Antiestrogen treatment of breast cancer: an overview.

The nonsteroidal antiestrogen tamoxifen has emerged as a highly effective, nontoxic endocrine therapy for women with Stage IV and II estrogen receptor-positive breast cancer. Tamoxifen appears to act by blocking endogenous estrogen action at the target tissue level rather than by suppression of circulating estrogen levels. In a series of 113 consecutive, selected patients with Stage IV breast cancer, tamoxifen induced objective remissions in 50% lasting an average period of 21 + months and a median period of 16 months. These results are comparable to previous results with surgical hypophysectomy. Recent randomized studies comparing pharmacological doses of estrogen versus tamoxifen in postmenopausal women with Stage IV breast cancer have shown comparable results with these two treatment modalities. Antiestrogen therapy has been shown to be effective in some patients after prior endocrine additive therapy and, in particularly, after ablative procedures, such as ovariectomy, adrenalectomy, and hypophysectomy. It has been shown that circulating estrogens are not completely eliminated following ablation of these endocrine glands, which may account for the effectiveness of antiestrogen in this setting. Other endocrine therapies have been shown to be effective after prior treatment with antiestrogen. Hypophysectomy can induced remissions in 60% of patients who initially responded to tamoxifen and in 25% of patients who failed to benefit from tamoxifen. Recent studies have shown that aminoglutethimide plus hydrocortisone may also induce remissions in some patients after prior treatment with tamoxifen. This latter finding is of particular interest since aminoglutethimide is thought to work by blocking estrogen production, and the finding suggests that tamoxifen does not completely block all endogenous estrogen activity. Fluoxymesterone has been shown to induce remissions after tamoxifen or after tamoxifen plus hypophysectomy, and there was no correlation between the response to antiestrogen abd subsequent response to androgen. Because of its effectiveness and minimal side effects, tamoxifen is considered to be an initial endocrine therapy of choice in women with breast cancer. However, it has its limitations, as demonstrated by the results of secondary endocrine therapies such as hypophysectomy, medical adrenalectomy, and androgen therapy.

Growth enhancement of N-nitrosomethylurea-induced rat mammary tumor cells in soft agar by estrogen or prolactin.

Cells obtained from N-nitrosomethylurea-induced rat mammary tumors were grown in vitro using the soft-agar clonogenic assay technique. Their growth was studied in regular media containing serum as well as in media lacking serum, but to which insulin was added. Deletion of serum from the media resulted in a mean decrease of 49% in the number of colonies formed in vitro in 13 of 18 tumors and was without effect in the remaining 5 tumors. The addition of either 17 beta-estradiol (10(-8) M) or ovine prolactin (OPRL, 100 ng/ml) to the defined media resulted in an increase in the number of colonies formed in 12 of 18 tumors. The mean numbers of colonies per Petri dish in 17 beta-estradiol- and OPRL-treated Petri dishes were 95 +/- 5.4 (S.E.) and 92 +/- 6.2% of the values seen in serum-containing media. Simultaneous addition of both hormones to the defined media resulted in a significant increase in the number of colonies formed which was greater than that seen when either hormone was added separately. Of four tumors where neither hormone influenced colony formation, the addition of both 17 beta-estradiol and OPRL resulted in an increase in the number of colonies formed in three tumors. We conclude that the N-nitrosomethylurea-induced mammary tumors can be grown in soft agar using defined media and that their growth can be enhanced by either 17 beta-estradiol or OPRL. These hormones have a synergistic effect on the growth of some of these tumors in vitro. These data are consistent with the known in vivo effects of these hormones on the N-nitrosomethylurea-induced rat mammary tumors.

Influence of estradiol and tamoxifen on the growth of N-nitrosomethylurea-induced rat mammary tumor cells in soft agar.

N-Nitrosomethylurea-induced rat mammary tumors were grown in vitro using the clonogenic soft agar technique. Cells from all tumors (n = 46) formed colonies in vitro. Tamoxifen (10(-7), 10(-6) M) inhibited colony formation to 72 and 53% of control values, respectively. The inhibitory effect of tamoxifen could be reversed with the addition of estradiol (10(-10) to 10(-8) M) to the medium. Estradiol (10(-10) to 10(-8) M), on the other hand, added alone to serum-containing medium did not influence the number of colonies formed in vitro. We conclude that the soft agar clonogenic assay is a feasible technique to study the influence of hormones and antihormones in vitro. The effects of tamoxifen and estradiol noted in vitro were similar to the known in vivo effects of these agents.

Effect of ovariectomy on hormone receptors and growth of N-nitrosomethylurea-induced mammary tumors in the rat.

Estrogen receptor(s) (ER), progesterone receptor(s) (PGR), androgen receptor(s) (ANR), and prolactin receptor(s) (PRLR) were measured in N-nitrosomethylurea-induced mammary tumors in intact female Sprague-Dawley rats and in rats 9 days after ovariectomy. Following ovariectomy, 12 of 15 tumors regressed to 47.7 +/- 5.5% of the original size (hormone-dependent tumors), while the remaining three had arrest of growth reaching 88.8 +/- 7.3% of their original sizes. Cytosol ER level was 50.3 +/- 6.6 fmol/mg protein in tumors of intact rats and was significantly lower (25.6 +/- 8.3 fmol/mg, p < 0.025) in the ovariectomized group. PGR was abundantly present in ten of 13 tumors of intact rats (mean, 144.5 +/- 46.8) but was undetectable in five of six hormone-dependent tumors after ovariectomy (p < 0.01). ANR ws detectable at low levels in only four of 13 tumors of intact rats but in none of six hormone-dependent tumors after ovariectomy. PRLR was not significantly different in tumors of intact and ovariectomized rats (20.6 +/- 2.4 and 15.6 +/- 1.8 fmol/mg, respectively). In three tumors that had arrest of growth after ovariectomy, the levels of ER, PGR, ANR, and PRLR were not significantly different from those of the hormone-dependent tumors. We conclude that the majority of N-nitrosomethylurea-induced rat mammary tumors are hormone dependent. ER, PGR, and PRLR were abundantly present in the majority of these tumors, while ANR was present in only four of 13 tumors. The levels of ER and PGR were significantly lower following ovariectomy, while PRLR was not significantly changed.

Influence of tamoxifen and estradiol on the growth of human breast cancer cells in vitro.

Cells obtained from freshly resected human breast cancer were grown in vitro utilizing the soft agar technique. The effects of adding an antiestrogen (tamoxifen, TAM) and 17 beta-estradiol alone or simultaneously on cell growth were assessed. The addition of TAM (10(-6) M) to the medium resulted in a significant decrease in cell growth in 26 of 36 (72%) estrogen receptor (ER)-positive tumors and in one of 5 ER-negative tumors (20%). The degree of inhibition caused by TAM was significantly higher in the ER-positive tumors that also contain the progesterone receptor (PgR) as compared to those that lacked that receptor (i.e., PgR negative) (46.2 +/- 2% versus 36.2 +/- 1.2% inhibition, P less than 0.01). The simultaneous addition of 17 beta-estradiol (10(-8) M) neutralized the inhibitory effect of TAM (10(-6) M) in the majority of tumors. With the presence of serum in the medium, the addition of 17 beta-estradiol alone resulted in an enhancement of cell growth in 6 of 17 tumors. However, because of the confounding effects of serum in the medium, we studied the individual effect of 17 beta-estradiol (10(-8) M) when added alone under serum-free conditions. Of 20 tumors studied, 17 beta-estradiol significantly enhanced cell growth in 12. There was a 67.8 +/- 12.6% increase in the number of colonies formed in these 12 responding tumors. One of these 12 responding tumors was ER negative as well as PgR negative, while the rest were all ER positive. These in vitro studies demonstrate that this approach can provide valuable information on endocrine mechanisms controlling the growth of human breast cancer.

Role of estrogen and prolactin in the growth and receptor levels of N-nitrosomethylurea-induced rat mammary tumors.

Forty-eight of 81 (59%) of N-nitrosomethylurea-induced rat mammary tumors regressed in average to almost one-half of the original size 10 days after ovariectomy (ovax) (hormone responsive), while 33 remained essentially unchanged (hormone resistant). AT 20 days after ovax, further decline in hormone-responsive tumors was observed when the rats were treated daily with 0.9% NaCl solution on the tenth day after ovax. Treatment for the same length of time with estrogen either alone or in combination with bromocryptine (to effectively suppress serum prolactin level) prevented tumor regression in hormone-responsive tumors. A similar effect was observed when rats were treated with perphenazine (to stimulate endogenous prolactin secretion) either alone or in combination with the antiestrogen tamoxifen. Estrogen receptors (ERs) significantly declined after ovax. Treatment with estrogen or perphenazine did not have any significant effect on ER level. Progesterone receptors (PGRs) became virtually undetectable after ovax. Treatments with estrogen, estrogen plus bromocryptine, and perphenazine plus tamoxifen but not perphenazine alone were able to partially restore PGRs although this effect was of borderline statistical significance. ER and PGR levels were not significantly different between hormone-responsive and -resistant tumors within each group. We conclude that both estrogen and prolactin play a role in the growth of the N-nitrosomethylurea-induced rat mammary tumor. Changes in ER and PGR levels did not correlate with tumor growth under the present experimental conditions.

Partial hypopituitarism following septic peritonitis with shock.

A 46-year-old man had a prolonged septic peritonitis with shock that resulted from a perforated appendix at the age of 29, followed, six months later, by the gradual development of partial hypopituitarism. Radiographic studies, including a pneumoencephalogram, did not reveal any evidence of sellar or surprasellar masses. Endocrine studies revealed growth hormone and gonadotropic deficiency and possible adrenocorticotropic hormone deficiency and possible adrenocorticotropic hormone deficiency. The nature of the disease course yielded much speculation in regard to pathogenesis of the condition.

Pituitary tumors: pathophysiology, clinical manifestations and management.

Pituitary tumors are frequently encountered intracranial neoplasms. They present with a variety of clinical manifestations that include symptoms and signs of excessive hormone secretion by the tumor, signs of hormone deficits by the normal pituitary gland and others related to expansion of the tumor mass and the resulting compression of surrounding structures such as the optic chiasm and cranial nerves. Advances in molecular biology, immunocytochemical staining and imaging, and the introduction of new treatment options have improved our understanding of the natural history of these adenomas and their management. Available treatments include surgical, medical and radiation therapy. Although the primary treatment for each tumor type may vary, it is important to consider all available options and select the most applicable for that patient. The interaction of all members of management team, including the primary care provider, the endocrinologist and the neurosurgeon in selecting the treatment course can only improve therapeutic outcome. Regardless of the initial choice of treatment,follow-up of all patients should be maintained indefinitely. The managing physician should be familiar with the natural history and long-term complications of pituitary adenomas, and with the side effects of treatments given over the years.

Hormone dependency in N-nitrosomethylurea-induced rat mammary tumors.

The majority (87%) of N-nitrosomethylurea-induced rat mammary tumors regressed within 1 week after hypophysectomy (hypox). After a hypox-induced tumor regression, ovine PRL (oPRL), and 17 beta-estradiol (E2) were administered separately or in combination in order to define the individual role of these hormones in regulating tumor growth and influencing estrogen (E), progesterone (Pg), and PRL receptor (R) levels. Administration of E2 (2.5 micrograms twice daily) or oPRL (20 IU daily, started 5 days after hypox and continued for 10 days, resulted in stabilization of tumor growth. Simultaneous administration of E2 and oPRL resulted in a synergistic effect and reactivation of tumor growth. ER levels in mammary tumors were significantly lower than those in the control 15 days after hypox (P less than 0.01). Treatment with E2, oPRL, or both simultaneously had no significant effect on ER levels. A significant decline in PgR levels was noted at both 5 and 15 days after hypox. Whereas treatment with oPRL had no significant effect on PgR levels, E2 administration either alone or in combination with oPRL restored PgR levels to control values. PRLR levels were unchanged from control values at 5 days, but significantly declined (P less than 0.005) 15 days after hypox. Treatment with E2, oPRL, or both hormones simultaneously partially maintained PRLR and prevented the decline to the extremely low level noted in the untreated group. We conclude that the growth of nitrosomethylurea-induced rat mammary tumors is dependent on both E2 and PRL. There was a synergistic effect between E2 and PRL on tumor growth but not on ER, PgR, or PRLR. Neither E2 nor PRL had any significant effect on ER after hypox. PgR is under E2 control. Either E2 or PRL or both hormones were able to maintain PRLR in mammary tumors after hypox.

Reversible hypopituitarism in patients with large nonfunctioning pituitary adenomas.

Detailed pituitary function studies were conducted on 26 patients with large nonfunctioning pituitary adenomas before and 2-3 months after transsphenoidal adenomectomy. Basal serum PRL, GH, TSH, LH, FSH, and ACTH levels were measured, and dynamic studies of their secretion were made. Preoperatively, GH deficiency was found in all 26 patients (100%), hypogonadism in 25 patients (96%), hypothyroidism in 21 patients (81%), and adrenal insufficiency in 16 patients (62%). Serum PRL levels were low (1.5-4 ng/ml) in 5 patients, normal (5-20 ng/ml) in 9 patients, and mildly elevated (21-53 ng/ml) in the remaining 12 patients. After selective adenomectomy, variable improvement in pituitary function occurred in 17 patients, worsening in 1 patient, and persistence of hypopituitarism in 8 patients. After surgery, normal thyroid function was documented in 12 of the 21 patients (57%) who were hypothyroid preoperatively. Similarly, 6 of the 16 patients (38%) with adrenal insufficiency recovered normal adrenal function, and 8 of the 25 patients (32%) with hypogonadism recovered normal gonadal function. GH deficiency persisted in all but 4 patients (15%). Serum PRL levels decreased in all patients, and only 5 had midly elevated levels after surgery. The presence of a normal or mildly elevated serum PRL level before surgery in these patients was of value in predicting possible recovery of pituitary function after surgery; none of the 5 patients with low preoperative serum PRL levels had any improvement in pituitary function after surgery. A rise in serum TSH levels after TRH administration before surgery also was helpful in predicting possible recovery from hypopituitarism. Most patients who had a rise in serum TSH level in response to TRH stimulation preoperatively recovered some pituitary function after adenomectomy. In contrast, no improvement in pituitary function occurred in patients who had blunted responses to TRH preoperatively. Improvement in pituitary function occurred more often in patients with tumors measuring 25 mm or less than in those with larger tumors. In conclusion, significant improvement in pituitary function may occur after surgical adenomectomy for nonsecreting pituitary tumors. A rise in serum TSH levels in response to TRH stimulation preoperatively suggested the presence of viable pituitary tissue in these patients with hypopituitarism. The presence of a normal or mildly elevated serum PRL level before surgery also suggested the presence of functioning pituitary lactotrophs. These observations suggest that compression of the portal circulation is a possible mechanism for hypopituitarism in this setting.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: is perioperative steroid therapy necessary?

Patients undergoing pituitary adenomectomy are usually given glucocorticoid therapy, although there are no data to document the need for such therapy. We prospectively studied hypothalamic-pituitary-adrenal axis (HPA) function in 88 consecutive pituitary adenoma patients before and after selective adenomectomy, excluding those with corticotroph adenomas. Preoperatively, 5 patients had adrenal insufficiency (AI); they were treated with glucocorticoids and excluded from the analysis. The remaining 83 patients had normal HPA function preoperatively and were not given glucocorticoids before, during, or immediately after surgery, but were closely monitored, and their serum cortisol levels were measured in the immediate postoperative period. Two patients were clinically suspected to have AI postoperatively and were treated accordingly. The remaining 81 patients had no clinical manifestations of AI and received no glucocorticoid therapy. Their serum cortisol levels in the immediate postoperative period were appropriately elevated. The mean serum cortisol level was 40.5 +/- 11.1 (+/- SD) micrograms/dL (1117 +/- 306 nmol/L) 6 h after surgery; serum cortisol levels decreased gradually thereafter. Morning serum cortisol levels were within the normal range on the fourth, fifth, and sixth days after surgery: day 4, 15.1 +/- 7.0 micrograms/dL (417 +/- 193 nmol/L); day 5, 16.4 +/- 5.6 micrograms/dL (453 +/- 155 nmol/L); and day 6, 16.3 +/- 5.7 micrograms/dL (450 +/- 157 nmol/L). When tested 3 months after surgery, all 81 patients had normal HPA function. We conclude that HPA function is rarely compromised after selective pituitary adenomectomy. Close observation and serum cortisol measurements in the immediate postoperative period can reliably predict the integrity of the HPA after surgery. Routine glucocorticoid therapy is not needed in patients undergoing selective adenomectomy whose preoperative adrenal function is normal.

Chronic hyperglycemia increases the density of glucose transporters in human erythrocyte membranes.

We investigated the effect of chronic hyperglycemia on glucose transporters in erythrocytes of subjects with and without diabetes mellitus. We found a 22% increase in D-glucose-displaceable cytochalasin-B binding in erythrocyte membranes of diabetic subjects over those of controls (311 +/- 13 vs. 254 +/- 8 pmol/mg protein; P less than 0.001). This increased binding was due to a higher density of binding sites without a significant change in binding affinity. Cytochalasin-B binding to erythrocyte membrane correlated positively with both erythrocyte glycohemoglobin and serum glucose levels, but not with plasma C-peptide levels. The data are compatible with up-regulation of glucose transporters in the erythrocytes of subjects with chronic hyperglycemia. We suspect that this is brought about by increased synthesis and membrane incorporation of the glucose transporter during erythropoiesis.

Modulation of tissue responsiveness to angiotensin-II in hyperprolactinemic subjects.

The present studies were designed to test the hypothesis that hyperprolactinemia modulates target tissue responsiveness to angiotensin-II (AII). Adrenal and pressor responses to AII infusions were determined in six patients with PRL-secreting pituitary microadenomas and in five normal controls during defined electrolyte balance. Hyperprolactinemic and normal subjects had similar mean blood pressures while on a regular Na intake (82.5 +/- 0.5 vs. 81.2 +/- 0.3 mm Hg). However, after 4 days of Na loading (200 meq/day), the mean blood pressure in hyperprolactinemic subjects was higher than that in normal (86.6 +/- 1 vs. 83.4 +/- 0.8 mm Hg; P less than 0.05). In addition, enhancement of the mean blood pressure response to three doses of AII was noted in hyperprolactinemic subjects (P less than 0.05) compared to that in normal subjects. After 4 days of Na restriction (10 meq/day), the mean blood pressure in hyperprolactinemic subjects was similar to that in normal subjects (79.7 +/- 0.6 vs. 78.9 +/- 1 mm Hg). However, despite adequate Na restriction, the pressor response to AII continued to be enhanced (P less than 0.05) in hyperprolactinemic subjects. There were no differences in plasma or urinary electrolytes or in PRA between hyperprolactinemic and normal subjects. Hyperprolactinemic subjects had higher basal (P less than 0.01), AII-stimulated (P less than 0.05), and ACTH-stimulated (P less than 0.02) aldosterone levels during Na loading, but not during Na restriction. The differences disappeared after the correction of the hyperprolactinemia. The data demonstrate significant alterations in adrenal and pressor responsiveness in hyperprolactinemic subjects and suggest a modulating role for PRL on vascular reactivity and steroid biosynthesis. The precise mechanism has not been determined, but may be secondary to PRL-induced up-regulation of adrenal and vascular AII receptors.

The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas.

Mild hyperprolactinemia frequently accompanies the hypopituitarism seen in patients with pituitary macroadenomas that do not secrete PRL. Recent data suggested that the hypopituitarism and mild hyperprolactinemia in this setting are largely due to compression of pituitary stalk and portal vessels. Headaches (HAs) are frequently seen in patients with large adenomas and at times in those with microadenomas. Because the walls of the sella turcica are relatively rigid, we postulate that tumor growth within the sella increases intrasellar pressure (ISP), which in turn impairs portal blood flow, resulting in mild hyperprolactinemia and hypopituitarism. We also postulate that increased mean ISP (MISP) contributes to the development of HAs. Normal MISP is not known but is unlikely to exceed normal intracranial pressure of less than 10-15 mm Hg. We determined MISP in 49 patients who had transsphenoidal surgery for pituitary adenomas. MISP was measured using a commonly available intracranial monitoring kit where a fiberoptic transducer was inserted through a 2-mm dural incision at the time of adenomectomy. Patients with deficient FSH, LH, ACTH, or TSH secretion were considered hypopituitary. Data on serum PRL levels were included for analysis only in patients whose adenomas had negative immunostaining for the hormone. MISP measurements ranged from 7-56 mm Hg, with a mean (+/-SD) of 28.8 +/- 13.5 and a median of 26 mm Hg. The pressure measurements were higher in patients with hypopituitarism than in those with normal pituitary function (P = 4.6013 x 10(-6)). Patients presenting with HAs had higher MISP than those who did not (P = 5.44 x 10(-7)), regardless of their pituitary function or tumor sizes. PRL levels correlated positively with MISP values (r = 0.715, P < 0.0001). Tumor size did not correlate with MISP or PRL levels. The findings of increased MISP in hypopituitary patients and the documented correlation with PRL levels, suggest that ISP is a major mechanism involved in the pathogenesis of hypopituitarism and hyperprolactinemia. Similarly, the increased MISP in patients with HAs, irrespective of tumor size or pituitary function, suggest that increased ISP is a major mechanism involved in the pathogenesis of this symptom. The data support the hypothesis that in patients with pituitary adenomas increased ISP is a major mechanism contributing to the development of hyperprolactinemia, hypopituitarism, and HAs. Increased ISP in these patients leads to compression of the portal vessels and the associated interruption of the delivery of hypothalamic hormones to the anterior pituitary. This would explain the reversibility of pituitary function observed in most patients after adenomectomy. However, increased ISP may also lead to decreased blood supply, resulting in ischemic necrosis in some regions of the pituitary. The latter could limit potential recovery of pituitary function after adenomectomy.

Immediate recovery of pituitary function after transsphenoidal resection of pituitary macroadenomas.

Mild hyperprolactinemia frequently accompanies the hypopituitarism associated with pituitary macroadenomas not secreting PRL. Because of this association, hypopituitarism was postulated to be due to compression of portal vessels. We postulate that resumption of hypothalamic control over pituitary function occurs immediately after adenomectomy. To test this hypothesis, we examined pituitary function before and after transsphenoidal adenomectomy in 26 ACTH-deficient patients and 23 subjects with normal adrenal and thyroidal functions (control group). Glucocorticoids, given only to ACTH-deficient subjects, were withdrawn 36 h after surgery. ACTH, cortisol, and PRL levels were measured twice daily in all patients. Both ACTH and PRL levels increased hours after surgery in controls and returned to baseline over 4 days. In all hypopituitary subjects, PRL levels decreased by 50% within hours of adenomectomy and remained so until discharge. ACTH levels, measured simultaneously, increased within hours in 17 of 26 hypopituitary patients, all of whom recovered normal adrenal function before discharge. Nine additional patients had low ACTH levels and required cortisol replacement. The reciprocal changes in PRL and ACTH levels measured simultaneously, hours after surgery, support the hypothesis that hypopituitarism is reversible and largely caused by compression of the protal vessels and the resulting interruption of delivery of hypothalamic hormones. The persistence of hypopituitarism in some patients suggests that ischemic necrosis of the anterior pituitary could limit recovery.

Improvement of pituitary function after surgical decompression for pituitary tumor apoplexy.

Hypopituitarism is a major manifestation of pituitary adenoma apoplexy. We postulated that the acute deterioration in pituitary function may be caused by compression of portal vessels and the pituitary stalk, secondary to a sudden increase in intrasellar contents. If this were the case, one would predict improvement in pituitary function to occur after surgical decompression. We studied pituitary function in eight patients presenting with the clinical syndrome of pituitary adenoma apoplexy before and on multiple occasions after urgent surgical decompression. Partial or complete hypopituitarism was seen in all subjects at the time of presentation. Serum cortisol levels were inappropriately low (5.9 +/- 1.4 micrograms/dL; 162.8 +/- 38 nmol/L) for the degree of stress in seven patients and appropriately elevated in only one subject (55.3 micrograms/dL; 1525.7 nmol/L). High normal increments in cortisol levels were noted in three subjects given test doses of cosyntropin. Patients were given glucocorticoids before, during, and for 2 days after surgery. Serum cortisol concentrations measured on or after the third day when glucocorticoids had already been stopped were normal in seven subjects and consistently low in one. These seven subjects were discharged on no replacement and were subsequently documented by dynamic testing to have normal pituitary-adrenal function. Gonadal function improved in two of four men and in one of two women who had hypogonadism on presentation. Improvement in thyroid function was documented in two of three subjects with preoperative hypothyroidism. Gradual improvement and almost complete resolution of the neuroophthalmological abnormalities occurred days to weeks after decompression. These observations demonstrate that urgent surgical decompression after pituitary tumor apoplexy was associated with improvement not only in neurological defects but also in pituitary function. The rapid improvement in pituitary function indicates not only that the hypopituitarism was reversible, but also that it might be caused by compression of the portal circulation and pituitary stalk by the sudden increase in intrasellar contents.

Inhibitory action of bromocriptine and tamoxifen on the growth of human pituitary tumors in soft agar.

Human pituitary tumors were studied in vitro using the clonogenic stem cell assay. Mechanical dispersion was used to prepare single cell suspensions for plating. Colony formation occurred in 21 of 24 tumors plated. Bromocriptine (Brc; 10 nM) added to the medium resulted in a significant decrease in the number of colonies formed in 5 of 10 prolactinomas and in 1 tumor secreting both PRL and GH. However, PRL secretion was decreased in 8 of 9 tumors tested. Brc had no effect on either colony formation or hormone secretion in other tumors secreting GH (n = 2), ACTH (n = 2), or FSH (n = 1) or in nonsecreting tumors (n = 4). Tamoxifen (Tam; 10(-7) M) inhibited colony formation in 6 of 10 prolactinomas and in 1 tumor secreting GH and PRL. PRL secretion into the medium correlated with the changes in the number of colonies. Tam was not effective in any other tumor tested. In only 1 instance was there a synergistic action between Brc and Tam on inhibition of colony formation. Brc, but not Tam, caused a significant decrease in the size of the colonies formed from cells of PRL-secreting tumors. The least numbers of colonies per plate were found in 3 prolactinomas from patients treated preoperatively with Brc. We conclude that the soft agar clonogenic assay technique is a feasible method to study human pituitary tumors in vitro. Both Brc and Tam inhibited colony formation in this system in a significant proportion of tumors. The potential antiproliferative action of Tam in vivo needs to be studied in view of these results.

Dynamics of prolactin secretion in patients with hypopituitarism and pituitary macroadenomas.

Mild hyperprolactinemia frequently accompanies the hypopituitarism seen in patients with pituitary macroadenomas that do not secrete PRL. We postulated that hypopituitarism in this setting, is primarily caused by compression of the portal vessels and/or pituitary stalk. If this were the case, the dynamics of PRL secretion in this instance would be similar to those in patients with stalk section, dopamine deficiency, or hypothalamic disease. Furthermore, as hypopituitarism in this setting is largely reversible, we postulate that PRL dynamics should also normalize after adenomectomy as a result of the resumption of hypothalamic regulation of pituitary hormone secretion. To test these hypotheses, we examined PRL responsiveness to TRH and the dopamine antagonist, perphenazine (PZ), in patients with pituitary macroadenomas who had hypopituitarism and others with intact pituitary function (controls). Dynamic studies were performed before and 2-3 months after total or subtotal adenomectomy, and the results were correlated with alterations in other pituitary function. In addition, plasma ACTH, cortisol, and PRL levels were measured hours to days after surgery to investigate immediate alterations in pituitary function following surgical decompression. Before surgery, hypopituitary patients had higher serum PRL level than controls (25.5 +/- 12 vs. 11 +/- 3 micrograms/L; P < 0.001). Preoperative dynamic testing of PRL secretion in hypopituitary patients demonstrated an increase in PRL levels after TRH, but not after PZ, administration. In contrast, PRL levels increased appropriately when either stimulus was given to controls. Hours after adenomectomy, PRL levels decreased by 50% in hypopituitary patients (P < 0.0001) and remained so until discharge. In contrast, controls had a transient increase in serum PRL levels after adenomectomy. After surgery, 25 of 43 previously hypopituitary patients recovered part or all pituitary function. Serum PRL levels in the latter subgroup became normal and increased appropriately after stimulation with either TRH or PZ. In contrast, patients who did not recover pituitary function had lower PRL levels that increased minimally after TRH or PZ. The mild increase in serum PRL levels in hypopituitary patients and the discordant responses to stimulation with TRH and PZ suggest dopamine deficiency as a cause of hyperprolactinemia. The drop in serum PRL levels immediately after surgery, at a time when other pituitary hormones (e.g. ACTH), were documented to rise suggests restoration of hypothalamic control over pituitary hormone secretion. The pattern of PRL responses to stimulation in patients recovering function postoperatively was similar to that in controls, although the incremental rise was subnormal.(ABSTRACT TRUNCATED AT 400 WORDS)

A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma.

Recent studies have provided new information regarding the optimal surveillance protocols for low-risk patients with differentiated thyroid cancer (DTC). This article summarizes the main issues brought out in a consensus conference of thyroid cancer specialists who analyzed and discussed this new data. There is growing recognition of the value of serum thyroglobulin (Tg) as part of routine surveillance. An undetectable serum Tg measured during thyroid hormone suppression of TSH (THST) is often misleading. Eight studies show that 21% of 784 patients who had no clinical evidence of tumor with baseline serum Tg levels usually below 1 micro g/liter during THST had, in response to recombinant human TSH (rhTSH), a rise in serum Tg to more than 2 micro g/liter. When this happened, 36% of the patients were found to have metastases (36% at distant sites) that were identified in 91% by an rhTSH-stimulated Tg above 2 micro g/liter. Diagnostic whole body scanning, after either rhTSH or thyroid hormone withdrawal, identified only 19% of the cases of metastases. Ten studies comprising 1599 patients demonstrate that a TSH-stimulated Tg test using a Tg cutoff of 2 micro g/liter (either after thyroid hormone withdrawal or 72 h after rhTSH) is sufficiently sensitive to be used as the principal test in the follow-up management of low-risk patients with DTC and that the routine use of diagnostic whole body scanning in follow-up should be discouraged. On the basis of the foregoing, we propose a surveillance guideline using TSH-stimulated Tg levels for patients who have undergone total or near-total thyroidectomy and (131)I ablation for DTC and have no clinical evidence of residual tumor with a serum Tg below 1 micro g/liter during THST.

Uterine oestrogen and progesterone receptors in the ovariectomized rat.

The effect was studied of repeated injections of oestradiol-17 beta (5, 10, 25, 50 micrograms) given for various lengths of time (3, 5, 9 days) on total cell content of oestrogen receptors and cytosol progesterone receptors in the uteri of ovariectomized rats. An additional group of rats was injected daily with 50 micrograms oestradiol benzoate (OB) for 9 days in order to achieve a more sustained concentration of oestradiol in the blood. Injections were begun 24h after ovariectomy and the rats were killed 24h after the last injection. Daily administration of 5 micrograms oestradiol prevented the initial transient rise in oestrogen receptors which was observed in the uteri of untreated rats after ovariectomy. Repeated injections of 10 micrograms oestrogen produced an initial lowering in oestrogen receptors after 3 days of treatment which was followed by a prompt rise at 5 and 9 days when treatment was continued. A significant reduction in oestrogen receptors occurred at all times studied when rats were injected daily with 25 and 50 micrograms oestradiol. A more profound reduction in oestrogen receptors was observed in the group of rats treated for 9 days with 50 micrograms OB. Synthesis of progesterone receptors was stimulated by all doses of oestrogen studied. Concentrations of progesterone receptors were significantly higher after 3 and 5 days of treatment with 25 and 50 micrograms oestrogen. After 9 days of treatment, however, concentrations of progesterone receptors were virtually identical in all treated groups, including the group treated with OB. We have concluded that large doses of oestrogen significantly decrease oestrogen receptor content in the rat uterus, especially when OB is used. The degree of reduction, however, is only moderate under these experimental conditions and is insufficient to inhibit synthesis of progesterone receptors.