PITUITARY FAILURE

HYPOPITUITARISM

DEFINITION

Hipopituitarism is a syndrome produced by complete or partial deficiency of one or more pituitary hormones

The disease develops and insidiously exception be those cases in which hypopituitarism develops during post partum period. The clinical pictures is correlated with etiology of the disease

Hipopituitarism may be primary disease due to disfunction or /and distruction of pituitary gland and secondary, due to the absence of hypothalamic stimulation of the pituitary gland

ETHIOLOGY of HYPOPITUITARISM

The 9 I1. Invasive – is produced by diseases, usually

tumorswhich destroy the pituitary. - Large pituitary tumors destroy the pituitary directly or

by compression of pituitary stalk which produces secondary hypopituitarism

- Chraniophariongiomul produces compressive effects on the hypothalamus and reduces secretion of releasing hormones , it may produces injuries of pituitary stalk or directly destroys the pituitary

- Other CNS tumors may indice hypopituitarism by mass effects over hypothalamic-pituitary system

CHRANIOPHARINGIOMA

ETIOLOGY of HYPOPITUITARISM

The 9 I2. Pituitary infarct – Sheehan syndrome ( first case was published in

1937It results from pituitary infarct of the pituitary due to ischemia during an

important post partum hemorrhage followed by collapse or due to an intravascular coagulation syndrome

Pituitary is more vulnerable to ischemia during post partum period due to its increase in volume due to multiplication of prolactine-secreting cells and and sometimes its vascularity does not increase un the same measure.

32 % of women with severe post partum bleeding develpt a certain degree of post partum hypopituitarism

The pituitary has enough reserves and hypopituitarism develops after 80 % of the gland is destroyed.

Pituitary apoplexy develops during infarct of large tumors with immediately hypopituitarism

ETIOLOGY of HYPOPITUITARISM

The 9 I2. Pituitary infarction – sindromul Sheehan ( first case

published:1937Conditions which lead to pituitary infarction - Large surgery on open hearth, with prolonged hypoxia

urată- Diabetes mellitus associated microangiopathy - During and after radiotherapy for pituitary tumors- Subclinical or silent which determines reduction of

tumroal secretion. (ex. reduction of GH)

Infarct of the pituitary followed by fibrosis

ETIOLOGY of HYPOPITUITARISM

The 9 I3. Pituitary infiltrative diseases- Sarcoidosis infiltrates the hypothalamus and produces secondary

pituitary failure. Sarcoidotic granuloma may destroy the entire hypothalamic-pituitary system with increase in volume of this area and visual field problems similar to those produced by pituitary tumors

- Hemochromatosis: produces hypopituitarism on gonadotropic line and gonadal failure due to gonadal infiltration

- Histiocytosis Langherhans: the infiltration of multiple organs with well differentiated histiocytes may affect the pituitary. This infiltration affects mostly posterior pituitary and the hypothalamus with diabetes insipidus and secondary pituitary failure.

IRM of pituitary infiltrated by histiocytosis

Histicytosis granuloma of the pituitary

Pituitary PET in a patient with histiocytosis and hypopituitarism

ETIOLOGY of HYPOPITUITARISM

The 9 I

4. Injuries – trauma

Cranial trauma during fractures of the base of the skull with section of the pituitary stalk by dura mater and disruption of relatioship between hypothalamus and pituitary;

In childeren with cranial trauma and closed hematoma followed by growth failure.

ETIOLOGY of HYPOPITUITARISM

The 9 I5. ImmunologicalAutoimmune hypophisitis develops during post partum

period and may be diagnosed as post partum pituitary failure

The disease develops slowly and may be associated with other autoimmune diseases such as adrenal failure, premature ovarian failure or autoimmune testicular failure

Pituitary imaging in MRI or CT shows empty sella in post partyum pituitary failure and increased volume of the pituitary in autoimmune hypophisitis due to lymphocytic infiltration of the gland

MRI– autoimmune hypophysitis

MRI – autommune hypophisitis

Lymphocytic infiltration on the pituitary

ETIOLOGY of HYPOPITUITARISM

The 9 I

6. Iatrogenic- The most frequent cause of iatrogenic pituitary failure in surgery

for pituitary or hypothalamic tumors- Pituitary irradiation for CNS tumors in children or for leukemia

may result in hypopituitarism and growth failure- Pituitary irradiation in adult patients with 4500-5000 cGy results in

pituitary failure in 50-60 % of cases- Heavy particles irradiation of the pituitary produces

hypopituitarism in 2-50 % of cases

ETIOLOGY of HYPOPITUITARISM

The 9 I

7. Infectious: tuberculosis , mycosis,

8. Idiopatic1. Isolated of multiple pituitary hormone defficiency

2. Genetic: 1. autosomal recesive or x- linked

2. As part of other genetic syndromes such as Prader Willi syndrome or septo-optic dysplasia

ETIOLOGY of HYPOPITUITARISM

The 9 I9. Isolated

a. Isolated GH deficiency in children may be sporadic or familail and results in growth failure which becomes obvios after 2 years, It may olso appear in emotionally-deprived children, in those with psychological trauma, or physical abused. b. Isolated ACTH may be produce by pituitary failure to synthesize ACTH of due to absence of hypothalamic stimulation. It results in secondary adrenal failure with weakness, hypotension and pale skin

ETIOLOGY of HYPOPITUITARISM

The 9 I9. Isolated

c. Isolated gonadotropin deficiency: most fewquent form is produced by isolated Gn-RH (LH-RH) which may be associated with anosmia (loss of sense of smell) (Kallman’ syndrome) usually in Xp22.3 mutation or isolated. It may be associated with anabillity to recognize colors or deafness.

d. isolated TSH deficiency may be determined by TRH deficiency or chronic kidney failure

e. Isolated prolactine deficiency occurs in autoimmune hypophystis but in most cases prolactine deficiency is a part of multiple pituitary pituitary hormone deficiency

f. Mutiple pituitary hormone deficiency may occur in severe developmental problems of the pituitary due to abnormalities of genes which encodes transcription factors which regulates pituitary development such as PIT-1 and PROP-1

Clinical signs and symptoms of pituitary failure

Clinical signs and symptoms of pituitary hormones:

GH deficiency: growth failure in children and less evident in adult patients:

- Hypoglicaemia, - Decreased lean body mass in increased fat body mass with

increased risk for atherosclerosis- Reduced muscle strength- Weakness- Decreased quality of life

Clinical signs and symptoms of pituitary failure

TSH deficiency- Cold intolerance - Slow thinking and memory troubles- Cold, dry skin- Discrete skin infiltration due to mucopolysacharides accumulation- Bradicardia- Slow muscle reactions

Isolated TSH deficiency

Clinical signs and symptoms of pituitary failure

ACTH deficiency:- Produces adrenal failure with:- Physical, psychological and sexual weakness- Arterial hypotension to shock and colaps- Inability to mobilize cortisole reserves during stress - Pale skin- Loss of sexual hair in axilarry and pubic areas especially

in women whom sexual hair is dependent of adrenal androgens

- Hypoglicaemia aggravated by GH deficiency- In ACTH deficiency there are no signs and symptoms of

aldosteone deficiency and its metabolic consequnces

Clinical signs and symptoms of pituitary failure

Gonadotropin deficiency ( primary or secondary to Gn-RH deficiency

In men:- Decreased sexual desire and sexual function - Testicular atrophy and infertility with azoospermia- Sexual hair loss (beard pubic and axilary hair)

In women: - Secondary (or) primary amenorrhea - Genital atrophy and loss of sexual desire- Sexual hair loss

Severe sexual hair loss and pale skin in a patient with pituitary failure

Panhypopituitarism due to chraniofaringioma

Clinical signs and symptoms of pituitary failure

To the aforementioned signs and symptoms may appear signes depending of the disease which produces the pituitary failure:

- Headache - Narrowing of the visual field in pituitary tumors

Clinical signs and symptoms of pituitary failure

Sheehan’ syndrome:It is a pure form of pituitary failure that occurs in postpartum period

and is recognized in most cases after years of evolution:- Loss of lactation in post partum period- Secondary amenorrhea - Loss of sexual hair in tge following 6 month after pituitary necrosis- Weakness which is physical, psychological and sexual (loss of

sexual desire)- Loss of interest in family and professional life - Anemia- Slow speech, ideas and reactions- Premature ageing

Premature ageing due to Sheehan’s syndrome

MRA in Sheehan’s syndrome

Pituitary coma:It occurs in the following conditions:- Stress exposure- Sedatives - Cold exposure- The occurrence of a disease which needs defending machanisms

dependent of the adrenal function

- Forms:- Hypoglicemic- Hypertermic

Assessment of hypopituitarism

Usual assessment:a. Determination of hormones produced by glands

normally stimulated by pituitary: fT4, cortisole, testosterone, estradiol.

b. Pituitary glands are stimulated with specific tropic hormon and respond confirming that their hypofunction is due to loss of pituitary stimulation :

• ACTH test – if cortisole incrases: pituitary failure• TSH test – if fT4 increases: pituitary failure• LH test: if estradiol or testosterone increase : pituitary

failure

Assessment of hypopituitarism

Ft4 cortisole testosterone estradiolA

TSH ACTH FSH şi LH

Administration in the same injection TRH, CRH şi Gn-RH

TSH, ACTH, FSh şi LH do not increase

TSH, ACTH, FSH şi LH increase

Pituitary failure Hypothalamic failure or interruption of connections between hypothalamus and pituitary

Treatment of hypopituitarismPRINCIPLES

• The usual treatment uses hormones of peripheral glands which are not stimulated by the pituitary

• At the beginning of the treatment the hormones are introduced in the following order: – Cortisole– Thyroxine– Gonadal hormones

Pituitary hormones are used in the following situations: - Induction of fertility in both sexes – Recently GH treatment was introduced in the adult patients, to

improve quality of life, but this is not absolutely needed.

Treatment of hypopituitarism

Dosage– Cortisole: 25 mg/day in 3 devided doses. The morning dose

dose must be the higher. In case of stressful situations cortisole dosage must be increased 4 fold until the stress is terminated.

– Thyroxine – 100 μg/day in one morning dose– Gonadal hormones:

• Men: Testosterone enanthate: 250 mg. monthly or 1000 mg testosterone undecanoate every 3 month, or 25 mg testosterone gel/day (skin application)

• Women: estro-progestitives or Estradiol 1mg /day for 21 days in a month with synthetic progestative in the last 10 days of 21 days of each cycle

Gh DEFICIENCY IN CHILDREN

IT RESULTS IN GROWTH DEFICIENCY. IN CONGENITAL FORMS GROWTH DEFICIENCY APPEARS AS OBVIOUS AFTER THE SECOND YEAR OF LIFE AND IN ACQUIRED FORMS, FROM THE MOMENT IN WHICH GH DEFICIENCY APPEARS.

CAUSES OF GH DEFICIENCY:ENDOCRINE CAUSES

- GH deficiency of different causes- Abnormalities of IGF1 generation in the liver (Laron dwarfs)- Primary IGF1deficiency, pigmeys, IGF1receptor abnormalities- Psychosocial dwarfism- Hypothyroidism- Glucocorticoid excess endogenous or exogenous (iatrogenic)- Type 1 pseudo hypoparathyroidim (Gs alpha protein inactivating

mutation- Diabetes mellitus in children- Adrenal insufficiency

Severe growth failure in a child after long time administration of a potent glucocorticoid -

Dermovate

GH deficiency and hypopituitarism in children

Causes of growth failure:Non-endocrine causes

Constitutional short statureIntrauterine growh retardation IUGRSGA small for gestational

Genetic syndromes associated with growth failure Turner’s syndrome and its variantsNoonan’s syndromePrader Willi syndromeLaurence- Moon Bardet Biedl syndromeChronic diseases during childhood

malabsorbtion CKD

GH deficiency and hypopituitarism in children

Chronic diseases during childhood Hearth diseases Lung diseases Malbsorbtion Afecţiuni hepatice Kidney failure Thalasemia Connective tissue diseases Malnutrition

Genetic syndromes affecting receptivity of cartilages or bones to IGF1

Hypochondrodisplasias Achondroplasia

Turner syndrome and Noonan syndrome

Idiopatic short stature

Silver Russel syndrome

Severe malnutrition

GH deficiency and hypopituitarism in children

Congenital causes• Congenital GH deficiency and its variats• Factors affecting pituitary development: PROP1, PAUF1,

HESX1, LHX1• Median line defects• Pituitary agenesis• Isolated GH deficiency

GH deficiency and hypopituitarism in children

Acquired GH deficiency• Tumors of the hypothalamus or pituitary• Hystiocytosis X• Infections • Cranial trauma• Vascular abnormalities• Cranial iradiations• Hydrocephalus• Empty sella syndrome

GH deficiency and hypopituitarism in children

Abnormalities of IGF1 secretion • Insensivity of GH liver receptors – Laron dwarfs• Primary IGF1 deficiency• Pigmeys• IGF1 receptors deficiency• Psyhosocial dwarfism

GH deficiency and hypopituitarism in children

Evaluation of growth failure in children• Data on birth: length and weight at birth, neonatal

trauma, neonatal hypoxia, micropenis, hypoglicemia, jaudice

• Personal history: cranial trauma, cranial irradiation, CNS infections

• Chronic diseases: anemia, malabsorbtion, severe cardio-vascular diseases, chronic kidney diseases

• Familial history: height of parents and brothers, familial history of short stature, delayed puberty, consaguinity

GH deficiency and hypopituitarism in children

Physical examination. • Growth must be assessed with the same stadiometer

and if possible by the same examinator• Propportion between different segments of the

body,cranial circumference, crown-pubis vs pubic floor distance

• Small penis, undescendent testes

• Growth pattern if such data may be followed

• Screening tests: GH, IGF1, glycaemia, Creatinine and BUN, Bone age

Growth chart

Wrist radiograph for bone age

assessment

GH deficiency and hypopituitarism in children

Classic picture of a child with GHH deficiency

Physical examination. • Heigth at – 2,5 SD raported to normal hegth for age as is

showed in growth charts• Micropenis• History of cranial trauma or hypoxia at birth• Hypogliecaemia at birth or developed after growth

became slowly

GH deficiency and hypopituitarism in children

Classic picture of a child with GH deficiency

Physical examination. • Armonic short stature with normal proportion

between segments of the body• The child has a “doll appearance”• Pale skin with • Abdominal obesity• Small hands and feet • Normal psychological development

Pituitary dwarfism

Pituitary dwarfism

Pituitary dwarfism

Micropenis

GH deficiency and hypopituitarism in children

Laboratory diagnosis in pituitary failure

• Markers of GH function: IGF1, IGFBP3 are less than -2DS

• Other pituitary hormones: TSH, ACTH, LH and FSH are extremely reduced during chidhood

GH deficiency and hypopituitarism in children

Laboratory diagnosis in pituitary failure • If decreased basal Gh, stimulation tests

– Effort stimulation: if Gh increases during a standard effort there is probably not a Gh deficiency (screening non accepted in all clinics

– Hypoglicaemia: insulin stimulation test: 0.05-0.1 IU ordinary insulin is given i.v. and ghicamia and GH are assessed in blood samples every 30 min. At a hypoglicaemia of 0.40 mg./dl or less GH must increased over 10 ng/L

– Arginine stimulation test ).5 mg/kg.bw– Ghrelin stimulation test (ghrelin is a highly potent GH stimulator)– Clonidine stimulation test– At least 2 negative tests are required to prove Gh deficiency

• Test for pituitary of hypothalamic cause –GH-RH test • IGF1generation test: GH is given for 3 days and IGF1 is assessed

before anf after GH

GH deficiency and hypopituitarism in children

Diagnosis of the cause of Gh deficiency

– Sella turcica radiograph– History – MRI of hipothalamo-pituitary and brain: – Abnormalities of medial line– Hypothalamic or pituitary tumors – Empty sella or pituitary hypoplasia

GH deficiency and hypopituitarism in children

GH deficiency treatment:

Recombinant Gh• In small children : 0,016 – 0,035 mg/kg. bw/day• At puberty: 0,035– 0,050 mg/kg. bw/day

• Cortisole and thyroid hormones if multiple pituitary hormone deficiency

• Estradiol and progesterone in girls or testosterone in boys to induce puberty if an appropriate stature was obtained

GH deficiency and hypopituitarism in children

Monitoring Gh treatment

• Bone age – yearly• Thyroid function tests - every 6 month if growth rate

decreases• IGF1, IGFBP3 - very 3 -12 months• GH every 3 month• Hb A1 C every 12 month• Side effects every visit:• Dose modification: based on response: if abnormal

other causes such as malnutrition must be assessed

DEFICITUL DE GH ŞI PANHIPOPITUITARISMUL COPILULUI

Diagnosticul paraclinic nanismului hipofizar - defictului de GH

• Determinarea markerilor acţiunii GH: IGF1, IGFBP3 care sunt mai reduse cu -2DS faţă de normal

• Testul de generare a IGF1 pentru stabilirea diagnosticului diferential intre deficitul de Gh şi cel de lipsa de răspuns la GH se efectuează prin administrare de GH 3 zile şi determinarea IGF1 inainte si dupa test

• Determinarea celorlalti hormoni hipofizari: TSH, ACTH, • Determinarea cauzei hipofizare sau hipotalamice a defictului de

GH – testul la GH-RH sau GH secretagoge

DEFICITUL DE GH ŞI PANHIPOPITUITARISMUL COPILULUI

Tabloul clinc caracteristic al deficitului de GH • Nanism armonic

Depilare si depigmentare severă a unui subiect adult cu insuficienţă hipofizară

IRM in sindromul Sheehan

Fenomeul de imbătrânire prematură în sindromul Sheehan