310 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs)

in food, which inhibits synthesis of thyroid of various hormones (hypothalamic releasing hor- hormones, may be also a cause of endocrine mones, hypothalamic inhibiting hormones or factors, disorder. antidiuretic hormone, and oxytocin). Hypothala- D. Iatrogenic causes. Endocrine disorders mus, therefore, has an important role in the reg- may occur as a complication of various ulation of endocrine system as well. In the hier- kinds of therapy (e.g., surgical interven- archy of endocrine glands hypothalamus has a role tion, radiotherapy, inadequate hormone of a control centre and along with hypophysis it treatment, or therapy with some non- forms a functional unit. In the consequence of its hormone drugs). organic or functional disorder, a hypothalamic syn- drome develops. In the clinical picture of this syn- E. Primary hyperplasia of endocrine gland drome only endocrine symptomatology is present, cells. As its consequence, a hyperfunc- or its endocrine symptomatology may be combi- tional endocrine syndrome develops. nated with neurovegetative symptomatology. These F. Other acquired causes. They are rather disorders are usually distinguished as: disorders of rare. They include, e.g., destruction of hypothalamic-neurohypophyseal system and disor- endocrine cells by hormone inactive neo- ders of hypothalamic-adenohypophyseal system. plasma, various kinds of vascular disorders (mostly aneurysm or hemorrhage), cyst, trauma, degenerative process, metabolic 5.3.1 Pathophysiology of hypothala- defect, and by toxic influences. mic-neurohypophyseal system 2. Genetic causes Antidiuretic hormone (ADH, vasopressin) and Relatively frequent genetic causes of endocrine oxytocin are the hormones of hypothalamic- disorders are defects of various enzymes (enzy- neurohypophyseal system. They are produced in mopathies) taking part in a hormone biosynthe- the nuclei of the front hypothalamus, i.e., in nucleus sis. The other inherent cause can be the synthe- supraopticus and in nucleus paraventricularis. They sis of a defective prohormone or hormone or the are transported to neurohypophysis via the axons of disorder of conversion of prohormone to active the cells of these nuclei, where they are stored and hormone. The existence of genetic disorder of released into the circulation when needed. Clinical cell receptors for hormones is assumed as well. symptoms of deficiency or overproduction of ADH Inborn causes of endocrine disorders can also in- are known only in human being. Disorders of oxy- clude hypoplasia or aplasia of endocrine gland as tocin secretion are unknown at present. well as chromosome anomalies concerning X or Y chromosomes (gonosomes). 5.3.1.1 Central Central diabetes insipidus (neurogenic diabetes in- sipidus, diabetes insipidus verus) is a rare disease caused by partial deficiency or total absence of ADH. The kidneys of a patient, therefore, are not able to 5.3 Pathophysiology of hypo- produce hypertonic urine and thus to prevent exces- sive loss of water from the organism. Most often it thalamic-hypophyseal sys- develops in the consequence of the damage of front tem hypothalamus, namely of nucleus supraopticus, e.g., by severe head trauma, intracranial tumors (cran- iopharyngioma, Rathke’s pouch tumor, germinoma, pinealoma, , and metastatic tu- Hypothalamus has an important integrative in- mors), cysts, inflammatory lesions, vessel lesions fluence on the function of vegetative nervous sys- (hemorrhage or aneurysm), sarcoidosis, or by sur- tem and also it is a place of various vital cen- gical intervention in the area of hypothalamus. Di- tres. It has a key role in regulation of basic bi- abetes insipidus, which is due to any organic lesion ological rhythms and it is the place of production mentioned above, is called symptomatic (secondary) 5.3. Pathophysiology of hypothalamic-hypophyseal system 311 diabetes insipidus. However, in about 45 % of cases frequently, however, urine volume is only moderately the cause of ADH deficiency is not found out. It is increased (from 3 to 6 litres per day). idiopathic diabetes insipidus. In rare instances, cen- Polyuria is the most expressive objective symp- tral diabetes insipidus may be inherited as an iso- tom, and excessive thirst is the main subjective lated defect (autosomal dominant inheritance) or as symptom. Polydipsia provides an adequate compen- a part of an autosomal recessive syndrome (Wolfram sation for large volumes of excreted water. The slight syndrome) consisting of diabetes insipidus, diabetes rise in serum osmolality, resulting from hypotonic mellitus, optic atrophy, and deafness. polyuria, stimulates thirst. Large volumes of fluid, From the point of view of etiopathogenesis pe- therefore, are imbibed, and cold drinks are preferred. ripheral diabetes insipidus (nephrogenic diabetes in- For the patient excessive thirst is hard to control, sipidus) can be also distinguished. It originates as a and due to that he often awakes throughout night. consequence of reduced sensitivity even of insensitiv- During the sleeping hours he often drinks and mic- ity of the distal tubules and mainly of the collecting turates (nycturia). Interrupted sleep may cause the ducts to ADH. It is caused by disorder or lack of cell origin of neuroasthenic syndrome. If the patient did receptors for this hormone. Peripheral diabetes in- not take adequate quantity of fluids he would de- sipidus is hypofunctional pseudoendocrinopathy.It velop severe dehydration, hypernatremia, plasma hy- may be inborn or acquired. Hereditary nephrogenic perosmolality, fever, psychic disturbances, prostra- diabetes insipidus is the disease with X chromosome- tion, collapse, and towards the end oligemic shock linked inheritance. The abnormal gene is localized and death may occur. on the long arm of this chromosome. It is trans- mitted by heterozygous women and clinically man- 5.3.1.2 Syndrome of inappropriate ADH se- ifestedinman. Acquired nephrogenic diabetes in- cretion sipidus has heterogeneous etiology. It may develop, e.g., due to chronic hyperkalemia, chronic renal in- The syndrome of inappropriate ADH secretion sufficiency, nephrocalcinosis caused by chronic hy- (Schwartz-Bartter syndrome, primary vasopressin perparathyroidism, amyloidosis, multiple myeloma, excess) is the term applied to persistent production or due to long-lasting therapy by some drugs, such as of ADH or ADH-like peptide despite body fluid hy- demeclocycline, methoxyflurane, and lithium (drug- potonicity and an expanded effective circulating vol- induced nephrogenic diabetes insipidus). ume. These peptides are syntethized and released autonomously, i.g., independently from plasma os- Pathophysiology and clinical features.Diabetes molality. There is sustained release of ADH in the insipidus refers to the passage through the body of a absence of either osmotic or nonosmotic (volume- large quantity of dilute fluid. This state of excessive mediated) stimuli. It means that simple feedback water intake (polydipsia) and hypotonic polyuria is control mechanism between plasma osmolality and due to failure of vasopressin (ADH) release in re- ADH secretion is broken (osmoreceptors of the front sponse to normal physiologic stimuli (neurogenic di- hypothalamus lost or cannot realize their control abetes insipidus) or due to inability of renal tubules function). to respond to ADH (nephrogenic diabetes insipidus). The syndrome of inappropriate ADH secretion Polyuria, excessive thirst and polydipsia are primary originates by numerous causes. Its most fre- symptoms almost invariably present in the patients. quent cause is an ectopic ADH or ADH-like pep- Characteristically, they are sudden in onset. The tide production from neoplastic tissue (small cell patient may recall the precise day or hour when bronchogenic carcinoma, pancreatic carcinoma, lym- polyuria and thirst began. phosarcoma, Hodgkin’s disease, reticulum cell sar- Urine osmolality is below that of the serum (less coma, thymoma, and carcinoma of duodenum or than 290 mmol/kg). A urine specific gravity is from bladder), and from lung cells during inflamma- 1.001 to 1.005. Persistent hypostenuria is the hall- tory pulmonary diseases (tuberculosis, lung abscess, mark of diabetes insipidus. In severe cases, the urine pneumonias, empyema). In other cases the cause of is pale color, and the volume may be immense (up this syndrome is organic disorder of hypothalamic- to 16–24 litres per day), requiring micturition every neurohypophyseal system (skull fracture, subdural 30 to 60 minutes through the day and night. More or subarachnoid hematoma, cerebral vascular trom- 312 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs) bosis, encephalitis, and purulent meningitis). Such serum osmolality and dilutive hyponatremia.Hy- cases are, however, very rare. ponatremia is paradoxically connected with in- The symptoms of permanent inadequate antidi- creased excretion of natrium by urine (inadequate uresis may also result from drug therapy.Some natriuresis), so that urine osmolality is higher drugs, such as vincristine, cyclophosphamide, clofi- than plasma osmolality. In paradoxically increased brate, carbamazepine, metoclopramide, and beta- glomerular filtration rate, decreased aldosterone se- adrenergic agents, may stimulate excessive ADH re- cretion and increased production of atrial natriuretic lease from the neurohypophyseal system, and other peptide take part. These changes arise secondary to drugs, as chlorpropamide and nonsteroidal anti- increased plasma volume. inflammatory agents, potentiate the antidiuretic ac- tion of ADH, what is the result of increase of sensi- 5.3.2 Pathophysiology of hypothala- bility of renal tubule receptors to ADH. In this sec- mic-adenohypophyseal system ond case it is, however, hyperfunctional pseudoen- docrinopathy. From the knowledge regarding the role of the hy- The persistent production of ADH or ADH-like pothalamus in regulating func- substances, or increased sensibility of renal tubules tion, it seems likely that some diseases may actually to ADH result in excessive retaining ingested wa- be due to disordered function of the hypothalamus ter and in the excretion of concentrated urine. The rather than at the level of the adenohypophysis or the excretion of concentrated urine (urine osmolality is target endocrine gland. Therefore, from the point usually over 300 mmol/kg) exists despite of subnor- of view of pathophysiology of hypotalamic-pituitary mal plasma osmolality and decreased plasma sodium system we distinguished between disorders of hy- concentration. In a patient, the dilution of extra- pothalamus with endocrine symptomatology and en- cellular fluid develops. And so, the ADH excess is docrine disorders of adenohypophysis. considered to be inappropriate because it occurs in the presence of plasma hypoosmolality. Water re- 5.3.2.1 Disorders of hypothalamus with en- tention and consequent dilution of body fluids lead docrine symptomatology to hypotonic hyperhydration. The patient becomes Some of the disorders of hypothalamus are connected hyponatremic, modestly volume expanded, and his with endocrine symptomatology because hypotha- body weight increases by 5 to 10 %. In spite of hy- lamus regulates secretion of adenohypophyseal hor- pervolemia there is no hypertension and no edema mones by means of releasing hormones (liberins) and (for an unknown reason). by means of inhibiting hormones or factors (statins). Because of permanently increased concentration of As hypothalamus has a key role also in regulating of ADH in circulating blood superfluous water cannot basic biological rhythms, it takes part in regulation be excreted by the kidneys as free water (without of the onset of puberty and also of sexual functions, solutes). Therefore, by urine only water linked to endocrine disordes may also originate as the conse- solutes excretes because ADH has no influence upon quence of changes of these regulatory functions of this water. In the clinical picture, therefore, symp- the hypothalamus. Hypothalamus is sexually differ- toms of water intoxication and symptoms of blood entiated and regulates the sexual functions through dilution are dominant. its own biorhythm, which regulates secretion of go- Symptoms of water intoxication. The extracellu- nadotropins (it is a monophasic type of their secre- lar hypotonicity, mainly if it is severe or acute at the tion in a man, but cyclical one in a woman). Hy- onset, leads to intracellular edema. Therefore, espe- pothalamus plays an important role in regulation of cially severe symptoms of cerebral edema and fol- lactation, too, which starts by combination of nerve lowing intracranial hypertension occur and become and several hormonal influences. predominant. They include nausea, vomiting, rest- From the point of view of etiology the disor- lessness, irritability, , desorientation, confu- ders of hypothalamus with endocrine symptomatol- sion, letargy, somnolence, convulsions, and coma. ogy can be divided to functional or organic,andin- Symptoms of blood dilution (hemodilution). The born or acquired. Most often they are manifested by most expressive of these symptoms are reduced various disorders of hypothalamic-pituitary-gonadal 5.3. Pathophysiology of hypothalamic-hypophyseal system 313 axis. As for intracranial organic disorders the fol- stantly involved in each other’s problems. Although lowing are most frequent: tumors (craniopharyn- family structure appears to play a primary role in gioma, pinealoma, glioma, meningioma, metastases), the genesis of anorexia nervosa, cultural issues and cyst, traumatic lesions, lesions after neurosurgical occupation are also important. interventions, inflammatory lesions (meningitis, en- How the psychodynamic dysfunction is translated cephalitis, tuberculosis), sarcoidosis, and vascular le- into biological disease remains a mystery. Numer- sions (ischemic lesions, local hemorrhage, aneurysm) ous neurotransmitter systems may play a mediating in hypothalamus or in its neighbouring region. role. The role of hypothalamus, in which centres of controlling food intake are situated, and which is the A. Anorexia nervosa (anorexia mentalis) place of gonadotropins releasing and inhibiting hor- Anorexia nervosa is an eating disorder of young, pre- mones as well, in the pathogenesis of anorexia ner- viously healthy women who develop a paralyzing fear vosa is not known. We do not know whether there of becoming fat. The driving force is the pursuit of is a certain predispose weakening of hypothalamic thinness, all other aspects of life being secondary. function (its latent dysfunction), or it is only a dys- This aim is achived primarily by radical restriction function of various internal interactions of the hy- of caloric intake, the end result being emaciation. pothalamus evoked by the influence of external fac- Anorexia nervosa is psychoneurosis,orrarelyitis tors. purposeful reaction. It is connected with remark- The patients permanently refuse food intake able lowering of body weight and with amenorrhea. (drastically restrict their own food intake) and later This disease occurs primarily in young women (to they gradually lose appetite. Sporadic dieting usu- 25 years of age), mainly in neurotic adolescent girls. ally begins about a year before the start of the proper The most common time appearance is 4 to 5 years disease,oftenatthepointatwhichmaximalweight after menarche. was reached. If social circumstances require them In etiology of this disease the combination of psy- to eat more than usual, vomiting is induced as soon choemotional factors and behavioral characteristics as possible, often in a public restroom. As noted, of the patient (e.g., mentally unbalanced personality, episodic binge eating may occur and also followed anxiety, depression, perfectionism, inadequate ambi- by emesis. The patient secretly self-induces vomit- tion) takes place. The onset of the desease frequently ing most often by putting her fingers or tooth-brush follows a stressful event in the subject’s life. The fre- into the pharynx, later she vomits reflexively. She quent cause of its origin is psychical stress, bad rela- may use enormous doses of laxatives. In the conse- tion between mother and daughter, improper family quence of this considerable loss of body weight may relations, inappropriate and frequent comments on be seen, as a rule from 15 to 25 % of the original body body weight or body proportions. It may be also weight. In spite of significant cachexia the patient is an abnormal reaction to adolescence (a refusal of the often physically and psychically overactive,andritu- role of adult woman and at the same time demand alized excercise is common. Despite profound weight for independence from the family influence and par- loss patients deny hunger, thinness or fatigue. ent’s authority). Its prevalence is 0.5–1.5 per 100 000 From the point of view of anorexia inhabitants (involves approximately 1 % of girls and nervosa is manifested by secondary amenorrhea young women between ages 14 and 25, generally from (menstruation was present for a variable time and middle to upper socio-economic families). then ceases), which is one of its basic and an almost The causes and pathogenesis of anorexia nervosa constant symptoms. It is now generally accepted are not fully explained. It has been argued that hy- that the primary cause of its origin is localized in pothalamic dysfunction is primary, but the evidence the hypothalamus and operates via impaired (insufi- appears persuasive that the disorder is a psychiatric cient) secretion of luteinizing hormone-releasing hor- one. The psychodynamic mechanisms are not clear mone (LHRH deficiency), also termed gonadotropin- and in fact may not be fixed. Whatever other fac- releasing hormone (GnRH). Functional gonadotropic tors operate in the genesis of the disease, the fami- is formed. Why the hypothalamus lies tend to be ”enmeshed”: they are blurred gener- is unable to release LHRH is not known, although ational boundaries so parents and children are con- abnormalities in norepinephrine and dopamine me- 314 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs) tabolism in the central nervous system (CNS) have B. Hypothalamic amenorrhea been postulated. All types of amenorrhea of the hypothalamic origin, with the exception of amenorrhea at anorexia ner- In the origin of secondary amenorrhea psychoe- vosa, rank among this titlle. They are secondary motive stress and significant body weight loss take amenorrheas caused by various functional or organic part. About one half of patients with anorexia ner- disorders of the hypothalamus, which result in disor- vosa develop amenorrhea consominant with the onset der of LHRH secretion. of dieting. However, up to 40 % of girls cease menses Among functional amenorrheas of the hypothala- before significant body weight loss. The latter one mic origin are included: points out to the fact that amenorrhea origin is likely not to be only a simple consequence of malnutrition. • psychogenic amenorrhea after psychic stress; Presumably, early amenorrhea is due to emotional stress antedating clinical illness. • amenorrhea at false pregnancy (pseudocyesis, pseudogravidity); Plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogens are • exercise-induced amenorrhea, which is associ- low. However, there is no evidence for primary dys- ated with intense and prolonged physical exer- function of the or gonads. Plasma tion, such as long-distance running, swimming, level is usually normal. Female secondary gymnastic, and ballet dancing. The patients are sexual characteristics (breasts and pubic hair) are always below ideal body weight and have low properly developed. stores of fat. The mass of fat may be a regula- tor of LHRH secretion; In the consequence of long-lasting malnutrition anemia, hypoproteinemia and hypokalemia may be • long-term starvation; developed. Anemia and occasional pancytopenia ap- • pear to be due to hypocellularity (hypoplasia) of the amenorrhea at hyperprolactinemia mediated by bone marrow. Later peripheral edema (mainly on decreased hypothalamic dopamine (prolactin- extremities) may apear. It is due to a failure to inhibiting factor – PIF). Hyperprolactinemia mobilize the normal extracellular fluid volume pro- causes amenorrhea by inhibition of LHRH re- portionately with body mass during starvation and lease. probably due to hypoalbuminemia. If vomiting is Organic causes of hypothalamic amenorrhea can severe and prolonged, hypochloremic alkalosis may be head trauma, tumor, inflammatory lesion and occur. Basal metabolic rate is decreased. vascular lesion in the hypothalamic gonadotropin- By clinical examination bradycardia (persistent regulating area. resting pulse of 60 beats per minute or less), arterial hypotension (less than 70 mmHg systolic), bradyp- C. Hypothalamic disorders of the onset of pu- nea (less than 15 breaths per min), hypothermia, and berty cold intolerance are found. These changes develop as Some functional or organic disorders of hypothala- a response of circulation to cachexia. Skin is usually mus may cause true precocious puberty or true de- pale and dry, hands and feet are cold. Anorexic pa- layed puberty. Puberty is considered precocious if tients may develop excessive vasoconstriction, and the symptoms of sexual maturity begin to apear prior Raynaud phenomenon has been noted. Hair is dry to age 8 in girls and age 10 in boys. Puberty is con- and soft. The patients often suffer from obstipation. sidered delayed if its spontaneous beginning appears Sometimes also psychical depression occurs. In the in both sexes by age 16 or older. consequence of long-term and severe malnutrition, True precocious puberty (pubertas praecox vera). various complications may develop (symptoms of vi- In girls this type of puberty has mostly functional tamin deficiency, osteoporosis and intercurrent in- origin (primary hypothalamic). The cause of the fections). If the treatment is delayed till the body precocious onset of hypothalamic regulatory mech- weight falls under 50 % of patient ideal weight, this anisms (precocious secretion of LHRH), and thus disease may end lethally. Mortality is about 4–7 %. also precocious gonadotropic hormone secretion from 5.3. Pathophysiology of hypothalamic-hypophyseal system 315 adenohypophysis is not known (idiopathic true pre- Besides obesity, Fr¨oehlich syndrome is charac- cocious puberty). In boys true precocious puberty terized by symptoms of hypogonadotropic hypog- occurs more rarely than in girls. Its cause is usu- onadism (sexual infantilism) and by shortness of ally organic, especially hypothalamic tumors (e.g., stature. Gonadotropic deficiency is due to LHRH hamartoma) or tumor of epiphysis (pinealoma), in- deficiency, which is caused by damage of crucial area ternal hydrocephalus or consequences of encephalitis. of hypothalamus that regulates synthesis and secre- True delayed puberty (pubertas tarda vera). In tion of gonadotropins. In the patient some of the boys and girls it is mostly constitutional deviation symptoms caused by compression of the hypotha- with familiar occurence in some members of the fam- lamus and its surrounding structures may occur, ily (constitutional delayed puberty). By the age of e.g., epileptic attacks, visual field defects, diabetes 18 it is usually spontaneously settled. It is caused by insipidus, and headache. This compression is sec- the delayed onset of hypothalamic mechanism (de- ondary to expansive growing tumor. layed secretion of LHRH, and thus by delayed go- nadotropic hormone secretion of adenohypophysis. E. Laurence-Moon-Biedl-Bardet syndrome This syndrome is an inborn disease with autosomal D. Adipose genital dystrophy (Babinski-Fr¨oe– recessive type inheritance. It is characterized by a hlich syndrome) set of various abnormalities and anomalies, e.g., hy- Adipose genital dystrophy is a rare organic disor- pogonadotropic hypogonadism (delayed puberty and der of hypothalamus affecting mostly boys. It is sexual infantilism), obesity, short stature, retinitis characterized by obesity and by symptoms of hypog- pigmentosa (visual impairments or blindness), men- onadotropic hypogonadism. This disorder may be tal retardation, polydactyly, syndactyly, and defec- caused by a wide variety of organic lesions of the hy- tive hearing even deafness. The basis of the origin of pothalamus, such as tumors, various degenerative or the above mentioned abnormalities is diencephalo- inflammatory changes in hypothalamus and its sur- reticular degeneration. Hypogonadism and obesity rounding area. are thought to be hypothalamic in origin. Besides this organically conditioned, so called true adipose genital dystrophy, also so called benign type F. Kallmann’s syndrome (dysplasia olfacto-ge- of adipose genital dystrophy (false adipose genital nitalis) dystrophy, Fr¨oehlich like type), which occurs more This disease is a rather rare form of isolated hypog- often, is known. It develops in boys in the con- onadotropic hypogonadism with familiar occurence, sequence of wrong regimen (inadequate alimentary which is connected with impaired sense of smell and and locomotor habits, inappropriate upbringing in a sometimes also with other anomalies. It is a het- family, i.e., overeating, mainly sweets, drinking sweet erogenous genetic disorder with X-linked as well as juices and limonades, not sufficient physical activ- autosomal inheritance with incomplete exppressivity ity, and too much protective influence from mother). (it affects boys). The course of puberty in boys with benign type of Kallmann’s syndrome is characterized by congen- adipose genital dystrophy is usually spontaneously ital hyposmia or anosmia (central type), due to the settled when regimen becomes normal. On the other olfactory bulb disorder (hypoplasia or agenesis). The hand, in organically conditioned true adipose genital olfactory bulbs (rhinencephalon) and the hypothala- dystrophy the disorder of the hypothalamus is per- mic defects originate in embryonic life and are due manent without surgical therapy and its prognosis is to failure of olfactory receptor neurons and LHRH- serious. synthetizing neurons migration from the olfactory Dominant symptom of Fr¨oehlich syndrome is obe- placode, where they arise, into the brain, along with sity with typical deposition of fat mostly in the sub- the olfactory and other nerves. Hypogonadotropic cutaneous tissue of abdomen, thighs, and gluteal hypogonadism is due to LHRH deficiency. In this area. Fat can deposit also in the subcutaneous tissue disorder, the young males fail to undergo puberty. of chest and suras. The presence of obesity implies They enter adulthood with an eunuchoid habitus and that there is damage of the food-regulating region of other evidences of androgen lack, such as immature the hypothalamus. genitalia (hypogenitalism), cryptorchidism (the size 316 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs) of testes correlates with the extent of the LHRH de- thy), which may sometimes be similar to those at ficiency), gynecomastia, imperfect or absence of fa- schizophrenia. cial hair, feminine body contour, and the absence of If hypothalamic hyperprolactinemia occurs in libido and potentia. Plasma FSH, LH, and testos- young women, who are not and have never been preg- terone levels are below the normal male range. The nant, it is defined as Ahumad-de Castill syndrome secretion of other pituitary hormones is normal. Less (some authors call it Forbers-Albright syndrome). commonly, these patients may have other congenital anomalies, such as cleft lip, cleft palate, deafness, and daltonism. H. Other hypothalamic disorders of adenohy- pophyseal regulation As a result of primary disorder of production of hy- G. Hypothalamic hyperprolactinemia pothalamic releasing or inhibiting hormones or fac- Hyperprolactinemia of hypothalamic origin is rare. tors is the origin of increased or decreased function It arises in the consequence of decreased secretion of adenohypophysis. This disorder is defined as cen- of prolactin inhibiting factor (dopamine) or due to tral hypothalamic hyperpituitarism or central hy- disorder of its transport from hypothalamus to ade- pothalamic hypopituitarism. However, if the disor- nohypophysis. Weakening or absence of inhibitory der of adenohypophyseal hormone production is not influence of dopamine causes permanent production the result of the change of production of hypotha- of prolactin by anterior lobe of pituitary. lamic releasing or inhibiting hormones, but it is the Hypothalamic hyperprolactinemia has many cau- result of a pathologic process which affects adeno- ses. It can be organic lesion in the hypothalamic hypophysis primarily, central adenohypophyseal hy- area or pituitary stalk (e.g., by tumor, inflammatory perpituitarism or central adenohypophyseal hypopi- or vascular lesions, trauma, sarcoidosis, and by stalk tuitarism develops. It is rather difficult to make the section) or hypothalamic disorder caused by long- difference between the primary hypothalamic disor- lasting drug therapy (phenothiazines, thioxanthenes, ders and the primary adenohypophyseal disorders. metoclopramide, methyldopa, reserpine, cymetidine, Primary hypothalamic and primary adenohy- estrogens, oral contraceptives, and opiates). This pophyseal endocrinopathies may be manifested ei- disease may be also of unknown origin (an idiopathic ther by the disorder of production of one type form of the disease). of adenohypophyseal hormones (isolated hyperpitu- In women hypothalamic hyperprolactinemia is itarism or hypopituitarism), or by the disorder of manifested by non-puerperal galactorrhea (contin- production of several types of adenohypophyseal hor- ual milk secretion in non-puerperal period), by sec- mones (combinated hyperpituitarism or hypopitu- ondary amenorrhea, and by atrophy of gonads and itarism). These combinated primary hypothalamic uterus. The set of these symptoms is called hyper- endocrinopathies are, however, very rare. prolactinemic syndrome. From the point of view of The cause of primary hypothalamic endocrine dis- endocrinology the clinical picture is the same as at order may be hypothalamic adenoma overproducing adenohypophyseal hyperprolactinemia. And, there- one of the releasing hormones, hormonally nonfunc- fore, its detailed description is given in the chapter tioning tumors situated in the surroundings of hy- on endocrine disorders of adenohypophysis. pothalamus, or a disorder of production of one of the If hypothalamic hyperprolactinemia develops post releasing or inhibiting hormones of unknown etiology partum, it is so-called Chiari-Frommel syndrome.It (idiopathic primary hypothalamic endocrinopathy). is defined as galactorrhea and amenorrhea persist- Following four types of isolated primary hypotha- ing more than 6 months post partum in the absence lamic endocrine disorders may be distinguished: of nursing and without an evident pituitary tumor. Some of these patients probably harbor occult mi- 1. Isolated TRH deficiency. Undersecretion of croadenomas stimulated by the hormones of preg- thyrotropin-releasing hormone (TRH, thyroliberin) nancy that may later become radiologically evident. leads to decreased thyroid-stimulating hormone In about half, menses eventually return over a period (TSH, thyrotropine) synthesis by the pituitary and of months or years. This syndrome is often connected thus gives rise to the syndrome of hypothalamic hy- with psychotic symptoms (depression and somnipa- pothyroidism, also called tertiary hypothyroidism. 5.3. Pathophysiology of hypothalamic-hypophyseal system 317

Its clinical picture is usually milder than the one of of -releasing hormone (GHRH, so- primary hypothyroidism. matoliberin, somatocrinin) in childhood causes hy- pothalamic hyposomatotropic nanism.GHRHdefi- 2. Isolated CRH oversecretion. Corticotropin- ciency, resulting in the growth hormone (GH, soma- releasing hormone (CRH, corticoliberin) causes the totropin) deficiency, appears in most patients with origin of tertiary hyperglucocorticoidism (Icenko- idiopathic dwarfism. The hypothalamic hyposoma- Cushing’s disease). Some authors assume that CRH totropic nanism is sometimes combined with hy- overproduction is probably the cause of Nelson’s syn- pothalamic hypogonadotropic hypogonadism. The drome development, which appears in about 10–15 % clinical picture of hypothalamic hyposomatotropic patients with hyperglucocorticoidism after bilateral nanism is the same as that of adenohypophyseal hy- total adrenalectomy realized for the purpose of the posomatotropic nanism. therapy of hyperglucocorticoidism. Despite perma- Special cause of isolated GHRH deficiency ori- nent adequate substitute glucocorticoid therapy in gin may be emotional (psychosocial) deprivation patients with Nelson’s syndrome, significant ACTH of a child. It is mostly secondary to insufficient (adrenocorticotropin hormone) oversecretion hence- care of the child in a family with improper rela- forth continues and increasing skin pigmentation is tions. Decreased production of GHRH results in present. This presence of ACTH excess is caused by hyperplasia or adenoma (Nelson’s adenoma) of corti- STH deficiency. Compared to his/her age group, the child’s growth is, therefore, retarded (psychoso- cotrope cells of the pituitary gland. This hyperplasia cial dwarfism). If the psychosocial relations in the or even adenoma develops secondary to permanent family improve, the child begins to grow evidently stimulation of corticotrope cells by CRH. Production faster and the growth retardation is gradually com- of CRH in hypothalamus is primarily autonomously increased, and, therefore, feedback inhibition of its pensated. secretion by exogenic cortisol, administrated for the 4. Isolated GHRH oversecretion.Itisnow purpose of substitute therapy, is not realized. Some known that excess GHRH can be induced (though other authors assume that exogenic cortisol is not rarely) by neurogenic tumors of the hypothala- equivalent to endogenic cortisol, therefore, its in- mus (GHRH-secreting gangliocytomas, gliomas, and hibiting influence upon the CRH secretion via feed- hamartomas), or by non-endocrine neoplastic tis- back mechanism is weaker. This fact is considered sue (most common by GHRH-secreting tumors of to be the cause of continual CRH overproduction, as the bronchi or pancreas, by medullary thyroid carci- well as Nelson’s syndrome. noma, and by carcinoids of small intestine and thy- Nelson’s adenomas sometimes grow more rapidly, mus). In the latter case it is ectopic GHRH produc- are frequently invasive, and some of them even bor- tion. der malignity (agressive ACTH-secreting pituitary GHRH hypersecretion causes somatotropes hyper- adenomas). In the clinical picture progressive skin plasia and thus excessive secretion of growth hor- hyperpigmentation (similar to that of Addison’s dis- mone. GH overproduction, dependent on the pa- ease) dominate. ACTH and MSH (melanocyte- cient’s age in which arises, causes or stimulating hormone) partake in its origin. Stimu- of hypothalamic origin. But, they lative ACTH effect on skin melanocytes equals 1/3 are clinically indistinguishable from gigantism and of MSH effect. It is due to the fact that the sequence acromegaly of primarily adenohypophyseal origin. of the first seven amino acids of ACTH and MSH molecules is identical. Besides that, the cells of the adenohypophyseal adenoma along with ACTH over- 5.3.2.2 Endocrine disorders of adenohy- secretion usually also overproduce MSH. pophysis In the clinical picture visual disturbances and vi- From the point of view of intensity of hormonal ac- sual field defects (due to compression of the optic tivity endocrine disorders of adenohypophysis can be chiasm by adenoma), severe headache, respectively classified as adenohypophyseal hyperfunction (hy- further symptoms of intracranial hypertension often perpituitarism) and adenohypophyseal hypofunction apear. (hypopituitarism). They are clinically manifested by 3. Isolated GHRH deficiency. Undersecretion endocrinological symptoms, which are conditioned 318 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs) by the change of secretion of one or more adeno- Permanent GH overproduction gives rise to the ex- hypophyseal hormones. If they are caused by the tu- cess growth of long bones of extremities, and thereby mors in the area of Turkish saddle (sella turcica), in accelerated and excessive linear body growth in the the clinical picture local symptoms, resulting from youth, as well as overgrowth of soft tissues. After compression of intrasellar or parasellar structures puberty, respectively in adulthood it results in ex- which is secondary to expansive tumor growth, may cessive growth of acral parts of the body. occur. Manifestation of these local symptoms de- Dependent on the age in which GH oversecre- pends on speed, range, and direction of tumor ex- tion occurs two clinical forms of somatotropic hy- pansion. perpituitarism originate. They are gigantism and acromegaly. I. Adenohypophyseal hyperfunctions Gigantism – It is the clinical form of soma- Hypersecretion of one or more hormones of the ante- totropic hyperpituitarism characterized by statural rior lobe of the pituitary gland is called as hyperpitu- overgrowth (giant’s growth), eunuchoid proportions itarism. There is usually isolated hyperpituitarism resulting from lower concentrations of gonadotropins which originates by oversecretion of only one ade- and thereby lower concentrations of sex hormones. nohypophyseal hormone (monohormonal hyperpitu- Atrophy of gonadotrope cells caused by expansive itarism). Isolated somatotropin oversecretion, iso- growth of somatotrope adenoma partakes in de- lated prolactin oversecretion, and isolated adreno- creased secretion of gonadotropins and sex hormones. corticotropin oversecretion most often occur. Iso- If STH overproduction starts at the onset of puberty lated thyrotropin hypersecretion, and isolated go- and continues also in adulthood, epiphyseal closure nadotropin (FSH or LH) hypersecretion are very is delayed and finishes around the age of 30. There- rare. In some cases combinated hyperpituitarism, fore, by the end of 3rd decennium, besides the giant’s e.g., simultaneous hyperproductions of STH and stature also acromegalic features begin to apear and prolactin (PRL), or simultaneous hyperproductions the clinical picture of gigantoacromegaly originates. of ACTH and MSH (bihormonal hyperpituitarism), The increased GH concentration does not influence may develop. longitudinal growth of bones directly, but through A. Somatotropic hyperpituitarism the stimulation of insulin-like growth factor I (IGF I, also called somatomedin C) production in liver (its This disorder is relatively rare and mostly caused main source), kidneys, muscles, chondrocytes, and by primary acidophilic (eosinophilic) adenoma (so- may be also in other tissues. IGF I (a 70-amino acid matotrope adenoma), or less frequently by chromo- basic peptide) is the important mediator of GH ac- phobic adenoma of adenohypophysis. These adeno- tion. It stimulates deposition of chondroitin sulphate mas have autonomous STH secretion. Over 99 % of in epiphyseal cartilage of long bones, and so increases cases of somatotropic hyperpituitarism result from a chondrogenesis followed by longitudinal growth of primary pituitary adenoma. As a rule this adenoma bones. grows slowly. Whether development of somatotrope adenoma is primarily a or the result In the clinical picture of gigantism some local of hypothalamic dysregulation is unresolved. How- symptoms (secondary to compression of intracranial ever, the majority of evidences suggest that it is a structures) induced by expansive growth of adenohy- primary pituitary disease. STH overproduction may pophyseal tumor (expansive adenoma) can be also be caused also by hyperplasia of acidophilic cells (so- observed. Prognosis of the disease, especially if it matotrophs) of the anterior pituitary. It is assumed develops in the early childhood, is usually bad. If that somatotropic hyperpituitarism caused by hyper- the patients are not given a successful therapy, they plasia of somatotrophs has a hypothalamic origin. mostly die prematurely, in the first years of adult- In fact it is hypothalamic somatotropic hyperpitu- hood. However, today, gigantism has become van- itarism caused by isolated GHRH overproduction in- ishingly rare. duced by a tumor or by other organic lesion in the Acromegaly – It is a clinical form of somatotropic hypotalamic region. In rare instances ectopic GHRH hyperpituitarism characterized by enlargement of secretion has been described. Ectopic STH produc- acral parts of the body, and by overgrowth of in- tion is very rare. ner organs (generalized organomegaly). It is the en- 5.3. Pathophysiology of hypothalamic-hypophyseal system 319 largement of the acral parts that gives the name to ges thickening followed by their degenerative chan- this disease. It develops if STH overproduction be- ges. gins during adulthood, i.e., after epiphyseal growth Hypersecretion of GH induces insulin resistance plates are closed. Therefore, excessive GH produc- and glucose intolerance in about 50 % and diabetes tion does not induce exessive longitudinal growth of mellitus in about 20 % of patients. bones, but causes only widening of bones by periostal In some patients, more often in acromegalic apposition, and overgrowth of soft tissues, especially women, combination of hypersomatotropinemia and of skin, subcutis, and inner organs. hyperprolactinemia is present. The cause of this combinated endocrine disorder may be the presence In the clinical picture the enlargement of acral of somatotrophs and lactotrophs in adenohypophy- parts of the body dominates. The result of widened seal adenoma, respectively adenoma consists of bi- phalanges, and skin and subcutis thickening is grad- hormonal somatolactotrophs. Probably, in the con- ual enlargement of fingers and toes, and hands and sequence of antagonistic effect of hyperprolactinemia feet, leading to the need of larger gloves, rings, and to gonadotropin production, in men decreased libido, shoes. The increased hand and finger size may cause and impotence, gynecomastia, and galactorrhea may difficulty with performing fine task, e.g., picking up occur. In acromegalic women gonadal dysfunction a pin. Head size increases because of the increase is manifested by loss of libido, oligomenorrhea, even in both soft tissue and skull mass (the need of a secondary amenorrhea, and infertility. larger hat). The mandible enlargement is man- ifested by expressive protrusion of the lower jaw At progressive adenoma expansion some of the lo- (prognatism), and by increased spaces between the cal symptoms secondary to compression of intracra- teeth. Supraorbital ridges, and cheek bones are made nial structures may gradually appear, too. These more expressive. Physical examination demonstrates symptoms are: chronic cephalalgia usually accom- the typical facial appearance with soft tissue thick- panied by nausea and vomiting, diminished visual ening, greasiness of skin, increased breadth of the acuity, , visual field defects, sometimes even nose, enlarged ears, protruding chin, and thicken- complete blindness, symptoms resulting from nerve ing of the lips. These changes gradually lead to damage of oculomotor muscles, changes in eyeground coarsening of the facial features. In patients gen- from optic nerve compression (paleness of optic nerve eralized organomegaly is usually present, including papilla, respectively even papilloedema), parosmias, enlargement of the tongue (macroglossia), and in- epileptic attacks, and symptoms from damage of hy- ner organs (visceromegaly), mainly enlargement of pothalamic centres (disorder of body temperature heart (cardiomegaly), liver (hepatomegaly), spleen regulation, somnipathy, obesity, emaciation). In x- (splenomegaly), and kidneys (nephromegaly). La- ray film changes of size or configuration of sella tur- ryngeal hypertrophy, vocal cords thickening, and si- cica can be seen. nus enlargement result in a characteristically deep, resonant, and hollow-sounding voice. B. Prolactic hyperpituitarism The patients with acromegaly have a gradual pro- Prolactic hyperpituitarism (adenohypophyseal hy- gression of all above mentioned symptoms. Thus the perprolactinemia) is the most frequent among hy- diagnosis is often delayed for as many as 15–20 years. perpituitarism. The cause of its origin are almost al- The symptoms usually begin inconspiciously and in- ways lactotrope adenomas (), belong- sidiously, therefore, they are unnoticed until compli- ing among the most often occuring hypophyseal tu- cations develop. mors (30–40 % out of their total number). Women are affected 5–8 times more often than men. The Along with bone thickening, osteoporosis (prob- adenomas can appear at any age, however, the most ably as a result of hypogonadism) also develops. It frequently from 20 to 40 years of age. If they occur in gives rise to bone deformations. The disease is, there- children, their puberty is delayed. In women simulta- fore, associated with dorsal kyphosis or kyphosco- neous occurrence of more small adenomas (microade- liosis. Joint pain resulting from accelerated os- nomas) are prevailingly present. In men mostly one teoarthrosis may also be the presenting symptom. larger adenoma (macroadenoma) occurs, which gives The osteoarthrosis is secondary to articular cartila- rise to local symptoms from its expansive growth. 320 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs)

The cause of prolactinomas is not known. Primary disease is mostly caused by corticotrope microade- hypothalamic disorder in the sense of insufficient pro- nomas (in 90 % of patients) and by a corticotrope duction of prolactin-inhibiting factor (PIF), or dis- macroadenoma in most of the rest. Microadeno- order of its transport to adenohypophysis are con- mas and macroadenoma autonomously overproduce sidered. In unique cases prolactic hyperpituitarism ACTH resulting in hyperplasia of adrenal cortex. may arise as a result of decreased perception of lac- Therefore, the adrenal glands overproduce glucocor- totrophs to PIF. But, this disorder is associated with ticoids, mainly cortisol. The microadenomas are of- pituitary lactotroph hyperplasia. ten small (3 to 6 mm or less) and may be difficult to The clinical picture of prolactic hyperpituitarism find. is characterized especially by the symptoms of hy- Central adenohypophyseal hyperglucocorticoidism pogonadism and by galactorrhea. It is diferent in (secondary hyperglucocorticoidism) represents 90 % both sexes. of the total number of cases of central hypergluco- In women the main symptom is a disturbance of corticoidism, and the rest 10 % represents central menstruation (oligomenorrhea or secondary amenor- hypothalamic hyperglucocorticoidism (tertiary hy- rhea) which is accompanied by infertility. Concen- perglucocorticoidism). The result of ACTH excess, trations of estrogen and progesterone in blood are de- which is common phenomenon of the both forms of creased. Galactorrhea is present in 30–80% of these the central hyperglucocorticoidism, is the origin of women and may be related to the duration of gonadal hyperplasia of adrenal cortex (mainly zona fascic- dysfunction. Women with long-standing amenorrhea ulata), and thus the origin of glucocorticoid over- are less likely to have galactorrhea, which proba- secretion with its subsequent clinical symptoms. The bly reflects prolonged estrogen deficiency. In some cause of origin of ACTH-secreting pituitary adeno- women patients (20–30 %) other features of estrogen masisnotknown. deficiency may occur, such as decreased libido, vagi- Cushing’s disease is seldom (5–10 %) caused by ec- nal dryness, dyspareumia, mastalgia, and hirsutism topic ACTH production (ectopic ACTH syndrome). and tendency to obesity may be also present. A unique possibility of ectopic CRH production is In men hyperprolactinemia is manifested by de- also admitted. Ectopic production of both these hor- crease or loss of libido, partial or complete im- mones is usually caused by malignant tumors, mostly potence, disorder of spermatogenesis (oligospermia by lung carcinoma, thymic carcinoma, duodenal car- or azoospermia), and decreased plasma testosterone cinoma, pancreatic carcinoma, thyroid medullary level, sometimes by gynecomastia, and rarely galac- carcinoma, and rarely bronchial carcinoid or neurob- torrhea. As to the fact that in men the cause lastoma. of adenohypophyseal hyperprolactinemia is mostly Cushing’s disease occurs 4 times more in women macroadenoma, in the clinical picture also local than in men, prevailingly from 25 to 45 years of age. symptoms from its expansive growth are present. Pathophysiology and clinical features of Cushing’s In both sexes the hypogonadism associated with disease (secondary hyperglucocorticoidism) are al- hyperprolactinemia appears to be due to inhibition of most the same as those of the primary hyperglucocor- hypothalamic release of LHRH by hyperprolactine- ticoidism (Cushing’s syndrome). Therefore, they are mia, resulting in decrease of LH and FSH secretion. detailed in the chapter on pathophysiology of adrenal Besides that, hyperprolactinemia decreases the ef- cortex. They differ from Cushing’s syndrome only by fect of gonadotropins at the gonad level (hypofunc- the presence of skin hyperpigmentation,whichorig- tional pseudoendocrinopathy). The damage of pitu- inates because the corticotrope adenomas, as well as itary gonadotrophs by macroadenoma compression the cells of malignant tumors with ectopic ACTH may be also considered. secretion, also produce MSH. The moderate stimu- lative effect of ACTH on skin melanocytes also par- C. Adrenocorticotropic hyperpituitarism ticipates in the origin of the skin hyperpigmentation. Adrenocorticotropic hyperpituitarism (central a- denohypophyseal hyperglucocorticoidism, Cushing’s disease) is the most frequent form of hypergluco- D. Other types of hyperpituitarism corticoidism. It represents 75 % of the total num- The occurrence of gonadotropic hyperpituitarism ber of the cases of hyperglucocorticoidism. This is unique. It is caused mainly by macroadenoma of 5.3. Pathophysiology of hypothalamic-hypophyseal system 321 gonadotrophs (gonadotropic adenoma), which over- totally absent. In about one third of cases it is an produces gonadotropins (usually FSH or FSH in con- isolated GH deficiency. However, in the rest of the junction with LH, rarely LH alone). It can be ob- patients the deficiency of GH is combinated with the served before puberty more often than in adulthood, deficiency of gonadotropins. five times more frequent in girls than in boys. In both In adults, STH deficiency is usually cryptic. Its sexes it results in true precocious puberty. Although presence in adults does not seem to be inevitable. in men LH plasma concentration is elevated, testos- But, the consequences of STH deficiency and re- terone level is often low. The reason for this subnor- placement in adults are still being explored. Phys- mal serum testosterone concentration is unclear, but iological production of GH is needed only in chil- by some authors it is attributed to secretion of bio- dren during the whole period of body growth, i.e., logically inactive gonadotropins. In postmenopausal till the epiphyseal growth plates are closed. Insu- women with macroadenomas, it may be difficult to ficient STH production in childhood or youth be- ascertain whether the increased plasma gonadotropin fore epiphyseal closure leads to impaired growth and concentration is due to normal menopause or due to short stature, respectivelly gives rise to the origin a gonadotropin-secreting adenoma. of hyposomatotropic dwarfism (pituitary dwarfism, Thyrotropic hyperpituitarism (pituitary hyper- pituitary nanism). However, it is more often a con- thyroidism, secondary hyperthyroidism) is very rare. sequence of hypothalamic GHRH deficiency than a It is caused by macroadenoma (thyrotropic ade- consequence of primary disorder of STH production noma) of thyrotrophs which overproduces TSH by pituitary somatotropes. (TSH-induced hyperthyroidism). In the patients the There are two forms of hyposomatotropic clinical symptoms of thyrotoxicosis are present, how- dwarfism: hypothalamic and pituitary. Hypothala- ever, they are usually milder than in primary (pe- mic dwarfism is usually caused by isolated STH defi- ripheral) hyperthyroidism. ciency, while pituitary dwarfism is mostly character- ized by combinated disorder, e.g., by STH deficiency II. Adenohypophyseal hypofunctions and gonadotropin deficiency. The cause of the both mentioned forms of hypo- Decreased ability of the anterior lobe of the pituitary somatotropic dwarfism can be found only in about gland to produce one or more tropic hormones is 35 % of affected children. It may be an organic dis- called hypopituitarism. Insufficient secretion of only order, e.g., tumor, cyst, aneurysm, trauma, or other one pituitary hormone (isolated hypopituitarism, pathological process endamaging the cells of compe- monohormonal hypopituitarism, monotropic hypopi- tent endocrine active tissue of hypothalamus or ade- tuitarism) occurs seldom and it is mostly STH defi- nohypophysis. In about 65 % of patients the cause ciency. Dependent on the cause, the monohormonal of GH deficiency can not be found (idiopathic hypo- hypopituitarism can be sometimes gradually changed somatotropic dwarfism). to plurihormonal hypopituitarism (combinated hy- The both forms of hyposomatotropic dwarfism are popituitarism). However, the most frequent form necessary to differ from those forms of dwarfism in of adenohypophyseal hypopituitarism is the disor- which plasma GH concentration is normal or even der manifesting insufficient secretion of all adenohy- increased. The following forms of dwarfism must be pophyseal hormones. This condition is called panhy- distinguished: popituitarism. If the adenohypophyseal hypofunc- tion orriginates as a result of the pathological process 1. Nanism caused by long-term severe nutritional of gradually destroying cells of its hormonally active insufficiency. tissue, isolated or combinated hypopituitarisms are only incipient phases of panhypopituitarism. Panhy- 2. Nanism caused by some chronic diseases, e.g., popituitarism may occur also suddenly, without the malabsorption or chronic inflammatory intestine two phases mentioned above. disease, chronic renal disease (renal nanism), se- vere congenital heart disease (cardial nanism), A. Somatotropic hypopituitarism severe pulmonary disease, and severe hemato- logical disease. In the patients with the somatotropic hypopitu- itarism STH deficiency is present or this hormone is 3. Dwarfism caused by insensitivity to GH at the 322 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs)

level of GH receptors. This disorder is due to ab- pubertal development. Plasma concentrations sent or defective GH receptors. It is also widely of STH and IGF I are usually normal. Familial known as Laron-type dwarfism, which probably short stature is a physiological variant of growth represents only one form of insensitivity to STH distance in which the velocity of bone age is nor- (familial form of short stature). Due to STH re- mal, whereas constitutional delay in growth and ceptors disorder IGF I (somatomedin C) is not adolescence is a disorder of growth and bone age produced in hepatocytes and in cells of other tempo that secondarily impairs growth distance. tissues. The serum IGF I concentration is low Of course, some children may have a combina- and does not increase in response to injection of tion of genetic short stature and constitutional human GH. Abnormalities of DNA restriction delay in growth and puberty. fragment length in some of these patients are consistent with defects in the gene encoding the Pathophysiology and clinical features of hyposo- GH receptor. matotropic dwarfism. The most expressive symptom of this disease is a disorder of body growth. Chil- 4. Constitutional delay in growth and puberty. dren with hyposomatotropic hypopituitarism are of Healthy individuals, who spontaneously enter a short stature and exhibit growth curves that devi- puberty after the age of 12 for girls and 14 ate progressively from normal. In idiopathic hypopi- for boys, have constitutional delay in growth tuitarism, growth failure may not be obvious until and adolescence. The syndrom of growth re- patients are 2 to 4 years old. In retrospect, however, tardation with delayed puberty accounts for a it is often possible to establish that growth failure high proportion of referrals for growth evalua- began in the first few months of life. The growth tion, particularly in boys. Height and bone age disorder is most evidently manifested at the onset are usually delayed by 2 to 4 years, and onset of puberty when the psychical problems from short of pubertal development is delayed by 2 years stature of the pacient may appear. or more. In the patients adrenarche and go- Retardation or precocious cessation of body nadarche occur later than in their classmates growth is the result of longitudinal bone growth dis- for years. However, the patients undergo spon- order, while epiphyseal growth plates are open for taneous puberty. longer than usual. Therefore, in the patient the slow GH secretion before the actual onset of puberty growth may be prolonged until age 30–40 years. A in these patients is suboptimal. However, their bone age retardation in relation to chronological age STH secretion and growth velocity return to (delayed skeletal maturation) is evident. Closure of normal after the onset of puberty. There is an the fontanelles and eruption of permanent teeth are interaction of IGF I and gonadotropins in the delayed. testis, and the relatively low secretion of GH The final height of hypophyseal dwarf varies from (and presumably intragonadal IGF I) may im- 120 to 150 cm. The stature is, however, usually pro- pair the gonadal response to gonadotropins. Af- portional (the patients exhibit normal body propor- fected boys seem to be more distressed by short tions). Overall look, especially facial appearance is stature than by delay in sexual development. infantile for quite a long time. On the contrary, in Final adult stature, which may not be reached adulthood the facial appearance is progeric (preco- until age 20 or more, is often in the low-normal ciously senile). There is no significant deviation of range, and sexual development and fertility are the patient intelect. In the first several years of life, normal. Anamnesis can show, that delay in approximately 10 % of children with somatotropic growth and in pubertal development may have hypopituitarism have hypoglycemic convulsions. An occurred in the father and other male relatives. additional 10 % or more have asymptomatic fasting This diagnosis of constitutional growth delay hypoglycemia. Hypoglycemia is usually secondary to should be made only after the exclusion of other combined deficiencies of cortisol and GH. causes of delayed growth and puberty. Somatotropic hypopituitarism in children is usu- ally associated with gonadotropin deficiency (com- 5. Familial (genetic) short stature. The patients binated hypopituitarism). In that case along with with familial short stature do not have delayed dwarfism also sexual infantilism occurs. When 5.3. Pathophysiology of hypothalamic-hypophyseal system 323 the hyposomatotropic dwarfism is due to expansive ing of the voice does not occur and facial appear- growing tumor, in the clinical picture of the disease ance remains infantile for a long time. Develop- also local symptoms from the damage of the sur- ment of muscles is insufficient and sometimes rounding intracranial structures can be present. gynecomastia is present. The testes are small In adults the clinical syndrom due to STH defi- and soft, and scrotum is not pigmented. Some- ciency is not known. In the patients only tendency times cryptorchism may be present. Spermio- to hypoglycemia resulting from the increased sensi- genesis is absent what leads to infertility. The tivity of tissues to insulin is observed. GH is insulin size of the penis remains the same as in child- antagonist, and, therefore, its deficiency is connected hood. If STH production is normal (isolated go- with the increased sensitivity of tissues to insulin. nadotropic hypopituitarism), epiphyseal fusion is retarded, and growth of long bones of ex- B. Gonadotropic hypopituitarism tremities continues also after 20 years of age. Forms and intensity of symptoms of gonadotropic Therefore, eunuchoid body proportions (exces- hypopituitarism (gonadotropic hypogonadism, sec- sive and disproportional body growth, charac- ondary hypogonadism) depend not only on the de- terized by too long extremities in relation to the gree of gonadotropin deficiency, but also especially trunk) develop in the patient. But, if STH secre- on the age and sex of a patient in the time of the ori- tion is decreased (combinated disorder) not only gin of gonadotropin deficiency. Isolated type of go- sexual infantilism, but also hypophyseal nanism nadotropic hypogonadism is very rare. Combinated appears in the patient. gonadotropic hypogonadism, characterized by simul- taneous deficiency of gonadotropins and GH, is more 2. Prepubertal hypogonadotropic hypogonadism frequent. in girls Isolated gonadotropic hypogonadism is usually in- In affected girls any symptoms of spontaneous born (see Kallmann’s syndrome). However, it is a onset of puberty are absent, sexual infantilism primary hypothalamic disorder (deficiency of GnRH continues. The main symptom of the disease is secretion). It can be caused also by a functional dis- primary amenorrhea. Neither primary nor sec- order, mainly in the female, e.g., by chronic psychoe- ondary sexual organs are being developed like motional stress. in women. Also secondary sexual characteris- Combinated gonadotropic hypogonadism, i.e., si- tics are not developed. If STH secretion is nor- multaneous gonadotropin and GH deficiency, is more mal, epiphyseal closure is retarded leading to often caused by organic disorder (see somatotropic disproportional body growth (eunuchoid habi- hypopituitarism). This organic disorder destroys the tus). But, if in the patient STH deficiency oc- hypothalamic cells producing GnRH and GHRH, or curs, hypophyseal dwarfism originates. destroys adenohypophyseal gonadotrophs and soma- totrophs. 3. Postpubertal hypogonadotropic hypogonadism The clinical picture of secondary hypogonadism in men depends on sex and the age of a patient in the time of the origin of this disease. Prepubertal or postpu- This disorder is very rare, and sometimes it can bertal hypogonadotropic hypogonadism can be dis- be the first symptom of development of panhy- tinguished. Their clinical picture depends on the sex popituitarism. It is manifested by gradual re- of a patient. Therefore, the following four types of gression of secondary sexual characteristics, di- hypogonadotropic hypogonadism may occur: minished libido and impotence appear. Axil- lary and pubic hair becomes thinner, and growth 1. Prepubertal hypogonadotropic hypogonadism of facial hair decelerated. Moderate atrophy of in boys. epididymides may occur, spermatogegenesis be- In an affected child the sexual development comes insufficient and leads to infertility. Mus- ceases, the symptoms of spontaneous onset of cle flaccidity and atrophy are present, female like puberty do not appear. Secondary sexual char- type of subcutaneous fat distribution appears. acteristics are not developed (sexual infantil- Chronically untreated hypogonadism may result ism). Axillary and pubic hair is missing, break- in the origin of osteoporosis. Some psychical 324 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs)

changes may appear as well, e.g., loss of aggres- Pathogenesis of Sheehan’s syndrome is not exactly sivity. known. But, mainly spasm of arterioles of portal vessel bed during obstetric posthemorrhagic shock 4. Postpubertal hypogonadotropic hypogonadism is supposed to participate in the origin of adenohy- in women pophyseal necrosis. Other pathogenic mechanism, Postpubertal hypogonadotropic hypogonadism however, may be involved, such as intravascular is more frequent in women than in men. It thrombosis or increased sensibility (vulnerability) of may be only the initial phase of gradually de- the anterior lobe of pituitary gland to hypoxia in veloping panhypopituitarism. The most evident parturient women. symptoms of hypogonadotropic hypogonadism Other causes of sudden origin of panhypopitu- in women are the secondary amenorrhea and in- itarism are: adenohypophyseal hemorrhage (pitu- fertility. Gradually the symptoms of different itary apoplexy), severe head trauma, hypophysec- degree of defeminization (atrophy of the breast, tomy, and ionizing irradiation applied in the area uterus and ovaries) appear. Inhibition of orgas- of sella turcica. mic function may appear. When hypogonadism The cause of gradually developing panhypopitu- is untreated for a long time, the symptoms of itarism may be expanding adenohypophyseal tumor osteoporosis may be gradually developed in the (mainly from chromophobic cells), craniopharyn- patients. gioma, pinealoma, large artery aneurysm, metas- tases, cyst, infiltrative diseases, infectious diseases, and lymphocytic (autoimmune pitu- C. Other types of hypopituitarism itary destruction). Because the functional capacity Due to primary disorder of adenohypophysis iso- of the adenohypophyseal tissue is rather large, pitu- lated TSH deficiency or isolated ACTH deficiency itary hypofunction is unlikely to be manifested un- can occur very rarely. Damage of thyrotropes or cor- til at least 75–85 % of anterior lobe is destroyed. In ticotropes is more frequently present in the patients most instances, there is destruction of 95–99 % of the with panhypopituitarism, when also other trope cells anterior lobe. Secondary to chronic deficiency of ade- are damaged. Secondary hypothyroidism as well nohypophyseal tropic hormones, atrophy of individ- as secondary hypoglucocorticoidism have essentially ual target endocrine glands (multiglandular atrophy) the same pathophysiology and clinical features as gradually develops. primary hypothyroidism or primary hypoglucocor- The clinical picture of panhypopituitarism de- ticoidism. The symptoms of secondary hypothy- pends on the age and sex of the patient in the time roidism are, however, usually milder than the symp- of the origin of this disease, and also on the degree toms of primary hypothyroidism. of deficiency of individual adenohypophyseal hor- mones. Prepubertal and pospubertal panhypopitu- D. Panhypopituitarism itarism can be distinguished. The term panhypopituitarism signifies a deficiency of all anterior pituitary hormones. Its symptoms Prepubertal panhypopituitarism originate either suddenly or are developing gradu- This disease is manifested especially by the symp- ally (even several years). It is caused by various or- toms resulting from STH and gonadotropic hormone ganic disorders of adenohypophysis. Sudden form deficiency. Deficiency of STH prior to epiphyseal fu- of panhypopituitarism in the past often occured in sion leads to retardation in bone age and in body some women as a result of postpartum necrosis of growth resulting in pituitary dwarfism. Central ade- adenohypophysis (pituitary infarction at the time nohypophyseal hypothyroidism may to a certain ex- of delivery), the clinical picture of which is known tent also participate in the body growth disorder. as Sheehan’s syndrome. Adenohypophyseal necro- GTH deficiency leads to absence of pubertal devel- sis induces sudden occurrence of symptoms of pan- opment (sexual infantilism), the clinical picture of hypopituitarism. This syndrome usually originated which depends on sex of the patient. As there is a in women with a long-lasting and complicated de- certain spontaneous basal production of the thyroid livery accompanied by excessive blood loss as a se- hormones, TSH deficiency in the dwarfish children quel of hemorrhagic shock at the time of delivery. is not usually expressively manifested. Therefore, 5.4. Pathophysiology of thyroid gland 325 mental retardation is not a common clinical symp- ciency (to a certain extent also ACTH deficiency) is tom. ACTH deficiency in children with panhypopi- manifested by hypopigmentation or depigmentation tuitarism results in the tendency to hypoglycemia of the skin, which is expressive mainly in physiolog- and neuroglycopenic attacks. Besides insufficient ically hyperpigmentated areas of the body (breast production of glucocorticoids, ACTH deficiency also areolae, perigenitally, perianally), and by decreased leads to a decreased secretion of sex hormones of tolerance to sunshine. adrenal cortex, which together with GTH deficiency If panhypopituitarism is caused by intrasellar or participates in the origin of hypogonadism. extrasellar expanding tumor, in the clinical picture also local symptoms resulting from compression of Postpubertal panhypopituitarism surrounding structures are present. The peripheral manifestations of panhypopituitarism In the past, gradually developing panhypopitu- in adults are mostly the consequences of deficiency of itarism was called Simmond’s cachexia, because five tropic hormones: gonadotropins (LH and FSH), in the clinical picture of this disease extreme loss TSH, ACTH, and MSH. Characteristically, evidence of body weight and atrophy of organs dominated. of target gland deficiencies appears in the above men- Those were the patients with severe total insuffi- tioned order, i.e., gonadal, thyroidal, and cortical de- ciency of adenohypophysis without longterm substi- ficiency. tution therapy. Due to present day system of health The early symptoms of developing panhypopitu- care, the patients do not reach such progressive phase itarism are usually the symptoms of gonadotropin of the disease, and, therefore, expressive cachexia deficiency. GTH deficiency in female leads to sec- does not occur in them. ondary amenorrhea and diminishing libido. In women with Sheehan’s syndrome the failure to lac- tate and resume menses after delivery are the most common initial clinical symptoms. In men loss of 5.4 Pathophysiology of thy- libido and impotence appear. TSH and ACTH deficiencies are manifested by roid gland the same clinical symptoms as at primary hypothy- roidism and at primary hypoglucocorticoidism. The symptoms of secondary hypothyroidism are, how- The thyroid gland is the largest classic endocrine ever, less intensive than at primary hypothyroidism. organ. Its disorders are very frequent. If diabetes Loss of the thyroid function causes dry skin, cold mellitus, which regularly ranks among metabolic dis- intolerance, somnolence, bradycardia, and constipa- eases, is not considered, the thyroid gland disor- tion. However, at secondary hypothyroidism typi- ders make about 4/5 of the total number of en- cal myxedema usually does not originate. Secondary docrinopathies. The thyroid gland disorders are adrenal insufficiency results from the lack of ACTH much more frequent in women than in men (7:1). stimulation of the adrenal cortex, and, therefore, af- They can be classified as follows: fects only adrenal steroids under predominant ACTH regulation, namely cortisol and adrenal androgens. 1. Simple goiter Mineralocorticoid secretion, primarily regulated by 2. Hypothyroidism renin and angiotensin, is preserved, although it may not be optimal. More common symptoms of glu- 3. Hyperthyroidism cocorticoid deficiency are malaise, anorexia, weight 4. Inflammations of the thyroid gland (Thyroiditis) loss, hypoglycemia or hypoglycemia-induced seizure, hypovolemia, postural hypotension, and orthostatic 5. Thyroid neoplasms dizziness. ACTH deficiency results also in abnormal response to stress, and a higher mortality rate. A de- 5.4.1 Goiter (struma) crease of adrenal androgen production causes in both sexes gradual thinning even loss of axillary and pubic Goiter is a clinical and morphological term signifying hair (in men there is a coexistent GTH deficiency). any enlargement of the thyroid gland situated in situ In men also facial hair may diminish. MSH defi- or ectopic. The goiter placed in situ can be diagnosed