Ovarian Tissue Cryopreservation versus Other Fertility Techniques for Chemoradiation-Induced Premature Ovarian Insufficiency in Women: A Systematic Review and Future Directions.

Current advances in cancer therapy have increased survival, emphasizing the need for life quality improvement. Fertility loss is common post-chemotherapy. Current guidelines establish embryo and oocyte cryopreservation to address premature ovarian insufficiency (POI). Ovarian tissue cryopreservation has also recently become an acceptable option for fertility preservation, particularly as it is the only option for pre-pubertal patients. Few definitions for optimum fertility outcomes, and few systematic reviews comparing embryo, oocyte, and ovarian tissue cryopreservation as a means of fertility preservation (FP) in pre- and post-pubertal female cancer patients exist. This systematic review aims to improve understanding of gonadotoxic effects of chemoradiation therapy in cancer patients, to analyze the different fertility preservation techniques and procedures available to women with chemoradiation induced ovarian insufficiency, and to compare and recognize the benefits of each technique in restoring fertility, sexual hormone function, and quality of life. Searches were conducted electronically on PubMed, Cochrane, and EBSCOHost, including clinical trials, prospective, and retrospective studies of female cancer patients undergoing anti-cancer therapy, with predefined MeSH terminology. Data were collected, analyzed, and compared. Non-randomized clinical studies were evaluated for risk bias through the Newcastle-Ottawa Scale. In total, 23 studies were included. From there, 647 patients opted for oocyte cryopreservation, 267 for embryo cryopreservation, and 1382 for ovarian tissue cryopreservation (OTC). A total of 175, 18, and 121 live births resulted respectively from oocyte, embryo, and OTC, respectively. Studies without live births discussed other fertility markers as indicators of improvement in sexual hormone function and fertility. The gonadotoxic effects of chemotherapy call for FP intervention. Oocyte and embryo cryopreservation/implantation are well-established procedures. With changing trends and life quality consideration, OTC is a promising interventional method for pre-pubertal patients facing the prospect of fertility loss.

Are There Any Developments in the Attitudes and Practices of Oncologists Regarding Fertility Preservation in Saudi Arabia After 12 Years?

INTRODUCTION: The current practice of offering fertility preservation (FP) counseling and treatment has become one of the focal points in patient care throughout cancer treatment. The turning point was the approval of the Council of Senior Religious Scholars four years ago to freeze tissues from the ovarian membrane, the entire ovary, and the eggs for later use in reproduction to preserve the offspring. Thus, we aimed to assess any development in oncologists' knowledge, attitude, and referral practices regarding FP in Saudi Arabia. METHODS: This is a cross-sectional survey using a self-administered questionnaire. We assessed oncologists' opinions on the importance of FP, their perception of the patient's preferences, and factors to consider when discussing the subject. Then, we assessed the knowledge and referral practices, including the timing of referral before starting cancer treatment. RESULTS: Most oncologists showed good knowledge and positive attitudes toward FP; however, their referral practices could be better. Most were familiar with FP options. The most significant factors influencing the oncologist-patient FP discussion were the number of existing children, marital status, cost, and type of cancer (96.6%, 76.7%, 65.7%, and 58.9%, respectively). CONCLUSIONS: There is a significant improvement in the knowledge and attitude of oncologists toward FP. However, patients' counseling and referral to fertility services still need to be improved. There is a shortfall in the clinical practice guidelines for FP in cancer patients in Saudi Arabia. The implementation of clinical practice guidelines would enhance FP. However, patients' counseling and referral to fertility services still need to be improved. The lack of proper guidelines on FP is affecting oncologists' practice.

Global Transcriptional Profiling of Granulosa Cells from Polycystic Ovary Syndrome Patients: Comparative Analyses of Patients with or without History of Ovarian Hyperstimulation Syndrome Reveals Distinct Biomarkers and Pathways.

Ovarian hyperstimulation syndrome (OHSS) is often a complication of polycystic ovarian syndrome (PCOS), the most frequent disorder of the endocrine system, which affects women in their reproductive years. The etiology of OHSS is multifactorial, though the factors involved are not apparent. In an attempt to unveil the molecular basis of OHSS, we conducted transcriptome analysis of total RNA extracted from granulosa cells from PCOS patients with a history of OHSS (n = 6) and compared them to those with no history of OHSS (n = 18). We identified 59 significantly dysregulated genes (48 down-regulated, 11 up-regulated) in the PCOS with OHSS group compared to the PCOS without OHSS group (p-value < 0.01, fold change >1.5). Functional, pathway and network analyses revealed genes involved in cellular development, inflammatory and immune response, cellular growth and proliferation (including DCN, VIM, LIFR, GRN, IL33, INSR, KLF2, FOXO1, VEGF, RDX, PLCL1, PAPPA, and ZFP36), and significant alterations in the PPAR, IL6, IL10, JAK/STAT and NF-κB signaling pathways. Array findings were validated using quantitative RT-PCR. To the best of our knowledge, this is the largest cohort of Saudi PCOS cases (with or without OHSS) to date that was analyzed using a transcriptomic approach. Our data demonstrate alterations in various gene networks and pathways that may be involved in the pathophysiology of OHSS. Further studies are warranted to confirm the findings.

Recurrent spontaneous oocyte activation causes female infertility.

PURPOSE: Spontaneous oocyte activation (SOA) is a recently classified phenomenon characterized by the presence of a single pronucleus immediately following oocyte retrieval, without the apparent involvement of sperm. SOA currently remains poorly understood in humans, with no clear genetic or pathological factor(s). Herein, we report two separate cases of recurrent spontaneous oocyte activation, investigating potential avenues to identify causative etiology. METHODS: Two patients with several cycles with SOA have undergone further genetic and embryologic investigation to reveal underlying causes for SOA and provide a treatment if possible. RESULTS: One case was a patient with recurrent pregnancy loss and the other was diagnosed as unexplained infertility. In the first case, 61 out of 69 oocytes retrieved exhibited SOA in five cycles while in the second case 44 out of 49 oocytes exhibited SOA in five cycles. Oocytes were injected with sperm; embryo development and presence of paternal contribution were investigated. No pregnancy is ensued following embryo transfer in both patients. Time-lapse imaging of embryogenesis from the second case did not reveal even momentary second pronucleus appearance. We also performed clinical whole exome sequencing for both patients but did not identify any disease-causing variant. CONCLUSION: Patients with SOA suffer from infertility. Our results indicate that more investigation is required to understand the etiology of SOA in humans concentrating on the molecular mechanisms that underpin regulation of oocyte activation and calcium dynamics need to be investigated to fully understand, and perhaps in the future rectify, recurrent SOA.

The Diagnostic Value of New Additional Antiphospholipid Antibodies in Antiphospholipid Syndrome.

BACKGROUND: The antiphospholipid syndrome (APS) is an autoimmune disease that is characterized by thrombosis and/or pregnancy failure and associated with the presence of all or at least one of three standard antibodies (anti-phospholipid (aPL) antibodies, including lupus anticoagulant (LA), anti-cardiolipin (aCL), and anti-ß2-glycoprotein I (anti-ß2GPI)). A growing body of evidence recommends adding additional aPL antibodies, such as anti-phosphatidylserine (aPS), anti-prothrombin (aPT), and anti-annexin A5 (aAA5), to conventional laboratory tests (revised Sapporo criteria), especially in seronegative APS cases. OBJECTIVES: We aimed to compare the diagnostic value, utility, and performance of these three additional antibodies along with the standard aPL antibodies in cases with confirmed and non-criteria APS (seronegative). METHODS: This was a prospective observational study on 59 patients who presented with clinical features of APS at the hematology, medical, rheumatology, and obstetric clinics. LA was detected by standard coagulation tests, while other aPL, IgG, and IgM antibodies (aCL, aß2GPI, aPS, aPT, aAA5) were detected with enzyme-linked immunosorbent assay (ELISA). RESULTS: Anti-PS antibody was more frequent compared to aPT and aAA5 in both confirmed cases (84.6%) and non-criteria (seronegative) (15.4%) APS. As a single test, the aPS antibody was significantly better (P<0.05) than the aPT and aAA5 antibodies in the detection of APS cases. Seven non-criteria patients were confirmed using additional aPL antibodies. Among these patients, four, two, and one patient was confirmed with aPS, aPT, and aAA5 antibodies, respectively. CONCLUSION: Our data support the findings of previously published studies and attribute the clinical significance of additional aPL antibodies, particularly aPS, in identifying non-criteria APS cases. In the future, along with conventional aPL antibodies, these additional antibodies should be included as standard laboratory tests in the revised Sapporo criteria.

A genomics approach to females with infertility and recurrent pregnancy loss.

Infertility affects 10% of reproductive-age women and is extremely heterogeneous in etiology. The genetic contribution to female infertility is incompletely understood, and involves chromosomal and single-gene defects. Our aim in this study is to decipher single-gene causes in infertile women in whom endocrinological, anatomical, and chromosomal causes have been excluded. Our cohort comprises women with recurrent pregnancy loss and no offspring from spontaneous pregnancies (RPL, n = 61) and those who never achieved clinical pregnancy and were referred for in vitro fertilization [primary infertility (PI), n = 14]. Whole-exome sequencing revealed candidate variants in 14, which represents 43% of those with PI and 13% of those with RPL. These include variants in previously established female infertility-related genes (TLE6, NLRP7, FSHR, and ZP1) as well as genes with only tentative links in the literature (NLRP5). Candidate variants in genes linked to primary ciliary dyskinesia (DNAH11 and CCNO) were identified in individuals with and without systemic features of the disease. We also identified variants in genes not previously linked to female infertility. These include one homozygous variant each in CCDC68, CBX3, CENPH, PABPC1L, PIF1, PLK1, and REXO4, which we propose as candidate genes for infertility based on their established biology or compatible animal models. Our study expands the contribution of single genes to the etiology of PI and RPL, improves the precision of disease classification at the molecular level, and offers the potential for future treatment and development of human genetics-inspired fertility regulators.

Description of cytogenetic abnormalities and the pregnancy outcomes of couples with recurrent pregnancy loss in a tertiary-care center in Saudi Arabia.

OBJECTIVES: To determine the prevalence of chromosomal abnormalities in couples with recurrent pregnancy loss (RPL), to determine other factors that may be associated with the chromosomal abnormalities, and to assess the outcomes of couples who had undergone multidisciplinary interventions according to associated etiological factors. METHODS: This retrospective cohort study involved 1074 couples who attended RPL clinic during an 11-year period from January 2006 to December 2016 at a single center, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. All of the couples had undergone complete RPL evaluations and were closely monitored and managed during pregnancy. RESULTS: Out of the 1074 couples, 77 (7.2%) carried some form of chromosomal abnormality, and the female (48, 62.3%) patients were affected more frequently than the male (29, 37.3%) patients. Out of the 77 cases with chromosomal abnormalities, 46.8% had reciprocal translocations, 10.3% had Robertsonian translocations, and 3.9% had complex structural abnormalities. Inversions had occurred in 14.3% and chromosomal additions had occurred in 2.6% of the patients. Isolated chromosomal abnormalities were detected in 25 out of 77 (32.5%) couples. The couples were closely followed, and 67% of the subsequent pregnancies resulted in live births. CONCLUSION: This study's findings provide an insight into the prevalence of chromosomal abnormalities in couples with RPL in our region and the factors that may be associated with RPL. This information will help to ensure the required resources are provided to care for these patients.

Intramuscular progesterone (Gestone) versus vaginal progesterone suppository (Cyclogest) for luteal phase support in cycles of in vitro fertilization-embryo transfer: patient preference and drug efficacy.

BACKGROUND: The requirement for luteal phase support (LPS) in stimulated IVF cycles is well established, however drug choice, and route of administration and duration of use are not. This report evaluates patients' preference and satisfaction by using either vaginal or intramuscular (IM) progesterone (P) supplementation for luteal phase support after in vitro fertilization and embryo transfer (IVF-ET). METHODS: It is a prospective cohort study done in a reproductive and infertility unit in a tertiary care hospital from March 2013 through February 2015 for four hundred and nine patients undergoing IVF-ET. Patients were allowed to choose either vaginal or IM P for LPS. Patient preference and satisfaction, as well as differences in clinical pregnancy rates between the two groups were assessed at one or two time points throughout the study. RESULTS: There were no statistically significant differences in the patients' characteristics and clinical outcomes between the two groups. There were 88 pregnancies (38.8%) among patients treated with vaginal p and 62 pregnancies (34%) among IM P patients. Average satisfaction score at the pregnancy test and ultrasound (U/S) visits was similar between both groups. CONCLUSIONS: Patients' satisfaction and pregnancy rates were similar between vaginal and IM P supplementation.

Hepatitis B and C virus prevalence in couples attending an in vitro fertilization clinic in a tertiary care hospital in Saudi Arabia: comparison with ten years earlier.

BACKGROUND: Viral hepatitis B (HBV) and C (HCV) are a major public health problem in Saudi Arabia. Recent data has indicated a major reduction in viral hepatitis prevalence in Saudi population. However, there is limited data for infertile Saudi couples. OBJECTIVES: To determine the prevalence of HCV and HBV attending an in vitro fertilization (IVF) clinic in Saudi Arabia between 2012 and 2015 to compare with the prevalence 10 years earlier in the same center. DESIGN: Retrospective prevalence study. SETTING: Tertiary care center in Riyadh. PATIENTS AND METHODS: Data on the prevalence of HBV and HCV was collected on all couples seen at the IVF unit between 2002-2005 and 2012-2015. MAIN OUTCOME MEASURE(S): Prevalence of HBV and HCV. RESULTS: In 4442 patients during 2002-2005 and 5747 patients during 2012-2015, the prevalence of HBV was significantly less in 2012-2015 compared with 2002-2005 (1.67% [97 patients] vs 4.7% [210 patients], P < .0001), respectively, but HCV prevalence was similar for the two periods (0.7% for both periods) (P=.887). The hepatitis B seroprevalence rate was higher in males compared to females during 2002-2005 (6.3% vs 3.1%) (P < .0001) and 2012-2015 (2.4% vs 1.1% ) (P < .0001), respectively. CONCLUSION: The significant drop in HBV prevalence was most likely due to the introduction of the vaccination program in 1989, while reasons for HCV prevalence remaining unchanged are unclear. LIMITATION: No data on confounding factors that may have affected the prevalence.

Association of blood groups with ovarian reserve and outcome of in vitro fertilization treatment.

BACKGROUND: The association between ABO blood groups and ovarian reserve in infertile patients has been a point of controversy. OBJECTIVES: The aim of this study was to assess the correlation of certain blood groups with ovarian reserve and response to treatment in patients undergoing infertility treatment. DESIGN: Retrospective medical record review. SETTING: Infertility clinic in the assisted reproductive technology (ART) unit at King Faisal Specialist Hospital and Research Center, Riyadh Saudi Arabia. PATIENTS AND METHODS: All patients under 40 years of age who attended the infertility clinic at a tertiary care centre in 2010 and underwent in vitro fertilization (IVF) treatment in 2010 and 2011 were divided into groups according to blood type, and clinical parameters were compared. MAIN OUTCOME MEASURE(S): The association between blood groups and ovarian reserve using day 3 luteinzing hormone (LH) and follicular stimulating hormone (FSH) levels, and antral follical count (AFC). RESULTS: In 424 patients who underwent 566 IVF cycles, age, LH, FSH and AFC were similar among the different blood groups (P=.9, .1, .5, respectively). with controlled ovarian stimulation, no difference was observed among the four groups in menopausal gonadotrophin (hMG) dose or the duration of stimulation. The number of oocytes retrieved, fertilization rate, cleavage rate, and number of embryos transferred were similar. There was no difference in the cancellation rate or pregnancy rate among the groups. CONCLUSION: There was no significant association between blood type and ovarian reserve or response during IVF treatment in our population. LIMITATIONS: Anti-Mullerian hormone levels are best correlated with ovarian reserve testing. Unavailability of AMH levels. Retrospective design.

Gene expression profiling of granulosa cells from PCOS patients following varying doses of human chorionic gonadotropin.

PURPOSE: Human chorionic gonadotrophin (hCG) has been used to induce ovulation and oocyte maturation. Although the most common dose of hCG used in IVF is 10,000 IU, there are reports that suggest 5,000 IU is sufficient to yield similar results. The objective of this study is to evaluate the dose dependent differences in gene expression of granulosa cells following various doses of hCG treatment. METHODS: Patients with polycystic ovarian syndrome (PCOS) were stimulated for IVF treatment. The hCG injection was either withheld or given at 5,000 or 10,000 IU. Granulosa cells from the follicular fluids have been collected for RNA isolation and analyzed using Affymetrix genechip arrays. RESULTS: Unsupervised hierarchical clustering based on whole gene expression revealed two distinct groups of patients in this experiment. All untreated patients were clustered together whereas hCG-treated patients separated to a different group regardless of the dose. A large number of the transcripts were similarly up- or down-regulated across both hCG doses (2229 and 1945 transcripts, respectively). However, we observed dose-dependent statistically significant differences in gene expression in only 15 transcripts. CONCLUSIONS: Although hCG injection caused a major change in the gene expression profile of granulosa cells, 10,000 IU hCG resulted in minimal changes in the gene expression profiles of granulosa cells as compared with 5,000 IU. Thus, based on our results, we suggest the use of 10,000 IU hCG should be reconsidered in PCOS patients.

First successful application of preimplantation genetic diagnosis and haplotyping for congenital hyperinsulinism.

Congenital hyperinsulinism is the most common cause of persistent hypoglycaemia in infancy. Early surgical intervention is usually required to prevent brain damage. The prevention of the transmission to the offspring is important in families carrying the mutated gene. Preimplantation genetic diagnosis (PGD) is an early genetic testing procedure for couples at risk of transmitting inherited diseases. A 36-year-old Saudi woman married to her first cousin with four affected children was referred for PGD. The hyperinsulinism disease was caused by a novel homozygous mutation in the KCNJ11 gene, an arginine 301 to proline (R301P) substitution.PGD was achieved by whole genome amplification followed by mutation detection combined with short tandem repeat identifier analysis in the first cycle and with haplotyping in the second cycle. The first and second cycles resulted in the births of healthy twin girls and a boy, respectively. As far as is known, this is the first application of PGD to hyperinsulinism. A feasible strategy including whole genome amplification followed by direct mutation detection combined with haplotyping is described.Utilizing haplotyping increases the efficiency of PGD diagnosis as well as confirming the genetic diagnosis. It reveals the parental origin of each inherited chromosome.

Poor prognosis in cycles following "genuine" empty follicle syndrome.

OBJECTIVES: The aim of this study was to investigate the prognosis in future IVF cycles of patients with empty follicle syndrome (EFS). STUDY DESIGN: EFS cases and their future cycles were reviewed. Clinical pregnancy rate per started cycle was taken as the primary outcome in assessing the future outcome in IVF treatment cycles. RESULTS: A total of 3023 patients underwent 5238 IVF treatment cycles. Twenty-six patients (1%) had a total of 58 (1%) cycles of EFS. Thirteen women went through 32 further IVF treatment cycles following the diagnosis of EFS, yielding only two clinical pregnancies, giving a clinical pregnancy rate of 6.25% per started cycle. In addition, four patients had recurrence in a total of 15 cycles. CONCLUSIONS: The occurrence of EFS will indicate poor IVF success in subsequent IVF cycles. Patients with "genuine EFS" should be counselled about the outcome of their future IVF cycles.

Infertility treatment outcome in sub groups of obese population.

BACKGROUND: Obesity is a common disorder with a negative impact on IVF treatment outcome. It is not clear whether morbidly obese women (BMI >= 35 kg/m2) respond to treatment differently as compared to obese women (BMI = 30-34.9 kg/m2) in IVF. Our aim was to compare the outcome of IVF or ICSI treatments in obese patients to that in morbidly obese patients. METHODS: This retrospective cohort study was conducted in a tertiary care centre. Patients inclusion criteria were as follows; BMI >or= 30, age 20-40 years old, first cycle IVF/ICSI treatment with primary infertility and long follicular pituitary down regulation protocol. RESULTS: A total of 406 obese patients (group A) and 141 morbidly obese patients (group B) satisfied the inclusion criteria. Average BMI was 32.1 +/- 1.38 kg/m2 for group A versus 37.7 +/- 2.99 kg/m2 for group B. Patient age, cause of infertility, duration of stimulation, fertilization rate, and number of transferred embryos were similar in both groups. Compared to group A, group B had fewer medium size and mature follicles (14 vs. 16), fewer oocytes collected (7 vs. 9) and required higher doses of HMG (46.2 vs. 38.5 amps). There was also a higher cancellation rate in group B (28.3% vs. 19%) and lower clinical pregnancy rate per started cycle (19.9% vs. 28.6%). CONCLUSION: In a homogenous infertile and obese patient population stratified according to their BMI, morbid obesity is associated with unfavorable IVF/ICSI cycle outcome as evidenced by lower pregnancy rates. It is recommended that morbidly obese patients undergo appropriate counseling before the initiation of this expensive and invasive therapy.

Preimplantation genetic diagnosis of Morquio disease.

OBJECTIVES: Morquio syndrome is an autosomal recessive disease and mutations in the N-acetylgalactosamine 6-sulfate sulfatase (GALNS) gene cause Morquio type A disease. Preimplantation genetic diagnosis (PGD), an early form of prenatal diagnosis for couples at risk of transmitting inherited diseases, was applied to prevent transmission of this disease. METHODS: A couple with three affected children, having homozygous W159C (p. Trp 159 Cys) mutation in GALNS gene, underwent in vitro fertilization (IVF) treatment and PGD. Mutation analyses from the embryos were performed following whole genome amplification of single blastomeres using multiple displacement amplification (MDA). RESULTS: Three embryos were diagnosed as normal and two were transferred on day 4. The cycle resulted in a pregnancy and a live birth of a carrier male infant. Genetic haplotyping analysis of the infant and the leftover MDA samples enabled us to determine which embryo was implanted. The discrepancy in results was explained by allele dropout (ADO) of the mutant allele from the MDA product. CONCLUSIONS: A feasible strategy for PGD of Morquio disease including whole genome amplification by MDA and the use of preimplantation genetic haplotyping is described. MDA product archiving will be useful for future investigations if needed.

The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome.

BACKGROUND: To evaluate the relationship between endometrial thickness on day of human chorionic gonadotrophin administration (hCG) and pregnancy outcome in a large number of consecutive in vitro fertilization and embryo transfer (IVF-ET) cycles. METHODS: A retrospective cohort study including all patients who had IVF-ET from January 2003-December 2005 conducted at a tertiary center. RESULTS: A total of 2464 cycles were analysed. Pregnancy rate (PR) was 35.8%. PR increased linearly (r = 0.864) from 29.4% among patients with a lining of less than or equal to 6 mm, to 44.4% among patients with a lining of greater than or equal to 17 mm. ROC showed that endometrial thickness is not a good predictor of PR, so a definite cut-off value could not be established (AUC = 0.55). CONCLUSION: There is a positive linear relationship between the endometrial thickness measured on the day of hCG injection and PR, and is independent of other variables. Hence aiming for a thicker endometrium should be considered.

Microsurgical resection of nonocclusive salpingitis isthmica nodosa is beneficial.

OBJECTIVE: To determine the effect of microsurgical resection and tubocornual anastomosis (TCA) of nonocclusive salpingitis isthmica nodosa (SIN) on fertility and risk for ectopic pregnancy (EP). DESIGN: Prospective cohort. SETTING: University-affiliated tertiary fertility clinic. PATIENT(S): Infertile women with hysterosalpingography evidence of SIN in patent fallopian tubes. INTERVENTION(S): Microsurgical resection and TCA for nonocclusive SIN. MAIN OUTCOME MEASURE(S): Occurrence of IUP and EP after TCA; comparison of duration of infertility preceding TCA with time to intrauterine pregnancy (IUP) after TCA; and comparison of numbers of women who conceived an EP before and after TCA. RESULT(S): Twelve (46%) of the women had IUPs with a mean time to pregnancy of 10.5 months, which is significantly shorter than the preceding period of infertility. Three women experienced EPs after TCA, which is reduced compared with the number of women with an EP preceding the TCA. CONCLUSION(S): The significant decrease in time to conceive an IUP after surgery as compared with the duration of infertility before surgery and the apparent reduction in risk for EP after surgery demonstrate the benefit of TCA for resection of nonocclusive SIN.

Metformin and polycystic ovary syndrome: a literature review.

Polycystic ovary syndrome (PCOS) is a common endocrine condition that affects women of reproductive age. Anovulation, menstrual irregularities, hirsutism, and infertility are common clinical presentations. Long-term health concerns such as type II diabetes mellitus and, possibly, cardiovascular disease, have been linked to PCOS. Metformin, an oral hypoglycemic agent, has been recently advocated as treatment for some women with PCOS due to the association of PCOS with hyperinsulinemia. Metformin is utilized as sole therapy for ovulation induction as well as in combination with traditional ovulation-induction therapies. This review identified 23 prospective studies addressing the effects of metformin on PCOS. Because of the heterogeneity of the published reports, only a qualitative assessment of the data was possible. Review of this literature confirms a beneficial role of metformin in reducing insulin resistance in some women with PCOS. Other favourable biochemical effects include reduced free testosterone levels and increased sex hormone-binding globulin (SHBG). Metformin may improve menstrual regularity, leading to spontaneous ovulation, and improve ovarian response to conventional ovulation-induction therapies. There is, however, little evidence supporting the use of metformin to facilitate weight reduction, or improve serum lipids or hirsutism. Further evaluation is required to define the long-term effectiveness of metformin, who will benefit from metformin treatment, and the optimal duration of metformin therapy.