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Published in: Endocrine 2/2023

23-09-2022 | Testosterone | Meta- Analysis

Ketogenic state improves testosterone serum levels—results from a systematic review and meta-analysis

Authors: Chiara Furini, Giorgia Spaggiari, Manuela Simoni, Carla Greco, Daniele Santi

Published in: Endocrine | Issue 2/2023

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Abstract

Background

It is widely demonstrated that obesity and hypogonadism are bi-directionally correlated, since the hypogonadism prevalence is higher in obese population, while weight loss increases testosterone serum levels. Several approaches are available to contrast weight excess, from simple dietary regimens to more complex surgical procedures. Ketogenic diets (KD) fit in this context and their application is growing year after year, aiming to improve the metabolic and weight patterns in obese patients. However, KD influence on testosterone levels is still poorly investigated.

Objectives

To systematically evaluate the potential effect of KD on testosterone levels.

Methods

A systematic literature search was performed until April 2022 including studies investigating testosterone levels before and after KD. Secondary endpoints were body weight, estradiol and sex-hormone binding globulin serum levels. Any kind of KD was considered eligible, and no specific criteria for study populations were provided.

Results

Seven studies (including eight trials) were included in the analysis for a total of 230 patients, five using normocaloric KD and three very low calories KD (VLCKD). Only three studies enrolled overweight/obese men. A significant total testosterone increase was recorded after any kind of KD considering 111 patients (2.86 [0.95, 4.77], p = 0.003). This increase was more evident considering VLCKD compared to normocaloric KD (6.75 [3.31, 10.20], p < 0.001, versus 0.98 [0.08, 1.88], p = 0.030). Meta-regression analyses highlighted significant correlations between the post-KD testosterone raise with patients’ age (R-squared 36.4, p < 0.001) and weight loss (R-squared 73.6, p < 0.001).

Conclusions

Comprehensively, KD improved testosterone levels depending on both patients’ age and KD-induced weight loss. However, the lack of information in included studies on hormones of the hypothalamic-pituitary-gonadal axis prevents an exhaustive comprehension about mechanisms connecting ketosis and testosterone homeostasis.
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Literature
1.
go back to reference G. Ugo-Neff, D. Rizzolo, Hypogonadism in men: updates and treatments. Jaapa 35(5), 28–34 (2022)CrossRef G. Ugo-Neff, D. Rizzolo, Hypogonadism in men: updates and treatments. Jaapa 35(5), 28–34 (2022)CrossRef
2.
go back to reference D.L. Pelzman, K. Hwang, Testosterone therapy: where do the latest guidelines agree and differ?. Curr. Opin. Endocrinol. Diabetes Obes. 27(6), 397–403 (2020)CrossRef D.L. Pelzman, K. Hwang, Testosterone therapy: where do the latest guidelines agree and differ?. Curr. Opin. Endocrinol. Diabetes Obes. 27(6), 397–403 (2020)CrossRef
3.
go back to reference S. Bhasin et al. Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 103(5), 1715–1744 (2018)CrossRef S. Bhasin et al. Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 103(5), 1715–1744 (2018)CrossRef
4.
go back to reference J. Erenpreiss et al. Prevalence of testosterone deficiency among aging men with and without morbidities. Aging Male 23(5), 901–905 (2020)CrossRef J. Erenpreiss et al. Prevalence of testosterone deficiency among aging men with and without morbidities. Aging Male 23(5), 901–905 (2020)CrossRef
5.
go back to reference X. Chen et al. Hypothalamic mechanisms of obesity-associated disturbance of hypothalamic-pituitary-ovarian axis. Trends Endocrinol. Metab. 33(3), 206–217 (2022)CrossRef X. Chen et al. Hypothalamic mechanisms of obesity-associated disturbance of hypothalamic-pituitary-ovarian axis. Trends Endocrinol. Metab. 33(3), 206–217 (2022)CrossRef
6.
go back to reference L. Yuxin et al. Research progress on the relationship between obesity-inflammation-aromatase axis and male infertility. Oxid. Med Cell Longev. 2021, 6612796 (2021)CrossRef L. Yuxin et al. Research progress on the relationship between obesity-inflammation-aromatase axis and male infertility. Oxid. Med Cell Longev. 2021, 6612796 (2021)CrossRef
7.
go back to reference L.T. van Hulsteijn et al. Prevalence of endocrine disorders in obese patients: systematic review and meta-analysis. Eur. J. Endocrinol. 182(1), 11–21 (2020)CrossRef L.T. van Hulsteijn et al. Prevalence of endocrine disorders in obese patients: systematic review and meta-analysis. Eur. J. Endocrinol. 182(1), 11–21 (2020)CrossRef
8.
go back to reference G. Corona et al. Treatment of functional hypogonadism besides pharmacological substitution. World J. Mens. Health 38(3), 256–270 (2020)CrossRef G. Corona et al. Treatment of functional hypogonadism besides pharmacological substitution. World J. Mens. Health 38(3), 256–270 (2020)CrossRef
9.
go back to reference G. Corona et al. The Role of testosterone treatment in patients with metabolic disorders. Expert Rev. Clin. Pharm. 14(9), 1091–1103 (2021)CrossRef G. Corona et al. The Role of testosterone treatment in patients with metabolic disorders. Expert Rev. Clin. Pharm. 14(9), 1091–1103 (2021)CrossRef
10.
go back to reference S. Sultan et al. Male obesity associated gonadal dysfunction and the role of bariatric surgery. Front Endocrinol. (Lausanne) 11, 408 (2020)CrossRef S. Sultan et al. Male obesity associated gonadal dysfunction and the role of bariatric surgery. Front Endocrinol. (Lausanne) 11, 408 (2020)CrossRef
11.
go back to reference G. Rastrelli et al. Metabolic syndrome in male hypogonadism. Front Horm. Res 49, 131–155 (2018)CrossRef G. Rastrelli et al. Metabolic syndrome in male hypogonadism. Front Horm. Res 49, 131–155 (2018)CrossRef
12.
go back to reference G. Corona et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur. J. Endocrinol. 168(6), 829–843 (2013)CrossRef G. Corona et al. Body weight loss reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and meta-analysis. Eur. J. Endocrinol. 168(6), 829–843 (2013)CrossRef
13.
go back to reference D.H. Ryan, S. Kahan, Guideline recommendations for obesity management. Med Clin. North Am. 102(1), 49–63 (2018)CrossRef D.H. Ryan, S. Kahan, Guideline recommendations for obesity management. Med Clin. North Am. 102(1), 49–63 (2018)CrossRef
14.
go back to reference A. Thorell et al. Guidelines for perioperative care in bariatric surgery: Enhanced Recovery After Surgery (ERAS) society recommendations. World J. Surg. 40(9), 2065–2083 (2016)CrossRef A. Thorell et al. Guidelines for perioperative care in bariatric surgery: Enhanced Recovery After Surgery (ERAS) society recommendations. World J. Surg. 40(9), 2065–2083 (2016)CrossRef
15.
go back to reference S.B. Heymsfield, T.A. Wadden, Mechanisms, pathophysiology, and management of obesity. N. Engl. J. Med 376(3), 254–266 (2017)CrossRef S.B. Heymsfield, T.A. Wadden, Mechanisms, pathophysiology, and management of obesity. N. Engl. J. Med 376(3), 254–266 (2017)CrossRef
16.
go back to reference A. Basolo, et al. Ketogenic diet and weight loss: is there an effect on energy expenditure? Nutrients 14, 1814 (2022).CrossRef A. Basolo, et al. Ketogenic diet and weight loss: is there an effect on energy expenditure? Nutrients 14, 1814 (2022).CrossRef
17.
go back to reference A. Paoli et al. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur. J. Clin. Nutr. 67(8), 789–796 (2013)CrossRef A. Paoli et al. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur. J. Clin. Nutr. 67(8), 789–796 (2013)CrossRef
18.
go back to reference M. Caprio et al. Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE). J. Endocrinol. Investig. 42(11), 1365–1386 (2019)CrossRef M. Caprio et al. Very-low-calorie ketogenic diet (VLCKD) in the management of metabolic diseases: systematic review and consensus statement from the Italian Society of Endocrinology (SIE). J. Endocrinol. Investig. 42(11), 1365–1386 (2019)CrossRef
19.
go back to reference K.J. Bough, J.M. Rho, Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 48(1), 43–58 (2007)CrossRef K.J. Bough, J.M. Rho, Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 48(1), 43–58 (2007)CrossRef
20.
go back to reference K.L. Harvey, L.E. Holcomb, S.C. Kolwicz, Jr, Ketogenic diets and exercise performance. Nutrients 11(10), 2296 (2019) K.L. Harvey, L.E. Holcomb, S.C. Kolwicz, Jr, Ketogenic diets and exercise performance. Nutrients 11(10), 2296 (2019)
21.
go back to reference A. Zajac et al. The effects of a ketogenic diet on exercise metabolism and physical performance in off-road cyclists. Nutrients 6(7), 2493–2508 (2014)CrossRef A. Zajac et al. The effects of a ketogenic diet on exercise metabolism and physical performance in off-road cyclists. Nutrients 6(7), 2493–2508 (2014)CrossRef
22.
go back to reference A.G. Tsai, T.A. Wadden, The evolution of very-low-calorie diets: an update and meta-analysis. Obesity 14(8), 1283–1293 (2006)CrossRef A.G. Tsai, T.A. Wadden, The evolution of very-low-calorie diets: an update and meta-analysis. Obesity 14(8), 1283–1293 (2006)CrossRef
23.
go back to reference L.M. Mongioì et al. Effectiveness of a very low calorie ketogenic diet on testicular function in overweight/obese men. Nutrients 12(10), 2967 (2020) L.M. Mongioì et al. Effectiveness of a very low calorie ketogenic diet on testicular function in overweight/obese men. Nutrients 12(10), 2967 (2020)
24.
go back to reference S. La Vignera et al. The ketogenic diet corrects metabolic hypogonadism and preserves pancreatic ß-cell function in overweight/obese men: a single-arm uncontrolled study. Endocrine 72(2), 392–399 (2021)CrossRef S. La Vignera et al. The ketogenic diet corrects metabolic hypogonadism and preserves pancreatic ß-cell function in overweight/obese men: a single-arm uncontrolled study. Endocrine 72(2), 392–399 (2021)CrossRef
25.
go back to reference K. Durkalec-Michalski et al. Is a four-week ketogenic diet an effective nutritional strategy in crossfit-trained female and male athletes? Nutrients 13(3), 864 (2021) K. Durkalec-Michalski et al. Is a four-week ketogenic diet an effective nutritional strategy in crossfit-trained female and male athletes? Nutrients 13(3), 864 (2021)
26.
go back to reference A. Paoli et al. Effects of two months of very low carbohydrate ketogenic diet on body composition, muscle strength, muscle area, and blood parameters in competitive natural body builders. Nutrients 13(2), 374 (2021) A. Paoli et al. Effects of two months of very low carbohydrate ketogenic diet on body composition, muscle strength, muscle area, and blood parameters in competitive natural body builders. Nutrients 13(2), 374 (2021)
27.
go back to reference V. Vidić et al. Effects of calorie restricted low carbohydrate high fat ketogenic vs. non-ketogenic diet on strength, body-composition, hormonal and lipid profile in trained middle-aged men. Clin. Nutr. 40(4), 1495–1502 (2021)CrossRef V. Vidić et al. Effects of calorie restricted low carbohydrate high fat ketogenic vs. non-ketogenic diet on strength, body-composition, hormonal and lipid profile in trained middle-aged men. Clin. Nutr. 40(4), 1495–1502 (2021)CrossRef
28.
go back to reference J.M. Wilson et al. Effects of ketogenic dieting on body composition, strength, power, and hormonal profiles in resistance training men. J. Strength Cond. Res 34(12), 3463–3474 (2020)CrossRef J.M. Wilson et al. Effects of ketogenic dieting on body composition, strength, power, and hormonal profiles in resistance training men. J. Strength Cond. Res 34(12), 3463–3474 (2020)CrossRef
29.
go back to reference N.K. Kumar et al. Adherence to low-carbohydrate diets in patients with diabetes: a narrative review. Diabetes Metab. Syndr. Obes. 15, 477–498 (2022)CrossRef N.K. Kumar et al. Adherence to low-carbohydrate diets in patients with diabetes: a narrative review. Diabetes Metab. Syndr. Obes. 15, 477–498 (2022)CrossRef
30.
go back to reference J. Whittaker, M. Harris, Low-carbohydrate diets and men’s cortisol and testosterone: systematic review and meta-analysis. Nutr. Health 2601060221083079 (2022) J. Whittaker, M. Harris, Low-carbohydrate diets and men’s cortisol and testosterone: systematic review and meta-analysis. Nutr. Health 2601060221083079 (2022)
31.
go back to reference J. Sterling, A.M. Bernie, R. Ramasamy, Hypogonadism: easy to define, hard to diagnose, and controversial to treat. Can. Urol. Assoc. J. 9(1-2), 65–68 (2015)CrossRef J. Sterling, A.M. Bernie, R. Ramasamy, Hypogonadism: easy to define, hard to diagnose, and controversial to treat. Can. Urol. Assoc. J. 9(1-2), 65–68 (2015)CrossRef
32.
go back to reference P. Dandona et al. Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome. Curr. Mol. Med. 8(8), 816–828 (2008)CrossRef P. Dandona et al. Hypogonadotrophic hypogonadism in type 2 diabetes, obesity and the metabolic syndrome. Curr. Mol. Med. 8(8), 816–828 (2008)CrossRef
33.
go back to reference S. Dhindsa et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care 33(6), 1186–1192 (2010)CrossRef S. Dhindsa et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care 33(6), 1186–1192 (2010)CrossRef
34.
go back to reference G. Corona et al. Testosterone and metabolic syndrome: a meta-analysis study. J. Sex. Med. 8(1), 272–283 (2011)CrossRef G. Corona et al. Testosterone and metabolic syndrome: a meta-analysis study. J. Sex. Med. 8(1), 272–283 (2011)CrossRef
35.
go back to reference V.A. Giagulli, J.M. Kaufman, A. Vermeulen, Pathogenesis of the decreased androgen levels in obese men. J. Clin. Endocrinol. Metab. 79(4), 997–1000 (1994) V.A. Giagulli, J.M. Kaufman, A. Vermeulen, Pathogenesis of the decreased androgen levels in obese men. J. Clin. Endocrinol. Metab. 79(4), 997–1000 (1994)
36.
go back to reference V.A. Giagulli et al. Weight loss more than glycemic control may improve testosterone in obese type 2 diabetes mellitus men with hypogonadism. Andrology 8(3), 654–662 (2020)CrossRef V.A. Giagulli et al. Weight loss more than glycemic control may improve testosterone in obese type 2 diabetes mellitus men with hypogonadism. Andrology 8(3), 654–662 (2020)CrossRef
37.
go back to reference C. Pelusi et al. Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: A randomized, double-blind, placebo-controlled study. PLoS ONE 12(9), e0183369 (2017)CrossRef C. Pelusi et al. Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: A randomized, double-blind, placebo-controlled study. PLoS ONE 12(9), e0183369 (2017)CrossRef
38.
go back to reference R. Cannarella et al. Effects of the selective estrogen receptor modulators for the treatment of male infertility: a systematic review and meta-analysis. Expert Opin. Pharmacother. 20(12), 1517–1525 (2019)CrossRef R. Cannarella et al. Effects of the selective estrogen receptor modulators for the treatment of male infertility: a systematic review and meta-analysis. Expert Opin. Pharmacother. 20(12), 1517–1525 (2019)CrossRef
39.
go back to reference J.M. Freeman, E.H. Kossoff, Ketosis and the ketogenic diet, 2010: advances in treating epilepsy and other disorders. Adv. Pediatr. 57(1), 315–329 (2010)CrossRef J.M. Freeman, E.H. Kossoff, Ketosis and the ketogenic diet, 2010: advances in treating epilepsy and other disorders. Adv. Pediatr. 57(1), 315–329 (2010)CrossRef
40.
go back to reference S. D’Andrea et al. Endogenous transient doping: physical exercise acutely increases testosterone levels-results from a meta-analysis. J. Endocrinol. Investig. 43(10), 1349–1371 (2020)CrossRef S. D’Andrea et al. Endogenous transient doping: physical exercise acutely increases testosterone levels-results from a meta-analysis. J. Endocrinol. Investig. 43(10), 1349–1371 (2020)CrossRef
41.
go back to reference A.H. Payne, D.B. Hales, Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr. Rev. 25(6), 947–970 (2004)CrossRef A.H. Payne, D.B. Hales, Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr. Rev. 25(6), 947–970 (2004)CrossRef
42.
go back to reference W.L. Miller, R.J. Auchus, The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 32(1), 81–151 (2011)CrossRef W.L. Miller, R.J. Auchus, The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr. Rev. 32(1), 81–151 (2011)CrossRef
43.
go back to reference T. Dong et al. The effects of low-carbohydrate diets on cardiovascular risk factors: a meta-analysis. PLoS ONE 15(1), e0225348 (2020)CrossRef T. Dong et al. The effects of low-carbohydrate diets on cardiovascular risk factors: a meta-analysis. PLoS ONE 15(1), e0225348 (2020)CrossRef
44.
go back to reference D. Ciocan et al. Modulation of the bile acid enterohepatic cycle by intestinal microbiota alleviates alcohol liver disease. Cells 11(6), 968 (2022) D. Ciocan et al. Modulation of the bile acid enterohepatic cycle by intestinal microbiota alleviates alcohol liver disease. Cells 11(6), 968 (2022)
45.
go back to reference Y. Lin et al. Dietary fibre supplementation improves semen production by increasing leydig cells and testosterone synthesis in a growing boar model. Front. Vet. Sci. 9, 850685 (2022)CrossRef Y. Lin et al. Dietary fibre supplementation improves semen production by increasing leydig cells and testosterone synthesis in a growing boar model. Front. Vet. Sci. 9, 850685 (2022)CrossRef
46.
go back to reference L.J. de Souza et al. Effect of dietary fiber on fecal androgens levels: an experimental analysis in brown brocket deer (Mazama gouazoubira). Gen. Comp. Endocrinol. 321-322, 114029 (2022)CrossRef L.J. de Souza et al. Effect of dietary fiber on fecal androgens levels: an experimental analysis in brown brocket deer (Mazama gouazoubira). Gen. Comp. Endocrinol. 321-322, 114029 (2022)CrossRef
47.
go back to reference N.E. Allen, T.J. Key, The effects of diet on circulating sex hormone levels in men. Nutr Res Rev 13(2), 159–184 (2000).CrossRef N.E. Allen, T.J. Key, The effects of diet on circulating sex hormone levels in men. Nutr Res Rev 13(2), 159–184 (2000).CrossRef
48.
go back to reference T.J. Key et al. Testosterone, sex hormone-binding globulin, calculated free testosterone, and oestradiol in male vegans and omnivores. Br. J. Nutr. 64(1), 111–119 (1990)CrossRef T.J. Key et al. Testosterone, sex hormone-binding globulin, calculated free testosterone, and oestradiol in male vegans and omnivores. Br. J. Nutr. 64(1), 111–119 (1990)CrossRef
49.
go back to reference C. Wang et al. Low-fat high-fiber diet decreased serum and urine androgens in men. J. Clin. Endocrinol. Metab. 90(6), 3550–3559 (2005)CrossRef C. Wang et al. Low-fat high-fiber diet decreased serum and urine androgens in men. J. Clin. Endocrinol. Metab. 90(6), 3550–3559 (2005)CrossRef
50.
go back to reference D.A. Cutler, S.M. Pride, A.P. Cheung, Low intakes of dietary fiber and magnesium are associated with insulin resistance and hyperandrogenism in polycystic ovary syndrome: a cohort study. Food Sci. Nutr. 7(4), 1426–1437 (2019)CrossRef D.A. Cutler, S.M. Pride, A.P. Cheung, Low intakes of dietary fiber and magnesium are associated with insulin resistance and hyperandrogenism in polycystic ovary syndrome: a cohort study. Food Sci. Nutr. 7(4), 1426–1437 (2019)CrossRef
51.
go back to reference K.S. Al Aamri et al. The effect of low-carbohydrate ketogenic diet in the management of obesity compared with low caloric, low-fat diet. Clin. Nutr. ESPEN 49, 522–528 (2022)CrossRef K.S. Al Aamri et al. The effect of low-carbohydrate ketogenic diet in the management of obesity compared with low caloric, low-fat diet. Clin. Nutr. ESPEN 49, 522–528 (2022)CrossRef
52.
go back to reference A. Jayedi et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 116(1), 40–56 (2022).CrossRef A. Jayedi et al. Dose-dependent effect of carbohydrate restriction for type 2 diabetes management: a systematic review and dose-response meta-analysis of randomized controlled trials. Am. J. Clin. Nutr. 116(1), 40–56 (2022).CrossRef
53.
go back to reference B. O’Neill, P. Raggi, The ketogenic diet: pros and cons. Atherosclerosis 292, 119–126 (2020)CrossRef B. O’Neill, P. Raggi, The ketogenic diet: pros and cons. Atherosclerosis 292, 119–126 (2020)CrossRef
54.
go back to reference M. Grossmann et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J. Clin. Endocrinol. Metab. 93(5), 1834–1840 (2008)CrossRef M. Grossmann et al. Low testosterone levels are common and associated with insulin resistance in men with diabetes. J. Clin. Endocrinol. Metab. 93(5), 1834–1840 (2008)CrossRef
Metadata
Title
Ketogenic state improves testosterone serum levels—results from a systematic review and meta-analysis
Authors
Chiara Furini
Giorgia Spaggiari
Manuela Simoni
Carla Greco
Daniele Santi
Publication date
23-09-2022
Publisher
Springer US
Published in
Endocrine / Issue 2/2023
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-022-03195-5

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