During adolescence, there is a significant change in the levels of hormones, particularly gonadotropic releasing hormone (GnRH), FSH and LH, as well sex gonadal sex steroids that lead to sexual development (37). Certain hormonal developments are unique to sex, such as mammary gland development, which accelerates during puberty. GH, IGF-1, and estrogen are thought to be the most important factors in pubertal mammary development, acting to support ductal growth (38). While puberty usually occurs at set times for males and females, precocious and delayed puberty inspired the field of research that investigates the causes and treatments for abnormal sex hormone levels. Recently, the gut microbiome has been a focus of metabolic research due to its role in health and homeostasis, intersecting several bodily systems. The microbiota, largely passed on from mother to child, has been shown to influence both metabolism and the production of certain hormones. Work on causes and treatment of precious puberty, for example, has examined the role of microorganisms (39).

With increasing attention paid to gender dysphoria and transgender health, there has been a rise in research on hormone modulation, including puberty blockers and their long-term sequelae. Mouse experiments using prepubertal administration of leuprolide acetate (LA) and testosterone found similar long-term outcomes in ovarian function and embryologic development when compared with controls, suggesting no permanent reproductive impairment with puberty blockers (40). However, current recommendations, based on studies on the effects of puberty blockers in humans, are to delay puberty blockade until after germ cell maturation to preserve future fertility. Fertility preservation has been most successful in transgender males (i.e., individuals assigned female at birth but who identify as male) likely because they are born with all the germ cells they will ever have. Puberty blocker administration has no effect on germ cell maturation in these individuals (41). Histrelin (GnRH agonist) implants act as puberty blockers by continuously eluding this drug. These implants have been shown to be a safe treatment for both precocious puberty and gender dysphoria (42).

After puberty, there is a period of continued somatic growth, after which the endocrine system has fully matured. Hormones then mainly serve the purposes of regulating adult metabolism and maintaining fertility.

Sex steroid hormones (SSH) are being studied for their role in treating certain depressive disorders in adults. While the mechanisms are still under investigation, future studies will examine the downstream effects of targeting GABA and other receptor signaling pathways across genders, ages, and health conditions (43). SSHs are also being assessed for their role in other body systems. One study found, for example, that while estradiol is not associated with periodontitis, sex hormone-binding globulin (SHBG), testosterone, and free androgen levels were negatively associated with periodontitis and even more strongly in individuals under 50 (44).

In the adult musculoskeletal system, hormones help maintain bone and soft tissue integrity. The sources of GH and IGF in the adult skeleton are still under investigation, though bone marrow stromal cells (BMSCs) are one source of IGF known to support osteogenesis while inhibiting adipogenesis in the adult skeleton (45). Growth hormone has also been explored for its role in other endocrine axes, including fertility research for its potential to improve IVF outcomes (46).

With an increasing number of transgender and gender non-binary individuals being prescribed long-term exogenous hormones, the prolonged effects of sex hormones on mature hormone-sensitive tissues is gradually coming to light. Testosterone, for example, induces cellular changes that alter glandular tissue density and fat distribution in the mature breast, leading to a decrease in breast size and modified ductal morphology (47). The implications for breast cancer risk in transgender men are unknown and studies on this subject have been largely inconclusive, due in part to small sample sizes. One systematic review found a slightly higher incidence of breast cancer after testosterone use in transgender men compared to cisgender men while others have found no such relationship (48, 49). There is evidence that elevated serum androgen levels are linked to higher breast cancer risk in post-menopausal women, and it is known that androgen receptor (AR) blockade may help treat some AR-positive breast cancers by inhibiting tumor growth, though this observed behavior varies with breast cancer subtype (50–52). Other areas of investigation specific to transgender individuals include the lifetime risk of osteoporosis, cardiovascular disease and non-breast glandular (e.g., prostate) cancers under the influence of prolonged exogenous hormone therapy (53, 54).

Hormones each play a unique and important role in development at different stages of life. During fetal development, placental hormones take main stage to support nutrient delivery, fetal growth, and maintain healthy hormone levels until fetal structures develop sufficiently to assume this role. Prior to puberty, development centers around proper musculoskeletal, neurologic, and metabolic development. During puberty, sex steroids along the hypothalamic-pituitary-gonadal axis support reproductive maturation. Following puberty into adulthood, hormones are most important for maintaining metabolism, musculoskeletal health, and fertility.

Research into each of these phases aims at understanding the role of hormones and interplay within, and across, their respective axes. This also includes better understanding how to restore physiologic levels of hormones in the midst of pathology. Hormone modulation is also critical in the treatment of conditions ranging from delayed puberty to gender dysphoria (39–41).

While research is ongoing to gain a more comprehensive understanding of all hormones involved in development, the greatest focus continues to be on sex hormones. This may be due to their role throughout the lifespan, from sexual development to fertility after puberty. The increase in attention to transgender and gender non-binary health also has sparked more investigation into safe and effective hormonal therapeutics. Continued work is needed to more completely piece together the mechanisms and interplay of hormonal axes and how these impact human development and health.

YA: Writing – original draft, Writing – review & editing. SF: Conceptualization, Writing – original draft. ER: Conceptualization, Project administration, Writing – original draft, Writing – review & editing.