Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study

Abstract

Objective: To evaluate the effects the administration of myo-inositol (MYO) on hormonal parameters in a group of polycystic ovary syndrome (PCOS) patients.

Design: Controlled clinical study.

Setting: PCOS patients in a clinical research environment.

Patients: 50 overweight PCOS patients were enrolled after informed consent.

Interventions: All patients underwent hormonal evaluations and an oral glucose tolerance test (OGTT) before and after 12 weeks of therapy (Group A (n¼10): MYO 2?g plus folic acid 200?mg every day; Group B (n¼10): folic acid 200?mg every day). Ultrasound examinations and Ferriman–Gallwey score were also performed.

Main outcome measures: Plasma LH, FSH, PRL, E2, 17OHP, A, T, glucose, insulin, C peptide concentrations, BMI, HOMA index and glucose-to-insulin ratio.

Results: After 12 weeks of MYO administration plasma LH, PRL, T, insulin levels and LH/FSH resulted significantly reduced. Insulin sensitivity, expressed as glucose-to-insulin ratio and HOMA index resulted significantly improved after 12 weeks of treatment. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic subjects. No changes occurred in the patients treated with folic acid.

Conclusions: MYO administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.     

Combined metformin and clomiphene citrate versus highly purified FSH for ovulation induction in clomiphene-resistant PCOS women: a randomised controlled trial

Aim.?To compare the effect of combined metformin–clomiphene citrate (CC) with highly purified urinary FSH (HP-uFSH) for ovulation induction in CC-resistant women with polycystic ovary syndrome (PCOS).

Methods.?One-hundred fifty-three anovulatory women with CC-resistant PCOS were selected in this randomised controlled trial. Patients received combined metformin–CC (n?=?75, 205 cycles) or HP-uFSH (n?=?78, 186 cycles) for three cycles. Outcome measures were; Ovulation rate, number of growing and mature follicles, serum E2, serum P, endometrial thickness, pregnancy and miscarriage rates.

Results.?The ovulation rate per cycle was significantly higher in the HP-uFSH group (83.8% vs. 62%, p?=?0.01). The number of follicles ≥12?mm ≥14?mm and ≥18?mm on the hCG day was significantly greater in the HP-uFSH group (p?=?0.01, p?=?0.02 and p?=?0.03, respectively). Pregnancy occurred in 23/205 cycles (11.2%) in combined metformin–CC group and 40/186 cycles (21.5%) in the HP-uFSH group; the difference was statistically significant (p?=?0.02). Two patients in the HP-uFSH group suffered mild OHSS.

Conclusions.?Combined metformin–CC resulted in modest ovulation and pregnancy rates without side effects. It is logical to offer this first for CC-resistant PCOS women before resorting to more expensive alternatives especially in developing communities where economic aspects of therapy are important.     

Ovulation induction with urinary FSH or recombinant FSH in polycystic ovary syndrome patients: a prospective randomized analysis of cost-effectiveness

The aim of this prospective, randomized trial was to compare the clinical results and the cost-effectiveness of urinary FSH (uFSH) and recombinant FSH (rFSH) in ovarian stimulation for intrauterine insemination (IUI) cycles in polycystic ovary syndrome (PCOS) patients. One-hundred and seventy PCOS infertile patients undergoing IUI were enrolled, and protocols of ovarian stimulation with uFSH or rFSH were randomly assigned. The total number of cycles performed was 379 (182 and 197, respectively). The main outcome measures were the number of mature follicles, the days of stimulation, the number of ampoules and IU used per cycle, the biochemical/clinical pregnancy rates, the number of multiple pregnancies and the cost-effectiveness. No statistically significant differences were found in the follicular development, length of stimulation, pregnancy rates, delivery rates and multiple pregnancies between the two groups. In the uFSH group, the cost per cycle remained significantly lower (218.51 +/- 88.69 versus 312.22 +/- 118.12; P < 0.0001), even though a significantly higher number of IU of gonadotrophins were used (809.3 +/- 271.9 versus 589.1 +/- 244.7; P < 0.0001). The cost-effectiveness (i. e. within a group, the total cost of all cycles divided by no. of clinical pregnancies) was 1729.08 in the uFSH group and 3075.37 in the rFSH group. In conclusion, uFSH and rFSH demonstrated the same effectiveness in ovarian stimulation in IUI cycles in PCOS patients. The urinary preparation is more cost-effective due to the difference of its cost per IU.     

Effect of luteal phase support after ovulation induction and intrauterine insemination

Objective: This study aimed to evaluate the effect of luteal phase support on clinical pregnancy and live birth rates after ovulation induction and intrauterine insemination (IUI).

Methods: 579 cycles from 2010 to 2013 were retrospectively evaluated. Ovarian stimulation was performed with gonadotropins, and rHCG was used for ovulation triggering. All patients received IUI. 451 cycles were supported by receiving vaginal micronized progesterone capsules (142 cycles) or vaginal progesterone gel (309 cycles) whereas 128 cycles were not supported.

Results: Clinical pregnancy (20.6 versus 9.4%; p?=?0.004) and live birth rates (14 versus 7%; p?=?0.036) were higher for supported group than for unsupported group. Progesterone gel and micronized progesterone subgroups achieved similar clinical pregnancy and live birth rates (21.4 versus 19%, p?=?0.567 and 14.2 versus 13.4%, p?=?0.807; respectively).

Conclusions: Luteal phase support improved the success of IUI cycles affecting both clinical pregnancy and live birth rates when gonadotropins were used for ovulation induction. The use of vaginal progesterone gel or micronized progesterone significantly improves clinical pregnancy rates. The live birth rates were higher in the progesterone gel group, but were similar in the micronized progesterone group compared to the unsupported group.     

Efficacy of laparoscopic ovarian diathermy in clomiphene citrate-resistant women with polycystic ovary syndrome: Relationships with chronological and ovarian age

Background. Laparoscopic ovarian diathermy (LOD) has been used successfully as a first-, second- and third-line treatment for ovulation induction in women with polycystic ovary syndrome (PCOS). However, little is known about the predictors for LOD efficacy. The aim of the present study was to evaluate reproductive outcomes in clomiphene citrate (CC)-resistant PCOS patients treated with LOD according to ovarian and chronological age.

Method. A total of 60 non-obese, primary infertile, CC-resistant women with PCOS were enrolled and treated with LOD. During the following 6 months, all patients underwent ovulation monitoring and timed intercourse. If spontaneous ovulation did not occur within 3 months from surgery, CC (100 mg/day) was administered for 5 days from day 3 of the remaining cycles. The ovulation, abortion and pregnancy rates were assessed and analyzed with patients categorized according to chronological age (group A, <25 years; group B, 25–30 years; group C, 30–35 years; group D, >35 years) and ovarian age (group 1, follicle stimulating hormone (FSH) < 10 mIU/ml; group 2, FSH > 10 mIU/ml).

Results. At the end of the study, total ovulation, pregnancy and abortion rates were 57.1, 13.0 and 18.2%, respectively. No difference in all reproductive outcomes was observed between groups A, B and C, whereas the efficacy of LOD was significantly lower in group D. A significant difference in all clinical endpoints was detected between groups 1 and 2.

Conclusions. Our data show that chronological age >35 years and basal FSH value > 10 mIU/ml are related to poor reproductive prognosis in CC-resistant PCOS patients treated with LOD.     

Exogenous hCG activity,but not endogenous LH activity,is positively associated with live birth rates in anovulatory infertility

Objective.?To evaluate, retrospectively, the roles of endogenous and exogenous luteinising hormone (LH) activity on live birth rate in ovulation induction cycles.

Methods.?Associations between LH activity at baseline, end of stimulation and live birth rate were analysed in relation to patient characteristics, baseline and end of stimulation variables in WHO group II anovulatory women (n?=?155) stimulated with recombinant follicle-stimulating hormone (rFSH) or highly purified human menopausal gonadotrophin (HP-hMG). HP-hMG provides FSH and exogenous LH activity mainly in the form of human chorionic gonadotrophin (hCG).

Results.?Serum LH concentrations at baseline or end of stimulation were not predictive of live birth rate in the rFSH group (n?=?79) or HP-hMG group (n?=?76). Serum hCG concentration at end of stimulation was a significant positive predictor in HP-hMG-treated women. Other variables were not independently predictive of live birth in either of the groups, except for a negative association between serum FSH concentrations at the start of stimulation and live birth in the rFSH-treated group.

Conclusions.?Endogenous LH concentrations are not predictive of live birth in anovulatory WHO group II patients undergoing ovulation induction with rFSH or HP-hMG. On the other hand, exogenous hCG activity during HP-hMG stimulation is positively associated with treatment outcome.     

Controlled ovarian hyperstimulation in women with polycystic ovarian syndrome with or without intrauterine insemination

Objective: To evaluate the value of intrauterine insemination (IUI) in controlled ovarian hyperstimulation (COH) among couples with polycystic ovary syndrome (PCOS) and normal semen analysis. Design: Retrospective cohort study Setting: University teaching center. Patients: PCOS couples with normal semen analysis that underwent COH with IUI or timed intercourse (TIC). Intervention: COH with clomiphene citrate, letrozole or gonadotropins with or without IUI. Main outcome measures: Clinical pregnancy rates. Results: Of a total 265 cycles, 151 cycles were with IUI and 114 others with TIC. No significant difference was found in the overall pregnancy rates between the TIC group (17.5%) and the IUI group (16.6%). Analysis of pregnancy rates according to the type of COH treatments did not demonstrate the advantages of IUI over TIC. Conclusion: Compared to timed intercourse, IUI does not increase the pregnancy rate in couples with PCOS and normal semen analysis treated with COH.     

Follicular Development and Hormonal Levels Following Highly Purified or Recombinant Follicle-Stimulating Hormone Administration in Ovulatory Women and WHO Group II Anovulatory Infertile Patients

Purpose: Our purpose was to compare ovarian performance and hormonal levels, after ovulation induction, in both normal ovulatory women undergoing intrauterine insemination (group 1) and World Health Organization (WHO) group II anovulatory infertile patients (group 2), using two different gonadotropin drugs. Methods: Patients (n = 20 per group) were treated during consecutive cycles, using the same stimulation protocol, with highly purified urinary FSH (HP-FSH) in the first treatment study cycle and recombinant FSH (rFSH) in the second one. Patients in group 1 were treated according to a late low-dose technique, and WHO group II anovulatory patients (group 2) received chronic low-dose FSH therapy. Results: Compared with HP-FSH, treatment with rFSH in group 2 required significantly less ampules of drug to induce follicular development but resulted in significantly higher plasma levels of estradiol and inhibin A on the day of human chorionic gonadotropin injection. No differences were found when both treatment modalities were compared in group 1. Conclusions: rFSH is more efficacious than urinary HP-FSH for ovulation induction in WHO group II anovulatory infertile patients as assessed by follicular development, hormonal levels, and the amount of FSH required.     

Anti-Müllerian hormone and antral follicle count for prediction of ovarian stimulation response in polycystic ovary syndrome

Abstract

Objective: To evaluate the ability of a combination of multiple ovarian reserve markers to predict ovarian stimulation response in polycystic ovary syndrome (PCOS).

Methods: On cycle Day 3 of 75 infertile patients with PCOS, serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and anti-Müllerian hormone (AMH) were measured, and antral follicle count (AFC) and ovarian volume (OV) were evaluated by transvaginal sonography (TVS). All patients underwent the same mild ovarian stimulation protocol using clomiphene citrate and highly purified FSH. Ovulation was monitored by TVS and confirmed by midluteal serum progesterone level.

Results: AMH, AFC, and “ovulation index” [OI, serum AMH (ng/ml)?×?bilateral AFC] were significantly lower in the ovulatory group (n?=?57, 76%) compared with the anovulatory group, whereas LH, FSH, LH/FSH ratio, and OV were not significantly different. Using receiver-operating characteristic curve analysis, the OI at a cutoff value of “85” had a sensitivity of 73.7% and a specificity of 72.2% in the prediction of ovulation, with an area under the curve of 0.733. Patients with OI?<?85 had significantly higher ovulation rate (p?<?0.001).

Conclusion: The OI, combining both AMH and AFC, is a potentially useful predictor of the outcome of ovarian stimulation in PCOS.     

Letrozole combined with low dose highly purified HMG for ovulation induction in clomiphene citrate-resistant infertile Chinese women with polycystic ovary syndrome: a prospective study

Background and aim: There are still open questions about ovulation induction in clomiphene citrate-(CC)-resistant infertile women. Especially little is known about efficacy and safety of letrozole (LTZ) combined with low-dose highly purified human menopausal gonadotropin (Hp-HMG) in women with polycystic ovary syndrome (PCOS).

Methods: Prospective, single-arm single-center trial in 200 infertile PCOS patients refractory for at least three CC-treatment cycles. Women with hyperandrogenism took Diane-35 for at least 3?months. All patients got LTZ on day 3 for 5?d in combination with Hp-HMG, starting with 75?IU from cycle day 7 and maintained for up to 3?d. The maximum dose was 150?IU. Primary end-points were ongoing and clinical pregnancy rate, secondary end-points mono-follicular development, ovulation rate, OHSS, multiple pregnancy and early pregnancy loss. Major safety end-point was the incidence of adverse events.

Results: Within 395 cycles the ongoing pregnancy rate was 28.24%, for cycles 35.23%, for patients 68%. The rate of ovulation per cycle was 97.7%, percentage of mono-follicular development 70.9%. No severe OHSS, multiple pregnancy, local or systemic side effects were seen.

Conclusions: LTZ combined with low-dose Hp-HMG is an effective and safe choice for reducing hyperstimulation and increasing pregnancy rate in CC-resistant women with PCOS.     

Efficacy of myo-inositol in the treatment of cutaneous disorders in young women with polycystic ovary syndrome

Background.?Polycystic ovary syndrome (PCOS) is the most common endocrine cause of hirsutism, acne and pattern alopecia, often characterised by ovulation disorders (usually manifested as oligo- or amenorrhea). In addition, 30–40% of women with PCOS have impaired glucose tolerance, and a defect in the insulin signalling pathway seems to be implicated in the pathogenesis of insulin resistance. For this reason, insulin-lowering medications represent novel approach in women with PCOS. The aim of this study was to evaluate the effects of myo-inositol (MYO), an isoform of inositol, belonging to the vitamin B complex, in the treatment of cutaneous disorders like hirsutism and acne.

Methods.?Fifty patients with PCOS were enrolled in the study. BMI, LH, FSH, insulin, HOMA index, androstenedione, testosterone, free testosterone, hirsutism and acne were evaluated at the baseline and after receiving MYO therapy for 6 months.

Results.?After 3 months of MYO administration, plasma LH, testosterone, free testosterone, insulin and HOMA index resulted significantly reduced; no significant changes were observed in plasma FSH and androstenedione levels. Both hirsutism and acne decreased after 6 months of therapy.

Discussion.?MYO administration is a simple and safe treatment that ameliorates the metabolic profile of patients with PCOS, reducing hirsutism and acne.     

Predictive factors for pregnancy during the first four intrauterine insemination cycles using gonadotropin

Abstract

Purpose: Although a variety of factors have been reported as affecting pregnancy rates after intrauterine insemination (IUI), there have been conflicting results on prognostic factors. This study aimed to determine predictive factors for pregnancy in patients undergoing the first four IUI cycles.

Methods: A total of 348 IUI cycles using clomiphene citrate or letrozole combined with gonadotropin, or gonadotropin only were analyzed. Baseline clinical characteristics, variables related to ovulation induction and sperm parameters were compared between pregnant (n?=?54) and non-pregnant groups (n?=?294). Logistic regression analysis was performed to identify factors that could predict a pregnancy.

Results: The overall clinical pregnancy rate was 15.5% (54/348) per cycle and 30.0% (54/180) per couple. During the first four IUI cycles, logistic regression analysis revealed that woman who were 39 years or older (OR: 0.263, 95% CI: 0.076–0.906, p?=?0.034), longer duration of infertility (OR: 0.967, 95% CI: 0.942–0.993, p?=?0.012), endometriosis (versus unexplained infertility; OR: 0.177, 95% CI: 0.040–0.775, p?=?0.022) and endometrial thickness below 7?mm (OR: 0.114, 95% CI: 0.015–0.862, p?=?0.035) were unfavorable factors to predict clinical pregnancy.

Conclusions: Women with old age, longer duration of infertility, the presence of endometriosis or thin endometrium in the preovulatory phase may have unfavorable outcomes during the first four IUI cycles.     

Valuable predictors of gestational diabetes mellitus in infertile Chinese women with polycystic ovary syndrome: a prospective cohort study

Objective: This study aimed to explore valuable preconception predictors of gestational diabetes mellitus (GDM) in PCOS patients.

Methods: A prospective cohort study enrolling infertile Chinese PCOS women treated with ovulation induction was performed. The endocrine, metabolic and physical features of all the patients were collected before pregnancy and then followed up to 6 weeks after delivery. The prevalence of GDM was determined during 24–28 gestational weeks. Logistic regression analysis and receiver operating characteristic (ROC) curves were applied to explore the risk factors and their predictive value for GDM.

Results: A total of 94 infertile PCOS women who got singleton pregnancy by ovulation induction were enrolled in the study. Logistic regression analysis showed that the preconception insulin under the curve (IAUC) and sex hormone-binding globulin (SHBG) levels were two most significant risk factors for developing GDM (p = 0.014; p = 0.042, respectively). The area of SHBG and IAUC under the ROC curve were 0.806 (p?) and 0.775 (p?=?0.001), respectively. The optimal cutoff values were failed to be calculated because of the limited group size.

Conclusions: Low SHBG level and hyperinsulinism were both strongly associated with the development of GDM and might be two valuable predictors in PCOS patients.     

Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome

Objective. To evaluate the effects the administration of myo-inositol (MYO) on hormonal parameters in a group of PCOS patients.

Design. Controlled clinical study.

Setting. PCOS patients in a clinical research environment.

Patients. 20 overweight PCOS patients were enrolled after informed consent.

Interventions. All patients underwent hormonal evaluations and an oral glucose tollerance test (OGTT) before and after 12 weeks of therapy (Group A (n = 10): myo-inositol 2 gr. plus folic acid 200 μg every day; Group B (n = 10): folic acid 200 μg every day). Ultrasound examinations and Ferriman-Gallwey score were also performed.

Main outcome measures. Plasma LH, FSH, PRL, E2, 17OHP, A, T, glucose, insulin, C peptide concentrations, BMI, HOMA index and glucose-to-insulin ratio.

Results. After 12 weeks of MYO administration plasma LH, PRL, T, insulin levels and LH/FSH resulted significantly reduced. Insulin sensitivity, expressed as glucose-to-insulin ratio and HOMA index resulted significantly improved after 12 weeks of treatment. Menstrual cyclicity was restored in all amenorrheic and oligomenorrheic subjects. No changes occurred in the patients treated with folic acid.

Conclusions. Myo-inositol administration improves reproductive axis functioning in PCOS patients reducing the hyperinsulinemic state that affects LH secretion.     

The effect of different hormone therapies on anti-müllerian hormone serum levels in anovulatory women of reproductive age

Objective.?To investigate the effect of oral contraceptives (OC), metformin and ovulation induction with gonadotropins on circulating anti-müllerian hormone (AMH).

Design.?Prospective clinical study.

Patients.?Thirty patients with PCOS (Group 1), 15 normogonadotropic anovulatory infertile women (WHO 2) (Group 2) and 15 normoovulatory control women (Group 3). Patients in Group 1 received OC (n?=?12), metformin (n?=?11) or no-treatment (n?=?7) for 6 months. Ovulation induction with FSH or hMG was used in Group 2.

Main outcome measures.?Total follicle number (TFN) and hormonal (fasting insulin and glucose, testosterone, SHBG, LH, androstenedione and AMH) measurements at baseline and during therapy.

Results.?Basal AMH and TFN were higher in Groups 1 and 2 than in controls. Only TFN was significantly related to AMH level in Groups 1 and 2. AMH level was significantly reduced during OC treatment, and there was a trend for AMH decrease during metformin therapy. No significant changes in AMH level were observed during ovulation induction. TFN was the only parameter showing a significant positive correlation with circulating AMH over the 6-month treatment period in patients in Group 2.

Conclusions.?AMH is an accurate marker of the antral follicle pool in WHO-2/PCOS women but the measurement of AMH is not likely to be helpful in the management of those patients.     

The association between follicular size at the time of spontaneous rupture and pregnancy rates in clomiphene citrate treated PCOS patients in coit cycles

Abstract

Objective: To investigate the follicular size at spontaneous rupture on pregnancy rate in patients with polycystic ovary syndrome (PCOS) undergoing clomiphene citrate (CC) ovulation.

Design: Cross-sectional study.

Patients and methods: One hundred and four women with ovulatory cycles after use of CC followed by ultrasound to determine the follicle size at the time of rupture, which was subsequently correlated with the occurrence of pregnancy or not in coit cycles.

Results: In the group of follicular rupture at a mean diameter ≤25?mm (n?=?54), pregnancy rate was 35.1% and when follicular rupture occurred at a mean diameter >25?mm (n?=?50), it was 34% (p?>?0.05). When different diameters at follicular rupture were randomly correlated with the pregnancy rate, there was no significant difference.

Conclusion: Our data suggest that the occurrence of pregnancy after ovulation induction with CC in women with PCOS is not associated with follicle size at the time of rupture.     

Luteal phase support after mild ovulation induction with intrauterine insemination: an on-going debate

Objective: To evaluate the effect of luteal phase support (LPS) using progesterone vaginal gel on pregnancy rate (PR) and live birth rate (LBR) during cycles in which controlled ovarian stimulation (COH) was performed using gonadotropins with intrauterine insemination (IUI) cycles in patients with unexplained infertility and polycystic ovarian syndrome.

Materials and methods: From 2010 to 2015, all IUI cycles in which COH was performed using gonadotropins were evaluated retrospectively. LPS was not used until July 2013, after which vaginal progesterone gel was applied in the luteal phase of IUI cycles. Both groups of patients were evaluated in terms of the effect of LPS on PR and LBR.

Results: In total, 1578 IUI cycles were evaluated, of which 481 were LPS (+) and 1097 LPS (?). PR and LBR per cycle were 10.6% and 7.4%, respectively, in the LPS (+) group, and 11.6% and 7.7%, respectively, in the LPS (?) group (p?=?0.31 and p?=?0.25). PR and LBR per patient were 17% and 12%, respectively, in the LPS (+) group, and 17.4% and 12.3%, respectively, in the LPS (?) group (p?=?0.48 and p?=?0.82).

Conclusions: We found no difference in PR and LBR per cycle and per patient according to the use of LPS in IUI cycles in which COH was performed using gonadotropins. Thus, routine use of LPS in gonadotropin-stimulated cycles requires further research involving larger numbers of patients.     

Can anti-Mullerian hormone (AMH) predict the outcome of intrauterine insemination with controlled ovarian stimulation?

Abstract

Objective: To assess whether the levels of anti-Mullerian hormone (AMH) are related to outcome of intrauterine insemination (IUI) in patients treated with gonadotropins.

Intervention(s): A total of 195 patients underwent controlled ovarian stimulation (COS) with recombinant follicle stimulating hormone (rFSH) (50–150 IU/d). All patients were submitted upto three cycles of IUI.

Outcome: Primary outcome was the ability of AMH levels to predict clinical pregnancy at first attempt and the cumulative clinical pregnancy probability of upto three IUI cycles. Secondary outcomes were the relation of AMH, LH, FSH, BMI, age, parity and basic estradiol levels with each other and the outcome of IUI.

Results: The area under the receiver operating characteristic (ROC) curve in predicting clinical pregnancy for AMH at first attempt was 0.53 and for cumulative clinical pregnancy was 0.76. AMH levels were positively correlated with clinical pregnancy rate at first attempt and with cumulative clinical pregnancy rate, but negatively correlated with patient’s age and FSH levels. Patient’s FSH, LH levels were negatively correlated with cumulative clinical pregnancy rate.

Conclusions: AMH levels seem to have a positive correlation and patient’s age and LH levels had a negative correlation with the outcome of IUI and COS with gonadotropins. AMH concentration was significantly higher and LH was significantly lower in patients with a clinical pregnancy after three cycles of IUI treatment compared with those who did not achieve pregnancy.