Uterine Notch2 facilitates pregnancy recognition and corpus luteum maintenance via upregulating decidual Prl8a2.

The maternal recognition of pregnancy is a necessary prerequisite for gestation maintenance through prolonging the corpus luteum lifespan and ensuring progesterone production. In addition to pituitary prolactin and placental lactogens, decidual derived prolactin family members have been presumed to possess luteotropic effect. However, there was a lack of convincing evidence to support this hypothesis. Here, we unveiled an essential role of uterine Notch2 in pregnancy recognition and corpus luteum maintenance. Uterine-specific deletion of Notch2 did not affect female fertility. Nevertheless, the expression of decidual Prl8a2, a member of the prolactin family, was downregulated due to Notch2 ablation. Subsequently, we interrupted pituitary prolactin function to determine the luteotropic role of the decidua by employing the lipopolysaccharide-induced prolactin resistance model, or blocking the prolactin signaling by prolactin receptor-Fc fusion protein, or repressing pituitary prolactin release by dopamine receptor agonist bromocriptine, and found that Notch2-deficient females were more sensitive to these stresses and ended up in pregnancy loss resulting from abnormal corpus luteum function and insufficient serum progesterone level. Overexpression of Prl8a2 in Notch2 knockout mice rescued lipopolysaccharide-induced abortion, highlighting its luteotropic function. Further investigation adopting Rbpj knockout and DNMAML overexpression mouse models along with chromatin immunoprecipitation assay and luciferase analysis confirmed that Prl8a2 was regulated by the canonical Notch signaling. Collectively, our findings demonstrated that decidual prolactin members, under the control of uterine Notch signaling, assisted pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, which was conducive to pregnancy recognition and maintenance.

Effect of chronic administration of a gonadotropin-releasing agonist on luteal function and pregnancy rates in dairy cattle.

Increased embryonic losses may be associated with inadequate progesterone (P4) concentrations in high-producing lactating dairy cattle. The objectives of the present studies were to determine if chronic administration of a gonadotropin-releasing hormone (GnRH) agonist, Deslorelin, would increase circulating P4 concentrations and subsequently increase pregnancy rates in dairy cattle. Administration of Deslorelin for 12 days increased (p < .05) luteal volume and circulating P4 concentrations in primiparous lactating dairy cows, but increased only luteal volumes in multiparous cows. Treatment with Deslorelin increased Day 45 pregnancy rates in cows as compared to untreated controls. Chronic treatment with Deslorelin in dairy cattle; (a) increased luteal volume of the primary CL, (b) induced accessory CL, (c) increased circulating P4 concentration in primiparous cows only, (d) did not lengthen the estrous cycle upon removal of treatment, and (e) increased pregnancy rates. Although luteal volume was increased in multiparous cows and circulating P4 concentrations were not with Deslorelin treatment, there was an apparent effect on pregnancy rates. This hormonal strategy may represent a suitable model to address local effects of P4 and GnRH/luteinizing hormone on uterine environment and subsequent embryonic survival.

Oral dydrogesterone vs. vaginal progesterone capsules for luteal-phase support in women undergoing embryo transfer: a systematic review and meta-analysis.

OBJECTIVE: To identify, appraise, and summarize the evidence from randomized controlled trials (RCTs) comparing oral dydrogesterone to vaginal progesterone capsules for luteal-phase support (LPS) in women offered fresh or frozen embryo transfers following in vitro fertilization. METHODS: Two independent authors screened the literature for papers based on titles and abstracts, then selected the studies, extracted data, and assessed the risk of bias. Dydrogesterone and progesterone were compared based on risk ratios (RR) and the precision of the estimates was assessed through the 95% confidence interval (CI). RESULTS: An electronic search performed on June 7, 2017 retrieved 376 records, nine of which were papers deemed eligible and included in this systematic review and quantitative analysis. Good quality evidence indicates that oral dydrogesterone provided at least similar results than vaginal progesterone capsules on live birth/ongoing pregnancy (RR=1.08, 95%CI=0.92-1.26, I2=29%, 8 RCTs, 3,386 women) and clinical pregnancy rates (RR 1.10, 95% CI 0.95 to 1.27; I2=43%; 9 RCTs; 4,061 women). Additionally, moderate quality evidence suggests there is no relevant difference on miscarriage rates (RR=0.92, 95%CI=0.68-1.26, I2=6%, 8 RCTs, 988 clinical pregnancies; the quality of the evidence was downgraded because of imprecision). CONCLUSIONS: Good quality evidence from RCTs suggest that oral dydrogesterone provides at least similar reproductive outcomes than vaginal progesterone capsules when used for LPS in women undergoing embryo transfers. Dydrogesterone is a reasonable option and the choice of either of the medications should be based on cost and side effects.

Gonadotropin-releasing hormone agonist (GnRHa) trigger - State of the art.

GnRH agonist (GnRHa) trigger for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI cycles significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS). GnRHa trigger followed by modifications of the standard luteal phase support (modified luteal phase support) secures fresh transfer in the majority of patients with excellent reproductive outcomes. In freeze all cycles (segmented cycles) GnRHa trigger allows oocyte retrieval with a minimal risk of early onset OHSS and good reproductive outcomes in subsequent frozen thaw cycles. Overall, two different luteal phase support strategies have been proposed when a fresh transfer is performed after GnRHa trigger. These involve either boosting the endogenous steroid production or adding exogenous steroids. The present review discusses the advancement of GnRHa trigger in fresh and segmented cycles and how a modified luteal phase support policy in fresh transfer cycles results in good reproductive outcomes as well as a high safety in terms of OHSS reduction. Finally, the new concept of an individualized luteal phase support policy taking the number of pre-ovulatory follicles into account when planning a fresh transfer in GnRHa triggered IVF/ICSI cycle is discussed.

Live birth rates are satisfactory following multiple IVF treatment cycles in poor prognosis patients.

This seven-year retrospective study analysed the live birth rate (LBR) for women undergoing IVF treatment with various antral follicle counts (AFC). The LBR decreased with lower AFC ratings, and in 290 treatment cycles for women in the poorest AFC category, ≤4 follicles (group E), the LBR was the lowest at 10.7%. The pregnancy loss rate (PLR) significantly increased with poorer AFC categories, from 21.8% in AFC group A (≥20 follicles), to 54.4% in AFC group E (p<0.0001). This trend was repeated with advancing age, from 21.6% for younger women (<35years), to 32.9, 48.5 and 100% for ages 35-39, 40-44 and ≥45 years, respectively (p<0.0001). However, LBR within the specific AFC group E cohort was also age-dependent and decreased significantly from 30.0% for <35 years old, to 13.3, 3.9 and 0% for patients aged 35-39, 40-44 and ≥45 years, respectively. Most, importantly, LBR rates within these age groups were not dependent on the number of IVF attempts (1st, 2nd, 3rd or ≥4 cycles), which indicated that cycle number should not be the primary deciding factor for cessation of IVF treatment in responding women <45years old.

Effect of combined exogenous progesterone with luteotrophic support via equine chorionic gonadotrophin (eCG) on corpus luteum development, circulating progesterone concentrations and embryo development in cattle.

The aim was to examine the effect of a single intramuscular (i.m.) injection of equine chorionic gonadotrophin (eCG) on Day 3 after oestrus on corpus luteum (CL) development, circulating progesterone and conceptus development in cross-bred beef heifers. In Experiment 1, heifers received: (1) saline, or a single i.m. injection of eCG on Day 3 at (2) 250IU (3) 500IU (4) 750IU or (5) 1000IU. Administration of eCG resulted in increased luteal tissue area and progesterone and oestradiol concentrations compared with controls. In Experiment 2, heifers received (1) a progesterone-releasing intravaginal device (PRID Delta) from Day 3 to 5 or (2) a PRID Delta from Day 3 to 5 plus a single injection of 750IU eCG on Day 3. In vitro-produced blastocysts (n=10 per recipient) were transferred on Day 7 and heifers were slaughtered on Day 14 to assess conceptus development. Administration of eCG reduced the number of short cycles (6.3% vs 31.3%) and increased mean luteal tissue weight (P=0.02). Insertion of a PRID Delta on Day 3 resulted in an elevation (P<0.05) in serum progesterone until removal on Day 5. Administration of eCG at the time of PRID Delta insertion resulted in higher progesterone levels (P<0.05) from Day 10 onwards. Conceptus dimensions were not affected. In conclusion, a single injection of eCG on Day 3 increased CL size and progesterone concentrations and, when given in conjunction with a progesterone-releasing device, appeared to reduce the number of short cycles, presumably due to its luteotrophic nature. The implications of the elevated oestradiol concentrations for embryo quality require further study.

Exposure to di(2-ethylhexyl) phthalate inhibits luteal function via dysregulation of CD31 and prostaglandin F2alpha in pregnant mice.

BACKGROUND: Di(2-ethylhexyl) phthalate (DEHP) exposure reduces embryo implantations, increases embryonic loss, and decreases fetal body weights. However, whether it is associated with the alteration of luteal function remains unknown. Thus, our aim in this study was to explore the effect and mechanism of DEHP on luteal function in pregnant mice in vivo. METHODS: Mice were administered DEHP by gavage at 125, 250, 500 mg/kg/day from gestational days (GD) 1 to 9 or 13. Levels of serum progesterone and estradiol were measured by radioimmunoassay. The numbers and sizes of corpora lutea were calculated by ovarian histomorphology. Steroidogenic enzymes were assessed by qRT-PCR. CD31 protein was detected by immunocytochemistry, and prostaglandin F2alpha (PGF2alpha) levels were evaluated by enzyme immunoassay. RESULTS: Treatment with DEHP significantly inhibited progesterone secretion in pregnant mice in a dose-dependent manner but did not inhibit estradiol production on GD 9 and 13. Treatment also showed concomitant decreases in transcript levels for key steroidogenic enzymes (CYP11A, 3ß-HSD, and StAR) on GD 13. Furthermore, DEHP administration significantly reduced the numbers and sizes of corpora lutea on GD 13. No significant changes in the ratio of ovary weight vs. body weight were observed between the control group and treated animals on GD 9 and 13. In addition, treatment with DEHP significantly inhibited CD31 expression of corpora lutea, whereas plasma PGF2alpha levels in DEHP treatment groups were significantly higher compared with the control groups on GD 9 and 13. CONCLUSIONS: The results show DEHP significantly inhibits luteal function of pregnant mice in vivo, with a mechanism that seems to involve the down-regulation of progesterone and steroidogenic enzymes message RNA, the decrease in CD31 expression, and the increase in PGF2alpha secretion.

Duration of luteal support after IVF is important, so why is there no consistency in practice? The results of a dynamic survey of practice in the United Kingdom.

Luteal support is considered as an essential component of IVF treatment following ovarian stimulation and embryo transfer. Several studies have consistently demonstrated a benefit of luteal support compared with no treatment and whilst a number of preparations are available, no product has been demonstrated as superior. There is an emerging body of evidence which suggests that extension of luteal support beyond biochemical pregnancy does not confer a benefit in terms of successful pregnancy outcome. We performed two surveys separated by 5 years of practice evolution, with the latter reporting on the use of luteal support in all IVF clinics in the UK. All clinics reported utilising luteal support with the majority favouring the use of Cyclogest 400 mg twice daily. In contrast, there was no consensus on the optimal duration of luteal support. Whilst 24% of clinics withdrew luteal support at biochemical confirmation of pregnancy, 40% continued treatment until 12 weeks gestation. Several clinics even extended luteal support beyond 12 weeks gestation. We observed no difference in practice based on the size of the IVF unit or treatment funding source. Although there was some change in practice between surveys in many clinics, there was no uniformity in the direction of change.

Which luteal phase support is better for each IVF stimulation protocol to achieve the highest pregnancy rate? A superiority randomized clinical trial.

In vitro fertilization (IVF) cycles generate abnormalities in luteal-phase sex steroid concentrations and this represent an important limiting factor to achieve a good pregnancy rate. Although there are evidences about the usefulness of luteal phase support (LPS) after IVF cycles, no consensus exist about the best dose and way of progesterone (PG) administration, the advantages of estradiol (E2) supplementation and which IVF protocol could benefit from one more than other LPS scheme. Aim of the study was to assess the best LPS (low-dose PG, high-dose PG, high-dose PG and E2 supplementation) to achieve the highest clinical/ongoing pregnancy rate according to stimulation protocol, E2 at ovulation induction, endometrial thickness at pick-up and women's age. We conducted a randomized trial on 360 women undergoing IVF (180 treated by long-GnRH agonist, 90 by short-GnRH agonist and 90 by short-GnRH antagonist protocol) and stimulated by recombinant follicle-stimulating hormone alone. Our data demonstrated that high-dose PG is better than low-dose to increase both clinical and ongoing pregnancy rate. E2 supplementation are mandatory in case of short-GnRH antagonist protocol and strongly suggested in all protocols when E2max <5 nmol/l and endometrial thickness <10 mm. In long-GnRH agonist protocols, as well as in patients >35 years, the real advantages of E2 supplementation remain debatable and require further confirmation.

Effect of luteal phase support after ovulation induction and intrauterine insemination.

OBJECTIVE: This study aimed to evaluate the effect of luteal phase support on clinical pregnancy and live birth rates after ovulation induction and intrauterine insemination (IUI). METHODS: 579 cycles from 2010 to 2013 were retrospectively evaluated. Ovarian stimulation was performed with gonadotropins, and rHCG was used for ovulation triggering. All patients received IUI. 451 cycles were supported by receiving vaginal micronized progesterone capsules (142 cycles) or vaginal progesterone gel (309 cycles) whereas 128 cycles were not supported. RESULTS: Clinical pregnancy (20.6 versus 9.4%; p = 0.004) and live birth rates (14 versus 7%; p = 0.036) were higher for supported group than for unsupported group. Progesterone gel and micronized progesterone subgroups achieved similar clinical pregnancy and live birth rates (21.4 versus 19%, p = 0.567 and 14.2 versus 13.4%, p = 0.807; respectively). CONCLUSIONS: Luteal phase support improved the success of IUI cycles affecting both clinical pregnancy and live birth rates when gonadotropins were used for ovulation induction. The use of vaginal progesterone gel or micronized progesterone significantly improves clinical pregnancy rates. The live birth rates were higher in the progesterone gel group, but were similar in the micronized progesterone group compared to the unsupported group.

Luteal phase support with progesterone in intrauterine insemination: a prospective randomized study.

OBJECTIVE: To determine the effect of vaginal progesterone as luteal support on pregnancy outcomes in infertile patients who undergo ovulation induction with gonadotropins and intrauterine insemination (IUI). DESIGN: Prospective randomized trial. SETTING: Tertiary referral center. PATIENT(S): About 398 patients with primary infertility were treated during 893 ovarian stimulation and IUI cycles from February 2010 to September 2012. METHODS: All patients underwent ovarian stimulation with gonadotropins combined with IUI. Patients in the supported group received vaginal micronized progesterone capsules 200 mg once daily from the day after insemination until next menstruation or continuing for up to 8 weeks of pregnancy. Women allocated in the control group did not receive luteal phase support. MAIN OUTCOME MEASURE(S): Livebirth rate, clinical pregnancy rate and early miscarriage rate per cycle. RESULT(S): Of the 893 cycles, a total of 111 clinical pregnancies occurred. There were no significant differences between supported with progesterone and unsupported cycle in terms of livebirth rate (10.2% versus 8.3%, respectively, with a p value = 0.874) and clinical pregnancy rate (13.8% compared with 11.0% in unsupported cycle with a p value = 0.248). An early miscarriage rate of 3.6% was observed in the supported cycles and 2.7% in the unsupported cycles, with no significant differences between the groups (p value = 0.874). CONCLUSION(S): In infertile patients treated with mildly ovarian stimulation with recombinant gonadotropins and IUI, luteal phase support with vaginal progesterone is not associated with higher livebirth rate or clinical pregnancy rate compared with patients who did not receive any luteal phase support.

Misregulated progesterone secretion and impaired pregnancy in Cyp11a1 transgenic mice.

Normal pregnancy is supported by increased levels of progesterone (P4), which is secreted from ovarian luteal cells via enzymatic steps catalyzed by P450scc (CYP11A1) and HSD3B. The development and maintenance of corpora lutea during pregnancy, however, are less well understood. Here we used Cyp11a1 transgenic mice to delineate the steps of luteal cell differentiation during pregnancy. Cyp11a1 in a bacterial artificial chromosome was injected into mouse embryos to generate transgenic mice with transgene expression that recapitulated endogenous Cyp11a1 expression. Cyp11a1 transgenic females displayed reduced pregnancy rate, impaired implantation and placentation, and decreased litter size in utero, although they produced comparable numbers of blastocysts. The differentiation of transgenic luteal cells was delayed during early pregnancy as shown by the delayed activation of genes involved in steroidogenesis and cholesterol availability. Luteal cell mitochondria were elongated, and their numbers were reduced, with morphology and numbers similar to those observed in granulosa cells. Transgenic luteal cells accumulated lipid droplets and secreted less progesterone during early pregnancy. The progesterone level returned to normal on gestation day 9 but was not properly withdrawn at term, leading to delayed stillbirth. P4 supplementation rescued the implantation rates but not the ovarian defects. Thus, overexpression of Cyp11a1 disrupts normal development of the corpus luteum, leading to progesterone insufficiency during early pregnancy. Misregulation of the progesterone production in Cyp11a1 transgenic mice during pregnancy resulted in aberrant implantation, anomalous placentation, and delayed parturition.

Oral oestradiol supplementation as luteal support in IVF/ICSI cycles: a prospective, randomized controlled study.

OBJECTIVE: To explore whether oral oestradiol (E2) supplementation (6 mg) in the luteal phase is beneficial to the outcome of patients undergoing gonadotrophin-releasing hormone agonist (GnRHa) long protocol in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. STUDY DESIGN: Prospective, randomized, controlled study at the IVF Clinic, Sun Yat-sen Memorial Hospital. In total, 402 patients with an indication for IVF or ICSI were recruited. Patients were prospectively randomized to receive either progesterone injection plus oral E2 supplementation (Group A, n=202) or progesterone injection alone (Group B, n=200) as luteal support after oocyte retrieval. The main outcome measure was the clinical pregnancy rate. RESULTS: No significant difference in the clinical pregnancy rate or miscarriage rate was observed between Group A and Group B (50.9% vs 58.0%, 14.6% vs 11.2%; p>0.05). In different age subgroups (≤35 years and >35 years) all measurements were comparable in patients with or without E2 supplementation, as well as in subgroups with different E2 levels on the day of human chorionic gonadotrophin injection (E2≥3000 pg/ml and E2<3000 pg/ml). CONCLUSION: Adding E2 as luteal support did not increase the clinical pregnancy rate or reduce the miscarriage rate. Routine use of a combination of E2 and progesterone as luteal support in GnRHa long protocol IVF/ICSI cycles is not recommended.

Premature luteal regression in a pregnant mare and subsequent pregnancy maintenance with the use of oral altrenogest.

Premature luteal demise or luteal insufficiency is not well characterised as a cause of pregnancy loss in domestic species, including horses. In this report, a mare inseminated with cooled-transported semen at our facility returned for a routine pregnancy diagnosis at 15 days post ovulation. Ultrasonography per rectum revealed endometrial oedema and the absence of visual indication of a corpus luteum on either ovary. Nonetheless, an embryonic vesicle small for the gestational age was identified. Daily oral altrenogest treatment was implemented immediately. Serum progesterone concentration was 0.67 ng/ml, which is below the threshold considered adequate for pregnancy maintenance in the mare. Examinations were repeated at 17, 25, 30, 39, 49, 72 and 120 days post ovulation. At 25 days post ovulation the embryonic vesicle presented normal development for the gestational age. In addition, sequential blood samples were collected to measure progesterone, equine chorionic gonadotrophin and oestrone sulphate concentrations. Although progesterone concentration did not exceed 2 ng/ml until 72 days post ovulation, all other results were unremarkable and a healthy filly was born uneventfully at 344 days post ovulation.

Effect of luteal-phase support on endometrial microRNA expression following controlled ovarian stimulation.

BACKGROUND: Studies suggested that microRNAs influence cellular activities in the uterus including cell differentiation and embryo implantation. In assisted reproduction cycles, luteal phase support, given to improve endometrial characteristics and to facilitate the implantation process, has been a standard practice. The effect of different types of luteal phase support using steroid hormones in relation to endometrial miRNA profiles during the peri-implantation period has not seen described. This study was designed to evaluate the expression of miRNAs during the luteal phase following controlled ovarian stimulation for IVF and the influence of different luteal phase support protocols on miRNA profiles. METHODS: The study was approved by the Johns Hopkins Hospital Institutional Review Board. Endometrial biopsies were obtained on the day of oocyte retrieval from 9 oocyte donors (group I). An additional endometrial biopsy was obtained 3-5 days later (Group II) after the donors were randomized into three groups. Group IIa had no luteal-phase support, group IIb had luteal support with micronized progesterone (P), and Group IIc had luteal support with progesterone plus 17-beta-estradiol (P + E). Total RNA was isolated and microarray analysis was performed using an Illumina miRNA expression panel. RESULTS: A total of 526 miRNAs were identified. Out of those, 216 miRNAs were differentially regulated (p < 0.05) between the comparison groups. As compared to the day of retrieval, 19, 11 and 6 miRNAs were differentially regulated more than 2 fold in the groups of no support, in the P support only, and in the P + E support respectively, 3-5 days after retrieval. During the peri-implantation period (3-5 days after retrieval) the expression of 33 and 6 miRNAs increased, while the expression of 3 and 0 miRNAs decreased, in the P alone and in the P + E group respectively as compared to the no steroid supplementation group. CONCLUSION: Luteal support following COS has a profound influence on miRNA profiles. Up or down regulation of miRNAs after P or P + E support suggest a role(s) of luteal support in the peri-implantation uterus in IVF cycles through the regulation of associated target genes.

Reproductive outcome of fresh or frozen-thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support.

BACKGROUND: Triggering ovulation by GnRH agonist (GnRHa) in GnRH antagonist IVF protocols coupled with adequate luteal phase support has recently been suggested as a means to prevent ovarian hyperstimulation syndrome (OHSS). Our objective was to examine the outcome of fresh embryo transfer (f-ET) after triggering ovulation by GnRHa and providing intensive luteal phase supplementation, compared with that of the next first frozen-thawed embryo transfer (ft-ET) after cycles with the same protocol and cryopreservation of all the embryos. METHODS: We performed a cohort study at a university-based IVF clinic. The study population was patients at high risk for OHSS. A daily dose of 50 mg i.m. progesterone in oil and 6 mg of oral 17-ß-estradiol initiated on oocyte retrieval day in the f-ET group (n= 70). In the ft-ET group (n= 40) the embryos were cryopreserved and transferred in the next cycle. RESULTS: The live birth rate per f-ET was 27.1 versus 20% in the ft-ET groups [P = 0.4; rate ratio = 1.36 (0.65-2.81)]. The implantation, pregnancy and spontaneous abortion rates were comparable in both groups. None of the patients developed OHSS. CONCLUSIONS: In this observational cohort study, we showed that triggering ovulation with GnRHa and intensive luteal phase support is a promising new modality to prevent OHSS without the cost of cycle cancellation, ET deferral and reduced clinical pregnancy rates. Confirmation of these findings by RCTs is now required.

Serum progesterone in pregnant bitches supplemented with progestin because of expected or suspected luteal insufficiency.

Progesterone profiles of individual bitches may vary considerably both between and within individuals during pregnancy and non-pregnancy. Suspected luteal deficiency is commonly purported but is difficult to evaluate in clinical cases when progesterone is supplemented because this masks the underlying hormone changes. Therefore, in this study, suspected cases of luteal deficiency (six pregnancies from five bitches) were supplemented with oral medroxyprogesterone acetate (MPA), allowing measurement of endogenous progesterone using conventional assay. MPA (0.1 mg/kg) treatment commenced between days 30 and 36 after estimated ovulation and was continued for 18-28 days. Endogenous progesterone was measured throughout treatment, and blood was additionally analysed for prolactin (PRL) and relaxin (RLN) as well as MPA. The latter revealed delayed MPA clearance in two bitches, in which Caesarean operation had to be performed because of a low foetal heart rate. In two cases with confirmed basal concentrations of both P(4) and MPA at term, spontaneous parturition occurred. Low endogenous progesterone during pregnancy was not apparent in three bitches that had previously had a short inter-oestrous interval of which two had previously had confirmed short luteal phase. However, in the remaining two cases, there had been previous pregnancy failure, but in only one of these, a premature decrease in endogenous progesterone to <2 ng/ml was detected. The latter had also low concentrations of PRL and RLN. The results of this preliminary clinical study suggest that abnormal progesterone profiles in pregnancy may be uncommon in bitches even when there has been previously documented short inter-oestrous interval. However, luteal deficiency may be suspected in bitches with a history of repeated pregnancy failure or abortion. MPA supplementation appears to be efficacious for management of suspected luteal deficiency and verification of the ovarian dysfunction, but care should be taken regarding the timing of MPA withdrawal and prolongation of pregnancy because of delayed elimination of MPA from blood circulation.

Increased live birth rates with GnRH agonist addition for luteal support in ICSI/IVF cycles: a systematic review and meta-analysis.

BACKGROUND: The aim of this systematic review and meta-analysis was to evaluate whether the addition of GnRH agonist for luteal support in ICSI/IVF cycles enhances the probability of live birth. METHODS: Systematic literature search (MEDLINE, EMBASE, CENTRAL and RCT registries) was conducted to identify relevant randomized controlled trials published as full manuscripts. Meta-analysis of data yielded pooled risk differences (RDs) and 95% confidence intervals (CIs). A random effects model was applied for pooling the studies. RESULTS: Six relevant RCTs were identified including a total of 2012 patients. The probability of live birth rate (RD: +16%, 95% CI: +10 to +22%) was significantly higher in patients who received GnRH agonist support compared with those who did not. The subgroup analysis according to the type of GnRH analogue used for LH suppression did not change the effect observed (studies in which GnRH agonist was used during ovarian stimulation, RD: +15%, 95% CI: +5 to +23%); (studies in which GnRH antagonist was used during ovarian stimulation, RD: +19%, 95% CI: +11 to +27%). CONCLUSIONS: The best available evidence suggests that GnRH agonist addition during the luteal phase significantly increases the probability of live birth rates.

Luteal phase support may improve pregnancy outcomes during intrauterine insemination cycles.

OBJECTIVES: To determine the impact of luteal phase support with vaginal progesterone on pregnancy outcomes in infertile couples undergoing intrauterine insemination when recombinant follicle-stimulating hormone was used for ovulation induction. STUDY DESIGN: This prospective randomized study was undertaken at the Infertility Unit, Armed Forces Hospital Southern Region, Kingdom of Saudi Arabia, and included 71 patients with either primary or secondary infertility who met the inclusion criteria. All 71 patients underwent intrauterine insemination. Thirty-seven were randomized to start with a supported cycle and 34 started with an unsupported cycle. In supported cycles, patients received vaginal progesterone once daily from the day after insemination for 14 days. No progesterone was given during unsupported cycles. For the second cycle, crossover occurred such that women who initially had a supported cycle underwent an unsupported cycle, and vice versa. The cycle types were alternated until the end of the study. The main outcome measures were clinical pregnancy rates and livebirth rates per cycle and per patient. RESULTS: In total, 132 supported cycles and 126 unsupported cycles were performed successfully. The clinical pregnancy rate per patient was higher for supported than unsupported cycles (54.92% vs. 35.21%, respectively; p=0.016), but the per-cycle difference was not significant (29.54% vs. 19.84%, respectively; p=0.07). Twenty-five pregnancies in supported cycles and seven pregnancies in unsupported cycles resulted in live births. When these rates were compared per cycle and per patient, significant differences were detected between the cycle types (18.9% and 35.2% vs. 5.5% and 9.8%; p=0.001 and <0.001, respectively). CONCLUSION: Luteal phase support with vaginal progesterone improved the success of intrauterine insemination cycles when recombinant follicle-stimulating hormone was used for ovulation induction. CONDENSATION: Luteal phase support may improve pregnancy outcomes during intrauterine insemination cycles, but large multicentre, placebo-controlled, double-blind trials are needed.

Oral micronized progesterone combined with vaginal progesterone gel for luteal support.

The aim of the present study was to compare the efficacy and satisfaction rate of combined therapy of oral micronized progesterone capsules and vaginal progesterone gel versus monotherapy with vaginal progesterone gel in luteal support. A case-control study was performed on a total number of 370 women aged <45 years undergoing IVF-ET treatment. The patients received either combination of Crinone 8% vaginal gel, 90 mg daily dose and Utrogestan oral capsules 3 x 100 mg, or Crinone 8% vaginal gel, 90 mg daily. Progesterone supplementation begun on the day of oocyte retrieval and continued until pregnancy was tested and in the case of pregnancy until week 8. The comparable rates of ongoing pregnancies were noted with use of combined-progesterone therapy (39.5%) and progesterone-monotherapy (33.5%). Abortion rate (6.4% vs. 15.6%) was significantly lower with the use of combined therapy. Tolerability and satisfaction of both supplements was almost equal but bleeding occurred more frequently in the progesterone-monotherapy group. In conclusion, the efficacy, satisfaction and tolerability of combined and vaginal progesterone supplements were comparable, but bleeding in early pregnancy and abortion rate presented more frequently with the use of vaginal progesterone.