Polycystic ovary syndrome (PCOS) is the most endocrinopathy comúnen women; It affects 5-7% of women of childbearing age, although the obesity epidemic currently affecting adolescents in developed countries will aumente1 frequency.
1. oligomenorrhea at least 6 or 9 months a year or anovulation.
2. Hyperandrogenism: main cause of metabolic syndrome and insulin resistance. You can increase the deshidroepoandrosterona sulfate (DHEAS) and testosterone (T), but the more specific is the increase in free T. It can manifest clinically with acne and hirsutism. For evaluation scale Ferriman-Gallwey used ≥ 8 points (see Fig. 1) and / or biochemical hyperandrogenism data.
Figure 1. Scale Ferriman-Gallwey.
4. The risk of PCOS is the most likely of endometrial cancer, estrogen constant encouragement and metabolic syndrome: obesity, hypertension and dyslipidemia, with subsequent increased cardiovascular risk.
diagnostic criteria
PCOS was defined for the first time in the consensus meeting of 1990 of the National Institutes of Health with the following criteria: a) chronic anovulation, and b) clinical and / or biochemical signs of hyperandrogenism, and exclusion of other afecciones2.oligoamenorrrea a) and / or: in 2003, in Rotterdam, in the working group formed by the European Society of Human Reproduction and the American Society for Reproductive Medicine, the diagnosis of PCOS was established if they met at least 2 of the following criteria anovulation; b) clinical or biochemical hyperandrogenism, and c) polycystic ovary on ultrasound. The problem of Rotterdam diagnostic criteria is that PCOS can be diagnosed without presenting hyperandrogenism, the most common in adolescentes3 sign.
For this reason, in 2009 the criteria of the Society of SOP and hyperandrogenism (EA-PCOS) were established: a) hyperandrogenism, hirsutism presence and / or elevated androgens in blood; b) ovarian dysfunction, and c) Polycystic ovary. They are diagnosed patients who meet criteria a) and at least one of the other two criteria, and exclusion of other causes of hyperandrogenism is necessary. None of the above groups has specific criteria for teenagers, so the same clinical criteria should be used in adults4.
Pathophysiology of PCOS
Although the pathophysiology of PCOS is unknown, studies in monozygotic and dizygotic twins have suggested that involves both genetic factors as ambientales5, causing: impaired release of gonadotropin-releasing hormone (Gn-RH), dysregulation of steroidogenesis, increased androgens and hyperinsulinemia.
The main cause of PCOS is hyperandrogenism, which may occur due to dysregulation of steroidogenesis. In the hypothalamus-pituitary-ovarian axis, the ovary has a regulation on the hypothalamus by inhibiting the secretion of Gn-RH (negative feedback). Increased androgen produced by the ovary, and to a lesser extent by the adrenal gland and peripheral tissues, it increases the frequency of the secretion of GnRH and inhibit the negative feedback exerted on the ovary hypothalamus. Simultaneously, the relative decrease in the secretion of follicle stimulating hormone (FSH), increasing the luteinizing hormone (LH), causes less aromatization of androgens to estradiol, deteriorating follicular development, which leads to oligomenorrhea and anovulation, increasing secretion LH, which it stimulates the ovarian theca cells, producing more androgens. Furthermore, insulin stimulates androgen secretion of ovarian theca cells and inhibits hepatic production of sex hormone binding protein, causing an increase of free T. Insulin resistance causes a decrease of lipoprotein lipase activity, favoring the non esterification of fatty acids and causing dyslipidemia with elevated triglycerides and decreased high-density lipoprotein (Fig. 2) 1,6,7.
Figure 2. Pathophysiology SOP7. FSH: follicle stimulating hormone; GnRH: gonadotropin-releasing hormone hypothalamic; LH: luteinizing hormone; 3β-HSD: 3beta hydroxysteroid dehydrogenase; 17β-HSD 1 beta hydroxysteroid dehydrogenase.
Figure 2. Pathophysiology SOP7. FSH: follicle stimulating hormone; GnRH: gonadotropin-releasing hormone hypothalamic; LH: luteinizing hormone; 3β-HSD: 3beta hydroxysteroid dehydrogenase; 17β-HSD 1 beta hydroxysteroid dehydrogenase.
Clinic
1. menstrual disorders: oligomenorrhea, amenorrhea, chronic anovulation, dysfunctional metrorrhagia.
2. Sterility.
3. Signs of hyperandrogenism: hypertrichosis (excessive growth of terminal hair in areas of normal presentation in women); hirsutism (excessive growth of terminal hair in androgen-dependent areas, unusual in women); Acne (severe acne that is persistent or resistant to treatment); seborrhea, frontoparietal alopecia.
4. Obesity android type.
5. Acanthosis nigricans.
Diagnosis of PCOS
1. Medical history should be supplemented with focus on:
- Personal history: virilization congenital disorders, low birth weight for gestational age, prematurity and early pubarche have been associated with an increased risk of developing PCOS.
- Family history: hyperinsulinemia, PCOS, diabetes mellitus, cardiovascular disease.
- Current History: onset of menarche, last menstrual period, regularly. Trouble losing weight, excess hair and acne treatment rebellious.
2. Clinical examination: sexual development (Tanner stage), obesity and acanthosis nigricans and hirsutism. The examination should include blood pressure and body mass index.
3. Complementary tests: van focused on differential diagnosis, confirm the SOP and once the diagnosis, to know if there is metabolic syndrome (Table 1). Given that many of the patients with PCOS have metabolic syndrome (hyperinsulinemia, hypertension, hypertriglyceridemia, hypercholesterolemia), with a consequent increase in cardiovascular risk, in addition to the hormonal profile, you must obtain a lipid profile (evidence) 1.
Table 1. Additional tests in polycystic ovary syndrome
The absolute levels of LH and FSH its relationship are increased in PCOS patients (↑ LH / FSH), this is due to an increase in the amplitude and frequency of LH pulses. A normal LH / FSH ratio does not exclude the diagnosis of PCOS. Define constraints androgen excess by measuring circulating levels of androgens are due, in part, to inaccuracy and variability of the laboratory methods used; It considered that measurement of free T is the most sensitive for determining hiperandrogenemia8 index. A small number of patients with PCOS may have only increased DHEAS levels. Regarding the differential diagnosis, see table 2.
Table 2. Differential diagnosis of polycystic ovary syndrome
Peculiarities of diagnosis of polycystic ovary syndrome in adolescents
1. oligomenorrhea or amenorrhea: menstrual irregularities are a common sign of PCOS; occurs in more than 75% of adult women with PCOS and are common as an early clinical sign in adolescents, the problem is that menstrual irregularities can be difficult to distinguish from anovulation caused by the immaturity of the hypothalamic-pituitary-ovarian typical this age, which can cause irregular menstrual cycles. You need to know that most teenagers establish regular cycles after 2 years of menarche. On the other hand, there have been several studies in healthy adolescents and has been shown that those who have regular or variable cycles (between 22 and 41 days) is uncommon to have abnormalities later cycle and those with oligomenorrhea to 15 years age in a high percentage persist with such alteration in adulthood. Therefore, menstrual abnormalities in adolescents should be followed in time and if it lasts or is associated with signs of hyperandrogenism requires a comprehensive study on suspicion of SOP.
2. Hyperandrogenism: more than 80% of adult women with PCOS have increased androgens. In the adolescent, clinical signs of elevated androgen, hirsutism and acne are sometimes difficult to assess. More than 80% of adolescent women age 18 have some form of acne and 23% require some kind of drug treatment; the prevalence decreases in adulthood. Hirsutism is present in approximately 60% of adult women with PCOS. In the adolescent, hirsutism is a sign that may not appear or may not be very striking, besides there is no specific classification for them. If a teen has a very striking hormonal hirsutism study is needed. The analytical parameter that relates to the SOP is increased free T, but can also increase DHEAS and total T.
3. Polycystic Ovary: is the least important parameter in the adolescent because: a) healthy adolescents may have ovaries on ultrasound may have a large size compared to adult women; b) you can mimic the appearance of PCOS, and c) in adolescent abdominal echo is preferred; the image quality decreases in obese patients.
Although as described above, as mentioned in the first point, there are no own diagnostic criteria of adolescent, so they should be used in adults; the criterion minor is in the adolescent is the sonographic criteria. In adolescent patients with diagnostic doubts a new revaluation should be performed at 6-12 months.
Early diagnosis is very important, given the high risk that these patients have metabolic syndrome and cancer endometrio1.
Treatment
The goals of treatment are: a) regulate menstruation and restore fertility; b) improve metabolic abnormalities: dyslipidemia, insulin resistance, and c) normalize weight and prevent comorbilidades6.
1. Changes in lifestyle and weight loss: a healthy and balanced diet and aerobic exercise kept it possible to reduce fatty tissue and weight. 60% of patients with PCOS are overweight, which promotes insulin resistance. Even patients with PCOS and normal weight have some increase in visceral fat and inflammatory adipocitoquininas.
Studies in adults with PCOS show that 5-10% loss of body weight through diet and exercise can reduce androgen levels and improve menstrual function (evidence B) 9 in approximately 50% of cases. Therefore, the lifestyle intervention is considered by many as the first line of treatment for PCOS in adults. However, weight loss fails to normalize insulin secretion or glucose tolerance, dyslipidemia or not always able to restore and menstrual cycles or reduce hirsutismo10.
In a Cochrane review conducted in 2011, concluded that current studies there is insufficient scientific evidence, but given the benefits and safety of improving lifestyle, it is highly recommended in patients with SOP11.
2. Drug therapy should be used in adolescents with PCOS who do not improve with changes in lifestyle or those who have obesity.
3. Oral contraceptives (AO):
- First line for mild to moderate hirsutism.
- Choose a low androgenic activity progestogen (desogestrel, gestodene, drospirenone).
- Progestogen contraceptives that have androgenic activity, such as levonorgestrel, are contraindicated.
- If moderate dermatological disorders, irregular cycles or need for contraception, AO should be used, preferably with cyproterone acetate (peripheral antiandrogen).
- In patients with severe dermatologic signs and menstrual disorders, it is necessary to establish the treatment for not less than 6 months before evaluating response period. Using general associations of estrogen and progesterone at low doses associated with peripheral antiandrogens (evidence C).
Teenage girls with PCOS have traditionally been treated with combined OCs estrogen and progesterone, and anti-androgens such as spironolactone or flutamide, which can increase the transport protein sex hormones, reducing the levels of free T, inhibits the growth of dependent hair androgens, restore menstruation and long-term decreases the risk of endometrial and ovarian cancer, but does not reduce metabolic risk. OCs can contribute to: increase cholesterol and triglycerides, lower adiponectin, increase or favor the persistence of insulin resistance can increase weight, increase blood pressure and increase the risk of thromboembolism in women who smoke or mutations in factor V Leiden10.
4.
Anti-androgens:
- Cyproterone acetate: is the best best treatment to induce ovulation (evidence) 9; It is a potent progestogen which inhibits LH decreasing ovarian androgens synthesis by this route, but also has peripheral action, preventing the binding of T and dihydrotestosterone (DHT) receptors. It is the only antiandrogen available in a contraceptive formulation (35 mg + 2 mg cyproterone ethinyl estradiol). It should be given the first 10 days of the cycle.- Spironolactone: aldosterone antagonist which acts by blocking the binding of T and DHT to the androgen receptor. It is used in doses of 25-100 mg / day.
- Finasteride: drug used primarily in the prostatic hypertrophy. It has a strong inhibitory activity of 5 α reductase peripheral. It can be used in doses of 1 to 2.5 mg / day, with good results and few side effects. Also it used generally associated with AO to achieve a suitable synergy and to avoid pregnancy.
- Flutamide: nonsteroidal substance binding with high affinity to the androgen receptor competition acting thereof. While it is very effective as an antiandrogen, a hepatotoxic drug is, so no higher doses should be used at 250 mg / day, always controlling liver function. It is reserved for severe cases.
- All antiandrogens above should be suspended for at least 3 months before pregnancy seeking to prevent malformations of the external genitalia of male fetuses and must be administered with contraceptives.
- In all cases, since hormonal treatments are slow, they should be recommended cosmetic corrections as soon as possible. The terminal hair and developed improvement, but does not disappear with hormonal treatment, so the dermatological treatment is always necessary.
5. The oral agents such as metformin and glitazones, improve metabolic dysfunction of PCOS. Its effects are: increase insulin sensitivity of liver and muscle, reduce circulating insulin, increasing the concentration of sex hormone binding protein, C-reactive protein reduce and increase the high density lipoprotein. Alone, it is less effective than the AO in restoring menstruation and reducing hirsutism. In combination with AO limit weight gain, reduced insulin and fasting glucose, triglycerides attenuate the increase caused by estrogen and lower triglycerides. Oral antidiabetic agents are especially indicated in patients with PCOS, obese and insulin resistance. The combination of low doses of metformin and antiandrogens, such as flutamide, is indicated in patients with early nonobese Adrenarche; It seems to delay or prevent the onset of PCOS, but there is little evidence científica12,13. Exenatide, mimetic incretin GLP-1 stimulates the secretion of insulin dependent glucose, inhibits glucagon release and slows gastric emptying, causing satiety. Used in diabetes mellitus type 2 (DM2), has been shown in adults with PCOS combined with metformin is more effective than any other drug in monotherapy, reducing androgen levels and regularizing the menstrual cycle, but there are no studies in adolescentes14 .
6. The SOP management should be individualized according to the patient's risk factors and needs. Adolescents should be informed of the need for changes in lifestyle: a) regular aerobic exercise; b) reducing the intake of sugars, especially refined that increase insulin and triglyceride levels, and c) to eliminate or reduce the intake of saturated fats that raise cholesterol and cardiovascular risk.
7. In patients with severe hirsutism or oligomenorrhea long evolution, initiate treatment with AO combined estrogen / progesterone and androgens, except in patients at high risk (factor V Leiden, increased lipoprotein, or family history of thromboembolism early) cardiovascular disease. Indications of metformin are: obesity is not controlled with changes in lifestyle, oral glucose intolerance or prediabetes, type 2 diabetes, family history of type 2 diabetes and in patients who are contraindicated, OCs. It is administered together with a supplement of vitamin B, because its deficiency produces. The most common side effects are gastrointestinal discomfort, which can be controlled by lowering the dose. Anti-androgens are teratogenic, so to be associated with some form of contraception.
Risk and disease polycystic ovary syndrome
1. Metabolic: given that insulin resistance often precedes type 2 diabetes, and most patients with PCOS are insulin-resistant, the risk of developing type 2 diabetes would be increased in these patients.
2. Cancer: Women with PCOS are at increased risk of developing endometrial carcinoma by chronic anovulation with consequent estrogenic stimulation of the endometrium unopposed by progesterone. There is a relationship between breast cancer and SOP, which is probably due to this often associated with obesity, but it still lacks conclusive epidemiological studies linking PCOS with breast cancer.
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