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.

Pituitary Adenoma Natural History

Pituitary Adenoma Natural History

Pituitary adenomas (PAs) are often detected as incidentalfindings. However, the natural history remains unclear. The objective of a study of Hwang et al., was to evaluate the natural history and growth pattern of untreated PAs.

Between 2003 and 2014, 59 PAs were managed with clinico-radiological follow up for longer than 12 months without any kind of therapeutic interventionTumor volumes were calculated at initial and last follow-up visit, and tumor growth during the observation period was determined. Data were analyzed according to clinical and imaging characteristics.

The mean initial and last tumor volume and diameter were 1.83±2.97 mL and 13.77±6.45 mm, 2.85±4.47 mL and 15.75±8.08 mm, respectively. The mean annual tumor growth rate was 0.33±0.68 mL/year during a mean observation period of 46.8±32.1 months. Sixteen (27%) PAs showed tumor growth. The initial tumor size (HR, 1.140; 95% confidence interval, 1.003-1.295; p=0.045) was the independent predictive factor that determined the tumor growth. Six patients (11%) of 56 conservatively managed non-symptomatic PAs underwent resection for aggravating visual symptoms with mean interval of 34.5 months from diagnosis. By Cox regression analysis, PAs of last longest diameter over 21.75 mm were a significant prognostic factor for eventual treatment.

The initial tumor size of PAs was independently associated with the tumor growth. Six patients (11%) of conservatively managed PAs were likely to be treated eventually. PAs of last follow-up longest diameter over 21.75 mm were a significant prognostic factor for treatment. Further studies with a large series are required to determine treatment strategy 1).


Despite the relatively high prevalence of pituitary incidentalomas (PIs)/nonfunctioning pituitary adenomas (NFPAs), the evidence on the natural history of these entities is scarce and of low quality. PIs/NFPAs seem to have fairly rare complications that may be more common when lesions are large (>10 mm) and solid 2).


The ‘watch and wait’ policy seems reasonable for microadenomas but is probably not a safe approach for macroadenomas, which appear to have a significant growth potential; in these cases, given the lack of established medical treatment, the decision for surgical intervention should balance the presence of significant comorbidities and the anaesthetic/peri-operative risks at presentation against the probability of tumour enlargement and its consequences, as well as the possible loss of advantages associated with early operation 3).

References

1)

Hwang K, Kwon T, Park J, Joo JD, Han JH, Oh CW, Kim CY. Growth Pattern and Prognostic Factors of Untreated Nonfunctioning Pituitary Adenomas. J Korean Neurosurg Soc. 2019 Mar;62(2):256-262. doi: 10.3340/jkns.2018.0153. Epub 2019 Feb 27. PubMed PMID: 30840981.
2)

Fernández-Balsells MM, Murad MH, Barwise A, Gallegos-Orozco JF, Paul A, Lane MA, Lampropulos JF, Natividad I, Perestelo-Pérez L, Ponce de León-Lovatón PG, Erwin PJ, Carey J, Montori VM. Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2011 Apr;96(4):905-12. doi: 10.1210/jc.2010-1054. Review. PubMed PMID: 21474687.
3)

Karavitaki N, Collison K, Halliday J, Byrne JV, Price P, Cudlip S, Wass JA. What is the natural history of nonoperated nonfunctioning pituitary adenomas? Clin Endocrinol (Oxf). 2007 Dec;67(6):938-43. Epub 2007 Aug 13. PubMed PMID: 17692109.
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