Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology

Anand-Ivell, Ravinder and Ivell, Richard (2018) Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology. Human Reproduction Update, 24 (6). pp. 639-651. ISSN 1460-2369

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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 a major product of testicular Leydig cells and has proved to be an important biomarker of Leydig cell functional capacity. However, INSL3 is also produced by theca interna cells of growing antral follicles and is secreted into the bloodstream in phases corresponding to the number and health of the follicles. Moreover, gene silencing experiments have shown that INSL3 is essentially required for androstenedione synthesis, which is the major steroid precursor for the granulosa cells of antral follicles to produce oestrogens. Knockout studies in mice confirm that loss of INSL3 or its receptor in females leads to partial infertility, with reduced follicle numbers, ovulations and litter size. Circulating INSL3 concentration corresponds to the reproductive lifespan, beginning with puberty and declining at the menopause, and thus may contribute to the physiology of other organ systems, particularly those relevant for hormone replacement strategies.


A literature review was carried out by exhaustive searching of literature databases (PubMed and Google Scholar) with the search terms INSL3, RLF, Ley-IL and RXFP2.


We present the first comprehensive review of INSL3 and its specific receptor RXFP2, and their roles in the context of female reproductive physiology. Moreover, we highlight the potential involvement of INSL3 in female reproductive pathology, such as PCOS, its clinical application as a valuable biomarker of reproductive processes, and its potential for therapeutic interventions.


In the female mammal, INSL3 is largely produced by the theca interna cells of growing antral follicles during the follicular phase of the menstrual (oestrous) cycle. Within the follicle, INSL3 acts via its G-protein-coupled receptor, RXFP2, in an autocrine/paracrine manner to orchestrate and drive the production of the major steroid precursor androstenedione and its conversion by granulosa cells into oestrogens. These in turn create a positive feedback loop promoting the expression of more theca cell INSL3. This is countered by the follicular production of bone morphogenetic proteins and by the LH surge. Thus, the activity of the theca cell INSL3-RXFP2 system effectively determines the production of estradiol within an antral follicle through the follicular phase. INSL3 is also secreted into the circulation where it acts as a valuable biomarker to monitor the growth of antral follicles; it is consequently increased in PCOS and decreased in women with premature ovarian failure (POF). As an endocrine factor, INSL3 may also influence bone metabolism and kidney function. Additionally, INSL3 or its analogues may prove valuable as an adjunct in hormone replacement therapy or to monitor or influence IVF protocols.


The INSL3-RXFP2 system represents a new regulatory pathway essential for the proper functioning of growing antral follicles. We still know very little about its involvement in pathologies such as PCOS or POF, and its role as a new biomarker of female function needs to be explored more widely to improve diagnosis and treatment of ovarian dysfunction. We need to examine how INSL3 might be used to improve IVF protocols and outcomes. Opportunities should also be investigated in regard to the systemic application of INSL3 as a rejuvenant therapy, with positive effects on bone or kidney function, and possibly also for fertility regulation. Most research to date has involved animal models; this now needs to be extended to include more human studies.

Item Type: Article
Additional Information: This paper summarizes our recent breakthrough research where we have revised and established a new concept for the ovarian 2-cell theory that operates within the growing ovarian follicle. Insulin like factor 3, a relaxin family peptide, is a major player in orchestrating the process of steroidogenesis in females. So far this is the major role of INSL3 that we have established. Topic: polycystic ovary syndrome hormone replacement therapy menopause bone morphogenetic proteins renal function estrogen estradiol fertilization in vitro biological markers cattle feedback fertility fertilization menstrual cycle, proliferative phase gene silencing objective (goal) granulosa cells hair follicle infertility interstitial cell of leydig litter size mammals menstruation animal model ovarian failure, premature ovarian follicle ovulation peptides relaxin reproductive physiological process steroids theca cell androstenedione diagnosis insulin mice ovary pathology physiology puberty disorder of endocrine ovary secondary follicle of ovary steroidogenesis autocrine paracrine bone metabolism female reproductive function therapeutic intervention functional capacity life span
Keywords: INSL3, RXFP2, antral follicle, follicular phase, theca cells, steroidogenesis, PCOS, androstenedione, estradiol, ovary
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Biosciences
Identification Number:
Depositing User: Anand-Ivell, Dr Ravinder
Date Deposited: 23 Oct 2018 10:51
Last Modified: 23 Oct 2018 10:51

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