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Long-term effect of hypophysectomy on various fractions of sulfhydryl groups in thyroid, adrenal and some other organs in rats.

The non-protein (NP-SH), total (T-SH) and protein bound sulfhydryl groups (PB-SH) were measured in the thyroid, adrenals, kidney, liver and skeletal muscle of hypophysectomized and sham operated adult male rats. After hypophysectomy, T-SH and PB-SH in the adrenals and thyroid decreased significantly (P less than 0.01). The maximal decline occurred at the intervals of 12-24 days after hypophysectomy. The NP-SH fraction, which is represented mainly by SH-glutathione, decreased within 24 h after hypophysectomy in both glands, then increased transiently and later it again decreased in parallel to the level of both T-SH and PB-SH. In the kidney, all fractions of SH groups increased at 4--8 days, then decreased markedly reaching control or even subcontrol levels. In contrast, we failed to observe hypophysectomy induced changes of any of the SH-fractions in the liver and muscle of rats.

Adrenal Glands↗

[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↗

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↗

Effect of hypophysectomy on cyclic 3',5'-nucleotidemetabolizing enzymes in the rat thyroid gland.

Adenylate cyclase and cyclic AMP phosphodiesterase activities in the thyroid gland were significantly reduced after hypophysectomy, followed by a gradual restoration of the enzyme activities to the levels seen in sham-operated rats whereas a slight and persistent reduction was evident in guanylate cyclase and cyclic GMP phosphodiesterase activities in the same tissue. These changes in enzyme activities were restored by TSH administration but not by ACTH. The recovery of activity produced by TSH administration was inhibited by cycloheximide. Hypophysectomy, or TSH and cycloheximide administration, did not produce any significant changes in the concentrations of calmodulin, suggesting that the alteration of these enzyme activities is not induced by a decrease in the concentration of calmodulin. Since forskolin activation of adenylate cyclase did not restore the reduced activity in the hypophysectomized rat thyroid to the level found in the sham-operated control rat thyroid, we conclude that there is a reduction of the amount of enzyme after hypophysectomy rather than a change of the active site on adenylate cyclase. The spontaneous restoration of adenylate cyclase and cyclic AMP phosphodiesterase activities after hypophysectomy implies that cyclic AMP-metabolizing enzymes are responsive to an autoregulatory mechanism in thyroid follicular cells.

3',5'-Cyclic-AMP Phosphodiesterases↗

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↗

Androgen-induced remissions after antiestrogen and hypophysectomy in stage IV breast cancer.

Fluoxymesterone (Halotestin), 10 mg p.o. BID, was given to 33 women with Stage IV breast cancer who had previously been treated wih the antiestrogen tamoxifen (Nolvadex) and of whom 17 had also undergone hypophysectomy. Objective remissions were obtained in 13 patients (39%) with an average duration of 11+ months. Response rate to fluoxymesterone was similar in patients who had previously responded to tamoxifen and in those who had failed. Duration of response was longer in the former group (12+ vs. 8 months), but this difference was not statistically significant. Of 17 patients who had been previously treated with tamoxifen and hypophysectomy, seven obtained further remission from fluoxymesterone for an average duration of ten months. Two patients with remissions from fluoxymesterone had previously failed to respond both to antiestrogen therapy and to the removal of the pituitary gland. Androgens appear to be an effective sequential endocrine treatment of Stage IV breast cancer after tamoxifen and hypophysectomy. The mechanism by which androgens induce tumor regression in some patients is probably not an antiestrogenic effect or an indirect effect mediated through the pituitary gland, but perhaps a direct action at the tumor level.

Breast Neoplasms↗

Transphenoidal hypophysectomy in the management of carcinoma of the prostate.

Fifteen consecutive patients with progressive metastatic prostate cancer who had failed primary endocrine therapy underwent surgical pituitary ablation by transphenoidal hypophysectomy. Eleven patients showed subjective improvement with reduced pain postoperatively. No patient had any evidence of an objective response although duration of survival was longer in subjective responders (15 months) than nonresponders (4 months). Neither the quality nor the duration of the initial endocrine-induced remission predicted the subsequent response to hypophysectomy. The lack of objective improvement in these patients suggests that the subjective responses seen in prostate cancer patients after hypophysectomy may be due to alterations in pain receptive mechanisms rather than to a favorable impact on the disease process itself.

Adult↗

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↗

Limb regeneration to digit stages occurs in well-fed adult newts after hypophysectomy.

Experiments were designed to determine the maximum survival time and extent of limb regeneration of well-fed adult newts (Notophthalmus viridescens) after complete hypophysectomy. Adult newts were either well-fed or fasted for 3 weeks at which time hypophysectomies were performed. Forelimbs were amputated 5 days posthypophysectomy. Fasted hypophysectomized newts did not survive beyond 4 weeks, and limb regeneration was either absent or abortive. All of the well-fed newts survived to 3 weeks posthypophysectomy, and even at 6 weeks posthypophysectomy showed 30% survival. In the complete absence of the pituitary gland, many of the fed newts regenerated limbs to digit stages. It is concluded that pituitary hormones are not an absolute requirement for limb regeneration of adult newts. Newts in good nutritional condition at the time of hypophysectomy survive longer and their limbs regenerate to more advanced stages.

Animals↗

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↗

Hypophysectomy produces analgesia and paraventricular lesions have no effect on formalin-induced pain.

Chemical destruction of the pituitary gland has been shown to alleviate severe cancer pain in a substantial proportion of patients. The underlying mechanisms, however, remain controversial. The present study investigated the effects of hypophysectomy in the formalin test, which provides an animal model of tonic pain, and attempted to determine a possible neural mechanism to explain the effectiveness of the procedure. Hypophysectomized rats displayed significantly less pain behavior in the formalin test than control rats that underwent a sham hypophysectomy, implicating the pituitary gland in the modulation of tonic pain. Since the paraventricular nucleus of the hypothalamus (PVN) provides a major source of input to the pituitary gland, the effects of electrolytic lesions of the PVN on tonic pain were examined. The results failed to show a significant effect of PVN lesions on pain responses in the formalin test. The results suggest that the pituitary gland modulates tonic pain in the formalin test and that the test provides an animal model to study possible mechanisms which underlie the relief of severe cancer pain by hypophysectomy. However, since PVN lesions did not affect the response of rats in the formalin test, it is possible that the PVN is only one of multiple interacting neural and endocrine structures that influence the functions of the pituitary.

Analgesia↗

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↗

Sex-dependent changes in the rat kidney after hypophysectomy.

Renal changes following hypophysectomy are investigated. Particular attention is given to sex differences in the ultrastructure of proximal tubule cells and in protein excretion. Regardless of gender, hypophysectomy is followed by an increase in urine volume. However, there is a concomitant reduction of proteinuria, which is much more pronounced in males than in females. Partial hypophysectomy with anterior pituitary function preserved also leads to increased urine excretion, but does not alter proteinuria. In both sexes there is a reduction of the tubule circumference, which again is more pronounced in males thereby moderating the sex difference. The proximal tubule cells display a segment- and sex-independent reduction in surface area, a decrease of Golgi areas and reduction of ribosomes. Mitochondrial changes (condensation of cristae) selectively affect the S3 segment. The changes in the lysosomes and microbodies are segment- and sex-dependent. The volume density of microbodies in the S3 segment increases considerably, particularly in females. The volume density of lysosomes undergoes an increase in the S1 cells of the males and a decrease in the S2 cells. In the females the volume density of these organelles shows little change in these tubule segments; a sex-dependent difference is not longer apparent in the S1 and S2 segments. By contrast, in S3, there is an increase in the volume density of lysosomes in both sexes. The present study confirms a connection between the morphology of lysosomes in the proximal tubule and proteinuria. The findings also point to a possible involvement of male sex hormones in the reabsorption of protein in the renal proximal tubule.

Animals↗

Immunohistochemical reactions of C-cell complexes in dogs after induced hypercalcemia, antithyroid drug treatment and hypophysectomy.

The C-cell complexes are remnants of ultimobranchial bodies retaining fetal characteristics. They contain C cells in various stages of differentiation, primordial follicles with small lacunae, follicular cell masses not yet forming follicles, and undifferentiated epithelial cells. By immunoperoxidase method using specific anti-calcitonin, anti-C-thyroglobulin and anti-19S thyroglobulin sera, the responses of C-cell complexes to hypercalcemia, thiourea, hypophysectomy and hypercalcemia after hypophysectomy were investigated systematically. These experimental conditions induced rapid differentiation and increased numbers of cells in the complexes. After chronic hypercalcemia, most of the complexes were occupied by mature C cells. The C cells in complexes similar to the cells in thyroid parenchyma presented increased mitotic activity, enlarged cell bodies and a marked decrease in materials immunoreactive for calcitonin and C-thyroglobulin. After prolonged administration of thiourea, follicular cell masses and small follicles, which underwent conspicuous hyperplasia and hypertrophy, markedly increased in the complexes and exceeded C cells in number. Typical undifferentiated cells were not recognized after hypercalcemia and treatment with thiourea, though they were unaffected by hypophysectomy. It is considered that undifferentiated cells develop into C cells after hypercalcemia and into follicular cells after treatment with thiourea; that is, undifferentiated cells seem to be the common precursor cell for both C cells and follicular cells.

Animals↗

Hypophysectomy and the sympatho-adrenal system in cold acclimation.

Hypophysectomy does not impair the increase in weight of brown adipose tissue and adrenals following cold acclimation of the rat. In brown fat, the cold-induced increases in NE and 5 HT contents are not modified by hypophysectomy. In adrenals, hypophysectomy does not change the NE content, but a fall in epinephrine content was observed.

Acclimatization↗

The effects of hypophysectomy and testosterone treatment on the composition and metabolism of testicular lipids.

The effects of hypophysectomy and of testosterone administration on lipid composition and metabolism of rat testicular tissue have been investigated. Increased concentrations of triacylglycerols and cholesterol were observed in testes of hypophysectomized compared to control (non-hypophysectomized) rats on the eighth day posthypophysectomy. Administration of testosterone maintained the concentrations of these lipids at about normal levels. The concentration of phospholipids was not affected by the hypophysectomy. Incorporation of 14C from 1-[14C] linoleate into testicular lipids was determined 24 hours after intratesticular injection. In hypophysectomized compared to control rats there was more 14C in C 16:0, C 20:2 and C 20:3 and less 14C in C 20:4 and C 22:4 of both phospholipids and triacylglycerols. After intratesticular injection of 1-[14C] eicosatrienoate there was more 14C in C 16:0 and C 20:3 and less 14C in C 20:4 and C 22:4 of both phospholipids and triacylglycerols of hypophysectomized compared to control rats. Intratesticular injection of 1-[14C]-arachidonate resulted in less 14C incorporation in C 22:4 in testes of hypophysectomized than in those of control rats. Treatment with testosterone did not affect the metabolism of any of the 14C-substrates. These results indicate that the testicular desaturation of C 20:3 to arachidonate, requiring a delta 5 desaturase, is inhibited by hypophysectomy and that testosterone by itself may control the concentrations of some testicular lipid classes but not the metabolism of the polyenoic acids.

Animals↗

Modulation of preoptic regulatory factor-2 (porf-2) mRNAs by castration and hypophysectomy.

Neuropeptides are central to the regulation of mammalian gender-dependent development and reproduction. Preoptic regulatory factor-2 is a neuropeptide gene that is known to be expressed in rat brain and testis. In the brain, expression is gender-dependent and age-dependent. Tissue-specific transcripts are found in the preoptic area (POA) of the hypothalamus and in the testis. In order to investigate the effects of reproductive hormone status on expression of porf-2 in the male rat, porf-2 transcripts were studied by Northern blot analysis in intact, hypophysectomized, and castrated rat POA, medial basal hypothalamus (MBH), cerebral cortex (CC), testis, and liver. Castration of hypophysectomy increased levels of the brain-specific 0.84 kb 5' porf-2 transcript in the POA, but did not affect levels of this transcript in the CC. There was a small decrease in the MBH following castration. Hypophysectomy also resulted in a fourfold increase in the 5' 1.1 kb testis-specific transcript. The affected transcripts are localized to the cytoplasm. A nontissue specific 3' transcript was also detected. Interestingly, this 0.6 kb transcript became non-detectable in all tissues examined following hypophysectomy. Porf-2 mRNA was also detected in human hypothalamus, testis, adrenal, placenta, and prostate with unique transcripts in each tissue examined . It has been shown elsewhere that porf-2 is a unique single copy gene in the rat genome. These data demonstrate that expression of the porf-2 gene is differentially regulated at the pretranslational level by intrinsic tissue-specific, as well as extrinsic pituitary and gonadal factors. The selected responses to reproductive hormonal status suggest that porf-2 may play a role in hypothalamic pituitary-gonadal interactions.

Animals↗

The effect of hypophysectomy on pancreatic islet hormone and insulin-like growth factor I content and mRNA expression in rat.

The growth arrest after hypophysectomy in rats is mainly due to growth hormone (GH) deficiency because replacement of GH or insulin-like growth factor (IGF) I, the mediator of GH action, leads to resumption of growth despite the lack of other pituitary hormones. Hypophysectomized (hypox) rats have, therefore, often been used to study metabolic consequences of GH deficiency and its effects on tissues concerned with growth. The present study was undertaken to assess the effects of hypophysectomy on the serum and pancreatic levels of the three major islet hormones insulin, glucagon, and somatostatin, as well as on IGF-I. Immunohistochemistry (IHC), in situ hybridization (ISH), radioimmunoassays (RIA), and Northern blot analysis were used to localize and quantify the hormones in the pancreas at the peptide and mRNA levels. IHC showed slightly decreased insulin levels in the beta cells of hypox compared with normal, age-matched rats whereas glucagon in alpha cells and somatostatin in delta cells showed increase. IGF-I, which localized to alpha cells, showed decrease. ISH detected a slightly higher expression of insulin mRNA and markedly stronger signals for glucagon and somatostatin mRNA in the islets of hypox rats. Serum glucose concentrations did not differ between the two groups although serum insulin and C-peptide were lower and serum glucagon was higher in the hypox animals. These changes were accompanied by a more than tenfold drop in serum IGF-I. The pancreatic insulin content per gram of tissue was not significantly different in hypox and normal rats. Pancreatic glucagon and somatostatin per gram of tissue were higher in the hypox animals. The pancreatic IGF-I content of hypox rats was significantly reduced. Northern blot analysis gave a 2.6-, 4.5-, and 2.2-fold increase in pancreatic insulin, glucagon, and somatostatin mRNA levels, respectively, in hypox rats, and a 2.3-fold decrease in IGF-I mRNA levels. Our results show that the fall of serum IGF-I after hypophysectomy is accompanied by a decrease in pancreatic IGF-I peptide and mRNA but by partly discordant changes in the serum concentrations of insulin and glucagon and the islet peptide and/or mRNA content of the three major islet hormones. It appears that GH deficiency resulting in a "low IGF-I state" affects translational efficiency of these hormones as well as their secretory responses. The maintenance of normoglycemia in the presence of reduced insulin and elevated glucagon serum levels, both of which would be expected to raise blood glucose, may result mainly from the enhanced insulin sensitivity, possibly due to GH deficiency and the subsequent decrease in IGF-I production.

Animals↗