The Expression of Estrogen Receptor Subtypes in Prolactinomas and Their Relationship to Tumor Biological Behavior

Dopamine agonists （DA） are a first-line therapy for prolactinomas （PA）. However, nearly 10% of prolactinomas do not respond to DA therapy. A considerable number of studies have shown that estrogen plays an important role in the development of prolactinomas. However, the expression of estrogen receptors （ER） in prolactinomas has not been fully explored. Accordingly, we examined the levels of ESR1 and its subtypes A5-DeI-ESR1 and ESR2 mRNA in prolactinomas. In the present study,

Diagnosis and treatment of prolactinoma:clinical analysis of 124 prolactinomas

Objective： To study the diagnostic and therapeutic features of prolactinoma. Methods： 124 patients with prolactinoma were studied in clinical manifestation, pathologic, endocrinological, radiographic and therapeutic features. Results： The average age of the male patients was 41.6 years, 32.3 years of females. The major clinical manifestation in males were sexual and visual disfunction. In females, disfunction of menstruates and galactorrhea. Average serum prolactin was 1875.22 in males, 376.6 ng/mL in females. Average diameter of the tumors was 38.05 mm in males, and 83.3% of the tumors were invasive, in females were 15.25 mm and 49%. After surgery, the average serum prolactin decreased to 385.84 ng/mL （P〈 0.05）, 13 of 15 patients improved in sexual function, 82.6% patients improved in eyesight and visual field. In females prolactin decreased to 23.93 ng/mL （P 〈 0.05）, and 81.25% infertility with microprolactinoma got pregnancy, higher than controls of drug therapy （P 〈 0.05）. Conclusion： In males, the tumors were usually larger and more invasive, and serum prolactin levels were higher. The patients were elder. But in females, much younger than males, most of the tumors were microadenoma, and after operation the prolactin usually decrease to normal level and more chance of pregnancy. Results of a single therapy were with less satisfaction, we advocate integrated therapy around operation.

Transsphenoidal surgery for prolactinomas in male patients:a retrospective study

Male patients with prolactinomas usually present with typical hyperprolactinemia symptoms,including sexual dysfunction and infertility.However,clinical factors related to sexual dysfunction and surgical outcomes in these patients remain unclear.This study aimed to investigate the outcomes of male patients with prolactinomas after transsphenoidal surgery and the risk factors affecting sexual dysfunction.This study was conducted on 58 male patients who underwent transsphenoidal surgery for prolactinomas between May 2014 and December 2020 at the First Affiliated Hospital of Sun Yat-sen University,Guangzhou,China.We evaluated the sexual function of patients before and after surgery through International Index of Erectile Function-5 scores,libido,and frequency of morning erection.Of the 58 patients,48(82.8%)patients had sexual intercourse preoperatively.Among those 48 patients,41(85.4%)patients presented with erectile dysfunction.The preoperative International Index of Erectile Function-5 scores in patients with macroprolactinomas were significantly higher than those in patients with giant prolactinomas(17.63±0.91 vs 13.28±1.43;P=0.01).Postoperatively,the incidence of erectile dysfunction was 47.9%,which was significantly lower than that preoperatively(85.4%;P=0.01).Twenty-eight(68.3%)patients demonstrated an improvement in erectile dysfunction.Tumor size and invasiveness were significantly correlated with the improvement of erectile dysfunction.Preoperative testosterone<2.3 ng ml^(-1)was an independent predictor of improvement in erectile dysfunction.In conclusion,our results indicated that tumor size and invasiveness were important factors affecting the improvement of sexual dysfunction in male patients with prolactinoma.The preoperative testosterone level was an independent predictor related to the improvement of erectile dysfunction.

Prolactin Adenomas in Senegal: Epidemiological, Diagnostic and Therapeutic Aspects of 89 Cases

Introduction: In Senegal, there is very little data on prolactinomas despite their negative impact on couples fertility. Patients and methods: This was a multicentre, retrospective, descriptive, analytical study conducted from 1 January 2008 to 31 December 2022 in the neurosurgery departments of the Fann and Principal hospitals and the endocrinology department of the Abass Ndao Hospital. Results: We included 89 patients, representing a prevalence of 36.7% among all cases of pituitary adenoma. The mean age was 35.6 ± 10 years and the sex ratio was 0.34. The mean time to consultation was 27.1 ± 29 months. Clinical symptoms were dominated by gonadotropic disorders represented by galactorrhoea (71 cases, 79.8%), amenorrhoea (61 cases, 68.5%), and infertility in the couple (31 cases, 34.8%). Fifty-seven (58) patients presented with a tumour syndrome (65.2%, including 57 cases of headache (64%), 34 cases of visual disorders (38.2%) and 8 patients with a dysmorphic syndrome (8.9%). Imaging revealed a macroadenoma in 68.5% (61 cases) and extension of the adenoma in 11 patients (12.4%). The hormonal profile was isolated lactotropic hypersecretion (80 cases, 89.9%) and mixed in 9 cases (including concomitant secretion of GH in 8 cases and ACTH in 1 case). All patients had initially benefited? from dopaminergic agonist-based medical treatment. Pituitary surgery was effective in 45 patients (50.6%), including 44 cases by transsphenoidal approach. Postoperative incidents included transient diabetes insipidus (77.7%) and cerebrospinal fluid leakage (20%). We noted 7 cases (7.9%) of death presenting with a tumour syndrome (100%), a macro-adenoma (85.7%), having undergone pituitary surgery (42.9%). The factors significantly associated with prolactinoma were young age (p Conclusion: This series also demonstrates the impact of prolactin adenomas on reproductive function. Delayed diagnosis explains the predominance of macroadenomas, which are a source of pre- and post-operative complications.

Expression of Prolactin Gene in Rat Prolactinoma Induced by 17-β-Estradiol

Rats were implanted subcutaneously with silastic capsules containing 10 mg 17-β-estradiol. After 30, 60 and 120 days, their pituitary weights and plasma PRL levels were found to increase significantly. The administration of β-estradiol also produced a marked rise of PRL mRNA concentrations in the rat total RNA, but the sharper rise of serum PRL levels indicates that estradiol not only promotes transcription of prolactin gene, but also improves the efficiency of translation of the transcription product.

μ-and m-calpain expression and activity changes following diethylstilbestrol injection in the rat anterior pituitary

Little is known about changes in calpain activity in the pituitary gland. In the present study,μ- and m-calpain activity changes were detected in the rat anterior pituitary following intraperitoneal injection of diethylstilbestrol. Double-immunofluorescence labeling confirmed colocalization of μ- and m-calpain in prolactin-secreting cells （lactotrophs）. Western blot analysis revealed significantly increased expression of both calpains, which accompanied upregulated cytosol and membrane zymographic activities at 12 weeks following diethylstilbestrol injection, compared with rats injected with sunflower oil. Moreover, following estrogen injection, pituitary gland pathological damage gradually worsened with increasing time. Results demonstrated that estrogen regulated calpain expression and activity, and both calpains participated in the pathophysiological processes of the pituitary gland. Ubiquitous calpain expression could serve as an effective target for anti-estrogen drugs.

Correlations between Expression of Estrogen and Androgen Receptors and the Clinical Characteristics of Prolactinoma~*

Objective： To study the correlations between estrogen receptor （ER） and androgen receptor （AR） and the clinical presentations of prolactinoma and investigate the effect of ER and AR expression on the pathogenesis of prolactinoma in sexual difference. Methods： The clinical data of 30 patients who had undergone transsphenoidal operations in Tongji Hospital from December 2000 to December 2001 were reviewed retrospectively. The clinical information included sex, age, serum-prolactin, size, tumor invasiveness, history of use of bromocriptine and frequency of recurrence. In 20 out of the 30 patients, the ER and AR expression was detected by using immunohistochemistry method. With help of Chi-square test, the relationship between ER, AR and the clinical presentations was analyzed. Results： The statistical values revealed that there was no significant correlation between the ER and AR expression levels with the clinical presentations such as sex, age, tumor size or tumor invasiveness among the 20 patients studied （P〉0.05）. Conclusion： The expression of ER or AR is not influenced by the clinical data of prolactinoma such as sex, age, tumor diameter or extent of tumor invasiveness. The tumor is more aggressive in males than in females. In maroadenoma or tumor with hyperprolactineamia （〉200 ng/mL） simple surgical treatment can＇t successfully cure the prolactinoma. Post-operative bromocriptine therapy can＇t be determined by the sex of the patients, but is greatly related to the tumor size and serum-prolactin level before operation.

Sex-related changes in tumor consistency in prolactinoma patients after bromocriptine pretreatment

Objective It has long been reported that prolactinomas treated with bromocriptine increase fibrosis and may affect surgical outcomes.We retrospectively studied 238 consecutive patients with histopathologically confirmed prolactinomas undergoing microsurgery in a single neurosurgery department of Tongji Hospital(Wuhan,China) from 2012 to 2015 in order to evaluate tumor consistency changes after bromocriptine pretreatment and surgical outcomes.Methods We divided the patients into four groups;males in the dopamine agonist(DA) group,females in the DA group,males in the no DA group,and females in the no DA group,and we compared the surgery process,specimen Masson staining,and clinical outcomes of the four groups.According to a previously published classification,the operative notes from an experienced neurosurgeon were reviewed to classify the consistency of tumors as "fibrous" or "nonfibrous".Results No differences in tumor consistency were found in male patients with or without DA treatment.However,in female patients with DA treatment,tumors were likely to be harder in texture than the tumors of female patients without DA treatment.Despite tumor consistency differences between sexes,the tumor biological remission rate was similar between groups,as was the rate of tumor resection.Discussion Our study indicates that preoperative DA therapy impacts tumor consistency in female patients but not male patients.Although the surgical and histopathological outcomes are not influenced,these findings may provide useful information for the choice of operative approach and surgery process for pituitary adenoma.

Long-term application of diethylstilbestrol upregulates expressions of μ-and m-calpains in pituitary intermediate lobe of female Wistar rats

BACKGROUND： During formation of prolactin neoplasia, how cells and its structure in adenohypophysis affect prolactin cells should be further studied. Intermediate lobe can be regarded as a driving region to release prolactin （PRL） and may promote formation of prolactin neoplasia in pituitary anterior lobe. OBJECTIVE： To observe the effect of diethylstilbestrol （DES） on the expressions of μ and m-calpains in pituitary intermediate lobe of female Wistar rats. DESIGN： Observational contrast animal study. SETTING： Beijing Neurosurgical Institute. MATERIALS： A total of 21 female Wistar rats, 3 weeks old weighing 70-80 g were housed with free access to tap water and standard pellet food. They were kept in a CL-grade condition, at （24±1）℃ and a humidity of （55±5）%, and with a 12 hours day-night cycle. Caprine anti-μ- and m-calpains antibodies were provided by Santa Cruz Biotechnology, CA, USA; rabbit-anti-PRL antibodies by Dako, Denmark; rabbit-anti-ACTH antibody by Boster Company, Wuhan. METHODS： The experiment was carried out in Pathophysiological Department and Animal Laboratory, Beijing Neurosurgical Institute from August 2006 to January 2007. ① Rats were randomly divided into groups with 7 in each group, including vehicle control group, in which rats were injected intraperitoneally with sun-flower seed oil （1 mL/kg, twice a week） for 16 weeks; DES group, where animals were administered with DES （5 mg/kg, twice a week） for 16 weeks; DES ＋ vehicle control group, in which DES was administered for 12 weeks at the same dose with those in DES group, and then was discontinued and replaced by sun-flower seed oil （1 mL/kg, twice a week） for the following 4 weeks. ② At 16 weeks later, pituitary tissue was dealt with HE staining and PRL immunohistochemical examination to observe evoke of tumor; meanwhile, immunohistochemical examination was used to observe expression of PRL of pituitary anterior lobe, expressions of μ- and m-calpains of pituitary intermediate lobe and distribution of adrenocorticotropin. MAIN OUTCOME MEASURES： ① Expression of PRL of pituitary anterior lobe, expressions of μ- and m-calpains of pituitary intermediate lobe and distribution of adrenocorticotropin. ② Morphological observation of pituitary tissue. RESULTS： All 21 rats were involved in the final analysis. ① Results of immunohistochemical examination： Morphological changes of neoplasia in DES group were strongly positive to PRL, and this suggested that formation of prolactin adenoma was observed in pituitary tissue. As compared with vehicle control group, expression of adrenoeorticotropic hormone （ACTH） was increased in both DES group and DES ＋ vehicle control group. In addition, expressions of μ- and m-calpains in pituitary intermediate lobe were higher in DES group than that in vehicle control group. Otherwise, expressions of m-calpains in pituitary intermediate lobe was decreased in DES ＋ vehicle control group, but expression of μ-calpains was still increased. ② Morphological observation of pituitary tissue： Gland tubes were orderly arranged in rats in vehicle control group. Anterior pituitary gland in rats of DES group demonstrated an apparent disappearance of gland tubes and a relatively large-scaled vasculature formation, namely the vascular lake lined by tightly arranged endothelial cells. Local integrated tumor cell arrangements were also detected. In addition, the border between the IL and the anterior lobe was locally blurred. The definite tumor-like changes in pituitary tissueswere confirmed in 6 of 7 female Wistar rats in DES group, and one spontaneous occurrence of tumor formation was found in vehicle control group. In DES ＋ vehicle control group, DES withdrawal led to the subtile emergence of gland tube cavity, although tumor-like cells still existed in 4 of 7 rats, suggesting occurrence of the tumor regression due to the withdrawal of DES. CONCLUSION： A long-term application of DES can enhance the expressions of ubiquitours neutral cysteine protease in pituitary intermediate lobe and this suggests that both of them play a key role in release of hormone and formation of prolactin neoplasia through directly promoting PRL expression and release of neighboring pituitary intermediate lobe.

BMP-4 accelerates PRL secreting,cell proliferation and invasiveness in human prolactinoma

Objective： The aim of the study was to explore the bone morphogenetic protein 4 （BMP-4） how to regulate pro- lactin （PRL） secreting, cell proliferation and invasiveness in human prolactinorna. Methods： Ten patients who diagnosed as prolactinoma by clinical characteristics and pathology were divided into two groups, one was sensitive to Brornocriptine, the other was insensitive to Brornocriptine. Every case was conducted by primal cell culture then treated by different concentrations of BMP-4. The cell configuration was observed and PRL hormone was measured in different times. The expressions of BMP-4 rnRNA and BMP-4 in 37 cases of prolactinorna and 8 cases of normal pituitary tissues samples were detected by immunohistochemical and in situ hybridization technique, and the results were analyzed by statistic methods. Results： BMP-4 （5 ng/rnL） could accelerate the secreting of PRL in prolactinorna cell, and it could reach the greatest effect in the concentration of 20 ng/mL. BMP-4 could increase prolactinoma cell proliferation, but when the concentration was 50 ng/rnL, the BMP-4 effect of increasing secreting decreased. When 100 ng/mL, the cell began to die. The effects of the BMP-4 in sensitive group and insensitive group had no difference. The BMP-4 was highly expressed in the prolactinornas and was positively related with the invasiveness grades. Conclusion： BMP-4 have positive regulation in prolactinoma secreting, proliferation, invasiveness effects, BMP-4 probably has the important role in prolactinoma pathogenesis.

Combined Treatment with Buserelin+Cabergoline in Patient with Prostate Cancer and Pituitary Macroprolactinoma

Twelve years following hemicolectomy for colon adenocarcinoma, a 75-year-old patient with prostate cancer was treated for 4 weeks with the antiandrogen nilutamide and then with the long-acting GnRH agonist buserelin. The serum testosterone and prostate-specific antigen levels had decreased dramatically after 3 months of treatment. After 2 years of buserelin administration, the hormonal state was examined. Serum estradiol, testosterone, DHEA, DHEAS, FSH and LH levels proved to be suppressed, but the serum PRL concentration was extremely high (3 365 mIU/l). The pituitary MRI revealed a macroadenoma. The patient was treated with the dopamine agonist cabergoline, together with buserelin. After 9 months of this combined treatment, the prostate-specific antigen and testosterone levels were very low;the serum estradiol, DHEA, DHEAS, FSH and LH concentrations remained suppressed. The serum PRL level fell dramatically to 6.95 mIU/l, and a significant reduction in tumor size was observed on MRI. In conclusion: Combined buserelin + cabergoline treatment proved a highly successful procedure to cure this patient with prostate carcinoma and subsequent pituitary macroprolactinoma.

Amyloidogenic Pituitary Prolactinoma

Prolactinomas are the most common benign pituitary neoplasms and the common cause of hyperprolactinemia. Most of them arise in women of reproductive age. In men, they are often functionally silent, but present with manifestations secondary to pressure effects when they become macro adenomas. We present a case of prolactinoma in a 54-year old male patient who presented with pressure effects because of the tumor, as head ache and bi-temporal hemianopsia. MRI Brain scan was done to identify the tumor. The patient underwent trans-sphenoidal resection of the pituitary macro adenoma. Histological examination revealed spheroid amyloid deposits, almost replacing the adenoma. No medical treatment was given but the tumor recurred after 6 months and a repeat surgery was done for total excision.

Optimization of transfection efficiency of small interfering RNA in purified human prolactinoma cells

Background Control of hypersecretion of certain hormones is one of the key targets in the treatment of pituitary adenomas. RNA interference has been shown to inhibit protein expression, and thus it may represent a promising method for the treatment of pituitary adenomas. In the present study, transfection efficiency of small interfering RNA （siRNA） was optimized in human prolactinoma cells. Methods First, a method was optimized to extract highly purified human prolactinoma cells in vitro. The extracted cells were verified to retain the physiological features of prolactin （PRL） secretion. Second, three conditions for siRNA transfection were tested by the evaluation of transfectfon efficiency and cell viability. The proper transfection condition was verified for human prolactinoma cells. Third, the siRNA for prolactin was transfected into the human prolactinoma cells, and the suppression of PRL mRNA was evaluated by quantitative real-time reverse transcription-PCR. Results The siRNA of 100 pmol with Lipofectamine 2000 of 5 μl for 1×10^6 cells was proved preferable, with transfection efficiency being 53.3% and cell viability being 69.7%. In the preliminary experiment the siRNA against PRL decreased the mRNA of PRL by 34.0%. Conclusion It is possible to inhibit hormone hypersecretion by RNA interference, that may eventually enable therapeutic siRNA drugs developed.

Prolactinoma coexisting with cerebrospinal fluid rhinorrhea and cavernous internal carotid aneurysm: Case report and literature review

Pituitary adenoma coexisting with cerebrospinal fluid(CSF) rhinorrhea and carotid aneurysm is extremely rare. CSF rhinorrhea may cause pneumocephalus and intracranial infection. Rupture of the aneurysm may cause fatal consequence. The authors report such a rare case to draw more attentions. A 55-year-old man presented with sexual dysfunction for 2 years. The serum prolactin was tested as 1,600 ng/ml(normal range, 1.39–24.2). Enhanced cranial MR showed an evident lesion at the sellar area, invading the right cavernous sinus. Prolactinoma was diagnosed. He took bromocriptine for one year and received gamma knife therapy thereafter. Four months after the treatment of gamma knife, he got CSF rhinorrhea and nasal bleeding. The endoscopic transnasalsphenoidal approach was performed to resect the tumor and repair the dura defect.The CSF rhinorrhea stopped after the surgery, however his nasal bleeding continued. The digital subtraction angiography(DSA) showed an aneurysm at the right cavernous internal carotid. The endovascular coil embolization was performed to treat the aneurysm. The patient recovered well. The coexistence of CSF rhinorrhea and pituitary adenoma is a high risk factor for the rupture of cavernous internal carotid aneurysm. When treating patients with pituitary adenoma and CSF rhinorrhea, doctors should exclude the aneurysm. When nasal bleeding occurs, the hemorrhage of internal carotid should be considered, and appropriate measures should be taken immediately.

Elevated levels of mitochonrial respiratory complexes activities and ATP production in 17-β-estradiol-induced prolactin-secretory tumor cells in male rats are inhibited by melatonin in vivo and in vitro

Background Our earlier studies indicate that melatonin inhibits the proliferation of prolactinoma and induces apoptosis of pituitary prolactin-secreting tumor in rats. Melatonin has also been shown to induce apoptosis and to reduce the production of ATP in breast tumor cells. This study analyzed the levels of the four mitochondrial respiratory complexes and the production of ATP and also the effects of melatonin treatment of prolactinoma. Methods In the in vivo study, mitochondria were harvested from control pituitaries or prolactinoma collected from the pituitaries of melatonin- and 17-13-estradiol （E2）-treated male rats. In the in vitro study, prolactinoma cells mitochondria were harvested. Activities of the four mitochondrial respiratory complexes were assayed using fluorometer. ATP production of prolactinoma cells was estimated using bioluminescent methods. Results Elevated levels of four mitochondrial respiratory complexes activities and ATP production were recorded in prolactinoma cells. Moreover, in both in vivo and in vitro studies, melatonin inhibited the activities of mitochondrial respiratory complexes and the production of ATP in prolactinoma cells. Conclusions There is a link between mitochondria[ function increase and tumorigenesis. Melatonin induces apoptosis of pituitary prolactin-secreting tumor of rats via the induction of mitochondrial dysfunction and inhibition of energy metabolism.

One hemodialysis patient with headache, blurred vision, and hypotension induced by pituitary prolactinoma

We reported a rare case of a dialysis patient coincident pituitary prolactinoma with calcification. A 55-year-old woman who had undergone hemodialysis for 8 years was admitted to the nephrology unit because of headache, blurred vision, and hypotension. Physical examination was normal; endocrinological examination demonstrated elevated serum levels of prolactin （〉4240 mlU/L）, but other hormonal profiles, such as growth hormon, adrenocorticotropic hormone, thyroid stimulating hormone, free triiodothyronine, free thyroxine, follicle-stimulating hormone and luteinizing hormone, were absolutely or relatively lower. A cranial computed tomography （CT） suggested saddle area a high-density screenage with an anteroposterior diameter of 1.0 cm. A cerebral magnetic resonance scan confirmed the pituitary adenoma accompanied with calcification. Contrast-enhanced Tl-weighted images revealed a less enhancing tumor, 14 mm wide round lesion with a high intensity signal. It enlarges the sella turcica, but the optic chiasma is not displaced. We suggest that in the differential diagnosis of any hemodialysis patient with severe headache, hypotension, and visual disturbances, this syndrome should be considered as prompt pituitary adenoma.