Neuro Primer: Pubertal Timing

By: Lauren Granata

The transition from childhood to adulthood is notoriously turbulent. Teens fumble through these years as they try to finesse a balance between school, extracurriculars, and their ever-shifting social spheres. Puberty, and the hormonal and bodily changes it brings, add to the awkward complexity encompassing adolescence.

Undergoing puberty too early or too late can negatively affect physical and mental well-being.


Puberty is a critical developmental period that prepares individuals for reproductive maturity. The age of puberty onset is different for everyone and is partially determined by genetic and environmental factors (Zhu et al., 2018). Undergoing puberty too early or too late can negatively affect physical and mental well-being. Both accelerated and delayed puberty are linked with increased vulnerability to mental health disorders, like anxiety, during adolescence and adulthood (Kaltiala-Heino et al., 2003). Self-awareness and comparisons between peers can contribute to feelings of isolation, distress, body dysmorphia, and gender dysphoria. Estrogen and testosterone, the reproductive hormones that start to circulate during puberty, impact other systems in the body including the brain, immunity, microbiome, and bones. Because there is so much crosstalk between these systems, puberty exerts unique effects on our overall health.

 

But how does the body know when to start puberty? The process begins in the hypothalamus, a small structure found deep in the brain. The hypothalamus is a control center where hormones are released to regulate body temperature, hunger cues, stress responses, and reproductive functions. Around the time of puberty, a specific set of neurons start producing a protein called gonadotropin-releasing hormone (GnRH). Unlike other neurotransmitters, GnRH is secreted in a pattern of surges known as pulses. These GnRH pulses are sent to the pituitary gland, located at the base of the brain. When it receives GnRH, the pituitary releases hormones called gonadotropins, which signal the sex organs to start making their respective sex hormones – testicles make testosterone, while ovaries make both estrogen and progesterone. Finally, sex hormones are sent back to the brain, completing a negative feedback loop and stopping further production of GnRH, keeping hormone levels in balance. Together, this pathway is called the hypothalamic-pituitary-gonadal axis, or HPG axis, named after the three major points of hormone secretion (Dwyer & Quinton, 2019).

The HPG axis begins its development well before puberty, even before we are born. HPG activity remains largely dormant until puberty, but its development is still amenable to influences from the external environment during childhood (Naulé et al., 2020). Today, children are undergoing puberty earlier than they were even 50 years ago (Euling et al., 2008). This trend could be an unexpected consequence of improved nutrition worldwide or the increased prevalence of endocrine disrupting chemicals (EDCs) found in some commonly manufactured products like plastic (Buluş et al., 2016). In addition to the worldwide acceleration of puberty, heightened exposure to these environmental triggers can further influence the timing of puberty on an individual level. There are still some contradictory findings that leave much to be learned about how the environment changes pubertal timing. For example, people who experience childhood stressors are more likely to begin puberty at a younger age. However, when stress is experienced more in older, prepubertal adolescents, puberty tends to be delayed (Jorm et al., 2004). The reason for these contradictory patterns is not fully understood, but new research is beginning to uncover the link between stress responses and pubertal timing.

…new research is beginning to uncover the link between stress responses and pubertal timing.

Before trying to figure out the intricacies of how stress impacts puberty, scientists first mapped out the different types of cells in the hypothalamus and how they control GnRH pulses. They found a family of neurons residing exclusively in the hypothalamus that communicate directly with GnRH neurons. These neurons were named KNDy neurons because they simultaneously express three proteins: Kisspeptin, Neurokinin B, and Dynorphin A. KNDy neurons form synapses directly onto GnRH neurons and are able to either stimulate or inhibit GnRH pulse secretion. KNDy neurons are now considered the gatekeepers of the HPG axis because they can use information from incoming signals, like from the stress response, and decide how GnRH will be released (Tena-Sempere, 2013). Scientists are still learning how exactly KNDy neurons are able to do this, but identifying their role as an influencer of GnRH was a big step.

Within this system, stress can suppress puberty by increasing the concentration of inhibitory neurotransmitters in the hypothalamus with the help of KNDy neurons. Experiments in mice have found that GnRH and KNDy neurons both have receptors for the stress hormone CRF (corticotropin-releasing factor), as well as GABA, the primary inhibitory neurotransmitter in the brain (Acevedo‐Rodriguez et al., 2018). Activating CRF or GABA receptors is like pushing a “slow down” button on GnRH and KNDy neurons. In mice, blocking CRF and GABA receptors means there is no way to push the slow down button, and puberty can no longer be delayed by stress (Lin et al., 2012). From an evolutionary standpoint, shutting down puberty in stressful times is thought to help conserve bodily resources, shifting priorities to staying alive rather than reproducing. It is not yet understood how chronic childhood stress causes earlier puberty, but some scientists argue that accelerated development can be advantageous in an unpredictable environment. This theory is supported by the finding that other circuits in the brain, like those regulating anxiety, also develop faster under chronic childhood stress, but the biological underpinnings of these effects still need to be identified.

Future research must also continue to uncover the biological pathways affecting puberty so that we can mitigate negative outcomes if puberty is derailed.

Investigating the genetic and environmental factors affecting puberty will continue to be important to render a more complete understanding of one of the most influential and tumultuous periods in a young person’s life. Future research must also continue to uncover the biological pathways affecting puberty so that we can mitigate negative outcomes if puberty is derailed. With a better understanding of the complexities necessary to orchestrate puberty, we can perhaps grant some forgiveness to the angsty teens in our lives.

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Written by Lauren Granata
Illustrated by Sarah Barron
Edited by Lauren Wagner, Rebeka Popovic, and Yuki Hebner

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References
Acevedo‐Rodriguez, A., Kauffman, A. S., Cherrington, B. D., Borges, C. S., Roepke, T. A., & Laconi, M. (2018). Emerging insights into hypothalamic-pituitary-gonadal axis regulation and interaction with stress signalling. Journal of Neuroendocrinology, 30(10), e12590. https://doi.org/10.1111/jne.12590

Buluş, A. D., Aşci, A., Erkekoglu, P., Balci, A., Andiran, N., & Koçer-Gümüşel, B. (2016). The evaluation of possible role of endocrine disruptors in central and peripheral precocious puberty. Toxicology Mechanisms and Methods, 26(7), 493–500. https://doi.org/10.3109/15376516.2016.1158894

Dwyer, A. A., & Quinton, R. (2019). Anatomy and Physiology of the Hypothalamic-Pituitary-Gonadal (HPG) Axis. In S. Llahana, C. Follin, C. Yedinak, & A. Grossman (Eds.), Advanced Practice in Endocrinology Nursing (pp. 839–852). Springer International Publishing. https://doi.org/10.1007/978-3-319-99817-6_43

Euling, S. Y., Selevan, S. G., Pescovitz, O. H., & Skakkebaek, N. E. (2008). Role of Environmental Factors in the Timing of Puberty. Pediatrics, 121(Supplement_3), S167–S171. https://doi.org/10.1542/peds.2007-1813C

Jorm, A. F., Christensen, H., Rodgers, B., Jacomb, P. A., & Easteal, S. (2004). Association of adverse childhood experiences, age of menarche, and adult reproductive behavior: Does the androgen receptor gene play a role? American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 125B(1), 105–111. https://doi.org/10.1002/ajmg.b.20114

Kaltiala-Heino, R., Marttunen, M., Rantanen, P., & Rimpelä, M. (2003). Early puberty is associated with mental health problems in middle adolescence. Social Science & Medicine, 57(6), 1055–1064. https://doi.org/10.1016/S0277-9536(02)00480-X

Naulé, L., Maione, L., & Kaiser, U. B. (2021). Puberty, A Sensitive Window of Hypothalamic Development and Plasticity. Endocrinology, 162(1), bqaa209. https://doi.org/10.1210/endocr/bqaa209

Skorupskaite, K., George, J. T., & Anderson, R. A. (2014). The kisspeptin-GnRH pathway in human reproductive health and disease. Human Reproduction Update, 20(4), 485–500. https://doi.org/10.1093/humupd/dmu009

Zhu, J., Kusa, T., & Chan, Y.-M. (2018). Genetics of Pubertal Timing. Current Opinion in Pediatrics, 30(4), 532–540. https://doi.org/10.1097/MOP.0000000000000642

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