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. 2021 Jun 3;31(1):13.
doi: 10.1186/s12610-021-00131-x.

D-chiro-inositol, an aromatase down-modulator, increases androgens and reduces estrogens in male volunteers: a pilot study

Giovanni Monastra  1   2 , Mónica Vazquez-Levin  2   3 , Maria Salome Bezerra Espinola  1   2   4 , Gabriele Bilotta  4 , Antonio Simone Laganà  2   5 , Vittorio Unfer  6   7
Affiliations

D-chiro-inositol, an aromatase down-modulator, increases androgens and reduces estrogens in male volunteers: a pilot study

Giovanni Monastra et al. Basic Clin Androl. .

Abstract
in English, French

Background: Androgen deficiency affects men in the adulthood, causing several harmful effects at the reproductive and behavioural levels. Since aromatase is an enzyme that catalyses the conversion of androgens to estrogens, and it is responsible for an adequate balance of both sex hormones in males and females, the administration of molecules acting as down modulators may contribute to restore an abnormal enzymatic activity. A prospective pilot study was carried out to investigate the effect of D-chiro-inositol, a putative aromatase down-modulator, on serum levels of testosterone, estradiol, estrone, dehydroepiandrosterone and epiandrosterone from a group of adult male volunteers. Glucose, insulin, follicle-stimulating hormone, luteinizing hormone, inhibin B, D-chiro-inositol and myo-inositol serum levels were also measured.

Results: Male volunteers were selected according to age and body mass index. Subjects with altered glycemia and/or hormonal status, due to advanced age or abnormal weight, were enrolled in the study. Each of the 10 volunteers enrolled took oral D-chiro-inositol (1 g/day) for 1 month. Serum assays of selected markers were performed at baseline (control) and after treatment. D-chiro-inositol administration was associated to reduced serum levels of estrone (- 85.0%) and estradiol (- 14.4%), and increased serum levels of testosterone (+ 23.4%) and dehydroepiandrosterone (+ 13.8%). In addition, epiandrosterone levels were higher (+39%) after treatment. On the other hand, follicle-stimulating hormone, luteinizing hormone and inhibin B did not change. A trend toward a decrease of glycemia, insulinemia and Homeostatic Model Assessment index was observed after D-chiro-inositol treatment, although differences did not reach statistical significance. D-chiro-inositol treatment did not cause any noticeable adverse effect.

Conclusions: Increased androgens and decreased estrogens seem to confirm that D-chiro-inositol acts as an aromatase down-modulator, but with a still unknown mechanism of action. This pilot study opens up new perspectives of research and therapeutic applications for D-chiro-inositol at different dosages and length of treatment. Authorization number 005/2020 released by the Local Ethics Committee of Alma Res Fertility Center, Rome.

Trial registration number: NCT04615767 (registry: ClinicalTrials.gov) Date of registration: November 3, 2020.

RéSUMé: CONTEXTE: L’insuffisance en androgènes affecte les hommes à l’âge adulte, causant plusieurs effets nocifs aux niveaux reproductif et comportemental. Puisque l’aromatase est. une enzyme qui catalyse la conversion des androgènes en œstrogènes, et qu’elle est. responsable d’un équilibre adéquat des hormones sexuelles chez les hommes et les femmes, l’administration de molécules agissant comme freinateurs peut contribuer à restaurer une activité enzymatique anormale. Une étude prospective pilote a été menée pour étudier l’effet du D-chiro-inositol, un potentiel freinateur de l’aromatase, sur les taux sériques de testostérone, estradiol, estrone, déhydroépiandrostérone et d’épiandrostérone d’un groupe d’hommes adultes volontaires. Le glucose, l’insuline, l’hormone folliculostimulante, l’hormone lutéinisante, l’inhibine B, le D-chiro-inositol et les taux sériques de myo-inositol ont également été mesurés. RéSULTATS: Les hommes volontaires ont été sélectionnés selon l’âge et l’indice de masse corporelle. Les hommes qui présentaient une glycémie et/ou un statut hormonal altérés en raison d’un âge avancé ou d’un poids anormal, ont été inclus dans l’étude. Chacun des 10 volontaires enrôlés a pris du D-chiro-inositol (1 g/jour) par voie orale pendant un mois. Des dosages sériques des marqueurs sélectionnés ont été réalisés avant (témoin) et après le traitement. L’administration de D-chiro-inositol a été associée à une réduction des taux sériques de l’estrone (− 85.0%) et de l’estradiol (− 14,4%), et a une augmentation des taux sériques de testostérone (+ 23,4%) et de déhydroépiandrostérone (+ 13,8%). En outre, les taux d’épiandrostérone étaient plus élevés (39%) après le traitement. D’autre part, les taux d’hormone folliculostimulante, d’hormone lutéinisante et d’inhibine B n’ont pas été modifiés. Une tendance à la diminution de la glycémie, de l’insulinémie et de l’indice d’évaluation du modèle homéostatique a été observée après traitement par D-chiro-inositol, bien que les différences n’aient pas atteint une signification statistique. Le traitement par D-chiro-inositol n’a causé aucun effet indésirable notable. CONCLUSIONS: L’augmentation des androgènes et la diminution des œstrogènes semblent confirmer que le D-chiro-inositol agit comme un freinateur de l’aromatase, mais avec un mécanisme d’action encore inconnu. Cette étude pilote ouvre de nouvelles perspectives de recherche et d’applications thérapeutiques pour le D-chiro-inositol à différents dosages et durées de traitement.

Keywords: DHEAS; Epiandrosterone; Estradiol; Estrone; Glycemia; HOMA index; Inhibin B; Insulinemia; Testosterone.

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Conflict of interest statement

Vittorio Unfer is an employee at Lo.Li. Pharma srl. (Rome, Italy). The other authors have no conflict of interest to disclose.

Figures

Fig. 1
Fig. 1
Effect of D-chiro-inositol (DCI) treatment on total testosterone (T) levels. Total serum T levels from 10 male volunteers at baseline (t0) and after 30 days of treatment (t1) with 1 g DCI per day are presented as: a median values of total T (box plots). The boxes denote the interquartile range between the first and third quartiles (25th and 75th percentiles, respectively), the whiskers represent the minimum and maximum values, and the line inside the boxes represents the median value (p = 0.0020; Wilcoxon signed rank sum test); b individual total T values (before-after treatment). The graph reports the values for each volunteer participating in the study
Fig. 2
Fig. 2
Effect of D-chiro-inositol (DCI) treatment on Estradiol (E2) levels. E2 levels from 10 male volunteers at baseline (t0) and after 30 days of treatment (t1) with 1 g DCI per day are presented as: a median values of E2 (box plots). (p = 0.0645; Wilcoxon signed rank sum test). Symbol explanation: see caption of Fig. 1a; b individual E2 values (before-after treatment). The graph reports the values for each volunteer participating in the study
Fig. 3
Fig. 3
Effect of D-chiro-inositol (DCI) treatment on testosterone/estradiol (T/E2) ratio. T/E2 ratio from 10 male volunteers at baseline (t0) and after 30 days of treatment (t1) with 1 g DCI per day are presented as: a median values of T/E2 ratio (box plots) (p = 0.0020; Wilcoxon signed rank sum test). Symbol explanation: see caption of Fig. 1a; b individual T/E2 ratio (before-after treatment). The graph reports the values for each volunteer participating in the study
Fig. 4
Fig. 4
Effect of D-chiro-inositol (DCI) treatment on estrone (E1) levels. E1 levels from 10 male volunteers at baseline (t0) and after 30 days of treatment (t1) with 1 g DCI per day are presented as: a median values of E1 (box plots) (p = 0.0020; Wilcoxon signed rank sum test). Symbol explanation: see caption of Fig. 1a; b individual E1 levels (before-after treatment). The graph reports the values for each volunteer participating in the study
Fig. 5
Fig. 5
Effect of D-chiro-inositol (DCI) treatment on dehydroepiandrosterone sulfate (DHEAS) levels. DHEAS levels from 10 male volunteers at baseline (t0) and after 30 days of treatment (t1) with 1 g DCI per day are presented as median values of DHEAS (box plots) (p = 0.0488; Wilcoxon signed rank sum test). Symbol explanation: see caption of Fig. 1a
Fig. 6
Fig. 6
Effect of D-chiro-inositol (DCI) treatment on glycemia levels. Glycemia levels from 10 male volunteers at baseline (t0) and after 30 days of treatment (t1) with 1 g DCI per day are presented as: a median values of glycemia (box plots) (p = 0.1113; Wilcoxon signed rank sum test). Symbol explanation: see caption of Fig. 1a; b individual glycemia levels (before-after treatment). The graph reports the values for each volunteer participating in the study
Fig. 7
Fig. 7
Effect of D-chiro-inositol (DCI) treatment on insulinemia and HOMA index levels. Insulinemia and HOMA index from 10 male volunteers at baseline (t0) and after 30 days of treatment (t1) with 1 g DCI per day are presented as median values of (a) insulinemia and (b) HOMA index (box plots) (insulinemia, p = 0.3750; HOMA index, p = 0.3594; Wilcoxon signed rank sum test). Symbol explanation: see caption of Fig. 1a
Fig. 8
Fig. 8
Effect of D-chiro-inositol (DCI) treatment on Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. LH and FSH levels from 10 male volunteers at baseline (t0) and after 30 days of treatment (t1) with 1 g DCI per day are presented as median values of (a) LH and (b) FSH levels (box plots) (LH, p = 0.3340; FSH, p = 0.5566; Wilcoxon signed rank sum test). Symbol explanation: see caption of Fig. 1a
Fig. 9
Fig. 9
D-chiro-inositol (DCI) pharmacokinetics. DCI concentration (μmol/l) in serum from 10 male volunteers at different time points after oral administration of 1 g DCI (single dose). Median values of DCI at different time points after oral administration are reported (Cmax: 9.40 μmol/l, Tmax: 240 min, AUC (0–420): 2750.59). After 420 min, DCI concentration is significantly decreased in comparison to 300 min (p = 0.0020). Symbol explanation: see caption of Fig. 1a
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