Testosterone and LH Levels Are Falling in Healthy Men: New Evidence of a Global Reset in Male Hormone Health

[madman]

Meta-regression analysis, using testosterone serum levels as effect of the regression, the years of sample collection as covariates and subjects’ number, age and BMI as co-factors (BMI was available for 742 study groups). Statistical details are reported in Supplementary material

PODCAST

Results of the Largest Study on Declining Male Fertility and Hormonal Trends | Nelson Vergel Beyond Testosterone Podcast

This podcast episode talks about new research showing that men’s hormone levels—specifically testosterone and luteinizing hormone (LH)—have dropped a lot over the past 50 years. The study looked at data from over a million healthy men and found that this drop isn’t just because men are older or...

nelsonvergel.podbean.com

Abstract

Purpose

Male fertility is progressively impairing over time, probably related to a multifactorial genesis. The aim of the study was the evaluation if a Temporal trend in serum testosterone levels exists in healthy men.


Methods

A search of the literature between 1971 and July 2024 was performed, selecting study groups in which testosterone serum levels were measured for any reason in healthy men. Exclusion criteria were: (i) age < 18 years old, (ii) conditions affecting testosterone levels, (iii) subjects’ enrolment based on testosterone serum levels and (iv) blood examinations performed in a time-frame interval > 10 years. Secondary endpoints: luteinising hormone (LH), follicle-stimulating hormone (FSH), sex hormone binding globulin (SHBG) serum levels and body mass index (BMI).


Results

1,256 papers, accounting for 1,504 study groups, were selected, including 1,064,891 subjects (age 42.0 ± 7.0 years). A significant negative linear regression between testosterone serum levels and year of measurement was detected (p = 0.033). The comprehensive decline in testosterone serum levels over the years was confirmed adjusting meta-regression analysis using the number of subjects included in each study, subjects’ age, BMI and the the assay used for testosterone measurement. No temporal trend was observed regarding BMI in this population. LH serum levels showed a significant decline over the years, adjusting for subjects’ age, while no trend emerged considering FSH.


Conclusion

This study is the first comprehensive analysis suggesting a progressive decrease in serum testosterone and LH levels in healthy men, independent of age and BMI. The observed decline in both testosterone and LH levels could be a consequence of an ongoing resetting of the hypothalamic-pituitary-testicular function.

Temporal trends in serum testosterone and luteinizing hormone levels indicate an ongoing resetting of hypothalamic-pituitary-gonadal function in healthy men: a systematic review - Journal of Endocrinological Investigation

Purpose Male fertility is progressively impairing over time, probably related to a multifactorial genesis. The aim of the study was the evaluation if a Temporal trend in serum testosterone levels exists in healthy men. Methods A search of the literature between 1971 and July 2024 was performed...

link.springer.com

With these questions in mind, we designed this study to evaluate the historical trend of testosterone serum levels in men enrolled in the clinical trials published so far. Finding a global testosterone decline could have broad implications both in reproductive medicine and considering the general male health decline suggested by many authors in recent years [20].




This study has several limitations. First, our analyses are based on data from healthy subjects obtained from studies available in the literature. Therefore, potential selection and participation biases cannot be ruled out, despite the rigorous literature search and quality checks performed. Indeed, biases related to the retrospective design of the study and the heterogeneity of subjects could not be eliminated. Second, we adjusted the meta-regression analyses with BMI, environmental and population-related parameters. However, these data were available for only a proportion of the studies included, limiting the statistical power of the correlation analyses. Finally, limitations inherent to the applied methodology (i.e., meta-regression analysis) cannot be excluded in the interpretation and discussion. In this systematic review of the literature, we sought to obtain more robust data by applying meta-regression analyses. However, these statistical approaches rely on aggregate data, which restricts the use of more rigorous methodological statistical techniques.

 

[Nelson Vergel]

Briefing Document: Declining Male Hormonal Health​

Source: "Temporal trends in serum testosterone and luteinizing hormone levels indicate an ongoing resetting of hypothalamic-pituitary-gonadal function in healthy men: a systematic review" by Santi et al. (Journal of Endocrinological Investigation, 2025).

Date of Review: October 26, 2023

Purpose: This briefing document summarizes the key findings of a comprehensive systematic review investigating temporal trends in serum testosterone and luteinizing hormone (LH) levels in healthy men over the past five decades. It also briefly contextualizes these findings with previously observed declines in sperm quality.

Executive Summary​

This systematic review and meta-analysis of 1,256 papers, encompassing over 1 million healthy men from 1971 to July 2024, reveals a significant and progressive decrease in mean total testosterone and luteinizing hormone (LH) serum levels over the past 55 years. This decline is independent of age and Body Mass Index (BMI), suggesting a fundamental shift in male endocrine function rather than merely age-related changes or rising obesity rates. The observed parallel decline in both testosterone and LH points to a potential "resetting" of the hypothalamic-pituitary-testicular axis, specifically at the hypothalamic level, rather than a primary testicular issue. This finding adds to existing concerns regarding a global decline in male fertility, previously observed through decreasing sperm counts. While environmental and demographic factors were investigated, their direct influence on these hormonal trends was not conclusively demonstrated.

Key Findings and Most Important Ideas​

1. Significant Decline in Testosterone Levels:

• The study found a "significant negative linear regression between testosterone serum levels and year of measurement (p = 0.033)."
• This "comprehensive decline in testosterone serum levels over the years was confirmed adjusting meta-regression analysis using the number of subjects included in each study, subjects’ age, BMI and the the assay used for testosterone measurement."
• The decline in testosterone was consistently observed regardless of the assay method (Immuno-assay, ELISA, Radio-immunoassay), though Mass-spectrometry data were limited for earlier years.
• The decline persisted even when the dataset was divided into pre-2000 and post-2000 periods, and when only studies from the USA were considered.
• Crucially, this decline in testosterone was observed "independent from BMI and age suggesting a genuine testosterone decrease." This refutes the common hypothesis that rising obesity rates are the primary driver of decreasing testosterone.

1. Parallel Decline in Luteinizing Hormone (LH) Levels:

• "LH serum levels showed a significant decline over the years (Coefficient − 0.1, SE: 0.1, p < 0.001), with patients’ age as the adjusting variable."
• This parallel decline with testosterone is a critical finding, as it suggests the issue is not solely within the testes (which would typically lead to elevated LH in response to low testosterone).

1. Implication of LH and Testosterone Co-decline: Hypothalamic-Pituitary Resetting:

• The simultaneous decrease in both testosterone and LH levels indicates that "the testosterone decline does not primarily originate in the testis."
• Instead, the authors propose an "ongoing resetting of the hypothalamic-pituitary-testicular function."
• Specifically, the "discrepancy between the trends observed in LH and FSH levels over time suggests that the underlying mechanism could involve the hypothalamic rather than pituitary function."
• The authors speculate that "the decline in testosterone serum levels over time is dependent on a reduction in LH, which, in turn, could be the consequence of subtle changes in GnRH pulsatility." GnRH (Gonadotropin-Releasing Hormone) is released from the hypothalamus and regulates LH and FSH.

1. No Significant Change in BMI or FSH:

• Despite the global rise in obesity, the "BMI in the studies evaluated here did not show any significant change across the years of observation (Coefficient 0.1, SE: 0.1, p = 0.617)." This strengthens the argument that the observed testosterone decline is independent of BMI.
• "FSH serum levels did not show any change across the years of observation (Coefficient − 0.1, SE: 0.1, p = 0.143), even after adjustment for subjects’ age." This is important because FSH regulation differs from LH regarding GnRH pulse characteristics, further supporting a hypothalamic rather than pituitary origin.

1. Limited Role of Environmental and Population Factors (Based on Available Data):

• The study included data on "energy production, consumption, trade, and emissions" (environmental factors) and "societal characteristics from online datasets provided by the World Health Organization (WHO)" (population-growth related parameters).
• After adjusting for these variables, "the decline in total testosterone serum levels across years was confirmed" and "the decline in LH serum levels across years was confirmed."
• This suggests that based on the parameters available for analysis, these broad environmental and demographic factors do not fully explain the observed hormonal decline. The authors note, however, that these results were based on a reduced dataset for adjustment.

1. Context with Sperm Quality Decline:

• The authors connect their findings to previous systematic reviews that "provide evidence of a decline in sperm counts world-wide since 1980s with an accelerated decline in both sperm concentration and total sperm count after 2000s."
• They state that "Our data, although not reporting semen parameters, add another suggestion in the alarming picture regarding male fertility decline."
• While previous hypotheses for sperm decline focused on "primary testicular damage due to exogenous factors, such as environment, pollution and endocrine disruptors," this study suggests an alternative: "the decreasing testicular function could be the result of impaired pituitary stimulation/pulsatile GnRH secretion, resulting in reduction of serum testosterone."

1. Future Implications and Unknown Mechanisms:

• The authors suggest that the declining trend could be an "adaptation to the current disequilibrium, necessary to achieve a new population homeostasis," though they emphasize that "neither our analyses, nor the current literature suggest this."
• The exact "mechanism behind the decrease in hypothalamic-pituitary gonadal function in healthy men described here remains unknown."
• The overall message is that "Testosterone serum levels have been progressively declining over the years in men, although they remain within reference ranges. The contribution of the declining testicular function, both in terms of testosterone and sperm, to the global reduction of fecundity/fertility remains to be investigated."

Limitations Noted by Authors:​

• Selection and Participation Biases: The analysis is based on existing literature, so biases related to study design and subject selection cannot be entirely ruled out.
• Data Availability for Confounders: BMI, environmental, and population-related parameters were not available for all included studies, limiting the statistical power of correlation analyses involving these factors.
• Methodological Limitations: Meta-regression analyses rely on aggregate data, which limits the use of more rigorous statistical techniques.

Conclusion:​

This study provides compelling evidence for a significant and continuous decline in both testosterone and LH levels in healthy men globally over the last 55 years. The independence of this trend from age and BMI, coupled with the differential response of LH and FSH, strongly points towards a central (hypothalamic) resetting of the male reproductive axis. This observed hormonal shift, alongside established declines in sperm quality, contributes to a concerning picture for overall male reproductive health, with underlying mechanisms yet to be fully elucidated.

 

[Nelson Vergel]

1. What is the central finding of this study regarding male hormone levels?​

This study reveals a significant and progressive decrease in mean total testosterone serum levels in healthy men over the last 55 years. This decline is also accompanied by a significant decrease in luteinizing hormone (LH) serum levels.

2. How does this study's finding relate to previous research on male reproductive health?​

The study builds upon previous research that identified a decline in semen quality, specifically sperm counts, worldwide since the 1980s, with an accelerated decline after 2000. While this study does not directly report on semen parameters, it suggests that the observed decline in testosterone and LH levels adds another layer of concern to the "alarming picture regarding male fertility decline." It supports the idea that the overall testicular function is progressively impairing over time.

3. Does the observed decline in testosterone levels appear to be influenced by age or BMI?​

No, the study found that the significant reduction in testosterone serum levels across the years of measurement was independent of both Body Mass Index (BMI) and age. This suggests that factors other than increasing age or global obesity rates are contributing to these hormonal changes. Despite the well-known increasing rate of obesity worldwide, the BMI in the evaluated studies did not show any significant change over the observation period in the healthy male population studied.

4. What does the parallel decline in testosterone and LH levels suggest about the origin of this trend?​

The parallel decline in both testosterone and LH serum levels indicates that the testosterone decline does not primarily originate in the testes. Instead, it suggests a central resetting of the hypothalamic-pituitary-testicular function, likely at the hypothalamic-pituitary level. The study speculates that this could be due to subtle changes in Gonadotropin-Releasing Hormone (GnRH) pulsatility, given that LH secretion is dependent on GnRH pulse frequency, while FSH (which did not show a clear decline) is more dependent on pulse amplitude.

5. Were environmental or societal factors found to be a definitive cause of the observed hormonal decline?​

While the study investigated the potential influence of environmental factors (like energy production, consumption, trade, and emissions) and population-growth related parameters, the decline in total testosterone and LH levels persisted even after adjusting for these variables. This suggests that, based on the parameters available for analysis, these specific environmental and societal factors are not solely responsible for the observed trends. The authors acknowledge that other factors, such as lifestyle habits and stress, are difficult to collect consistently on a global scale, making it challenging to assess their role.

6. What role do the different assay methods for measuring testosterone play in the findings?​

The study confirmed the decline in total testosterone serum levels across years for studies using immunometric assay (IA), enzyme-linked immunosorbent assay (ELISA), and radio-immunoassay (RIA). However, for studies utilizing mass spectrometry (MS), the decline was not confirmed. The authors note that the MS subgroup had a limited number of studies, particularly before 2000, suggesting that more data over a longer observation period are needed for a conclusive analysis with this method.

7. What are the potential implications of these findings for male health and fertility?​

The progressive impairment of male fertility is suggested by the observed decline in testosterone and LH levels. While the study doesn't directly measure sperm parameters, it reinforces the existing concern about declining sperm quality. The implications extend to general male health, as low testosterone can affect various bodily functions beyond reproduction. The study highlights the need for further investigation into the contribution of this declining testicular function to the global reduction of fecundity and fertility.

8. What are the limitations of this study, and what questions remain unanswered?​

The study acknowledges several limitations, including potential selection and participation biases due to its reliance on published data from healthy subjects. The availability of data for adjusting variables like BMI, environmental, and population-related parameters was limited for a proportion of studies, potentially affecting statistical power. The meta-regression analysis relies on aggregated data, which restricts the use of more rigorous statistical techniques. A key unanswered question is the precise mechanism behind the progressive decline in hypothalamic-pituitary-gonadal function in healthy men and whether it represents an adaptation to overpopulation or an as-yet-unknown disturbing factor.

 

[Nelson Vergel]

More on the subject:

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In an analysis of data from 4045 adolescent and young men aged 15 to 39 years who participated in the National Health and Nutrition Examination Surveys (NHANES) and had their total testosterone (TT) levels measured during 1999-2016, TT was significantly lower among those in the later (2011-2016) compared with earlier (1999-2000) survey cycles. Mean TT decreased over time from 605.39 ng/dL in 1999-2000 to 567.44, 424.96, 431.76...

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"From 1999 to 2016, testosterone levels have declined in adolescent and young adult men (AYA), according to results presented at the 2020 American Urological Association Virtual Experience.

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Thread 'Decline in Serum Testosterone Levels Among Adolescent and Young Adult Men in the USA'

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Testosterone deficiency has a prevalence of 20% among adolescent and young adult (AYA) males. Although previous studies have shown that total testosterone (TT) levels are declining in the population compared to prior decades, no study has identified TT level trends for AYA males specifically. Using data from the National Health and Nutrition Examination Surveys, we investigated TT levels for 4045 men from 1999 to 2016. After controlling for confounders, we found that...

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