1. ACROMEGALY

2. Definition, Prevalence
= the characteristic clinical features are the consequence of chronic GH hypersecretion; the secretion of GH is autonomic, persistent and the GH’s dynamic control is abnormal
Prevalence: rare disease (3-4 cases/ )
There is no known predisposing factor ( genetic, sex)

3. Physiology of GH secretion
GHRH - SS
(-)
(-) GH
IGF-I mediated
DIRECT
IGF-I
Liver
IGF-I
Target tissues
glycemia
IGF-I = insulin-like growth factor

4. Physiology of GH secretion
Growth promoting
Metabolic effects: carbohydrate, lipid, phospo-calcic, hydroelectrolytic metabolisms
Most of the deleterious effects of chronic GH hypersecretion are caused by its stimulation of excessive amounts of IGF-1. The growth-promoting effects of IGF-1 (DNA, RNA, and protein synthesis) lead to characteristic proliferation of bone, cartilage and soft tissues and ↑ in size of other organs to produce the classic clinical manifestations of acromegaly. The insulin resistance and carbohydrate intolerance seen in acromegaly appear to be direct effects of GH and not due to IGF-1 excess. GH has also direct effects on lipid, phospho-calcic, hydroelectrolytic metabolisms→ lipolysis, hypercalciuria, ↑ renal tubular resorption of phosphate , Na and water resorption

5. Clinical ad pathogenetical forms of GH excess
Clinical features of GH hypersecretion depend on the age at the onset of pathological lesion :
The onset of chronic GH excess in childhood and adolescence (! Prior fusion of the epiphyses)= GIGANTISM
! Most of these patients have associated hypogonadism, which delays epiphysial closure, and the combination of IGF-1 excess and hypogonadism leads to a striking acceleration of linear growth.
The onset Of GH hypersecretion in adulthood
(after the fusion of the epiphysis of long bones, linear growth does not occur )
= ACROMEGALIE, characterized by local overgrowth of bone, particularly of the skull and mandible

6. Etiology
1. GH- SECRETING PITUITARY ADENOMA OR MIXT GH-PRL SECRETING PITUITARY ADENOMA - >95-99% of cases
2.MEN (Multiple endocrine neoplasia) TYPE I ( Wermer SDR)
GH-secreting oituitary adenoma
Primary hyperparathyroidism
Pancreatic tumors ( gastrinomas, islet cell tumors..)
3. PARANEOPLASTIC SECRETION OF GH-like/GHRH-like substances
lung tumors, pancreatic tumors, carcinoids

7. Clinical features The characteristic clinical manifestation=
ACROFACIAL DYSMORFISM (DISFIGUREMENT)
Bone and cartilage changes affect chiefly the face and skull: thickening of the calvarium, ↑ size of the frontal sinuses→ proeminence of the supraorbital ridges; enlargement of the nose; downward and forward growth of the mandible→ prognatism, jaw malocclusion and overbite and widely spaced teeth; soft tissue growth also contributes to the facial appearance, with coarsening of the features and facial and infraorbital puffiness; macroglossia; large lips; sonorous deepening voice occurs in association with laryngeal hypertrophy and enlarged paranasal sinuses.
The hands and the feet are predominantly affected by skeletal hypertrophy and soft tissue growth ; they are large, thickened and bulky, with blunt, spade-like fingers and toes
→ ↑ in ring, glove, hat and shoe size
SOFT TISSUE CHANGES: thickening of the skin, with increased oilines and sweating; acne, sebaceous cysts, and fibromata mollusca ( skin tags and papillomas); acanthosis nigricans of the axillae and neck; hypertrichosis in women

8. Clinical features ARTICULAR AND NEURAL MANIFESTATIONS
Bone and cartilage overgrowth → arthralgias and in long-standing cases to degenerative arthritis of the spine, hips and knees; spinal involvement : osteophytosis, disc space widening, and ↑ AP vertebral length →dorsal kyphosis; osteophytes commonly occur at the phalangeal tufts and over the anterior aspects of spinal vertebrae; = acromegalic arthropathy
Neural enlargement and wrist tissue swelling →CARPAL TUNNEL SDR (← painful median nerve compression)→ acroparesthesias; proximal myopathy → myalgias, cramps
RESPIRTORY MANIFESTATION
- prognatism, thick lips, macroglosia, and hypertrophied nasal structures may obstruct airways; tracheal intubation may be difficult; both central respiratory depression and airway obstruction lead to paroxysmal daytime sleep ( narcolepsy), sleep apnea, and habitual excessive snoring

9. Clinical features GENERALIZED VISCEROMEGALY
Cardiomegaly
Hepatosplenomegaly
Nefromegaly
Megacolon (! Adenomatous colonic polyps → ↑ risk for colon cancer)
thyromegaly
CARDIOVASCULAR MANIFESTATIONS
Hypertension-in 25% of patients;
Acromegalic cardiomiopathy ← left ventricular hypertrophy, which is followed by cardiac cavities enlargement and cardiac failure may occur;
cardiac enlargement may be secondary to -hypertension
-atherosclerotic disease
-acromegalic cardiomiopathy
! Cardiovasculare disease accounts for 60% of deaths in patients with acromegaly
ENDOCRINE MANIFESTATIONS
Diffuse or nodular goiter
Galactorrhea/ gynecomastia (mixt adenoma)
Diabetes mellitus
Features of pituitary tumors: hypopituitarism +/_ local mass effect

10. Other clinical features
Renal calculi
Systemic manifestation
Lethargy or fatigue
Weight gain
Hyperhidrosis
Heat intolerance

11. Diagnosis in acromegaly
A. LABORATORY FINDINGS
1. GH
-A. Basal determinations
GH – levels vary according to age (VN =1-5 ng/ml)
!however, single, random measurements are not entirely reliable, because GH secretion vary with the time of the day, is episodic in acromegaly and because other conditions may  GH secretion
Factors affecting GH secretion
 – exercise, sleep, stress (physical or psychologic, ex. Venous puncture ), hypoglycemia
 – postprandial hyperglycemia, elevated free fatty acids
B. Dynamic tests
Glucose suppression test – 75 g oral glucose with GH determinations at 0’, 30’ and 60’
Suppression with oral glucose is the simplest and most specific dynamic test for acromegaly; in healthy subjects OGTT – GH at 60’< 2 ng/ml (<1 ng/ml-new criteria!!!); the lack of response establishes the diagnosis
2. IGF-I ( IGF-1 results must be interpreted according to the patient’s age and sex!)
3. PRL
Test pituitary function ( hypopituitarism?) FSH, LH, estradiol/testosterone, TSH/FT4, ACTH/cortisol( the assessment of the anterior pituitary gland function)

12. Diagnosis in acromegaly
B. IMAGING STUDIES AND PERIMETRY (VISUAL FIELDS), ACUITY
Lateral plain film of the skull ( focused on the sella turcica)
a.sella turcica abnormalities common to the pituitary tumoral syndrom
b. abnormalities specific to GH hypersecretion
MRI/CT scan- of pituitary fossa
Radiographs of the hand:  soft tissue bulk
‘’arrowhead ‘’ tufting of the distal phalanges
 width of intra-articular cartilages
cystic changes of the carpal bone
Radiographs of the feet show similar changes and there is  thicckness of the heel pad (normal <22 mm)
C. THYROID AND ABDOMINAL ULTRASONOGRAPHY (→ VISCEROMGALY)
D. COLONOSCOPY – polyp/ colon cancer
E. OTHERS
Calcium and phosphorus metabolism
serum phosphorus,calciuria,  AF
Carbohydrate metabolism – ITG (impaired glucose tolerance)/DM
ECG si ecocardiography - LVH/global, ventricular enlargement (cardiomegaly); allows evaluation for systolic (EF) or diastolic ventricular impairment (heart failure)

13. COMMON Radiologic Signs→ Pyuitary Tumoral Sdr
Radiologic Signs SPECIFIC TO ACROMEGALY:
Thickening of the calvarium
Enlargement of the frontal and maxillary sinuses
Prognatism
Hypertrophy of the anterior clinoids= “acromegalic beak “ SS
Lateral plain film of the skull

14. Diagnosis
Radiograph of the hand

15. Treatment Surgical treatment 2. Radiotherapy THERAPEUTICAL METHODS
transsfenoidal selective adenoma removal is the procedure of choice
craniotomy is necessary in the rare patients in whom the major suprasellar and lateral extension precludes the transsphenoidal approach
The current guidelines for remission: fasting GH of 1 ng/ml or less
glucose-supressed GH<=1 ng/ml
normal level of IGF-1
! Patients with persistent GH hypersecretion after surgery should receive medical treatment. Radiation therapy should be reserved for those patients with inadequate response to surgery and medical therapy.
Radiotherapy
conventional radiotherapy- because of prolonged delay in achieving reduction in GH levels and the appreciable incidence of hypopituitarism, is in general reserved for patients with persistent GH secretion following surgery and medical treatment
gamma knife radiosurgery -used for tumors confined to the sella (70% remission rate at 2 years following therapy is reported in some limited series)

16. Treatment 3. Medical treatment
A.SPECIFIC TREATMENT = Inhibitors of GH secretion
a Somatostatin analogs
 GH secretion and  (shrink) the tumor
OCTREOTIDE (SANDOSTATIN) 3x g/day s.c.
LANREOTIDE (SOMATULINE) 30mg /2 WEEKS
OCTREOTIDE RETARD (SANDOSTATIN LAR) 10, 20, 40 mg/month i.m.
= has become the therapy of choice for those with residual GH hypersecretion following surgery
- may be used as primary therapy to patients who refuse surgery or with whom the risks of surgery or anesthesia are unacceptable
- SE: gallstones, gastrointestinal
b GH receptor antagonist
PEGVISOMANT-for patients who failed therapy with surgery and SS analogs
c DOPA agonists
GH + PRL mixt tumors
GH-secreting pituitary tumor
BROMOCRIPTINA >=20 mg/day; CABERGOLINA
B. REPLACEMENT TREATMENT FOR HYPOPITUITARISM

17. HYPERPROLACTINEMIA

18. Etiology PATHOLOGIC 1. Prolactinomas ( tumoral secretion of PRL)
PRL is secreted from the anterior pituitary and release is inhibited by dopamine produced in the HPT
PATHOLOGIC
1. Prolactinomas ( tumoral secretion of PRL)
2. Pituitary stalk compression/ hypotalamic lesions→ local dopamine levels ( “disinhibition”) : head trauma , suprasellar surgery, infiltrative disease (sarcoidosis…), craniopharyngima
Systemic diseases
Hypothyroidism
CRF
Sever liver disease
PCOS
PHARMACOLOGIC
-Dopamine antgonists (phenothiazines, haloperidol, risperidone, metoclopramide), estrogen, cimetidine, ranitidine eg.
PHYSIOLOGIC
-Pregnancy, nursing, exercise, sleep, stree (hypoglycemia)…

19. Clinical features In women
Galactorrhea : spontaneous/ induced , permanent/ intermittent
Menstrual disorders
primary/secondary amenorrhea
oligomenorrhea
Infertility; estrogen deficiency symptoms : ↓ vaginal lubrication, osteopenia, irritability
↓ libido, weight gain, hirsutism
In men : the usual manifestations are those of hypogonadism
Erectile dysfunction
gynecomastia
galatorrhea – exceptional
infertility
↓ libido= the initial symptom
+/- tumoral pituitary syndrome manifestations ( features of a pituitary mass )

20. Diagnosis 1. HORMONE EVALUATION
PRL – normal: women<20 ng/ml; men<12ng/ml
FSH N, LH N/, E2 (levels-characteristic to follicular phase), Pg 
TSH, liver and kidney function to rule out hypothyroidism, liver and renal failure; pregnancy test
! There is a general correlation between the PRL elevation and the size of the pituitary adenoma
2. IMAGING STUDIES ( Radiograph of sella turcica, MRI/CT scan)
3. PERIMETRY

21.  PRL levels si  tumoral size
Treatment of hyperPRL
Medical treatment = DOPAMINE AGONISTS
= The treatment of choice (in prolactinomas and “disinhibition” hyperPRL)
 PRL levels si  tumoral size
BROMOCRIPTINE (BROCRIPTINA, PARLODEL) 2,5 mg/tb
the dosage: 5-30 mg/day in divided doses
CABERGOLINE (DOSTINEX) 0,5 mg/tb, ½--2tb/zi twice/week ( has a better side-effect profile; it is as effective as bromocriptine in ↓ macroadenoma size and is more effective in ↓ PRL levels)
SE: dizziness, postural hypotension, nausea, vomiting
Surgical treatment
In macroprolactinomas with visual symptoms
Medical therapy failure from drug intolerance or resistance
Radiotherapy- for patients with PRL-secreting macroadenomas who have persistent hyperPRL and who have not responded to attempts to control their pituitary adenomas with surgery and dopamine agonists (→prevents further tumor expansion)

22. PITUITARY INSUFFICIENCY

23. = manifested by diminished or absent secretion of one or more pituitary hormones
The classic course of progressive hypopituitarism is:
Impairment of GH and gonadotropin secretion
TSH deficiency
ACTH deficiency
PRL deficiency

24. Etiology of pituitary failure
A. HYPOTHALAMIC DISORDERS ( deficiency of HPT stimulatory factors normally acting on the pituitary)
B. PITUITARY DISORDERS
1.INVASIVE : large pituitary adenoma, craniopharyngioma, meningioma, metastasis
2. INFARCTION:
- ischemic pituitary necrosis: SHEEHAN sdr,
- spontaneous hemorrhagic infarction of a pituitary tumor (pituitary apoplexy)
3. Infiltration – lymphoma, leukaemia, histiocytosis X, hemochromatosis hpt/hpf, sarcoidosis
4. Infectious – tuberculosis, siphilis, mycotic infections,
5.Immunologic – lymphocytic hypophysitis- occuring most often during pregnancy or postportaum period
6. INJURY : severe head trauma
7. Iatrogenic – both surgical and radiation to the pituitary gland may compromise its function
8. Inherited – Kallman sdr (isolated defect in GnRH secretion + maldevelopment of the olfactory center with hyposmia or anosmia
9. IDIOPATHIC

25. SHEEHAN SYNDROM
Pathogenesis= ischemic pituitary necrosis following postpartum hemorrhage and vascular collapse; hypotension + vasospasm of the hypophysial arteries→ compromise arterial perfusion of the ant pituitary; during pregnancy, the pituitary gland may be more sensitive to hypoxemia because of its increased metabolic needs or more susceptible to vasoconstrictive influences because of the hyperestrogenic state.
1. FAILURE TO LACTATE AFTER PARTURITION = the initial clinical features
2. GONADOTROPIN deficiency
Secondary amenorrhea
Loss of axillae and pubic hair
Breast atrophy
Decreased vaginal lubrication (dyspareunia)
Uterine atrophy
3. THYROTROPIN deficiency – insidious onset
fatigue, apathy
Non-pitting edema (eg eyelids, hands, feet)
Cold intolerance, dry, pale skin
diurnal sleepiness
constipation
bradycardia
mentall dullness
hoarseness

26. SHEEHAN SYNDROME 5. GH deficiency
4. CORTICOTROPHIN deficiency ( “white” Addison )
Weakness, ! Depigmentation and ↓ tanning ( ← ACTH insufficiency)
Arterial hypotension
Hypoglycemia
Gastrointestinal symptoms :nausea, vomiting
5. GH deficiency
Fatigue, muscular hypotrophy, dry wrinkly skin, increased fat mass (especially abdominal and visceral), atherosclerosis
exercise ability↓, ↓sense of well-being, ↓ cardiac output, hyperlipidemia, insulin resistance
Osteoporosis
In MEN - Gonadotropin deficiency
Erectile dysfunction and ↓libido
Loss of pubic and body hair
Testis and prostate atrophy DI
Galactorrhea
In hypotalamic form

27. Diagnosis in pituitary insufficiency
HORMONAL EVALUATION
a. BASAL DETERMINATION OF EACH ANTERIOR PITUITARY HORMONE COUPLED TO TARGET GLAND SECRETION

28. b. STIMULATION TESTS
Provocative endocrine testing may be employed to confirm the diagnosis and to assess the extent of hypofunction.
● utility : in partial/ mild pituitary insufficiency
● assessed with hypotalamic hormones (“liberine”)
─ for TSH secretory reserve →TRH test
─ for LH and FSH secretory reserves →GnRH test ( use synthetic GnRH (gonadorelin))
─ for ACTH reserve : short Synacthen test provides sufficient information concerning ACTH deficiency: do plasma cortisol before and 30’ after Synacthen 250 µg IV or IM; exclude CSRI if plasma cortisol at 30’ >20 µg/dl (550 nmol/l)
─ for GH and ACTH secretory reserve : Insulin hypoglycemia test : the test involves giving insulin IV (0,1-0,2 unit/kg )and assessing its effect on GH and cortisol; Glucose must fall <40mg/dl and the patient should become symptomatic for adequate stimulation; Normal values are: GH : 60’ after insulin adm >10ng/ml and a peak cortisol : 30’,60’ >=550nmol/l

29. Diagnosis in pituitary insufficiency
ETIOLOGYC INVESTIGATIONS
Accurate neuroradiologic assessment of the hypotalamus and pituitary and neuro-ophtalmologic evaluation are essential in confirming the existence and defining the extent of hypotalamic-pituitary lesion
Sella turcica radiograph
MRI
Perimetry, ophthalmoscopy

30. Treatment of pituitary insufficiency
A. HORMONAL REPLACEMENT TREATMENT
THERAPEUTICAL PRINCIPLES
 The correction of the pituitary hormone deficits should be started conversely to their classic course of onset
 Treatment for ACTH and TSH deficits are for life
It is managed with the hormones of target gland (exception: GH deficiency)
1.ACTH deficiency –must include glucocorticoid support; mineralocorticoid therapy is not usually required
HIDROCORTISONE (20-30MG/day) or PREDNISONE 5mg/tb (5-7,5 mg/day orally) in 2-3 divided doses
2.TSH deficiency
Levothyroxine g/zi, (! The adrenal disorder should be treated first, because thyroid hormone replacement may aggravate even partial adrenal insufficiency)
Response to therapy : fT4

31. Treatment of pituitary insufficiency
3. FSH, LH deficiency
In women – estrogen and progesterone replacement is essential (→ withdrawal bleeding )
ETINILESTRADIOL g/day or TRANSDERMAL ESTRADIOL g/day :on days-5-25 a c.m. cycled with a progestin compound MEDROXIPROGESTERON 5-10 mg, daily during the last 10 days (on days:16-25) of estrogen therapy each month .
In men
TESTOSTERONE ENANTHAT or CYPIONAT im 200mg every 2 weeks; TESTOSTERONE UNDECANOAT (NEBIDO) 1000mg every 3 months
Transdermal testosterone patches: daily application
TESTOSTERONE GEL (ANDROGEL) 50mg daily
Restoring the fertility implies ovulation induction (clomiphene citrat or pulsatle subcutaneous injections of GnRH in gonadal failure of hypotalamic origin, combined treatment with FSH and LH in those with intrinsic pituitary failure) or spermatogenesis induction (the combined use of hCG and FSH or pulsatile GnRH infusion pumps)
B. ETIOLOGIC TREATMENT
surgery/ radiotherapy

32. PITUITARY DEFICIENCY IN CHIDREN (GH deficit-Pituitary “dwarfism”)
ETIOLOGY
a. GHRH deficit: idiopathic, tumors
b. GH deficit : dysplasia, trauma, surgery, or tumor of the pituitary gland, gene defect with impaired GH biosynthesis
c. IGF-I deficit (Laron’ s dwarfism )= GH receptor defect →↑GH and ↓IGF-1
FEATURES
Short stature→ dwarfism : 1,10-1,20 m
Immature facial appearance, obesity, hypoglycemia
Immature high-pitched voice
Delay in skeletal maturation;± microphallus
Mentally: normal
If gonadotrop deficiency is also present → microphallus, cryptorchidism, sexual infantilism (delayed puberty or absent puberty)
If TSH deficiency is also present → features of secondary hypothyroidism
If ACTH deficiency is also present → hypoglycemia is usually more severe (→seizures)

33. PITUITARY DEFICIENCY IN CHIDREN (GH deficit-Pituitary “dwarfism”)
DIAGNOSIS OF GH deficiency
basal values of (↓GH,↓ IGF-I) ; but diagnosis of GH deficiency rests upon demonstration of an inadequate rise of serum GH after provocative stimuli (eg inability of GH to rise above 10 ng/ml after hypoglycemia induced by IV insulin)
Radiographs of the left hand and wrist ( bone age)→ delayed bone age advancement
investigations→ etiology
DIFERENTIAL DIAGNOSIS
1. ENDOCRINE DWARFISM
True precocious puberty
Cushing’s syndrome
Hypothyroidism
pseudohypoparathyroidsm, disorders of vit D metabolism
DM, DI UNTRETED
2. NONENDOCRINE DWARFISM
Achondroplasia, Turner’s srd, Prader-Willi sdr
Chronic diseases: cardiac, pulmonary, renal, gastrointestinal disorders

34. PITUITARY DEFICIENCY IN CHIDREN (GH deficit-pituitary “dwarfism”)
TREATMENT
Treatment of GH deficiency= a replacement therapy with human GH produced by recombinant DNA technology
-!!! Precedes the sexual hormone replacement therapy ( gonadal steroid replacement may advance bone age and lead to epiphysial fusion and a decrease in ultimate stature !!!
- Sexual hormone replacement may be started after the target height is reached
Human biosynthetic somatropin (natural sequence GH)(SOMATROPIN, NORDITROPIN)
0,1-0,3 mg/kg/week