Cushing’s disease Cushing’s disease 70 % of cases F/B = 3 – 8 / 1 20 – 40 years Pituitary Microadenoma: bazohilic sau cromophob, secreting : ACTH,  LPH,  endorfins 80 –90 % au < 10 mm 50 % < 5 mm (less than 2 mm) Macroadenoma corticotrop cell hyperplasia CRH – secreting gangliocytoma+ corticotroph cell hyperplasia ADRENALS Hyperplasia of zona fasciculata and zona glomerularis in ACTH secreting adenoma may have 8-10 g to 12 –24 g bilateral nodular hyperplasia – may be initialy ACTH –dependent and than may become autonomous by modifying its ACTH receptors

Cushing’s syndrome ACTH –dependent Cushing’s syndrome due to ectopic ACTH secretion 15 % din total M / F = 3 / 1 40 – 60 years ACTH –dependent Cushing’s syndrome due to ectopic ACTH secretion – causes and characteristics Small cell lung carcinoma pancreatic carcinoid tumors Other carcinoids: lung, small bowel, timus, ovary Medullary thyroid carcinoma PHeochromocitom a Characteristics Very high level of SCTH, POMC DXM does not inhibit ACTH and cortisole secretion it is an important aldosterone and androgen secretion

Hyperglicaemia, insulin -resistance GLUCOCORTICODS Protein metabolism Glucose metabolism Fat metabolism Catablic effects Hyperglicaemia, insulin -resistance Lypolisis in hands and feet (a few insulin receptors) Incresed fat distribution over the trunc, thorax, face, neck, interscapular area (high concentration of insulin receptors) Effects Skin Muscles Arteries Bone Eyes CNS Growth(childhood) Obesity facial and truncal Skin atrophy (purple striae) Lost of muscle mass of the limbs Vascular fragility Osteoporosis Glaucoma Euphoria, depression and suicidal trends Inhibition of GH, IGF-1 and protein catabolism Mineralocorticoids excess Arterial hypertension Severe hypokalemia in adrenal tumors and ectopic ACTH secretind tumors ANDROGEN Excess Acne, seborhea, hirsutism, frontal balding Antigonadotropic effects: infertility, amenorrhea these effects are more obvious in adrenal tumors and ectopic ACTH secreting tumors Physiopathology of Cushing’s syndrome

Menstrual abnormalities Hypertension Muscle weakness Lumbar pains Clinical aspects Frequency % Obesity Facial pletora Hirsutism Menstrual abnormalities Hypertension Muscle weakness Lumbar pains Purple striae Acne Psychological symptoms Easy bruising Hearth failure (congenstive) Oedemas Kydney stones Headache Polyuria/polydipsia Skin pigmentation 94 84 82 76 72 58 52 40 36 22 18 16 14 10 6 CUSHING’S DISEASE AND SYNDROME – CLINICAL SIGHNS AND SYMPTOMS

Severe muscle weakness during Cushing’s syndrome

Inferior petrosal sinus catheterism

CONGENITAL ADRENAL HYPERPLASIA They are genetically produced autosomal recessive deficiencies in the steroidogensis in the adrenals with effects on prenatal and /or post natal sexual development. Steroidogeentic defects during fetal life produce cortisole deficiency followed by ACTH increase and adrenal hyperplasia. Forms: clasic – obvious at birth non-clasic – onset during puberty criptic – detectable only by specific tests Prenatal sexual development involves the differentiation of the gonads and beginning of their function, (first 2 months), internal genital organs differentiation month 2-3, external genital organs development (months 3-4) brain sexual differentiation (months 6-9). Postnatal sexual development includes gender identity and gender development, sexual morphology during puberty, sexual behavior. According with severity of steroidogenic defects, these syndromes are associated with more or less severe sexual development impairment, which may affect entire life.

During critical period of 3-4 months development of external genitalia occurs. They evolve from a common primordium called genital sinus formed of: genital tubercle, urethral folds, genital swelling. In the presence of testosterone (male sex, testosterone secretion of the testis) the genital tubercle become glans penis urethral folds become penile shaft, and genital swelling fuse on median line to form the scrotum. In normal female fetus in the absence of androgens genital tubercle becomes gland clitoris, urethral folds remain separate and form labia minora, and genital swelling also separated will form labia majora. If female fetus has an androgen excess their genitalia will develop more ore less to the male phenotype resulting in ambiguous genitalia. Depending of the severity of androgen excess this ambiguity may evolve from clitoral enlargement to more important male-like appearance. These ambiguities are classified into 5 degrees by Prader (see below). In the same time female brain may suffer androgen imprinting with gender identity and gender role abnormalities. This ambiguities are called female pseudohermphroditism: chromosomal and gonadal sex are those of a female and external genitalia are ambiguous. If male fetus has no possibilities to produce enough testosterone to produce normal virilisation of external genitalia, these will have the same ambiguities. The situation is called male pseudohermaphroditism – chromosomal and gonadal sex is that of a male but external genitalia are ambiguous. The Prader’s classification of ambiguous genitalia are presented below

Physiopathology of congenital adrenal hyperplasia: 1. Congenital enzyme deficiency involved in the cortisole synthesis occurs early during fetal life with cortisole deficiency and increased ACTH secretion that will result in adrenal hyperplasia 2. Sterodogenesis in strongly stimulated with increased production of sterodogenetic products situated before the affected enzyme and of those products that are formed within the unaffected steroidogenetic chain. 3. Steroidogenetic products situated before affected enzyme will accumulate in large concentration in fetal and child blood and will be excreted in urine allowing the diagnosis of sterodogenetic defect. 4. If sterodogenesis is unaffected in the androgen biosynthesis chain fetuses of both sexes will have increased concentration of androgens that will result in virilization female external genitalia ( female pseudo hermaphroditism) in female fetus and newborn. 5. If steroidogenesis of androgens is affected , this event will occur also in the testes and ovaries. According to the degree of androgen deficiency male genitalia will be undervirilized or will have a female aspect. – male pseudo hermaphroditism. During puberty and adulthood testosterone and oestradiol synthesis will be impaired. During childhood CAH with androgen excess will produce further virilization in females resulting a heterosexual pseudoprecoccious puberty in girls at 5-6 years (muscle development, acne, sexual hair growths, deepening of voice, absence of breast development and precocious fusion of epiphiseal growth plates with impaired final height). and isosexual psudoprecoccious puberty in boys, 5-6 years (muscle development, excessive sexual hair growth, deepening of the voice, small testes) . In CAH forms which affect testosterone synthesis puberty does not occur in both sexes. Metabolic abnormalities depend of cortisole deficiency and aldosterone deficiency or excess according to the affected enzyme

CAH treatment Lawson Wilkins European Society of Pediatric Endocrinology - Joint LWPES/ESPE CAH Working Group Consensus Statement on 21-hydroxylasis. Every newborn with ambigous genitalia must be screened for 21 hydroxilase deficiency The assessement is formed of: family history for other cases, clinical examination, adrenal ultrasound, chariotype determination by “in vitro” hibridisation, serial 17 OH progesterone determination in premature newborn. The neonatal screening for 21 Hydroxilase deficiency is made by 17 OH progesterone in blood 48-72 hours after birth. Non classical forms are detected by basal and ACTH –stimulated 17 OH progesterone after 30 minutes. Neonatal screening is necessary in both sexes to prevent further complications regarding gender identity and role. Hydrocortisone is the optimal glucocotrticoid for treatment in children. The dosage is of 25 mg/m2 : 10-15 mg/m2/day in 3 daily doses. Overdosage will result in growth problems, cushingoid features, obesity. Prednisone 2-4mg-m2/day or dexametasone 0,25-0,375 mg/m2/zi may be used at the final growth period. Minorelocorticoids: 9 alpha fluoro hydrocortisone must be given in dose of 0,05-0,300 mg/day immediately after birth and adjusted after ionograme and plasma renin concentration.

CAH treatment Surgical correction of external genitalia must be made at 2-6 months and its targets are: an appearence of external genitalia compatible with patient’s sex gender. Correction of clitoral enlargement and labial fusion must be made into the same time. Vaginal correction could be made at puberty. Decision for education of the patient according to his sex depends of his social and cultural environment. Treatment monitoring is made by dosage of 17 OH progesterone , androstendione, and plasma renin activity During stress the dose of glucocorticoids will be inceased by 2-3 times of the daily dose by rectal administration , in small children under 3 years 50 mg hydrocortisone in bolus will be followed by 25 mg per day. Children between 3-12 years will received a 50 mg bolus followed by 50 mg/day, adolescents will received 100 in bolus and then 100 mg / day. Treatment with glucocorticoid must be continued in affected males to preserve fertility and avoid the risk of development of testicular masses of adrenal tissue which may be surgically removed if not responsive to glucocorticoid suppresie therapy There were attempts for bilateral adrenalectomy in non responsive cases

Prenatal diagnosis of CAH: Prenatal diagnosis must be preceeded by parents’and proband genotyping Chorial biopsy must be made before 9 week of gestation. On biopsy specimen the genotype of the fetus is assessed . XY fetuses need no treatment of the mother. Treatment suppose the informed consent of parents. Including criteria for prenatal treatment: a proband or a first degree relative affected, acces to rapid investigations, family do not agree abortion, Treatment is made with Dexametasone: 20 g/b.w. in 3 divided doses, from the proved conception and not later than 9 weeks. Monitoring the treatment for mother’s weight, glicaemia, Hb A1c, Blood pressure, DHEA suphate and oestriol. The treatment reduces inetrsexuality in all affected female fetuses and eliminates it in 85 % of cases.