Metastin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome

doi:10.1016/j.ejogrb.2014.06.004

European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 180, September 2014, Pages 56-60

https://doi.org/10.1016/j.ejogrb.2014.06.004 Get rights and content

Abstract

Objective

The aim of the present study was to evaluate serum concentrations of metastin in relation with hormonal and metabolic profile in patients with and without polycystic ovary syndrome (PCOS).

Study design

The study was a clinical study. Eighty-three women with PCOS and 66 body mass index (BMI) matched controls were divided into two groups, based on BMI: overweight and obese (BMI ≥ 25 kg/m²) and normal weight. (BMI < 25 kg/m²) Hirsutism scores, hormonal and metabolic profile as well as metastin levels were evaluated in each subject. Blood samples were collected in the early follicular phase (between day 2 and day 5 of the menstrual cycle) at 9:00 AM, after an overnight fast. Circulating levels of LH, FSH, PRL, TSH, T, fT, DHEAS, 17-OH-P, sex hormone-binding globulin (SHBG), insulin, glucose, lipid profile and metastin were measured.

Results

Metastin levels were significantly higher in the PCOS group compared to controls (2.02 ng/ml versus 1.16 ng/ml, p < 0.001). Metastin levels correlated significantly positively with luteinizing hormone (LH), total testosterone (T), dehydroepiandrosteronesulphate (DHEA-SO4) levels, modified Ferriman–Gallwey (mFG) scores and free androgen index (FAI); however, correlated negatively with sex hormone binding globulin (SHBG) levels (p < 0.05). When overweight or obese (BMI ≥ 25 kg/m²) and normal weight (BMI < 25 kg/m²) women with PCOS were compared to body mass index (BMI) matched controls, higher metastin levels were also found in PCOS groups (1.94 ng/ml versus 1.18 ng/ml, and 2.06 ng/ml versus 1.08 ng/ml, p < 0.05, respectively).

Conclusions

These findings suggest that metastin levels were higher in women with PCOS as compared to controls regardless of BMI. Furthermore, metastin levels can be used as a specific marker for androgenic profile and this marker might play a role in the pathogenesis of PCOS.

Introduction

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women, with a prevalence of 6–12% in women of reproductive age [1]. It is characterized by androgen excess, chronic oligoanovulation and polycystic ovaries (PCO) on ultrasound. Clinically, the androgen excess presents as hirsutism and acne, whereas anovulation presents as subfertility and menstrual irregularity. In addition, severe physiological abnormalities such as insulin resistance, inflammation, visceral fat, cardiovascular disease, infertility are common among women with PCOS [2].

Metastin is a 54 amino-acid peptide, which was first isolated from the human placenta in 2001 [3]. It is encoded by the Kiss-1 gene, therefore it is also known as Kiss-1 peptide (kisspeptin) [4]. Metastin action is exerted by a trans-membrane G-protein coupled receptor, named GPR54, AXOR12, or HoT7T175 [3], [4], [5], [6]. Loss of Kiss-1 gene function is reported to be associated with hypogonadotropic hypogonadism in humans and animal models [7], [8]. Metastin has recently been shown to regulate the secretion of luteinizing hormone (LH) during the promotion of ovulation [9] by stimulating gonadotropin releasing hormone (GnRH) release from the hypothalamus [10], [11].

Women with PCOS commonly display deregulated gonadotropin secretion with higher LH pulsatility and perturbed LH/FSH (follicle stimulating hormone) ratios, which likely contributes to the ovarian phenotype and might be indicative of disrupted GnRH secretory activity. Given the complex relationship between metastin and hypothalamic-pituitary gonadal axis, the present study aimed to investigate whether there was a difference in serum metastin levels between women with and without PCOS, a condition associated with aberrant gonadotropin secretion and hyperandrogenemia. This study also set out to correlate serum metastin levels in relation with hormonal and metabolic profile to evaluate the possible correlations between metastin and PCOS-related reproductive and metabolic disturbances.

Section snippets

Materials and methods

The design of the present study was approved by the ethical committee and institutional review board of Selcuk University, Faculty of Medicine, where the study was conducted. Written informed consents were obtained from all participants. A total sample size of 88 (22 cases for each group) was required to detect at least 0.58 (ng/ml) difference in metastin levels between groups with a power of 80% at the 5% significance level. The difference of 0.58 (ng/ml) was taken from both pilot study and

Results

Demographic, clinical, biochemical and hormonal characteristics of women with PCOS and controls are summarized in Table 1. Age, fasting insulin, T, fT, DHEA-SO4, LH levels and mFG and FAI scores were significantly higher, whereas SHBG and fasting plasma glucose levels were lower in PCOS group compared to controls (p < 0.05). Metastin levels were also found to be higher in women with PCOS than controls (2.02 [056–443] ng/ml versus 1.16 [045–200] ng/ml, p < 0.001) (Fig. 1). Table 2 shows the

Discussion

The Kiss-1 system has emerged in the recent years as a fundamental player in the control of the reproductive axis, with essential roles in differentiation and pubertal activation of the reproductive system as well as key functions in the regulation of ovulation and the metabolic control of fertility. These features make it tempting to predict that alterations of this system might result in substantial perturbations of the gonadotropic axis, some of which may resemble those seen in PCOS [16]. As

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Ovarian cancer and KiSS-1 gene expression: A consideration of the use of Kisspeptin plus Kisspeptin aptamers in diagnostics and therapy
2022, European Journal of Pharmacology
Gynaecological cancers continue to present a significant health burden upon the health of the global female population. This deficit is most prominent with ovarian cancer which possesses the lowest survival rate compared to all other cancers occurring within this anatomical region, with an annual UK-mortality of 7,300. The poor tolerability and selectively of the treatment options that are currently available is likely to have contributed to this high mortality rate thus, demonstrating the need for the development of enhanced therapeutic approaches. Aptamer technology would involve the engineering of specifically sequenced oligonucleotide chains, which bind to macromolecular targets with a high degree of affinity and selectively. Recent in-vitro studies conducted upon the clinical utility of this technique have supported its superiority in targeting individual therapeutic drug targets compared to various other targeting moieties currently within therapeutic use such as, monoclonal antibodies. For this reason, the employment of this technique is likely to be favourable in reducing the incidence of non-specific, chemotherapy-associated adverse effects. Kisspeptin is a naturally expressed polypeptide with an established role in the development of the reproductive system and other proposed roles in influencing the ability of ovarian cancer growths to exhibit the metastasis hallmark. This distinctive feature would indicate the potential for the manipulation of this pathway through the application of aptamer structures in developing a novel prophylactic strategy and improve the long-term outcome for ovarian cancer patients.
Circulating kisspeptin and anti-müllerian hormone levels, and insulin resistance in women with polycystic ovary syndrome: A systematic review, meta-analysis, and meta-regression
2021, European Journal of Obstetrics and Gynecology and Reproductive Biology
Citation Excerpt :
PCOS sample sizes across studies ranged from 20 [33] to 250 [37]. The PCOS diagnosis followed (i) the Rotterdam criteria in 17 studies [29–43,45–47], and (ii) 1 study was based on the association of chronic anovulation (< 6 cycles in 12 months) with hyperandrogenemia [44]. Six studies were carried out in Turkey [33,37,38,41,42,47], 2 in China [34,46], 2 in Iraq [29,39], and 1 in each of the following countries: Bulgaria [43], Egypt [45], Ghana [31], Greece [44], Korea [40], Kuwait [36], Saudi Arabia [35] and Sri Lanka [32].
This systematic review and meta-analysis aimed to summarize the available evidence regarding circulating kisspeptin and anti-müllerian hormone (AMH) and the homeostasis model assessment of insulin resistance (HOMA-IR) index in adolescents and women with and without polycystic ovary syndrome (PCOS).
We performed a comprehensive literature search in Medline, Embase, Cochrane, Scopus, and Web of Science for studies evaluating circulating kisspeptin levels in women with and without PCOS published until September 24th, 2020. Co-primary outcomes were the HOMA-IR index and AMH. The quality of included studies was assessed using the Newcastle-Ottawa Scale. Random-effects models were used to estimate outcomes, and effects reported as mean difference (MD) or standardized MD (SMD) and their 95 % confidence interval (CI). The systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42020205030.
We evaluated 18 studies including, 1282 PCOS cases and 977 controls. Participants with PCOS were younger (MD = −2.38 years, 95 %CI -4.32 to -0.44), with higher BMI (MD = 1.16, 95 % CI 0.54–1.78), waist-to-hip ratio (MD = 0.04, 95 %CI 0.02 to 0.05), circulating kisspeptin (SMD = 1.15, 95 %CI 0.68–1.62), luteinizing hormone (SMD = 1.29, 95 %CI 0.76–1.83), AMH (SMD = 0.97, 95 %CI 0.60–1,34), total testosterone (SMD = 2.48, 95 %CI 1.73–3.23), free testosterone (SMD = 1.37, 95 %CI 0.56–2.17), and dehydroepiandrosterone sulphate (SMD = 0.72, 95 %CI 0.32–1.13) levels, and Ferriman-Gallwey score (SMD = 5.08, 95 %CI 2.76–7.39), and lower sex hormone-binding globulin level (SMD = −1.34, 95 %CI −2.15 to −0.52). Besides, participants with PCOS had higher HOMA-IR index (SMD = 0.76, 95 %CI 0.35–1.17), and circulating insulin (SMD = 0.75, 95 %CI 0.30–1.19), leptin (SMD = 2.82, 95 %CI 1.35–4.29), and triglycerides (SMD = 2.15, 95 %CI 1.08–3.23) levels than participants without the syndrome. The meta-regression did not identify significant factors influencing circulating kisspeptin.
Patients with PCOS showed higher kisspeptin, LH, insulin, AMH, and androgen levels and HOMA-IR index, and lower sex hormone-binding globulin levels than those without the syndrome.
Pathological pulses in PCOS
2019, Molecular and Cellular Endocrinology
Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder associated with hyperandrogenism and anovulation. Although a spectrum disorder, many women with PCOS exhibit elevated luteinizing hormone (LH) pulse frequency and an elevated LH to follicle stimulating hormone ratio. This aberrant pattern of gonadotrophin signalling drives many of the downstream ovarian features of PCOS, including increased androgen synthesis, and indicates neuroendocrine impairments upstream. Decreased responsiveness to gonadal steroid hormone negative feedback in PCOS patients points toward dysfunction within the gonadotropin-releasing hormone (GnRH) neuronal network in the brain. Excessive androgen exposure during development or over pubertal onset can recapitulate the neuroendocrine pathology of PCOS in pre-clinical models, and these models have been fundamental in beginning to pick apart the specific central mechanisms involved. This mini-review will briefly describe the pathology of PCOS associated with high frequency GnRH/LH pulses and then highlight what is currently known, and yet to be discovered, about the central mechanisms involved.
Circulatory metastin/kisspeptin-1 in polycystic ovary syndrome: a systematic review and meta-analysis with diagnostic test accuracy
2019, Reproductive BioMedicine Online
Citation Excerpt :
The suggested positive correlation between KISS-1 and LH substantiates previous speculation that KISS-1 plays a role in initiating GnRH secretion and the ability of KISS-1 in eliciting LH secretion in vivo (Gottsch et al., 2004; Navarro and Tena-Sempere, 2012). Correlations of KISS-1 with testosterone and DHEAS, however, reflect the hyperandrogenism associated with PCOS (Yilmaz et al., 2014). Owing to the contradicting results reported previously (Panidis et al., 2006; Jeon et al., 2013; Yilmaz et al., 2014; Nyagolova et al., 2016; Ozay et al., 2016; Albalawi et al., 2018), we also did not notice significant correlations between KISS-1 with BMI and insulin resistance in this meta-analysis.
A close association between Kisspeptin-1 (KISS-1) and reproductive physiology has been reported, but the results on circulatory KISS-1 are ambiguous in patients with polycystic ovary syndrome (PCOS). A systematic review and meta-analysis were conducted to evaluate the association between KISS-1 and PCOS, and to test its diagnostic test accuracy (DTA) through DTA meta-analysis.
Relevant studies were identified by searching PubMed and other databases in addition to manual searching of cross-references. Random-effects model was used to obtain standardized mean differences (SMD), pooled correlation coefficients and summary of DTA. Meta-regression and sub-group analyses were conducted to explore heterogeneity. The presence of publication bias was tested using funnel plot analysis.
This meta-analysis finally included 12 studies. Compared with controls, women with PCOS showed significantly increased circulatory KISS-1 levels (SMD = 0.47; P = 0.002). Meta-analysis of correlations showed positive associations between KISS-1 and anti-Müllerian hormone (AMH) (P = 0.03), testosterone (P < 0.001) and dehydroepiandrosterone (P = 0.004). The pooled diagnostic odds ratio and area under curve were 13.71 and 0.835, respectively. A one-study leave-out sensitivity analysis indicated that no single study had a significant influence on the overall outcome, suggesting the robustness of this meta-analysis.
This meta-analysis showed significantly increased KISS-1 level in PCOS, and its association with AMH reflects its role in reproductive physiology. In our DTA meta-analysis, KISS-1 showed good accuracy for PCOS detection. Further large-scale studies are required to establish its validity.
Kisspeptin and body weight homeostasis in relation to phenotypic features of polycystic ovary syndrome; metabolic regulation of reproduction
2019, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Citation Excerpt :
Similar to our result, a study conducted by Gorkem et al. observed that women with PCOS had increased serum KISS levels compared to controls [20]. In agreement with our results, Yilmaz et al. observed metastin (KISS) levels were higher in women with PCOS as compared to controls regardless of BMI [21]. Our findings are in concordance with Katulski et al. who detected a significantly higher KISS pulse frequency as well as integrated serum concentrations group of PCOS patients with oligomenorrhea than the eumenorrheic group of PCOS subjects [22].
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by a diverse collection of reproductive and metabolic abnormalities. kisspeptin (KISS) is novel peptides associated with regulation of metabolism, food intake, puberty and reproduction. The aim of the present study was to estimate KISS level in patients with PCOS, and to evaluate the possible relationship between KISS level with anthropometric measures as well as clinic-morphological features of PCOS.
cross section control study enrolled 90 control group and 105 patients with PCOS and they were stratified according to their body mass index (BMI) to; underweight (n = 9, BMI ˂19), normal weight (n = 25, BMI = 19.1–25), over weight (n = 34,BMI = 25.1–30), obese grade I (n = 12, BMI = 30.1–35) , obese grade II (n = 13, BMI 35.1–40) and obese grade III (n = 12, BMI˃40).Circulating KISS levels were measured using ELISA.
Our results revealed that, KISS levels were higher in PCOS patients compared to controls. Among PCOS group, there were significant lower level of KISS levels in underweight, overweight and obese compared to normal weight group. Even more importantly, KISS levels decreased with increasing of BMI as the following, grade I, grade II and grade III. Moreover, it was negatively correlated to anthropometric measures, glycemic, lipid profile and positively correlated the phenotype characteristics of PCOS. Linear regression test observed that hirsutism score, HOMA-IR and LH were the main predictors of KISS levels in PCOS.
Conclusion: circulating KISS is an important regulator of body weight and reproduction especially in PCOS women.
Is There an Association Between Circulating Kisspeptin Levels and Ovarian Reserve in Women of Reproductive Age?
2023, In Vivo

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Metastin levels in relation with hormonal and metabolic profile in patients with polycystic ovary syndrome

Abstract

Objective

Study design

Results

Conclusions

Introduction

Section snippets

Materials and methods

Results

Discussion

Fertil Steril

Biochem Biophys Res Commun

J Biol Chem

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Am J Obstet Gynecol

Metabolism

Eur J Obstet Gynecol Reprod Biol

Fertil Steril