Lactotroph adenoma radiosurgery

Lactotroph adenoma radiosurgery

Lactotroph adenoma radiosurgery also serves as an option for those refractory to medical and surgical therapy 1).

GKRS plays a significant role in the treatment of non-functioning [NFA] and hormonal-active [HAA] pituitary adenoma. It affords high rate of tumor control and offers low risk of collateral neurological or endocrine axis injury. A study showed that control of tumor growth was achieved in 90% patients, shrinkage of tumor in 54% and arrest of progression in 36% cases after GKRS treatment. The biochemical remission rate in GH secreting adenoma was 57%, ACTH adenoma was 67% and prolactinoma was 40%. Age less than 50 years and tumor volume less than 5cm3 were associated with a favourable radiosurgical outcome 2).

Case series

retrospective study included lactotroph adenoma treated with SRS between 1997 and 2016 at ten institutions. Patients’ clinical and treatment parameters were investigated. Patients were considered to be in endocrine remission when they had a normal level of prolactin (PRL) without requiring dopamine agonist medications. Endocrine control was defined as endocrine remission or a controlled PRL level ≤ 30 ng/ml with dopamine agonist therapy. Other outcomes were evaluated including new-onset hormone deficiency, tumor recurrence, and new neurological complications.

The study cohort comprised 289 patients. The endocrine remission rates were 28%, 41%, and 54% at 3, 5, and 8 years after SRS, respectively. Following SRS, 25% of patients (72/289) had new hormone deficiency. Sixty-three percent of the patients (127/201) with available data attained endocrine control. Three percent of patients (9/269) had a new visual complication after SRS. Five percent of the patients (13/285) were recorded as having tumor progression. A pretreatment PRL level ≤ 270 ng/ml was a predictor of endocrine remission (p = 0.005, adjusted HR 0.487). An increasing margin dose resulted in better endocrine control after SRS (p = 0.033, adjusted OR 1.087).

In patients with medically refractory prolactinomas or a residual/recurrent prolactinoma, SRS affords remarkable therapeutic effects in endocrine remission, endocrine control, and tumor control. New-onset hypopituitarism is the most common adverse event 3).

2015

Radiotherapy as an alternative and adjuvant treatment for prolactinomas has been performed at the Department of Radiation Oncology, Prince of Wales Cancer Centre, Sydney, New South Wales, Australia, with the linear accelerator since 1990.

In a retrospective review of 13 patients managed with stereotactic radiosurgery (SRS) and 5 managed with fractionated stereotactic radiotherapy (FSRT), as well as 5 managed with conventional radiotherapy, at the Prince of Wales Hospital. Patients with a histopathologically diagnosed prolactinoma were eligible. Those patients who had a confirmed pathological diagnosis of prolactinoma following surgical intervention, a prolactin level elevated above 500 μg/L, or a prolactin level persistently elevated above 200 μg/L with exclusion of other causes were represented in this review.

At the end of documented follow-up (SRS median 6 years, FSRT median 2 years), no SRS patients showed an increase in tumour volume. After FSRT, 1 patient showed an increase in size, 2 showed a decrease in size and 2 patients showed no change. Prolactin levels trended towards improvement after SRS and FSRT, but no patients achieved the remission level of <20 μg/L. Seven of 13 patients in the SRS group achieved a level of <500 μg/L, whereas no patients reached this target after FSRT.

A reduction in prolactin level is frequent after SRS and FSRT for prolactinomas; however, true biochemical remission is uncommon. Tumour volume control in this series was excellent, but this may be related to the natural history of the disease. Morbidity and mortality after stereotactic radiation were very low in this series 4).


Cohen-Inbar et al., reviewed the outcome of patients with medically and surgically refractory prolactinomas treated with Gamma Knife radiosurgery (GKRS) during a 22 years follow-up period.

They reviewed the patient database at the University of Virginia Gamma Knife center during a 25-year period (1989-2014), identifying 38 patients having neurosurgical, radiological and endocrine follow-up.

Median age at GKRS treatment was 43 years. Median follow-up was 42.3 months (range 6-207.9). 55.3 % (n = 21) were taking a dopamine agonist at time of GKRS. 63.2 % (n = 24) had cavernous sinus tumor invasion. Endocrine remission (normal serum prolactin off of a dopamine agonist) was achieved in 50 % (n = 19). GKRS induced hypopituitarism occurred in 30.3 % (n = 10). Cavernous sinus involvement was shown to be a significant negative prognosticator of endocrine remission. Taking a dopamine agonist drug at the time of GKRS showed a tendency to decrease the probability for endocrine remission.

GKRS for refractory prolactinomas can lead to endocrine remission in many patients. Hypopituitarism is the most common side effect of GKRS 5).

2013

evaluated the efficacy of Gamma knife stereotactic radiosurgery (GKSR) as an adjunctive management modality for patients with drug resistant or intolerant cavernous sinus invasive prolactinomas. Twenty-two patients with cavernous sinus invasive prolactinoma underwent GKSR between 1994 and 2009. Thirteen patients were dopamine agonist (DA) resistant. Six patients were intolerant to DA. Three patients chose GKSR as their initial treatment modality in hopes they might avoid life long suppression medication. The median tumor volume was 3.0 cm3 (range 0.3–11.6). The marginal tumor dose (median= 15 Gy, range 12–25 Gy) prescribed was based on the dose delivered to the optic apparatus. The median follow-up interval was 36 months (range, 12–185). Endocrine normalization was defined as a normal serum prolactin level off DA (cure) or on DA. Endocrine improvement was defined asa decreased but still elevated serum prolactin level. Endocrine deterioration was defined as an increased serum prolactin level. Endocrine normalization was achieved in six(27.3%) patients. Twelve (54.5%) patients had endocrine improvement. Four patients (18.2%) developed delayed increased prolactin. Imaging-defined local tumor control was achieved in 19 (86.4%) patients, 12 of whom had tumor regression. Three patients had a delayed tumor progression and required additional management. One patient developed a new pituitary axis deficiency after GKSR. Invasive prolactinomas continue to pose management challenges. GKSR is a non invasive adjunctive option that may reduce prolactin levels in patients who are resistant to or intolerant of suppression medication. In a minority of cases, patients may no longer require long term suppression therapy 6).

2006

Twenty-three patients were included in analysis of endocrine outcomes (median and average follow-up of 55 and 58 mo, respectively) and 28 patients were included in analysis of imaging outcomes (median and average follow-up of 48 and 52 mo, respectively). Twenty-six percent of patients achieved a normal serum prolactin (remission) with an average time of 24.5 months. Remission was significantly associated with being off of a dopamine agonist at the time of GKRS and a tumor volume less than 3.0 cm3 (P < 0.05 for both). Long-term image-based volumetric control was achieved in 89% of patients. Complications included new pituitary hormone deficiencies in 28% of patients and cranial nerve palsy in two patients (7%).

Clinical remission in 26% of treated patients is a modest result. However, because the GKRS treated tumors were refractory to other therapies and because complication rates were low, GKRS should be part of the armamentarium for treating refractory prolactinomas. Patients with tumors smaller than 3.0 cm3 and who are not receiving dopamine agonist at the time of treatment will likely benefit most 7).

2000

Twenty patients with prolactinomas were followed after GKS. Five patients were treated successfully; their prolactin (PRL) levels dropped into the normal range and dopaminergic drugs could be discontinued. Two spontaneous pregnancies were observed and 11 patients experienced improvement. Improvement was defined as normal PRL levels with the continued possibility of reduced medical treatment or a substantially reduced medical treatment dose with some degree of hyperprolactinemia maintained. The treatment failed in three patients who experienced no improvement. Patients treated with dopaminergic drugs during GKS did significantly less well in comparison with the untreated group when a cumulative distribution function (Kaplan-Meier estimate) was used. CONCLUSIONS:

The results of GKS for prolactinomas in this investigation are better than the results published by others. This may be an effect of case selection because there were no “salvage cases” in our group of patients. Because a dopamine agonist seemed to induce radioprotection in this series, it is suggested that GKS be performed during an intermission in drug therapy when the dopamine agonist is discontinued 8).

References

1)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.
2)

Narayan V, Mohammed N, Bir SC, Savardekar AR, Patra DP, Bollam P, Nanda A. Long term Outcome of Non-functioning and Hormonal-active Pituitary Adenoma after Gamma Knife Radio Surgery. World Neurosurg. 2018 Mar 21. pii: S1878-8750(18)30576-X. doi: 10.1016/j.wneu.2018.03.094. [Epub ahead of print] PubMed PMID: 29574220.
3)

Hung YC, Lee CC, Yang HC, Mohammed N, Kearns KN, Nabeel AM, Abdel Karim K, Emad Eldin RM, El-Shehaby AMN, Reda WA, Tawadros SR, Liscak R, Jezkova J, Lunsford LD, Kano H, Sisterson ND, Martínez Álvarez R, Martínez Moreno NE, Kondziolka D, Golfinos JG, Grills I, Thompson A, Borghei-Razavi H, Maiti TK, Barnett GH, McInerney J, Zacharia BE, Xu Z, Sheehan JP. The benefit and risk of stereotactic radiosurgery for prolactinomas: an international multicenter cohort study. J Neurosurg. 2019 Aug 2:1-10. doi: 10.3171/2019.4.JNS183443. [Epub ahead of print] PubMed PMID: 31374549.
4)

Wilson PJ, Williams JR, Smee RI. Single-centre experience of stereotactic radiosurgery and fractionated stereotactic radiotherapy for prolactinomas with the linear accelerator. J Med Imaging Radiat Oncol. 2015 Jun;59(3):371-8. doi: 10.1111/1754-9485.12257. Epub 2014 Nov 20. PubMed PMID: 25410143.
5)

Cohen-Inbar O, Xu Z, Schlesinger D, Vance ML, Sheehan JP. Gamma Knife radiosurgery for medically and surgically refractory prolactinomas: long-term results. Pituitary. 2015 Dec;18(6):820-30. doi: 10.1007/s11102-015-0658-1. PubMed PMID: 25962347.
6)

Liu X, Kano H, Kondziolka D, Park KJ, Iyer A, Shin S, Niranjan A, Flickinger JC, Lunsford LD. Gamma knife stereotactic radiosurgery for drug resistant or intolerant invasive prolactinomas. Pituitary. 2013 Mar;16(1):68-75. PubMed PMID: 22302560.
7)

Pouratian N, Sheehan J, Jagannathan J, Laws ER Jr, Steiner L, Vance ML. Gamma knife radiosurgery for medically and surgically refractory prolactinomas. Neurosurgery. 2006 Aug;59(2):255-66; discussion 255-66. PubMed PMID: 16883166.
8)

Landolt AM, Lomax N. Gamma knife radiosurgery for prolactinomas. J Neurosurg. 2000 Dec;93 Suppl 3:14-8. PubMed PMID: 11143231.

Dopamine agonist resistant lactotroph adenoma

Dopamine agonist resistant lactotroph adenoma

While dopamine agonists are a primary method of therapeutic treatment for Lactotroph adenoma, the rate of resistance to these drugs continues to increase each year.

Surgery is typically indicated for patients who are resistant to medical therapy or intolerant of its adverse side effects, or are experiencing progressive tumor growth. Surgical resection can also be considered as a primary treatment for those with smaller focal tumors where a biochemical cure can be expected as an alternative to lifelong dopamine agonist treatment. Stereotactic radiosurgery also serves as an option for those refractory to medical and surgical therapy 1).


Coopmans et al., reported a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy , a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis, or both was observed after PAS-LAR administration suggesting an antitumor effect. This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin receptor 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis, or both in prolactinomas 2).


During previous long-term clinical investigations, Hu et al., from Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital, Sun Yat-sen University, GuangzhouChina, found that partial resistant prolactinomas exhibited significantly more fibrosis than did sensitive adenomas, suggesting a role of fibrosis in their drug resistance. Furthermore, resistant adenomas with extensive fibrosis mainly express type I and type III collagens. Since TGF-β1 is the key factor in the initiation and development of tissue fibrosis, including in the pituitary, in this study, they aimed to determine whether TGF-β1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using immunochemistry and western blotting, they found that the TGF-β1/Smad3 signaling pathway-related proteins were elevated in resistant prolactinoma specimens with high degrees of fibrosis compared to levels in sensitive samples, suggesting that this pathway may play a role in prolactinoma fibrosis. In vitro, TGF-β1 stimulation promoted collagen expression in normal HS27 fibroblasts. Furthermore, the sensitivity of rat prolactinoma MMQ cells to bromocriptine decreased when they were co-cultured with HS27 cells treated with TGF-β1. The TGF-β1/Smad3 signaling-specific inhibitor SB431542 counteracted these effects, indicating that TGF-β1/Smad3-mediated fibrosis was involved in the drug-resistant mechanisms of prolactinomas. These results indicate that SB431542 may serve as a promising novel treatment for preventing fibrosis and further improving the drug resistance of prolactinoma3).

References

1)

Wong A, Eloy JA, Couldwell WT, Liu JK. Update on prolactinomas. Part 2: Treatment and management strategies. J Clin Neurosci. 2015 Oct;22(10):1568-74. doi: 10.1016/j.jocn.2015.03.059. Epub 2015 Aug 1. Review. PubMed PMID: 26243714.
2)

Coopmans EC, van Meyel SWF, Pieterman KJ, van Ipenburg JA, Hofland L, Donga E, Daly AF, Beckers A, Van der Lely AJ, Neggers SJCMM. Excellent response to pasireotide therapy in an aggressive and dopamine-resistant prolactinoma. Eur J Endocrinol. 2019 Jun 1. pii: EJE-19-0279.R1. doi: 10.1530/EJE-19-0279. [Epub ahead of print] PubMed PMID: 31167168.
3)

Hu B, Mao Z, Jiang X, He D, Wang Z, Wang X, Zhu Y, Wang H. Role of TGF-β1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma. Brain Res. 2018 Jul 26. pii: S0006-8993(18)30408-6. doi: 10.1016/j.brainres.2018.07.024. [Epub ahead of print] PubMed PMID: 30055965.

Clinically Nonfunctioning Pituitary Adenoma Outcome

Clinically Nonfunctioning Pituitary Adenoma Outcome

Clinically nonfunctioning pituitary macroadenomas, although benign in nature, need individualized treatment and lifelong radiological and endocrinological follow-up 1).

There are anecdotal reports of tumor shrinkage during therapy with either dopamine agonists or somatostatin agonists; however tumor response to medical treatment is not reliable. For most patients, transsphenoidal resection of the tumor is the preferable primary treatment. Surgery improves visual deficits in the majority of patients and a lesser number will recover pituitary function. In the past, pituitary radiation was commonly administered following pituitary surgery; however the need for routine radiation has been reevaluated. Although tumor recurrence at 10 years post surgery may be as high as 50%, few patients with recurrence will have clinical symptoms. Close follow-up with surveillance pituitary scans should be performed after surgery and radiation therapy reserved for patients having significant tumor recurrence 2).


Hypopituitarism is observed in NFPAs due to tumour- or treatment-related factors and may increase mortality risk.

The main aim of surgical treatment is improvement of visual function, which is achieved in over 80% of cases 3) 4).

Studies on the effect of surgery in NFMA on pituitary function show conflicting results. Some studies report, to a variable degree, an improvement in pituitary function 5) 6) 7) 8) 9) 10), whereas others could not demonstrate significant improvement in pituitary function, or even showed decreased pituitary function after transsphenoidal surgery 11) 12) 13).

The microscopic and endoscopic techniques provide similar outcomes in the surgical treatment of Knosp Grades 0-2 nonfunctioning pituitary macroadenomas 14)

The surgical removal of a nonfunctioning pituitary macroadenoma (NFP-Mac) is often incomplete.

Studies on the effect of surgery in NFMA on pituitary function show conflicting results. Some studies report, to a variable degree, an improvement in pituitary function.

Quality of Life

The QOL of NFMA patients is affected both physically and mentally by surgical treatment and symptoms. This QOL assessment is important for planning treatment strategies 15).

Cognition

Patients with NFA score significantly worse on cognition compared to reference populations. Radiotherapy does not appear to have a major influence on cognition. 16).

Sleeping

Daytime sleepiness is increased despite normal sleep patterns in patients treated for NFMA 17).

Patients treated for nonfunctioning pituitary macroadenoma (NFMA) with suprasellar extension show disturbed sleep characteristics, possibly related to hypothalamic dysfunction. In addition to hypopituitarism, both structural hypothalamic damage and sleep restriction per se are associated with the metabolic syndrome, mainly due to decreased HDL-cholesterol and increased triglycerides. Risk factors included hypopituitarism and preoperative visual field defects. Hypothalamic dysfunction may explain the metabolic abnormalities, in addition to intrinsic imperfections of hormone replacement therapy. Additional research is required to explore the relation between derangements in circadian rhythmicity and metabolic syndrome in these patients 18).

Recurrence/Residual tumor

The outcome of surgical treatment of NFPAs was improved by the use of intraoperative MRI owing to more radical resection. The remission rate seems to depend on tumor characteristics. Recurrent disease might be reduced by the use of intraoperative MRI leading to more complete surgical resection of NFPAs 19).

Tumour progression rates are high in patients with postoperative remnants. Therefore, long-term monitoring is necessary to detect tumour growth, which may be asymptomatic or manifest with visual field defects and/or pituitary dysfunction. In view of the generally slow-growing nature of these tumours, yearly magnetic resonance imaging, neuro-ophthalmologic and pituitary function evaluation are appropriate during the first 3-5 years after surgery. If there is no evidence for tumour progression during this period, testing intervals may be extended thereafter 20).

see Recurrent Nonfunctioning pituitary macroadenoma


Early and effective surgical treatment is essential for rapid recovery of visual and/or hormonal deficits, particularly in symptomatic cases 21).

Tumor size and cavernous sinus extension are the main predictors for subtotal resection STR. Notably, recovery of the gonadal axis in a large proportion of patients supports the surgical resection of NFPAM in patients suffering from gonadal deficiency, even in the absence of visual field defect (VFD) 22).


Of 18 grossly complete resection was achieved in 71% of patients. Knosp grade 0-2 tumors and tumor volumes <10 cm were significantly more likely to have received a grossly complete resection. There were 7 (12%) recurrences in patients who had received grossly complete resections, with a mean time to recurrence of 53 months. Among the 23 patients who had subtotal resections, 11 (61%) progressed radiographically and 3 (17%) had symptomatic progression. Knosp score, surgical and radiographic evidence of invasion, and preoperative visual deficits were predictive of recurrence in a univariate analysis, but Knosp grade was the only independent predictor in a multivariate analysis. Kaplan Meier analysis projected a 10-year progression-free survival rate of 80% and 21% for patients with grossly total resections and subtotal resections, respectively23).

References

1)

Dekkers OM, Pereira AM, Romijn JA. Treatment and follow-up of clinically nonfunctioning pituitary macroadenomas. J Clin Endocrinol Metab. 2008 Oct;93(10):3717-26. doi: 10.1210/jc.2008-0643. Epub 2008 Aug 5. Review. PubMed PMID: 18682516.
2)

Jaffe CA. Clinically non-functioning pituitary adenoma. Pituitary. 2006;9(4):317-21. Review. PubMed PMID: 17082898.
3)

Comtois R, Beauregard H, Somma M, Serri O, Aris-Jilwan N & Hardy J. The clinical and endocrine outcome to trans-sphenoidal microsurgery of nonsecreting pituitary adenomas. Cancer 1991 68 860–866.
4)

Soto-Ares G, Cortet-Rudelli C, Assaker R, Boulinguez A, Dubest C, Dewailly D & Pruvo JP. MRI protocol technique in the optimal therapeutic strategy of non-functioning pituitary adenomas. European Journal of Endocrinology 2002 146 179–186.
5)

Marazuela M, Astigarraga B, Vicente A, Estrada J, Cuerda C, Garcia-Uria J & Lucas T. Recovery of visual and endocrine function following transsphenoidal surgery of large nonfunctioning pituitary adenomas. Journal of Endocrinological Investigation 1994 17 703–707.
6)

Arafah BM. Reversible hypopituitarism in patients with large nonfunctioning pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 1986 62 1173–1179.
7)

Greenman Y, Tordjman K, Kisch E, Razon N, Ouaknine G & Stern N. Relative sparing of anterior pituitary function in patients with growth hormone-secreting macroadenomas: comparison with nonfunctioning macroadenomas. Journal of Clinical Endocrinology and Metabolism 1995 80 1577–1583.
8)

Nomikos P, Ladar C, Fahlbusch R & Buchfelder M. Impact of primary surgery on pituitary function in patients with nonfunctioning pituitary adenomas – a study on 721 patients. Acta Neurochirurgica (Wien) 2004 146 27–35.
9)

Webb SM, Rigla M, Wagner A, Oliver B & Bartumeus F. Recovery of hypopituitarism after neurosurgical treatment of pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 1999 84 3696–3700.
10)

Arafah BM, Kailani SH, Nekl KE, Gold RS & Selman WR. Immediate recovery of pituitary function after transsphenoidal resection of pituitary macroadenomas. Journal of Clinical Endocrinology and Metabolism 1994 79 348–354.
11)

Wichers-Rother M, Hoven S, Kristof RA, Bliesener N & Stoffel-Wagner B. Non-functioning pituitary adenomas: endocrinological and clinical outcome after transsphenoidal and transcranial surgery. Experimental and Clinical Endocrinology and Diabetes 2004 112 323–327.
12)

Dekkers OM, Pereira AM, Roelfsema F, Voormolen JH, Neelis KJ, Schroijen MA, Smit JW & Romijn JA. Observation alone after transsphenoidal surgery for nonfunctioning pituitary macroadenoma. Journal of Clinical Endocrinology and Metabolism 2006 91 1796–1801.
13)

Greenman Y, Ouaknine G, Veshchev I, Reider-Groswasser II, Segev Y & Stern N. Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and regrowth. Clinical Endocrinology 2003 58 763–769.
14)

Dallapiazza R, Bond AE, Grober Y, Louis RG, Payne SC, Oldfield EH, Jane JA Jr. Retrospective analysis of a concurrent series of microscopic versus endoscopic transsphenoidal surgeries for Knosp Grades 0-2 nonfunctioning pituitary macroadenomas at a single institution. J Neurosurg. 2014 Sep;121(3):511-7. doi: 10.3171/2014.6.JNS131321. Epub 2014 Jul 4. PubMed PMID: 24995783.
15)

Tanemura E, Nagatani T, Aimi Y, Kishida Y, Takeuchi K, Wakabayashi T. Quality of life in nonfunctioning pituitary macroadenoma patients before and after surgical treatment. Acta Neurochir (Wien). 2012 Oct;154(10):1895-902. doi: 10.1007/s00701-012-1473-3. Epub 2012 Aug 25. PubMed PMID: 22922980.
16)

Brummelman P, Elderson MF, Dullaart RP, van den Bergh AC, Timmer CA, van den Berg G, Koerts J, Tucha O, Wolffenbuttel BH, van Beek AP. Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy. Clin Endocrinol (Oxf). 2011 Apr;74(4):481-7. doi: 10.1111/j.1365-2265.2010.03947.x. PubMed PMID: 21133979.
17)

van der Klaauw AA, Dekkers OM, Pereira AM, van Kralingen KW, Romijn JA. Increased daytime somnolence despite normal sleep patterns in patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab. 2007 Oct;92(10):3898-903. Epub 2007 Jul 31. PubMed PMID: 17666479.
18)

Joustra SD, Claessen KM, Dekkers OM, van Beek AP, Wolffenbuttel BH, Pereira AM, Biermasz NR. High prevalence of metabolic syndrome features in patients previously treated for nonfunctioning pituitary macroadenoma. PLoS One. 2014 Mar 7;9(3):e90602. doi: 10.1371/journal.pone.0090602. eCollection 2014. PubMed PMID: 24608862; PubMed Central PMCID: PMC3946551.
19)

Hlavica M, Bellut D, Lemm D, Schmid C, Bernays RL. Impact of ultra-low-field intraoperative magnetic resonance imaging on extent of resection and frequency of tumor recurrence in 104 surgically treated nonfunctioning pituitary adenomas. World Neurosurg. 2013 Jan;79(1):99-109. doi: 10.1016/j.wneu.2012.05.032. Epub 2012 Oct 5. PubMed PMID: 23043996.
20)

Greenman Y, Stern N. How should a nonfunctioning pituitary macroadenoma be monitored after debulking surgery? Clin Endocrinol (Oxf). 2009 Jun;70(6):829-32. doi: 10.1111/j.1365-2265.2009.03542.x. Epub 2009 Feb 16. PubMed PMID: 19222490.
21)

Yildirim AE, Sahinoglu M, Ekici I, Cagil E, Karaoglu D, Celik H, Nacar OA, Belen AD. Nonfunctioning Pituitary Adenomas Are Really Clinically Nonfunctioning? Clinical and Endocrinological Symptoms and Outcomes with Endoscopic Endonasal Treatment. World Neurosurg. 2016 Jan;85:185-92. doi: 10.1016/j.wneu.2015.08.073. Epub 2015 Sep 4. PubMed PMID: 26344636.
22)

Najmaldin A, Malek M, Madani NH, Ghorbani M, Akbari H, Khajavi A, Qadikolaei OA, Khamseh ME. Non-functioning pituitary macroadenoma: surgical outcomes, tumor regrowth, and alterations in pituitary function-3-year experience from the Iranian Pituitary Tumor Registry. Hormones (Athens). 2019 Apr 27. doi: 10.1007/s42000-019-00109-5. [Epub ahead of print] PubMed PMID: 31030405.
23)

Dallapiazza RF, Grober Y, Starke RM, Laws ER Jr, Jane JA Jr. Long-term Results of Endonasal Endoscopic Transsphenoidal Resection of Nonfunctioning Pituitary Macroadenomas. Neurosurgery. 2014 Sep 24. [Epub ahead of print] PubMed PMID: 25255271.
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