A decrease in endometrial thickness before embryo transfer is not associated with preterm birth and placenta-mediated pregnancy complications.

RESEARCH QUESTION: Does a decrease in endometrial thickness (compaction ≥10%) before embryo transfer prognosticate the risk for preterm birth and placenta-mediated pregnancy complications among IVF pregnancies? DESIGN: Retrospective cohort study at a large private fertility practice. Patients with a singleton live birth after a fresh or frozen embryo transfer between 2016 and 2019 were included. The primary outcome was preterm birth (delivery before 37 weeks gestational age). Secondary outcomes included gestational hypertension, pre-eclampsia, intrauterine growth restriction and placental abruption. RESULTS: Of the 252 patients that met the study criteria, 122 (48%) demonstrated endometrial compaction (≥10%) and 130 (52%) did not. Age, body mass index (BMI), parity, history of preterm birth or history of pre-existing maternal conditions between the compaction and no-compaction groups were not significantly different. The overall prevalence of placenta-mediated complications across all participants was 25% (n = 62). The number of preterm births between the compaction and no-compaction groups (13% and 6%, respectively, P = 0.09) as well as the prevalence of placenta-mediated complications (29.5% and 20%, respectively, P = 0.08) were not significantly different. Findings for the primary outcome (preterm birth) persisted even after adjustment for potential confounding variables, including maternal age, parity, BMI, embryo score and type of embryo transfer (fresh versus frozen) (adjusted OR 1.86, 95% CI 0.64 to 5.38). CONCLUSIONS: Endometrial compaction (or decrease in endometrial thickness) before embryo transfer is not associated with preterm birth or placenta-mediated pregnancy complications.

PGT-A: Houston, we have a problem.

Preimplantation genetic testing for aneuploidy (PGT-A) is a common add-on to IVF cycles. As it is presently performed, PGT-A relies on whole genome amplification of small amounts of DNA from cells removed from the trophectoderm (TE) of a blastocyst for determination of gain or loss of chromosomal material by next-generation sequencing. Whole genome amplification may introduce artifacts such as allele dropout and loss of heterozygosity in up to 25% of cases. In addition, the high prevalence of mosaicism in human embryos is a complicating factor in interpreting the results of PGT-A screening. In the presence of mosaicism, biopsy of TE cells cannot provide accurate results regarding the chromosomal make-up of the inner cell mass. The available clinical data suggest that PGT-A is probably harmful when IVF outcomes are analyzed by intention to treat or by live birth rate per cycle started rather than per embryo transfer, especially in women with three or fewer blastocysts. In addition, hypothesized advantages of reduced spontaneous abortion rate and reduced time to conception may be modest at best.

Preimplantation genetic testing for aneuploidy in patients with low embryo numbers: benefit or harm?

PURPOSE: We sought to explore the utility of preimplantation genetic testing for aneuploidy (PGT-A) in a poor prognosis group of women with few embryos available for transfer. METHODS: This was a retrospective matched cohort study examining records for first or second-cycle IVF patients with 1 to 3 blastocysts. The study group comprised 130 patients who underwent PGT-A on all embryos. The control group included 130 patients matched by age, BMI, and blastocyst number and quality who did not undergo PGT-A during the same time period. RESULTS: The live birth rate (LBR) per embryo transfer (ET) were similar in the PGT-A and control groups, and the spontaneous abortion (SAB) rate was the same (23%). However, we found a significantly higher LBR per oocyte retrieval in the control group vs the PGT-A group (43% vs 20%, respectively) likely due to the many no-euploid cycles in the PGT-A group. In a subgroup analysis for age, the similar LBR per ET persisted in women < 38. However, in older women, there was a trend to a higher LBR per ET in the PGT-A group (43%) vs the control group (22%) but a higher LBR per oocyte retrieval in the control group (31%) vs the PGT-A group (13%). CONCLUSIONS: Overall, we observed a significant increase in LBR per oocyte retrieval in women in the control group compared to women undergoing PGT-A, and no difference in SAB rate. Our data suggests that PGT-A has no benefit in a subpopulation of women with few embryos and may cause harm.

Does gonadotropin-releasing hormone agonist cause luteolysis by inducing apoptosis of the human granulosa-luteal cells?

OBJECTIVES: To evaluates the effect of different modes of final follicular maturation triggering on the degree of apoptosis of granulosa cells (GCs) and the potential effect on progesterone secretion. METHODS: Thirty patients undergoing controlled ovarian hyperstimulation for IVF who received hCG, GnRH agonist, or dual trigger for final follicular maturation were included in the study. Granulosa cells were obtained at the time of oocyte retrieval. The proportion of apoptotic cells was evaluated via TUNEL and immunohistochemistry. RESULTS: The proportion of apoptotic cells was significantly higher in the GnRH agonist-alone group compared to hCG-alone and the dual trigger groups (13.5 ± 1.5% vs. 7.8% ± 1.8 vs. 10.1% ± 2, respectively, P < 0.01). Moreover, the expression of active-caspase-3 was also significantly increased in the GnRH agonist-alone group compared with the hCG-alone and the dual trigger groups (15.5% ± 2.9 vs. 8.4% ± 1.6 vs. 12.7% ± 2.6, respectively, P < 0.01). The progesterone levels measured in the granulosa-luteal cell culture medium after 24 h of incubation were similar between the three groups. CONCLUSIONS: The levels of apoptosis are increased after GnRH agonist/dual trigger. The increased apoptosis might be one of the culprit of the subsequent premature demise of the corpus luteum post GnRH agonist trigger.

Cleavage vs blastocyst stage embryos: how are they interrelating?

PURPOSE: To assess the variables that may predict which cleavage-stage embryo may develop into a blastocyst, and vice versa, to determine whether the cleavage-stage embryo morphology should be taken into consideration when transferring the embryo at the blastocyst stage. METHODS: A single center, retrospective cohort study. The study cohort included 3072 patients undergoing 3607 retrieval cycles and 23,124 embryos at the cleavage stage. We assessed the blastulation rate and evaluated which variables impact the ongoing pregnancy rate. RESULTS: High blastulation rate correlates with higher embryos' grading (I > II > III > IV > V) and higher number of blastomeres (8 > 7 > 6 > 5 > 4). 949 patients had fresh single blastocyst transfers. The ongoing pregnancy rate was 28.9% per transfer. Patients with ongoing pregnancies were significantly younger (34.3 vs. 36 years, p < 0.001), had higher number of oocyte yield (9.8 vs. 9, p = 0.02), and an increased rate of good-quality embryos transferred (70.7% vs. 47.7%, p = 0.001). When evaluating embryos progression, we found that whenever embryo developed to a good-quality blastocyst, its appearance at the cleavage stage did not affect ongoing pregnancy rate. CONCLUSION: Higher the number of blastomeres and better embryo grading were found to correlate with a higher blastulation rate. Nevertheless, if the embryo has already developed to a top-quality blastocyst, its morphology at the cleavage stage did not impact ongoing pregnancy rate.

The Affordability and Accessibility of Ontario's Publicly Funded IVF Program: A Survey of Patients.

OBJECTIVE: On December 21, 2015, the Province of Ontario created the Ontario Fertility Program to fund one cycle of in vitro fertilization (IVF) to improve IVF affordability and access for Ontarians below age 43. The objective of this study was to determine whether the Program was meeting this goal, based on the experiences of participating patients. METHODS: Participation in an electronic survey was invited through posters and brochures placed within the waiting rooms of all 25 IVF clinics providing funded IVF in Ontario and by a survey link placed on websites focused on fertility issues. RESULTS: The survey was carried out at the end of the second year of the Program (September to December 2017), with 514 participants completing >75% of it. Program strengths were noted as follows: decreases in financial inequities of family building for the infertile; lowering of the opportunity cost of accessing IVF; and destigmatizing and raising public awareness of infertility as a legitimate medical condition. Weaknesses were as follows: lack transparency and consistency in clinics' patient prioritization schemes; clinic concentration in cities leading to geographic inequities in access; and high ancillary costs being financially burdensome. The following opportunities were suggested: funding of more than one IVF cycle and its supporting medications; standardization of prioritization schemes; and tying Program access to means testing. CONCLUSION: Patients strongly support the Program and noted improved IVF affordability, but the Program's reliance on existing private clinics for treatment provision has meant unresolved geographic inequities and inconsistent prioritization schemes. Because this is the first Program study of patients' experience, the results will help policymakers determine areas to re-evaluate for continued or increased funding and opportunities to collaborate with health care providers and clinic owners to improve provision and access.

What is the optimal timing of embryo transfer when there are only one or two embryos at cleavage stage?

Today, most IVF programs have moved to blastocyst transfer but there is still uncertainty regarding when to transfer if there are only one or two embryos at the cleavage stage. The aim of this study was to compare the pregnancy rate of day 3 transfers vs. blastocyst stage transfers in patients who had only one or two embryos on day 3. We conducted a retrospective study of 102 patients with one or two cleavage stage embryos that had their embryos transferred on day 3 and 429 patients had their embryos cultured to day 5 for transfer. The number of mature oocytes (4.0 vs 4.6, p = NS) and number of cleavage stage embryos on day 3 was similar in the two groups (1.3 vs. 1.5, p = NS). The clinical pregnancy rate per retrieval (22% vs. 24.6%, p= NS) and the ongoing pregnancy rate per retrieval (20% vs. 20.2%, p = NS) was comparable between the groups. Fifty seven (13.2%) of the patients had cleavage embryo arrest and did not have an embryo to transfer on day 5. We conclude that the cumulative pregnancy rate is the same for patients with 1-2 cleavage stage embryos regardless of whether the embryo is transferred on day 3 or day 5.

N° 244 - Endométriose : Diagnostic et prise en charge (résumé/déclarations sommaires et recommandations).

OBJECTIF: Améliorer la compréhension de l'endométriose et fournir une directive clinique factuelle pour ce qui est du diagnostic et de la prise en charge de l'endométriose. ISSUES: Parmi les issues évaluées, on trouve les effets de la prise en charge médicale et chirurgicale de l'endométriose sur la morbidité et l'infertilité que connaissent les femmes. MéTHODES: Les membres du comité voué à la présente directive clinique ont été sélectionnés en fonction de leur expertise respective, et ce, en vue de représenter une gamme d'expériences pratiques et universitaires tant au niveau de la représentation géographique au Canada que du type de pratique (nous avons également cherché à nous assurer de représenter l'expertise des sous-spécialités et l'expérience en gynécologie générale). Le comité a analysé toutes les données disponibles issues de la littérature médicale (en anglais et en français), ainsi que les données disponibles issues d'un sondage mené auprès de Canadiennes. Les recommandations ont été formulées sous forme de déclarations de consensus. Le document final a été analysé et approuvé par le comité exécutif et le Conseil de la Société des obstétriciens et gynécologues du Canada. RéSULTATS: Le présent document offre un résumé des derniers résultats en ce qui concerne le diagnostic, les explorations et la prise en charge médicale et chirurgicale de l'endométriose. Les recommandations qui en résultent peuvent être adaptées par chacun des fournisseurs de soins de santé offrant ses services à des femmes qui présentent cette pathologie. CONCLUSIONS: L'endométriose est une pathologie courante et parfois débilitante qui affecte les femmes en âge de procréer. Une approche multidisciplinaire mettant en jeu une combinaison de modifications du mode de vie, de médicaments et de services paramédicaux devrait être utilisée pour limiter les effets de cette pathologie sur les activités de la vie quotidienne et la fertilité. Dans certaines circonstances, le recours à la chirurgie s'avère nécessaire pour confirmer le diagnostic et fournir un traitement cherchant à atteindre l'objectif visé en matière de soulagement de la douleur ou d'amélioration de la fertilité. Les femmes qui obtiennent une stratégie acceptable de prise en charge de cette pathologie peuvent connaître une amélioration de leur qualité de vie ou atteindre leur objectif quant à l'obtention d'une grossesse réussie. DONNéES: Des recherches ont été menées dans les bases de données Medline et Cochrane en vue d'en tirer les articles publiés, en anglais et en français, entre janvier 1999 et octobre 2009 sur les sujets liés à l'endométriose, à la douleur pelvienne et à l'infertilité, et ce, en vue de la rédaction d'une directive clinique de consensus canadienne sur la prise en charge de l'endométriose. VALEURS: La qualité des résultats a été évaluée au moyen des critères décrits par le Groupe d'étude canadien sur les soins de santé préventifs. Les recommandations quant à la pratique ont été classées en fonction de la méthode décrite par le groupe d'étude. Reportez-vous au Tableau 1. AVANTAGES, DéSAVANTAGES ET COûTS: La mise en œuvre des recommandations de la présente directive clinique entraînera l'amélioration des soins offerts aux femmes dont les douleurs et l'infertilité sont associées à l'endométriose.

Sub-endometrial contractility or computer-enhanced 3-D modeling scoring of the endometrium before embryo transfer: are they better than measuring endometrial thickness?

PURPOSE: Recent studies have focused on transvaginal ultrasound measurement (TVUS) of sub-endometrial contractility and computer-enhanced 3-D modeling scoring of the endometrium prior to embryo transfer (ET).The aim of this study was to compare pregnancy outcome of patients who performed the 3-D scoring or the sub-endometrial measurement prior to the ET with patients that did not perform those procedures. METHODS: A single center retrospective cohort study of 635 freeze/thaw cycles of blastocysts vitrified on day 5 and transferred between January 2016 and August 2016. RESULTS: We compared the patients who performed 3-D scoring with the control group and found comparable patients' characteristics, clinical pregnancy rates (42% vs. 44.3, p = NS, respectively), and ongoing pregnancy rates (31.7% vs. 33.9%, p = NS).We then compared the patients who performed the sub-endometrial wave measurements with the control group and found similar findings. The clinical pregnancy rate (38.2% vs. 44.3, p = NS, respectively) and the ongoing pregnancy rate (30.8% vs. 33.9%) were comparable between the two groups. We performed a regression analysis to examine the independent contribution of different variables to the ongoing pregnancy rates. Both the 3-D and the wave count procedures were not found to have any influence on the ongoing pregnancy rates. CONCLUSIONS: Although new ultrasonic methods of evaluating the endometrium have been proposed during the last years, these methods have not been shown to improve the pregnancy rates compared to the original method of assessing the endometrium by measuring the endometrial thickness.

The VEGF and PEDF levels in the follicular fluid of patients co- treated with LETROZOLE and gonadotropins during the stimulation cycle.

BACKGROUND: Previous studies have shown that androgens, in addition to serving as precursors for ovarian estrogen synthesis, also have a fundamental role in primate ovarian follicular development by augmentation of FSH receptor expression on granulosa cells. Recent studies have shown that aromatase inhibitor, letrozole, improves ovarian response to FSH in normal and poor responder patients, possibly by increasing intraovarian androgen levels. Studies in mice also showed an effect of letrozole to increase pigment epithelium-derived factor (PEDF) and to lower vascular epithelial growth factor (VEGF), which might be expected to reduce the risk of ovarian hyperstimulation syndrome (OHSS) with stimulation. The aim of this study was to compare the VEGF and PEDF levels in the follicular fluids of normal responders treated with letrozole and gonadotropins during the ovarian stimulation with patients treated with gonadotropins only. METHODS: A single center, prospective clinical trial. We collected follicular fluid from 26 patients, on a GnRH antagonist protocol, dual triggered with hCG and GnRH agonist. The patients in one group were co-treated with letrozole and gonadotropins during the ovarian stimulation and the patients in the other group were treated with gonadotropins only. VEGF, PEDF, estrogen, progesterone and testosterone levels were measured by ELISA kits. RESULTS: The age of the patients, the total dose of gonadotropins and the number of oocytes were comparable between the two groups. In the follicular fluid, the estrogen levels (2209 nmol/l vs. 3280 nmol/l, p = 0.02) were significantly decreased, and the testosterone levels (246.5 nmol/l vs. 40.7 nmol/l, p < 0.001) were significantly increased in the letrozole group compared to the gonadotropin only group. The progesterone levels (21.4 µmol/l vs. 17.5 p = NS) were comparable between the two groups. The VEGF levels (2992 pg/ml vs. 1812 pg/ml p = 0.02) were significantly increased and the PEDF levels (9.7 ng/ml vs 17.3 ng/ml p < 0.001) were significantly decreased in the letrozole group. CONCLUSIONS: Opposite to observations in the mouse, we found that VEGF levels were increased and PEDF levels were decreased in the follicular fluid in patients treated with letrozole during the stimulation cycles. Further investigation is required to determine if patients treated with letrozole during the IVF stimulation protocol are at increased risk for developing OHSS as a result of these findings.

Oral contraceptive pills as an option for non-surgical management of retained products of conception - a preliminary study.

Many Patients with persistent retained products of conception prefers to avoid surgical interventions, such as a dilatation and curettage (D&C) that might pose an additional future risk to their already compromised fertility or obstetric performance. The aim of this study was to the possibility of induced withdrawal bleeding following oral contraceptive administration as a non-surgical treatment for patients with persistent retained products of conception (RPOC). A retrospective study of patients presenting with retained products of conception (RPOC) after failed expectant management or after treatment with PGE1 was performed. Twelve women presenting with RPOC at ≤8 weeks gestation with minimal to mild vaginal bleeding and no signs of infection were treated with oral contraceptive pill (OCP) containing 0.03 mg ethinylestradiol and 0.15 mg of desogestrel for 3 weeks. Out of the 12 patients treated, nine women (75%) successfully expelled the RPOC after completing the three-week course of OCPs. The three cases (25%) that did not resolve following OCP treatment had pregnancy products with positive blood flow on Doppler examination. We conclude that OCPs may be a useful medical treatment option for persisting RPOC in selected patients with absence blood flow on Doppler examination wishing to avoid surgical intervention.

Intramuscular versus Vaginal Progesterone Administration in Medicated Frozen Embryo Transfer Cycles: A Randomized Clinical Trial Assessing Sub-Endometrial Contractions.

OBJECTIVE: The study aimed to assess whether sub-endometrial contractility is reduced by the use of intramuscular (IM) progesterone. DESIGN: This is a randomized clinical trial. Patients assigned to a medicated day 5 frozen embryo transfer (FET) were randomly allocated to "vaginal progesterone" or "IM progesterone": patients randomized to the vaginal arm were treated with 200 mg micronized progesterone 3 times daily while patients randomized into the IM progesterone arm were treated with a single daily injection of 50 mg progesterone in oil. The main outcome measure was the number of sub-endometrial contractions (waves) per minute 1 day before a blastocyst embryo transfer. RESULTS: Thirty-four patients were enrolled. The progesterone serum concentration was significantly higher in patients using the IM progesterone (85.2 ± 50.1 vs. 30.3 ± 11.2 nmol/L, respectively) but this did not translate into a lower sub-endometrial contractility (2.4 ± 4.8 vs. 1.4 ± 1.1 contraction/min, respectively). Clinical pregnancy rates were comparable between groups. The number of sub-endometrial waves was significantly lower among pregnant patients (p = 0.02). CONCLUSIONS: The use of IM progesterone in medicated FET cycles does not reduce the sub-endometrial activity compared to vaginal progesterone administration. Our data support a poor clinical pregnancy outcome with high wave activity, regardless of the progesterone mode.

Prolonged culture of blastocysts after thawing as a tool for improving prediction of success.

PURPOSE: A few years ago, we started to use a new freeze-thaw protocol for the frozen embryo transfer cycles. Instead of thawing the embryos 2-4 h prior to the transfer, we started thawing the embryos 20-22 h prior to the transfer. The aim of this study was to compare the pregnancy rate in cases of embryos that continued to develop in the post-thawing culture to that of embryos that did not. METHODS: A retrospective cohort study of blastocyst freeze/thaw cycles vitrified on day 5, thawed and transferred after 20-22 h in the culture, between January 2012 and December 2016. RESULTS: A total of 375 patients were included in the analysis. Two hundred twenty-eight embryos graded as good, 87 graded as fair, and 60 graded as poor embryos were transferred. The clinical pregnancy rate (50% vs. 19.5% vs 3.3% p < 0.01) and the ongoing pregnancy rate (38.5% vs. 13.6% vs 1.7% p < 0.01) were higher in cases of good embryo quality compared with fair and poor-quality embryos, respectively. For good embryos, progressing to a better grade during the culture did not change the clinical pregnancy rate (51.3% vs. 46.2% p = NS) or the ongoing pregnancy rate (38.5% vs. 37.5% p = NS). For fair embryos, progressing to a better grade during the culture resulted in a higher clinical pregnancy rate (25.4% vs 9% p = 0.05). CONCLUSIONS: The development of the fair embryos in the culture has a highly positive impact on the pregnancy rate and this factor should be taken into consideration before deciding how many embryos to transfer.

Does the endometrial receptivity array really provide personalized embryo transfer?

PURPOSE: The aim of the present study was to determine the percentage of infertility patients who are diagnosed with a non-receptive endometrium according to the endometrial receptivity array (ERA) test and to examine whether adjusting the embryo transfer day according to the proposed shift in the window of implantation improves the pregnancy rate compared to non-ERA-tested patients. METHODS: A single-center retrospective cohort study, including 53 consecutive good prognosis patients (0-2 previous frozen embryo transfers) admitted to our IVF unit for a mock cycle prior to their frozen day-5 embryo (blastocyst) transfer cycle. The mock cycle included an endometrial biopsy for both the ERA test and histological assessment by the Noyes criteria (study group). The next cycle frozen embryo transfer (FET) in the study group was adjusted according to the ERA results. The control group consisted of patients who underwent FET cycles at our clinic during the same period, without performing the endometrial biopsy and ERA testing. RESULTS: During the study period, 503 patients (control group) underwent FET cycles without performing the ERA testing and 41 patients had FET following an ERA test. There were no between-group differences in patients' age, number of previous transfers, endometrial thickness, number of transferred embryos, and ongoing pregnancy rates (35.2 vs. 39%, respectively, p = NS). Out of the 53 patients who performed the ERA test before their first or second FET, five endometrial samples (9.4%) were found to be post-receptive, 29 (54.7%) pre-receptive, and only 19 samples (35.8%) were receptive. Women in the study group with pre- or post-receptive endometrium on ERA testing, the appropriate adjustment in timing of FET according to the ERA test resulted in a 33.3% pregnancy rate, which is comparable to the 35.2% background ongoing pregnancy rate of the control group. CONCLUSIONS: Performing the ERA test in a mock cycle prior to a FET does not seem to improve the ongoing pregnancy rate in good prognosis patients. Further large prospective studies are needed to elucidate the role of ERA testing in both good prognosis patients and in patients with recurrent implantation failure.

Does daily co-administration of letrozole and gonadotropins during ovarian stimulation improve IVF outcome?

BACKGROUND: For the last year we have been treating normal responders with gonadotropins and letrozole during the whole stimulation in order to improve response to FSH by increasing the intrafollicular androgen concentration, and to reduce circulating estrogen concentrations. The aim of this study was to compare the IVF outcome of normal responders treated with letrozole and gonadotropins during ovarian stimulation with patients treated with gonadotropins only. METHODS: A single centre retrospective cohort study of 174 patients (87 in each group). RESULTS: The age of the patients was comparable between the groups. Estradiol levels were significantly higher in the control group (6760 pmol/L vs. 2420 pmol/L respectively, p < 0.01), and the number of follicles ≥15 mm at the trigger day was significantly lower in the control group (7.9 vs. 10, p = 0.02). The number of retrieved oocytes (10 vs. 14.5, p < 0.01), MII oocytes (7.9 vs. 11.2, p < 0.01) and blastocysts (2.7 vs. 4.0, p = 0.02) was significantly higher in the study group. We found no significant differences in the cumulative pregnancy outcome between the two groups (65.2% vs 58.3% p = NS). CONCLUSIONS: We conclude that co-treatment with letrozole improves the IVF outcome in normal responders in terms of increased number of blastocysts obtained without increasing the pregnancy rate or the risk of OHSS.

Case Report: Use of Tumor and Germline Y Chromosomal Analysis to Guide Surgical Management in a 46, XX Female Presenting With Gonadoblastoma With Dysgerminoma.

Gonadoblastomas are rare mixed gonadal tumors that are almost always found in individuals with 46, XY karyotype or some other form of Y chromosome mosaicism. It is extremely rare to diagnose gonadoblastoma in phenotypically normal 46, XX females. Herein, we present a 20-year-old 46, XX female diagnosed with gonadoblastoma and dysgerminoma. Use of cytogenetic and molecular analyses to identify the presence of Y chromosome material in peripheral blood, gonadal, and tumor tissue can exclude mosaicism to provide reassurance to undertake conservative surgical management and preserve fertility.

Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways.