Endocrine Pathophysiology

Endocrine pathophysiology

257

Parvocellular hypophyseotropic
neurons

Magnocellular neurons

Hypothalamic projection
neurons

258

Hyperpituitarism
●
●
●
●

Primary hypothalamic disorders (rare)
Primary pituitary hyperplasia (rare)
Functioning carcinomas (extremely rare)
Functioning adenomas
○ 1. Prolactinomas – see later
○ 2. Somatotroph (GH) adenomas – see later
○ 3. Corticotroph (ACTH) adenomas: Cushing’s disease
○ 4. Gonadotroph (FSH/LH) adenomas
■ Majority produce FSH, some FSH & LH, rarely only LH
■ Occur in middle-aged men & women
■ Symptoms related only to local mass effects, may cause
amenorrhea or galactorrhea, ↓ libido in men

○ 5. Thyrotroph (TSH) adenomas: TSH → hyperthyroidism
○ 6. Pleurihormonal adenomas (GH + PRL)

259

Prolactin (PRL)
During fetal development, prolactin cells
appear to differentiate from GH cells, some
cells maintain the ability to produce both GH
and prolactin
Lactotrophs which make up 40-50% of the
endocrine cells of the anterior pituitary
Prolactin binds to a specific receptor, similar
to GHR (cytokine receptor)
PRL secretion: tonic inhibition by tuberohypophyseal dopaminergic pathway
Primary target of PRL: mammary gland
Development during pregnancy
Induces milk protein synthesis
Initiates and maintains lactation
Milk ejection is a reflex process
mediated by oxytocin
260

Hyperprolactinemia
● Hyperprolactinemia is the most common hormone secreting
pituitary tumor
● Causes of hyperprolactinemia
○ 1. Hypothalamic dopamine deficiency
■ Tumors, arterio-venous malformations, inflammatory processes
(sarcoidosis) result in either diminished synthesis or release of
dopamine
■ a-methyldopa and reserpine is capable of depleting the central
dopamine stores

○ 2. Defective transport mechanism
■ Section of the pituitary stalk, pituitary or stalk tumors

261

○ 3. Lactotroph insensitivity to dopamine
■ Dopamine-receptor-blocking agents: phenothiazines
(chlorpromazine), butyrophenones (haloperidol), and benzamides
(metoclopramide, sulpiride, and domperidone). They block the
effects of endogenous dopamine → release lactotrophs from their
hypothalamic inhibition → hyperprolactinemia

○ 4. Stimulation of lactotrophs
■ Hypothyroidism with increased TRH production →
hyperprolactinemia
■ Estrogens act directly at the pituitary level, → enhance prolactin
secretion, increase the mitotic activity of lactotrophs.
■ Injury to the chest wall (herpes zooster [HHV-3], post thoracotomy,
piercing)
262

● Consequences of hyperprolactinemia
○ Inhibits pulsatile GnRH secretion → hypogonadism
■ Female: luteal phase is shortened → anovulation, galactorrhea,
amenorrhea, infertility, ↓ libido
■ Male: decreased testosterone synthesis, spermatogenesis and
libido or impotence; rarely galactorrhea & gynecomastia

○ Bitemporal hemianop(s)ia

263

264

The effect prolaction on GnRH secretion and pharmacotherapeutic
options in hyperprolactinemia

Hypothalamus
GnRH

Dopamin

Hypophysis
Pergolide

Hyperprolactinemia

Gonadotroph

LH

Gonads ↓
Cabergoline

Ergot-derived dopamine agonists

265

● Treatment of hyperprolactinemia
○ Dopamine agonists for GH or prolactin hyper secretion
■ Most useful when GH and prolactin secretion also is elevated
■ Paradoxical inhibitory effect on GH secretion: Somatroph
adenomas express receptor characteristics of lactotrophs
■ Given orally; adverse effects: nausea, vomiting, dizziness, postural
hypotension

○ Transsphenoidal microsurgery
■ Microadenomas - 85% long term remission
■ Macroadenomas – outcome less satisfactory

266

An almost complete bitemporal hemianop(s)ia (pre-therapy), which had almost disappeared after 1
year of treatment with bromocriptine, returned on cessation of therapy and began to subside after
reinstitution of bromocriptine.
The black periphery indicates a normal visual field for comparison.
267

Hypopituitarism
● Subnormal basal or stimulated secretion of one or more pituitary
hormones
○ > 50% of secretory cells – detectable deficiency, > 80% lost for severe
basal loss
○ In pituitary failure a common sequence of hormone loss is GH >
FSH/LH > TSH > ACTH > PRL
○ Prolactin is often increased from compression of the pituitary stalk and
interruption of dopamine inhibition

● Loss of pituitary hormones generally results in milder symptoms than
when the target gland itself is inadequate
○ Tendency for residual function of target glands to continue, yielding
basal serum levels that overlap with normal persons
○ ! Need to perform dynamic tests of many pituitary hormones to assess
maximal responses !
268

● Hypopituitarism is caused by hypothalamic or pituitary lesions
○ Hypothalamic lesions – anterior and posterior lobe deficiencies
■ Craniopharyngioma, gliomas & teratomas; metastatic carcinoma,
infections, infiltrative diseases: sarcoidosis, tuberculosis, mycoses,
hemochromatosis

○ Pituitary lesions (anterior lobe deficiencies)
■ Adenomas (10-15% of all brain tumors): majority are benign and
remain within the sella turcica (microadenoma)
□ Nonsecretory adenomas
□ Prolactin-secreting adenomas – most common

■ Sheehan’s syndrome (see later), irradiation or destruction/removal
of  75% of the gland
■ Rare: metastatic carcinoma, inflammatory disorders, infections,
genetic defects (Pit-1 {pituitary-specific transcription factor} gene)
269

Rathke’s pouch

270

Clinical forms of hypopituitarism
● 1. Panhypopituitarism or Simmonds’ disease due to destruction
of pituitary tissue by tumor or infarction
○ In children → dwarfism & infantilism (retarded physical & sexual
development)
○ In adults → hypogonadism, hypothyroidism & hypoadrenalism

● 2. Sheehan’s syndrome
○ Ischemic necrosis of the anterior pituitary due to postpartum
hemorrhage and/or shock
○ Predisposing factors
■ Anterior pituitary doubles in size during pregnancy, low pressure
portal system unable to ↑ blood supply
■ Abrupt onset of hypotension (eg bleeding) → hypoperfusion →
infarction
271

○ Early symptoms: breast atrophy and failure of lactation, within
first 7 days postpartum; later amenorrhea
○ Low TSH: fatigue, slow speech, slow movements, cold
intolerance, dry skin, constipation.
○ Low ACTH: fatigue, hypotension, poor tolerance of stress and
infection, hypoglycemia, loss of pubic and auxiliary hair,
decreased body hair, decreased pigment in skin, waxy skin
○ Posterior lobe: usually is not affected

● 3. Isolated hormone deficiencies
○ GnRH deficiency
■ Acquired in hyperprolactinemia and in hyper-cortisolemia because
PRL and cortisol decrease GnRH gene expression
■ Acute and chronic illness, and poor nutrition → GnRH deficiency
■ Kallmann syndrome
272

Migration of GnRH-secreting neurons (color)
from the nose anlage into the hypothalamic
portion of the brain. This migration does not
occur in Kallmann syndrome.

Kallmann’s syndrome
Isolated hypogonadotropic hypogonadism with anosmia (inability to smell) defect in KAL gene (Xlinked form)
Dominant, recessive and X-linked recessive/dominant forms are known
Mutation in a neural cell adhesion protein (anosmin encoded by KAL) which guides axon growth
and allows GnRH neurons to migrate from their site of origin in the cribriform plate to the anterior
hypothalamus
Because GnRH neurons are not in their appropriate anatomical location, axons to the anterior
pituitary do not develop; defective synthesis/release GnRH (FSH, LH, testosterone ↓); Anosmia,
273
microphallus

○ FSH/LH deficiency
■ Prepubertal hormone deficiency
□ Impaired development of secondary sex characteristics, primary
amenorrhea (♀)
□ Eunuchoid habitus due to delayed epiphyseal closure (arm span: 5
cm > height)

■ Adult women: amenorrhea, infertility, hot flashes, decreased libido
and low estradiol
■ Adult men: hypogonadism and/or infertility, hot flashes, testicular
atrophy, low testosterone
□ Fertile eunuch (LH deficiency)

○ TSH deficiency: see secondary hypothyroidism
○ ACTH deficiency see white Addison’s
○ PRL deficiency
■ Congenital PRL deficiency is a very rare disorder, occurs together
with GH and TSH deficiency due to mutations of Pit-1
■ Inability to lactate (as in Sheehan’s)
274

275

Growth-hormone excess
● Childhood – gigantism
● Adults – acromegaly (rare, 3-4 new cases per million)
○ Progressive enlargement of head, face, hands, feet, thorax; heat
intolerance, sweating, fatigue, lethargy
○ Levels of IGF-1 are greatly increased in acromegalics but IGF-2
levels are not.
○ Etiology
■ 98%: benign GH-producing pituitary tumor
■ 2%: Ectopic GHRH secretion
□ Small cell lung cancer, bronchial or intestinal carcinoid tumors,
pancreatic islet cell tumor, pheochromocytoma

276

● Complications
○ Local – due to mass effect (marcoadenoma)
○ Abnormal glucose tolerance (DM – 1/3) – GH is insulin antagonist
○ ↑ se triglyceride
○ Cardiovascular complications
■ Left or bi ventricular hypertrophy → heart failure, arrhythmia
■ Hypertension: due to Na retention, ↑ sympathetic activity

○ Obstructive sleep apnea
○ Colorectal cancer

● Diagnosis
○ Abnormal net GH secretion over time & non-suppressible GH
secretion
■ 24 hour GH profile (night-time GH levels)
■ Elevated IGF-1 and IGFBP-3 (most important binding protein of
IGF-1)
277

278

Disorders of growth in childhood
● I. Dwarfism due to growth hormone deficiency
○ 1. Genetic
■ Transcription factor abnormalities
□ Multiple pituitary hormone deficiency (Pit-1, PROP-1 [prophet of Pit1])

■ GHRH receptor abnormalities
■ Defects of GH gene – structural growth hormone mutations
■ Bioinactive GH syndrome – normal to high GH level, low IGF-1

○ 2. Congenital/developmental abnormalities
■ Structural brain development disorders (septo-optic dysplasia, agenesis
of corpus callosum); midline facial defects (cleft lip/palate)

○ 3. Craniopharyngioma (tumor of Rathke’s pouch) → compression
signs: increased intracranial pressure and visual field defects
○ 4. Cranial irradiation (leukemia)
■ 50% chance of deficiency in 5 yrs, 100 % in 10 yrs
279

○ 5. Psychosocial dwarfism (stress dwarfism)
■ Growth problems in kids over 3 yrs
■ Possible mechanisms
□ Hypophyseal insensitivity to GHRH
□ Cells become insensitive to GH and IGF-1
□ Too much somatostatin or the pituitary is too sensitive to somatostatin
□ Sympathetic system over activity: blocks GH secretion
□ Glucocorticoids ↑: block GH secretion; decrease sensitivity to GH;
decrease synthesis of new proteins and DNA
♦ Hormone levels 2 to 3 ↑ normal – disrupt growth, major stressors
increase hormone levels up to 10 ↑ normal

● Children who are GH deficient have short stature of varying
degree with normal proportions (proportionate dwarfism) but may
appear younger than their age
○ Increased insulin sensitivity
■ Hypoglycemia (mostly infants and small children)

○ Decreased muscle mass, increased fat mass
280

● II. Etiology of growth hormone insensitivity
○ Laron syndrome: Normal/high se GH level but reduced circulating
levels of IGF-1 due to a defect in the GH receptor
■ Treatment: biosynthetic IGF-1 before puberty

Laron syndrome
•Dwarfism
•Prominent forehead, depressed
nasal bridge, underdeveloped
mandibule
•Truncal obesity
•Hypoglycemic episodes
•Resistance to DM and cancer
•Intellectual retardation

281

Short stature
(dwarfism) is defined
as height less than 2
standard deviations
below the mean,
which is near the
third percentile.

Human recombinant GH (in GH
deficiency)

Thus, 3-5% of all
children are
considered short.

Human recombinant IGF-1 ( in GH
insensitivity syndrome)

282

● III. Growth failure due to other conditions
○ 1. Familial short stature – not a true growth failure
■ Parents with short stature. These children have a normal growth
velocity and puberty and finish their growth with a short adult
height.

○ 2. Constitutional delay in growth and maturation – delayed
puberty
■ A period of slow growth velocity occurs during the first year of life,
and, just before the onset of puberty (normal adult height)
■ Children with constitutional delay may have a family history of the
same

○ 3. Malnutrition – the most common cause of growth failure
worldwide
283

○ 4. Chronic or systemic disorders
■ Nervous system: microcephaly
■ Circulatory system: cyanotic heart diseases
■ Gastrointestinal system: Gluten sensitive enteropathy, ulcerative
colitis, or Crohn’s disease
■ Liver, chronic renal failure: renal tubular acidosis
■ Lung: cystic fibrosis
■ Connective tissue: dermatomyositis

○ 5. Chromosomal abnormalities
■ Turner syndrome (45,X) and Down syndrome (trisomy 21)

284

○ 6. Other (non-chromosomal) syndromes
■ Noonan syndrome: Short stature, heart disease (pulmonary
stenosis), unusual facies, mental retardation, bleeding diathesis;
neurological, genitourinary, lymphatic, eye, and skin findings may
be present to varying degrees (should be differentiated from
Turner’s syndrome)
□ Abnormal Ras-MAP kinase signalization

■ Prader-Willi syndrome: obesity, hypotonia, mental retardation,
short stature, hypogonadotropic hypogonadism, strabismus, and
small hands and feet

285

○ 7. Target tissue defects
■ Intrauterine growth retardation
□ Fetal alcohol syndrome and placental insufficiency syndromes.

■ Bone and cartilage disorders - due to mutations of the fibroblast
growth factor receptor 3
□ Achondroplasia – autosomal dominant disorder
♦ Decreased endochondral ossification, inhibited proliferation of
chondrocytes in growth plate cartilage, decreased cellular hypertrophy,
and decreased cartilage matrix production
♦ Growth retardation, disproportionably short arms and legs, lumbar
lordosis. The head is large, the forehead is prominent.

□ Hypochondroplasia – disproportion is subtle

286

287

○ 8. Endocrine causes
■ GH deficiency and GH insensitivity (IGF-1 deficiency) – see earlier
■ Thyroid hormone deficiency (hypothyroidism)
□ Thyroid hormone is necessary for normal growth (thyroid hormone
levels should be measured in all children with slow growth)

■ Parathormone resistance: Albright hereditary osteodystrophy
■ Glucocorticoid excess (Cushing’s syndrome, Cushing’s disease)
□ Children with glucocorticoid excess almost always have growth
failure

■ Androgen excess
□ Due to exogenous androgen, precocious puberty, and congenital
adrenal hyperplasia
□ The growth velocity increases in the short term, but epiphyseal fusion
occurs early, resulting in a short adult height
288

Adult GH deficiency
● Adult-onset pituitary/hypothalamic disease, craniopharyngioma, surgery,
irradiation therapy, or trauma
● Features of GH deficiency in adults
○
○
○
○
○
○
○

Increased fat mass (apple type obesity) and reduced lean body mass
Decreased insulin sensitivity, impaired glucose tolerance
Accelerated atherosclerosis (↑LDL, ↓HDL cholesterol)
Impaired cardiac function
Decreased bone density
Mood changes
Hypopituitarism is associated with premature mortality (mainly in females)

● Replacement therapy in GH-deficient adults alters body composition and
energy metabolism through its lipolytic, protein anabolic and antinatriuretic
actions, resulting in decreased fat mass, increased fat-free mass Na
retention and increased energy expenditure
289

290

Iodine
● Deficiency
○ Moderate iodine deficiency – euthyreoid goiter
○ Severe iodine deficiency
■ Endemic myxedema in adults; endemic cretinism in infants

● Toxicity
○ Increased iodine uptake – inhibition of thyroid hormone synthesis
(Wolff-Chaikoff effect)
○ Hyperthyroidism („Jod-Basedow” phenomenon = iodine-induced
hyperthyroidism)
○ Very high doses of iodide
■ A brassy taste, increased salivation, and acneiform skin lesions

291

● Wolff-Chaikoff effect
○ Increasing doses of I- increase hormone synthesis initially
○ Higher doses cause cessation of hormone formation.
○ This effect is countered by the iodide leak from normal thyroid
tissue and the hormone synthesis resumes.
○ Patients with autoimmune thyroiditis may fail to adapt and
become hypothyroid (suppressive effect of iodide persist)

● Jod-Basedow effect
○ Aberration of the Wolff-Chaikoff effect
○ Excessive iodine loads induce hyperthyroidism
○ Observed in several disease processes
■ Basedow-Graves’ disease
■ Multinodular goiter
292

Well

Sick

Recovery

Well

reverseT3

freeT4
Reference range

T3

totalT4

Mortality↑

Sick euthyroid syndrome
•Occurs in critically ill patients (sepsis, MI), but may occur with DM, malnutrition, iodine
loads, or medications (amiodarone [rich in I], glucocorticoids)
•Euthyroid condition (TSH normal) but thyroid hormone (T3, T4) level is low. Inactivation of
5’-deiodinase, resulting in conversion of free T4 to reverseT3.
•Pathomechanism: still at large, inflammatory cytokines (eg sepsis)
•Treatment: Avoid above medications, treat primary illness; T3, T4 not helpful
293

Thyrotoxicosis
● With thyroid hyperfunction (Hyperthyroidism – sustained
hormone overproduction)
○ Excess production of TSH: hypophyseal tumor
○ Abnormal thyroid stimulation
■ Basedow-Graves’ disease (see autoimmune diseases),
throphoblast tumor (chorionic gonadotophin-induced)

○ Intrinsic thyroid autonomy
■ Toxic multinodular goiter
■ Toxic adenoma
□ Activating mutations of the TSH-R

294

● Without thyroid hyperfunction (transient hormone excess)
○ Disorders of hormone storage
■ Subacute thyroiditis or chronic thyroiditis with transient
thyrotoxicosis

○ Extrathyroid source of hormone
■ Thyrotoxicosis factitia (overdose with thyroid hormone products)
■ Ectopic thyroid tissue
□ Struma ovarii (ovarian teratoma), functioning follicular thyroid
carcinoma

295

Hypothyroidism
● A hypometabolic state caused by deficiency of T3 & T4
● 1. Primary hypothyroidism – thyroid gland failure (95%)
○ Thyroid gland dysfunction
■ Congenital developmental disturbances
■ Radioactive iodine therapy or subtotal thyreoidectomy in BasedowGraves’ disease

○ Congenital biochemical disturbances (hormone synthesis)
○ Cretinism
■ Sporadic cretinism: congenital –thyroid dysgenesis, inherited
defects in thyroid hormone synthesis, inherited peripheral tissue
resistance to thyroid hormone
■ Endemic cretinism: due to dietary iodine deficiency – in certain
geographical regions; Central Africa, Andes, Himalaya
□ Severe mental retardation, short stature, coarse facial features,
protruding tongue, possible deafness

296

○ Myxedema: adult hypothyreosis
■ Hashimoto’s thyreoiditis
■ Subacute thryroiditis (DeQuervain’s, granulomatous)
□ Acute viral infection of thyroid gland: Presents with viral prodrome,
thyroid tenderness, and hyperthyroid symptoms

■ Surgical ablation
■ Iodine deficiency
■ Drugs (lithium, thio-uracyl)
■ Idiopathic primary hypothyroidism
■ Hypothalamic and hypophyseal disturbances

● 2. Secondary – pituitary ablation, failure or necrosis
■ TRH normal & low free thyroxin. Note that the TSH cannot be used
as a screening test for TSH deficiency!
■ Hypothyroidism is less severe than in primary hypothyroidism

● 3. Tertiary – hypothalamic failure (rare)
○ No TRH and TSH
297

Pathogenesis of Hashimoto’s thyroiditis
● Familial predisposition, associated with HLA-DR3 or HLA-DR5
● Defective function of thyroid-specific suppressor T cells →
emergence of helper T cells reactive with thyroid antigens
● Helper T cells stimulate B cells to secrete antithyroid antibodies,
directed against: thyroid peroxidase (TPO), TSH-receptors,
iodine transporter, & thyroglobulin (TBG) etc.
● Thyroid injury is mediated by complement fixing cytotoxic
antibodies, ADCC & CD8+ cytotoxic cells
● Ninety % of gland is destroyed before hypothyroidism develop

298

Hashimoto’s thyroiditis

299

Myxedema (hypothyroidism in adults)
Fatigue, lethargy, slowed speech, mental
sluggishness, cold intolerance, weight gain,
constipation, ↓sweating, bradycardia,
accumulation of ECM substances
(glycosaminoglycans), coarsening of facial
features, nonpitting edema

24 yrs. old athyreotid cretin

300

Myxedema

Myxedema: showing periorbital bags under eyes
Loss of lateral eyebrow; Anne’s sign
Swollen inner eyelid: Julesz’ sign

After treatment
301

Goiter (enlargement of the thyroid)
↓ thyroid hormone synthesis
→ TRH & TSH↑ →
hyperplasia & hypertrophy of
follicular cells → gross
enlargement
Functionally: decreased,
normal or hyperfunctional

History of goiters
Aristotle: individuals with goiter are spirited and rash
Galen: tumor of larynx and pharynx
Aetius of Amida: bronchocele that is a rupture of larynx
Paul of Aegina: two varieties: the steatomatous and the aneurysmatic
Emperor Leon VI the Wise: the man, who has a great walnut around the
neck, and has bulging eyes, is considered as healthy

302

Diffuse non-toxic (simple) goiter
● Endemic goiter
○ Dietary deficiency of iodide
○ Goitrogens (e.g. cabbage,
cauliflower, turnips, cassava root)
manioc: linnamarin thiocyanate:
blocs uptake of iodine at the
thyroid, competitive inhibition
○ Usually results in cretinism

● Sporadic goiter
○ Goitrogens
○ Hereditary defect in thyroid
hormone synthesis

● Clinical: most patients are
euthyroid

Multinodular goiter
● Nodular enlargement, derived
from diffuse goiter (both
monoclonal & polyclonal
nodules (adenomatous goiter)
● Clinical
○ Most patients are euthyroid
○ Mass effects: compression of
trachea, vessels & nerves, &
dysphagia
○ Hyperthyroidism (toxic
multinodular goiter)
■ Due to a hyperfunctioning nodule
but not accompanied by
opthalmopathy or dermopathy

303

304

hypoglycemia, hypovolemia, fever

Vasopressin
Pro-inflammatory
cytokines

Adrenal gland
↑ gluconeogenesis and ↓ uptake of glucose by fat & muscle
↓ protein synthesis, ↑ protein degradation
↑ vascular tone, some mineralocorticoid activity, antiinflammatory & immunosuppressive effects

305

Adrenal gland
Connective tissue
capsule
Adrenal cortex

Adrenal medulla
Kidney

Adrenal medulla

Androgens (mainly dehydroepinandrosterone [DHEA])
•Converted to estrogens in females and promote libido and the
only source of androgens after menopause
•Excess testosterone in females: defemenization &
virilization; (hirsutism, acne, amenorrhea, clitoral
enlargement, atrophy of the breasts & uterus,
deepening of the voice & frontal balding).
•In boys leads to precocious puberty.

Androgens

Adrenal cortex

Zona
reticularis

Glucocorticoids

Zona
fasciculata

Zona
glomerulosa

Synthesis of aldosterone –
C-18-OH present only here
ACTH dependent
ACTH acts on
melanocortin-2 receptors
[MC2-R]
306

Angiotensinogen
Renin

Cathepsin
t-PA

Angiotensin I (1-10)

Bradykinin
Inactive fragments

Prorenin

ACE
(lung)

Chymase

Angiotensin II (1-8)

ACE-2
NEP
ACE-2

PRR

Contractility
Hypertrophy
Fibrosis
Apoptosis

Mas

Vasodilatation
Anti remodeling
Anti fibrotic
Anti thrombotic

Angiotensin (1-9)
ACE

Angiotensin (1-7)

APA

Angiotensin (2-8)

AT1
Vasoconstriction
Antidiuresis/antinatriuresis
Cell growth and proliferation
Aldosterone and vasopressin
release
Oxidative stress

AT2
Vasodilatation
Diuresis/natriuresis
Anti-proliferation
Bradykinin and NO production

APN/APB

Angiotensin (3-8)

AT1
AT2
AT4

NFB activation
Proinflammatory factors:
TNF-a, MCP-1, IL-6, ICAM-1
PAI-1

307

Diseases of the adrenal cortex
Hyperadrenalism
● Cushing’s syndrome
● Hyperaldosteronism /
aldosteronism
○ Primary or secondary

● Adrenogenital syndromes
(congenital adrenal hyperplasia)

Hypoadrenalism
● Acute „Addisonian or adrenal
crisis” (e.g. WaterhouseFriderichsen syndrome)
● Chronic
○ Primary (due to adrenal cortical
insufficiency, e.g. Addison’s
disease)
○ Secondary (due to ACTH
deficiency)
○ Tertiary (rarely – due to
hypothalamic CRH deficiency)
308

Cushing’s syndrome
● Overproduction of glucocorticoids
○ ACTH-dependent forms
■ Primary bilateral macronodular adrenal hyperplasia
□ Increased intra-adrenal ACTH release stimulates MC2-Rs to produce
cortisol by paracrine manner

■ Secondary bilateral macronodular adrenal hyperplasia
□ Cushing’s disease : pituitary hypersecretion of ACTH. Nelson’s
syndrome: after adrenalectomy (due to inoperable pituitary tumor)
ACTH-dependent hyperpigmentation of the skin ( MSH)
□ Ectopic production of ACTH or CRH by bronchogenic small cell
carcinoma

○ Non-ACTH-dependent forms
■ Autonomous hypersecretion of cortisol by an adrenal adenoma,
carcinoma
■ Exogenous/iatrogenic: high dose cortisone therapy

309

Mood changes: irritability,
depression, psychosis

Endocrine changes:
↓LH,FSH
↓TSH
↓GH
Glaucoma

Carbohydrate/lipid metabolism
•Glucogenolysis & gluconeogenesis ↑
•Free fatty acid (FFA) ↑
•Impaired glucose tolerance, insulin
resistance, diabetes mellitus
Fat distribution: Obese, visceral
obesity, centripetal fat distribution:
supraclavicular fat (buffalo hump),
facies lunata (moon face)

Osteopenia/osteoporosis
Skin/muscle/connective tissue:
•Loss of muscle, proximal myopathy,
•Plethora, striae rubrae distensae, increased capillary fragility
•Short stature

Peptic ulcer

Cardiovascular & renal: Salt & water
retention, hypertension, K loss
Blood & immune function
•Lymphocyte and eosinophil # decreased
•Anti-inflammatory and immuno
suppressive effect
•Neutrophil and total WBC increased
•RBC and HT increased
Changes in sexual function
•Androgen effect in females
(masculinisation)
•Loss of libido
•Menstruation abnormalities
310

311

Primary aldosteronism / hyperaldosteronism
● Excessive secretion of aldosterone independent of renin-angiotensin
system (low renin) with hypervolemia, hypertension, hypokalemia (in
30% of patients normal serum K) and metabolic alkalosis
● Forms
○ 1. Conn syndrome – aldosterone-secreting solitary adenoma
○ 2. Idiopathic aldosteronism – diffuse bilateral hyperplasia
○ 3. Rare subtypes
■ Familial hyperaldosteronism type I or glucocorticoid-suppressible
hypertension
□ Hybrid cells produce both cortisol & aldosterone, ACTH-dependent
aldosterone production, suppressible by administration of dexamethasone

■ Unilateral hyperplasia
■ Aldosterone-producing cortical carcinoma
312

Glucocorticoid-remediable hyperaldosteronism (primary
hyperaldosteronism autosomal dominant form)
Unequal crossing over in the promoter region of 11ß-hydroxylase
Aldosterone secretion is regulated by ACTH
313

Secondary aldosteronism / hyperaldosteronism
● A diverse group of disorders characterized by physiologic
activation of the renin-angiotensin-aldosterone axis to maintain
serum Na concentrations or fluid volume.
○ In the presence of normal renal function, it may lead to
hypokalemia

● 1. Presence of hypertension
○ Reninism
○ Decreased kidney perfusion (renovascular, parenchymal
hypertension)

314

● 2. Absence of hypertension – usually with edema formation
○ Homeostatic mechanism to maintain Na or circulatory volume or
to reduce plasma K
○ Congestive heart failure, and hypoalbuminemia due to liver or
renal disease or nephrotic syndrome
○ Diarrhea, excessive sweating, low cardiac output states

● 3. No high blood pressure and no edema
○ Bartter’s, Gitelman’s syndrome
■ Autosomal recessive disease, Kidney is unable to keep Na, Cl, K
(thick ascending segment)

315

Adrenogenital syndromes
● Adrenogenital syndromes: ambiguous genitalia & virilism in
girls, and precocious puberty in boys
● Causes
○ 1. Androgen-secreting adrenal cortical neoplasms
○ 2. Congenital adrenal hyperplasia (CAH): corticosteroid
biosynthetic defect
■ C-21-hydroxylase deficiency (90% of CAH cases; autosomal
recessive)
□ ↓cortisol → feedback inhibition of ACTH ↓ → ↑ ACTH levels →
bilateral adrenocortical hyperplasia
□ Aldosterone synthesis is blocked → salt wasting adrenogenitalism
(se Na+ ↓, ↑ K+, hypovolemia)
□ ↑ production of androgens
316

■ C-11 ß-hydroxylase deficiency (Israel, Moroccan descents)
□ Hypergonadism: masculinization of female newborn, precocious
puberty in boys
□ Hypertension (ACTH-mediated DOC accumulation), renin↓,
aldosterone↓, hypokalemia, metabolic alkalosis
□ Other forms: salt-wasting, non-classical (see clinical studies)

■ C-17 α-hydroxylase deficiency (~150 cases)
□ Hypertension (ACTH-mediated DOC accumulation), hypogonadism,
(sexual infantilism) renin↓, aldosterone↓, hypokalemia, metabolic
alkalosis

317

* DOC

*

Estradiol

318

Acute adrenocortical insufficiency „Addisonian crisis”
● Acute adrenocortical insufficiency is sudden withdrawal of
corticosteroids in cases of long-term steroid therapy, or
destruction of adrenals by massive hemorrhage
● Waterhouse-Friderichsen syndrome: overwhelming
meningococcal septicemia
○ Disseminated intravascular coagulation (DIC) with widespread
purpura, rapidly progressive hypotension → shock, massive
bilateral adrenal hemorrhage → acute adrenocortical
insufficiency

319

Primary chronic adrenocortical insufficiency
(Addison’s disease)
● Due to autoimmune adrenalitis, tuberculosis, metastatic
cancers
● Destruction of  90% of the cortex → decreased cortisol and
aldosterone production,
○ Cortisol deficiency with feed-back elevation of ACTH and MSH
→ hyperpigmentation of skin (♀ bra; ♂ belt)
○ Mineralocorticoid deficiency → ECF volume contraction → GFR
reduction
■ Enhanced proximal salt absorption (glomerulotubular feedback)
■ Volume-mediated, non-osmotic ADH release ↑
■ ↑ K+, ↓ Na+, ↓ BP, weakness, anorexia, hypoglycemia

320

Secondary chronic adrenocortical insufficiency (white
Addison’s)
● ACTH deficiency due to hypothalamic/pituitary
lesion → bilateral adrenal cortical atrophy,
sparing the zona glomerulosa, which is primarily
regulated by renin and angiotensin
○ ACTH deficiency leads to cortisol and adrenal
androgen deficiency, but aldosterone secretion is
preserved

● Common symptoms are fatigue, muscle
weakness, anorexia and weight loss, fair skin
pigmentation and hair. Hyponatremia and
hypoglycemia may be present, but severe
dehydration and hyperkalemia do not occur
321

Adrenal medulla
● Composed of specialized neuroendocrine (chromaffin) cells, and is the
major source of catecholamines: epinephrine, norepinephrine & dopamine
○ Chromaffin cells secrete catecholamines in response to signals from
preganglionic sympathetic nerve fibers and variety of bioactive amines
and peptides, such as: histamine, serotonin, & neuropeptide hormones

322

Paraganglial tumors: pheochromocytoma &
paraganglioma
● Highly vascular, catecholamine-secreting, mostly benign tumors
(10% are malignant); pheochromocytomas are involving one or
both adrenal glands. Paragangliomas are derived from thoracic
and abdominal paraganglia along the sympathetic chain
● Clinical appearance of paraganglial tumors
○ Sporadic
○ Inherited
■ Mutation of one of at least 12 genes from wide range of functional
classes
■ Paraganglial tumors carry the highest degree of heritability in
human tumors
■ Components of multiple endocrine neoplasia-2 (MEN-2)
323

sympathetic
Catecolamine secretion

parasympathetic
No catecolamine secretion

324

● Release of excess amounts of catecholamines → paroxysmal
or sustained hypertension (blood pressure fluctuations and
predisposition to orthostatic hypotension is detectable),
tachycardia, arrhythmias, tremors, sweating, sense of
apprehension, attacks can be fatal
○ Paroxysms (< 50% of patients) are precipitated by exercise,
bending over, urination, defecation, induction of anesthesia,
infusion of intravenous contrast media, smoking

● Diagnosis
○ Serum & collected urine (24 hour) for catecholamines,
metanephrine, normetanephrine & vanillylmandelic acid (VMA)
determination
○ Free metanephrine has the highest diagnostic sensitivity and
specificity
325

326

Female reproductive disorders – menstrual disorders
● Polymenorrhea – intervals between uterine bleeding < 24 days
● Oligomenorrhea – intervals between uterine bleeding > 35 days
● Amenorrhea – absence of menstruation
○ Primary amenorrhea
■ Menarche never occurred: usually due to genetic disorders or
congenital defects

○ Secondary amenorrhea
■ Absence of menstruation for a time equivalent to 3 or more cycles
or 6 months in women who have previously menstruated
■ May result from impediment in hypothalamic-pituitary axis or from
dramatic weight loss or other physiologic conditions

● Hypermenorrhea – regular intervals (24-35 days) but excessive
flow (over 80ml [normal: 30 ml] and/or duration (normal: 4-6
days) of bleeding
327

● Hypomenorrhea – diminution of flow and/or duration of bleeding
● Dysmenorrhea – painful menstruation
○ Primary dysmenorrhea
■ Results from periodic uterine contractions due to excessive
prostaglandin F in secretory endometrium.
■ Prostaglandins may also cause headache, syncope and GI
complaints (diarrhea)
■ Increase in myometrial contractions and constricting endometrial
vessels, ischemia, pain

○ Secondary dysmenorrhea results from pelvic disorders:
endometriosis, uterine polyps, tumors, pelvic inflammatory
disorders or congenital anomalies
328

● Uterine bleeding in response to steroid hormones
○ Estrogen withdrawal bleeding
■ Bleeding due to acute cessation of estrogen support (in the
absence of progesterone) to the endometrium
■ Bilateral oophorectomy, radiation of mature follicles

○ Estrogen breakthrough bleeding (unpredictable)
■ Chronic exposure to estrogen stimulates continuous endometrial
growth (e.g extragonadal production of estrogen in PCOS), but
after a time the amount of estrogen is insufficient to support
endometrial function → bleeding

○ Progesterone withdrawal bleeding (predictable)
■ Physiologic: bleeding after ovulation (in the absence pregnancy)
■ Discontinuation of progesteron or progestins (synthetic form)

○ Progesterone breakthrough bleeding (pharmacologic
phenomenon)
■ Oral contraceptives – Depo-Provera: low-dose estrogen, high
dose, long acting progestin

329

● Causes of irregular uterine bleeding
○ Complications of pregnancy
■ Ectopic pregnancy, miscarriage

○ Anovulations
■ Physiologic: pubertal and postmenopausal anovulation
■ Chronic anovulations

○ Anatomic defects affecting the uterus
■ Leiomyomas, polyps, endometriosis

○ Coagulation defects (as hypermenorrhea)
■ Von Willebrand’s disease etc

○ Extrauterine, genital bleeding (may mimic uterine bleeding)
■ Genital trauma, foreign body
330

Disorders of the female reproductive system
● 1. Chronic anovulation
○ Estrogen deficiency (with osteopenia and osteoporosis)
■ Hypothalamic anovulation
■ Hyperprolactinemia-galactorrhea (see earlier)
■ Premature ovarian failure in reproductive years

○ Androgen excess (risk of endometrial carcinoma etc)
■ Polycystic ovarian syndrome

● 2. Hormone-dependent benign gynecological disease:
endometriosis (see gynecology)
● 3. Menopause (see gynecology)

331

Chronic anovulation due to estrogen deficiency
● Functional hypothalamic anovulation: aberrant but reversible
defect in the neuroendocrine regulatory pathway; may be
associated with excessive exercise (CRH and ß-endorphins ↑),
dieting (anorexia, bulimia) or emotional distress
○ Slowdown in the frequency of LHRH secretion
■ Changes in dopaminergic activity (↓↑)
■ Increased endogenous opioid peptides
■ Chronic activation of the hypothalamo-pituitary axis
□ Can be prevented by administration of CRH and opiate antagonist

○ Low estrogen and gonadotropins levels
○ Secondary amenorrhea

332

● Premature ovarian failure in reproductive years: depletion of
follicles before age of 40
○ In most cases the etiology is not clear
■ Perhaps genetic cause to cause ovarian follicles disappear at a
faster rate
□ Mutations of FSH, LH receptors
□ Galactosemia (accumulation of galactose-1-phosphate at toxic level
due to lack of galactose-1 phosphate uridyltransferase)
□ 45X, 47XXY {mosaicism}

■ Autoimmune process (polyendocrine syndromes: hypothyroidism,
hypoadrenalism, hypoparathyroidism, DM or SLE)
■ Chemotherapy, radiation

○ Amenorrhea, oligomenorrhea, infertility with usually high FSH &
LH

333

Chronic anovulation due to androgen excess
Causes of androgen excess
Adrenal – overproduction of testosterone precursors
(DHEAS, DHEA, androstendione)
Cushing’s syndrome
Glucocorticoid resistance
Virilizing adrenal tumor
Other
Idiopathic hirsutism,
hyperprolactinemia etc

Ovarian
Polycystic ovarian syndrome (PCOS)
Hyperthecosis (severe variant of PCOS)
Ovarian tumor (Sertoli-Leydig cell tumor)
Testosterone or androstendione ↑

Testosterone is
directly secreted
by the ovaries to
the blood

Skin

Aromatase

17ßHSD

Fat
A – Androstendione
E1 – Estrone
T – Testosterone

17ßHSD
Estradiol
Estrogen dependent
Malignancies of breast
& endometrium

5-a reductase
Dihydrotestosterone
Androgen dependent
Hirsutism & virilization

Hirsutism: presence of terminal
hair: cheek, upper lip, chin, middle
chest hair; male escutcheon: inner
thighs, intergluteal area
Idiopathic hirsutism: female with
Mediterranean origin (cutaneous
5α-reductase activity ↑)
Virilization: thickening of voice,
clitoromegaly, temporal balding,
decrease in breast size, increase in
muscle mass
334

Polycystic ovarian syndrome (PCOS)
● The most common endocrine disorder affecting ~6% of women
of reproductive age with uncertain origin & elusive
pathophysiology. PCOS risk is significantly increased with
positive family history for anovulation and androgen excess
(polygenic inheritance ?)
○ Antonio Vallisneri (1721): “Young peasant woman, married,
moderately plump, infertile, with ovaries larger than normal, like
doves’ eggs, lumpy, shiny and whitish”

○ Stein-Leventhal syndrome (1935)
● Major components of the syndrome
○ 1. Clinical: polycystic ovaries,menstrual abnormalities,
anovulatory infertilities, repeated miscarriages, hirsutism, acne,
alopecia

335

Central opiate tone ↓
↓
Increased GnRH
pulsatile activity

Estradiol

↑ LH ↓ FSH

Low circulating
progesterone level

↑ Androgens

Hyperinsulinemia
Inzulin resistance

Obesity

Dyslipidemia

336

○ 2. Endocrine: elevated androgens, luteinizing hormone,
estrogen and prolactin
■ Exaggerated GnRH pulse frequency and amplitude in the
hypothalamus → LH ↑ → LH-dependent androgen synthesis ↑ in
thecal cells in the ovary w clinical sign of hyperandrogenism
□ Theca cells are more effective in PCOS to convert androgen
precursors to testosterone, than normal cells

■ Adrenal androgen production is also enhanced
■ High estrogen levels can cause suppression of FSH and a relative
increase in LH
□ Unopposed estrogen action → well-rugated vagina

■ Low FSH level is not enough to mediate androgen → estrogen
metabolism in folliculi → anovulation
□ Exclusion of other causes of anovulation: thyroid disorders,
hyperprolactinemia, Cushing’s syndrome, late onset congenital
adrenal hyperplasia, ovarian and adrenal tumors
337

○ 3. Metabolic: hyperinsulinemia, insulin resistance, obesity,
impaired glucose tolerance, type 2 DM, lipid abnormalities
■ Hyperinsulinemia
□ Stimulates hypothalamic LH secretion
□ Stimulates theca cells androgen production
□ Decreased production of testosterone-binding globulin and IGFbinding protein 1 in the liver → circulating androgen hormone level ↑
□ Enhanced adrenal androgen production (sensitivity to ACTH ↑)

■ PCOS „diabetes of bearded woman” – 1921
□ 30% of women with PCOS have IGT & 8-10% will have undiagnosed
Type 2 DM

338

339

Hormonal regulation in males

340

Disorders of the male reproductive tract
● I. Abnormalities of androgen metabolism and testicular function
○ Fetal life
○ Neonatal life
○ Puberty
○ Adult life

■ Infertility with abnormal virilization (hypothalamic, pituitary and
testicular diseases)
■ Infertility with normal virilization (hypothalamic, pituitary, testicular
and sperm transport diseases)

○ Old age: disorders of the prostate gland (see urology)

● II. Abnormalities in estrogen metabolism

○ Estrogen excess: gynecomastia
○ Impairment of estrogen formation and action: aromatase
deficiency; estrogen receptor a deficiency
341

Abnormalities of androgen metabolism and testicular
function
● Fetal life

○ Cryptorchism: ; Most common congenital condition of testes; one or both testes fail to
descend into scrotum; testis that is not 4 cm or more below the pubic trabecule in an
infant
○ Does not interfere with puberty or maintenance of secondary sex characteristics
○ Increased risk of testicular cancer;
○ Untreated – infertility
○ Treat with hormonal therapy or surgery – preferably by age 2

Intra-abdominal testis (10%)
Canalicular testis (20%)
High scrotal testis (40%)
Obstructed testis (30%)

342

● Neonatal life

○ Temporary inhibition of pituitary-testicular axis → impaired
testicular function at puberty

● Puberty

○ 1. Sexual precocity
■ Sexual development prior to age 9
□ Complete: virilization with spermatogenesis
□ Incomplete: virilization no spermatogenesis

■ Virilizing syndromes
□ Hypothalamo-pituitary activity is normal, testosterone level is ↑
♦ Leydig cell tumors
♦ Human chorionic gonadotropin-secreting tumors
♦ Congenital adrenal hyperplasia

■ Premature activation of hypothalamo-pituitary axis
□ Idiopathic or CNS tumors

○ 2. Delayed/incomplete puberty
■ See hypothalamic and pituitary diseases with undervirilization and
infertility
343

Infertility in adult life
Hypothalamic-pituitary disorders
with undervirilization
•Congenital isolated gonadotropin deficiency
•Hypogonadotropic hypogonadism (see
Kallman’s syndrome)
•Fertile eunuch syndrome: FSH normal →
normal spermatogenesis; LH↓ testosterone ↓
•Panhypopituitarism
•Hyperprolactinemia
•GnRH receptor, LHß and FSHß mutations
•Adrenal hypoplasia congenita: mutation in DAX1
gene (hypogonadotropic hypogonadism + adrenal
insufficiency), X-linked
•Cushing’s syndrome: high plasma cortison
depresses LH secretion
•Hemochromatosis: iron deposition in testes and
pituitary (no LH response to GnRH)

with normal virilization
•Isolated FSH deficiency: no or low FSH, LH
and testosterone normal
•Congenital adrenal hyperplasia (C-17, 21 OH
defect)
•Pharmacologic doses of androgens (anabolic
steroids)

344

Testicular defects – Developmental/structural defects
with undervirilization

with normal virilization

•LH receptor inactivating mutation
(psedohermaphroditsm)
•Klinefelter's syndrome (classic form: 47,XXY; mosaic
form: 46,XX/47,XXY)
Small, firm testes, azospermia, gynecomastia, tall
stature (longer lower body segment), elevated
gonadotropin levels, low testosterone, learning
disabilities; taurodontism (abnormal dental pulp)
•XX male (Klinefelter's variant)
Male psychosexual identification, normal height,
no cognitive impairment
Plasma testosterone is low and plasma levels of
estradiol and gonadotropins are high
Male development in absence of Y chromosome
Mosaicism for Y containing cell line
Gain of function mutation for some
autosomal genes
Y chromosome translocation to X
chromosome (~ 80%, often only SRY gene
[mediates testicular development])

•Germinal cell defects; Sertoli-cell only syndrome:
lack of germinal elements; LH usually normal,
FSH high
•FSH receptor inactivating mutation (oligospermia
& normal testosterone level)
•Cryptorchism
•Varicocele – 10-15% in general population
(pampiniform plexus)
•Kartagener’s syndrome: Immotile cilia syndrome
+ situs inversus

345

Acquired testicular defects
with undervirilization

with normal virilization

Mumps (viral orchitis)
Trauma
Radiation
Drugs
Spironolacton, ketoconazole and cyproteron: block of testosterone
synthesis (C-17)
Anti-epileptic dugs (phenytoin and carbamazepine): ↓ bioavailable
testosterone
Ethanol: inhibition of testosterone synthesis (3ß-HSD),
spermatogenesis and hypothalamic-pituitary disease
Environmental toxin: lead
Generalized autoimmune diseases & granulomatous diseases
(lepromatous leprosy)
Systemic disease-related testicular defects
Renal failure: 50% of dialysis patients, decrease in plasma
testosterone and increase in plasma FSH and LH
Hepatic disease: cirrhosis – SHBG level ↑, plasma estradiol ↑
(extra glandular conversion of testosterone to estradiol),
testosterone ↓
Sickle cell anemia: due to hypothalamic or testicular defect –
arrested spermatogenesis
Chronic illness: malnutrition, cancer, COPD, cystic fibrosis
Hereditary androgen resistance (LH, testosterone ↑)
Point mutations in androgen receptor

Mycoplasma infection
Radiation
Drugs: alkylating agents
Environmental toxins: ethylene glycol,
cadmium, lead
Autoimmunity
Antibodies to the basement membrane
of seminiferous tubules or to sperms
Anti-sperm antibodies – prevent
penetration of cervical mucus
Systemic disease-related testicular defects
Acute febrile illness
Celiac disease
Spinal cord injury
Acquired androgen resistance
Increased CAG sequence in androgen
receptor
Sperm transport defects
Obstruction of epididymis or vas
deferens: cystic fibrosis, vasectomy

346

Estrogen excess – gynecomastia
● Physiologic gynecomastia
○ Newborn, adolescent, aging

● Pathologic gynecomastia
○ Relative estrogen excess (decrease in
testosterone)
■ Congenital defects
□ Congenital anorchia
□ Klinefelter’s syndrome
□ Reinfenstein’s syndrome (partial deficiency of the
androgen receptors)
□ Defects in testosterone synthesis: 3ß-HSD and 17ßHSD deficiency

■ Secondary testicular failure: viral orchitis, trauma,
castration, renal failure etc
347

○ Increased estrogen production
■ Increased testicular estrogen secretion: testicular tumors, hCG
producing tumors (bronchogenic carcinoma)
■ Increased substrate for extraglandular aromatase
□ Adrenal (C-21 OH defect), liver diseases; starvation, thyrotoxicosis

■ Increased extraglandular aromatase

○ Drugs that
■ Act like estrogens (diethyl stilbestrol, cosmetics, phytoestrogens)
■ Enhance endogenous estrogen production (gonadotropins)
■ Inhibit testosterone synthesis (see before)
■ Act by unknown mechanism (e.g. marihuana, heroin)

● Idiopathic gynecomastia
348

Impairment of estrogen formation and action
● Aromatase deficiency
○ Loss of function mutation (C-19 gene)

● Estrogen receptor a-subunit deficiency
● Common features of estrogen deficiency
○ Tall stature, no growth spurt at puberty, rather continuous growth
without epiphyseal closure

349

Dehydration
Osmotic
concentration
of blood increases
Negative
feedback

Lowers
blood
volume
and
pressure
Negative
feedback

Osmoreceptors
ADH
synthesized by
neurosecretory
cells in
hypothalamus
ADH

Increased
water
retention

Reduced
urine
volume

ADH released
from posterior
pituitary into
blood

Increased
vasoconstriction
leading to higher
blood pressure
350

Vasopressin: physiology & pathophysiology
● Osmotic stimulation
○ Due to increase in plasma
osmotic concentration

● Non-osmotic stimulation
○ Baroreceptors: cardiopulmonary, sino-aortic
○ Intracardial, intra-aortic
pressure ↓
○ Angiotensin II (AT-II)
○ Central a2 adrenergic, opiate,
dopamine receptor

351

2% increase
ECF osmolality

10% decrease in
circulating volume

CNS
osmoreceptor

Baroreceptor

ADH release

Angiotensin II

Antidiuresis

Thirst

ET-1

Oropharyngeal
reflex

Water
conservation

PGE2 incr

Diseases with nonosmotic
ADH release
1.

2.

3.

Decrease in
circulating volume:
bleeding, GI and
renal fluid loss
After surgery: due to
pain, hypotension,
hypoxia and
anesthesia
Edema formation:
cardiac, liver,
pregnancy

Water
acquisition

Circulating volume incr.
ANP incr.

352

Vasopressin: clinical uses
● Diagnostic use: To differentiate central and nephrogenic DI.
○ One hour after treatment, urine osmolality should increase > 50
% if cause is AVP deficiency

● V1-mediated contraction of GI smooth muscle

■ To treat post-operative ileus
■ To dispel intestinal gas before abdominal imaging
■ Emergency treatment of bleeding esophageal varices (varicose
veins)
■ Acute hemorrhagic gastritis

● V2 antagonist: to treat edema

353

Diabetes insipidus
● Common features of diabetes insipidus
○ Decreased reabsorption of free water in kidney → isovolemic
hyperosmotic hypernatremia (plasma osmolality > 295
mOmsol/kg)
○ Excretion of large volumes of dilute (< 200 mOmsol/kg) urine
(polyuria, nocturia)
○ Stimulation of thirst (polydipsia)

354

● 1. Pituitary / Central diabetes insipidus (CDI): defect in
vasopressin production and/or release
○ 50 % of cases are idiopathic: DI becomes symptomatic only with
an 80-85 % reduction of AVP cells
○ Congenital central diabetes insipidus (CDI)
■ Autosomal dominant – caused by mutation in vasopressinneurophysin II gene
■ Autosomal recessive – Wolfram syndrome: CDI, DM, optic atrophy
and deafness

○ Acquired central diabetes insipidus
■ Trauma, cysts, histiocytosis, granuloma (tuberculosis, sarcoidosis),
aneurysms, meningitis, encephalitis, Guillain-Barré syndrome
■ Metastatic tumor from breast cancer, craniopharyngioma,
pinealoma
355

● 2. Nephrogenic DI – the renal collecting duct does not respond
appropriately to ADH
○ Congenital nephrogenic DI
■ Autosomal recessive form of NDI is caused by mutation in AQP2
■ X-linked NDI: V2 receptor mutation – cyclic AMP is not generated in
response to AVP

○ Acquired nephrogenic DI: more common but less severe
■ Diseases
□ Chronic renal failure, hypercalcemia and hypokalemia
□ Sickle cell anemia or trait (medullary vascular injury)

■ Excessive water intake or primary polydipsia (decreased medullary
tonicity)
■ Severe protein restriction (decreased medullary urea & tonicity)

● 3. Gestational DI
○ Vasopressinase produced by placenta inactivates circulating
vasopressin
○ Treatment: desmopressin (DDAVP – resistant to vasopressinase)
356

Physiological conditions

Congenital nephrogenic diabetes insipidus

>90%

357

Syndrome of inappropriate ADH secretion
(SIADH)
● Causes of SIADH
○ Malignancies (Schwartz-Bartter syndrome)
■ Small-cell lung carcinoma, duodenum, pancreas and olfactory
neuroblastoma – ectopic ADH production

○ Pulmonary disease
■ Pneumocystis jirovecii – HIV + CNS infections and malignancies

○ CNS disorders
■ Tumors, infections, trauma – releasing excess ADH

358

● Impaired water excretion in the presence of hyponatremia
(isovolemic, hypotonic) and hypoosmolality. Defective
osmoregulation → a urinary concentration inappropriately high
(↑ ADH → excessive reabsorption of free water) to the degree
of hypoosmolality
○ The commonest cause of hyponatremia in hospital patients with
oliguria, and high specific gravity (with inability to dilute it)
○ Hypoosmolality may produce lethargy, anorexia, nausea and
vomiting, muscle cramps; may lead to coma, convulsions, and
death

● Therapy
○ Restriction of fluid intake, inhibition of ADH
359

Resetting of the osmostat
● Functional disease
○ In one-third of SIADH patients
○ Chronic diseases: lung tuberculosis, hepatic cirrhosis,
malnutrition, pregnancy

● Osmolality is kept at 250 mOsmol/kg and serum Na at 120
mmol/l
● Features
○ Upon exogenous water load: Urine dilution is appropriate to water
load; Low Na concentration is maintained
○ In water depletion: concentrated urine; Low Na concentration is
maintained
360

Oxytocin (OT)
● Action and mechanism of action: specific G protein-coupled receptors

○  frequency and force of uterine smooth muscle contraction during parturition
○  contraction of mammary myoepithelial cells and milk ejection

● Clinical uses
○ OT test for uteroplacental insufficiency: indicates whether placental reserve is
sufficient for continuation of a high-risk pregnancy (Fetal heart rate used as a
measure of distress)
○ Induction of term labor
○ Control of postpartum bleeding
○ For increasing milk ejection: administered as a nasal spray 2 to 3 minutes
before breast-feeding

● Other effects of OT
○ OT attenuates endocrine and autonomic responses to stress, mediator for the
stress-protective effects of social support, attenuate amygdala reactivity to
social stimuli and reduce brainstem activity to autonomic arousal and
enhanced readiness to show social approach behavior and empathy
361

Hypothalamic neurons release
oxytocin, which travels down the
axon to the posterior
hypophysis

The posterior hypophysis
releases oxytocin into the
bloodstream
Oxytocin travels to target cells
with receptors specific to this
hormone

Efferent neurons relay the message to
the paraventricular nucleus (PVN) within
the hypothalamus

Afferent neurons carry information from sensory
receptors to the spinal chord
362

Parathyroid gland

363

Parathyroid glands and Ca homeostasis
● Main role is to regulate Ca, Mg and phosphate (Pi)
● Parathyroid hormone (PTH)
● Produced by parathyroid chief cells in response to low iCa++
● PTH → Type 1 PTH receptor (PTH1R) → activation of Gsα →
cAMP↑
○ Stimulates renal Ca++ & Mg++ absorption in distal tubules and
thick ascending limb and decreases the reabsorption of
phosphate PO43- in the proximal tubules
○ Stimulates proximal renal tubular conversion of 25-(OH)D3 to
1,25-(OH)2D3 which increases intestinal Ca++ and phosphate
absorption
○ Stimulates osteoclastic resorption of bone
364

PTH anticalciuric effect

Ca

Phosphate
PTH phosphaturic effect
365

Calcitonin
● Non-essential hormone.
Patients with total
thyroidectomy maintain normal
Ca++ concentrations
● Produced by parafollicular C
cells of thyroid gland in
response to increased iCa++
● Inhibit osteoclastic resorption of
bone and Ca resorption from
intestine
● Inhibit renal Ca++ and PO43reabsorption

Vitamin D
● Sources
○ Food – Vitamin D2
○ UV light mediated cholesterol
metabolism – D3

● Metabolism

○ D2 and D3 are converted to
25(OH)D3 by the liver
○ 25(OH)D3 is converted to
1,25(OH)2D3 by α hydroxylase
upon PTH stimulus in the proximal
tubulus

● Function
○ Stimulation of osteoblasts
○ Increases GI absorption of dietary
Ca++ and phosphate

366

● Calcium (2.1-2.6 mmol/l; iCa++ 1.14-1.2 mmol/l)
○ Required for muscle contraction, intracellular messenger
systems, cardiac repolarization.
○ Exists in free and bound states
■ Free (50% - biologically active) iCa++
■ Albumin bound (40% total Ca)
■ Complexes with anions: bicarbonate, lactate, sulphate, phosphate
and citrate (10% total Ca)

○ Concentration of iCa++ mediated by
■ Parathyroid gland, parafollicular C cells, kidney, bone
■ Ca level should be corrected in hypoalbuminemia and acidosis

367

Hypocalcaemia (< 2.1 mmol/l; iCa2+ <1.14 mmol/l)
● I. Lack/ineffective PTH
○ 1. Hypoparathyroidism
■ Idiopathic (familial or autoimmune disorders)
■ Surgical removal of the gland
■ Infiltrative diseases (amyloidosis)
■ Congenital lack of the gland: see DiGeorge syndrome

○ 2. Defects in PTH1R (chondrodysplasia)
■ Low PTH, however in activating PTH1R mutation plasma Ca can
be high

368

○ 3. PTH resistance or pseudohypoparathyroidism: inactivating
mutation of Gsα protein encoding gene; end-organ insensitivity to
PTH
■ Low Ca++, and increased phosphate and PTH levels
■ There are several forms of pseudohypoparathyroidism: one is
associated with Albright hereditary osteodystrophy (short stature,
round face, short neck, short metacarpals and metatarsals) and
resistance to TSH, GHRH and gonadotropins

○ 4. Hypomagnesemia (low Ca and K level)
■ Mg is essential for normal PTH function
■ Decreased PTH secretion, diminished response to PTH

369

● II. Inappropriate vitamin D metabolism
○ Genetic defects of vitamin D metabolism: vitamin D dependent
rickets (rachitis)
■ Type 1: pseudo vitamin D deficient rickets: Inactivating mutation of
1-OH gene
■ Type 2: vitamin D resistance: Vitamin D receptor gene defect

○ Malnutrition: vitamin D deficiency
○ Malabsorption: hepatobiliary diseases
○ Kidney diseases
■ Chronic renal insufficiency: ↓ in renal mass ↓ 1,25-(OH)2D3 → →
secondary hyperparathyroidism
■ Nephrotic syndrome (loss of vitamin D binding protein)
370

● III. Increased Ca complexation
○ Pancreatitis: pancreatic lipase – degradation of retroperitoneal
omental fat (Ca and Mg soap)
○ Oxalic acid / fluoride / citrate (blood products) poisoning
○ Iatrogenic: after ACTH, steroid, EDTA and furosemide
administration
○ „Hungry bone” syndrome
■ Rapid bone mineralization after parathyroid surgery of osteitis
fibrosa cystica (von-Recklinghausen’s disease), or
■ vitamin D administration in rickets

○ Increased plasma phosphorus level
■ Crush syndrome, trauma, renal failure
■ Phosphate-containing laxatives, infusions
371

Symptoms of hypocalcaemia
● Neuromuscular irritability: Paraesthesiae of the distal extremities and
circumoral area; muscle cramps, laryngospasm, tetany and seizures
■ Erb sign: Increased electric excitability of the muscles to the galvanic
current, and frequently to the faradic, in tetany
■ Chvostek sign: Facial twitch elicited by tapping on the facial nerve just
below the zygomatic bone with the patient’s mouth slightly open
■ Trousseau sign: Brachial artery occlusion with a sphygmomanometer cuff
inflated above the systolic blood pressure for 3 min: Wrist and
metacarpophalangeal joint flexion, hyperextended fingers, and flexion of
the thumb on to the palm
■ Peroneal sign: dorsiflexion and abduction of the foot on tapping the
peroneal nerve on the lateral surface of the fibula just before the knee

○ Cardiac manifestations – prolonged QT interval which may progress to
ventricular fibrillation or heart block
372

Hypercalcaemia (> 2.6 mmol/l; iCa++ >1.2 mmol/l)
● I. Excess PTH production
○ 1. Primary hyperparathyroidism – autonomous parathyroid
hyperfunction
■ Parathyroid adenoma
□ 80% of cases of hyperparathyroidism
□ Stepwise acquired mutations of MEN1 (inactivating) and cyclin D1
(activating) genes

■ Type 1 Multiple Endocrine Neoplasia (MEN1)
□ Sequential inactivation of both copies of MEN1 gene (tumor
suppressor)

■ Familial hypocalciuric hypercalcemia
□ Monoallelic inactivation of Ca-sensing receptor genes (decreases the
Ca sensing by parathyroid cells and renal tubules)
373

■ Neonatal severe primary hyperparathyroidism
□ Biallelic inactivation of Ca-sensing receptor genes (decreases
the Ca sensing by parathyroid cells and renal tubules) often
lethal
■ Multiple Endocrine Neoplasia Type 2a (MEN 2a)
□ Activating mutation of the RET protoncogene

○ 2. Tertiary hyperparathyroidism
■ Increased PTH response persists (to renal and intestinal
hypocalcaemia)
■ Adenoma formation in patients with secondary
hyperparathyroidism due to parathyroid hyperplasia

374

● II. Pseudo-hyperparathyroidism
○ Neoplasia without skeletal involvement (circulating tumor-derived
agents with bone-resorbing capacity
○ Immunologically distinct form PTH; e.g. EGF, PDGF causes
prostaglandin dependent bone resorption)
○ PTH level is not high

● III. Excess 1,25(OH)2D3
○ Vitamin D intoxication
○ Boeck sarcoidosis

■  bone reabsorption and intestinal absorption) and  sensitivity to
vitamin D (conversion of 25(OH)D3 to 1,25(OH)2D3

○ Neoplastic production of 1,25(OH)2D3 – lymphoma

375

● IV. Increased bone reabsorption
○ Metastatic tumor
■ Breast, colon, prostate

○ Neoplasia with skeletal involvement
■ Circulating, tumor-secreted (PTH-related peptide, 1,25(OH)2D3) –
lung, renal cc.
■ Locally acting, non-circulating, tumor-secreted factors (osteoclast
activating factor, IL-1, PG-s) – in myeloma, lymphoma

○ Overdose of vitamin A
○ Immobilization: bed rest over 4 weeks

● V. Endocrine disorders
○ Hyperthyroidism and pheochromocytoma (↑ bone resorption)
○ Adrenal insufficiency (nonionic compartment of Ca ↑)
○ Acromegaly
376

● VI. Increased intestinal absorption of Ca
○ Milk-alkali syndrome (Burnett’s syndrome) [rare]
■ Alkali is known to exert hypocalciuric effect on distal nephron
■ Increased Ca reabsorption from milk

○ Excess Ca or Ca-carbonate intake to prevent osteoporosis
[frequent]
○ Vitamin D intoxication

● VII. Decreased renal excretion of Ca
○ Familial hypocalciuric hypercalcemia (see earlier)

● VIII. Impaired bone formation and incorporation of Ca
○ Aluminum intoxication
○ Adynamic (low turnover) bone diseases (chronic renal failure)
○ Administration of corticosteroids
377

Symptoms of hypercalcaemia
● Neurological manifestations
○ Mild drowsiness, progressing to weakness, depression, lethargy,
stupor, and coma

● Gastrointestinal symptoms
○ Constipation, nausea, vomiting, anorexia, and peptic ulcer
disease
○ Recurrent pancreatitis (Ca deposition and ductal obstruction)

● Renal symptoms
○ Nephrogenic diabetes insipidus - polyuria leading to ECF volume
depletion and a reduction in the glomerular filtration rate (GFR),
which may lead to a further increase in Ca concentration.
○ Nephrolithiasis, nephrocalcinosis
■ Ca kidney stones, metastatic calcification of glomerulus

378

● Cardiac symptoms
○ Potentiating digitalis toxicity
○ Arrhythmia
○ Tachycardia
○ Decreased Q-T interval

● Osteitis fibrosis cystica (von-Recklinghausen disease)
○ Lytic bone lesions caused by hyperparathyroidism
○ Resorption of the distal phalanges characteristically occurs.

● Metastatic calcification
○ Calcification of soft tissues resulting from hypercalcemia or
hyperphosphatemia

● Easy to remember: signs & symptoms of hypercalcaemia
○ Bones (osteitis fibrosa cystica, osteoporosis, rickets)
○ Stones (renal stones)
○ Groans (constipation, peptic ulcer)
○ Moans (lethargy, depression, confusion)

379

QTc 0.48/0.92=0.52

RR=71/min, SR, Normal axis
PR=0.22 sec, RR=0.84 sec, √RR=0.92 sec

RR=79/min, SR, Normal axis
PR=0.16 sec

RR=115/min, ST, -30o
PR=0.12 sec
380

Multiple endocrine neoplasia: MEN Familial
hyperparathyroidism
● Multiple Endocrine Neoplasia (MEN) are autosomal dominant
syndromes characterized by overproduction of a variety of hormonal
substances
● MEN 1(Wermer’s syndrome)
○ Genetic defect on chromosome 11. defect in MEN1 gene – which is
likely a tumor suppressor gene (MEN1 encodes menin protein which
suppresses tumor growth)
■ 1. Parathyroid hyperplasia or adenoma (95%)
■ 2. Pancreatic islet cell tumors (75%) with excessive secretion of
□ Gastrin → peptic ulcers (Zollinger-Ellison syndrome)
□ Insulin → hypoglycemia
□ Serotonin → carcinoid syndrome
□ VIP → watery diarrhea

■ 3. Pituitary adenoma (66%);
□ Prolactinoma, but GH & ACTH producing adenomas

381

● MEN 2a (Sipple’s syndrome)
○ Inherited mutation in the RET proto oncogene on chromosome
10*.
■ 1. C cell hyperplasia or medullary thyroid carcinoma (100%)
■ 2. Pheochromocytoma (50%), often bilateral and may arise in the
extra-adrenal paraganglia
■ 3. Parathyroid hyperplasia or adenoma (25%)

● MEN 2b (Gorlin’s syndrome)
○ Inherited mutation in the RET protooncogene on chromosome
10*, different from that seen in MEN 2a
○ Neoplasms are as in MEN 2a and mucosal neuroma syndrome:
■ Ganglioneuromas of the skin, eyes and mucous membranes of the
mouth, GI tract, respiratory tract & bladder (100%)
■ Marfanoid body habitus (65%)
*due to RET mutation early thyroidectomy

382