Ultrasound in polycystic ovary syndrome--the measuring of ovarian stroma and relationship with circulating androgens: results of a multicentric study.

BACKGROUND: The introduction of transvaginal approach in ultrasound (US) has enabled the accurate evaluation of the structure of the ovary and stroma. Stroma represents an acknowledged US marker for polycystic ovary syndrome (PCOS). The proportion revealed between the stroma and the ovary surface in the median section (S/A ratio) had been indicated as a reliable marker for hyperandrogenism. In order to verify the feasibility of this determination in routine use and to confirm the efficacy of S/A ratio in predicting hyperandrogenism in PCOS, a multicentric study was performed in association with five Italian research groups. METHODS: A total of 418 subjects of fertile age presenting oligomenorrhoea or secondary amenorrhoea, enlarged ovaries measuring >10 cm(3) and/or >12 follicles measuring 2-9 mm in diameter took part in the study. Clinical, US and hormonal evaluations were performed in the early follicular phase or on random days in amenorrhoeic subjects. US assessment included ovarian volume, follicle number, ovarian and stroma area in median section. The hormonal study included a baseline plasma determination of LH, FSH, estradiol (E(2)), androstenedione (A), testosterone (T), dehydroepiandrosteronesulphate, 17-hydroxy-progesterone, sex hormone-binding globulin and prolactin. Correlations and receiver operator curves were used in statistical analysis of data. RESULTS: S/A was found to be the best significant predictor of elevated A and T levels. In order to ascertain significant cut-off values in relation to A and T levels Youden indexes were calculated and indicated 0.32 as the best cut-off for the S/A ratio. CONCLUSIONS: This work underlines the importance of stroma measure in improving US diagnosis of PCOS and suggest that this parameter may be used in routine clinical practice. In fact, multicentre study demonstrated the easy feasibility of such procedure without need of sophisticated machines or intensive training for operators.

Is the PCOS diagnosis solved by ESHRE/ASRM 2003 consensus or could it include ultrasound examination of the ovarian stroma?

BACKGROUND: The clinical heterogeneity of polycystic ovary syndrome (PCOS) is mirrored by the unceasing debate on the most appropriate diagnostic criteria. METHODS AND RESULTS: To highlight differences and inconsistencies between NIH and ESHRE/ASRM criteria, we applied them to 375 patients with oligo/amenorrhoea and signs of hyperandrogenism. Among them, we identified 273 women with PCOS according to NIH, whereas up to 345 patients fulfilled ESHRE/ASRM criteria. The 72 patients, constituting the gap between the two classifications, exhibited a lower expression of clinical signs compared with the 273 patients matching both criteria. To the whole group, we then applied the ESHRE/ASRM criteria modified to include an easily reproducible ultrasound examination of the ovarian stroma (UCSC criteria). In this way, we identified 30 women who were healthy according to all criteria, 37 affected by PCOS according only to the ESHRE/ASRM Consensus, 35 affected according only to the UCSC and ESHRE/ASRM criteria and 273 who were considered to have PCOS by all criteria. These groups showed a progressively increasing expression of PCOS features. CONCLUSION: In the grey area between NIH and ESHRE/ASRM classifications, UCSC criteria could identify a subgroup of women, missed by NIH criteria, with more pronounced stigmas than those identified by ESHRE/ASRM criteria alone, and who may profit more from a targeted therapy.

Pituitary-ovarian response to the gonadotrophin-releasing hormone-agonist test in anovulatory patients with polycystic ovary syndrome: predictive role of ovarian stroma.

OBJECTIVE: To evaluate the influence of ovarian stroma on basal and poststimulus androgen secretion in patients affected by secondary amenorrhoea and polycystic ovaries (PCO) at ultrasound (US). DESIGN: Prospective study. PATIENTS: Fifty-one patients with PCO selected from a group of 72 normal weight women aged 20-25 years affected by secondary amenorrhoea and 10 normal ovulatory controls. METHODS: All subjects underwent US to evaluate volume, area, stromal area and stromal/total area ratio of both ovaries. Plasma levels of gonadotrophins, oestradiol (E2) and androgens were measured before and 24 h after GnRH-a injection. 60 min after stimulus LH and FSH were also assayed. RESULTS: Thirty patients had increased ovarian stroma (IS) and 21 patients normal ovarian stroma (NS). Significantly higher LH levels characterized the IS group, both basally and after GnRH-a stimulation compared with NS and controls (P < 0.01). Baseline levels of androstenedione, testosterone and 17-OHprogesterone (17-OHP) were significantly higher in IS group. Moreover, 17-OHP hyper-response to GnRH-a was demonstrated in IS group in comparison to NS and control groups (P < 0.005). CONCLUSIONS: Stroma evaluation may be of use in discriminating between different pathogenic factors in secondary amenorrhoea. This criterion may be applied to support the correct diagnosis of polycystic ovary syndrome (PCOS). Indeed, in line with the most recently proposed guidelines, patients affected by multifollicular ovaries could be classified as PCOS. The possibility of taking into account more than one US criterion or of carefully reanalysing the significance of increased stroma volume should be considered.

Longitudinal metabolic observation of metformin effects during pregnancy in hyperinsulinemic women with polycystic ovary syndrome: a case report.

Obese hyperinsulinemic women with polycystic ovary syndrome (PCOS) present a markedly increased risk of developing glycaemic alterations during pregnancy, commonly recognized as a "diabetogenic" condition. This risk seems to be safely reduced by the administration of metformin during gestation. We analyzed the metabolic changes in two hyperinsulinemic PCOS women, who became pregnant after 8 weeks of metformin therapy and continued taking the drug till delivery. An oral glucose tolerance test and an euglycemic hyperinsulinemic clamp were performed at baseline and, during metformin therapy, in pre-conceptional state and at each trimester of gestation. A pronounced decrease in peripheral insulin sensitivity occurred as the pregnancies proceeded (at the third trimester 51.7% and 41.1% of pregestational values in patient 1 and 2 respectively), along with an increase in stimulated insulin secretion (at the third trimester 120% and 50.6% of pregestational values in patient 1 and 2 respectively). Despite these findings, none of the studied subjects developed gestational diabetes or impaired glucose tolerance. This confirms that metformin may exert a protective role against such disturbances in hyperinsulinemic PCOS patients, probably by avoiding the gestational physiologic changes leading to a loss of the metabolic balance achieved by these subjects out of pregnancy.

[Diagnosis of polycystic ovary syndrome]. / Diagnosi della sindrome dell'ovaio policistico.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorders among women in reproductive age, but diagnostic criteria used in clinical practice are still controversial. In 1990 the National Institute of HEALTH (NIH) conference on PCOS recommended that diagnostic criteria should include biochemical evidence of hyperandrogenism and ovarian dysfunction (in the absence of non-classical adrenal hyperplasia) without considering the morphological diagnosis of polycystic ovary by ultrasound as an essential part of the diagnosis. In the Rotterdam PCOS workshop of May 2003, however, PCOS is diagnosed when 2 of the following criteria are recognized: oligomenorrhea and/or anovulation, clinical or biochemical signs of hyperandrogenism, ultrasound findings of polycystic ovary. Further-more, it is underlined that the metabolic study is not necessary for PCOS diagnosis, while it is suggested for "at risk patients" (obesity, diabetes, familiar and obstetrical history) with an oral glucose tolerance test (OGTT). A recent study carried out by our group underlined the role of ultrasound parameter, in particular suggesting a ratio between ovarian stroma area and total area of the ovarian section (S/A), with a cut-off of 0.34, as "gold parameter" for PCOS diagnosis, because it shows high sensitivity and specificity (96.3%, 97.0% for the S/A).

The effect of age on the ovarian response to gonadotropin and on pregnancy rate in polycystic ovary syndrome.

Recent studies have proposed that, in women affected by the polycystic ovary syndrome (PCOS), aging is able to regularize the menstrual cyclicity. To evaluate the ovarian response in PCOS patients according to their age, we studied 33 PCOS patients, 20 of whom with an age ranging from 28 to 34 years (younger PCOS) and 13 ranging from 35 to 45 years (older PCOS). All patients underwent an ovulation induction therapeutic protocol with low-dose recombinant follicle stimulating hormone, for a total of 80 cycles (44 cycles for the younger PCOS group and 36 cycles for the older PCOS group). No significant difference was found between the days of therapy (12.3 +/- 5.4 vs. 13.5 +/- 5.6 days), total amount of drugs (980.7 +/- 568.9 IU vs. 1063.9 +/- 469.5 IU) or ovulation rate (93% vs. 89%) in the two groups. The two groups showed a significant difference in the maximum estradiol level (2053.5 +/- 1497.2 vs. 1269.0 +/- 911.5 pmol/l, p < 0.01), the number of the recruited and preovulatory follicles (1.7 +/- 2.5 vs. 0.64 +/- 0.9, p < 0.05 and 1.7 +/- 1.1 vs. 1.2 +/- 0.5, p < 0.01, respectively) and the pregnancy rate (36% vs. 14%, p < 0.05). In conclusion, our data clearly showed that, also in PCOS, advanced age is a negative prognostic factor in the ovarian response to ovulation induction therapies.

Insulin and GH secretion in adolescent girls with irregular cycles: polycystic vs multifollicular ovaries.

In the present study insulin (I) and GH secretion was studied in a group of twenty-five young adolescent girls (mean age: 15 +/- 0.23 yr) with cycle irregularity associated to clinical signs of hyperandrogenism in comparison with that observed in eleven normal matched subjects with regular menses. All patients underwent basal hormone measurements and, on two consecutive days, an oral glucose tolerance test (OGTT) and a GHRH iv test. Therefore, all subjects had a transabdominal US scan for the measurement of ovarian volume and the characterization of ovarian morphology. On the basis of the US examination we found patients with polycystic ovaries (PCO-like group) and subjects with multifollicular ovaries (MFO group). PCO-like group exhibited T (p<0.01) and LH (p<0.05) plasma levels higher than control group and the highest free androgen index (FAI) values (13 +/- 0.87). All patients with irregular menses showed plasma concentrations of AUC for I (AUC-I) significantly higher in respect to control group (7359.4 +/- 709 vs 5447 +/- 431 microIU/ml x 180 min, p<0.01) as well as both PCO-like group and MFO group did (p<0.001 and p<0.01) respectively. MFO group showed higher values of the AUC for GH (AUC-GH) (2809 +/- 432 ng/ml x 120 min) in respect to controls (1708 +/- 208 ng/ml x 120 min, p<0.05) and PCO-like subjects (p<0.001), who on the contrary showed the lowest AUC-GH values (618 +/- 119 ng/ml x 120 min). In conclusion, PCO-like patients associated hyperinsulinemia with a blunted GH secretion while MFO patients had higher GH secretion associated with higher AUC-I values in a way suggesting an immature and still developing reproductive system.

Recombinant versus urinary follicle-stimulating hormone in the low-dose regimen in anovulatory patients with polycystic ovary syndrome: a safer and more effective treatment.

BACKGROUND: We studied polycystic ovarian syndrome (PCOS) in fifty 25- to 37-year-old women who failed to conceive with clomiphene citrate treatment. METHODS: Twenty patients were submitted to treatment with low-dose (75 IU) urinary FSH (uFSH) in order to achieve ovulation and 30 patients were treated with recombinant FSH (rFSH) according to the same protocol. RESULTS: Ovulation was achieved in 75 and 97% of the cycles after uFSH and rFSH, respectively (p < 0.02). The length of treatment needed to achieve ovulation, the number of ampules given and dose per kilogram were significantly lower in the rFSH group. Mild ovarian hyperstimulation syndrome (OHSS) was observed in 9 uFSH cycles, whereas only 1 of the women treated with rFSH developed an OHSS (1/38 vs. 9/36; p < 0.01). CONCLUSION: rFSH is more efficient than uFSH in inducing ovulation in PCOS patients. The high prevalence of ovulatory cycles using a lower dose guaranteed greater safety of treatment and significantly reduced the incidence of OHSS.

Metabolic and endocrine consequences of acute suppression of FFAs by acipimox in polycystic ovary syndrome.

To evaluate the effects of acute lowering of FFAs on glucose-induced insulin secretion and GH response to GHRH in polycystic ovary syndrome (PCOS), 27 PCOS subjects (11 lean and 16 obese) and 17 body mass index-matched controls (8 lean and 9 obese) were investigated. Patients underwent an oral glucose tolerance test and a GHRH test before and after administration of the antilipolytic drug acipimox (250 mg orally 3 h and 1 h before the starting of the tests). Blood samples were collected for 2 h after GHRH bolus and for 4 h after the oral glucose tolerance test. Serum concentrations of GH, insulin, glucose, and c-peptide were assayed in each sample, and the results were expressed as area under the curve (AUC). No significant differences were found as to glucose, insulin, and c-peptide AUC before and after acute FFA plasma reduction in any of the investigated groups. Basally, lower GH-AUC was found in lean PCOS compared with body mass index-matched controls and in obese vs. lean controls; no significant differences were found as to the same variable between the two obese groups. The acipimox induced FFA suppression elicited in the four groups a sustained increase in the GH response to its trophic hormone; indeed, the GH-AUC nearly doubled with respect to basal evaluation in all the studied groups. However, the antilipolytic drug was not able to abolish the differences found between lean groups in basal conditions. In conclusion, the presented data confirm that FFAs have a main role in regulating GH secretion at the pituitary level; however, it does not seem that they could explain the GH as well as insulin dysfunction of PCOS.

Naltrexone effect on pulsatile GnRH therapy for ovulation induction in polycystic ovary syndrome: a pilot prospective study.

The aim of the present study was to analyze the opioid influence on LH pulsatility in polycystic ovary syndrome (PCOS) patients and to evaluate the effectiveness of a long-term opioid antagonist (naltrexone) treatment in improving the pulsatile GnRH therapy which is successful in this syndrome. Ten obese women affected by PCOS participated in the study. Patients were hospitalized during the early follicular phase and underwent an oral glucose tolerance test (OGTT) with 75 g of glucose and a pulse pattern study followed by a GnRH test (100 pg i.v.). All patients were then treated for ovulation induction with pulsatile administration of GnRH (5 microg/bolus every 90 min). Since pregnancies did not occurr in any patient, after spontaneous or progestin-induced menstrual cycles, all patients received naltrexone at a dose of 50 mg/day orally for 8 weeks and during treatment repeated the basal protocol study and the ovulation induction cycle with the same modalities. The naltrexone treatment significantly reduced the insulin response to OGTT and the LH response to GnRH bolus, whereas it did not affect the FSH and LH pulsatility patterns. Concerning the ovulation induction by pulsatile GnRH, naltrexone treatment was able to improve, although not significantly, the ovulation rate (60% pre-treatment vs 90% post-treatment). Furthermore, the maximum diameter of the dominant follicle and the pre-ovulatory estradiol concentration were higher after long-term opioid blockade (follicular diameter 19.5+/-1.76 mm pre-treatment vs 21.6+/-2.19 mm post-treatment, p<0.001; maximum estradiol level 728.7+/-288.5 pmol/l pre-treatment vs 986.4+/-382.1 pmol/l post-treatment, p<0.05). During the naltrexone-pulsatile GnRH co-treatment two pregnancies occurred. In conclusion, our data show that naltrexone-pulsatile GnRH co-treatment is able to improve the ovarian responsiveness to ovulation induction in obese PCOS patients when compared to pulsatile GnRH alone. This action seems to be related to a decrease of insulin secretion. Further randomized studies should be performed in order to obtain significant conclusions on the possible clinical application.

A new ultrasound criterion for the diagnosis of polycystic ovary syndrome: the ovarian stroma/total area ratio.

OBJECTIVE: To evaluate whether some ultrasound parameters of ovarian morphology can discriminate between control women and patients with polycystic ovary syndrome (PCOS). DESIGN: Retrospective data analysis. SETTING: Volunteers women in an academic research environment. PATIENT(S): Eighty amenorrheic or oligomenorrheic women and 30 normal ovulatory control participants. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We evaluated ovarian volume, area, stroma, and the stroma/total area (S/A) ratio by use of transvaginal pelvic ultrasound; and we assayed serum levels of gonadotropin, androgen, and estradiol during the early follicular phase (days 2 to 5) of the menstrual cycle in regularly cycling controls and on a random day in amenorrheic patients. RESULT(S): Patients with PCOS showed significantly higher ovarian volume, area, stroma, and mean S/A ratio when compared to multifollicular and control groups. Cut-off values have been defined for ovarian volume (13.21 mL), area (7.00 cm2), stroma (1.95 cm2), and S/A ratio (0.34). The sensitivity for PCOS diagnosis was 21%, 4%, 62%, and 100%, respectively. The S/A ratio showed the most significant correlation with the androgen levels. CONCLUSION(S): The evaluation of the S/A ratio can differentiate between PCOS and control or multifollicular women with both a sensitivity and a specificity of 100%. Furthermore, this ultrasound parameter is strictly related to hormonal milieu and to anthropometric characteristics.

Opioid blockade effect on insulin beta-cells secretory patterns in polycystic ovary syndrome. Oral glucose load versus intravenous glucagon bolus.

In order to evaluate the involvement of endogenous opiates in the insulin disorders of polycystic ovary syndrome (PCOs) a total of 25 PCOs women and 11 normo-ovulatory controls were studied by comparing the effect of a chronic opioid blockade on beta-cells responsiveness to oral glucose load and to intravenous glucagon bolus. Each patient, studied on follicular phase, underwent to oral glucose tolerance test (OGTT), and, 2 days later, to a glucagon intravenous bolus (1 mg); these tests were then repeated after 6 weeks of naltrexone treatment (50 mg orally). Naltrexone treatment did not modify the insulin secretory patterns of control subjects, whereas the same therapy significantly reduced, in hyperinsulinemic PCOs women, the beta-cell hyperresponsiveness both to oral glucose load and to intravenous glucagon (p < 0.05 and p < 0.01, respectively), even if with different mean percent decrease (32% OGTT vs. 45% glucagon, p < 0.05). Moreover, normoinsulinemic PCOs patients showed a slight, but not significantly increase in the beta-cells response to OGTT after opioid blockade, whereas, in the same situation, the insulin release after glucagon bolus was significantly reduced (p < 0.01). Chronic opioid blockade did not modify gonadotropins, steroids and SHBG levels in either group. Our data show that naltrexone treatment is able to reduce the beta-cell response to a direct intravenous secretagogue stimulus in all PCOs patients, while only in hyperinsulinemic PCOs subjects the same treatment is effective in reducing the exaggerated insulin secretion after oral glucose load. The reason for such a discrepancy could be ascribed to a different effect of opioids on first- and second-phase insulin secretion, or, alternatively, to an involvement of other secretagogue factors, such as glucoincretins.