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INSL3 Variation in Dogs Following Suppression and Recovery of the HPG Axis (2024)
Journal Article
Anand-Ivell, R., Coutinho, A. R., Dai, Y., England, G., Goericke-Pesch, S., & Ivell, R. (2024). INSL3 Variation in Dogs Following Suppression and Recovery of the HPG Axis. Animals, 14(5), Article 675. https://doi.org/10.3390/ani14050675

Insulin-like peptide 3 (INSL3) is a constitutive product of mature, adult-type Leydig cells of the testes and consequently in most mammals is an ideal biomarker with which to monitor pubertal development. A new heterologous time-resolved fluorescence... Read More about INSL3 Variation in Dogs Following Suppression and Recovery of the HPG Axis.

Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men (2022)
Journal Article
Abbara, A., Koysombat, K., Phylactou, M., Chia Eng, P., Clarke, S., Comninos, A. N., …Dhillo, W. S. (2022). Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men. Frontiers in Endocrinology, 13, Article 1076984. https://doi.org/10.3389/fendo.2022.1076984

Background: Delayed puberty in males is almost invariably associated with constitutional delay of growth and puberty (CDGP) or congenital hypogonadotrophic hypogonadism (CHH). Establishing the cause at presentation is challenging, with “red flag” fea... Read More about Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men.

The Leydig cell biomarker INSL3 as a predictor of age-related morbidity: Findings from the EMAS cohort (2022)
Journal Article
Ivell, R., Heng, K., Severn, K., Antonio, L., Bartfai, G., Casanueva, F. F., …Anand-Ivell, R. (2022). The Leydig cell biomarker INSL3 as a predictor of age-related morbidity: Findings from the EMAS cohort. Frontiers in Endocrinology, 13, Article 1016107. https://doi.org/10.3389/fendo.2022.1016107

Background: Insulin-like peptide 3 (INSL3) is a constitutive hormone secreted in men by the mature Leydig cells of the testes. It is an accurate biomarker for Leydig cell functional capacity, reflecting their total cell number and differentiation sta... Read More about The Leydig cell biomarker INSL3 as a predictor of age-related morbidity: Findings from the EMAS cohort.

Influence on the adult male Leydig cell biomarker insulin-like peptide 3 of maternal exposure to estrogenic and anti-androgenic endocrine disrupting compound mixtures: A retrospective study (2022)
Journal Article
Ivell, R., Vinggaard, A. M., Soyama, H., & Anand-Ivell, R. (2022). Influence on the adult male Leydig cell biomarker insulin-like peptide 3 of maternal exposure to estrogenic and anti-androgenic endocrine disrupting compound mixtures: A retrospective study. Andrologia, 54(11), Article e14566. https://doi.org/10.1111/and.14566

Insulin-like peptide 3 (INSL3) is a peptide biomarker secreted specifically by the mature Leydig cells of the testes. It is constitutive, has low within-individual variance, and effectively measures the functional capacity of Leydig cells to make tes... Read More about Influence on the adult male Leydig cell biomarker insulin-like peptide 3 of maternal exposure to estrogenic and anti-androgenic endocrine disrupting compound mixtures: A retrospective study.

Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort (2022)
Journal Article
Anand-Ivell, R., Heng, K., Severn, K., Antonio, L., Bartfai, G., Casanueva, F. F., …Ivell, R. (2022). Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort. Andrology, 10(7), 1328-1338. https://doi.org/10.1111/andr.13220

Background: Aging in men is accompanied by a broad range of symptoms, including sexual dysfunction, cognitive and musculoskeletal decline, obesity, type 2 diabetes, cardiovascular disease and hypertension, organ degeneration/failure, and increasing n... Read More about Association of age, hormonal, and lifestyle factors with the Leydig cell biomarker INSL3 in aging men from the European Male Aging Study cohort.

Expression and Role of INSL3 in the Fetal Testis (2022)
Journal Article
Ivell, R., Mamsen, L. S., Andersen, C. Y., & Anand-Ivell, R. (2022). Expression and Role of INSL3 in the Fetal Testis. Frontiers in Endocrinology, 13, Article 868313. https://doi.org/10.3389/fendo.2022.868313

Insulin-like peptide 3 (INSL3) is a small peptide hormone of the insulin-relaxin family which is produced and secreted by the fetal Leydig cells in the testes only. It appears to be undetectable in female fetuses. In the human fetus INSL3 synthesis b... Read More about Expression and Role of INSL3 in the Fetal Testis.

Maternal exposure to dibutyl phthalate (Dbp) or diethylstilbestrol (des) leads to long-term changes in hypothalamic gene expression and sexual behavior (2021)
Journal Article
Hunter, D., Heng, K., Mann, N., Anand-Ivell, R., & Ivell, R. (2021). Maternal exposure to dibutyl phthalate (Dbp) or diethylstilbestrol (des) leads to long-term changes in hypothalamic gene expression and sexual behavior. International Journal of Molecular Sciences, 22(8), 1-14. https://doi.org/10.3390/ijms22084163

Xenobiotic exposure during pregnancy and lactation has been linked to perinatal changes in male reproductive outcomes and other endocrine parameters. This pilot study wished to assess whether brief maternal exposure of rats to xenobiotics dibutyl pht... Read More about Maternal exposure to dibutyl phthalate (Dbp) or diethylstilbestrol (des) leads to long-term changes in hypothalamic gene expression and sexual behavior.

The Physiology of Reproduction – Quo vadis? (2021)
Journal Article
Ivell, R., & Anand-Ivell, R. (2021). The Physiology of Reproduction – Quo vadis?. Frontiers in Physiology, 12, Article 650550. https://doi.org/10.3389/fphys.2021.650550

The reproductive system in males and females reflects a highly dynamic underlying physiology. Yet our current understanding of this system is still largely based upon relatively simplistic snapshots of individual component cells and tissues. Gamete p... Read More about The Physiology of Reproduction – Quo vadis?.

Male seminal parameters are not associated with Leydig cell functional capacity in men (2021)
Journal Article
Anand?Ivell, R., Tremellen, K., Soyama, H., Enki, D., & Ivell, R. (2021). Male seminal parameters are not associated with Leydig cell functional capacity in men. Andrology, 9(4), 1126-1136. https://doi.org/10.1111/andr.13001

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 differentiati... Read More about Male seminal parameters are not associated with Leydig cell functional capacity in men.

Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism (2020)
Journal Article
Abbara, A., Eng, P. C., Phylactou, M., Clarke, S. A., Mills, E., Chia, G., …Dhillo, W. S. (2021). Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism. Neuroendocrinology, 111(12), 1176-1186. https://doi.org/10.1159/000513248

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. Ki... Read More about Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism.

Physiology and evolution of the INSL3/RXFP2 hormone/receptor system in higher vertebrates (2020)
Journal Article
Ivell, R., Alhujaili, W., Kohsaka, T., & Anand-Ivell, R. (2020). Physiology and evolution of the INSL3/RXFP2 hormone/receptor system in higher vertebrates. General and Comparative Endocrinology, 299, https://doi.org/10.1016/j.ygcen.2020.113583

© 2020 Elsevier Inc. Although the insulin-like peptide hormone INSL3 and its cognate receptor RXFP2 (relaxin-family peptide receptor 2) have existed throughout chordate evolution, their physiological diversification appears to be linked closely with... Read More about Physiology and evolution of the INSL3/RXFP2 hormone/receptor system in higher vertebrates.

Effects of acute hCG stimulation on serum INSL3 and 25?OH vitamin D in Klinefelter syndrome (2020)
Journal Article
Santi, D., Ivell, R., Anand‐Ivell, R., De Toni, L., Fanelli, F., Mezzullo, M., …Simoni, M. (2020). Effects of acute hCG stimulation on serum INSL3 and 25‐OH vitamin D in Klinefelter syndrome. Andrology, https://doi.org/10.1111/andr.12851

© 2020 American Society of Andrology and European Academy of Andrology Background: It has recently been suggested that the hypergonadotropic hypogonadism characterizing Klinefelter syndrome (KS) might not be due to a steroidogenic dysfunction per se,... Read More about Effects of acute hCG stimulation on serum INSL3 and 25?OH vitamin D in Klinefelter syndrome.

Prepubertal nutrition alters Leydig cell functional capacity and timing of puberty (2019)
Journal Article
Anand-Ivell, R., Byrne, C. J., Arnecke, J., Fair, S., Lonergan, P., Kenny, D. A., & Richard, I. (2019). Prepubertal nutrition alters Leydig cell functional capacity and timing of puberty. PLoS ONE, 14(11), https://doi.org/10.1371/journal.pone.0225465

Leydig cell functional capacity reflects the numbers and differentiation status of the steroidogenic Leydig cells in the testes and becomes more or less fixed in early adulthood with the final establishment of the hypothalamo-pituitary-gonadal (HPG)... Read More about Prepubertal nutrition alters Leydig cell functional capacity and timing of puberty.

Insulin-Like Peptide 3 (INSL3) (2018)
Book Chapter
Anand-Ivell, R., & Ivell, R. (2018). Insulin-Like Peptide 3 (INSL3). In I. Huhtaniemi, & L. Martini (Eds.), Encyclopedia of Endocrine Diseases (793-806). (Second). Elsevier. https://doi.org/10.1016/B978-0-12-801238-3.65735-5

© 2019 Elsevier Inc. Insulin-like peptide 3 (INSL3) is a major secretory product of the steroidogenic Leydig cells of the testes in the fetus as well as in the adult. It is a constitutive product of the mature Leydig cells and hence acts as an excell... Read More about Insulin-Like Peptide 3 (INSL3).

Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology (2018)
Journal Article
Ivell, R., & Anand-Ivell, R. (2018). Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology. Human Reproduction Update, 24(6), (639-651). doi:10.1093/humupd/dmy029. ISSN 1355-4786

BACKGROUND Insulin-like peptide 3 (INSL3) is a member of the relaxin family of neohormones which has evolved to address specifically mammalian aspects of reproduction related to viviparity and internal fertilization. It was originally identified as... Read More about Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology.

Testicular function and bone in young men with severe childhood-onset obesity. (2018)
Journal Article
Anand-Ivell, R., Ivell, R., Laakso, S., Viljakainen, H., Lipsanen-Nyman, M., Turpeinen, U., …Mäkitie, O. (2018). Testicular function and bone in young men with severe childhood-onset obesity. Hormone Research in Paediatrics, 89(6), 442–449. https://doi.org/10.1159/000489818

Background: Previous studies suggest increased risk for hypoandrogenism and fractures in men with obesity. We aimed to describe the effects of severe childhood-onset obesity on the cross talk between metabolic state, testes and skeleton at late puber... Read More about Testicular function and bone in young men with severe childhood-onset obesity..

Oxytocin (2018)
Book Chapter
Ivell, R., Anand-Ivell, R., Tribe, R., & Ludwig, M. (2018). Oxytocin. In Encyclopedia of reproduction (597-606). (Second Edition). Elsevier. https://doi.org/10.1016/B978-0-12-801238-3.64691-3

The small peptide hormone oxytocin has long been recognized as a key factor in the natural induction of the birth process at the end of pregnancy, as well as in the release of milk upon suckling by the infant. It has additional roles within the brain... Read More about Oxytocin.

Development and validation of a mass spectrometry-based assay for quantification of insulin-like factor 3 in human serum (2018)
Journal Article
Anand-Ivell, R., Frederiksen, H., Juul, A., Andersson, A., Albrethsen, J., Nordkap, L., …Jørgensen, N. (2018). Development and validation of a mass spectrometry-based assay for quantification of insulin-like factor 3 in human serum. Clinical Chemistry and Laboratory Medicine, 56(11), https://doi.org/10.1515/cclm-2018-0171

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 devel... Read More about Development and validation of a mass spectrometry-based assay for quantification of insulin-like factor 3 in human serum.

Amniotic fluid INSL3 measured during the critical time window in human pregnancy relates to cryptorchidism, hypospadias and phthalate load: a large case-control study (2018)
Journal Article
Anand-Ivell, R., Cohen, A., Norgaard-Pedersen, B., Joenssen, B., Bonde, J., Hougaard, D. M., …Ivell, R. (2018). Amniotic fluid INSL3 measured during the critical time window in human pregnancy relates to cryptorchidism, hypospadias and phthalate load: a large case-control study. Frontiers in Physiology, 9, Article 408. https://doi.org/10.3389/fphys.2018.00406

The period of the first to second trimester transition in human pregnancy represents a sensitive window for fetal organogenesis, particularly in regard to the development of the male reproductive system. This is a time of relative analytical inaccess... Read More about Amniotic fluid INSL3 measured during the critical time window in human pregnancy relates to cryptorchidism, hypospadias and phthalate load: a large case-control study.

Theca cell INSL3 and steroids together orchestrate the growing bovine antral follicle (2017)
Journal Article
Dai, Y., Ivell, R., & Anand-Ivell, R. (2017). Theca cell INSL3 and steroids together orchestrate the growing bovine antral follicle. Frontiers in Physiology, 8, https://doi.org/10.3389/fphys.2017.01033

Insulin-like peptide 3 (INSL3) and its specific receptor RXFP2 are both expressed by theca interna cells of the growing antral follicle where they form an essential regulatory element in the production of the steroid precursor androstenedione. Using... Read More about Theca cell INSL3 and steroids together orchestrate the growing bovine antral follicle.

Neohormones in milk (2017)
Journal Article
Ivell, R., & Anand-Ivell, R. (2017). Neohormones in milk. Best Practice and Research: Clinical Endocrinology and Metabolism, 31(4), https://doi.org/10.1016/j.beem.2017.10.005

Neohormone systems evolved specifically to regulate those mammalian traits, such as internal fertilization, pregnancy and lactation, which have proved to be central to the success, environmental independence, and adaptability of mammals as a vertebra... Read More about Neohormones in milk.

Male seminal relaxin contributes to induction of the post-mating cytokine response in the female mouse uterus (2017)
Journal Article
Glynn, D. J., Heng, K., Russell, D. L., Sharkey, D. J., Robertson, S. A., Anand-Ivell, R., & Ivell, R. (2017). Male seminal relaxin contributes to induction of the post-mating cytokine response in the female mouse uterus. Frontiers in Physiology, 8, Article 422. https://doi.org/10.3389/fphys.2017.00422

The hormone relaxin is important in female reproduction for embryo implantation, cardiovascular function, and during labor and lactation. Relaxin is also synthesized in males by organs of the male tract. We hypothesized that relaxin might be one comp... Read More about Male seminal relaxin contributes to induction of the post-mating cytokine response in the female mouse uterus.

Relaxin-family peptide receptors 1 and 2 are fully functional in the bovine (2017)
Journal Article
Dai, Y., Ivell, R., Liu, X., Janowski, D., & Anand-Ivell, R. (2017). Relaxin-family peptide receptors 1 and 2 are fully functional in the bovine. Frontiers in Physiology, 8, Article 359. https://doi.org/10.3389/fphys.2017.00359

In most mammals the peptide hormone relaxin is a key physiological component regulating early pregnancy and birth. However, synteny analysis shows that the gene encoding ovarian relaxin-2 is deleted in cows and sheep. While, these ruminants appear to... Read More about Relaxin-family peptide receptors 1 and 2 are fully functional in the bovine.

Relaxin-like peptides in male reproduction: a human perspective (2017)
Journal Article
Ivell, R., Agoulnik, A. I., & Anand-Ivell, R. (2017). Relaxin-like peptides in male reproduction: a human perspective. British Journal of Pharmacology, 174(10), 990-1001. https://doi.org/10.1111/bph.13689

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... Read More about Relaxin-like peptides in male reproduction: a human perspective.

Endocrinology of the Fetal Testis (2017)
Book Chapter
Ivell, R., Anand-Ivell, R., & Morley, S. D. (2017). Endocrinology of the Fetal Testis. In M. Simoni, & I. Huhtaniemi (Eds.), Endocrinology of the Testis and Male Reproduction (245-272). Springer. https://doi.org/10.1007/978-3-319-44441-3_7

The human fetus, already at a very early stage in its development, is hormonally active, with the testis and adrenal gland being major contributors. Following sex determination at around weeks 5–6, the somatic cells of the testis begin to differentia... Read More about Endocrinology of the Fetal Testis.

The male fetal biomarker INSL3 reveals substantial hormone exchange between fetuses in early pig gestation (2016)
Journal Article
Vernunft, A., Ivell, R., Heng, K., & Anand-Ivell, R. (2016). The male fetal biomarker INSL3 reveals substantial hormone exchange between fetuses in early pig gestation. PLoS ONE, 11(3), Article e0152689. https://doi.org/10.1371/journal.pone.0152689

The peptide hormone INSL3 is uniquely produced by the fetal testis to promote the transabdominal phase of testicular descent. Because it is fetal sex specific, and is present in only very low amounts in the maternal circulation, INSL3 acts as an idea... Read More about The male fetal biomarker INSL3 reveals substantial hormone exchange between fetuses in early pig gestation.

Perfluorooctane sulfonate concentrations in amniotic fluid, biomarkers of fetal Leydig cell function, and cryptorchidism and hypospadias in Danish boys (1980–1996) (2015)
Journal Article
Toft, G., Jönsson, B. A., Bonde, J. P., Nørgaard-Pedersen, B., Hougaard, D. M., Cohen, A., …Lindhard, M. S. (2016). Perfluorooctane sulfonate concentrations in amniotic fluid, biomarkers of fetal Leydig cell function, and cryptorchidism and hypospadias in Danish boys (1980–1996). Environmental Health Perspectives, 124(1), 151-156. https://doi.org/10.1289/ehp.1409288

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 h... Read More about Perfluorooctane sulfonate concentrations in amniotic fluid, biomarkers of fetal Leydig cell function, and cryptorchidism and hypospadias in Danish boys (1980–1996).

Longitudinal assessment of circulating insulin-like peptide 3 levels in healthy peripubertal girls (2014)
Journal Article
Hagen, C. P., Mieritz, M. G., Nielsen, J. E., Anand-Ivell, R., Ivell, R., & Juul, A. (2015). Longitudinal assessment of circulating insulin-like peptide 3 levels in healthy peripubertal girls. Fertility and Sterility, 103(3), https://doi.org/10.1016/j.fertnstert.2014.11.014

Objective: To elucidate the natural course of circulating insulin-like peptide 3 (INSL3) levels according to puberty as well as its relation to other reproductive hormones. Design: Population-based cohort study. Setting: Not applicable. Patient(s)... Read More about Longitudinal assessment of circulating insulin-like peptide 3 levels in healthy peripubertal girls.

Amniotic fluid phthalate levels and male fetal gonad function (2014)
Journal Article
Jensen, M. S., Anand-Ivell, R., Nørgaard-Pedersen, B., Jönsson, B. A., Bonde, J. P., Hougaard, D. M., …Toft, G. (2015). Amniotic fluid phthalate levels and male fetal gonad function. Epidemiology, 26(1), 91-99. https://doi.org/10.1097/EDE.0000000000000198

Background: Prenatal exposure to phthalates may pose a threat to human male reproduction. However, additional knowledge about the in vivo effect in humans is needed, and reported associations with genital abnormalities are inconclusive. We aimed to s... Read More about Amniotic fluid phthalate levels and male fetal gonad function.

Cryptorchidism in the orl rat is associated with muscle patterning defects in the fetal gubernaculum and altered hormonal signaling (2014)
Journal Article
Barthold, J. S., Robbins, A., Wang, Y., Pugarelli, J., Mateson, A., Anand-Ivell, R., …Akins, R. E. J. (2014). Cryptorchidism in the orl rat is associated with muscle patterning defects in the fetal gubernaculum and altered hormonal signaling. Biology of Reproduction, 91(2), https://doi.org/10.1095/biolreprod.114.119560

Cryptorchidism, or undescended testis, is a common male genital anomaly of unclear etiology. Hormonal stimulation of the developing fetal gubernaculum by testicular androgens and insulin-like 3 (INSL3) is required for testicular descent. In studies o... Read More about Cryptorchidism in the orl rat is associated with muscle patterning defects in the fetal gubernaculum and altered hormonal signaling.

Insulin-like factor 3 and the HPG axis in the male (2014)
Journal Article
Ivell, R., Heng, K., & Anand-Ivell, R. (in press). Insulin-like factor 3 and the HPG axis in the male. Frontiers in Endocrinology, 5(6), https://doi.org/10.3389/fendo.2014.00006

The hypothalamic–pituitary–gonadal (HPG) axis comprises pulsatile GnRH from the hypothalamus impacting on the anterior pituitary to induce expression and release of both LH and FSH into the circulation. These in turn stimulate receptors on testicular... Read More about Insulin-like factor 3 and the HPG axis in the male.

Serum levels of insulin-like factor 3, anti-Müllerian hormone, inhibin B, and testosterone during pubertal transition in healthy boys: a longitudinal pilot study (2014)
Journal Article
Johansen, M. L., Anand-Ivell, R., Mouritsen, A., Hagen, C. P., Mieritz, M. G., Søeborg, T., …Juul, A. (2014). Serum levels of insulin-like factor 3, anti-Müllerian hormone, inhibin B, and testosterone during pubertal transition in healthy boys: a longitudinal pilot study. Reproduction, 147, https://doi.org/10.1530/REP-13-0435

Insulin-like factor 3 (INSL3) is a promising marker of Leydig cell function with potentially high clinical relevance. Limited data of INSL3 levels in relation to other reproductive hormones in healthy pubertal boys exist. In this study, we aimed to e... Read More about Serum levels of insulin-like factor 3, anti-Müllerian hormone, inhibin B, and testosterone during pubertal transition in healthy boys: a longitudinal pilot study.

Human Testicular Insulin-Like Factor 3 and Endocrine Disrupters (2014)
Book Chapter
Bay, K., & Anand-Ivell, R. (2014). Human Testicular Insulin-Like Factor 3 and Endocrine Disrupters. In Endocrine Disrupters (327-348). Elsevier. https://doi.org/10.1016/B978-0-12-800095-3.00012-2

The hormone insulin-like factor 3 (INSL3) is produced by testicular Leydig cells. Production of INSL3 is dependent on the state of Leydig cell differentiation and is stimulated by the long-term trophic effects of luteinizing hormone. INSL3 is, along... Read More about Human Testicular Insulin-Like Factor 3 and Endocrine Disrupters.

Insulin-like factor 3 as a monitor of endocrine disruption (2013)
Journal Article
Anand-Ivell, R., & Ivell, R. (2014). Insulin-like factor 3 as a monitor of endocrine disruption. Reproduction, 147, Article R87-R95. https://doi.org/10.1530/REP-13-0486

Insulin-like factor 3 (INSL3) is generated and secreted by differentiated interstitial Leydig cells of the testes in both fetal and adult males of all mammalian species so far analyzed. All evidence to date suggests that it is produced constitutively... Read More about Insulin-like factor 3 as a monitor of endocrine disruption.

Circulating insulin-like factor 3 (INSL3) in healthy and infertile women (2013)
Journal Article
Anand-Ivell, R., Tremellen, K., Dai, Y., Heng, K., Yosida, M., Knight, P., & Ivell, R. (2013). Circulating insulin-like factor 3 (INSL3) in healthy and infertile women. Human Reproduction, 28(11), https://doi.org/10.1093/humrep/det3

Study question: How does insulin-like factor 3 (INSL3) concentration in blood vary across the menstrual cycle in women? Summary answer: INSL3 is secreted by the theca interna cells of growing antral follicles and is phasic in its expression. What i... Read More about Circulating insulin-like factor 3 (INSL3) in healthy and infertile women.

Circulating insulin-like factor 3 (INSL3) in healthy and infertile women (2013)
Journal Article
Anand-Ivell, R., Tremellen, K., Dai, Y., Heng, K., Yoshida, M., Knight, P. G., …Ivell, R. (2013). Circulating insulin-like factor 3 (INSL3) in healthy and infertile women. Human Reproduction, 28(11), 3093-3102. https://doi.org/10.1093/humrep/det349

STUDY QUESTIONHow does insulin-like factor 3 (INSL3) concentration in blood vary across the menstrual cycle in women?SUMMARY ANSWERINSL3 is secreted by the theca interna cells of growing antral follicles and is phasic in its expression.WHAT IS KNOWN... Read More about Circulating insulin-like factor 3 (INSL3) in healthy and infertile women.

Regulation of the reproductive cycle and early pregnancy by relaxin family peptides (2013)
Journal Article
Anand-Ivell, R., & Ivell, R. (2014). Regulation of the reproductive cycle and early pregnancy by relaxin family peptides. Molecular and Cellular Endocrinology, 382(1), https://doi.org/10.1016/j.mce.2013.08.010

The relaxin family of peptide hormones are structurally closely related to one another sharing a heterodimeric A–B structure, like that of insulin. They may also be active as unprocessed B–C–A pro-forms. Relaxin has been shown to pay a key role withi... Read More about Regulation of the reproductive cycle and early pregnancy by relaxin family peptides.

Non-classical mechanisms of steroid sensing in the ovary: lessons from the bovine oxytocin model (2013)
Journal Article
Ivell, R., Dai, Y., Mann, N., & Anand-Ivell, R. (2014). Non-classical mechanisms of steroid sensing in the ovary: lessons from the bovine oxytocin model. Molecular and Cellular Endocrinology, 382(1), https://doi.org/10.1016/j.mce.2013.04.016

Steroidogenic tissues such as the ovary, testes or adrenal glands are paradoxical in that they often indicate actions of steroid hormones within a dynamic range of ligand concentration in a high nanomolar or even micromolar level, i.e. at the natural... Read More about Non-classical mechanisms of steroid sensing in the ovary: lessons from the bovine oxytocin model.

INSL3 as a biomarker of Leydig cell functionality (2013)
Journal Article
Ivell, R., Wade, J. D., & Anand-Ivell, R. (2013). INSL3 as a biomarker of Leydig cell functionality. Biology of Reproduction, 88(6), https://doi.org/10.1095/biolreprod.113.108969

Insulin-like factor 3 (INSL3) is a small peptide hormone made and secreted uniquely by mature Leydig cells in the testes of all mammals. Importantly, this expression and secretion appears to be constitutive and therefore reflects the differentiation... Read More about INSL3 as a biomarker of Leydig cell functionality.

Ovarian expression of Insulin-Like peptide 3 (INSL3) and its receptor (RXFP2) during development of bovine antral follicles and corpora lutea and measurement of circulating INSL3 levels during synchronized estrous cycles (2013)
Journal Article
Satchell, L., Glister, C., Bleach, E. C., Glencross, R. G., Bicknell, A. B., Dai, Y., …Knight, P. G. (2013). Ovarian expression of Insulin-Like peptide 3 (INSL3) and its receptor (RXFP2) during development of bovine antral follicles and corpora lutea and measurement of circulating INSL3 levels during synchronized estrous cycles. Endocrinology, 154(5), https://doi.org/10.1210/en.2012-2232

Insulin-like peptide 3 (INSL3), a major product of testicular Leydig cells, is also expressed by the ovary, but its functional role remains poorly understood. Here, we quantified expression of INSL3 and its receptor RXFP2 in theca interna cell (TIC)... Read More about Ovarian expression of Insulin-Like peptide 3 (INSL3) and its receptor (RXFP2) during development of bovine antral follicles and corpora lutea and measurement of circulating INSL3 levels during synchronized estrous cycles.

Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production (2013)
Journal Article
Glister, C., Satchell, L., Bathgate, R. A., Wade, J. D., Dai, Y., Ivell, R., …Knight, P. G. (2013). Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production. Proceedings of the National Academy of Sciences, 110(15), Article E1426-E1435. https://doi.org/10.1073/pnas.1222216110

Bone morphogenetic proteins (BMPs) are firmly implicated as intraovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (... Read More about Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production.

Neohormones as biomarkers of reproductive health (2013)
Journal Article
Anand-Ivell, R., Dai, Y., & Ivell, R. (2013). Neohormones as biomarkers of reproductive health. Fertility and Sterility, 99(4), https://doi.org/10.1016/j.fertnstert.2012.12.023

Neohormone systems are defined as evolutionarily new endocrine or paracrine adaptations that supplement basic physiologic functions and define mammalian success. The relaxin family of peptide hormones are typical neohormones. Because they define the... Read More about Neohormones as biomarkers of reproductive health.

Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring (2013)
Journal Article
Ivell, R., Heng, K., Nicholson, H., & Anand-Ivell, R. (2013). Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring. Asian Journal of Andrology, 15(2), https://doi.org/10.1038/aja.2012.138

Maternal exposure to estrogenic xenobiotics or phthalates has been implicated in the distortion of early male reproductive development, referred to in humans as the testicular dysgenesis syndrome. It is not known, however, whether such early gestatio... Read More about Brief maternal exposure of rats to the xenobiotics dibutyl phthalate or diethylstilbestrol alters adult-type Leydig cell development in male offspring.

Phthalates and perfluorooctanesulfonic acid in human amniotic fluid: Temporal trends and timing of amniocentesis in pregnancy (2012)
Journal Article
Jensen, M. S., Norgaard-Pedersen, B., Toft, G., Hougaard, D. M., Bonde, J. P., Cohen, A., …Jönsson, B. A. (2012). Phthalates and perfluorooctanesulfonic acid in human amniotic fluid: Temporal trends and timing of amniocentesis in pregnancy. Environmental Health Perspectives, 120(6), 897-903. https://doi.org/10.1289/ehp.1104522

Background: Measures of prenatal environmental exposures are important, and amniotic fluid levels may directly reflect fetal exposures during hypothesized windows of vulnerability. Objectives: We aimed to detect various phthalate metabolites and perf... Read More about Phthalates and perfluorooctanesulfonic acid in human amniotic fluid: Temporal trends and timing of amniocentesis in pregnancy.

The endocrine disruptors dibutyl phthalate (DBP) and diethylstilbestrol (DES) influence Leydig cell regeneration following ethane dimethane sulphonate treatment of adult male rats (2011)
Journal Article
Heng, K., Anand-Ivell, R., Teerds, K., & Ivell, R. (2012). The endocrine disruptors dibutyl phthalate (DBP) and diethylstilbestrol (DES) influence Leydig cell regeneration following ethane dimethane sulphonate treatment of adult male rats. International Journal of Andrology, 35(3), 353-363. https://doi.org/10.1111/j.1365-2605.2011.01231.x

The manner by which endocrine-disrupting xenobiotics, such as phthalates, can induce changes in the development of the male reproductive system still remains largely unknown. Herein, we have explored the application of ethane dimethane sulphonate (ED... Read More about The endocrine disruptors dibutyl phthalate (DBP) and diethylstilbestrol (DES) influence Leydig cell regeneration following ethane dimethane sulphonate treatment of adult male rats.

Biological role and clinical significance of insulin-like peptide 3 (2011)
Journal Article
Ivell, R., & Anand-Ivell, R. (2011). Biological role and clinical significance of insulin-like peptide 3. Current Opinion in Endocrinology, Diabetes and Obesity, 18(3), 210-216. https://doi.org/10.1097/MED.0b013e3283453fe6

Purpose of Review: Insulin-like peptide 3 (INSL3) is the subject of a fast expanding literature reflecting increasing clinical application, particularly as a diagnostic parameter. This review summarizes the recent INSL3 literature published within th... Read More about Biological role and clinical significance of insulin-like peptide 3.

The special systems biology of the sperm (2011)
Journal Article
Anand-Ivell, R., & Ivell, R. (2011). The special systems biology of the sperm. Biochemical Journal, 436(3), e3-e5. https://doi.org/10.1042/BJ20110766

Spermatozoa represent a highly specialized cell type, with a minimalist structure designed to fulfil a single principal function: the transport of an intact single-copy haploid genome to the site of fertilization in the oviduct, and consequent zygote... Read More about The special systems biology of the sperm.

INSL3 in the ruminant: A powerful indicator of gender- and genetic-specific feto-maternal dialogue (2011)
Journal Article
Anand-Ivell, R., Hiendleder, S., Viñoles, C., Martin, G. B., Fitzsimmons, C., Eurich, A., …Ivell, R. (2011). INSL3 in the ruminant: A powerful indicator of gender- and genetic-specific feto-maternal dialogue. PLoS ONE, 6(5), 1-7. https://doi.org/10.1371/journal.pone.0019821

The hormone Insulin-like peptide 3 (INSL3) is a major secretory product of the Leydig cells from both fetal and adult testes. Consequently, it is a major gender-specific circulating hormone in the male fetus, where it is responsible for the first pha... Read More about INSL3 in the ruminant: A powerful indicator of gender- and genetic-specific feto-maternal dialogue.

Relaxin family peptides in the male reproductive system-a critical appraisal (2010)
Journal Article
Ivell, R., Kotula-Balak, M., Glynn, D., Heng, K., & Anand-Ivell, R. (2011). Relaxin family peptides in the male reproductive system-a critical appraisal. Molecular Human Reproduction, 17(2), 71-84. https://doi.org/10.1093/molehr/gaq086

The human genome project has identified, besides ovarian relaxin (RLN), six other relaxin-like molecules (RLN3, H1-RLN, INSL3-6), most of which appear to be expressed in the testis and/or male reproductive system, together with four different G-prote... Read More about Relaxin family peptides in the male reproductive system-a critical appraisal.

Dynamics of INSL3 Peptide Expression in the Rodent Testis (2009)
Journal Article
Anand-Ivell, R., Heng, K., Hafen, B., Setchell, B., & Ivell, R. (2009). Dynamics of INSL3 Peptide Expression in the Rodent Testis. Biology of Reproduction, 81(3), 480-487. https://doi.org/10.1095/biolreprod.109.077552

The Leydig cell-specific factor insulin-like peptide 3 (INSL3) is involved in testicular descent during embryo development, and has been suggested to regulate spermatogenesis and bone metabolism in the adult. Using a new, sensitive assay specific for... Read More about Dynamics of INSL3 Peptide Expression in the Rodent Testis.

Demographic, physical and lifestyle factors associated with androgen status: The Florey Adelaide Male Ageing Study (FAMAS) (2009)
Journal Article
Atlantis, E., Martin, S. A., Haren, M. T., O'Loughlin, P. D., Taylor, A. W., Anand-Ivell, R., …Wittert, G. A. (2009). Demographic, physical and lifestyle factors associated with androgen status: The Florey Adelaide Male Ageing Study (FAMAS). Clinical Endocrinology, 71(2), 261-272. https://doi.org/10.1111/j.1365-2265.2008.03463.x

Objective Plasma androgen levels are inversely associated with health in men, the age-related decline of which may result from factors other than ageing per se. This study aimed to determine the effects of demographic, physical and lifestyle factors... Read More about Demographic, physical and lifestyle factors associated with androgen status: The Florey Adelaide Male Ageing Study (FAMAS).

Biology of insulin-like factor 3 in human reproduction (2009)
Journal Article
Ivell, R., & Anand-ivell, R. (2009). Biology of insulin-like factor 3 in human reproduction. Human Reproduction Update, 15(4), 463-476. https://doi.org/10.1093/humupd/dmp011

Background: Insulin-like factor 3 (INSL3) is a neohormone that has evolved to address specific mammalian traits, in particular, the first phase of testicular descent towards the scrotum during mid-gestation. Methods: A thorough literature search was... Read More about Biology of insulin-like factor 3 in human reproduction.

Prenatal induced chronic dietary hypothyroidism delays but does not block adult-type Leydig cell development (2009)
Journal Article
Rijntjes, E., Swarts, H. J., Anand-Ivell, R., & Teerds, K. J. (2009). Prenatal induced chronic dietary hypothyroidism delays but does not block adult-type Leydig cell development. AJP - Endocrinology and Metabolism, 296(2), E305-E314. https://doi.org/10.1152/ajpendo.90750.2008

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

Relaxin signalling in primary cultures of human myometrial cells (2008)
Journal Article
Heng, K., Ivell, R., Wagaarachchi, P., & Anand-Ivell, R. (2008). Relaxin signalling in primary cultures of human myometrial cells. Molecular Human Reproduction, 14(10), 603-611. https://doi.org/10.1093/molehr/gan051

In myometrium of pigs and rats, though not humans, relaxin appears to mediate an inhibition of spontaneous and oxytocin-induced contractility, presumably acting through a G-protein coupled receptor (RXFP1) to generate cAMP. In humans, circulating rel... Read More about Relaxin signalling in primary cultures of human myometrial cells.

Insulin-like factor 3 levels in amniotic fluid of human male fetuses (2008)
Journal Article
Anand-Ivell, R., Ivell, R., Driscoll, D., & Manson, J. (2008). Insulin-like factor 3 levels in amniotic fluid of human male fetuses. Human Reproduction, 23(5), 1180-1186. https://doi.org/10.1093/humrep/den038

BACKGROUND: Rodent studies suggest that the peptide hormone insulin-like factor 3 (Insl3) made by the fetal testis is responsible for the first transabdominal phase of testicular descent, and may be affected by xenobiotics to disrupt male reproductiv... Read More about Insulin-like factor 3 levels in amniotic fluid of human male fetuses.

Panel discussion [of paper: Thyroid disrupting chemicals: mechanisms and mixtures] (2008)
Journal Article
Anand-Ivell, R., Crofton, K., Ivell, R., Köhrle, J., & Kortenkamp, A. (2008). Panel discussion [of paper: Thyroid disrupting chemicals: mechanisms and mixtures]. International Journal of Andrology, 31(2), 222-223. https://doi.org/10.1111/j.1365-2605.2007.00857.x

This is a panel discussion (pages 222-223) of Kevin M. Crofton's paper Thyroid disrupting chemicals: mechanisms and mixtures. Summary of main paper: Environmental contaminants are known to act as thyroid disrupting chemicals (TDCs). Broadly def... Read More about Panel discussion [of paper: Thyroid disrupting chemicals: mechanisms and mixtures].

Panel discussion [of paper: Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat] (2008)
Journal Article
Ivell, R., Hass, U., Anand-Ivell, R., & Gray, E. (2008). Panel discussion [of paper: Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat]. International Journal of Andrology, 31(2), 247-248. https://doi.org/10.1111/j.1365-2605.2008.00866.x

This is a panel discussion of: Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat / S. Christiansen, M. Scholze, M. Axelstad, J. Boberg, A. Kortenkamp, U. Hass. Summary of main paper: The incidence... Read More about Panel discussion [of paper: Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat].

Diverse signalling mechanisms used by relaxin in natural cells and tissues: The evolution of a "neohormone" (2007)
Book Chapter
Ivell, R., Heng, K., & Anand-Ivell, R. (2007). Diverse signalling mechanisms used by relaxin in natural cells and tissues: The evolution of a "neohormone". In A. I. Agoulnik (Ed.), Relaxin and Related Peptides (26-33). Springer Verlag. https://doi.org/10.1007/978-0-387-74672-2_3

The small peptide hormone relaxin is a member of a rapidly evolving family of hormones and growth factors, whose mode of action appears to be particularly adapted to purely mammalian physiology. It is representative of a new category of hormones, ref... Read More about Diverse signalling mechanisms used by relaxin in natural cells and tissues: The evolution of a "neohormone".

Relaxin signalling in THP-1 cells uses a novel phosphotyrosine-dependent pathway (2007)
Journal Article
Anand-Ivell, R., Heng, K., Bartsch, O., & Ivell, R. (2007). Relaxin signalling in THP-1 cells uses a novel phosphotyrosine-dependent pathway. Molecular and Cellular Endocrinology, 272(1-2), 1-13. https://doi.org/10.1016/j.mce.2007.04.001

The heterodimeric peptide hormone relaxin acts through the novel G-protein coupled receptor LGR7 to elicit the production of cAMP in the human monocyte cell line THP-1. The very small number of receptors on the cell surface, and the lack of response... Read More about Relaxin signalling in THP-1 cells uses a novel phosphotyrosine-dependent pathway.

Peripheral INSL3 concentrations decline with age in a large population of Australian men (2006)
Journal Article
Anand-Ivell, R., Wohlgemuth, J., Haren, M. T., Hope, P. J., Hatzinikolas, G., Wittert, G., & Ivell, R. (2006). Peripheral INSL3 concentrations decline with age in a large population of Australian men. International Journal of Andrology, 29(6), 618-626. https://doi.org/10.1111/j.1365-2605.2006.00714.x

The novel peptide hormone insulin-like peptide 3 (INSL3) is a major secretory product of the Leydig cells of the testis, and in adult men is secreted into the blood, giving rise to circulating concentrations ranging from 0.5 to 2.5 ng/mL. We studied... Read More about Peripheral INSL3 concentrations decline with age in a large population of Australian men.

Expression of the insulin-like peptide 3 (INSL3) hormone-receptor (LGR8) system in the testis (2006)
Journal Article
Anand-Ivell, R. J., Relan, V., Balvers, M., Coiffec-Dorval, I., Fritsch, M., Bathgate, R. A., & Ivell, R. (2006). Expression of the insulin-like peptide 3 (INSL3) hormone-receptor (LGR8) system in the testis. Biology of Reproduction, 74(5), 945-953. https://doi.org/10.1095/biolreprod.105.048165

The new peptide hormone insulin-like peptide 3 (INSL3) is a member of the insulin-relaxin family, yet, unlike insulin, it signals through a new G-protein coupled receptor, LGR8, distantly related to the receptors for LH and FSH. INSL3 is produced in... Read More about Expression of the insulin-like peptide 3 (INSL3) hormone-receptor (LGR8) system in the testis.

Constitutive regulation of the Insl3 gene in rat Leydig cells (2005)
Journal Article
Sadeghian, H., Anand-Ivell, R., Balvers, M., Relan, V., & Ivell, R. (2005). Constitutive regulation of the Insl3 gene in rat Leydig cells. Molecular and Cellular Endocrinology, 241(1-2), 10-20. https://doi.org/10.1016/j.mce.2005.03.017

Insulin-like factor 3 (Insl3) is a major new product of the Leydig cells in all mammalian species so far examined. The rat Insl3 gene is encoded by two exons in close juxtaposition to the Jak3 gene. Using RT-PCR analysis we now show that in the rat t... Read More about Constitutive regulation of the Insl3 gene in rat Leydig cells.

Insulin-like factor 3: Where are we now? (2005)
Journal Article
Ivell, R., Hartung, S., & Anand-Ivell, R. (2005). Insulin-like factor 3: Where are we now?. Annals of the New York Academy of Sciences, 1041(1), 486-496. https://doi.org/10.1196/annals.1282.073

Insulin-like factor 3 (INSL3), previously known as the relaxin-like factor (RLF), is a major peptide hormone secreted from the testicular Leydig cells of adult men and circulating in the blood at a concentration of approximately 1 ng/mL. Women also p... Read More about Insulin-like factor 3: Where are we now?.

Relaxin Signaling from Natural Receptors (2005)
Journal Article
Ivell, R., Anand-Ivell, R., & Bartsch, O. (2005). Relaxin Signaling from Natural Receptors. Annals of the New York Academy of Sciences, 1041(1), 280-287. https://doi.org/10.1196/annals.1282.041

The heterodimeric peptide hormone relaxin in most cells appears to signal through a G-protein-coupled receptor, LGR7. Whereas in artificial cell systems, made by transfection of receptor-expressing gene constructs into cells normally not presenting t... Read More about Relaxin Signaling from Natural Receptors.

Understanding relaxin in the female reproductive system (2002)
Journal Article
Ivell, R., & Anand-Ivell, R. (2003). Understanding relaxin in the female reproductive system. Current Medicinal Chemistry Immunology Endocrine and Metabolic Agents, 5(5), 383-389. https://doi.org/10.2174/156801305774322394

Recent advances in our understanding of the hormone relaxin, and the discovery of its specific receptor LGR7, have provided a series of new tools and paradigms, with which to re-examine many aspects of female reproductive physiology classically assoc... Read More about Understanding relaxin in the female reproductive system.