madman
Super Moderator
Abstract
Introduction: Inositols have a key role in ovarian physiology and the literature reports a wealth of studies about the major isomer, myo-inositol (MI). However, information about D-chiro-inositol (DCI) is still scarce, despite the ratio MICI is tissue-specific and actively maintained by an insulin-dependent epimerase enzyme.
Areas Covered: This expert opinion provides an overview of the physiological contribution of DCI in regulating steroidogenesis. DCI indeed mediates the intracellular signaling of insulin, which induces the biosynthesis of androgens. Studies on second messengers of insulin also revealed that DCI has a specific role in modulating the activity of aromatase enzyme. Specifically, recent findings demonstrated that DCI influence the enzyme gene expression, thus reducing the conversion of androgens into estrogens.
Expert opinion: available evidence suggests that the effects of DCI administration may be similar to those of aromatase inhibitors, but without causing hypo-estrogenic states. Therefore, DCI treatments should be evaluated for either estrogen-dependent gynecological conditions or low testosterone states in male subjects.
Article highlights
• D-chiro-inositol (DCI), besides being a second messenger of insulin, regulates female steroidogenesis by enhancing testosterone biosynthesis and downregulating the expression of aromatase.
• As second messenger of insulin, short-term administration of DCI may reduce androgen levels in insulin-resistant women; extended treatments result in androgen increase due to the activity on aromatase and on testosterone biosynthesis.
• Taking into account the modulatory action on aromatase, DCI may find application for estrogen-dependent gynecological diseases characterized by increased expression of the enzyme.
• Tailoring the dosage and the duration of the intervention, DCI treatment may represent an appealing therapeutic approach for increasing the androgen-to-estrogen ratio in men with late-onset hypogonadism.
6. Conclusions
Besides carrying the intracellular message of insulin, DCI influences the steroid biosynthesis by inducing the testosterone production and modulating the aromatase activity. Such an effect on aromatase may be exploited in the treatment and prevention of all the conditions that are generally treated with AIs and/or insulin sensitizers. The use of DCI prevents the build-up of a hypo-estrogenic environment, avoiding the onset of side effects generally associated with therapies with AIs.
7. Expert opinion
Accumulating evidence suggests that biologically active metabolites of DCI are deeply involved in modulating steroidogenesis, even though the exact underlying mechanisms remain to be elucidated. In particular recent data proved that DCI, besides being one of the intracellular second messengers of insulin, affects the activity of aromatase and regulates the androgen-to-estrogen ratio. The mechanistic insights lately reported by Sacchi et al. demonstrated that DCI downregulates the gene expression of the enzyme [17], rather than inhibiting its activity. Hence, DCI modulates the levels of estrogens, and DCI treatment may reduce them without completely blocking their biosynthesis. In a recent publication, we speculated about a possible similar therapeutic role of DCI compared to AIs [18], even though the effects are markedly different and DCI administration avoids the onset of hypo-estrogenic states. Because of such an advantage over AIs, investigating the potentialities of DCI treatment for estrogen-dependent conditions is particularly appealing. In our opinion, future studies should be planned to assess the potential therapeutic effect of DCI administration on the symptoms of gynecological benign conditions such as endometriosis and uterine fibroids, as well as the preventive activity on pre-cancerous lesions. Likewise, DCI treatment should be evaluated as an adjuvant strategy to AIs in the post-operative management of estrogen-sensitive tumors, or as a prevention protocol for subjects presenting with risk factors. Specifically, obese women, particularly in menopause, may benefit from a double advantage of the long-term supplement of DCI due to the effects on insulin resistance and to the modulation of the activity of the aromatase in adipose tissue. Nevertheless, particularly in fertile age, we take the opportunity to underline that long-term treatments with elevated doses of DCI may cause an unwanted increase in testosterone levels as a secondary effect. Such occurrence should be considered in evaluating the therapeutic approach with DCI, especially for those pathological conditions whose symptoms may be exacerbated by increased androgen levels, such as PCOS [16]: in these cases, we believe that the mechanism of action fails to support a rationale for the use of high doses of DCI alone as successful treatment.
DCI is an insulin-sensitizing agent, and short-term supplementation may be beneficial to treat hyperandrogenic or hyper-estrogenic states associated with hyper-insulinemia. Nevertheless, the effect of DCI on aromatase can further explain why short-term treatments with DCI successfully induced ovulation in a dose-dependent manner in PCOS patients [28]. DCI is able to reduce the negative feedback on gonadotropin release not only by reducing systemic insulin levels but even reducing estrogen production. On that basis, we suggest that a similar effect may potentially be observed also in non-PCOS, non-IR anovulatory women, which may benefit from an initially increased FSH release by reduced estrogens. Thus, evaluating the possibility of high-doses supplementation with DCI and the duration of the treatment would be an interesting option in such patients.
Interestingly, hypogonadal men can benefit from an increase of testosterone, which is unwanted in women. They, indeed, exhibit low testosterone levels and altered androgen-to-estrogen ratios, suffering from reduced fertility and altered physical characteristics. Treatment with DCI, by reducing the androgen to-estrogen conversion, may help to decrease the negative feedback of estradiol on the hypothalamus also in this case, stimulating the release of endogenous gonadotropins and improving the clinical condition of men with secondary hypogonadism. Particularly in men with obesity-related hypogonadism, the long-term supplement of DCI may be useful for both to the effects on insulin resistance and on the activity of the aromatase in adipose tissue [82, 83, 84].
Based on the available evidence, we suggest that the administration of DCI should be carefully considered in light of the patient’s specific situation (the type of condition, insulin status, gender), evaluating the proper dosage and treatment duration accordingly. Further studies based on DCI administration should aim to define the safety profile and the therapeutic rationale for each specific condition, such as estrogen-dependent gynecological pathologies (endometriosis, uterine fibroids) as well as high estrogen production in obese male and female patients, a possible target of DCI supplementation. In this scenario, potential hypo-estrogenic state caused by high levels of DCI may play a positive role to counteract the typical proestrogenic microenvironment associated with the progression of endometriosis and enlargement of fibroids. Nevertheless, targeted trials will be mandatory in order to define the best dose/duration of DCI therapy for each disease, considering the patients’ condition.
Introduction: Inositols have a key role in ovarian physiology and the literature reports a wealth of studies about the major isomer, myo-inositol (MI). However, information about D-chiro-inositol (DCI) is still scarce, despite the ratio MICI is tissue-specific and actively maintained by an insulin-dependent epimerase enzyme.
Areas Covered: This expert opinion provides an overview of the physiological contribution of DCI in regulating steroidogenesis. DCI indeed mediates the intracellular signaling of insulin, which induces the biosynthesis of androgens. Studies on second messengers of insulin also revealed that DCI has a specific role in modulating the activity of aromatase enzyme. Specifically, recent findings demonstrated that DCI influence the enzyme gene expression, thus reducing the conversion of androgens into estrogens.
Expert opinion: available evidence suggests that the effects of DCI administration may be similar to those of aromatase inhibitors, but without causing hypo-estrogenic states. Therefore, DCI treatments should be evaluated for either estrogen-dependent gynecological conditions or low testosterone states in male subjects.
Article highlights
• D-chiro-inositol (DCI), besides being a second messenger of insulin, regulates female steroidogenesis by enhancing testosterone biosynthesis and downregulating the expression of aromatase.
• As second messenger of insulin, short-term administration of DCI may reduce androgen levels in insulin-resistant women; extended treatments result in androgen increase due to the activity on aromatase and on testosterone biosynthesis.
• Taking into account the modulatory action on aromatase, DCI may find application for estrogen-dependent gynecological diseases characterized by increased expression of the enzyme.
• Tailoring the dosage and the duration of the intervention, DCI treatment may represent an appealing therapeutic approach for increasing the androgen-to-estrogen ratio in men with late-onset hypogonadism.
6. Conclusions
Besides carrying the intracellular message of insulin, DCI influences the steroid biosynthesis by inducing the testosterone production and modulating the aromatase activity. Such an effect on aromatase may be exploited in the treatment and prevention of all the conditions that are generally treated with AIs and/or insulin sensitizers. The use of DCI prevents the build-up of a hypo-estrogenic environment, avoiding the onset of side effects generally associated with therapies with AIs.
7. Expert opinion
Accumulating evidence suggests that biologically active metabolites of DCI are deeply involved in modulating steroidogenesis, even though the exact underlying mechanisms remain to be elucidated. In particular recent data proved that DCI, besides being one of the intracellular second messengers of insulin, affects the activity of aromatase and regulates the androgen-to-estrogen ratio. The mechanistic insights lately reported by Sacchi et al. demonstrated that DCI downregulates the gene expression of the enzyme [17], rather than inhibiting its activity. Hence, DCI modulates the levels of estrogens, and DCI treatment may reduce them without completely blocking their biosynthesis. In a recent publication, we speculated about a possible similar therapeutic role of DCI compared to AIs [18], even though the effects are markedly different and DCI administration avoids the onset of hypo-estrogenic states. Because of such an advantage over AIs, investigating the potentialities of DCI treatment for estrogen-dependent conditions is particularly appealing. In our opinion, future studies should be planned to assess the potential therapeutic effect of DCI administration on the symptoms of gynecological benign conditions such as endometriosis and uterine fibroids, as well as the preventive activity on pre-cancerous lesions. Likewise, DCI treatment should be evaluated as an adjuvant strategy to AIs in the post-operative management of estrogen-sensitive tumors, or as a prevention protocol for subjects presenting with risk factors. Specifically, obese women, particularly in menopause, may benefit from a double advantage of the long-term supplement of DCI due to the effects on insulin resistance and to the modulation of the activity of the aromatase in adipose tissue. Nevertheless, particularly in fertile age, we take the opportunity to underline that long-term treatments with elevated doses of DCI may cause an unwanted increase in testosterone levels as a secondary effect. Such occurrence should be considered in evaluating the therapeutic approach with DCI, especially for those pathological conditions whose symptoms may be exacerbated by increased androgen levels, such as PCOS [16]: in these cases, we believe that the mechanism of action fails to support a rationale for the use of high doses of DCI alone as successful treatment.
DCI is an insulin-sensitizing agent, and short-term supplementation may be beneficial to treat hyperandrogenic or hyper-estrogenic states associated with hyper-insulinemia. Nevertheless, the effect of DCI on aromatase can further explain why short-term treatments with DCI successfully induced ovulation in a dose-dependent manner in PCOS patients [28]. DCI is able to reduce the negative feedback on gonadotropin release not only by reducing systemic insulin levels but even reducing estrogen production. On that basis, we suggest that a similar effect may potentially be observed also in non-PCOS, non-IR anovulatory women, which may benefit from an initially increased FSH release by reduced estrogens. Thus, evaluating the possibility of high-doses supplementation with DCI and the duration of the treatment would be an interesting option in such patients.
Interestingly, hypogonadal men can benefit from an increase of testosterone, which is unwanted in women. They, indeed, exhibit low testosterone levels and altered androgen-to-estrogen ratios, suffering from reduced fertility and altered physical characteristics. Treatment with DCI, by reducing the androgen to-estrogen conversion, may help to decrease the negative feedback of estradiol on the hypothalamus also in this case, stimulating the release of endogenous gonadotropins and improving the clinical condition of men with secondary hypogonadism. Particularly in men with obesity-related hypogonadism, the long-term supplement of DCI may be useful for both to the effects on insulin resistance and on the activity of the aromatase in adipose tissue [82, 83, 84].
Based on the available evidence, we suggest that the administration of DCI should be carefully considered in light of the patient’s specific situation (the type of condition, insulin status, gender), evaluating the proper dosage and treatment duration accordingly. Further studies based on DCI administration should aim to define the safety profile and the therapeutic rationale for each specific condition, such as estrogen-dependent gynecological pathologies (endometriosis, uterine fibroids) as well as high estrogen production in obese male and female patients, a possible target of DCI supplementation. In this scenario, potential hypo-estrogenic state caused by high levels of DCI may play a positive role to counteract the typical proestrogenic microenvironment associated with the progression of endometriosis and enlargement of fibroids. Nevertheless, targeted trials will be mandatory in order to define the best dose/duration of DCI therapy for each disease, considering the patients’ condition.
