Impact of Metformin on Gonadotropic Hormones, Prolactin Fractions, and Androgen Profile in Women with Polycystic Ovary Syndrome and Prediabetes: A Prospective Comparative Study

Background: Polycystic ovary syndrome (PCOS) is one of the most prevalent endocrine disorders in women and is associated with reproductive and metabolic abnormalities, including excessive androgen production, insulin resistance (IR), and disturbance of the hypothalamic–pituitary–ovarian axis. Metformin improves many of the metabolic abnormalities associated with PCOS (off-label use in most countries); however, its impact on the secretion of gonadotropic hormones and prolactin subfractions is not fully understood and might also be distinct from that in non-PCOS women with similar metabolic dysfunctions. Objective: To investigate the impact of metformin treatment on concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), the ratio of LH-to-FSH, and prolactin fractions, as well as their metabolic and hormonal state in women with PCOS compared with a control group of prediabetic women without PCOS. Methods: This prospective, comparative, open-label study with a metabolically matched comparison group (no untreated arm) evaluated 240 women equally divided into two groups: 120 women with PCOS and 120 women with prediabetes without PCOS. Both groups were similar in their baseline characteristics. Each participant was given oral metformin for six months, starting at a low dose and gradually increasing to a maximum of 2.55–3.0 g/day. Clinical assessment, anthropometric measurements, and laboratory investigations including glucose metabolism indices, prolactin fractions, gonadotropins, and androgen profiles were conducted before and after treatment. Between-group and within-group comparisons were performed, and exploratory correlation analyses were conducted. Results: After six months of metformin therapy, women with PCOS experienced a significant decrease in fasting glucose levels from baseline (112.24 ± 5.78 mg/dL) to follow-up (105.50 ± 5.93 mg/dL; p < 0.001). this reduction did not differ significantly from that observed in controls (mean change −6.74 vs. −7.61 mg/dL; p = 0.37). The Homeostatic Model Assessment for Insulin Resistance (HOMA1-IR) also decreased significantly, from 3.27 ± 0.36 to 2.83 ± 0.39 (p < 0.001); however, the reduction was smaller than in controls (change −0.44 ± 0.55 vs. −0.95 ± 0.49; p < 0.001). Total prolactin levels did not change significantly in the PCOS group (45.85 ± 5.06 to 45.00 ± 5.04 ng/mL; p = 0.22), whereas they decreased significantly in controls (45.51 ± 5.05 to 37.87 ± 4.63 ng/mL; p < 0.001). Monomeric prolactin levels decreased significantly in women with PCOS (33.43 ± 4.03 to 31.46 ± 3.94 ng/mL; p < 0.001), but less than in controls (change −1.97 ± 5.33 vs. −6.56 ± 5.54 ng/mL; p < 0.001), and remained higher than in controls. In women with PCOS, LH decreased significantly from 11.28 ± 1.34 to 8.55 ± 1.11 IU/L (p < 0.001) and the LH/FSH ratio from 1.85 ± 0.27 to 1.42 ± 0.24 (p < 0.001), reaching values similar to those of controls at follow-up (partly because LH and the LH/FSH ratio increased in controls), while FSH levels remained unchanged (p > 0.05). Testosterone declined significantly from 0.81 ± 0.07 to 0.73 ± 0.08 ng/mL (p < 0.001) and free androgen index (FAI) decreased from 7.01 ± 1.30 to 5.11 ± 0.72 (p < 0.001), concurrently with a significant increase in sex hormone-binding globulin (SHBG) (41.12 ± 6.48 to 50.37 ± 5.51 nmol/L; p < 0.001). Because SHBG levels increased in both groups, FAI also decreased significantly in controls (4.12 ± 0.96 to 3.01 ± 0.63; p < 0.001), although the reduction was greater in PCOS (−1.90 ± 1.47 vs. −1.11 ± 1.23; p < 0.001). In contrast, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and estradiol levels remained higher in women with PCOS than in controls after treatment, without significant within-group changes. Similarly, no significant changes were observed in macroprolactin, thyrotropin, adrenocorticotropic hormone (ACTH), or insulin-like growth factor-1 (IGF-1) (p > 0.05). Conclusion: Women with PCOS and metabolically matched prediabetic women without PCOS showed different metabolic and endocrine changes during six months of identical metformin treatment. Improvements in insulin resistance and prolactin levels were greater in controls, whereas reductions in LH, the LH/FSH ratio and testosterone occurred only in women with PCOS. FAI decreased in both groups (more in PCOS), reflecting the increase in SHBG levels, and androgen excess in PCOS was reduced but not normalized. Because both groups received metformin and there was no untreated comparator, these changes cannot be attributed specifically to metformin. The findings suggest context-dependent endocrine responses and should be confirmed in placebo-controlled studies.