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Abstract

The development of pubertal characteristics may be influenced by exogenous factors, including endocrine disruptors. Phytoestrogens, plant-derived compounds with estrogenic activity, have been studied for their potential impact on pubertal timing. This scoping review assessed the available evidence on the association between dietary phytoestrogen consumption and early pubertal development. A systematic search of 5 databases identified 16 studies: 1 clinical trial, 3 experimental animal studies, and 12 observational studies. Study designs and methodological quality were heterogeneous. Prospective cohort studies, offering higher-quality evidence, reported an inverse association between phytoestrogen intake and early pubertal development, while cross-sectional studies of lower quality found a direct association. Although findings are inconsistent, the best-quality evidence suggests that phytoestrogen consumption may delay pubertal onset. Further research with robust designs and standardized measures is required to clarify this relationship.

Keywords

puberty phytoestrogens endocrine disruptors sexual development

Introduction

The development of pubertal characteristics, such as breast budding, pubarche, and menarche in girls, and testicular enlargement and pubarche in boys, is a complex biological process influenced by both genetic and environmental factors.^1,2 While the typical age range for pubertal onset varies, there has been increasing concern over the earlier emergence of these characteristics in recent decades.² This trend, often referred to as early pubertal development, may not always meet the clinical definition of precocious puberty—characterized by onset before the age of 8 in girls and 9 in boys—but it raises important health considerations.³

Early pubertal timing has been associated with long-term health implications, including an elevated risk of polycystic ovary syndrome, breast cancer, insulin resistance, reduced adult height relative to genetic potential, and menstrual disturbances in adulthood.^4,5 Several environmental factors, particularly exposure to endocrine-disrupting chemicals found in insecticides, plastics, personal care products, cosmetics, and certain foods, have been proposed as potential contributors to this shift.^6,7

Plant-based foods with high estrogen content, known as phytoestrogens,⁸ have attracted attention for their potential health benefits, especially in peri- and postmenopausal women, due to their capacity to alleviate hot flashes, help maintain bone mass, and possibly reduce the risk of breast and prostate cancer.⁹ However, the effects of phytoestrogen exposure during early life remain controversial, particularly regarding their potential influence on the timing of pubertal development.^9,10

Phytoestrogens are present in various plant-based foods, including soy and its derivatives (soy milk, tofu, flour, among others), flaxseeds, alfalfa, and fennel. Through their selective activity on estrogen receptors, particularly ER-β, phytoestrogens may influence pathways involved in sexual maturation. While their biological effects do not necessarily involve changes in circulating hormone levels—given that prepubertal levels of estradiol, LH, and FSH are naturally low—they may exert modulatory effects on estrogen-sensitive tissues.¹¹ Nevertheless, the relationship between phytoestrogen intake and the timing of pubertal development remains a topic of scientific debate. Therefore, this study aims to synthesize and evaluate the available evidence on this association through a systematic scoping review.

Methods

Study Design

This scoping review aimed to summarize the evidence on the relationship between phytoestrogen-containing food consumption and the development of pubertal characteristics. The review followed the guidelines outlined in the Joanna Briggs Institute’s manual for scoping reviews¹² and adhered to the PRISMA-ScR reporting guidelines.¹³ The protocol was registered on the Figshare platform before its implementation.¹⁴

Information Sources and Search Strategy

The search was conducted in 5 bibliographic databases: Web of Science (Core Collection), SCOPUS, Embase via Ovid, PubMed/MEDLINE, and EBSCO Host. The search was performed on April 15, 2024, using terms related to “phytoestrogens,” “isoflavones,” “soy,” “precocious puberty,” “early puberty,” “puberty timing,” and “early menarche.” The search strategy was adapted for each database, and the specific strategies are provided in the Supplemental Material. Additionally, a manual search of references from narrative reviews and clinical guidelines was conducted to ensure comprehensive coverage of relevant documents.

Document Selection

The document selection process was conducted using Rayyan¹⁵ based on predefined inclusion and exclusion criteria. Two independent reviewers (GT-S and LU-C) evaluated the studies. In cases of disagreement regarding study inclusion or exclusion, a third reviewer (VR-L) made the final decision.

Inclusion and Exclusion Criteria

Studies were included if they reported original results from observational studies (cohort, case-control, and cross-sectional studies), experimental studies (human or animal trials), or case reports. Additionally, studies were required to provide clear descriptions of phytoestrogen exposure (type of food and quantity) and development of pubertal characteristics (breast development, menarche, pubarche, testicular size, Tanner staging, or serologically confirmed early puberty or signs suggestive of early pubertal development).

Secondary studies, such as clinical practice guidelines or narrative reviews, were excluded. Studies involving pregnant women or those in which phytoestrogen exposure occurred exclusively during gestation were also excluded. Furthermore, studies published before the year 2000 and those without full-text availability were not considered (Figure 1).

Figure 1.

Flowchart of article selection for the scoping review according to PRISMA guidelines.

Data Extraction

Two independent authors (VR-L and DP-L) extracted the relevant data to ensure information quality. The extracted data included the study title, authors, publication year, study type (observational, experimental, or case report), specific study design (randomized clinical trial, non-randomized clinical trial, animal experiment or preclinical study, cross-sectional study, cohort study, case-control study, or case report), country where the study was conducted, data collection period, study population, sample characteristics and size, study objective, methodology, phytoestrogen administration or exposure (type of food, quantity, and duration), and primary outcomes (absolute frequencies, relative frequencies, means, medians, and association measures).

Quality Assessment of Evidence

Three independent authors (AÑ-C, GT-S, and VR-L) assessed the quality of evidence in human studies. The Risk of Bias II (RoB II) tool was used to evaluate randomized clinical trials.¹⁶ For observational studies, a modified version of the Newcastle-Ottawa Scale was applied, assigning quality ratings as follows: low quality (1-3 stars), moderate quality (4-6 stars), and high quality (7-9 stars).¹⁷ A detailed evaluation of each study is available in the Supplemental Material.

Study Synthesis

The collected information was summarized in tables that included bibliographic details, methodological aspects, and study results.

Ethical Considerations

This study was conducted using publicly available published data. No personal or confidential patient information was disclosed. Therefore, ethical committee approval was not required.

Results

A total of 16 studies were included, comprising 12 observational and 4 experimental studies, all published between 2001 and 2022. Specifically, the review identified 2 experimental studies in humans, 2 experimental studies in animals, 4 cross-sectional studies, and 5 cohort studies. Additionally, 7 of the included studies were conducted in the United States (Table 1).

Table 1.

General Characteristics of the Selected Studies Addressing the Relationship Between Phytoestrogen Consumption and Early Puberty Development.

Author	Title	Year publication	Study design	Country where was conducted	Date of data collection
Storm BL	Exposure to Soy-Based Formula in Infancy and Endocrinological and Reproductive Outcomes in Young Adulthood	2001	Observational	USA	1999, March to August
Maskarinec G	Urinary Sex Steroid Excretion Levels During a Soy Intervention Among Young Girls: A Pilot Study	2005	Experimental	USA	Not specified
Takashima-Sasaki K	Effect of Exposure to High Isoflavone-Containing Diets on Prenatal and Postnatal Offspring Mice	2006	Experimental	Japan	Not specified
Bernbaum JC	Pilot studies of estrogen-related physical findings in infants	2008	Observational	USA	2004-2005
Türkyılmaz Z	A striking and frequent cause of premature thelarche in children: Foeniculum vulgare	2008	Observational	Turkey	2001-2007
Wolff MS	Environmental Exposures and Puberty in Inner-City Girls	2008	Observational	USA	1996-1997
Zung A	Breast Development in the First 2 Years of Life: An Association With Soy-based Infant Formulas	2008	Observational	Israel	January 2023 to December 2024
Wolff MS	Investigation of relationships between urinary biomarkers of phytoestrogens, phthalates, and phenols and pubertal stages in girls	2010	Observational	USA	2004-2007
Cheng G	Relation of isoflavones and fiber intake in childhood to the timing of puberty	2010	Observational	Germany	Not specified
Adgent MA	Early-life soy exposure and age at menarche	2011	Observational	UK	1999-2007
Dewi FN	Dietary Soy Effects on Mammary Gland Development during the Pubertal Transition in Nonhuman Primates	2013	Experimental	USA	Not specified
Segovia-Siapco G	Is soy intake related to age at onset of menarche? A cross-sectional study among adolescents with a wide range of soy food consumption	2014	Observational	USA	Not specified
Sinai T	Consumption of soy-based infant formula is not associated with early onset of puberty	2018	Observational	Israel	2004-2006
Felicio JS	Association of Soy and Exclusive Breastfeeding With Central Precocious Puberty: A Case-Control Study	2021	Observational	Brazil	2010-2018
Xiong J	Prospective association of dietary soy and fibre intake with puberty timing: a cohort study among Chinese children	2022	Observational	China	2013-2018
Duitama SM	Soy protein supplement intake for 12 months has no effect on sexual maturation and may improve nutritional status in pre-pubertal children	2018	Experimental	Colombia	June 2012 to September 2012

Abbreviations: USA, United States of America; UK, United Kingdom.

Among the experimental studies, a randomized controlled trial was conducted in Colombia with 51 children aged 7 to 9 years attending community dining facilities. The intervention group received a soy-based supplement (3.49 mg of isoflavones per day) for 12 months, while the control group received a whole milk-based formula. The results showed no significant differences in sexual maturation between the intervention and control groups. However, the study was classified as having moderate evidence quality based on the RoB II tool.

In addition to this study, a pre- and post-intervention study in children reported no significant results, while 2 preclinical animal studies observed anatomical and physiological differences suggestive of early pubertal development. Details are summarized in Table 2.

Table 2.

Objectives, Methodology, and Results of the Included Experimental Studies on the Relationship Between Phytoestrogen Consumption and Early Puberty Development.

Study	Specific design of study	Population	Sample size	Aim of study	Intevention	Results
Maskarinec G, 2005	Pre- and post-intervention study	Girls aged 8 to 14 years from the Cancer Research Center of Hawaii, affiliated with the University of Hawaii	Seventeen girls who completed the 8-week follow-up	To explore the relationship between urinary sex steroid levels and pubertal development following an intervention involving soy consumption.	Thirty milligrams of isoflavones were administered daily through soy-based foods (milk, tofu, toast, etc.)	Following the intervention, changes in the urinary excretion of hormonal steroids were not significant.
Duitama SM, 2018^a	Randomized controled trial^a	Children aged 2 to 9 years attending a community dining facility in Bogotá, Colombia.	Subsample from an initial study (n = 150) https://doi.org/10.1080/19390211.2017.1409851, including 51 children aged 7 to 9 years.	To evaluate the effects of daily consumption of a soy protein-based supplement (SPS) over 12 months on pubertal characteristics in children aged 7 to 9 years.	Forty-five grams of protein supplement, equivalent to 3.49 mg of isoflavones per day, were administered. These were diluted in juices of various flavors.	No differences were observed in sexual maturation, assessed using the Tanner scale, or in bone age between the two groups. Regarding anthropometric changes, girls in the intervention group showed greater height-for-age (133 cm versus 129 cm) and higher weight-for-age (an increase of 0.30 kg compared to a decrease of 0.68 kg in the control group).
Takashima-Sasaki K, 2006	Preclinical	Pregnant C57BL/6Cr Slc strain mice and their litters under follow-up.	Ten pregnant female mice and their litters, consisting of 6 to 8 pups per litter.	To examine whether chronic exposure to high levels of isoflavones (IF) through diet has adverse effects on the reproductive development of mouse offspring.	Isoflavones accounted for 0.05% of the total diet weight in both pregnant females and their offspring.	In female offspring, earlier vaginal opening was observed (23.8 days vs 25.9 days in the control group) along with a higher number of multiovular follicles (11.3 vs 1 in the control group). No changes were observed in male offspring.
Bateman HL, 2008	Preclinical	Population of non-human primates (Macaca fascicularis) imported from Indonesia.	Thirty females approximately 1.5 years old were included, with 28 primates analyzed. Two primates died due to causes unrelated to the intervention.	To evaluate the influence of a soy-based diet on mammary differentiation, pubertal progression, and hormonal profiles during this developmental period in non-human primate models.	The control group was fed a diet based on casein/lactalbumin as the protein source, while the experimental group received isolated soy protein, providing a human equivalent of 120 mg/day of isoflavones (in aglycone form).	In the group fed a soy protein-based diet, five times more large mammary lobules were observed compared to the control group. No differences were found in menarche timing, anthropometric parameters, or bone mineral density.

The quality of evidence was assessed using the Risk of Bias 2 tool, yielding a moderate quality rating.

Among the 12 observational studies, 5 were cohort studies (4 prospective and 1 retrospective), 4 were cross-sectional studies, 2 were case-control studies, and 1 was a case series (including 4 cases). Four studies reported an association between phytoestrogen consumption and earlier sexual development (1 case-control study, 2 cross-sectional studies, and 1 case series). Five studies found no association between phytoestrogen intake and pubertal development (1 retrospective cohort study, 1 prospective cohort study, 2 cross-sectional studies, and 1 case-control study). Meanwhile, 3 prospective cohort studies suggested a relationship between phytoestrogen consumption and delayed sexual development.

Only 2 studies, both prospective cohort studies, were rated as having high-quality evidence (Table 3). The methodological quality assessment of the observational studies (excluding the case series, n = 11) classified 4 studies as low quality, 5 as moderate quality, and 2 as high quality. The detailed quality assessment for each domain is provided in the Supplemental Material.

Table 3.

Objectives, Methodology, Results, and Evidence Quality of the Included Observational Studies on the Relationship Between Phytoestrogen Consumption and Early Puberty Development.

Study	Specific design of study	Population	Sample size	Aim of study	Exposition	Results	Evidence quality ^a
Strom BL, 2001	Cohort retrospective	Infants were preselected at the University of Iowa in Iowa.	811 infants (248 exposed to soy formula)	To examine the association between exposure to soy-based infant formulas during infancy and health outcomes in young adulthood, with a special emphasis on reproductive health	Soy formula. With an estimated intake ranging from 4.2 to 9.4 mg/kg per day during the first 16 weeks of life.	No differences were found in the male group. In females exposed to soy formula, a slightly longer menstrual bleeding duration (0.37 days more) and a higher frequency of extreme menstrual pain (18% vs 11.2%) were observed.	Moderate
Bernbaum JC, 2007	Cross Sectional^b	Newborns in Philadelphia (Children’s Hospital of Philadelphia, affiliated clinics, and the Hospital of the University of Pennsylvania).	72 full-term newborns with adequate birth weight and no diagnosed pathologies at that time.	To investigate estrogen-related effects on the physical development of infants fed with different dietary regimens (breast milk, cow’s milk formula, and soy formula).	Soy formula, not quantified, self-reported by parents.	A possible increase in the vaginal maturation index in girls at 6 months, but it was not statistically significant (P = .07). No changes were observed in the external genitalia.	Low
Türkyılmaz Z, 2008	Case Series	Four girls under 5 years old with premature thelarche who presented at a hospital between 2001 and 2007.	No apply	No apply	Foeniculum vulgare tea at different doses per case.	The patients exhibited breast development between Tanner stages 2 and 3, with values 15 to 20 times higher than normal for their age.	No apply
Wolff MS, 2008	Cross Sectional	Pediatric patients from Mount Sinai Hospital in New York and a nearby private pediatric clinic affiliated with the hospital between 1996 and 1997.	200 girls who met the inclusion criteria (apparently healthy and residing in New York).	To determine the relationship between environmental disruptors and phytoestrogens with pubertal status in 9-year-old girls residing in New York.	Diet based on isoflavones, flavonoids, lignans, and phytosterols (food frequency questionnaire), along with environmental disruptors.	Girls with higher urinary concentrations of daidzein and genistein were less likely to have reached breast development (Tanner B2+) (PR: 0.89, P < .05). No association was found between phytoestrogens and pubic hair development.	Low
Zung A, 2008	Cross Sectional	Girls aged 3 to 24 months from 10 pediatric clinics in Israel.	694 girls, 92 in the exposure group and 604 in the comparator group.	To evaluate the estrogenic effect of soy-based infant formulas in girls.	Soy-based formulas in the last 3 months (food frequency questionnaire), reported by parents.	In the second year of life, a higher percentage of breast bud development was observed in the soy-based formula group compared to the cow’s milk formula or breast milk group (OR: 2.45. P < .05)	Low
Cheng G, 2010	Cohort prospective	The population included healthy Caucasian boys and girls participating in the longitudinal DONALD study (Dortmund Nutritional and Anthropometric Longitudinally Designed Study) conducted in Germany.¹⁸	227 children, including 119 girls and 108 boys. Apparently healthy, with no significant medical history during the gestational period or birth. Recruited between 3 and 6 months of age.	To determine whether isoflavone intake and a fiber-based diet during childhood are associated with the timing of puberty onset.	Recording and identification of isoflavone intake ranging from 2 to 62 mg/day.	Girls with higher isoflavone intake experienced a later puberty onset in terms of Tanner B2 (0.7 years later, P = .04) and APHV (0.6 years later, P = .04). No differences were found in other pubertal markers. In boys, no changes were observed in any pubertal marker.	Moderate
Adgent MA, 2011	Cohort prospective	Caucasian girls born at term between 1991 and 1992 who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC).¹⁹	2920 girls, 54 were exposed before 4 months of age, and 111 were exposed between 5 and 15 months. The remaining girls served as the comparator group.	To determine the relationship between early and late exposure to soy formula during infancy and the age at menarche.	Soy-based formulas (not quantified) before 15 months of age during follow-up (parent questionnaire).	Girls fed with early soy formula had an earlier age at menarche (12.4 years vs 12.8 years), although the results were not significant.	Moderate
Mervish, 2013	Cohort pospective	Girls aged 6 to 8 years recruited from three regions in the United States: New York, Cincinnati, and Northern California.	1178 girls included who met the inclusion criteria (apparently healthy) and exclusion criteria (metabolic disorders).	To evaluate the association between dietary intake of lignans and flavonols and the age of puberty onset in girls (breast and pubic hair development).	Flavonol and lignan intake (in milligrams per day) collected through a food frequency questionnaire.	Flavonol intake greater than 5 mg/day was associated with a later onset of breast development (9.38 years vs 8.92 years on average, HR: 0.74, P = .006). No changes were observed regarding lignan intake.	High
Segovia-Siapco, 2014	Cross Sectional	Adolescent girls aged 12 to 18 years recruited from public and private schools near two Adventist universities in California and Michigan	327 adolescent girls with complete information on soy intake and age at menarche onset.	To determine the association between soy food intake and the age at menarche onset in a population with a broad and relatively high soy consumption.	Dietary information on soy-based foods (not quantified in milligrams) collected through a food survey.	No association was found between soy consumption and age at menarche.	Low
Sinai, 2018	Case-control	Participants were from a prospective cohort of newborns cared for at Assaf Harofeh Medical Center (Israel) between 2004 and 2006, followed from birth to age 3, and later assessed between ages 7 and 11.	89 participants (29 cases and 60 controls). Cases were identified with IgE-mediated allergy (leading to a soy-based formula diet), and controls were randomly selected.	To evaluate the association between soy-based formula consumption during infancy and the development of early pubertal signs, compared to cow’s milk formula consumption.	Soy protein servings (6 g per serving). Cases were those consuming more than 0.3 servings per day (over 2 g per day).	No association was found between soy consumption and early pubertal signs or growth.	Moderate
Felicio, 2021	Case-Control	Girls who attended João de Barros Barreto University Hospital in Brazil, treated in a specialized pediatric endocrinology setting.	161 participants: 84 girls with central precocious puberty (cases) and 77 control girls (apparently healthy with no metabolic conditions).	To evaluate the association between soy-based feeding and exclusive breastfeeding with the development of central precocious puberty.	Soy-based formulas not quantified in amount or frequency (dichotomized as consumed or not consumed).	Girls exclusively breastfed for more than 6 months had a lower likelihood of developing CPP (OR = 0.18). Girls who consumed soy-based products had a higher risk of CPP (OR = 3.50).	Low
Xiong, 2022	Cohort prospective	Children aged 6 to 8 years from 23 schools in China.	4781 children, including 2152 girls and 2629 boys.	To determine the association between higher soy intake during childhood and a later onset of puberty.	Soy-containing foods and dietary fiber (collected through a food frequency questionnaire).	Higher soy intake during childhood was associated with a later onset of puberty in both sexes. In girls with low soy consumption, puberty onset occurred at an average age of 9.1 years, compared to 9.5 years in those with higher intake. In boys with low soy consumption, puberty onset occurred at an average age of 10.8 years, compared to 11.4 years in those with higher intake.	High

Details on the evaluation and justification of the evidence quality scores are provided in the complementary material.

Although the study mentions a mixed cross-sectional design, the results follow a cross-sectional approach.

Discussion

This study analyzed various investigations related to the objective of synthesizing current evidence on phytoestrogen consumption and its potential association with early development puberty. Overall, the included studies exhibited significant heterogeneity in design, contradictory findings, and varying levels of evidence.

Studies suggesting a relationship between phytoestrogen intake and early development puberty generally had low to moderate evidence quality. First, animal model experiments conducted by Takashima-Sasaki et al²⁰ and Bateman and Patisaul²¹ reported an association between phytoestrogen exposure and early pubertal development in rats and primates. These findings align with those of other studies^22-24 that have used various animal models to assess the effects of parenteral administration of flavonoids, isoflavones, or genistein. However, due to the inherent limitations of animal models, extrapolating these results to humans remains challenging,^25,26 particularly because the administered doses in these experiments are often significantly higher than those typically consumed in a regular diet. In this regard, a key strength of the studies by Takashima-Sasaki et al and Bateman and Patisaul is their use of enteral diets in animal models, which could serve as a foundation for designing future human studies with a more robust hypothesis.

Regarding human studies, 2 experimental studies did not identify a relationship between phytoestrogen consumption and precocious puberty. One was a pre- and post-intervention study,²⁷ while the other was a randomized clinical trial.²⁸ However, both studies had methodological limitations, including small sample sizes. Randomized clinical trials represent the optimal design for establishing causal relationships between exposure and outcomes; however, their validity depends on methodological rigor and study design quality.²⁹ Conducting additional randomized trials would help mitigate confounding bias present in observational studies. However, the ethical implications of assessing potential “risk factors” in experimental human studies must be carefully considered.³⁰

The pre- and post-intervention study also had a short follow-up period, which limits the ability to extrapolate long-term results. Additionally, this study design has inherent methodological constraints.³¹

Observational studies have shown heterogeneous and, in some cases, contradictory results. Among the studies suggesting an association between phytoestrogen consumption and precocious puberty or early development puberty,^32-35 methodological quality ranged from low to moderate based on the corresponding assessment tools. In contrast, prospective cohort studies have reported an inverse relationship between phytoestrogen intake and pubertal onset.^36-38 It is important to highlight that both Mervish et al³⁷ and Xiong et al³⁸ provided high-quality evidence due to their large sample sizes and longitudinal follow-up. Xiong et al observed delayed puberty in both sexes with higher soy intake, while Mervish et al found that greater flavonol consumption was associated with a later onset of breast development in girls. Together, these findings suggest that specific phytoestrogens may have a protective or modulatory effect on pubertal timing. The discrepancy between observational studies may be explained by the SERM activity of phytoestrogens, with effects influenced by ER-α/ER-β affinity, dose, bioavailability,³⁹ and gut microbiota–dependent metabolism, including equol production.⁴⁰ However, the highest-quality evidence indicates that phytoestrogen consumption is inversely associated with early pubertal development.

The timing of exposure also plays a crucial role: while phytoestrogens may modulate the hypothalamic-pituitary-gonadal axis during early childhood, they can alter hormone levels in later stages closer to puberty.⁴¹ Furthermore, the dose-response relationship does not appear to be linear; low and prolonged exposures may have protective effects, whereas high and short-term exposures could accelerate pubertal development. External factors, such as exposure to other endocrine disruptors and nutritional status, may further modify these effects, contributing to the variability observed across studies.^42,43

On the other hand, the consumption of foods rich in isoflavones, such as soy, has demonstrated protective effects against chronic diseases and menopausal symptoms, along with potential benefits in breast cancer prevention.^44-46 However, the effects of phytoestrogen consumption during childhood remain uncertain.^47,48 Some studies suggest that an intake below 40 mg/day or 3-4 mg/kg/day in children may not have direct repercussions, whereas higher intakes could lead to variable effects depending on physiological and individual contexts.

Compounds such as daidzein, genistein, and circulating isoflavones have been well-studied due to their specific affinities for estrogen receptors, particularly ER-β, potentially influencing sexual development.⁴⁹ The role of other endocrine disruptors, including bisphenol A (BPA), phthalates, and organochlorine pesticides, must also be considered as potential confounders that may interact synergistically or antagonistically with phytoestrogens. Importantly, phytoestrogen metabolism—especially the conversion of daidzein to the potent metabolite equol by certain gut microbiota—can significantly affect estrogenic activity.⁵⁰ Measuring serum concentrations, such as plasma genistein levels above 10-15 μg/L, may help clarify dose-response relationships and improve the interpretation of phytoestrogen effects on pubertal development.⁵¹

Strengths and Limitations

This study has several strengths, including its methodological rigor and comprehensive search strategy, which utilizes high-coverage, scientifically relevant databases. Additionally, the quality of the included studies was assessed using standardized tools based on their methodological design. The research question was clearly defined, allowing for a systematic collection of information without restricting the measurement approach for the independent variable, thereby ensuring broader data coverage.

However, certain limitations must be considered. The inclusion of studies with heterogeneous designs prevented the establishment of a precise relationship between phytoestrogen consumption and pubertal development. Moreover, the methods used to measure phytoestrogen intake varied, including assessments based on habitual dietary patterns, populations with significantly high consumption, and direct intervention studies, which complicated the standardization of the independent variable. Notably, the use of food frequency questionnaires (FFQs) has inherent limitations, as they rely on self-reported data and retrospective recall, making them susceptible to information bias and potentially compromising the accuracy of dietary exposure assessment.

Furthermore, the outcome measurement was not uniform across the analyzed studies, ranging from Tanner staging to various anthropometric parameters. This variability, along with inadequate adjustments for potential confounders, limited the validity of the results. Finally, as this review was narrative rather than a meta-analysis, the synthesis relied on describing findings from individual studies rather than generating an overall measure of association, which was due to the high heterogeneity of the data.

Therefore, future studies with more robust designs are needed to better identify the association between phytoestrogen consumption and precocious puberty, particularly by considering the quantity and type of food consumed before the onset of pubertal characteristics. Long-term follow-up studies could provide more robust answers, particularly in children with cow’s milk protein allergies. However, such studies would involve a highly specific population, thereby limiting the generalizability of their findings to the broader population. Additionally, other dietary components, such as the intake of animal-based foods, may raise important questions for future research, particularly given the conflicting evidence regarding the effects of animal proteins—such as cow’s milk⁵² and red meat^53,54—on pubertal development.

Conclusion

The reviewed studies present contradictory findings regarding the relationship between phytoestrogen consumption and early puberty development. While some studies suggest a positive association, others find no evidence of such a relationship or even report a slight delay in the onset of sexual characteristics. This variability in findings may stem from differences in study design, phytoestrogen intake measurement, and pubertal development assessment.

Given the heterogeneity of the available evidence, further high-quality studies are essential. These should include precise quantification of phytoestrogen intake and standardized measurement of early puberty development. Additionally, better control of confounding factors that may influence this association is necessary to obtain more consistent conclusions regarding the impact of phytoestrogens on pubertal development.

Supplemental Material

sj-pdf-1-gph-10.1177_30502225251361989 – Supplemental material for Phytoestrogenic Food Intake and the Early Development of Pubertal Characteristics: A Scoping Review and Evidence Assessment

Supplemental material, sj-pdf-1-gph-10.1177_30502225251361989 for Phytoestrogenic Food Intake and the Early Development of Pubertal Characteristics: A Scoping Review and Evidence Assessment by Diana Palma-Lozano, Gustavo Tapia-Sequeiros, Leonardo J. Uribe-Cavero, Alvaro M. Ñaña-Cordova and Victor Roman-Lazarte in Sage Open Pediatrics

Footnotes

ORCID iD

Victor Roman-Lazarte

Ethical Considerations

This study was conducted using publicly available published data. No personal or confidential patient information was disclosed. Therefore, ethical committee approval was not required.

Author Contributions

Diana Palma-Lozano: contributed to conception and design; contributed to acquisition and analysis; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. Gustavo Tapia-Sequeiros: contributed to design; contributed to analysis and interpretation; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. Leonardo J. Uribe-Cavero: contributed to design; contributed to analysis; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. Alvaro M. Ñaña-Cordova: contributed to analysis; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy. Victor Roman-Lazarte: contributed to conception and design; contributed to acquisition, analysis, and interpretation; drafted manuscript; critically revised manuscript; gave final approval; agrees to be accountable for all aspects of work ensuring integrity and accuracy.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by the authors.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The pre-selected articles are included as supplementary material.

Supplemental Material

Supplemental material for this article is available online.

References

Fortenberry

JD.

Puberty and adolescent sexuality. Horm Behav. 2013;64:280-287. doi:10.1016/j.yhbeh.2013.03.007

Schwanz

Georges

Sexual development and the environment: conclusions from 40 years of theory. Sex Dev. 2021;15:7-22. doi:10.1159/000515221

Zevin

Eugster

EA.

Central precocious puberty: a review of diagnosis, treatment, and outcomes. Lancet Child Adolesc Health. 2023;7:886-896. doi:10.1016/S2352-4642(23)00237-7

Soliman

Alaaraj

De Sanctis

Alyafei

Ahmed

Hamed

Long-term health consequences of central precocious/early puberty (CPP) and treatment with Gn-RH analogue: a short update. Acta Biomed. 2023;94:e2023222. doi:10.23750/abm.v94i6.15316

Cheng

Ong

Biro

FM.

Adverse effects of early puberty timing in girls and potential solutions. J Pediatr Adolesc Gynecol. 2022;35:532-535. doi:10.1016/j.jpag.2022.05.005

Wang

Asokan

Onnela

J-P

, et al. Menarche and time to cycle regularity among individuals born between 1950 and 2005 in the US. JAMA Netw Open. 2024;7:e2412854. doi:10.1001/jamanetworkopen.2024.12854

Czarnywojtek

Jaz

Ochmańska

, et al. The effect of endocrine disruptors on the reproductive system - current knowledge. Eur Rev Med Pharmacol Sci. 2021;25:4930-4940. doi:10.26355/eurrev_202108_26450

Patra

Gorai

Pal

Ghosh

Pradhan

Chakrabarti

A review on phytoestrogens: current status and future direction. Phytother Res. 2023;37:3097-3120. doi:10.1002/ptr.7861

Glazier

Bowman

MA.

A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy. Arch Intern Med. 2001;161:1161-1172. doi:10.1001/archinte.161.9.1161

10.

Canivenc-Lavier

M-C

Bennetau-Pelissero

Phytoestrogens and health effects. Nutr. 2023;15:317. doi:10.3390/nu15020317

11.

Lecomte

Demay

Ferrière

Pakdel

Phytochemicals targeting estrogen receptors: beneficial rather than adverse effects?

Int J Mol Sci. 2017;18:1381. doi:10.3390/ijms18071381

12.

Jordan

Lockwood

Munn

Aromataris

The updated Joanna Briggs Institute model of evidence-based healthcare. Int J Evid Based Healthc. 2019;17:58-71. doi:10.1097/xeb.0000000000000155

13.

Tricco

Lillie

Zarin

, et al. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018;169:467-473. doi:10.7326/M18-0850

14.

Roman-Lazarte

Consumo de fitoestrógenos y desarrollo de pubertad precoz, evaluación de la evidencia a partir de una revisión de alcance. n.d. doi:10.6084/m9.figshare.25563627

15.

Ouzzani

Hammady

Fedorowicz

Elmagarmid

Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016;5:210. doi:10.1186/s13643-016-0384-4

16.

Sterne

JAC

Savović

Page

, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898

17.

Wells

Shea

O’Connell

Peterson

Welch

Losos

, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. n.d. Accessed February 3, 2025. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

18.

Buyken

Alexy

Kersting

Remer

[The DONALD cohort. An updated overview on 25 years of research based on the Dortmund nutritional and anthropometric longitudinally designed study]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2012;55:875-884. doi:10.1007/s00103-012-1503-6

19.

Fraser

Macdonald-Wallis

Tilling

, et al. Cohort profile: the Avon longitudinal study of parents and children: ALSPAC mothers cohort. Int J Epidemiol. 2013;42:97-110. doi:10.1093/ije/dys066

20.

Takashima-Sasaki

Komiyama

Adachi

, et al. Effect of exposure to high isoflavone-containing diets on prenatal and postnatal offspring mice. Biosci Biotechnol Biochem. 2006;70:2874-2882. doi:10.1271/bbb.60278

21.

Bateman

Patisaul

HB.

Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased Gnrh activation and kisspeptin fiber density in the hypothalamus. Neurotoxicol. 2008;29:988-997. doi:10.1016/j.neuro.2008.06.008

22.

Zhao

Diao

Xiao

Postweaning dietary genistein exposure advances puberty without significantly affecting early pregnancy in C57BL/6J female mice. Reprod Toxicol. 2014;44:85-92. doi:10.1016/j.reprotox.2013.12.003

23.

Marraudino

Ponti

Moussu

, et al. Early postnatal genistein administration affects mice metabolism and reproduction in a sexually dimorphic way. Metabolites. 2021;11:449. doi:10.3390/metabo11070449

24.

Padilla-Banks

Jefferson

Newbold

RR.

Neonatal exposure to the phytoestrogen genistein alters mammary gland growth and developmental programming of hormone receptor levels. Endocrinology. 2006;147:4871-4882. doi:10.1210/en.2006-0389

25.

Pound

Ritskes-Hoitinga

Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. J Transl Med. 2018;16:304. doi:10.1186/s12967-018-1678-1

26.

Van Norman

. Limitations of animal studies for predicting toxicity in clinical trials: is it time to rethink our current approach? JACC Basic Transl Sci. 2019;4:845-854. doi:10.1016/j.jacbts.2019.10.008

27.

Maskarinec

Morimoto

Novotny

Nordt

Stanczyk

Franke

AA.

Urinary sex steroid excretion levels during a soy intervention among young girls: a pilot study. Nutr Cancer. 2005;52:22-28. doi:10.1207/s15327914nc5201_3

28.

Duitama

Zurita

Cordoba

Duran

Ilag

Mejia

Soy protein supplement intake for 12 months has no effect on sexual maturation and may improve nutritional status in pre-pubertal children. J Paediatr Child Health. 2018;54:997-1004. doi:10.1111/jpc.13934

29.

Gale

Zhang

M-J

Lazarus

HM.

The role of randomized controlled trials, registries, observational databases in evaluating new interventions. Best Pract Res Clin Haematol. 2023;36:101523. doi:10.1016/j.beha.2023.101523

30.

Varkey

Principles of clinical ethics and their application to practice. Med Princ Pract. 2021;30:17-28. doi:10.1159/000509119

31.

Aggarwal

Ranganathan

Study designs: part 4 - Interventional studies. Perspect Clin Res. 2019;10:137-139. doi:10.4103/picr.PICR_91_19

32.

Felício

de Alcântara

Janaú

, et al. Association of soy and exclusive breastfeeding with central precocious puberty: a case-control study. Front Endocrinol. 2021;12:667029. doi:10.3389/fendo.2021.667029

33.

Zung

Glaser

Kerem

Zadik

Breast development in the first 2 years of life: an association with soy-based infant formulas. J Pediatr Gastroenterol Nutr. 2008;46:191-195. doi:10.1097/MPG.0b013e318159e6ae

34.

Türkyilmaz

Karabulut

Sönmez

Can Başaklar

A striking and frequent cause of premature thelarche in children: Foeniculum vulgare. J Pediatr Surg. 2008;43(11):2109-2111. doi:10.1016/j.jpedsurg.2008.07.027

35.

Bernbaum

Umbach

Ragan

, et al. Pilot studies of estrogen-related physical findings in infants. Environ Health Perspect. 2008;116:416-420. doi:10.1289/ehp.10409

36.

Cheng

Remer

Prinz-Langenohl

Blaszkewicz

Degen

Buyken

AE.

Relation of isoflavones and fiber intake in childhood to the timing of puberty. Am J Clin Nutr. 2010;92:556-564. doi:10.3945/ajcn.2010.29394

37.

Mervish

Gardiner

Galvez

, et al. Dietary flavonol intake is associated with age of puberty in a longitudinal cohort of girls. Nutr Res. 2013;33:534-542. doi:10.1016/j.nutres.2013.04.005

38.

Xiong

Liu

, et al. Prospective association of dietary soy and fibre intake with puberty timing: a cohort study among Chinese children. BMC Med. 2022;20:145. doi:10.1186/s12916-022-02320-5

39.

Luo

Liu

Lei

, et al. Association of estrogen receptor gene polymorphisms with human precocious puberty: a systematic review and meta-analysis. Gynecol Endocrinol. 2015;31:516-521. doi:10.3109/09513590.2015.1031102

40.

Mayo

Vázquez

Flórez

AB.

Equol: a bacterial metabolite from the daidzein isoflavone and its presumed beneficial health effects. Nutr. 2019;11:2231. doi:10.3390/nu11092231

41.

Ferrari

Cravello

Muzzoni

, et al. Age-related changes of the hypothalamic-pituitary-adrenal axis: pathophysiological correlates. Eur J Endocrinol. 2001;144:319-329. doi:10.1530/eje.0.1440319

42.

Lopez-Rodriguez

Franssen

Heger

Parent

A-S.

Endocrine-disrupting chemicals and their effects on puberty. Best Pract Res Clin Endocrinol Metab. 2021;35:101579. doi:10.1016/j.beem.2021.101579

43.

Oehme

NHB

Roelants

Bruserud

, et al. Low BMI, but not high BMI, influences the timing of puberty in boys. Andrology. 2021;9:837-845. doi:10.1111/andr.12985

44.

Chen

Lin

Liu

CF.

Efficacy of phytoestrogens for menopausal symptoms: a meta-analysis and systematic review. Climacteric. 2015;18:260-269. doi:10.3109/13697137.2014.966241

45.

Najaf Najafi

Ghazanfarpour

. Effect of phytoestrogens on sexual function in menopausal women: a systematic review and meta-analysis. Climacteric. 2018;21:437-445. doi:10.1080/13697137.2018.1472566

46.

Micek

Godos

Brzostek

, et al. Dietary phytoestrogens and biomarkers of their intake in relation to cancer survival and recurrence: a comprehensive systematic review with meta-analysis. Nutr Rev. 2021;79:42-65. doi:10.1093/nutrit/nuaa043

47.

Messina

Rogero

Fisberg

Waitzberg

Health impact of childhood and adolescent soy consumption. Nutr Rev. 2017;75:500-515. doi:10.1093/nutrit/nux016

48.

Merritt

Jenks

BH.

Safety of soy-based infant formulas containing isoflavones: the clinical evidence. J Nutr. 2004;134:1220S-1224S. doi:10.1093/jn/134.5.1220S

49.

Sri Harsha

PSC

Wahab

Garcia-Aloy

, et al. Biomarkers of legume intake in human intervention and observational studies: a systematic review. Genes Nutr. 2018;13:25. doi:10.1186/s12263-018-0614-6

50.

Saha

Kroon

PA.

A simple and rapid LC-MS/MS method for quantification of total daidzein, genistein, and equol in human urine. J Anal Methods Chem. 2020;2020:1-9. doi:10.1155/2020/2359397

51.

Kim

Huh

Kim

Joung

Park

High serum isoflavone concentrations are associated with the risk of precocious puberty in Korean girls. Clin Endocrinol. 2011;75:831-835. doi:10.1111/j.1365-2265.2011.04127.x

52.

Kwok

Leung

Lam

Schooling

CM.

Breastfeeding, childhood milk consumption, and onset of puberty. Pediatrics. 2012;130:e631-e639. doi:10.1542/peds.2011-3697

53.

Jansen

Marín

Mora-Plazas

Villamor

Higher childhood red meat intake frequency is associated with earlier age at Menarche. J Nutr. 2015;146:792-798. doi:10.3945/jn.115.226456

54.

Feng

, et al. Dietary pattern and precocious puberty risk in Chinese girls: a case-control study. Nutr J. 2024;23:14. doi:10.1186/s12937-024-00916-6

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