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Update in polycystic ovary syndrome: new criteria of diagnosis and treatment in Japan

Abstract Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women of reproductive age. In 2006 the Japanese Society of Obstetrics and Gynecology (JSOG) proposed new, revised diagnostic criteria that in the future could also be valued internationally. Based on the new diagnostic criteria, the JSOG has also proposed the revised treatment criteria in 2008. In PCOS obese patients desiring children, weight loss and exercise is recommended. Nonobese patients, or those obese women who do not ovulate after lifestyle changes, are submitted to ovulation‐induction therapy with clomiphene citrate (CC). Obese CC‐resistant patients who have impaired glucose tolerance or insulin resistance are treated with a combination of metformin and CC. If these treatments options are unsuccessful, ovulation induction with exogenous gonadotropin therapy or laparoscopic ovarian drilling (LOD) is recommended. A low‐dose step‐up regimen is recommended with careful monitoring in order to reduce the risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies. Alternatively, with LOD high successful pregnancy rates of around 60 % are expected with a low risk of multiple pregnancies. If ovulation induction is unsuccessful, IVF‐ET treatment is indicated. In high OHSS‐risk patients, systematic embryo freezing and subsequent frozen embryo transfer cycles are recommended. In nonobese, anovulatory PCOS patients not desiring children, pharmacological treatments such as Holmström, Kaufmann regimens or low‐dose oral anticonceptives are used to induce regular withdrawal bleeding. These treatments are especially important for preventing endometrial hyperplasia and endometrial cancer. These new diagnostic and treatment criteria hopefully will contribute to an improved care of PCOS patients in Japan.


Introduction
Polycystic ovary syndrome (PCOS) is a common endocrine disorder occurring in 5-10 % of women in reproductive age [1]. Hyperandrogenism, chronic anovulation, and infertility are the main features of this heterogeneous condition [2]. It affects female reproductive performance as well as it has effects on female health. It was originally described in 1935 by Stein IF and Levental ML as a syndrome consisting of oligomenorrhea and obesity with enlarged polycystic ovaries [3]. The diagnosis of PCOS is based on a combination of clinical, biological, and ultrasound criteria that have been used variably to define PCOS [4,5]. Diagnosis criteria and PCOS definitions used by clinicians and researchers are almost as heterogenous as the syndrome. Currently, PCOS is defined by 2003 Rotterdam criteria [5], which requires at least two of three features for diagnosis: chronic anovulation, clinical and/or biochemical signs of hyperandrogenism, or polycystic ovaries. In Japan, compared to other countries, the usual clinical presentation of PCOS is slightly different, with less frequently encountered cases of hyperandrogenism, therefore established European or US guidelines are clinically less useful. In 2006, the Japanese Society of Obstetrics and Gynecology (JSOG) has proposed new, revised diagnostic criteria that in the future could also be valued internationally [6].

Clinical data of PCOS in Japan
In 2005, JSOG performed the questionnaire research concerning about the clinical data of PCOS which were examined by 125 institutes or clinics in Japan. 1498 cases of ovarian dysfunction were divided into the PCOS group and the non-PCOS group. Rates of abnormal range of serum hormone levels in PCOS and the other ovarian dysfunction in Japan are shown in Fig. 1 [6]. Rates of abnormal range of androstenedione, LH/FSH and LH in PCOS were significantly higher than those in the other anovulation (P \ 0.01). Body mass index (BMI) values and frequency rates of obesity, DM and hyperlipidemia in the PCOS group are shown in Fig. 2. BMI values were 23.1 ± 6.0 kg/m 2 in PCOS and 21.9 ± 5.8 kg/m 2 in non-PCOS, therefore the former was significantly higher than the latter (P \ 0.01). Rate of BMI higher than 25 kg/m 2 is 25.9 % in PCOS and significantly higher than that of the other group (P \ 0.01). Figure 3 shows the rate of insulin resistance of PCOS in Japan. Rate of HOMA-R higher than 2.5 is 32.8 %, and that of HOMA-R lower than 1.6 is 50.1 %. So, rate of high insulin resistance is about 1/3 of PCOS in Japan. Serum hormone levels and insulin resistance in PCOS are shown in Fig. 4. PCOS with high HOMA-R (]2.5) shows significantly higher values (P \ 0.01) of free testosterone and BMI over 25 kg/m 2 in Japan [6].

Clinical feature of PCOS
Diagnostic criteria of PCOS is based on three main features: (1) cycle irregularities, (2) polycystic changes in the ovary by ultrasonography, (3) endocrine anomalies (LH or androgen hypersecretion). The diagnosis of PCOS was recently debated and suggestions followed in the Rotterdam Consensus statement [5] and in JSOG statement [6]. Figure 5 shows the diagnostic criteria of PCOS in Western countries and Japan.
Amenorrhea and oligomenorrhea are always present. Menstrual disturbances are present of obese PCOS and 72 % with lean PCOS. It is estimated that 40 to 60 % of women with PCOS in Western countries [7,8] and 26 % of them in Japan [6] are overweight or obese. Obesity has  Obesity, DM and hyperlipidemia in PCOS; BMI of PCOS is significantly higher than that in the other. Rate of BMI higher than 25 kg/m 2 is 25.9 % and significantly higher than that of the others [6] been associated with infertility and an increased risk of menstrual irregularity or amenorrhea [9]. Transvaginal sonography (TVS) plays an essential role in diagnosis and treatment of PCOS. JSOG mentioned criteria for PCO, i.e., atypical polycystic pattern was defined by the presence of 10 or more cysts measuring 2-9 mm in diameter in a single plane arranged peripherally around stroma [6]. TVS has got important role in diagnosing, monitoring and treatment of PCOS patients. So careful clinical, biochemical, and TVS monitoring with tender loving care is required [10].

Endocrine anomalies and insulin resistance in PCOS
Serum hormone levels Abnormal LH/FSH ratio is the main issue in the continuation of anovulatory state in PCOS subjects. Increased LH and decreased or normal FSH are due to (a) GnRH pulsatile secretion, i.e. at hypothalamic level. (b) high estrogen environment, i.e., at pituitary level [10]. In PCOS, clinically intense androgenization due to excess androgen production is observed. Hyperandrogenemia induces the increase in testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA-S, 17-hydroxyprogesterone and estrone (E1) (excess androgen converted to E1 by peripheral fat). Decrease in the sex hormone binding protein in the liver, increase in insulin response in the ovary and the effect of high LH, induce the increase in androgen secretion in the ovary. After that, follicle growth and maturation are suppressed [5,6,11].

Insulin resistance and concomitant hyperinsulinemia
Insulin resistance and concomitant hyperinsulinemia are frequently found in obese PCOS women [11,12]. Approximately 50-60 % of PCOS patients suffer from insulin resistance in Western countries [10] and 33 % in Japan [6]. Seventy % of obese PCOS and 20 % of thin PCOS have hyperinsulinemia in Western countries. Increased insulin resistance causes hyperglycemia leading to hyperinsulinemia and it amplifies LH action on theca  cells and again increase in androgen level [10,13]. Hyperinsulinemia, insulin resistance, and an increase in androgen production are all linked together in PCOS patients. It is also known that patients with insulin resistance are often resistant to ovulation induction [10,12].

New criteria of PCOS treatment in Japan
Based on the above-mentioned diagnostic criteria, the JSOG has also proposed the revised treatment criteria of PCOS in 2008 (Fig. 6) [14].

Treatment of obesity in PCOS
For obese PCOS patients (BMI ]25 kg/m 2 ), weight loss and exercise are recommended as a first option. Norman et al. [15]. demonstrated that lifestyle modification led to increased insulin sensitivity and resulted in improved ovulation and fertility in obese women with PCOS. This approach of lifestyle modification, which includes weightreducing diet and exercise, should be the first step in the management of them [16]. Increase in physical activity and loss of at least 10 % of body weight are given in the form of lifestyle modification. Weight reduction causes spontaneous ovulation and dose of stimulation of medicine is less required [17,18]. Lifestyle management should also be used as the primary therapy in overweight and obese women with PCOS for the treatment of metabolic complications [19].

Clomiphene citrate for PCOS
Clomiphene citrate (CC) is the standard drug used for ovulation induction in women with PCOS [20][21][22][23][24]. Successful ovulation is achieved in 70-85 % of them and 40-50 % will conceive [25]. Nonobese patients or those obese women who do not ovulate after lifestyle changes are submitted to ovulation induction therapy with CC. CC is antiestrogenic and it binds with estrogen receptors causing decreased concentration of receptors. So activation of GnRH, increase in FSH and/or LH and growth of the dominant follicle occur. All cycles of CC should be monitored by ultrasound. To prevent ovarian hyperstimulation syndrome (OHSS), we should have control over the growing follicle and E2 levels. Hyperandrogenism and obesity affect the CC response adversely. Failure to ovulate with 3 months of use of CC 150 mg/day for 5 days is called CC resistance, and 20 % of PCOS patients will be CC resistant [10]. In CC resistant PCOS patients with hirsutism and high androgen concentrations, the combination of dexamethasone and CC is effective, because dexamethasone reduces the levels of androgens [26]. In CC resistant PCOS patients with galactorrhea or hyperprolactinemia, both CC and dopamine agonists should be used [27].

Combination of metformin and clomiphene citrate(CC) for PCOS with insulin resistant
Numerous articles have been published where insulin sensitizers such as biguanides (metformin) [28][29][30] and thiazolidinediones (troglitazone) [31] have been used and proven to improve metabolic abnormalities in PCOS patients. Metformin declines the peripheral glucose level without interfering with pancreatic b-cell function [10], by inhibiting hepatic gluconeogenesis and increasing insulin receptor affinity. Metformin reduces levels of LH, hyperinsulinemia and decrease ovarian levels of androgen [32]. Hyperinsulinemic and hyperandrogenic PCOS patients with thecal hyperplasia are best downregulated with metformin. Several trials were prospective double-blind placebo controlled [33][34][35][36]. Each of those trials randomized metformin with placebo in the CC-resistant patient. In one trial [35] there was no difference in outcome. The other trials had a statistically significant improvement when metformin was added to CC in the CC-resistant patients.
Kurabayashi et al. [37] also reported that combination of metformin and CC could improved ovulation rates in CC-resistant infertile Japanese women with PCOS in spite of no effect of metformin treatment alone. Therefore, obese CC-resistant PCOS patients who have impaired glucose tolerance or insulin resistance are treated with a combination of metformin and CC [38]. Fig. 6 New criteria of PCOS treatment in Japan [14] Ovulation induction of gonadotropin therapy in PCOS Ovulation induction with exogenous gonadotropin therapy is recommended for unsuccessful patients in the previously mentioned treatments. During ovulation induction, a chronic, low-dose step-up regimen of FSH-only preparations is recommended [39,40] with careful monitoring in order to reduce the risk of OHSS [41] and multiple pregnancies. Purified FSH has a theoretical advantage of avoiding additional LH in PCOS. It is always better to start with the smallest dose, and always be watchful on vaginal ultrasonography for number of follicles stimulated and how they are growing. But E2 level should always be kept suitable prior to hCG injection when there is evidence of multiple follicles [10]. If 4 or more numbers of follicles are found to be getting ]16 mm diameter, hCG injection should be canceled [14,42]. These results demonstrate that the low-dose step-up regimen for with PCOS is the safest protocol among the stimulation regimens for reducing multiple follicular development.

Laparoscopic ovarian drilling (LOD) in PCOS
The history of management of PCOS has been sharp turns from surgical management to medical therapy and later a renewed interest in surgery [43]. Gjonnaess proposed that ovulation was initiated by either stromal destruction or extensive capsular destruction with discharge of the contents of multiple follicle cysts [44]. At present, LOD is indicated in clomiphene resistant cases and another approach of gonadotropin therapy [45]. LOD is an effective procedure in properly selected cases, because drilling appears to be equally effective with lesser chances of multiple pregnancies [45,46]. In LOD treatment, high success pregnancy rates of around 60 % are expected after treatment within 6 months of time with a low risk of adverse effects in PCOS, and peak pregnancy rate is seen around 6-9 months after surgery [47]. The exact mechanism of induction of ovulation by LOD is not understood. This may be attributed to the improved intraovarian stromal blood flow following the procedure [43]. Daniell and Miller [48] suggested that physical opening of subcapsular cysts led to the removal of androgen-containing follicular fluid from the ovarian environment, thus lowing the androgen content of ovaries. The total and free testosterone is decreased to 40-50 % of the preoperative levels. LH levels also decreased following the procedure. Change in FSH levels is less marked and normal inhibin pulsality is restored. The normalization of hormonal relationships leads to recruitment of a new cohort of follicles and resumption of ovarian function. These endocrine changes occur rapidly and are sustained for years [43]. The number of holes to be drilled depends upon the size of the ovaries and the sonographic appearance which had been noted during the preoperative work-up. In moderately enlarged ovaries, about 10-12 holes are sufficient but more may be required in voluminous ovaries [43]. Treatment patients when followed sonographically show spontaneous ovulation or much more improved sensitivity to CC [45]. Overall LOD is simple procedure with lots of benefits for fertility preservation, but it should be judiciously employed with strict selection protocol.

IVF-ET treatment in PCOS
If ovulation induction is unsuccessful or conception cannot be accomplished as mentioned above, IVF-ET treatment is indicated. PCOS has been associated with various negative effects on ovulation induction and IVF-ET outcomes [49][50][51][52][53][54]. During ovarian stimulation for IVF-ET, the low-dose step-up regimens of pure FSH preparation are used for women with PCOS to prevent adverse effects [39,40]. In order to achieve ovulation in those patients, it needs ovarian stimulation with more risk for OHSS [41]. In high OHSS-risk patients, systematic embryo freezing and subsequent frozen embryo transfer cycles are recommended [49,55].
In vitro maturation (IVM) of oocyte procedure would be a best option for PCOS treatment in terms of complete prevention of OHSS [56]. Since the technology has been clinically applied, the number of centers undergoing it has increasing. In IVM procedure, the immature oocytes in germinal vesicle or metaphase I stage are cultured with medium, gonadotropins and serum for 24-48 h. About 50-60 % of immature oocytes commonly mature to metaphase II stage [57]. In order to acquire better outcome, it is essential to elucidate maturation process of human oocytes.

Treatment of PCOS not desiring for children
For obese PCOS patients, weight loss and exercise are recommended [17][18][19]. In non-obese and anovulatory patients, pharmacological treatments such as Holmström, Kaufmann regimens or low-dose oral anticonceptives are used to induce regular withdrawal bleeding. Early detection of PCOS mitigate the risks of endometrial hyperplasia and cancer [9], which caused by 'unopposed estrogen' condition of PCOS. There are moderate quality data to support that women with PCOS have a 2.7-fold increased risk for endometrial cancer [58]. Most endometrial cancers are known to be well differentiated and have a good prognosis. These hormone therapies are especially important for preventing endometrial hyperplasia and endometrial cancer [59].

Conclusion
New, revised diagnostic criteria and revised treatment criteria of PCOS reported by JSOG are proposed in this review. These new criteria hopefully will contribute to an improved care of PCOS patients in Japan.