Adolescent Health Month

Impact of Vitamin D on Puberty and Menarche: A Review of Research

By: Laura Olivieri

Director’s Note: During Adolescent Health Month, we are featuring research on the importance of adequate vitamin D levels in female pubertal development. Summarized by former FACTS elective participant, Laura Olivieri, this 2023 study [1] identified vitamin D as a key regulator of endocrine pathways with implications for the timing of menarche in adolescence. The study by Calcaterra et al is titled, “Association between Vitamin D Levels, Puberty Timing, and Age at Menarche.” Drawing from the article and information learned in the FACTS elective, Olivieri wonders whether screening for Vitamin D deficiency in adolescence may be indicated, especially in light of the rise in early onset puberty.

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Introduction

Vitamin D deficiency is associated with diverse conditions such as low bone mass, inflammation, altered immune response, respiratory infections, hypertension, metabolic syndrome, and depression. [1] Mediated primarily through the vitamin D Receptor (VDR), vitamin D impacts almost every cell in the body, including action in the hypothalamic-pituitary-gonadal (HPG) axis, an integral pathway for sexual maturation. [1] Consequences to changes in pubertal development can be significant and long term. Early pubertal development in females has been associated with several adverse outcomes, including altered growth velocity and final height, an increased risk of obesity, type 2 diabetes, ischemic heart disease, estrogen-dependent cancers, and adverse mental health outcomes such as depression, anxiety, and eating disorders. [1] Recognizing these potential outcomes and vitamin D’s role as a regulator of endocrine and ovarian function, it is important to assess whether abnormal vitamin D levels could be a modifiable cause of early pubertal timing and a potential target for its prevention.

“Mediated primarily through the vitamin D Receptor, vitamin D impacts almost every cell in the body, including action in the hypothalamic-pituitary-gonadal axis, an integral pathway for sexual maturation.”

Methodology

 The researchers conducted a narrative review to investigate the role of vitamin D in pubertal development, focusing on vitamin D deficiency, levels, timing of puberty, and age of menarche. The literature review was completed on PubMed and Embase, screening articles published within the last 15 years that utilized certain keywords. A total of 82 manuscripts were considered by the authors for analysis.

Results

 Studies reviewed were divided based on their association with precocious puberty, age of menarche, and potential mechanisms in sexual maturation. A meta-analysis of six studies involving 3,016 patients with precocious puberty and 8,296 healthy individuals revealed that subjects deficient in vitamin D were more likely to develop precocious puberty. [1] While studies on vitamin D levels and age of menarche yielded mixed findings, one study indicated low baseline 25-hydroxy vitamin D was associated with early menarche, independent of body mass index (BMI). [1]

“A meta-analysis of six studies involving 3,016 patients with precocious puberty and 8,296 healthy individuals revealed that subjects deficient in vitamin D were more likely to develop precocious puberty.”

Potential mechanisms of vitamin D’s role in sexual maturation were proposed and supported by various studies. One such mechanism is vitamin D’s regulation of adipocyte gene expression and influence on the timing of menarche through its association with obesity. Another hypothesis suggests the vitamin D receptor influences GnRH neuron function. Vitamin D was also found to potentially influence anti-Müllerian hormone (AMH) concentration, contributing to the quality and development of ovarian reserve. [1]

Discussion

This review article supports existing data suggesting vitamin D levels can impact the body in numerous ways, including sexual maturation. Although some studies demonstrated mixed results, enough data supports vitamin D’s role as one of the factors influencing the timing of puberty. In the setting of vitamin D deficiency, supplementation is a relatively safe and simple intervention that may have lasting benefits. Despite the prevalence of vitamin D deficiency, many physicians who treat children and adolescents do not routinely check vitamin D levels. Given its role in development, this raises the question of whether physicians should be checking this vitamin at a young age.

Through the FACTS elective, students learn about natural methods for family planning that can aid one’s understanding of menstrual cycle health and fertility. This article relates well to this objective; since vitamin D plays an important role in how the female cycle develops, supplementation, when needed, may optimize a woman’s cycle. Given the potential consequences of early menarche, it is vital to recognize any modifiable factors to educate patients about their options.

“Since vitamin D plays an important role in how the female cycle develops, supplementation, when needed, may optimize a woman’s cycle.”

The authors provided several potential mechanisms of how vitamin D could affect sexual maturation and fertility. The HPG axis contains vitamin D receptors which mediate the effects of vitamin D on reproductive physiology. Deficiencies in vitamin D may lead to dysregulation in GnRH activity, resulting in early menarche. The authors also noted vitamin D₃ influences AMH concentration, likely through gene promoter sequences. Studies have shown a positive correlation between plasma concentration of vitamin D₃ and AMH. [1] Since low levels of AMH are an indicator of low ovarian reserve, low levels of vitamin D₃ and AMH may also be associated with infertility. Given this mechanism, perhaps vitamin D₃ should be supplemented to support fertility.

This research was limited by the lack of human studies available for review; most studies were done with animal subjects. Furthermore, several studies included confounding variables such as BMI and ethnicity which are known to play a role in puberty progression. On the other hand, a strength of this research was the meta-analysis and large sample available to analyze the association between vitamin D and precocious puberty.

In conclusion, the reported data supports vitamin D as a key regulator of endocrine pathways, with implications for timing of menarche and puberty. Further studies that control for confounding variables are needed to establish vitamin D levels as a significant modifiable risk factor for pubertal development. As this is a relatively simple and safe intervention, it seems reasonable for clinicians to evaluate vitamin D levels routinely and consider supplementation when deficient.

References

[1] Calcaterra V, Magenes VC, Tagi VM, Grazi R, Bianchi A, Cena H, Zuccotti G, Fabiano V. Association between Vitamin D Levels, Puberty Timing, and Age at Menarche. Children (Basel). 2023 Jul 19;10(7):1243. doi: 10.3390/children10071243. PMID: 37508740; PMCID: PMC10378582.

ABOUT THE AUTHOR

Laura Olivieri

Laura Olivieri is a fourth-year medical student at University of New England in Biddeford, Maine. She completed her undergraduate education at Ohio State University in Columbus, Ohio and plans to pursue residency in child neurology. She is interested in advocacy in medicine and mental health reform. She enrolled in the FACTS elective to gain a better understanding of fertility. Aware that some neurology medications can be a limiting factor in family planning, she plans to educate her patients about methods that may make them feel more in control of their reproductive choices.