A Bridge Too Far? Towards Medical Therapy for Clinically Nonfunctioning Pituitary Tumors
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. CNFPTs Represent a Heterogenous Group of Pituitary Tumors
3.1.1. Gonadotroph Tumors
3.1.2. Silent Corticotroph Tumors
3.1.3. Silent Somatotroph Tumors
3.1.4. Silent Thyrotroph Tumors
3.1.5. Silent Lactotroph Tumors
3.1.6. Null Cell Tumors
3.2. Current Management of CNFPTs
3.3. Current Role of Medical Therapy in CNFPTs
3.3.1. Somatostatin Receptor Ligands
First Author (Year) Reference | Number of Treated Patients with CNFTs | Medication | Dose | Duration of Therapy (Mths) | Number of Patients (%), [Median Change (IQR)] Exhibiting Tumor Shrinkage; Measurement Method | Number of Patients (%) Exhibiting Stable Tumor Size | Number of Patients (%), [Median Change (IQR)] Exhibiting Tumor Growth; Measurement Method |
---|---|---|---|---|---|---|---|
Katznelson (1992) [31] | 6 | Octreotide SC | 50 µg BID–250 µg TID | 2 | 2, [insuff]; V (%) | 4 | 0, [NA]; V (%) |
Gasperi (1993) [39] | 8 | Octreotide SC | 100 µg TID | 3–6 | 3, [−5 (insuff)]; D (mm) | 1 | 4, [1.5 (1–2)]; D (mm) |
Merola (1993) [40] | 19 | Octreotide SC | 150–300 µg QD | 1–12 | 15, [−12 (−6–−30)]; A (mm2) | 0 | 4, [5 (2–14)]; A (mm2) |
Plockinger (1994) [42] | 14 | Octreotide SC | 300–1500 µg QD | 3 | 2, [−76.5 (insuff)]; V (%) | 12 | 0, [NA]; V (%) |
Warnet (1997) [43] | 7 with imaging before and after treatment | Octreotide SC | 100 µg QD–200 µg TID | 2 | 3, [−38 (insuff)]; V (%) | 1 | 3, [48 (insuff)]; V (%) |
Colao (1999) [41] | 9 | Octreotide SC | 50 µg TID–600 µg QD | 6–12 | 3, [insuff]; V (%) | insuff | insuff, [insuff]; V (%) |
Fusco (2012) [5] | 26 | Octreotide LAR | 20 mg Q1M | 37 ± 18 | 0, [NA]; D (mm) | 21 | 5, [insuff]; D (mm) |
Boertien (2024) [45] | Lanreotide (n = 22) Placebo (n = 22) | Lanreotide LAR SC | 120 mg Q28D | 18 | Lanreotide 3/22 (14%), [insuff]; D (mm), V (mm3) Placebo 0/22 (0%), [NA]; D (mm), V (mm3) | Lanreotide 8/22 (36%), [insuff]; D (mm), V (mm3) Placebo 14/22 (64%), [insuff]; D (mm), V (mm3) | Lanreotide 11/22 (50%), [insuff]; D (mm), V (mm3) Placebo 8/22 (36%), [insuff]; D (mm), V (mm3) |
Total Number (%) | 111 | 31 (28%) | insuff | insuff |
3.3.2. Dopamine Agonist Therapy
First Author (Year) Reference | Number of Treated Patients with CNFTs | Medication | Dose | Duration of Therapy (Mths) | Number of Patients (%), [Median Change (IQR)] Exhibiting Tumor Shrinkage; Measurement Method | Number of Patients (%) Exhibiting Stable Tumor Size | Number of Patients (%), [Median Change (IQR)] Exhibiting Tumor Growth; Measurement Method |
---|---|---|---|---|---|---|---|
Wollesen (1982) [53] | 11 | BCP | 15–60 mg/d | 2–33 | 9, [−32 (−21.5–−41.5)]; A (%) | 0 | 2, [14 (insuff)]; A (%) |
Barrow (1984) [54] | 7 | BCP | 2.5–7.5 mg/d | 1.5 | 1, [−2.1 (insuff)]; A (cm2) | 5 | 1, [0.1 (insuff)]; A (cm2) |
Pullan (1985) [55] | 5 | BCP | 15–37.5 mg/d | 3–27 | 1, [insuff]; NA | 4 | 0 [NA]; NA |
Verde (1985) [56] | 20 | BCP | 7.5–20 mg/d | 1–32 | 1, [insuff]; NA | 19 | 0 [NA]; NA |
Zarate (1985) [57] | 7 | BCP | 15–22.5 mg/d | 0.5–12 | 0, [NA]; NA | 7 | 0 [NA]; NA |
van Schaarde-nburg (1989) [58] | 25 (11/25 had imaging) | BCP | 5–22.5 mg/d | 1–73 | 2, [insuff]; NA | 7 | 2 [insuff]; NA |
Ferone (1998) [60] | 6 | QUI | 300–600 µg/d | 6–12 | 2, [insuff]; NA | 4 | 0 [NA]; NA |
Colao (2000) [65] | 10 | QUI CBG | 600 µg/d (QUI) 3 mg/w (CBG) | 12 | 2, [insuff]; V (%) | 8 | 0 [NA]; V (%) |
Nobels (2000) [59] | 10 | QUI | 300 µg/d | 36–93 | 2, [−1.8 (insuff)]; V (cm3) [−37.3% (insuff)]; V (%) | 0 | 8, [2.3 cm3 (1.1–3.5)]; V (cm3) [31.3% (13.1–54.8)]; V (%) |
Lohmann (2001) [61] | 13 | CBG | 0.25–1.0 mg/w | 12 | 7, [−15 (−12–−18)]; V (%) | 5 | 1, [25 (insuff)]; V (%) |
Pivonello (2004) [50] | 9 | CBG | 1–3 mg/w | 12 | 5, [−49.3 (−38.9–−57.2)]; V (%) | 0 | 4, [8.7 (6.2–29.5)]; V (%) |
Greenman (2005) [62] | Preventative (I): n = 20 Secondary (II): n = 13 Control I (CI): n = 47 Control II (CII): n = 38 | BCP QUI CBG | 10 mg QD (BCP) 300 mg QD (QUI) 1.5 mg/week (CBG) | 40 ± 48 | I: 9/20 (45%), [insuff]; D (mm) II: 2/13 (15%), [insuff]; D (mm) CI: 0 (0%), [NA]; D (mm) CII: 0 (0%), [NA]; D (mm) | I: 9/20 (45%), [insuff]; D (mm) II: 6/13 (46%), [insuff]; D (mm) CI: 18/47 (38%), [insuff]; D (mm) CII: 18/38 (47%), [insuff]; D (mm) | I: 2/20 (10%), [insuff]; D (mm) II: 5/13 (39%), [insuff]; D (mm) CI: 29/47 (62%), [insuff]; D (mm) CII: 20/38 (53%), [insuff]; D (mm) |
Garcia (2013) [64] | 19 | CBG | 2 mg/w | 6 | 9, [−26.7 (−16.7–−43.4); V (%) | 6 | 4, [14.8 (12.5–74.4)]; V (%) |
Vieira Neto (2015) [66] | 9 | CBG | 3 mg/w | 6 | 8, [−29.2 (−18.9–−39.5)]; V (%) by 3D [−17.3 (−9.6–−30.9)]; V (%) by Di Chiro and Nelson | 0 | 1, [2.6 (insuff)]; V (%) by 3D [0.2 (insuff)]; V (%) by Di Chiro and Nelson |
Greenman (2016) [6] | Preventative (P) (n = 55) Remedial (R) (n = 24) Control (C) (n = 60) | CBG BCP | 10 mg QD (BCP) 2 mg/w (CBG) | 105.6 ± 78 | P: 21/55 (38%), [insuff]; D (mm) R: 7/24 (29%), [insuff]; D (mm) C: 0/60 (0%), [NA]; D (mm) | P: 27/55 (49%), [insuff]; D (mm) R: 7/24 (29%), [insuff]; D (mm) C: 28/60 (47%), [insuff]; D (mm) | P: 7/55 (13%), [insuff]; D (mm) R: 10/24 (42%), [insuff]; D (mm) C: 32/60 (53%), [insuff]; D (mm) |
Batista (2019) [63] | Medical Therapy (MT) (n = 59) Control (C) (n = 57) | CBG | 0.5 mg/d | 24 | MT: 17/59 (29%), [insuff]; V (%) C: 6/57 (11%), [insuff]; V (%) | MT: 39/59 (66%), [insuff]; V (%) C: 42/57 (74%), [insuff]; V (%) | MT: 3/59 (5%), [insuff]; V (%) C: 9/57 (16%), [insuff]; V (%) |
Iglesias (2022) [67] | Medical Therapy (CAB) (n = 22) Observation (OBS) (n = 40) | CBG | 0.5–1.5 mg/w | 13 (10.5–17) | CAB: 3/22 (14%), [insuff]; D (mm) OBS: 2/40 (5%), [insuff]; D (mm) | CAB: 17/22 (77%), [insuff]; D (mm) OBS: 32/40 (80%), [insuff]; D (mm) | CAB: 2/22 (9%), [insuff]; D (mm) OBS: 6/40 (15%), [insuff]; D (mm) |
Ayalon-Dangur (2024) [68] | 25 | CBG | ≥ 1 mg/w | 24 | 5, [6 (−2–−75)]; D (mm) | 12 | 8, [4 (2.5–8)]; D (mm) |
Total Number (%) | 355 | 113 (33%) | 182 (51%) | 60 (17%) |
3.3.3. GnRH Analog Therapy
3.3.4. Peptide Receptor Radionuclide Therapy and Temozolomide
3.4. Emerging Experimental Novel Treatment Modalities of CNFPT
3.4.1. Immune Checkpoint Inhibitor Therapy
3.4.2. Folate Receptor-Mediated Drug Targeting
3.4.3. mTOR Inhibitors
3.4.4. Targeting Tumor Angiogenesis
4. Discussion
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
Abbreviations
CNFPTs | Clinically nonfunctioning pituitary tumors |
NFPAs | Nonfunctioning pituitary adenomas |
RT | Radiation therapy |
SSTR | Somatostatin receptor |
SF-1 | Steroidogenic factor 1 |
FSH | Follicular stimulating hormone |
LH | Luteinizing hormone |
ACTH | Adrenocorticotropic hormone |
POMC | Proopiomelanocortin |
GH | Growth hormone |
IGF-1 | Insulin like growth factor-1 (IGF-1) |
TSH | Thyroid stimulating hormone |
GATA | GATA binding protein |
ERα | Estrogen receptor alpha |
PRL | Prolactin |
SYP | Synaptophysin |
GTR | Gross total resection |
DR | Dopamine receptor |
GnRH | Gonadotrophin-releasing hormone |
VEGF | Vascular endothelial growth factor |
SRL | Somatostatin receptor ligand |
IQR | Interquartile range |
FR | Folate receptors |
LAR | Long-acting release |
BID | Twice daily |
TID | Thrice daily |
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Tumor Type | Subtype | Frequency (% of All CNFTs) | Lineage Specific Transcription Factor | Hormone Produced |
---|---|---|---|---|
Silent Gonadotroph Tumor | 40–79% | SF-1 (NR5A1), GATA2, ERa | FSHb, LHb, a-subunit | |
Silent Corticotroph Tumor | Sparsely Granulated Corticotroph Tumor | 3–6% | Tpit (TBX19) | ACTH |
Crooke’s Cell Adenoma | Tpit (TBX19) | ACTH | ||
Silent Somatotroph Tumor | Sparsely Granulated Somatotroph Tumor | 2–4% | Pit-1 (POU1F1) | GH (or PRL) |
Mammosomatotroph Tumor | Pit-1 (POU1F1), ERa | GH and PRL (same cells) | ||
Mixed GH-PRL Tumor | Pit-1 (POU1F1), ERa | GH and PRL (different cells) | ||
Plurihormonal Tumor | Pit-1 (POU1F1), ERa | GH, PRL, TSHb | ||
Silent Lactotroph Tumor | Sparsely Granulated Lactotroph Tumor | 1% | Pit-1 (POU1F1), ERa | PRL |
Mammosomatotroph Tumor | Pit-1 (POU1F1), ERa | GH and PRL (same cells) | ||
Mixed GH-PRLTumor | Pit-1 (POU1F1), ERa | GH and PRL (different cells) | ||
Plurihormonal Tumor | Pit-1 (POU1F1), ERa | GH, PRL, TSHb | ||
Acidophilic Stem Cell Adenoma | Pit-1 (POU1F1), ERa | GH, PRL | ||
Silent Thyrotroph Tumor | 1–2% | Pit-1 (POU1F1), GATA2 | TSHb | |
Null Cell Tumor | 17% | None | None |
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Mogar, N.; Zhang, D.; Heaney, A.P. A Bridge Too Far? Towards Medical Therapy for Clinically Nonfunctioning Pituitary Tumors. Int. J. Mol. Sci. 2025, 26, 5898. https://doi.org/10.3390/ijms26125898
Mogar N, Zhang D, Heaney AP. A Bridge Too Far? Towards Medical Therapy for Clinically Nonfunctioning Pituitary Tumors. International Journal of Molecular Sciences. 2025; 26(12):5898. https://doi.org/10.3390/ijms26125898
Chicago/Turabian StyleMogar, Nikita, Dongyun Zhang, and Anthony P. Heaney. 2025. "A Bridge Too Far? Towards Medical Therapy for Clinically Nonfunctioning Pituitary Tumors" International Journal of Molecular Sciences 26, no. 12: 5898. https://doi.org/10.3390/ijms26125898
APA StyleMogar, N., Zhang, D., & Heaney, A. P. (2025). A Bridge Too Far? Towards Medical Therapy for Clinically Nonfunctioning Pituitary Tumors. International Journal of Molecular Sciences, 26(12), 5898. https://doi.org/10.3390/ijms26125898