The DOI matches its Crossref record; 72 of the 72 references it cites were found in a registry or an index; none of the 98 sources its claims cite is checked for support yet.
Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit
Open accessAbstract
Context: Although gonadal axis dysregulation from energy deficit is well recognized in women, the effects of energy deficit on the male gonadal axis have received much less attention. Evidence acquisition: To identify relevant articles, we conducted PubMed searches from inception to May 2021. Evidence synthesis: Case series and mechanistic studies demonstrate that energy deficit (both acutely over days or chronically over months) either from inadequate energy intake and/or excessive energy expenditure can lower serum testosterone concentration as a result of hypothalamic-pituitary-testicular (HPT) axis dysregulation in men. The extent to which this has clinical consequences that can be disentangled from the effects of nutritional insufficiency, concomitant endocrine dysregulation (eg, adrenal and thyroid axis), and coexisting comorbidities (eg, depression and substance abuse) is uncertain. HPT axis dysfunction is primarily the result of loss of GnRH pulsatility resulting from a failure of leptin to induce kisspeptin signaling. The roles of neuroendocrine consequences of depression, hypothalamic-pituitary-adrenal axis activation, proinflammatory cytokines, Ghrelin, and genetic susceptibility remain unclear. In contrast to hypogonadism from organic pathology of the HPT axis, energy deficit-associated HPT dysregulation is functional, and generally reversible by restoring energy balance. Conclusions: The clinical management of such men should aim to restore adequate nutrition and achieve and maintain a healthy body weight. Psychosocial comorbidities must be identified and addressed. There is no evidence that testosterone treatment is beneficial. Many knowledge gaps regarding epidemiology, pathophysiology, and treatment remain and we highlight several areas that require future research.
Overview
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TL;DR
This minireview synthesizes evidence that energy deficit—from inadequate intake and/or excessive exercise—suppresses the male hypothalamic-pituitary-testicular (HPT) axis, primarily via loss of GnRH pulsatility from failure of leptin to induce kisspeptin signaling. The resulting hypogonadism is functional and generally reversible with restoration of energy balance, and testosterone treatment is not recommended.
Key findings
- Acute fasting (water only) in healthy young men reduced total testosterone from 13.8 nmol/L to 10.9 nmol/L and LH from 2.9 to 1.1 IU/L within 48 hours; 3–5 days of fasting lowered total and free testosterone by 50% and LH by 30%, changes completely prevented by pulsatile GnRH infusion. Older men (mean age 67) showed no significant fasting-associated changes, whereas young men (mean age 28) fell 46% (total) and 40% (free) testosterone.
- Chronic energy deficit: an early series of 28 Indian men with severe protein-calorie malnutrition had total testosterone reduced ~50%; a case-control study of 31 men with anorexia nervosa (BMI 15.8 kg/m²) had total testosterone 9.2 nmol/L vs 23.5 nmol/L in controls. In the CALERIE 2-year, 25% caloric-restriction RCT, men (n = 66) showed no difference in total testosterone or LH, but higher SHBG and lower calculated free testosterone at 12 months (between-group difference 100 pmol/L [2.89 ng/dL]), with improved sexual drive and arousal.
- Exercise: serum testosterone fell 60% after a marathon, and −67% ± 18% after a 1230-km ultra-endurance cycling event; men running ≥64 km/week had ~20% lower total and ~30% lower free testosterone than sedentary controls. In US Army Ranger training with 8% weight loss, testosterone decreased ~70%, recovering within 2–6 weeks; in another cohort testosterone fell from 16.3 to 2.2 nmol/L but recovered promptly with refeeding despite ongoing stressors.
- Mechanisms: leptin replacement during 72-hour fasting prevented starvation-induced HPT changes; ghrelin administration reduced LH pulse amplitude and frequency and lowered testosterone; IL-2 infusion suppressed testosterone secretion more markedly in younger than older men. Testosterone treatment during a 28-day energy deficit increased lean mass by 2.5 kg (95% CI, 1.6–3.3) but had no effect on muscle function, and there is no evidence it improves clinically important outcomes.
Methods
- Narrative minireview; PubMed searches from inception to May 2021 to identify relevant articles.
- Evidence synthesis drawn from case series, cross-sectional and case-control studies, randomized controlled trials, and mechanistic/preclinical studies in men and animal models.
- No primary data were generated or analyzed (data sharing not applicable).
Limitations
- Stated: the true population frequency of energy deficit-associated HPT dysregulation is unknown; most evidence comes from men with pronounced energy deficit, and effects of lesser deficits are unclear; the degree to which symptoms reflect HPT suppression versus comorbidities or other endocrine changes (adrenal, thyroid, GH/IGF-1) is uncertain; SHBG is commonly increased, complicating interpretation of total testosterone; effects on sperm concentration and fertility are unknown; no prospective data on management approaches or long-term health outcomes; roles of HPA-axis activation, ghrelin, and genetic susceptibility require further study.
- Evident from the text: the literature relies heavily on convenience samples and single case reports likely representing the severe end of the spectrum, and several cited studies are small (e.g., n = 6–10 in exercise and ghrelin studies).
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In the paper
“suggesting that the energy deficit, not the exercise in itself, is the key factor in HPT axis suppression even in a multistressor environment (23).”
§ Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit > Effects of a Relative Energy Deficit on the HPT Axis: Role of Excessive Exercise
What the sources say
- Not checked yetcites [23] Friedl, 2000, Endocrine markers of semistarvation in healthy lean men in a multistressor environment, J Appl Physiol (1985). source
hedgedstates a cause- Asserted: passes — The authors put it forward as true.
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In the paper
“in a secondary analysis, on self-reported measures of appetite (61)”
§ Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit > Management
What the sources say
- Not checked yetcites [61] Karl, 2020, Effects of testosterone supplementation on ghrelin and appetite during and after severe energy deficit in healthy men, J Endocr Soc source
plainn = 50- Asserted: passes — The authors put it forward as true.
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In the paper
“This may be, in addition to the observation that young men are more susceptible to the HPT axis-suppressive effects of inflammation than older men (see Proinflammatory Cytokines) (8), 1 of the contributing reasons why energy deficit-associated functional hypogonadism has been predominantly reported in younger men (9,10).”
§ Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit > Effects of an Acute Energy Deficit
What the sources say
- Not checked yetcites [8] Veldhuis, 2016, proinflammatory cytokine infusion attenuates LH’s feedforward on testosterone secretion: modulation by age, J Clin Endocrinol Metab. source
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plainstates a cause- Asserted: passes — The authors put it forward as true.
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In the paper
“In a randomized controlled trial (RCT) of healthy nonobese adults subjected to 2 years of 25% caloric restriction achieving an 11.5% weight loss, a secondary analysis among men (n = 66) showed no difference in serum total testosterone and LH concentrations between the calorie restricted and ad libitum groups at either at 12 months or at study end.”
§ Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit > Effects of a Chronic Energy Deficit
What the sources say
- Not checked yetcites [18] Martin, 2016, Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: the CALERIE 2 randomized clinical trial, JAMA Intern Med. source
plainn = 66- Asserted: passes — The authors put it forward as true.
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In the paper
“An early case series of 28 Indian men (mean age 41 years) with severe chronic protein-calorie malnutrition (mean body weight 33 kg), but no evidence of other clinical disease, reported clinical features of hypogonadism (diminished body hair and beard growth and small soft testes) accompanied by low total testosterone (reduced by ~50% compared with healthy controls).”
§ Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit > Effects of a Chronic Energy Deficit
What the sources say
- Not checked yetcites [11] Smith, 1975, The pituitary-gonadal axis in men with protein-calorie malnutrition, J Clin Endocrinol Metab. source
plainstates an associationn = 28- Asserted: passes — The authors put it forward as true.
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In the paper
§ Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit > Effects of a Chronic Energy Deficit
“total testosterone 3 nmol/L”
§ Dysregulation of the Hypothalamic-Pituitary-Testicular Axis due to Energy Deficit > Effects of a Chronic Energy Deficit
“(0.6-21.3 mmol/L)”
Citations
Cites
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Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males
Dhillo, W. S., Chaudhri, O. B., Patterson, M., Thompson, E. L., Murphy, K. G., Badman, M. K., McGowan, B. M., Amber, V., Patel, S., Ghatei, M. A., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1468 · Cited by 656
The effects of opioids and opioid analogs on animal and human endocrine systems
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Leptin indirectly regulates gonadotropin-releasing hormone neuronal function
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Endocrine markers of semistarvation in healthy lean men in a multistressor environment
Friedl, K. E., Moore, R. J., Hoyt, R. W., Marchitelli, L. J., Martinez-Lopez, L. E., & Askew, E. W. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.88.5.1820 · Cited by 316
Leptin is an effective treatment for hypothalamic amenorrhea
Chou, S. H., Chamberland, J. P., Liu, X., Matarese, G., Gao, C., Stefanakis, R., Brinkoetter, M. T., Gong, H., Arampatzi, K., & Mantzoros, C. S. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1015674108 · Cited by 287
Reduced serum testosterone and prolactin levels in male distance runners
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The association of hypogonadism with depression and its treatments
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Metadata
- Authors
- Grossmann, M., & Wittert, G. A.
- Affiliations
- The University of Melbourne (AU)
- Queen Elizabeth Hospital (AU)
- Corresponding author
- Grossmann, Mathis
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2021-07-15
- Volume
- 106
- Issue
- 12
- Pages
- e4861-e4871
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W3179455916
- Cited by
- 24
- References
- 71
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 7 · 2023: 5 · 2022: 4
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (am)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- hypothalamic-pituitary-testicular axis, negative energy balance, male hypogonadism, testosterone, GnRH pulsatility, kisspeptin, leptin signaling, depression, hypothalamic-pituitary-adrenal axis, ghrelin, inflammatory cytokines, energy balance, nutritional insufficiency
- MeSH terms
- Energy Metabolism, Humans, Hypogonadism, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Prognosis, Testis
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