POD1 Prolactin Levels Predict Long-Term Outcomes After Prolactinoma Resection

Postoperative Prolactin Levels: A Window into Long-Term Prolactinoma Outcomes

Prolactinomas are the most prevalent secretory pituitary adenomas, with patients often presenting due to hyperprolactinemia or mass effect [1]. While dopamine agonists are a common first-line therapy, transsphenoidal surgery remains a critical option for patients with macroadenomas, intolerance to medical therapy, or dopamine agonist resistance [2, 3, 4, 5]. A significant clinical challenge is the variability in long-term biochemical control following surgery. Patients face risks of hyperprolactinemia rebound or recurrence, which can necessitate further treatment and prolonged monitoring [6]. Therefore, identifying a reliable, early postoperative indicator of long-term outcomes is essential for stratifying patient risk, managing expectations, and guiding follow-up care.

Study Design and Patient Characteristics

To determine if an early biomarker could predict long-term success, researchers evaluated the prognostic value of postoperative day 1 (POD1) prolactin levels. The study involved a retrospective review of 260 patients who underwent surgical resection for prolactinoma between 1998 and 2020. The cohort, with a mean age of 35.4 (11.4) years, was predominantly female, with women comprising 78.1% (n = 203) of the participants. A key aspect of the analysis was stratifying patients by their preoperative use of dopamine agonists (DAs), as these medications can suppress prolactin and potentially confound postoperative measurements. The DA-positive group included 112 patients (43.1%) who had used DAs within three weeks of surgery, while the DA-negative group consisted of 148 patients (56.9%) with no recent use.

The investigators categorized POD1 prolactin levels to provide a granular view of early biochemical status: low normal (0-10 ng/ml for men, 0-12.5 ng/ml for women), high normal (10-20 ng/ml for men, 12.5-25 ng/ml for women), and mildly hyperprolactinemic (20-40 ng/ml for men, 25-50 ng/ml for women). To track outcomes, prolactin was measured at six intervals up to and beyond one year post-surgery. The study defined remission as persistent prolactin normalization for the entire first year. It also distinguished between rebound hyperprolactinemia, defined as a return of elevated prolactin requiring treatment within the first year, and recurrent hyperprolactinemia, where this elevation occurred one year or more after the initial surgery. These definitions are clinically important for differentiating early versus late treatment failure.

Postoperative Prolactin Levels and Long-Term Outcomes

The findings demonstrate that POD1 prolactin levels, when interpreted in the context of prior dopamine agonist (DA) use, are strongly associated with long-term biochemical outcomes. Among patients with no recent DA use (DA-negative), achieving a low-normal POD1 prolactin level was highly predictive of success: 90.2% of these patients achieved remission, defined as sustained prolactin normalization for the first year. In stark contrast, remission was achieved by only 37.0% of DA-negative patients with a high-normal POD1 prolactin level. For those who were still mildly hyperprolactinemic on POD1, the prognosis was poor, with 78.9% having persistent elevation. This pattern held for the DA-positive group, although remission rates were generally lower. Remission was achieved in 72.6% of DA-positive patients with low-normal POD1 levels and 50.0% with high-normal levels. A substantial 81.8% of DA-positive patients who were mildly hyperprolactinemic on POD1 remained so.

The risk of later treatment failure also varied significantly based on these early markers. For DA-negative patients, the rate of rebound hyperprolactinemia (elevation within one year) was just 2.0% for those with low-normal POD1 levels but jumped to 33.3% for those with high-normal levels. In the DA-positive group, the rebound rates were 12.6% and 33.3% for low-normal and high-normal patients, respectively. Similarly, the risk of recurrent hyperprolactinemia (elevation after one year) in the DA-negative group was 7.8% for low-normal versus 25.9% for high-normal patients. The cumulative incidence of both rebound (p < 0.001) and recurrence (p < 0.001) was statistically different across the groups, confirming that these are not chance findings. The data clearly identify DA-negative patients with a low-normal POD1 prolactin level as the group least likely to experience either early or late treatment failure.

Implications for Retreatment and Clinical Management

These results directly inform which patients are most likely to require retreatment with medical therapy during the first year post-surgery. The need for retreatment was significantly higher in patients with elevated POD1 prolactin levels, a trend amplified by prior dopamine agonist (DA) use (p < 0.001 for both DA-positive and DA-negative cohorts). Among patients who were mildly hyperprolactinemic on POD1, 47.4% of DA-negative patients required retreatment, a figure that rose to 81.8% in the DA-positive group. This effect was also evident in patients with high-normal POD1 levels, where retreatment was needed for 18.5% of DA-negative patients versus 33.3% of DA-positive patients. Most strikingly, even a low-normal POD1 level did not guarantee freedom from retreatment if DAs were used preoperatively: 18.1% of these DA-positive patients required therapy within a year, compared to only 1.0% of their DA-negative counterparts.

In summary, while the POD1 prolactin level is a valuable prognostic tool, the authors caution that it should not be viewed as a definitive sign of cure. The data strongly suggest that a normal POD1 prolactin, particularly a high-normal result or any normal result in a patient with recent DA use, warrants increased clinical vigilance. The risk of rebound hyperprolactinemia is substantial in these populations. These findings provide clinicians with a framework for risk stratification, enabling more informed patient counseling about the likelihood of remission and the potential need for ongoing monitoring or future intervention after prolactinoma surgery.

References

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2. Ma Q, Su J, Li Y, et al. The Chance of Permanent Cure for Micro- and Macroprolactinomas, Medication or Surgery? A Systematic Review and Meta-Analysis. Frontiers in Endocrinology. 2018. doi:10.3389/fendo.2018.00636

3. Penn MC, Cardinal T, Zhang Y, et al. Cure and Hormonal Control After Prolactinoma Resection: Case Series and Systematic Review.. Journal of the Endocrine Society. 2021. doi:10.1210/jendso/bvab074

4. Cai X, Zhu J, Yang J, Tang C, Cong Z, Ma C. Are dopamine agonists still the first-choice treatment for prolactinoma in the era of endoscopy? A systematic review and meta-analysis. Chinese Neurosurgical Journal. 2022. doi:10.1186/s41016-022-00277-1

5. Wang AT, Mullan RJ, Lane MA, et al. Treatment of hyperprolactinemia: a systematic review and meta-analysis. Systematic Reviews. 2012. doi:10.1186/2046-4053-1-33

6. Roelfsema F, Biermasz NR, Pereira AM. Clinical factors involved in the recurrence of pituitary adenomas after surgical remission: a structured review and meta-analysis. Pituitary. 2011. doi:10.1007/s11102-011-0347-7