Ovulation In Polycystic Ovary Syndrome Patients Research Articles

Luteolin and its analog luteolin-7-methylether from Leonurus japonicus Houtt suppress aromatase-mediated estrogen biosynthesis to alleviate polycystic ovary syndrome by the inhibition of tumor progression locus 2

Ethnopharmacological relevanceLeonurus japonicus Houtt (L. japonicus, Chinese motherwort), known as Yi Mu Cao which means “good for women”, has long been widely used in China and other Asian countries to alleviate gynecological disorders, often characterized by estrogen dysregulation. It has been used for the treatment of polycystic ovary syndrome (PCOS), a common endocrine disorder in women but the underlying mechanism remains unknown. Aim of the studyThe present study was designed to investigate the effect and mechanism of flavonoid luteolin and its analog luteolin-7-methylether contained in L. japonicus on aromatase, a rate-limiting enzyme that catalyzes the conversion of androgens to estrogens and a drug target to induce ovulation in PCOS patients. Materials and methodsEstrogen biosynthesis in human ovarian granulosa cells was examined using ELISA. Western blots were used to explore the signaling pathways in the regulation of aromatase expression. Transcriptomic analysis was conducted to elucidate the potential mechanisms of action of compounds. Finally, animal models were used to assess the therapeutic potential of these compounds in PCOS. ResultsLuteolin potently inhibited estrogen biosynthesis in human ovarian granulosa cells stimulated by follicle-stimulating hormone. This effect was achieved by decreasing cAMP response element-binding protein (CREB)-mediated expression of aromatase. Mechanistically, luteolin and luteolin-7-methylether targeted tumor progression locus 2 (TPL2) to suppress mitogen-activated protein kinase 3/6 (MKK3/6)-p38 MAPK-CREB pathway signaling. Transcriptional analysis showed that these compounds regulated the expression of different genes, with the MAPK signaling pathway being the most significantly affected. Furthermore, luteolin and luteolin-7-methylether effectively alleviated the symptoms of PCOS in mice. ConclusionsThis study demonstrates a previously unrecognized role of TPL2 in estrogen biosynthesis and suggests that luteolin and luteolin-7-methylether have potential as novel therapeutic agents for the treatment of PCOS. The results provide a foundation for further development of these compounds as effective and safe therapies for women with PCOS.

Comparing the effect of sitagliptin and metformin on the oocyte and embryo quality in classic PCOS patients undergoing ICSI.

Insulin resistance plays a major role in the pathogenesis of polycystic ovary syndrome (PCOS). Therefore, there is a growing interest in the use of insulin sensitizer drugs in the treatment of PCOS. Research in recent years has shown that sitagliptin has been reported to improve ovarian cycles and ovulation in PCOS patients. We aimed to compare the effects of metformin and sitagliptin on PCOS individuals undergoing ICSI. Sixty PCOS patients were divided into 3 groups: metformin, sitagliptin, and placebo group. Treatment was carried out 2months before the start of the ovulation cycle and continued until the day of oocyte aspiration. The serum levels of total testosterone, estradiol, and fasting insulin along with the total number of retrieved, normal and abnormal MII, and fertilized oocytes, the number of transferred embryos (grades I, II and III), and biochemical and clinical pregnancy rates as well as the ovarian hyperstimulation syndrome (OHSS) were evaluated. There was a significant reduction in the serum levels of Insulin and total testosterone in the treated groups compared with the placebo. The number of mature and normal MII oocytes increased significantly in the treated groups compared with the placebo. Moreover, the number of immature oocytes decreased significantly and the number of grade I embryos increases significantly in the sitagliptin group compared with the placebo group. We conclude that sitagliptin can improve the maturation of oocytes and embryos' quality more effectively than metformin, in PCOS patients undergoing ICSI. Trial registration is NCT04268563 ( https://clinicaltrials.gov ).

Successful Natural Pregnancy Using Whole Systems Traditional Chinese Medicine in a Complex Anovulatory Patient After Multiple Unsuccessful In Vitro Fertilization Treatments: A Case Report

Background: Women who have anovulatory infertility due to polycystic ovary syndrome (PCOS) rely primarily on medical fertility treatment to conceive. If this treatment fails, the odds of success of conceiving naturally are extremely small, limited by the lack of ovulation and its unpredictability. Whole systems Traditional Chinese Medicine (WS-TCM), which includes acupuncture, Chinese herbs, nutrition and supplements, and lifestyle recommendations, has traditionally been used to prepare the body for pregnancy and to induce ovulation in PCOS patients with anovulatory infertility. Case: This case describes the treatment of a complex anovulatory PCOS patient using a WS-TCM approach to induce ovulation and produce a natural uncomplicated pregnancy after multiple rounds of in vitro fertilization with and without preimplantation genetic screening and also with and without acupuncture were unsuccessful. Results: After 9 unsuccessful frozen embryo transfers, 3 of which with genetically tested euploid embryos, this previously anovulatory patient was able to ovulate, conceive, and carry a healthy pregnancy to term. Conclusions: This case suggests that in challenging cases of infertility in the setting of PCOS, the multifaceted approach of WS-TCM may provide an alternative means to induce ovulation and increase the odds of conceiving.

Androgen upregulates NR4A1 via the TFAP2A and ETS signaling networks.

Hyperandrogenism is one of the clinical and biochemical characteristics of polycystic ovary syndrome (PCOS). Our previous studies confirmed that nuclear receptor subfamily 4 group A member 1 (NR4A1), as a differentially expressed gene in the ovaries of PCOS patients, was upregulated by increased androgen. However, the potential mechanism of NR4A1 upregulation remains unknown. To elucidate the molecular mechanisms involved in NR4A1 regulation, we cloned and characterized the promoter regions of the NR4A1 gene using a series of truncated promoter plasmids in luciferase reporter assays. We identified two unique core promoters of NR4A1 located within the +1055/+1251 and +3183/+3233 regions relative to the transcription start site. TFAP2A downregulated NR4A1 expression, while five ETS transcription factors, ETS1, ELK1, ERG, FLI1 and SPI1, could upregulate NR4A1 promoter activity in HeLa cells. Of these transcription factors, ETS1 and ELK1 were the most effective ones. Moreover, all six transcription factors were confirmed to interact directly with the NR4A1 promoter. In conclusion, this study presents the first description that TFAP2A and ETS family signaling networks are involved in the androgen-mediated transcriptional regulation of NR4A1, which contributes to the understanding of the molecular mechanisms involved in the TFAP2A-NR4A1 and ETS-NR4A1 signaling networks in PCOS.

Towards stem cell therapy of polycystic ovary syndrome (PCOS): therapeutic effect of human mesenchymal stem cells transplantation in pcos mouse model by regulating ovarian vascularization

Background & Aim Background Women with the polycystic ovarian syndrome (PCOS) have an increase in ovarian androgen production. Recent studies report that angiogenesis is aberrantly increased in ovaries of PCOS patients. Angiogenesis play an important role in inflammatory response as well as it might be promoted by inflammation as well. We have recently reported that intra-ovarian implanted human mesenchymal stem cells (hMSCs) can decrease serum androgen levels in a PCOS animal model. However, it is still unknown how hMSCs exert its effect on PCOS ovary. The hMSCs are well known regulator of inflammatory response and angiogenesis. These abilities of hMSCs could be strong candidate to explain the mechanism of how they reverse the phenotype of PCOS. Hypothesis We hypothesis that hMSCs can reverse PCOS ovary into normal phenotype by regulating inflammatory response and blood vessel formation. Methods, Results & Conclusion Material and Method In this study, we induced PCOS in C57/BL6 mice by daily Letrozole from week 4 to week 9 of age. We then engrafted hMSCs (500,000 cells/ovary) by direct intra-ovarian injection. 2 weeks later, we sacrificed the mice and collected the ovaries to analyze the inflammatory markers IL-6, IL-1α, the angiogenesis markers VEGFA, ANGPT1, and the blood vessels markers αSMA, vWF by PCR, immunohistochemistry and western blot examination. Result Implantation of hMSCs significantly suppressed the levels of IL-6 and IL-1α (P Conclusion Our data reveal that ovary of letrozole induced PCOS mouse showed increased inflammation and angiogenesis compared to healthy controls. This alteration can be reversed by intra-ovarian hMSCs transplantation. Our study showed that hMSCs injection in PCOS ovaries can normalize inflammatory status and angiogenesis and may present a novel treatment modality for PCOS patients.

Wilms’ Tumor 1 Overexpression in Granulosa Cells Is Associated with Polycystic Ovaries in Polycystic Ovary Syndrome Patients

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by chronic ovulatory dysfunction, hyperandrogenism, and polycystic ovaries. Wilms’ tumor 1 (WT1) encoding a transcription factor involved in the differentiation of granulosa cells (GCs) regulates androgen receptor in the development of male genitalia. However, the expression pattern and possible role of WT1 in ovaries of PCOS patients are still unknown. Methods: GCs from 95 PCOS patients (PCOS group) and 62 healthy controls (control group) were isolated. The expression of WT1 in GCs was quantified using the reverse transcription-polymerase chain reaction. The correlation between WT1 expression and clinical characteristics was evaluated in PCOS patients. Results: WT1 expression was increased in PCOS patients compared with the normal controls. The expression of WT1 was moderately correlated with testosterone (r = 0.334, p = 0.001) and luteinizing hormone (r = 0.357, p = 0.001) levels and the antral follicle counts (r = 0.337, p = 0.001). Conclusions: Our study provided novel insights into the relationship between hyperandrogenism and polycystic ovaries of PCOS and WT1.

N-acetyl cysteine in ovulation induction of PCOS women underwent intrauterine insemination: An RCT

N-acetyl cysteine (NAC) was proposed as an adjuvant to clomiphene citrate for ovulation induction in patients with polycystic ovary syndrome (PCOS) without clomiphene citrate resistance. To evaluate the effect of NAC on pregnancy rate in PCOS patients who were candidates for intrauterine insemination. In this randomized clinical trial, 97 PCOS women aged 18-38 years were enrolled in two groups, randomly. For the case group (n=49), NAC (1.2 gr)+ clomiphene citrate (100 mg) + letrozole (5mg) were prescribed daily from the third day of menstruation cycle for five days. The control group (n=48) had the same drug regimen without NAC. In order to follicular development, recombinant human follicle stimulating hormone (r-hFSH; Gonal-F®) was injected on days of 7-11 menstrual cycles in all participants. When the follicle size was 18mm or more, 10000 IU human chorionic gonadotropin was injected intramuscular and the intrauterine insemination was performed after 34-36 hr. There were not significant differences between study groups regarding mean endometrial thickness (p=0.14), the mean number of mature follicles (p=0.20), and the pregnancy rate (p=0.09). NAC is ineffective in inducing or augmenting ovulation in PCOS patients who were candidates for intrauterine insemination and cannot be recommended as an adjuvant to CC in such patients.

Primum Non Nocere.

Surgical ovarian wedge resection was the first established treatment for women with anovulatory polycystic ovary syndrome (PCOS) but was largely abandoned both due to the risk of postsurgical adhesions and the introduction of medical ovulation induction. Laparoscopic ovarian drilling (LOD) is an alternative method to induce ovulation in PCOS patients with clomiphene citrate resistance instead of gonadotropins. Surgical therapy with LOD may avoid or reduce the need for gonadotropins or may facilitate their use. However, the procedure, though effective, can be traumatic on the ovaries, which may cause postoperative adhesions and/or diminished ovarian reserve. In over-enthusiastic hands, this day-care procedure might lead to iatrogenic premature ovarian failure in young women. Some trials have compared LOD with gonadotropins, but, because of variations in study design and small sample size, the results are inconsistent and definitive conclusions about the relative efficacy of LOD and gonadotropins cannot be extracted from the individual studies. Today, evidence-based reviews conclude that there is no evidence of a significant difference in rates of clinical pregnancy, live birth or miscarriage in women with clomiphene-resistant PCOS undergoing LOD compared to other medical treatments. The reduction in multiple pregnancy rates in women undergoing LOD is the only pro-LOD argument. However, there are ongoing serious concerns about the long-term effects of LOD on ovarian function.

Intraindividual right–left comparison of sonographic features in polycystic ovary syndrome (PCOS) diagnosis

ObjectiveSonographic features of polycystic ovaries consist of elevated antral follicle count or ovarian volume of at least one ovary. The aim of this prospective cross-sectional study was to estimate intraindividual differences in sonographic measurements between the both ovaries of PCOS patients and controls and clinical consequences. Study designBoth ovaries of 85 PCOS patients and 48 controls were scanned transvaginally and agreement of sonographic measurements was analyzed using the Bland–Altman method. Concordance correlation coefficients (CCC) were computed. ResultsMean differences between right and left ovaries were 0.24 (95% confidence interval [95% CI]: −0.32–0.80) follicles for AFC and 1.14 (95% CI: 0.34–1.92)ml for OV in the whole study population, 0.14 (95% CI: −0.68–0.96) follicles for AFC and 1.48 (95% CI: 0.39–2.58)ml for OV in PCOS patients, 0.42 (95% CI: −0.19–1.02) follicles for AFC and 0.53 (95% CI: −0.50–1.56)ml for OV in controls. Rather wide limits of agreement and low CCCs (<0.7 for all estimates) indicated poor agreement between the ovaries for both sonographic measurements. Width between lower and upper limits of agreement was higher for PCOS patients than for controls. 23.5% of the PCOS patients showed polycystic ovarian morphology (PCOM) only in one ovary, resulting in 9.4% potentially missed PCOS diagnosis according to the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. ConclusionSubstantial differences in antral follicle count and ovarian volume between the right and left ovary were observed. In approximately 10% of the PCOS patients in our study only the examination of both ovaries has led to a reliable diagnosis of PCOS. In clinical practice it is recommended to scan both ovaries for a reliable diagnosis of abnormal sonographic findings in PCOM and PCOS diagnosis.

Brachial-to-ankle pulse wave velocity as an independent prognostic factor for ovulatory response to clomiphene citrate in women with polycystic ovary syndrome.

BackgroundPolycystic ovary syndrome (PCOS) has a risk for cardiovascular disease. Increased arterial stiffness has been observed in women with PCOS. The purpose of the present study was to investigate whether the brachial-to-ankle pulse wave velocity (baPWV) is a prognostic factor for ovulatory response to clomiphene citrate (CC) in women with PCOS.MethodsThis study was a retrospective cohort study of 62 women with PCOS conducted from January 2009 to December 2012 at the university hospital, Yamagata, Japan. We analyzed 62 infertile PCOS patients who received CC. Ovulation was induced by 100 mg CC for 5 days. CC non-responder was defined as failure to ovulate for at least 2 consecutive CC-treatment cycles. The endocrine, metabolic, and cardiovascular parameters between CC responder (38 patients) and non-responder (24 patients) groups were analyzed.ResultsIn univariate analysis, waist-to-hip ratio, level of free testosterone, percentages of patients with dyslipidemia, impaired glucose tolerance, and diabetes mellitus, blood glucose and insulin levels at 60 min and 120 min, the area under the curve of glucose and insulin after 75-g oral glucose intolerance test, and baPWV were significantly higher in CC non-responders compared with responders. In multivariate logistic regression analysis, both waist-to-hip ratio (odds ratio, 1.77; 95% confidence interval, 2.2–14.1; P = 0.04) and baPWV (odds ratio, 1.71; 95% confidence interval, 1.1–2.8; P = 0.03) were independent predictors of ovulation induction by CC in PCOS patients. The predictive values of waist-to-hip ratio and baPWV for the CC resistance in PCOS patients were determined by the receiver operating characteristic curves. The area under the curves for waist-to-hip ratio and baPWV were 0.76 and 0.77, respectively. Setting the threshold at 0.83 for waist-to-hip ratio offered the best compromise between specificity (0.65) and sensitivity (0.84), while the setting the threshold at 1,182 cm/s for baPWV offered the best compromise between specificity (0.80) and sensitivity (0.71).ConclusionsBoth metabolic and cardiovascular parameters were predictive for CC resistance in PCOS patients. The measurement of baPWV may be a useful tool to predict ovulation in PCOS patients who receive CC.

Polycystic Ovary Syndrome: Fertility Management

Polycystic ovary syndrome (PCOS) is characterized by a series of symptoms, including oligomenorrhea or amenorrhea anovulation or infertility; it is associated with insulin resistance and compensatory hyperinsulinemia. Several treatment options are available for women with anovulatory infertility related to PCOS. Clomiphene citrate (CC) is the first-choice for induction of ovulation in PCOS patients. Laparoscopic ovarian drilling (LOD) or gonadotropin ovarian stimulation can be offered after failure of CC to achieve pregnancy. Hyperinsulinemia related to PCOS can be corrected by weight loss or insulin-sensitizing agents, such as metformin, which alone or in combination with other agents are capable of restoring ovulation. Only very limited clinical data are available on the use of letrozole at present, so letrozole cannot be recommended for routine use in ovulation induction. When all treatments fail, in vitro fertilization and embryo transfer (IVF/ET) can be tried and can have excellent results. Many treatment options available today ensure that the majority of women who are subfertile due to PCOS can be treated successfully.

Maitake Mushroom (Grifola frondosa) Extract Induces Ovulation in Patients with Polycystic Ovary Syndrome: A Possible Monotherapy and a Combination Therapy After Failure with First-Line Clomiphene Citrate

Insulin resistance is a prominent feature of polycystic ovary syndrome (PCOS), and insulin-sensitizing drugs are used to induce ovulation. Recently, it was reported that an extract from Maitake mushroom (Grifola frondosa) improves insulin resistance. The objective was to explore the effects of Maitake extract (SX-fraction: MSX) to induce ovulation in patients with PCOS in comparison with and in combination with clomiphene citrate (CC). We conducted an open trial with 80 patients with PCOS at three clinics in Japan. Seventy-two (72) new patients were randomly assigned to receive MSX or CC monotherapy for up to 12 weeks. Eighteen (18) patients who did not respond to MSX or CC were subjected to combination therapy of MSX and CC for up to 16 weeks. Eight (8) patients with documented history of failure to CC received combination therapy from the beginning. Ovulation was assessed by ultrasonography. Twenty-six (26) patients in the MSX group and 31 in the CC group were evaluated for ovulation. The ovulation rates for MSX and CC were as follows: 76.9% (20/26) and 93.5% (29/31), respectively by the patients (NS), and 41.7% (30/72) and 69.9% (58/83), respectively, by the cycles (p = 0.0006). In the combination therapy, 7 of 7 patients who failed in MSX monotherapy and 6 of 8 patients who failed in CC monotherapy showed ovulation. The present study suggests that MSX alone may induce ovulation in PCOS patients and may be useful as an adjunct therapy for patients who failed first-line CC treatment.

Ovulation Induction in Anovulatory Patients with Polycystic Ovary Syndrome

Ovarian dysfunction is probably the pivotal feature of polycystic ovary syndrome (PCOS) making this syndrome a major cause of anovulatory infertility in developed countries. Several approaches have been proposed to induce ovulation in PCOS patients. Notwithstanding lifestyle modifications, clomiphene citrate, surgery and, finally, gonadotropins are the classical and still effective therapeutic options. New drugs, such as metformin and aromatase inhibitors are today available in the treatment of anovulation related to PCOS. The aim of the present review is to describe all therapeutic approaches to the anovulatory PCOS patients.

Letrozole for Induction of Ovulation in PCOS Patients: Resistant to Clomiphene Citrate

ABSTRACT Objective To assess the efficacy of aromatase inhibitor letrozole for induction of ovulation in anovulatory polycystic ovary syndrome (PCOS) patients in whom clomiphene citrate (CC) treatment was unsuccessful. Design Prospective, nonrandomized, interventional, crossover trial, using anovulatory PCOS infertile patients previously treated with clomiphene citrate as their own historic controls. Setting Center for Assisted Reproduction (CARE), Department of Obstetrics and Gynecology, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka, Bangladesh. Patients 60 anovulatory PCOS infertile patients who received 150 mg of clomiphene citrate for at least 4 cycles on days 2 to 6 of the cycle with an unsatisfactory outcome (No mature follicle and/or endometrial thickness of equal or less than 0.7 cm) were the target population. Intervention 5.0 to 7.5 mg of letrozole was given orally on days 2 to 6 of the cycle. Main outcome measures: Number and size of mature follicles, endometrial thickness and occurrence of ovulation. Results There was a statistically significant increase in the follicular size and endometrial thickness after the administration of letrozole. Ovulation occurred in 38 patients (63.33%) in the letrozole treated cycles. Most of developed follicles (68.42%-26 patients) were multiple and majority patients (63.16%) responded to the higher 7.5 mg dose. Conclusion Oral administration of letrozole is an effective agent for ovulation induction in clomiphene citrate resistant PCOS patients.

Polycystic Ovary Syndrome—Increased or Preserved Ovarian Sensitivity to Insulin?

I HAS BEEN proposed recently that polycystic ovary syndrome (PCOS) develops as a result of increased ovarian sensitivity to insulin (1). Although there is evidence to support the notion of preserved ovarian sensitivity to insulin in the ovaries of patients with PCOS, in my view the evidence for increased ovarian sensitivity in such ovaries is lacking. The three main pieces of evidence advanced in favor of the hypothesis proposing increased ovarian sensitivity to insulin in PCOS patients are as follows: first, ovarian cells from patients with PCOS produce higher amounts of androgens in response to stimulation by insulin than ovarian cells from patients without PCOS; second, not all patients with PCOS are insulin resistant or hyperinsulinemic; and third, treatment with insulin-sensitizing agents reduces ovarian androgen synthesis, even in those patients whose circulating insulin levels change only modestly with administration of these medications (1). In regard to the first observation, it is important to remember that ovarian cells from patients with PCOS produce larger-than-normal amounts of androgens not only in response to insulin but also regardless of the stimulus used (2). Therefore, the larger-than-normal production of androgens in response to insulin in cultured ovarian cells from patients with PCOS is likely to be a consequence of the presence of PCOS, rather than a primary defect that precedes the development of PCOS. Further arguing against the presence of increased sensitivity to insulin in the ovaries of PCOS patients are the studies in obese children (3) and PCOS patients (4 and reviewed in Ref. 5), which demonstrated that serum androgen levels normalize after weight loss. Additionally, studies of granulosa cells from PCOS patients revealed no difference in their steroidogenic response to insulin, compared with the granulosa cells from the normal ovaries, and abnormalities of glucose uptake in the granulosa cells from PCOS patients were demonstrated only in the presence of supraphysiological concentrations of insulin (100 or 1000 ng/ml) (6). Insulin, particularly if present in high concentrations, stimulates not only ovarian androgen production but also synthesis of estrogens and progesterone, affects a variety of steroidogenic enzymes, inhibits production of IGF binding protein (IGFBP)-1, up-regulates ovarian IGF-I binding, promotes ovarian growth and cyst formation, stimulates theca cell proliferation, and enhances ovulation (reviewed in Ref. 7). It seems unlikely that increased sensitivity to insulin in the ovary would affect only one of its multiple effects, namely androgen synthesis. Besides, to describe a state of increased ovarian sensitivity to insulin, one would need to define normal ovarian sensitivity to insulin for each of its effects in the ovary, a task that has not yet been accomplished. In regard to the second point, the lack of insulin resistance in many nonobese PCOS patients (8), who comprise up to 50% of PCOS population (reviewed in Ref. 5), does not necessarily imply increased ovarian sensitivity to insulin in these patients but may be interpreted rather as evidence against significant involvement of insulin in the pathogenesis of PCOS in individuals who are not insulin resistant. Furthermore, insulin hypersecretion may be present even in those PCOS patients who are not insulin resistant (8), once again arguing against increased ovarian sensitivity to insulin. Finally, in regard to the third point, it is important to remember that the insulin-sensitizing agents used for the treatment of PCOS exhibit a variety of direct ovarian effects, both insulin independent and insulin sensitizing (9). Thiazolidinediones, for example, directly inhibit ovarian androgen production in human ovarian cells in the absence of insulin (9). In addition, insulin-sensitizing agents elicit a variety of nonovarian effects. For instance, because SHBG production in the liver is under inhibitory control by insulin (reviewed in Ref. 7), serum SHBG levels rise with thiazolidinedione administration and a fall in circulating free androgen levels follows (10). But as mentioned above, ovarian androgen production is inhibited by thiazolidinediones directly as well (9). Therefore, when one tries to analyze the causes of a reduction in free testosterone levels observed in vivo with thiazolidinedione administration, it is necessary to take into account contributions of both direct (ovarian) and indirect (SHBG-related action in the liver) effects of thiazolidinediones on serum testosterone. Thus, serum androgen responses to insulin-sensitizing agents do not necessarily reflect the state of ovarian insulin sensitivity. For these reasons it may be premature to postulate either global or effect-specific increased sensitivity to insulin in the ovaries of patients with PCOS. On the other hand, there is significant evidence for the hypothesis proposing preserved ovarian insulin sensitivity in patients with PCOS who exhibit systemic insulin resistance (reviewed in Ref. 11). This hyFirst Published Online May 9, 2006 Abbreviations: IGFBP, IGF binding protein; PCOS, polycystic ovary syndrome.

Ovulation Induction in Anovulatory Patients with Polycystic Ovary Syndrome

Ovarian dysfunction is probably the pivotal feature of polycystic ovary syndrome (PCOS) making this syndrome a major cause of anovulatory infertility in developed countries. Several approaches have been proposed to induce ovulation in PCOS patients. Notwithstanding lifestyle modifications, clomiphene citrate, surgery and, finally, gonadotropins are the classical and still effective therapeutic options. New drugs, such as metformin and aromatase inhibitors are today available in the treatment of anovulation related to PCOS. The aim of the present review is to describe all therapeutic approaches to the anovulatory PCOS patients.

Position of alternatives: insulin sensitizers and others

The association between the polycystic ovary syndrome (PCOS) and insulin resistance has led to the use of insulin-sensitizing drugs to induce ovulations. Metformin was shown to lower insulin levels effectively, and metformin alone, as well as in combination with clomiphene citrate (CC), has been shown to enhance ovulation in PCOS patients. However, insulin-sensitizing medications have considerable side-effects, and lifestyle improvements (weight reduction and increased exercise) should be considered as first-line treatments in overweight women with PCOS. At present, metformin may best be used as an adjuvant therapy in CC-refractory PCOS patients.

Is ovulation induction still a therapeutic problem in patients with polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases affecting women of fertile age, and is characterized by hyperandrogenism, chronic anovulatory cycles and oligomenorrhea or amenorrhea. Given the repercussions of chronic anovulation on sterility, PCOS is a heavy social burden. Here we describe the procedures used to induce ovulation in PCOS patients, the surgical approach and medical treatments that are still being experimented.

Surgical or medical treatment of polycystic ovary syndrome: a cost–benefit analysis

With the availability of laparoscopic ovarian cautery, there has been a resurgence in interest in the surgical treatment of clomiphene citrate-resistant polycystic ovary syndrome (PCOS). Comparison of ovulationand pregnancy rates has found no difference in success rates between ovarian cautery and gonadotropin ovulation induction for such women. We have therefore compared the cost of laparoscopic ovarian cauterywith that of a typical cycle of gonadotropin ovulation induction, and also found that there is little difference. Because of the potential advantages of ovarian cautery, we recommend this surgery as thenext line of treatment if clomiphene citrate fails to induce ovulation in PCOS patients, before gonadotropins are introduced.