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PubMed1978

Endocrinologically incomplete transethmoidal trans-sphenoidal hypophysectomy with relief of bone pain in breast cancer.

To assess endocrinologic completeness of transethmoidal trans-sphenoidal hypophysectomy and the relation between postoperative pituitary hormone levels and relief of bone pain, we tested pituitary reserve by measuring base-line values of follicle-stimulating hormone and luteinizing hormone, thyrotropin-relasing-factor-stimulated thyrotropin and prolactin, and levodopa-stimulated growth hormone after hypophysectomy in 15 menopausal women with metastatic breast cancer. In all 15 bone pain diminished or disappeared within 24 hours of operation. Pituitary-function testing identified only one patient as having had an endocrinologically complete hypophysectomy. Base-line gonadotropin levels and thyrotropin-releasing-factor-stimulated prolactin were the most reliable measures of residual pituitary function. We conclude that transethmoidal trans-sphenoidal hypophysectomy may not totally ablate pituitary endocrine function; effective relief of bone pain in patients with metastic breast cancer can follow this procedure despite residual pituitary function and the lack of objective tumor remission.

Bone Neoplasms↗

PubMed1992

Inhibition of metastatic behavior of murine osteosarcoma by hypophysectomy.

BACKGROUND: We recently reported that human osteogenic sarcoma cells are mitogenically responsive in tissue culture to insulin-like growth factor I (IGF-I), a mitogen important in the regulation of cellular proliferation of many tissues, including bone. PURPOSE: The present study was designed to determine whether these in vitro observations could be extended to an in vivo experimental system and whether reduction of IGF-I levels by hypophysectomy could inhibit the aggressive metastatic behavior of osteosarcoma. METHODS: We used standard competitive binding and affinity-labeling techniques to characterize the IGF-I-binding sites of MGH-OGS, a model of human osteosarcoma. Radioimmunoassay of serum, preprocessed to remove IGF-binding proteins, was used to quantitate IGF-I levels. In vitro proliferative response of MGH-OGS cells to IGF-I and other pituitary-dependent factors was determined by thymidine-incorporation experiments. In vivo growth of the neoplasm in 12 hypophysectomized C3H mice and in 14 control C3H mice was determined by serial measurements of implanted tumors and by gross and microscopic examination of the lungs for metastases. RESULTS: MGH-OGS exhibited specific binding sites for 1.39 pmol IGF-I per milligram MGH-OGS cellular membrane protein, a concentration similar to that which we previously reported for human osteosarcoma. In tissue culture, MGH-OGS exhibited mitogenic response to IGF-I (P less than .01) but not to other pituitary-dependent factors. Hypophysectomy reduced levels of circulating IGF-I to 15% of control, significantly inhibited local growth of MGH-OGS tumors (increased time for growth to 1 cm3 from 49 to 84 days, P less than .001), and profoundly inhibited metastatic behavior (decrease in mean number of metastases per host from 16 to less than one; P less than .001). CONCLUSIONS: This study is the first to document the profound inhibitory effect of hypophysectomy on the metastatic behavior of an experimental sarcoma. We conclude that the metastatic behavior exhibited by MGH-OGS osteosarcoma is dependent on pituitary factors, and we suggest that the inhibitory effects of hypophysectomy are related, at least in part, to the reduction of IGF-I levels.

Animals↗

PubMed1975

Response of the hypothalamic neurosecretory system of the female catfish, Heteropneustes fossilis (Bloch), to hypophysectomy.

The effect of hypophysectomy on the hypothalamic neurosecretory system of the catfish, H. fossilis, was studied. Hypophysectomy resulted initially in an accumulation of NSM at the distal ends of the cut axons. The axons had grown and were reorganized into a neurohypophysis-like structure 3 weeks after hypophysectomy, and this persisted even more than 3 years post-hypophysectomy.

Animals↗

PubMed1977

Differential effect of hypophysectomy on the synthesis of beta-glucuronidase and other androgen-inducible enzymes in mouse kidney.

The levels of several androgen responsive enzymes including beta-glucuronidase, alcohol dehydrogenase, D-amino acid oxidase and arginase, were compared in kidneys of normal and hypophysectomized female mice after treatment with testosterone. While hypophysectomy did not alter the basal level of glucuronidase, the androgen-mediated accumulation of kidney beta-glucuronidase was greatly decreased in hypophysectomized mice. Measurements of the rate of synthesis of glucuronidase showed that after androgen treatment the enzyme was synthesized in kidney of hypophysectomized mice at only 5% the normal rate. Glucuronidase activity in seven other organs was not appreciably affected by treatment with androgens or by hypophysectomy. Unlike the effect of hypophysectomy on kidney glucuronidase, there was no reduction in the accumulation of alcohol dehydrogenase or D-amino acid oxidase in kidney of hypophysectomized mice after androgen treatment. Hypophysectomy caused a large reduction in kidney arginase activity. However, subsequent administration of testosterone restored much of this activity. It is concluded that there are at least two mechanisms by which androgens increase enzyme activity in kidney. The normal increase in activity or rate of synthesis of beta-glucuronidase following androgen administration requires pituitary hormones and/or products of these hormones, while the increase in activity of enzymes like alcohol dehydrogenase and D-amino acid oxidase does not require pituitary hormones.

Adrenalectomy↗

PubMed1975

Hormonal influences on the level of testicular androgen binding activity: effect of FSH following hypophysectomy.

Concentrations of high affinity (Ka equals 5.5 plus or minus 0.83 times 10-8M-1) androgen binding activity in carbonextracted rat testicular supernatants have been determined by Scatchard plot analysis under a variety of hormonal situations: (a) 0-90 days following hypophysectomy; (b) 0-60 days of daily injection of NIH-FSH-P1 (150 mug) beginning 1 day after hypophysectomy; and (c) 0-60 days of daily FSH treatment beginning 30 days after hypophysectomy. The high affinity binding component declined from 0.32 pmoles/mg protein intact adults to 0.28, 0.17, and less than 0.08 (limit of detectability) pmoles/mg protein at 11, 16 and 31 days, respectively. FSH treatment beginning immediately after surgery slowed this decline, giving values of 0.30, 0.17, and 0.12 pmoles/mg protein after 11, 29, and 54 days of treatment, respectively. Expressed as pmoles per testis this represented 96, 61, and 40% of the intact control level. Similar effects on the level of androgen binding protein (Rf 0.54) were measured by steady-state polyacrylamide gel electrophoresis (PAGE). The concentration in both testis and epididymis declined gradually to nondetectable levels by 30 days after surgery. FSH treatment for 11, 29, and 54 days, respectively, resulted in 0.37, 0.38, and 0.03 pmoles of sites/mg protein in testis compared to 0.34 in intact controls and 5.7, 2.6, and 0.2 pmoles/mg protein in epididymis compared to 2.8 in intact controls. Doses of 80, 150, and 300 mug FSH/rat/day for 3 days beginning 30 days after hypophysectomy when postmeiotic elements of the germinal epithelium had degenerated caused graded increases in both testicular and epididymal levels of androgen binding protein. Prolonged FSH treatment (150 mug) under these conditions resulted in an increase in binding activity to a level of 0.12, 0.19, 0.17, and 0.20 pmoles/mg protein after 3, 11, 25, and 56 days of treatment. On a per testis basis this represented less than 20% of intact control levels. PAGE estimates were comparable except at the long treatment intervals. These results indicate that FSH treatment influences the level of androgen binding protein in adult testis and epididymis. This may reflect a direct influence on synthesis, degradation, and transport and/or indirect effects on general maintenance and responsiveness of the pertinent cell types.

Animals↗

PubMed1975

The effect of hypophysectomy and prolactin therapy on water balance of the brown trout Salmo trutta.

A technique for the hypophysectomy of the brown trout is described which might be applicable to other salmonids. Hypophysectomy produced a decrease in water turnover which was corrected by prolactin therapy. Hypophysectomy resulted in a decrease in the next flux of osmotic water. Both osmotic and diffusional water permeabilities were evenly decreased after hypophysectomy, such that the ratio of the osmotic and diffusional permeability coefficients (Pos/Pd) retained a value of approximately unity. The data suggest that calcium and prolactin have opposing actions on water balance and that their modes of action are likely to separate.

Animals↗

PubMed1977

The influence of hypophysectomy on NSILA concentrations in the dog: evidence for partially pituitary-independent regulation.

Non-suppressible insulin-like activity (NSILA) was determined in 5 dogs before and after hypophysectomy. All NSILA determinations were carried out on serum samples after acidic Sephadex G-50 chromatography by two different assay systems, i.e. a bioassay and a protein binding assay. The levels of NSILA decreased significantly after hypophysectomy and returned to near normal levels after 2 weeks. T3-, T4- and cortisol levels were drastically reduced during the entire period of the experiment. Several GH determinations after hypophysectomy revealed very low levels. Insulin-induced hypoglycaemia failed to provoke a rise of GH levels as late as 4 months after hypophysectomy. These findings indicate that: 1) The pituitary gland cannot be the site of synthesis of NSILA. 2) NSILA concentrations in the dog are maintained at a near normal level in the presence of very low growth hormone and thyroid hormone concentrations, so that these latter hormones do not appear to be the only regulatory factors concerned in NSILA synthesis.

Animals↗

PubMed1975

Relatively greater increase of oxytocin than vasopressin in the supraoptic nucleus of rats after hypophysectomy.

The vasopressor and milk ejection activities were estimated in the supraoptic region of the hypothalamus of rats which had been hypophysectomized 30 min, 4 and 8 days earlier. Both pressor and milk ejection activities were significantly greater 4 days after hypophysectomy than those in sham-operated control rats. Eight days after hypophysectomy, pressor activity decreased below control values but milk ejection activity was still significantly raised. Increased biological activity after hypophysectomy is thus associated with the previously observed increase in neurosecretory material within the supraoptic nucleus so these results provide additional evidence that neurosecretory material represents stored hormone. Milk ejection activity increased relatively more than pressor activity which supports the suggestion that the final stage in the formation of neurohypophysial hormones occurs as they pass from the hypothalamus to the neural lobe. If this final maturation normally occurs more slowly for oxytocin than for vasopressin, the obstruction to the flow of hormones down the neural stalk caused by hypophysectomy would result in a greater increase in milk ejection than pressor activity.

Animals↗

PubMed1979

Transsphenoidal hypophysectomy for disseminated carcinoma of the prostate gland. Results in 53 patients.

Transsphenoidal microsurgical hypophysectomy was performed in 53 men with disseminated carcinoma (Stage IV) of the prostate gland. The mean age was 64.8 years. Forty-three of the 53 men had severe pain due to their disease. Significant pain relief was obtained following hypophysectomy, usually within 24 hours, in 39 (91%) of these 43 patients. Objective remission occurred in 16 (36%) of 45 patients in whom the follow-up review was adequate to make this decision. Although dramatic, pain relief was not permanent in every patient. Four patients died in the early postoperative period, and in one, death was directly related to the operative procedure. Significant complications included partial diabetes insipidus in 40 cases (75.5%), and cerebrospinal fluid leaks in six (11.3%). The authors conclude that hypophysectomy is an appropriate operation in patients with disseminated carcinoma of the prostate gland, particularly when pain is a significant feature of the illness. Further, the transsphenoidal microsurgical approach appears to be the operative procedure of choice for performing hypophysectomy.

Aged↗

PubMed1979

[The effect of hypophysectomy on the epiphyseal cartilage plate of the rat tibia--electron microscopy and histochemistry of the epiphyseal proliferative zone (author's transl)].

It is a well-known fact that longitudinal bone growth is affected especially by hypophysis among other various endocrine organs. Using young rats, changes in body weight and in length of the tibia were studied after removal of hypophysis, and alterations occurring in the proximal epiphyseal cartilage plate of the tibia playing an important role in longitudinal bone growth were examined under light and electron microscopes, with special emphasis on the proliferative zone. Alterations of ATP-ase activity of ruthenium red affinity were also examined electron microscopically. Further, quantitative analyses of the alterations of cell organelles were performed using low power electron micrographs. 1) Following hypophysectomy, immediate suppression in weight gain occured, and little or no gain was seen from 14 to 28 days after removal of the gland with plateau in body weight. Longitudinal bone growth of tibia was also suppressed, and little or no growth was seen from the 14th day afterward as was the case for body weight. 2) Changes revealed by light microscopic examination included reduced width of epiphyseal cartilage plate, decreased number and disturbed arrangement of chondrocytes, rapid transition from proliferative zone to degenerative zone, and disturbed formation of the subchondral trabecula. 3) Electron microscopic examination revealed poor development of rough surfaced endoplasmic reticulum in the cell of proliferative zone, Golgi apparatus ocnsisting of lamellae and a relatively large numbers of vesicles and pronounced decrease in vacuoles. In addition, accumulation of lipid droplets and glycogen granules were seen together with mitochondria exhibited swelling and elevation of electron density in their matrices. ATP-ase activity was decreased. In the cartilage matrix of the proliferative zone, collagen fibrils and ruthenium red positive granules were decreased in number. 4) Rough surfaced endoplasmic reticulum, Golgi apparatus, and cytoplasmic vacuoles were treated quantitatively by dividing the proliferative zone into two parts of upper and lower layers. The data showed marked decrease in the every item examined after hypophysectomy. 5) These results indicate that hypophysectomy causes a decrease in intracellular metabolism of chondrocytes in the proliferative zone with a reduced function of matrix formation. The suppression of longitudinal bone growth after hypophysectomy appears to occur under an intimate correlation with a decrease in matrix formation by the chondrocytes of proliferative zone and inhibition of proliferation of the cells in this zone.

Animals↗

PubMed1977

Treatment of breast cancer with antiestrogen: approach to medical hypophysectomy?

Tamoxifen (ICI 46474), an antiestrogen, was given to 89 selected patients with stage IV breast cancer at a dose of 20 mg orally every 12 hours. Forty-seven percent of the patients had objective tumor regression averaging 11+ months with 25 of 42 women still in remission. In the first 39 patients where the minimum follow-up period is 16 months the average duration of remission is more than 15 months with 8 of 19 patients still in remission. These results are approaching those of surgical hypophysectomy, where, in our experience the average remission lasts about 18 months. Thus, Tamoxifen is a highly effective antitumor agent and is probably the initial treatment of choice for women with hormone responsive breast cancer. Antiestrogen induced objective remissions in 5 of 19 patients who had previously responded to surgical hypophysectomy, and 5 additional patients showed no progression of disease lasting 15+ months. Estradiol and estrone were detectable in the serum of these patients whereas, prolactin and growth hormone were not detectable. Thus, antiestrogen can induce remissions in some patients in the absence of the pituitary gland, and this constitutes additional palliation and provides evidence that estrogens can directly stimulate tumor growth. Four of 7 patients who obtained remissions from Tamoxifen obtained further improvement from hypophysectomy, and 1 of 8 patients who failed to benefit from antiestrogen improved after hypophysectomy. These results suggest that prolactin and growth hormone may also play a role in stimulating tumor growth in some patients.

Animals↗

PubMed1975

Hypophysectomy in metastatic breast cancer.

Experience with 50 women undergoing extracranial transethmoidal-sphenoidal hypophysectomy for metastatic breast carcinoma with 12-month follow-up showed an objective remission of metastases after hypophysectomy in 58% of patients. The highest incidence of remission following the operation occurred in those women with only osseous metastases (83%) or with previous remission to both therapeutic oophorectomy and androgen administration (86%). No patient with primary central nervous system metastases, only one of ten with hepatic metastases, and none who had failed to respond to both oophorectomy and exogenous androgen administration experienced remission after hypophysectomy. The operative approach to the pituitary was via a periorbital incision, the posterior ethmoid cells, and the sphenoid sinus. Cerebrospinal fluid rhinorrhea occurred in three early patients, and has been successfully avoided in later ones by a fascia lata graft. Diabetes insipidus, seen in 13 patients, and extraocular palsies, seen in two, were transient.

Adult↗

PubMed1975

Trans-sphenoidal hypophysectomy in disseminated carcinoma of the breast.

One hundred and eight patients with advanced carcinoma of the breast were treated by trans-sphenoidal hypophysectomy and followed up for at least 1 year. The results were assessed both by clinical response and objectively by survival following hypophysectomy, as expressed by the survival ratio. The two methods showed close correlation. The results show that there is a variation in response relating to menopausal status and age at diagnosis, subsequent hormonal manipulaton and physical condition at hypophysectomy. Younger patients whose carcinoma is diagnosed after menopause carry a good prognosis, yet the older premenopausal patients, especially if their clinical condition is poor, do not benefit. Easily available clinical information can be a guide to prognosis.

Activities of Daily Living↗

PubMed1977

Post-hypophysectomy insulin response in patients with advanced breast cancer.

Seven postmenopausal women with metastic breast cancer underwent transsphenoidal hypophysectomy. The rate of disappearance, k*, of iv glucose and insulin following iv glucose and l-arginine infusion was determined before and after the ablation. The k* was estimated with a linear least squares weighted regression method. The insulin secretory capacity of the pancreas before and after the ablation was evaluated with the index of insulinogenic reserve, the index representing the quantity of insulin secreted per unit of glycemic stimulus. Following iv glucose and arginine, there was no significant difference in the mean k* for glucose and insulin, before and after the ablation. The insulinogenic index before was lower than the normal. After hypophysectomy, the index decreased further for the first 30 min following iv glucose. In patients with advanced cancer the index of insulinogenic reserve is lower than normal and is suppressed further by hypophysectomy.

Blood Glucose↗

PubMed1977

Long term effect of hypophysectomy and prolactin treatment on kidney structure in the eel in fresh water.

Long term effects of hypophysectomy and ovine prolactin treatment on the histological picture of the kidney were investigated in European eels. The epithelial cell height is very slowly affected after hypophysectomy, the decrease being highly significant after 50 days only in the distal and the initial collecting tubules. Nuclear surfaces were more rapidly reduced, the regressive changes being first detected in the initial collecting tubule (5 days), then in the distal portion and the two proximal segments. No degenerative changes were observed. These structural responses may be correlated with the slow reduction of the urine flow and of the plasma electrolytes in the same species. Ovine prolactin treatment (10mug/g/day) overcompensates the effects of hypophysectomy on the epithelial cell height and the nuclear area, and even after 50 days still induces the proliferation of new tubules although its action remains less intense than in intact eels. Other histological criteria (brush border thickness, mitotic activity, basal structure of proximal 2 cells) and sodium retention do suggest that these structural modifications reflect an increased functional activity of the kidney in addition to the effect of prolactin on sodium fluxes in the gills.

Anguilla↗

PubMed1979

Effect of hypophysectomy on alpha-melanotropin in discrete regions of the rat brain.

The effect of hypophysectomy on alpha-melanotropin (alpha MSH) concentrations in discrete brain regions was investigated. Hypophysectomy resulted in a 38-69% decrease in alpha MSH concentration in alpha MSH terminal regions 4 weeks after surgery. In contrast, the alpha MSH concentration in the arcuate nucleus, site of alpha MSH containing perikary, was unaffected by hypophysectomy. These results indicate that the brain alpha MSH system is distinct from, but related to that of the pituitary.

Animals↗

PubMed1979

Effect of hypophysectomy on the rates of protein synthesis and degradation in rat liver.

The effect of hypophysectomy on the protein metabolism of the liver in vivo was studied. Fractional rates of protein synthesis and degradation were determined in the livers of normal and hypophysectomized rats. Synthesis was measured after the injection of massive amounts of radioactive leucine. Degradation was estimated either as the balance between synthesis and accumulation of stable liver proteins or from the disappearance of radioactivity from the proteins previously labelled by the injection of NaH14CO3. The results indicate that: (1) hypophysectomy diminishes the capacity of the liver to synthesize proteins in vivo, mainly of those that are exported as plasma proteins; (2) livers of both normal and hypophysectomized rats show identical protein-degradation rates, whereas plasma proteins are degraded slowly after hypophysectomy.

Animals↗

PubMed1976

Effect of hypophysectomy and insulin on lipogenesis in cockerels.

Hypophysectomy increases hepatic lipogenesis in cockerels. In an attempt to find the possible hormonal mechanism for this we have examined the effects of hypophysectomy, insulin and pituitary homogenates on hepatic lipogenesis. Insulin (5 U/kg) injected intravenously, simultaneously with glucose-14C tracer, increased the amount of 14C found in liver lipids at 30 min after the injection. Similarly, insulin injected 5 min before killing, increased the incorporation of glucose-14C and acetate-14C by liver slices during a 30 min incubation. Hypophysectomy increased lipogenesis within 24 hours. The effect of insulin was most pronounced in hypophysectomized cockerels. The activity of the lipogenic enzyme, acetyl CoA carboxylase was similarly affected. A homogenate of chicken pituitaries added to the medium reduced lipid synthesis from glucose-14C by liver slices. This effect was larger in liver slices in which lipogenesis had been stimulated by insulin. The increased rate of hepatic lipgenesis in hypophysectomized cockerels may be caused partly by increased hepatic sensitivity to the lipogenic action of insulin or by the removal of a direct inhibition by pituitary hormones.

Acetyl-CoA Carboxylase↗