Insulin resistance and metformin in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with widespread systemic manifestations affecting 5-10% of women of reproductive age. The accompanying insulin resistance and hypeinsulinemia mark this syndrome as a prediabetic state, with high incidence of impaired glucose tolerance, gestational diabetes, and overt diabetes. Other metabolic and biochemical changes, such as hypertension and dyslipidemia, increase the risk of cardiovascular disease. Fertility may also be impaired due to anovulation, impaired implantation, and higher rates of spontaneous abortions. All of these effects may also be related to hyperinsulinemia. Metformin, as insulin-sensitizing drug, is being evaluated for its potential long-term disease-modifying effect, such as prevention of diabetes. Its use may also help restore spontaneous ovulation and improve menstrual cyclicity, improve the success rate of induction of ovulation with clomiphene citrate and FSH, and decrease the high rate of ovarian hyperstimulation and early pregnancy loss. Nevertheless, these new exiting potential benefits of metformin should be evaluated in large randomized controlled studies, and clinicians must counsel women appropriately before the initiation of metformin therapy.     

Endocrine effects of laparoscopic ovarian electrocautery in patients with polycystic ovarian disease, resistant to clomiphene citrate

Endocrine responses to laparoscopic ovarian electrocautery were studied in 14 patients with polycystic ovarian disease (PCOD), resistant to clomiphene citrate. Patients who did not conceive within 6 months of treatment were evaluated for up to that period. Testosterone and androstenedione levels decreased after electrocautery in a way which is comparable with the reduction in androgens after wedge resection of the ovary. Androstenedione levels tended to return to pretreatment values at 6 months; four of the five pregnancies were achieved within this period. The reduction in androgens may break the vicious circle of PCOD, and lead to normal menstrual cycles.     

胰岛素抵抗、脂肪因子与多囊卵巢综合征

多囊卵巢综合征(polycystic ovary syndrome,PCOS)在育龄期妇女中的发生率为5%-10%,患者中胰岛素抵抗(insulinresistance,IR)的发生率高达50%。PCOS患者IR机理十分复杂,可能涉及胰岛素调节葡萄糖合成、运输、利用、贮存及降解等代谢过程的多个器官。根据胰岛素调节糖代谢作用过程的不同环节,IR可分为受体前水平、受体水平和受体后水平。PCOS患者IR的主要原因是胰岛素受体后信号传导障碍。近十多年来,脂肪组织为内分泌器官已成为学术界的共识,瘦素(leptin)、脂联素(adiponectin)、抵抗素(resistin)相继被发现。这些脂肪因子与IR及PCOS之间的联系是复杂和多样化的,其相互作用的途径和机制尚未完全清楚,尚需进行进一步研究。     

Ultra-short metformin pretreatment for clomiphene citrate-resistant polycystic ovary syndrome.

OBJECTIVE: To evaluate the effect of ultra-short (12 days) metformin pretreatment in clomiphene-citrate (CC) resistant polycystic ovary syndrome (PCOS). METHOD: Eighty women with CC-resistant PCOS were randomly allocated to metformin pretreatment or usual treatment. Forty women received 1500 mg metformin daily for 12 days, followed by clomiphene 150 mg daily for 5 days along with metformin. Forty women (control group) received the same dose of clomiphene but no metformin pretreatment. RESULTS: In the metformin group, 17 (42.5%) women ovulated, and 6 (15%) conceived. In the control group, 5 (12.5%) women ovulated but none conceived. Compared with the control group, the metformin group had significantly higher ovulation (P = 0.03) and pregnancy rates (P = 0.026). CONCLUSION: Twelve days of metformin pretreatment improves ovulation and pregnancy rates in women with CC-resistant PCOS.     

Laparoscopic ovarian drilling in clomiphene citrate-resistant women with polycystic ovary syndrome.

STUDY OBJECTIVE: To analyze the efficacy of laparoscopic ovarian drilling using monopolar diathermy in women with anovulatory infertility with clomiphene-resistant polycystic ovary syndrome (PCOS), and to determine factors influencing pregnancy rate and pregnancy outcomes. DESIGN: Prospective study (Canadian Task Force classification II-2). SETTING: Infertility clinic in a tertiary referral teaching hospital. PATIENTS: Seventy women with clomiphene-resistant PCOS. INTERVENTION: Laparoscopic ovarian drilling, with follow-up for 4.5 years. MEASUREMENTS AND MAIN RESULTS: Follow-up data, which were available for 66 patients, showed a spontaneous ovulation rate of 81.8%, cumulative ovulation rate of 93.9%, and pregnancy rate of 54.5%. Successful pregnancies were commonly complicated by gestational diabetes mellitus and pregnancy-induced hypertension. Pregnancy rates (23.5%) were low in women with tuboperitoneal disease and those whose partners had subfertile male factors. Statistical evaluation using a proportion test (Z test) and multivariable logistical regression analysis showed that elevated luteinizing hormone levels (>10 IU/L), short duration of infertility (<3 yrs), and absence of preexisting tubal disease were associated with better outcomes. CONCLUSION: Laparoscopic ovarian drilling is an effective surgical procedure in women with clomiphene-resistant PCOS.     

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.     

Endocrine effects of ovarian electrocautery in patients with polycystic ovarian disease

The mechanism by which ovarian electrocautery induces regular ovulatory cycles was studied in 16 women with polycystic ovarian disease (PCO) and compared with 25 normal fertile women who were undergoing sterilization by tubal electrocautery. Gonadotrophins (LH and FSH), prolactin, androgens, oestrogens, 17-hydroxyprogesterone and progesterone were determined immediately before operation and 24 h later. Following the sampling of blood for these tests, 100 micrograms of gonadotrophin releasing hormone (GnRH) was given intravenously and the LH and FSH responses were measured at 30 min. In the PCO-group, these tests were repeated after the first induced ovulatory cycle. After operation, LH increased only in the patients with PCO and this increase was associated with an enhanced response to GnRH, FSH showed a similar response to GnRH, also confined to the PCO-group. These pituitary responses are best explained by a change in ovarian feedback induced by the direct electrocautery of the glands in the PCO-group. There was little change in serum oestrogen. Prolactin showed an increment in all cases and serum androgens were reduced in all groups, most pronounced in the PCO patients, possibly as a result of the stress of operation. An ovarian factor--released or reduced by the electrocautery--seems to be responsible for the changes.     

Short-term metformin treatment for clomiphene citrate-resistant women with polycystic ovary syndrome

Objective

To evaluate the effect of a short-course pretreatment with metformin on hyperandrogenism, insulin resistance, cervical scores, and pregnancy rates in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS).

Methods

Thirty-seven women with CC-resistant PCOS were randomly assigned to be pretreated with 500 mg of metformin or placebo 3 times per day for 2 cycles, and 100 mg of CC was given on days 5 through 9 of the second cycle in both groups. Luteinizing hormone (LH), follicle stimulating hormone (FSH), dehydroepiandrostendione sulfate (DHEAS), total testosterone (T), glucose, and insulin levels were measured at baseline and after the first cycle, as well as body mass index (BMI), cervical score, and pregnancy rate.

Results

After 1 cycle, BMI, total T level, and percentage of participants with insulin resistance were significantly decreased in the metformin group, without any significant decrease in LH, FSH, and DHEAS levels; and in the second cycle, CC treatment resulted in a higher ovulation rate and a thicker endometrium in the metformin group. The pregnancy rate and cervical scores were also higher in that group.

Conclusion

The short-course pretreatment with metformin decreased hyperandrogenism and insulin resistance and improved cervical sores, ovulation rate, and pregnancy rate among women with CC-resistant PCOS.     

Endocrine effects of ovarian electrocautery in patients with polycystic ovarian disease

Summary. The mechanism by which ovarian electrocautery induces regular ovulatory cycles was studied in 16 women with polycystic ovarian disease (PCO) and compared with 25 normal fertile women who were undergoing sterilization by tubal electrocautery. Gonadotrophins (LH and FSH), prolactin, androgens, oestrogens, 17-hydroxy-progesterone and progesterone were determined immediately before operation and 24 h later. Following the sampling of blood for these tests, 100 μg of gonadotrophin releasing hormone (GnRH) was given intravenously and the LH and FSH responses were measured at 30 min. In the PCO-group, these tests were repeated after the first induced ovulatory cycle. After operation, LH increased only in the patients with PCO and this increase was associated with an enhanced response to GnRH, FSH showed a similar response to GnRH, also confined to the PCO-group. These pituitary responses are best explained by a change in ovarian feedback induced by the direct electrocautery of the glands in the PCO-group. There was little change in serum oestrogen. Prolactin showed an increment in all cases and serum androgens were reduced in all groups, most pronounced in the PCO patients, possibly as a result of the stress of operation. An ovarian factor—released or reduced by the electrocautery—seems to be responsible for the changes.     

Effects of metformin on inappropriate LH release in women with polycystic ovarian syndrome and insulin resistance

The role of hyperinsulinaemia in neuroendocrine abnormalities in polycystic ovarian syndrome (PCOS) is controversial. The present study applied frequent blood sampling to assess the response of LH to metformin treatment in insulin-resistant women with PCOS. Thirteen predominantly overweight women with PCOS were studied before and after treatment with 1.5 g/day metformin for 3 months. Serum LH and testosterone were measured every 10 min for 10 h; LH was measured for an additional 2 h after gonadotrophin-releasing hormone (GnRH) administration. LH pulses were characterized by cluster analysis, secretory LH episodes by a deconvolution procedure, and synchronicity of paired LH-testosterone concentrations by lag-specific cross-correlation. After treatment, basal LH concentrations, amplitude of LH pulses, LH secretory amplitude, response to exogenous GnRH, and basal testosterone concentrations significantly decreased in seven patients, whereas in the remaining women these parameters remained unaltered. Before treatment, decreased coordinate LH and testosterone release was manifested by all patients; metformin treatment led to re-establishment of the feed-back control of testosterone on LH secretory rates by -20 to 0 min. Treatment did not modify the glucose:insulin ratio or serum insulin concentrations. In conclusion, administration of metformin allowed the identification of two subsets of PCOS women in whom neuroendocrine abnormalities may improve independently of the presence of insulin resistance or hyperinsulinaemia.     

Effects of metformin on insulin resistance and on ovarian steroidogenesis in women with polycystic ovary syndrome]

BACKGROUND: Polycystic ovary syndrome is considered the most frequent endocrine abnormality during the fertile age. Hyperinsuli-nemia, typical of this syndrome, alters the functionality of the cytochrome P450 c 17 alfa and this causes an exaggerated secretion of male hormones produced by the female gonad. Objective of this study was to verify if the reduction of the circulating insulin levels, obtained through therapy with metformin, caused the reduction of LH levels, LH:FSH ratio, of testosterone and androstenedione levels, but also of cholesterolemia, triglyceridemia, BMI, and naturally of insulinemia, glycemia, as well as an increase in HDLC (high density lipoprotein cholesterol). METHODS: The presence of insulin-resistance and hyperinsulinemia, in 15 women aged between 20 and 30 with BMI >26 kg/m2, has been verified with test loaded with glucose; 500 mg of metformin have been given to these women three times a day before meals for 12 weeks. LH and FSH levels, LH:FSH ratio testosterone, androstenedione, progesterone, estradiol levels, cholesterolemia, trygliceridemia, HDLC and BMI have been considered in each patient before and after therapy. RESULTS: A statistically significant modification of all measured parameters was observed but the most important data is the reduction of the androgens. CONCLUSIONS: The reduction of insulinemia seems to be actually associated with a reduction of circulating androgens in women with polycystic ovary syndrome. As well as the reproductive function, this insulin-sensitizing agent has the further advantage of a possible favourable effect also on the complications of the polycystic ovary syndrome specifically connected with: glucose-intolerance, dislipidemia, arteriosclerosis and hypertension. To consider the effects on the complications of the syndrome it would be necessary to give the drug for a period longer than 12 weeks.     

Effects of metformin therapy on hyperandrogenism in women with polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine diseases in women. This syndrome is characterized by hyperandrogenism, chronic anovulation, infertility and obesity. The association between PCOS-related hyperandrogenemia and insulin resistance is well documented in the literature. Insulin resistance and the resulting raised plasma levels of insulin are reported to be responsible for the high androgen concentration observed in patients with PCOS. In this prospective study, blood samples for levels of testosterone (T), dehydroepiandrosterone sulfate (DHEAS), luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH, prolactin and fasting blood sugar (FBS) before starting metformin administration were obtained randomly from 40 women who were apparently obese, had PCOS and had been referred to a university hospital. Metformin was then given at a dose of 500 mg three times a day for 8 weeks, after which time the pretreatment study was repeated. Clinical symptoms of PCOS, including acne and hirsutism score and body mass index (BMI), were assessed before and after the treatment cycle. Metformin therapy resulted in a significant decrease in total testosterone levels and FBS. There was also a significant decline in BMI, length of the menstrual cycle, acne and hirsutism score. There were no significant changes in the levels of DHEAS, prolactin, FSH or LH, or in LH/FSH. The effect of metformin on subjects with elevated DHEAS levels was different to that on individuals with normal DHEAS levels. In the latter group there were only significant improvements in the length of the menstrual cycle, BMI and testosterone and DHEAS levels. It is concluded that metformin therapy in subjects with PCOS results in a decrease in fasting blood sugar and testosterone levels, and leads to a significant improvement in the clinical manifestation of hyperandrogenism. These responses also related to the level of adrenal function.     

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.     

Daily or alternate-day FSH therapy in patients with polycystic ovarian disease resistant to clomiphene citrate treatment

The effectiveness of intramuscular follicle stimulating hormone (FSH) administered as daily or alternate-day injections to patients with polycystic ovarian disease (PCOD) who previously failed to ovulate on clomiphene citrate was compared. The study comprised 20 treatment cycles of daily FSH and 19 of alternate-day FSH in 12 patients. The overall ovulation rate per cycle was 78% and was similar for both groups. Nine out of 12 patients achieved a pregnancy, with twice as many occurring in the alternate-day group. It is concluded that alternate-day FSH therapy is as effective as daily FSH in achieving ovulation and pregnancies in patients with PCOD resistant to treatment with clomiphene citrate.     

二甲双胍与复方醋酸环丙孕酮联合应用对多囊卵巢综合征患者内分泌及代谢的影响

目的　观察二甲双胍与复方醋酸环丙孕酮 (复方环丙孕酮 )联合应用 ,对多囊卵巢综合征 (PCOS)患者内分泌及代谢的影响。方法　对 4 5例患者进行前瞻性研究 ,为观察组 ;2 0例非PCOS不孕妇女为对照组。测定体重指数 (BMI)、腰臀围比值 (WHR)、多毛评分 (F G评分 )及生殖内分泌激素、糖、脂代谢指标等。观察组根据随机应用不同药物又分为复方环丙孕酮组、二甲双胍组及二甲双胍与复方环丙孕酮联合用药组 (联合用药组 ) ,每组各 15例。经 12周治疗后 ,比较上述各项指标的变化。结果　观察组治疗前BMI、WHR、F G评分、黄体生成激素 (LH)、睾酮 (T)、空腹胰岛素 (FI)、胰岛素抵抗 (IR)及甘油三酯等均较对照组增高 ;高密度脂蛋白胆固醇 (HDL C)较对照组降低 (P <0 0 1)。观察组 3组治疗前各项指标差异均无显著性 (P >0 0 5 )。治疗 12周后 ,联合用药组及二甲双胍组LH分别从 (13 9± 5 9)IU/L降低为 (5 8± 2 2 )IU/L ,从 (13 8± 7 6 )IU/L降低为 (11 8±6 5 )IU/L ;T分别从 (2 1± 0 8)nmol/L降低为 (1 2± 0 4 )nmol/L ,从 (2 2± 1 1)nmol/L降低为(1 8± 0 8)nmol/L ;游离睾酮 (FT)分别从 (2 8± 2 3)nmol/L降低为 (0 8± 0 5 )nmol/L ,从 (2 5±1 9)nmol/L降低为 (1