The Microalbuminuria Education Medication and Optimisation (MEMO) study: 4 years follow-up of multifactorial intervention in high-risk individuals with type 2 diabetes.

AIMS: The Microalbuminuria Education Medication and Optimisation (MEMO) study, revealed improved cardiovascular risk and glycaemic control with 18 months of intensive multifactorial intervention in high-risk people with type 2 diabetes, without any increase in severe hypoglycaemia. Our aim was to assess longer-term outcomes at 4-year follow-up in these participants. METHODS: Some 189 individuals with type 2 diabetes and microalbuminuria were recruited from a multi-ethnic population in Leicestershire, UK. The intervention group (n = 95) received multifactorial intervention with self-management education, and the control group (n = 94) received usual care. The primary outcome was change in HbA1c , and secondary outcomes were blood pressure (BP), cholesterol, microalbuminuria, estimated GFR, cardiovascular risk scores and major adverse cardiovascular events. RESULTS: Some 130 participants (68.7%), mean (sd) age 60.8 (10.4) years, duration of diabetes 11.5 (9.7) years, completed 4 years of follow-up. Mean change [95% confidence intervals (CI)] in HbA1c over 4 years was greater with intensive intervention compared with control (-3 mmol/mol, 95% CI -4.95,-1.11; -0.4%, 95% CI -0.67,-0.15; P = 0.002). Significant improvements over the 4 years were also seen in systolic BP (-7.3 mmHg, 95% CI -11.1, -3.5; P < 0.001), diastolic BP (-2.9 mmHg, 95% CI -5.4, -0.3; P = 0.026), cholesterol (-0.3 mmol/l, 95% CI -0.52,-0.12; P = 0.002), and 10-year coronary heart disease (-5.3, 95% CI -8.2,-2.3; P < 0.001) and stroke risk (-4.4, 95% CI -7.5, -1.3; P < 0.001). CONCLUSION: Multifactorial intervention with structured diabetes self-management education compared with usual diabetes care has benefits for cardio-metabolic risk factor profile. There was no increase in severe hypoglycaemia and cardiovascular mortality despite intensive glycaemic control, although the study was not powered to assess these outcomes.

Association of cardiac and non-cardiac chronic disease comorbidity on glycaemic control in a multi-ethnic population with type 1 and type 2 diabetes.

AIMS: To determine the prevalence of chronic disease comorbidity in south Asians (SAs) and white Europeans (WEs) with diabetes and to quantify the relationship of cardiac disease comorbidity (CDCM) and non-cardiac disease comorbidity (NCCM) to glycaemic control in SAs and WEs with type 1 and type 2 diabetes mellitus. METHODS: A cross-sectional study using a database of patients of SA (25.5%) and WE (74.5%) origin attending a specialist diabetes clinic in the UK between 2003 and 2005 (n=5664). RESULTS: The prevalence of SAs and WEs with type 1 diabetes was 12% and 88%, respectively; for those with type 2 diabetes the prevalence was 30% and 70%, respectively. Overall, the prevalence of comorbidity in people with type 1 diabetes was 25.5% and with type 2 diabetes was 47%. NCCM was more prevalent in WEs than SAs (17.6% vs 12.8%, p<0.001). In type 2 diabetes, the prevalence of suboptimal glycaemic control was significantly greater in SAs compared to WEs with NCCM and CDCM (79% vs 62%, p<0.001; 78% vs 65%, p<0.001, respectively). SAs with type 2 diabetes and comorbidity had excess odds of suboptimal glycaemic control compared to WEs: OR 2.27 (95% CI 1.50 to 3.43) for those with NCCM and OR 1.91 (95% CI 1.49 to 2.44) for those with CDCM. CONCLUSIONS: The prevalence of CDCM is higher in SAs compared to WEs with type 2 diabetes, whereas the prevalence of NCCM is higher in WEs compared to SAs. Taking into account comorbidities, SAs (compared to WEs) with type 2 diabetes had an excess risk of having HbA1c ≥7% ranging from 1.86- to 2.27-fold. Further research is needed to identify the reasons for unfavourable metabolic conditions in SAs and also develop and evaluate interventions.

Insulin U-500 in severe insulin resistance in type 2 diabetes mellitus.

Some patients with type 2 diabetes mellitus (T2DM) are profoundly insulin resistant and require large insulin doses to achieve optimal glycaemic control. However, large volumes of subcutaneous conventional U-100 insulin can cause discomfort at the injection site, resulting in poor concordance with insulin therapy. One therapeutic option is the use of U-500 insulin, thus reducing the insulin volume by 80%. This review will address the practical issues associated with the use of U-500, clinical efficacy and safety aspects of this concentrated insulin, which has an important role in a subgroup of patients with T2DM.

Glargine versus NPH insulin: efficacy in comparison with insulin aspart in a basal bolus regimen in type 1 diabetes--the glargine and aspart study (GLASS) a randomised cross-over study.

The aim of the study was to compare the efficacy of insulin glargine and aspart with NPH insulin and aspart in a basal bolus regimen in type 1 diabetes. In this 36-week randomised open-label two-period cross-over trial, subjects received 16 weeks' treatment with either once-daily insulin glargine or twice-daily NPH insulin after 4-week run-in. Primary outcome was HbA1c and secondary outcomes were fasting plasma glucose (FPG), weight change, incidence of hypoglycaemia, effect on lipid profile and patient satisfaction. Sixty patients with type 1 diabetes were recruited (33 male, mean age 42.7 years, mean HbA1c 8.53%) with 53 completing the study. At completion, HbA1c was lower with glargine and aspart than with NPH and aspart (8.07% versus 8.26%, difference -0.19 [95% CI 0.37-0.01]%, p=0.04). FPG was significantly different between glargine and NPH (p=0.002), with mean FPG on glargine 3mmol/L lower than on NPH at the end of the study. There were no differences in hypoglycaemia rate (p=0.63), weight (p=0.45) or lipid profile (p=0.18). Patient satisfaction was greater with glargine (DTSQ, p=0.001). Three patients discontinued as they wished to remain on glargine. We suggest that glargine combined with aspart is an effective basal bolus regimen in type 1 diabetes.

Impaired endothelium-dependent relaxation in isolated resistance arteries of spontaneously diabetic rats.

1. Previous studies have shown that endothelium-dependent relaxation in the aorta of spontaneously diabetic bio bred rats (BB) is impaired. 2. We have investigated noradrenaline (NA) contractility, endothelium-dependent acetylcholine (ACh) and bradykinin (BK) relaxation, and endothelium-independent sodium nitroprusside (SNP) relaxation in mesenteric resistance arteries of recent onset BB rats and established insulin treated BB rats, compared to their age-matched non diabetic controls. 3. There was no significant difference in the maximum contractile response or sensitivity to noradrenaline in either of the diabetic groups compared to their age-matched controls. 4. Incubation with the nitric oxide synthetase inhibitor NG-nitro-L-arginine (L-NOARG) resulted in a significant increase in maximum contractile response to noradrenaline in the recent onset age-matched control group (P < 0.05). Analysis of the whole dose-response curve (using ANOVA for repeated measures with paired t test) showed a significant left-ward shift following the addition of L-NOARG (P < 0.001). A similar but less marked shift (P < 0.01) was evident in vessels from recent onset diabetics. An overall shift in both sensitivity and maximum response was also evident in the age-matched non diabetic controls of the insulin-treated group (P < 0.05). However, by contrast, there was no significant change in sensitivity in the insulin-treated diabetic rats. 5. ACh-induced endothelium-dependent relaxation was significantly impaired in the recent onset diabetic rats compared to their age-matched controls (47 +/- 11% versus 92 +/- 2%, P < 0.05, n = 6), and in the insulin treated diabetic rats (34 +/- 5% versus 75 +/- 6%, P < 0.05, n = 6). The relaxation responses to BK also were significantly impaired in the diabetic rats compared to their age-matched controls (recent onset: 20 +/- 3% versus 72 +/- 7%, P < 0.05, n = 6; insulin treated: 12 +/- 9% versus 68 +/- 7%, P < 0.05, n = 7). 6. Incubation with either the nitric oxide synthetase substrate, U-arginine, or the free radical scavenging enzyme superoxide dismutase (150 mu ml-1) failed to improve the attenuated response of acetylcholine-induced relaxation in the diabetic vessels. 7. Endothelium-dependent relaxation mediated by ACh and BK was significantly attenuated in both the diabetic and control vessels after incubation with L-NOARG. 8. Pretreatment with a cyclo-oxygenase inhibitor, indomethacin, significantly enhanced the relaxation to ACh in both the recent onset and insulin treated diabetic rats (42 +/- 10%, n = 7 versus 64 +/- 7%, n = 7, P < 0.05, and 40 +/- 5%, n = 7 versus 65 +/- 9%, n = 6, P < 0.05). 9. Following endothelium removal, there was a marked impairment in endothelium-dependent relaxation responses to ACh and BK in both the diabetic and control vessels. 10. Incubation with the thromboxane A2 receptor antagonist SQ29548, did not significantly improve the ACh endothelium-dependent relaxation response in the diabetic vessels. 11. Endothelium-independent relaxation to sodium nitroprusside was significantly impaired in the first group of diabetic vessels studied; however, subsequent studies showed no impairment of the sodium nitroprusside response in the diabetic vessels. 12. In conclusion, the ability of the endothelium to regulate vascular contractility is reduced in recent onset diabetic vessels, and significantly impaired in established insulin treated diabetics. Relaxation to the endothelium-dependent vasodilators ACh and BK was impaired in both the recent onset and the established insulin treated diabetics, and the ACh response was significantly improved following pretreatment with indomethacin, suggesting a role for a cyclo-oxygenase-derived vasoconstrictor. Preliminary studies with a thromboxane A2, receptor antagonist, SQ29548 did not significantly improve the impaired relaxation to ACh, indicating that the vasoconstrictor prostanoid is not thromboxane A2.

Prevalence of diabetes in elderly patients requiring permanent cardiac pacemaker insertion.

Diabetes mellitus increases the rate of atrioventricular block after a myocardial infarction; right bundle branch block is more common than expected in the diabetic outpatient population. We decided to assess whether diabetic subjects were more likely to need permanent cardiac pacemaker insertion. Data from patients in Leicestershire who had undergone permanent cardiac pacemaker insertion during a 4-year period were analysed. The capture recapture technique was used: Hospital Activity Analysis data as capture, ward admission book and case note confirmation as recapture. Diabetes coding accuracy was confirmed from the central register and from an analysis of 100 sets of case notes. The number of these patients with diabetes was then recorded. Data for the reference population was obtained using a survey of a market town in Leicestershire. There were 688 patients, most (79%) aged over 65 years. Our analysis was performed on this group. Of this age group undergoing pacemaker insertion. 11.1% was diabetic. In the same age group, 8.3% of the controls were diabetic: a relative risk of 1.34 (P < 0.01, 95% confidence interval 1.25-1.44). This relative risk is likely to be an underestimate. The aetiology of this excess risk is uncertain: it is most likely due to ischaemic heart disease, but microangiopathy or increased cholinergic sensitivity may play a role.

A comparison of stress test referral rates and outcome between Asians and Europeans.

The Asian population is at greater risk from a myocardial infarction than their European counterparts. Fewer Asians are referred for coronary angiography. We studied referral rates for exercise stress testing following acute myocardial infarction in Asians and Europeans and also examined stress test outcome. A retrospective analysis was performed using hospital activity analysis data, ward admission book and stress test referral forms and reports. There were 962 acute myocardial infarctions with 90% being European. Fewer Asian patients were referred for stress testing (32.3% versus 45%, P < 0.001). Asian patients were more likely to have a positive test (42.9% versus 31.3%, P < 0.02). Fewer Asian patients completed the test (14.3% versus 31.3%, P < 0.001). Possible reasons for the decreased referral rates include communication difficulties and real or perceived poor exercise tolerance. More Asian patients should be referred for stress testing. Interpreters and information leaflets in multiple languages may help achieve this aim.

Multifactorial intervention in individuals with type 2 diabetes and microalbuminuria: the Microalbuminuria Education and Medication Optimisation (MEMO) study.

AIMS: To determine whether tighter cardiovascular risk factor control with structured education in individuals with type 2 diabetes (T2DM) and microalbuminuria benefits cardiovascular risk factors. METHODS: Participants from a multiethnic population, recruited from primary care and specialist clinics were randomised to intensive intervention with structured patient (DESMOND model) education (n=94) or usual care by own health professional (n=95). PRIMARY OUTCOME: change in HbA1c at 18months. SECONDARY OUTCOMES: changes in blood pressure (BP), cholesterol, albuminuria, proportion reaching risk factor targets, modelled cardiovascular risk scores. RESULTS: Mean (SD) age and diabetes duration of participants were 61.5 (10.5) and 11.5 (9.3) years, respectively. At 18months, intensive intervention showed significant improvements in HbA1c (7.1(1.0) vs. 7.8(1.4)%, p<0.0001), systolic BP (129(16) vs. 139(17) mmHg, p<0.0001), diastolic BP (70(11) vs. 76(12) mmHg, p<0.001), total cholesterol (3.7(0.8) vs. 4.1(0.9) mmol/l, p=0.001). Moderate and severe hypoglycaemia was 11.2 vs. 29.0%; p=0.001 and 0 vs. 6.3%; p=0.07, respectively. More intensive participants achieved ≥3 risk factor targets with greater reductions in cardiovascular risk scores. CONCLUSIONS: Intensive intervention showed greater improvements in metabolic control and cardiovascular risk profile with lower rates of moderate and severe hypoglycaemia. Intensive glycaemic interventions should be underpinned by structured education promoting self-management in T2DM.

U-500 insulin: why, when and how to use in clinical practice.

Some patients with type 2 diabetes mellitus (T2DM) have severe insulin resistance. Their insulin requirements are significantly greater. These patients need to take 2-3 injections at the same time to take the correct insulin dose or to redial the insulin pen. When daily insulin requirements are in excess of 300 units/day, the volume of the injected insulin becomes an issue. Large-volume injection can cause discomfort and lead to poor concordance with treatment. Using high-strength insulin e.g. U-500 insulin can reduce the volume of the injected insulin. Despite publications of small case reports or case series, no universal guidelines exist on the use of U-500 insulin. We discuss common sense approaches when considering the use of U-500 insulin in clinical practice.

A randomized controlled trial examining combinations of repaglinide, metformin and NPH insulin.

AIMS: To compare combination use of repaglinide, metformin and bedtime Neutral Protamine Hagedorn (NPH) insulin with conventional approaches of insulin initiation in patients with Type 2 diabetes (T2DM). METHODS: Eighty-two patients with T2DM with suboptimal glycaemic control on oral glucose-lowering agents were randomized to one of three treatment regimens for 4 months. Group 1 received metformin and twice daily biphasic 30/70 human insulin mixture (n = 27), group 2 metformin and bedtime NPH insulin (n = 26) and group 3 metformin, bedtime NPH insulin and mealtime repaglinide (n = 25). RESULTS: Seventy-five patients completed the study. Baseline and end-point mean HbA1c levels fell from 9.0 +/- 1.1 to 7.9 +/- 1.1% in group 1, 10.0 +/- 2.2 to 9.2 +/- 1.4% group 2 and 10.0 +/- 1.7 to 8.1 +/- 1.5% in group 3, respectively. All groups showed improvements in HbA1c. There was no significant difference between groups in the proportions of patients experiencing hypoglycaemia (29.6, 25.0 and 16.7%, respectively; P = 0.55) or in mean weight gain (2.9, 0.7 and 2.2 kg, respectively; P = 0.06). By 4 months, insulin doses were 0.63 +/- 0.32 IU/kg in group 1, 0.58 +/- 0.21 IU/kg in group 2 and 0.37 +/- 0.22 IU/kg in group 3 (group 3 vs. groups 1 and 2: P < 0.002). CONCLUSIONS: The approach using repaglinide, metformin and NPH insulin improved glycaemic control with a similar safety profile to conventional insulin initiation in T2DM and produced final glycaemic control similar to metformin and a twice daily biphasic insulin mixture.

Myocardial infarction and thrombolysis: a comparison of the Indian and European populations on a coronary care unit.

We reviewed the ward admission notes of 211 Indian and 192 European patients admitted over a period of 12 months to a coronary care unit. More Indian patients had myocardial infarctions (34% vs 27%, p < 0.05); they were more likely to have diabetes mellitus (47% vs 14%, p < 0.001), but less likely to smoke (19% vs 67%, p < 0.001). Fewer Indian patients were treated with thrombolysis (49% vs 80%, p < 0.001), late presentation being the principal reason (62% vs 40%, p < 0.05). The referral rates for exercise stress testing and cardiac catheterisation were not significantly lower for Indian patients. The Indian patient admitted into a coronary care unit is more likely to have had a myocardial infarction and yet less likely to receive care comparable to that of his European counterpart.

An atypical case of atypical pneumonia.

A 23-year-old man, previously fit and well, presented with an atypical pneumonia, associated with microangiopathic anaemia, thrombocytopenia, rhabdomyolysis and renal impairment. Despite administration of intravenous fluids and antibiotics, his condition rapidly deteriorated, and the possibility of an aggressive connective tissue disorder was raised. Thus he was treated with high-dose oral steroids and plasma exchange until autoantibodies were shown to be negative. At this stage it transpired that the patient had swallowed water from a stream three weeks earlier, and leptospira antibody titres were subsequently found to be elevated. Antibiotics were continued, and after a protracted course he made a full recovery. Leptospirosis should be remembered as a rare cause of atypical pneumonia, particularly if there is associated hepatic or renal impairment.

The effect of insulin on the vascular reactivity of isolated resistance arteries taken from healthy volunteers.

Impaired reactivity of the resistance vasculature may contribute to the development of diabetic microangiopathy by altering microvascular haemodynamics. This study investigates the acute effects of insulin on the contractility and relaxation properties of isolated human resistance arteries (< 300 microns internal diameter) taken from gluteal subcutaneous fat of 33 (18 male: 15 female) normotensive healthy volunteers (supine blood pressure 115.6 +/- 1.6/70.0 +/- 1.5 mm Hg [mean +/- SEM], with no family history of hypertension or diabetes mellitus. Resistance arteries were mounted in a small vessel myograph to measure isometric tension. Contractile responses to noradrenaline were reduced after incubation in 1 mU/ml of insulin for 20 min (p < 0.01; Group 1). Increasing concentrations of insulin were found to reduce the contractile response to noradrenaline in a dose-dependent manner (Group 2; 0.1 mU/ml by 8% [p < 0.01], 1 mU/ml by 17% [p < 0.02] and 10 mU/ml by 22% [p < 0.01]). Sensitivity to insulin (ED50) only decreased at the highest concentration of insulin. However, acetylcholine-induced relaxation was not altered by insulin (Group 2). Time control studies (Group 3) showed that contractile and relaxation responses over the 4-h study period were unchanged. Furthermore, the length of time the vessels were exposed to insulin did not progressively impair responses (Group 4). These findings suggest that insulin may induce abnormalities in vascular smooth muscle contractility, a factor that may contribute to or exacerbate the abnormal haemodynamics observed in the capillary microcirculation of numerous vascular beds in diabetes.

Is impaired baroreflex sensitivity a predictor or cause of sudden death in insulin-dependent diabetes mellitus?

Sudden death at night is known to occur in young patients with insulin-dependent (Type 1) diabetes mellitus (IDDM) but the aetiology is uncertain. A cardiac arrhythmia has been postulated, but there has been little evidence to support this. We present the case of a 31-year-old man with IDDM of 17 years duration, who died suddenly while asleep. Over preceding months, he had had strict glycaemic control (HbA1 8.9%), normal 24 h blood pressure (mean 131 +/- 2.1/76 +/- 2.2 mmHg), no evidence of microangiopathy or endothelial dysfunction and normal standard clinical tests of autonomic function. An electrocardiogram was similarly unremarkable, with a QTc interval of 0.414 s, and an echocardiogram had demonstrated normal left ventricular mass index (96.4 g m-2). However, there was no nocturnal dip in heart rate (daytime 74 +/- 2.7, and nocturnal 68 +/- 1.6 beats min-1), and he had grossly impaired baroreflex sensitivity during Phase 4 of the valsalva manoeuvre (0.5 ms mmHg-1), with power spectral analysis studies suggesting an abnormality of parasympathetic function. The coroner's autopsy demonstrated no structural abnormalities. We hypothesize that abnormal baroreflex sensitivity could either predict a risk of or account for some of the unexplained deaths in IDDM, in that relative overactivity of the sympathetic nervous system could cause ventricular arrhythmias.

Correcting impotence in the male dialysis patient: experience with testosterone replacement and vacuum tumescence therapy.

Sexual dysfunction remains a common and often distressing problem in the male dialysis population. Traditionally its management has consisted of correction of anemia, optimization of dialysis, removal of implicated medication, and finally depot injections of a testosterone ester. At a dedicated renal impotence clinic, we studied the effectiveness of testosterone replacement in men with biochemically proven hypogonadism and then vacuum tumescence therapy in those with continued erectile dysfunction. Depot testosterone was given to 27 patients (aged 52.4+/-2.5 years; duration of dialysis, 2.00+/-0.40 years; and duration of sexual dysfunction, 2.92+/-0.49 years): sexual function was fully restored in only three (11.1%), and two gradually lost the response over 18 months. Nineteen patients (70.3%) had partial responses, varying from an increased sense of well-being alone to restored sexual function apart from an impairment of the duration of penile erection. Five patients (18.5%) had no response, and testosterone was contraindicated in another four. Four of the treated patients (14.8%) reported fluid retention. Vacuum tumescence devices were then offered to 32 patients who remained impotent but declined by six. Twenty-six patients (aged 49.6+/-2.2 years; duration of dialysis, 2.50+/-0.58 years; and duration of sexual dysfunction, 3.26+/-0.56 years) used the devices, with 19 (73.1%) having full correction of their erectile dysfunction; six also continued with depot testosterone to maintain their libido. Penile discomfort was described by five patients (19.2%) whose potency was not restored. A further five predialysis patients have used the devices, and all had correction of their erectile dysfunction. The correction of biochemical hypogonadism in the male dialysis population with testosterone rarely restores sexual function to normal, whereas vacuum tumescence therapy corrects penile erection dysfunction in most patients.

Erythropoietin and sexual dysfunction.

BACKGROUND: Erythropoietin (rHuEpo) therapy has been shown to improve sexual function in the male dialysis population, with several studies suggesting a direct effect upon endocrine function, as well as correction of anaemia. Nevertheless many male dialysis patients receiving rHuEpo continue to complain of sexual dysfunction. METHODS: At a dedicated renal impotence clinic, 65 male dialysis patients were screened for endocrine disturbances. Baseline serum sex hormones were compared between those receiving and not receiving rHuEpo, using either the two-sample t test or the Mann-Whitney U test, after assessing for normality. Results from four patients were excluded on account of either medications (antiemetic phenothiazines), hepatic dysfunction, or carcinomatosis. RESULTS: Twenty-five patients (41.0%) were receiving rHuEpo, the recipients and non-recipients being well matched for haemoglobin (10.19 +/- 0.29 vs 10.55 +/- 0.25 g/dl, n.s.), age (51.1 +/- 1.9 vs 53.6 +/- 2.1 years, n.s.) and duration of sexual dysfunction (median, 3.0 vs 3.0 years, n.s.). The rHuEpo recipients had a higher median creatinine (1090 vs 972 micromol/l, P < 0.02), but similar nutritional status to the non-recipients (albumin 41.0 vs 39.0 g/l, n.s.). The total duration of rHuEpo therapy was 0.85 +/- 0.14 years. Prolactin levels were similar in both the rHuEpo recipients and non-recipients (440 vs 541 mu/l, n.s.), as were LH (11.0 vs 10.5 iu/l, n.s.) and FSH (8.0 vs 6.5 iu/l, n.s.). However, there were significant elevations of testosterone (19.8 +/- 1.3 vs 16.1 +/- 1.1 nmol/l, P < 0.05) and sex hormone binding globulin (SHBG) (40.5 vs 26.0 nmol/l, P < 0.01), with a trend toward elevated oestradiol (304 vs 248 pmol/l, P = 0.095) in the rHuEpo-treated group. Forty-eight subjects (78.7%) received peritoneal dialysis (PD), with the 19 rHuEpo recipients (39.6%) demonstrating increased serum testosterone (21.0 +/- 1.5 vs 16.6 +/- 1.3 nmol/l, P < 0.05), SHBG (40.5 vs 26.5 nmol/l, P < 0.01), LH (15.0 vs 10.0 iu/l, P < 0.01) and FSH (12.0 vs 5.3 iu/l, P < 0.05). These differences were not demonstrated in the 13 haemodialysis (HD) subjects. CONCLUSIONS: Male dialysis patients complaining of sexual dysfunction after correction of anaemia with rHuEpo are characterized by higher levels of serum testosterone and SHBG, but not suppression of hyperprolactinaemia or hyperoestrogenism. Male PD subjects receiving rHuEpo also demonstrated increased LH and FSH.