Exploring the Role of Kisspeptin in Polycystic Ovary Syndrome and Its Associated Pregnancy Complications.

PCOS is a common endocrine disorder that affects women of childbearing age. Although its exact etiology is not fully understood, both genetic and environmental factors are believed to be significant contributors [ 10 ]. The diagnosis of PCOS requires the presence of at least two of the following three features—clinical or biochemical hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology (PCOM)—after exclusion of other endocrine or metabolic disorders [ 11 ]. According to the 2023 International Evidence‐Based Guideline, in adults, a diagnosis can be made if any two of these three criteria are met. PCOM may be confirmed by transvaginal ultrasound or, when ultrasound is not feasible, by elevated anti‐Müllerian hormone (AMH) levels, provided assay‐ and population‐specific thresholds are applied [ 12 ]. In adolescents, both hyperandrogenism (clinical or biochemical) and persistent ovulatory dysfunction are required for diagnosis. Importantly, pelvic ultrasound is clearly opposed in this age group due to the high likelihood of transient and physiological polycystic ovarian changes during puberty, which may lead to overdiagnosis [ 12 ]. Although recent guidelines recognize AMH as a potential surrogate marker for PCOM in adults—especially when imaging is impractical—its use is limited by a lack of standardized thresholds and assay variability. In adolescents, AMH is not recommended for diagnostic purposes due to insufficient evidence and poor specificity. This updated framework emphasizes a comprehensive clinical approach that integrates hormonal, menstrual and (where appropriate) imaging parameters while carefully excluding alternative diagnoses to ensure diagnostic accuracy and guide individualized management [ 12 ]. PCOS affects approximately 6%–10% of women of reproductive age worldwide [ 13 ]. Its epidemiology and prevalence vary worldwide. According to a 2019 Global Burden of Disease Study covering 204 countries and regions, the global incidence of PCOS was 30.4 cases per 100,000 people in 2019 [ 14 ]. In addition, a previous study revealed that the global age‐standardized point prevalence and annual incidence of PCOS have increased by 30.4% and 29.5%, respectively, since 1990 [ 14 ]. Collectively, these findings underscore the growing recognition of PCOS as a widespread and significant public health concern that poses a major threat to women's long‐term health. The pathophysiology of PCOS is characterized by a complex interplay of changes in reproductive hormones, described by Rebar et al. as a “vicious cycle” [ 15 , 16 ]. This cycle is driven by hyperinsulinemia and hyperandrogenism [ 17 ], which play crucial roles in the reproductive and metabolic characteristics of PCOS. There are two proposed theories regarding the etiology of hyperandrogenemia in PCOS patients. One is the theory of altered gonadotropin secretion, whereby an increase in gonadotropin‐releasing hormone (GnRH) pulse frequency results in an increase in luteinizing hormone (LH) levels and a slight increase in follicle‐stimulating hormone (FSH) levels [ 17 , 18 , 19 ]. In this case, high levels of LH stimulate theca cells to produce androgens, whereas slightly elevated FSH affects follicle development and the conversion of androgens into estrogens [ 17 , 18 ]. The abnormal fluctuations in GnRH secretion may be due to KP, an upstream regulator of GnRH neurons, which has been extensively studied and found to play a critical role in the female reproductive system [ 20 ]. It is a key component of the complex network of neurotransmitters and neuropeptides that regulate the activity of the hypothalamic–pituitary–gonadal (HPG) axis [ 21 , 22 ]. Through experimental verification, it has been found that the level of KP at the hypothalamic level significantly increases in the PCOS model [ 23 ]. KP binds to its receptor (KISSSR) on GnRH neurons to promote the release of GnRH into the portal circulation [ 24 , 25 ]. During this process, the activity of KP neurons varies throughout the menstrual cycle and is strictly regulated by estradiol (E2) [ 26 ]. After the injection of KP antagonists, in addition to inhibiting KP‐induced GnRH neuronal firing and reducing average GnRH levels, the pulse rhythm of GnRH secretion is also affected [ 27 ]. Moreover, there are variations in the metabolic phenotypes and expression patterns of KP among PCOS patients during pregnancy, and these phenotypes and expression patterns are strongly correlated with metabolism [ 28 ], pregnancy physiology [ 29 ], and various pregnancy complications [ 8 ]. The other theory posits functional ovarian or adrenal hyperandrogenism as the underlying cause, whereby dysregulated steroidogenesis at the ovarian or adrenal level leads to hyperandrogenism. High levels of androgens promote follicular recruitment but also lead to follicular atresia, resulting in the typical manifestations of polycystic ovaries [ 15 , 19 ]. Hyperandrogenemia reduces the responsiveness of cells in the body to insulin and may directly promote increased insulin production by pancreatic β cells. Additionally, insulin can stimulate ovarian androgen production, reduce the production of hepatic sex hormone‐binding globulin (SHBG) and further increase the levels of total and free androgens [ 30 ]. Insulin resistance (IR) is another core feature that is closely associated with hyperandrogenism, obesity, and metabolic abnormalities. Studies have shown that at least 50%–70% of PCOS patients have IR [ 31 , 32 ]. Furthermore, IR in PCOS patients is independent of obesity and is not related to changes in body composition or impaired glucose tolerance [ 33 ]. It is important to note that nearly all women with PCOS exhibit reduced insulin sensitivity, with studies reporting an average reduction of 27% [ 33 ]. The distinction between IR and reduced insulin sensitivity lies in their clinical and pathological significance [ 34 ]. IR refers to a pathological state where cells exhibit a significantly diminished response to insulin, often accompanied by hyperinsulinemia and typically diagnosed through specific tests such as HOMA‐IR or hyperinsulinemic–euglycemic clamp [ 34 ]. In contrast, reduced insulin sensitivity describes a broader phenomenon where the responsiveness of cells to insulin is decreased but not yet at the pathological level of IR [ 35 ]. This can occur in healthy individuals or in the early stages of metabolic disorders. Whereas all women with PCOS exhibit reduced insulin sensitivity, not all meet the diagnostic criteria for IR. The specific mechanism of IR involves various components, including impaired insulin receptor function, defects in the insulin signaling pathway, and associations with inflammatory markers. The effects of insulin occur via its binding to a specific cell surface receptor composed of a glycoprotein tetramer consisting of two alpha subunits and two beta subunits [ 30 ]. Upon binding, insulin initiates a signaling cascade that may involve conformational changes within the receptor subunits [ 30 ]. In PCOS patients, although the binding capacity of the insulin receptor appears to be unaltered, normal autophosphorylation of insulin receptor subunits is observed in the absence of insulin, whereas autophosphorylation upon maximal insulin stimulation is significantly decreased (30% lower than that in the control group), suggesting a postreceptor defect in the insulin signaling chain [ 36 ]. In addition, PCOS patients necessitate higher insulin levels to achieve the equivalent glucose transport rate than normal patients do, indicating that IR not only is a problem of the insulin receptor but also involves other links in the insulin signaling chain [ 36 ]. Research has shown that IR in PCOS patients is related to the levels of inflammatory markers such as tumor necrosis factor‐α (TNF‐α), C‐reactive protein (CRP) and interleukin‐6 (IL‐6) [ 37 ]. These inflammatory markers may participate in the development of IR by affecting insulin signaling or directly affecting insulin sensitivity. Systematic low‐grade chronic inflammation also plays a pivotal role in PCOS. An imbalance between immune cells and inflammatory cytokines is evident in the serum, ovaries, and organs of PCOS patients [ 38 , 39 ]. Chronic inflammation exacerbates IR by activating proinflammatory factors (such as TNF‐α and IL‐6) and inhibiting the insulin signaling pathway, whereas IR promotes the release of free fatty acids (FFAs) and inflammatory factors from adipose tissue through hyperinsulinemia, further aggravating the inflammatory response [ 38 , 39 ]. Adipose tissue plays an important role in this process because adipose tissue dysfunction leads to an imbalance in the secretion of inflammatory cytokines and adipose factors (such as leptin and adiponectin), thereby affecting systemic insulin sensitivity and inflammatory status [ 33 , 34 , 35 ]. This cycle in turn leads to hyperinsulinemia and hyperandrogenism, and these mechanisms together trigger a series of metabolic and endocrine disorders. The pathophysiology of PCOS involves complex interactions among hormonal, metabolic, and inflammatory pathways. Central mechanisms include gonadotropin dysregulation, functional hyperandrogenism, and insulin resistance, which collectively drive reproductive and metabolic dysfunction. Given the impact of the complex pathophysiology of PCOS on pregnancy, it is important to emphasize the significant challenges that women with PCOS face in their reproductive journeys [ 1 ]. Despite infertility, women are still confronted by severe challenges, including risks of miscarriage and pregnancy complications [ 40 ], which result from the complex endocrine disorders of PCOS, including metabolic abnormalities such as IR and hyperinsulinemia, as well as changes in the intrauterine environment caused by high androgen levels. The interplay of physiological factors in patients with PCOS contributes to increased susceptibility to complications such as GDM, gestational hypertension (GH), and PE during pregnancy, which are increased by 50%–80% in obese PCOS patients [ 41 ]. GDM is a type of diabetes that occurs during pregnancy that was not present prior to the pregnancy, and GDM is characterized by high blood sugar levels during pregnancy [ 42 ]. The International Association for the Study of Diabetes in Pregnancy (IADPSG) revised the diagnostic criteria for GDM [ 43 , 44 ]. The diagnosis of GDM is based mainly on a 75 g OGTT at 24–28 weeks of gestation. With the OGTT, only a single high blood glucose value is needed to diagnose GDM. Diagnostic thresholds were determined on the basis of mean blood glucose levels in the Hyperglycemia and Adverse Pregnancy Outcome Follow‐up Study (HAPO FUS) cohort to reflect the increased risk of perinatal complications [ 42 ]. The relationship between PCOS and GDM is close and complex, with shared pathophysiological mechanisms, including IR and hyperinsulinemia. PCOS is a significant condition that is closely associated with the development of GDM. Previous studies have shown that PCOS patients, irrespective of body weight, have a higher risk of impaired glucose tolerance (IGT) and Type 2 diabetes, particularly at a young age [ 45 ]. Moreover, the degree of IR in PCOS patients is independent of obesity [ 46 ], and significant IR problems exist even in nonobese patients. During pregnancy, changes in maternal glycemic physiology primarily include IR, relative deficiency in insulin secretion, and lipotoxic β‐cell damage. Increased IR is a significant feature, primarily attributed to changes in hormone levels and increased obesity during pregnancy. The placenta produces many hormones, including growth hormone, corticotropin‐releasing hormone, human placental prolactin, prolactin, estrogen, and progesterone, which are antagonistic to insulin‐like substances [ 42 ]. As gestational age increases, pregnant women experience a gradual decrease in insulin sensitivity, leading to elevated levels of maternal FFAs [ 47 , 48 ]. Although FFAs inhibit maternal glucose uptake, they also stimulate gluconeogenesis in the liver, further aggravating IR [ 49 ], which consequently results in elevated postprandial glucose levels and an increase in FFAs [ 50 , 51 ]. This resistance also facilitates placental diffusion, thereby increasing the availability of glucose for fetal growth and development [ 52 ]. Additionally, there is an increase in insulin secretion, particularly in the first trimester, in response to decreased insulin sensitivity and increased demand for glucose by the fetus [ 53 , 54 ]. High levels of placental hormones not only induce IR but also promote the proliferation of β cells and the secretion of insulin [ 55 , 56 ]. GDM occurs when increased insulin secretion cannot compensate for the blood glucose fluctuations caused by IR during pregnancy. One possible reason for this result is that the lipotoxic β‐cell damage caused by hyperlipidemia, which is characterized mainly by elevated serum triglycerides, affects insulin secretion [ 57 , 58 ]. This is also similar to the pathogenesis of Type 2 diabetes. Some studies have shown that abnormal insulin secretion in women with GDM occurs before pregnancy and increases in early pregnancy, independent of insulin changes [ 42 , 59 , 60 ]. On the basis of these observations, it is possible that circulating hormones such as leptin mediate the chronic or preexisting β‐cell dysfunction that many women with GDM experience [ 61 ]. Specifically, GDM is associated with an increased risk of Type 2 diabetes and cardiovascular disease (CVD) later in life for the mother [ 62 , 63 ] and an increased risk of obesity, diabetes, and metabolic syndrome in the offspring [ 64 ]. A meta‐analysis revealed that women with a history of GDM had a significantly increased risk of Type 2 diabetes, with a risk ratio (RR) of 13.2 and a 95% confidence interval (CI) of 8.5–20.7 [ 65 ]. In another study, GDM was suggested to be an important risk factor for future CVD [ 66 ]. GDM has implications not only for maternal health but also for fetal well‐being, potentially leading to various neonatal complications. Offspring with GDM are more likely to be obese, have diabetes, and have metabolic syndrome. For example, research has revealed that obesity and diabetes in pregnant mothers have an impact on fetal growth and development and may increase the likelihood that offspring will develop metabolic syndrome and Type 2 diabetes [ 67 ]. A different study also revealed that the higher birth weight of children whose mothers had GDM is associated with a higher adult risk of Type 2 diabetes [ 68 ]. GDM is associated with hormonal and metabolic disorders in pregnant women and fetuses. In GDM, the levels of insulin and IGF‐II in pregnant women and fetuses are elevated, and abnormal levels of these hormones stimulate the expression of membrane type 1–matrix metalloproteinase (MT1‐MMP) in fetal placental endothelial cells (fpEC) through the phosphatidylinositol 3‐kinase signaling pathway [ 69 ]. MT1‐MMP is a key angiogenic and vasodilator factor, and its upregulation in GDM may be associated with placental hypervascularization and vascular dysfunction in the villi [ 69 ]. The abnormal placental function caused by GDM may also be an important factor affecting the risk of T2DM in pregnant women later in life by affecting the angiogenesis and vasodilation of the placenta, thereby affecting the growth and development of the fetus and the metabolic status of pregnant women [ 69 ]. These findings suggest that GDM has enduring consequences for the well‐being of fetuses in addition to affecting the health of expectant mothers. Therefore, for PCOS patients, especially those who develop GDM during pregnancy, their glycemic status needs to be monitored regularly, and appropriate management and preventive measures should be provided to reduce the risk of Type 2 diabetes in the future. According to the 2023 International Guidelines, lifestyle interventions, including dietary modifications, regular physical activity, and weight management, are the cornerstone of reducing the progression of GDM to T2DM [ 12 , 70 ]. In one study, an intensive lifestyle intervention involving weight loss through diet and increased physical activity reduced the risk of Type 2 diabetes by 50% after 3 years of follow‐up compared with placebo [ 71 ]. A long‐term follow‐up study further supports that lifestyle interventions can significantly lower the risk of developing T2DM in women with a history of GDM [ 72 ]. However, the success of these interventions relies heavily on consistent medical supervision and management. Physicians play a critical role in providing personalized guidance and regular follow‐ups to ensure that lifestyle changes are sustainable and tailored to individual needs, ultimately maximizing their preventive impact. PE is a serious complication of pregnancy and a complex multisystem disorder characterized by the sudden onset of hypertension (> 20 weeks of gestation) and at least one other associated complication, including proteinuria, maternal organ dysfunction, or uteroplacental dysfunction [ 73 ]; these complications are also a major cause of morbidity and mortality in both mothers and newborns [ 74 ]. PE is associated with multiple risk factors, including obesity, diabetes, chronic kidney disease, autoimmune diseases, advanced maternal age, nulliparous women, and family history of PE [ 75 ]. The definition of PE includes various symptoms, including but not limited to hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg), which occurs after 20 weeks of pregnancy and is accompanied by proteinuria (urinary protein ≥ 300 mg/24 h) and/or elevated serum enzymes, liver enlargement, jaundice, upper abdominal pain, headache, visual impairment, convulsions, or coma [ 76 , 77 , 78 ]. PE may further develop into eclampsia, which is a more serious condition that may endanger the lives of both mothers and babies [ 76 ]. The placenta develops mostly at the end of the first trimester, and healthy placental function depends on significant placental villus branching and vascularization throughout the early stage of pregnancy [ 79 ]. The uterine spiral arteries undergo remodeling early in pregnancy to become high‐flow, low‐resistance vessels to accommodate the growing demands of the placenta on the oxygen supply later in pregnancy [ 80 ]. However, in PE, aberrant placental development—specifically, insufficient spiral artery remodeling and trophoblastic invasion—reduces placental blood flow, which results in hypoxia and ischemia–reperfusion damage [ 81 ]. Owing to oxidative stress, endoplasmic reticulum stress, and mitochondrial damage caused by these injuries, proinflammatory cytokines, reactive oxygen species, and antiangiogenic factors (such as sFLT1 and fetal cell‐free DNA) are abnormally released into the mother's bloodstream [ 82 , 83 ]. Additionally, the dysregulation of key angiogenic factors, including placental growth factor (PlGF), contributes to these pathological processes [ 84 ]. This results in maternal endothelial dysfunction and disruptions to the multiorgan system, such as decreased vascular relaxation, systemic inflammation, and thrombus formation [ 84 ]. Together, these events lead to the onset of PE and other HDPs with poor outcomes. Women with PCOS have a significantly increased risk of PE, which further exacerbates the associated maternal and fetal complications [ 85 ]. In our previous prospective observational study of 92 pregnant women with PCOS, 15 patients (16.3%) were diagnosed with PE during follow‐up throughout pregnancy [ 4 ]. Compared with women without PCOS, women with PCOS have an increased risk of CVD and a higher risk of developing pregnancy‐induced hypertension (PIH) and PE during pregnancy [ 86 ]. Potential risk factors for PE in women with PCOS, including low SHBG levels before pregnancy, overweight/obesity, and hyperinsulinemia, were identified and may be associated with subsequent PE in PCOS patients [ 4 ]. Current research shows no direct evidence linking PCOS to the onset of HDP, such as PE. However, numerous studies indicate that cardiovascular risk factors, including IR, dyslipidemia, and inflammation, are prevalent in PCOS patients and are associated with the development of GH [ 87 ]. Moreover, hyperandrogenism and IR in PCOS patients may affect the normal development and function of the placenta. The high‐hormone environment in Kaohsiung may lead to resistance of the endometrium to progesterone, thereby affecting the process of decidualization [ 88 ]. IR not only affects glucose metabolism but may also indirectly impact placental development and function by affecting the expression of growth factors and other signaling molecules [ 89 ]. Additionally, other serious pregnancy complications, such as miscarriage and fetal growth restriction, are also considered. A meta‐analysis was conducted up to July 13, 2022, and included 106,690 PCOS and non‐PCOS participants from 104 studies [ 90 ]. In addition to GDM and PE, pregnancy‐related issues including miscarriage and intrauterine growth restriction (IUGR) are more common in women with PCOS [ 90 ].

In a meta‐analysis by Faustino et al., circulating kisspeptin (KP) levels were found to be higher in nonpregnant women with PCOS compared to healthy nonpregnant controls [ 28 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 ], with elevated KP levels closely associated with hyperinsulinemia [ 165 ]. However, a few studies reported no significant differences in KP levels between PCOS patients and healthy women [ 166 , 167 , 168 , 169 ] (Table  1 ). Comparative analysis of kisspeptin levels in nonpregnant PCOS patients and healthy controls. n  = 87 BMI 25.59 ± 0.65 n  = 42 BMI 24.88 ± 0.89 n  = 28 BMI 33.02 ± 0.56 n  = 28 BMI 20.63 ± 0.26 n  = 13 BMI 32.13 ± 1.85 Adolescent PCOS n  = 19 BMI 21.46 ± 4.60 Adult PCOS n  = 21 BMI 27.60 ± 3.47 Adolescent n  = 20 BMI 20.11 ± 2.31 BMI < 23 n  = 33 BMI 20.23 ± 2.19 BMI ≥ 23 n  = 21 BMI 27.60 ± 3.47 n  = 36 BMI 19.77 ± 1.51 n  = 83 BMI 24.5 (18.1–34.8) n  = 66 BMI 23.1 (18–34.8) n  = 250 BMI 24.32 ± 3.40 n  = 150 BMI 23.44 ± 4.08 High ovarian reserve group (PCOS) n  = 60 BMI 26.34 ± 4.69 Normal ovarian reserve group n  = 57 BMI 26.34 ± 4.69 n  = 28 BMI 46.04 ± 7.3 n  = 30 BMI 36.6 ± 8.17 n  = 29 BMI 28.6 ± 5.08 n  = 27 BMI 26.4 ± 3.32 n  = 55 BMI 26.89 ± 0.716 n  = 110 BMI 25.25 ± 0.344 n  = 105 BMI 28.4 ± 7.872 n  ± 90 BMI 27.73 ± 6.37 n  = 73 BMI 26.52 ± 5.97 n  = 63 BMI 22.29 ± 4.31 n  = 60 BMI 26.05 ± 3.76 n  = 40 BMI 25.93 ± 3.7 n  = 104 BMI 29.4 ± 5.9 n  = 109 BMI 29.9 ± 7.3 NS Higher ( p  = 0.415) n  = 70 BMI 24.53 ± 5.22 n  = 58 BMI 22.78 ± 3.48 NS Higher ( p  > 0.05) Note: Diagnostic criteria: Rotterdam (most), NIH‐NICHHD/ESHRE/ASRM (some). Kisspeptin levels were elevated in PCOS vs. controls (14/19 studies), with nonsignificant differences (NS) in 3 studies and lower levels in one. Abbreviations: BMI, body mass index; ESHRE/ASRM, European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine; NIH‐NICHHD, National Institutes of Health–National Institute of Child Health and Human Development; NS, non‐significant; PCOS, polycystic ovary syndrome. The role of KP in PCOS appears complex based on current evidence. Most studies support that KP levels are elevated in PCOS patients, consistent with the hyperinsulinemia and increased luteinizing hormone (LH) levels commonly observed in this population, which contribute to clinical manifestations such as amenorrhea and ovulatory dysfunction. KP exhibits distinct fluctuations throughout the menstrual cycle, with lower levels during the first 5 days and two peaks around Days 11 and 14, corresponding to the development of dominant follicles and pre‐ovulatory preparation [ 123 ]. KP likely plays a critical role in this process by regulating gonadotropin‐releasing hormone (GnRH) secretion, leading to elevated LH levels and consequent ovarian androgen overproduction, which underlies typical PCOS symptoms. However, Elham et al. reported that KP levels in PCOS patients were lower than those in healthy women [ 172 ], and in some studies, significant variations in KP levels were not detected between PCOS patients and healthy women [ 166 , 167 , 168 , 169 , 171 ]. These inconsistencies may stem from differences in study design, sample size, age, PCOS phenotypes, and diagnostic criteria. Additionally, KP levels vary with diurnal rhythms and physiological factors such as menstrual cycle, body weight, and insulin sensitivity. Due to PCOS heterogeneity, KP levels likely differ among individuals, reflecting the syndrome's complex pathophysiology. Abnormal levels of KP are particularly important in the discussion of pregnancy problems in PCOS patients (Table  2 ). Changes in KP levels are associated with different trends in pregnancy complications, such as HDP, IUGR, preterm birth (PTB), and GDM. Studies have shown that KP levels in HDP patients during the third trimester are significantly higher than those in controls, whereas levels in IUGR patients are lower [ 8 ]. Furthermore, a positive correlation was observed between plasma KP levels and the likelihood of developing HDP, with a 30% increase in risk per 1 nmol/L increase, whereas the risk of IUGR decreased by 28% with the same increase in KP concentration [ 8 ]. Pregnancy‐specific median KP values were higher in PTB‐affected pregnancies, but this was not significant according to the multivariate analysis [ 8 ]. KP levels are lower in patients with GDM [ 140 , 150 ]. These findings support the potential of KP as a marker of pregnancy complications, although its mechanism of action may differ according to the complication. Circulating kisspeptin levels associated with pregnancy complications. n  = 20 391 (152–951) * n  = 20 5783 (3168–9953) Plasma at 7–18 weeks KP‐10 n  = 50 0.42 ± 0.39 * n  = 899 1.06 ± 0.42 Plasma at 7–14 weeks All KP forms n  = 30 215.11 ± 34.14 * n  = 28 296.23 ± 12 Serum before pregnancy All KP forms n  = 20 0.20 (0.07–0.37) * n  = 20 1.50 (0.55–3.72) Serum at 6–10 weeks KP‐54 n  = 28 434.9 ± 215.1 n  = 47 420.9 ± 201.5 Serum at 14 days after embryo transfer KP‐54, KP‐10 n  = 21 No significant difference n  = 28 No significant difference Serum at 12 days after blastocyst transfer All KP forms n  = 95 0.21 (0.08–0.47) * n  = 265 1.00 (0.63–1.31) Plasma every 2 weeks between 6 and 14 weeks All KP forms n  = 30 102.5 (79.5–123.5) n  = 30 86.7 (69.5–112.4) Serum at 7–9 weeks KP‐54 n  = 23 0.11 (0.08–0.16) * n  = 23 1.48 (1.29–1.80) Serum at 5–6 weeks KP form unclear n  = 24 356.59 (307.85–468.91) n  = 145 397.70 (313.72–512.60) Serum at 5 weeks KP form unclear n  = 25 4.51 ± 3.18 * n  = 20 10.33 ± 2.65 Plasma at 21–25 weeks KP‐10, KP‐14, KP‐54 n  = 26 889.9 ± 96.6 * n  = 62 1270.9 ± 67.1 Plasma at 26–34 weeks KP form unclear n  = 76 187.6 ± 132.3 n  = 82 161.3 ± 78.2 Serum at 24–28 weeks KP‐54 n  = 35 Lower but no difference Plasma at < 9, 9–13, 14–27, and 28–40 weeks KP‐10, KP‐14, KP54 PE ( n  = 57) 1109 (442–3903)* n  = 317 1188 (494–2298) Serum at 16–20 weeks KP‐54 PE ( n  = 9) 3519 ± 357 PIH ( n  = 78) 2696 ± 299 n  = 78 2878 ± 157 Plasma at 27–40 weeks KP‐10, KP‐14, KP‐54 Severe PE ( n  = 24) 1.17 ± 0.24 * Mild PE ( n  = 15) 2.61 ± 0.40 * n  = 50 9.69 ± 1.35 Plasma at 33–37 weeks KP‐10, KP‐14, KP‐54 PE ( n  = 28) 4.46 ± 3.73* PIH ( n  = 18) 8.46 ± 6.24 * n  = 25 10.33 ± 2.65 Plasma at 21–25 weeks KP‐10, KP‐14, KP‐54 n  = 7 Lower in obese PE compared to uncomplicated obese and controls Plasma at 16, 28,and 36 weeks KP form unclear PE ( n  = 31) 1554 ± 385 * n  = 30 1995 ± 375 Plasma at 11–14 weeks KP form unclear Early‐onset PE ( n  = 19) 0.58 ± 0.39 * n  = 30 1.66 ± 0.59 ng/mL Serum at 32–39 weeks KP‐10 Severe PE ( n  = 21) 2.39 Mild PE ( n  = 39) 2.16 ± 0.48 * n  = 40 2.95 ± 1.82 Plasma at 28–40 weeks KP‐10 PE ( n  = 20) 3519 ± 357 (NS) PIH ( n  = 12) 2696 ± 299 (NS) Plasma at 9, 913, 14–27, and 28–40 weeks KP‐10, KP‐14, KP‐54 n  = 31 1376 ± 1317 * n  = 31 2035 ± 1260 Plasma at 8–14 weeks KP‐10 Ab n  = 118 1164 (442–3903) * n  = 317 1188 (494–2298) Serum at 16–20 weeks KP‐54 n  = 10 1630 ± 300 * n  = 10 2900 ± 600 Serum at 34–38 weeks KP‐10 n  = 17 KP lower in FGR than controls Plasma at < 9, 913, 14–27, and 28–40 weeks KP‐10, KP‐14, KP‐54 n  = 45 79.4 (3.9–230.2) * n  = 45 39.8 (0.4–188.3) Note: Kisspeptin isoforms measured: KP‐10, KP‐14, KP‐54, or unspecified forms. Biospecimen types: plasma or serum. Sampling timepoints varied across gestational weeks (5–40 weeks). Abbreviations: FGR, fetal growth restriction; GDM, gestational diabetes mellitus; KP, kisspeptin; NS, non‐significant; PE, preeclampsia; PIH, pregnancy‐induced hypertension. p  < 0.05. On the other hand, KP can promote glucose‐dependent insulin secretion by binding to the KP receptor KISS1R on pancreatic β cells [ 145 , 188 ]. Changes in hormone levels during pregnancy may lead to physiological IR. A decrease in placental KP production resulting in an inadequate balance may contribute to the development of GDM [ 150 , 189 ], as evidenced by a prospective study [ 140 ]. In particular, KP may play a key role in regulating IR [ 190 ]. By affecting the insulin signaling pathway or regulating insulin release, KP may influence the occurrence and development of IR, thereby increasing the risk of GDM [ 188 ]. Therefore, there is a close connection between PCOS, KP, and GDM, in terms of not only reproduction but also metabolic regulation. The literature suggests a negative correlation between KP levels and IR indicators such as homeostasis model assessment (HOMA)‐IR and serum insulin levels [ 7 ]. In patients, PCOS is often accompanied by IR. When their KP levels were examined in a stratified analysis by BMI, KP levels in patients with obesity were found to be significantly reduced [ 151 , 191 ], and this decreased over the course of the pregnancy. It is not yet clear whether these changes in levels play a role in the increased incidence of GDM. The human placenta is an extremely complex organ that provides a protective interface between the maternal and fetal circulatory systems, thereby eliminating waste and delivering nutrients to the developing embryo. It mediates the exchange of metabolic substances between the maternal and fetal bloodstreams [ 29 ]. Furthermore, the placenta secretes hormones into the circulation of both the mother and fetus to regulate various processes associated with gestation, such as metabolism, fetal development, parturition, and other functions connected to pregnancy [ 192 ]. Early studies have shown that in humans, the expression levels of KP and KISS1R are elevated in the placenta [ 91 ] during early pregnancy, with a subsequent decline as placental maturation progresses. However, some studies have shown that KISS1 expression is higher in early pregnancy than in late pregnancy and that KISS1R expression gradually decreases during placental maturation [ 144 , 193 , 194 ]. Collectively, these findings provide important clues for understanding the role of KP in placental development and function. A critical aspect of successful embryo development is proper implantation of the placenta, which serves as a vital connection between the mother and the embryo [ 195 ]. Although the exact role of KP in embryo implantation is not fully understood, the significant increase in circulating KP levels during early pregnancy [ 127 ], as well as the changes in Kiss1 and Kiss1R expression in the uterus and placenta [ 93 ], indirectly supports the role of the KP system in the embryo implantation process. By regulating these key factors, KP may play an important role in regulating embryo implantation and mother–embryo interactions, thereby contributing to the maintenance of a healthy pregnancy [ 29 ]. Dysregulation of endometrial receptivity and embryo implantation can directly affect placental development. Therefore, KP, which is primarily derived from the placenta, may be impaired due to abnormal placental development and could also influence placental quality [ 196 ]. Both GDM and GH are associated with macroscopic and microscopic morphological pathological changes in the placenta, including calcification, fibrin deposition, placental infarction, and altered vascular density [ 195 , 197 , 198 , 199 ]. These changes, as determined by histological and immunohistochemical techniques, affect the nutrient supply to the fetus, thereby affecting its growth and development [ 199 ]. Specifically, GDM is often associated with increased vascular density and villous vascular hyperplasia, whereas GH is associated with decreased vascular density and incomplete spiral artery remodeling, which may lead to placental hypoxia and impaired fetal development [ 199 ]. Here, we propose several hypotheses regarding KP in PCOS patients. First, the KP signaling pathway may be dysfunctional and unable to effectively promote embryo implantation or pregnancy maintenance. Additionally, there may be abnormalities in the expression of the Kiss1 or Kiss1r genes or abnormal regulation of other members within the signaling pathway, limiting the effectiveness of KP in regulating embryo implantation and maintaining pregnancy in PCOS patients. Second, PCOS is often accompanied by other endocrine disorders, such as hyperinsulinemia and hyperandrogenism, which can interfere with the normal function of KP. Finally, metabolic disorders in PCOS patients, such as IR and obesity, may affect KP function through a complex endocrine–metabolic network. These results underscore the importance of thoroughly evaluating the role of KP signaling and its interplay with other endocrine and metabolic variables in the care and therapeutic interventions used to manage PCOS patients, with the aim of enhancing pregnancy outcomes and safeguarding the health of both the mother and fetus. In summary, abnormal KP levels in PCOS patients can hinder embryo implantation and placental development, affecting endometrial receptivity and proper embryo attachment. This dysfunction, which is influenced by hyperinsulinemia, hyperandrogenism, IR, and obesity, increases the risk of pregnancy complications such as GDM. The evidence shows that PCOS patients have higher KP levels than healthy women and that higher KP levels are correlated with symptom severity and metabolic complications. We speculate that maintaining kisspeptin (KP) levels within an appropriate threshold before pregnancy is crucial to ensure endometrial receptivity, embryo implantation, and placental development. Deviations from this threshold may lead to infertility, miscarriage, and placental maldevelopment. Achieving this balance can be approached through a combination of lifestyle interventions and exogenous medical strategies. Lifestyle changes, such as dietary modification, regular physical activity, circadian rhythm, and weight management, are fundamental to regulating KP levels [ 200 , 201 ]. These interventions align with the 2023 International Guidelines for PCOS [ 12 ], which emphasize the importance of pre‐pregnancy lifestyle changes in reducing pregnancy complications. For example, maintaining a BMI within the range of 18.5–24.9 kg/m 2 , ensuring adequate intake of essential nutrients, and adhering to a regular sleep–wake cycle can help stabilize KP secretion and restore the physiological pulsatility of the HPG axis [ 201 , 202 ]. In cases where lifestyle interventions alone are insufficient, exogenous interventions such as KP analogs or antagonists may be considered. KP analogs (e.g., KP‐54) have shown promise in stimulating GnRH release and improving reproductive outcomes in conditions like hypogonadotropic hypogonadism (HH) or during assisted reproductive techniques [ 203 ]. Conversely, KP antagonists (e.g., p‐271) could be used to manage conditions like precocious puberty or endometriosis by modulating excessive KP signaling [ 97 ]. However, the long‐term safety and efficacy of these pharmacological approaches require further investigation, particularly regarding their impact on bone density, cardiovascular health, and tissue‐specific effects [ 20 ]. Additionally, KP may serve as a potential biomarker for predicting gestational complications [ 9 , 40 , 127 , 160 , 164 , 176 , 178 , 204 , 205 ]. Monitoring KP levels before and during early pregnancy could help identify women at risk for preeclampsia, fetal growth restriction, or spontaneous preterm birth. This predictive capability could enable targeted interventions to mitigate risk and improve outcomes. Combining KP monitoring with existing prenatal screening strategies could improve the accuracy of risk assessment and intervention planning.

In this narrative review, the existing research results on the relationships among PCOS, KP, and pregnancy complications are summarized. The search covered the period from the inception of each database to October 2023. Keywords included “Kisspeptin,” “KISS1,” “KISS1R,” “Metastin,” “GPR54,” “Polycystic Ovary Syndrome,” “PCOS,” “polycystic ovarian syndrome,” “Stein–Leventhal Syndrome”; “Pregnancy,” “Gestation,” “Prenatal,” “Antenatal”; and “Gestational Diabetes Mellitus,” “GDM,” “Preeclampsia,” “PE,” “Hypertensive Disorders of Pregnancy,” “Miscarriage,” “Preterm Birth,” “Fetal Growth Restriction,” “Placental Dysfunction,” and “Gestational Hypertension.” Boolean operators (AND, OR) and truncation symbols (*) were used to construct the search strategy. The retrieved records were imported into EndNote for deduplication and screening. Inclusion criteria were studies focusing on the association between kisspeptin and pregnancy complications in women with PCOS. Exclusion criteria included studies unrelated to the topic, those not addressing pregnancy complications, or non‐English publications. The final selected studies were analyzed to explore the mechanisms of kisspeptin in pregnancy complications among women with PCOS.

Regulating KP levels is essential for optimizing reproductive and pregnancy outcomes in PCOS. Additionally, KP holds promise as a biomarker for predicting gestational complications, enabling early identification of at‐risk individuals and timely interventions to reduce maternal and perinatal morbidity and mortality. This review highlights the critical role of KP in PCOS and pregnancy complications, such as GDM and HDP. Abnormal KP levels in PCOS are associated with impaired embryo implantation, placental dysfunction, and metabolic disturbances, which collectively contribute to adverse pregnancy outcomes. However, the intricate regulatory mechanisms of KP during pregnancy and its interactions with endocrine and metabolic factors remain incompletely understood. Further research is needed to elucidate these mechanisms and develop more effective prevention and treatment strategies. Future research should focus on the following key areas: Mechanistic insights: Clarify the specific role of KP in the pathogenesis of PCOS and pregnancy complications, including its interactions with hormonal and metabolic pathways. Biomarker potential: Investigate the utility of KP level changes as early predictive biomarkers for pregnancy complications in PCOS patients, enabling personalized risk assessment and intervention. Therapeutic applications: Explore the potential of KP‐targeted therapies, such as tissue‐specific KP analogs or antagonists, in improving reproductive and pregnancy outcomes. Mechanistic insights: Clarify the specific role of KP in the pathogenesis of PCOS and pregnancy complications, including its interactions with hormonal and metabolic pathways. Biomarker potential: Investigate the utility of KP level changes as early predictive biomarkers for pregnancy complications in PCOS patients, enabling personalized risk assessment and intervention. Therapeutic applications: Explore the potential of KP‐targeted therapies, such as tissue‐specific KP analogs or antagonists, in improving reproductive and pregnancy outcomes. By addressing these research priorities, we can advance our understanding of KP.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder known for its complex pathogenesis involving disordered follicular development, hypothalamus–pituitary–ovary (HPO) axis dysfunction, hyperandrogenism, and insulin resistance (IR) [ 1 ]. PCOS, initially characterized by Stein and Leventhal as a form of amenorrhea accompanied by hirsutism, acne, and obesity, poses significant risks to women's reproductive health, particularly during the childbearing years [ 2 ]. Individuals with PCOS have a high risk of gestational complications such as hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), impaired placental function, and subsequent intrauterine fetal growth restriction (IUGR). Our previous studies revealed that the morbidity rates of GDM and preeclampsia (PE) among individuals with PCOS were 32.98% [ 3 ] and 16.3% [ 4 ], respectively. In comparison, the incidence rates in the general adult population ranged from 2.7% to 27% and 3% to 6%, emphasizing the need to explore the underlying mechanisms triggering these complications in PCOS pregnancies. Kisspeptin (KP) is widely expressed in a variety of tissues, including the hypothalamus, limbic system, gonads, pancreas, and liver. Notably, it is abundantly expressed in the placenta and is therefore thought to play an important role in pregnancy [ 5 , 6 ]. After extensive research, scientists have reported notable variations in peripheral KP levels between women experiencing gestational complications and women in the control group of pregnancies [ 7 , 8 , 9 ]. Despite the preliminary evidence provided by this finding, little is known about how serum KP levels fluctuate throughout pregnancy in patients with PCOS and the association between this variation and the development of pregnancy complications. Therefore, the aim of the current review is to explore the role of KP in PCOS and the association between abnormal KP levels and pregnancy complications in women with PCOS. In this review, we hope to offer new ideas for managing and preventing pregnancy complications that can serve as a valuable reference for future research and clinical practice in PCOS (Figure  1 ). Proposed mechanisms of kisspeptin in PCOS pathophysiology and pregnancy‐related complications. Kisspeptin neurons and KNDY neurons modulate gonadotropin secretion, influencing luteinizing hormone (LH), follicle‐stimulating hormone (FSH), anti‐Müllerian hormone (AMH), and estradiol (E2) levels, thereby affecting ovulatory function. Hyperandrogenism and insulin resistance, common features of PCOS, exacerbate metabolic disturbances and may negatively impact pregnancy outcomes. The kisspeptin/KISS1R signaling axis is implicated in regulating endometrial receptivity—via LIF signaling, cell adhesion molecules, and matrix metalloproteinases (MMPs)‐ and enhancing glucose‐stimulated insulin secretion (GSIS) through pancreatic β‐cell modulation. Additionally, KP interacts with inflammatory markers, adipose tissue, prolactin, cortisol, and metabolic peptides such as GLP‐1, indicating a broader role in glucose metabolism during pregnancy. The schematic also includes the structural depiction of kisspeptin peptides, highlighting the relationship between their molecular architecture and physiological function (Created in BioRender. https://BioRender.com ).

The authors declare no conflicts of interest.

In the previous section, we elaborated on the pathophysiology, clinical characteristics, and challenges of PCOS, especially its pregnancy complications. As a neuropeptide, KP not only plays a fundamental role in the regulation of the female HPO axis but also directly participates in key pregnancy processes, such as embryo implantation, placenta formation, and metabolic regulation. Therefore, in this section, we review the physiological and pathological mechanisms of KP during pregnancy. KPs are peptide products of the KISS1 gene, a human metastasis suppressor gene that was initially discovered in 1996 [ 91 ]; however, subsequent research has revealed its involvement in a distinct biological pathway unrelated to cancer biology. The KISS1 gene, located on chromosome 1q32, encodes a precursor polypeptide consisting of 145 amino acids [ 92 ]. This precursor is posttranslationally cleaved to produce various physiologically active KP peptides, which are denoted by suffixes such as ‐54, ‐14, ‐13, and ‐10 [ 5 , 92 , 93 ]. After years of investigation into the mechanisms behind KP, it has emerged that this molecule plays a key role in the female reproductive system, serving as a key component in the complex network of neurotransmitters and neuropeptides that regulate the activity of the HPG axis [ 21 , 22 ]. KP is primarily synthesized in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) of the hypothalamus, where it is expressed in specific neuronal populations [ 94 ]. KP binds to KISS1Rs on GnRH neurons to facilitate the release of GnRH into the portal circulation. Following KP antagonist injection, the pulse rhythm of GnRH secretion is affected, KP‐induced GnRH neuron firing is inhibited, and average GnRH levels decrease [ 95 , 96 , 97 ]. KP determines the initiation of the pubertal gonadal axis and the maintenance of gonadal hormones through the regulation of GnRH neurons and is involved in the pathophysiologic processes of several disorders related to reproductive and metabolic functions, such as congenital hypogonadotropic hypogonadism (CHH), central precocious puberty (CPP), and PCOS [ 20 ]. Numerous studies have demonstrated that, in addition to its regulatory role inside the hypothalamus, KP has potential pathophysiological effects [ 94 , 98 , 99 , 100 ] that occur via autocrine/paracrine means in several systems [ 29 ], including the hippocampus, forebrain, ovary, uterus, placenta, testis, adipose tissue, pancreas, and liver, especially in diseases involving reproductive and metabolic functions [ 101 , 102 , 103 , 104 , 105 , 106 , 107 ]. KP plays a significant role in the pathophysiology of PCOS. Research indicates that the FSH and LH dynamics of individuals with PCOS are disrupted; this disruption is characterized by elevated LH/FSH ratios [ 108 , 109 ], leading to irregular menstrual cycles and impaired ovulation. These abnormalities with hyperandrogenemia lead to increased levels of AMH and follicular developmental arrest [ 109 ], both of which impact reproductive function [ 110 ]. KP neurons play a central role in regulating the pulsatile secretion of GnRH by coexpressing neurokinin B and dynorphin to form “KP‐Neurokinin B‐Dynorphin” (KNDy) neurons [ 111 ] while also mediating negative feedback from estradiol (E2) [ 27 ]. Excessive release of LH is caused by elevated expression levels of KP and its receptors in the hypothalamus, according to previous studies [ 112 , 113 ]. Overproduction of LH causes ovarian follicular membrane cells to produce more testosterone; however, because comparatively less FSH is present, there is less granular aromatization of testosterone to E2, which results in hyperandrogenism, a characteristic of PCOS [ 10 ]. Therefore, the pathophysiology of PCOS is significantly influenced by increased KP production. In addition to its effects on KP production and release, hyperandrogenism also causes irregularities in GnRH and LH pulse frequencies because it interferes with progesterone's negative feedback control of KNDy neurons [ 114 ]. Furthermore, studies in animals have shown that KP is linked to genetic variations associated with PCOS, which may have an impact on the functionality of KP and its receptors [ 115 , 116 ]. In conclusion, KP regulates GnRH release and affects sex hormone levels, which play an important role in the pathophysiology of PCOS. KP also has a certain effect on energy homeostasis, but the mechanism remains unclear. Existing evidence suggests that KP affects energy homeostasis directly by modulating connections and feedback between key appetite‐regulating neurons [ 117 , 118 ] and indirectly through connections with energy‐regulating hormones, especially during pregnancy [ 119 , 120 , 121 ]. The correlations between KP and energy‐regulating hormones, food intake, body weight, and fat mass were also confirmed in a study by Tolson et al. [ 122 ]. Impaired KP signaling may lead to a reduced metabolic rate and decreased energy expenditure, thereby promoting increased fat accumulation, ultimately leading to the development of obesity [ 122 ]. The impact on glucose metabolism may lead to reduced glucose tolerance and is related to chronic low‐grade inflammation caused by obesity [ 122 ]. Kisspeptin (KP) and its receptor KISS1R play an important role in regulating endometrial receptivity and embryo implantation. In reproductive‐aged women, serum KP levels fluctuate across the menstrual cycle, rising sharply during the late secretory phase in parallel with endometrial decidualization. KP expression is minimal during the proliferative and early secretory phases but increases significantly in the late secretory phase, aligning with dominant follicle development and rising sex steroid levels. This dynamic has been confirmed in animal models and highlights KP's involvement in preparing the endometrium for placental formation [ 123 , 124 ]. In previous studies, KP levels were reportedly elevated in PCOS patients compared with healthy women. This finding suggested that the regulatory mechanism of KP in PCOS patients might differ from that in normal women of childbearing age and might have different effects on embryo implantation and endometrial receptivity. During early pregnancy, cellular activities in the placental villi are crucial because these activities directly affect the success of embryo implantation. During this process, cytotrophoblasts interact with the maternal decidualized endometrium and differentiate into extravillous trophoblasts (EVTs), forming the so‐called cell column structure, which enables EVTs to acquire the ability to penetrate the decidualized endometrium [ 124 ]. Moreover, cytotrophoblasts in floating villi differentiate into multinucleated syncytiotrophoblasts, which participate in the exchange of gases and nutrients [ 125 ]. In this complex process, KP plays a key role as an important regulatory factor. Studies have shown that KP is expressed in the stromal cells of the decidualized endometrium, whereas KISS1R is expressed in cytotrophoblasts [ 126 , 127 ]. In the BPH/5 mouse model, the expression levels of KP and KISS1R increased significantly during the peak decidualization period of the endometrium. This process is also related to the inhibition of trophoblast invasion by the endometrium and the promotion of decidualization [ 128 ]. KP regulates the receptivity of the endometrium to the embryo by binding to its receptor, namely, KISS1R. In mouse endometrial tissue, KP triggers the phosphorylation of p38 and ERK1/2 in the uterus on the fourth day of pregnancy, suggesting the potential impact of KP/KISS1R on the function of the mouse endometrium [ 129 ]. In another study, conditional uterine Kiss1r knockout (KO) mice revealed that although these knockout female mice presented normal ovarian function after mating with stallions, their implantation sites were abnormal. As a result, the litter size decreased, and neonatal mortality increased [ 130 ]. These results indicate that KISS1R in the uterus is required for successful embryo implantation and healthy pregnancy. Further research revealed that KISS1R in the uterus plays an important regulatory role by inhibiting the overexpression of ERα and preventing the harmful effects of high ERα activity on the implantation process [ 130 ]. KP is produced in high quantities by the placenta during pregnancy, remains markedly raised throughout the gestational period, and is positively correlated with gestational age [ 8 ]. The placenta is a major source of KP throughout pregnancy, as evidenced by a notable reduction in levels during the first 5 days postpartum [ 127 ]. Previous studies have shown that KP treatment increases the adhesion of mouse blastocysts to collagen [ 131 ], which may be achieved by downregulating the activity of MMPs (MMP‐2 and MMP‐9) through the ERK1/2 and protein kinase C signaling pathways [ 131 , 132 , 133 ]. These studies suggest that the KP/KISS1R system acts on the blastocyst and the endometrium to promote the embryo implantation process. In the Kiss1(−/−) mouse model, deficient expression of leukemia inhibitory factor (LIF) in uterine glands on the day of implantation was observed, and exogenous LIF partially restored implantation in hormone‐treated Kiss1(−/−) female mice [ 134 ]. LIF is another cytokine essential for implantation in mice [ 135 , 136 ] and is secreted by the uterine glands to facilitate embryo–uterine communication, leading to embryo attachment and the onset of stromal cell decidualization [ 137 ]. These data suggest that KP is an upstream regulator of LIF and that KP affects implantation by increasing LIF levels. However, in Kiss1 knockout mice, although LIF partially reversed implantation failure, estradiol (E2) failed to achieve this effect, suggesting that kiss1 may act downstream of E2 or work in concert with E2 to trigger LIF expression. In summary, the E2–KP–LIF pathway plays a key role in regulating implantation [ 29 ]. Several studies have demonstrated that the levels of KP are lower in women with PE than in those with uncomplicated pregnancies [ 9 , 138 , 139 , 140 , 141 , 142 , 143 ]. This further validates its ability to inhibit MMP‐2 and MMP‐9 [ 144 ] and its impact on angiogenesis and the establishment of uterine spiral arteries [ 139 ]. These findings support the role of KP in the pathophysiology of PE. KP also plays a role in implantation because it increases stromal metaphase by upregulating LIF [ 29 ] and facilitates embryo attachment to the endometrium through interactions with cell adhesion molecules. The fetus requires glucose, free fatty acids, and amino acids for optimal development during pregnancy. To obtain these nutrients, IR occurs during normal pregnancy. This necessitates the occurrence of IR, a gradual process induced by maternal overweight and elevated levels of hormones such as prolactin, cortisol, progesterone, growth factors, and human placental lactogen. In healthy mothers, compensation for IR can occur by increasing the production and release of insulin to maintain blood glucose levels. However, due to the pathological mechanism of IR, patients with PCOS experience a more difficult compensatory process than healthy women do, and this process leads to a high incidence of GDM. The impact of the KP system on metabolism can be analyzed from two directions: On the one hand, KP promotes the release of insulin [ 145 ]; on the other hand, KP may increase the sensitivity of insulin receptors [ 146 ], thereby compensating for IR to a certain extent. These mechanisms may be particularly important for PCOS patients and further explain why PCOS patients are more susceptible to GDM during pregnancy and why regulating the KP system may be a potential strategy to improve their pregnancy outcomes. There is evidence that KP can enhance insulin‐stimulated insulin secretion (GSIS) through direct or indirect means, and this is reflected in the dose of the drug [ 145 , 147 ]. In experiments conducted on INS 832/3 cells and pseudoisland models, KP10, a synthetic 10‐amino acid mimetic of KP, was able to significantly increase GSIS [ 148 ]. The enhanced effect of KP on insulin secretion from pancreatic β‐cells is applicable mainly to specific cell types, namely, those expressing both KP and GLP‐1 (glucagon‐like peptide‐1) receptors [ 149 ]. The coexpression of KP and GLP‐1 receptors on pancreatic beta cells leads to enhanced GSIS through distinct downstream signaling pathways. Although KP alone does not affect insulin secretion in the absence of glucose, it can double GSIS in the presence of glucose, indicating that KP has an enhancing effect on pancreatic β‐cells under specific physiological conditions [ 149 ]. There is currently insufficient evidence that KP increases insulin sensitivity, but studies have shown the potential role of KP in regulating insulin receptor sensitivity [ 146 ]. In their study, prenatal testosterone (T) exposure altered neuropeptide expression in KNDy (coexpressing KP and neurokinin B/dynorphin) and agouti‐related peptide (AgRP) neurons in the arcuate nucleus, both of which coexpressed the insulin receptor β subunit (IRb) [ 146 ]. This process reduced the percentage of KNDy and AgRP neurons that colocalized with IRb, which also matched the reduced insulin sensitivity. In subsequent experiments, the administration of antiandrogen drugs improved the reduction in IRb colocalization in AgRP, but the improvement in IRb colocalization in KNDy neurons was minimal [ 146 ]. Therefore, the study also shows the complexity and uncertainty of the role of KP in this process. In summary, abnormalities in embryo implantation and placental development caused by abnormal KP levels in PCOS patients affect the level of KP produced by the placenta during pregnancy. Owing to the pathological basis of IR that may exist in PCOS patients, the reduction in KP levels during pregnancy [ 140 , 150 ] cannot compensate for the imbalance in blood glucose homeostasis caused by overweight during pregnancy and increased maternal and placental hormones.