Hypothalamic hamartoma with precocious puberty--a case report

A case of hypothalamic hamartoma with precocious puberty is presented and the literature of reported cases is reviewed. An 8-year-old boy was admitted to our hospital because of precocious puberty and mental retardation. His genital development was Tanner's stage 4 and pubic hair was Tanner's stage 3. Bone age was 11 years. Plain CT showed an isodense mass in the suprasellar cistern which was not enhanced following contrast administration. Metrizamide CT cisternography showed a filling defect in the suprasellar cistern. Endocrinological evaluation revealed high levels of serum luteinizing hormone (LH) and testosterone with a marked response of LH to LH-RH injection. A left frontotemporal craniotomy was performed and the tumor was partially removed. The tumor was gray, firm and well-circumscribed with poor vascularity. Postoperatively, a right oculomotor palsy and transient diabetes insipidus developed. He was discharged ambulatory one month later. Serum LH and testosterone returned to normal and the response of LH to LH-RH injection became normal. Hamartoma was diagnosed on histological examination. Electron micrographic study showed numerous dense granules with approximately 0.1 mu in diameter, in which Judge proved LH-RH by immunofluorescent study in 1977. Our case supports the hypothesis that hypothalamic hamartoma may cause precocious puberty by autonomous secretion of LH-RH and we consider that neurosurgical treatment is recommended.     

A case of HCG-producing ectopic pinealoma in a girl with precocious puberty (author's transl)

HCG-producing ectopic pinealoma of two cell pattern type was demonstrated in a 5-year old girl who presented precocious puberty and bilateral choked discs. The tumor was localized at the anterior third ventricle and suprasellar region. Endocrinological findings are as following: Plasma basal LH was markedly elevated to 306 mIU/ml and HCG was elevated to 1,192 ng/ml. Provocative test of hypophyseal function revealed low response. Plasma estrogen was not detectable. HCG content of resected tumor tissue was elevated to 400 ng/mg. FSH, however, was not detectable. Histological findings of this tumor showed atypical teratoma, so-called two cell pattern pinealoma. Electron microscopic findings revealed two types of cells, dark and clear cells. Many secreting granules were found in the dark cells. In this case, HCG in plasma, CSF and tumor tissue was remarkably elevated. In addition, plasma FSH was also elevated to 8.9 mIU/ml. Precocious puberty associated with tumor in the pineal-suprasellar region has been seen only in boys. There has been no case report of precocious puberty in girls. This case is the first female case is which HCG-producing ectopic penealoma is caused in precocious puberty.     

Precocious puberty due to a hypothalamic hamartoma.

A case of precocious puberty due to a hypothalamic hamartoma is presented. Concentrations of plasma LH and FSH, testosterone and its derivatives were found to be elevated. Circadian rhythms of LH were also observed. After removal of the mass, plasma LH and FHS concentrations declined to nearly half the preoperative levels.     

A case of hypothalamic astrocytoma with precocious puberty]

A case of hypothalamic astrocytoma with precocious puberty is presented. In July 1989, a 2-year-old girl was admitted to our hospital because of vaginal bleeding and enlargement of breasts. Breast development was Tanner's stage 3 and no pubic hair was present. Endocrinological evaluation revealed a slightly high level of LH, but the responses of LH and FSH to LH-RH test resulted in exceedingly high values similar to those in adults. Plain CT scan showed an isodense mass in the suprasellar cistern which was not enhanced following administration of contrast medium. MR imaging revealed the precise location of the mass attached to the posterior hypothalamus between the pituitary stalk and the mamillary bodies in sagittal view. The signal intensity of the mass was homogenous and isointense relative to the gray matter on T1 weighted image. But on T2 weighted image, it showed high signal intensity compared with the normal brain parenchyma. A right fronto-temporal craniotomy was performed and the tumor was partially removed. Histological examination disclosed moderate hypercellularity of glial cells but no neurons were visible. This appeared to be astrocytoma grade II. In the literature, CT and MRI behaviour of hypothalamic hamartomas are almost similar to our case. Therefore we think it is not possible at the present time to differentiate a low grade astrocytoma from hamartoma when using CT and MRI alone. In this case, the mechanism of development of precocious puberty seemed to be due to hypothalamic compression by the tumor.     

A super long-acting LH-RH analogue induces regression of hypothalamic hamartoma associated with precocious puberty

Summary We treated a 1-year-old female with a hypothalamic hamartoma and precocious puberty with leuprolide acetate depot, a super long-acting hormone-releasing hormone analogue (Tap-144-SR; [D-Leu⁶-[des-Gly¹⁰-NH₂]-LH-RH ethylamide acetate). The infant's major symptoms were genital bleeding and gynaecomastia. The LH-RH analogue (30 g/kg) was injected subcutaneously once every 4 weeks. Clinical and laboratory manifestations of precocious puberty showed marked improvement. A follow-up after 16 months of treatment, the size of the tumour decreased significantly and remained unchanged for 2 years of further follow-up. To the best of our knowledge, this is the first hypothalamic hamartoma case in whom a decrease of tumour size under treatment with LH-RH analogue has been documented. But, because diagnosis of hamartoma is only based on neuroradiological and not on histological examinations, the possibility of a gangliocytoma cannot be excluded with certainty.     

Suprasellar arachnoid cyst associated with precocious puberty: report of an operated case and review of the literature]

The pathogenesis remains unknown in the majority of patients with precocious puberty, and yet infrequently such causative cerebral lesions as hypothalamic hamartomas are associated with sexual precocity. We reported a rare case of suprasellar arachnoid cyst in an infant presenting with precocious puberty, which eventually disappeared after a cyst-peritoneal shunt. It was believed that the mass effect of the arachnoid cyst upon the hypothalamus was, at least in part, responsible for development of precocious puberty. The role of surgical decompression of the cyst was also discussed. A one-year-old girl was admitted to the hospital for evaluation of genital bleeding which had persisted on and off for two months. The height, 80cm, and the weight, 12.4kg, exceeded by far the two standard deviations from the mean level of the normal population. In addition she had the development of breast tissue as classified Tanner's Stage II, and both pubic and axillary hair. The bone age by skeletal survey of the hand was rated as 3 years. Endocrinological examination showed that serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol had increased for her age, to levels equivalent to those for females at puberty. An LH-RH test revealed an excessive LH reaction. There were no definite neurological deficits. CT and MRI demonstrated the presence of a large arachnoid cyst involving the suprasellar region as well as the right middle and posterior fossa. After the patient underwent a cyst-peritoneal shunt, the cyst decreased in size and such symptoms as genital bleeding and breast growth disappeared. Serum levels of her LH and FSH also significantly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypothalamic hamartoma successfully treated by operation. Case report

An 18-month-old boy was diagnosed as having a hypothalamic hamartoma. When he was 1 year old, he developed precocious puberty, and at 18 months old, endocrinological tests revealed abnormally high follicle-stimulating hormone, luteinizing hormone, and testosterone levels. The center of the hamartoma was subtotally excised, as confirmed on the postoperative computerized tomography scan. Precocious puberty subsided after the operation.     

Microsurgical treatment for hypothalamic hamartoma in children with precocious puberty

BACKGROUND: We review the surgical treatment of hypothalamic hamartoma causing precocious puberty. METHODS: Six children (three girls and three boys) with precocious puberty secondary to hypothalamic hamartoma were recruited for our study. The mean age of the patients was 30 months old (range 13 months to 5 years), and the mean age of the onset of puberty was 7.3 months. All patients were treated by microsurgery. RESULTS: All patients had higher then normal stature, body weight, bone growth, and serum levels of sexual hormones. The boys presented with mature external genitalia, pubic hair, frequent erection, and acne, while the girls presented with growth of breasts and menarche. Magnetic resonance image (MRI) revealed an isointense mass below the tuber cinereum extending into the supersellar and interpeduncular cistern, ranging from 4 to 12 mm in diameter, consistent with pedunculate hamartoma. The hamartoma was removed completely via a right pterional approach. The symptoms and signs of precocious puberty resolved completely, and sexual hormone levels decreased to the pre-pubertal range in all six patients without any postoperative complications. CONCLUSION: We report a series of six children with hypothalamic hamartoma-induced precocious puberty who underwent microsurgical treatment. All of them recovered completely to their age-appropriate state. Microsurgery is a good choice of treatment for pedunculate hypothalamic hamartoma.     

Testicular endocrine function in patients with prostatic cancer receiving medical castration by long-term administration of LH-RH agonists

Six patients with advanced prostatic cancer who had been treated by long-term administration of LH-RH agonistic preparations (Buserelin or Leupron) were tested for their pituitary-testicular endocrine functions. Serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), prolactin (PRL), estradiol (E2) and dihydrotestosterone (DHT) were measured consecutively. In all medically castrated patients, serum levels of LH, FSH, T, DHT and E2 were suppressed and particularly serum T levels were below the castration level of 1.0 ng/ml. On the other hand, serum PRL levels were unchanged after the long-term treatment with the agonists. Serum LH and FSH levels failed to respond to LH-RH stimulation after the treatment, whereas serum T responded to stimulation by human chorionic gonadotropin (hCG) to various degrees. It was remarkable that, in 4 out of 6 medically castrated patients treated up to more than 3 years, serum T response levels above 1.0 ng/ml were noted. It is suggested that testicular endocrine function to secrete T and DHT in patients under treatment with long-term LH-RH agonist administration are still preserved in response to hCG stimulation.     

Endocrine profile in patients with Klinefelter's syndrome

Twenty-seven patients with Klinefelter's Syndrome, aged 19-38 years were divided according to the basal testosterone (T) levels into sub-eugonadal (less than or equal to 3 ng/ml) and eugonadal (greater than 3ng/ml) groups. The pretreatment T level was 3.21 +/- 1.59 ng/ml. The LH and FSH levels, 14.54 +/- 6.68 mIU/ml and 21.51 +/- 10.74 mIU/ml respectively, were above the upper eugonadal range. Short-term hCG treatment stimulated T production significantly and a further increase was observed following long-term hCG treatment. In patients with sub-eugonadal levels of basal T, a greater relative increment of the T level was observed following the hCG stimulation but not in the absolute T increase. Thus, the assumption that in Klinefelter's patients, the low basal T levels and the relative refractoriness to hCG stimulation are secondary to chronic exposure to elevated LH levels, could not be supported. Higher FSH levels were associated with elevated plasma T levels (p less than 0.025). No such association was established with the LH.     

Isosexual precocious pseudopuberty secondary to a testosterone-secreting Leydig cell testicular tumour: true isosexual development early after surgery

The paper reports on a 6-year-old boy with precocious pseudopuberty due to androgen hypersecretion by a testicular interstitial cell tumour. Steroidogenesis, characterized by high testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone and 17-hydroxyprogesterone plasma levels, was not modified by ACTH, dexamethasone or HCG administration. Gonadotropins were subnormal and unresponsive to LRH stimulation. TSH and prolactin levels were normal both in basal and dynamic conditions. The hormonal profile progressively returned to prepubertal value and persisted normal for 6 months after removal of the tumour. The patient entered puberty spontaneously at 7,6/12 years showing a normal pubertal basal and LRH stimulated FSH and LH and a pubertal circadian rhythm of both gonadotropins and testosterone.     

Hypothalamic hamartoma: the role of surgery

A hypothalamic hamartoma associated with true precocious puberty in a 7-month-old girl is hereby reported. Hormonal studies disclosed elevated serum levels of luteinizing hormone (LH) and follicle stimulating hormone, both of which responded well to LH-releasing hormone stimulation. Following a subtotal removal of the tumor, the clinical manifestations of precocious puberty as well as associated endocrinological abnormalities returned to normal. The role of surgery for this lesion, which appears to be safe when a planned microsurgical course is employed, is discussed.     

Pubertas praecox and hypothalamic hamartoma

Summary Precocious puberty of cerebral origin is classified into pseudoprecocious puberty and true precocious puberty. Pseudoprecocious puberty is caused by HCG secreting tumours. True precocious puberty is caused by various hypothalamic diseases. Among them, hypothalamic hamartoma is the most common cause. Precocious puberty is caused by elevated blood pituitary gonadotropin concentration, secondary to the elevated hypothalamic LHRH secretion. The hypothalamic hamartoma is not infrequently associated with laughing (gelastic) seizures as well as convulsions. Diagnosis of a hypothalamic hamartoma is easily made by CT. Although the hypothalamic hamartoma is difficult to operate on, the value of surgery is stressed for treatment of precocious puberty. This is also confirmed by recent reports.     

Individual variation of hormonal recovery after cessation of luteinizing hormone-releasing hormone agonist therapy in men receiving long-term medical castration therapy for prostate cancer

OBJECTIVE: To evaluate the process of hormonal recovery after cessation of luteinizing hormone-releasing hormone (LHRH) agonist treatment in patients who had received long-term LHRH agonist therapy for prostate cancer. MATERIAL AND METHODS: Men who had successfully undergone androgen deprivation therapy with only monthly LHRH agonist therapy for > 30 months were enrolled and the administration of LHRH agonist was discontinued. Serum total testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prostate-specific antigen (PSA) were measured before the cessation of LHRH agonist therapy and every 4 weeks thereafter, and the administration of LHRH agonist remained suspended until the total testosterone level recovered to > 50 ng/dl. RESULTS: Ten patients were enrolled in the study. The median (range) castration period and the levels of serum LH, FSH, total testosterone and PSA at cessation of therapy were 39 (30-56) months,<0.5 (<0.5-1.8) mIU/ml, 6.4 (3.0-15.9) mIU/ml, 15.3 (5.8-34.7) ng/dl and 0.13 (0.02-0.89) ng/ml, respectively. Testosterone recovered to > 50 ng/dl in all cases. There were large variations in the times required for recovery of LH and FSH (30-100 days) and serum testosterone (30-330 days). PSA began to increase at various testosterone levels, and there was a large variation (0-83%; median 41%) in the ratio of the androgen suppression (testosterone < 50 ng/dl) time to the period of LHRH agonist cessation. CONCLUSIONS: There was considerable variation in the hypothalamus-pituitary-testicular hormone profiles during recovery from long-term medical castration. These findings are noteworthy when interruption of androgen deprivation therapy is applied with the intention of delaying the progression of hormone-refractory cancer or improving the patient's quality of life.     

Effect of chronic oral testosterone undecanoate administration on the pituitary-testicular axes of hemodialyzed male patients

Testosterone undecanoate (TU) or placebo was administered orally (for 12 weeks) in a double blind study, to 19 patients with chronic renal insufficiency on hemodialysis in a daily dose of 240 mg. Effect on plasma testosterone (T), dihydrotestosterone (DHT), androstenedione (A), 110H androstenedione (110A), FSH, LH and PRL concentration and the pituitary responsiveness to LH-RH/TRH stimulation was studied. These hormone levels were determined before the study and after 6 and 12 weeks of treatment. There was a rise in plasma androgen concentration in all treated patients. Mean plasma DHT, A and 110A increased at 12 weeks from 0.3, 0.85 and 1.13 ng/ml to 1.13 (p less than 0.05), 1.4 (p less than 0.05) and 1.44 (p less than 0.05) respectively. There was no change in plasma T or free testosterone. However, basal LH, FSH fell progressively from 5.51 and 5.51 ng/ml to 2.13 and 1.84 ng/ml (p less than 0.05). The level of significance of these changes was confirmed when the response to LH-RH was considered. Basal plasma PRL also decreased from 376 microU/nl to 306 (p less than 0.05), but PRL response to TRH remained unchanged. In contrast, none of these modifications were observed in placebo-treated patients. We conclude that oral TU restored to normal the pituitary-testicular axis. This form of treatment should be preferentially chosen instead of intramuscular injections in these frequently heparinized patients on hemodialysis.     

Testosterone-producing hepatoblastoma in a 3-year-old boy with precocious puberty

The syndrome of isosexual precocious puberty (PP) associated with a primary malignant hepatic tumor is rare and previously reported in only 17 cases with poor prognosis. Twelve cases are well-documented gonadotropin-producing tumors. We here describe a new case of virilizing hepatoblastoma in a 2-year-10-month-old boy with evidence of testosterone (T) production by the tumor itself, and survival with a 3 1/2-year follow-up after an extended right hepatic lobectomy. Preoperative laboratory findings showed high levels of serum alpha-fetoprotein (AFP) and T:350,000 ng/mL and 4.92 ng/mL, respectively, which normalized after surgery. There was no circulating gonadotropin nor stimulation of the hypothalamic-pituitary axis. Testicular biopsy showed neither interstitial-cell maturation nor Leydig-cell hyperplasia. Moreover, demonstration of T secretion by tumor cells and T synthesis in presence of C14 progesterone was performed in an in vitro culture system. These data seem to provide supportive evidence of a T-producing hepatoblastoma.     

Identification of gonadotropin-releasing hormone in neurons of a hypothalamic hamartoma in a boy with precocious puberty

We have studied a 3 1/12-year-old boy who presented with a hypothalamic mass and precocious puberty. His history suggested a course of isosexual precocity progressing from birth. Gelastic seizures also began at an early age. Endocrine evaluation revealed normal thyroid-stimulating hormone and growth hormone secretion, elevated basal and stimulated prolactin concentrations, and luteinizing hormone responses to sequential intravenous injections of gonadotropin-releasing hormone (GnRH) that were pubertal in pattern and magnitude. A needle biopsy of the mass recovered tissue that contained neurons histologically similar to those found in the normal hypothalamus, and the mass was characterized as a hypothalamic hamartoma. Immunohistochemical staining of this tissue with anti-GnRH antiserum demonstrated positive staining for GnRH immunoreactivity in neurons. This suggests a neurosecretory pathogenesis for the precocious puberty found in patients with hamartomas in the hypothalamic region.     

Three cases of Klinefelter syndrome in childhood--endocrinological and gonadal changes in puberty

Three children at the ages of 4, 10 and 12 years, with external genital malformation, were diagnosed to be with the Klinefelter syndrome by chromosome analysis. To clarify the pubertal changes in this syndrome, all of them were studied for physical and endocrinological examinations and two underwent testicular biopsy. Before puberty any remarkable abnormality were not observed in the hypothalamus-pituitary-gonadal axis and in the physical status. After the onset of puberty they started showing increases of the basal levels of plasma FSH and LH with over-response to LH-RH stimulation test. During the period of this study the levels of plasma testosterone were in the normal range and increased gradually with age. One boy showed a transient high level of plasma testosterone at early puberty. The reactions of plasma testosterone to HCG stimulation of all cases showed the normal pattern. The histological examination of the testis revealed that the number of spermatogonia was reduced in both cases compared with that of normal boys reported by Mancini et al. These findings indicate that most endocrinological and histological abnormalities in adult Klinefelter syndrome occur after the onset of puberty. These changes may be induced at puberty by hypergonadotrophic condition which result from slightly impaired testicular function which is present before puberty.     

Effect of hyperprolactinemia and age on the hypogonadism of uremic men on hemodialysis

Primary hypogonadism has been commonly reported among uremic men on hemodialysis, characterized by low testosterone levels, increased luteinizing hormone and sometimes follicle-stimulating hormone levels. Little is known about the influence of hyperprolactinemia and age on this hypogonadism. In 149 hemodialysis patients and in 60 healthy subjects the serum levels of testosterone (T), gonadotropins (LH and FSH) and prolactin (PRL) were assessed through radioimmunoassay. Mean +/- SD hormone levels were: T 274 +/- 125 ng/100 ml, lower than controls; LH 44.7 +/- 46.1 mlU/ml and FSH 17.6 +/- 18.4 mIU/ml, both higher than controls. PRL 31.3 +/- 49.4 ng/ml, higher than controls. A positive correlation between LH and FSH, a negative correlation between PRL and both T and LH was found. Moreover T and FSH were correlated with age only in the normoprolactinemic patients. These data suggest: a common damaging mechanism by uremia on both interstitial and tubular structures of the testis; a central antigonadal influence of hyperprolactinemia even if a direct action on the testis cannot be excluded; a worsening action of age on the gonadal function of these patients.     

Is testosterone involved in the initiation of spermatogenesis in humans? A clinicopathological presentation and physiological considerations in four patients with Leydig cell tumours of the testis or secondary Leydig cell hyperplasia

The purpose of this study was to evaluate the role of testosterone on the puberal development of spermatogenesis and to present additional clinicopathological data which bring about new information to this controversial subject. Four pre-pubertal patients are presented, 2 of them bearing Leydig cell tumours of the testis in the form of nodular masses. In both cases seminiferous tubules in the immediate vecinity to the tumours showed complete development of spermatogenesis, while those located away from the tumours were infantile in nature. Gonadotrophic levels were within the normal pre-pubertal range in these 2 cases. In one of the patients, testosterone concentration in the testis showed higher values than normal, and a concentration gradient was detected between the tumoral nodule and non-tumoral parenchyma. The 3rd patient had a pineal choriocarcinoma producing high amounts of hCG and consequently a diffuse hyperplasia of Leydig cells with high levels of plasma testosterone. Seminiferous tubules showed development up to pachytene spermatocytes. The last case was a precocious puberty in a boy with a tumour of the 3rd ventricle area. He had elevated levels of testosterone in the testis and plasma. In the testicular biopsy, stimulation of Leydig cells was detected. The seminiferous tubules showed mature Sertoli cells and pachytene spermatocytes. FSH levels were abnormally low. These 4 cases present in common different situations in which abnormally high amounts of testos-happens in the immature rat, the interaction between testosterone and gonadotrophins is essential for the normal initiation of spermatogenesis in normal puberty. Considerations are discussed on the possible synergistic role of gonadotrophins or other factors in relation with stimulation of seminiferous tubules by testosterone.