Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC RLw5RjQGMFGSkDn5Ydk8Bxh S0066-782X2018001400228 10.5935/abc.20180132 Letter to the editor The Need for Sex Hormone Analysis in Addition to Long-Term Follow-Up of Phytosterol Supplementation Santos Heitor Oliveira Universidade Federal de Uberlândia Uberlândia MG Brazil Universidade Federal de Uberlândia, Uberlândia, MG - Brazil Mailing Address: Heitor Oliveira Santos Av. Pará, 1720. CEP 38400-902, Umuarama, Uberlândia, MG - Brazil. E-mail: heitoroliveirasantos@gmail.com, heitor13cam@hotmail.com 08 2018 111 2 228 229 07 01 2018 23 05 2018 23 05 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Keywords: Cardiovascular Diseases/prevention&control Hypercholesterolemia Phytosterois Steroids

Dear Editor,

I read with great interest the article entitled “Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases”, by Cabral and Klein, published in the Brazilian Archives of Cardiology.1 The authors discuss phytosterol doses in the treatment of hypercholesterolemia, showing the current consensus of renowned guidelines and approval by global regulatory agencies.

As already mentioned, the main phytosterol mechanism of action occurs through the reduction (30% to 50%) in the intestinal absorption of cholesterol.1 The authors, however, make it clear that long-term follow-up is essential to assess the association of phytosterol supplementation with the risk of cardiovascular diseases. Additionally, I emphasize another important investigation: analyses of serum sex hormones during randomized clinical trials based on phytosterol administration.

I recently showed that cholesterol intake may be related to increased total testosterone in men, whereas statin use may annul this potential.2 Perhaps the use of phytosterols can also attenuate serum total testosterone levels in men (Figure 1).

Proposal to analyze serum testosterone levels during phytosterol supplementation. Phytosterols increase the excretion of cholesterol, resulting in serum cholesterol decrease. Since cholesterol is important for the synthesis of sex hormones, the decrease in serum testosterone combined with phytosterol supplementation is a hypothesis. Therefore, the testing of this concept is a useful and, at first, an innovative concept. Dotted arrows indicate the conduction of phytosterols; continuous arrows indicate decreased levels of serum cholesterol and testosterone.

In one test, the ingestion of 8.6 g/d of phytosterols reflected in the daily excretion of 28 mg cholesterol/g of fecal dry weight, resulting in an increase of 20 mg / g in comparison to the period prior to the test.3 These proportions reflect in the daily excretion of approximately 230 mg of fecal cholesterol without the ingestion of phytosterols and 810 mg with the ingestion of phytosterols, since the average daily fecal excretion in humans is 128 g of wet weight, which corresponds to 29 g of dry weight.4

I point out that daily intake of 500 to 1,000 mg of cholesterol may result in an approximate increase of 130 ng/dL of total testosterone in men. In rats, the ingestion of phytosterols for 22 days reduced serum testosterone by 33%, in comparison to controls.5 To the best of my knowledge, there are no studies that analyzed sex hormones in association with phytosterol administration in humans. Therefore, in addition to the aforementioned need to analyze the long-term administration of phytosterols, it is also important to consider sex hormone measurements in this context.

References 1 Cabral CE, Klein MR. Phytosterols in the treatment of hypercholesterolemia and prevention of cardiovascular diseases. Arq Bras Cardiol. 2017;109(5):475-82. Cabral CE Klein MR Phytosterols in the treatment of hypercholesterolemia and prevention of cardiovascular diseases Arq Bras Cardiol 2017 109 5 475 482 2 Santos HO. Ketogenic diet and testosterone increase: Is the increased cholesterol intake responsible? To what extent and under what circumstances can there be benefits? Hormones(Athens).2017;16(3):150-60. Santos HO Ketogenic diet and testosterone increase: Is the increased cholesterol intake responsible? To what extent and under what circumstances can there be benefits? Hormones(Athens) 2017 16 3 150 160 3 Weststrate JA, Ayesh R, Bauer-Plank C, Drewitt PN. Safety evaluation of phytosterol esters. Part 4. Faecal concentrations of bile acids and neutral sterols in healthy, normalipidaemic volunteers consuming a controlled diet either with or without a phytosterol ester-envirched margarine. Food Chem Toxicol. 1999;37(11):1063-71. Weststrate JA Ayesh R Bauer-Plank C Drewitt PN Safety evaluation of phytosterol esters. Part 4. Faecal concentrations of bile acids and neutral sterols in healthy, normalipidaemic volunteers consuming a controlled diet either with or without a phytosterol ester-envirched margarine Food Chem Toxicol 1999 37 11 1063 1071 4 Rose C, Parker A, Jefferson B, Cartmell E. The Characterization of feces and urine: A review of the Literature to Inform Advanced Treatment Technology. Crit Rev Environ Sci Technol. 2015;45(17):1827-79. Rose C Parker A Jefferson B Cartmell E The Characterization of feces and urine: A review of the Literature to Inform Advanced Treatment Technology Crit Rev Environ Sci Technol 2015 45 17 1827 1879 5 Awada AB, Hartatia MS, Finka CS. Phytosterol feeding induces alteration in testosterone metabolism in rat tissues. J Nutr Biochem. 1998;9(17):712-7. Awada AB Hartatia MS Finka CS Phytosterol feeding induces alteration in testosterone metabolism in rat tissues J Nutr Biochem 1998 9 17 712 717 Reply Cabral Carlos Eduardo Klein Márcia Regina Simas Torres

We thank you for your interest and comments related to our recent review article entitled “Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases,”1 which aimed specifically to address the available evidence in the literature on the association between phytosterols and risk of cardiovascular diseases.

We agree that it is important to investigate the effects of phytosterols on serum levels of sex hormones, especially due to the potential risk of reducing plasma testosterone levels. We are not aware of studies carried out in humans that have performed such an evaluation. Experimental animal studies are scarce, and a reduction in plasma testosterone levels has been observed in some,2,3 but not all of them.4

Sincerely,

Carlos Eduardo CabralMárcia Regina Simas Torres Klein 1 Cabral CE, Klein MR. Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases. Arq Bras Cardiol. 2017;109(5):475-482. Cabral CE Klein MR Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases Arq Bras Cardiol 2017 109 5 475 482 2 Qasimi MI, Nagaoka K, Watanabe G. The effects of phytosterols on the sexual behavior and reproductive function in the Japanese quail (Coturnix coturnix japonica). Poult Sci. 20171;96(9):3436-44. Qasimi MI Nagaoka K Watanabe G The effects of phytosterols on the sexual behavior and reproductive function in the Japanese quail (Coturnix coturnix japonica) Poult Sci 2017 1 96 9 3436 3444 3 Awad AB, SriHartati M, Fink CS. Phytosterol feeding induces alteration in testosterone metabolism in rat tissues. J Nutr Biochem. 1998; 9(12):712–7 Awad AB SriHartati M Fink CS Phytosterol feeding induces alteration in testosterone metabolism in rat tissues J Nutr Biochem 1998 9 12 712 717 4 Ryökkynen A, Käyhkö UR, Mustonen AM, Kukkonen JV, Nieminen P. Multigenerational exposure to phytosterols in the mouse. Reprod Toxicol. 2005; 19(4): 535-40. Ryökkynen A Käyhkö UR Mustonen AM Kukkonen JV Nieminen P Multigenerational exposure to phytosterols in the mouse Reprod Toxicol 2005 19 4 535 540 Carta ao Editor A Necessidade da Análise de Hormônios Sexuais além do Acompanhamento a Longo Prazo da Suplementação de Fitosteróis Santos Heitor Oliveira Universidade Federal de Uberlândia, Uberlândia, MG - Brasil Correspondência: Heitor Oliveira Santos Av. Pará, 1720. CEP 38400-902, Umuarama, Uberlândia, MG - Brasil. E-mail: heitoroliveirasantos@gmail.com, heitor13cam@hotmail.com Palavras-chave: Doenças Cardiovasculares/prevenção &controle Hipercolesterolemia Fitosteróis Esteróides

Caro Editor,

Foi com grande prestígio que li o artigo “Fitosteróis no Tratamento da Hipercolesterolemia e Prevenção de Doenças Cardiovasculares”, de Cabral e Klein, publicado nos Arquivos Brasileiros de Cardiologia.1 Os autores discorrem sobre a posologia de fitosteróis no tratamento da hipercolesterolemia, mostrando o consenso atual de renomadas diretrizes e a aprovação por agências reguladoras mundiais.

Como mencionado, o principal mecanismo de ação dos fitosteróis é por meio da redução (30% a 50%) na absorção intestinal de colesterol.1 Os autores, no entanto, deixam claro que é primordial o acompanhamento a longo prazo, para explorar a relação da suplementação de fitosteróis com o risco de doenças cardiovasculares. Adicionalmente, reforço outra investigação importante: a análises de hormônios sexuais séricos durante ensaios clínicos randomizados baseados na administração de fitosteróis.

Recentemente mostrei que a ingestão de colesterol pode estar relacionada com aumento da testosterona total em homens, ao passo que o uso de estatinas pode anular este potencial.2 Talvez o uso de fitosteróis também pode atenuar os níveis séricos de testosterona total em homens (Figura 1).

Proposta para analisar os níveis séricos de testosterona durante suplementação de fitosteróis. Os fitosteróis aumentam a excreção do colesterol, repercutindo na diminuição do colesterol sérico. Visto que o colesterol é importante na síntese de hormônios sexuais, a diminuição da testosterona sérica aliada à suplementação de fitosteróis é uma hipótese. Portanto, testar este conceito é útil e, a princípio, inovador. Setas pontilhadas significam a condução de fitosteróis; setas lisas significam diminuição de níveis séricos de colesterol e testosterona.

Em um teste, a ingestão de 8,6 g/d de fitosteróis refletiu na excreção diária de 28 mg de colesterol/g de peso seco fecal, sendo resultante de um aumento em 20 mg/g em comparação com o período antecedente ao teste.3 Tais proporções refletem na excreção de colesterol fecal diária aproximadamente em 230 mg sem a ingestão de fitosteróis e 810 mg com a ingestão de fitosteróis, pois a média de excreção fecal diária dos seres humanos é de 128 g de peso úmido, o qual corresponde a 29 g de peso seco.4

Aponto que a ingestão diária de 500 a 1.000 mg de colesterol pode resultar no aumento aproximadamente de 130 ng/dL de testosterona total em homens. Em ratos, a ingestão de fitosteróis durante 22 dias reduziu a testosterona sérica em 33%, em comparação com o controle.5 De acordo com meu conhecimento, não há estudos que analisaram hormônios sexuais em associação com a administração de fitosteróis em humanos. Portanto, além da necessidade citada de analisar a longo prazo a administração de fitosteróis, também é substancial cogitar mensurações de hormônios sexuais neste âmbito.

Carta-resposta Cabral Carlos Eduardo Klein Márcia Regina Simas Torres

Agradecemos o interesse e os comentários relacionados ao nosso recente artigo de revisão “Fitosteróis no Tratamento da Hipercolesterolemia e Prevenção de Doenças Cardiovasculares”,1 que teve como objetivo abordar especificamente as evidências disponíveis na literatura sobre a relação entre fitosteróis e risco de doenças cardiovasculares.

Concordamos que seja importante investigar os efeitos dos fitosteróis sobre os níveis séricos de hormônios sexuais, em especial devido ao potencial risco de reduzir a concentração plasmática de testosterona. Não temos conhecimento de estudos conduzidos em seres humanos que tenham realizado tal avaliação. Os estudos experimentais com animais são escassos, tendo sido observada redução na testosterona plasmática em alguns,2,3 porém não em todos.4

Atenciosamente,

Carlos Eduardo CabralMárcia Regina Simas Torres Klein 1 Cabral CE, Klein MR. Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases. Arq Bras Cardiol. 2017;109(5):475-482. Cabral CE Klein MR Phytosterols in the Treatment of Hypercholesterolemia and Prevention of Cardiovascular Diseases Arq Bras Cardiol 2017 109 5 475 482 2 Qasimi MI, Nagaoka K, Watanabe G. The effects of phytosterols on the sexual behavior and reproductive function in the Japanese quail (Coturnix coturnix japonica). Poult Sci. 20171;96(9):3436-44. Qasimi MI Nagaoka K Watanabe G The effects of phytosterols on the sexual behavior and reproductive function in the Japanese quail (Coturnix coturnix japonica) Poult Sci 2017 1 96 9 3436 3444 3 Awad AB, SriHartati M, Fink CS. Phytosterol feeding induces alteration in testosterone metabolism in rat tissues. J Nutr Biochem. 1998; 9(12):712–7 Awad AB SriHartati M Fink CS Phytosterol feeding induces alteration in testosterone metabolism in rat tissues J Nutr Biochem 1998 9 12 712 717 4 Ryökkynen A, Käyhkö UR, Mustonen AM, Kukkonen JV, Nieminen P. Multigenerational exposure to phytosterols in the mouse. Reprod Toxicol. 2005; 19(4): 535-40. Ryökkynen A Käyhkö UR Mustonen AM Kukkonen JV Nieminen P Multigenerational exposure to phytosterols in the mouse Reprod Toxicol 2005 19 4 535 540