Download A chief of endocrinology department, prof. Vlasenko MV

MINISTRY OF HEALTH PROTECTION OF UKRAINE
Vynnitsa national medical university named after M.I.Pyrogov
«CONFIRM»
on methodical meeting of
endocrinology department
A chief of endocrinology
department, prof. Vlasenko M.V.
_________________
“_31_”_august___ 2012 y
METHODOLOGICAL RECOMMENDATIONS
FOR INDEPENDENT WORK OF STUDENTS
BY PREPARATION FOR PRACTICAL CLASSES
Scientific discipline
Мodule № 1
substantial module №1
Topic
Course
Faculty
Internal medicine
Basis of Internal medicine
“Diagnostic, treatment and prophylactic basis of
main endocrinology diseases”
Topic №18: Cusing‘s syndrome and disease. Etiology,
pathogenesis,
clinics,
diagnostics,
differential
diagnosis, treatment.
4
Medical № 1
Vynnitsa – 2012
METHODOLOGICAL RECOМMENDATIONS
for the students of 4-th course of medical faculty for preparation to the practical
classes from endocrinology
1.Тopic №18: Cusing‘s syndrome and disease. Etiology, pathogenesis, clinics, diagnostics,
differential diagnosis, treatment.
2. Relevance of topic: The hypothalamic area is the integrator of vegetative and endocrine
functions. It occupies the leading part in supporting of a constancy of inner medium of an organism
- a homeostasis, and also keeping periodicity of endocrine functions. The lesion of hypothalamic
area has polymorphic character, that’s why participation of experts of various medical directions is
necessary for its identifcation. The pituitary body is bound directly to a hypothalamus. Its tropic
hormones сontrol peripheric endocrine glands’ activity. The lesion of a pituitary body also is shown
by a polymorphic symptomatology. Somatic displays of a pituitary body’s pathology are various,
variable; they have catastrophic character in case of acute development, and demand precise and
resolute actions for saving patient’s life.
Age and sex play an important role in the frequency of a given type of Cushing’s syndrome.
Adrenal carcinoma is the cause in 65 % of patients younger than 15, nonpituitary ACTH secretion
predominates in males, and 75 % of patients with pituitary – dependent Cushing’s syndrome are
females.
3. Aim of lesson:
 To learn etiology, pathogenesis, diagnostic criteria and principles of the treatment of
Cushing’s disease and syndrome and hypothalamic syndrome of pubertal period.
4. References
4.1. Main literature
1. Endocrinology. Textbook/Study Guide for the Practical Classes. Ed. By Petro M. Bodnar: Vinnytsya: Nova Knyha Publishers, 2008.-496 p.
2. Basіc & Clіnіcal Endocrіnology. Seventh edіtіon. Edіted by Francіs S. Greenspan, Davіd G.
Gardner. – Mc Grew – Hіll Companіes, USA, 2004. – 976p.
3. Harrison‘s Endocrinology. Edited J.Larry Jameson. Mc Grew – Hill, USA,2006. – 563p.
4. Endocrinology. 6th edition by Mac Hadley, Jon E. Levine Benjamin Cummings.2006. –
608p.
5. Oxford Handbook of Endocrinology and Diabetes. Edited by Helen E. Turner, John A. H.
Wass. Oxford, University press,2006. – 1005p.
4.2. Additional literature
6. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New
York: WC Graw-Hill Book, 1985. - P. 232-236. Pediatric Endocrinology. 5th edition. –
2006. – 536p.
Basic Level.
Students must know:
1. Anatomy and physiology of a hypothalamo – pituitary system.
Students should be able to:
1. Ask and examine the patient.
2. Interpret data of the laboratory and instrumental methods of examination
Students’ Independent Study Program.
You should prepare for the practical class using the existing text books and lectures. Special
attention should be paid to the following:
1. Clinic of Cushing’s disease.
2. Features of Cushing’s disease diagnostics.
3. Principles of differential diagnostics of Cushing’s syndrome from Cush-ing’s disease.
4. The basic directions of treatment of Cushing’s disease.
5. Definition of the Cushing’s syndrome.
6. Etiology, pathogenesis of Cushing’s syndrome.
7. Clinical features of Cushing’s syndrome.
8. Aboratory and instrumental findings in patients with Cushing’s syndrome.
9. Treatment patients with Cushing’s syndrome.
10. Clinical features of hypothalamic syndrome of pubertal period.
11.Treatment of patients with hypothalamic syndrome of pubertal period.
12.Clinical features of hypothalamo-hypophysial obesities.
Short content of theme
Cushing's syndrome
is a constellation of signs and symptoms caused by prolonged excessive amounts of circulating
cortisol.
The source of cortisol excess can be:
- the adrenal gland (endogenous Cushing's syndrome);
- administration of supraphysiologic doses of a glucocorticoid (exogenous Cushing's syndrome).
Endogenous Cushing's syndrome can be:
1) ACTH – dependent, caused by:
- increased pituitary ACTH secretion (it has frequently been reffered to as Cushing’s disease,
implying a partucular physiologic abnormality. Patients with Cushing’s disease may have a
basophilic adenoma of the pituitary, or a chromophobe adenoma. In some cases, no histologic
abnormality is found in the pituitary despite clear evidence of ACTH overproduction.
Microadenomas, which are difficult to visualize radiographically, are often the cause);
- nonpituitary ACTH secretion by nonendocrine tumors;
2) Non – ACTH – dependent:
- caused by cortisol secretion by benign or malignant adrenal tumors;
- micronodular or macronodular dysplasia of the adrenal (the condition occurs most commonly in
children and young adults).
THE ICENKO-CUSHING DISEASE
The Icenko-Cushing disease is a hypothalamo-hypophysial pathology, characterized with
surplusial secretion of corticotrophin and following bilateral adrenal hyperplasia with their hyper
function (hypercorticoidism).
Disease often is observed in females, in the base in 20-50 years age.
The hypercorticoidism syndrome consists of the several diseases accompanied with hyper
secretion of steroidal hormones by the adrenal cortex.
Classification of hypercorticoidism (by N.I. Makov with collaborators, 1992).
1. Endogenic hypercorticoidism.
1.1. The Icenko-Cushing disease of hypothalamo-hypophysial genesis, tumor of the pituitary
body.
1.2. The Icenko-Cussing syndrome - the adrenal tumor - corticosteroma, corticoblastoma;
juvenile dysplasia of the adrenal cortex - the disease of primary- adrenal genesis.
1.3. ACTH - ectopiraed syndrome - tumors of bronchi, pancreas, thymus gland, liver, intestine,
ovaries; secreting ACTH or corticotrophin - release hormone (corticoliberine) or the similar
substances.
2. Exogenal hypercorticoidism.
Prolonged use of synthetic corticosteroids - is an iatrogenic Icenko- Cussing syndrome.
3. Functional hypercorticoidism
3.1. Pubertat-juvenile dyspituitarism (the juvenile hypothalamic syndrome).
3.2. Hypothalamic syndrome.
3.3. Pregnancy.
3.4. Obesity.
3.5. Diabetes mellitus.
3.6. Alcoholism.
3.7. Hepatic diseases.
From this classification it becomes clear, that the Icenko- Cussing disease is led to endogenic
hypercorticoidism group.
Etiology
Etiology isn't completely defined. The predisposed factors are a craniocerebelle injuries,
concussion of the brain, encephalitises, arachnoiditises, labor and pregnancy.
In the most cases there is a basophilic hypophysial adenoma in the Icenko-Cushing disease.
Among all hypophysial adenomas, the 90% are a microadenomas and 10% - macroadenomas. Only
in some cases the hypophysial adenoma isn't diagnosed, there is only the pituitary body basophilic
cells hyperplasia, which producing corticotrophin.
Pathogenesis
On a base of the Icenko- Cussing disease is a poor neuromediatoric hypothalamic control for
corticoliberine secretion (reducing of the dofaminergic and serotoninergic activity).
As a result there is changed the circadian cycle of corticoliberine secretion and mechanism of
reverse regulation of its production. The corticoliberine production becomes constantly increased,
that causes corticotrophin by the anterior lobe of the pituitary body. This leads to adenoma or
hypophysial hyperplasia development. Corticotrophin hypersecretion causes bilateral hyperplasia of
adrenal cortex and increasing of corticosteroidal hormones secretion. So, there is developed a
hypercorticoidism, causing development of all clinic symptomatology.
Figure №19
Dysplastic obesity
Encephalopathy
Trophic dermal
impairments
Hypercorticoidi
sm
Arterial
hypertension
Myopathy
h
Secondary
Clinical manifestation
immunodeficien
cy
1.
2.
-
Symptomatic
Systemical
Sexual
diabetes mellitus
osteoporosis
function
disorders
Complains during the Icenko- Cussing disease are very typic:
change of appearance;
obesity development;
excessive total and muscular weakness;
appearance of red over extensional stripes on abdominal, thoracic, femoral skin;
dermal dryness;
hairs shedding on head;
hyperpilosis oh face and trunk;
reduced libido and potency in men;
menstrual cycle disorders in women
pains in bones of vertebral column;
sleep disorders, headaches;
thirst (if the diabetes mellitus develops).
Results of visual examination have a great diagnostic meaning.
There are the next pathognomonic signs:
dysplastic spreading of the subcutaneous fat with surpluses in region of brachial girdle, thorax,
abdomen, cervical vertebral column ("climacteric humpback "), face ("moon", round face) in
this upper and lower limbs stay relatively slim, buttocks- are plat;
-
dryness, slenderness, marbleizes of skin, impetigo of different localization;
- a red- crimson face. In female there is hyperpilosis on face (moustaches, beard), acne and
impetigo;
- sties - a wide stripes of extension with red - violet, crimson color in axillary spaces, in region of
mammary glands, femurs, lower and lateral abdominal parts;
- petechial and ecchymoses on skin of shoulders, forearms, anterior surface of cruses;
- hairs shedding on head in women and men, surplus growth of hairs in femurs, cruses region of
females;
- reducing of excessiveness of the secondary sexual characters in men;
- gynecomastia in males;
- decreasing of tomes and straight of muscles and their atrophy.
This symptomatology diagnosed during visual examination, is caused by surplus of the
glucocorticoid hormones and their catabolic effect, that is expressed in atrophy of skin and
muscles. Hypertrichosis in women in region of face, thighs and hairs shedding on a head are
caused by the androgens surplus (adrenal genesis).
3. Condition of the cardiovascular system. Glucocorticoids surplus, hypernatremia promote a
development of arterial hypertension (BP may oscillate from 150/100 until 240/160 Hg. Pr.).
After putting of blood pressure cult there are appearing a petechial. Arterial hypertension causes
a headache, vertigo, reduced vision, the left ventricle hypertrophy. Glucocorticoids surplus and
potassium deficiency came a steroid cardiopathy development, that is showed with feeble first
sound above cardiac apex, cow systolic murmur above all auscultation points. Owing to arterial
hypertony there is auscultated the accent second sound above aorta. The excessive cardiopathy
may lead to development of variety stades of blood circulation insufficiency. ECY alterations
are characterized by decreasing of the T wave amplitude, displacement of ST interval to down
from isoline in some loads.
4. State of the respiratory organs. Patients have predisposition to immunal system activity (the
secondary immunodeficiency).
5. State of the digestive system. In patient there are often observed a gingivitis, caries, chronic
gastritis with hypersecretion, it may be appeared the "steroid" ulcers of stomach and duodenum.
In the excessive disease from it is possibly the enlargement of liver and changing of its
functional activity.
6. The urinary system state. It may be developed the urolithiasis, bursting of small concrements
during resizes. Appearance of urolithiasis is caused by hypercalciemia and calciuria (owing to
dysbalance of calcium- regulated hormones in blood and osteoporosis). Because of development
of urolithiasis and secondary immunodeficiency oftenly is appearing the chronic pyelonephritis.
7. Sexual system. In women frequently there are develop a colpitis, hypoplastic uterus,
amenorrhea. On men there are a gynecomastia, change of consistantion and volume of testicles,
prostate, development of impotency. These changes are caused by hypercorticoidism, higher
level of hydrocarbon in blood, in females - increasing of androgens level, in males - estrogens
level increasing and reducing of the testosterone producing.
8. Osteoarticulat system. The basic characteric sign of the osteoarticular system affection is a
steroid osteoporosis. First all there is alliterated the vertebral column, that manifestoes with
pains, pathologic fractures, reducing of growth. Also there are a typical pain and in offer bones
and articules.
Result of the laboratory examinations
1. Total blood count - increasing of hemoglobin, erithrocytosis, leukocytosis advantagly (owing to
the segmented neutrophils increasing), lymphopenia, eosinopenia, stab deviation to the left, a
higher ESR.
2. Analysis of the urine : reaction frequently is alkaline, glucosuria, proteinuria, leukocyturia,
triplphosphaturia.
3. Biochemical blood analysis - hypokaliemia, hypernatremia, moderative hypercholesterinemia,
increasing of the common and ionisated potassium level, activity of alkaline phosphates, alanine
and asparagin aminotransferases, increasing of beta- lipoproteid concentration, triglycerids, a
higher prothrombin index, decreasing of the common protein, hyperphosphatemia.
4. Immunal blood test: reducing of the IgM and IgG level, decreasing of phagocytic activity of
neutrophils, absolute quantity of T- lymphocytes, concentration of seric and leukocytic
interferon.
5. Results of the hormones blood level test:
- the hypothalamo-hypophysial system: increasing secretion of corticoliberine, endorphins,
corticotrophin, melanocyte - stimulating hormone, prolactin, reducing of concentration in blood
the somatotrophin, gonadotrophins;
- the hypophysial - adrenal system: increasing of level in blood the corticotrophin, hydrocarbon,
corticosteron in the morning (in 79 hours) and evening (in 22 - 24 hours), that is a distortion of
circadian cycle of secretion of corticotrophin mid hydrocarbon. Contents of aldosteron may be
higher. Increasing of the excretion (per day) with urine the 17 - OCS, 17 - CS,
dehydroepiandrosteron;
- the hypophysial - gonad system: reducing of gonadotrophins testosterone levels in blood of
men, oestradiole in women and increasing of testosterone level in females blood:
- the calcium - regulating harmonies: higher level of parathormones in blood and lower of
calcitonine;
- Functional test:
"Major test" with dexamethasone: preparation is used to 2 mg in 6 hours per two days, then
is tested the urinal excretion of the independent hydrocarbon and 17-OCS per day and
comparing results with rates before probe. In the Icenko- Cussing disease excretion of the
independent hydrocarbon and 17-OCS in urine decreases in comparing with the initial on
50% and more over (the principle of the reversal connection is retained during use of
dexamethasone with days doses - 8mg; if there was used a 2mg days doses, then the
suppression is absent). In corticosteroma (the Icenko - Cussing syndrome) depression of the
surplus secretion of hydrocarbon isn't, even if there is using the 8mg of days doses of
dexamethasone (corticosteroma has an ability to autonomic hydrocarbon hypersecretion)
and the 17-OCS and independent hydrocarbon excretion doesn't decrease per day.
Test with adrenal stimulation with synasten-depo (ACTH) is used in two modifications. The
minor test is conducted so: in 8hours (morning) intramusculary is injected 250mg of
synancten and in 30 and 60 minutes is defined contains of hydrocarbon or 17-OCS in blood.
Normally and during the Icenko -Cussing disease - concentration of hydrocarbon and 17OCS in blood grouting in two and more over ones, during corticosteroma it doesn't. The
major test is conducted if there is absent reaction during the minor test. In 8 hours (in the
morning) to inject intramusculary 1mg of the synancten-depo and to discovery the contains
of hydrocarbon and 17-OCS in blood (in 1,4, 6, 8, 24 hours). During the Icenko-Cussing
disease rates growthing, but on corticosteroma they don't.
Results of instrumentally examinations
1. ECY: sign of kaliemia, the left ventricular cardial hypertrophy.
2. USE of suprarenal glands: diffuse or diffusonodular enlargement of suprarenal glands (more
over then 3 sm. over the altitude).
3. USE of kidneys abdominal organs: characters of chronic pyelonephritis, lined hepatosis,
lipomatosis of pancreas, concrements in kidneys.
4. Computed and magnific - resonant adrenal tomography: diffuse or diffusonodular adrenal
hyperplasia.
5. Radioimmual adrenal scanning: bilateral increasing of the iod-cholesterol absorption by
suprarenal glands.
6. Visualization of pituitary body with using of craniography, computed ad magnitic - resonant
tomography.
On craniogram there are a cranial bones and dorsum seller osteoporosis, signs of intracranial
hypertension, in 19 - 20% there is an enlargement of the dorsum seller sizes, which is owing to
hypophysial adenoma.
Using of computed and magnitic resonant tomography in 60 - 65% of patients there is a
hypophysial adenoma, who in 10% cases, locates extrasellary. MIT may be observed an
increasing intracranial pressure signs.
7. Neuroophthalmologic examination: narrowing off the visual fields (during hypophysial
adenoma presence) ; congestion phenomenon on the funds of eyes, hypertonic angiopathia.
8. Roentgenologic osteal examination: osteoporosis of bones of the axial skeleton (in 95% of
patients), of peripheries departments (in 55% of patients), aseptic necrosis of heads of the
femurs in different patients. On the excessive disease form, there are a compressive fractures of
bodies of vertebras of the thoracic and lumbar vertebral column departments.
9. Densimetry of bones discoveries an early signs of osteoporosis (look an "Osteoporosis" chapter).
Diagnosis.
There are two phases of investigation:
- confirmation of the presence or absence of Cushing’s syndrome;
- differential diagnosis of its case.
1. Exogenous Cushing's syndrome should offer no problems in diagnosis since a history of chronic
ingestion of suprapliysiologic doses of glucocorlicoids is usually present. However,
occasionally patients deny, either deliberately or because of ignorance, that they have been
taking the glucocorticoid. In this case, the diagnosis can easily be made by obtaining a blood
sample at 8 a.m. for corlisol and ACTH, both of which are characteristically low.
Glucocorlicoids suppress ACTH secretion, causing adrenal atrophy and decreased cortisol synthesis. Current radioimmunoassay techniques for measuring cortisol in plasma are very specific
and do not detect appreciable quantities of any of the synthetic glucocorticoids (prednisone,
prednisolone, dexamethasone, etc.) that the patient may be taking. Cortisol is unlikely to yield a
significant plasma level as well since the steroid has a short half-life; it disappears from blood 4
to 8 h after oral administration. If a plasma ACTH assay is not available, a plasma cortisol
determination is sufficient.
2. Single-dose dexamethasone suppression test. This is the preferred procedure for screening
patients for Cushing's syndrome. The patient ingests 1.0 mg of dexamethasone at bedtime (10 to
12 p.m.), and a blood sample for plasma cortisol is obtained the following morning at 8 a.m. In
normal patients, the steroid suppresses plasma cortisol below 5 mkg/dl. whereas patients with
Cushing's syndrome do not respond and cortisol values of greater than 20 mkg/dl are not
unusual. This procedure is simple, convenient, and inexpensive since it does not require
hospitalization. It is also very reliable, being accurate in about 95 percent of the patients. A few
patients with Cushing's syndrome will respond to 1.0 mg of dexamethasone by suppression of
plasma cortisol. If the clinical suspicion is strong, 0.5 mg of dcxamethasone should be given and
cortisol determination should again be made. This procedure takes advantage of the fact that
while normal subjects suppress equally well with 0.5 and 1.0 mg of dexathasone, the few
patients with Cushing's syndrome who suppress with 1.0 mg will not suppress with the lower
dosage.
(There are a few clnical situations in which failure of dexamethasone suppression occurs in the
absence of Cushing's syndrome. Patients who are under acute stress, particularly those with fever
and infections, and depressed individuals may not respond to dexamelhasone. Therapy with
estrogen, and occasionally phenobarbital or phenothiazines may alter the response to
dexamethasone. To some extent, all these drugs induce the hepatic microsomal enzymes that
metabolize dexamethasone, and acceleration of the hepatic metabolism of the steroid results in
insufficient plasma levels to yield A normal response. In these conditions, and in any others in
which an abnormality in the metabolism of dexamethasone is suspected, simultaneous quantitation
of the plasma dexamethasone concentration offers extremely useful information. Compared with
individuals who exhibit no abnormalities in the metabolism of the steroid, individuals with altered
hepatic metabolism have a much lower plasma concentration. Estrogens also increase the synthesis
of corticusteroid-binding globulin (CBG) by the liver. Since plasma cortisol assays measure both
bound and free cortisol, values are high in people on estrogen medication.)
3. 48 – hour low dose dexamethasone test. The results obtained with the single-dose
dexamethasone suppression test are comparable to those of the first suppression test developed
by Liddle. In this procedure, eight 0.5-mg doses of dexamethasone at 6-h intervals are given
orally; 24-h urine samples for 17-hydroxycorticosteroids (17-OHCS) excretion are collected
before and during dexamethasone administration. In normal subjects, 17-OHCS values are
below 3 mg per 24 h on the second dexamethasone day. Patients with Cushing's syndrome fail
to suppress. Not only is this test less convenient and more expensive but it may not be accurate
if incomplete urine collections have been obtained.
4. High-dose dexamethasone suppression test. After the oral administration of a single dose of 4.0
mg of dexamethasone between 10 p.m. and midnight, the measured 8 a.m. cortisole the
following morning is less than 2 mkg/dl in normal individuals. Patients with pituitary-dependent
Cushing’s syndrome demonstrate a plasma cortisol suppression of more than 50 % compared
with the baseline values. Those wiyh adrenal tumors or nonpituitary ACTH-secreting tumors do
not respond. (This procedure is comparable to the high-dose dexamethasone suppression test
developed by Liddle(2.0 mg dexamethasone every 6 h for eight doses with three 24-h urine
sample collections for 17-OHCS, one collection before and two during dexamethasone
administration). The single-dose 4.0 mg dexamethasone suppression test is simpler, less
expensive, and more convinient.
5. RADIOLOGIC DIAGNOSIS Includes X-ray examination for a pituitary tumor, and computed
tomography which is the most popular procedure for visualizing the adrenals in patients with
Cushing's syndrome.
Degrees of excessiveness of the Icenko-Cussing disease
(by N.I. Makov and others, 1992).
The easy degree - it is observed in combination with 3-4 and more over typic for hypercorticoidism
syndromes.
The middle form - almost all disease manifestations develop, but without complications from
cardiovasculary, osteal, immune systems.
The poor form (excessive degree) - is an excessive hypercorticoidism syndrome with complications:
cardiovascular decompensation, excessive osteoporosis, compressive fractures of the bodies
of the vertebras, aseptic necrosis of the heads of the femurs, coastal fractures, purulent
processes. If there is present the steroid psychosis, then is diagnosed the poor form of the
Icenko-Cussing disease.
Differential diagnosis
There is a differential diagnostics of the Icenko-Cussing disease with corticosteroma (by N.I.Makov
and others, 1992).
Differential diagnosis of the Icenko-Cussing disease with corticosteroma
Signs
Icenko-Cussing disease
Icenko-Cussing syndrome
(corticosteroma)
Hypercorticoidism
clinic Are excessive
Are excessive
manifestations
Patients a age
20 - 40 years
20 - 50 years
Melanodermy
Is poor, not frequent
Is absent
Corticotrophin blood level
Until 20 mg/ml (is very Acutely decreased or isn't
higher)
observed
Hydrocarbon blood level
Increases in 2 - 3 ones
Increases in 2 - 3 ones
The major dexamethasone test Positive
Negative
Test with corticotrophin
Positive
Negative
Radioisotopes scanning of the Increasing accumulation of Increasing
isotope
suprarenal glands
isotope in both suprarenal accumulation in one glands
glands
who is injured by tumor
Use of the suprarenal glands
Bilateral
enlargement
of A large formation in one gland
suprarenal glands
region
Computed tomography of Deformation and enlargement Supplementary formation in
suprarenal glands
of glands over the length more projection of one of the glands
over than 3 sm. and over the has a density more over than
density over - 16 H
30 H
Hypophysial
computed In 65% of cases there is a Hypophysial pathology isn't
tomography
microadenoma in the Turkish defined
saddle region
Cusing‘s disease treatment
Cushing's disease treatment programm:
1. Pathogenic treatment.
1 -1. Irradial therapy.
1-2. Surgical treatment (transsphenoidal hypophysis corticotropinoma removal,
adrenalectomia, suprarenal destruction);
1-3. Drug therapy.
1-3-1. Corticotropine secretion suppressing drugs.
1-3-2. Suprarenal steroid's biosynthesis blocking drugs.
2. Symptomatic treatment.
1. Pathogenic treatment.
Basic sight of pathogenic treatment is a hypothalamus-hypophysis disorders normalization.
1-1. Irradial therapy.
-therapy and proton hypophysis irradiation are used now for Kushing's disease treatment.
-therapy applies as a separate method of treatment and in combination with surgical and drug
therapy, -therapy - irradiation of hypothalamus-hypophysis region with apparatus in which Co60 is
the source of irradiation.
Irradiation conducts on static (AGAT-S), rotational (AGAT-R) and rotational-convergent
(IROKUS') vehicles. Fractional methods of irradiation are used in doses of 1,5 - 1,8 Gy 5 -6 times
at week, summary dose is 40-50 Gy.
-therapy effect appears in 5-6 months after end of the treatment course and maximal effect
appears in 12-24 months.
-therapy causes the remission onset in 60 % of patients, effect is more expressed in patients
under 40.
The advantage of -therapy is a small quantity of radial complications and rarely development
of after-radial hypopituitarism. The drawbacks of -therapy are the durance of treatment, slow
development of therapeutically effect, low efficiency in moderate and hard forms of Kushing's
disease treatment without use of other methods of treatment.
In last 10-15 years for Kushing's disease treatment the hypophysis irradiation by narrow
fascicle of heavy protons. The indications for proton irradiation of hypophysis are the light and
moderate grade of Cushing's disease.
A convergent method is used for patient's irradiation. Treatment lasts 20 min and lightly bears
by patients. Summary dose in Cushing's disease is 80-100 Gy.
Hypophysis proton irradiation has next advantages as compared with -therapy:
• High dose local hypophysis irradiation probability;
• Absence of surrounding tissues' lesion;
• Possibility of second hypophysis irradiation after 6 months and later;
• Efficiency of proton therapy in light and moderate forms of Kushing's disease is 80-100%;
• After-irradial panhypopituitarism is not typical and appears rarely.
The development of clinical improvement o full remission usually occurs in 6-8 months, last
time of remission onset is 2 years after the treatment.
It is possible to use proton therapy for Kushing's disease even if the not efficient the course
ofroentgenotherapy or -therapy was applicated.
But proton therapy has the next limitations:
• Proton therapy is used only for patients with Kushing's disease with endocel-lular adenoma
or hypophysis hyperplastic processes treatment;
• Seize of sella turcica ahs to be not more than 15 mm with it's round shape;
• Proton therapy is not recommended for patients with head traumas and intra-cranial
hypertension. Also with lack of breath, cough, increased nervous excitement.
In hypophysis adenoma with supra- and paracellular development, in it's diameter more than
15 mm with it's oval shape which are not corresponding to the section of the proton fascicles - the
method of the choice is y-therapy.
Irradial therapy could be used in combination with surgical and drug's treatment.
By E.I. Marova data (1991) in majority of the cases in moderate grade of Kushing's disease
the combination of surgical removal of one adrenal gland and irradial therapy of interbrain hypophysis region applies.
1-2. Surgical treatment.
7-2-7. Transsphenoidal adenomectomia.
In bond of intensive development and application of microsurgical technique the
transsphenoidal adenomectomia is the most adequate method of Kushing's disease treatment.
Usually microadenoma's and small adenoma's of hypophysis removes transsphe-noidally.
Remission observed in 60 % of the cases and by Boggan data (1988) in 90 % of the cases. After this
operation preserves other hormones secretion, the level of corticotropin normalizes in 6-12 months.
The indications to the transsphenoidal adenomectomia are light and moderate forms of
Kushing's disease.
In case of hypophysis macroadenoma the transsphenoidal adenomectomia applies.
7-2-2. Adrenalectomia.
Adrenalectomia could be homo- or bilateral.
Homolateral adrenalectomia is not the independent method of treatment, because of after
removal of one adrenal gland the remaining gland became more active functionate under the
influence of continuing corticotropin secretion. That's why the homolateral adrenalectomia has to be
combined with hypophysis irradiation.
Combination of irradial therapy with homolateral adrenalectomia is indicated in moderate
grade of Kushing's disease in case of the absence of the separate irradial therapy effect. In this case
a homolateral adrenalectomiaare carried out in year, in symptomatics of Kushing's disease
progression even in 6 months after irradial therapy.
Bilateral adrenalectomia indicated in hard forms of Kushing's disease and in hypercorticoidism complications progression. The operation fulfils in 2 stages. On first stage removes
on e adrenal gland, after the close of operation wound the second adrenal gland removes with
autotransplantation of the part of adrenal gland into the roughage to decrease the dose o
substitutional therapy (2 stages).
The life substitutional gluco- and mineralcorticoide therapy is applicated to these patients.
Nelson's syndrome develops in 38 % of patients - a syndrome of hyperpigmenta-tion, third
nerve damage and enlarging sella turcica caused by development of a pituitary tumor after
adrenalectomia.
y-therapy or proton therapy applies after total adrenalectomy for Nelson's syndrome
prevention.
Drugs blocking a corticotripin secretion are used for Nelson's syndrome (Cypro-heptadin,
Bromergocryptin, Sodium valproate, irradiate therapy and surgical remove-ment ofadenoma are
used too.
1-2-3. Destruction of adrenal glands.
Destruction of adrenal glands in Kushing's disease consist in destruction of hyper-plastic
adrenal gland (apolexia) by injection of contrast substation or ethanol. Method is used only in
complex treatment (i.e. in combination with irradial and drug therapy). The efficiency in combined
therapy is 50-60 %.
1-3. Drug therapy of Cushing's disease.
1-3-1. Corticotropin secretion suppressing drugs.
These drugs are decreasing a corticotropin level and improving a Kushing's disease clinics
could be used like the addition to the basic treatment only. It is not recommended to begin treatment
from these drugs or use them before irradial therapy because of decrease of it's efficiency.
Parlodel - dophamin receptor's agonist, adenohypophysis hormone's secretion decreases. This
drug applies in Kushing's disease treatment after the irradial therapy, adrenalectomy and in
combination with steroidogenesis blockers in adrenal glands. Parcodel is specially indicated in
increased level of blood prolactin. The drug produces in 2,5 mg tablets.
The treatment begins from 0,5-1 mg daily, gradually increases to 5-7,5 mg in 10 -15 days.
Supporting daily doses of the drug is 2,5 - 5 mg, treatment lasts 6-24 months. Drug action ceases
soon after it's abolition.
Parlodel's possible undesirable actions: nausea, decreasing of blood pressure.
Peritol - antiserotonin drug, decreases corticotropin secretion by it's action on the
serotoninergic system. The specific daily dose is 8 - 24 mg. The drug could cause the sleeplessness,
raise appetite. Usually it is used like additive drug. The drug produces in 0,004 g tablets.
GABA-ergic medicines.
GABA (y-aminobutiric acid) - a constituent of the CNS suggested as a transmitter of
inhibitary nerve impulses. GABA-ergic drugs produces the action similar to GABA action and
decrease corticotropin production.
GABA-ergic drugs has a positive action in encephalopathy and indicated for patients with
Kushing's disease after irradial therapy and in Nelson's syndrome.
Aminalon (GABA) - produces in 0,25 g tablets, applies in 3 tablets 3 times daily, treatment
course duration is 2 - 6 months.
Phenibut - a phenyl derivative of GABA, produces in 0,25 g tablets, applies in 2 tablets 3
times daily in 2 - 3 months.
7-3-2. Suprarenal steroidogenesis blockers.
Suprarenal steroidogenesis blockers devides into cortisteroid biosynthesis blockers drugs
which causes the destruction of the suprarenal cells and drugs which blocks steroids biosynthesis
only.
Chloditan - o,n - dichlorphenyldichoethane. The drug causes degeneration and atrophia of
adrenal gland's cortical secretory cells, suppresses corticosteroid secretion. The drug produces in 0,5
g tables.
Chloditan uses in combination with irradial therapy in middle glade of hypercorti-coidism
befbreor after the irradial therapy. Chloditan applies for temporary normalization of suprarenal
cortical function in patients with Cushing's disease preparation to homo- or bilateral adrenalectomy.
Besides that, chloditan applies in Cushing's syndrome in inoperable malignance. The drug applies in
2 - 4 g daily up to the suprarenal cortical function normalization than it applies as substitutive
therapy in 1 - 2 g daily in 6-12 months.
Undesirable action of chloditan: nausea, decreasing of appetite, headache, sleep-lessness.
Aminoglutatimid (Mamomit, Elipten) - corticosteroides synthesis inhibitor, mainly cortisole
inhibitor. The drug applies for the adrenalectomypredoperational preparation, also in 1 - 2 months
before irradial therapy in doses of 0,75 - 1,5 g daily in a smooth expressed middle grade cortisolism.
Suprarenal steroidogenesis blocker' treatment has to be applied under the control of liver
function and block thrombocyte contention. It is better to use hepatic protectors in steroidogenesis
blocker's treatment (Essenciale, Carsil).
2. Symptomatic hypercorticoidism treatment.
2-1. Hypotensive therapy.
For arterial hypertension treatment it is better to use Adelfan, Adelfan-Esidrex, etc. Doses of
these drugs has to be applied individually (1-3 tablets daily).
Corinfar (Niphedipine) could be used in 0,01 - 0,02 tablets 3 times daily in absence of
tachycardia.
2-2. Steroid cardiopathy and hypokaliemia treatment.
Potassium drugs, Spironolactone, anabolic steroid drugs, ryboxin, polyvitamin complexes,
phosphaden applies.
2-3. Osteoporosis treatment.
It is recommended to use calcium preparations in combination with calcitonin and vitamin 03
under the control of blood calcium, oosyn, osteoxyn, in moderate grade of osteoporosis, anabolic
steroids. Osteoporosis treatment lasts about 12-18 months.
Differential diagnosis of the Icenko - Cussing disease with juvenile hypothalamic syndrome is
described in the "Juvenile hypothalamic syndrome" chapter.
Hypothalamic syndrome of pubertal period.
Particularities.
1. Obesity is not cushingoid (not central).
2. Striae (pink and not very large).
3. Hypertension (constant or permanent).
4. Glucose intolerance.
Treatment.
1. Diet 8.
2. Parlodel (2.5 – 5 mg for 3 – 6 month).
3. Peritol (4 mg 2 times a day for 1 month).
4. Dehydration therapy (hypothiasid 50 – 100 mg/day MgSO4 25 % solution intramuscular 10 –
15 times).
5. Nonsteroid antiinflammatory drugs (indometacine).
6. Biogenic stimulators (aloe, plasmol).
7. Increasing of microcirculation of the blood in the brain (cavinton, piracetam).
8. Vitamintherapy.
9. Symptomatic therapy (hypotensive therapy).
10. Phisiotherapy.
Tests and Assignments for Self-assessment.
Multiple Choice.
Choose the correct answer/statement:
1. Where is localized pathologic process in patients with Cushing’s syndrome?
a. The anterior pituitary.
b. The posterior pituitary.
c. Hypothalamus.
d. The adrenal cortex.
e. The adrenal medulla.
2. What is the therapy of choice in patients with pituitary-dependent Cushing’s disease?
a. Transsphenoidal hypophysectomia.
b. Bilateral adrenalectomia.
c. An exploratory laparotomy.
d. Start pituitary irradiation.
e. Observe patient without treatment.
Answer: 1 – d. 2 – a.
Real-life situations to be solved:
A 43-year-old female is evaluated for hypertension and glucose intolerance of recent onset.
During the past year, she has experienced weakness, a 40 Kg weight gain, depression, easy bruising,
menstrual irregularities, head aches, and dysuria. The patient has been treated for hypertension with
hydrochlorothiazide for 5 years. She has had 3 normal pregnancies and deliveries. Physical
examination reveals an obese female with pletoric face and marked dorsocervical and
supraclavicular fat pads, facial hirsutism, acne, thin skin, pink striae on the abdomen, thin
extremities in comparison to the trunk, hypertension.What is your previous diagnosis?
Answer: Cushing’s syndrome.
As a part of a check-up obesity and pink striae on the skin were found in a 16-year-old
patient. She complaints on headache and dysmenorrhea.What is your previous diagnosis?
Answer: Hypothalamic syndrome of pubertal period
Students Practical Activities.
Work 1 : Students’ group is divided into 2 sub-groups, that work near the patients’ bed: ask the
patients on organs and systems, take anamnesis of the disease , anamnesis of life, make objective
exam. With the teacher’s presence. In the class-room they discuss the patients, learn data of
laboratory and instrumental exam. of these patients.
1.To group the symptoms into the syndromes.
2.To find out the leading syndrome and make differential diagnosis.
3.To formulate the diagnosis.
4.To make a plan of treatment.
Methodological recommendation prepared assistant, c.m.s. Chernobrova O.I.
It is discussed and confirm on endocrinology department meeting
" 31 " august 2012 y. Protocol № 1.