Polycystic Ovarian Syndrome (PCOS) is the leading endocrine disorder in women of childbearing
age with a prevalence of more than 15% among this group.[1] These women are predisposed to obesity, have a predominance of the abdominal obesity
phenotype associated with the hyperandrogenic state, insulin resistance (IR) and compensatory
hyperinsulinemia.[2]
[3] It is estimated that 80% of women with PCOS have IR, and this scenario worsens in
the presence of obesity.[4]
[5]
A few authors suggest that there are abnormalities in the energy expenditure of women
with PCOS, resulting from a reduction in the resting metabolic rate, especially in
those with IR.[6] In PCOS, has been considered a lower postprandial response of gastrointestinal hormones
involved in neural control of food intake.[7]
[8]
[9]
[10] Food intake is controlled by complex interrelationships between homeostatic mechanisms
that regulate caloric intake through a neuroendocrine system involving central and
peripheral signals as well as mechanisms related to eating behavior. The central mechanisms
are regulated by learning, memory and the reward system that acts in the mesolimbic
circuit present in the central nervous system.[11]
[12] Gastrointestinal peripheral signs encompass several hormones that act on hunger
(ghrelin) and satiation/satiety (cholecystokinin, YY peptide, oxintomodulin, glucagon
like peptide - GLP-1, glucagon and amylin), and play an important role in regulating
appetite and caloric intake.
Some studies have shown that the plasma levels of GLP-1 and PYY in the postprandial
period are lower in women with PCOS,[13]
[14] and the exogenous administration of these hormones triggers the sensation of fullness
and reduces caloric intake in animals and humans.[15] Agonists of the GLP-1 have been used to promote weight loss in diabetic patients,
and there is suggestion that these drugs could also benefit patients with PCOS.[16]
[17]
[18]
[19]
Signs of body fat storage, such as insulin, leptin and adiponectin, also participate
in the process of controlling food intake, as they indicate the state of energy reserve
and alter appetite when necessary.[20] Ghrelin is a gastrointestinal hormone known to stimulate food intake and its secretion
is regulated by insulin levels and body reserves.[21]
[22] Women with PCOS have lower levels of fasting ghrelin and less postprandial suppression
of ghrelin compared with obese women without PCOS.[7]
[9] A common finding in the literature is the negative correlation between insulin resistance
and ghrelin plasma concentrations.[23]
[24]
[25] When studying two groups of obese women (PCOS versus non-PCOS), we observed a lower
ratio of preprandial ghrelin/insulin in the PCOS group. The postprandial ghrelin response
was similar in both groups, and there was a significant negative correlation between
ghrelin and insulin in both groups as well. However, when the patients were split
into two groups, according to IR and regardless of PCOS, the negative correlation
between ghrelin and insulin did not occur in the group with IR. These results suggest
that the mechanism of ghrelin suppression by insulin may be impaired in women with
IR, regardless of PCOS.[25] Since IR is highly prevalent in obese PCOS patients, with rates above 90%,[4] control of the satiation/satiety process is likely to function inadequately in these
patients. In fact, in the patients we studied, an earlier increase in postprandial
hunger was observed in obese women with PCOS than in obese women without PCOS. These
observations have already been described by others,[7] indicating the possibility that patients with PCOS would have impaired regulatory
mechanisms of ingestion and satiation/satiety when compared with women without PCOS,
which could explain the greater difficulty in weight loss of women with PCOS.
Weight loss has been the main option for treating PCOS. Low-glycemic diets and lifestyle
changes associated or not to physical exercise lead to weight loss, reduce hyperandrogenism,
increase ovulation and pregnancy rates, and are also beneficial in reducing hyperinsulinemia
and its metabolic consequences.[26]
[27]
[28]
[29]
[30] The main limitation of this type of therapy are the difficulties of maintaining
weight loss for an extended period of time, and relapses are unfortunately frequent.
Consequently, there is a growing use of bariatric surgery for the treatment of obesity
in women with PCOS, which has significantly better results in terms of sustainable
weight loss.[31]
The association of PCOS with IR, and, consequently, with hyperinsulinemia is known
for decades, and in addition to its effect on the reproductive system, it is related
to the high prevalence of obesity, glucose intolerance (GI), type 2 diabetes mellitus
(DM2), dyslipidemia and vascular inflammatory processes. Consistent pictures with
the metabolic syndrome, elevated triglycerides and LDL, and reduced HDL are frequent.[32]
[33]
By considering these evidences, it is reasonable to propose that the main focus addressed
in therapeutic strategies for weight loss in PCOS should also take into account the
approach to IR. The use of insulin sensitizers reduces endogenous insulin requirements,
with preservation of β cells, and it may protect insulin-resistant patients from developing
DM2.[34]
[35]
Despite the extensive literature on the deleterious role of IR in the evolution of
PCOS and its association with changes in control mechanisms of caloric intake and
satiation/satiety and the benefits of insulin sensitizers in disease therapy, important
international societies have been reluctant to recommend its use associated with diet,
lifestyle and physical exercise as the primary therapy of PCOS.
In the first consensus published as a group in 2004, even though the European Society
of Human Reproduction (ESHERE) and the American Society of Reproductive Medicine (ASRM)
recognized the high prevalence of IR in women with PCOS, they did not recommend IR
screening in these patients by considering the restricted validity of clinical tests
for its diagnosis. The group recognized some studies that showed the progression of
GI to DM2 may be delayed by lifestyle changes and pharmacological intervention with
insulin sensitizers, but did not recommend the use of these drugs routinely in the
treatment of PCOS with IR.[1]
Four years later, the Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group
proposed that “before any intervention is initiated, preconceptional counseling should
be emphasized on the importance of lifestyle, especially weight reduction and exercise
in overweight women, smoking, and alcohol consumption,” and recommended restricting
the use of metformin (MTF) to women with PCOS and GI. Thus, the presence of IR should
not be a reason for prescribing MTF.[36]
If IR is a step preceding GI, it did not seem reasonable to wait for the worsening
of the metabolic profile in order to introduce insulin-sensitizing therapy. Considering
the poor results obtained with lifestyle and diet changes on weight loss, we believe
it is unreasonable to let the patient stay for a longer time under high levels of
insulinemia and all its consequences.
However, the ESHERE and ASRM maintained the same position in a new version of the
Amsterdam consensus published in 2011: “Diet and lifestyle are the first choice in
improving fertility and prevention of diabetes (Level B). Metformin may be used for
impaired glucose tolerance (IGT) and DM2 (Level A.).” Management of women at risk
for DM2 should include diet and lifestyle improvement as first-line treatment. Treatment
with MTF is indicated to those patients with IGT who do not respond adequately to
calorie restriction and lifestyle changes.”[37] The authors considered there is insufficient scientific evidence to recommend the
use of insulin sensitizers beyond that situation, which indicates great caution in
its use.
In a debate (pro x con) between two experts (Marshall and Dunaif),[38] numerous justifications were offered for using MTF as an important adjuvant factor
in the therapy of patients with PCOS, given the high prevalence of IR, obesity, GI,
DM2, dyslipidemia, increased evidence of inflammatory process and metabolic syndrome.[38] Marshal concluded that “the majority of evidence in adult women indicate that treatment
of insulin resistance, either by lifestyle changes or metformin, leads to improvement
in reproductive and metabolic abnormalities and probably reduces future development
of diabetes and arterial disease.”[38] Although Dunaif does not support the use of insulin sensitizers in all women with
PCOS, she acknowledges this measure could be taken in view of the difficulties of
maintaining diet and lifestyle in a younger population.[38] In fact, several other societies have recommended the use of MTF in youngsters and
adolescents with PCOS as a first-line therapy, combined or not with oral contraceptives
and antiandrogens for the treatment of hyperandrogenemia and its symptoms, reestablishment
of menses, aid with reduction of weight and IR, aiming at the prevention of long-term
cardiovascular complications, even in lean adolescents.[39]
[40]
[41]
[42]
[43] The fight against hyperandrogenism plays a key role in the process of containing
the metabolic degeneration of these patients. The risk of GI and/or DM2 is greater
in women who have oligo-anovulation and hyperandrogenism and this risk is even greater
if they are obese.[44]
If the use of MTF has been practically a consensus for treating young, lean or obese,
adolescents for some time, why not also apply it to adult women in the age group of
20 to 35 years, which corresponds to the prevailing age of patients with PCOS seeking
care for the treatment of menstrual disorders and infertility? These are relatively
young patients who may have their prognosis worsened and increased risk of metabolic
syndrome if there is no intervention. Hence, it is reasonable to think that the benefits
of insulins sensitizers could also reach this age group.
According to some authors, there are no data supporting the treatment of PCOS with
MTF based on the measures of IR by arguing that the parameters for its calculation
are not sensitive neither specific.[38] However, other authors have contested this suggestion through the composition of
various methods of calculations based on measurements of glucose and fasting insulin.[4]
Another argument against the use of MTF as first-line treatment for PCOS is the lack
of data on the results of IR treatment per se in PCOS. Therefore, the metabolic assessment
of women with PCOS should focus on detecting conditions that justify the intervention,
such as GI, metabolic syndrome and elevated HDL levels.[38] Metabolic syndrome and its indiviual components are common in patients with PCOS,
particularly in those with elevated insulin levels (therefore, with IR) and increased
weight. However, in patients with PCOS and normal body mass index (BMI), the diagnosis
of metabolic syndrome is rare, although the literature shows that 19% of patients
without metabolic syndrome may have GI,[32] and, certainly, a much higher percentage may have IR, since it can be found in up
to 70% of non-obese patients with PCOS.[4] For example, is there any doubt about IR in patients with Acanthosis Nigricans,
even if they are lean?
In fact, randomized clinical trials in women with PCOS are needed to check the efficacy
of insulin sensitizers for the improvement of metabolic endpoints. The criticism of
the literature is that much information was obtained in studies investigating non-metabolic
endpoints in PCOS or that non-PCOS populations were studied.[36]
[37]
[38] Randomized clinical trials are an essential tool in the construction of scientific
evidence for clinical practice, although not always the most useful for some evaluations.
Generally, their performance is complex, costly, with numerous operational difficulties,
and many of them do not have adequate sample size for evaluating therapeutic practices.
Moreover, although the findings of controlled therapeutic trials are statistically
significant, there is no guarantee they will serve the totality of individuals. Considering
the vast medical scenario, there are few situations in which decision-making is supported
by evidence-based medicine. Most health practices are based on experimental cohort
or case-control studies, or even non controlled observation of a set of cases.
In the specific case of PCOS, it is easy to imagine how difficult it would be to carry
out a randomized clinical study to identify patients at risk and conduct a longitudinal
study of cohorts of women with PCOS beyond 60 years of age to determine with greater
precision the time and efficacy of the interventions studied for answering if insulin
sensitizers used in patients with IR definitely prevent GI or DM2. Many patients would
be followed up for decades and after entering their postmenopausal period.
The lack of these studies may mean we do not have definitive answers to elucidate
endpoints. However, the lack of these answers should not be enough reason to stop
prescribing those drugs for these patients. Numerous evidences based on experimental
cohort or epidemiological studies also have their value. By exclusively valuing evidence-based
medicine obtained in randomized clinical trials or systematic reviews with meta-analysis,
we certainly fail to cover numerous clinical situations, as in the case of PCOS. In
these situations, it is absolutely pertinent to use evidence based on medicine rather
than evidence-based medicine for decision-making in the face of individualized clinical
situations. Thus, studies with less rigorous designs may have their place in everyday
practice for the care of a particular individual.[45]
Although the FDA has approved MTF for DM2 treatment, it has been used off label for
more than 40 years to reduce the signs and symptoms of PCOS and normalize the various
parameters that assess risks for DM2, obese and non-obese, children, adolescents and
adults.[35]
[41]
[46]
[47]
[48]
[49] For these reasons, we have been asking ourselves: why not routinely prescribe it
for hyperandrogenic and obese patients with PCOS, regardless of whether they have
GI or DM2? Should we expect the worsening of the insulin resistance picture for its
prescription?[50]
Finally, in the last ASRM/ESHERE consensus, it was recognized the validity of a more
comprehensive use of MTF in the treatment of PCOS, based on evidence of its clear
benefits in the specific PCOS group or subgroups by improving weight, BMI, hip-waist
ratio, testosterone and glucose, especially in obese patients, since metabolic benefits
are more accentuated in patients with increased BMI. Thus, in addition to lifestyle
changes, the use of MTF was recommended in adult women with PCOS for the treatment
of overweight and hormonal and metabolic changes. The benefit of MTF use in adolescents
diagnosed with PCOS was also considered.[51] Although not specified, note that a more comprehensive introduction of insulin sensitizers
may also contribute to a better observation and comprehension of the effects of IR
on the control mechanisms of ingestion/satiation/satiety that are possibly committed
in PCOS.
Faced with so much evidence, restricting the use of insulin sensitizers for patients
with PCOS no longer made sense. This new position of the most important societies
of the specialty expands the range to patients with PCOS that can benefit from these
drugs. The restriction on its use until recently may have deprived thousands of patients
of the benefit of reducing IR and its consequences. It is known that IR is related
to endothelial dysfunction and that it progresses with time. Endothelial dysfunction
caused by IR has been related to reduced nitric oxide bioavailability and changes
in endothelial regeneration. Research on the use of insulin sensitizers for the treatment
of polycystic ovaries in rats has shown that endothelial dysfunction is the direct
result of hyperandrogenism induced by IR, and treatment with MTF improves insulin
sensitivity and blood pressure and reestablishes normal endothelial function, even
with the weight gain of animals.[52] Some studies have also shown that pioglitazone, an insulin sensitizer, has effects
on glucose homeostasis, and exerts pleiotropic effects, thereby improving endothelial
dysfunction.[53]
Professionals from all over the world follow guidelines of the major American and
European specialty societies, which impact direct on the therapeutics adopted globally.
Therefore, the wider use of insulin sensitizers brings great prospects of more concrete
clinical results regarding this therapy for both young and adult patients with PCOS,
especially obese patients, as a first-line treatment. We believe that gynecologists
are able to prescribe this drug because international experience has shown this is
a low-risk product that has been increasingly used in patients with PCOS, youngsters,
adolescents and adults, obese or non-obese, including pregnant patients with PCOS
and gestational diabetes, and in hypertension during pregnancy.[54]
