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PubMed1989

Clonogenic cells and rat mammary cancer: effects of hormones, X rays, and fission neutrons.

On Day 0, young adult female F344 rats were adrenalectomized and intrasplenically implanted with a pituitary gland and capsule containing estrone. All were thereafter given 2.5 mg deoxycorticosterone per week and the choice of saline or tap water. This treatment yields high prolactin levels and glucocorticoid deficiency (Prl+/Glc-). On Day +48, total recoverable mammary DNA was increased by more than sevenfold, tritiated thymidine uptake by nearly fourfold, and total mammary clonogens by about fivefold. Irradiation with 4, 40, and 80 cGy X rays on Day +48 increased total mammary carcinomas per rat day at risk linearly with dose, and 40 and 80 cGy significantly decreased first carcinoma latency. A dose of 40 cGy X rays on Day -1 yielded tumor latencies and frequencies insignificantly different from unirradiated controls and significantly different from the dose on Day +48. Total carcinomas per rat day at risk were better fit by a function of dose to the power 0.4 than by a linear function after exposure to 1, 10, and 20 cGy fission neutrons, and 10 and 20 cGy significantly shortened the time to appearance of the first cancer. In contrast to results with X rays, 10 cGy neutrons on Day -1 yielded tumor frequencies and latencies insignificantly different from 10 cGy neutrons on Day +48. The carcinogenic action of X rays was thus influenced by total clonogen numbers and/or proliferation rates; that of neutrons was not.

Animals↗
PubMed1980

Effect of combination chemotherapy on pituitary-gonadal function in patients with lymphoma and leukemia.

After at least four courses of intermittent chemotherapy, 14 of the 15 men with malignant lymphoma had elevated serum follicle-stimulating hormone (FSH). In three of these subjects, serial studies showed progressive increases in basal FSH and exaggerated FSH responses to luteinizing hormone releasing hormone (LHRH). Although gonadal biopsies were not done, this elevation of FSH is indicative of progressive and severe damage to the germinal epithelium by chemotherapy. Elevated leutinizing hormone (LH) was found in seven and decreased testosterone (T) in two of these subjects. Increased LH responses to LHRH stimulation were also found in the three subjects studied. These findings suggest that the testicular damage is not restricted to the germinal tissue. In four male subjects with acute myeloid leukemia treated by intermittent chemotherapy not containing any alkylating agents, FSH, LH, and T levels were normal. Three of the 4 female patients with malignant lymphoma and two with acute myeloid leukemia had normal basal, serial, and LHRH-stimulated FSH, LH, and estradiol (E2) levels. Elevated gonadotropins and low E2 were found only in subjects who had received abdominal irradiation.

Adult↗
PubMed1987

[Dosimetric characteristics of internal irradiation with radioactive nuclides of iodine].

The paper is concerned with some data on mean absorbed dose values in the animals' organs, the time course of their formation and the character of microdistribution of an absorbed dose around thyroid follicles in internal irradiation of the rat body with 131I and 125I. A raised level of irradiation of the animals' pituitary body is noted. The authors provide dosimetric characteristics of irradiation of thyroid microstructures noting that 125I creates more inhomogeneous distribution of an absorbed dose around thyroid follicles compared to 131I, irradiating, to a greater extent, the follicular membrane and, to a lesser degree, the nuclei of surrounding cells whereas 131I provides homogeneous irradiation of thyroid cells. The authors give a comparative critical analysis of the quantitative and microdosimetric characteristics and literature data.

Absorption↗
PubMed1996

Giant growth-hormone secreting pituitary tumour with extracranial extension.

A 19 year old female patient with typical features of acromegaly was found to have an extensive pituitary tumour with suprasellar, lateral and inferior extensions. Magnetic resonance imaging (MRI) also showed a portion of the tumour extending from the right cavernous sinus through the foramen ovale to become extracranial. Serum growth hormone (GH) was 52.6 mU/L basally and remained elevated after oral glucose, confirming the diagnosis of acromegaly. Treatment with the long-acting somatostatin analogue, octreotide, for 6 months led to a 30% reduction in tumour volume of the intracranial portion but no effect on the extracranial and sphenoidal extensions. She was subsequently treated with trans-sphenoidal surgery followed by external irradiation. The possibility of perineural spread of the tumour was considered.

Acromegaly↗
PubMed1994

Changes in hypothalamic-pituitary function following bone marrow transplantation in children.

Patients who undergo bone marrow transplantation (BMT) frequently experience impaired pituitary function, but precise assessment using repeated provocative tests has not been described. We studied 32 children (16 boys) who had BMT after receiving preparative irradiation. Assessment of pituitary function was performed by infusing insulin, luteinizing hormone-releasing hormone (LHRH), and thyrotropin-releasing hormone (TRH) on several occasions at various intervals during the follow-up period. Serum free thyroxine (FT4) and thyrotropin (TSH) levels tended to be low during the early period following BMT. Serum FT4 concentrations reverted to the low-normal range 1 year after transplant, and eight of 29 patients had subnormal and delayed TSH response to TRH consecutively. No children showed overt hypothyroidism. Basal and peak serum gonadotropin levels in response to LHRH were elevated in the patients who had received transplant around the time of puberty. Leydig cell function assessed by human chorionic gonadotropin test was normal. Three girls experienced menarche, and one male patient fathered a normal boy 7 years after BMT. Pituitary-adrenal function and prolactin secretion were not affected. A high incidence of transient hypothyroidism which did not require replacement therapy and gonadal failure among pubertal children were observed. Shielding of gonads should be attempted, if possible, at the time of preparative irradiation to prevent resultant hypogonadism.

Adolescent↗
PubMed1999

Dosimetry and growth hormone deficiency following cranial irradiation of childhood brain tumors.

BACKGROUND: Dosimetry of the hypothalamus-pituitary (HP) region could allow prediction of the risk of growth hormone deficiency (GHD) following cranial irradiation. PROCEDURE: Nineteen children (15 boys) with a median age of 6.3 years (range 1.7-16.5) at the time of irradiation of a brain tumor not involving the HP axis were followed for 1.2-6.3 years (median 3.4) from radiotherapy (RT). The dose to a standardized anatomical model including the HP region was calculated from dose-volume histograms of 10% to 100% in steps of 10% of the HP model based on data from a computer-based treatment planning system. If GHD was suspected from insulin-like growth factor-I, serum insulin-like growth factor binding protein-3, and/or height velocity measurements, an arginine stimulation test was performed. GHD was defined by a peak GH <15mU/liter. RESULTS: Ten patients developed GHD 10-26 months from irradiation. Cox regression analysis identified the 90% dose-volume of the HP box as the strongest predictor of development of GHD (P = 0.03). The median dose to the 90% dose-volume of the HP region was 37.5 Gy (range 2. 3-55.3). The cumulated risk of GHD 2.5 years after radiotherapy for children receiving more than and less than 37.5 Gy to the HP region was 87% and 33%, respectively (P = 0.036). CONCLUSIONS: Dosimetry of a defined HP volume provides the opportunity to 1) calculate the exact dose delivered to this region, 2) predict the risk of GHD and, 3) in the future revise the treatment planning and thus reduce the risk of endocrine adverse effects.

Adolescent↗
PubMed1988

[Two autopsy cases of primary pituitary carcinoma].

We studied two autopsy cases of primary pituitary carcinoma. Case-1. A 45 year old female was admitted on Oct. 4 1978, with a complaint of right homonymous hemianopsia. And diagnosis was pituitary adenoma. Partial removal of pituitary tumor was performed on Oct. 23 1978. She died on Dec. 5 1978 due to bleeding of gastrointestinal tract. Autopsy disclosed a pituitary carcinoma invading the left hypothalamus, mamillary body, optic and V cranial nerves, and mid brain as well as sphenoid bone. No extracranial metastasis was noted. Case-2. A 44 year old female with a history of acromegaly for 6 years was admitted with a complaint of headache on May 8 1976. She was diagnosed as having pituitary adenoma. The subtotal removal of pituitary tumor was performed on May 21 1976 and followed by 4500 rad irradiation. At this time, pathological diagnosis was eosinophilic adenoma. Seven years later, she complained of progressive right hearing disturbance, dysarthria and ataxic gait 1983. The second subtotal removal of pituitary tumor was performed with a diagnosis of recurrence of pituitary adenoma on Oct. 7 1983. After the operation, she complicated sepsis and died on Jan. 14 1984. An autopsy disclosed a pituitary carcinoma from residual pituitary gland, continuously extending to the subarachnoid space of the pons, and invading right cerebello-pontine angle and cerebellum. The histological examination revealed pituitary carcinoma with high pleomorphism and glioblastoma multiform-like feature were within the tumor.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1994

CNS germinomas: curable tumours in two adolescents.

Two cases of central nervous system germinoma are described which highlight the various presentations of this tumour in different anatomical locations. The first case is that of a 15 year old boy with a suprasellar germinoma who presented with the classical triad of diabetes insipidus, visual disturbance and hypopituitarism. The need for full hormonal evaluation and replacement therapy is stressed. In the second case a 14 year old boy with pineal germinoma presented with features of raised intracranial pressure, Parinaud's syndrome and normal anterior pituitary function. Both cases were treated with corticospinal irradiation which resulted in regression of the tumours. Follow up has now been for over 4 years with no sign of recurrence.

Adolescent↗
PubMed1989

Radiation-induced hypopituitarism is dose-dependent.

Radiation-induced hypopituitarism has been studied prospectively for up to 12 years in 251 adult patients treated for pituitary disease with external radiotherapy, ranging in dose from 20 Gy in eight fractions over 11 days to 45 Gy in 15 fractions over 21 days. Ten further patients were studied 2-4 years after whole-body irradiation for haematological malignancies using 12 Gy in six fractions over 3 days and seven patients were studied 3-11 years after whole-brain radiotherapy for a primary brain tumour (30 Gy, eight fractions, 11 days). Five years after treatment, patients who received 20 Gy had an incidence of TSH deficiency of 9% and in patients treated with 35-37 Gy, 40 Gy and 42-45 Gy, the incidence of TSH deficiency (22, 35 and 52% respectively) increased significantly (P less than 0.001) with increasing dose. A similar relationship was observed for both ACTH and gonadotrophin deficiencies when the 20 Gy group was compared to patients treated with 35-45 Gy (P less than 0.01 and P less than 0.05 respectively). Growth hormone deficiency was universal by 5 years over the dose range 35-45 Gy. In seven patients who were treated with 30 Gy in eight fractions over 11 days, deficiencies were observed at a similar frequency to the 40 Gy group (15 fractions, 21 days). No evidence of pituitary dysfunction was detected in the ten patients who received 12 Gy (six fractions, 3 days). Both total radiation dose and fractionation schedule may determine the incidence of pituitary hormone deficiencies. The dose below which deficiencies do not occur is probably irrelevant to therapeutic irradiation of pituitary and other intracranial neoplasms.

Adolescent↗
PubMed1990

Growth hormone secretion in children after therapy for acute lymphoblastic leukaemia.

In eight children, after the termination of therapy for acute lymphoblastic leukaemia (ALL) the secretion of growth hormone (GH) was determined by the stimulation test with clonidine. The children were treated in the period from 1983 till 1988 and they were administered chemotherapy, intrathecal methotrexate therapy and cranial irradiation 60CO in a dose of 1800 rads. In one case a complete GH deficiency was found, in three cases there was a partial deficiency and in the remaining cases the secretion was regular. No correlation was found between the biochemical values of GH and the clinical stature. There was also no interrelation between the duration of therapy (chemotherapy) and the degree of pituitary gland failure. We have compared the results of GH output in children treated for ALL with those of 44 children in whom short stature was diagnosed. The age in both groups was similar.

Child↗
PubMed1983

Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis.

Entrapment of surface epithelium within the ovarian stroma was proposed as an initial event in the pathogenesis of cystadenocarcinoma of the ovary. Subsequent events, including differentiation, proliferation, and eventual malignant transformation of the entrapped epithelium, may occur as a consequence of stimulation by estrogen or estrogen precursors. These events were more likely when the steroid producing stroma itself had been stimulated by high gonadotropins. Animal experiments suggested that gonadotropin excess and stromal stimulation may result by disturbing normal feedback inhibition between ovary and pituitary or by destroying ovarian follicles. By analogy, in humans, a number of common chemicals and drugs may increase gonadotropins by enhancing estrogen degradation in the liver or by directly stimulating production by the pituitary. Elevated gonadotropins may also result via mechanisms that cause primary ovarian failure including pelvic irradiation, exposure to chemicals or metabolites toxic to follicles, or ovarian infections such as mumps.

Cell Differentiation↗
PubMed1995

Proliferation-independent growth factor modulation of the radiation sensitivity of human prostate cells.

The survival of human prostatic epithelial cells irradiated in different physiological states is reported. Exponentially growing cells and contact-inhibited cells grown and irradiated in the presence of the growth factors epidermal growth factor (EGF) and bovine pituitary extract (bPE) had overlapping radiation dose-cell survival curves. However, when EGF and bPE were removed from exponentially growing cells before irradiation, an increase in radiosensitivity was observed if the cells were replated into medium containing growth factors (EGF and bPE) immediately after irradiation. Treating cells with the nonspecific growth factor receptor antagonist suramin had similar effects as did growth factor deprivation. In contrast, when growth factor-deprived cells were maintained in this same medium for 12 h postirradiation, an increase in radiation survival was observed. This increase in survival is attributed to the repair of potentially lethal damage (PLD). Both the increase in radiosensitivity induced by deprivation of growth factor before irradiation and the repair of PLD caused by deprivation of growth factor after irradiation were independent of changes in cellular proliferation.

Animals↗
PubMed1994

Pulsatile gonadotrophin-releasing hormone therapy in patients with pituitary tumours treated by surgery and irradiation.

OBJECTIVE: Pulsatile administration of GnRH for induction of ovulation is effective for women with idiopathic hypogonadotrophic hypogonadism. We were interested to assess the pituitary-ovarian response to pulsatile GnRH infusion and the therapeutic effectiveness of restoring ovulation in a group of hypogonadotrophic women previously treated with surgery and irradiation to pituitary tumours. PATIENTS: The group of patients comprised 15 hypogonadotrophic women, aged 29-40 years (mean 32.4 years), who had undergone transsphenoidal adenomectomy or craniotomy and irradiation with a total of 4500-5400 cGy in 25 fractional doses divided over 5-6 weeks. The time interval from irradiation to study was 6.3 +/- 2.0 years (mean +/- SD). TREATMENT: A single bolus GnRH (100 micrograms) test and pulsatile infusion of GnRH were performed to assess the pituitary gonadotrophin reserve and induce ovulation. We tried to correlate the pituitary response with characteristics of intracranial lesions on computerized tomography findings. We undertook ovarian biopsy in one patient who failed to respond to gonadotrophin therapy and pulsatile infusion of GnRH. RESULTS: Twelve women (80%) showed evidence of ovulation in response to pulsatile GnRH treatment and five subsequently became pregnant. Four of 12 ovulators were previous non-ovulators to exogenous gonadotrophin therapy. There was no correlation between pituitary response and character of lesions based on computerized tomography findings. A patient who failed to respond to either gonadotrophin or pulsatile infusion of GnRH had premature ovarian failure on ovarian histology. CONCLUSIONS: The functional reserve capacity of pituitary gonadotrophs may remain less impaired by tumour encroachment, pituitary surgery or irradiation than had previously been thought. This holds promise for ovulation induction in hypogonadotrophic patients who had been treated with surgery and irradiation for pituitary tumours.

Adult↗
PubMed2002

Growth in disorders of adrenal hyperfunction.

Growth is disturbed by adrenal hypersecretion of androgens or cortisol. Androgen excess in virilizing adrenal tumours causes advanced growth and bone age. In 9 girls with virilizing tumours, mean heights at diagnosis and final heights were 1.23 +/- 0.42 and 1.3 +/- 0.37 SDS respectively. In poorly controlled CAH, excess androgens cause early epiphyseal fusion and adult short stature. Increased growth occurs only after 18 months of age, even in untreated CAH, i.e. hydrocortisone >10 mg/m(2)/day is not generally required and may suppress infantile growth, affecting childhood and adult height. Growth was studied in 19 patients, aged 6.4-17.8 years, with Cushing's disease (CD). At diagnosis, mean height SDS was -1.81 (1.2 to -4.17), 53% < -1.8 SDS, height velocity in 6 was 0.9-3.8 cm/year and mean BMI SDS 2.29 (0.7-5.06). From 1983 to 2001, CD was cured in 18 patients (61%) by transsphenoidal surgery (TSS) alone and 39% by TSS plus pituitary irradiation (RT). In 13 patients, growth hormone (GH) was assessed by ITT/glucagons at 1-108 months after cure. Four had severe GH deficiency (<9 mU/l), 7 subnormal (10-29 mU/l) and 2 normal (>30 mU/l) GH status. Subnormal GH was present in 7 subjects >2 years after TSS or RT cure. In 10 subjects, aged 12.9 +/- 3.4 years, growth after cure was studied for 9.1 +/- 5.0 years. Nine had no catch-up growth in the interval of 0.3-1.1 years after cure (mean HV 5.3 +/- 2.4 cm/year). All these had GH deficiency peak GH 0.5-20.9 mU/l, and received hGH 2.7 mg/m(2)/week, 3 with GnRHa. All 10 showed long-term catch-up growth with mean delta SDS at diagnosis (Ht SDS-target Ht SDS) -1.72 +/- 1.26 improving to -0.83 +/- 1.08 (p = 0.0005) at latest of final Ht. At diagnosis, virilization was present in 82% of 17 patients with CD. Mean SDS values of serum androstenedione, DHEA-S and testosterone were normal, i.e. 0.72 (-2.9 to 3.0), -0.8 (6.0 to 2.2), 0.7 (-7.9 to 9.5) respectively, whereas SHBG was reduced at -2.1 (-5.3 to 1.2), increasing free androgen levels. Bone age (BA) was delayed (mean 1.46 years) in 14/16 patients, suggesting cortisol excess contributed more then androgen effect to skeletal maturation. In conclusion, most paediatric patients with CD had subnormal linear growth with delayed BA. After cure by TSS or pituitary irradiation, GH deficiency was frequent and persisted for many years. Treatment with hGH induced significant long-term catch-up growth leading to reasonable final height.

Adolescent↗
PubMed1975

Hypopituitarism after external irradiation. Evidence for both hypothalamic and pituitary origin.

Endocrine complications after radiotherapy for tumors of the head and neck are thought to be relatively rare. The availability of synthetic hypothalamic hormones for clinical investigations and the radioimmunoassay of hormones have enabled us to study function of the hypothalamic pituitary axis in 15 patients who had radiotherapy for nasopharyngeal cancer. Fourteen had evidence of endocrine deficiency. Twelve patients had evidence of hypothalamic dysfunction, 7 developed primary pituitary hormone deficiencies, and 3 developed primary hypothyroidism. These results indicate that [1] secondary hypopituitarism due to a hypothalamic lesion after radiotherapy for nasopharyngeal cancer may be more common than suspected in the past; [2] primary hypopituitarism after irradiation of extracranial tumors can occur; and [3[ primary hypothyroidism may result from irradiation of regional neck nodes.

Adolescent↗
PubMed1996

Bilateral simultaneous cavernous sinus sampling using corticotropin-releasing hormone in the evaluation of Cushing disease.

PURPOSE: To determine whether bilateral, simultaneous, cavernous sinus sampling after corticotropin-releasing hormone (CRH) stimulation offers as accurate detection and lateralization of Cushing disease as inferior petrosal sinus sampling does. METHODS: Seventeen consecutive patients with hypercortisolism and with high-dose dexamethasone suppression test results suggesting Cushing disease underwent bilateral cavenous sinus sampling with CRH stimulation. The diagnosis of Cushing disease was established in all patients by histologic examination or, if no tumor was found at surgery, by subtotal resection of the gland or radiation therapy resulting in eventual hypocortisolism or normal adrenal function and clinical remission. RESULTS: The sensitivity of cavenous sinus sampling with and without CRH in detecting Cushing disease was 94% and 71%, respectively. The abnormal side of the pituitary was correctly identified in all patients who had criteria for lateralization, yielding a positive predictive value of 100%. CONCLUSIONS: This small series suggests that cavernous sinus sampling with CRH is as accurate as inferior petrosal sinus sampling in detecting Cushing disease and perhaps more accurate in lateralizing the abnormality within the pituitary gland.

Adenoma↗
PubMed2000

[Multihormonal and multifunctional hypophyseal adenoma and the acromegaly syndrome].

Woman 75-year-old treated 30 years for syndrome of acromegaly refused pituitary surgery and irradiation. Five years and nine months before death she had a colon carcinoma successfully removed. Multinodular hyperfunctional goitre was treated with carbimazole. For six last years of life corticosteroids were given as a replacement therapy. Her cause of death was the heart failure due to acromegalic heart disease. In autopsy a large intrasellar and extrasellar pituitary adenoma without rests of nonneoplastic tissue was found. Nevertheless the target peripheral endocrine glands except ovaries, were not atrophic. A multinodular goitre and diffuse adrenocortical hyperplasia were revealed. Histology, and immunohistochemistry demonstrated that mot neoplastic cells were producing GH and ACTH, dispersly Prl, scattered cells were positive for beta-subunit of FSH, LH, TSH. Electron microscopy proved most of the cells to be densely granulated. We classify the adenoma according to the newly proposed WHO pituitary tumours classification (1) as plurihormonal, hyperfunctional, extrasellar, typical adenoma from densely granulated cells. We conclude that in plurihormonal adenomas with dominant (in the case referred acromegalic) symptomatology the additional hormonal production should be monitored as a possible source of important complications.

Acromegaly↗