Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study

Prolactinomas in women commonly present as small intrasellar tumors, but are usually much larger in men. This discrepancy has generally been attributed to differences in the delay before diagnosis. However, studies comparing clinical and pathological correlates of growth of these tumors in both sexes are lacking. We conducted a retrospective study comparing 45 men and 51 women bearing prolactinoma to determine whether the predominance of large tumors in men was due to a delay in diagnosis or, rather, to a fundamental sex-related difference in tumor growth. Basal PRL levels (mean +/- SEM, 2789 +/- 573 ng/mL) and mean tumor diameter (26 +/- 2 mm) were significantly higher in men than in women (292 +/- 74 ng/mL and 10 +/- 1 mm, respectively; P < 0.001), but were not correlated to the age at diagnosis or the duration of symptoms. Giant tumors (n = 8) occurred in males only. The frequencies of bromocriptine-resistant tumors (30 vs.5%; P < 0.01) and invasive macroadenomas (52 vs.27%; P < 0.001) were significantly greater in men than those in women. Lastly, macroprolactinomas in males exhibited higher indexes of proliferating cells by Ki-67 immunoreactivity (2.6 +/- 1.1% of positive nuclei) than did similar tumors in female patients (0.4 +/- 0.2%; P = 0.08). We conclude that the predominance of large prolactinomas in men is due to a high frequency of rapidly growing tumors, which are often invasive and frequently bromocriptine resistant.     

Improvement in cumulative response rates following implementation of a financial incentive

We present our experience in the treatment of growth hormone (GH)-producing pituitary adenomas using irradiation alone. Between 1983 and 1991, 21 patients suffering from GH-secreting pituitary adenomas were treated with radiotherapy alone. Two bilateral opposing coaxial fields were used in 10 patients and in the remaining 11 a third frontovertex field was added. Treatment was given in 1.8-2 Gy daily fractions and total dose ranged between 45 and 54 Gy. Treatment was given using a cobalt unit. Four patients treated with somatostatin prior to and 14 patients treated after the end of radiotherapy experienced symptom relief for 6-28 weeks. The 5-year actuarial rate of disease control was 72%. Five out of six failed patients had macroadenomas. Hypopituitarism was observed in 5/21 (24%) patients. Whereas RT alone is effective in the treatment of microadenomas, this is not true for large infiltrative macroadenomas.     

Detection of Salmonella in animal protein by Rappaport-Vassiliadis broth using indirect impediometry

To determine if glipizide could enhance remission induction in new onset type 1 diabetes compared to intensive insulin treatment alone, 27 patients with type 1 diabetes were intensively treated in an open randomized trial with subcutaneous injections for one month. The insulin was randomly either discontinued (Group A) or the insulin discontinued and glipizide begun (Group B) Three patients in Group A (22%) and 7 in Group B (54%, p < .05) underwent insulin-free remissions for 10.3 +/- 4.4 and 8.7 +/- 2.6 months, respectively (p = NS). Mean blood glucose levels during insulin treatment were lower in patients entering remissions (94 +/- 3 mg/dl versus 102 +/- 5 mg/dl, p < 0.05). C-peptide levels were performed 0, 4, 8, and 24 weeks after insulin treatment. When all patients were examined, mean stimulated C-peptide levels at 4 weeks (0.58 +/- 0.09 pm/ml) were increased compared to time 0 (0.32 +/- 0.05 pm/ml, p < 0.02). Patients not entering remission had higher 4-week stimulated values (0.67 +/- 0.12 pm/ml) compared to time 0 values (0.29 +/- 0.06 pm/ml, p < .01), whereas remission patients' mean C-peptide levels remained similar at 0, 4, 8 and 24 weeks. These data indicate that a) insulin treatment plus glipizide induces higher rates of remission compared to intensive insulin treatment alone, b) the intensity of initial metabolic control may be an important determinant for remission induction, and c) endogenous insulin secretion is not associated with remission induction, suggesting that glipizide alters insulin sensitivity or is immunomodulatory in the context of new onset type 1 diabetes.     

Establishment of functional human pituitary tumor cell cultures

Five primary human pituitary tumor cell cultures were initiated from adenoma fragments obtained from patients with prolactin-secreting adenomas and acromegaly. Functional cell cultures were maintained and propagated in monolayer or suspension culture for up to 9 months. Optimal cell viability and growth were achieved using Ham's F10 medium enriched with 20% fetal bovine serum, although cells from a patient with acromegaly also grew in serum-free, defined, hormone-containing medium. Bromocriptine (100 ng/ml) did not alter the growth curve of replicating cells derived from a patient with acromegaly. These cells initially secreted 5.5 micrograms human growth hormone/10(6) cells, and hormone production diminished after 6 wk. Prolactin secretion by cells derived from prolactinomas (0.5 to 1.3 micrograms/10(6) cells/24 h) was stimulated by thyrotropin-releasing hormone (10 ng/ml) in two of the cultures. Both dopamine (10 ng/ml) and nickel chloride (1 mM) suppressed PRL secretion. These studies demonstrate that responsive human pituitary tumor cell cultures can be initiated and maintained.     

Phase II trial of titanocene dichloride in advanced renal-cell carcinoma

We report on a series of 48 patients, ages 14 to 20 year, with hypophyseal adenomas. Of these, 46 (96%) had secreting tumors, 3 had Cushing's disease, 9 had somatotrophinomas, and 34 (29 females and 5 males) had prolactinomas. Thirty cases were diagnosed as intrasellar adenomas (62%) while the remaining eighteen (38%) presented extrasellar expansion. Of 9 acromegalic patients, 7 had typical clinical and biochemical features 2 were exclusively prognatic with normal basal GH levels, but abnormal dynamic tests. Prolactinomas were noninvasive in women and faster growing and more extensive in men. Forty seven patients underwent surgery. Five of these required craniotomy and the rest approached through the sphenoidal bone (TSE). Remission was achieved in Cushing's disease, acromegaly, and female intrasellar prolactinomas. Larger tumors such as nonsecreting adenomas and male prolactinomas showed poor results after undergoing subtotal resections, with persistence of endocrinological disturbances. From our findings it appears that these tumors are aggressive in youth than in adults. Because there was a close relationship between tumor size, invasiveness, and the patients' final outcome, we conclude that early diagnosis and treatment is essential. Frequent complaints in adolescents such as irregular menses, retarded puberty, and growth disorders should be thoroughly investigated and not merely considered as transient or 'functional'.     

Coagulative and fibrinolytic activation in cerebrospinal fluid and plasma after subarachnoid hemorrhage

OBJECTIVE: Intrathecal fibrinolytic therapy has been used as one of the anticerebral vasospasm (VS) preventative therapies in patients with subarachnoid hemorrhage (SAH). However, the changes in coagulation and fibrinolysis in the blood and cerebrospinal fluid (CSF) after SAH remain unknown. METHODS: Fifty patients with SAH caused by ruptured cerebral aneurysms were studied postoperatively to detect the serial changes of the thrombin-antithrombin III complex, active plasminogen activator inhibitor (PAI)-1, and tissue plasminogen activator (tPA)-PAI complex (tPA-PAI) activities in the plasma and CSF collected from cisternal drainage catheters. RESULTS: The CSF levels of all parameters and plasma PAI-1 levels were significantly higher in patients with severe SAH than in those with mild SAH. There was no relationship between the CSF and plasma levels of these parameters (except the CSF levels of tPA-PAI) and the initial neurological statuses. The CSF PAI-1 levels increased to greater than 20 ng/ml near the time of the occurrence of cerebral VS, whereas they remained below 20 ng/ml in patients without VS. The CSF tPA-PAI levels showed the highest peak near the time of VS remission. The CSF PAI-1 and tPA-PAI levels were significantly lower in patients with good outcomes than in those with poor outcomes. CONCLUSION: Both the coagulative and fibrinolytic systems were activated in the CSF and plasma after SAH in correlating to the amount of SAH clot. The intrathecal administration of fibrinolytic agents should be started early after surgery, before CSF PAI-1 levels increase, for patients with severe SAH. Patients with CSF PAI-1 levels greater than 20 ng/ml experienced high incidence of VS and poor outcomes.     

Malignant prolactinoma: case report and review of the literature

BACKGROUND: Malignant prolactinomas are rare events. To date, only 14 patients with metastases in- or outside the central nervous system have been reported. CASE DESCRIPTION: We present a patient who developed a metastasis to the cauda equina, which is the first case documented with MRI. A giant prolactinoma in this 51-year-old man was partially removed by a transcranial approach. After radiotherapy and treatment with bromocriptine, the patient had a remission for 3 years. Thereafter, a sacral intraspinal tumor was diagnosed. Because of increasing prolactin levels not responding to bromocriptine and a radiologically suspected intrasellar tumor, we operated transsphenoidally first and found only fibrous tissue. We performed a sacral laminectomy and almost totally removed an intradural tumor. Histopathology and immunohistochemistry confirmed the diagnosis of a prolactinoma metastasis. The patient received radiotherapy and bromocriptine and has no evidence of recurrent tumor or metastases after a follow-up of 38 months, thus being the second reported patient with long-term remission of the disease. DISCUSSION: We review the literature on this topic and try to establish common features of the course of this rare malignant disease and the efficacy of therapy in the cases reported hitherto.     

Reassessment of the role of radiation therapy in the treatment of endocrine-inactive pituitary macroadenomas

OBJECTIVE: This prospective clinical trial was undertaken to assess the rate of tumor recurrence in patients with endocrine-inactive pituitary macroadenomas who underwent gross total surgical resection of their tumors and did not receive adjuvant radiotherapy. METHODS: Between December 1987 and July 1994, 45 patients with endocrine-inactive pituitary macroadenomas underwent transsphenoidal surgery. In 38 (84%) of these patients, gross total surgical resection was achieved and was confirmed by postoperative magnetic resonance imaging (n = 37) or computed tomography (n = 1). After receiving counseling from the neurosurgeon concerning the risks and benefits of radiation therapy, 32 of the 38 patients elected not to receive adjuvant radiotherapy. Patients were followed through March 1998 with radiographic imaging obtained every 6 months for the first 2 years, annually for postoperative Years 3 and 4, and then every 2 to 3 years thereafter. The study end point was defined as radiographic tumor recurrence or patient death. RESULTS: The mean follow-up duration for the study group was 5.5 years. During that time, 2 of 32 (6%) patients developed recurrence, at 18 and 24 months, respectively, after initial surgery. Both were successfully treated using radiation therapy, with one requiring additional surgery. Three additional patients died as a result of unrelated causes 9, 12, and 49 months, respectively, after initial surgery. Immunocytochemical analysis revealed 66% of the tumors to be weak gonadotroph cell adenomas, 22% to be null cell adenomas, 9% to be silent prolactinomas, and 3% to be silent corticotroph cell adenomas. CONCLUSION: This study demonstrates a 6% 5-year recurrence rate in patients with endocrine-inactive pituitary macroadenomas treated using gross total surgical resection alone. Reserving radiation therapy for the infrequent patient with recurrence and sparing the majority of patients the associated risks inherent in its use seems reasonable.     

The case-control study as data missing by design: estimating risk differences

OBJECTIVE: To determine the DNA content and S-phase fraction (SPF) of pituitary adenomas by image analysis and to correlate them with clinical and morphologic parameters. STUDY DESIGN: The study group consisted of 26 prospectively collected cases of operated pituitary adenomas (3 microadenomas and 23 macroadenomas). The tumors were classified by histology, immunocytochemistry and electron microscopy. DNA measurement was performed on imprints from fresh pituitary tissue. Samples of nontumorous adenohypophysial parenchyma served as normal controls. RESULTS: Overall, 31% of adenomas, all but one functioning one, were aneuploid. The remaining nonfunctioning aneuploid tumor was a null cell adenoma with glycoprotein differentiation. All aneuploid tumors were macroadenomas, mostly at advanced stages, III and IV. Dural invasion, although frequent in macroadenomas (78%), was not correlated with DNA ploidy and SPF. An increased number of hyperpentaploid aneuploid cells was noted primarily in aneuploid tumors. The mean SPF was < 2.50%, with a statistically significant difference between aneuploid and diploid adenomas (3.60% vs. 1.70%). CONCLUSION: The results suggest that quantitative assessment of DNA content may provide important information, particularly in functioning adenomas. In addition, fresh tissue imprints represent excellent material for optimum cytometric measurements by image analysis systems, even for microadenomas.     

Different sensitivity to sodium valproate in healthy, non-tumoral and tumoral hyperprolactinemic subjects

GABAergic drugs affect PRL secretion in both rat and man. Sodium valproate (SV) inhibits GABA transaminase so increasing the endogenous GABAergic tone. The aim of this study was to evaluate the effects of SV at low and high doses on PRL release in healthy subjects and hyperprolactinemic patients. Fifteen patients with prolactinomas, 8 patients with non-tumoral hyperprolactinemia and 10 healthy subjects were studied: in non consecutive days, all subjects received placebo and SV at the dose of 400 and 800 mg po. Serum PRL levels were assessed 30, 15 and 5 min before and every 30 min for 4 hours after administration. SV at the dose of 400 mg induced a significant decrease of serum PRL in healthy subjects (p < 0.05), whereas no effect was noted in both tumoral and non-tumoral hyperprolactinemia. The administration of 800 mg SV induced a significant decrease of PRL levels in healthy subjects and in patients with non-tumoral hyperprolactinemia (p < 0.05). Conversely, in prolactinomas a paradoxical increase of serum PRL concentration (p < 0.05) was observed 120 min after the administration of the drug. These data confirm the inhibitory activity of SV on PRL release in healthy subjects, and suggest the existence of a partial resistance to GABA in non-tumoral hyperprolactinemia. In prolactinomas, the paradoxical PRL increase after high dose of SV suggests the existence of a complete pituitary resistance to GABA. This finding might be explained by the appearance of the stimulatory effect of GABA at hypothalamic level that could have been unmasked by the lack of pituitary GABA effects on adenomatous lactotrophs.     

Hyperprolactinaemia and verapamil: prevalence and potential association with hypogonadism in men

OBJECTIVE: Verapamil has been associated with hyperprolactinaemia, but there have been no population-based studies. Our objective was to determine the prevalence and degree of hyperprolactinaemia associated with verapamil in the clinical setting. DESIGN: Observation with cross-sectional and longitudinal components in the setting of an urban teaching hospital and its satellite out-patient clinics. PATIENTS: Male out-patients excluding those taking other drugs known to raise PRL, renal failure and known primary hypothyroidism (1265 eligible subjects). Control subjects were drawn from eligible out-patients not taking verapamil. MEASUREMENTS: Serum PRL levels, frequency of persistent hyperprolactinaemia and total testosterone levels. RESULTS: Prolactin levels were obtained in 449 subjects on verapamil (35.5% response rate) and 166 controls. The proportions of individuals with hyperprolactinaemia (PRL > 460 mU/l) were 0.085 and 0.030 in the verapamil and control groups, respectively (P = 0.012, X2-test). The mean (+/- SD) serum PRL levels were 267 +/- 205 and 203 +/- 118 mU/l in the verapamil and control groups, respectively (P < 0.001, independent t-test). Of the 38 patients with previously determined elevated PRL levels, follow-up data were obtained in 25 (65.8%); one was found to have a pituitary adenoma and was excluded from the analysis. Fifteen of the 24 were still on verapamil (Group 1) and 14 (93.3%) continued to be hyperprolactinaemic. In 9 patients verapamil had been discontinued (Group 2) and all had normal PRL levels. Continued verapamil use was associated with persistent hyperprolactinaemia (odds ratio > 120, P < 0.00001). The mean +/- SD serum testosterone levels at follow-up were significantly lower in Group 1 (6.16 +/- 2.52 nmol/l) than in Group 2 (9.42 +/- 3.92 nmol/l, P = 0.029, independent t-test). CONCLUSIONS: The prevalence of hyperprolactinaemia associated with verapamil use in this study of male out-patients was 8.5% (95% CI 5.9-11.1%). The persistence of hyperprolactinaemia when verapamil was continued (Group 1) and the return to normal PRL levels when verapamil was discontinued (Group 2) confirm verapamil's causal role in the development of hyperprolactinaemia. While low testosterone levels were common in both groups, testosterone levels were lower in patients on verapamil. Our data suggest that screening for hyperprolactinaemia should be considered in male patients taking verapamil.     

Neuro-ophthalmological alternations in patients with pituitary adenomas and intrasellar arachnoidocele

INTRODUCTION, MATERIAL AND METHODS: We studied 103 patients with hypophyseal tumors aged between 15 and 74, with a marked predominance of females. Results. Of these, 49 patients were diagnosed as having macroadenomas (47.5%), 27 with microadenomas (26.2%), 25 with arachnoidoceles (24.3%) and two with craniopharyngiomas (1.9%). Of the total there were 78.9% functioning tumors of which the commonest was prolactinoma. CONCLUSIONS: Kinetic and static perimetry complement each other as diagnostic methods to obtain information about damage to the visual pathway caused by these tumors.     

The use of dimethylsulfoxide for fixation of yeasts for electron microscopy

Increasing numbers of young women with ovarian failure and women of advanced reproductive age (> 40 yrs) utilize oocyte donation to treat their infertility. In both groups, women who become pregnant frequently experience multiple gestation, occurring in up to 30% of pregnancies. Advanced maternal age and high-order multiple gestations are associated with an increased risk for obstetric complications. We reviewed the pregnancies of patients with high-order multiple gestations (> or = 3 gestational sacs) with respect to their antepartum course and neonatal outcomes. Mothers were divided into two groups according to age at conception; Group I (> or = 40 yr, n = 20) and Group II (< 40 yr, n = 10). These 30 high-order multiple gestations were found among 127 successful oocyte donation cycles (23.6% of all pregnant patients). Data regarding pregnancy outcomes were gained by chart review and telephone interview. Results demonstrated spontaneous reductions in the number of implantation sites were similar between groups (Group I: 21.4% vs. Group II: 17.6%). Multifetal pregnancy reduction (MFPR) was more often chosen by older women (Group I: 45% vs. Group II: 10%; P < 0.05). Antenatal complications were commonly experienced by both groups (> 80%) as were operative deliveries (> 85%). However, neonatal outcomes were generally good, with only one death occurring in the 79 delivered infants (1.3%). We conclude transferring supernumerary embryos to women undergoing ovum donation places patients at great risk for high-order multiple gestations. These pregnancies are associated with increased antenatal and neonatal complications. Although advanced maternal age is normally an added risk factor, well-screened older patients carrying high-order multiple gestations experienced similar outcomes as younger mothers.     

Tc-99m DTPA renal scintigraphy using deconvolution analysis with six functional images of the mean time to evaluate acute pyelonephritis

The objective of the present study was to evaluate the cyclic changes and regional localization of immunoreactive c-fos and prolactin (PRL) in the human endometrium, using immunohistochemistry. Immunoreactive PRL was found in the epithelium of 9.1% of the proliferative specimens and in 55.6% of the secretory specimens (p < 0.05, Fisher's exact test). In the endometrial stroma, immunoreactive PRL was present in 9.1 and 66.7% of the proliferative and secretory samples, respectively (p < 0.01). Immunoreactive c-fos predominated in the stroma and was identified in 54.5% of the specimens in the proliferative phase, but in only 7.1% of those in the secretory phase (p < 0.05). The progesterone/estradiol ratio was lower in the patients expressing immunoreactive c-fos (median = 13.1 ng/ml) compared to those who did not (median = 84.5 ng/ml, p < 0.05). We conclude that immunoreactive c-fos is found mostly in stromal cells during the proliferative phase of the menstrual cycle, and is sharply reduced during the secretory phase, when the endometrium is under progesterone stimulation - attested by PRL production.     

Long-term prognosis for tonsillectomy patients with IgA nephropathy

A retrospective study of 85 patients with IgA nephropathy was undertaken to determine the long-term effect of tonsillectomy. Forty-three patients (24 males and 19 females) had received tonsillectomies (Group A) and 42 patients (17 males and 25 females) had not (Group B). These patients had been followed up for more than 5 years after renal biopsy. The average age at the initial renal biopsy was 25.72 years in Group A, and 33.16 years old in Group B. The average period of renal biopsy to tonsillectomy in Group A was 10.47 months. The average follow-up period was 8 years and 9 months in both groups. At the beginning of treatment, the two groups were well matched in terms of creatinine clearance, urinalysis, and blood pressure. Six patients in Group A and eight patients in Group B were treated with steroids. The glomerular injury detected at the renal biopsy was more extensive in Group A than in Group B. Renal function in the two groups was compared. The clinical remission rate in Group A was significantly higher than in group B (P<0.05). The stable renal function rate in Group A was significantly higher than in Group B (P<0.05). The renal survival rate was 97.7% in Group A and 83.3% in Group B, but there was no significant difference between the two groups. Histologically, the rate of remission of the minor lesion in Group A was significantly higher than in Group B (P < 0.05). Our results showed that tonsillectomy for IgA nephropathy was clinically of great value.     

Does alpha-melanocyte-stimulating hormone from the pars intermedia regulate suckling-induced prolactin release? Supportive evidence from morphological and functional studies

Recent evidence suggests that substances derived from the hypophyseal intermediate lobe (IL) play a crucial role in the regulation of suckling-induced PRL secretion. The purpose of the present study was to explore this possibility further by determining whether the suckling stimulus acutely increases the secretory activity of the IL and whether alpha MSH, a major secretory product of the IL, plays a specific role in suckling-induced PRL release. Light microscopic morphometric analysis of serial pituitary sections obtained from lactating rats revealed that as little as 1 min of suckling caused a significant increase in the proportion of the IL that was in secretory configuration (11.8 +/- 0.7% vs. 6.7 +/- 0.5%; 1-min suckled vs. nonsuckled control; mean +/- SE). Moreover, the fraction of the IL in secretory configuration continued to increase after 5 and 10 min of nursing (to 16.0 +/- 0.8% at 5 min and 18.2 +/- 0.7% at 10 min). In contrast, serum PRL was not significantly elevated above the control level after 1 min of suckling (18.1 +/- 13.5 vs. 9.9 +/- 6.5 ng/ml, 1-min suckled vs. control). In fact, a significant rise in PRL levels (to 314.4 +/- 19.4 ng/ml) could be detected only after 10 min of nursing. Thus, secretion by the IL in response to suckling preceded the release of adenohypophyseal PRL, suggesting that a secretory product(s) from the pars intermedia is involved in the modulation of nursing-induced PRL release. Having established a sequential temporal relationship between these two phenomena, we next investigated whether alpha MSH was the IL factor involved in the regulation of suckling-induced PRL secretion. To this end, lactating rats were injected either with antiserum to alpha MSH or preimmune serum and then allowed to nurse their pups. Serial blood samples were taken from the mothers 15, 30, 60, and 90 min after the litters were returned, and serum PRL was measured by RIA. We found that the suckling-induced rise in serum PRL was severely attenuated in animals that received anti-alpha MSH serum. This suppression was most evident at 15 min (70.1 +/- 13.4 vs. 323.5 +/- 127.0 ng/ml, antibody treated vs. preimmune serum control) and persisted throughout the entire 90-min test period. When taken together, our results suggest that suckling-induced PRL secretion is mediated at least in part by alpha MSH released from the hypophyseal IL.     

Effectiveness of the dopamine agonist lisuride in the treatment of acromegaly and pathological hyperprolactinemic states

We have studied the effects of the chronic administration of the dopamine agonist lisuride (L) in 21 acromegalics (group 1) and in 25 patients with pathological hyperprolactinemia (group 2). Before starting the treatment levels of PRL and/or GH were determined during acute tests with L (0.3 mg po) or TRH (0.2 mg iv). L was given in doses ranging between 0.4 and 2.4 mg/day. GH and/or PRL were determined at monthly intervals, TRH (6 patients of group 1 and 10 of group 2) was repeated during L therapy. In 10 patients of group 1 GH levels were reduced below 10 ng/ml by L therapy; in the remaining patients GH levels were reduced by 50% of the pretreatment values or they were unchanged. The correlation (p less than 0.01) found between GH levels during acute and chronic L administration indicates that GH changes after acute test are predictive of the outcome of the treatment. In all patients PRL was reduced during the therapy to at least 50% of the basal values and in most patients PRL fell to the normal range. No correlation was found between PRL levels during acute and chronic L administration. During the therapy TRH still increased GH levels in most patients whereas it failed to raise PRL. The withdrawal of L was followed by a rapid return of GH to the pretreatment values whereas PRL showed a slower increase. In acromegalics whose GH was lowered by L there was also a marked amelioration of clinical and metabolic parameters. The lowering of PRL was accompanied by the resumption of ovulatory menses even in patients with tumoral hyperprolactinemia. Males reported improvement in sexual performance. An improvement of visual field occurred in 1 patient. In 1 patient with a large prolactinoma serial computerized tomography scans performed during 2 yr of treatment showed a marked reduction of the tumor size.     

Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation

OBJECTIVE: To study the response of cortisol and of prolactin (PRL) to specific stimuli in rheumatoid arthritis (RA). METHODS: We measured the response of cortisol to insulin induced hypoglycemia and of PRL to thyrotropin releasing hormone (TRH) in 10 patients with active RA and in 10 paired control subjects. All were women with regular menstrual cycles. They had never received corticosteroids before the study. The PRL concentration was assessed by chemiluminescence immune assay and the cortisol concentration by radioimmunoassay. RESULTS: The basal serum levels of cortisol (14.47+/-2.5 microg/dl) and PRL (10.1+/-1.3 ng/ml) in the RA group were not significantly different from those of the control group (12.3+/-1.1 microg/dl and 13.7+/-2.4 ng/ml, respectively). The peak value of cortisol after hypoglycemia was comparable in both groups (25.5+/-2.4 microg/dl in RA vs. 26.0+/-1.5 ng/ml in controls). The integrated cortisol response to hypoglycemia expressed as area under the response curve (AUC) did not differ significantly in either group (1927+/-196 in RA vs. 1828+/-84 in controls). The interval-specific "delta" cortisol response was significantly higher for the 30 to 45 min interval in controls compared to patients with RA (9.8+/-0.9 microg/dl vs. 6.1+/-1.1 microg/dl; p = 0.02). The peak of PRL after TRH did not differ significantly in both groups (56.4+/-6.4 ng/ml in RA vs. 66.3+/-7.7 ng/ml in controls) and the AUC of PRL secretion after TRH was comparable in both groups (3245+/-321 vs. 4128+/-541). CONCLUSION: Our findings suggest that active RA is associated with subtle dysfunction of the hypothalamic-pituitary-adrenal glucocorticoid function and normal PRL secretion.     

Endocrinological evaluation of sellar and suprasellar tumor cases (the sixth report)-on pituitary hormone secretion of acromegalic patients before treatment (author's transl)

1) Pituitary hormone secretion of 14 acromegalic patients was studied before treatment. Incidence of hyporeactive response was 0%, 43%, 29%, 71% and 9% in ACTH, LH, FSH, TSH and PRL respectively. 2) Relatively higher incidence of hyporeactive TSH response in TRH test seems to be characteristic in acromegalic patients. 3) Six of 13 acromegalic patients examined on blood PRL level revealed relatively high blood PRL level over 50ng/ml.     

Prolactin and MA-10 Leydig cell steroidogenesis: biphasic effects of prolactin and signal transduction

The present investigation was designed to study the direct role of PRL on testicular Leydig cell steroidogenesis, using the MA-10 murine Leydig tumor cell line as a model system. We have previously reported on the presence of specific PRL binding sites in those cells, and we now demonstrate the functionality of those sites and the biological responses induced by the binding of PRL. When cultured MA-10 cells were exposed for 24 h to increasing concentrations of PRL, washed, and then subjected to a 3-h human CG (hCG) stimulation test, a clear dose-dependent biphasic effect of PRL on the steroidogenic response was observed, even though PRL had no effect on MA-10 cell proliferation: at low PRL concentrations (0.1-10 ng/ml), hCG-induced steroidogenesis was stimulated (maximal stimulation by 1 ng/ml PRL being 200-250% of control); at higher concentrations, hCG-induced steroidogenesis was inhibited (60% inhibition was achieved by 1000 ng/ml PRL). When steroidogenesis was induced with various concentrations of cholera toxin, instead of hCG, no effect of the prior exposure to increasing concentrations of PRL was observed, indicating that PRL acts either at the level of the LH/hCG receptor or at some stage proximal to adenylate cyclase. Indeed, further study revealed that 24 or 72 h exposure of MA-10 cells to PRL caused a dose-dependent reduction in hCG binding. Thus, the maximal inhibition of 62% after 72 h with 500 ng/ml PRL, may explain, at least in part, the inhibitory effects of high PRL concentrations on hCG-induced progesterone secretion. Evidence demonstrating possible involvement of a pertussis toxin-(PT-)sensitive G protein in the signal transduction mechanism of PRL receptors is also presented: 1. GTP caused a dose-dependent reduction in affinity (Ka) of PRL binding by its receptors (from Ka = 1.66 +/- 0.2 x 10(9) M(-1) for control MA-10 cell membranes to Ka 3.03 +/- 0.6 x 10(8) M(-1) for membranes incubated with 8 mM GTP). 2. Prior exposure of MA-10 cells to PRL (10 pg/ml) caused a significant reduction in the ability of a 44-kDa membrane protein to undergo PT-induced [32P]ADP-ribosylation. These results demonstrate that MA-10 Leydig cells possess highly specific and biologically functional PRL receptors mediating direct and dose-dependent biphasic effects of PRL on hCG-induced progesterone secretion. These cells thus offer a suitable model to study the mechanism(s) of PRL action and signal transduction of its receptor on a physiologically relevant differentiated function.