5.8. Endocrine disorders of the testes 397 extensive dysfunction of hypothalamus in women 5.7.3 Secretion of hormones atypical with Stein-Leventhal syndrome. for the ovaries

Because the plasma androgens are a substrate for The ovaries may produce human chorionic go- peripheral aromatization (mainly in the cells of fat nadotrophin (hCG), thyroid hormone, or serotonin. tissue) their permanently elevated concentration in Thyroxine is secreted by some specialized ovarian circulating blood usually results in an increased for- teratomas. High level of hCG is caused by ovar- mation of extraglandular estrogens. The increased ian choriocarcinomas, occasionally dysgerminomas, plasma estrogen concentration, conditioned by the and rare immature malignant teratomas. Serotonin mentioned mechanism, is considered as the cause of may secrete primary or metastatic intestinal ovarian inhibition of FSH secretion by a negative feedback, carcinoids. and the cause of stimulation of LH secretion by a Ovarian choriocarcinomas. They are very malig- positive feedback, giving the characteristic LH/FSH nant tumors. Most of them exist in combination with ratio in plasma. In women with Stein-Leventhal syn- other germ cell tumors, pure ovarian choriocarcino- drome (with or without obesity) insulin resistance mas are extremely rare. Ovarian choriocarcinoma has been discovered. The increased plasma insulin usually originates in girls before puberty. As hCG concentration is supposed to stimulate androgen se- itself (also LH itself), without simultaneous presence cretion in ovarian stroma. Insulin may probably act of FSH, does not stimulate ovarian estrogen produc- on the ovary via IGF receptors. tion. Therefore, the increased plasma level of hCG does not induce precocious sexual maturation of af- Stein-Leventhal syndrome begins clinically mani- fected girls. Precocious pseudopuberty cannot origi- fest usually in the period of adolescence or in young nate unless estrogens have been simultaneously pro- women (in 2nd or 3rd decennium). Varying degrees duced by ovarian choriocarcinoma. of hirsutism appear. In adolescent girls it may cause Specialized ovarian teratomas. The most com- late onset of menarche, but uterine bleeding is dys- mon of them are struma ovarii and carcinoid. They functional and is unpredictable in onset, duration, are unilateral. Teratomas that contain mature thy- and amount. Oligomenorrhea (prolonged menstrual roid tissue (struma ovarii) may secrete thyroxine, al- cycle over 35 days), hypomenorrhea (weak menstrual though rarely in sufficient quantities to cause thy- bleeding), and amenorrhea ensue after a variable rotoxicosis. This type of teratomas is usually be- time. About 5–10 % of affected women present with nign. Primary ovarian and metastatic intestinal car- primary amenorrhea. Due to hormonal inbalance cinoids may secrete serotonin (5-hydroxytryptamine) ovarian follicles mature insufficiently, and, therefore, in quantities sufficient to produce the carcinoid syn- multiple atretic follicles are found. These women drome. The primary ovarian carcinoid presum- have persistent anovulation and are infertile. About ably rises from intestinal epithelium in a teratoma. 40 % of affected women are obese. Metastatic ovarian carcinoid is virtually always bilat- eral. A combination of struma ovarii and carcinoid Stein-Leventhal syndrome is considered a special in the same ovary is very rare. type of polycystic ovarian syndrome.Thetermpoly- cystic ovarian syndrome includes those endocrine states which lead to the origin of multiple ovarian cysts associated with similar functional abnormal- ities to those occuring in the patients with Stein- Leventhal syndrome. Such diseases include: clas- 5.8 Endocrine disorders of the sic and nonclassic virilizing adrenal enzymopathies, testes virilizing tumors of adrenal cortex, Cushing syn- drome, hyperthyroidism, hypothyroidism, and acan- thosis nigricans. Heterogenity of polycystic ovarian syndrome points up the fact that polycystic ovaries Classification of endocrine disorders of the testes, may also occur in about 20 % of healthy and fertile similarly as classification of endocrine disorders of women. the ovaries, has not been yet sufficiently transparent 398 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs) and uniform. At present pathogenetic classification testes syndrome”), bilateral cryptorchidism, testicu- has been considered most convenient. It is based on lar biosynthetic defect (enzymopathy), and agenesis the following three criteria: of Leydig cells. The most common form of inborn primary male 1. The type of intensity of hormonal secretion, hypogonadism is Klinefelter syndrome. Other forms i.e., hyposecretion or hypersecretion of testicu- of gonosomal anomalies are rare. lar steroid hormones. Klinefelter syndrome 2. The place of origin of an endocrine disorder, i.e., Klinefelter syndrome (syndrome of seminiferous primary, secondary, or tertiary disorder of hor- tubular dysgenesis) is the most common form of pri- monal secretion. mary male hypogonadism. Its incidence is approx- 3. The basic cause of endocrine disorder, i.e., in- imately 0.1–0.2% of male population. It originates born or acquired endocrine disorder. due to gonosomal anomaly. From the cytogenetic point of view it is a simple trisomy XXY mani- fested by the 47,XXY karyotype of all cells of the pa- 5.8.1 Hyposecretion of testicular hor- tient (the classic form of Klinefelter syndrome). The mones mosaic form of Klinefelter syndrome has been also found. There are several variants of the mosaic form. Deficiency of testicular androgens is also denoted as The most common of them being the one with the male hypogonadism (hypogonadismus masculinus). 47,XXY/46,XY karyotype. Other mosaic patterns, It is almost always accompanied also by insufficient e.g., 47,XXY/48,XXXY or 47,XXY/48,XXYY, are spermatogenesis, however, in most adult men with rarer. The classic form accounts for about 80–90 % insufficient spermatogenesis regulated by FSH, the and the mosaic form for about 10–20 % of all cases deficiency of testicular androgens regulated by LH is of Klinefelter syndrome. not present. Hyposecretion of testicular androgens Pathogenesis. The classic form of the 47,XXY occurs more often than their hypersecretion. trisomy results from nondisjunction of the chromo- Pathogenesis of hyposecretion of testicular hor- somes during either the first or second meiotic divi- mones is variable. Principally, the male hypogo- sions in the course of gametogenesis in one of the par- nadism may be divided into peripheral and central ents. About 40 % of the responsible meiotic nondis- hypogonadism. Hypogonadism conditioned by the junctions occur in the father during spermatogene- disorder on the level of peripheral tissues (resistance sis, and 60 % occur in the mother during oogenesis. of target tissues to androgens or the disorder of their The result of meiotic nondisjunction of XX chromo- degradation by cells of peripheral tissues) is a sepa- somes during oogenesis is the origin of one ovum with rate form of hypogonadism. XX chromosomes (its karyotype is 24,XX) and the other ovum has no X chromosome (its karyotype is 5.8.1.1 Primary male hypogonadism 22,O). After fertilization of an ovum with the 24,XX The cause of its origin is within the testes them- karyotype by a sperm with the 23,Y karyotype, the selves, therefore, it is also denoted as peripheral or zygote with the 47,XXY karyotype originates. The testicular hypogonadism. It may be inborn (con- result of meiotic nondisjunction of XY chromosomes genital) or acquired. Primary male hypogonadism during spermatogenesis is the origin of one sperm is characterized by the increased concentration of with the 24,XY karyotype and the other sperm with gonadotropins (mainly LH) and decreased plasma the 22,O karyotype. After fertilization of a 23,X testosterone level. It is, therefore, also denoted as ovum by a 24,XY sperm the 47,XXY zygote origi- hypergonadotropic male hypogonadism. nates. The 47,XXY zygote may also originate after fertilization of a 24,XX ovum by a 23,Y sperm. There is no phenotypic difference between those who re- A. Inborn primary male hypogonadism ceive the extra X chromosome from their father and Its most common cause are gonosomal anomalies. those who receive it from their mother. The cause of Occasionally it may originate due to testicular age- meiotic nondisjunction of XX chromosomes during nesis, gonadal dysgenesis, anorchia (the ”vanishing oogenesis may be advanced maternal age. The influ- 5.8. Endocrine disorders of the testes 399 ence of age on paternal nondisjunction of XY chro- in the liver. The increased plasma concentration of mosomes is not assumed. Some authors consider also TeBG is the cause of even greater decrease of free the existence of genetic predisposition to the origin testosterone in circulating blood. of meiotic nondisjunctions. The participation of ir- radiation or viral infection as predisposing factors of The clinical picture of Klinefelter syndrome is meiotic nondisjunctions has not been found for the characterized mainly by signs and symptoms result- present. ing from seminiferous tubular dysgenesis and hyper- The mosaic form of Klinefelter syndrome results gonadotropic hypogonadism. Though it is congen- from chromosomal mitotic nondisjunctions after fer- ital gonosomal anomaly, the boys usually develop tilization of the zygote (mainly during the first cell normally before puberty. However, most prepuber- divisions) and can arise either in a 46,XY zygote or tal patients have a distinctive body habitus with an a 47,XXY zygote. The latter situation, i.e., dou- increase in length between the soles and the pubic ble nondisjunction (meiotic and mitotic), may be the bone, which creates the appearance of an elongated usual of the mosaic form and thus explain why the body. The disorder begins clinically manifested al- mosaic form is less common than the classic form of ready in the time of expected puberty. Classic man- Klinefelter syndrome. ifestation of this disease is the origin of sexual infan- tilism. However, such severe degree of the disorder is Chromosomal aberration is usually manifested at not frequent. The intensity of the disorder of sexual the time of expected puberty, when plasma FSH con- development in the patients is usually variable. In centration is physiologically increased. However, its some affected boys only delayed puberty may orig- effect on primary dysgenetically changed germinal inate. It is also possible that the onset of puberty epithelium of seminiferous tubules of the testes does is not delayed, but impaired Leydig cell reserve and not lead to their enlargement, but cause their pro- low testosterone levels may lead to slow progression gressive fibrotization and hyalinization. With the or arrest of pubertal development. In other patients onset of puberty, progressive histological changes puberty may be normal, spermatogenesis is, how- also originate in Leydig cells, but their number is ever, missing. normal or more often increased (pseudoadenomatous changes of the Leydig cells). The ability of impaired The classic form is characterized by small, firm Leydig cells to synthetize testosterone is, therefore, testes, impaired spermatogenesis, a male phenotype, gradually reduced. Plasma testosterone concentra- insufficient androgenization, and later by a variable tion gradually decreases resulting in the origin of degree of feminization. The reduced spermatogene- primary male hypogonadism. Plasma LH level is sis is related to the degree of morphologic changes gradually increasing by feedback mechanism (hyper- in the testes. Most of affected men are infertile. gonadotropic male hypogonadism). The small atrophic testes are often associated with The increased plasma LH concentration initially a small penis, and the lack of such secondary male stimulates production of estradiol in Leydig cells. characteristics as deep voice, beard, and male distri- Later, due to progressive impairment of testes, ev- bution of pubic hair. Gynecomastia occurs in about ident decrease not only of testicular testosterone 90 % of patients, and is probably secondary to an secretion, but also of testicular estradiol secretion increased ratio of serum estradiol to testosterone. develops. Extraglandular production of estrogens, The eunuchoid body habitus with abnormally long however, continues. They are formed by aromatiza- legs is also characteristic. Most individuals have a tion of adrenal androgens in extraglandular tissues. male psychosexual orientation and function sexually Though plasma estrogen level is low, with regard to as men. Potency may be initially normal, but due to very low plasma testosterone concentration it is rela- progressive decrease of plasma testosterone concen- tively high. Due to the increased ratio of circulating tration it may decrease. The mean IQ is somewhat estrogen to androgen various degrees of feminization lower than normal, but mental retardation is uncom- of the patients, including gynecomastia, have been mon. Plasma gonadotropin concentrations, particu- developed. Besides that, relative predominance of larly FSH, are consistently elevated, whereas testos- plasma estradiol over plasma testosterone increases terone levels are variably reduced. Mean plasma production of testosterone-binding globulin (TeBG) estradiol levels are relatively elevated. The ratio of 400 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs) circulating estrogen to testosterone determines the curs in childhood and adulthood. The best known degree of feminization in individual cases. of them is mumps orchitis. Other viral agents may The mosaic form is present in about 10–15% of act in a similar fashion, including echovirus, lym- the patients with Klinefelter syndrome. The most phocytic choriomeningitis virus, and group B ar- common of mosaic patterns is the one with the boviruses. Primary hypogonadism may originate 47,XXY/46,XY karyotype. The presence of a normal also secondary to extensive impairment of testes in XY cell line in these patients can modify the clinical patients with autoimmune orchitis,andalsowith expression of the 47,XXY cell line. Thus, in general, gonorrheal or syphilitic orchitis. The testes can also these patients manifest a lesser degree of testicular be damaged after long-lasting therapy by antineo- pathology, testosterone deficiency, and gynecomas- plastic and chemotherapeutic drugs, after radiother- tia. The testes may be normal in size. The decreased apy, or after trauma. The cause of its origin may libido and potency may not appear until the fourth be also castration of the patients with malignant tu- or fifth decade. Secondary sexual characteristics are mors of the testes. Certain signs of peripheral hy- less impaired than those of patients with the clas- pogonadism may originate due to chronic alcohol in- sic form. In many patients with the mosaic form gestion. Large doses of ethanol damage not only ger- seminiferous tubules exhibit spermatogenesis being minal epithelium, but also Leydig cells. usually insufficient (oligospermia), however, some of The clinical picture of acquired primary male hy- them may be even fertile. pogonadism depends on the age at which the tes- Many other variants of Klinefelter syndrome have ticular hormone deficiency develops (before or after been described, including those with uniform cell puberty). The consequences of extensive impairment lines (such as 48,XXYY, 48,XXXY, 49,XXXYY, and of the testes in childhood begin manifested clinically 49,XXXXY) and various mosaic patterns. All these as late as in the time of expected onset of puberty. forms are rare. With an increase in the number of 1. Prepubertal testicular hypogonadism.Itis X chromosome, the severity and frequency of vari- manifested by the disorder of spontaneous on- ous somatic anomalies also increase. The presence set of puberty or it may result in the origin of of three or more X chromosomes in genotype is usu- sexual infantilism. A degree of the disorder de- ally associated with a severer degree of mental re- pends on the extent of Leydig cell damage, and tardation of the patients. The presence of two or thereby on the degree of testicular androgen de- more Y chromosomes in genotype is usually associ- ficiency. It is manifested by hypogenitalism and ated with antisocial, deliquent behavior. In general, by the disorders in the development of secondary the greater the degree of chromosomal abnormality sexual characteristics which may be sometimes (and in mosaic forms the more cell lines that are ab- completely absent. In an affected subject break- normal), the severer are the clinical manifestations. ing the voice does not occur, libido is absent, female fat distribution and sometimes also gy- necomastia originate. B. Acquired primary male hypogonadism 2. Postpubertal testicular hypogonadism. It need It is a rare disorder, because the organic fac- not evidently influence a masculine look of the tors damaging the testes most frequently affect only patient. Pubic hair may be thinned. Moustache seminiferous tubules (germinal epithelium). Rarely, and beard growth is slowed. Sometimes also only due to severe form of damage also Leydig cells partial regression of genitalia, though impercep- are affected leading to hyposecretion of testosterone tible at the first sight, may occur. In some pa- and thus to peripheral male hypogonadism. Due tients libido and potence may be decreased, in to lowered plasma testosterone level hypothalamic- others may be preserved (due to psychic condi- pituitary system is stimulated to an increased secre- tional nature of sexuality). Possible change of tion of GTHs by positive feedback mechanism. Their behavior may be manifested by the loss of ag- plasma concentration is, therefore, increased (hyper- gressiveness. Anemia, osteoporosis, and muscle gonadotropic male hypogonadism). weakeness may originate. Obesity also develops. One of the most common causes of acquired pe- The change of fat distribution may be associated ripheral male hypogonadism is viral orchitis.Itoc- with the loss of typical masculine figure. 5.8. Endocrine disorders of the testes 401

5.8.1.2 Central male hypogonadism 8. severe chronic systemic disease (renal failure and cirrhosis of the liver) altering the overall In the patients with central male hypogonadism health state of a patient; plasma concentrations of gonadotropins are low, and, therefore, it is also denoted as hypogonadotropic 9. long-term starvation. male hypogonadism. The causes and consequences of the origin of adenohypophyseal and hypothalamic The clinical picture of central male hypogonadism male hypogonadism have been partially mentioned is essentially the same as that of in the patients with in the chapter on pathophysiology of hypothalamic- primary hypogonadism. It depends on the age of a adenohypophyseal system. patient at the time of the origin of testicular andro- gen deficiency. It is quite often only a part of more Central male hypogonadism originates due to: complex clinical picture determined by the cause of its origin. In boys either true delayed puberty or 1. organic lesion in hypothalamic-pituitary area sexual infantilism originate. In adult men hypogo- (tumors, aneurysms, hemorrhages, inflamma- nadism is manifested by a decrease even loss of libido tory processes, surgical interventions, irradia- and potence, regression of secondary sexual charater- tion, head trauma, and others); istics, and muscle weakness. 2. various inborn syndromes (Laurence-Moon- Biedl-Bardet syndrome, Kallmann syndrome, 5.8.2 Hypersecretion of testicular Babinski-Fr¨oehlich syndrome); hormones

3. hyperprolactinemia (hypothalamic or adenohy- Hypersecretion of testicular androgens is denoted as pophyseal); male hypergonadism (hypergonadismus masculinus). The cause of its origin may be within the testes 4. fertile eunuch syndrome being a special form of themselves (primary male hypergonadism) or is lo- central prepubertal male hypogonadism. This calized in the hypothalamic-pituitary area (central syndrome is conditioned by a selective resis- male hypergonadism). Male hypergonadism occurs tance of gonadotrope cells of adenohypophysis much more rarely than male hypogonadism. The to LHRH. FSH secretion is normal, LH secre- clinical picture of hypersecretion of testicular andro- tion is, however, missing. LH deficiency is the gens depends on the age at which the hypersecretion cause of disorder of Leydig cell development and appears. The clinical features are similar to those subsequent testosterone deficiency. Due to nor- originated in male individuals with oversecretion of mal concentration of FSH in circulating blood adrenal androgens. seminiferous tubules and testes are of normal size after puberty and spermatogenesis is usu- 5.8.2.1 Primary male hypergonadism ally preserved, therefore, the term fertile eunuch Peripheral male hypergonadism originates due to is used. However, as a consequence of testos- hormonally active testicular tumors autonomously terone deficiency, spermatogenesis is often insuf- producing testosterone and sometimes also estradiol. ficient. The clinical picture is characterized by It occurs very rarely. Excess testosterone is secreted the contrast between the well developed testes mainly by Leydig cell tumors and rarely by Ser- and decreased length of penis and by the pres- toli cell tumors (androblastomas). Leydig cell tu- ence of eunuchoid habitus; mors may elaborate androgens, or sometimes an- 5. combinated disorder of pituitary hormone pro- drogens and estrogens (estradiol). They are usually duction, mainly deficiency of gonadotropins unilateral. Sertoli cell tumors may elaborate estra- with deficiency of growth hormone; diol (more commonly) or androgens, but only infre- quently in sufficient quantity to cause masculiniza- 6. constitutional delay in growth and puberty; tion or feminization. They are frequently bilateral. Both kinds of these testicular tumors may arise at 7. prepubertal or postpubertal panhypopituita- any age, although the majority of the reported causes rism; of Leydig cell tumors have been noted between 20–40 402 Chapter 5. Pathophysiology of endocrine system ( L. Zlatoˇs) years of age and those of Sertoli cell tumors have been ical picture of isosexual precocious pseudopuberty found in childhood. Leydig cell tumors and Sertoli (incomplete isosexual precocity) originates. It is cell tumors account for about 2 % of all testicular tu- manifested by precocious development of genitalia mors. Approximately 10 % of these both kinds of tes- and secondary sexual characteristics. Spermato- ticular tumors are malignant, the great majority of genesis is absent, indicating that androgen forma- them are benign. In some patients the mixed tumors tion is not the result of premature activation of the containing cells of germinal (germ cells) and stromal hypothalamic-pituitary system. If hypersecretion of (Leydig and Sertoli cells) origin may occur. Most testosterone originates in adulthood,itneednotbe distinctive of them is the gonadoblastoma which pre- evidently clinically manifested. vailingly synthesize androgens. When the cells of a testicular tumor produce also Enhanced formation of testosterone and estradiol estradiol, in the clinical picture the symptoms of fem- by Leydig cells may be also present in patients with inization are simultaneously also present. Enhanced germ cell tumors secreting endocrinologically active formation of estradiol by testicular tumors is more hCG. The hCG acts to increase testosterone and common in adult men than in boys. Feminization is estradiol production in unaffected areas of the testes. manifested by the origin of gynecomastia, thinning This secretion of testosterone and estradiol is inde- of pubic hair, decrease even loss of potence, and di- pendent of the hypothalamic LHRH. The testicular minishing of prostate. germ cell tumors include seminoma, embryonal car- cinoma, choriocarcinoma, and benign or malignant 5.8.2.2 Central male hypergonadism teratomas. They account approximately for 95 % In the patients with central male hypergonadism of all testicular neoplasms. Germ cell tumors of all plasma concentrations of gonadotropins (mainly LH types can also originate in extragonadal sites, most concentration) are primarily increased. Therefore, it commonly in the brain or in the mediastinum. These is also denoted as hypergonadotropic male hyperg- extragonadal germ cell tumors presumed to arise ei- onadism. The causes and consequences of its origin ther from aberrant migration of germ cells early in have been partially mentioned in the chapter on the embryogenesis or, alternatively, from some common pathophysiology of hypothalamic-adenohypophyseal precursor stem cell line that normally gives rise to system. germ cells and to cells of the thymus and the pineal. A primary germ cell tumor localized in the pineal or The cause of central male hypergonadism may be in the suprasellar regions is denoted as germinoma. various organic (mainly CNS tumors) or functional disorders of the hypothalamic-pituitary area. The Increased plasma testosterone and estradiol con- functional disorders are usually of unknown etiology centrations cause suppression of the production (idiopathic form of central male hypogonadism). The of endogenous adenohypophyseal gonadotropins by best known organic causes of central male hyper- feedback mechanism. Plasma gonadotropin levels gonadism include hypothalamic hamartoma, pineal are, therefore, low (hypogonadotropic male hypogo- tumors, other tumors of the pineal region, and go- nadism). When production of testosterone and estra- nadotrope adenomas of hypophysis. Gonadotrope diol by testicular tumor is autonomous, testosterone adenomas most often occur in the middle age, mainly secretion by uninvolved portions of the testes is de- between the ages 35 and 45. Less common causes of pressed (due to low plasma LH level), and azoosper- central male hypergonadism include hydrocephalus, mia and decreased size of the contralateral testis are intracranial aneurysms, encephalitis, sarcoid or tu- common (due to low plasma FSH level). The clinical berculous granulomas of the hypothalamus, arach- picture of hormonally active testicular tumors de- noid cysts, or brain abscess. pends on the age of patients at which the neoplasms The above mentioned organic or functional dis- originate. It also depends on the fact whether the orders of the hypothalamic-hypophyseal area most testicular tumor secretes only testosterone or testos- commonly cause increased secretion of LHRH and terone and estradiol as well. Similar clinical fea- subsequently increased secretion of gonadotropins. tures can result from endocrinologically active hCG- Primary increase of production of GTHs (without secreting testicular and extratesticular tumors. preceding increase of LHRH) is rare. If excess testosterone occurs in childhood, a clin- The clinical picture of central male hypergonadism 5.8. Endocrine disorders of the testes 403 depends on the age at which the cause of increased pothalamic hamartomas are not associated with true secretion of LHRH or GTHs originates. If the cen- precocious puberty. trally conditined hyperfunction of the testes occurs Hamartomas of the tuber cinereum are most fre- prepubertaly in boys, isosexual true precocious pu- quently associated with true precocious puberty. berty originates. Its occurrence in boys is, however, They are congenital tumors composed of heterotopic rarer than in girls. In affected boys spermatogene- mass of neurosecretory mature neurons, fiber bun- sis is present and possible fertility may also occur. If dles, and glial cells. These neurosecretory cells are the oversecretion of gonadotropins originates in adult similar to the LHRH-containing neurons in the me- men (rare occurrence) its clinical consequence may dial basal hypothalamus. LHRH neurosecretory cells be low plasma testosterone concentration and the of the tumor are unrestrained by the intrinsic CNS origin of impotence. It is apparently paradoxical ori- mechanism that inhibits the normal LHRH pulse gin of testicular hypogonadism in the affected adult generator and act as an ectopic LHRH pulse genera- men with increased plasma concentration of GTHs. tor independently on the LHRH neurosecretory neu- The pathogenesis of this testicular hypogonadism in rons in the medial basal hypothalamus to produce in- adult men with overproduction of gonadotropic hor- termittent secretory bursts of LHRH. It seems, that mones is not exactly known. It is supposed that long- many causes previously thought to be idiopathic true lasting increased concentration of gonadotropins in precocious puberty are due to hamartomas of the tu- circulating blood leads to down-regulation of recep- ber cinereum (sometimes miniature). Hamartomas tor number, i.e., to reduction of LH receptors on the grow slowly, if in fact they do enlarge. Leydig cell membrane. The relationship between the origin of true pre- In the clinical picture of central male hyperg- cocious puberty and the presence of tumors of the onadism, which is caused by expansive growth of pineal gland has been known for a longer time. A cerebral tumors, some local symptoms induced by tumor of the pineal parenchymal cells is termed compression of intracranial structures may be also pinealoma. According to its degree of differentiation present. it can be a pineocytoma or pineoblastoma. Other In about 40 % of boys with true precocious puberty tumors localized in the pineal region include mainly the cause of origin of precocious LHRH production astrocytoma, glioma, glioblastoma, germinoma, and is not known (idiopathic true precocious puberty). ependymoma. True precocious puberty in boys with Tumors and other organic cerebral causes of true a pineal tumor or with other tumor of the pineal re- precocious puberty probably activate precocious re- gion is probably due to the effect of this tumor on leasing of LHRH by their effect on hypothalamus, function of the adjacent hypothalamus. In the hy- However, hypothalamic hamartomas associated with pothalamus precocious production of LHRH occurs. true precocious puberty may secrete LHRH them- The hypothesis, that pineal tumors and tumors of selves, because they are composed of disordered but the pineal region influence the function of the hy- mature neural elements. LHRH secretion by these pothalamus, is supported also by frequent simulta- ectopicly placed LHRH peptidergic neurons is prob- neous occurrence of insipidus diabetes, polyphagia, ably not subject to the normal restraining influences obesity, somnolence, or behavioral disturbance. It of the anterior hypothalamus, and early pubertal de- is likely, therefore, that tumors of the pineal gland velopment is likely the consequence of unrestrained and tumors of the pineal region cause true precocious LHRH secretion. Precocious puberty is believed to puberty by mechanism similar to that of other types occur when the cells of the hamartoma make connec- of cerebral tumors or other types of brain organic tions with the median eminence and thus serve as an lesions. ”accessory hypothalamus”. About 10 % of hy-