36 results found
Jonas K, Rivero-Müller A, Oduwole O, et al., 2021, The luteinizing hormone receptor knock-out mouse as a tool to probe the in vivo 1 actions of gonadotropic hormones/receptors in females, Endocrinology, Vol: 162, Pages: 1-13, ISSN: 0013-7227
Mouse models with altered gonadotropin functions have provided invaluable insight into the functions of these hormones/receptors. Here we describe the repurposing of the infertile and hypogonadal luteinizing hormone receptor (LHR) knockout mouse model (LuRKO), to address outstanding questions in reproductive physiology. Using crossbreeding strategies and physiological and histological analyses, we first addressed the physiological relevance of forced LHR homomerization in female mice using BAC expression of 2 ligand-binding and signaling deficient mutant LHR, respectively, that have previously shown to undergo functional complementation and rescue the hypogonadal phenotype of male LuRKO mice. In female LuRKO mice, coexpression of signaling and binding deficient LHR mutants failed to rescue the hypogonadal and anovulatory phenotype. This was apparently due to the low-level expression of the 2 mutant LHR and potential lack of luteinizing hormone (LH)/LHR-dependent pleiotropic signaling that has previously been shown at high receptor densities to be essential for ovulation. Next, we utilized a mouse model overexpressing human chorionic gonadotropin (hCG) with increased circulating “LH/hCG”-like bioactivity to ~40 fold higher than WT females, to determine if high circulating hCG in the LuRKO background could reveal putative LHR-independent actions. No effects were found, thus, suggesting that LH/hCG mediate their gonadal and non-gonadal effects solely via LHR. Finally, targeted expression of a constitutively active follicle stimulating hormone receptor (FSHR) progressed antral follicles to preovulatory follicles and displayed phenotypic markers of enhanced estrogenic activity but failed to induce ovulation in LuRKO mice. This study highlights the critical importance and precise control of functional LHR and FSHR for mediating ovarian functions and of the potential repurposing of existing genetically modified mouse models in answering outstanding questions in
Oduwole OO, Poliandri A, Okolo A, et al., 2021, Follicle-stimulating hormone promotes growth of human prostate cancer cell line-derived tumor xenografts, FASEB JOURNAL, Vol: 35, ISSN: 0892-6638
Oduwole OO, Peltoketo H, Huhtaniemi IT, 2018, Role of follicle-stimulating hormone in spermatogenesis, Frontiers in Endocrinology, Vol: 9, ISSN: 1664-2392
Spermatogenesis is a concerted sequence of events during maturation of spermatogonia into spermatozoa. The process involves differential gene-expression and cell-cell interplay regulated by the key endocrine stimuli, i.e., follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-stimulated testosterone. FSH affects independently and in concert with testosterone, the proliferation, maturation and function of the supporting Sertoli cells that produce regulatory signals and nutrients for the maintenance of developing germ cells. Rodents are able to complete spermatogenesis without FSH stimulus, but its deficiency significantly decreases sperm quantity. Men carrying loss-of-function mutation in the gene encoding the ligand (FSHB) or its receptor (FSHR) present, respectively, with azoospermia or suppressed spermatogenesis. Recently, the importance of high intratesticular testosterone concentration for spermatogenesis has been questioned. It was established that it can be completed at minimal intratesticular concentration of the hormone. Furthermore, we recently demonstrated that very robust constitutive FSHR action can rescue spermatogenesis and fertility of mice even when the testosterone stimulus is completely blocked. The clinical relevance of these findings concerns a new strategy of high-dose FSH in treatment of spermatogenic failure.
Oduwole OO, Peltoketo H, Poliandri A, et al., 2018, Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis, Journal of Clinical Investigation, Vol: 128, Pages: 1787-1792, ISSN: 0021-9738
Spermatogenesis is regulated by the 2 pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This process is considered impossible without the absolute requirement of LH-stimulated testicular testosterone (T) production. The role of FSH remains unclear because men and mice with inactivating FSH receptor (FSHR) mutations are fertile. We revisited the role of FSH in spermatogenesis using transgenic mice expressing a constitutively strongly active FSHR mutant in a LH receptor–null (LHR-null) background. The mutant FSHR reversed the azoospermia and partially restored fertility of Lhr–/– mice. The finding was initially ascribed to the residual Leydig cell T production. However, when T action was completely blocked with the potent antiandrogen flutamide, spermatogenesis persisted. Hence, completely T-independent spermatogenesis is possible through strong FSHR activation, and the dogma of T being a sine qua non for spermatogenesis may need modification. The mechanism for the finding appeared to be that FSHR activation maintained the expression of Sertoli cell genes considered androgen dependent. The translational message of our findings is the possibility of developing a new strategy of high-dose FSH treatment for spermatogenic failure. Our findings also provide an explanation of molecular pathogenesis for Pasqualini syndrome (fertile eunuchs; LH/T deficiency with persistent spermatogenesis) and explain how the hormonal regulation of spermatogenesis has shifted from FSH to T dominance during evolution.
Papacleovoulou G, Nikolova V, Oduwole O, et al., 2017, Gestational disruptions in metabolic rhythmicity of the liver, muscle, and placenta affect fetal size, FASEB JOURNAL, Vol: 31, Pages: 1698-1708, ISSN: 0892-6638
Brew O, Nikolopoulou E, Hughes A, et al., 2016, Quality of placental RNA: Effects of explant size and culture duration, PLACENTA, Vol: 46, Pages: 45-48, ISSN: 0143-4004
Oduwole O, Poliandri A, Rawson P, et al., 2016, FSH supplementation increases the growth of PC-3 human prostate cancer cell xenograft in gonadotropin-suppressed nude mice, 18th European Congress of Endocrinology
Oduwole O, Rawson P, Rahman N, et al., 2016, Effect of FSH supplementation on the GnRH antagonist suppressed growth of PC-3 cell xenografts in nude mice., Genitourinary Cancers Symposium, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Oduwole O, Peltoketo H, Poliandri A, et al., 2015, Restoration of fertility in hypogonadal LH receptor null background male mice by a constitutive active mutant FSH receptor, 17th European Congress of Endocrinology
Ebesunun MO, Bankole OL, Oduwole OO, 2014, Plasma oxidised low-density lipoprotein cholesterol correlates inversely with testosterone in young adult male smokers, Pan African Medical Journal, Vol: 19, ISSN: 1937-8688
Introduction: there are indications that oxidized low density lipoprotein cholesterol (Ox-LDLC) may play an important role in cardiovascular disease (CVD) events. In most developing countries, the interplay between the different lipid fractions and cigarette smoking has not been studied. This study assessed the effect of cigarette smoking on the alterations in plasma lipid fractions and their associations with the gonadal hormone, testosterone (T). Methods: one hundred and sixty male participants, consisting of eighty smokers and eighty apparently healthy non-smokers were recruited. Anthropometric indices and biochemical parameters were determined using standard procedures. Results: significant increases were obtained in plasma total cholesterol (TC), triglyceride (TG), oxidized low density lipoprotein (Ox-LDLC) and Ox-LDLC/TT ratio (p<0.001) in smokers compared with the non-smokers. Plasma high density cholesterol (HDLC) (p<0.001) was significantly reduced in smokers compared with the non-smokers. The plasma mean T result was not significantly different from the non-smokers, but inversely correlated with Ox-LDLC and significantly correlated with the lipids and lipoproteins. Significantly high plasma TC, TG and LDLC (p<0.001) and low HDLC (p<0.001) were also obtained in smokers when co-founding factors such as duration and number of cigarette smoked per day were applied. Conclusion: this study showed an inverse correlation between Ox-LDLC and testosterone as well as strong association between the number of tobacco and cigarettes usage per day. These changes in part, could be major causes of premature CVD and decreased fertility in young adults.
Jonas KC, Oduwole OO, Peltoketo H, et al., 2014, Mouse models of altered gonadotrophin action: insight into male reproductive disorders, REPRODUCTION, Vol: 148, Pages: R63-R70, ISSN: 1470-1626
Oduwole OO, Vydra N, Wood NEM, et al., 2014, Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception, FASEB JOURNAL, Vol: 28, Pages: 2566-2576, ISSN: 0892-6638
Papacleovoulou G, Nikolova V, Oduwole O, et al., 2014, Maternal metabolic adaptations in pregnancy are associated with altered circadian rhythmicity, Endocrine Abstracts
Ebesunun M, 2014, Association between Anthropometric Indices, Plasma Insulin, Lipids and Lipoproteins in Overweight and Obese Nigerians, British Journal of Medicine and Medical Research, Vol: 4, Pages: 2526-2535
Oduwole OO, Huhtaniemi IT, 2014, Feasibility of male hormonal contraception: lessons from clinical trials and animal experiments., Curr Mol Pharmacol, Vol: 7, Pages: 109-118
The general interest in the availability of male contraceptives is on the increase across different cultures and ethnic backgrounds, due in part to the fact that men are now willing more than ever, to share the responsibility of family planning. Despite the expression of interest and tremendous advances in research however, a modern male hormonal contraceptive method has remained an elusive goal. Testosterone (T) alone, or in combination with a progestin currently provides the most promising lead to male hormonal contraception. The principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the endocrine stimulus for the process of spermatogenesis. A serious drawback is the inconsistent suppression among men of different ethnic backgrounds. This has increased the quest for development to include other nonhormonal methods. In reality many obstacles still have to be overcome before an acceptable method is available. In this review, we highlight recent developments in male hormonal contraceptives methods. Based on our recent findings from animal experiment, we shed light on why the method is not achieving the intended results, and suggest possible ways forward.
Oduwole O, Peltoketo H, Steel JH, et al., 2013, A constitutively active mutant FSH receptor is able to restore fertility in male mice with hypogonadal LH receptor null background, 95th Annual Meeting of The Endocrine Society
Nautiyal J, Steel JH, Mane MR, et al., 2013, The transcriptional co-factor RIP140 regulates mammary gland development by promoting the generation of key mitogenic signals, Development, Vol: 140, Pages: 1079-1089, ISSN: 0950-1991
Oduwole OO, Vydra N, Wood N, et al., 2012, Why androgen based male hormonal contraception lacks efficacy: evidence from a mouse model, 7th European Congress of Andrology
Abu-Hayyeh S, Papacleovoulou G, Lovgren-Sandblom A, et al., 2012, Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit FXR resulting in a pro-cholestatic phenotype, Hepatology
Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3alpha-sulfated progesterone metabolites have been shown to be elevated in ICP leading us to study the impact of sulfated progesterone metabolites on farnesoid x receptor (FXR) mediated bile acid homeostasis pathways. Here we report that the 3beta-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, co-administration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR,resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using co-factor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of co-factor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3beta-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis. (HEPATOLOGY 2012.)
Oduwole O, Vydra N, Wood N, et al., 2012, Testosterone-dependent spermatogenesis: Insight from a mouse model, 17th European Workshop on Molecular and Cellular Endocrinology of the Testis
Nautiyal J, Steel JH, Rosell M, et al., 2011, The transcriptional regulator RIP140 regulates ductal morphogenesis in the mammary gland by regulating key mitogenic signals, EMBO Conference on Nuclear Receptors
Nautiyal J, Steel JH, Wood N, et al., 2010, The transcriptional regulator RIP140 is a mediator of hormonal signalling and ductal morphogenesis in the mammary gland, 14th International Congress on Hormonal Steroids and Hormones and Cancer
Oduwole O, Peltoketo V, Huhtaniemi I, 2008, Sex differences in pubertal timing in mouse strains with early and late puberty, Joint 15th European Testis Workshop/Annual Meeting of Nordic Association for Andrology
JS VTMMTSOOHAHRIVT, 2005, Estrogen receptors and estrogen-metabolizing enzymes in human ovaries during fetal development, J Clin Endocrinol Metab, Vol: 90(6), Pages: 3752-3756
Oduwole OO, Li Y, Isomaa VV, et al., 2004, 17 beta-hydroxysteroid dehydrogenase type 1 is an independent prognostic marker in breast cancer, CANCER RESEARCH, Vol: 64, Pages: 7604-7609, ISSN: 0008-5472
Vhko PT, Harkonen P, Soronen P, et al., 2004, 17beta-hydroxysteroid dehydrogenase - their role in pathophysiology, Mol Cell Endocrinol
Vihko P, Harkonen P, Soronen P, et al., 2004, 17 beta-Hydroxysteroid dehydrogenases - their role in pathophysiology, 4th Workshop on Molecular Steroidogenesis, Publisher: ELSEVIER IRELAND LTD, Pages: 83-88, ISSN: 0303-7207
Oduwole OO, Makinen MJ, Isomaa VV, et al., 2003, 17 beta-hydroxysteroid dehydrogenase type 2: independent prognostic significance and evidence of estrogen protection in female patients with colon cancer, JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, Vol: 87, Pages: 133-140, ISSN: 0960-0760
Oduwole OO, Makinen JNM, Isomaa VV, et al., 2003, Sex steroid metabolism in human gastric mucosa: 17 beta-hydroxysteroid dehydrogenase type 2 in normal, inflamed and neoplastic gastric tissues, ANTICANCER RESEARCH, Vol: 23, Pages: 3889-3897, ISSN: 0250-7005
Vihko PT, Harkonen P, Oduwole O, et al., 2003, 17beta-hydroxysteroid dehydrogenases and cancers, J Steroid Biochem Mol Biol
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