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1. Insulin-like peptide 3 (INSL3) as an indicator of leydig cell insufficiency (LCI) in Middle-aged and older men with hypogonadism: reference range and threshold

Author

Anand-Ivell, Ravinder, primary, Heng, Kee, additional, Antonio, Leen, additional, Bartfai, Gyorgy, additional, Casanueva, Felipe F., additional, Maggi, Mario, additional, O’Neill, Terence W., additional, Punab, Margus, additional, Rastrelli, Giulia, additional, Slowikowska-Hilczer, Jolanta, additional, Tournoy, Jos, additional, Vanderschueren, Dirk, additional, Wu, Frederick CW., additional, Huhtaniemi, Ilpo T., additional, and Ivell, Richard, additional

Published
2024
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3. Endocrinology of the Fetal Testis

Author

Ivell, Richard, Anand-Ivell, Ravinder, Morley, Steven D., Lenzi, Andrea, Series editor, Jannini, Emmanuele A., Series editor, Simoni, Manuela, editor, and Huhtaniemi, Ilpo T., editor

Published
2017
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7. Oxytocin

Author

Ivell, Richard, primary, Ludwig, Mike, additional, Tribe, Rachel M., additional, and Anand-Ivell, Ravinder, additional

Published
2018
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8. Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men

Author

Abbara, Ali, primary, Koysombat, Kanyada, additional, Phylactou, Maria, additional, Eng, Pei Chia, additional, Clarke, Sophie, additional, Comninos, Alexander N., additional, Yang, Lisa, additional, Izzi-Engbeaya, Chioma, additional, Hanassab, Simon, additional, Smith, Neil, additional, Jayasena, Channa N., additional, Xu, Cheng, additional, Quinton, Richard, additional, Pitteloud, Nelly, additional, Binder, Gerhard, additional, Anand-Ivell, Ravinder, additional, Ivell, Richard, additional, and Dhillo, Waljit S., additional

Published
2022
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9. The Leydig cell biomarker INSL3 as a predictor of age-related morbidity: Findings from the EMAS cohort

Author

Ivell, Richard, primary, Heng, Kee, additional, Severn, Katie, additional, Antonio, Leen, additional, Bartfai, Gyorgy, additional, Casanueva, Felipe F., additional, Huhtaniemi, Ilpo T., additional, Giwercman, Aleksander, additional, Maggi, Mario, additional, O’Connor, Daryl B., additional, O’Neill, Terence W., additional, Punab, Margus, additional, Rastrelli, Giulia, additional, Slowikowska-Hilczer, Jolanta, additional, Tournoy, Jos, additional, Vanderschueren, Dirk, additional, Wu, Frederick C. W., additional, and Anand-Ivell, Ravinder, additional

Published
2022
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12. Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort

Author

Anand‐Ivell, Ravinder, primary, Heng, Kee, additional, Severn, Katie, additional, Antonio, Leen, additional, Bartfai, Gyorgy, additional, Casanueva, Felipe F., additional, Huhtaniemi, Ilpo T., additional, Giwercman, Aleksander, additional, Maggi, Mario, additional, O'Neill, Terence W., additional, Punab, Margus, additional, Rastrelli, Giulia, additional, Slowikowska‐Hilczer, Jolanta, additional, Tournoy, Jos, additional, Vanderschueren, Dirk, additional, Wu, Frederick C. W., additional, and Ivell, Richard, additional

Published
2022
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20. Male seminal parameters are not associated with Leydig cell functional capacity in men

Author

Anand?Ivell, Ravinder, Tremellen, Kelton, Soyama, Hiroaki, Enki, Doyo, and Ivell, Richard

Subjects
endocrine system
Abstract

Background: Insulin-like peptide 3 (INSL3) is a constitutive, secreted peptide produced in the male uniquely by the Leydig cells of the testes. It is a biomarker for Leydig cell functional capacity, which is a measure of the numbers and differentiation status of these steroidogenic cells and lacks the biological and technical variance of the steroid testosterone. This retrospective study was carried out to examine the relationship between seminal parameters and the Leydig cell compartment, and secondarily to assess other factors responsible for determining Leydig cell functional capacity. Methods: INSL3 was assessed together with seminal, anthropometric, and hormonal parameters in a Swedish cohort of 18-year-old men, representing the average population, and in a smaller, more heterogeneous cohort of men visiting an Australian infertility clinic. Results and discussion: Average INSL3 concentration at 18years is greater than that reported at younger or older ages and indicated a large 10-fold variation. In neither cohort was there a relationship between INSL3 concentration and any semen parameter. For the larger, more uniform Swedish cohort of young men, there was a significant negative relationship between INSL3 and BMI, supporting the idea that adult Leydig cell functional capacity may be established during puberty. In both cohorts, there was a significant relationship between INSL3 and FSH, but not LH concentration. No relationship was found between INSL3 and androgen receptor trinucleotide repeat polymorphisms, reinforcing the notion that Leydig cell functional capacity is unlikely to be determined by androgen influence alone. Nor did INSL3 correlate with the T/LH ratio, an alternative measure of Leydig cell functional capacity, supporting the view that these are independent measures of Leydig cell function.

Published
2021

24. Prenatal induced chronic dietary hypothyroidism delays but does not block adult-type Leydig cell development

Author

Rijntjes, Eddy, Swarts, Hans J.M., Anand-Ivell, Ravinder, and Teerds, Katja J.

Subjects
Hypothyroidism -- Development and progression, Leydig cells -- Properties, Cell proliferation -- Research, Thyroxine -- Properties, Testosterone -- Properties, Biological sciences
Abstract

Transient hypothyroidism induced by propyl-2-thiouracyl blocks postpartum Leydig cell development. In the present study, the effects of chronic hypothyroidism on the formation of this adult-type Leydig cell population were investigated, using a more physiological approach. Before mating, dams were put on a diet consisting of an iodide-poor feed supplemented with a low dose of perchlorate and, with their offspring, were kept on this diet until death. In the pups at day 12 postpartum, plasma thyroid-stimulating hormone levels were increased by 20-fold, whereas thyroxine and free tri-iodothyronine levels were severely depressed, confirming a hypothyroid condition. Adult-type progenitor Leydig cell formation and proliferation were reduced by 40-60% on days 16 and 28 postpartum. This was followed by increased Leydig cell proliferation at later ages, suggesting a possible slower developmental onset of the adult-type Leydig cell population under hypothyroid conditions. Testosterone levels were increased 2- to 10-fold in the hypothyroid animals between days 21 and 42 postpartum compared with the age-matched controls. Combined with the decreased presence of 5[alpha]-reductase, this implicates a lower production capacity of 5[alpha]reduced androgens. In 84-day-old rats, after correction for body weight-to-testis weight ratio, plasma insulin-like factor-3 levels were 35% lower in the hypothyroid animals, suggestive of a reduced Leydig cell population. This is confirmed by a 37% reduction in the Sertoli cell-to-Leydig cell ratio in hypothyroid rats. In conclusion, we show that dietary-induced hypothyroidism delays but, unlike propyl-2-thiouracyl, does not block the development of the adult-type Leydig cell population. thyroxine; testosterone; insulin-like factor-3; Leydig cell proliferation

Published
2009

26. Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism

Author

Abbara, Ali, primary, Eng, Pei Chia, additional, Phylactou, Maria, additional, Clarke, Sophie A., additional, Mills, Edouard, additional, Chia, Germaine, additional, Yang, Lisa, additional, Izzi-Engbeaya, Chioma, additional, Smith, Neil, additional, Jayasena, Channa N., additional, Comninos, Alexander N., additional, Anand-Ivell, Ravinder, additional, Rademaker, Jesse, additional, Xu, Cheng, additional, Quinton, Richard, additional, Pitteloud, Nelly, additional, and Dhillo, Waljit S., additional

Published
2020
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29. Kisspeptin-54 accurately identifies hypothalamic dysfunction in men with congenital hypogonadotropic hypogonadism

Author

Abbara, Ali, primary, Chia, Eng Pei, additional, Phylactou, Maria, additional, Clarke, Sophie, additional, Mills, Edouard, additional, Chia, Germaine, additional, Yang, Lisa, additional, Izzi-Engbeaya, Chioma, additional, Jayasena, Channa, additional, Comninos, Alexander, additional, Ivell, Richard, additional, Anand-Ivell, Ravinder, additional, Rademaker, Jesse, additional, Cheng, Xu, additional, Quinton, Richard, additional, Pittelout, Nelly, additional, and Dhillo, Waljit, additional

Published
2020
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30. Effects of acute hCG stimulation on serum INSL3 and 25‐OH vitamin D in Klinefelter syndrome

Author

Santi, Daniele, primary, Ivell, Richard, additional, Anand‐Ivell, Ravinder, additional, De Toni, Luca, additional, Fanelli, Flaminia, additional, Mezzullo, Marco, additional, Pelusi, Carla, additional, Pagotto, Uberto, additional, Belli, Serena, additional, Granata, Antonio R. M., additional, Roli, Laura, additional, Rochira, Vincenzo, additional, Trenti, Tommaso, additional, Ferlin, Alberto, additional, and Simoni, Manuela, additional

Published
2020
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34. Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism.

Author

Abbara, Ali, Eng, Pei Chia, Phylactou, Maria, Clarke, Sophie A., Mills, Edouard, Chia, Germaine, Yang, Lisa, Izzi-Engbeaya, Chioma, Smith, Neil, Jayasena, Channa N., Comninos, Alexander N., Anand-Ivell, Ravinder, Rademaker, Jesse, Xu, Cheng, Quinton, Richard, Pitteloud, Nelly, and Dhillo, Waljit S.

Subjects
HYPOTHALAMIC hormones, HYPOGONADISM, KALLMANN syndrome, RECEIVER operating characteristic curves, GENETIC variation
Abstract

Background: Hypogonadotropic hypogonadism (HH) is hypogonadism due to either hypothalamic or pituitary dysfunction. While gonadotropin-releasing hormone (GnRH) can directly test pituitary function, no specific test of hypothalamic function exists. Kisspeptin-54 (KP54) is a neuropeptide that directly stimulates hypothalamic GnRH release and thus could be used to specifically interrogate hypothalamic function. Congenital HH (CHH) is typically due to variants in genes that control hypothalamic GnRH neuronal migration or function. Thus, we investigated whether KP54 could accurately identify hypothalamic dysfunction in men with CHH. Methods: Men with CHH (n = 21) and healthy eugonadal men (n = 21) received an intravenous bolus of either GnRH (100 μg) or KP54 (6.4 nmol/kg), on 2 occasions, and were monitored for 6 h after administration of each neuropeptide. Results: Maximal luteinizing hormone (LH) rise after KP54 was significantly greater in healthy men (12.5 iU/L) than in men with CHH (0.4 iU/L; p < 0.0001). KP54 more accurately differentiated CHH men from healthy men than GnRH (area under receiver operating characteristic curve KP54: 1.0, 95% CI 1.0–1.0; GnRH: 0.88, 95% CI 0.76–0.99). Indeed, all CHH men had an LH rise <2.0 iU/L following KP54, whereas all healthy men had an LH rise >4.0 iU/L. Anosmic men with CHH (i.e., Kallmann syndrome) had even lower LH rises after KP54 than did normosmic men with CHH (p = 0.017). Likewise, men identified to have pathogenic/likely pathogenic variants in CHH genes had even lower LH rises after KP54 than other men with CHH (p = 0.035). Conclusion: KP54 fully discriminated men with CHH from healthy men. Thus, KP54 could be used to specifically interrogate hypothalamic GnRH neuronal function in patients with CHH. [ABSTRACT FROM AUTHOR]

Published
2021
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37. Perfluorooctane sulfonate concentrations in amniotic fluid, biomarkers of fetal leydig cell function, and cryptorchidism and hypospadias in Danish boys (1980-1996)

Author

Toft, Gunnar, Jonsson, Bo A.G., Bonde, Jens Peter, Nergaard-Pedersen, Bent, Hougaard, David M., Cohen, Arieh, Lindh, Christian H., Ivell, Richard, Anand-Ivell, Ravinder, and Lindhard, Morten S.

Subjects
Amniotic fluid -- Physiological aspects, Leydig cells -- Physiological aspects, Organic fluorine compounds -- Environmental aspects -- Health aspects, Environmental issues, Health
Abstract

BACKGROUND: Exposure to perfluorooctane sulfonate (PFOS) may potentially disturb fetal Leydig cell hormone production and male genital development. OBJECTIVES: We aimed to study the associations between levels of amniotic fluid PFOS, fetal steroid hormone, and insulin-like factor 3 (INSL3) and the prevalence of cryptorchidism and hypospadias. METHODS: Using the Danish National Patient Registry, we selected 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls with stored maternal amniotic fluid samples available in a Danish pregnancy-screening biobank (1980-1996). We used mass spectrometry to measure PFOS in amniotic fluid from 645 persons and steroid hormones in samples from 545 persons. INSL3 was measured by immunoassay from 475 persons. Associations between PFOS concentration in amniotic fluid, hormone levels, and genital malformations were assessed by confounder-adjusted linear and logistic regression. RESULTS: The highest tertile of PFOS exposure (> 1.4 ng/mL) in amniotic fluid was associated with a 40% (95% CI: -69, -11%) lower INSL3 level and an 18% (95% CI: 7, 29%) higher testosterone level compared with the lowest tertile (< 0.8 ng/mL). Amniotic fluid PFOS concentration was not associated with cryptorchidism or hypospadias. CONCLUSIONS: Environmental PFOS exposure was associated with steroid hormone and INSL3 concentrations in amniotic fluid, but was not associated with cryptorchidism or hypospadias in our study population. Additional studies are needed to determine whether associations with fetal hormone levels may have long-term implications for reproductive health. http://dx.doi.org/10.1289/ehp.1409288, Introduction Perfluorooctane sulfonate (PFOS) has until recently been widely used in a variety of applications, especially in surface coatings used to make products water- and oil-resistant. PFOS is highly biopersistent [...]

Published
2016
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41. Development and validation of a mass spectrometry-based assay for quantification of insulin-like factor 3 in human serum

Author

Anand-Ivell, Ravinder, Juul, Anders, Albrethsen, Jacob, Frederiksen, Hanne, Andersson, Anna-Maria, Nordkap, Loa, and Kirstine Bang, Anne

Subjects
endocrine system, assay development, insulin-like factor 3 (INSL3), mass spectrometry
Abstract

BACKGROUND:The circulating level of the peptide hormone insulin-like factor 3 (INSL3) is a promising diagnostic marker reflecting Leydig cell function in the male. Few commercial immunoassays of varying quality exist. Therefore, we decided to develop and validate a precise method for quantification of INSL3 by mass spectrometry.METHODS:We developed an assay in which the INSL3 A-chain is released from the INSL3 A-B heterodimer by chemical reduction and alkylation. The alkylated INSL3 A-chain is quantitated by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as substitute for serum INSL3. The method was compared to a validated and sensitive in-house serum INSL3 immunoassay using 97 serum samples from 12 healthy boys during pubertal transition. Adult levels were determined based on sera from 72 adult healthy males aged 18-40 years.RESULTS:An LC-MS/MS assay with limit of detection and limit of quantification (LOQ) of 0.06 and 0.15 ng/mL, respectively, and intra-assay CVs

Published
2018

44. Relaxin-like peptides in male reproduction: a human perspective

Author

Ivell, Richard, Agoulnik, Alexander I., and Anand-Ivell, Ravinder

Subjects
endocrine system, urogenital system, GEO, gene expression omnibus, INSL3–6, insulin-like peptide 3–6, LH, luteinizing hormone, RXFP1–4, relaxin family peptide receptor 1–4, RLN2, H2-relaxin, LGR7, leucine-rich repeat-containing GPCR 7, synonymouswith RXFP1, RLN3, relaxin-3
Abstract

The relaxin family of peptide hormones and their cognate GPCRs are becoming physiologically well-characterized in the cardiovascular system and particularly in female reproductive processes. Much less is known about the physiology and pharmacology of these peptides in male reproduction, particularly as regards humans. H2-relaxin is involved in prostate function and growth, while insulin-like peptide 3 (INSL3) is a major product of the testicular Leydig cells and, in the adult, appears to modulate steroidogenesis and germ cell survival. In the fetus, INSL3 is a key hormone expressed shortly after sex determination and is responsible for the first transabdominal phase of testicular descent. Importantly, INSL3 is becoming a very useful constitutive biomarker reflecting both fetal and post-natal development. Nothing is known about roles for INSL4 in male reproduction and only very little about relaxin-3, which is mostly considered as a brain peptide, or INSL5. The former is expressed at very low levels in the testes, but has no known physiology there, whereas the INSL5 knockout mouse does exhibit a testicular phenotype with mild effects on spermatogenesis,probably due to a disruption of glucose homeostasis. INSL6 is a major product of male germ cells, although it is relatively unexplored with regard to its physiology or pharmacology, except that in mice disruption of the INSL6 gene leads to a disruption of spermatogenesis. Clinically, relaxin analogues may be useful in the control of prostate cancer, and both relaxin and INSL3 have been considered as sperm adjuvants for in vitro fertilization.

Published
2017

45. Amniotic Fluid INSL3 Measured During the Critical Time Window in Human Pregnancy Relates to Cryptorchidism, Hypospadias, and Phthalate Load: A Large Case–Control Study

Author

Anand-Ivell, Ravinder, primary, Cohen, Arieh, additional, Nørgaard-Pedersen, Bent, additional, Jönsson, Bo A. G., additional, Bonde, Jens-Peter, additional, Hougaard, David M., additional, Lindh, Christian H., additional, Toft, Gunnar, additional, Lindhard, Morten S., additional, and Ivell, Richard, additional

Published
2018
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48. Oxytocin

Author

Ivell, Richard, Ludwig, Mike, Tribe, Rachel M., and Anand-Ivell, Ravinder

Published
2015
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