The prospect of artificial intelligence to personalize assisted reproductive technology.

Infertility affects 1-in-6 couples, with repeated intensive cycles of assisted reproductive technology (ART) required by many to achieve a desired live birth. In ART, typically, clinicians and laboratory staff consider patient characteristics, previous treatment responses, and ongoing monitoring to determine treatment decisions. However, the reproducibility, weighting, and interpretation of these characteristics are contentious, and highly operator-dependent, resulting in considerable reliance on clinical experience. Artificial intelligence (AI) is ideally suited to handle, process, and analyze large, dynamic, temporal datasets with multiple intermediary outcomes that are generated during an ART cycle. Here, we review how AI has demonstrated potential for optimization and personalization of key steps in a reproducible manner, including: drug selection and dosing, cycle monitoring, induction of oocyte maturation, and selection of the most competent gametes and embryos, to improve the overall efficacy and safety of ART.

Endocrine Requirements for Oocyte Maturation Following hCG, GnRH Agonist, and Kisspeptin During IVF Treatment.

Objective: The maturation of oocytes to acquire competence for fertilization is critical to the success of in vitro fertilization (IVF) treatment. It requires LH-like exposure, provided by either human chorionic gonadotropin (hCG), or gonadotropin releasing hormone agonist (GnRHa). More recently, the hypothalamic stimulator, kisspeptin, was used to mature oocytes. Herein, we examine the relationship between the endocrine changes following these agents and oocyte maturation. Design: Retrospective cohort study. Methods: Prospectively collected hormonal data from 499 research IVF cycles triggered with either hCG, GnRHa, or kisspeptin were evaluated. Results: HCG-levels (121 iU/L) peaked at 24 h following hCG, whereas LH-levels peaked at ~4 h following GnRHa (140 iU/L), or kisspeptin (41 iU/L). HCG-levels were negatively associated with body-weight, whereas LH rises following GnRHa and kisspeptin were positively predicted by pre-trigger LH values. The odds of achieving the median mature oocyte yield for each trigger were increased by hCG/LH level. Progesterone rise during oocyte maturation occurred precipitously following each trigger and strongly predicted the number of mature oocytes retrieved. Progesterone rise was positively associated with the hCG-level following hCG trigger, but negatively with LH rise following all three triggers. The rise in progesterone per mature oocyte at 12 h was greater following GnRHa than following hCG or kisspeptin triggers. Conclusion: The endocrine response during oocyte maturation significantly differed by each trigger. Counter-intuitively, progesterone rise during oocyte maturation was negatively associated with LH rise, even when accounting for the number of mature oocytes retrieved. These data expand our understanding of the endocrine changes during oocyte maturation and inform the design of future precision-triggering protocols.

SARS-Cov-2 viral and serological screening of staff in 31 European fertility units.

STUDY QUESTION: What is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral presence and seroconversion in staff members in European fertility units prior to recommencement of clinical activity? SUMMARY ANSWER: A large proportion of fertility clinic staff remain susceptible to SARS-CoV-2 with no evidence of seroconversion, indicating that continued comprehensive risk mitigation strategies are essential. WHAT IS KNOWN ALREADY: In response to the coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2, routine fertility treatment was temporarily stopped in several European countries. The SARS-CoV-2 prevalence and seroconversion in fertility clinic staff, who are at potentially lower risk than routine healthcare workers, are unknown. STUDY DESIGN SIZE DURATION: This cross-sectional study included 554 staff in 16 European IVF clinics, 13 ultrasound clinics, one diagnostic laboratory and one head office in four European countries (Austria, Denmark, Germany and the UK) between 15 April and 30 June 2020. PARTICIPANTS/MATERIALS SETTING METHODS: There were 554 staff members returning for resumption of clinical activity. Paired nucleic acid amplification tests of oropharyngeal swabs for SARS-CoV-2 and serological testing for SARS-CoV-2 IgG were performed. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 554 staff members tested, 0.19% (95% CI 0.03, 1.10%) had evidence of SARS-CoV-2 as detected by RT-PCR. In contrast, 23 staff members, i.e. 4.15% (95% CI 2.78, 6.15%), had antibodies against SARS-CoV-2, with a wide range of antibody titres. There was no evidence of differences in seroconversion between countries with estimates ranging from 2.78% (95% CI 0.77, 9.58) in Austria to 6.75% (95% CI 4.46, 10.1) for the UK. There was no strong evidence of clustering within the clinics, with 21 of the 30 facilities having no staff members affected (prevalence estimates ranging from 0% to 35%), and one clinic having seven staff members affected (35% (95% CI 18.1%, 56.7%)). The single staff member who tested positive for SARS-CoV-2 virus was in the pre-symptomatic phase and was isolated, with no contacts having evidence of infection on repeat testing. LIMITATIONS REASONS FOR CAUTION: This was a cross-sectional study prior to resumption of clinical activity, with repeat testing not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: The low prevalence of seroconversion of fertility clinic staff highlights the need for continued comprehensive risk mitigation strategies and engagement with national endeavours to identify and isolate new cases and their contacts as we embark on the resumption of fertility services. STUDY FUNDING/COMPETING INTERESTS: The Fertility Partnership funded the study. S.M.N. reports personal fees from Access Fertility, personal fees from Merck, personal fees from Ferring, grants and personal fees from Roche Diagnostics, personal fees from The Fertility Partnership and personal fees from Modern Fertility, outside the submitted work. T.C. reports personal fees from Merck and personal fees from Ferring, outside the submitted work. G.T. reports personal fees from Merck, personal fees from Ferring and personal fees from Roche Diagnostics, outside the submitted work. S.E. and P.S.G. report no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Anti-Müllerian hormone (AMH) in the Diagnosis of Menstrual Disturbance Due to Polycystic Ovarian Syndrome.

Introduction: Polycystic ovarian syndrome (PCOS) is a leading cause of female subfertility worldwide, however due to the heterogeneity of the disorder, the criteria for diagnosis remains subject to conjecture. In the present study, we evaluate the utility of serum Anti-Müllerian hormone (AMH) in the diagnosis of menstrual disturbance due to PCOS. Method: Menstrual cycle length, serum AMH, gonadotropin and sex-hormone levels, total antral follicle count (AFC), body mass index (BMI) and ovarian morphology on ultrasound were analyzed in a cohort of 187 non-obese women, aged 18-35 years, screened for participation in a clinical trial of fertility treatment between 2013 and 2016 at a tertiary reproductive endocrine center. Results: Serum AMH was higher in women with menstrual disturbance when compared to those with regular cycles (65.6 vs. 34.8 pmol/L; P < 0.0001). The odds of menstrual disturbance was increased 28.5-fold (95% CI 3.6-227.3) in women with serum AMH >60 pmol/L, in comparison to those with an AMH < 15 pmol/L. AMH better discriminated women with menstrual disturbance (area under ROC 0.77) from those with regular menstrual cycles than AFC (area under ROC 0.67), however the combination of the two markers increased discrimination than either measure alone (0.83; 95% CI 0.77-0.89). Serum AMH was higher in women with all three cardinal features of PCOS (menstrual disturbance, hyperandrogenism, polycystic ovarian morphology) when compared to women with none of these features (65.6 vs. 14.6 pmol/L; P < 0.0001). The odds of menstrual disturbance were increased by 10.7-fold (95% CI 2.4-47.1) in women with bilateral polycystic morphology ovaries than those with normal ovarian morphology. BMI was a stronger predictor of free androgen index (FAI) than either AMH or AFC. Conclusion: Serum AMH could serve as a useful biomarker to indicate the risk of menstrual disturbance due to PCOS. Women with higher AMH levels had increased rates of menstrual disturbance and an increased number of features of PCOS.

FSH Requirements for Follicle Growth During Controlled Ovarian Stimulation.

Introduction: Ovarian follicle growth is a key step in the success of assisted reproductive treatment, but limited data exists to directly relate follicle growth to recombinant FSH (rFSH) dose. In this study, we aim to evaluate FSH requirements for follicular growth during controlled ovarian stimulation. Method: Single center retrospective cohort study of 1,034 IVF cycles conducted between January 2012-January 2016 at Hammersmith Hospital IVF unit, London, UK. Median follicle size after 5 days of stimulation with rFSH and the proportion of antral follicles recruited were analyzed in women treated with rFSH alone to induce follicular growth during IVF treatment. Results: Starting rFSH dose adjusted for body weight (iU/kg) predicted serum FSH level after 5 days of rFSH (r 2 = 0.352, p < 0.0001), median follicle size after 5 days of rFSH, and the proportion of antral follicles recruited by the end of stimulation. Day 5 median follicle size predicted median follicle size on subsequent ultrasound scans (r 2 = 0.58-0.62; p < 0.0001), and hence time to oocyte maturation trigger (r 2 = 0.22, P < 0.0001). Insufficient rFSH starting dose that required >5% dose-increase was associated with increased variability in follicle size on the day of oocyte maturation trigger, and negatively impacted the number of mature oocytes retrieved. Conclusion: Weight-adjusted rFSH dose correlates with follicular growth during ovarian stimulation. Early recruitment of follicles using a sufficient dose of rFSH from the start of stimulation was associated with reduced variability in follicle size at time of oocyte maturation trigger and an increased number of mature oocytes retrieved.

Follicle Size on Day of Trigger Most Likely to Yield a Mature Oocyte.

OBJECTIVE: To identify follicle sizes on the day of trigger most likely to yield a mature oocyte following hCG, GnRH agonist (GnRHa), or kisspeptin during IVF treatment. DESIGN: Retrospective analysis to determine the size of follicles on day of trigger contributing most to the number of mature oocytes retrieved using generalized linear regression and random forest models applied to data from IVF cycles (2014-2017) in which either hCG, GnRHa, or kisspeptin trigger was used. SETTING: HCG and GnRHa data were collected at My Duc Hospital, Ho Chi Minh City, Vietnam, and kisspeptin data were collected at Hammersmith Hospital, London, UK. PATIENTS: Four hundred and forty nine women aged 18-38 years with antral follicle counts 4-87 were triggered with hCG (n = 161), GnRHa (n = 165), or kisspeptin (n = 173). MAIN OUTCOME MEASURE: Follicle sizes on the day of trigger most likely to yield a mature oocyte. RESULTS: Follicles 12-19 mm on the day of trigger contributed the most to the number of oocytes and mature oocytes retrieved. Comparing the tertile of patients with the highest proportion of follicles on the day of trigger 12-19 mm, with the tertile of patients with the lowest proportion within this size range, revealed increases of 4.7 mature oocytes for hCG (P < 0.0001) and 4.9 mature oocytes for GnRHa triggering (P < 0.01). Using simulated follicle size profiles of patients with 20 follicles on the day of trigger, our model predicts that the number of oocytes retrieved would increase from a mean 9.8 (95% prediction limit 9.3-10.3) to 14.8 (95% prediction limit 13.3-16.3) oocytes due to the difference in follicle size profile alone. CONCLUSION: Follicles 12-19 mm on the morning of trigger administration were most likely to yield a mature oocyte following hCG, GnRHa, or kisspeptin.

A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial.

STUDY QUESTION: Can increasing the duration of LH-exposure with a second dose of kisspeptin-54 improve oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS)? SUMMARY ANSWER: A second dose of kisspeptin-54 at 10 h following the first improves oocyte yield in women at high risk of OHSS. WHAT IS KNOWN ALREADY: Kisspeptin acts at the hypothalamus to stimulate the release of an endogenous pool of GnRH from the hypothalamus. We have previously reported that a single dose of kisspeptin-54 results in an LH-surge of ~12-14 h duration, which safely triggers oocyte maturation in women at high risk of OHSS. STUDY DESIGN, SIZE, DURATION: Phase-2 randomized placebo-controlled trial of 62 women at high risk of OHSS recruited between August 2015 and May 2016. Following controlled ovarian stimulation, all patients (n = 62) received a subcutaneous injection of kisspeptin-54 (9.6 nmol/kg) 36 h prior to oocyte retrieval. Patients were randomized 1:1 to receive either a second dose of kisspeptin-54 (D; Double, n = 31), or saline (S; Single, n = 31) 10 h thereafter. Patients, embryologists, and IVF clinicians remained blinded to the dosing allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study participants: Sixty-two women aged 18-34 years at high risk of OHSS (antral follicle count ≥23 or anti-Mullerian hormone level ≥40 pmol/L). Setting: Single centre study carried out at Hammersmith Hospital IVF unit, London, UK. Primary outcome: Proportion of patients achieving an oocyte yield (percentage of mature oocytes retrieved from follicles ≥14 mm on morning of first kisspeptin-54 trigger administration) of at least 60%. Secondary outcomes: Reproductive hormone levels, implantation rate and OHSS occurrence. MAIN RESULTS AND THE ROLE OF CHANCE: A second dose of kisspeptin-54 at 10 h following the first induced further LH-secretion at 4 h after administration. A higher proportion of patients achieved an oocyte yield ≥60% following a second dose of kisspeptin-54 (Single: 14/31, 45%, Double: 21/31, 71%; absolute difference +26%, CI 2-50%, P = 0.042). Patients receiving two doses of kisspeptin-54 had a variable LH-response following the second kisspeptin dose, which appeared to be dependent on the LH-response following the first kisspeptin injection. Patients who had a lower LH-rise following the first dose of kisspeptin had a more substantial 'rescue' LH-response following the second dose of kisspeptin. The variable LH-response following the second dose of kisspeptin resulted in a greater proportion of patients achieving an oocyte yield ≥60%, but without also increasing the frequency of ovarian over-response and moderate OHSS (Single: 1/31, 3.2%, Double: 0/31, 0%). LIMITATIONS, REASONS FOR CAUTION: Further studies are warranted to directly compare kisspeptin-54 to more established triggers of oocyte maturation. WIDER IMPLICATIONS OF THE FINDINGS: Triggering final oocyte maturation with kisspeptin is a novel therapeutic option to enable the use of fresh embryo transfer even in the woman at high risk of OHSS. STUDY FUNDING/COMPETING INTEREST(S): The study was designed, conducted, analysed and reported entirely by the authors. The Medical Research Council (MRC), Wellcome Trust & National Institute of Health Research (NIHR) provided research funding to carry out the studies. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Clinicaltrial.gov identifier NCT01667406. TRIAL REGISTRATION DATE: 8 August 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 August 2015.

A first-in-human, randomized, controlled, subject- and reviewer-blinded multicenter study of Actamax™ Adhesion Barrier.

PURPOSE: Post-surgical adhesions remain a significant concern following abdominopelvic surgery. This study was to assess safety, manageability and explore preliminary efficacy of applying a degradable hydrogel adhesion barrier to areas of surgical trauma following gynecologic laparoscopic abdominopelvic surgery. METHODS: This first-in-human, prospective, randomized, multicenter, subject- and reviewer-blinded clinical study was conducted in 78 premenopausal women (18-46 years) wishing to maintain fertility and undergoing gynecologic laparoscopic abdominopelvic surgery with planned clinically indicated second-look laparoscopy (SLL) at 4-12 weeks. The first two patients of each surgeon received hydrogel, up to 30 mL sprayed over all sites of surgical trauma, and were assessed for safety and application only (n = 12). Subsequent subjects (n = 66) were randomized 1:1 to receive either hydrogel (Treatment, n = 35) or not (Control, n = 31); 63 completed the SLL. RESULTS: No adverse event was assessed as serious, or possibly device related. None was severe or fatal. Adverse events were reported for 17 treated subjects (17/47, 36.2%) and 13 Controls (13/31, 41.9%). For 95.7% of treated subjects, surgeons found the device "easy" or "very easy" to use; in 54.5%, some residual material was evident at SLL. For 63 randomized subjects who completed the SLL, adjusted between-group difference in the change from baseline adhesion score demonstrated a 41.4% reduction for Treatment compared with Controls (p = 0.017), with a 49.5% reduction (p = 0.008) among myomectomy subjects (n = 34). CONCLUSION: Spray application of a degradable hydrogel adhesion barrier during gynecologic laparoscopic abdominopelvic surgery was performed easily and safely, without evidence of clinically significant adverse outcomes. Data suggest the hydrogel was effective in reducing postoperative adhesion development, particularly following myomectomy.

GnRH agonist trigger with intensive luteal phase support vs. human chorionic gonadotropin trigger in high responders: an observational study reporting pregnancy outcomes and incidence of ovarian hyperstimulation syndrome.

A retrospective, cohort study of high-risk patients undergoing IVF treatment was performed to assess if there is a difference in clinical pregnancy rate, live birth rate and the incidence of ovarian hyperstimulation syndrome, when a GnRH agonist (GnRHa) trigger with intensive luteal support is compared to human chorionic gonadotropin (hCG) with standard luteal support. The control group consisted of 382 high-risk patients having a GnRH antagonist protocol with 194 receiving an hCG trigger. All patients had ≥18 follicles ≥11mm or serum oestradiol >18,000pmol/l on the day of trigger. Patients had a single or double embryo transfer at cleavage or blastocyst stage. Logistic regression was used to adjust for differences between the groups. An intention-to-treat analysis of all cycles was performed. No statistically significant differences were observed in terms of positive pregnancy test, clinical pregnancy rate and live birth rate. Only one patient (0.3%) was hospitalized with severe OHSS in the GnRHa group, compared to 26 patients (13%) in the hCG group. In conclusion, GnRHa trigger is associated with similar pregnancy rates with hCG trigger and a significant reduction in hospitalization for severe OHSS after an intention to treat analysis was performed.

Rescue hCG to treat empty follicle syndrome after the use of a GnRH agonist as oocyte maturation trigger: First report on fresh embryo transfer and clinical pregnancy.

We present a case series and literature review on the use of rescue human chorionic gonadotropin (hCG) in cases of empty follicle syndrome (EFS) after a gonadotropin-releasing hormone agonist (GnRHa) trigger. EFS was diagnosed after failure to collect any oocytes from one ovary. In such cases, a single dose of hCG was administered and the oocyte retrieval was repeated 36 h later. The main outcome measures were the number of mature oocytes (M2) and embryos (2PN), incidence of hospitalisation for severe ovarian hyperstimulation syndrome (OHSS) and clinical pregnancy when fresh embryo transfers occurred. Our population consisted of 322 patients, who had a GnRH agonist as oocyte maturation trigger (2-mg subcutaneous buserelin). Six patients (1.8%) developed EFS after the use of a GnRHa trigger. Mature oocytes were retrieved in 5 patients after the use of rescue hCG. One patient developed severe OHSS. Two patients had a fresh embryo transfer and one clinical pregnancy was reported. This is the first case series to report fresh embryo transfers and a clinical pregnancy with the use of rescue hCG after failure of the GnRHa trigger.

Predicting formation of adhesions after gynaecological surgery: development of a risk score.

PURPOSE: Risk factors for post-surgical adhesions following gynaecological surgery have been identified, but their relative importance has not been precisely determined. No practical tool exists to help gynaecological surgeons evaluate the risk of adhesions in their patients. The purpose of the study was to develop an Adhesion Risk Score to provide a simple tool that will enable gynaecological surgeons to routinely quantify the risk of post-surgical adhesions in individual patients. METHODS: A group of European gynaecological surgeons searched the literature to identify the risk factors and the surgical operations reported as carrying a risk of post-surgical adhesions. Through consensus process of meetings and communication, a four-point scale was then used by each surgeon to attribute a specific weight to each item and collective agreement reached on identified risk factors and their relative importance to allow construct of a useable risk score. RESULTS: Ten preoperative and 10 intraoperative risk factors were identified and weighed, leading to the creation of two sub-scores to identify women at risk prior to and during surgery. The Preoperative Risk Score can range from 0 to 36, and the Intraoperative Risk Score from 3 to 31. Several thresholds between these limits may be used to identify women with low, medium, and high risk of post-surgical adhesions. CONCLUSIONS: Gynaecological surgeons are encouraged to use this Adhesion Risk Score to identify the risk of adhesions in their patients. This will allow better informed use of available resources to target preventive measures in women at high risk of post-surgical adhesions.

Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy.

CONTEXT: In vitro fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication, ovarian hyperstimulation syndrome (OHSS). OBJECTIVE: This study aimed to investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS. SETTING AND DESIGN: This was a phase 2, multi-dose, open-label, randomized clinical trial of 60 women at high risk of developing OHSS carried out during 2013-2014 at Hammersmith Hospital IVF unit, London, United Kingdom. INTERVENTION: Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomly assigned to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2 nmol/kg, n = 5; 6.4 nmol/kg, n = 20; 9.6 nmol/kg, n = 15; 12.8 nmol/kg, n = 20). Oocytes were retrieved 36 h after kisspeptin-54 administration, assessed for maturation, and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS. MAIN OUTCOME MEASURE: Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥ 14 mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy. RESULTS: Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8 nmol/kg kisspeptin-54, which was +69% (confidence interval, -16-153%) greater than following 3.2 nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy, and live birth rates per transfer (n = 51) were 63, 53, and 45%, respectively. Highest pregnancy rates were observed following 9.6 nmol/kg kisspeptin-54 (85, 77, and 62%, respectively). No woman developed moderate, severe, or critical OHSS. CONCLUSION: Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization.

BACKGROUND: Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy. METHODS: Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. RESULTS: Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54-treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively. CONCLUSION: This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01667406.

Role of Insulin-like growth factors in initiation of follicle growth in normal and polycystic human ovaries.

CONTEXT: Polycystic ovary syndrome (PCOS), the commonest cause of anovulatory infertility, is characterized by disordered follicle development including increased activation and accelerated growth of preantral follicles. Data from experimental animals and preliminary results from studies of human ovarian tissue suggest that IGFs affect preantral follicle development. OBJECTIVE: Our objectives were to investigate the expression of the type-1 IGF receptor (IGFR-1) in the human ovary and to determine whether IGFs are involved in stimulating the transition of follicles from primordial to primary stage in normal and polycystic ovaries. DESIGN: We used archived ovarian tissue for protein expression studies and small cortical biopsies for follicle isolation and for tissue culture. SETTING: This was a laboratory-based study, using clinical tissue samples. PATIENTS: A total of 54 women, 33 with normal ovaries and 21 with polycystic ovaries, were classified by reference to menstrual cycle history and ultrasonography. MAIN OUTCOME MEASURES: We evaluated expression of IGFR-1 mRNA in isolated preantral follicles and of IGFR-1 protein in archived ovarian tissue samples from normal and polycystic ovaries and effects of exogenous IGF-1 on preantral follicle development and survival in cultured fragments of normal and polycystic ovaries. RESULTS: IGFR-1 mRNA and protein was expressed in preantral follicles at all stages of development and enhanced expression was noted in PCOS follicles during early preantral development. IGF-1 stimulated initiation of follicle growth in normal tissue but had little effect on preantral follicle growth in polycystic ovaries in which, characteristically, there was a higher proportion of follicles that had entered the growing phase even before culture. CONCLUSIONS: IGFs are plausible candidates in regulation of initiation of human follicle growth, and accelerated preantral follicle growth in PCOS may be due to increased activity of endogenous IGFs.

The current place of tubal surgery in the management of subfertility.

Treatment of tubal disease can be challenging and complex. It requires accurate assessment of the extent of disease and evaluation of all fertility parameters. Although traditionally treatment involved salpingectomy or IVF or a combination of the two, less invasive treatment options may prove beneficial. We evaluated the various diagnostic tools for disease assessment and the treatment options available.

Endocrinological insights into different in vitro fertilization treatment aspects.

The science of reproductive endocrinology/in vitro fertilization (IVF) has moved forward considerably since the first IVF baby was born in 1978. IVF was originally indicated for women with tubal factor infertility, but it has now become the treatment for couples with unexplained subfertility, male subfertility, cervical factor, failed ovulation induction, endometriosis or unilateral tubal pathology. IVF was initially performed with the single dominant ovarian follicle produced during a spontaneous menstrual cycle. This was very inefficient and pregnancy rates were dismal. Consequently, superovulation protocols using parenteral gonadotrophins to induce maturation of multiple follicles were soon adopted worldwide. In addition, any supernumerary embryos remaining after embryo transfer may be cryopreserved for future embryo transfers without the need for another fresh IVF cycle. A greater understanding of IVF endocrinology has led to improved IVF pregnancy outcomes and satisfaction for the anxious parents. However, with the greater success of IVF treatment, new complications associated with the treatment arise, namely the ovarian hyperstimulation syndrome. Ovarian hyperstimulation can be associated with severe morbidity and may be even fatal. Ovarian hyperstimulation syndrome is an iatrogenic condition secondary to medical stimulation of the ovary, and was virtually unknown until IVF treatment was initiated. This article will discuss the recent developments in IVF treatment endocrinology and protocols, as well as prevention/treatment of its complications.

Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure.

Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations. Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival, is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional importance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling and abolished embryo implantation. By contrast, implantation was unhindered in Sgk1-/- mice, but pregnancy was often complicated by bleeding at the decidual-placental interface and fetal growth retardation and subsequent demise. Compared to wild-type mice, Sgk1-/- mice had gross impairment of pregnancy-dependent induction of genes involved in oxidative stress defenses. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from human subjects with RPL and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.