The study was designed as a single-center retrospective cohort analysis of treatment-naive patients who had undergone a standardized low-dose bromocriptine test as a marker for dopamine agonist response. Between 2008 and 2017, the test was performed routinely at the Norwegian center as part of the baseline workup for newly diagnosed acromegaly. Of 141 consecutive patients diagnosed during that decade, 71 underwent the test, and 69 were included in the final retrospective analyses after exclusions for logistical reasons, contraindications, acute surgery, hypotension or syncope during testing, prior dopamine agonist treatment, lactose intolerance, pituitary apoplexy, loss to follow-up, or lack of consent.

The bromocriptine test itself is elegantly simple. After an overnight fast, three baseline growth hormone samples are drawn 30 minutes apart and averaged. The patient then swallows a single 2.5 mg oral dose of bromocriptine, and growth hormone is measured again at 2, 4, and 6 hours. A positive response was defined as more than a 50 percent reduction in the nadir growth hormone concentration compared with the baseline mean. In the cohort, responders showed a median growth hormone decline of 74 percent, while non-responders declined only 37 percent. This acute hormonal snapshot served as the surrogate for longer-term dopamine agonist effectiveness, a concept rooted in clinical studies from the 1970s and 1980s that linked early bromocriptine-induced growth hormone suppression with later therapeutic benefit.

To probe the biology behind variable responsiveness, the researchers combined several complementary approaches. Baseline serum hormones, including growth hormone, prolactin, and insulin-like growth factor 1 (IGF1), were measured with standard immunoassays and calibrators. Magnetic resonance images were evaluated retrospectively for tumor size, volume, and invasiveness using the Knosp criteria for cavernous sinus invasion. Immunohistochemical staining of tumor tissue assessed growth hormone, prolactin, thyroid-stimulating hormone, cytokeratin 8, estrogen receptor alpha, and somatostatin receptor subtypes 1, 2, and 5, with staining intensity scored using the immunoreactive score system. Slides were evaluated by an investigator and a senior pathologist, both blinded to clinical data.

A key technical challenge emerged with the dopamine receptor D2 protein itself. Immunohistochemistry using two different commercial antibodies failed repeatedly: on postmortem central nervous system tissue, both showed distinct intracellular granular labeling, but background staining was high and could not be reduced, and on surgical pituitary specimens the staining was diffuse and nonspecific. The team therefore turned to gene expression analysis. Tumor tissue collected during surgery was snap-frozen and stored at minus 80 degrees Celsius, RNA was extracted with a column-based kit after TRIzol homogenization, and dopamine receptor D2 mRNA was quantified by real-time quantitative PCR normalized to two validated reference genes, GAPDH and PSMC4. Gene expression data were available in 54 patients.

The central result was striking. Dopamine agonist test response correlated with higher tumor dopamine receptor D2 gene expression, with a Spearman correlation coefficient of 0.53 and a p-value below 0.001. Patients with a positive test had significantly higher receptor expression than those with a negative test. Crucially, this association remained statistically significant after statistical adjustment for gender, age, tumor volume, growth hormone and prolactin concentrations, and their staining intensities, indicating that the receptor expression carried independent information about drug responsiveness. Higher receptor expression also tracked with higher serum prolactin, stronger tumor prolactin staining, and lower IGF1 levels relative to the age-adjusted upper limit of normal.

Prolactin emerged as a clinically accessible indirect marker. Stronger tumor prolactin expression correlated with better test response, and when prolactin staining was dichotomized as positive or negative, the association with test outcome was significant, with a phi coefficient of 0.39. Notably, 57 of 66 tumors showed prolactin expression by immunohistochemistry, a far higher proportion than the 20 to 30 percent hyperprolactinemia typically reported in acromegaly, reflecting that many tumors secrete prolactin histologically without elevating serum levels beyond normal. When prolactin staining was used as the marker and test response as the outcome, sensitivity was 97 percent, meaning nearly all responders stained positive, while specificity was only 30 percent, since many non-responders also stained positive. The negative predictive value of 89 percent suggests that a prolactin-negative tumor is a strong signal that dopamine agonist therapy will fail.

The statistical architecture of the analysis clarified the causal chain. When the correlation between prolactin and test response was adjusted for dopamine receptor D2 expression, it disappeared, implying that the drug effect is mediated through the receptor itself and that prolactin expression serves as an indirect proxy for receptor abundance and responsiveness. This mechanistic interpretation aligns with known pharmacology: activation of the D2 receptor reduces hormone release and can induce apoptosis in pituitary tumor cells, with the short receptor isoform appearing to exert stronger effects. Somatostatin receptor staining showed no correlation with test response, and the hypothesized link between somatostatin receptor 1 and dopamine receptor D2 expression was not borne out in this cohort.

Estrogen receptor alpha added a second layer of tumor biology. Its expression correlated with prolactin expression, and both were associated with smaller tumor volume and lower invasiveness by Knosp grade. Patients whose tumors stained negative for prolactin were older and had higher IGF1 levels relative to normal. These findings echo the 2022 World Health Organization classification, which distinguishes pure somatotroph tumors from those with combined somatotroph and lactotroph differentiation marked by growth hormone, prolactin, and estrogen receptor alpha positivity. However, the authors caution that the clinical applicability of the estrogen receptor findings remains unclear, as previous studies on estrogen receptor alpha and tumor aggressiveness in acromegaly have yielded conflicting results.

The study has limitations that temper enthusiasm. Gene expression does not necessarily reflect protein abundance, cellular localization, or receptor function, and the analysis did not distinguish between the long and short isoforms of the D2 receptor, which may differ in mechanism. The bromocriptine test is a surrogate for acute response and cannot replace studies of long-term dopamine agonist effectiveness. The 70 patients who did not undergo testing had lower prolactin concentrations and greater growth hormone excess, potentially introducing bias, although age, sex, and tumor size were comparable. Still, the large well-characterized cohort with standardized dynamic testing, supported by molecular and histological analyses, represents a methodological strength over registry-based studies. The authors conclude that readily available prolactin staining of tumor tissue may add valuable information for individualized pharmaceutical management, potentially sparing non-responders from ineffective therapy while guiding responders toward optimized treatment regimens.

Subject of Research: Acromegaly treatment markers

Article Title: Tumor expression of dopamine receptor and prolactin is associated with acute dopamine agonist response in acromegaly

Article References: Atai, S., Abusdal, M., Wessel, M. I., Casar-Borota, O., Øystese, K. A., Winther, J., Bollerslev, J., & Heck, A. (2026). Tumor expression of dopamine receptor and prolactin is associated with acute dopamine agonist response in acromegaly. Frontiers in Endocrinology, 17, Article 1930467. https://doi.org/10.3389/fendo.2026.1930467

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1930467

Keywords: acromegaly, dopamine agonist, prolactin, pituitary tumor, personalized medicine, Tumor, expression, dopamine, receptor, associated, acute, agonist