Real-world practices of hormone monitoring during ovarian stimulation in assisted reproductive technology: a global online survey.

Objective: The aim of this study is to understand the global practice of routine hormonal monitoring (HM) during ovarian stimulation (OS) in the context of assisted reproductive technique (ART) treatment. Methods: An open-access questionnaire was available to 3,845 members of IVF-Worldwide.com from September 8 to October 13, 2021. The survey comprised 25 multiple-choice questions on when and how ultrasound (US) and hormone tests were conducted during ovarian stimulation OS. For most questions, respondents were required to select a single option. Some questions allowed the selection of multiple options. Results: In all, 528 (13.7%) members from 88 countries responded to the questionnaire. Most respondents (98.9%) reported using US to monitor OS cycles. HM was used by 79.5% of respondents during any of the cycle monitoring visits and was most commonly performed on the day of, or a day prior to final oocyte maturation. Overall, 87% of respondents claimed adjusting the dose of gonadotropin during OS, with 61.7% adjusting the dose based on hormonal levels. Oestradiol (E2) was the most frequently monitored hormone during all visits and was used by 74% of respondents for the prediction of ovarian hyperstimulation syndrome (OHSS). On or a day prior to ovulation triggering (OT), the number of respondents who measured progesterone increased from 34.3% in the second/third visit to 67.7%. Approximately one-third of respondents measured luteinizing hormone during all visits. Conclusion: Globally, most ART specialists (~80%) use HM, along with US, for monitoring OS, especially for the prevention of OHSS.

Normative cut-offs for polycystic ovary syndrome diagnostic features in adolescents using cluster analysis.

OBJECTIVE: The diagnosis of polycystic ovary syndrome (PCOS) remains challenging with international guidelines prioritising accurate cut-offs for individual diagnostic features. These diagnostic cut-offs are currently based on arbitrary percentiles, often from poorly characterised cohorts, and are dependent on variable laboratory ranges defined by assay manufacturers, limiting diagnostic accuracy. Cluster analysis is the recommended approach for defining normative cut-offs within populations for clinical syndromes. Few PCOS adult studies have applied cluster analysis, with no studies in adolescents. We aimed to define normative cut-offs for individual PCOS diagnostic features in a community-based population of adolescents using cluster analysis. DESIGN: This analysis utilised data from the Menstruation in Teenagers Study, a subgroup of the Raine Study, which is a population based prospective cohort of 244 adolescents whose mean age at PCOS assessment was 15.2 years. METHODS: K-means cluster analysis and receiver operating characteristics curves were used to define normative cut-offs for modified Ferriman-Gallwey (mFG) score, free testosterone (free T), free androgen index (FAI), and menstrual cycle length. RESULTS: Normative cut-offs for mFG, free T, FAI, and menstrual cycle lengths were 1.0, 23.4 pmol/L, 3.6, and 29 days, respectively. These corresponded to the 65th, 71st, 70th, and 59th population percentiles, respectively. CONCLUSION: In this novel study, we define the normative diagnostic criteria cut-offs in this unselected adolescent population and show that these cut-offs correspond to lower percentiles than conventional cut-offs. These findings highlight the pertinent need to re-define PCOS diagnostic cut-offs in adolescents. Validation is required in larger, multi-ethnic, and well-characterised adolescent cohorts.

The effect of obesity on cost of total laparoscopic hysterectomy.

STUDY OBJECTIVE: To test for the association between increasing patient body mass index (BMI) and the cost of total laparoscopic hysterectomy (TLH). Secondary outcomes include the relationship between increasing BMI and both peri- and post-operative morbidity. MATERIALS AND METHODS: Retrospective cohort study of patients (N = 510) who underwent TLH between January 2017 and December 2018 at a single public tertiary teaching hospital. RESULTS: Morbid obesity (n = 63) was associated with significantly higher total admission costs ($19 654 vs $17 475 Australian dollars, P = 0.002), operative costs ($9447 vs $8630, P = 0.017) and total costs including readmissions ($20 476 vs $18 399, P = 0.016) when compared to patients with normal BMI (n = 103) and adjusting for age, indication for surgery, additional procedures and conversion to total abdominal hysterectomy. Costs for overweight (n = 134) and obese (n = 210) BMI groups did not differ from costs for the normal BMI group. Increased operative costs observed in the morbidly obese group, were largely driven by the time associated with set-up, transfer and anaesthetic time while surgical and recovery times were not statistically significant. CONCLUSION: The total cost of TLH is increased in the morbidly obese category of patients. The operative costs appear to be related to pre-operative measures such as theatre set-up and anaesthetic requirements. TLH in the obese and morbidly obese category group is not associated with increased intra-operative or post-operative complications. There may be a role for exploring improvements in managing morbidly obese patients in the pre-operative setting.

Environmental factors in declining human fertility.

A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.

Sex-dependent associations between maternal prenatal stressful life events, BMI trajectories and obesity risk in offspring: The Raine Study.

Background: There is a high and growing prevalence of childhood obesity which increases the risk of adult obesity and adverse physical and mental health outcomes in adulthood. Experimental and clinical data suggest that the early life environment, particularly prenatal stress, may program development of obesity in the offspring. But few studies have assessed the associations between prenatal maternal stress and rapid (ascending) weight gain, which is the strongest predictor of adult obesity and metabolic disease. Experimental data indicate that the associations may be sex dependent, but the sex-dependent association between prenatal stress and growth in the human offspring during childhood and adolescence is largely unexplored. The aim of this study is to investigate the association between prenatal exposure to stressful life events and childhood obesity in the offspring and whether maternal smoking during pregnancy and breastfeeding mediate this. Method: Participants from a large prospective population-based Australian pregnancy cohort study (The Raine Study, n=2868) were closely and frequently followed from prenatal life (18 weeks gestation) through to adolescence. Maternal stressful life events were prospectively recorded at 18 and 34 weeks and childhood BMI (categorized into six z-score trajectories) was measured from 3 to age 14 years. We studied the prospective association between maternal exposure to stressful life events and BMI z-score trajectories in 2056 offspring (1082 boys). Mothers prospectively reported stressful life events at 18- and 34-weeks' gestation using a standardized and validated 10-point questionnaire. Age- and gender-specific z-scores for BMI were obtained from height and weight at age 3, 5, 8, 10 and 14 years using standardized methods. Latent class group analysis identified six distinct trajectory classes of BMI z-score. Multinomial logistic regression was used to examine the associations between maternal stressful life events and gender-specific BMI z-score trajectories as well as risk of overweight/obesity at each age point. Mediation analyses were also conducted to model the indirect associations through maternal smoking during pregnancy and breastfeeding. Results: Of the 2056-included offspring, 1322 (64.3%) were exposed to at least one maternal stressful life event during early gestation and 1203 (58.5%) were exposed in late gestation. In boys, exposure to stressful life events in early but not late gestation was significantly associated with ascending (accelerated) weight-gain (ages 3-14 years) (adjusted odds ratio (aOR): 1.25, 95% CI: 1.02, 1.52) and increased risk of overweight (aOR: 1.18, 95% CI: 1.00, 1.39) aged 10 years. No similar associations were observed in girls. We observed that 29.2% of the association between more maternal stressful life events and obesity in male offspring was mediated by breastfeeding for less than 6 months. Likewise, up to 35% of the association between more maternal stressful life events and obesity in male offspring was mediated by maternal smoking during the index pregnancy. Conclusion: Prenatal stress in early gestation is directly associated with accelerated childhood weight gain (assessed by childhood BMI z-score trajectories) and risk of obesity in adolescent boys, but not girls and breastfeeding and maternal smoking significantly mediates this association.

Updated adolescent diagnostic criteria for polycystic ovary syndrome: impact on prevalence and longitudinal body mass index trajectories from birth to adulthood.

BACKGROUND: Polycystic ovary syndrome (PCOS) is challenging to diagnose. While the 2003 Rotterdam criteria are widely used for adults, the 2018 international PCOS guideline recommended updated Rotterdam criteria with both hyperandrogenism and oligo-anovulation for adolescents based on evidence-informed expert consensus. This study compared the prevalence of PCOS using updated and original Rotterdam criteria in community-based adolescents and explored long-term body mass index (BMI) trajectories across different diagnostic phenotypes. METHODS: Overall, 227 postmenarchal adolescent females from the prospective cohort Raine Study undertook comprehensive PCOS assessment at age 14-16 years. Detailed anthropometric measurements were collected from birth until age 22 years. Cross-sectional and longitudinal BMI were analyzed using t tests and generalized estimating equations. RESULTS: PCOS was diagnosed in 66 (29.1%) participants using original criteria versus 37 (16.3%) participants using updated Rotterdam criteria. Using updated criteria, participants with PCOS had higher BMI than participants without PCOS from prepubertal. Only the phenotype meeting the updated criteria was significantly associated with higher long-term BMI gain whereas other PCOS phenotypes had similar BMI trajectories to participants without PCOS (p < 0.001). CONCLUSIONS: The use of the 2018 updated Rotterdam criteria reduces over-diagnosis of PCOS in adolescents and identifies those at the greatest risk of long-term weight gain, a key contributor to disease severity and long-term health implications. The BMI trajectories of females with PCOS on updated criteria diverge prepubertally compared to those without PCOS. This work supports targeting adolescents diagnosed with PCOS on the 2018 updated criteria for early lifestyle interventions to prevent long-term health complications.

Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes.

BACKGROUND: A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo fresh embryo transfer (ET) cycles with embryos derived from donated oocytes. In both situations, the endometrium is primed with oestrogen and progestogen in different doses and routes of administration. OBJECTIVES: To evaluate the most effective endometrial preparation for women undergoing transfer with frozen embryos or embryos from donor oocytes with regard to the subsequent live birth rate (LBR). SEARCH METHODS: The Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trials registers and abstracts of reproductive societies' meetings were searched in June 2020 together with reference checking and contact with study authors and experts in the field to identify additional studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. We analysed all available interventions versus placebo, no treatment, or between each other. The primary review outcome was live birth rate. Secondary outcomes were clinical and multiple pregnancy, miscarriage, cycle cancellation, endometrial thickness and adverse effects. MAIN RESULTS: Thirty-one RCTs (5426 women) were included. Evidence was moderate to very low-quality: the main limitations were serious risk of bias due to poor reporting of methods, and serious imprecision. Stimulated versus programmed cycle We are uncertain whether a letrozole-stimulated cycle compared to a programmed cycle, for endometrial preparation, improves LBR (odds ratio (OR) 1.26, 95% confidence interval (CI) 0.49 to 3.26; 100 participants; one study; very low-quality evidence). Stimulating with follicle stimulating hormone (FSH), letrozole or clomiphene citrate may improve clinical pregnancy rate (CPR) (OR 1.63, 95% CI 1.12 to 2.38; 656 participants; five studies; I2 = 11%; low-quality evidence). We are uncertain if they reduce miscarriage rate (MR) (OR 0.79, 95% CI 0.36 to 1.71; 355 participants; three studies; I2 = 0%; very low-quality evidence). Endometrial thickness (ET) may be reduced with clomiphene citrate (mean difference(MD) -1.04, 95% CI -1.59 to -0.49; 92 participants; one study; low-quality evidence). Other outcomes were not reported. Natural versus programmed cycle We are uncertain of the effect from a natural versus programmed cycle for LBR (OR 0.97, 95% CI 0.74 to 1.28; 1285 participants; four studies; I2 = 0%; very low-quality evidence) and CPR (OR 0.79, 95% CI 0.62 to 1.01; 1249 participants; five studies; I2 = 60%; very low-quality evidence), while a natural cycle probably reduces the cycle cancellation rate (CCR) (OR 0.60, 95% CI 0.44 to 0.82; 734 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and ET. No study reported other outcomes. Transdermal versus oral oestrogens From low-quality evidence we are uncertain of the effect transdermal compared to oral oestrogens has on CPR (OR 0.86, 95% CI 0.59 to 1.25; 504 participants; three studies; I2 = 58%) or MR (OR 0.55, 95% CI 0.27 to 1.09; 414 participants; two studies; I2 = 0%). Other outcomes were not reported. Day of starting administration of progestogen When doing a fresh ET using donated oocytes in a synchronised cycle starting progestogen on the day of oocyte pick-up (OPU) or the day after OPU, in comparison with recipients that start progestogen the day prior to OPU, probably increases the CPR (OR 1.87, 95% CI 1.13 to 3.08; 282 participants; one study, moderate-quality evidence). We are uncertain of the effect on multiple pregnancy rate (MPR) or MR. It probably reduces the CCR (OR 0.28, 95% CI 0.11 to 0.74; 282 participants; one study; moderate-quality evidence). No study reported other outcomes. Gonadotropin-releasing hormone (GnRH) agonist versus control A cycle with GnRH agonist compared to without may improve LBR (OR 2.62, 95% CI 1.19 to 5.78; 234 participants; one study; low-quality evidence). From low-quality evidence we are uncertain of the effect on CPR (OR 1.08, 95% CI 0.82 to 1.43; 1289 participants; eight studies; I2 = 20%), MR (OR 0.85, 95% CI 0.36 to 2.00; 828 participants; four studies; I2 = 0%), CCR (OR 0.49, 95% CI 0.21 to 1.17; 530 participants; two studies; I2 = 0%) and ET (MD -0.08, 95% CI -0.33 to 0.16; 697 participants; four studies; I2 = 4%). No study reported other outcomes. Among different GnRH agonists From very low-quality evidence we are uncertain if cycles among different GnRH agonists improves CPR or MR. No study reported other outcomes. GnRH agonists versus GnRH antagonists GnRH antagonists compared to agonists probably improves CPR (OR 0.62, 95% CI 0.42 to 0.90; 473 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and MPR. No study reported other outcomes. Aspirin versus control From very low-quality evidence we are uncertain whether a cycle with aspirin versus without improves LBR, CPR, or ET. Steroids versus control From very low-quality evidence we are uncertain whether a cycle with steroids compared to without improves LBR, CPR or MR. No study reported other outcomes. AUTHORS' CONCLUSIONS: There is insufficient evidence on the use of any particular intervention for endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. In frozen embryo transfers, low-quality evidence showed that clinical pregnancy rates may be improved in a stimulated cycle compared to a programmed one, and we are uncertain of the effect when comparing a programmed cycle to a natural cycle. Cycle cancellation rates are probably reduced in a natural cycle. Although administering a GnRH agonist, compared to without, may improve live birth rates, clinical pregnancy rates will probably be improved in a GnRH antagonist cycle over an agonist cycle. In fresh synchronised oocyte donor cycles, the clinical pregnancy rate is probably improved and cycle cancellation rates are probably reduced when starting progestogen the day of or day after donor oocyte retrieval. Adequately powered studies are needed to evaluate each treatment more accurately.

The Impact of Prenatal Exposure to Bisphenol A on Male Reproductive Function.

Bisphenol A (BPA) is a recognized xenoestrogen, in that it possesses oestrogenic and anti-androgenic properties. These endocrine-disrupting effects of BPA at the estrogen receptor (ER) occur despite the very low affinity of BPA for the ERß, which is 10,000 times lower than that of 17-ß estradiol, and despite the European regulatory authorities stating that BPA is safe, at usual exposure concentrations, the use of BPA in baby drink bottles was banned in 2011. There exists conflicting evidence from human epidemiological studies as to its influence on adult male reproductive function, although animal data is more convincing. This mini-review will report on the limited epidemiological data from human studies relating early life exposure to BPA on adult male reproductive function. A long term follow-up study from Western Australia using a birth cohort, the Raine Study, demonstrated no adverse associations of antenatal exposure to BPA, and potentially a positive association with antenatal BPA exposure with sperm concentration and motility at 20 years of age, although recent scientific reports suggest traditional measures of BPA exposure may underestimate exposure levels, which makes data interpretation potentially flawed.

A brief update on the evidence supporting the treatment of infertility in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. AIMS: This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. MATERIALS AND METHODS: International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. RESULTS: Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where first- or second-line ovulation induction therapies have failed. CONCLUSION: This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.

A Review of Second- and Third-line Infertility Treatments and Supporting Evidence in Women with Polycystic Ovary Syndrome.

In clomiphene-citrate-resistant anovulatory women with polycystic ovary syndrome (PCOS) and no other infertility factors, either metformin combined with clomiphene citrate or gonadotrophins could be used as a second-line pharmacological therapy, although gonadotrophins are more effective. Gonadotrophins could also be used as a second-line pharmacological therapy in anovulatory women with PCOS and clomiphene-citrate-failure. Laparoscopic ovarian surgery can also be used as a second-line therapy for ovulation induction in anovulatory women with clomiphene-citrate-resistant PCOS and no other infertility factors. The usefulness of letrozole as a second-line pharmacological treatment for ovulation induction in clomiphene-citrate-resistant women with PCOS requires further research. In terms of improving fertility, both pharmacological anti-obesity agents and bariatric surgery should be considered an experimental therapy in anovulatory women with PCOS and no other infertility factors. Where first- or second-line ovulation induction therapies have failed, in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI) could be offered as a third-line therapy in women with PCOS in the absence of an absolute indication for IVF/ICSI. For women with PCOS undergoing IVF/ICSI treatment, the gonadotropin-releasing hormone (GnRH) antagonist protocol is preferred and an elective frozen embryo transfer strategy could be considered. In assisted conception units with sufficient expertise, in-vitro maturation (IVM) of oocytes could be offered to women with PCOS.

The interval transfer of a frozen-thawed embryo is more successful than a fresh embryo transfer for women undergoing IVF with recurrent implantation failure after cleavage stage embryo biopsy.

BACKGROUND: Recurrent implantation failure (RIF) is repeated unsuccessful embryo transfers (ETs). AIMS: To identify predictive embryonic markers of implantation in RIF, following pre-implantation genetic screening (PGS) of cleavage stage embryos, after accounting for male and female factors. MATERIALS AND METHODS: Retrospective analysis of RIF patients undergoing PGS after correction of modifiable causes. RESULTS: Eighty-four patients underwent 140 in vitro ferilisation cycles. Forty-one cycles were excluded: 12 (no embryo for transfer), four (double ETs) and 25 (no biopsy). Sixty-three patients underwent 99 single euploid ETs (48 fresh, 51 frozen) resulting in 11 biochemical pregnancies, 36 clinical pregnancies (CP), and six miscarriages and 30 live births (LB). Frozen ET was more successful than fresh; respective live birth rate (LBR) and clinical pregnancy rate (CPR), 39.2% versus 20.8%, (P = 0.02), 45.1% versus 27.1% (P = 0.04). LBR and CPR were lower when 5-6 blastomeres were present at embryo biopsy, compared to embryos with ≥7 blastomeres: 15.4% versus 32.6% (P = 0.185) and 15.4% versus 39.5% (P = 0.074) respectively. Serum ß human chorionic gonadotropin (ßhCG) concentration was greater when a more developed embryo was biopsied (r = 0.448, P = 0.017 and r = 0.476, P = 0.118, fresh and frozen transfers, respectively). Embryo morphokinetic analysis demonstrated faster development to blastocyst stage when more cells were present at biopsy: mean 103.3, 102.2 and 96.0 h for biopsy at the 5-6, 7-8 or ≥9 cell stage respectively (P = 0.040 for difference between 7-8 cells vs ≥9). CONCLUSIONS: After cleavage stage biopsy, frozen ET was more successful than fresh ET. Chance of conception and serum ßhCG concentration correlated with number of cells present at time of biopsy.

Age at menarche and childhood body mass index as predictors of cardio-metabolic risk in young adulthood: A prospective cohort study.

OBJECTIVE: This study aimed to examine the association between age at menarche and a range of cardiovascular disease (CVD) risk factors at 17 and 20 years of age, and whether this was influenced by childhood body mass index (BMI). METHODS: Of the 1413 girls born in the Western Australian Pregnancy Cohort (Raine) Study, 846 had age at menarche recorded. Subsequently 557 underwent metabolic assessment at 17 years and 541 at 20 years. Associations between age at menarche and cardiovascular risk factors, and being in a high-risk metabolic cluster at 17 and 20 years, or having the metabolic syndrome at 20 years, were investigated by linear mixed effects and logistic regressions, respectively. RESULTS: Each year later of onset of menarche was associated with a 0.75 kg/m2 reduction in BMI (coefficient -0.75 [95%CI -1.06, -0.44]), and an approximate 30% reduction in the odds of being in the high-risk metabolic cluster at 17 years (OR = 0.73 [95%CI 0.57, 0.94]) and 20 years of age (OR = 0.68 [95%CI 0.52, 0.87]), and a 40% reduction in the odds of having the metabolic syndrome at 20 years (OR = 0.60 [95% CI 0.41, 0.88]). These data show earlier age at menarche was associated with increased BMI and odds of being in the high-risk metabolic cluster at 17 and 20 years, and increased odds of having the metabolic syndrome at 20 years. However, these associations were no longer statistically significant after adjustment for BMI at age 8 years. Current smoking, alcohol consumption, physical activity, socio-economic status, or hormonal contraceptives use did not affect these associations. CONCLUSIONS: Earlier age at menarche may be indicative of a higher risk profile for CVD in young adulthood. Our findings suggest that targeted interventions to reduce BMI in girls who experience menarche at younger age may reduce CVD risk in the future.

Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome.

INTRODUCTION: We have developed the first international evidence-based guideline for the diagnosis and management of polycystic ovary syndrome (PCOS), with an integrated translation program incorporating resources for health professionals and consumers. The development process involved an extensive Australian-led international and multidisciplinary collaboration of health professionals and consumers over 2 years. The guideline is approved by the National Health and Medical Research Council and aims to support both health professionals and women with PCOS in improving care, health outcomes and quality of life. A robust evaluation process will enable practice benchmarking and feedback to further inform evidence-based practice. We propose that this methodology could be used in developing and implementing guidelines for other women's health conditions and beyond. Main recommendations: The recommendations cover the following broad areas: diagnosis, screening and risk assessment depending on life stage; emotional wellbeing; healthy lifestyle; pharmacological treatment for non-fertility indications; and assessment and treatment of infertility. Changes in management as a result of this guideline: •Diagnosis:▪when the combination of hyperandrogenism and ovulatory dysfunction is present, ultrasound examination of the ovaries is not necessary for diagnosis of PCOS in adult women;▪requires the combination of hyperandrogenism and ovulatory dysfunction in young women within 8 years of menarche, with ultrasound examination of the ovaries not recommended, owing to the overlap with normal ovarian physiology; and▪adolescents with some clinical features of PCOS, but without a clear diagnosis, should be regarded as "at risk" and receive follow-up assessment.•Screening for metabolic complications has been refined and incorporates both PCOS status and additional metabolic risk factors.•Treatment of infertility: letrozole is now first line treatment for infertility as it improves live birth rates while reducing multiple pregnancies compared with clomiphene citrate.

Relationship between umbilical cord sex hormone binding globulin, sex steroids, and age at menarche: a prospective cohort study.

OBJECTIVE: To study the role of the prenatal environment in regulating reproductive development by measuring the prospective association between umbilical cord concentrations of sex hormone binding globulin (SHBG; principal regulator of sex steroid activity), bioavailable sex steroids, and age at menarche. DESIGN: Prospective population-based cohort. SETTING: Not applicable. PATIENT(S): In 286 female members of the Western Australian Pregnancy (Raine) cohort, concentrations of SHBG and steroids (estrogens: estrone, estradiol, estriol and estetrol [E4]; androgens: total testosterone, Δ4-androstenedione, androstenedione and dehydroepiandrosterone) were measured by liquid chromatography-tandem mass spectrometry from archived umbilical cord blood samples collected at birth. Bioavailable concentrations of testosterone and estradiol were calculated along with total composite measures of androgen and estrogen bioactivity. SHBG was measured by ELISA. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Age of menarche was calculated from date of menarche, collected prospectively by questionnaire sent home with participants at the year 10 follow-up. RESULT(S): Higher maternal education, higher body mass index, and the presence of antepartum hemorrhage were all significantly associated with earlier age at menarche. The bioavailable sex steroid measures accounted for 8.3% of the variance in age at menarche. Further, both SHBG and E4 concentrations accounted for a significant proportion of unique variance in age at menarche. CONCLUSION(S): Lower SHBG and higher E4 concentrations in umbilical cord blood were associated with earlier age at menarche. These results suggest that the prenatal sex steroid environment contributes toward pubertal development and age at menarche.

In vitro maturation.

In vitro maturation (IVM) is an in vitro fertilisation (IVF) technique modified to collect immature oocytes from antral follicles, with the final stages of meiosis completed during in vitro culture. The primary benefit of IVM is that it reduces gonadotrophin stimulation in the patient, thereby eliminating the risk of ovarian hyperstimulation syndrome (OHSS) in high-risk patients such as those with polycystic ovaries (PCO) and polycystic ovary syndrome (PCOS). IVM has additional benefits for fertility preservation, particularly in oncofertility patients. IVM research has progressed in recent years to significantly improve success rates and to provide evidence of safety in terms of neonatal and childhood outcomes. More recently, pre-maturation protocols and the discovery of new culture media additives have demonstrated potential to maximise maturation and oocyte developmental competence. In this chapter, we discuss current methodologies used in clinics routinely performing IVM, target patient populations and areas of future research that may improve IVM success.

The Possible Impact of Antenatal Exposure to Ubiquitous Phthalates Upon Male Reproductive Function at 20 Years of Age.

Phthalates are ubiquitous environmental endocrine-disrupting chemicals suspected to interfere with developmental androgen action leading to adverse effects on male reproductive function. Prenatal exposure studies in rodents show cryptorchidism, hypospadias and reduced testicular volume (TV), testosterone and anogenital distance in males. It is postulated that there is a developmental window in utero when phthalate exposure has the most potent adverse effects. Some human studies show associations between prenatal phthalate exposure and reduced calculated "free" serum testosterone in infant boys and shorter anogenital distance. However, there are no data available yet which link antenatal exposure to long-term effects in men. We aimed to correlate antenatal phthalate exposure with adult TV, semen parameters and serum reproductive hormone concentrations. 913 men from the Western Australian (Raine) Pregnancy Cohort were contacted aged 20-22 years. 423 (56%) agreed to participate; 404 underwent testicular ultrasound examination; 365 provided semen samples, and reproductive hormones were measured in 384. Maternal antenatal serum phthalate metabolite measurements were available for 185 and 111 men, who provided serum and semen, respectively. Maternal serum collected at 18 and 34 weeks gestation, stored at -80°C, was pooled and analyzed for 32 phthalate metabolites by liquid chromatography-tandem mass spectrometry. TV was calculated, semen analysis performed by WHO approved methods, and serum concentrations of gonadotrophins, inhibin B, and testosterone measured. Eleven phthalate metabolites were detected. Primary and secondary metabolites of di-(2-ethyl-hexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP) were positively correlated. After correction for adult height, BMI, presence of a varicocele and exposure to maternal smoking mono-iso-nonyl phthalate (MiNP) (r = -0.22) and sums of DEHP and DiNP metabolites (r = -0.24) and the sum of the metabolites of the high molecular weight phthalates (r = -0.21) were negatively correlated with TV (all p < 0.05). After adjustment for BMI adult serum total testosterone was positively associated with exposure to the following antenatal serum phthalate metabolites: mono-(2-ethylhexyl) phthalate (r = 0.26), MiNP (r = 0.18), the sum of metabolites for DEHP (r = 0.21) and DiNP (r = 0.18), and the sum of high molecular phthalates (r = 0.20) (p = 0.0005 to p = 0.02). Given sample size, storage duration and confounding through postnatal exposures, further studies are required.

The impact of antenatal Bisphenol A exposure on male reproductive function at 20-22 years of age.

Bisphenol A (BPA) is a ubiquitous chemical suspected to possess oestrogenic hormonal activities. Male population studies suggest a negative impact on testicular function. As Sertoli cell proliferation occurs during fetal or early postnatal life, it is speculated that oestrogenic environmental exposures may influence mature testicular function. Among 705 Western Australian Pregnancy Cohort (Raine) Study men aged 20-22 years, 404 underwent testicular ultrasound examination (149 had maternal serum available), and/or 365 provided semen (136 had maternal serum) and/or 609 serum samples for sex steroids, gonadotrophins and inhibin B analysis (244 had maternal serum). Maternal serum collected at 18 and 34 weeks' gestation was pooled and assayed for concentrations of total BPA (free plus conjugated) as an estimate of antenatal exposure. Testicular volume was calculated by ultrasonography, and semen analysis performed. Serum LH, FSH and inhibin B were measured by immunoassay; testosterone, oestradiol, oestrone andBPA were measured by liquid chromatography-mass spectrometry. BPA levels were detectable in most (89%) maternal serum samples. After adjustment for maternal smoking, abstinence and varicocele, sperm concentration and motility were significantly correlated to maternal serum BPA (r = 0.18; P = 0.04 for both). No other associations of maternal serum BPA with testicular function were observed.

Pregnancy-related outcomes for women with polycystic ovary syndrome.

The polycystic ovary syndrome is a common endocrine disorder that has profound implications for women throughout their reproductive years. A diagnosis of polycystic ovary syndrome is associated with reproductive challenges including a difficulty in conceiving as well as the pregnancy-related complications of miscarriage, hypertensive disorders, gestational diabetes and prematurity. Consequently, polycystic ovary syndrome has profound implications for women and their offspring with regard to reproductive function in the short term and in the longer term the risk of chronic illness and congenital anomalies, and health care resources should be directed accordingly to mitigate against these risks.