Polycystic ovary syndrome: a common reproductive syndrome with long-term metabolic consequences.

Polycystic ovary syndrome is the most common endocrine disorder among women of reproductive age. Although traditionally viewed as a reproductive disorder, there is increasing appreciation that it is associated with significantly increased risk of cardiometabolic disorders. Women with polycystic ovary syndrome may present to clinicians via a variety of different routes and symptoms. Although the impact on reproduction predominates during the reproductive years, the increased cardiometabolic problems are likely to become more important at later stages of the life course. Women with polycystic ovary syndrome have an approximately 2- to 5-fold increased risk of dysglycaemia or type 2 diabetes, and hence regular screening with oral glucose tolerance test is warranted. Although the diagnostic criteria for polycystic ovary syndrome are still evolving and are undergoing revision, the diagnosis is increasingly focused on the presence of hyperandrogenism, with the significance of polycystic ovarian morphology in the absence of associated hyperandrogenism or anovulation remaining uncertain. The management of women with polycystic ovary syndrome should focus on the specific needs of the individual, and may change according to different stages of the life course. In view of the clinical manifestations of the condition, there is recent debate about whether the current name is misleading, and whether the condition should be renamed as metabolic reproductive syndrome.

Effects of laparoscopic ovarian drilling in treating infertile anovulatory polycystic ovarian syndrome patients with and without metabolic syndrome.

OBJECTIVE: To compare the effects of laparoscopic ovarian drilling in treating infertile polycystic ovarian syndrome in patients with and without metabolic syndrome. DESIGN: Retrospective review. SETTING: A university-affiliated hospital in Hong Kong. PATIENTS: A total of 89 infertile anovulatory polycystic ovarian syndrome patients, who underwent laparoscopic ovarian drilling with completed metabolic screening and seen over a 5-year period from 2002 to 2007. MAIN OUTCOME MEASURES: The clinical, hormonal, and metabolic characteristics as well as spontaneous ovulation rates, reproductive outcomes, and diabetes risks during pregnancy observed after laparoscopic ovarian drilling. RESULTS: Approximately one fifth (21%) of polycystic ovarian syndrome patients had the metabolic syndrome. There were no differences in spontaneous ovulation rates (68% vs 61%, P=0.76), cumulative pregnancy rates (68% vs 61%, P=0.77), and diabetes risks during pregnancy (64% vs 42%, P=0.13) between patients with and without metabolic syndrome. CONCLUSION: Laparoscopic ovarian drilling was equally effective in inducing ovulation in polycystic ovarian syndrome patients with metabolic syndrome. Thus, patients with metabolic syndrome should not be precluded from laparoscopic ovarian drilling, which has the additional advantage of enabling full tubo-peritoneal assessment at the same time.

The relationship between visceral adiposity and cardiometabolic risk in Chinese women with polycystic ovary syndrome.

OBJECTIVE: To compare the extent to which visceral adiposity, as measured by mesenteric fat thickness, contribute to cardiometabolic risk, especially insulin resistance, in women with PCOS and healthy control. METHODS: This is a cross-sectional study with a total of 190 women with PCOS fulfilling the Rotterdam diagnostic criteria. Women without PCOS were recruited from a previous study, which comprised 416 healthy women controls with normal glucose tolerance. All subjects underwent OGTT, biochemical assessment, and sonographic assessment with measurements of mesenteric, preperitoneal and subcutaneous fat thickness. RESULTS: Mesenteric fat thickness was strongly correlated to cardiometabolic traits including blood pressure, fasting and 2-h glucose, triglycerides, HOMA-IR; and was negatively correlated to HDL-C in both cohorts (all p < 0.01). In PCOS, positive correlation was observed between mesenteric fat thickness and free androgen index (p < 0.01). Compared with controls, the regression line between mesenteric fat and HOMA-IR is much steeper in PCOS (p < 0.01). CONCLUSION: Women with PCOS remain more insulin resistant compared to controls at any given degree of visceral adiposity.

Embryo migration following ART documented by 2D/3D ultrasound.

Embryos have traditionally been thought to implant at the exact site they are transferred during assisted reproductive technology (ART). The introduction of 2D/3D ultrasound has allowed for mapping of the transfer site using air bubbles as a surrogate marker of embryo location. This study's aim was to compare the location of embryo transfer (ET) on ultrasound to that of embryo implantation. We present four cases of ectopic pregnancy at four sites: tubal, cervical, interstitial and ovarian. We compare the site of implantation on 2D/3D ultrasound at six weeks of pregnancy to that of transfer as assessed on 2D/3D ultrasound. In all four cases, the embryo flash was visualised in the centre of the uterine cavity on ultrasound at ET. At six weeks of pregnancy, the uterine cavity was empty and an ectopic pregnancy was identified. The tubal and ovarian ectopics were managed surgically whilst the cervical and interstitial pregnancies were treated with systemic methotrexate. These cases demonstrate embryo implantation distal to the ultrasound-confirmed site of transfer. These cases provide visually compelling evidence of embryo migration following ET and lend support to the theory that ectopic pregnancy may occur as a result of embryo migration, rather than poor ET technique.

Presence of Hepatitis B virus DNA in follicular fluid in female Hepatitis B carriers and outcome of IVF/ICSI treatment: A prospective observational study.

OBJECTIVE: To determine the relationship between the presence of detectable HBV DNA in the follicular fluid in HBV carriers with IVF/ICSI treatment outcome. STUDY DESIGN: A prospective observational study conducted in the Assisted Reproductive Unit, a tertiary referral centre affiliated with the Department of Obstetrics and Gynecology, The Chinese University of Hong Kong; and the Union Reproductive Medicine Centre at Union Hospital, Hong Kong. The primary outcome measure was pregnancy rate. Secondary outcome measures were the prevalence of detectable HBV DNA in the follicular fluid, implantation rate, clinical pregnancy rate, ongoing pregnancy rate and live birth rate. RESULTS: HBV DNA was detected in the follicular fluid of 28 (43.8%) of the 64 women, and the mean level in this group in log10 copies/mL (±SD) was 4.36 ± 1.85. Women with detectable follicular fluid HBV DNA were younger, lighter, had longer duration of infertility, higher incidence of detectable serum HBV DNA (OR 4.592, 95% C I 2.333-9.038), and significantly wider range in the number of total fertilized, viable embryos, and blastocyst rate, but no difference in cycle characteristics, stimulation and pregnancy outcomes, although the almost doubled ongoing pregnancy/live birth rate per cycle initiated (60.7% versus 38.9%) failed to reach statistical significance due to the small numbers. CONCLUSION: Our results suggested HBV infection did not appear to be detrimental to the outcome of IVF/ICSI treatment.

Cardiovascular risks and metabolic syndrome in Hong Kong Chinese women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) frequently exhibit central obesity, glucose intolerance, atherogenic dyslipidaemia and hypertension which are characteristic features of the metabolic syndrome (MetS). METHODS: A total of 295 premenopausal Chinese women with PCOS diagnosed by the Rotterdam criteria (mean age: 30.2 +/- 6.4 years) and 98 control subjects without PCOS were evaluated for prevalence of MetS and cardiovascular risk factors, including dyslipidaemia and dysglycaemia. RESULTS: Using the 2005 modified Adult Treatment Panel III criteria, MetS (presence of three or more risk factors) was found in 24.9% of PCOS women compared to 3.1% of controls. The prevalence of MetS in PCOS women increased from 16.7% at under 30 years of age to 53.3% at over 40 years. MetS was also more prevalent in overweight and obese (41.3%) than normal-weight PCOS women (0.9%). However, multivariate regression analysis showed that women with PCOS had a 5-fold increase in risk of MetS (odds ratio 4.90; 95% confidence interval: 1.35-17.84) compared with women without PCOS even after controlling for age and BMI, suggesting PCOS alone is an independent risk factor for MetS. CONCLUSIONS: There is high prevalence of MetS in Hong Kong Chinese women with PCOS despite their relatively young age. Recognition of these cardiometabolic risk factors requires a high level of awareness in conjunction with early and regular screening.

Polycystic ovarian syndrome in Hong Kong Chinese women: patient characteristics and diagnostic criteria.

OBJECTIVES: To identify the characteristics of Hong Kong Chinese women with polycystic ovarian syndrome and to compare different diagnostic criteria. DESIGN: Retrospective study. SETTING: Gynae-endocrinology Clinics in the Prince of Wales Hospital, Hong Kong. PATIENTS: Ninety Hong Kong Chinese women with polycystic ovarian syndrome who were diagnosed according to the hospital's criteria. MAIN OUTCOME MEASURES: Prevalence of typical features of polycystic ovarian syndrome, including anovulation and hyperandrogenism (with other endocrine causes excluded), polycystic ovarian features on ultrasonography, luteinising hormone predominance, obesity, and insulin resistance. RESULTS: Almost all (98.9%) patients with polycystic ovarian syndrome presented with anovulation, only 48.9% of them had clinical or biochemical evidence of hyperandrogenism. Typical ultrasound appearances of polycystic ovaries were observed in 86.7% of patients. Luteinising hormone predominance and insulin resistance were demonstrated in 67.8% and 40.7% of the cohort, respectively. Eight-six (95.6%) patients should have also been diagnosed with polycystic ovarian syndrome based on the 2003 Rotterdam new criteria. About 60% of patients who screened positive for insulin resistance had normal fasting serum glucose levels. The same proportion who had full screening for insulin resistance by oral glucose tolerance tests and fasting serum glucose to insulin ratios had discordant results of these two tests. CONCLUSIONS: The 2003 Rotterdam new diagnostic criteria for polycystic ovarian syndrome are generally applicable to the Hong Kong Chinese population. Early detection of insulin resistance in patients with polycystic ovarian syndrome can be ensured by performing an oral glucose tolerance test combined with measurement of fasting serum glucose to insulin ratio.

Changes in atherogenic lipids and lipoproteins during natural and hyperstimulated cycles in healthy women.

OBJECTIVE: To compare changes in the concentrations of Lp(a) lipoprotein and other atherogenic lipids and lipoproteins in natural and hyperstimulated ovarian cycles. DESIGN: Open, prospective study. SETTING: Academic department in a teaching hospital. PATIENT(S): Normal ovulatory women served as controls and the treatment group consisted of women undergoing ovarian hyperstimulation. INTERVENTION(S): The treatment group received hMG on a fixed regimen. MAIN OUTCOME MEASURE(S): Measurements of serum lipids and lipoproteins were made in both natural and hyperstimulated cycles. RESULT(S): There was a significant increase in the median concentration of Lp(a) lipoprotein from 10.1 to 10.7 mg/dL in the luteal compared with the proliferative phase of unstimulated cycles. In hyperstimulated cycles, there was a significant increase in the median concentration of Lp(a) lipoprotein from 9.7 mg/dL in the proliferative phase to 11.3 mg/dL in the luteal phase. Reductions in concentrations of total cholesterol and low-density lipoprotein cholesterol were found in the luteal phase of hyperstimulated cycles. CONCLUSION: Concentrations of Lp(a) lipoprotein increase during the luteal phase of both natural and hyperstimulated ovarian cycles.

Spontaneous abortion: a randomized, controlled trial comparing surgical evacuation with conservative management using misoprostol.

OBJECTIVE: To compare the efficacy of surgical evacuation of the uterus with medical evacuation using misoprostol in cases of spontaneous abortion. DESIGN: A prospective, randomized, controlled trial. SETTING: A university teaching hospital. PATIENT(S): Six hundred thirty-five women who aborted spontaneously and who consented to pretreatment randomization. INTERVENTION(S): Routine surgical evacuation or medical evacuation of the uterus using misoprostol. MAIN OUTCOME MEASURE(S): Immediate, short-term (2-3 weeks), and medium-term (6 months) medical complications. RESULT(S): There was a significantly lower incidence of immediate and short-term complications in the group treated with misoprostol compared with the surgically treated group. There were also fewer major complications in the 6 months after treatment in the medically treated group. Approximately 50% of the medically treated group subsequently required surgical evacuation, and these subjects required significantly more analgesia. CONCLUSION(S): Treatment with misoprostol can reduce the demand for surgical evacuation in cases of spontaneous abortion, and its use is associated with fewer medical complications.

Regulation of human oviductin mRNA expression in vivo.

OBJECTIVE: To examine changes in oviductin mRNA expression in oviductal mucosal tissue from fertile women throughout an ovulatory cycle. DESIGN: Semiquantitative reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis of oviductin mRNA. SETTING: University-based obstetrics and gynecology department. SUBJECT(S): Twenty women undergoing laparoscopy for tubal sterilization or hysterectomy for uterine fibroids. INTERVENTION(S): The mucosal layer was isolated from the oviduct tissue, and semiquantitative RT-PCR was performed. MAIN OUTCOME MEASURE(S): The relationship between serum estradiol, luteinizing hormone, and progesterone concentrations and the expression of oviductin mRNA. RESULT(S): There was a significant positive correlation between serum estradiol and luteinizing hormone concentrations and oviductin mRNA expression. There was a significant inverse correlation between serum progesterone concentrations and oviductin mRNA expression. CONCLUSION(S): Little is known about the regulation of human oviductin. This study was the first to examine the relationship between oviductin mRNA expression and serum estradiol and luteinizing hormone and progesterone concentrations in fertile women. Estradiol and luteinizing hormone both have a stimulatory effect on oviductin mRNA in humans, however, it is difficult to determine whether the effects are independent of one another, as the luteinizing hormone surge is dependent on the estradiol increase. Progesterone shows a clear inhibitory effect on oviductin mRNA.

Psychiatric morbidity following miscarriage: a prevalence study of Chinese women in Hong Kong.

OBJECTIVE: Previous studies reported that 48-51% of women in Western countries developed depressive disorder following a miscarriage. There is, however, little data among non-Western populations. The aim of this study was to measure the prevalence of psychiatric morbidity following miscarriage among Chinese women in Hong Kong. METHODS: Subjects were interviewed immediately after a miscarriage to collect medical, psychiatric, and sociodemographic data. Six weeks following the miscarriage, 150 subjects were assessed with the Structured Clinical Interview for DSM-III-R (SCID) to establish psychiatric diagnoses. RESULTS: 18 subjects (12%) met the DSM-III-R criteria for major depression and 2 subjects (1.3%) were diagnosed anxiety disorder NOS six weeks after the miscarriage. CONCLUSIONS: Chinese women in Hong Kong have a lower rate of psychiatric morbidity after a miscarriage.

Compliance with hormone replacement therapy in Chinese women in Hong Kong.

Compliance with hormone replacement therapy (HRT) has been extensively studied in western countries. However, there is little data concerning women in Asian countries. A retrospective study was performed to determine compliance in a group of Hong Kong Chinese women who commenced HRT over a 2 year period. Two years after the commencement of HRT, 68.3% were still taking HRT, although not always in the original formulation. The highest drop out rate occurred during the first 6 months. Factors which were associated with a higher degree of compliance were young age at menopause and at the time of initial consultation and the use of unopposed HRT. A number of significant medical problems were identified during the 2 years of follow up which may have remained otherwise undetected. Compliance with HRT appears to be comparable to that reported in other western specialist centres. Nearly 9% of women who stopped HRT did so because other doctors told them that they did need the treatment and another 6.5% because of the fear of breast cancer.

The treatment of cervical intra-epithelial neoplasia: when could we 'see and loop'.

OBJECTIVE: To determine the possible role of the selective 'see and loop' approach with a loop electrosurgical excision procedure (LEEP) for high grade cervical intra-epithelial neoplasia (CIN). DESIGN: Comparison of the colposcopic and histological diagnosis in patients who received LEEP treatment. SUBJECTS: Subjects included 95 patients from May to October 1994. SETTING: Department of Obstetrics and Gynaecology, the Prince of Wales Hospital, the Chinese University of Hong Kong. MAIN OUTCOME MEASURES: Agreement between colposcopic and histological diagnosis and between histological diagnosis by biopsy and by LEEP. Sensitivity and false positive rate of colposcopic diagnosis in different classifications of high grade CIN lesions. Decision analysis on the cost of three proposed strategies based on the study results. RESULTS: The colposcopic diagnosis was correct in 58% of cases with 31% overall and 11% undercall rates. The false positive rate of colposcopic examination was 11.4% in the diagnosis of CIN III or more advanced lesions and 36.8% if CIN II lesions are also classified as high grade. Decision analysis showed a saving of: (i) US$53,000: or (ii) US$73,000 per annum if 'see and loop' was performed on all cases where colposcopic diagnosis is: (i) CIN III or more; or (ii) CIN II or more. If the cost of inappropriate surgery by LEEP is estimated to be more than US$550 per person over-treated (i) becomes the preferred strategy. CONCLUSIONS: Selective 'see and loop' approach for high grade CIN III lesions suspected on colposcopy will not over-treat significantly but will reduce the number of colposcopy appointments, waiting list for colposcopy and subsequent expenses.

Patient selection for assisted reproductive technology treatments.

Assisted reproductive technologies refer to procedures in which the oocyte is handled or manipulated in vitro before replacement, either as an oocyte or an embryo. Because of rapid advances in this area, infertile couples may seek direct referral for assisted reproductive treatments, instead of trying simpler measures such as ovulation induction and intrauterine insemination. It is important to establish whether these conventional infertility treatments are appropriate, as such treatments are generally safer, less stressful, and more affordable. On the other hand, subjecting infertile couples to unnecessary delay by offering inappropriate treatments-for example, ovulation induction for tubal infertility or intrauterine insemination for severe male-factor infertility-would reduce the overall chance of success because of the age-related decline in female fecundity. The choice of infertility treatments thus depends on a balance of factors: the chance of pregnancy without treatment; the chance with simpler and safer, but less successful, infertility treatments; or the chance with the more complex and costly, but more effective, assisted reproductive treatments. The factors that should be taken into consideration include the age of the woman, the duration of infertility, the causes of infertility, the availability and cost of alternative treatments, and-most importantly-the acceptability.

Sonographic measurement of mesenteric fat predicts presence of fatty liver among subjects with polycystic ovary syndrome.

OBJECTIVE: Visceral fat is believed to be important in the pathogenesis of metabolic syndrome and fatty liver. In this study, we examined the relationship between mesenteric fat thickness and other sonographic indices of adiposity and the presence of fatty liver among subjects with polycystic ovary syndrome (PCOS). SUBJECTS AND METHODS: A total of 117 Chinese subjects with PCOS were evaluated (mean age, 28.6 ± 6.5 yr; mean body mass index, 24.3 ± 5.3 kg/m(2)). Anthropometric measurements and metabolic risk profile, including a standard oral glucose tolerance test, were assessed in all subjects. All subjects underwent an ultrasound examination for measurement of thickness of mesenteric, preperitoneal, and sc fat as well as evaluation for fatty liver. RESULTS: Forty-six (39.3%) of the subjects had fatty liver. PCOS subjects with fatty liver had higher body mass index, waist circumference, waist-hip ratio, and systolic blood pressure; a more unfavorable lipid profile with higher triglyceride; lower high-density lipoprotein cholesterol; higher fasting glucose and insulin; higher 2-h glucose during oral glucose tolerance test; lower SHBG; and higher alanine aminotransferase. Subjects with fatty liver had increased thickness of preperitoneal, mesenteric, and sc fat, as well as increased carotid intima-media thickness. Abdominal fat thickness showed moderate correlation to alanine aminotransferase as well as fasting insulin. On multivariate logistic regression, fasting insulin and mesenteric fat thickness were identified as independent predictors of fatty liver among subjects with PCOS. CONCLUSION: Fatty liver is present in a significant proportion of Chinese patients with PCOS. Sonographic measurement of mesenteric fat is an independent determinant of fatty liver among subjects with PCOS and identifies subjects at increased cardiovascular risk.

Inappropriate ADH secretion due to immature ovarian teratoma.

Inappropriate antidiuretic hormone secretion syndrome (IADHS) is usually associated with postoperative pain, stress, chest infection, drugs or carcinoma. It is rarely found in patients with gynaecological malignancy. IADHS was found in a 17-year-old girl with an immature ovarian teratoma. Hyponatraemia was persistent and did not respond to fluid restriction therapy before the operation. The plasma sodium level however returned to normal after the removal of the tumour. This is the first reported case of IADHS due to an immature ovarian teratoma or germ cell tumour.

Revisit of metformin treatment in polycystic ovarian syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women; its traditional pharmacological therapy mainly addresses short-term symptom control and does not correct the associated long-term metabolic risks. Recently, there has been increasing evidence that insulin resistance has an important implication in the pathogenesis of PCOS and that insulin-sensitizing drugs are a useful therapeutic approach. Therefore this review aims to discuss the current evidence on the use of metformin, a commonly used insulin-sensitizing agent, in treating both the short-term and the long-term problems of women with PCOS.

Deep fascial hyperintensity in soft-tissue abnormalities as revealed by T2-weighted MR imaging.

OBJECTIVE: The purpose of this study was to determine whether recently described criteria, including hyperintense T2-weighted signal or other abnormalities revealed by MR imaging within deep fascial planes, are specific for necrotizing soft-tissue infections. MATERIALS AND METHODS: We reviewed 22 MR imaging examinations that revealed abnormally high signal intensity within deep fascial planes on T2-weighted images. Twenty-one of the patients had clinical diagnoses other than necrotizing soft-tissue infection, including nonnecrotizing cellulitis (n = 4), abscess without evidence of necrotizing fasciitis (n = 5), and cellulitis with accompanying vascular thrombosis (n = 2). MR imaging was performed using T1-weighted spin-echo (range of TRs/range of TEs, 300-800/9-30) and fat-saturated T2-weighted fast spin-echo (3000-5000/76-108) sequences. Gadolinium-enhanced T1-weighted spin-echo MR images with fat saturation were obtained for 14 patients. Two reviewers, unaware of clinical diagnoses, evaluated each study for abnormalities in superficial and deep soft tissues and submitted a consensus diagnosis. RESULTS: Using only the described MR imaging criteria, we interpreted all cases as necrotizing cellulitis, including the cases of 21 patients who had nonnecrotizing conditions. CONCLUSION: Hyperintense T2-weighted signal within deep fascial planes and muscle, with or without contrast enhancement, is not specific for necrotizing soft-tissue infection. A variety of conditions exhibited similar findings and were indistinguishable from necrotizing soft-tissue infection.

A medical approach to management of spontaneous abortion using misoprostol. Extending misoprostol treatment to a maximum of 48 hours can further improve evacuation of retained products of conception in spontaneous abortion.

BACKGROUND: To compare a 48 hour non surgical policy in the management of spontaneous abortion with a policy of routine, universal uterine curettage. METHODS: A prospective, observational study on 354 women admitted to hospital with spontaneous abortion. Of these, 225 who had retained products of conception were treated with misoprostol for up to 48 hours after 101 were excluded because they had an empty uterus on transvaginal scan (TVS) and another 28 women because they were unsuitable for conservative management. Follow-up was conducted over a 3 week period to assess morbidity. A reference group of 137 women, all of whom had an evacuation of retained products of conception (ERPC) as a routine after they had a TVS documenting retained products of conception (POCs), was used for comparison. RESULTS: Evacuation of the uterus occurred within 24 hours in 107 women and in 148 at 48 hours after misoprostol treatment was started. There were three uterine curettages up to 14 days after discharge from hospital for persistent bleeding and two cases of pelvic infection. An ectopic pregnancy was diagnosed at follow-up in one woman. In the reference group, there were nine women who had complications, four requiring another ERPC and five had infection, an overall complication rate of 6.6% in the reference group and 1.7% in the protocol treatment group. CONCLUSION: A 48 hour regimen using transvaginal ultrasound and misoprostol for the management of spontaneous abortion was successful in avoiding surgery in 249 out of a possible 354 (70.6%) women with spontaneous abortion, with a low rate of subsequent morbidity.

PIP: A prospective, observational study of 354 women admitted to a Hong Kong hospital with a confirmed diagnosis of spontaneous abortion confirmed the effectiveness of a non-surgical 48-hour regimen using transvaginal ultrasound and misoprostol administration. 101 women were excluded because they had an empty uterus on transvaginal scan and another 28 were considered unsuitable for conservative management. The 225 remaining women were treated with up to 1200 mcgs of misoprostol administered orally in 3 divided doses per day for up to 48 hours; a comparison group of 137 women underwent surgical evacuation of retained products of conception. Evacuation of the uterus occurred within 24 hours of misoprostol administration in 107 women and by 48 hours after misoprostol administration in 148 women. The cumulative success rate was 69.6%. There were 3 uterine curettages for persistent bleeding up to 14 days after discharge, 2 cases of pelvic infection, and 1 ectopic pregnancy. In the reference group, 4 women required a repeat evacuation and 5 had infection. The overall complication rate in up to 3 weeks of follow-up was 6.6% in the surgical reference group and 1.7% in the medical treatment group.