Gynecological Endocrinology

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Update on the combination of myo-inositol/d-

chiro-inositol for the treatment of polycystic ovary
syndrome

Iñaki Lete, Ainara Martínez, Irene Lasaga, Eva Centurión & Amaia Vesga

To cite this article: Iñaki Lete, Ainara Martínez, Irene Lasaga, Eva Centurión & Amaia
Vesga (2024) Update on the combination of myo-inositol/d-chiro-inositol for the
treatment of polycystic ovary syndrome, Gynecological Endocrinology, 40:1, 2301554, DOI:
10.1080/09513590.2023.2301554

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Gynecological Endocrinology
2024, VOL. 40, NO. 1, 2301554
https://doi.org/10.1080/09513590.2023.2301554

REVIEW

Update on the combination of myo-inositol/d-chiro-inositol for the treatment

of polycystic ovary syndrome
Iñaki Lete , Ainara Martínez, Irene Lasaga, Eva Centurión and Amaia Vesga
Obstetrics and Gynaecology Clinical Management Unit, Araba University Hospital, Vitoria, Spain

ABSTRACT ARTICLE HISTORY

In this article, we present a narrative review on the use of inositol in the treatment of polycystic ovary Received 3 October 2023
syndrome (PCOS). Of the different inositols that exist, only myo-inositol (MYO) and D-chiro inositol (DCI) Revised 19 December 2023
have been studied in the treatment of PCOS. The results of the studies show that there is insufficient or Accepted 27 December
2023
controversial evidence to recommend the use of DCI alone, while MYO alone shows positive results and,
Published online 19 January
above all, the MYO/DCI combination is effective when used at a ratio of at least 40:1, but there is enough 2024
rationale to further study ratios such as 66:1 to 100:1 as other possible effective combinations.
KEYWORDS
Polycystic ovary syndrome;
inositol; MYO/DCI ratio

Introduction inositols, especially the combination of myo-inositol (MYO) and

D-chiro-inositol (DCI) in the treatment of PCOS patients.
Polycystic ovary syndrome (PCOS) is one of the most prevalent
endocrine-metabolic disorders and is estimated to affect 5%–10%
of women of childbearing age [1]. Its most frequent clinical fea- Inositols
tures are the occurrence of menstrual disturbances, hyperandro-
genism and infertility due to anovulation, recruitment of Inositol is an organic compound of the polyol or polyalcohol
immature follicles, altered oocyte quality and even an increase in family found in plasma membranes and other natural product
first trimester miscarriages [2]. In addition, insulin resistance structures. Inositol is considered a member of the vitamin
occurs in PCOS patients, leading to hyperinsulinemia. These Bcomplex [10]. There are nine possible stereoisomers, of which
high levels of insulin resistance lead to increased plasma levels of the most common and widespread in nature is cis-1,2,3,5-trans-
luteinising hormone (LH), plasma androgens, and decreased cir- 4,6-cyclohexanehexol, or myo-inositol (MYO). Other natural iso-
culating levels of sex hormone binding globulin (SHBG) as well mers, although present in much smaller proportions, are scyllo-,
as some degree of metabolic compromise with an increased ten- muco-, D-chiro- (DCI) and neo-inositol. Other possible isomers
dency to develop diabetes or metabolic syndrome [3]. are L-chiro-, allo-, epi- and cis-inositol [11].
Patients with PCOS have higher rates of infertility, phenotypic Inositol is present in all animal tissues, with the highest levels
androgen disorders, obesity, metabolic syndrome and increased observed in the heart and brain. It is part of all cell membranes
risk of endometrial cancer and should be treated in a compre- and has the function of helping the liver to process fats as well
hensive manner to reduce the risks associated with their dis- as contributing to muscle and nerve function [12]. Inositol is
ease [4]. necessary for nerve cell health and lipid metabolism as, together
For years, PCOS has been treated with combined hormonal with choline (also related to the B vitamins), it is responsible for
contraceptives (CHCs), with generally satisfactory results [5]. the creation of neurotransmitters and for preventing lipids from
The limitations to the use of CHCs lie in their safety profile, being deposited in the liver and promoting their transport and
which involves an increased risk of venous thromboembolism penetration into cells [13].
(VTE) in this type of patient [6]. Another drug commonly used The most abundant stereoisomer in nature is MYO, which is
in the treatment of PCOS has been and continues to be met- considered a member of the vitamin B complex. It is synthesized
formin [7], which has a high rate of gastrointestinal side effects by the human body from glucose [14]. MYO can be transformed
[8], which leads to low compliance and adherence. Therefore, to into DCI through the action of the enzyme epimerase, which is
avoid hormonal treatments and improve the safety profile of stimulated by insulin [15]. In healthy women, the plasma MYO/
PCOS therapies, one of the proposed treatments for PCOS, apart DCI ratio is 40:1 [16], while in ovarian follicular fluid, the ratio
from lifestyle changes and weight loss, is the use of agents that is 100:1 [17]. In women with PCOS, this ratio between MYO
increase insulin sensitivity, leading to improved ovulatory func- and DCI becomes inverted and can go as low as 0.2:1 [17].
tion and a reduction in circulating levels of androgens [9]. This Altered inositol ratios may account for pathological conditions,
group of drugs that increase insulin sensitization includes inosi- causing an imbalance in sex hormones [18]. Therefore, the ther-
tols. In this review, we conducted an analysis of the efficacy of apeutic goal when treating a patient with PCOS is to reverse the

CONTACT Iñaki Lete [email protected] Obstetrics and Gynaecology Clinical Management Unit, Araba University Hospital, Txagorritxu Campus,
José Atxotegi s/n. 01009 Vitoria, Spain
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distri-
bution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in
a repository by the author(s) or with their consent.
2 I. LETE ET AL.

MYO/DCI ratio and make it as similar as possible to the follic- beneficial effects of inositols observed in lean patients, not resis-
ular and plasma rates of healthy women. tant to insulin, cannot be explained only by advocating the
hypothesis first suggested by Larner who postulated a defect in
insulin transduction. Independently from insulin, PCOS subjects
Clinical applications of inositols show a significant downregulation in both FSH-receptor and aro-
matase expression in the ovaries. These findings have prompted
Inositol and some of its mono- and polyphosphates are involved to reconsider old hypothesis and to formulate new ones [38].A
in several biological processes, including signal transduction study conducted on primary cultures of human granulosa cells,
(insulin), cytoskeleton assembly, nerve guidance, and control of reported that D-Chiro inhibits aromatase synthesis, and it could
intracellular calcium (Ca2+) concentration, breakdown of fats and help explaining why, despite the beneficial effects induced on
reduction of blood cholesterol [19]. In addition, MYO phospho- insulin activity, D-Chiro-Ins finally worsen the clinical response
lipids are messengers of Follicle Stimulating Hormone (FSH) in PCOS women [39].
activity and some studies have shown that patients with PCOS However, the safety profile, especially in a situation of chro-
and hyperinsulinemia present enhanced MYO to DCI epimerisa- nicity and long-term treatment, affects patients’ quality of life
tion in the ovary, leading to MYO deficiency that impairs FSH and adherence. A meta-analysis established that no difference in
signaling, resulting in reduced oocyte quality [17]. efficacy on endocrine changes was found between metformin
Some but not all studies suggest that high doses of inositol and myo-inositol, emphasizing that the better tolerability of
may be useful in treating psychological or psychiatric illnesses MYO makes it more acceptable for the recovery of androgen and
[20–24]. In addition, a small double-blind study designed to metabolic profiles in women with PCOS [8].
assess whether inositol is useful for the treatment of severe pre- The first controlled clinical trial on the use of inositols in
menstrual dysphoric disorder failed to obtain conclusive results, PCOS was published in 1999. In that study, the use of 1200 mg
so this line of work was stopped [25]. Consequently, research DCI versus placebo, administered orally once daily for 6–8 weeks,
with inositol as a therapeutic agent focused on other areas. was compared in 44 obese women with PCOS. An improvement
The therapeutic area in which inositol has shown the greatest in insulin sensitivity and a decrease in circulating free testoster-
effectiveness is in PCOS, especially in helping to induce ovula- one levels were observed in the group of women taking DCI,
tion. Several studies have shown that taking 2 grams of Inositol while there was no effect in the placebo group. In addition, ovu-
daily helps restore ovarian function [26] with a success rate lation occurred in 19 out of 22 women (86%) in the DCI group,
equal to or higher than that of clomiphene citrate, but with a while only 6 out of 22 women (27%) ovulated in the placebo
better safety profile due to fewer side effects [27]. This effect in group [40]. This trial was continued with a follow-up study of
PCOS patients is because inositols in general, and MYO and the same group of women, and the results were similar in terms
DCI in particular, have insulin-sensitising activity and beneficial of efficacy in inducing ovulation in the DCI-treated group [41].
effects on metabolism [28] as well as PCOS-related infertility Based on these previous good results, a large multicenter
[29]. Insulin regulates glucose metabolism, and the concept of placebo-controlled trial was launched in women with PCOS
insulin resistance refers to the reduced ability of insulin to act using twice the dose of DCI (2400 mg). However, the results
effectively on peripheral target tissues (especially muscle and were never published and were both surprising and disappoint-
liver). In PCOS patients, there is insulin resistance, which gener- ing [42]. The higher dose of DCI failed to reproduce the results
ates hyperinsulinemia that, in turn, acts as a secondary messen- of the two previous studies in terms of improved ovulatory fre-
ger leading to an increase in LH and an increase in granulosa quency. The lack of efficacy in the latter trial was attributed to
cell sensitivity to LH, which ultimately leads to hyperandro- the higher dosage of DCI administered, and the development of
genism and alterations in ovulation and decreased plasma levels high-dose DCI products was halted [42]. The interpretation of
of SHBG, a decrease that, in turn, leads to increased plasma lev- these results was that increasing the doses of DCI not only does
els of free androgens [30]. not improve ovulation outcomes, but it actually worsens them, so
Several studies have shown insulin resistance and compensa- the use of only DCI in the treatment of PCOS was abandoned
tory hyperinsulinemia in approximately 80% of obese women [42].It is known that follicular fluid volume and MYO content
with PCOS and in 305–40% of lean women [31, 32]. The pres- were significantly higher in follicles containing mature oocytes
ence of insulin receptors on ovarian cells in both healthy women and subsequently in fertilized oocytes compared to follicles with
and women with PCOS supports the suggestion that excess insu- recovered but unfertilized oocytes. The ratio of MYO to DCI in
lin may have a high endocrine impact on the ovary [33, 34].In the follicular fluid of mature oocytes in women without PCOS is
studies in isolated ovarian thecal tissue, insulin has shown an 100:117, clearly above the 40:1 ratio found in plasma. Furthermore,
ability to directly stimulate androgen secretion and a greater the levels of MYO in follicular fluid were positively correlated
LH-mediated response than in tissue isolated from healthy ova- with embryo quality, and subsequently with fertility in women
ries. In vivo, the frequent coexistence of elevated LH levels and [43]. Accordingly, a randomized clinical trial was conducted in
increased insulin concentrations leads to a more severe expres- 30 PCOS patients undergoing intracytoplasmic sperm injection
sion of this syndrome [35]. (ICSI) for infertility and treated with 4 g of MYO daily from the
Increasing insulin sensitization is accompanied by an improve- time they started taking gonadotropin-releasing hormone (GnRH)
ment in ovulatory function, a decrease in the number of imma- [44]. The study showed that an increase in the frequency of
ture oocytes recruited and a reduction in both plasma and spontaneous menstrual cycles was observed in the group of
intrafollicular androgen levels and thus improved fertilization women treated with MYO, and the findings suggested that MYO
rates [5]. might be useful in the treatment of infertility in PCOS. Another
The role of insulin resistance in PCOS has supported multiple study also found that administration of MYO to women with
studies evaluating treatment with hypoglycemic agents such as PCOS undergoing in vitro fertilization (IVF) was associated with
metformin in women with PCOS, especially in situations of a reduction in the total amount of recombinant FSH (rFSH)
anovulation [7, 36, 37].Insulin resistance has been observed only administered and the number of days required for ovarian stim-
in a fraction (50%–70%) of PCOS patients. Consequently, ulation [45]. The evidence shows that MYO improves FSH
 Gynecological Endocrinology 3

sensitivity, and its use beneficially affects the ovary and oocyte DCI alone, MYO alone or the MYO/DCI combination available
function and development when used alone. In 2011, Unfer et al. on the market at that time, in 2019, a clinical trial was published
conducted a comparative study of the effects of MYO versus DCI in which a total of seven different formulations of MYO/DCI
administration on oocyte quality in PCOS patients [46]. The (DCI alone, and 1:3.5; 2.5:1; 5:1; 20:1; 40:1, 80:1) were used to
study concluded that the number of mature oocytes was signifi- treat 56 women with PCOS (eight patients per group) and the
cantly increased, with a parallel decrease in the number of efficacy of each formulation in inducing ovulation was evaluated
immature oocytes, in the MYO group compared to the DCI as the primary endpoint [51]. The trial found that the adminis-
group, although the total number of oocytes retrieved did not tration of DCI alone, especially if high doses are used, does not
differ between the two treatment groups. A potential explanation give good results and should be avoided; that MYO alone can be
for this phenomenon of better response to MYO could be related effective in the treatment of PCOS, but that the MYO/DCI com-
to the different and specific tissue-dependent response to insulin bination is effective when DCI is administered at a low ratio to
resistance in PCOS patients. In these patients, while the muscle MYO and that increased doses of DCI lead to a worsening of
and liver show resistance to the action of insulin, the ovaries reproductive outcomes. Given the results of the above-mentioned
maintain normal insulin sensitivity, highlighting this different studies, there is a consensus that the MYO/DCI ratio should
insulin resistance, which has come to be known as the DCI par- favor MYO and provide low doses of DCI, which could be
adox [47]. The paradox is because the enzyme epimerase, respon- explained by the ovarian paradox effect discussed above.
sible for converting MYO to DCI, is stimulated by insulin, and Dysregulation of epimerase activity affects the MYO/DCI
in PCOS patient’s insulin resistance leads to hyperinsulinemia, ratio and may impair signaling of hormones such as insulin and
which stimulates epimerase activity leading to increased produc- FSH. The findings published in the scientific literature are con-
tion of DCI and depletion of MYO. Therefore, if epimerase sistent in demonstrating a defect in the availability and/or utili-
activity increases, some of the MYO is converted into DCI, so zation of the MYO/DCI combination in ovarian tissue in women
the amount of MYO does not increase and, in fact, in PCOS the with PCOS [52]. At the ovarian level, DCI is responsible for
ratio of MYO vs DCI can reach 0.2:1.15 What explains the para- insulin-mediated overproduction of testosterone [53] while MYO
dox is that the MYO/DCI ratio in women without PCOS is 100: is involved in FSH signalling [46]
1, whereas in PCOS patients it can be as low as 0.2:1. Based on the fact that epimerase activity, regulating the MYO/
DCI ratio, is insulin-dependent while the ovaries never become
insulin-resistant, several studies have shown that PCOS patients
The combination of myo-inositol and D-chiro-inositol are likely to have increased epimerisation of MYO to DCI in the
ovary. This would result in an overproduction of DCI and defi-
It has previously been mentioned that the plasma MYO/DCI ciency of MYO, which is accompanied by poorer reproductive
ratio is 40:1, which is why many of the pharmacological formu- outcomes [53]. In PCOS patients, the MYO/DCI ratio is much
lations for the treatment of PCOS use this ratio, although this is lower than in patients without PCOS (0.2:1 versus 100:1) and the
the plasma ratio and not the follicular ratio, which it should be depletion of MYO levels affects the oocyte quality of these
remembered is 100:1. This is also due to the fact that, although patients [53]. Therefore, it seems advisable to increase the MYO/
MYO shows satisfactory results, its combination with DCI DCI ratio to improve the results. In this regard, it is worth not-
improves the results due to the reduction of circulating insulin ing the wide variety of combinations that can be found in exist-
levels and the restoration of MYO levels in the ovary, which ing formulations, with MYO/DCI ratios ranging from 0.4:1 to
enables an improvement in oocyte quality [47]. In addition, 104:1, although the rationale for these ratios is based on the 40:1
MYO increases cellular glucose uptake and DCI increases glyco- plasma ratio rather than the 100:1 plasma ratio.
gen synthesis, leading to a decrease in insulin resistance [48]. Despite the above, there are studies that have shown satisfac-
A meta-analysis evaluated the efficacy of treatment with MYO tory results with higher concentrations of DCI. A multicenter
alone or MYO combined with DCI in a 40:1 ratio in nine clin- comparative clinical trial in Spain, which recruited 60 women with
ical trials that included 247 PCOS patients and 249 controls [49]. PCOS who were undergoing ICSI assisted reproduction and com-
The authors concluded that both MYO alone and MYO in com- pared the MYO/DCI combination at 3.6:1 versus 40:1, concluded
bination with DCI are effective for the treatment of PCOS and that higher DCI concentrations are associated with better preg-
induce higher ovulation rates and a better metabolic profile. nancy rates [54]. Similar results were obtained by the same
Another meta-analysis involving 10 clinical trials and 573 authors, although in a small sample of 11 patients in whom high
patients also confirmed the efficacy of the two forms of inositols doses of DCI were also associated with better reproductive out-
in the treatment of PCOS and showed that low doses of DCI in comes [55]. The results of these latter studies should be analyzed
combination with MYO decrease insulin resistance, correct with due caution because of the small number of patients included.
hyperinsulinemia and consequently improve ovulation rates [50]. Therefore, in PCOS as well as in other pathologies, the cor-
Since the efficacy of the MYO/DCI combination first became rect posology of MI and DCI administered in therapy plays a
known, different doses of the two compounds have been investi- pivotal role to provide the correct supplementation and the
gated and experimented with to try to find the most effec- expected results, avoiding unwanted effects (currently, the admin-
tive ratio. istration of the 40:1 ratio between MI and DCI proved effective
A study conducted in an animal model of PCOS-induced rats in PCOS). This important issue has to be managed considering
compared the efficacy of different MYO/DCI combinations (5;1, the two stereoisomers use the same transporter. Therefore, when
20;1, 40;1 and 80;1) in reversing PCOS symptoms, concluding MI and DCI are administered together, their absorption can be
that the 40;1 combination was the most effective and the fastest decreased in an unequal way as consequence of this competition.
in reversing the disease [52]. The conclusions of this study MI and DCI have higher affinity for their transporter as com-
should be viewed with caution as they reflect what happens in pared to glucose; nonetheless, compounds that reduce glucose
an animal model, which cannot always be extrapolated to the absorption at intestinal level may interfere with MI absorption if
human model. For this reason, to determine the impact on administered together. This causes an inadequate supplementa-
humans and with the aim of evaluating the different doses of tion [56].
4 I. LETE ET AL.

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Disclosure statement
in the treatment of polycystic ovary syndrome: experimental and liter-
No potential conflict of interest was reported by the author(s). ature evidences. In: genazzani, A., Tarlatzis, B., editors. Frontiers in
gynecological endocrinology. ISGE Series. Springer, Cham; 2016.
doi:10.1007/978-3-319-23865-4_13.
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Funding
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