Background: Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. Design and methods: A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB R2.0 mg weekly. Results: Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (PZ0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CAB max/w ) was 3.5 mg (2.0–10.5). Despite a higher CAB max/w in patients treated with multimodal therapy (PZ0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (PZ0.006) and a significant reduction in CAB max/w (PZ0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CAB max/w or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). Conclusion: CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

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Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients

Resistance to dopamine agonists is defined here as failure to normalize prolactin levels and failure to decrease macroprolactinoma size by ≥50 %. Failure to normalize prolactin levels is found in about 25 % of patients treated with bromocriptine and 10-15 % of those treated with cabergoline. Failure to achieve at least a 50 % reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10-15 % of those treated with cabergoline. Treatment approaches for patients resistant to dopamine agonists include changing to another dopamine agonist and increasing the dose of the drug as long as there is continued response to the dose increases and no adverse effects with higher doses. Transsphenoidal surgery is also an option. Clomiphene, gonadotropins, and GnRH can be used if fertility is desired. For those not desiring fertility, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. In many patients modest or even no reduction in tumor size may be acceptable as long as there is not tumor growth. Hormone replacement [estrogen or testosterone] may cause a decrease in efficacy of the dopamine agonist. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches. Temozolomide may be useful as a last resort for aggressive, invasive tumors refractory to other medical and ablative therapies.

Management of medically refractory prolactinoma

Context Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues. Evidence acquisition A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized. Evidence synthesis The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or "whispering" adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification. Conclusions A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients.

Clinical and Pathological Aspects of Silent Pituitary Adenomas.

Objective Clinically nonfunctioning pituitary adenoma (NFPA) remains the only pituitary tumor subtype for which no effective medical therapy is available or recommended. We evaluated dopamine agonist (DA) therapy for preventing growth of postsurgical pituitary tumor remnants. Design The study design included historical cohort analysis of clinical results at two pituitary referral centers with different standard practices for postoperative NFPA management: DA therapy or conservative follow-up. Methods Seventy-nine patients followed for 8.8±6.5 years were treated with DA, initiated upon residual tumor detection on postoperative MRI (preventive treatment (PT) group, n=55), or when tumor growth was subsequently detected during follow-up (remedial treatment (RT) group, n=24). The control group (n=60) received no medication. Tumoral dopamine and estrogen receptor expression assessed by quantitative RT-PCR and immunostaining were correlated with response to treatment. Results Tumor mass decreased, remained stable, or enlarged, respectively, in 38, 49, and 13% of patients in the PT group, and in 0, 53, and 47% of control subjects; shrinkage or stabilization was achieved in 58% of enlarging tumors in the RT group, P Conclusions Dopamine agonist therapy in patients with NFPA is associated with decreased prevalence of residual tumor enlargement after transsphenoidal surgical resection.

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Treatment of clinically nonfunctioning pituitary adenomas with dopamine agonists

Cabergoline (CAB), a long-lasting dopamine-agonist, specific for the D2 receptor, is effective in normalizing serum PRL levels in most patients with microprolactinoma or idiopathic hyperprolactinemia. Because few data are presently available on the effects of CAB treatment in macroprolactinomas, the aim of this open-label study was to investigate whether this drug was effective in producing tumor shrinkage, as well as in normalizing PRL levels. Twenty-three patients with macroprolactinoma entered this study: 15 patients had had no treatment, whereas the remaining 8 patients had been previously treated with bromocriptine, which was withdrawn because of intolerance. Three of 23 patients had undergone unsuccessful surgery. Pretreatment serum PRL levels ranged from 100-3860 μg/L. CAB was administered at a dose of 0.5–3 mg once or twice a week for 12–24 months. Magnetic resonance imaging (MRI) scans were performed before and 3, 6, 12, and 24 months after the beginning of treatment, to evaluate tumor shrinkage,...

Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage

Objective: Previous studies attempting to define the natural history of postoperative nonfunctioning pituitary adenomas (pNFPAs) were somewhat limited by selection bias and/or small numbers and/or lack of consistency among the study findings. The aim of this study was to scrutinize the literature in order to analyze the natural history of pNFPAs. Methods: Electronic database including MEDLINE, PubMed and Cochrane CENTRAL were searched. The literature relating to the patients with pNFPAs without postoperative radiotherapy and pharmacotherapy was collected. Eligible studies reported on the rate of tumor recurrence, the tumor growth-free survival rate (TGFSR) at 5 and 10 years, and/or the residual tumor volume doubling time (TVDT). Results: 19 studies met the criteria. The pNFPAs were divided into two groups: the pooled recurrence rate of group I without detectable residual tumor (371 patients) was 12% (95% CI 6–19%), the TGFSR at 5 and 10 years were 96% (95% CI 89–99%) and 82% (95% CI 65–94%), respectively. The pooled recurrence rate of group II with residual tumor (600 patients) was 46% (95% CI 36–56%), the TGFSR at 5 and 10 years were 56% (95% CI 41–71%) and 40% (95% CI 27–53%), respectively. The mean TVDT was 3.4 years (95% CI 2.4–4.5 years). Conclusions: pNFPAs, with or without detectable residual tumor, need stratification of treatment and radiological/endocrinological follow-up strategy. According to the TVDT, residual tumor regrowth is very slow, which permits an extensive and safe follow-up program for most patients.

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Natural history of postoperative nonfunctioning pituitary adenomas: a systematic review and meta-analysis

Invasive prolactinomas are more likely to be resistant to drug therapy but the mechanism of this is still unknown. The objective of this study was to analyze the different expression of ERmRNA and D2RmRNA isoforms in prolactinomas responsive and resistant to dopamine agonist (DA), and to discuss the correlation of such gene expression with tumor biological behavior. A prospective study of 20 consecutive patients who harbored prolactinomas was designed. Patients were classified as responsive (14 cases) or resistant (six cases) according to their clinical and biochemical response to bromocriptine. Tumor tissue samples were examined by means of QRT-PCR analysis. Median D2SmRNA expression in responsive patients was about 2.5-fold that in resistant ones (13.5 +/- 10.4 and 5.4 +/- 2.4, respectively, P = 0.09). No significant difference was found between D2LmRNA expression levels (P = 0.77). However, there was a significant difference between D2S/D2LmRNA ratios for responsive and resistant tumors (P = 0.012). A significant difference was not found between these two groups in levels of ERalphamRNA and ERbetamRNA expression (P = 0.20 and 0.06, respectively). D2SmRNA expression was significantly different for invasive and noninvasive tumors (6.2 +/- 3.6 vs. 17.0 +/- 11.2, respectively, P = 0.02). The D2S/D2L ratio is related to the responsiveness of prolactinomas to DA medication, in which D2SmRNA plays an important role. Lower expression of D2SmRNA in invasive tumor patients suggests that invasive prolactinomas may be more likely to be resistant to DA medication.

Expression of D2RmRNA isoforms and ERmRNA isoforms in prolactinomas: correlation with the response to bromocriptine and with tumor biological behavior.

Treatment of Middle Cranial Fossa Arachnoid Cysts: A Systematic Review and Meta-Analysis.

A Novel Invasive-Related Biomarker in Three Subtypes of Nonfunctioning Pituitary Adenomas

Objective: The aim of this study was to scrutinize the literature to determine the efficacy and safety of gamma knife surgery (GKS) for the treatment of nonfunctioning pituitary adenomas (NFPAs) with volumetric classification. Methods: Electronic databases including MedLine, PubMed, and Cochrane Central were searched. The literature related to patients with NFPAs treated with GKS was collected. Eligible studies reported on the rate of tumor control (RTC), the rate of radiosurgery-induced optic neuropathy injury (RRIONI), the rate of radiosurgery-induced endocrinological deficits (RRIED), and other parameters. Results: A total of 17 studies met the criteria. Based on the tumor volume, NFPAs were divided into three groups: the RTC of group I (93 patients) with tumor volumes !2 ml was 99% (95% CI 96‐ 100%), the RRIONI was 1% (95% CI 0‐4%), and the RRIED was 1% (95% CI 0‐4%). The RTC of group II (301 patients) with volumes from 2 to 4 ml was 96% (95% CI 92‐99%), the RRIONI was 0 (95% CI 0‐2%), and RRIED was 7% (95% CI 2‐14%). The RTC of group III (531 patients) with volumes larger than 4 ml was 91% (95% CI 89‐94%), the RRIONI was 2% (95% CI 0‐5%), and the RRIED was 22% (95% CI 14‐31%). There were significant differences in the RTC and in the RRIED among the three groups (P!0.001), indicating that there were higher RRIED and lower RTC with the increase of tumor volume. Conclusions: NFPAs, according to tumor volume classification, need stratification for GKS treatment. GKS is the optimal choice for the treatment of group II NFPAs. Patients with residual tumor volumes of !4 ml will benefit most from GKS treatment. European Journal of Endocrinology 169 487‐495

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Yong Chen

Papers

Natural history of postoperative nonfunctioning pituitary adenomas: a systematic review and meta-analysis

Expression of D2RmRNA isoforms and ERmRNA isoforms in prolactinomas: correlation with the response to bromocriptine and with tumor biological behavior.

Treatment of Middle Cranial Fossa Arachnoid Cysts: A Systematic Review and Meta-Analysis.

A Novel Invasive-Related Biomarker in Three Subtypes of Nonfunctioning Pituitary Adenomas

Gamma knife surgery for patients with volumetric classification of nonfunctioning pituitary adenomas: a systematic review and meta-analysis