A multicenter study of clinical outcomes and volumetric trends in suspected microprolactinomas

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Hong, Jeremy Chabros, John Kilgallon, Jakob Gerstl, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3855108/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose The diagnosis of pituitary microprolactinomas is often obscured by relatively low levels of elevated prolactin compared to macroprolactinomas. This may lead to varying patterns of medical therapy versus observation. We sought to correlate prolactin levels in suspected microprolactinomas with tumor volumes and clinical outcomes. Methods This was a multicenter retrospective study of patients with pituitary microadenomas with baseline prolactin levels > 18ng/ml for males and > 30ng/ml for females. A linear-mixed model was used to depict changes in tumor volume over time. Results There were 65 patients with a mean tumor volume of 95.9mm 3 and mean prolactin level of 59.4ng/ml. There were significantly higher prolactin levels in patients with tumors above the mean volume versus below (74.0 versus 53.4ng/ml, p = 0.027). 26 patients were observed, 31 were treated with anti-dopaminergic therapy, and 8 had surgery. There were significantly greater baseline prolactin levels for patients who were treated surgically (mean 86.4ng/ml) than those treated medically (mean 61.7g/ml) or observed (mean 48.5ng/ml) (p = 0.02). Among the 26 patients who were surveilled, 13 patients demonstrated spontaneous tumor shrinkage, 12 remained stable, and 1 patient’s tumor grew but was lost to follow-up. Linear mixed modeling demonstrated a statistically significant rate of tumor shrinkage over time of 3.67mm 3 /year (p = 0.03). When analyzing patients who were observed versus those requiring surgery after initially being surveilled, there were significantly greater baseline PRL/volume ratios in surgical patients versus those observed (8.1 ng/ml/mm 3 versus 2.4 ng/ml/mm 3 , p = 0.025). Conclusions Suspected microprolactinomas may demonstrate more convincingly elevated prolactin levels when measuring over 95.9mm 3 . Tumors with baseline prolactin levels over 50ng/ml may be more inclined to undergo medical treatment. In tumors with levels below 50ng/ml, it may be reasonable to undergo surveillance as these tumors tend to spontaneously shrink over time. In tumors that are surveilled, an elevated baseline PRL/volume ratio of > 8 ng/ml/mm 3 may be indicate serial tumor growth that may necessitate medical and/or surgical intervention. pituitary prolactinoma microadenoma prolactin Figures Figure 1 INTRODUCTION Prolactinomas are the most common pituitary adenomas (approximately 40%) and make up the vast majority of hormonally functional pituitary adenomas.[ 1 ] Clinically, patients typically present with galactorrhea, menstrual irregularities, loss of libido and/or infertility, as well as sexual dysfunction and hypogonadism particularly in men. Larger tumors may also cause headaches, visual field deficits, and hypopituitarism.[ 2 ] First-line treatment for prolactinomas remains dopamine agonists, which have been shown to shrink tumors and restore gonadal function with concomitant decrease in prolactin (PRL) levels. In patients with tumors that are resistant to dopamine agonists, surgical resection is recommended. Non-functioning pituitary adenomas are commonly an incidental finding on imaging, obtained to work-up other symptoms. Compared to macroadenomas, microadenomas of this type are more likely to remain stable or decrease in size with long-term follow-up.[ 3 ] Of note, guidelines released by the Endocrine Society state that asymptomatic patients with microprolactinomas do not necessarily require treatment upfront, given that a natural history study of untreated hyperprolactinemia, albeit decades old, found that these tumors were unlikely to grow.[ 4 , 5 ] In addition, hypogonadal premenopausal women may also be treated with oral contraceptives in lieu of dopamine agonists.[ 4 ] Previous studies have suggested that prolactin levels correlate with tumor size. That said, these studies have typically looked at a wide range of tumor volumes.[ 6 , 7 , 8 ] However, in cases of small tumors, the diagnosis of a pituitary microprolactinoma is often obscured by relatively low levels of elevated prolactin compared to macroprolactinomas, and patients may not always exhibit classical symptoms of hyperprolactinemia. As a result, in cases of microprolactinomas, there may be varying patterns of management, ranging from initiating medical therapy, considering surgery, or observation. In this study, we sought to correlate baseline prolactin levels with tumor volumes in suspected microprolactinomas. We also compared baseline prolactin levels and volumes amongst patients who were managed with medical therapy, surgery, or observation. METHODS This was a multicenter retrospective study of patients with pituitary microadenomas with baseline prolactin levels > 18ng/ml for males and > 30ng/ml for females. Data collected included basic patient demographics, presenting symptoms, relevant endocrine laboratory values, radiographic findings on initial and subsequent MRI, and clinical outcomes. Volumes were calculated via the ABC/2 formula, approximating the lesion shape as an ellipsoid. This study was conducted under an institutional board approved protocol. To analyze the data, we employed a linear mixed-effects model, which allowed us to account for the correlation between repeated measurements taken from the same patient. The analysis was performed using Julia (v1.9.1) programming language, specifically employing the MixedModels.jl package. The model was formulated as follows: Volume ∼ Time + (1 + Time ∣ PatientID) In this model, the response variable volume represents the tumor volume, while time is the fixed effect representing the number of days between consecutive MRI scans. To account for the variability and correlation in tumor growth rates across patients, we included a random intercept and a random slope for time within patientID. This random effects structure allows each patient to have a unique baseline tumor volume and a unique tumor growth rate over time. By employing this approach, we were able to assess the overall trend in tumor growth while also considering the variability among individual patients. To quantify the uncertainty in our predictions and obtain robust estimates of the confidence intervals for the fixed-effect coefficients, we employed a bootstrapping approach. Bootstrapping is a resampling technique that involves repeatedly drawing random samples from the dataset (with replacement) and recalculating the estimates on each sample. We performed bootstrapping with 1,000 iterations which enabled us to estimate the variability in our predictions and provided 95% confidence intervals around the estimated tumor volumes over time. RESULTS There were 65 patients (18 male, 47 female; mean age 44 years, range: 15–74 years). At time of diagnosis, mean tumor volume was 95.9 mm 3 (SD: 114.2 mm 3 , range: 4-500 mm 3 ), and mean prolactin level was 59.4 ng/ml (SD: 34.4 ng/ml, range: 19.1–170 ng/ml). The mean follow-up duration as measured from time of first MRI to the last scan was 85.1 months (SD: 56.8 months) and the mean number of MRI scans obtained was 4.3 (SD: 1.9). When analyzing the whole cohort, there was no significant correlation between prolactin levels and tumor volume at diagnosis (Pearson R = 0.09,p = 0.47). Upon sub-group analysis of patients with tumor volumes above (n = 19) and below (n = 46) the mean, there were significantly higher prolactin levels in patients with tumors above the mean volume of 95.9mm 3 versus below (74.0 versus 53.4ng/ml,95% CI 2.432–38.8,p = 0.027). 26 patients were observed, 31 were treated with anti-dopaminergic therapy, and 8 had surgery (4 had surgery after failing medical therapy). They presented with the following symptoms. Among the 26 patients who were observed, 11 had mild menstrual irregularities, 2 had hypogonadal symptoms, and the rest were asymptomatic. Among the 31 patients who were treated with anti-dopaminergic therapy, 8 had hypogonadal symptoms, 5 had galactorrhea, 4 had menstrual irregularities, and the rest were asymptomatic. Among the 8 patients who had surgery, 2 had menstrual irregularities, 2 had hypogonadism, and the rest were asymptomatic. There were significantly greater baseline prolactin levels for patients who treated surgically (mean: 86.4 ng/ml, SD: 39.6 ng/ml) than those treated medically (mean 61.7 ng/ml, SD: 38.2 ng/ml), or were observed (mean 48.5 ng/ml, SD: 22.0 ng/ml) (p = 0.02; F = 4.2; R 2 = 0.12). However, there were no significant differences in baseline volumes for patients treated surgically (mean 120.0 mm 3 , SD: 122.4 mm 3 ), medically (mean 111.2mm 3 , SD: 118.2 mm 3 ), or observed (mean 70.24 mm 3 , SD: 106.1 mm 3 ) (p = 0.33; F = 1.1; R 2 = 0.04). Among the 26 patients who were surveilled, 13 patients demonstrated spontaneous tumor shrinkage, 12 remained stable, and 1 patient’s tumor grew but was lost to follow-up. Linear mixed modeling demonstrated a statistically significant rate of tumor shrinkage over time of 3.67mm 3 /year (p = 0.03) (Fig. 1 ). There were no significant differences in baseline prolactin in patients whose tumors spontaneously shrunk (mean 46.1 ng/ml, SD: 22.3 ng/ml) versus remained stable (mean 52.3 ng/ml, SD: 22.7 ng/ml) (95% CI:-12.4-24.9, p = 0.50). Likewise, there were no significant differences in baseline volumes (mean 56.2mm 3 , SD: 65.1 mm 3 versus 91.0 mm 3 , SD 140.9 mm 3 respectively) (95% CI: 54.8-124.4, p = 0.43). A baseline PRL/volume ratio metric was then explored to predict clinical outcomes. When analyzing patients who were observed versus those requiring surgery after initially being surveilled, there were significantly greater baseline PRL/volume ratios in surgical patients versus those observed (8.1 ng/ml/mm 3 versus 2.4 ng/ml/mm 3 , 95% CI:0.80–10.7, p = 0.025). However, PRL/volume ratio did not predict patterns of medical treatment failure for patients successfully managed with medical treatment versus those who failed and required surgery (2.25 ng/ml/mm 3 versus 0.91 ng/ml/mm 3 , 95% CI:-7.7-5.03, p = 0.67). DISCUSSION In this study, we studied relationships between baseline prolactin levels and volumes of suspected microprolactinomas in 65 patients with > 1 MRI over an average follow-up period of 7 years. We found significantly elevated baseline prolactin levels for patients with tumor volumes above the mean cohort volume, compared to below. Likewise, patients with greater baseline prolactin levels and PRL/volume ratios were more likely to require surgery and/or medical treatment versus those who were observed. We also found a significant rate of tumor shrinkage over time in the tumors of patients that were observed who also exhibited lower levels of baseline prolactin and PRL/volume ratios. The diagnosis between a prolactinoma and a non-functioning pituitary adenoma can be difficult, particularly when the size of the tumor in question is small. The most recent consensus statement put forth by the Pituitary Society in 2023 suggested that prolactin levels above 200 ng/ml in the setting of a sellar mass are strongly suggestive of a prolactinoma.[ 9 ] However, for levels below 200 ng/ml, size-adapted cut-offs for prolactin levels have been studied to differentiate between prolactinomas versus other pituitary tumors. In a prior study from our institution, we compared prolactin levels and pre-operative tumor volume from surgically resected, histopathologically confirmed prolactinomas versus non-functioning pituitary adenomas. There was a strong correlation between prolactinoma size and serum prolactin level with cut-offs of 43.65 ng/ml for tumors under 0.5 cm 3 , 60.05 ng/ml for those between 0.5-4 cm 3 , and 248.15 ng/ml for those > 4 cm 3 .[ 6 ] Others have proposed a diagnostic prolactin cut-off value of 55.65 ng/ml,[ 10 ] 94 ng/ml,[ 11 ] even some as low as 38.6 ng/ml.[ 12 ] The mean prolactin level in our current study of 59.4 ng/ml is comparable to these previous studies. Unlike our previous study,[ 6 ] we did not find a significant correlation between prolactin levels and tumor volume. That said, our cohort was limited to microadenomas, defined by measuring up to 1 cm in greatest diameter, with a mean volume of 95.9 mm 3 , well below the tumor volumes studied in our previous study. In addition, when we compared patients with tumor volumes above and below this mean volume, we did find a significant difference in baseline prolactin levels. With a greater sample size, we suspect there might be an underlying correlation between prolactin levels and tumor volume, even when limited to microadenomas. In addition to prolactin level cut-offs for various tumor volume thresholds, we explored the utility of a PRL/volume ratio in predicting clinical outcomes. Within our microadenoma cohort, we found that among patients who were initially surveilled, those who would go on to need surgery had significantly greater baseline PRL/volume ratios than in those who were successfully monitored with serial imaging. That said, our sample size for surgically treated patients was extremely small and therefore, our findings should be interpreted with caution. On the other hand, the PRL/volume ratio did not predict patterns of failure with medical management, likely reflecting the fact that the biology of tumor resistance to dopaminergic therapy is not dependent upon baseline prolactin levels. Other studies in the literature have also explored the role of PRL/volume ratios in diagnosing prolactinomas from other pituitary tumors with mild to moderately elevated prolactin levels albeit in tumor of much larger size and measured in cm 3 rather than mm 3 in our study. Cho et al performed a prolactin to volume ratio analysis and found that tumors with a PRL/volume ratio > 100 ng/ml/cm 3 were predictive of distinguishing prolactinomas from other pituitary tumors.[ 13 ] Likewise, Huang et al reported a PRL/volume ratio of 54 ng/ml/cm 3 to have the highest diagnostic value in patients with pituitary adenomas and elevated prolactin levels but still under 250 ng/ml.[ 10 ] Faje et al reported that a cutoff of 65 ng/ml/cm 3 could discriminate between prolactinomas versus nonfunctioning pituitary adenomas with elevated prolactin levels due to stalk effect.[ 14 ] There are no clear guidelines on treatment of suspected microprolactinomas. The proposed treatment algorithm put forth most recently by the Pituitary Society recommends initiating treatment based on factors such as male sex, the desire to conceive, young age, a history of a psychiatric disorder, among others. Surveillance may be considered for postmenopausal women and/or eugonadal premenopausal women not interested in conceiving.[ 9 ] Additionally, there can be mild but undesirable side effects with dopamine agonist therapy that can significantly impair quality of life with long-term usage, including gastric issues, nausea, dizziness, and fatigue.[ 15 , 16 ] Likewise, there can be mood changes and impulsivity that make patients with existing psychiatric disorders a relative contraindication to use of dopamine agonists.[ 17 ] In our study, we found that essentially all patients who were surveilled, aside from one, demonstrated either stability of their lesion size and/or spontaneous shrinkage on further surveillance imaging. In addition, these patients presented either asymptomatically as incidental radiographic findings or with symptoms, most commonly mild menstrual irregularities that were not significantly impairing their quality of life. The decision to surgically resect prolactinomas upfront remains controversial, particularly for microadenomas that are not causing visual deficits, and is largely due to patient preference.[ 18 , 19 ] In our cohort, half of the surgically treated patients had failed prior medical therapy while the remaining half preferred surgery after their tumors demonstrated interval growth on repeat imaging. Although we found significantly higher baseline prolactin levels in patients who were surgically treated versus medically treated or observed, our small sample size limits any overarching conclusions on whether any meaningful cut-off exists to recommend surgery upfront over medical therapy for suspected microprolactinomas. Despite recommendations that certain patients with microprolactinomas may be reasonably observed, there is a lack of data in the literature on the natural history of observed prolactinomas.[ 4 ] Schlechte et al performed a prospective study of 30 women with hyperprolactinemia, 13 of whom had serial radiographic studies and initial findings suggestive of a pituitary adenoma.[ 5 ] Four of these patients had tumor shrinkage, 7 remained stable, and 2 had tumor progression. Feldkamp et al likewise conducted a prospective study of 67 patients with incidental findings of a pituitary adenoma, 42 of whom had microadenomas and 8 of whom had prolactinomas. Only 3.2% of patients with microadenomas demonstrated tumor growth over a mean follow-up period of 2.7 years.[ 20 ] Compared to the existing literature, our study is to our knowledge the largest thus far to report the natural history of microprolactinomas. Notably, we found that among the 26 patients that were surveilled, only 1 patient’s tumor grew over the follow-up period, while half of these patients demonstrated spontaneous tumor shrinkage at a statistically significant rate of 3.67 mm 3 /year. While we did not find significant differences in baseline prolactin levels or volumes in tumors that shrunk versus remained stable, we did find significant variations in baseline prolactin levels and PRL/volume ratios in patients who were successfully surveilled versus requiring intervention. Currently, the literature on microprolactinomas has been focused on diagnostically differentiating these tumors from other pituitary adenomas. Additional studies correlating these tumors with clinical outcomes are needed to ascertain whether certain prolactin and volume relationship cut-offs can be made to identify patients for whom these tumors can be surveilled without any initial intervention. A limitation of our study is that the majority of our patient cohort did not have histopathologic diagnosis of a prolactinoma, given very few patients underwent surgical resection. As such, it is entirely possible that a subset of our patients, particularly those with very low prolactin levels, may have been harboring non-functioning pituitary adenomas with elevated prolactin levels due to stalk effect, resulting in mild hyperprolactinemia. That said, stalk effect is rare in pituitary microadenomas due to their inherent small size.[ 11 ] Regardless, even if our sample size may have been diluted by the undetected presence of true non-functioning pituitary adenomas, our data suggest that small pituitary adenomas with mildly elevated prolactin levels may be reasonably observed, regardless of their true underlying histology. CONCLUSIONS In this multicenter retrospective study, we reported observations from the largest known cohort of microprolactinomas to date. We found that within this subset of microadenomas of prolactinoma origin, tumors that exhibit over 95.9 mm 3 demonstrate more convincingly elevated prolactin levels. Likewise, tumors with baseline prolactin levels over 50 ng/ml were more inclined to undergo medical treatment. Of note, through volumetric analysis of tumors that were surveilled over the long-term, we found that tumors with prolactin levels below 50 ng/ml tended to spontaneously shrink over time. Likewise, we found that in tumors that were surveilled, an elevated baseline PRL/volume ratio of > 8 ng/ml/mm 3 may be indicative of potential tumor growth that may necessitate medical and/or surgical intervention. Further studies focused particularly on the management of small pituitary adenomas with elevated prolactin, suggestive of a microprolactinoma, are needed to better define prolactin and volumetric cut-offs that may guide the decision to observe these tumors versus intervene. Declarations The authors have no conflicts of interest to disclose Author Contribution CEC, LM, and TRS provided study oversight. CSH wrote the main manuscript. CSH, JC, JLK, JVG, CO, and TRS analyzed and interpreted the data. CSH and JC performed statistical analysis and prepared figures. All authors contributed data and reviewed the manuscript. References Gillam MP, Molitch ME, Lombardi G, Colao A (2006) Advances in the treatment of prolactinomas. Endocr Rev 27(5):485–534 Vroonen L, Daly AF, Beckers A (2019) Epidemiology and Management Challenges in Prolactinomas. Neuroendocrinology 109(1):20–27 Pernik MN, Montgomery EY, Isa S, Sundarrajan C, Caruso JP, Traylor JI et al (2022) The natural history of non-functioning pituitary adenomas: A meta-analysis of conservatively managed tumors. J Clin Neurosci 95:134–141 Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA et al (2011) Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(2):273–288 Schlechte J, Dolan K, Sherman B, Chapler F, Luciano A (1989) The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 68(2):412–418 Burke WT, Penn DL, Castlen JP, Donoho DA, Repetti CS, Iuliano S et al (2019) Prolactinomas and nonfunctioning adenomas: preoperative diagnosis of tumor type using serum prolactin and tumor size. J Neurosurg. :1–8 Osorio RC, Pereira MP, Oh T, Joshi RS, Haddad AF, Pereira KM et al (2022) Correlation between tumor volume and serum prolactin and its effect on surgical outcomes in a cohort of 219 prolactinoma patients. J Neurosurg. :1–11 Wright K, Lee M, Escobar N, Pacione D, Young M, Fatterpekar G et al (2021) Tumor volume improves preoperative differentiation of prolactinomas and nonfunctioning pituitary adenomas. Endocrine 74(1):138–145 Petersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BMK et al (2023) Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol 19(12):722–740 Huang Y, Ding C, Zhang F, Xiao D, Zhao L, Wang S (2018) Role of prolactin/adenoma maximum diameter and prolactin/adenoma volume in the differential diagnosis of prolactinomas and other types of pituitary adenomas. Oncol Lett 15(2):2010–2016 Karavitaki N, Thanabalasingham G, Shore HC, Trifanescu R, Ansorge O, Meston N et al (2006) Do the limits of serum prolactin in disconnection hyperprolactinaemia need re-definition? A study of 226 patients with histologically verified non-functioning pituitary macroadenoma. Clin Endocrinol (Oxf) 65(4):524–529 Kawaguchi T, Ogawa Y, Tominaga T (2014) Diagnostic pitfalls of hyperprolactinemia: the importance of sequential pituitary imaging. BMC Res Notes 7:555 Cho A, Vila G, Marik W, Klotz S, Wolfsberger S, Micko A (2022) Diagnostic criteria of small sellar lesions with hyperprolactinemia: Prolactinoma or else. Front Endocrinol (Lausanne) 13:901385 Faje A, Jones P, Swearingen B, Tritos NA (2022) The Prolactin per Unit Tumor Volume Ratio Accurately Distinguishes Prolactinomas From Secondary Hyperprolactinemia due to Stalk Effect. Endocr Pract 28(6):572–577 Johnson MD, Woodburn CJ, Vance ML (2003) Quality of life in patients with a pituitary adenoma. Pituitary 6(2):81–87 Stumpf MAM, Pinheiro FMM, Silva GO, Cescato VAS, Musolino NRC, Cunha-Neto MBC et al (2023) How to manage intolerance to dopamine agonist in patients with prolactinoma. Pituitary 26(2):187–196 Ioachimescu AG, Fleseriu M, Hoffman AR, Vaughan Iii TB, Katznelson L (2019) Psychological effects of dopamine agonist treatment in patients with hyperprolactinemia and prolactin-secreting adenomas. Eur J Endocrinol 180(1):31–40 Kreutzer J, Buslei R, Wallaschofski H, Hofmann B, Nimsky C, Fahlbusch R et al (2008) Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients. Eur J Endocrinol 158(1):11–18 Tampourlou M, Trifanescu R, Paluzzi A, Ahmed SK, Karavitaki N (2016) THERAPY OF ENDOCRINE DISEASE: Surgery in microprolactinomas: effectiveness and risks based on contemporary literature. Eur J Endocrinol 175(3):R89–96 Feldkamp J, Santen R, Harms E, Aulich A, Modder U, Scherbaum WA (1999) Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas - results of a prospective study. Clin Endocrinol (Oxf) 51(1):109–113 Tables Table 1. Patient demographic data. Variable Total (n) 65 Male sex (n) 18 Average age (years) 44 Mean follow-up (months) 85.1 Mean # of MRI scans (n) 4.3 Treatment modality Observation (n) 26 Surgery alone (n) 4 Surgery after failing medical therapy (n) 4 Medical therapy (n) 31 Presenting Symptoms Menstrual irregularities (n) 17 Hypogonadal symptoms (n) 12 Galactorrhea (n) 5 Asymptomatic (n) 29 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3855108","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266838957,"identity":"43eb1741-57a9-4897-af04-66842eb0b88c","order_by":0,"name":"Christopher S. 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Ryba","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"prefix":"","firstName":"Alice","middleName":"S.","lastName":"Ryba","suffix":""},{"id":266838965,"identity":"75354f2e-4888-4a57-8e0c-c298cb26365f","order_by":8,"name":"Diego Mazzatenta","email":"","orcid":"","institution":"IRCCS Institute of Neurological Sciences of Bologna","correspondingAuthor":false,"prefix":"","firstName":"Diego","middleName":"","lastName":"Mazzatenta","suffix":""},{"id":266838966,"identity":"a9d7608d-cb1b-4e0e-9267-50fe2529e17f","order_by":9,"name":"Federica Guaraldi","email":"","orcid":"","institution":"IRCCS Institute of Neurological Sciences of Bologna","correspondingAuthor":false,"prefix":"","firstName":"Federica","middleName":"","lastName":"Guaraldi","suffix":""},{"id":266838967,"identity":"f91ab6c1-d195-4e99-a2ff-e8a073da966e","order_by":10,"name":"Carleton E. Corrales","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Carleton","middleName":"E.","lastName":"Corrales","suffix":""},{"id":266838968,"identity":"6f0a974f-d747-45f7-8d2f-de1bf7966aac","order_by":11,"name":"Le Min","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Le","middleName":"","lastName":"Min","suffix":""},{"id":266838969,"identity":"348897e1-d97f-472a-ae3f-fd4c168a65b3","order_by":12,"name":"Timothy R. Smith","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Timothy","middleName":"R.","lastName":"Smith","suffix":""},{"id":266838970,"identity":"2dc43069-e858-42fe-928c-ec9b8d1700ae","order_by":13,"name":"Chady Omara","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Chady","middleName":"","lastName":"Omara","suffix":""}],"badges":[],"createdAt":"2024-01-12 00:31:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3855108/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3855108/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49644268,"identity":"47cf844c-0890-4a77-9953-2bc3095957bf","added_by":"auto","created_at":"2024-01-15 20:15:06","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":238929,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMixed model analysis of patients with microprolactinomas who were observed without any intervention.\u003c/strong\u003e The x-axis demonstrates time in days from diagnosis since tumor size was recorded. The y-axis demonstrates changes in tumor volume over time in mm\u003csup\u003e3\u003c/sup\u003e. Each gray line represents the trajectory of each patient. The blue line and light blue band represent the mean trajectory and 95% CI of the entire cohort.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3855108/v1/b8b3154ff29316ab3aa656a1.jpeg"},{"id":49914781,"identity":"64141a85-c49f-4252-a65d-880787511332","added_by":"auto","created_at":"2024-01-20 15:07:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":303119,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3855108/v1/dde67cb2-785c-41e5-b900-6acc0986d9bd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A multicenter study of clinical outcomes and volumetric trends in suspected microprolactinomas","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eProlactinomas are the most common pituitary adenomas (approximately 40%) and make up the vast majority of hormonally functional pituitary adenomas.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Clinically, patients typically present with galactorrhea, menstrual irregularities, loss of libido and/or infertility, as well as sexual dysfunction and hypogonadism particularly in men. Larger tumors may also cause headaches, visual field deficits, and hypopituitarism.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] First-line treatment for prolactinomas remains dopamine agonists, which have been shown to shrink tumors and restore gonadal function with concomitant decrease in prolactin (PRL) levels. In patients with tumors that are resistant to dopamine agonists, surgical resection is recommended.\u003c/p\u003e \u003cp\u003eNon-functioning pituitary adenomas are commonly an incidental finding on imaging, obtained to work-up other symptoms. Compared to macroadenomas, microadenomas of this type are more likely to remain stable or decrease in size with long-term follow-up.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Of note, guidelines released by the Endocrine Society state that asymptomatic patients with microprolactinomas do not necessarily require treatment upfront, given that a natural history study of untreated hyperprolactinemia, albeit decades old, found that these tumors were unlikely to grow.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] In addition, hypogonadal premenopausal women may also be treated with oral contraceptives in lieu of dopamine agonists.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003cp\u003ePrevious studies have suggested that prolactin levels correlate with tumor size. That said, these studies have typically looked at a wide range of tumor volumes.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] However, in cases of small tumors, the diagnosis of a pituitary microprolactinoma is often obscured by relatively low levels of elevated prolactin compared to macroprolactinomas, and patients may not always exhibit classical symptoms of hyperprolactinemia. As a result, in cases of microprolactinomas, there may be varying patterns of management, ranging from initiating medical therapy, considering surgery, or observation.\u003c/p\u003e \u003cp\u003eIn this study, we sought to correlate baseline prolactin levels with tumor volumes in suspected microprolactinomas. We also compared baseline prolactin levels and volumes amongst patients who were managed with medical therapy, surgery, or observation.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis was a multicenter retrospective study of patients with pituitary microadenomas with baseline prolactin levels\u0026thinsp;\u0026gt;\u0026thinsp;18ng/ml for males and \u0026gt;\u0026thinsp;30ng/ml for females. Data collected included basic patient demographics, presenting symptoms, relevant endocrine laboratory values, radiographic findings on initial and subsequent MRI, and clinical outcomes. Volumes were calculated via the ABC/2 formula, approximating the lesion shape as an ellipsoid. This study was conducted under an institutional board approved protocol.\u003c/p\u003e \u003cp\u003eTo analyze the data, we employed a linear mixed-effects model, which allowed us to account for the correlation between repeated measurements taken from the same patient. The analysis was performed using Julia (v1.9.1) programming language, specifically employing the MixedModels.jl package. The model was formulated as follows:\u003c/p\u003e \u003cp\u003eVolume \u0026sim; Time + (1\u0026thinsp;+\u0026thinsp;Time ∣ PatientID)\u003c/p\u003e \u003cp\u003eIn this model, the response variable volume represents the tumor volume, while time is the fixed effect representing the number of days between consecutive MRI scans. To account for the variability and correlation in tumor growth rates across patients, we included a random intercept and a random slope for time within patientID. This random effects structure allows each patient to have a unique baseline tumor volume and a unique tumor growth rate over time. By employing this approach, we were able to assess the overall trend in tumor growth while also considering the variability among individual patients.\u003c/p\u003e \u003cp\u003eTo quantify the uncertainty in our predictions and obtain robust estimates of the confidence intervals for the fixed-effect coefficients, we employed a bootstrapping approach. Bootstrapping is a resampling technique that involves repeatedly drawing random samples from the dataset (with replacement) and recalculating the estimates on each sample. We performed bootstrapping with 1,000 iterations which enabled us to estimate the variability in our predictions and provided 95% confidence intervals around the estimated tumor volumes over time.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThere were 65 patients (18 male, 47 female; mean age 44 years, range: 15\u0026ndash;74 years). At time of diagnosis, mean tumor volume was 95.9 mm\u003csup\u003e3\u003c/sup\u003e (SD: 114.2 mm\u003csup\u003e3\u003c/sup\u003e, range: 4-500 mm\u003csup\u003e3\u003c/sup\u003e), and mean prolactin level was 59.4 ng/ml (SD: 34.4 ng/ml, range: 19.1\u0026ndash;170 ng/ml). The mean follow-up duration as measured from time of first MRI to the last scan was 85.1 months (SD: 56.8 months) and the mean number of MRI scans obtained was 4.3 (SD: 1.9). When analyzing the whole cohort, there was no significant correlation between prolactin levels and tumor volume at diagnosis (Pearson R\u0026thinsp;=\u0026thinsp;0.09,p\u0026thinsp;=\u0026thinsp;0.47). Upon sub-group analysis of patients with tumor volumes above (n\u0026thinsp;=\u0026thinsp;19) and below (n\u0026thinsp;=\u0026thinsp;46) the mean, there were significantly higher prolactin levels in patients with tumors above the mean volume of 95.9mm\u003csup\u003e3\u003c/sup\u003e versus below (74.0 versus 53.4ng/ml,95% CI 2.432\u0026ndash;38.8,p\u0026thinsp;=\u0026thinsp;0.027).\u003c/p\u003e \u003cp\u003e26 patients were observed, 31 were treated with anti-dopaminergic therapy, and 8 had surgery (4 had surgery after failing medical therapy). They presented with the following symptoms. Among the 26 patients who were observed, 11 had mild menstrual irregularities, 2 had hypogonadal symptoms, and the rest were asymptomatic. Among the 31 patients who were treated with anti-dopaminergic therapy, 8 had hypogonadal symptoms, 5 had galactorrhea, 4 had menstrual irregularities, and the rest were asymptomatic. Among the 8 patients who had surgery, 2 had menstrual irregularities, 2 had hypogonadism, and the rest were asymptomatic.\u003c/p\u003e \u003cp\u003eThere were significantly greater baseline prolactin levels for patients who treated surgically (mean: 86.4 ng/ml, SD: 39.6 ng/ml) than those treated medically (mean 61.7 ng/ml, SD: 38.2 ng/ml), or were observed (mean 48.5 ng/ml, SD: 22.0 ng/ml) (p\u0026thinsp;=\u0026thinsp;0.02; F\u0026thinsp;=\u0026thinsp;4.2; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.12). However, there were no significant differences in baseline volumes for patients treated surgically (mean 120.0 mm\u003csup\u003e3\u003c/sup\u003e, SD: 122.4 mm\u003csup\u003e3\u003c/sup\u003e), medically (mean 111.2mm\u003csup\u003e3\u003c/sup\u003e, SD: 118.2 mm\u003csup\u003e3\u003c/sup\u003e), or observed (mean 70.24 mm\u003csup\u003e3\u003c/sup\u003e, SD: 106.1 mm\u003csup\u003e3\u003c/sup\u003e) (p\u0026thinsp;=\u0026thinsp;0.33; F\u0026thinsp;=\u0026thinsp;1.1; R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003cp\u003eAmong the 26 patients who were surveilled, 13 patients demonstrated spontaneous tumor shrinkage, 12 remained stable, and 1 patient\u0026rsquo;s tumor grew but was lost to follow-up. Linear mixed modeling demonstrated a statistically significant rate of tumor shrinkage over time of 3.67mm\u003csup\u003e3\u003c/sup\u003e/year (p\u0026thinsp;=\u0026thinsp;0.03) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There were no significant differences in baseline prolactin in patients whose tumors spontaneously shrunk (mean 46.1 ng/ml, SD: 22.3 ng/ml) versus remained stable (mean 52.3 ng/ml, SD: 22.7 ng/ml) (95% CI:-12.4-24.9, p\u0026thinsp;=\u0026thinsp;0.50). Likewise, there were no significant differences in baseline volumes (mean 56.2mm\u003csup\u003e3\u003c/sup\u003e, SD: 65.1 mm\u003csup\u003e3\u003c/sup\u003e versus 91.0 mm\u003csup\u003e3\u003c/sup\u003e, SD 140.9 mm\u003csup\u003e3\u003c/sup\u003e respectively) (95% CI: 54.8-124.4, p\u0026thinsp;=\u0026thinsp;0.43).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA baseline PRL/volume ratio metric was then explored to predict clinical outcomes. When analyzing patients who were observed versus those requiring surgery after initially being surveilled, there were significantly greater baseline PRL/volume ratios in surgical patients versus those observed (8.1 ng/ml/mm\u003csup\u003e3\u003c/sup\u003e versus 2.4 ng/ml/mm\u003csup\u003e3\u003c/sup\u003e, 95% CI:0.80\u0026ndash;10.7, p\u0026thinsp;=\u0026thinsp;0.025). However, PRL/volume ratio did not predict patterns of medical treatment failure for patients successfully managed with medical treatment versus those who failed and required surgery (2.25 ng/ml/mm\u003csup\u003e3\u003c/sup\u003e versus 0.91 ng/ml/mm\u003csup\u003e3\u003c/sup\u003e, 95% CI:-7.7-5.03, p\u0026thinsp;=\u0026thinsp;0.67).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we studied relationships between baseline prolactin levels and volumes of suspected microprolactinomas in 65 patients with \u0026gt;\u0026thinsp;1 MRI over an average follow-up period of 7 years. We found significantly elevated baseline prolactin levels for patients with tumor volumes above the mean cohort volume, compared to below. Likewise, patients with greater baseline prolactin levels and PRL/volume ratios were more likely to require surgery and/or medical treatment versus those who were observed. We also found a significant rate of tumor shrinkage over time in the tumors of patients that were observed who also exhibited lower levels of baseline prolactin and PRL/volume ratios.\u003c/p\u003e \u003cp\u003eThe diagnosis between a prolactinoma and a non-functioning pituitary adenoma can be difficult, particularly when the size of the tumor in question is small. The most recent consensus statement put forth by the Pituitary Society in 2023 suggested that prolactin levels above 200 ng/ml in the setting of a sellar mass are strongly suggestive of a prolactinoma.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] However, for levels below 200 ng/ml, size-adapted cut-offs for prolactin levels have been studied to differentiate between prolactinomas versus other pituitary tumors. In a prior study from our institution, we compared prolactin levels and pre-operative tumor volume from surgically resected, histopathologically confirmed prolactinomas versus non-functioning pituitary adenomas. There was a strong correlation between prolactinoma size and serum prolactin level with cut-offs of 43.65 ng/ml for tumors under 0.5 cm\u003csup\u003e3\u003c/sup\u003e, 60.05 ng/ml for those between 0.5-4 cm\u003csup\u003e3\u003c/sup\u003e, and 248.15 ng/ml for those\u0026thinsp;\u0026gt;\u0026thinsp;4 cm\u003csup\u003e3\u003c/sup\u003e.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Others have proposed a diagnostic prolactin cut-off value of 55.65 ng/ml,[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] 94 ng/ml,[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] even some as low as 38.6 ng/ml.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] The mean prolactin level in our current study of 59.4 ng/ml is comparable to these previous studies. Unlike our previous study,[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] we did not find a significant correlation between prolactin levels and tumor volume. That said, our cohort was limited to microadenomas, defined by measuring up to 1 cm in greatest diameter, with a mean volume of 95.9 mm\u003csup\u003e3\u003c/sup\u003e, well below the tumor volumes studied in our previous study. In addition, when we compared patients with tumor volumes above and below this mean volume, we did find a significant difference in baseline prolactin levels. With a greater sample size, we suspect there might be an underlying correlation between prolactin levels and tumor volume, even when limited to microadenomas.\u003c/p\u003e \u003cp\u003eIn addition to prolactin level cut-offs for various tumor volume thresholds, we explored the utility of a PRL/volume ratio in predicting clinical outcomes. Within our microadenoma cohort, we found that among patients who were initially surveilled, those who would go on to need surgery had significantly greater baseline PRL/volume ratios than in those who were successfully monitored with serial imaging. That said, our sample size for surgically treated patients was extremely small and therefore, our findings should be interpreted with caution. On the other hand, the PRL/volume ratio did not predict patterns of failure with medical management, likely reflecting the fact that the biology of tumor resistance to dopaminergic therapy is not dependent upon baseline prolactin levels. Other studies in the literature have also explored the role of PRL/volume ratios in diagnosing prolactinomas from other pituitary tumors with mild to moderately elevated prolactin levels albeit in tumor of much larger size and measured in cm\u003csup\u003e3\u003c/sup\u003e rather than mm\u003csup\u003e3\u003c/sup\u003e in our study. Cho et al performed a prolactin to volume ratio analysis and found that tumors with a PRL/volume ratio\u0026thinsp;\u0026gt;\u0026thinsp;100 ng/ml/cm\u003csup\u003e3\u003c/sup\u003e were predictive of distinguishing prolactinomas from other pituitary tumors.[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Likewise, Huang et al reported a PRL/volume ratio of 54 ng/ml/cm\u003csup\u003e3\u003c/sup\u003e to have the highest diagnostic value in patients with pituitary adenomas and elevated prolactin levels but still under 250 ng/ml.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Faje et al reported that a cutoff of 65 ng/ml/cm\u003csup\u003e3\u003c/sup\u003e could discriminate between prolactinomas versus nonfunctioning pituitary adenomas with elevated prolactin levels due to stalk effect.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e There are no clear guidelines on treatment of suspected microprolactinomas. The proposed treatment algorithm put forth most recently by the Pituitary Society recommends initiating treatment based on factors such as male sex, the desire to conceive, young age, a history of a psychiatric disorder, among others. Surveillance may be considered for postmenopausal women and/or eugonadal premenopausal women not interested in conceiving.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Additionally, there can be mild but undesirable side effects with dopamine agonist therapy that can significantly impair quality of life with long-term usage, including gastric issues, nausea, dizziness, and fatigue.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] Likewise, there can be mood changes and impulsivity that make patients with existing psychiatric disorders a relative contraindication to use of dopamine agonists.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] In our study, we found that essentially all patients who were surveilled, aside from one, demonstrated either stability of their lesion size and/or spontaneous shrinkage on further surveillance imaging. In addition, these patients presented either asymptomatically as incidental radiographic findings or with symptoms, most commonly mild menstrual irregularities that were not significantly impairing their quality of life.\u003c/p\u003e \u003cp\u003eThe decision to surgically resect prolactinomas upfront remains controversial, particularly for microadenomas that are not causing visual deficits, and is largely due to patient preference.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] In our cohort, half of the surgically treated patients had failed prior medical therapy while the remaining half preferred surgery after their tumors demonstrated interval growth on repeat imaging. Although we found significantly higher baseline prolactin levels in patients who were surgically treated versus medically treated or observed, our small sample size limits any overarching conclusions on whether any meaningful cut-off exists to recommend surgery upfront over medical therapy for suspected microprolactinomas.\u003c/p\u003e \u003cp\u003eDespite recommendations that certain patients with microprolactinomas may be reasonably observed, there is a lack of data in the literature on the natural history of observed prolactinomas.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Schlechte et al performed a prospective study of 30 women with hyperprolactinemia, 13 of whom had serial radiographic studies and initial findings suggestive of a pituitary adenoma.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Four of these patients had tumor shrinkage, 7 remained stable, and 2 had tumor progression. Feldkamp et al likewise conducted a prospective study of 67 patients with incidental findings of a pituitary adenoma, 42 of whom had microadenomas and 8 of whom had prolactinomas. Only 3.2% of patients with microadenomas demonstrated tumor growth over a mean follow-up period of 2.7 years.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Compared to the existing literature, our study is to our knowledge the largest thus far to report the natural history of microprolactinomas. Notably, we found that among the 26 patients that were surveilled, only 1 patient\u0026rsquo;s tumor grew over the follow-up period, while half of these patients demonstrated spontaneous tumor shrinkage at a statistically significant rate of 3.67 mm\u003csup\u003e3\u003c/sup\u003e/year. While we did not find significant differences in baseline prolactin levels or volumes in tumors that shrunk versus remained stable, we did find significant variations in baseline prolactin levels and PRL/volume ratios in patients who were successfully surveilled versus requiring intervention. Currently, the literature on microprolactinomas has been focused on diagnostically differentiating these tumors from other pituitary adenomas. Additional studies correlating these tumors with clinical outcomes are needed to ascertain whether certain prolactin and volume relationship cut-offs can be made to identify patients for whom these tumors can be surveilled without any initial intervention.\u003c/p\u003e \u003cp\u003eA limitation of our study is that the majority of our patient cohort did not have histopathologic diagnosis of a prolactinoma, given very few patients underwent surgical resection. As such, it is entirely possible that a subset of our patients, particularly those with very low prolactin levels, may have been harboring non-functioning pituitary adenomas with elevated prolactin levels due to stalk effect, resulting in mild hyperprolactinemia. That said, stalk effect is rare in pituitary microadenomas due to their inherent small size.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Regardless, even if our sample size may have been diluted by the undetected presence of true non-functioning pituitary adenomas, our data suggest that small pituitary adenomas with mildly elevated prolactin levels may be reasonably observed, regardless of their true underlying histology.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eIn this multicenter retrospective study, we reported observations from the largest known cohort of microprolactinomas to date. We found that within this subset of microadenomas of prolactinoma origin, tumors that exhibit over 95.9 mm\u003csup\u003e3\u003c/sup\u003e demonstrate more convincingly elevated prolactin levels. Likewise, tumors with baseline prolactin levels over 50 ng/ml were more inclined to undergo medical treatment. Of note, through volumetric analysis of tumors that were surveilled over the long-term, we found that tumors with prolactin levels below 50 ng/ml tended to spontaneously shrink over time. Likewise, we found that in tumors that were surveilled, an elevated baseline PRL/volume ratio of \u0026gt;\u0026thinsp;8 ng/ml/mm\u003csup\u003e3\u003c/sup\u003e may be indicative of potential tumor growth that may necessitate medical and/or surgical intervention. Further studies focused particularly on the management of small pituitary adenomas with elevated prolactin, suggestive of a microprolactinoma, are needed to better define prolactin and volumetric cut-offs that may guide the decision to observe these tumors versus intervene.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003eThe authors have no conflicts of interest to disclose\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eCEC, LM, and TRS provided study oversight. CSH wrote the main manuscript. CSH, JC, JLK, JVG, CO, and TRS analyzed and interpreted the data. CSH and JC performed statistical analysis and prepared figures. All authors contributed data and reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGillam MP, Molitch ME, Lombardi G, Colao A (2006) Advances in the treatment of prolactinomas. Endocr Rev 27(5):485\u0026ndash;534\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVroonen L, Daly AF, Beckers A (2019) Epidemiology and Management Challenges in Prolactinomas. Neuroendocrinology 109(1):20\u0026ndash;27\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePernik MN, Montgomery EY, Isa S, Sundarrajan C, Caruso JP, Traylor JI et al (2022) The natural history of non-functioning pituitary adenomas: A meta-analysis of conservatively managed tumors. J Clin Neurosci 95:134\u0026ndash;141\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMelmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA et al (2011) Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(2):273\u0026ndash;288\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchlechte J, Dolan K, Sherman B, Chapler F, Luciano A (1989) The natural history of untreated hyperprolactinemia: a prospective analysis. J Clin Endocrinol Metab 68(2):412\u0026ndash;418\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurke WT, Penn DL, Castlen JP, Donoho DA, Repetti CS, Iuliano S et al (2019) Prolactinomas and nonfunctioning adenomas: preoperative diagnosis of tumor type using serum prolactin and tumor size. J Neurosurg. :1\u0026ndash;8\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOsorio RC, Pereira MP, Oh T, Joshi RS, Haddad AF, Pereira KM et al (2022) Correlation between tumor volume and serum prolactin and its effect on surgical outcomes in a cohort of 219 prolactinoma patients. J Neurosurg. :1\u0026ndash;11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWright K, Lee M, Escobar N, Pacione D, Young M, Fatterpekar G et al (2021) Tumor volume improves preoperative differentiation of prolactinomas and nonfunctioning pituitary adenomas. Endocrine 74(1):138\u0026ndash;145\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetersenn S, Fleseriu M, Casanueva FF, Giustina A, Biermasz N, Biller BMK et al (2023) Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement. Nat Rev Endocrinol 19(12):722\u0026ndash;740\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang Y, Ding C, Zhang F, Xiao D, Zhao L, Wang S (2018) Role of prolactin/adenoma maximum diameter and prolactin/adenoma volume in the differential diagnosis of prolactinomas and other types of pituitary adenomas. Oncol Lett 15(2):2010\u0026ndash;2016\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaravitaki N, Thanabalasingham G, Shore HC, Trifanescu R, Ansorge O, Meston N et al (2006) Do the limits of serum prolactin in disconnection hyperprolactinaemia need re-definition? A study of 226 patients with histologically verified non-functioning pituitary macroadenoma. Clin Endocrinol (Oxf) 65(4):524\u0026ndash;529\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawaguchi T, Ogawa Y, Tominaga T (2014) Diagnostic pitfalls of hyperprolactinemia: the importance of sequential pituitary imaging. BMC Res Notes 7:555\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCho A, Vila G, Marik W, Klotz S, Wolfsberger S, Micko A (2022) Diagnostic criteria of small sellar lesions with hyperprolactinemia: Prolactinoma or else. Front Endocrinol (Lausanne) 13:901385\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFaje A, Jones P, Swearingen B, Tritos NA (2022) The Prolactin per Unit Tumor Volume Ratio Accurately Distinguishes Prolactinomas From Secondary Hyperprolactinemia due to Stalk Effect. Endocr Pract 28(6):572\u0026ndash;577\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson MD, Woodburn CJ, Vance ML (2003) Quality of life in patients with a pituitary adenoma. Pituitary 6(2):81\u0026ndash;87\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStumpf MAM, Pinheiro FMM, Silva GO, Cescato VAS, Musolino NRC, Cunha-Neto MBC et al (2023) How to manage intolerance to dopamine agonist in patients with prolactinoma. Pituitary 26(2):187\u0026ndash;196\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIoachimescu AG, Fleseriu M, Hoffman AR, Vaughan Iii TB, Katznelson L (2019) Psychological effects of dopamine agonist treatment in patients with hyperprolactinemia and prolactin-secreting adenomas. Eur J Endocrinol 180(1):31\u0026ndash;40\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKreutzer J, Buslei R, Wallaschofski H, Hofmann B, Nimsky C, Fahlbusch R et al (2008) Operative treatment of prolactinomas: indications and results in a current consecutive series of 212 patients. Eur J Endocrinol 158(1):11\u0026ndash;18\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTampourlou M, Trifanescu R, Paluzzi A, Ahmed SK, Karavitaki N (2016) THERAPY OF ENDOCRINE DISEASE: Surgery in microprolactinomas: effectiveness and risks based on contemporary literature. Eur J Endocrinol 175(3):R89\u0026ndash;96\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeldkamp J, Santen R, Harms E, Aulich A, Modder U, Scherbaum WA (1999) Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas - results of a prospective study. Clin Endocrinol (Oxf) 51(1):109\u0026ndash;113\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTable\u0026nbsp;1. Patient demographic data.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAverage age (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean follow-up (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean # of MRI scans (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment modality\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObservation (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgery alone (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSurgery after failing medical therapy (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedical therapy (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePresenting Symptoms\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMenstrual irregularities (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypogonadal symptoms (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGalactorrhea (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsymptomatic (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e\u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"pituitary, prolactinoma, microadenoma, prolactin","lastPublishedDoi":"10.21203/rs.3.rs-3855108/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3855108/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe diagnosis of pituitary microprolactinomas is often obscured by relatively low levels of elevated prolactin compared to macroprolactinomas. This may lead to varying patterns of medical therapy versus observation. We sought to correlate prolactin levels in suspected microprolactinomas with tumor volumes and clinical outcomes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis was a multicenter retrospective study of patients with pituitary microadenomas with baseline prolactin levels\u0026thinsp;\u0026gt;\u0026thinsp;18ng/ml for males and \u0026gt;\u0026thinsp;30ng/ml for females. A linear-mixed model was used to depict changes in tumor volume over time.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThere were 65 patients with a mean tumor volume of 95.9mm\u003csup\u003e3\u003c/sup\u003e and mean prolactin level of 59.4ng/ml. There were significantly higher prolactin levels in patients with tumors above the mean volume versus below (74.0 versus 53.4ng/ml, p\u0026thinsp;=\u0026thinsp;0.027). 26 patients were observed, 31 were treated with anti-dopaminergic therapy, and 8 had surgery. There were significantly greater baseline prolactin levels for patients who were treated surgically (mean 86.4ng/ml) than those treated medically (mean 61.7g/ml) or observed (mean 48.5ng/ml) (p\u0026thinsp;=\u0026thinsp;0.02). Among the 26 patients who were surveilled, 13 patients demonstrated spontaneous tumor shrinkage, 12 remained stable, and 1 patient\u0026rsquo;s tumor grew but was lost to follow-up. Linear mixed modeling demonstrated a statistically significant rate of tumor shrinkage over time of 3.67mm\u003csup\u003e3\u003c/sup\u003e/year (p\u0026thinsp;=\u0026thinsp;0.03). When analyzing patients who were observed versus those requiring surgery after initially being surveilled, there were significantly greater baseline PRL/volume ratios in surgical patients versus those observed (8.1 ng/ml/mm\u003csup\u003e3\u003c/sup\u003e versus 2.4 ng/ml/mm\u003csup\u003e3\u003c/sup\u003e, p\u0026thinsp;=\u0026thinsp;0.025).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSuspected microprolactinomas may demonstrate more convincingly elevated prolactin levels when measuring over 95.9mm\u003csup\u003e3\u003c/sup\u003e. Tumors with baseline prolactin levels over 50ng/ml may be more inclined to undergo medical treatment. In tumors with levels below 50ng/ml, it may be reasonable to undergo surveillance as these tumors tend to spontaneously shrink over time. In tumors that are surveilled, an elevated baseline PRL/volume ratio of \u0026gt;\u0026thinsp;8 ng/ml/mm\u003csup\u003e3\u003c/sup\u003e may be indicate serial tumor growth that may necessitate medical and/or surgical intervention.\u003c/p\u003e","manuscriptTitle":"A multicenter study of clinical outcomes and volumetric trends in suspected microprolactinomas","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-15 20:15:01","doi":"10.21203/rs.3.rs-3855108/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"56373198-c7d2-457f-bb02-cfe79cd69833","owner":[],"postedDate":"January 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-01-20T14:59:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-15 20:15:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3855108","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3855108","identity":"rs-3855108","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}