___cm length of testes; Tanner 4: __-___cm length of tests, Tanner 5: >__cm
A
Tanner 1 <2.5cm, Tanner 2: 2.5-3.3cm length of testes, Tanner 3: 3.4-4cm length of testes; Tanner 4: 4.1-4.5cm length of tests, Tanner 5: >4.5cm
32
Q
Workup is recommended for onset of puberty in boys less than __yo or absence by __yo and girls less than __yo and absence by __yo
A
Workup is recommended for onset of puberty in boys <9yo or absence by 14yo and girls <8yo and absence by 13yo
33
Q
Normal female puberty is considered late if there are no secondary sexual characteristics after __yo or if >__ years have passed between the beginning and completion of puberty.
A
Normal female puberty is considered late if there are no secondary sexual characteristics after 13yo or if >5 years have passed between the beginning and completion of puberty.
34
Q
Average time to complete puberty is _ years
A
Average time to complete puberty is 4 years
35
Q
Order for girls: Breast, hair, growth, menarche (TPGM) (BHHP)
- Thelarche = Breast bud (___yo), first sign of puberty
- Adrenarche/Pubarche = Pubic hair. Follows thelarche by 0.5-1 year
- Growth = Peak height velocity (SMR 2-3 breast) (___yo)
- Initiation of growth spurt (IGS) typically begins at around 9.5yo, with average peak height velocity of 9cm/yr (6-10cm/year) achieved at 11.5 years of age when most girls are at sexual maturity rating SMR 2-3 roughly 6 months before menarche.
- Menarche = Period (SMR breast Stage 3-4) (Mean age ___yo)
- Occurs about 2-2.5 years after thelarche, but can be as long as 5 years.
- Once menarche has started, most girls have about 3 inches (7cm) of growth left
- Physiologic leukorrhea precedes menarche by 6-12 months
A
Order for girls: Breast, hair, growth, menarche (TPGM) (BHHP)
- Thelarche = Breast bud (10yo), first sign of puberty
- Adrenarche/Pubarche = Pubic hair. Follows thelarche by 0.5-1 year
- Growth = Peak height velocity (SMR 2-3 breast) (11.5yo)
- Initiation of growth spurt (IGS) typically begins at around 9.5yo, with average peak height velocity of 9cm/yr (6-10cm/year) achieved at 11.5 years of age when most girls are at sexual maturity rating SMR 2-3 roughly 6 months before menarche.
- Menarche = Period (SMR breast Stage 3-4) (Mean age 12.5yo)
- Occurs about 2-2.5 years after thelarche, but can be as long as 5 years.
- Once menarche has started, most girls have about 3 inches (7cm) of growth left
- Physiologic leukorrhea precedes menarche by 6-12 months
36
Q
Order for boys: penis/testicular enlargement, hair/pubarche, growth/peak height velocity, spermarche (development of sperm)
- Gonadarche / Testicular enlargement (SMR Genital 2, >4mL testicular volume or >2.5cm in long axis) (__yo)
- Adrenarche/Pubarche = Pubic hair growth
- Growth spurt (SMR 3-4) (__yo)
- Initiation of growth spurt at 11.5 years, and reach PHV 10.3cm/year (5.8-13.1cm) at 13.5 year of age
- Compared to girls, boys have an additional 2 years of growth (at a rate of 5 cm/year) before growth spurt initiation. As a result, girls are about 10cm shorter than boys at IGS
A
Order for boys: penis/testicular enlargement, hair/pubarche, growth/peak height velocity, spermarche (development of sperm)
- Gonadarche / Testicular enlargement (SMR Genital 2, >4mL testicular volume or >2.5cm in long axis) (10yo)
- Adrenarche/Pubarche = Pubic hair growth
- Growth spurt (SMR 3-4) (13.5yo)
- Initiation of growth spurt at 11.5 years, and reach PHV 10.3cm/year (5.8-13.1cm) at 13.5 year of age
- Compared to girls, boys have an additional 2 years of growth (at a rate of 5 cm/year) before growth spurt initiation. As a result, girls are about 10cm shorter than boys at IGS
37
Q
PRECOCIOUS PUBERTY
- Girls <8yo, boys <9yo
- An earlier initiation of growth spurt means earlier cessation of growth that may result in shorter adult height.
- _________ is an important discriminator between central and peripheral precocious puberty.
- Workup: Measurement of LH, FSH, TSH, DHEAS, estradiol in girls, and testosterone in boys, and a bone age radiograph.
- Look for elevated LH and FSH for central sources of precocious puberty, 17-OHP to evaluate for CAH, DHEAS to evaluate for the possibility of adrenal tumors, and testosterone and estradiol for gonadal sources.
A
PRECOCIOUS PUBERTY
- Girls <8yo, boys <9yo
- An earlier initiation of growth spurt means earlier cessation of growth that may result in shorter adult height.
- Size of the testes is an important discriminator between central and peripheral precocious puberty.
- Workup: Measurement of LH, FSH, TSH, DHEAS, estradiol in girls, and testosterone in boys, and a bone age radiograph.
- Look for elevated LH and FSH for central sources of precocious puberty, 17-OHP to evaluate for CAH, DHEAS to evaluate for the possibility of adrenal tumors, and testosterone and estradiol for gonadal sources.
38
Q
CENTRAL PRECOCIOUS PUBERTY (Gonadotropin-dependent precocious puberty)
- Path: Early activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in increased LH and FSH levels
- CPP is much more common in girls than boys.
- Approx 95% of true precocity in females are sporadic and idiopathic.
- _______ is much more common in boys (25-75%) with central precocious puberty than in girls
- Pt:
- In boys and girls, height and weight are advanced, typically with marked linear growth acceleration.
- Bone maturation is accelerated, as evidenced by an advanced bone age.
- Because of early closure of the epiphyses, a majority of those who do not receive tx end up being <5%ile for height.
- Physical exam:
- Testes are _____ in volume (>__ ml) in central precocious puberty as they are stimulated by LH. Or an increase in size in ovaries (by US)
- Testicular size is an important discriminator bw central and peripheral precocious puberty in boys
- Testes are _____ in volume (>__ ml) in central precocious puberty as they are stimulated by LH. Or an increase in size in ovaries (by US)
- Labs: Detect by pubertal LH level, basal or stimulated
- __level > __ IU/L (pubertal level) is consistent with central precocious puberty
- Use of GnRH as a stimulation test can be helpful
- Elevated peak LH can be diagnostic.
- Bone age is typically quite advanced.
- Diagnosis- confirm with elevated serum __
- Be careful how you diagnose CPP - it is very specific.
- In girls, there must be ____ AND ____ involvement manifested by clinical features of both estrogen and androgen secretion
- In boys, all you need is____
- Need to rule out organic CNS etiologies with an MRI of brain
- As a rule, males with central precocious puberty have a ____ until proven otherwise.
- Be careful how you diagnose CPP - it is very specific.
- Tx:
- For almost all boys and girls with the rapidly progressive form of CPP, use long-acting _____ to interrupt the endogenous pulsatile GnRH from stimulating progression of sexual maturity.
- Because you want to have a constant level (depot preparations work well), _____ acetate
- For almost all boys and girls with the rapidly progressive form of CPP, use long-acting _____ to interrupt the endogenous pulsatile GnRH from stimulating progression of sexual maturity.
A
CENTRAL PRECOCIOUS PUBERTY (Gonadotropin-dependent precocious puberty)
- Path: Early activation of the hypothalamic-pituitary-gonadal (HPG) axis, resulting in increased LH and FSH levels
- CPP is much more common in girls than boys.
- Approx 95% of true precocity in females are sporadic and idiopathic.
- CNS pathology is much more common in boys (25-75%) with central precocious puberty than in girls
- Pt:
- In boys and girls, height and weight are advanced, typically with marked linear growth acceleration.
- Bone maturation is accelerated, as evidenced by an advanced bone age.
- Because of early closure of the epiphyses, a majority of those who do not receive tx end up being <5%ile for height.
- Physical exam:
- Testes are pubertal/larger in volume (>4 ml) in central precocious puberty as they are stimulated by LH. Or an increase in size in ovaries (by US)
- Testicular size is an important discriminator bw central and peripheral precocious puberty in boys
- Testes are pubertal/larger in volume (>4 ml) in central precocious puberty as they are stimulated by LH. Or an increase in size in ovaries (by US)
- Labs: Detect by pubertal LH level, basal or stimulated
- LH level > 0.3 IU/L (pubertal level) is consistent with central precocious puberty
- Use of GnRH as a stimulation test can be helpful
- Elevated peak LH can be diagnostic.
- Bone age is typically quite advanced.
- Diagnosis- confirm with elevated serum LH
- Be careful how you diagnose CPP - it is very specific.
- In girls, there must be adrenal AND gonadal involvement manifested by clinical features of both estrogen and androgen secretion
- In boys, all you need is gonadal involvement
- Need to rule out organic CNS etiologies with an MRI of brain
- As a rule, males with central precocious puberty have a brain tumor until proven otherwise.
- Be careful how you diagnose CPP - it is very specific.
- Tx:
- For almost all boys and girls with the rapidly progressive form of CPP, use long-acting GnRH analogs (GnRHa) to interrupt the endogenous pulsatile GnRH from stimulating progression of sexual maturity.
- Because you want to have a constant level (depot preparations work well), leuprolide acetate
- For almost all boys and girls with the rapidly progressive form of CPP, use long-acting GnRH analogs (GnRHa) to interrupt the endogenous pulsatile GnRH from stimulating progression of sexual maturity.
39
Q
Common Organic Brain Lesions Causing Central Precocious Puberty
- ________ is the most common brain lesion that causes CPP.
- This lesion contains ectopic neural tissue that contains GnRH-secretory neurons
- Pt:
- If it is a rapidly progressive precocity, hypothalamic hamartoma is the most likely etiology.
- Can cause _____, frequently manifested by inappropriate laughter.
- Tx: Traditional surgical intervention is not recommended for hypothalamic hamartomas, except for those pts with intractable seizures
- Other lesions causing CPP include postencephalitic scars, tuberculous brain involvement, hydrocephalus, tuberous sclerosis, head trauma, and neoplasms (about 50% are germinomas or astrocytomas)
A
Common Organic Brain Lesions Causing Central Precocious Puberty
- Hypothalamic hamartoma is the most common brain lesion that causes CPP.
- This lesion contains ectopic neural tissue that contains GnRH-secretory neurons
- Pt:
- If it is a rapidly progressive precocity, hypothalamic hamartoma is the most likely etiology.
- Can cause gelastic seizures, frequently manifested by inappropriate laughter.
- Tx: Traditional surgical intervention is not recommended for hypothalamic hamartomas, except for those pts with intractable seizures
- Other lesions causing CPP include postencephalitic scars, tuberculous brain involvement, hydrocephalus, tuberous sclerosis, head trauma, and neoplasms (about 50% are germinomas or astrocytomas)
40
Q
PERIPHERAL PRECOCIOUS PUBERTY (Gonadotropin-independent precocious puberty)
- Pt:
- A clue to a gonadotropin-independent cause of precocious puberty in a boy is virilization without ________ bc the testis grows from FSH stimulation.
- Dx:
- In girls with signs of excess exposure and in boys with prepubertal sized testes, measurement of 17-hydroxyprogesterone (for CAH), DHEA-S marker of adrenal androgen production), and testosterone (in girls) is indicated. Testicular US is indicated if a testicular tumor is suspected.
Tumors
- Rare tumors exist that can secrete androgen, estrogen, or gonadotropin (such as hCG), thereby causing gonadotropin-independent precocious puberty.
- A boy with an hCG-secreting tumor has testicular enlargement bc the hCG acts as LH. Therefore, you can recognize an hCG-secreting tumor bc the boy has testicular enlargement with a suppressed LH level (and a detectable hCG)
- The majority of tumors that cause peripheral precocious puberty are germ cell tumors.
A
PERIPHERAL PRECOCIOUS PUBERTY (Gonadotropin-independent precocious puberty)
- Pt:
- A clue to a gonadotropin-independent cause of precocious puberty in a boy is virilization without increase in testicular size bc the testis grows from FSH stimulation.
- Dx:
- In girls with signs of excess exposure and in boys with prepubertal sized testes, measurement of 17-hydroxyprogesterone (for CAH), DHEA-S marker of adrenal androgen production), and testosterone (in girls) is indicated. Testicular US is indicated if a testicular tumor is suspected.
Tumors
- Rare tumors exist that can secrete androgen, estrogen, or gonadotropin (such as hCG), thereby causing gonadotropin-independent precocious puberty.
- A boy with an hCG-secreting tumor has testicular enlargement bc the hCG acts as LH. Therefore, you can recognize an hCG-secreting tumor bc the boy has testicular enlargement with a suppressed LH level (and a detectable hCG)
- The majority of tumors that cause peripheral precocious puberty are germ cell tumors.
41
Q
McCune-Albright
- Path
- Due to a missense mutation in the _____ gene that encodes for the protein cAMP formation,
- Any receptors that operate with a cAMP-dependent mechanism can be affected (TSH, FSH, LH, GHRH, and ACTH receptors).
- Starts as GnRH independent and becomes GnRH dependent precocious puberty
- Pt:
- P___, p___ (cafe au lait Coast of ___) (vs “coast of California” in NF1), P____
- Usually, vaginal bleeding becomes evident by 3yo
- ______, by itself, is the classic endocrine presentation for MAS in girls!
- (Classic exam question is a female toddler with clearly developed breasts and a large, irregular CALM)
- LH and FSH are low, and there is no response to GnRH.
- Tx: Management varies depending on endocrine abnormalities present.
- GnRH agonists can be used if the puberty has switched to the gonadotropin-dependent form.
- For GH excess, _____ is useful.
- Prognosis is good, but significant bone deformities and fractures can result from the bony lesions.
A
McCune-Albright
- Path
- Due to a missense mutation in the GNAS1 gene that encodes for the protein cAMP formation,
- Any receptors that operate with a cAMP-dependent mechanism can be affected (TSH, FSH, LH, GHRH, and ACTH receptors).
- Starts as GnRH independent and becomes GnRH dependent precocious puberty
- Pt:
- Precocious puberty, patchy pigmentation (cafe au lait Coast of Maine) (vs “coast of California” in NF1), Polyostotic fibrous dysplasia of the skeletal system
- Usually, vaginal bleeding becomes evident by 3yo
- Vaginal bleeding, by itself, is the classic endocrine presentation for MAS in girls!
- (Classic exam question is a female toddler with clearly developed breasts and a large, irregular CALM)
- LH and FSH are low, and there is no response to GnRH.
- Tx: Management varies depending on endocrine abnormalities present.
- GnRH agonists can be used if the puberty has switched to the gonadotropin-dependent form.
- For GH excess, octreotide is useful.
- Prognosis is good, but significant bone deformities and fractures can result from the bony lesions.
42
Q
Benign premature thelarche
- Isolated breast development that occurs in the first 2 years of life.
- No involvement of the adrenal glands (no body odor, pubic hair, axillary hair development, acne)
- Dx: Diagnosis of exclusion
- You must rule out excessive exposure to estrogen (such as estrogen cream or estrogen- or placenta-containing shampoo, ingestion of OCPs, ingestion of excessive soy products, or excessive use of lavender or tea tree oil).
- Consider evaluating with an estradiol level, FSH level, LH level, and a bone age. Labs are normal for age.
- Isolated premature thelarche does not require further evaluation and workup. Evidence of true puberty such as signs of adrenarche, acne, and vaginal discharge in combination with thelarche points to an increased likelihood of central precocious puberty which requires further work up.
- Benign condition. Breast tissue usually persists for 3-5 years but can regress during this time.
- What appears to be benign premature thelarche may be the 1st sign of actual precocious puberty, so you must follow the child.
- If isolated breast development occurs after 3yo, it is almost always due to some other condition.
A
Benign premature thelarche
- Isolated breast development that occurs in the first 2 years of life.
- No involvement of the adrenal glands (no body odor, pubic hair, axillary hair development, acne)
- Dx: Diagnosis of exclusion
- You must rule out excessive exposure to estrogen (such as estrogen cream or estrogen- or placenta-containing shampoo, ingestion of OCPs, ingestion of excessive soy products, or excessive use of lavender or tea tree oil).
- Consider evaluating with an estradiol level, FSH level, LH level, and a bone age. Labs are normal for age.
- Isolated premature thelarche does not require further evaluation and workup. Evidence of true puberty such as signs of adrenarche, acne, and vaginal discharge in combination with thelarche points to an increased likelihood of central precocious puberty which requires further work up.
- Benign condition. Breast tissue usually persists for 3-5 years but can regress during this time.
- What appears to be benign premature thelarche may be the 1st sign of actual precocious puberty, so you must follow the child.
- If isolated breast development occurs after 3yo, it is almost always due to some other condition.
43
Q
Benign Premature Adrenarche
- Pt:
- Any combination of pubic or axillary hair, body odor, or acne before 8yo in girls and before 9yo in boys.
- There is no gonadal involvement (no breast development in girls and no testicular enlargement in boys).
- Dx: Rule out other causes of androgen excess, which can be exogenous or endogenous.
- A common cause of exogenous androgen exposure is accidental exposure.
- An example is when an adult male in the family uses transdermal androgen gel for testosterone replacement
- Endogenous causes of premature adrenarche include tumors or late-onset congenital adrenal hyperplasia.
- A common cause of exogenous androgen exposure is accidental exposure.
- Evaluation: Measure testosterone, DHEAS, androstenedione, 17-OHP, and bone age
- If any of the screening tests are abnormal, the pt must be evaluated for pathological conditions including late-onset CAH and adrenal tumors.
A
Benign Premature Adrenarche
- Pt:
- Any combination of pubic or axillary hair, body odor, or acne before 8yo in girls and before 9yo in boys.
- There is no gonadal involvement (no breast development in girls and no testicular enlargement in boys).
- Dx: Rule out other causes of androgen excess, which can be exogenous or endogenous.
- A common cause of exogenous androgen exposure is accidental exposure.
- An example is when an adult male in the family uses transdermal androgen gel for testosterone replacement
- Endogenous causes of premature adrenarche include tumors or late-onset congenital adrenal hyperplasia.
- A common cause of exogenous androgen exposure is accidental exposure.
- Evaluation: Measure testosterone, DHEAS, androstenedione, 17-OHP, and bone age
- If any of the screening tests are abnormal, the pt must be evaluated for pathological conditions including late-onset CAH and adrenal tumors.
44
Q
Premature Menarche
- Pt: Most girls have only 1-3 episodes of bleeding; then puberty occurs at the normal time, and subsequent menstrual cycles are normal
- In a child with isolated vaginal bleeding, first rule out more common causes such as foreign body, vulvovaginitis, or sexual abuse.
A
Premature Menarche
- Pt: Most girls have only 1-3 episodes of bleeding; then puberty occurs at the normal time, and subsequent menstrual cycles are normal
- In a child with isolated vaginal bleeding, first rule out more common causes such as foreign body, vulvovaginitis, or sexual abuse.
45
Q
There is no such thing as benign premature testelarche!
- If you see a boy <9yo with enlarged testes, the pt has a 27-75% chance of having a brain tumor. Order a brain MRI promptly!
A
There is no such thing as benign premature testelarche!
- If you see a boy <9yo with enlarged testes, the pt has a 27-75% chance of having a brain tumor. Order a brain MRI promptly!
46
Q
Pubertal Gynecomastia
- Occurs at puberty. Reaching peak prevalence at 14yo and SMR stages 2-3 or 3-4.
- Is a very specific diagnosis - you must evaluate pubertal status with a genital exam prior to diagnosing pubertal gynecomastia. If you diagnosed pubertal gynecomastia, the pt must be in puberty!
- Can occur in boys in SMR genital Stage 2, 3, or 4 puberty.
- If they are Stage __ or Stage ___, this is abnormal and requires evaluation!
- Tx:
- Breast size almost always reduces in a few months but can persist for up to __ years. No further workup or treatment but should be followed in subsequent exams.
- Pubertal gynecomastia generally measures <4cm and does not require specific workup or therapy
- Gynecomastia measuring >___cm (similar to SMR 2-3 female) commonly does not regress.
A
Pubertal Gynecomastia
- Occurs at puberty. Reaching peak prevalence at 14yo and SMR stages 2-3 or 3-4.
- Is a very specific diagnosis - you must evaluate pubertal status with a genital exam prior to diagnosing pubertal gynecomastia. If you diagnosed pubertal gynecomastia, the pt must be in puberty!
- Can occur in boys in SMR genital Stage 2, 3, or 4 puberty.
- If they are Stage 1 or Stage 5, this is abnormal and requires evaluation!
- Tx:
- Breast size almost always reduces in a few months but can persist for up to 2 years. No further workup or treatment but should be followed in subsequent exams.
- Pubertal gynecomastia generally measures <4cm and does not require specific workup or therapy
- Gynecomastia measuring >5cm (similar to SMR 2-3 female) commonly does not regress.
47
Q
Pathologic gynecomastia
- Occurs in pts who are SMR genital Stage 1 or 5 and who have an abnormal estrogen:testosterone ratio
- Evaluate any boy who falls outside of the normal pubertal gynecomastia diagnosis. This includes
- Atypical SMR genital stage (1 or 5)
- Atypical age (<10 or >16yo)
- Chronic illness of liver, thyroid, or renal
- Abnormal pubertal progression
- Pts requesting surgery
- Pts with macrogynecomastia (breast sizes greater than SMR 3), which does not resolve with time
- Evaluation
- Estradiol, estrone, testosterone, DHEAS, LH to rule out an LH-secreting tumor, and hCG to screen for a germ cell tumor.
A
Pathologic gynecomastia
- Occurs in pts who are SMR genital Stage 1 or 5 and who have an abnormal estrogen:testosterone ratio
- Evaluate any boy who falls outside of the normal pubertal gynecomastia diagnosis. This includes
- Atypical SMR genital stage (1 or 5)
- Atypical age (<10 or >16yo)
- Chronic illness of liver, thyroid, or renal
- Abnormal pubertal progression
- Pts requesting surgery
- Pts with macrogynecomastia (breast sizes greater than SMR 3), which does not resolve with time
- Evaluation
- Estradiol, estrone, testosterone, DHEAS, LH to rule out an LH-secreting tumor, and hCG to screen for a germ cell tumor.
48
Q
Thyroxine-binding globulin (TBG)
- Increased TBG can cause a clinically irrelevant and often incidentally found high TOTAL T4, and decreased TBG can similarly cause low TOTAL T4
- 2 common clinical scenarios and possible questions:
- 1) Newborn boy with TBG deficiency fails the newborn screen with a low total T4. What to do? These pts are euthyroid and have a normal free T4 and a normal TSH and so do not require levothyroxine. No further follow-up is indicated. Occasionally, there is an affected brother due to the X-linked inheritance of this condition.
- 2) A teenage girl has an elevated total T4 on labs but is not clinically hyperthyroid. What to know? This may be due to OCPs with resultant elevated estrogen causing an increase in TBG. If so, labs will show a high T4 but a normal free T4 and a normal TSH. These pts are clinically euthyroid and do not require medication.
A
Thyroxine-binding globulin (TBG)
- Increased TBG can cause a clinically irrelevant and often incidentally found high TOTAL T4, and decreased TBG can similarly cause low TOTAL T4
- 2 common clinical scenarios and possible questions:
- 1) Newborn boy with TBG deficiency fails the newborn screen with a low total T4. What to do? These pts are euthyroid and have a normal free T4 and a normal TSH and so do not require levothyroxine. No further follow-up is indicated. Occasionally, there is an affected brother due to the X-linked inheritance of this condition.
- 2) A teenage girl has an elevated total T4 on labs but is not clinically hyperthyroid. What to know? This may be due to OCPs with resultant elevated estrogen causing an increase in TBG. If so, labs will show a high T4 but a normal free T4 and a normal TSH. These pts are clinically euthyroid and do not require medication.
49
Q
Interpretation of thyroid function studies
- High TSH
- Low Free T4 - Primary hypothyroidism
- Normal Free T4 - Compensated/subclinical hypothyroidism
- High Free T4 - Pituitary resistant hyperthyroidism; nonadherence to thyroid hormone replacement with recent adherence
- Low TSH
- High Free T4 - Hyperthyroidism
- Normal Free T4 - Incipient / Subclinical hyperthyroidism
- Low Free T4 - Secondary / Central hypothyroidism
A
Interpretation of thyroid function studies
- High TSH
- Low Free T4 - Primary hypothyroidism
- Normal Free T4 - Compensated/subclinical hypothyroidism
- High Free T4 - Pituitary resistant hyperthyroidism; nonadherence to thyroid hormone replacement with recent adherence
- Low TSH
- High Free T4 - Hyperthyroidism
- Normal Free T4 - Incipient / Subclinical hyperthyroidism
- Low Free T4 - Secondary / Central hypothyroidism
50
Q
Drugs and conditions that affect thyroid function
- Increased TBG
- Estrogen: Supplements, OCP, pregnancy
- Tamoxifen, clofibrate, narcotics (heroin), hepatitis, biliary cirrhosis
- Decreased TBG
- Androgens
- Glucocorticoids
- Nephrotic syndrome
- Inherited TBG deficiency
- Slow release nicotine
- Blocks peripheral conversion of T4 to T3
- Propranolol
- Glucocorticoids
- Propylthiouracil
- Amiodarone
A
Drugs and conditions that affect thyroid function
- Increased TBG
- Estrogen: Supplements, OCP, pregnancy
- Tamoxifen, clofibrate, narcotics (heroin), hepatitis, biliary cirrhosis
- Decreased TBG
- Androgens
- Glucocorticoids
- Nephrotic syndrome
- Inherited TBG deficiency
- Slow release nicotine
- Blocks peripheral conversion of T4 to T3
- Propranolol
- Glucocorticoids
- Propylthiouracil
- Amiodarone
51
Q
Radioiodine uptake (RAIU) - Useful in differentiating nonpituitary thyrotoxic states (low TSH, high free thyroxine)
- Has NO use in diagnosing causes of hypothyroidism
- RAIU is increased in association with:
- Graves disease
- Hot nodules (eg multinodular goiter, toxic solitary nodule, hCG-secreting tumor)
- RAIU is decreased in association with:
- Self-limited, thyroiditis-induced thyrotoxic states (painless chronic thyroiditis, postpartum thyroiditis, subacute, thyroiditis, and the potential hyperthyroid phase of Hashimotor’s)
- Thyroiditis factitia
- Amiodarone
- RAIU is low bc the thyroid is already saturated with iodine prior to the 123I dose.
A
Radioiodine uptake (RAIU) - Useful in differentiating nonpituitary thyrotoxic states (low TSH, high free thyroxine)
- Has NO use in diagnosing causes of hypothyroidism
- RAIU is increased in association with:
- Graves disease
- Hot nodules (eg multinodular goiter, toxic solitary nodule, hCG-secreting tumor)
- RAIU is decreased in association with:
- Self-limited, thyroiditis-induced thyrotoxic states (painless chronic thyroiditis, postpartum thyroiditis, subacute, thyroiditis, and the potential hyperthyroid phase of Hashimotor’s)
- Thyroiditis factitia
- Amiodarone
- RAIU is low bc the thyroid is already saturated with iodine prior to the 123I dose.
52
Q
Thyroid scan (aka scintiscan or radionuclide scan)
- The thyroid scan is used only for nodular disease - in determining whether a nodule is hot (functioning) or cold (nonfunctioning).
- On a thyroid scan, cold nodules are more likely to be malignant than hot nodules.
Thyroid scan produces a picture
A
Thyroid scan (aka scintiscan or radionuclide scan)
- The thyroid scan is used only for nodular disease - in determining whether a nodule is hot (functioning) or cold (nonfunctioning).
- On a thyroid scan, cold nodules are more likely to be malignant than hot nodules.
Thyroid scan produces a picture
53
Q
Tests for evaluation of symmetric goiter
- Hypothyroid
- Free T4, TSH, ATA, Anti-TPO
- Hyperthyroid
- Free T4, TSH, ATA, Anti-TPO, TSI
- Euthyroid
- Free T4, TSH, ATA, Anti-TPO
A
Tests for evaluation of symmetric goiter
- Hypothyroid
- Free T4, TSH, ATA, Anti-TPO
- Hyperthyroid
- Free T4, TSH, ATA, Anti-TPO, TSI
- Euthyroid
- Free T4, TSH, ATA, Anti-TPO
54
Q
Congenital Hypothyroidism
- Path:
- Thyroid dysgenesis (including dysgenesis, agenesis, and ectopic thyroid) is the most common cause (90%)
- Note that thyroid dysgenesis and inadvertent administration of radioiodine during pregnancy are causes of permanent hypothyroidism.
- Or rarely 2nd most prevalent cause is dyshormonogenesis (defect in intrathyroid metabolism and hormone production).
- Transient congenital hypothyroidism occurs in geographic regions with endemic iodine deficiency when the mother, and consequently the fetus, are iodine deficient.
- Another cause is central hypothyroidism (hypopituitarism), which would not be detected by newborn screens that use TSH detection methodology.
- Transient hypothyroidism can occur with excess iodine exposure (topical betadine for a procedure) causing suppression of the thyroid gland (Wolff-Chaikoff effect), with maternal thyroid hormone receptors blocking antibodies that are are associated with Graves disease (transplacentally passed), or with anti-thyroid medication (taken for maternal Graves disease)
- Transient hypothyroidism persists until the antibody disappears, typically by 3 months of age.
- Maternal Hashimoto thyroiditis does NOT cause congenital hypothyroidism
- Thyroid dysgenesis (including dysgenesis, agenesis, and ectopic thyroid) is the most common cause (90%)
- Pt:
- Most infants appear normal/asymptomatic at birth (as there is some placental transfer of maternal thyroxine T4). However, this vertical transmission of thyroxine provides only 33% of normal levels; so, neonatal screening still finds a high TSH and a low T4.
- If symptoms are present, large anterior fontanelle, large posterior fontanelle, prolonged jaundice, umbilical hernia.
- Look particularly for an enlarged posterior fontanelle. Only 3% of normal infants have an opening wider than 0.5cm.
- Dentition is delayed, and the tongue is large and thick.
- Myxedema
- Present during the 1st month of life with feeding problems, sluggishness, lack of interest, choking spells when nursing, somnolence, respiratory difficulties caused by enlargement of the tongue due to myxedema, and constipation.
- Developmental delay
- Most children have hypotonic muscles, but a few have pseudohypertrophy, known as Kocher-Debre-Semelaigne syndrome
- Bone maturation is slowed, and this is demonstrated on XR in about 60% of those affected
- A good example is the distal femoral epiphysis, which is normally present at birth. In hypothyroid infants, it is absent.
- Screening for all states: TSH with reflex to total T4 or T4 with reflex to TSH
- Newborn screening is important for detecting congenital hypothyroidism bc neonates are often asymptomatic due to placental passage of some maternal thyroid hormone.
- Goal of screening programs is to identify children with neonatal hypothyroidism early and to begin tx as close to 2 weeks of age as possible.
- The ideal time for screening for congenital hypothyroidism is day 3 (but most babies are home by then).
- Dx: low T4 and high TSH. When TSH >40 mIU/L on filter paper newborn screening, confirmatory venous TSH and free thyroxine should be drawn
- Thyroid scan can be used to pinpoint the underlying absence of thyroid tissue or to locate ectopic thyroid.
- Be aware there are 2 other conditions in which a scan showing no thyroid tissue is possible:
- 1) In neonates with a blocking TSH-receptor antibody (similar to neonatal Graves’ but blocking instead of stimulating)
- 2) With an iodine-trapping defect
- These are both rare conditions. A thyroid US shows thyroid tissue in these settings.
- Be aware there are 2 other conditions in which a scan showing no thyroid tissue is possible:
- Thyroid scan can be used to pinpoint the underlying absence of thyroid tissue or to locate ectopic thyroid.
- Tx: If filter paper TSH is >40 mIU/L, Start on thyroid replacement therapy levothyroxine immediately
- When tx is initiated within 1mo or less after birth, the prognosis is normal intellectual development is excellent
- Do NOT give T3 and do NOT give liquid preparations - stable thyroxine liquid preparations are not consistently reliable in the commercial US markets - give tablets only!
- Levothyroxine is best absorbed in a fasted state; many foods decrease its absorption, esp those high in dietary fiber
- Prognosis:
- Is good for those started on replacement therapy in the first few weeks of life.
- About 20%, however, have a neurosensory hearing deficit.
- Without therapy, affected infants progress to global developmental delay with significantly poor linear growth. Affected infants <3yo lose IQ points for every week they are not treated.
A
Congenital Hypothyroidism
- Path:
- Thyroid dysgenesis (including dysgenesis, agenesis, and ectopic thyroid) is the most common cause (90%)
- Note that thyroid dysgenesis and inadvertent administration of radioiodine during pregnancy are causes of permanent hypothyroidism.
- Or rarely 2nd most prevalent cause is dyshormonogenesis (defect in intrathyroid metabolism and hormone production).
- Transient congenital hypothyroidism occurs in geographic regions with endemic iodine deficiency when the mother, and consequently the fetus, are iodine deficient.
- Another cause is central hypothyroidism (hypopituitarism), which would not be detected by newborn screens that use TSH detection methodology.
- Transient hypothyroidism can occur with excess iodine exposure (topical betadine for a procedure) causing suppression of the thyroid gland (Wolff-Chaikoff effect), with maternal thyroid hormone receptors blocking antibodies that are are associated with Graves disease (transplacentally passed), or with anti-thyroid medication (taken for maternal Graves disease)
- Transient hypothyroidism persists until the antibody disappears, typically by 3 months of age.
- Maternal Hashimoto thyroiditis does NOT cause congenital hypothyroidism
- Thyroid dysgenesis (including dysgenesis, agenesis, and ectopic thyroid) is the most common cause (90%)
- Pt:
- Most infants appear normal/asymptomatic at birth (as there is some placental transfer of maternal thyroxine T4). However, this vertical transmission of thyroxine provides only 33% of normal levels; so, neonatal screening still finds a high TSH and a low T4.
- If symptoms are present, large anterior fontanelle, large posterior fontanelle, prolonged jaundice, umbilical hernia.
- Look particularly for an enlarged posterior fontanelle. Only 3% of normal infants have an opening wider than 0.5cm.
- Dentition is delayed, and the tongue is large and thick.
- Myxedema
- Present during the 1st month of life with feeding problems, sluggishness, lack of interest, choking spells when nursing, somnolence, respiratory difficulties caused by enlargement of the tongue due to myxedema, and constipation.
- Developmental delay
- Most children have hypotonic muscles, but a few have pseudohypertrophy, known as Kocher-Debre-Semelaigne syndrome
- Bone maturation is slowed, and this is demonstrated on XR in about 60% of those affected
- A good example is the distal femoral epiphysis, which is normally present at birth. In hypothyroid infants, it is absent.
- Screening for all states: TSH with reflex to total T4 or T4 with reflex to TSH
- Newborn screening is important for detecting congenital hypothyroidism bc neonates are often asymptomatic due to placental passage of some maternal thyroid hormone.
- Goal of screening programs is to identify children with neonatal hypothyroidism early and to begin tx as close to 2 weeks of age as possible.
- The ideal time for screening for congenital hypothyroidism is day 3 (but most babies are home by then).
- Dx: low T4 and high TSH. When TSH >40 mIU/L on filter paper newborn screening, confirmatory venous TSH and free thyroxine should be drawn
- Thyroid scan can be used to pinpoint the underlying absence of thyroid tissue or to locate ectopic thyroid.
- Be aware there are 2 other conditions in which a scan showing no thyroid tissue is possible:
- 1) In neonates with a blocking TSH-receptor antibody (similar to neonatal Graves’ but blocking instead of stimulating)
- 2) With an iodine-trapping defect
- These are both rare conditions. A thyroid US shows thyroid tissue in these settings.
- Be aware there are 2 other conditions in which a scan showing no thyroid tissue is possible:
- Thyroid scan can be used to pinpoint the underlying absence of thyroid tissue or to locate ectopic thyroid.
- Tx: If filter paper TSH is >40 mIU/L, Start on thyroid replacement therapy levothyroxine immediately
- When tx is initiated within 1mo or less after birth, the prognosis is normal intellectual development is excellent
- Do NOT give T3 and do NOT give liquid preparations - stable thyroxine liquid preparations are not consistently reliable in the commercial US markets - give tablets only!
- Levothyroxine is best absorbed in a fasted state; many foods decrease its absorption, esp those high in dietary fiber
- Prognosis:
- Is good for those started on replacement therapy in the first few weeks of life.
- About 20%, however, have a neurosensory hearing deficit.
- Without therapy, affected infants progress to global developmental delay with significantly poor linear growth. Affected infants <3yo lose IQ points for every week they are not treated.
55
Q
Acquired Hypothyroidism
- Path: Many pts have high levels of circulating antithyroid antibodies
- ____ antibody and _____ usually indicate hypothyroidism
- Causes:
- Most common cause is autoimmune thyroiditis
- Pt:
- Weight for age is proportionately greater than height for age.
- ____ is a hallmark - growth practically ceases!
- ____, which is a fracture of the growth plate in the femoral head, is associated with any disorder that slows or speeds up growth, and hypothyroidism is such a disorder.
- Dx:
- Expect a high TSH and a low free T4 with hypothyroidism due to a thyroid deficiency state.
- Low TSH and low free T4 levels indicate either a hypothalamic problem (tertiary hypothyroidism) or a pituitary problem (secondary hypothyroidism)
- Tx: L-thyroxine
A
Acquired Hypothyroidism
- Path: Many pts have high levels of circulating antithyroid antibodies (antithyroglobulin antibody and antithyroperoxidase antibody)
- Thyroid peroxidase antibody and antithyroglobulin usually indicate hypothyroidism
- Causes:
- Most common cause is autoimmune thyroiditis
- Pt:
- Weight for age is proportionately greater than height for age.
- Growth failure is a hallmark - growth practically ceases!
- SCFE, which is a fracture of the growth plate in the femoral head, is associated with any disorder that slows or speeds up growth, and hypothyroidism is such a disorder.
- Dx:
- Expect a high TSH and a low free T4 with hypothyroidism due to a thyroid deficiency state.
- Low TSH and low free T4 levels indicate either a hypothalamic problem (tertiary hypothyroidism) or a pituitary problem (secondary hypothyroidism)
- Tx: L-thyroxine
56
Q
Chronic Autoimmune Thyroiditis (Hashimoto disease or chronic lymphocytic thyroiditis)
- Hashimoto thyroiditis is the most common cause of acquired hypothyroidism and the most common cause of thyroid enlargement in children >6yo.
- Occurs with the increased frequency in children with ______
- Pt:
- Can occur with normal thyroid function
- Hashitoxicosis:
- 5-10% of children with autoimmune thyroiditis develop tachycardia, nervousness, and other signs of thyroid excess with elevations in free T4 and suppression of TSH early in the course of illness.
- But in most adolescents, this phase does not develop or goes unnoticed, and they present initially with euthyroid goiter or goiter with mild hypothyroidism.
- Poor linear growth, mild weight gain, relative bradycardia, and delayed return of deep tendon reflexes.
- A firm rubbery enlarged thyroid gland with heterogeneous texture is typical of Hashimoto thyroiditis.
- Associations:
- Annually screen all children with ______ for autoimmune thyroid disease.
- Also appears with increased incidence in pts with trisomy 21, Turner syndrome, or Klinefelter syndrome.
- Dx:
- Elevated TSH is the best initial test
- Most pts have antithyroperoxidase antibodies and anti-thyroglobulin antibodies.
- Be aware that these are not specific to autoimmune thyroiditis and can also develop in Graves’ and in normal individuals. Still, consider Hashimoto disease in pts with these antibodies - esp if there is a family hx of thyroid disease.
- Biopsy confirms the diagnosis and shows lymphocytes, but it is rarely indicated.
- Tx:
- Levothyroxine replacement
- Use FNA to biopsy a nodule that remains prominent bc thyroid cancer has developed in pts with autoimmune thyroiditis.
A
Chronic Autoimmune Thyroiditis (Hashimoto disease or chronic lymphocytic thyroiditis)
- Hashimoto thyroiditis is the most common cause of acquired hypothyroidism and the most common cause of thyroid enlargement in children >6yo.
- Occurs with the increased frequency in children with Trisomy 21
- Pt:
- Can occur with normal thyroid function
- Hashitoxicosis:
- 5-10% of children with autoimmune thyroiditis develop tachycardia, nervousness, and other signs of thyroid excess with elevations in free T4 and suppression of TSH early in the course of illness.
- But in most adolescents, this phase does not develop or goes unnoticed, and they present initially with euthyroid goiter or goiter with mild hypothyroidism.
- Poor linear growth, mild weight gain, relative bradycardia, and delayed return of deep tendon reflexes.
- A firm rubbery enlarged thyroid gland with heterogeneous texture is typical of Hashimoto thyroiditis.
- Associations:
- Annually screen all children with Type 1 diabetes for autoimmune thyroid disease.
- Also appears with increased incidence in pts with trisomy 21, Turner syndrome, or Klinefelter syndrome.
- Dx:
- Elevated TSH is the best initial test
- Most pts have antithyroperoxidase antibodies and anti-thyroglobulin antibodies.
- Be aware that these are not specific to autoimmune thyroiditis and can also develop in Graves’ and in normal individuals. Still, consider Hashimoto disease in pts with these antibodies - esp if there is a family hx of thyroid disease.
- Biopsy confirms the diagnosis and shows lymphocytes, but it is rarely indicated.
- Tx:
- Levothyroxine replacement
- Use FNA to biopsy a nodule that remains prominent bc thyroid cancer has developed in pts with autoimmune thyroiditis.
57
Q
Low T3 Syndrome (Nonthyroidal illness) (aka “____ sick”)
- Low T3 syndrome occurs in critically ill pts (such as DKA) and in anorexia nervosa.
- Path: T4 is converted into inactive reverse T3 instead of the biologically active T3, likely as a way to conserve proteins from metabolism in times of severe stress.
- Pt has low total and free T3, normal/low total T4, low/normal/high free T4, and normal TSH.
- ________ is used to confirm the diagnosis
- Tx directed at primary illness. No replacement of T3 or T4 is necessary.
A
Low T3 Syndrome (Nonthyroidal illness) (aka “Euthyroid sick”)
- Low T3 syndrome occurs in critically ill pts (such as DKA) and in anorexia nervosa.
- Path: T4 is converted into inactive reverse T3 instead of the biologically active T3, likely as a way to conserve proteins from metabolism in times of severe stress.
- Pt has low total and free T3, normal/low total T4, low/normal/high free T4, and normal TSH.
- Reverse T3 is used to confirm the diagnosis
- Tx directed at primary illness. No replacement of T3 or T4 is necessary.
58
Q
Subacute (de Quervain) Thyroiditis
- Self-limited inflammation of the thyroid, typically following a URI
- Pt:
- Fever, thyroid gland pain, tenderness
- Labs
- Initially, there are signs and symptoms of ___thyroidism, with release of T4 and T3 from the damaged gland. This is usually followed by a more prolonged period of hypothyroidism.
A
Subacute (de Quervain) Thyroiditis
- Self-limited inflammation of the thyroid, typically following a URI
- Pt:
- Fever, thyroid gland pain, tenderness
- Labs
- Initially, there are signs and symptoms of hyperthyroidism, with release of T4 and T3 from the damaged gland. This is usually followed by a more prolonged period of hypothyroidism.
59
Q
Suppurative Thyroiditis
- Bacterial infection of the thyroid gland
- Most common organisms are Staph aureus, Strep pyogenes, and Strep pneumoniae.
- Thyroid function tests are normal.
- Can be difficult to differentiate from subacute thyroiditis, but hyperthyroidism is uncommon, pts tend to be more ill-appearing, and the duration of illness is usually only 2-4 weeks.
- Tx with antibiotics aimed at the primary cause.
A
Suppurative Thyroiditis
- Bacterial infection of the thyroid gland
- Most common organisms are Staph aureus, Strep pyogenes, and Strep pneumoniae.
- Thyroid function tests are normal.
- Can be difficult to differentiate from subacute thyroiditis, but hyperthyroidism is uncommon, pts tend to be more ill-appearing, and the duration of illness is usually only 2-4 weeks.
- Tx with antibiotics aimed at the primary cause.
