Prolactin (PRL) was first identified as a pituitary hormone essential for lactation, but it is now recognized as a pleiotropic regulator of endocrine balance, metabolism, immune function, and tissue remodeling. PRL is secreted systemically by the anterior pituitary and is also produced locally in many peripheral tissues via distinct promoters, forming autocrine/paracrine circuits. It signals through the PRL receptor (PRLR), which is expressed broadly in epithelial, stromal, immune, and sensory neuronal cells, and activates canonical pathways such as JAK/STAT, MAPK/ERK, and PI3K/AKT, as well as context-specific signals affecting the cytoskeleton and motility. With widespread cellular distribution and versatile signaling cascades, the PRL–PRLR axis functions as an important integrator of endocrine, inflammatory, metabolic, and nociceptive processes. Beyond its classic systemic endocrine role, local PRL synthesis allows tissue-specific regulation, contributing to immune surveillance, angiogenesis, and neuronal plasticity, positioning the PRL–PRLR signaling as a nexus between peripheral physiological responses and central neuroendocrine control. Dysregulated PRL–PRLR signaling is increasingly implicated in several gynecological and female‑predominant disorders. In gynecological conditions such as endometriosis and adenomyosis, up-regulated PRLR and altered local PRL availability contribute to the ectopic survival of endometrial tissue, expansion of lesions, uterine fibrosis and inflammation, as well as exacerbation of pain. In polycystic ovary syndrome, PRL signaling cross-talks with gonadotropin dysregulation, androgen excess, and insulin resistance, which may increase the risks of cardiometabolic and reproductive dysfunction. Beyond reproductive tissues, the PRL–PRLR axis is also involved in the pathogenesis and progression of female‑prevalent autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus. In sensory neurons and glia, the PRL–PRLR axis links inflammation to nociceptor sensitization, which contributes to the development of migraine. Across these conditions, the role of PRL–PRLR is highly context‑dependent. Circulating PRL levels do not consistently reflect disease risk or activity, underscoring the potential greater relevance of local pathway engagement and cell‑type‑specific signaling in certain pathological contexts. This tissue-specific signaling may explain why some patients with normal serum PRL still exhibit PRL-driven pathology, and why hyperprolactinemia does not always correlate with symptom severity. Moreover, PRL isoforms and post-translational modifications, as well as differential expression of PRLR isoforms, add additional layers of complexity to its biological activity. The crosstalk between PRL signaling and other hormonal systems—such as estrogen, progesterone, and growth factors—further modulates disease phenotypes, creating heterogeneous clinical presentations that challenge straightforward biomarker development and uniform treatment strategies. Translational prospects are emerging, with dopamine agonists, PRL‑neutralizing strategies, and PRLR‑targeted biologics under development and evaluation. While bromocriptine and cabergoline are already used to lower systemic PRL levels, their efficacy in PRLR-driven conditions remains limited. Novel approaches, such as PRL‑neutralizing antibodies and PRLR antagonistic antibodies, are being explored in preclinical studies and clinical trials. Successful clinical translation of PRL–PRLR–targeted interventions requires a deep understanding of the underlying pathology, which is essential not only for selecting the optimal therapeutic modality but also for identifying the most responsive patient population.
Xu et al. (Thu,) studied this question.