Endocrinology

HYPOPITUITARISM

insufficiency of anterior pituitary hormones, which can be total (complete compromisation) or
partial. It is a rare condition, accounting for 12-42 cases/1 million per year, with a prevalence of about
300-455/1million.
Etiology: primary → diseases affecting the pituitary gland, secondary → lesions affecting the
hypothalamus or the pituitary stalk:
Hypothalamic diseases Pituitary diseases
● Head injury ● Postpartum pituitary necrosis or
● CNS tumors + metastases Sheehan syndrome: enlargement of the
● Craniopharyngioma (children) pituitary during pregnancy
● Brain surgery/radiation ● Empty sella syndrome
● Stroke ● Macroadenoma = compression
● Brain infections (e.g. meningitis) ● Pituitary apoplexy: bleeding into or
● Infiltrative diseases (Sarcoidosis) insufficient blood supply to the pituitary
Traumatic brain injury: one of leading causes of hypopituitarism (30% of TBIs) caused by
vulnerability of the pituitary stalk and the pituitary gland.
● Symptoms: a-specific (tiredness, weight loss or gain etc.), history for previous TBI is essential.
● Main consequences:
○ Hypogonadism (40% of men)
○ Central hypothyroidism (6%)
○ GH deficiency (6%)
Empty sella syndrome: herniation of the subarachnoid space in the sella turcica that can be:
● Primary: congenital, no history of pituitary tumors → 35% hypopituitarism in children
● Secondary: acquired, associated to tumor or surgery for pituitary tumor → 60% in adults
● Main consequences:
○ GH deficiency
○ Rarely hypogonadism, hypothyroidism and hypoadrenalism
○ Hyperprolactinemia (20%) → gynecomastia, galactorrhea, hypogonadism (PRL excess
= disruption in normal pulsatility of FSH and LH → reduction in estradiol and
testosterone).
Hypophysitis: infiltrative and inflammatory disease → increase in size + possible destruction of the
pituitary cells → hypopituitarism. Very rare condition.
● Symptoms: headache (>50%), mass effects, hypo-adrenalism and hypo-gonadism
(especially in lymphocytic), ADH-deficiency and diabetes insipidus (pituitary stalk +
neurohypohysis are involved)
Classical lymphocytic hypophysitis: linked to pregnancy or postpartum period → headache,

diabetes insipidus and hypopituitarism. Hypertrophy of hypophysis → may touch the optic chiasm
→ visual defect
Granulomatous hypophysitis: can be primary or secondary to systemic diseases (e.g. sarcoidosis).

Female predominance, in general seems to be very severe.
Immune checkpoint therapy related hypophysitis: related to chemotherapy (e.g. Lipimubab can in
50% of cases), higher predominance in females.
○ Symptoms: after 5-36 weeks from start of treatment, no significant increase in size of gland
with no headache and no visual disturbance but hypopituitarism is present in 70% of cases →
especially TSH and ACTH deficiency.

GH DEFICIENCY
Clinical presentation:
Children Adults
- Short stature (decreased May lead to metabolic syndrome (characterized by central

linear growth and reduced adiposity, reduced lean mass, reduced bone mass) → important
action of IGF1) risk factor for CV diseases, highly affecting QoL of the patient
- Reduced growth velocity → this may be linked to glucose intolerance, diabetes,
- Hypoglycemia (GH usually dislipidemia, and hypertension.
raises plasma glucose
concentration by promoting
lipolysis)
Diagnosis:
● GH: limitation → daily fluctuation + modified by stressors, physical exercise, stress…
● IGF1: more accurate
Dynamic testing:
● GHRH infusion: to stimulate GH secretion
● Insulin tolerance test: induced hypoglycemia to induce GH secretion
● Arginine testing: somatostatin suppression.

PITUITARY ADENOMA:
Pituitary adenomas → most common type of pituitary tumors (15% of all intracranial neoplasms,
commonly encountered at autopsy)
● May cause hormone hypersecretion, hyposecretion (due to compression of pituitary) but also
functionally silent.
● Most commonly benign but can also be aggressive and locally invasive (e.g. in cavernous
sinus) or compressive to vital central structures (e.g. optic chiasm).
● They are also the most common types of pituitary incidentalomas (lesion discovered on
advanced imaging study performed for an unrelated reason (e.g. neurological symptoms such
as dizziness, vertigo, headache etc).
● Other types of incidentalomas: cystic lesions 10-50% → aggressive craniopharyngiomas 60%,
Rathke’s cleft cysts 40%
● Remember: increase in pituitary size does not mean pituitary adenoma! Normally → 6 mm in
height, may be higher in healthy subjects (>7 mm in 6.2% and >8mm in 1.1 %) but also in
certain conditions, like in fertile or pregnant women.
Classification:
● Size: micro: < 1cm in diameter, macro: > 1cm in diameter
● Extension: endosellar: tumor in the sella turcica, suprasellar (compression of optic chiasm
and compression of the pituitary stalk), parasellar: inside the cavernous sinus
● Invasiveness: independent from the size of the adenoma
● Hormone secretion:
○ Non functional adenoma (NFPA) (30%): (may cause deafferentation hyperPRL)
○ PRL secreting adenoma (40%) → mostly micro
○ GH secreting adenoma (15%) → mostly macro
○ ACTH secreting adenoma (10%) → hypercortisolism
○ TSH secreting adenoma → mostly macro
○ LH/FSH secreting adenoma
Epidemiology: incidence increased from 6 to 11 cases/1.000.000 in 33 years (possible advanced

knowledge but also a real increase).
● Age: secreting tumors → young population, NFPAs → elderly (60-90 y.o.)
○ PRL-secreting adenomas diagnosed earlier → hypogonadism (women =
amenorrhea, galactorrhea ; men = gynecomastia, loss of libido) → effects will make
them seek a physician.
● Sex: PRLoma is more frequent in women (76%), NFPA in men.
Symptoms of macroadenoma:
Pituitary adenomas are majorly characterized by normal pituitary function (80%).
However, due to their size, macro a denomas may produce mass effects, leading to:
● Hypopituitarism (compression of cells ) → more frequently hypogonadism
● Headache: stretching of meninges and gradual increase in intrasellar pressure.
● Bitemporal hemianopsia, scotomas, blindness: optic chiasm compression + optic nerve
atrophy.
● Ptosis, ophthalmoplegia, diplopia: cavernous sinus invasion, compression CN III
(oculomotor), IV (trochlear), VI (abducens).
● Hypothalamic syndrome (diabetes insipidus, obesity, temperature dysregulation) due to
hypothalamus invasion.
● Deafferentation hyperprolactinemia: when compressing the pituitary stalk, causing inability of
hypothalamus to tonically inhibit, via dopamine, PRL release from the pituitary.
HYPERPROLACTINEMIA
Epidemiology:
● Hyperprolactinemia: > 20 ng/mL in men, >
25 ng/mL in women, prevalence of ~0.4%
○ More frequent in women with galactorrhea and amenorrhea (75-80%), women with
alterations of reproductive functions (9-17%).
Causes of hyperprolactinemia:
● Physiological: pregnancy, lactation (action of milk production in mammary glands), exercise
(at rest = decrease), stress, sleep, coitus
● Pharmacological: anticonvulsants, antidepressants, antihypertensives, antipsychotics, oral
contraceptives, dopamine receptor blockers, neuropeptides, opiate and opiate antagonists.
● Pathological:
○ Hypothalamic-pituitary stalk injury (trauma, granulomas, infiltration, Rathke’s cyst,
suprasellar pituitary adenoma)
○ Pituitary (acromegaly, plurihormonal adenoma, surgery, trauma etc.) → PRLoma: ~20%
- Microadenomas: 65-70%, F:M ratio 20:1, peak of prevalence 21-30 years-
- Macroadenomas: 30-35%, F:M ratio 1:1, peak of prevalence 41-50 years→
deafferentation hyperPRL = compression of pituitary stalk → lack of tonic
inhibitory function of dopamine (by hypothalamus)
● Systemic disorders: chronic renal failure, cirrhosis, polycystic ovarian disease.
Clinical presentation of hyperprolactinemia:
Women Men
● Decreased libido, infertility ● Gynecomastia (may occur physiologically in ⅓ of

● Oligomenorrhea (menstrual young men but also due to drugs e.g.
intervals > 35 days) or spironolactone (in primary aldosteronism) or
amenorrhea anti-androgens for prostate cancer.
● Galactorrhea (milk breast) ● Decreased libido, Infertility, Impotence
PRL has different effects on fertility as it:

● Suppresses GnRH secretion
● Decreases LH pulse amplitude and frequency
● Blunts the positive estrogen f eedback on LH secretion at mid cycle
● Directly suppresses progesterone and estrogen secretion from ovaries
● Inhibits aromatase and blocks stimulatory effects of FSH to decrease e
strogen levels
Diagnosis of hyperprolactinemia:
1. Exclude pharmacological/physiological causes of hyperprolactinemia.
2. Measure PRL at rest: measured according to clinical symptoms (to avoid false positives +
unnecessary exams and treatments): if stressed, measure every 12 mins.
● PRL > 200 ng/ml → prolactinoma (independent of MRI result, performed to differentiate
between micro and macroadenoma)
● PRL < 200 ng/ml → MRI to correlate PRL levels and size of the tumor.
3. MRI: exclude deafferentation hyperprolactinemia (with PRL < 200)
● Mass >1 cm → NFPA → deafferentation hyperprolactinemia
● Mass < 1 cm → microprolactinoma
● Absence of mass → Idiopathic hyperprolactinemia (stress or other causes)
Treatment: bromocriptine and cabergoline (dopamine agonists) can be used to normalize PRL
and resolve mass effects.
ACROMEGALY
disorder that results from excessive GH after closure of growth plates (before closure = gigantism)
→ mainly caused by pituitary adenomas (>95%), mainly macroadenomas; the remaining 5% may
be caused by a hypothalamic source (e.g. hypothalamic tumor) or ectopic source (e.g.
neuroendocrine tumor) of GHRH excess.
Epidemiology: annual incidence rate is 0.2 - 1.1 cases per 100,000 and the prevalence is 2.8 - 13.7
cases per 100,000. Mean age at diagnosis is 40 to 45 years due to subtle symptoms.
Clinical presentation: mild or asymptomatic in 50%, or may result in:

● Enlargement of hands and feet (enlargement of rings or frequent change in shoe size)
● Mandibular overgrowth: prognathism, teeth spacing (diastema), malocclusion.
● Acromegalic facies: large fleshy lips, macroglossia, frontal skull bossing, cranial ridges,
pronounced nose
● Laryngeal hypertrophy and enlarged paranasal sinuses → voice deepening.
● Mass effects of macroadenoma: headache, bitemporal hemianopsia, scotomas, blindness
(optic chiasm compression, optic nerve atrophy), ptosis, ophthalmoplegia, diplopia (oculomotor,
trochlear, abducens nerve compression).
Compliations: can be due to the excess in GH and IGF-1 that may cause:
● Goiter (22%): IGF-1 is a growth factor for thyrocytes.
● OSAS (25-60%): due to craniofacial deformities, hypertrophy of pharyngeal soft tissue,

macroglossia, mucosal thickening → increased mortality. Risk factors: age, male, BMI, disease
duration, neck circumference, tongue size.
● Bone effects: stiffness, articular pain, limitations, vertebral fractures (30%):
1. Osteopathy: enhancement of bone turnover (increased bone resorption)
2. Arthropathy → hyperfunctioning of chondrocytes and connective tissue cells, leading to
increased growth of articular cartilage + periarticular ligaments (reversible in first phases).
● Hypopituitarism (25.7%): due to the presence of macroadenoma, main cause of acromegaly.
● Increased mortality (32%): due to
1. Increased risk for CV disease (14%): direct effect on the heart (due to concentric
cardiac hypertrophy → heart failure) + additional complications (hypertension,
valvulopathies, vascular endothelial dysfunction, diabetes)
2. Increased risk for specific malignancies (IGF1 is a growth factor) → Colon cancer (OR
4.0), thyroid cancer (OR 7.9)
Diagnosis of acromegaly:
● GH measurement: not standard → does not correlate with disease severity, + daily fluctuation
(“undetectable” up to 30 μg/L) + affected by exercise, stress, fasting, sleep and protein meals
(that stimulate GH, whilst glucose inhibits it).
● IGF-1 measurement: highly specific, correlates with clinical indices of disease activity and
severity. Age dependent + increase during pregnancy, in pro athletes and in kidney and liver
diseases.
● Oral glucose tolerance test (OGTT): dynamic test that allows to confirm diagnosis. Oral
glucose administration (75g) in patients with acromegaly does not affect GH secretion (should
be suppressed) or may induce its paradoxical increase.
Treatment: somatostatin analogues (normalization of GH only in ~45% + shrinkage of the tumor in

~50%) or surgery (first line treatment performed by a skilled neurosurgeon)
HYPOTHYROIDISM
reduced peripheral action of thyroid hormones, that can be:
● Primary: failure of thyroid function → actual reduced thyroid hormone production
● Autoimmune thyroiditis (Hashimoto’s)
● Congenital hypothyroidism
● Severe iodine deficiency (rare)
● Infiltrative disease
● Subacute thyroiditis
● Iatrogenic: radioactive iodine, thyroidectomy, antithyroid drugs (methimazole,
propylthiouracil);
● Other drugs: lithium, amiodarone (largely used)
● Secondary: failure of adequate TSH secretion from the pituitary gland or TRH from the
hypothalamus (cannot be measured)
TSH FT4 FT3
Overt ⬆ ⬇ ⬇/N
Primary
hypothyroidism
Subclinical ⬆ N N
Secondary (central)
⬇/N ⬇ ⬇/N
hypothyroidism
Note: there can be also resistance to thyroid hormones: presence of a mutation affecting T3
receptors → abnormal feedback mechanism → abnormally ⬆ TSH + ⬆ T3 and T4. These patients
are considered hypothyroid patients as the presence of unsensitive thyroid hormone receptors will
result in clinical consequences of a true hypothyroidism.
Adults Children
● Cold intolerance, weight gain → reduced Mainly related with congenital forms leading to
metabolic action and tissue musculoskeletal and nervous system
thermogenesis abnormalities
● Tiredness, constipation, bradycardia, ● Dwarfism → reduced action on growth
slow mental processing → reduced action and tissue development
of sympathetic NS on CNS, heart ● Cretinism → reduced action on brain
(reduced cardiac output, chronotropy, development
inotropy)
● Hair loss, dry skin → reduced effect of TH
on tissue development
Congenital hypothyroidism
genetic disease, affects 1:3000 newborns → may be linked to complete absence (athyreosis 25%),
goiter (20%), hypoplasia (36%) or ectopy of the gland (35-42%). MUST BE IMMEDIATELY
DIAGNOSED to begin levothyroxine supplementation, allowing normal development (especially
mental).
Clinical features:
● Increased gestational age (> 42 weeks gestation), birth weight > 4 Kg
● Open posterior fontanelle, macroglossia (accumulation of mucopolysaccharides), stuffiness
and discharge, dry and pale skin, low hairline, hypothermia and cyanosis, feeding problems
and vomiting, constipation and abdominal distention (reduced TH action on bowel), umbilical
hernia.
● Musculoskeletal abnormalities: infantile proportions, hip and knee flexion, exaggerated
lordosis, delayed teeth eruption, underdeveloped mandible.
● Nervous system abnormalities: hypotonia and spasticity, lethargy, ataxia, mental
retardation, cretitism, deafness/mutism.

Hashimoto’s thyroiditis
is an autoimmune disease of the thyroid, characterized by the presence of anti-thyroid antibodies,
that can either be goitrous or atrophic and has a higher incidence in women (7:1).
Etiology: genetic susceptibility, thyroid injury (infection, radiation, drugs), stress, pregnancy, iodine
(defect and excess) → presence of anti-thyroid Abs, in particular anti-TPO and anti-Tg
● Anti-TG and anti-TPO Abs → also present in the general population, relatives of patients
with AIT, patients with Graves’ disease (+ anti-TSHR) or with other autoimmune diseases
such as type 1 diabetes → autoimmune diseases are a risk factor for development of AIT.
Disease progression: euthyroidism → subclinical hypothyroidism → overt hypothyroidism,

with progressively ⬆ TSH and ⬇ T4 levels
Symptoms: initially may be asymptomatic and, as the disease progresses:
Early symptoms Late symptoms
● Cold intolerance, weight gain → ● Decreased sense of taste and smell

decreased metabolic action ● Hoarseness
● Menstrual disorders
● Fatigue, weakness, depression,
● Puffy face, hands, and feet
constipation → decreased action in
sympathetic NS ● Slow speech
● Thicker but dry and flaky skin
● Paleness, water retention → ● Thinning of eyebrows
accumulation of mucopolysaccharides in
subcutaneous tissue (no degradation)
● Thin, brittle hair and fingernails, dry +

itchy skin → decreased action on tissue
growth
Complications:
● Myopathy: muscle symptoms in 25-79% of adult patients with hypothyroidism.
○ Signs and symptoms: pain, cramps, stiffness, easy fatigability and asthenia.
○ ⬆ serum muscle enzyme levels (creatinine kinase, myoglobin, lactate dehydrogenase)
are present (also up to 90% of asymptomatic patients).
● Myxedema coma: rare but most severe complication → mortality rate: 40-50%
○ Signs and symptoms: low temperature, decreased breathing rate, low BP, low blood
sugar, unresponsiveness.
● Other complications:
○ Infertility, miscarriage → due to decreased TH action in Follicular development and
ovulation in female, maintenance of pregnancy, spermatogenensis in male
○ Depression, heart disease, increased infections.
● Pituitary tumors: dysregulation of negative feedback mechanism (= stimulation from tropins)
Treatment: replace lacking hormone → improve symptoms, normalize TSH, reduce goiter and
avoid over supplementation (risk of atrial fibrillation in elderly + risk of and bone loss).
● Levothyroxine: most frequent drug used at lowest dose possible (usually 1.2-1.6
mcg/Kg/die) to relieve symptoms and normalize blood tests → brand name should be used +
timed with meals to respect circadian oscillations → 1h hour before breakfast/at bedtime 3h
after meals. (check lactose intolerance, gastritis, HP infection, TKI inhibitors)
Subclinical hypothyroidism:
defined biochemically as a normal serum free thyroxine (T4) concentration in the presence of
elevated serum thyroid stimulating hormone (TSH).
● Some patients may have vague non specific symptoms suggestive of the disease.
● Prevalence 4-15%, especially in areas of iodine insufficiency.
● More frequent in women and elderly.
Progression and predictors of the disease:

● Most women with mild TSH elevation (4.5 - 10 mU/L) do not progress to overt
hypothyroidism and TSH may even normalize (0.35 - 4.3 mU/L).
● Initial TSH levels mainly predict the progression to overt (even more than presence of
anti-TPO Abs or US appearance)
Treatment: very important because:

● High levels of TSH (especially >10 mU/L) → high risk of strict correlation with overt
hypothyroidism and CV risk (especially in the elderly → due to high prevalence of
dyslipidemia and endothelial vascular dysfunction).
● Levothyroxine will have a beneficial effect on levels of LDL-c and on clinical symptoms +
reduction of mortality in up to 30%
● However treatment will have no effects on fat mass → in subclinical hypothyroidism it will
only have an effect on fluid accumulation and edema!! → lose weight only in overt
hypothyroidism!!
Hypothyroidism in pregnancy:
Overt hypothyroidism in pregnancy: has important consequences in pregnancy, and when

untreated can lead to:
Mother: Baby:
● Preeclampsia ● Preterm birth
● Gestational hypertension ● Low birth weight
● Placental abruption ● Perinatal morbidity and mortality
● Preterm delivery, very preterm delivery ● Increased NICU admission
(<32 weeks) ● Neuropsychological and cognitive
● Increased rate of caesarean section impairment (e.g. congenital cretinism,
● Postpartum hemorrhage growth restriction, deafness etc.)
Pregnant women with pre-existing hypothyroidism → 75-85% will need more T4 due to → weight
gain, high serum Tg concentration, placental deiodinase type 3 (increased T4 clearance), transfer of
T4 to fetus (1st trimester), reduced GI absorption of Levothyroxine!!
Subclinical hypothyroidism in infertility/pregnancy:
● Fertility: not enough data to confirm role of subclinical hypothyroidism in fertility, but TSH >2.5
m/UL seems associated with unexplained infertility + presence of Abs may be negatively
correlated with n° of pregnancies and born children.
● Miscarriage: no clear correlation, probably related to TSH >4 in infertile women with Abs →
they should be treated!
● Fetal development: overt hypothyroidism → clear impact on mental development, subclinical
hypothyroidism → weak correlation with lower IQ.

THYROTOXICOSIS
state of thyroid hormone excess that can occur with and without hyperthyroidism, and can be
classified as primary (actual hyperfunctioning thyroid gland) or secondary (hyperfunctioning thyroid
due to the presence of increased pituitary activity e.g. TSHoma).
PRIMARY THYROTOXICOSIS WITH HYPERTHYROIDISM: hyperfunctioning thyroid gland

which can be either overt ( fT3 and fT4 and ⬇ TSH) or subclinical (normal fT3 and fT4 and ⬇TSH)
Causes:
● GRAVE’S BASEDOW DISEASE: auto-immune disease characterized by production of
anti-TSHR Abs that stimulate (independently from TSH) the whole gland → increased thyroid
size + thyroid hormone hypersecretion (diffuse toxic goiter).
○ More frequent in females, peak of incidence between 20 - 40 years.
○ Biochemical features: Anti-TSHR Ab (but also anti-TPO Ab, anti-Tg Ab) → patients may
develop Hashimoto’s thyroiditis due to similar immune mechanisms (but patients with
Hashimoto instead will never shift to Graves (Hashi is characterized by apoptosis of the
thyroid with parenchymal destruction).
○ Specific signs and symptoms: stimulation of TSH receptors → Grave’s orbitopathy (15%
swelling + exophthalmos), dermopathy (pretibial myxedema), goiter
● PLUMMER’S ADENOMA OR TOXIC NODULAR ADENOMA: chronic disease sustained by an

autonomous hyper-functioning thyroid nodule which produces and secretes thyroid
hormones independently of stimulation by TSH. It is due to a somatic mutation affecting
G-proteins of TSH receptors.
○ Frequent in both male and female, peak of incidence >40 years.
● TOXIC MULTINODULAR GOITER active multinodular goiter produced by the occurrence of

somatic mutations in follicular thyroid cells. This occurs after several years of exposure to
iodine deficiency with chronic stimulation of cell growth and is frequent in older subjects.
○ Specific signs and symptoms: symptoms of compression of neck structures, in particular
discomfort during swallowing or breathing
PRIMARY THYROTOXICOSIS WITHOUT HYPERTHYROIDISM: increased TH and suppressed

TSH without hyperfunctioning of the thyroid, that can occur in:
● SILENT AND POST-PARTUM THYROIDITIS: self-limited disease in patients affected by /

predisposed to Hashimoto’s thyroiditis (in the first phases, due to drugs or stress,). Post
partum thyroiditis specifically occurs 3-6 months postpartum → due to exacerbation of the
immune response after delivery.
○ Symptoms: hyperthyroid (destruction) → hypothyroid → euthyroid (2-5 weeks).
Sometimes chronic hypothyroidism may occur (especially in postpartum). No pain.
○ Biochemical features: A nti-TPO Ab, Anti-Tg Ab
● SUBACUTE THYROIDITIS (DE QUERVAIN’S THYROIDITIS): acute inflammatory

self-limiting disease of the thyroid occurring after an acute infection of the upper airways →
during the SARS-CoV-2 outbreak a peak of patients developing subacute thyroiditis was
observed!!
○ Symptoms: hyperthyroid → hypothyroid → euthyroid (2-5 weeks). Sometimes chronic
hypothyroidism may occur (especially in postpartum) + pain, hard thyroid at palpation
○ Biochemical features: elevated inflammatory biomarkers (ESR, WBC), very high T4
(which is stored in colloid, destroyed by inflammation)
● EXOGENOUS THYROTOXICOSIS: that can occur in:
● Over-treatment of hypothyroidism: incorrect dosage of hormone replacement
● Factitia: incorrect extra-therapeutic use of thyroid hormones → weight loss (somatoline).
● Amiodarone-induced thyrotoxicosis: drug used in atrial fibrillation that contains 37.7% of
iodine (→ type 1: with hyperthyroidism, type 2: with destructive thyroiditis, usually coexist).
○ Biochemical features: suppressed thyroglobulin (TSH is low due to negative feedback
from T3 → no stimulation of thyroid → no production of Tg)
SECONDARY THYROTOXICOSIS WITH HYPERTHYROIDISM: hyperfunctioning thyroid

gland in presence of increased pituitary activity (TSH hypersecretion, e.g TSH secreting
adenoma), characterized by ⬆ fT3 and fT4 and normal TSH levels (or ⬆) → due to negative
feedback counteracted by TSH hypersecretion.
● TSHoma: very rare (prevalence: 1-2 per million), 3% of pituitary adenomas (mainly macro),
mostly 50-60 y.o., both men and women. Up to 20% → co-secrete GH or PRL (→ acromegaly or
hyperprolactinemic syndrome).
○ Macroadenoma (84%): mass effects (headache in 20% and visual field defects 40%).
○ Atrial fibrillation and/or cardiac failure are rarely observed.
DD: Note → resistance to thyroid hormones: presence of a mutation affecting T 3 receptors →

abnormal feedback mechanism → abnormally ⬆ TSH + ⬆ T3 and T4. These patients are
considered hypothyroid patients as the presence of unsensitive thyroid hormone receptors will
result in c linical consequences of a true hypothyroidism
● Dynamic tests: to differentiate TSH-omas and thyroid hormone resistance (RTH):
○ TRH stimulation test: TRH will not stimulate TSH in patients with TSH-omas.
○ T3 suppression test: T3 is unable to suppress TSH in patients with TSH-omas.
● MRI with gadolinium
General signs and symptoms of thyrotoxicosis:

● Weight loss + increased appetite: T3 increases O2 consumption and heat production by
stimulating ATP-ase in several tissues → increase in basal metabolism
● Heat intolerance and sweating: increased heat production
● Nervousness → increased sympathetic activity in CNS → problems in sleeping, fatigue
● Increased differential BP: high systolic and low diastolic BP due to
○ Stimulation of systolic function (increased heart chronotropy and inotropy +
increased stroke volume so increased cardiac output + up-regulation of catecholamine
receptors)
○ Lowering of peripheral vascular resistance due to relaxation of smooth muscle cells
→ further stimulating the renin-angiotensin-aldosterone system and increasing cardiac
output.
● Palpitations and tachycardia: increased chronotropy and number of β-adrenergic receptors
● Increased GI motility, diarrhea → stimulation of β-adrenergic receptors
● Goiter
Specific signs and symptoms:

● Grave’s orbitopathy (15%): exophthalmos + swelling or edema of periorbital tissue →
anti-TSHR Abs activate TSH receptors on fibroblasts → inflammatory reaction → increase
in retro-orbital fat, glycosaminoglycans and swelling of extraocular muscles.
○ It begins with soft tissue involvement followed by proptosis, extraocular muscle
involvement (diplopia), corneal involvement (keratosis) until optic nerve
involvement and vision loss.
● Grave’s dermopathy (1-2%): usually occurs as pretibial myxedema, due to accumulation of
glycosaminoglycans in the dermis caused by Ab stimulation of fibroblasts expressing TSH
receptors.
● Graves → diffuse goiter: due to the stimulatory action of Abs on thyroid activity and size
(trophic action)
● Subacute → pain and hard thyroid at palpation
● Toxic multinodular goiter → compression of neck structures, in particular discomfort during
swallowing or breathing
Imaging: US, scintiscan
Ultrasound Scintigraphy Treatment
Thionamides
Graves-Basedow Diffuse goiter, increased (Methimazole or
disease vascularization Diffuse hyper-uptake
Propylthiouracil)
Surgery if unresponsive
Plummer’s disease or Surgery or radio-iodine

One nodule Focal uptake
toxic adenoma treatment (iodine-131)
Toxic multinodular Multiple nodules (2 or

Focal uptake Surgery
goiter more)
Diffuse goiter, low-absent Β-blockers in transient

Silent thyroiditis Low diffuse uptake
vascularization hyperthyroidism
Postpartum thyroiditis Diffuse goiter with Β-blockers in transient

low-absent Low diffuse uptake
hyperthyroidism
vascularization
Focal area of Corticosteroids and

Subacute thyroiditis Low diffuse uptake
inflammation Β-blockers
Destructive exogenous Low diffuse uptake Interruption or adjustment

thyrotoxicosis of treatment
→ US features of Malignancy: >1cm hypoechoic nodules, irregular margins, microcalcifications, taller (if
cystic appearance → benign → no FNAB)
Complications: in case of severe or longstanding thyrotoxicosis but also in case of longstanding

subclinical hyperthyroidism (old patients and post-menopausal women especially):
● Atrial fibrillation, myocardial infarction
● Osteoporosis with high turnover (⬆bone resorption) → increased risk of fractures
● Cerebrovascular effects, dementia
● Thyroid storm/crisis: rare + severe (potentially life-threatening) → fever, marked
tachycardia (lead to heart failure up to shock), marked agitation (may lead to delirium +
coma), nausea, vomiting, diarrhea (+ possible jaundice), hypokalemia (may lead to
paralysis).
○ Treatment → high dose methimazole (anti-thyroid drug, 20 mg every 6 hours), liquid
intake, iodine at high dosage + corticosteroids, admission to emergency unit
HYPERTHYROIDISM:
hyperfunctioning thyroid gland that can be primary or secondary:
● Primary: overactivation of the thyroid itself, further divided in
○ Overt = ⬆ fT3 and fT4 and ⬇ TSH Subclinical = normal fT3 and fT4 and ⬇TSH.
○ Causes:
- Grave’s disease: autoimmune disease with anti-TSHR Abs → stimulation of thyroid
- Plummer’s adenoma: autonomous hyperfunctioning thyroid nodule due to somatic
mutation affecting G-proteins of TSH receptors.
- Toxic multinodular goiter: occur due to somatic mutations in the thyroid after
prolonged exposure to iodine insufficiency
Note → also conditions of destructive thyroiditis, such as subacute thyroiditis (occurring after upper
airway infections), silent and postpartum thyroiditis (in patients with or predisposed to Hashimoto),
may initially give rise to hyperthyroidism but, after a period of approx. 2 weeks, they will acquire a
state of of hypothyroidism and eventually of euthyroidism. In these patients, when suspected, it is
important to acquire a “wait and see” approach (test thyroid hormones after 2 weeks, B blockers).
● Secondary: caused by increased pituitary activity (TSH hypersecretion, e.g TSH secreting
adenoma usually macroadenomas), characterized by ⬆ fT3 and fT4 but normal/⬆TSH.
TSHoma: very rare (prevalence: 1-2 per million), mainly macro, in 50-60 y.o., both sexes
Note → resistance to thyroid hormones: p 3 receptors →
resence of a mutation affecting T
abnormal feedback mechanism → abnormally ⬆ TSH + ⬆ T3 and T4. These patients are
considered hypothyroid patients as the presence of unsensitive thyroid hormone receptors will
result in c linical consequences of a true hypothyroidism
General signs and symptoms:

● Weight loss + increased appetite: T3 increases O2 consumption and heat production by
stimulating ATP-ase in several tissues → increase in basal metabolism
● Heat intolerance and sweating: increased heat production
● Nervousness → increased sympathetic activity in CNS → problems in sleeping, fatigue
● Increased differential BP: high systolic and low diastolic BP due to
○ Stimulation of systolic function (increased heart chronotropy and inotropy +
increased stroke volume so increased cardiac output + up-regulation of catecholamine
receptors)
○ Lowering of peripheral vascular resistance due to relaxation of smooth muscle cells
→ further stimulating the renin-angiotensin-aldosterone system and increasing cardiac
output.
● Palpitations and tachycardia: increased chronotropy and number of β-adrenergic receptors
● Increased GI motility, diarrhea → stimulation of β-adrenergic receptors
● Goiter
Symptoms can be present in other diseases, such as:

● Pheochromocytoma: due to hypersecretion of catecholamines. Presents with: diaphoresis =
sweating but it is usually “cold”, palpitations, flushing, nausea, weight loss, anxiety and panic..
● Adrenal insufficiency: weakness, fatigue, weight loss but with anorexia (D.D. due to
decreased orexigenic effect of glucocorticoids)
Specific signs and symptoms:

● Grave’s:
○ Orbitopathy: exophthalmos + swelling or edema of periorbital tissue due to activation
of TSH receptors on fibroblasts → inflammatory reaction → increase in retro-orbital
fat, GAGs and swelling of extraocular muscles (may be followed by proptosis,
extraocular muscle involvement (diplopia), corneal involvement (keratosis) until
optic nerve involvement and vision loss)
○ Dermopathy: usually presenting as pretibial myxedema, due to accumulation of
glycosaminoglycans in the dermis (stimulation of TSH receptors on fibroblasts by Abs)
● TSHoma: (84%): mass effects (headache in 20% and visual field defects 40%).
Lab tests: TSH, fT3 and fT4, thyroid auto-antibodies, thyroglobulin → papillary carcinoma, follicular
carcinoma.
Imaging: US, scintiscan with pertechnetate, MRI for TSHoma

Complications of long standing subclinical hyperthyroidism (old patients and post-menopausal

women especially):
● Atrial fibrillation, myocardial infarction
● Osteoporosis with high turnover (⬆bone resorption) → increased risk of fractures
● Cerebrovascular effects, dementia
● Thyroid storm/crisis: rare + severe (potentially life-threatening) → fever, marked
tachycardia (lead to heart failure up to shock), marked agitation (may lead to delirium +
coma), nausea, vomiting, diarrhea (+ possible jaundice), hypokalemia (may lead to
paralysis).
○ Treatment → high dose methimazole (anti-thyroid drug, 20 mg every 6 hours), liquid
intake, iodine at high dosage + corticosteroids, admission to emergency unit
Treatment:
● Thionamides → methimazole (propylthiouracil only in case of allergy or pregnancy (safer for
the fetus) for 1-1.5 years.
● Surgery or radio-iodine treatment: if medical therapy is not effective and in presence of toxic
adenoma or multinodular goiter.

GOITER:
Enlargement of the thyroid gland which may be diffuse or nodular. Thyroid function may be normal
(nontoxic goiter), overactive (toxic goiter), or underactive (hypothyroid goiter).
Epidemiology: thyroid nodules are relatively common → about 4% of the population presents a
palpable nodule and in 50% of healthy individuals it is possible to detect a thyroid nodule with US
evaluation (prevalence increases in older subjects).
Causes:
● Iodine deficiency: one of the main endemic causes of thyroid nodules → toxic multinodular
goiter
○ Low iodine levels → increased TSH to stimulate increased iodine uptake → gland
hypertrophy)
● Excess iodine (Wolff-Chaikoff effect) → rare cause of goiter (auto-regulatory phenomenon

that inhibits organification, synthesis and release of thyroid hormones)
● Continuous stimulation of thyrocytes by autoantibodies → Grave’s Basedow disease,

Hashimoto’s thyroiditis (silent, post partum → self limiting autoimmune diseases related to
Hashimoto)
● Continuous stimulation of thyrocytes by TSH → TSH secreting pituitary adenoma (mainly

macroadenomas), resistance to thyroid hormones (no inhibitory effect on TSH)
● Goitrogens: drugs such as Propylthiouracil, lithium, phenylbutazone, aminoglutethimide,

iodine-containing expectorants → inhibit TH synthesis by interfering with iodine uptake →
increase TSH → hyper-stimulation.
● GH/IGF1 excess (acromegaly): growth factor for thyrocytes, and is also a risk factor for
thyroid cancer (OR 7.9). Goiter is prevalent in 22% of patients with acromegaly.
● Subacute thyroiditis: self limiting inflammatory condition of the thyroid following acute upper
respiratory tract infection.
● Radiation therapy: for H&N cancers → inflammation
● Thyroid cancer (see below)
Clinical presentation: three possible presentations:

1. Incidental discovery, no signs and symptoms/only neck swelling → most common
2. Signs and symptoms of hyperthyroidism due to a hyperfunctioning nodule (or
hypothyroidism)
3. Compressing symptoms due to a large goiter (dysphagia, dyspnea stridor, hoarseness).
Anamnesis:
● Family history, female, older age
● Lifestyle: diet and smoking
● Drugs/radiation
Physical examination: evaluation of the shape, asymmetry, size, and consistency + presence of
lymphadenopathy.
● Patient upright, sitting or standing + side inspection (to see thyroid profile, may bulge)
● Swallow → thyroid should move.
● Palpation: hard → malignancy or subacute (+pain), palpation of cervical lymph nodes
● Growth pattern: present for many years/change has occurred in recent past → accelerated
growth should raise suspicion of malignancy.
● Obstruction: must be assessed e.g. distention of jugular veins, facial erythema, cutaneous
varicosities may suggest jugular obstruction.
Biochemical tests:
● TSH, fT3, fT4
● Thyroid auto-antibodies → autoimmune disease
● Inflammatory Indices → subacute thyroiditis
● Thyroglobulin → papillary carcinoma, follicular carcinoma
● Calcitonin → medullary carcinoma
Ultrasound:
● Graves: diffuse goiter with increased vascularization (thyroid stimulated)
● Plummer adenoma: one nodule
● Toxic multinodular goiter: multiple nodules
● Silent and post-partum: diffuse goiter with low/absent vascularisation (thyroid destroyed)
● Subacute thyroiditis: focal area of inflammation
Scintigraphy with pertechnetate:

● Grave’s : diffuse hyperuptake
● Plummer adenoma: focal uptake
● Toxic multinodular goiter: multiple focal uptake
● Silent and post-partum: low diffuse uptake
● Subacute thyroiditis: low diffuse uptake
FNAB: in presence of malignant features

MRI: in suspicion of TSHoma
PET-CT: for metastases
THYROID CANCER:
Thyroid cancer represents 3-4% of all cancers, and most commonly affects females in their 40s-60s
→ risk factors: low iodine intake, female, age, smoke.
Classification: most common types are:

● Papillary carcinomas (80%)
● Follicular carcinomas (10%)
● Medullary thyroid carcinomas (5-10%): cancer of parafollicular cells, 25% familial in case of:
○ MEN 2A (most common): medullary carcinoma, pheochromocytoma,
hyperparathyroidism
○ MEN 2B: medullary carcinoma, pheochromocytoma, mucosal neuroma/Marfanoid habitus
Clinical symptoms: mostly asymptomatic, but may also present with:

● Nodules/goiter (4% of the population presents a palpable nodule and in 50% of healthy
individuals it is possible to detect a thyroid nodule with US evaluation), possibly with
lymphadenopathy
● Signs and symptoms of hyperthyroidism in hyperfunctioning nodule (papillary/follicular)
● Compressing symptoms due to a large goiter (hoarseness, coughing, dysphagia, dyspnea)
Thyroid cancer diagnostic workup:

1. TSH measurement: low <0.5 mu/L or subnormal 0.5-1 mU/L → hypersecreting nodule
2. US: malignancy suggested by hypoechoic nodules >1cm, irregular margins,

microcalcifications, t aller (if cystic appearance → benign → no FNAB)
3. FNAB: using a 20-25 gauge, gold standard to distinguish benign from malignant nodules,
performed under palpation or US-guidance
4. Scintigraphy with pertechnetate: distribution of active tissue and display the differential
accumulation of the tracer in the investigated cells.
Cytopathological classification: is based on presence or absence of colloid and features of
thyrocytes → 5 classifications:
● THYR1: non diagnostic (insufficient), cancer risk 1-4% (10% of cases)
● THYR2: benign nodule (high colloid, low cells), 80% of cases, cancer risk 0-3%
● THYR3A: atypia of undetermined significance or follicular lesion of undetermined significance,
cancer risk 5-15% → re-perform FNAB or molecular testing → surveillance/surgical excision
● THYR3B: follicular lesion, risk 15-30% → surgery, you cannot evaluate capsule and vessels
● THYR4: suspicion of malignancy, risk 60-75%
● THYR5: malignant, risk 90-95%
WHO Classification (histopathological):

● Papillary thyroid carcinoma (PTC) → can be further divided in different histotypes
● Follicular thyroid carcinoma → shows vascular and/or capsular invasion (minimally invasive,
angioinvasive, widely invasive).
● Hurthle cell adenoma and carcinoma
● Poorly differentiated thyroid carcinoma
● Anaplastic thyroid carcinoma
● Medullary thyroid carcinoma
Treatment:
● Thyroidectomy (+ administration of levothyroxine)
● Radioiodine (RAI) therapy: not first-line treatment, performed only after surgical treatment.
Follow up:
● Scintigraphy
● Thyroglobulin levels (marker) for papillary and follicular

Medullary thyroid carcinoma:
originates from parafollicular cells (C cells) of the thyroid, which produce calcitonin.
● It is familial in 25% of cases, where it can be isolated or linked to MEN2A (especially, linked to
pheochromocytoma and hyperparathyroidism) or MEN2B (pheochromocytoma + neuromas or
Marfan habitus) → this is why it is important to check for pheochromocytoma in suspicion of
medullary carcinoma with:
○ Catecholamine and metanephrine urine and plasma analysis
○ CT scan
○ Possible screening (for c-RET mutation) may also be important in suspect cases
related to age or relevant comorbidities.
● Parafollicular cells do not express TSH receptors so diagnosis will not depend on TSH levels.
Also, RAI will not be used as treatment as parafollicular cells do not uptake Iodine.
● Surgical approach should be more extensive → this cancer is more aggressive → early lymph
node metastases are frequently present.
Diagnosis:
● Calcitonin: marker produced by parafollicular cells used in diagnosis and follow-up of MTC.
should be physiologically < 10 pg/ml, diagnosis is certain with > 100 pg/ml.
● Calcium test: performed if values of calcitonin is in the grey area between 10 - 100 pg/ml. In
patients with MTC it will cause a robust calcitonin increase (> 300 pg/ml) with respect to normal
subjects (using calcium or pentagastrin).
● FNAB: may be performed even if high values of calcitonin may be sufficient for a direct
operation without cytological diagnosis (tumors may also be small and may be difficult to catch
with the needle)
MEN - MULTIPLE ENDOCRINE NEOPLASIA:

● MEN 1: mutation of MENIN gene on chr 11
● Hyperplasia/malignancy of parathyroids → hyperparathyroidism (95%)
● NE tumors (pancreatic insulinoma and duodenal gastrinoma) (30-80%)
● Hypophyseal adenoma, mostly PRL-oma (50-90%)
● MEN 2A: mutation of proto-oncogene c-RET (extracellular domain), chr 10
● Medullary carcinoma of the thyroid (especially)
● Pheochromocytoma
● Hyperplasia/ malignancy of parathyroids → hyperparathyroidism
● MEN 2B: mutation in proto-oncogene c-RET (intracellular domain) on chr 10:
● Medullary carcinoma of the thyroid
● Pheochromocytoma
● Mucocutaneous neuromas (95%)
● Habitus Marfanoide
APS - AUTOIMMUNE POLYENDOCRINE SYNDROMES

● APS type 1: autosomal recessive syndrome → mutation of the AIRE gene → in
hypoparathyroidism, adrenal insufficiency, hypogonadism, vitiligo, candidiasis.
● APS type 2: autosomal dominant syndrome → multifactorial gene involvement → adrenal
insufficiency + hypothyroidism + type 1 diabetes
HYPERCORTISOLISM - CUSHING’S SYNDROME:
a complex syndrome comprising a large group of signs and symptoms that reflect prolonged and
inappropriately high exposure of tissues to glucocorticoids. Can be denied as ACTH-dependent
or ACTH-independent:
ACTH dependent:
● ACTH-secreting pituitary adenoma (60-70%) or Cushing’s disease, typically
microadenomas.
○ More frequent in females (F:M = 5:1), age at diagnosis peaks between 20 and 40 years.
○ Presents with: normal or mildly elevated plasma ACTH, high serum/urinary cortisol.
● Ectopic ACTH secretion (10-15%): malignant neoplasia external to pituitary-adrenal axis.

○ Thoracic tumors are the most common (e.g. lung carcinoma, pancreatic tumors, thymic
tumors).
○ More common in men, peak age incidence is 40 - 60 years.
○ Presents with: ⬆⬆ ACTH levels, severe hypercortisolism, skin pigmentation and the
presence of hypokalemia and metabolic alkalosis (retention of Na+, K+ excretion) →
supersaturation of mineralocorticoid receptors → worse prognosis.
● Ectopic CRH secretion: extremely rare, difficult to diagnose (may secrete ACTH + CRH)
ACTH independent:
● Iatrogenic: chronic glucocorticoid administration in 1% of population (3% in > 70 y.o.).
○ Used in asthma and COPD, lupus, multiple sclerosis, IBD, pain in joints or muscles
(arthritis, tennis elbow), irritated or trapped nerve (sciatica).
● Adrenal adenoma (10%): unilateral cortisol-secreting adrenal adenomas characterized by

predominance of clear cells of the zona fasciculata + atrophy of cortex (due to low ACTH).
● Adrenal carcinoma (5%): rare, big, palpable abdominal masses, the adrenal cortex is usually
atrophic.
● Bilateral nodular adrenal hyperplasia (may also be ACTH dependent, where the cortex will
not be atrophic → removal of ACTH source will usually cause their regression)
● Moon facies (88%) and facial plethora (92%): round and puffy face, small eyes
● Central obesity and muscle atrophy at extremities: fat accumulation in face, neck, trunk and
abdomen → due to the orexigenic effect of glucocorticoids + lipogenic effects of
hyperinsulinemia, caused by the state of insulin resistance) → increased CV risk.
● Diabetes: increased gluconeogenesis, hepatic glycogen uptake, free fatty acid production →
increased insulin resistance → diabetes or glucose intolerance.
● Hypertension: very common, contributes to morbidity of CS because glucocorticoids increase
cardiac output, increase expression of adrenergic receptors in vascular smooth muscles and
increase sensitivity to angiotensin II, causing increased peripheral vascular resistance.
● Thirst and polyuria: rare, due to overt hyperglycaemia and more commonly due to inhibition of
ADH due to action on mineralocorticoid receptors and direct enhancement of free water
clearance.
● Skin changes: epidermal atrophy = thin and transparent skin, easy bruising and striae
rubrae.
● Hypogonadism: hypersecretion of adrenal androgens from zona reticularis, producing a
negative feedback on GnRH causing decreased secretion of LH and FSH:
○ Female: amenorrhoea (pre-menopausal women), acne, hirsutism (↑ testosterone)
○ Male: soft testes, infertility, impotence, decreased libido
● Osteoporosis (50%) (low turnover → decreased bone formation) → multiple fragility fractures of
the feet, ribs and vertebrae and back pain are common.
○ Unexplained osteopenia in the young = raised suspicion of CS
○ Osteoporotic fractures in 30-76% of patients with Cushing’s disease, + spinal deformities
○ Lack of linear growth
● Renal calculi: due to hypercalciuria, frequent renal colics
● CNS disturbance: psychological changes with a very wide range of severity.
Mortality: up to 90% increased mortality mostly due to increased CV risk (due to increased central
obesity + onset of diabetes or glucose intolerance + hypertension → dyslipidemia)
and infections (immunosuppression caused by persistent cortisol levels).
Diagnosis of hypercortisolism:
1. Exclude chronic glucocorticoid treatment
2. 24-h UFC (urinary free cortisol):

● < 50 mcg/24 h: normal values
● >4 x ULN increase: very rare except in CS.
3. Low dose DST (dexamethasone suppression test): administration of 1mg dexamethasone

(synthetic glucocorticoid, suppresses ACTH) administered orally at midnight → fasted morning
serum cortisol measurement:
● Serum cortisol level < 1.8 mcg/dL → probable CS exclusion
- False positives: drugs which cause acceleration of dexamethasone metabolism (barbiturates)
- False negative: drugs that impair dexamethasone metabolism or that elevate cortisol by
increasing CBG (cortisol binding globulin), such as estrogen.
4. Late night salivary cortisol: evaluation of salivary cortisol at midnight, when levels should be
very low (< 0.15 mcg/dL or < 150 ng/dL).
● Elevated salivary cortisol: suggests CS due to loss of circadian rhythm of cortisol
- Disadvantage: false results due to factors that alter circadian regulation (e.g. jetlag, stress or
shift work)
Plasma ACTH measurement: allows differentiation between ACTH-dependent from

ACTH-independent in order to choose correct imaging modality to study the origin of the disease:
● ACTH > 20 pg/mL: ACTH-dependent CS.
○ Possible causes: ACTH-secreting pituitary adenoma, ectopic ACTH-secreting tumor.
● ACTH < 10 pg/mL: ACTH-independent CS
○ Possible causes: adrenal adenoma/carcinoma, bilateral adrenal nodular hyperplasia.
○ Also shows a blunted response to CRH stimulation.
● ACTH 10-20 pg/mL: grey zone → dynamic testing
Exclusion of ectopic ACTH production:
1. High dose DST (8 mg): 2mg dexamethasone every 6 hours for 2 days + 24H urine samples
before and after the test (low diagnostic sensitivity, rarely performed):
● Cortisol inhibition > 50% → ACTH-oma (supraphysiologic doses of glucocorticoids
partially suppress the HPA axis in Cushing’s disease)
● Cortisol inhibition < 50% → ectopic ACTH
2. CRH stimulation test: IV CRH injection + ACTH measurement every 15 minutes for 2 hours.
● Increase > 50%: ACTH-oma
● Increase < 50%: ectopic ACTH
3. Hypokalemia and metabolic alkalosis → raise suspicion for ectopic ACTH production due
to higher cortisol secretion that easily saturates mineralocorticoid receptors in the kidneys.
4. Inferior petrosal sinus sampling (IPSS): in patients with equivocal results, most attendible
but also most invasive test → ACTH in inferior petrosal sinus to peripheral venous blood (high
in blood = ectopic production, high in petrosal sinus = ACTH-oma).
- Side effects: referred aural pain, thrombosis (requires experienced referral centre).
DD: Pseudo-Cushing’s syndrome: caused by conditions altering blood and urinary tests causing
presence of some/all clinical features + evidence of sustained or intermittent hypercortisolism (e.g.
poorly controlled DM, alcoholism, depression, obesity) →
Dexamethasone suppression + CRH stimulation test: patient is given dexamethasone in 8 doses
of 0.5 mg in 6 hours + CRH stimulation test. Cortisol levels are measured after 15 mins:
● CS: cortisol > 1.4 mcg/dl → even if axis is suppressed.
● Pseudo-CS: usually no response → suppression of HPA axis → adrenal not stimulated.
Imaging:
● Pituitary MRI with gadolinium enhancement: gold standard (discrete adenomas in 60%).
→ pituitary microadenoma: hypodense lesion after contrast + deviation of pituitary stalk
● HRCT or MRI of the chest → ectopic ACTH production (e.g. small bronchial carcinoid
tumors or carcinoids in the abdomen).
Treatment:
● Cushing syndrome → unilateral adrenalectomy: now mostly performed laparoscopically.
○ Mitotane: steroidogenesis inhibitor (for adrenal carcinomas if metastatic)
● Cushing disease: pituitary microsurgery, radiation therapy (+ bilateral adrenalectomy)
● Ectopic: therapy against tumor (+ adrenalectomy, glucocorticoid inhibitors or receptor
inhibitors)

ADRENAL INSUFFICIENCY:
Condition characterized by inadequate production of glucocorticoids, that can be classified as
primary, secondary and tertiary:
Addison’s disease - primary adrenal insufficiency:

damage, destruction or impaired function of steroid-producing adrenocortical cells inducing a
deficit of glucocorticoid, androgen ± mineralocorticoid production
● Very rare (prevalence ~100/ 1 million, peak age 40 years)
Causes: mostly caused by AUTOIMMUNE ADRENALITIS 90% of cases, characterized destruction of

the adrenal cortex induced by adrenal cortex autoantibodies (ACA) and anti 21-OH antibodies.
● It may present either in an isolated form or in the context of:
○ Autoimmune polyendocrine syndrome 1: AI + hypoparathyroidism + chronic
candidiasis (40%) or hypogonadism (premature ovarian failure 5-10%)
○ Autoimmune polyendocrine syndrome 2: AI + hypothyroidism + type 1 diabetes
● It progresses in stages, from an initial state of absence of autoantibodies and abnormal
hormone levels to initial development of hormonal imbalance (high renin, high ACTH) to a
final stage of overt adrenal insufficiency with complete destruction of zona fasciculata and
reticularis → very low cortisol and aldosterone → increased renin, ACTH (no negative
feedback).
Other causes:
● INFECTIONS (TB, systemic fungal infections, AIDS): up to 20% of cases
● RARE CAUSES: adrenal metastasis, lymphoma involving adrenals, bilateral adrenal
haemorrhage, bilateral adrenalectomy.
● NEW GENETIC CAUSES: mutations of nuclear receptors that regulate adrenal & reproductive
function:
● DAX-1 mutation → very severe AI + hypogonadotropic hypogonadism and infertility
(some boys may have paradoxical macrophallia or early puberty).
● SF1 mutation → wide spectrum of phenotypes → in males it can lead to testicular
dysgenesis or dysfunction, severe hypospadias and male factor infertility.
Secondary adrenal insufficiency:

Deficit of glucocorticoid and androgen production due to damage, destruction or impaired function of
ACTH-secreting pituitary cells (+ possible coexistence of pituitary hormone deficiencies). There is
no decrease in aldosterone because it is under control of angiotensin II and renin and not ACTH.
● Rare, 150-280/million people, peak age at diagnosis is 60 yo.
● Causes: conditions affecting hypothalamus/pituitary, mainly hypothalamic/pituitary tumors
including craniopharyngioma 90%, pituitary adenoma 50-70% but also:
○ Pituitary irradiation (68%), infiltrative diseases (neurosarcoidosis, histiocytosis etc.)
○ Withdrawal of exogenous glucocorticoids (up to 60%) used in several inflammatory
and rheumatological conditions (correlated to mean dosage → 5% never recover!!).
Tertiary adrenal insufficiency:

deficit of glucocorticoid and androgen production caused by:
● Drugs acting on adrenal steroidogenesis (e.g. Ketoconazole (immunosuppressor),
abiraterone for prostate cancer)
● Immunotherapy induced hypophysitis and adrenaliti
● Prolonged exposure to glucocorticoids (rheumatological, neurological, oncological
diseases) leading to suppression of pituitary ACTH-secreting cells.
Signs and symptoms of AI: late and progressive development + poor specificity
● Weakness, fatigue, depression
● Weight loss, anorexia (most prominent symptom → reduced orexigenic effect of GCs)
● GI symptoms: nausea/vomiting + possible abdominal pain
● Muscle/joint pain
● Hypotension: decreased peripheral vascular resistance + cardiac output, w
orse in PAI
● Postural dizziness, syncope
● Hypoglycemia → decreased GC → increased insulin sensitivity
● Body hair loss, sexual dysfunction in women
Specific signs and symptoms in Addison’s:
● Hyperpigmentation, vitiligo (10-20%: skin and mucosal hyperpigmentation due to increased
secretion of POMC (precursor of ACTH and MSH) + action ACTH on MSH receptors
(spillover specificity) → increased melanin production.
● Hyponatremia and hyperkalemia (mineralocorticoid deficiency) → dehydration
Diagnosis of AI:
Pharmacological anamnesis: exclude chronic use of glucocorticoids, glucocorticoid withdrawal
or steroidogenesis inhibitors (e.g. abiraterone for prostate cancer, ketoconazole → antimicotic).
Plasma cortisol: often in the low-normal range, performed in the morning. Measurement alone
cannot exclude the diagnosis (due fluctuations), but some assumptions can be made:
● Cortisol > 400 nmol/L (or > 14 mcg/%) → HPA axis is intact
● Cortisol < 80 nmol/L (or < 3 mcg/%) → GC deficiency assumed
● Cortisolemia between 3-18 mcg/% (grey zone) → dynamic tests required
ACTH measurement: becomes useful to identify the likely etiology:

● ACTH > 100 pg/mL → Addison’s d isease (no feedback from adrenals on pituitary)
● ACTH levels normal → s econdary AI (pituitary not responding to negative feedback)
ACTH-stimulation test: IV administration of 250mcg tetracosactrin (ACTH analogue) + plasma

cortisol measurement on the moment of administration and 30 min after.
● Normally: cortisol level should be > 550 nmol/L (or >20 mcg/dL)
● Lack of this response, expected in:
○ PAI → adrenal destruction (no ACTH sensitivity)
○ SAI: chronic ACTH deficiency → adrenal atrophy and reduced ACTH sensitivity
ITT - insulin tolerance test: IV administration of rapid insulin (0.1-0.15 U/kg) to reach an adequate
hypoglycemia (blood glucose < 2.2 mmol/L) with signs of neuroglycopenia (sweating, tachycardia).
Normally = cortisol peak > 18 mcg/dL (stress response). Lack of response → AI
● Flaws: unpleasant, need of continuous medical surveillance, contraindicated in elderly, CV
disease and epileptic individuals.
Additional laboratory findings in PAI:

● When decompensated → hyponatremia and hyperkalemia (mineralocorticoid deficiency)
● Anti adrenal cortex Abs (ACA) and anti 21-OH Abs (autoimmune adrenalitis)
Remember to check for:

● Pregnancy: ⬆ CRH by placenta, ⬆ CBG production, ⬆ set point for negative feedback
○ Cortisol < 3.0 mcg/dL → AI suggestive. If cortisol is > 3.0 mcg/dL → dynamic tests
○ ACTH-stimulation: cutpoint raised to 25 (1st) 29 (2nd) 32 mcg/dL (3rd) trimesters
● Critical illness: major stress condition (e.g. infection) → HPA axis overactivation. In this case
AI may be due decreased cortisol production (adrenal/pituitary disease) or adrenal exhaustion
syndrome (due to long term critical illness → cortisol and ACTH resistance, CBG depletion
etc.)So: So, if cortisol < 400 nmol/L (< 15mcg/dL) → suggests corticosteroid insufficiency.
● Aging: also induces physiological hormonal changes (increased plasma and salivary cortisol,
flattened cortisol circadian rhythm, cortisol increase after ACTH stimulation test, reduced ACTH
and cortisol increase in stressful events).
Treatment of AI:
consists in hormone replacement
● PAI: glucocorticoids + mineralocorticoids (.. possibly dehydroepiandrosterone → precursor)
● SAI: glucocorticoids
1. Glucocorticoids: hydrocortisone and cortisone acetate → h ave a short duration of action and
are administered in the morning to mimic circadian rhythm (higher dose in males, elderly and in
stressful events e.g. illness, surgery). Side effects:
● Metabolic syndrome (⬆ waist circumference, triglycerides, total cholesterol, LDL-c) →
increased CV risk.
● Reduced bone health → due to low bone turnover and decreased bone formation
● Lower QoL and impact on cognitive functions, in particular sleep quality (due to
higher midnight cortisol levels).
2. Modified release cortisone: plenadren, c hronocort → substitutive treatment, more
physiological to reproduce normal circadian rhythm.
3. Mineralocorticoids → fludrocortisone (oral 0,1 mg/die): in PAI as replacement therapy
AI Complication → adrenal crisis:

medical emergency characterized by hypotension, marked acute abdominal symptoms and
marked laboratory abnormalities → immediate treatment due to high mortality rates.
● Causes: acute events (gastrointestinal illnesses, other infections and physical/surgical stress)
→ precipitation of AI, due to lack of compensation from inadequate
hydrocortisone/cortisone acetate dosage.
● Incidence: 5-8/100 patients per year, higher in patients with glucocorticoid-induced adrenal
insufficiency (52% in PAI and 36% in SAI), in the elderly and patients with comorbidities
(diabetes, asthma etc.)
● Signs and symptoms: of AI more severe, possibly with pyrexia, confusion and impaired
consciousness (most severe)
● Lab tests: hyponatremia, hyperkalemia, hypercalcemia, hypoglycemia, neutropenia,
eosinophilia, lymphocytosis, mild normocytic anemia.
● Treatment: IV hydrocortisone 100mg (every 6-8 H) + detection of possible cause, 1L of
saline in the 1st hour if patient is in shock, clinical improvement should be seen in 6H, after
24H dose can be reduced to 5mg IM and then oral (first high dosage then standard)
Morbidity and mortality of adrenal insufficiency: recent data from the European Adrenal Insufficiency
Registry states that CV diseases (35%) and infections (15%) are the major causes of death in these
patients.

ADRENAL INCIDENTALOMA:
mass detected on imaging not performed for suspected adrenal disease → umbrella definition
comprising different conditions that affect either the adrenal medulla or/and the adrenal cortex (e.g.
medulla → pheochromocytoma, ganglioneuroma etc.; cortex → adenoma, nodular hyperplasia;
benign pathologies → infections, granuloma; metastases)
○ Malignant: pheochromocytoma, ganglioneuroma, ganglio-neuroblastoma, neuroblastoma,
carcinoma.
○ Benign: myelolipoma, lipoma, lymphoma, hemangioma, angiomyolipoma
● Pathologies of the adrenal cortex: adenoma, nodular hyperplasia, carcinoma
● Benign adrenal pathologies: infections, granuloma, cysts, pseudocysts
● Metastases (breast, kidney, lung, ovaries, melanomas, lymphomas, leukemias etc.): 10-25% of
cancer patients, simultaneously with primary cancer in ~2/3 of cases, bilateral in 50% of cases.
Epidemiology: prevalence of 1-2%, majorly in elderly (uncommon < 30 yo) and no sex difference:
● Adenoma 80% (non-functioning 75%, cortisol secreting 12.5% or aldosterone secreting
2.5%)
● Pheochromocytoma 75%, carcinoma 8%, metastasis 5%
Diagnostic workup: adrenal mass >1cm on radiological imaging require a radiological (malignant
or benign) and endocrinologic (secreting or not) workup evaluation:
1. Abdominal CT: identification + differentiation benign vs malignant lesions,
a. Size: correlates with histology (↑ size = ↑ cancer probability) (<4cm = 2%, 4-6cm =
6%, >6cm = 25%).
b. Intracellular lipid content:
- Adenomas: a high intracellular lipid content (low density ≤ 10HU)
- Adrenal cortical carcinoma + pheochromocytomas → high attenuation
c. Margins: regular = benign, lobulated = malignant
d. Contrast washout: < 50% at 10-15 minutes in benign lesions.
2. Endocrine workup: to exclude possible adrenal hypersecretion
a. ⬆ UFC, ACTH<10 pg/ml, Nugent’s test (low dose DST) cortisol >1.8 mcg/dL →
Cushing’s syndrome (+ central obesity, mood alterations, striae rubrae, thin skin etc)
b. Hypotension, hypokalemia, suppressed renin, normal/high aldosterone levels →
primary aldosteronism (Conn adenoma)
c. High plasma and urinary catecholamines and metanephrines → pheochromocytoma
d. FSH, LH, estrogen, testosterone → androgen production tumors (+hirsutism
menstrual irregularities and virilization in women)
3. No biopsy! → can cause life-threatening hypertensive crises in the presence of
pheochromocytoma or needle track metastases in case of adrenal cortical carcinoma! (only in
suspected cases e.g. suspicion of cancer metastasis)

PHEOCHROMOCYTOMA - CHROMAFFIN CELL TUMORS:

○ PHEOCHROMOCYTOMA (80-85%): adrenomedullary chromaffin-cell tumor that
commonly produces 1 or more catecholamines, very rarely biochemically silent.
○ PARAGANGLIOMA (15-20%): extra-adrenal chromaffin-cell tumors of the sympathetic

paravertebral ganglia of the thorax, abdomen and pelvis.
Epidemiology: rare disease with prevalence of 0.2 - 0.6% in patients with hypertension.
Genetics:
● ⅓ of patients have germline mutations, 50% have mutations in PPGL susceptibility genes,
10% have familiarity for PPGL
● It may also associated to different syndromes, such as:
○ Hereditary paraganglioma syndromes → mutations in succinate dehydrogenase
○ Von Hippel-Lindau: CNS or retinal hemangioblastomas, pancreatic NE tumours
○ Multiple endocrine neoplasia syndrome:
- MEN 2A: PPGL + medullary thyroid cancer, primary hyperthyroidism,
- MEN 2B: PPGL + medullary thyroid cancer, mucocutaneous neuromas, Marfanoid
habitus
● Neurofibromatosis type 1: neurofibromas, osseous lesions, optic gliomas, cafè-au-lait spots.
Clinical presentation: 8% asymptomatic patients (e.g. familiar form, cystic tumor), but depending on
secretory activity there may be also effects on BP:
● Pure norepinephrine secreting → hypertension
● Epinephrine / norepinephrine secreting → episodic hypertension
● Pure epinephrine producing → hypotension
However → there is no correlation between circulating levels of catecholamines and hypertension.
Episodes of sudden BP rise + headache (80%), diaphoresis (70%) and palpitations (60%) that:
● Usually last minutes or hours, may not recur for months or may recur many times daily
● Increase in frequency + severity over time
● May occur: spontaneously, with bladder catheterization, anesthesia, surgery or
seemingly benign activities (rolling over in bed, abdominal palpation, micturition).
● Episodes of orthostatic hypotension and syncope in patients with sustained hypertension
are due to vasomotor receptor desensitization or diminished intravascular volume.
● Associated symptoms: flushing, nausea, weight loss, psychological symptoms (anxiety, panic)
Symptoms are not so specific → may be shared by different conditions (hyperthyroidism,

insulinoma, carcinoid syndrome) → pheochromocytoma must be suspected in the presence of: signs
and symptoms (particularly if paroxysmal) + presence of adrenal incidentaloma, hereditary
predisposition or presence of syndromic features.
Diagnosis of pheochromocytoma:
1. Biochemical testing: assessment of catecholamine hypersecretion (likely diagnostic values):
● Urinary catecholamines and fractionated metanephrines (nmol/24H)
○ Likely (normetanephrine: > 7.70, metanephrine: > 1.20)
● Plasma catecholamines and metanephrines (nmol/L)
○ Likely (normetanephrine: > 6650, metanephrine: >2880)
False positive: 19-21%, there are some drugs that affect catecholamine assays which must be
withdrawn before performing biochemical tests (tricyclic antidepressants, antipsychotics,
buspirone, levodopa, cocaine etc.)
2. Imaging:
● Abdominal CT: first line to detect mass, patients should be protected from a hypertensive
crisis or cardiac arrhythmia by combined blockade of α and β adrenoreceptors
● MRI: recommended in suspected metastatic PPGL or skull base/neck paraganglioma +
(functional imaging such as PET if inconclusive)
3. Genetic testing: performed in case of family history, evidence of a specific syndrome, multiple
primary tumors, early age at diagnosis, malignancy, extra-adrenal location in sporadic cases
with a single tumor.
Treatment:
● Surgery: first line, only curative option + preoperative medical treatment always required (i.e.
α1 selective antagonist) to avoid hypertensive crisis, arrhythmias and post-operative shock.
● Mortality causes are mainly CV (shock, myocarditis, dilated cardiomyopathy, arrhythmias,
pulmonary edema, heart failure) and neurological (stroke, seizures).

PRIMARY ALDOSTERONISM:
condition characterized by hypertension, suppressed plasma renin activity (PRA), and
increased aldosterone. It is especially suspected in patients with hypertension and spontaneous
hypokalemia (0.5%) or increased levels of aldosterone (5-10%).
Etiology:
● Bilateral adrenal hyperplasia: 65-70%
● Aldosterone-producing adenoma (rarely carcinoma): 30-35%
● Familial hyperaldosteronism type I: 1-3%’
Symptoms: NO specific SIGNS of primary hyperaldosteronism.

● Hypertension: moderate to severe, due to K depletion and increased Na retention →
expansion of extracellular volume and plasma volume.
○ Possibly resistant to treatment, typically in patients in their 3rd - 6th decade of life.
● Hypokalemia → muscle weakness, cramping, headache, palpitations, polydipsia, polyuria,
nocturia.
● Tetany: rare, associated with decreased ionized Ca + marked hypokalaemic alkalosis.
● Long term consequences:
○ Greater LV mass than patients with other types of hypertension (e.g.
pheochromocytoma, Cushing’s syndrome, essential hypertension)
○ Higher rate of CV events: (e.g. stroke, AF, MI) than patients with essential
hypertension.
Diagnosis of primary aldosteronism:

1. Biochemical screening:
● ARR - plasma aldosterone to plasma renin activity ratio → increased due to
suppressed renin levels + normal/high aldosterone levels (not diagnostic, needs
confirmation)
○ Factors affecting ARR: time of day, diet (sodium content, Liquorice), posture, method
of blood collection, estrogen, glucocorticoid, antihypertensive therapy etc.
○ Drugs affecting renin activity: should be withdrawn for at least 2-6 weeks or more eg.
spironolactone (6-8w, aldosterone antagonist) → must be substituted with other drugs.
● Saline infusion test: IV infusion of 500mL of 0.9% saline for 4 H + blood sample:
○ 5 ng/mL → confirm diagnosis of primary aldosteronism
Aldosterone <
○ Aldosterone 5 - 10 ng/ml → grey zone
2. Radiology
● CT and MRI: not adequate for DD between aldosterone-secreting adenoma and bilateral
aldosterone-secreting hyperplasia because the majority of these adenomas are < 10-15 mm
● Adrenal vein sampling: catheterization to localize an aldosterone producing adenoma.
Treatment
● Laparoscopic adrenalectomy: low morbidity and mortality → standard procedure for unilateral
aldosterone producing adenomas
● Spironolactone for bilateral adrenal hyperplasia, normal BP in nearly 50% of treated patients.
○ Side effects: male → gynecomastia (50% at >150 mg/g), loss of libido, erectile
dysfunction, female → menstrual disturbances, breast tenderness.
● Glucocorticoids (dexamethasone or prednisolone 2.5-5 mg daily) for familial
hyperaldosteronism type I (partial suppression of ACTH secretion).
HYPERTENSION:
Endocrine causes of hypertension can be adrenal, thyroid, parathyroid or pituitary dependent.
Adrenal dependent:
● Pheochromocytoma: chromaffin cell tumor causing hypersecretion of catecholamines →
increased chronotropy, inotropy and EDV = increased cardiac output + increased systemic
vascular resistance.
● Primary aldosteronism: excess aldosterone → K depletion + Na retention, → expansion of
extracellular volume and plasma volume + direct effects on the heart (increased remodelling
and decreased compliance)
● Cushing’s syndrome: glucocorticoids increase cardiac output, increase expression of
adrenergic receptors in vascular smooth muscles and increase sensitivity to angiotensin II and
increased peripheral vascular resistance.
● Hyper-deoxycorticosterone, congenital adrenal hyperplasia, 11β-hydroxylase deficiency,
17α-hydroxylase deficiency, deoxycorticosterone-producing tumor, primary cortisol
resistance,
Thyroid dependent:
● Hyper-thyroidism: high systolic + low diastolic BP due to:
○ Stimulation of systolic function (depolarization and repolarization of SA node,
increased heart chronotropy and inotropy + increased stroke volume = increased
cardiac output + up-regulation of catecholamine receptors)
○ Lowering of peripheral vascular resistance due to relaxation of smooth muscle cells →
further stimulating the renin-angiotensin-aldosterone system and increasing cardiac
output.
● Hypo-thyroidism: due to increased peripheral vascular resistance (lack of TH =
peripheral vasoconstriction) + hypercholesterolemia and increased LDL-c → increased CV
risk.
Parathyroid dependent:
● Hyperparathyroidism: PTH favors renal and intestinal calcium reabsorption + Ca2+
release in the extracellular space → hypercalcemia → increase in vascular smooth muscle
→ increased vascular resistance.
Pituitary dependent:
● Acromegaly: frequently associated with insulin resistance and hyperinsulinemia which
may induce hypertension by stimulating renal sodium absorption and sympathetic nervous
activity.
● Cushing’s disease: ACTH hypersecretion from pituitary adenoma → increased
glucocorticoid secretion → same as Cushing's syndrome.

DIABETES:
group of metabolic disorders characterized by chronic hyperglycemia caused by defective
insulin secretion, defective insulin action, or b
oth. It can be classified as:
● Diabetes mellitus
○ Type 1 DM: characterized by autoimmune destruction of β cells, usually resulting in
absolute insulin deficiency
○ Type 2 DM: characterized by predominant insulin resistance that may be associated
with a defect in insulin secretion. Most common in older subjects.
● Diabetes insipidus: rare, characterised by excretion of large volume of urine (“diabetes”) that
is hypotonic, dilute and tasteless (“insipid”), caused by the absence or inadequate response to
ADH (also called arginine vasopressin).
Epidemiology: diabetes is continuously increasing. Prevalence in Italy is 5 - 6,2% (~6 million people)
→ majority has type 2 DM (95-97%), and a minority 3-5 has type 1 DM (3-5%).
Clinical manifestations: occur due to a

utoimmune destruction or increased insulin resistance:
● Polyuria (abnormally large volumes of diluted urine) and polydipsia (excessive thirst), related
to impairment of renal glucose reabsorption as the amount of glucose in blood exceeds the
renal capacity to absorb it.
● Unexplained weight loss: as there is an attempt to use alternative sources of energy → loss
of fat and lean mass → possible polyphagia (abnormally strong sensation of hunger or
desire to eat often), myalgia and fatigue.
● Blurred vision, related to loss of liquids in the eye’s humor
Diagnosis:
● Symptomatic pts: one random venous sample of plasma glucose ≥ 200mg/dL (11.1 mmol/L)
● Asymptomatic patients: diagnosis requires one of the following:
a. Fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L) in at least 2 different occasions
b. Plasma glucose ≥ 200 mg/dL (11.1mmol/L) in a oral glucose tolerance test
c. Glycated hemoglobin HbA1c ≥ 6.5%
Fasting plasma glucose:

● Normal glucose levels: glucose < 100 mg/dL
● Impaired fasting glucose (IGF: pre diabetes): glucose ≥ 100 but < 125 mg/dL → monitoring
● Overt diabetes mellitus: glucose ≥ 200 mg/dL
Oral glucose tolerance test (OGTT): measurement of glycemia before and 2 hours after
administration of 75g of oral glucose. Diabetes mellitus → plasma glucose >200 mg/dL, in particular:
● Normal glucose tolerance: post-load glycemia < 140 mg/dL
● Impaired glucose tolerance (IGT: pre-diabetes): ≥ 140 but < 200 mg/dL
● Overt diabetes mellitus: post-load glycemia ≥ 200 mg/dL

Type 1 diabetes:
condition characterized by destruction of β cells due to a cell-mediated autoimmune process,
which usually results in absolute insulin deficiency. It can be classified as:
● Immune-mediated type 1a diabetes (80-85%): Abs against pancreatic islets + no insulin
production, mainly in children and young individuals (< 30 y.o.), but can occur at any age. β
cell disruption can be rapid (children and adolescents) or slow (typically in adults).
● Idiopathic type 1b diabetes: rare variant with permanent insulinopenia in the absence of
autoantibodies. Frequent in specific countries, mostly Africa and Asia.
Pathogenesis: involves genetic susceptibility + environmental factors.

Possible molecular mimicry induced by previous viral infections (mostly Coxsackie B virus,
echoviruses, CMV, HSV) → Abs generation and activation of T lymphocytes → infiltrate pancreatic
islets causing inflammation (insulitis) and β cell destruction → when β cell mass < 20% → overt DM.
Clinical manifestations: polyuria, polydipsia (impairment of renal glucose reabsorption), unexplained

weight loss (loss of fat and lean mass as alternative source of energy) → polyphagia, myalgia.
Diagnosis: serum glucose >200 mg/dL + markers of immune-mediated destruction of β cells are:
● Islet cell Abs (ICA, 80-90%)
● Glutamic acid decarboxylase Abs (GAD, 80-90%).
● Anti-tyrosine phosphatases autoantibodies (IA-2 and IA-2β, 60-75%).
● Insulin autoantibodies (IAA, 30-50%).
Type 2 diabetes:
characterized by predominant insulin resistance, possibly associated defects in insulin secretion.
Characteristics:
● Late stage onset (40-50 years), mostly in obese pts (contributes to development)
● Often remains undiagnosed for years, due to gradual development of hyperglycemia.
● Patients are subject to a greater risk of microvascular and macrovascular complications.
Etiology: strong genetic component, still unrecognized transmission model which needs competition
of acquired factors (biological, behavioral, environmental, social etc.) for phenotype expression.
Pathophysiology: new model of development of type 2 DM, includes at least 8 fact

1. Increased glucose reabsorption in the kidney
2. Increased hepatic glucose production
3. Increased lipolysis
4. Impaired insulin secretion by β cells
5. Decreased incretin effect → blunted insulin response after meals
6. Decreased glucose uptake by muscles
7. Dysfunction of neurotransmitters
8. Increased glucagon secretion by α cells
New medications:
● GLP-1 mimicking drugs: subcutaneous injection → increased insulin (and decreased
glucagon) secretion by the pancreas in response to meal (increase incretin effect)
● SGLT-2 inhibitors: induce “artificial glycosuria” and reduce glycemia. Polyuria, natriuresis
and weight loss are observed during the first days of assumption. In 2-3 weeks, patients
adapt with stable glycosuria and decreased polyuria (reset of reabsorption pumps via
tubuloglomerular feedback involving the macula densa → new setting of the kidney), reduce
glomerular damage related to diabetic nephropathy.
Complications of diabetes:
Hyperglycemic hyperosmolar syndrome: majorly in T2DM, where extreme polyuria and

polydipsia occur due to the extremely high glucose concentration (there is no ketoacidosis because
insulin is sufficient enough to inhibit lipolysis and ketogenesis but insufficient to prevent
hyperglycemia).
Ketoacidosis: severe consequence, eventually fatal, which can occur in untreated T1DM that,
characterized by complete lack of insulin (occasionally in T2DM).
● Impossibility of using glucose → need of other energetical substrates, among which ketone
bodies (acids) → excess acids in blood → acute metabolic acidosis.
Macrovascular and microvascular complications: in both, due to increased protein and

lipoprotein glycation, inflammation and promote activation of the polyol pathway eventually leading
to vascular dysfunction,
● Microvascular:
● Eyes:
○ Diabetic retinopathy: complication related to damage of blood vessels in the retina
that develops from a non-proliferative condition (with microaneurysms + distortion +
fluid leakage) to a proliferative state (abnormal neovascularization in retina and
vitreous gel) → eventually causing vision l oss.
○ Other complications: glaucoma, cataracts
● Kidneys:
○ Diabetic nephropathy: characterized by an initial stage of glomerular hyperfiltration
(kidney tries to maintain normal level of glomerular filtrate) → thickened glomerular
basal membrane + expanded mesangium → microalbuminuria and macroalbuminuria
with progressive decline in GFR → possible leading to hypertension and ESRD.
● Peripheral nervous system:

○ Peripheral neuropathy: most common complication 50% in type 1 (after many years)
and 2 (at diagnosis or after a few years) where hyperglycemia produces:
■ Sensory desensitization especially at extremities + reduced blood and
oxygen supply → eventual development of ulcers that may not be noticed
and may cause the typical diabetic foot (gangrenous necrosis) or
Charcot’s f oot (deformity and fractures due to bone weakening)
■ Motor and autonomic NS symptoms (delayed Gi emptying, incontinence)
● Macrovascular:
● Brain and cerebral circulation: stroke, transient ischemic attack (TIA)
● Heart and coronary circulation: angina, MI, congestive heart failure
● Peripheral vascular tree: peripheral vascular disease, gangrene, amputation

Other types of diabetes:
● M.O.D.Y. (maturity onset diabetes of the young): caused by specific genetic defects of β
cells function or insulin action (e.g. ABs against insulin receptors), for some of these forms the
genetic defects are known.
● Exocrine pancreatic diseases: e.g. acute pancreatitis may lead to diabetes due possible
inflammatory involvement of Langerhans islets.
● Endocrinopathies:
- Acromegaly: chronic GH excess (counterregulatory hormone) impairs insulin
sensitivity, increases gluconeogenesis, reduces glucose uptake in adipose tissue
and muscle and alters pancreatic β cells’ function.
- Cushing syndrome: overproduction of cortisol (counterregulatory hormone)
contributing to glucose intolerance and increased insulin resistance.
● Genetic diseases: Prader-Willi syndrome, Wolfram syndrome and Down syndrome, APS 2
● Drugs: steroids e.g.cortisol
● Chemical substances: e.g. streptozotocin (chemotherapeutic agent in the treatment of
pancreatic β cell carcinoma → damage of cells → hypoinsulinemia + hyperglycemia)
● Infection
● Gestational diabetes: any glucose alteration for the 1st time during pregnancy and resolved at
the end.
○ Epidemiology: 1-7% more common in african american and south americans.
○ Diagnosis: oral glucose tolerance test performed from 16 to 20 weeks of pregancy in a
woman at risk (obese, with familiarity)
○ Pathogenesis: hyperglycemia → fetal macrosomia and malfunctioning placenta → risk of
abortion
○ Treatment : start immediately + correct diet and if it doesn't work give insulin that is able to
cross the placenta and maintain a normal glycemia in the fetus too!

DIABETES INSIPIDUS (DI):
rare condition, characterised by the excretion of a large volume of urine (“diabetes”) that is
hypotonic, dilute and tasteless (“insipid”), caused by the absence or inadequate response to ADH
(or arginine vasopressin)
ADH is normally secreted in response to high blood osmolarity to increased water retention via
expression of aquaporin 2 on renal collecting tubules and (at high concentration) to increase
vasoconstriction and increase BP by peripheral vascular resistance.
Etiology of polyuria and polydipsia:

● Primary polydipsia/psychogenic polydipsia: psychiatric condition with excess intake of
water.
● Hypothalamic DI: decreased synthesis or secretion of vasopressin from posterior pituitary.
● Gestational DI: increased vasopressinase (enzyme that metabolizes vasopressin) expression
during pregnancy,
● Nephrogenic DI: vasopressin resistance (lack of appropriate renal response to ADH)
● Diabetes mellitus: particularly type 1 (excluded via measurement of glycemia, glycated Hb
and evaluation of glycosuria).
Symptoms: related to dehydration → extreme thirst (polydipsia + polyuria), fatigue, dizziness,

confusion.
● If the patient is not able to respond to thirst by drinking (e.g., elderly or altered
consciousness), there is the risk of hypernatremic encephalopathy, which may lead to
epilepsy and convulsions.
Diagnosis:
● 24-hour urine volume: to assess urine output (normal = 800-2000 mL with 2L water intake)
● Plasma Na+ and K+: to evaluate dehydration (hypernatremia → only in decompensation).
● Dehydration test: gold standard → patient is prevented from drinking in a controlled
environment + repeated monitoring of urine and plasma osmolarity, plasma Na and K.
○ DI → diluted urine, increase in plasma osmolarity, hypernatremia followed by
hypokalemia.
○ These parameters are measured before, during dehydration and after administration
of vasopressin /analogue (desmopressin → to differentiate between the hypothalamic
and nephrogenic DI → problem in vasopressin synthesis or kidney).
ELECTROLYTE DISORDERS:
presence of excessively low or high electrolyte concentrations, where prevalence of the specific
electrolyte disorders varies depending on the electrolyte involved:
● Hyponatremia:
○ Mild (serum Na 13 - 135 mEq/L): 15-22% of hospitalised, 7% of ambulatory pts.
○ Moderate (serum Na 125 - 130 mEq/L)
○ Severe (serum Na < 125 mEq/L) 3%
● Hyperkalemia (normal = 3.5 - 5.0 mEq/L): 2-5% of patients
● Hypercalcemia (normal = 8.8 - 10.5 mg/dL): <1% of patients
Hyponatremia: common in hospitalised patients, several causes:

● Endocrinological disorders: SIADH, decompensated Addison’s, hypothyroidism, hypocortisolism
● Kidney disorders with Na loss
● Extrarenal losses
● Reduced effective volume (Na reuptake < water reabsorption)
● Vomiting and diarrhea (acute) cause dehydration and consequent hypernatremia (but they
may also cause hyponatremia if the volume loss is enough to elicit ADH secretion).
Mortality: significantly associated with serum [Na+] < 138 mEq/L and > 142 mEq/L.
● Hyponatremia must always be corrected, even if mild, in order to reduce risks → mortality,
CV risk, cognitive alterations, direct effect on bone structure, increased fracture risk.
Classification: direct/indirect evaluation of plasma osmolarity. Indirect evaluation: formula with

natremia, glycemia and blood urea nitrogen.
● Hypotonic hyponatremia: most common, true hyponatremia
● Non hypotonic hyponatremia:
○ Hypertonic hyponatremia: water shifts from cells to the extracellular fluid, due to the
presence of solutes confined in the extracellular compartment (e.g. hyperglycaemia).
○ Isotonic hyponatremia: retention of large volumes of isotonic fluid (no sodium) in the
extracellular space (e.g. treatment with irrigants contained in flushing solutions e.g.
after transurethral resection of the prostate (TURP) or hysteroscopy).
○ Pseudo-hyponatremia: factitious form of isotonic hyponatremia due to an increase of
the solid phase of plasma, as occurs in severe hyperlipidaemia or hyperproteinemia
Hypotonic hyponatremia:
excess of body water relative to levels of Na+ (that can be normal, reduced or increased → hypo-
hyper- or euvolemia). This water excess may be due to excess water intake with:
● Normal renal excretion (primary polydipsia → rare, only when intake exceeds 18L approx.)
● Impaired renal excretion
○ Hypovolemic hyponatremia → water ⬇, sodium ⬇⬇, ECV ⬇
- Causes: CHF, cirrhosis, nephrotic syndrome, acute/chronic renal failure
○ Euvolemic hyponatremia → water ⬆, sodium normal, ECV normal/⬆
- Causes: SIADH, glucocorticoid deficiency, hypothyroidism
○ Hypervolemic hyponatremia → water ⬆⬆, sodium ⬆, ECV ⬆⬆
- Causes: renal absolute loss (diuretics, mineralocorticoid deficiency) or
extrarenal solute loss (chronic vomiting or diarrhea, pancreatitis, third space
burns)
Clinical manifestations: symptomatic variable degree neurological manifestations

● Headache, irritability, nausea or vomiting, mental slowing, unstable gait or falls, confusion
or delirium, disorientation, all typical of chronic hyponatremia
● Acute hyponatremia → stupor/coma, convulsions and respiratory arrest (life-threatening)
Diagnosis of hyponatremia:
1. Clinical history: comorbidities, severity + duration of hyponatremia and pharmacological
history
2. Clinical examination: extracellular fluid volume (volume depletion, excess or none) + rule out
or confirm associated endocrinopathies e.g. adrenal failure or hypothyroidism.
3. Laboratory tests, particularly
a. 1st level:
○ Plasma electrolytes, glycemia, urea, creatinine, uric acid
○ Plasma and urine osmolality
○ Urinary electrolytes
○ Hematocrit (assess ECV)
b. 2nd level: lipids, total proteins, plasma cortisol, TSH, fT4 (to exclude:
pseudo-hyponatremia, hypo-cortisolism, hypothyroidism in the setting of euvolemic
hyponatremia).

SIADH - SYNDROME OF INAPPROPRIATE ADH SECRETION
SIADH is a disorder of hydro-saline homeostasis characterized by inappropriate ADH
secretion, accounting for >40% of cases of hypotonic hyponatremia (ADH secretion is inappropriate
because it occurs due to other causes rather than normal conditions causing its release →
hyperosmolarity, hypotension or hypovolemia).
Causes:
● Ectopic production of vasopressin by cancer
● Drug-induced SIADH:
○ Drugs affecting Na+ and H2O homeostasis e.g diuretics (thiazides, loop diuretics).
→ hypovolemic hyponatremia with renal loss of Na.
○ Drugs affecting H2O homeostasis:
- Increasing hypothalamic production of ADH (antidepressants, antipsychotic
drugs, antiepileptics and anticancer agents).
- Potentiating ADH effect on the kidney (antiepileptic drugs, antidiabetic
drugs, anticancer agents and NSAIDs).
- Resetting the osmostat: antidepressants (Venlafaxine) and antiepileptics
drugs (Carbamazepine).
● Lesions in the pathway of the baroreceptor system (CNS or pulmonary disorders)
● Acute infections → IL-6 may have a role in osmoregulation.
Diagnosis: ADH not useful because in some cases of nephrogenic SIADH ADH may not be
elevated → so we use : natremia and ECV → SIADH diagnosis:
● Natremia < 135 mmol/L → hyponatremia
● Plasma osmolarity < 275 mOsm/kg → hypo-osmolar plasma
● Urine osmolarity > 100 mOsm/kg → hyperosmolar urine
● Increased urinary Na excretion > 40 mmol/L with normal salt and water intake
● Clinical euvolemia: no clinical signs of hypovolemia (orthostatic decreases in BP,
tachycardia, decreased skin turgor, dry mucous membranes) nor clinical signs of
hypervolemia (edema or ascites).
● Exclusion of other potential causes of euvolemic hypo-osmolarity: diuretic use, renal
disease, hypo-thyroidism (decreased GFR, decreased mucopolysaccharide degradation
that accumulated in subcutaneous tissue etc.) and hypocortisolism (decreased GFR,
decreased BP and peripheral vascular resistance)
Treatment: depends on type and duration of hyponatremia, severity of symptoms:

● Hyponatremia secondary to an easily treatable condition, non severe symptoms → directly
tackle the primary cause.
● SIADH due to a specific drug → shift to another drug
● Induced by infections → treat infection → normalisation of natremia.
● In patients with SIADH hyponatremia → reduce water intake, administer diuretics +
slowly infused hypertonic 3% NaCl solution (rapid infusion of Na may lead to pontine
myelinolysis → changed brain osmolarity → neurons shrinking + severe damage
● Hypovolemic hyponatremia → infusion of isotonic saline to suppress secondary ADH
secretion

HYPERCALCEMIA
elevation of total serum Ca above normal range (8.8-10.5 mg/dL), can be PTH-dependent or
PTH-independent.
PTH-DEPENDENT HYPERCALCEMIA: characterized by increased PTH, which can be due to:
1. PRIMARY HYPERPARATHYROIDISM: characterized by excess PTH production by

parathyroids (e.g. due to an adenoma 80-85%, hyperplasia 10-15%, carcinoma 1-2%).
● In this case there are ⬆/normal PTH levels which induces hypercalcemia by stimulating
bone resorption, increasing Vit D activation and increasing intestinal Ca2+ absorption.
● It can be sporadic (most common form) or familial, either isolated or in presence of:
○ MEN 1: primary hyperparathyroidism (>90%), enteropancreatic NETs, pituitary
adenomas, adrenal adenomas
○ MEN-2A: medullary thyroid carcinoma, pheochromocytoma, primary
hyperparathyroidism (< 25%, less frequent with respect to MEN I).
○ Jaw tumor syndrome: hyperPTH, jaw tumors, renal cysts, Wilms tumors and
hamartomas (rarely
2. SECONDARY HYPERPARATHYROIDISM: where excess PTH can be caused by:

● ViTD deficiency due to low intestinal calcium absorption
● Renal failure that causes reduced Ca reabsorption by kidneys
3. TERTIARY HYPERPARATHYROIDISM: where excess PTH is due to a long history of

secondary hyperparathyroidism and chronic renal failure, following occurrence of hyperplasia
or adenoma of the parathyroid.
4. VARIANT FORMS of PRIMARY HYPERPARATHYROIDISM: which are benign and cause no

clinically relevant complications, therefore do not require any treatment. They include:
a. Familial hypocalciuric hypercalcemia: caused by a loss of function mutation in the
gene coding for CaSR. Hypercalcemia is caused by reduced sensitivity for calcium
(increased threshold) at the level of:
● The parathyroids leading to increased PTH levels (lack of negative feedback)
● In the kidney causing increased calcium renal reabsorption.
b. Lithium-induced hypercalcemia: where lithium also causes reduced parathyroid
sensitivity to serum calcium (acts downstream with respect CaSR, exact locus is still
unknown) and produces increased PTH levels (more likely to normalize if used <1 year)
PTH-INDEPENDENT HYPERCALCEMIA: increase in calcium which is independent from PTH

as the parathyroids are normally functioning and respond to high calcium levels by suppressing
PTH secretion. Possible causes:
1. MALIGNANT TUMORS: cause hypercalcemia via:

etastases, primary bone tumors that increase bone resorption.
● Direct effects on bone: m
● Indirect effects on bone:
○ Ectopic production of PTH related peptide, that increases bone resorption
○ Hyperactivation of VitD which increases intestinal calcium absorption (e.g. lymphomas
or leukemias).
2. GRANULOMATOUS DISORDERS: TBC and sarcoidosis → increase VitD activation →

increased intestinal calcium absorption
3. ENDOCRINOPATHIES:
● Hyperthyroidism → increases bone resorption
● Adrenal insufficiency → decreased GFR, increased tubular calcium reabsorption
● Pheochromocytoma → can secrete PTH analogues or calcitonin
4. DRUG-INDUCED:
● Milk-alkali syndrome: increased calcium and alkali intake (renal failure)
● Vitamin D intoxication (hypervitaminosis D): increases intestinal calcium absorption
● Thiazide diuretics: increase renal calcium reabsorption
Signs and symptoms of hypercalcemia:

● CNS: depression, psychosis, loss of memory (longstanding hypercalc.), ataxia, confusion,
stupor, coma
● Neuromuscular: weakness (mainly of proximal muscles)
● CV: hypertension, shortened QT interval, bradycardia
● Renal: polyuria
● Gastro-intestinal: constipation, nausea, vomiting, anorexia
○ Vicious cycle may be established, worsening hypercalcemia: nausea, vomiting and
polyuria → dehydration → decreased renal excretion of calcium → further increase in
the circulating calcium → signs + symptoms are related to severity.
Complications of hypercalcemia
Occur in long standing hypercalcemia or in asymptomatic primary hyperparathyroidism:
● Renal: increased renal calcium load can lead to kidney stones, nephrocalcinosis, renal
insufficiency.
● Skeletal: osteoporosis may occur in PTH dependent hypercalcemia as it stimulates
osteoclastic activity and osteoclastogenesis increasing bone resorption and causing bone
fragility, leading to:
○ Low bone mineral density and fragility fractures: particularly vertebral
○ Osteitis fibrosa cystica: skeletal fragility, fractures and skeletal alterations evidenced
by X ray studies (salt-and-pepper skull, osteoclastomas, subperiosteal resorption)
○ Peptic ulcer disease ○ Eye calcifications
○ Pancreatitis ○ Chondrocalcinosis
○ Vascular diseases: stroke, MI
Diagnosis of hypercalcemia:
● Total serum calcium measurement: (normal values 8.8-10.5 mg/dL)
○ Mild hypercalcemia: 10.5-12 mg/dl
○ Moderate hypercalcemia: 12-14 mg/dL
○ Severe hypercalcemia: >14 mg/dL
● Calcium correction in patients with hypoalbuminemia: (total ca + 0.8 mg/dL x each 1gr/dL
of albumin below 4gr/dL).
● PTH measurement: to discriminate PTH-dependent and independent hypercalcemia.

○ Hypercalcemia + ⬆/normal PTH levels → primary hyperparathyroidism
Other biochemical parameters suggestive of primary hyperparathyroidism:

● Hypercalciuria (> 4 mg/Kg/24h): calcium filtered by kidneys overcomes calcium
reabsorption stimulated by PTH.
● Hypophosphatemia (< 2.5 mg/dL) + hyperphosphaturia (excretion fraction > 20%): PTH
stimulates phosphate excretion.
Treatment:
● Short-term: promptly normalize calcemia in case of severe hypercalcemia.
○ IV Bisphosphonates: inhibit osteoclast function and osteoclastogenesis.
○ Corticosteroids: inhibit osteoclast function + inhibit intestinal calcium absorption.
○ NaCl solution with furosemide (loop diuretic inhibiting NKCC): increase calcium
excretion without altering volemia
● Long-term: in PTH-dependent hypercalcemia, with normalized/non-severe hypercalcemia:

○ Cinacalcet: activates CaSR → decreased PTH secretion (even in primary).
○ Parathyroidectomy: in primary hyperparathyroidism
Surgery in primary hyperPTH indications:

● Renal insufficiency (creatinine clearance < 60 ml/min) → major indication
● Hypercalciuria, kidney stones or nephrocalcinosis → major indication
● Age < 50 years
● Calcium levels > 1 mg/dL above ULN (10,5 mg/dL)
● Osteoporosis: BMD T-score ≤ -2.5 SD
● Vertebral fractures (clinical or morphometric)
HYPER-PTH
→ excess PTH production that can be primary, secondary, tertiary or due to variant forms
(familial hypocalciuric hypercalcemia or lithium-induced) → see below.
1. PRIMARY HYPERPARATHYROIDISM: characterized by excess PTH production by

parathyroids (e.g. due to an adenoma 80-85%, hyperplasia 10-15%, carcinoma 1-2%).
● In this case there are ⬆/normal PTH levels which induces hypercalcemia by stimulating
bone resorption, increasing Vit D activation and increasing intestinal Ca2+ absorption.
● It can be sporadic (most common form) or familial, either isolated or in presence of:
○ MEN 1: primary hyperparathyroidism (>90%), enteropancreatic NETs, pituitary
adenomas, adrenal adenomas
○ MEN-2A: medullary thyroid carcinoma, pheochromocytoma, primary
hyperparathyroidism (< 25%, less frequent with respect to MEN I).
○ Jaw tumor syndrome: hyperPTH, jaw tumors, renal cysts, Wilms tumors and
hamartomas (rarely
2. SECONDARY HYPERPARATHYROIDISM: where excess PTH can be caused by:

● ViTD deficiency due to low intestinal calcium absorption
● Renal failure that causes reduced Ca reabsorption by kidneys
3. TERTIARY HYPERPARATHYROIDISM: where excess PTH is due to a long history of

secondary hyperparathyroidism and chronic renal failure, following occurrence of hyperplasia
or adenoma of the parathyroid.
4. VARIANT FORMS of HYPERPARATHYROIDISM: which are benign and cause no clinically

relevant complications, therefore do not require any treatment. They include:
● Familial hypocalciuric hypercalcemia: caused by a loss of function mutation in the gene
coding for CaSR. Hypercalcemia is caused by reduced sensitivity for calcium (increased
threshold) in the parathyroids leading to increased PTH levels (lack of negative
feedback), and in the kidney causing increased calcium renal reabsorption.
● Lithium-induced hypercalcemia: where lithium also causes reduced parathyroid
sensitivity to serum calcium (acts downstream with respect CaSR, exact locus is still
unknown) and produces increased PTH levels (more likely to normalize if used <1 year)
Signs and symptoms:

● CNS: depression, psychosis, loss of memory (longstanding hypercalc.), ataxia, confusion,
stupor, coma
● Neuromuscular: weakness (mainly of proximal muscles)
● CV: hypertension, shortened QT interval, bradycardia
● Renal: polyuria
● Gastro-intestinal: constipation, nausea, vomiting, anorexia
○ Vicious cycle may be established, worsening hypercalcemia: nausea, vomiting and
polyuria → dehydration → decreased renal excretion of calcium → further increase in
the circulating calcium → signs + symptoms are related to severity.
Complications:
Occur in long standing hypercalcemia or in asymptomatic primary hyperparathyroidism:
● Renal: increased renal calcium load can lead to kidney stones, nephrocalcinosis, renal
insufficiency.
● Skeletal: osteoporosis may occur in PTH dependent hypercalcemia as it stimulates
osteoclastic activity and osteoclastogenesis increasing bone resorption and causing bone
fragility, leading to:
○ Low bone mineral density and fragility fractures: particularly vertebral
○ Osteitis fibrosa cystica: skeletal fragility, fractures and skeletal alterations evidenced
by X ray studies (salt-and-pepper skull, osteoclastomas, subperiosteal resorption)
○ Peptic ulcer disease ○ Chondrocalcinosis
○ Pancreatitis
○ Vascular diseases: stroke, MI
○ Eye calcifications
Diagnosis of hyper PTH:

● Total serum calcium measurement: (normal values 8.8-10.5 mg/dL)
○ Mild hypercalcemia: 10.5-12 mg/dl
○ Moderate hypercalcemia: 12-14 mg/dL
○ Severe hypercalcemia: >14 mg/dL
● Calcium correction in patients with hypoalbuminemia: (total ca + 0.8 mg/dL x each 1gr/dL
of albumin below 4gr/dL).
● PTH measurement: hypercalcemia + ⬆/normal PTH levels → primary hyperparathyroidism
Other biochemical parameters suggestive of primary hyperparathyroidism:

● Hypercalciuria (> 4 mg/Kg/24h): calcium filtered by kidneys overcomes calcium
reabsorption stimulated by PTH. → kidney stones.
● Hypophosphatemia (< 2.5 mg/dL) + hyperphosphaturia (excretion fraction > 20%): PTH
stimulates phosphate excretion.
Approach to patients with primary hyperparathyroidism

1. Exclude variants that do not require specific treatment:
● Familial hypocalciuric hypercalcemia: low urinary calcium levels with mild hypercalcemia
● Lithium-induced hypercalcemia: diagnosis is anamnestic.
2. Identify whether complications are present or not:
● Serum Cr and Cr clearance (CrCl) to evaluate renal function
● Abdominal US to identify renal stones
● DXA (Dual-Energy X-ray Absorptiometry): BMD at lumbar spine, femur neck, total hip and
distal radius for diagnosis of osteoporosis
● Vertebral morphometry on spine RX or DXA images for diagnosis of vertebral fractures.
3. Identify whether primary hyperparathyroidism is familial or not:
● MEN I: genetic screening for MENIN gene mutation in presence of associated neoplasms.
● MEN IIa: genetic screening for RET gene mutation in presence of associated neoplasms,
presence of calcitonin (medullary thyroid cancer).
4. Localize the hyperfunctioning parathyroid gland, responsible for PTH hypersecretion:
● Neck US, CT, PET/CT scintigraphy MRI → 30-40% negative on imaging studies
Treatment:
● Short-term: promptly normalize calcemia in case of severe hypercalcemia.
○ IV Bisphosphonates: inhibit osteoclast function and osteoclastogenesis.
○ Corticosteroids: inhibit osteoclast function + inhibit intestinal calcium absorption.
○ NaCl solution with furosemide (loop diuretic inhibiting NKCC): increase calcium
excretion without altering volemia
● Long-term: in PTH-dependent hypercalcemia, with normalized/non-severe hypercalcemia:
○ Cinacalcet: activates CaSR → decreased PTH secretion (even in primary).
○ Parathyroidectomy: in primary hyperparathyroidism
Surgery in primary hyperPTH indications:

● Renal insufficiency (creatinine clearance < 60 ml/min) → major indication
● Hypercalciuria, kidney stones or nephrocalcinosis → major indication
● Age < 50 years
● Calcium levels > 1 mg/dL above ULN (10,5 mg/dL)
● Osteoporosis: BMD T-score ≤ -2.5 SD
● Vertebral fractures (clinical or morphometric)
HYPOCALCEMIA:
total serum calcium < 8.8 mg/dL in presence of normal plasma protein concentrations or serum
ionized calcium concentration < 4.7 mg/dL. Can be PTH dependent or PTH independent.
PTH-DEPENDENT HYPOCALCEMIA: can occur in hypoparathyroidism (⬇ PTH

secretion) or pseudo hypoparathyroidism (normal PTH production but ⬇ PTH activity due to
inactivity of PTH or malfunctioning PTH receptors). These cause: ⬇ VitD activation (so ⬇ intestinal
calcium absorption) + ⬇ renal calcium reabsorption + ⬇ bone turnover leading to hypocalcemia.

Hypoparathyroidism:
● Thyroid surgery: most common, especially when extensive and/or in presence of previous
neck surgeries. Up to 10% of patients develop permanent hypoparathyroidism.
● Autoimmune: stimulating antibodies against CaSR cause persistent inhibition of PTH
secretion. May be present in autoimmune polyglandular syndrome type 1 (APS-1) →
autosomal recessive mutation of the AIRE gene associated with other autoimmune diseases
like Addison’s, Hashimoto’s, mucocutaneous candidiasis, autoimmune hypogonadism.
● Familial: rare, genetically determined → isolated or associated with dysmorphic features
○ Familial hypoPTH (can be autosomal recessive causing PTH mutations and abnormal
gland development, or dominant causing CaSR mutations)
○ DiGeorge syndrome: presence of dysmorphic facies, cardiac defects, immune
deficiency
○ HDR syndrome: deletion of GATA3 (TF) + sensorineural deafness, renal
abnormalities.
● Systemic diseases: like granulomatous diseases, hemochromatosis and Wilson’s diseases,
→ infiltration of organs and tissues.
Pseudohypoparathyroidism: rare genetic form where PTH is normally produced but is not
biologically active due to actual inactivity of PTH or malfunctioning PTH receptors.
Classification:
● Type 1 or 1A: AD trait, loss of function of one allele in the gene encoding for α-subunit of
the stimulatory G protein of PTH receptors → associated with typical somatic features such
as short stature, obesity, brachydactyly and subcutaneous ossifications.
● Type 1B: epigenetics induced, like abnormal methylation in g-protein.
PTH-INDEPENDENT HYPOCALCEMIA: alterations in calcium homeostasis generally

caused by VitD deficiency or intestinal diseases associated with malabsorption. Serum PTH values
are high → secondary hyperPTH.
Possible causes:
● Severe hypovitaminosis D: ⬇ VitD → ⬇ intestinal calcium absorption
● Malabsorption syndrome: intestinal disease → ⬇ intestinal calcium absorption
● Renal insufficiency: ⬇ VitD activation → ⬇ intestinal calcium absorption
● Vitamin D dependent congenital rickets: ⬇ VitD activation/action → ⬇ intestinal calcium
absorption.
Clinical presentation of hypocalcemia:

● CNS: depression, irritability, confusion, convulsion
● Neuromuscular/skeletal: numbness, tingling (paresthesia), cramps, bone pain (Vit D def.)
● CV: prolonged QT tract + alterations of the ST segment → mimics myocardial infarction
● Respiratory: dyspnea and wheezing, throat tightness (severe)
● GI: abdominal cramps
● Pseudohypoparathyroidism: symptoms of hypocalcemia with short stature, obesity,
brachydactyly and subcutaneous ossifications (type 1).
● Rickets: hypocalcemia symptoms + dysmorphic features (e.g. rachitic rosary → beads growing
on ribs), bowed limbs.
● Osteomalacia: patients also complain of bone pain.
● Subclinical hypocalcemia may be suggested in presence of latent tetany (Chvostek’s sign →
ipsilateral contraction of facial muscle when percussing facial nerve, Trousseau’s sign → carpal
spasm and strong pain if blood pressure cuff is applied for more than 3 mins).
This is caused by hyper-responsiveness of the peripheral NS due to lower than normal calcium
levels.
Complications: in longstanding hypocalcemia, in particular extraskeletal calcifications (e.g. kidney

stones), renal insufficiency, convulsions/seizures and depression. There can also be ischemic heart
disease and cataract.
Diagnosis:
● Serum calcium < 8.8 mg/dL
● Calcium correction in hypoalbuminemia (+ 0.8 mg/dL x each 1gr/dL of albumin reduction
below 4gr/dL).
● PTH:
○ HypoPTH: low/inappropriately normal
○ PseudohypoPTH and PTH-independent hypocalcemia: normal
● Serum and urine phosphate: discriminate pseudohypoPTH and PTH-independent.
○ PseudohypoPTH → phosphate is low in urine and high in serum (PTH is not
biologically active so there will be abscence of phosphate excretion by the kidneys).
○ PTH-independent → phosphate is high in urine, low in serum (Vitamin D
insufficiency does not allow phosphorus to be absorbed by the intestinal tract).
● 25-OH Vitamin D:
○ VitD Sufficiency: > 30 ng/mL
○ VitD Insufficiency: 10-30 ng/mL
○ VitD Deficiency: < 10 ng/mL
Treatment
● IV calcium: in severe symptomatic hypocalcemia
● Oral calcium: after acute treatment
● Vitamin D:
○ Active vitamin D (calcitriol) is required for PTH-dependent hypocalcemia.
○ Inactive vitamin D (cholecalciferol/vitamin D3, or calcifediol/25OH vitamin D) for
PTH-independent hypocalcemia, because VitD can be activated by circulating PTH.

OSTEOPOROSIS:
Systemic disease characterized by quantitative and/or qualitative abnormalities in bone
microstructure associated with decreased bone strength and increased bone fragility and
susceptibility to fractures (commonly in spine, femoral neck, distal forearm, proximal humerus).
Epidemiology: very frequent disease → Europe (2010) >20 million women and 5 million men + > 3.5
million new fractures were recorded (⅔ in women).
Classification: primary or secondary

Primary osteoporosis: (no secondary causes of skeletal fragility)
● Post-menopausal osteoporosis (type 1)
● Senile osteoporosis, in aging women (type 2)
● Idiopathic male osteoporosis

Secondary osteoporosis → disease induced or drug induced osteoporosis
● Autoimmune disorders: psoriasis, celiac disease, IBD etc.
● Genetically determined osteoporosis:
○ Osteogenesis Imperfecta: disease sustained by alterations of collagen type I
○ Ehlers Danlos syndrome: disease caused by alterations of collagen III and V, in
which impairment of skeletal strength is associated with dermal fragility, internal organ
and vessel rupture, joint abnormality and hypermobility
● Endocrine diseases: hormone excess/defect that can lead to two endocrinological
scenarios:
○ Osteoporosis with low turnover → decreased bone formation (+ resorption)
- Cushing syndrome/disease
- GH deficiency suppression of bone formation
○ Osteoporosis with high turnover → increased bone resorption
- Primary hyperparathyroidism
- Hyperthyroidism
- Acromegaly
- Hypogonadism
- Hyperprolactinemia
● Drug-induced osteoporosis:
○ Glucocorticoids or thyroid hormones
○ Aromatase inhibitors and androgen deprivation therapy: commonly used for
treatment of breast cancer and prostate cancer respectively, may cause a severe
osteoporosis with severe risk of fractures.
○ Anti-retroviral therapy: for HIV, inhibited osteoblastogenesis + increased bone
resorption → increased fracture risk.
Diagnosis of osteoporosis:
1. Bone mass measurement - DXA (Dual-energy X-ray Absorptiometry): gold standard

densitometric measurement of bone mineral density ( at sites rich in mineral bone density such
as hip, lumbar spine, femoral neck). BMD is generally expressed as:
● T score: comparison of the patient’s bone density with mean reference in the young
population. Used in patients > 50y.o. + post-menopausal women.
○ Normal: T score > -1 SD
○ Osteopenia: T score from -1 to -2.5
○ Osteoporosis: Tscore ≤ -2.5 SD
● Z score: comparison of the patient’s bone density with that of the reference population
of the same age and sex. Used in younger patients (< 50y.o.) and premenopausal
women.
○ Normal: Z score > - 2.0 SD
○ Pathological: Z score ≤ -2.0 SD
This is a measurement of bone quantity and alterations in bone microstructures are not
captured by DXA → this discrepancy between bone quantity and bone quality is particularly
frequent in patients with secondary osteoporosis (e.g. patients exposed to glucocorticoids
excess, patients on high treatment with levothyroxine for thyroid cancer) so we must also
perform
2. Exclusion of secondary osteoporosis - clinical history and biochemical exams:

● Measurement of alterations in calcium metabolism:
○ PTH
○ Serum/urinary calcium
○ Serum/urinary phosphorus
○ 25-OH Vitamin D (sufficiency >30 ng/mL, insufficiency 20-30, deficiency < 20) →
hypovitaminosis D is frequent in the elderly and women
● Other hormones in suspicion of endocrinopathy
3. Identification of fractures - clinical history + vertebral morphometry

● Clinical fractures (non vertebral): clinical history may be sufficient for identification
● Radiological fractures (vertebral): mostly without specific symptoms and signs →
VERTEBRAL MORPHOMETRY usually performed on images obtained from DXA →
vertebral fracture = decreased height of at least 20% in at least 1 vertebra. Can be further
classified in:
○ Mild: 20-25% reduction (anterior, middle and/or posterior height)
○ Moderate: 25-40% reduction
○ Severe: >40% reduction
● Pre-existing fractures: increase risk of further fractures even in short term follow ups.
Treatment of osteoporosis:
● Antiresorptive drugs → inhibit osteoclasts 1st line
○ Bisphosphonates = oral or parenteral → apoptosis of osteoclasts by inhibition of
RAS pathway.
○ Denosumab = monoclonal Ab that blocks RANK-ligand (regulator of
osteoblastogenesis and bone resorption)
○ SERMS (selective estrogen REC modulators) = inhibit bone resorption
○ Calcitonin
● Anabolic drugs → promote osteoblast activity
○ Teriparatide = analogue of PTH (usually stimulates bone resorption) but intermittent
exposure promotes osteoblastogenesis and bone formation.
○ Romosozumab = monoclonal Ab that promotes osteoblastogenesis and inhibits
osteoclasts by inhibiting sclerostin (a protein that inhibits Wnt pathway), thus allowing
bone formation.
● Vitamin D: supplement to provide normal remineralization and to correct hypovitaminosis.
○ Precursors of vitamin D (vitamin D3 and D2): not biologically active (hydroxylated in
liver and then in kidney). Suggested by guidelines (safer, have long term effects)
○ Calcifediol (vitamin D hydroxylated in position 25) in patients with liver disease
○ Calcitriol (bioactive, hydroxylated in position 1) in renal insufficiency or absent/low
PTH (needed for activation).
MALE HYPOGONADISM:
clinical syndrome characterized by insufficient production of male androgens (in particular
testosterone) that can further be classified in primary (testes dysfunction), secondary
(pituitary-hypothalamic dysfunction) and congenital or acquired (further classified in pre-pubertal
and post pubertal).
Primary Secondary
● Klinefelter syndrome ● Isolated GnRH deficiency

most common genetic form, (Kallmann disease)
presence of an extra disease characterized by genetic
heterogeneity. It causes
X-chromosome (47 XXY; 48 XXXY
congenital hypogonadism in both
etc.), occurring due to sexes, leading to an absent onset
nondisjunction in parental of puberty + partial or total
gametogenesis or in mitotic anosmia.
Congenital division, whereby it is
characterized by mosaicism. Others:
● Isolated LH deficiency
Others: ● Prader-Willi syndrome
● Laurence-Moon-Biedl syndrome
● Noonan syndrome
● Inborn errors of testosterone
biosynthesis
● Androgen resistance state
● Trauma ● Pituitary tumors/Irradiation

● undescended testes ● Trauma
● Bilateral torsion of testes ● Craniopharyngioma
● Hyperprolactinemia (PRL
● Orchidectomy
Acquired suppresses GnRH and has
● Gonadal toxin inhibitory effects on LH and FSH).
(radiotherapy/chemotherapy) ● Hemochromatosis
● Acute/chronic systemic disease ● Inflammatory pituitary disease
● Aging
Clinical presentation: depends on the onset of hypogonadism (congenital, pre or post pubertal)
Congenital presentation: depends on time of testosterone absence:

● First weeks of fetal life → male pseudohermaphroditism (e.g. inborn deficiency of
testosterone synthesis, androgen resistance) → ambiguity of genitalia in XY subjects (+
female phenotype).
● After 6th month of fetal development → micropenis and cryptorchidism = unilateral or
bilateral absence of testes in the scrotum due to failed testicular descent (requires DHT).
○ Can be located in the external inguinal ring (50%), inguinal tract (20%) and more
rarely in the abdomen or ectopic.
○ Their altered structure can possibly lead to infertility (impaired spermatogenesis) and
altered cellular proliferation → high risk of malignancy if not corrected → orchiectomy
is recommended in post-pubertal diagnosis.
○ May also occur in premature male infants (20-25%), where it mostly resolves during
the first year of life.
Pre-pubertal presentation: normal childhood male phenotype but lack of pubertal development,
presenting:
● Small testes, small penis, no rugae on the scrotum
● No stimulation of sexual hair growth (sparse axillary, pubic, facial, chest hair), no change in
voice
● No closure of epiphyses + eunuchoidal skeletal proportion: legs + arms longer than the
trunk
This phenotype may also be present in patients with congenital hypogonadism that has not been
diagnosed at birth and has not been treated before puberty.
Post-pubertal presentation: patient will not be eunuchoid but will present:

● Decreased libido, erectile dysfunction, infertility
● Decrease in sexual hair growth, decrease in muscle strength
● Abnormal body fat d
istribution (gynoid body shape → fat around hips and thighs)
● Depression, altered sense of well-being, hot flushes.
● Gynecomastia: benign proliferation of male glandular breast tissue (pseudogynecomastia =
fat deposition without glandular proliferation → in obese)
○ May physiologically occur in ⅓ of young subjects during puberty due to transient
increase in gonadotropins → transient peripheral conversion of androgens in
estrogens.
○ May also be due to drugs e.g. spironolactone, aldosterone analogue→ primary
aldosteronism) or anti-androgens for prostate cancer.
Complications:
● Infertility
● Sarcopenia
● Osteoporosis with high turnover (no testosterone = no inhibition of osteoclastogenesis and
bone reabsorption) → fractures
● CV events:, and predisposing to higher risk of CV death
● Depression/cognitive impairment
Diagnosis of male hypogonadism:

Clinical history: question patient on libido, erectile function, mood and well being, presence of
fractures, infertility and CV events.
Physical examination: size of penis in the flaccid state (in adults 12-16cm), testicular volumes by
Prader orchidometer (>15ml in adults), consistency of testicles and epididymis, skeletal proportion,
hair presence and distribution, presence of gynecomastia, body composition: BMI and waist
circumference.
Lab tests:
● Testosterone: measured in the morning (physiological peak) → normal: ≥ 347 ng/dL, grey
zone: 231-346 ng/dL, hypogonadism: < 231 ng/dL
● FSH and LH: differentiation between primary and secondary:
○ Primary hypogonadism: ⬆ FSH and LH levels (lack of negative feedback)
○ Secondary hypogonadism: ⬇ gonadotropins (direct involvement of the pituitary or
hypothalamus).
● Calculation of bioavailable testosterone: in presence of apparently normal testosterone
levels because some conditions that alter sex hormone BG may caused missed diagnosis
○ ⬆ SHBG in diabetes, obesity, hypothyroidism, acromegaly, cushing disease, GC
○ ⬇ SHBG in hepatopathy, antiepileptics, hyperthyroidism, estrogens, Gh deficiency
● Semen analysis: in case of infertility (semen volume 2-4ml, sperm count >15.000.000/ml,
motility >50%, morphology >30%.
Treatment: replacement therapy to restore beneficial effects of testosterone and restore fertility
(whenever possible).
● Testosterone → primary hypogonadism
● Recombinant gonadotropins (FSH/LH) → only in secondary hypogonadism (expensive,
not feasible for long-term treatment as there is the need for several weekly IM
administrations)
Contraindications: patients with active prostate cancer, breast cancer, untreated OSAS, CHF,
psychiatric disease.
Klinefelter syndrome (KS):

most common genetic form of primary hypogonadism, characterized by the presence of an
extra X-chromosome derived by meiotic non-disjunction during parenteral gametogenesis (47 XXY;
48 XXXY etc.) When the nondisjunction occurs after fertilization in mitotic division, KS is sustained
by a mosaicism. Prevalence of 152:100,000 live born males.
● Phenotype of infancy is usually normal, since androgens are produced during fetal life by the
adrenal gland → makes it severely underdiagnosed or diagnosed late in life (during puberty
or later). 25% of the expected cases are diagnosed, of which 10% are diagnosed before
puberty
● Typical signs:
○ Small and firm testes (sustained by fibrosis and hyalinization of seminiferous
tubules) → infertility
○ Gynecomastia
○ Erectile dysfunction, decreased libido
○ Eunuchoid physical proportions (long arm and legs), abnormal fat distribution
○ Osteoporosis + fracture
○ Learning difficulties
● Diagnosis: increase in FSH and LH + low or normal testosterone + evaluating the
presence of an extra X chromosome in a karyotype.

Kallmann disease:
Also known as isolated GnRH Deficiency, rare cause of secondary hypogonadism characterized
by genetic heterogeneity (can be autosomal dominant, autosomal recessive, X-linked recessive or
multigenic/multifactorial).
● It has a prevalence of 1-9/100,000.
● It causes congenital hypogonadism in both sexes, leading to absent onset of puberty +
partial or total anosmia (impairment of sense of smell).
● Most cases are diagnosed at puberty due to the lack of sexual development, but Kallmann
disease may also be suspected in infant males with cryptorchidism, micropenis or
associated non reproductive signs.
Abnormal uterine bleeding:
Types of abnormal uterine bleeding:
● Oligomenorrhea: menstrual intervals > 35 days
● Polymenorrhea: menstrual intervals of ≤ 21 days
● Hypomenorrhea: reduced menstrual flow (< 10 ml)
● Hypermenorrhea/menorrhagia: increased menstrual flow (> 80 ml)
● Amenorrhea: absence of menses
AMENORRHEA:
absence of menses that can be transient, intermittent or permanent, and can result from dysfunction
of different systems (hypothalamus, pituitary, ovaries, uterus or vagina) classified into:
● Primary amenorrhea: absence of menarche by the age of 15
● Secondary amenorrhea: absence of menses for > 3 months in women with previously
normal menses or for ≥ 6 months in women with previously irregular menses
PRIMARY AMENORRHEA:
generally caused by genetic or anatomical abnormalities.
Causes of primary amenorrhea include:

● Gonadal Dysgenesis (43%)
Turner's Syndrome genetic condition where a female is completely or partly missing an X
chromosome, and so is characterized by karyotype 45, X. Its prevalence is 1 / 2,500 females.
○ Signs and symptoms:
- Hypogonadism (absence of breast development + primary amenorrhea)
- Short stature and s
tocky appearance (treated with GH)
- Abnormalities of the skeleton like scoliosis (20%) or kyphosis (50%)
○ This disease may also affect other systems: CV (congenital malformations, 75%),
Renal (+ possible uncontrollable hypertension), Skeletal: osteoporosis due to estrogen
decrease, Auditory (hearing loss), Immunity: autoimmune disorders in particular
hypothyroidism (37%), celiac disease (6%), inflammatory bowel disease (3%),
Metabolism: metabolic syndrome due to increased risk of insulin resistance.
● Morris syndrome (or complete androgen insensitivity syndrome): rare disease in females
where androgen receptors are not able to bind to testosterone → primary amenorrhea reduced
sexual hair + inguinal hernias and labial masses (underdeveloped male sex organs or
undescended testes) → female phenotype with male karyotype (46, XY).
○ Hormonal profile: ⬆ FSH LH, low estradiol and testosterone - normal adult male range
○ Other signs and symptoms:
- Normal breast development: testosterone still converted into estrogen by
adipose tissue
- Absent uterus, blind vaginal pouch
● Mullerian agenesis (15%): absent formation of vagina or uterus, usually with normal hormone
production
● Physiological delay in puberty (15%): can be a constitutional delay, or can be due to a
chronic systemic illness or an acute illness
● Isolated GnRH deficiency (5%)
● Weight loss or anorexia (2%)
● Hypopituitarism (2%)
● Polycystic ovary syndrome (7%) more frequent in secondary
Diagnostic workup for primary amenorrhea:
1. Anamnesis:
● Family history of primary amenorrhea
● Symptoms of hyperandrogenism (e.g. acne increase, increase in body hair, muscle
growth).
● Changes in weight, diet or exercise
● Drugs (e.g. glucocorticoids, steroids, contraceptive pill, chemotherapy, antipsychotics
which increase PRL secretion → inhibitory stimulus for gonadal synthesis).
● Exclude hypothalamic-pituitary diseases (alteration in visual field, galactorrhea, loss of
libido, recurrent headaches).
2. Physical examination:
● Tanner staging: assesses breast development, directly correlated to lack of estrogens
● Check for: hirsutism and acne, striae (Cushing syndrome), pigmentation and vitiligo
(autoimmune adrenal insufficiency).
3. Lab tests: LH, FSH, PRL, TSH and FT4 + US of pelvic region
○ Elevated FSH: suspicion of gonadal dysgenesis e.g. Turner’s syndrome → karyotype
○ Normal FSH in absence of uterus: Mullerian agenesis / androgen insensitivity
syndrome (+ circulating testosterone in the male range)
○ Normal FSH, normal breast development, presence of blood in the uterus
(hematometra) or in the vagina (hematocolpos): anatomically obstructed outflow tract
○ Low/normal FSH, normal uterus: may be a sign of constitutional delay of puberty
SECONDARY AMENORRHEA:
Causes:
● Ovarian dysfunction (PCOS 30%, primary ovarian insufficiency (10%)
● Hypothalamic diseases (35%)
● Pituitary diseases (20% - hyperprolactinemia, empty sella syndrome, Cushing syndrome).

Polycystic ovary syndrome (PCOS) (30%): one of the most common endocrine-metabolic
disorders in women, prevalence up to 10%. It is associated with menstrual irregularity, infertility,
metabolic dysfunction and hyperandrogenism (17%) with ovulatory disorders in up to 90% of
patients.
● It is caused by increased GnRh pulse frequency → increase FSH and LH pulse ratio →
increased androgens and direct inhibition of aromatase → decreased conversion of
testosterone into estrogens
● Clinical signs:
○ Menstrual abnormalities: oligomenorrhea + absence of ovulation, peripubertal onset
and higher risk of endometrial neoplasia and carcinoma (also increased by obesity
and insulin resistance).
○ Hyper-androgenism: hirsutism and acne
○ Metabolic alterations (20%): obesity, insulin resistance, diabetes mellitus,
dyslipidemia (low HDL, high LDL) → increased risk of coronary artery disease, which
may also be associated with the chronic inflammatory state underlying PCOS.
○ Psychosocial disorders: e.g. depression and anxiety
○ Alimentary d isorders: e.g. bulimia and binge eating
● Lab testing: ⬆ total testosterone, FSH, LH in 5-20 mlU/ml range (LH often 2 or 3 times
higher). For DD:
○ 17-hydroxyprogesterone: to exclude congenital adrenal hyperplasia
○ Prolactin: usually <25 ng/ml, to rule out pituitary tumor
○ hCG: to rule out a possible pregnancy
● Management: to correct hyperandrogenism possibly inducing ovulation, manage metabolic
dysfunction, prevent endometrial tumors and reduce the risk of diabetes onset:
○ Estradiol (negative feedback on FSH and LH → suppression of ovarian androgen
production), progestins (antiandrogenic properties),
○ Weight loss and exercise, metformin (in insulin insensitivity, often associated with
improvement in ovulation rate).
Functional hypothalamic amenorrhea: characterized by a presumed decrease in

hypothalamic GnRH secretion, suspected only after exclusion of all other pathologic diseases that
could cause amenorrhea.
● Pathogenesis: Abnormal GnRH secretion → reduction of FSH and LH pulsatility → absence
of normal follicular development, absent midcycle surges in LH secretion, anovulation, and
low serum estradiol concentrations.
● Risk factors:
○ Weight loss: at least 10% of body fat → important for gonadal conversion of
testosterone into estrogen
○ Excessive exercise, nutritional deficiencies e.g. celiac disease
○ Emotional and physical stress: with usual recovery after the stress ceases.
- Cortisol, released in situations of stress (inflammation, exercise) → inhibitory
effect on ovaries and on GnRH
- PRL is also released during stress and has an inhibitory action on gonadal
function.
Hyperandrogenism: a
drenal endocrine condition, characterized by:
● Hypertrichosis or hirsutism: excessive terminal hair growth in women (up to 10% of women
affected), that appears in a typical male pattern. Graded by Ferriman-Gallwey hirsutism scoring
system if ≥ 8 androgen excess.
● Virilization: implies a more severe androgen excess, characterized by lower voice, hair loss,
acne, increased muscle mass and clitoromegaly
● Increased androgen synthesis: testosterone 30% produced by the ovaries, 70% converted
from androstenedione peripheral tissues (from prohormones DHEA and DHEAS →
androstenedione → testosterone) → all these parameters must be measured.
● Causes:
○ Ovarian: PCOS, hyperthecosis (nests of luteinized theca cells in the ovarian
stroma), ovarian tumor.
○ Adrenal: adrenal hyperplasia, Cushing’s syndrome, glucocorticoid resistance,
adrenal tumor
○ Idiopathic hyperandrogenism: use of drugs such as anabolizing agents or those
used in epilepsy
Laboratory exams: for differential diagnosis of androgen excess:

● Testosterone + androstenedione: elevated in both ovarian and adrenal hyperandrogenism
● 17-Hydroxyprogesterone: precursor of androgens, marker of congenital adrenal hyperplasia.
● Cortisol: clinical suspicion of Cushing syndrome + Nugent test (low doses DST)
● DHEA-sulphate: >500 mcg/dL (13.6 μmol/L) in young women → adrenal tumor.
● US of ovaries
● CT or MRI of the adrenal glands.
Congenital adrenal hyperplasia: group of autosomal recessive disorders caused by
deficient adrenal corticosteroid biosynthesis.
● Mainly caused by 21-hydroxylase enzyme dysfunction (95%) → accumulation of
17-hydroxy-progesterone + subsequent accumulation of androstenedione + reduction of
aldosterone and cortisol production.
● Clinical signs: 3 forms:
○ Salt Wasting form: most severe, presents after first 2 weeks of life with a salt
wasting crisis (due to decreased glucocorticoids + mineralocorticoids, can even
cause death) → suspected in neonates with atypical genitalia and/or electrolyte
abnormalities, lethargy, hypoglycemia, hypotension or shock, or failure to thrive.
○ Simple Virilizing Form: normal mineralocorticoid production, normal or subnormal
glucocorticoid production + increased androgen production → virilization in females,
or signs of premature puberty in males.
○ Late-onset 21-Hydroxylase deficiency: generally observed in childhood and early
adulthood, with premature puberty, and in females with similar characteristics of
PCOS (hirsutism, primary or secondary amenorrhea and anovulatory infertility).

MENOPAUSE:
Natural event, defined as final menstrual period (FMP), confirmed after 1 year of amenorrhea.
It can be considered as hyper-gonadotropic hypo-gonadism (or primary hypogonadism) with
loss of ovarian follicular function causing permanent cessation of menses, according to the critical
threshold in oocyte number. It is defined as:
● Physiological: onset at age >45;
● Premature (primary ovarian insufficiency): onset at age < 40;
● Early: onset between the ages of 40 and 45 (in up to 10% of women).
Menopause age: mean age is 48.8 years, varies according to different ethnicities:
● Africa, Latin America and Middle Eastern countries → 47.2 - 48.4 years
● Europe and Australia → 50.5 - 51.2 years in
Mean age influenced by:

● Genetic factors: family history (≤ 45 years onset → 6x increase of risk of early
menopause), genetic variants
● Reproductive factors: early menarche (≤ 11 years) + nulliparity → higher risk of early
menopause
● Lifestyle factors: cigarette smoking (2x higher risk of early menopause → anti-estrogenic
effect and increased hepatic clearance of estradiol), BMI (fat mass → increased aromatase
activity = increased estradiol, underweight = early, overweight = late)
● Early-life and social/environmental factors
Physiology: menopause is a continuum of events:

1. Late reproductive: beginning, subtle changes in menstrual cycle + slight elevation in FSH
2. Menopause transition or perimenopause (1-3 years): increase FSH, reduction of antral
follicle count, increased intervals of amenorrhea, possible vasomotor symptoms:
3. Post-menopause (2-4 years) complete absence of menses, increase in FSH and increased
vasomotor symptoms.
2 events contribute to this:

● Loss of feedback at the ovarian level: loss of follicle cells and granulosa → decrease in
inhibin B → FSH increase and decrease in estradiol → increased GnRH pulse amplitude +
increased gonadotropins (early post-menopausal period.)
● Aging of the hypothalamus and pituitary: producing decrease in GnRH pulsation
frequency and causing subsequent 30% to 40% decrease in LH and FSH secretion.
Menopause signs and symptoms:

can be specific or a-specific, and are related to the different effects of estrogens of the body:
● Vasomotor symptoms - hot flashes: a sensation of heat, sweating, anxiety and chills lasting
up to 5 minutes, considered as a heat-dissipation response (vasodilation + sweating,) seems
to be correlated to LH → may lead to night sweats and sleep disturbance (+ depression,
anxiety, poor sleep quality etc.) → increased CV risk.
● ody changes and weight gain → central obesity
Weight and metabolic changes: b
● Metabolic syndrome (40%): change in body composition during menopause leads to →
central obesity (increased waist circumference) + insulin resistance (increased fasting blood
sugar) + dyslipidemia, T2DM
● Cardiovascular system: higher risk of atherosclerosis, stroke, ischemic heart disease → due
to: increase in oxidative stress, vascular cell proliferation and inflammation and arterial
stiffness and endothelial dysfunction
● Central nervous system:
○ Cognitive changes: estradiol has neuroprotective effects, and its lack has been
associated with a reduction in verbal, learning and memory performances in many
studies.
○ Sleep disturbance: frequent awakening → depressive symptoms, tiredness + difficulty
in falling asleep → night sweats (linked to vasomotor symptoms) + OSAS (weight gain
+ fat distribution changes) → increased CV risk
○ Mood disorders: depressive symptoms
● Musculoskeletal system: reduced lean mass and strength (less significant reduction in
testosterone)+ osteopenia (T score between -1SD and -2.5 SD) and osteoporosis (T score <
-2.5 SD + significant increase in fracture risk)
● Urogenital symptoms: due to presence of estrogen receptors in vagina, vulva, urethra and
bladder trigone →
○ Itching and vaginal thinning, decreased distensibility, reduced secretions, → vaginal
dryness and dyspareunia ( pain in intercourse)
○ PH changes → changes in vaginal flora → increased incidence of vaginal and UT
infections. Also dysuria and urinary urgency are commonly experienced
● Skin, mucosae and hair: skin thickness, elasticity and hydration reduction
DYSLIPIDEMIA
= clinical condition characterized by excess of cholesterol, LDLs and triglycerides and/or by low
HDL cholesterol levels. It is one of the main risk factors for atherosclerotic cardiovascular disease
(e.g. coronary heart disease, ischemic stroke and peripheral arterial disease).
Etiology:
1. Primary dyslipidemia: caused by gene mutations that result in overproduction / defective
clearance of triglycerides and LDL, or underproduction / excessive clearance of HDL.
● Familial hypercholesterolemia: most common form of primary dyslipidemia,
autosomal dominant inherited disorder of lipid metabolism, characterized by very high
plasma concentrations of LDL-c and increased risk of premature CHD (80% of cases
mutation in LDLR gene) There are 2 types of FH:
○ Heterozygous form: most frequent, affecting 1/500 people. In untreated patients
CHD usually develops before age 55-60.
○ Homozygous form: both alleles mutated, very rare but if unrecognized or
untreated these patients typically develop CHD very early and often die before age
20.
2. Secondary dyslipidemia: associated with several pathological conditions, where increase in
plasma lipids is not linked to defects in lipid metabolism.
Symptoms: usually asymptomatic but, if unrecognized, it can lead to atherosclerotic CV disease

(e.g. myocardial infarction, peripheral arterial disease).
Signs:
● Arcus corneae: deposition of phospholipids + cholesterol → peripheral corneal opacity.
● Tendinous xanthomas: deposition of yellowish cholesterol rich material appearing as
nodules and papules at the levels of tendons (Achille’s, elbow, knee and
metacarpophalangeal joints) of hands, feet and heel, associated with familial forms of
hypercholesterolemia
● Xanthelasma: lipid rich yellow plaques on the medial eyelids
● Acute pancreatitis (higher TG levels)
● Lipemia retinalis: creamy white appearance of retinal vessels (higher TG levels)
● Eruptive xanthomas: small lumps in the skin, sometimes itchy (higher TG levels)
Diagnosis: no universally accepted criteria most commonly used are Simon Broome criteria, Dutch
lipid clinic network criteria, MEDPED criteria → measurement of blood lipids total cholesterol, HDL
cholesterol and triglycerides (fasting state, as they increase with meals)
● LDLs measurement:
○ Calculated via Friedewald formula: (LDL-C= total cholesterol - [HDL cholesterol +
(triglycerides/5)] → only when TGs are < 400mg/dL
○ Measured directly via plasma ultracentrifugation / immunoassay.
Indications for blood lipid measurement:

- Suspect of dyslipidemia: in patients with possible complications of dyslipidemia
(atherosclerotic cardiovascular disease or metabolic syndrome).
- Suspect of familial hypertriglyceridemia
Management: for all patients with atherosclerosis (secondary prevention) and for some without
(primary prevention) → therapy is different depending on the patient’s risk profile
● SCORE system: in apparently healthy individuals, to estimate 10 year cumulative risk of a
first fatal atherosclerotic event considering age, gender, smoking, systolic BP, total
cholesterol.
● Correct management begins with a healthy lifestyle, correct diet and physical activity →
can lower up tp 50% the risk for CHD.
Treatment → drugs:
● Statins: 1st line to lower LDL up to 60% → competitive inhibitors of HMG Coa reductase →
reduction in intracellular cholesterol → increased LDL receptor expression at the surface of
hepatocytes → increased uptake of LDL from blood → small increase in HDL and
decreased TGs + anti inflammatory and anti thrombotic effects
○ Side effect: 10-15% myalgia; 0.1% risk of serious muscle injury (e.g.
Rhabdomyolysis, severe pain, necrosis, hemoglobinuria, renal failure, death); mild
elevation of transaminases (rare) liver failure; modest increase in risk of DM (0.2%
per year).
● Ezetimibe: block Niemann-Pick C1-like protein 1 (NPC1L1) inhibiting uptake of dietary and
biliary cholesterol at brush border of the intestine → hepatic upregulation of LDLR →
increased clearance of LDL from blood.
● Bile acids sequestrants (cholestyramine and colestipol): bind bile acids, preventing their
uptake blocking their return to the liver. Increased hepatic demand for cholesterol →
increase in LDLR expression → decrease of circulating LDL.
● Fibrates: agonists of Peroxisome Proliferator-Activated Receptor-alpha (PPAR-alpha) =
transcription factors increase HDL, reduce of LDL and VLDL.
Glucocorticoids long term use:

It can induce osteoporosis or adrenal insufficiency,

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HYPOPITUITARISM

Classical ​lymphocytic hypophysitis: linked to pregnancy or postpartum period → ​headache​,

Granulomatous ​hypophysitis​: can be primary or secondary to systemic diseases (e.g. sarcoidosis).

- Short stature (decreased May lead to ​metabolic syndrome (characterized by central

Epidemiology​: incidence increased from 6 to 11 cases/1.000.000 in 33 years (possible advanced

● Decreased libido, infertility ● Gynecomastia (may occur physiologically in ⅓ of

PRL has different effects on ​fertility​ as it:

Clinical presentation:​ ​mild​ or ​asymptomatic​ in ​50%,​ or may result in:

● OSAS (25-60%): due to craniofacial deformities, hypertrophy of pharyngeal soft tissue,

Treatmen​t​: ​somatostatin analogues (normalization of GH only in ~45% + shrinkage of the tumor in

TSH FT4 FT3

Disease ​progression​: ​euthyroidism → ​subclinical ​hypothyroidism → ​overt ​hypothyroidism​,

Symptoms​:​ initially may be asymptomatic and, as the disease progresses:

Early symptoms Late symptoms

● Cold intolerance, weight gain → ● Decreased sense of taste and smell

● Thin, brittle hair and fingernails, dry +

Progression and predictors of the disease​:

Treatment​: very important ​because​:

Overt hypothyroidism in pregnancy​: has important consequences in pregnancy, and when

PRIMARY THYROTOXICOSIS WITH HYPERTHYROIDISM​: ​hyperfunctioning thyroid gland

● PLUMMER’S ADENOMA OR TOXIC NODULAR ADENOMA: ​chronic disease sustained by an

● TOXIC MULTINODULAR GOITER active ​multinodular ​goiter produced by the occurrence of

PRIMARY THYROTOXICOSIS WITHOUT HYPERTHYROIDISM​: increased TH and suppressed

● SILENT AND POST-PARTUM THYROIDITIS: ​self-limited disease in patients ​affected by /

● SUBACUTE THYROIDITIS (DE QUERVAIN’S THYROIDITIS): ​acute ​inflammatory

SECONDARY THYROTOXICOSIS WITH HYPERTHYROIDISM​: ​hyperfunctioning thyroid

DD: Note → ​resistance to thyroid hormones​: ​presence of a mutation affecting T ​ 3 receptors →

General signs and symptoms of thyrotoxicosis:

Specific signs and symptoms:

Imaging​: US, scintiscan

Ultrasound Scintigraphy Treatment

Plummer’s disease or Surgery or radio-iodine

Toxic multinodular Multiple nodules (2 or

Diffuse goiter, low-absent Β-blockers in transient

Postpartum thyroiditis Diffuse goiter with Β-blockers in transient

Focal area of Corticosteroids and

Destructive exogenous Low diffuse uptake Interruption or adjustment

Complications​: in case of severe or longstanding thyrotoxicosis but also in case of longstanding

General signs and symptoms​:

Symptoms can be present in other diseases, such as​:

Specific signs and symptoms:

Imaging​: US, scintiscan with pertechnetate, MRI for TSHoma

Complications of long standing subclinical hyperthyroidism ​(old patients and post-menopausal

● Excess iodine (​Wolff-Chaikoff effect​) ​→ rare cause of goiter (auto-regulatory phenomenon

● Continuous stimulation of thyrocytes by​ ​autoantibodies → Grave’s Basedow disease​,

● Continuous stimulation of thyrocytes by TSH​ → TSH secreting pituitary adenoma (mainly

● Goitrogens​: drugs such as Propylthiouracil, lithium, phenylbutazone, aminoglutethimide,

● Radiation therapy:​ for H&N cancers → inflammation

● Thyroid cancer​ (see below)

Clinical presentation:​ three possible presentations:

Scintigraphy with pertechnetate:

FNAB​:​ in presence of malignant features

Classification​: most common types are:

Clinical symptoms​: mostly asymptomatic, but may also present with:

Thyroid cancer diagnostic workup​:

2. US​: malignancy suggested by ​hypoechoic​ nodules >1cm, ​irregular​ ​margins​,

WHO Classification (histopathological):

MEN - MULTIPLE ENDOCRINE NEOPLASIA:

APS - AUTOIMMUNE POLYENDOCRINE SYNDROMES

● Ectopic ACTH secretion (10-15%)​: malignant neoplasia ​external to pituitary-adrenal axis​.

● Adrenal adenoma (10%)​: unilateral cortisol-secreting adrenal adenomas characterized by

2. 24-h UFC (urinary free cortisol​):

Classical lymphocytic hypophysitis: linked to pregnancy or postpartum period → headache,

Granulomatous hypophysitis: can be primary or secondary to systemic diseases (e.g. sarcoidosis).

- Short stature (decreased May lead to metabolic syndrome (characterized by central

Epidemiology: incidence increased from 6 to 11 cases/1.000.000 in 33 years (possible advanced

PRL has different effects on fertility as it:

Clinical presentation: mild or asymptomatic in 50%, or may result in:

Treatment: somatostatin analogues (normalization of GH only in ~45% + shrinkage of the tumor in

Disease progression: euthyroidism → subclinical hypothyroidism → overt hypothyroidism,

Symptoms: initially may be asymptomatic and, as the disease progresses:

Progression and predictors of the disease:

Treatment: very important because:

Overt hypothyroidism in pregnancy: has important consequences in pregnancy, and when

PRIMARY THYROTOXICOSIS WITH HYPERTHYROIDISM: hyperfunctioning thyroid gland

● PLUMMER’S ADENOMA OR TOXIC NODULAR ADENOMA: chronic disease sustained by an

● TOXIC MULTINODULAR GOITER active multinodular goiter produced by the occurrence of

PRIMARY THYROTOXICOSIS WITHOUT HYPERTHYROIDISM: increased TH and suppressed

● SILENT AND POST-PARTUM THYROIDITIS: self-limited disease in patients affected by /

● SUBACUTE THYROIDITIS (DE QUERVAIN’S THYROIDITIS): acute inflammatory

SECONDARY THYROTOXICOSIS WITH HYPERTHYROIDISM: hyperfunctioning thyroid

DD: Note → resistance to thyroid hormones: presence of a mutation affecting T 3 receptors →

Imaging: US, scintiscan

Complications: in case of severe or longstanding thyrotoxicosis but also in case of longstanding

General signs and symptoms:

Symptoms can be present in other diseases, such as:

Imaging: US, scintiscan with pertechnetate, MRI for TSHoma

Complications of long standing subclinical hyperthyroidism (old patients and post-menopausal

● Excess iodine (Wolff-Chaikoff effect) → rare cause of goiter (auto-regulatory phenomenon

● Continuous stimulation of thyrocytes by autoantibodies → Grave’s Basedow disease,

● Continuous stimulation of thyrocytes by TSH → TSH secreting pituitary adenoma (mainly

● Goitrogens: drugs such as Propylthiouracil, lithium, phenylbutazone, aminoglutethimide,

● Radiation therapy: for H&N cancers → inflammation

● Thyroid cancer (see below)

Clinical presentation: three possible presentations:

FNAB: in presence of malignant features

Classification: most common types are:

Clinical symptoms: mostly asymptomatic, but may also present with:

Thyroid cancer diagnostic workup:

2. US: malignancy suggested by hypoechoic nodules >1cm, irregular margins,

● Ectopic ACTH secretion (10-15%): malignant neoplasia external to pituitary-adrenal axis.

● Adrenal adenoma (10%): unilateral cortisol-secreting adrenal adenomas characterized by

2. 24-h UFC (urinary free cortisol):

3. Low dose DST (dexamethasone suppression test): administration of 1mg dexamethasone

Plasma ACTH measurement: allows differentiation between ACTH-dependent from

Causes: mostly caused by AUTOIMMUNE ADRENALITIS 90% of cases, characterized destruction of

ACTH measurement: becomes useful to identify the likely etiology:

ACTH-stimulation test: IV administration of 250mcg tetracosactrin (ACTH analogue) + plasma

Additional laboratory findings in PAI:

AI Complication → adrenal crisis:

○ PARAGANGLIOMA (15-20%): extra-adrenal chromaffin-cell tumors of the sympathetic

Symptoms are not so specific → may be shared by different conditions (hyperthyroidism,

Symptoms: NO specific SIGNS of primary hyperaldosteronism.

Clinical manifestations: occur due to a

Pathogenesis: involves genetic susceptibility + environmental factors.

Clinical manifestations: polyuria, polydipsia (impairment of renal glucose reabsorption), unexplained

Pathophysiology: new model of development of type 2 DM, includes at least 8 fact

Hyperglycemic hyperosmolar syndrome: majorly in T2DM, where extreme polyuria and

Macrovascular and microvascular complications: in both, due to increased protein and

● Peripheral nervous system:

Symptoms: related to dehydration → extreme thirst (polydipsia + polyuria), fatigue, dizziness,

Hyponatremia: common in hospitalised patients, several causes:

Classification: direct/indirect evaluation of plasma osmolarity. Indirect evaluation: formula with

Clinical manifestations: symptomatic variable degree neurological manifestations

Treatment: depends on type and duration of hyponatremia, severity of symptoms:

PTH-DEPENDENT HYPERCALCEMIA: characterized by increased PTH, which can be due to:

1. PRIMARY HYPERPARATHYROIDISM: characterized by excess PTH production by

2. SECONDARY HYPERPARATHYROIDISM: where excess PTH can be caused by:

3. TERTIARY HYPERPARATHYROIDISM: where excess PTH is due to a long history of

4. VARIANT FORMS of PRIMARY HYPERPARATHYROIDISM: which are benign and cause no

PTH-INDEPENDENT HYPERCALCEMIA: increase in calcium which is independent from PTH

1. MALIGNANT TUMORS: cause hypercalcemia via:

2. GRANULOMATOUS DISORDERS: TBC and sarcoidosis → increase VitD activation →

● PTH measurement: to discriminate PTH-dependent and independent hypercalcemia.

Other biochemical parameters suggestive of primary hyperparathyroidism:

● Long-term: in PTH-dependent hypercalcemia, with normalized/non-severe hypercalcemia:

1. PRIMARY HYPERPARATHYROIDISM: characterized by excess PTH production by

2. SECONDARY HYPERPARATHYROIDISM: where excess PTH can be caused by:

3. TERTIARY HYPERPARATHYROIDISM: where excess PTH is due to a long history of

4. VARIANT FORMS of HYPERPARATHYROIDISM: which are benign and cause no clinically

● PTH measurement: hypercalcemia + ⬆/normal PTH levels → primary hyperparathyroidism

Other biochemical parameters suggestive of primary hyperparathyroidism: