Polycystic ovary syndrome (PCOS) is a common disorder in women of reproductive age with heterogeneous clinical manifestations that can be characterized by hyperandrogenemia, prolonged anovulation and ovarian polycystic changes. Hyperandrogenemia and anovulation are closely associated with insulin resistance and compensatory hyperinsulinemia, in which the ovaries synthesize excess androgens in a highly responsive manner due to circulating insulin stimulation.
There is increasing evidence that lipotoxicity, a key pathogenic factor in the pathogenesis of insulin resistance and type 2 diabetes, may explain the excessive synthesis of androgens in patients with PCOS. Because of the increased risk of future type 2 diabetes and metabolic complications in patients with PCOS, the importance of a definitive diagnosis cannot be overlooked, although the diagnosis of PCOS in adolescence remains difficult.
PCOS patients begin to develop metabolic disorders in adolescence, and adolescent relatives of PCOS patients may already have metabolic changes, although they do not present with clinical manifestations of PCOS for a while. Therefore, it is necessary to screen this population for impaired glucose tolerance and type 2 diabetes, and to intervene not only for the clinical manifestations of PCOS, but also for the long-term metabolic risk.
1. Introduction
1.1 Definition of PCOS
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Early diagnosis and treatment are particularly important because of the complexity of the clinical presentation, the consequent severe psychological impact on the patient and the increased long-term risk of metabolic and cardiovascular disease. There are three recommended definitions that consistently emphasize the reliance on exclusionary diagnoses for the diagnosis of this disease.
The earliest diagnosis of PCOS, given by the NIH in 1990, required both (1) prolonged anovulation or scanty menstruation and (2) biochemical tests suggesting hyperandrogenemia or clinical manifestations of androgen excess (hirsutism, acne, androgenic alopecia, etc.).
In 2003, the diagnostic criteria for PCOS were updated at the Rotterdam Consensus Conference to meet two of the following three criteria: (1) prolonged oligo-ovulation or anovulation; (2) clinical or biochemical tests suggestive of hyperandrogenism; and (3) ultrasound suggestive of polycystic ovarian changes.
In 2006, the Androgen Excess and PCOS Society further revised the diagnostic criteria for PCOS to include significant hyperandrogenemia with prolonged oligoovulation or anovulation or ovarian polycystic pattern.
Recent guidelines from the Endocrine Society, based on a recent NIH-funded evidence-based workshop, have endorsed the Rotterdam consensus diagnostic criteria. These different definitions and the associated controversies are emphasizing that PCOS remains a heterogeneous syndrome that may present with different phenotypes, including hyperandrogenemia with ovarian polycystic changes but still ovulating, or ovarian polycystic changes and anovulation without a basis for hyperandrogenemia, as described in the Rotterdam Consensus.
1.2 Diagnosis of PCOS in adolescent girls
Because the clinical manifestations of PCOS may be physiologic in adolescence, there is still controversy as to whether these diagnostic criteria should be applied to the pediatric population. Irregular menstrual cycles are common during the progressive maturation of the hypothalamic-pituitary-ovarian axis, especially in the pre-maturation phase. Typically, one year after menarche, 75% of adolescent girls establish a regular cycle (ranging from 21-45 days), but nearly half of them still do not ovulate even though their menstrual cycle is regular.
Based on this consideration, it has been suggested that at least 2 years after menarche is required to conclude the presence of persistent menstrual irregularity, although this would be considered normal in individuals with early PCOS symptoms such as hyperandrogenemia. In addition, the use of clinical and biochemical tests to identify androgen excess in adolescents has been challenged.
Acne in adolescence is often not associated with hyperandrogenemia. Hirsutism in adolescents is also difficult to define because the standard Ferriman-Gallwey score is based on data from the adult Caucasian population (roughly 18-38 years of age) and has a cut-point value of ≥8. For young girls with average sparse facial hair, a lower cut-point value is more appropriate.
Although biochemical hyperandrogenemia is easily confirmed, the same reference range does not apply well to adolescent girls, and laboratory tests for testosterone are highly variable. In a prospective cohort study of 244 healthy adolescents, the 95th percentile concentration of free testosterone was 45.6 pmol/L, compared with 26 pmol/L in a healthy adult population.
Caution is needed when making direct comparisons, given the many different tests available to measure testosterone levels, and the fact that healthy adolescents have higher average androgen levels than adults.
The Rotterdam Consensus defines polycystic ovarian changes as an excess of 12 follicles of 2-9 mm diameter in each ovary, with or without an increase in ovarian volume (>10 ml). Especially in obese women, transvaginal ultrasound can be used to obtain clearer images. However, due to ethical restrictions, transvaginal ultrasound cannot be performed in adolescents.
In addition, 35-55% of healthy adolescents without hyperandrogenemia meet the definition of adult ovarian polycystic changes, depending on the number of years since menarche, so ovarian polycystic changes are a common physiological alteration in adolescence. It should be noted that adolescent ovaries often show an increase in size, while multifollicular ovaries are less common.
This makes diagnosis in the adolescent population difficult, but in the absence of more consistent evidence for specific markers, the diagnosis of PCOS in the adolescent population remains based on adult criteria. Clinicians must be careful not only to differentiate between the physiologic features of adolescents and the pathologic features of PCOS, but also to diagnose adolescent PCOS early and to properly treat the clinical manifestations and long-term metabolic complications.
1.3 Prevalence of PCOS in adolescents
PCOS accounts for 6-8% of all sports-aged women, making it the most prevalent endocrine disorder in this group. Among adolescents aged 15-19 years, approximately 1% are estimated to have PCOS based on NIH adult diagnostic criteria, but half of these cases are not diagnosed by a clinician and undiagnosed findings are more common in the non-overweight girl population.
The relative risk ratios (ORs) for clinicians to diagnose PCOS in overweight and obese girls compared to normal weight adolescents were 3.85 and 23.1, respectively, but the ORs decreased significantly to 2.95 and 14.7 when considering the overall population. the difference in ORs between these two conditions reflects a greater preference for clinicians to diagnose PCOS in obese girls. In the overall population of women of childbearing age, obesity and overweight only slightly increase the risk of PCOS and are an important reference bias for PCOS.
Although the prevalence of PCOS in the adolescent population appears to be lower than in the adult population due to the lack of strong evidence and the lack of rigorous validation of diagnostic criteria, obese girls with PCOS and obese girls with a predisposition to PCOS may present earlier or with more dominant clinical symptoms.
2. Pathological changes of PCOS
2.1 Insulin resistance and hyperandrogenemia in the ovary
The role of insulin resistance and hyperandrogenemia in ovarian hyperresponsiveness to insulin
Ovarian and adrenal hyperresponsiveness to LH and ACTH, respectively, are important features in women with PCOS. On the other hand, several studies have pointed to the role of insulin-mediated mechanisms in the pathogenesis of PCOS, which could explain hyperandrogenemia, anovulation and other manifestations of the syndrome. Insulin resistance and compensatory hyperinsulinemia have been demonstrated in the majority of women with PCOS, irrespective of their weight (40-77%).
Using the gold standard for insulin sensitivity assessment, the hyperinsulin orthoglucose clamp technique, Lewy et al. found a 50% decrease in peripheral insulin sensitivity in adolescents with PCOS compared to controls, implying that insulin resistance is present early in the disease. In this study, insulin resistance was independent of BMI and abdominal wall hyperlipidemia. Many studies have also shown that medications or lifestyle modifications can increase insulin sensitivity and have an effect on improving hyperandrogenemia in both fat and lean PCOS patients.
After a 6-month diet and exercise lifestyle intervention, adult obese PCOS patients showed a 70% increase in insulin sensitivity, accompanied by a significant reduction in anovulation, although weight loss was not significant (2-5% from baseline). In adolescent PCOS patients, a 3-12 month lifestyle intervention also significantly improved the menstrual cycle and hyperandrogenemia, and Lass N et al. reported that decreased testosterone levels were associated with improved insulin resistance (assessed using HOMA), but not with decreased BMI, further suggesting a role for insulin resistance in the development of hyperandrogenemia in adolescents.
The direct reduction of hyperinsulinemia with diazoxide was also able to significantly reduce androgen levels in obese women with hyperinsulinemic PCOS. Diazoxide, a drug that directly reduces beta-cell secretion, does not alter androgen levels in non-PCOS lean women. Interestingly, however, diazoxide also exerts a hypoandrogenic effect on insulin levels and sensitivity in lean PCOS women with normal insulin levels. This study suggests that even in lean PCOS women with normal insulin levels, androgen production is associated with insulin and may be increased due to high responsiveness to insulin.
Extensive studies have been conducted in obese women with PCOS with insulin resistance and hyperinsulinemia and have demonstrated that increasing insulin sensitivity with metformin or thiazolidinediones reduces hyperandrogenemia levels. Even in lean PCOS women with normal insulin levels, 6 months of treatment with metformin or rosiglitazone (a thiazolidinedione) resulted in increased ovulation frequency and decreased androgen levels. These results suggest that insulin or insulin sensitization can affect ovarian synthesis of androgens even in insulin-normal women with PCOS.
In a study of lean prepubertal girls with early maturation due to adrenal androgen excess, treatment with metformin to increase insulin sensitivity for 6 months was found to reduce androgen levels and treatment of adolescents aged 8-12 years prevented them from developing clinical PCOS after the onset of puberty (15 years). Therefore, insulin resistance or hyperinsulinemia plays an important role in hyperandrogenemia as early as prepubescence, and early treatment of insulin sensitivity in high-risk girls can prevent the development of PCOS.
2.2 Lipotoxicity
Excessive exposure of non-adipose tissues to fatty acids will lead to abnormalities in lean organ or tissue function, which is the concept of lipotoxicity. Several human, animal and in vitro studies have shown that lipotoxicity is a key mechanism of insulin resistance and islet β-cell dysfunction and so also plays an important role in the development of type 2 diabetes. In lean, healthy young women, acute elevations in triglycerides and non-esterified fatty acids (NEFA) occur after temporary infusion of fat milk/heparin, causing significant elevations in circulating androgen levels.
In in vitro experiments, immersion of bovine adrenal cells in saturated fatty acid palmitate increased androgen production. In comparison to control rats, the PCOS obese rat model showed a 60% increase in NEFA uptake by ovarian tissue in an in vivo 18F-FTHA fatty acid analogue tracer marker assay and was significantly correlated with circulating testosterone levels.
Taken together, both in vivo and in vitro studies reveal that increased ovarian exposure to circulating NEFA or triglycerides can lead to excessive androgen production in the adrenal glands and ovaries, which may be achieved through a lipotoxic mechanism. Thus, lipotoxicity may explain the disease characteristics of adolescents and adults with PCOS who are at risk for both hyperandrogenemia and insulin resistance/diabetes mellitus.
2.3 Adipose tissue dysfunction in PCOS
Adipose tissue has multiple endocrine and metabolic functions, and the disease of PCOS itself is associated with functional and morphological changes in adipose tissue. subcutaneous adipocyte volume in women with PCOS is larger than in normal individuals with the same amount of fat and BMI. Adipocyte hypertrophy is strongly associated with insulin resistance, and this is also seen in patients with type 2 diabetes.
In addition, type 2 diabetics and women with PCOS have decreased activity of lipoprotein lipase (LPL), a key enzyme that hydrolyzes lipoprotein-associated triglycerides into free fatty acids, allowing triglycerides to be stored in adipocytes. After a meal, the patient’s body spills over as NEFA exceeds the capacity of the adipocytes, further leading to the development of lipotoxicity.
Conflicting results exist for the detection of secreted adipokines in women with PCOS, and levels of lipocalin, an insulin-sensitive adipokine, appear to be decreased in patients with classic anovulatory PCOS compared with women with similar BMI. In studies of adolescents, a recent study did not confirm this finding, suggesting that lipocalin levels are dependent on BMI rather than PCOS disease itself. These differences in results may be explained by differences in study design, study population, or possibly by the fact that adolescent PCOS patients are not deficient in lipocalin.
It has been suggested that low birth weight and early infant weight gain catch-up may be involved in the development of PCOS in non-obese prepubertal individuals and in adolescents with hyperandrogenemia and hyperinsulinemia. This hypothesis is based on the fact that subcutaneous adipose tissue is expandable, whereas in low birth weight neonates subcutaneous fat expansion is limited, but when growth catch-up occurs after birth, lipids are more likely to be deposited in lean and visceral adipose tissue than in subcutaneous adipose tissue.
This greater tendency to deposit in visceral fat, the limiting lipid storage capacity of hypertrophic adipocytes, combined with lipid spillage, in turn leads to the development of lipotoxicity and insulin resistance. Later in life, this pathological condition can still occur even if positive caloric balance and overweight do not occur.
These low birth weight children may develop excess visceral fat and insulin resistance as early as 4-6 years of age. Metformin treatment of these at-risk girls during 8-12 years of age reduces the amount of abdominal fat without affecting the amount of subcutaneous fat, while significantly decreasing the incidence of PCOS.
2.4 Genetic susceptibility to PCOS
PCOS is a multifactorial disease in which environmental factors, such as positive caloric balance and obesity, interact with genetic susceptibility to cause the disease. Studies have made good observations of familial aggregation of PCOS, suggesting that the disease is inherited in a dominant form or with multiple genes involved.
In addition to the individual’s own susceptibility to PCOS, relatives of women with PCOS acquire high risk factors for the development of metabolic disorders and hyperandrogenemia. first-degree relatives of healthy adolescent girls with PCOS begin to have decreased insulin sensitivity, decreased beta-cell function, hyperinsulinemia, decreased glucose tolerance, increased ovarian volume, and decreased lipocalin levels long before any clinical manifestations of PCOS appear. levels.
Two studies comparing peripubertal girls in first-degree relatives of women with PCOS with girls of the same age without a family history of PCOS found that half of the PCOS-associated girls had a two-thirds decrease in beta-cell function. One of the studies also showed a significant decrease in the ability of insulin to inhibit fasting NEFA in these girls, reflecting the body’s resistance to the inhibitory effects of insulin on adipocyte lipolysis.
All these results suggest that girls with a family history of PCOS are more likely to develop abnormal adipose tissue function and lipotoxicity, leading to detectable metabolic complications during adolescence.
3. Adolescent PCOS patients
Metabolic status of adolescent PCOS patients
3.1 Occurrence of the metabolic syndrome in adolescent PCOS
The metabolic syndrome represents a spectrum of cardiovascular risk factors, including increased waist circumference, elevated fasting glucose, blood pressure and triglyceride levels, and decreased HDL cholesterol. The definition of metabolic syndrome is controversial in the pediatric population, and the lack of stability limits the use of metabolic syndrome criteria to classify individuals in adolescence, with approximately 50% of adolescents no longer meeting the criteria for metabolic syndrome at 3 years of follow-up.
Although age-specific normal reference values for lipids, waist circumference, and blood pressure have been established as diagnostic criteria for the pediatric population, only a few mice are clearly defined, and none of the indicators are validated to be associated with cardiovascular outcomes.
The data from NHANES 1999-2002 realistically indicate that the prevalence of metabolic syndrome in adolescents is 2-9% according to the usual diagnostic criteria and 12-44% in obese adolescents (defined as having a BMI above the 95th percentile).
In a cross-sectional study comparing 43 obese adolescents with PCOS (BMI ≥30-46) with 31 BMI-matched controls, there were no significant differences in the prevalence of metabolic syndrome, lipids, blood pressure, or waist circumference between the PCOS and control groups. In this study, 26-53% of obese adolescents with PCOS were classified as having metabolic syndrome based on the usual indicators and the occurrence of metabolic syndrome was associated with BMI.
However, when comparing adolescents with PCOS to a reference group with lower levels of obesity and a mismatched BMI, the rate of metabolic syndrome was significantly higher in the PCOS group. Therefore, PCOS itself does not increase the risk of metabolic syndrome in adolescents, but overweight and obesity, which are common in adolescents with PCOS, may increase the risk of metabolic syndrome. In addition, in the overall PCOS population, a family history of type 2 diabetes may increase the risk of metabolic syndrome, increased abdominal adiposity, dyslipidemia, hypertension, and prediabetes.
3.2 Development of type 2 diabetes in adolescents with PCOS
Cross-sectional and prospective studies have consistently suggested that PCOS is associated with an increased risk of type 2 diabetes and impaired glucose tolerance (IGT) in comparison to the overall population or age- and race-matched control populations.
These studies found prevalence of IGT and type 2 diabetes in the overall PCOS population to be 20-37% and 7.5-15%, respectively, while data from NHANES 2005-2006 suggested prevalence of IGT and type 2 diabetes in the total population aged 20-39 years to be only 7% and 3%, respectively. Studies that looked at non-obese women with PCOS alone showed a slightly lower prevalence of IGT (10-13%) or type 2 diabetes (1.5%).
The largest prospective controlled study to date evaluated the risk of developing type 2 diabetes at 8 years of follow-up (mean age 47 years) in women with PCOS who were diabetes-free at baseline. This study found that 12.8% of patients with PCOS developed type 2 diabetes, compared to 3.6% of age- and race-matched controls.
The risk ratio for type 2 diabetes in white women (40 to 59 years of age at follow-up) compared to age-matched controls was 6.5, which decreased to 4.0 after correction for BMI. when all races were included in the analysis, the relative risk decreased further to 3.72, but was still statistically significant. In addition, women with PCOS were diagnosed with type 2 diabetes at an earlier age than controls (median age 43 and 48 years).
To date, only a few studies including a limited number of patients have reported the prevalence of IGT and type 2 diabetes in adolescent girls with PCOS. These studies confirm an increased rate of glucose abnormalities early in the course of the disease.
In a study including 27 adolescents with PCOS aged 14-19 years screened by a 75g oral glucose tolerance test, eight (33%) had IGT and one (4%) had type 2 diabetes, but this study did not include a non-PCOS population as a control group. There were no statistical differences in BMI, waist-to-hip ratio, clinical and biochemical hyperandrogenism, or race between adolescent PCOS patients with normal and abnormal blood glucose.
In the previously mentioned study by Rossi et al, which evaluated metabolic syndrome characteristics in obese adolescents, the results suggested that impaired fasting glucose or IGT (based on 75 g OGTT) was the only significantly increased component of the former in the diagnostic criteria for metabolic syndrome in the PCOS group compared to control adolescents (6/43, 25%; 1/31, 3.2%).
All of these findings, along with the previously mentioned evidence of similar changes in adolescents with a family history of PCOS, suggest that young girls with PCOS or at risk for PCOS exhibit a number of key risk factors in early life that lead to the development of type 2 diabetes later in life.
3.3 Accuracy of methods for diagnosing glucose abnormalities in adolescents with PCOS
The 2h OGTT with a 75g glucose load is the standard diagnostic screening test for type 2 diabetes or impaired glucose tolerance, yet even though the OGTT test has been shown to be a predictor of long-term risk for cardiovascular and microvascular complications in the adult population, its relevance to clinical outcomes has never been validated in the pediatric population.
The use of recommended fasting glucose cut-point values to predict OGTT diagnosis of IGT or type 2 diabetes is not reliable in the adult and adolescent PCOS populations. Even when the optimal cut point is selected based on the ROC curve, fasting glucose values are still too low to exclude IGT or type 2 diabetes in the PCOS population. Fasting glucose insulin ratios and HOMA-IR have also been shown to be unreliable in predicting IGT or type 2 diabetes in the adolescent PCOS population.
In a recent study of 68 adolescents with PCOS, HbA1c was retrospectively compared with OGTT in the diagnosis of glucose abnormalities, and the cut point was determined based on the ADA guidelines “increased risk of diabetes” cut point value of HbA1c ≥5.7%, with a sensitivity of only 60% and specificity of 69%. The specificity was 69%. Accordingly, the OGTT remains the most reliable test for the diagnosis of prediabetes or diabetes.
Because of the increased risk of IGT or type 2 diabetes in women with PCOS, expect the consensus guidelines to recommend screening for IGT and diabetes using the OGTT in all adolescent girls with PCOS, in other words, screening needs to be performed every 2-5 years based on other risk factors for type 2 diabetes at puberty.
4. Treatment of Adolescent PCOS
Given the critical metabolic effects of PCOS and the long-term metabolic consequences, the primary treatment goal for adolescents with PCOS should be lifestyle interventions for overweight and obese adolescents, including physical activity and calorie-restricted weight loss.
However, these changes take time to take effect, may be difficult to adhere to, and it is difficult to recommend treatment for thin adolescents. For these reasons, lifestyle changes often need to be combined with oral contraceptive pills (OCP), insulin sensitizers (mainly metformin), and anti-androgens.
4.1 Oral contraceptive pills
OCP contains estrogens that improve hyperandrogenemia by inhibiting the hypothalamic-pituitary-ovarian axis and increasing sex hormone-binding globulin (SHBG), thereby reducing free testosterone levels and improving acne and hirsutism. Progesterone exerts a protective effect by regulating the menstrual cycle as well as counteracting endometrial hyperplasia caused by prolonged anovulation. However, insufficient evidence exists to prove that the use of OCP is immune to endometrial cancer.
However, a small sample of clinical trials suggests that there is also a need to be concerned about the possible increased risk of insulin resistance in women with PCOS due to the use of OCP. In a 6-month prospective study involving 20 adolescents aged 10-20 years, drospirenone/ethinyl estradiol did not affect insulin sensitivity (assessed by hyperinsulinized orthoglucose clamp), glucose tolerance (assessed by OGTT), insulin secretion and disposition index.
On the other hand, a 12-month trial comparing desogestrel/ethinyl estradiol and cyproterone acetate/ethinyl estradiol in 36 adolescents (14-19 years) found increased levels of insulin resistance in both groups, but the degree of islet resistance was assessed using HOMA-IR only in the study.
In addition, OCPs increased not only LDL cholesterol but also HDL cholesterol, resulting in no change in the overall cholesterol/HDL ratio, and there was no correlation between OCP and changes in endothelial intima-media thickness when assessed in adolescents after only 6 months of treatment.
Although these short-term treatment benefits were found in the adolescent population, the long-term effects of OCP on cardiovascular and diabetes risk remain unknown. 2005 our group conducted a meta-analysis of case-control studies evaluating the cardiovascular risk effects of low-dose OCP and showed that the expected risk of myocardial infarction and ischemic stroke was twice as high in the OCP-using group as in the general population.
More recently, a 15-year cohort study of more than 1 million women from the general population confirmed a doubling of the relative risk of myocardial infarction and ischemic stroke with the currently used low-dose OCP (30-40 mcg ethinyl estradiol).
In such cases, we prefer to reserve the use of OCP when the patient is willing to use contraception, especially in the absence of other cardiovascular risk factors and without IGT or type 2 diabetes. If other risk factors are also present, we prefer to use insulin sensitizers. When considering the development of IGT or type 2 diabetes in adolescents, it is also recommended to change the original contraception or combine OCP with insulin sensitizers.
4.2 Insulin sensitizers
Metformin is the most widely used insulin sensitizer and, according to a meta-analysis published in 2007, appears to be less effective than OCP in improving menstrual cyclicity and lowering androgen levels in women with PCOS, but has comparable effects in improving hirsutism and acne. Some of the published studies comparing the use of OCP and metformin in the adolescent population have conflicting results, so it is not possible to understand the differences between the two treatments in this specific population.
There is little evidence to support the effectiveness of metformin treatment in the adolescent population, with studies enrolling only 10-35 patients and with little randomized controlled design. Overall, however, these studies suggest that treatment of adolescents with metformin for 3-13 months, combined with or without lifestyle interventions, can reduce serum androgen levels, decrease clinical hyperandrogenic symptoms, and improve lipid profiles and prolonged anovulation.
Thiazolidinediones, a class of insulin sensitizers that act through the nuclear receptor PPAR-γ, have been shown to lower androgens, reduce anovulation, and reduce insulin resistance in adult women. These findings were also confirmed in adolescents in a 6-month randomized, controlled, double-blind clinical trial comparing the thiazolidinedione rosiglitazone with an OCP.
In these adolescents, rosiglitazone also reduced visceral fat, elevated lipocalin levels, lowered triglycerides, and improved insulin sensitivity in liver and peripheral tissues. The beneficial effects of thiazolidinediones on visceral adipose tissue were also confirmed in a randomized controlled clinical trial comparing the addition of pioglitazone (7.5 mg/day) or placebo to OCP, low-dose flutamide and metformin given to non-obese women (18-24 years) with PCOS.
The results of the study showed that the addition of pioglitazone reduced visceral fat, but did not cause an overall weight loss, while lipocalin levels were significantly increased. In addition, there was an improvement in endothelial intima-media thickness.
These results in terms of potential long-term cardiovascular risk factors are of particular interest in the young female PCOS population, but no studies have yet evaluated whether there is long-term protection against cardiovascular events and type 2 diabetes in adolescent PCOS patients on insulin sensitizers.
Until strong evidence is available, we are using insulin sensitizers in clinical practice for adolescent PCOS patients who do not require contraception, and during communication with patients about their preference for metformin or OCP, metformin is often chosen given that it has more evidence to support it.
Metformin should be preferred over OCP when metabolic comorbidities such as the metabolic syndrome component occur as adolescence increases; current guidelines clearly recommend metformin treatment for girls with IGT or type 2 diabetes in combination with lifestyle interventions.
4.3 Anti-androgen drugs
Antiandrogenic medications are often chosen to improve aesthetic concerns such as acne and hirsutism. Adolescents can benefit from the use of flutamide or ambrisentin alone to improve hyperandrogenemia and hirsutism. In a non-blinded study comparing the treatment of adolescents with androgens and metformin, it was shown that androgens improved hirsutism better and had higher patient acceptance, but also that metformin had better menstrual cycle and insulin sensitization effects.
Antiandrogen therapy is effective in the treatment of hirsutism, but treatment for women with PCOS often requires a combination of other drugs to reduce androgen production (insulin sensitizers or OCP). It is important to note that the teratogenic effects of these drugs must be noted when using them and that patients should use effective contraception.
4.4 Combination therapy
In a non-blinded trial involving 34 adolescents, the efficacy of combined treatment with low-dose thiazolidinediones (pioglitazone, 7.5 mg/day), metformin (850 mg/day) and flutamide (62.5 mg/day) was compared with OCP treatment alone for 18 months.
At 6-month follow-up after discontinuation, combination therapy was found to provide better improvement in anovulation, visceral adiposity, inflammatory markers, and carotid intima-media thickness than OCP, while both regimens showed acceptable and similar improvement in hyperandrogenemia.
These results suggest that combination therapy may be a good option to safely control the clinical manifestations of PCOS and improve cardiovascular disease risk factors, but the study is only predictive of long-term efficacy and needs to be confirmed in a longitudinal randomized controlled study.
5. Conclusion
Adolescent girls with a predisposition to PCOS exhibit reduced efficiency of lipid storage in normal subcutaneous fat masses, which triggers lipotoxicity that induces ovarian and adrenal hyperresponsiveness to insulin, LH, and ACTH, which in turn synthesizes excess androgens. These mechanisms also explain the increased risk of insulin resistance and type 2 diabetes in these girls. Therefore, even in young adolescent female patients with PCOS, screening and prevention of type 2 diabetes is of utmost importance, as otherwise it may worsen glucose tolerance and cardiovascular disease risk.
Although insulin sensitizers take longer to work to improve the clinical manifestations of PCOS and may be slightly less effective, they are a valuable option for preventing type 2 diabetes by improving glucose tolerance. Further clinical research needs to focus on long-term cardiometabolic risk factors in this young and vulnerable population.