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: Cushings 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

Sheehans 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

Rathkes 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. Sheehans 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.

Kallmanns 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 Addisons
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 Sheehans)
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 Rathkes 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 Crohns 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
Turners 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 (Cushings syndrome, Cushings 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

Hashimotos thyreoiditis
Subacute thryroiditis (DeQuervains, 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 Hashimotos 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

Hashimotos 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; Annes 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

NFB activation
Proinflammatory factors:
TNF-a, MCP-1, IL-6, ICAM-1
PAI-1

307

Diseases of the adrenal cortex

Hyperadrenalism
Cushings 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. Addisons
disease)
Secondary (due to ACTH
deficiency)
Tertiary (rarely due to
hypothalamic CRH deficiency)
308

Cushings 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

Cushings disease : pituitary hypersecretion of ACTH. Nelsons
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 11-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

Bartters, Gitelmans 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 -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 -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

(Addisons 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

Addisons)
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 Willebrands 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 -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)
Cushings 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

17HSD

Fat
A Androstendione
E1 Estrone
T Testosterone

17HSD
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
5-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, Cushings 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
Kallmans syndrome)
Fertile eunuch syndrome: FSH normal
normal spermatogenesis; LH testosterone
Panhypopituitarism
Hyperprolactinemia
GnRH receptor, LH and FSH mutations
Adrenal hypoplasia congenita: mutation in DAX1
gene (hypogonadotropic hypogonadism + adrenal
insufficiency), X-linked
Cushings 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)
Kartageners 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 (3-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
Klinefelters syndrome
Reinfensteins syndrome (partial deficiency of the
androgen receptors)
Defects in testosterone synthesis: 3-HSD and 17HSD 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-Barr 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 Gs
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 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 Gs 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-Recklinghausens 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 patients 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
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 VI. Increased intestinal absorption of Ca

Milk-alkali syndrome (Burnetts 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
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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

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 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)

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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
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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(Wermers 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

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 MEN 2a (Sipples 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 (Gorlins 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

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