Publications
932 results found
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.
Prior T, Lees C, 2018, Control and monitoring of fetal growth, Encyclopedia of Endocrine Diseases Vol 5, Editors: Huhtaniemi, Martini, Publisher: Academic Press, Pages: 1-9, ISBN: 9780128121993
Encyclopedia of Endocrine Diseases, Second Edition, comprehensively reviews the extensive spectrum of diseases and disorders that can occur within the endocrine system.
Rastrelli G, O'Neill TW, Ahern T, et al., 2018, Symptomatic androgen deficiency develops only when both total and free testosterone decline in obese men who may have incident biochemical secondary hypogonadism: Prospective results from the EMAS, CLINICAL ENDOCRINOLOGY, Vol: 89, Pages: 459-469, ISSN: 0300-0664
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- Citations: 39
Kaprara A, Huhtaniemi IT, 2018, The hypothalamus-pituitary-gonad axis: Tales of mice and men, METABOLISM-CLINICAL AND EXPERIMENTAL, Vol: 86, Pages: 3-17, ISSN: 0026-0495
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- Citations: 141
Huhtaniemi I, 2018, MECHANISMS IN ENDOCRINOLOGY Hormonal regulation of spermatogenesis: mutant mice challenging old paradigms, EUROPEAN JOURNAL OF ENDOCRINOLOGY, Vol: 179, Pages: R143-R150, ISSN: 0804-4643
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- Citations: 27
Huhtaniemi I, Hovatta O, La Marca A, et al., 2018, Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency, TRENDS IN ENDOCRINOLOGY AND METABOLISM, Vol: 29, Pages: 400-419, ISSN: 1043-2760
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- Citations: 86
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.
Eriksson AL, Perry JRB, Coviello AD, et al., 2018, Genetic determinants of circulating estrogen levels and evidence of a causal effect of estradiol on bone density in men, Journal of Clinical Endocrinology and Metabolism, Vol: 103, Pages: 991-1004, ISSN: 0021-972X
ContextSerum estradiol (E2) and estrone (E1) levels exhibit substantial heritability.ObjectiveTo investigate the genetic regulation of serum E2 and E1 in men.Design, Setting, and ParticipantsGenome-wide association study in 11,097 men of European origin from nine epidemiological cohorts.Main Outcome MeasuresGenetic determinants of serum E2 and E1 levels.ResultsVariants in/near CYP19A1 demonstrated the strongest evidence for association with E2, resolving to three independent signals. Two additional independent signals were found on the X chromosome; FAMily with sequence similarity 9, member B (FAM9B), rs5934505 (P = 3.4 × 10−8) and Xq27.3, rs5951794 (P = 3.1 × 10−10). E1 signals were found in CYP19A1 (rs2899472, P = 5.5 × 10−23), in Tripartite motif containing 4 (TRIM4; rs17277546, P = 5.8 × 10−14), and CYP11B1/B2 (rs10093796, P = 1.2 × 10−8). E2 signals in CYP19A1 and FAM9B were associated with bone mineral density (BMD). Mendelian randomization analysis suggested a causal effect of serum E2 on BMD in men. A 1 pg/mL genetically increased E2 was associated with a 0.048 standard deviation increase in lumbar spine BMD (P = 2.8 × 10−12). In men and women combined, CYP19A1 alleles associated with higher E2 levels were associated with lower degrees of insulin resistance.ConclusionsOur findings confirm that CYP19A1 is an important genetic regulator of E2 and E1 levels and strengthen the causal importance of E2 for bone health in men. We also report two independent loci on the X-chromosome for E2, and one locus each in TRIM4 and CYP11B1/B2, for E1.
Eendebak RJAH, Ahern T, Swiecicka A, et al., 2018, Elevated luteinizing hormone despite normal testosterone levels in older mennatural history, risk factors and clinical features, CLINICAL ENDOCRINOLOGY, Vol: 88, Pages: 479-490, ISSN: 0300-0664
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- Citations: 22
Jonas KC, Chen S, Virta M, et al., 2018, Temporal reprogramming of calcium signalling via crosstalk of gonadotrophin receptors that associate as functionally asymmetric heteromers, Scientific Reports, Vol: 8, ISSN: 2045-2322
Signal crosstalk between distinct G protein-coupled receptors (GPCRs) is one mechanism that underlies pleiotropic signalling. Such crosstalk is also pertinent for GPCRs activated by gonadotrophic hormones; follicle-stimulating hormone (FSH) and luteinising hormone (LH), with specific relevance to female reproduction. Here, we demonstrate that gonadotrophin receptor crosstalk alters LH-induced Gαq/11-calcium profiles. LH-induced calcium signals in both heterologous and primary human granulosa cells were prolonged by FSHR coexpression via influx of extracellular calcium in a receptor specific manner. LHR/FSHR crosstalk involves Gαq/11 activation as a Gαq/11 inhibitor abolished calcium responses. Interestingly, the enhanced LH-mediated calcium signalling induced by FSHR co-expression was dependent on intracellular calcium store release and involved Gβγ. Biophysical analysis of receptor and Gαq interactions indicated that ligand-dependent association between LHR and Gαq was rearranged in the presence of FSHR, enabling FSHR to closely associate with Gαq following LHR activation. This suggests that crosstalk may occur via close associations as heteromers. Super-resolution imaging revealed that LHR and FSHR formed constitutive heteromers at the plasma membrane. Intriguingly, the ratio of LHR:FSHR in heterotetramers was specifically altered following LH treatment. We propose that functionally significant FSHR/LHR crosstalk reprograms LH-mediated calcium signalling at the interface of receptor-G protein via formation of asymmetric complexes.
Swiecicka A, Eendebak RJAH, Lunt M, et al., 2018, Reproductive Hormone Levels Predict Changes in Frailty Status in Community-Dwelling Older Men: European Male Ageing Study Prospective Data, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 103, Pages: 701-709, ISSN: 0021-972X
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- Citations: 24
Adibi JJ, Zhao Y, Zhan LV, et al., 2017, An Investigation of the Single and Combined Phthalate Metabolite Effects on Human Chorionic Gonadotropin Expression in Placental Cells, ENVIRONMENTAL HEALTH PERSPECTIVES, Vol: 125, ISSN: 0091-6765
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- Citations: 27
Overman MJ, Pendleton N, O'Neill TW, et al., 2017, Evaluation of cognitive subdomains, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D in the European Male Ageing Study, EUROPEAN JOURNAL OF NUTRITION, Vol: 56, Pages: 2093-2103, ISSN: 1436-6207
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- Citations: 12
Swiecicka A, Lunt M, Ahern T, et al., 2017, Nonandrogenic Anabolic Hormones Predict Risk of Frailty: European Male Ageing Study Prospective Data, JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, Vol: 102, Pages: 2798-2806, ISSN: 0021-972X
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- Citations: 17
Cook MJ, Oldroyd A, Pye SR, et al., 2017, Frailty and bone health in European men, AGE AND AGEING, Vol: 46, Pages: 635-641, ISSN: 0002-0729
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- Citations: 20
Overman MJ, Pendleton N, O'Neil TW, et al., 2017, Glycemia but not the Metabolic Syndrome is Associated with Cognitive Decline: Findings from the European Male Ageing Study, AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY, Vol: 25, Pages: 662-671, ISSN: 1064-7481
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- Citations: 14
Doroszko M, Chrusciel M, Belling K, et al., 2017, Novel genes involved in pathophysiology of gonadotropin-dependent adrenal tumors in mice, MOLECULAR AND CELLULAR ENDOCRINOLOGY, Vol: 444, Pages: 9-18, ISSN: 0303-7207
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- Citations: 4
Faraoni EY, Andrea Camilletti M, Abeledo-Machado A, et al., 2017, Sex differences in the development of prolactinoma in mice overexpressing hCGβ: role of TGFβ1, JOURNAL OF ENDOCRINOLOGY, Vol: 232, Pages: 535-546, ISSN: 0022-0795
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- Citations: 18
Rahman NA, Huhtaniemi I, 2017, Zika virus infection-do they also endanger male fertility?, SCIENCE CHINA-LIFE SCIENCES, Vol: 60, Pages: 324-325, ISSN: 1674-7305
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- Citations: 3
Han TS, Correa E, Lean MEJ, et al., 2017, Changes in prevalence of obesity and high waist circumference over four years across European regions: the European male ageing study (EMAS), ENDOCRINE, Vol: 55, Pages: 456-469, ISSN: 1355-008X
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- Citations: 19
Ploeckinger U, Chrusciel M, Doroszko M, et al., 2017, Functional Implications of LH/hCG Receptors in Pregnancy-Induced Cushing Syndrome, JOURNAL OF THE ENDOCRINE SOCIETY, Vol: 1, Pages: 57-71, ISSN: 2472-1972
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- Citations: 19
Doroszko M, Chrusciel M, Stelmaszewska J, et al., 2017, Luteinizing Hormone and GATA4 Action in the Adrenocortical Tumorigenesis of Gonadectomized Female Mice, CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, Vol: 43, Pages: 1064-1076, ISSN: 1015-8987
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- Citations: 6
Potorac I, Trehan A, Fudvoye J, et al., 2017, A compound heterozygous mutation in the luteinizing hormone/chorionic gonadotrophin receptor gene leading to Leydig cell hypoplasia type 1, Publisher: TAYLOR & FRANCIS LTD, Pages: 16-16, ISSN: 1784-3286
Huhtaniemi IT, Howard S, Dunkel L, et al., 2017, The Gonadal Axis: A Life Perspective, HORMONES, BRAIN AND BEHAVIOR, VOL 4: CLINICALLY IMPORTANT HORMONE EFFECTS ON BRAIN AND BEHAVIOR, 3RD EDITION, Editors: Lightman, Pfaff, Joels, Publisher: ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD, Pages: 3-58
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- Citations: 4
Ahern T, Swiecicka A, Eendebak RJAH, et al., 2016, Natural history, risk factors and clinical features of primary hypogonadism in ageing men: Longitudinal Data from the European Male Ageing Study, CLINICAL ENDOCRINOLOGY, Vol: 85, Pages: 891-901, ISSN: 0300-0664
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- Citations: 28
Potorac I, Rivero-Mueller A, Trehan A, et al., 2016, A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation, JOURNAL OF ENDOCRINOLOGY, Vol: 231, Pages: 197-207, ISSN: 0022-0795
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- Citations: 22
Eendebak RJAH, Huhtaniemi IT, Pye SR, et al., 2016, The androgen receptor gene CAG repeat in relation to 4-year changes in androgen-sensitive endpoints in community-dwelling older European men, EUROPEAN JOURNAL OF ENDOCRINOLOGY, Vol: 175, Pages: 583-593, ISSN: 0804-4643
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- Citations: 10
Stelmaszewska J, Chrusciel M, Doroszko M, et al., 2016, Revisiting the expression and function of follicle-stimulation hormone receptor in human umbilical vein endothelial cells, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322
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- Citations: 26
Laurent MR, Cook MJ, Gielen E, et al., 2016, Lower bone turnover and relative bone deficits in men with metabolic syndrome: a matter of insulin sensitivity? The European Male Ageing Study, OSTEOPOROSIS INTERNATIONAL, Vol: 27, Pages: 3227-3237, ISSN: 0937-941X
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- Citations: 26
Laurent MR, Hammond GL, Blokland M, et al., 2016, Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis, SCIENTIFIC REPORTS, Vol: 6, ISSN: 2045-2322
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- Citations: 100
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