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BMJ Open Nov 2023Serum prokineticin-1 (s-PROK1) in the second and third trimester of pregnancy is positively correlated to preeclampsia, intrauterine growth restriction (IUGR) and... (Randomized Controlled Trial)
Randomized Controlled Trial
Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials.
OBJECTIVE
Serum prokineticin-1 (s-PROK1) in the second and third trimester of pregnancy is positively correlated to preeclampsia, intrauterine growth restriction (IUGR) and preterm delivery. Women with polycystic ovary syndrome (PCOS) are prone to these adverse pregnancy outcomes. However, the contribution of PROK1 to the development of pregnancy complications and the effect of metformin and hyperandrogenism on s-PROK1 in PCOS have not been studied previously.
DESIGN
This work is a post hoc analysis of two prospective, randomised, placebo-controlled trials.
SETTING
Pregnant women with PCOS were included from 11 study centres in Norway.
PARTICIPANTS
From 313 women, 264 participated in the present study after exclusions due to dropouts or insufficient serum samples.
INTERVENTION
Women with PCOS were randomly administered with metformin or placebo, from first trimester to delivery.
PRIMARY AND SECONDARY OUTCOME MEASURES
s-PROK1 was analysed using ELISA at gestational week 19 and related to pregnancy complications, fasting insulin levels, homoeostatic model assessment for insulin resistance (HOMA-IR), testosterone, or androstenedione levels, metformin use, PCOS phenotype and hyperandrogenism.
RESULTS
Maternal s-PROK1 in the second trimester did not predict pregnancy-induced hypertension, pre-eclampsia or late miscarriage/preterm delivery in women with PCOS. However, s-PROK1 was lower in women who used metformin before inclusion, both in those randomised to metformin and to placebo, compared with those who did not. s-PROK1 was also lower in those who used metformin both at conception and during pregnancy compared with those who used metformin from inclusion or did not use metformin at all. s-PROK1 was lower in hyperandrogenic compared with normo-androgenic women with PCOS.
CONCLUSIONS
Maternal s-PROK1 in the second trimester did not predict pregnancy complications in PCOS. Those who used metformin at conception and/or during pregnancy had lower s-PROK1. PCOS women with hyperandrogenism exhibited lower s-PROK1 compared with normo-adrogenic phenotypes.
TRIAL REGISTRATION NUMBER
NCT03259919 and NCT00159536.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Metformin; Polycystic Ovary Syndrome; Hypoglycemic Agents; Hyperandrogenism; Premature Birth; Prospective Studies; Pregnancy Complications; Pre-Eclampsia; Gastrointestinal Hormones; Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
PubMed: 37989369
DOI: 10.1136/bmjopen-2023-073619 -
European Journal of Endocrinology Sep 2023The essential role of ACTH on the growth and function of the human foetal adrenal (HFA) has long been recognized. In addition, many studies have suggested a role of the...
OBJECTIVE
The essential role of ACTH on the growth and function of the human foetal adrenal (HFA) has long been recognized. In addition, many studies have suggested a role of the pituitary hormone prolactin (PRL) in the regulation of the HFA, but the effects of this hormone on steroidogenesis and gene expression are still unknown. Our objective was to investigate the effect of ACTH and PRL on the steroidogenic capacities of the HFA.
DESIGN
In vitro/ex vivo experimental study.
METHODS
We used a hanging drop in vitro organ culture system. First trimester HFA samples were cultured for 14 days in basal conditions or treated with ACTH, PRL, or a combination of the 2 (3 to 11 replicates depending on the experiment). Steroids were measured by liquid chromatography/tandem mass spectrometry or immunoassay, gene expression by RT-qPCR, and protein expression by immunoblot.
RESULTS
ACTH significantly increased corticosterone, cortisol, and cortisone production, both by itself and when used together with PRL. PRL stimulation by itself had no effect. Combined stimulation with ACTH + PRL synergistically and selectively increased adrenal androgen (DHEAS and Δ4-androstenedione) production and CYP17A1 expression in the HFA, while treatment with each single hormone had no significant effect on those steroids.
CONCLUSIONS
These results have important implications for our understanding of the hormonal cues regulating adrenal steroidogenesis in the HFA during the first trimester in physiological and pathological conditions and warrant further studies to characterize the molecular mechanisms of converging ACTH and PRL signalling to regulate CYP17A1 expression.
Topics: Humans; Prolactin; Androgens; Organ Culture Techniques; Steroid 17-alpha-Hydroxylase; Adrenocorticotropic Hormone
PubMed: 37638769
DOI: 10.1093/ejendo/lvad118 -
The Journal of Steroid Biochemistry and... Oct 2023Polycystic ovary syndrome (PCOS) is defined by androgen excess and ovarian dysfunction in the absence of a specific physiological diagnosis. The best clinical marker of...
CONTEXT
Polycystic ovary syndrome (PCOS) is defined by androgen excess and ovarian dysfunction in the absence of a specific physiological diagnosis. The best clinical marker of androgen excess is hirsutism, while the best biochemical parameter is still a matter of debate. Current consensus guidelines recommend, among other hormones, serum free testosterone as an important serum parameter to measure androgen excess. Recently, however, novel active androgens and androgen metabolic pathways have been discovered.
OBJECTIVE
To assess the contribution of novel androgens and related steroid biosynthetic pathways to the serum steroid pool in PCOS women in comparison to healthy controls.
DESIGN
This is a case control study, wherein PCOS was diagnosed according to the AE-PCOS 2009 criteria. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry.
SETTING
Yeditepe University and associated clinics in Istanbul, Turkey, together with Bern University Hospital Inselspital, Bern, Switzerland.
PARTICIPANTS
42 PCOS women and 42 matched, healthy control women.
MAIN OUTCOME MEASURES
Assessment of 34 steroids compartmentalized in four androgen related pathways: the classic androgen pathway, the backdoor pathway, the C11-oxy backdoor pathway, and the C11-oxy (11β-hydroxyandrostenedione) pathway.
RESULTS
Metabolites of all four pathways were identified in healthy and PCOS women. Highest concentrations were found for progesterone in controls and androstenedione in PCOS. Lowest levels were found for 11-ketotestosterone in controls compared to PCOS, and for 20α-hydroxyprogesterone in PCOS compared to controls. PCOS also had higher serum testosterone levels compared to the controls. PCOS women had overall higher levels of steroid metabolites of all four androgen pathways compared to healthy controls.
CONCLUSIONS
Novel alternative pathways contribute to the androgen production in healthy and PCOS women. Hyperandrogenism in PCOS is characterized by an overall increase of serum androgens in the classic, backdoor and C11-oxy pathways. While monogenetic disorders of steroid biosynthesis can be recognized by a specific pattern in the steroid profile, no diagnostic pattern or classifier was found in the serum for PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Androgens; Case-Control Studies; Steroids; Testosterone; Hyperandrogenism
PubMed: 37499841
DOI: 10.1016/j.jsbmb.2023.106366 -
Frontiers in Endocrinology 2023Sex steroid hormones are associated with the advancement of metabolic diseases such as dyslipidemia. This cross-sectional study aimed to investigate the relationship...
OBJECTIVE
Sex steroid hormones are associated with the advancement of metabolic diseases such as dyslipidemia. This cross-sectional study aimed to investigate the relationship between dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone levels and the risk of dyslipidemia in people with type 2 diabetes mellitus.
MATERIALS AND METHODS
The analysis included 1,927 patients with type 2 diabetes mellitus. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone levels were determined using lipid chromatography-tandem mass spectrometry. Multivariable analyses were performed to investigate the association between the variables and dyslipidemia.
RESULTS
The multivariable-adjusted odds ratio (OR) and 95% confidence interval (CI) of dyslipidemia across DHEA tertiles were 0.39 and 0.24-0.64, respectively (p trend = 0.001). This relationship was still maintained when analyzed as a continuous variable (odds ratio, 0.96; 95% confidence interval, 0.92-0.99; P < 0.01). However, in males with type 2 diabetes mellitus, no significant correlations were found between rising levels of dehydroepiandrosterone sulfate, androstenedione, and total testosterone and the risk of dyslipidemia (all P > 0.05). Furthermore, there was no significant association between androgen precursors and total testosterone with regard to the risk of developing dyslipidemia (all P > 0.05).
CONCLUSIONS
Serum dehydroepiandrosterone levels were substantially and adversely correlated with dyslipidemia in adult men with T2DM. These results indicated that dehydroepiandrosterone may have an essential role in the development of dyslipidemia. More prospective research is required to validate this link.
Topics: Adult; Humans; Male; Androstenedione; Cross-Sectional Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Diabetes Mellitus, Type 2; Prospective Studies; Testosterone; Dyslipidemias; Risk Factors
PubMed: 38075062
DOI: 10.3389/fendo.2023.1272797 -
Gynecologic Oncology Reports Apr 2024Sertoli-Leydig cell tumors (SLCT) are a rare form of sex cord stromal tumors. germline mutations have been identified in a portion of these cases. We report a...
Sertoli-Leydig cell tumors (SLCT) are a rare form of sex cord stromal tumors. germline mutations have been identified in a portion of these cases. We report a 15-year-old individual who presented to a well-child visit with secondary amenorrhea and subjective observations of a deepening voice and broadening shoulders. Elevations were noted in serum testosterone, inhibin B, androstenedione, and DHEA. Pelvic ultrasound and magnetic resonance imaging (MRI) revealed a left ovarian complex lesion measuring 5.8 x 5.5 x 4.6 cm. A laparoscopic unilateral salpingo-oophorectomy was performed with negative pelvic washings and a diagnosis of stage 1A, poorly differentiated/grade 3 SLCT of the ovary. Somatic and germline testing both demonstrated pathologic variations. Adjuvant chemotherapy with cisplatin/etoposide/ifosfamide (PEI) was completed under the care of pediatric oncology, and this patient is now undergoing surveillance with no signs of recurrence. Syndrome is associated with multiple tumors, including SLCT, pleuropulmonary blastoma (PPB), cystic sarcomas, and Wilms tumor among others. Patients with SLCT found to have a mutation should undergo genetic testing and cancer screening, which may help to identify neoplasms associated with the mutation at an early stage. This case will serve as a useful addition to the literature and review suggested pre-operative, operative, and surveillance guidelines.
PubMed: 38571566
DOI: 10.1016/j.gore.2024.101353 -
Life (Basel, Switzerland) Mar 2024Hyperandrogenism is a condition in which the levels of androgen hormones in the blood are significantly increased and could be of an adrenal or ovarian origin. The... (Review)
Review
Hyperandrogenism is a condition in which the levels of androgen hormones in the blood are significantly increased and could be of an adrenal or ovarian origin. The adrenal androgens, normally secreted by the zona reticularis, are steroid hormones with weak androgen activity. The causes of hyperandrogenism are diverse and could be endogenous and exogenous. Androgen excess affecting different tissues and organs results in clinical features such as acne, hirsutism, virilization, and reproductive dysfunction such as oligomenorrhoea/amenorrhoea. Although androgen excess is rarely associated with adrenal tumours, it is important as it could be predictive of malignancy. A careful evaluation of the androgen pattern, also in patients with clear signs of hyperandrogenism, could be useful. Laboratory evaluation should focus on measuring total testosterone levels, followed by the estimation of other androgens such as dehydroepiandrosterone and androstenedione, and using visualisation procedures in the further management. The treatment of adrenal hyperandrogenism is eminently surgical, in consideration of the frequent malignant origin. The aim of this review is to elaborate and summarize the prevalence and clinical management of hyperandrogenism of an adrenal origin by describing the physiological mechanisms of adrenal androgen steroidogenesis, the clinical manifestations of hyperandrogenism with a special reference to hyperandrogenism in adrenal adenomas and carcinomas, and the diagnostic methods that will lead us to establishing the correct diagnosis and different treatment options to manage this condition according to the clinical presentation of the patient.
PubMed: 38541685
DOI: 10.3390/life14030360 -
Journal of Assisted Reproduction and... Jul 2023Despite the significant advances in the in vitro development of human primordial follicles, it is still a challenging approach with great potential for improvements....
PURPOSE
Despite the significant advances in the in vitro development of human primordial follicles, it is still a challenging approach with great potential for improvements. Therefore, the present study aimed to investigate the effect of a feeder layer of human theca progenitor cells (hTPCs) on the development of primordial follicles embedded in human ovarian tissue.
METHODS
Fragments of frozen-thawed ovarian tissue were activated using the vanadate-derivative dipotassium bisperoxo (5-hydroxy-pyridine-2-carboxylic) oxovanadate (V) and kit ligand for 24 h. Then, the specimens were divided into the co-culture and mono-culture groups and were cultured with and without a hTPC feeder layer for 6 days, respectively. Afterward, the follicles were counted and classified, and the hormone levels and expression levels of apoptosis- and folliculogenesis-related genes were assessed.
RESULTS
Both culture groups showed significant follicle growth (P < 0.05). However, the co-culture group had a significantly higher number of growing follicles compared to the other group (P < 0.05). Moreover, the expression levels of ZP1, ZP2, ZP3, BMP-7, AMH, and GDF9 were significantly higher in the co-culture group compared to the other group (P < 0.05), while the expression levels of P53 and CASP3 were significantly lower (P < 0.05). Also, the concentrations of estradiol, progesterone, testosterone, and androstenedione were significantly higher in the co-culture group compared to the other group (P < 0.05).
CONCLUSION
The present study results provided novel evidence on the direct role of hTPCs in the growth and development of human primordial follicles. However, there is a need for future studies to illustrate the underlying mechanisms. Schematic summary of the results. According to our results, the expression of ZP1, ZP2, ZP3, and GDF9 in the oocytes, AMH in the granulosa cells, and BMP4 in the theca cells of the co-culture group were significantly higher than those of the mono-culture and non-culture groups, while the expression of apoptotic genes (BAX, CASP3, and P53) was significantly lower. Moreover, the co-culture group showed significantly increased levels of estradiol, progesterone, testosterone, and androstenedione in its culture media compared to the mono-culture groups.
Topics: Female; Humans; Theca Cells; Caspase 3; Progesterone; Androstenedione; Coculture Techniques; Tumor Suppressor Protein p53; Granulosa Cells; Estradiol; Testosterone
PubMed: 37079226
DOI: 10.1007/s10815-023-02799-8 -
Journal of Clinical Medicine Aug 2023The effect of metformin on prolactin concentration seems to be sex-dependent. The aim of this study was to determine whether the androgen status modulates the impact of...
The effect of metformin on prolactin concentration seems to be sex-dependent. The aim of this study was to determine whether the androgen status modulates the impact of metformin on plasma prolactin levels in women. This study included two matched groups of prediabetic women with hyperprolactinemia: 25 with PCOS and 25 control subjects with androgen levels within the reference range and with normal ovarian morphology. Glucose homeostasis markers, prolactin, the remaining anterior pituitary hormones, sex hormones, SHBG and IGF-1 were determined before and after six months of metformin treatment. At baseline, both groups differed in LH, LH/FSH ratio, testosterone, FAI, DHEA-S, androstenedione and estradiol. Although metformin improved insulin sensitivity and increased SHBG in both study groups, these effects were more pronounced in control subjects than in women with PCOS. In control subjects, the drug decreased total and monomeric prolactin and increased LH. In women with PCOS, metformin reduced LH, LH/FSH ratio, testosterone and FAI. In the control group, the impact on total and monomeric prolactin positively correlated with their baseline levels and with the degree of improvement in insulin sensitivity, as well as negatively correlated with testosterone and FAI. In women with PCOS, treatment-induced changes in testosterone and FAI positively correlated with the changes in LH and LH/FSH ratio. The obtained results suggest that the prolactin-lowering properties of metformin are less pronounced in women with coexisting PCOS than in women with elevated prolactin levels, probably owing to the increased production of endogenous testosterone.
PubMed: 37685540
DOI: 10.3390/jcm12175474 -
Endocrine Sep 2023Polycystic ovarian syndrome (PCOS) is a common heterogeneous condition with probably multifactorial genesis. Animal studies have proven the essential role of the...
PURPOSE
Polycystic ovarian syndrome (PCOS) is a common heterogeneous condition with probably multifactorial genesis. Animal studies have proven the essential role of the sympathetic nervous system in the syndrome development, while human studies are still contradictory. The present study aims to investigate the possible influence of plasma-free metanephrine (MN), and normetanephrine (NMN), nerve growth factor (NGF), and renalase (RNL) on the hormonal and metabolic parameters in women with PCOS and healthy controls.
METHODS
Fifty patients with PCOS and 30 healthy women participated in the study. The plasma-free MN and NMN, NGF, RNL, anti-Mullerian hormone (AMH), gonadotropin, androgen levels, and metabolic parameters were investigated.
RESULTS
Plasma-free NMN and NGF concentrations were increased in PCOS individuals, while RNL levels were decreased compared to healthy volunteers. Increased plasma-free NMN (OR = 1.0213 [95%CI 1.0064-1.0364], p = 0.005) and NGF (OR = 1.0078 [95%CI 1.0001-1.0155], p = 0.046) but not MN or RNL levels were associated with a higher risk of PCOS after adjustment for age. Plasma-free NMN levels were positively associated with the LH (r = +0.253; p = 0.039). androstenedione (r = +0.265; p = 0.029), 17-OH progesterone (r = +0.285; p = 0.024), NGF (r = +0.320; p = 0.008), and AMH (r = +0.417; p < 0.001) concentrations of the investigated women. RNL levels were inversely related to the BMI (r = -0.245; p = 0.029), HOMA-IR (r = -0.250; p = 0.030), free testosterone (r = -0.303; p = 0.006) levels. systolic (r = -0.294; p = 0.008) and diastolic (r = -0.342; p = 0.002) blood pressure.
CONCLUSIONS
Increased sympathetic noradrenergic activity and NGF synthesis might be related to the increased AMH and delta-4 androgen levels in a subgroup of PCOS patients. RNL levels might influence the metabolic status of PCOS patients. Further studies are needed to explore the significance of adrenal medullar and autonomic dysfunction for developing different PCOS phenotypes and their subsequent cardiovascular complications.
Topics: Humans; Female; Polycystic Ovary Syndrome; Metanephrine; Androgens; Nerve Growth Factor; Anti-Mullerian Hormone
PubMed: 37248367
DOI: 10.1007/s12020-023-03404-9 -
European Journal of Endocrinology Jan 2024Classic androgens such as dehydroepiandrosterone, androstenedione, and testosterone are generally measured for diagnosis and treatment monitoring in children and...
OBJECTIVE
Classic androgens such as dehydroepiandrosterone, androstenedione, and testosterone are generally measured for diagnosis and treatment monitoring in children and adolescents with hyperandrogenism, as can occur in congenital adrenal hyperplasia, premature pubarche, or polycystic ovarian syndrome. However, adrenally-derived 11-oxygenated androgens also contribute to the androgen pool and should therefore be considered in clinical management. Nevertheless, paediatric reference intervals are lacking. Therefore, we developed a serum assay to establish reference intervals for four 11-oxygenated androgens in addition to four classic androgens.
DESIGN
Reference interval study for serum 11-oxygenated androgens in children.
METHODS
We developed and validated a sensitive LC-MS/MS assay and quantified eight serum androgens, including four 11-oxygenated androgens, in serum of 256 healthy children (aged 0-17 years old). An age-dependency for all androgens was observed, and therefore we divided the cohort based on age (prepubertal (n=133; 94 boys, 39 girls) and pubertal (n=123; 52 boys, 71 girls)) to compute reference intervals (2.5th - 97.5th percentiles).
RESULTS
In the prepubertal group, there was no significant sex-difference for any of the measured androgens. In the pubertal group, androstenedione, testosterone, and dihydrotestosterone showed a significant difference between boys and girls. In contrast, adrenal androgens dehydroepiandrosterone, 11-hydroxyandrostenedione, 11-ketoandrostenedione, 11-hydroxytestosterone, and 11-ketotestosterone did not.
CONCLUSIONS
We developed and validated an assay for 11-oxygenated androgens, in addition to four classic androgens and established reference intervals. This enables a comprehensive evaluation of serum androgen status in children with clinical symptoms of hyperandrogenism.
PubMed: 38243909
DOI: 10.1093/ejendo/lvae008