Introduction:
Hormones are crucial in maintaining various physiological processes within the human body, and the INSL3 hormone is no exception. Insulin-like factor 3 (INSL3) belongs to the peptide hormone family, encompassing insulin, IGF1, IGF2, relaxin, and other lesser-known peptides. While its primary function is associated with reproductive health, emerging research suggests that INSL3 may also influence various aspects of long-term health in men. INSL3 as HPG (hypothalamic-pituitary-gonadal) axis endpoint affects Leydig and male germ cells, supporting spermatogenesis. Unlike testosterone, INSL3 is not influenced by episodic HPG changes, making it a useful marker for Leydig cell status and function. It helps access puberty, treats hypogonadal patients, and stabilizes HPG output.
What Is INSL3 Hormone?
INSL3, or Insulin-like 3, is a peptide hormone released by the Leydig cells in the testes of men. In male mammals, the primary site of INSL3 synthesis is within the interstitial Leydig cells found in both the fetal and adult testes. Although there might be localized synthesis in specific peripheral tissues, these don't influence hormone levels in circulation. Testes are solely responsible for producing the hormone, which can only affect nearby cells through autocrine or paracrine mechanisms. While Leydig cells are recognized for generating androgenic steroids like testosterone (T), androstenedione (A4), and dihydrotestosterone (DHT), they also release substantial amounts of INSL3. This contributes to around 1 ng/ml of circulating hormone concentration in adult men, with higher levels in some other mammals. It plays a significant role in the development of the male reproductive system, particularly during fetal development. One of its essential functions is to regulate the descent of the testes into the scrotum, a critical process for proper spermatogenesis and fertility in adult men.
In addition to its role in reproductive health, INSL3 may have potential implications for various aspects of long-term health in men. Emerging research suggests that INSL3 could influence bone health, metabolic regulation, cardiovascular function, aging, and longevity. However, much of this research is still in its early stages, and further studies are needed to fully understand the hormone's multifaceted roles and impact on overall well-being.
What Is the Role of INSL3 in Males?
INSL3, or Insulin-like 3, plays a significant role in males, primarily within the realm of reproductive health. Its main functions include:
Fetal Development: During fetal development, the primary role of INSL3 is to initiate the initial phase of testicular descent through the abdomen. This process occurs shortly after sex determination and correlates with the appearance of INSL3 or its mRNA in the fetus or amniotic fluid. INSL3 acts on its specific receptor RXFP2 (relaxin family peptide receptor 2), a G-protein coupled receptor usually associated with Gs. This activation triggers adenylyl cyclase. In the male fetus, RXFP2 is expressed by the cells in the gubernacular bulb. The gubernaculum is a ligament that connects the front aspect of the developing testis to the inguinal region.
Spermatogenesis: INSL3 is involved in the regulation of testicular function and the production of testosterone. Proper levels of testosterone are necessary for the development of sperm cells and the maintenance of reproductive health in adult men.
Reproductive Function: INSL3 helps maintain the health of Leydig cells in the testes, which are responsible for producing testosterone. Adequate testosterone levels are essential for developing and maintaining male reproductive organs, libido, and fertility.
Androgenic Action: INSL3, often called a 'neohormone', has evolved to address functions unique to mammals specifically. One of its key roles is promoting the descent of the testes and their location in the scrotum. Additionally, it enhances the growth of horns and bones in males, closely tied to male reproductive behavior, which is another characteristic of neohormone. When examining how INSL3 functions as both an endocrine hormone and a paracrine or autocrine hormone, it becomes apparent that it primarily synergizes directly or indirectly with the androgen action induced by gonadotropins. This synergy is observed in various aspects, such as bone and horn growth, the development of the male reproductive tract during embryonic stages, and support of germ cell survival within seminiferous tubules.
How Does INSL3 Impact Long-Term Health in Men?
The impact of INSL3 on long-term health in men is an area of ongoing research, and many of its effects are still being explored. Here are some potential ways INSL3 could impact men's long-term health:
Bone Health: It has been proposed that INSL3, through its receptor RXFP2, could influence bone density and remodeling by affecting osteoblast (bone-forming cells) and osteoclast (bone-resorbing cells) activity. INSL3 plays a role in regulating this activity, which is vital for maintaining bone health. It has been proposed that INSL3 regulates the gene expression involved in the differentiation and maturation of primary osteoblasts and osteonectin.
Metabolic Regulation: Evidence indicates that INSL3 might be involved in metabolic regulation, including glucose homeostasis and insulin sensitivity. These factors are crucial in preventing metabolic disorders such as type 2 diabetes and obesity. If INSL3 plays a role in metabolic health, it could contribute to better long-term metabolic outcomes in men.
Cardiovascular Health: Some preliminary studies suggest that INSL3 may have a vasodilatory effect, which could improve blood flow and potentially contribute to the prevention of hypertension. Cardiovascular health is critical for overall well-being and longevity. If INSL3 has a positive impact, it could have implications for reducing the risk of heart-related issues.
Aging and Longevity: Although this area is still speculative, some researchers propose that maintaining optimal INSL3 levels might contribute to healthier aging in men and potentially extend their lifespan. However, the exact mechanisms and causative relationships between INSL3 and aging require further exploration.
Pathology: Given its role within a synergistic network that modulates gonadotropin action, it is unlikely for INSL3 alteration to lead to particular effects. Males experiencing a complete loss of INSL3 function or its receptor exhibit osteopenia, osteoporosis, and cryptorchidism. While decreased INSL3 in the ovary is linked to reduced antral follicle growth and maturation, the adult testis does not exhibit such clear abnormalities, especially when targeting the receptor knockout, specifically to avoid cryptorchidism-related impacts. INSL3's buffering effect might be more apparent in the puberty phase. In cases of testicular dysgenesis syndrome induced by endocrine-disrupting agents like phthalates, fetal Leydig cells reduced INSL3 production. Leydig cell development and function, showing less random function compared to androgens.
Leydig cell numbers remain stable post-puberty, with minimal evidence of adult Leydig cell loss or proliferation. Although some reports suggest Leydig cell loss in old age, these studies often exclude potentially differentiated cells.
Conclusion:
While INSL3's primary role in reproductive health is well-established, its influence on men's long-term health is an area of ongoing research. The hormone's potential involvement in bone health, metabolic regulation, cardiovascular function, and aging suggests a complex interplay between INSL3 and various physiological systems. As scientific understanding advances, further insights into the role of INSL3 could lead to innovative approaches for promoting men's overall well-being and longevity. However, it's important to note that much of this research is still in its early stages, and additional studies are needed to confirm and expand upon these intriguing findings.
