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  • Nerenz, Robert D.; Yarbrough, Melanie L.; Stenman, Ulf-Hakan; Gronowski, Ann M. (2016)
    Objective: Elevated concentrations of hCG beta core fragment (hCG beta cf) are known to cause false-negative results in qualitative urine pregnancy test devices, but the pattern of urinary hCG beta cf during normal pregnancy has not been well characterized. Here, we evaluate the relationship between urine hCG, hCG beta cf, and hCG free beta subunit (hCG beta) during pregnancy. Design and methods: Banked second trimester urine specimens from 100 pregnant women were screened for high concentrations of hCG beta cf using a qualitative point-of-care device known to demonstrate false-negative results in the presence of elevated hCG beta cf concentrations. Additional first and third trimester specimens from the same pregnancy were obtained from 10 women who generated negative/faint positive results, 5 women who generated intermediate positive results, and 10 women who generated strong positive results on the point-of care device. Intact hCG, hCG beta cf, hCG beta, and specific gravity were quantified in these 75 specimens. Results: Urinary hCG beta cf concentrations were greater than intact hCG concentrations at all times. A strong correlation (r(2) = 0.70) was observed between urine intact hCG and hCG beta cf concentrations. A poor correlation was observed between specific gravity and intact hCG (r(2) = 0.32), hCG beta (r(2) = 0.32), and hCG beta cf (r(2) = 0.32). The highest hCG beta cf concentrations were observed between 10 and 16 weeks gestation but individual women demonstrated very different patterns of hCG beta cf excretion. Conclusions: Urine specimens with elevated hCG beta cf are frequently encountered during pregnancy but hCG beta cf excretion patterns are unpredictable. Manufacturers and clinicians must appreciate that hCG beta cf is the major immunoreactive component in urine during pregnancy and must design and interpret qualitative urine hCG test results accordingly. (C) 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
  • Young, Jacques; Xu, Cheng; Papadakis, Georgios E.; Acierno, James S.; Maione, Luigi; Hietamäki, Johanna; Raivio, Taneli; Pitteloud, Nelly (2019)
    The initiation and maintenance of reproductive capacity in humans is dependent on pulsatile secretion of the hypothalamic hormone GnRH. Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder that results from the failure of the normal episodic GnRH secretion, leading to delayed puberty and infertility. CHH can be associated with an absent sense of smell, also termed Kallmann syndrome, or with other anomalies. CHH is characterized by rich genetic heterogeneity, with mutations in >30 genes identified to date acting either alone or in combination. CHH can be challenging to diagnose, particularly in early adolescence where the clinical picture mirrors that of constitutional delay of growth and puberty. Timely diagnosis and treatment will induce puberty, leading to improved sexual, bone, metabolic, and psychological health. In most cases, patients require lifelong treatment, yet a notable portion of male patients (approximate to 10% to 20%) exhibit a spontaneous recovery of their reproductive function. Finally, fertility can be induced with pulsatile GnRH treatment or gonadotropin regimens in most patients. In summary, this review is a comprehensive synthesis of the current literature available regarding the diagnosis, patient management, and genetic foundations of CHH relative to normal reproductive development.
  • Mazina, Olga; Allikalt, Anni; Tapanainen, Juha S.; Salumets, Andres; Rinken, Ago (2017)
    Determination of biological activity of gonadotropin hormones is essential in reproductive medicine and pharmaceutical manufacturing of the hormonal preparations. The aim of the study was to adopt a G-protein coupled receptor (GPCR)-mediated signal transduction pathway based assay for quantification of biological activity of gonadotropins. We focussed on studying human chorionic gonadotropin (hCG) and follicle-stimulating hormone (FSH), as these hormones are widely used in clinical practice. Receptor-specific changes in cellular cyclic adenosine monophosphate (cAMP, second messenger in GPCR signalling) were monitored by a Forster resonance energy transfer (FRET) biosensor protein (T)Epac(VV) in living cells upon activation of the relevant gonadotropin receptor. The BacMam gene delivery system was used for biosensor protein expression in target cells. In the developed assay only biologically active hormones initiated GPCR-mediated cellular signalling. High assay sensitivities were achieved for detection of hCG (limit of detection, LOD: 5 pM) and FSH (LOD: 100 pM). Even the smallscale conformational changes caused by thermal inactivation and reducing the biological activity of the hormones were registered. In conclusion, the proposed assay is suitable for quantification of biological activity of gonadotropins and is a good alternative to antibody- and animal-testing-based assays used in pharmaceutical industry and clinical research.
  • Äyräs, Outi; Rahkola-Soisalo, Päivi; Kaijomaa, Marja; Tikkanen, Minna; Paavonen, Jorma; Stefanovic, Vedran (2019)
    Objective: To bring new accuracy to the prognosis of outcomes of euploid fetuses with an extremely high risk in the first-trimester combined screening when compared to the low-risk group. Study design: The data included pregnancies with a trisomy 21 risk >= 1:50 in the combined first-trimester screening but normal fetal chromosomes. The control group had a risk value Results: The study comprised 483 women (161 cases and 322 controls). The mean follow-up time of children born alive was 61.4 months. An adverse outcome was detected in 11.8% of the cases and in 5.9% of the controls. After adjusting the values of mothers age, parity, and smoking habit the odds ratio for an adverse outcome was 2.1 (95% CI: 1.0-4.5, p = 0.05) for cases. When evaluating the effect of 1 SD increase in MOM of PAPP-A or 1 SD decrease in MOM of NT or beta-hCG to any adverse outcome, 1 SD increase in PAPP-A MOM decreased the risk of adverse outcome by OR 0.48 (95% CI: 0.3 - 0.8, p = 0.05) while the others were not significant. Conclusion: Euploid fetuses with a high risk in the combined first-trimester screening have a twofold risk for adverse outcomes when compared to those with a low risk. (C) 2019 Elsevier B.V. All rights reserved.
  • Koistinen, Hannu; Koel, Mariann; Peters, Maire; Rinken, Ago; Lundin, Karolina; Tuuri, Timo; Tapanainen, Juha S.; Alfthan, Henrik; Salumets, Andres; Stenman, Ulf-Håkan; Lavogina, Darja (2019)
    While human chorionic gonadotropin (hCG) appears to have an essential role in early pregnancy, it is controversial whether the hyperglycosylated form of hCG (hCG-h), which is the major hCG isoform during the first 4-5 weeks of pregnancy, is able to activate LH/hCG receptor (LHCGR). To address this, we utilized different extensively characterized hCG and hCG beta reference reagents, cell culture- and urine-derived hCG-h preparations, and an in vitro reporter system for LHCGR activation. The WHO hCG reference reagent (99/688) was found to activate LHCGR with an EC50-value of 3.3 +/- 0.6 pmol/L (n = 9). All three studied hCG-h preparations were also able to activate LHCGR, but with a lower potency (EC50-values between 7.1 +/- 0.5 and 14 +/- 3 pmol/L, n = 5-11, for all P <0.05 as compared to the hCG reference). The activities of commercial urinary hCG (Pregnyl) and recombinant hCG (Ovitrelle) preparations were intermediate between those of the hCG reference and the hCG-h. These results strongly suggest that the hCG-h is functionally similar to hCG, although it has lower potency for LHCGR activation. Whether this explains the reduced proportion of hCG-h to hCG reported in patients developing early onset pre-eclampsia or those having early pregnancy loss remains to be determined.
  • Erkkilä, K.; Aito, H.; Aalto, K.; Pentikäinen, V.; Dunkel, L. (2002)
    Dysregulation of male germ cell apoptosis has been associated with the pathogenesis of male infertility. Therefore, factors involved in the regulation of germ cell death are being actively investigated. Here, we studied the effects of lactate on human male germ cell death, using as a model a testis tissue culture in which physiological contacts are maintained between the germ cells and the supportive somatic Sertoli cells. Apoptosis of spermatocytes, spermatids and a few spermatogonia was induced by culturing segments of seminiferous tubules under serum-free conditions. This germ cell death was inhibited effectively and dose-dependently by lactate, indicating that it plays a crucial role in controlling cell death cascades of male germ cells. Interestingly, the anti-apoptotic role of lactate was not associated with changes in testicular adenine nucleotide (ATP, ADP and AMP) levels. In the seminiferous tubules, the final site of the death-suppressing action of lactate appeared to be downstream along the cell death pathway activated by the Fas receptor of the germ cells. In conclusion, testicular cell death was effectively regulated by lactate, which may be regarded as a potential compound for optimizing in-vitro methods involving male germ cells for assisted reproduction.
  • Adibi, JJ; Xun, XS; Zhao, YQ; Yin, Q; LeWinn, K; Bush, NR; Panigrahy, A; Peddada, S; Alfthan, H; Stenman, UH; Tylavsky, F; Koistinen, H (2021)
    Adequate maternal thyroid hormone (TH) is necessary for fetal brain development. The role of placental human chorionic gonadotropin (hCG) in ensuring the production of TH is less well understood. The objective of the study was to evaluate 1) associations of placental hCG and its subunits, and maternal TH in the second trimester, and 2) the single and joint effects of TH and placental hormones on cognitive development and communication at ages 1 and 3 years. Fifty individuals (5%) were selected from the CANDLE (Conditions Affecting Neurocognitive Development and Early Learning) pregnancy cohort in Memphis, Tennessee, with recruitment from 2006 to 2011, to equally represent male and female fetuses. Participants were 68% Black and 32% White. Hormones measured were maternal thyroid (thyrotropin [TSH] and free thyroxine [FT4]) and placental hormones (hCG, its hyperglycosylated form [hCG-h], and free alpha- [hCG alpha] and beta-subunits [hCG beta]) in maternal serum (17-28 weeks). The primary outcome measurement was the Bayley Scales of Infant and Toddler Development. All forms of hCG were negatively associated with FT4 and not associated with TSH. hCG alpha was associated with cognitive development at age 1 year and jointly interacted with TSH to predict cognitive development at age 3 years. This pilot study added insight into the thyrotropic actions of hCG in the second trimester, and into the significance of this mechanism for brain development. More research is warranted to elucidate differences between hCG alpha, hCG beta, and hCG-h in relation to TH regulation and child brain function.
  • Lehikoinen, Anni; Voutilainen, Raimo; Romppanen, Jarkko; Heinonen, Seppo (2020)
    Background: The purpose of this study was to determine whether first trimester trisomy screening (FTS) parameters are affected by alcohol and drug use. Methods: A routine combined FTS including measurements of maternal serum levels of free beta-human chorionic gonadotropin subunit (free beta-hCG) and pregnancy-associated plasma protein A (PAPP-A) were measured at 9-11 weeks of gestation, and fetal nuchal translucency thickness (NTT) at 11-13 weeks of gestation. In total 544 women with singleton pregnancies [71 alcohol and drug abusers, 88 smokers, 168 non-smokers delivering a small for gestational age (SGA) child, and 217 unexposed control women] were assessed. Results: Free beta-hCG levels were higher in alcohol and drug abusing than in unexposed pregnant women [mean 1.5 vs. 1.2 multiples of medians (MoM); P=0.013]. However, stepwise multiple linear regression analyses suggested that smoking could explain increased free beta-hCG. Additionally, we observed lower PAPP-A levels in the smoking mothers (0.9 vs. 1.2 MoM; P=0.045) and in those giving birth to an SGA child compared to the controls (1.1 vs.. 1.2 MoM; P Conclusions: The present study shows increased free beta-hCG levels in alcohol and drug abusers, but maternal smoking may explain the result. Maternal serum PAPP-A levels were lower in smoking than non-smoking mothers, and in mothers delivering an SGA child. However, FTS parameters (PAPP-A, free beta-hCG and NTT) seem not to be applicable for the use as alcohol biomarkers because of their clear overlap between alcohol abusers and healthy controls.