A Systematic Review of the Efficacy and Safety of Didroxyprogesterone Combined with Progesterone in the Treatment of Luteal Insufficiency-Induced Abortion

Objective: To systematically evaluate the efficacy and safety of didroxyprogesterone combined with progesterone in the treatment of luteal insufficiency abortion. Methods: We searched CNKI database, VIP database, Wanfang database, PubMed database, EMBASE database and Cochrane library database for literatures on the treatment of luteal insufficiency-induced abortion with didroxyprogesterone and progesterone. Meta-analysis was performed using Revman 5.3 software after literature extraction and further quality evaluation. Results: Ten randomized controlled trial-related articles that describe studies on a total of 1145 patients, 570 in the combination group and 575 in the control group, were included. The results of meta-analysis showed that combination therapy could improve the effective rate of fetal protection (OR = 0.14, 95% CI [0.07, 0.27], P < 0.00001). The safety of the combination group was significantly higher than that of the control group (OR = 3.09, 95% CI [1.13,8.48], P = 0.03). Conclusion: To sum up, compared with the control group, the combination of progesterone and progesterone is more effective and safer in the treatment of luteal insufficiency abortion. However, the sample size of the data is relatively small and the quality of the literature is low. This conclusion still needs to be further verified in high-quality randomized controlled trials that involve large samples.

Bovine Embryonic Mortality with Special Reference to Mineral Deficiency, Heat Stress and Endocrine Factors: A Review

Embryonic Mortality is the major cause of reproductive and economic loss in cattle and Buffaloes. Embryonic Mortality is more common during the early than the late embryonic period, i.e., from day 8th to 16th at the hatching of blastocysts and initiation of elongation and commencement of implantation without affecting cycle lengths. Early embryonic mortality is a major source of embryonic and economic loss with mortality rate up to 40%. Embryonic mortality is also reported due to mineral deficiency and heat stress in cattle and buffaloes. Physical modifications of animal environment, nutritional management with Antioxidant, trace minerals and genetic development of breeds that are less sensitive to heat stress should be best solution. Embryonic death occurs at the time of maternal recognition of pregnancy, probably related to a failure of the Interferon tau (IFNι) secretory mechanism along with progesterone deficiency and luteal insufficiency. Recent research, both in terms of physiological mechanisms and pharmacological treatments has mostly focused on the period of maternal recognition of pregnancy or the anti-luteolytic effect. hCG/ GnRH /Progesterone supplementation have shown positive results. Supplementation of interferon as anti-luteolytic agent and supplementing Omega-3 has shown encouraging results. Ovarian examination, Animal history, blood/milk progesterone levels, PAG test and ultrasound appear to be the only practical tool presently available for diagnosis of embryonic mortality. This present review article is covering all the aspects of embryonic mortality with special reference totrace minerals, heat stress, hormonal impact and interferon tau.

HIF-1α/BNIP3-Mediated Autophagy Contributes to the Luteinization of Granulosa Cells During the Formation of Corpus Luteum

During the luteinization after ovulation in mammalian ovary, the containing cells undergo an energy consuming function re-determination process to differentiate into luteal cells under avascular environment. Previous evidences have delineated the contribution of autophagy to the cell differentiation and the catabolic homeostasis in various types of mammalian cells, whereas few interest had been focused on the involvement of autophagy in the luteinization of granulosa cells during the formation of early corpus luteum. Herein, the present study investigated that expression and contribution of autophagy during granulosa cell luteinization and early luteal development through in vivo and in vitro experiments. The results clearly demonstrated that HIF-1α/BNIP3-mediated autophagy plays a vital role in the luteinization of granulosa cells during the early luteal formation in vivo and in vitro. In the neonatal corpus luteum, HIF-1α up-regulated BNIP3 expressions, which contributed to the autophagic initiation by disrupting beclin1 from Bcl-2/beclin1 complex and protected cells from apoptosis by curbing the skew of mitochondria balance under avascular niche. Notably, Inhibition of HIF-1α activity by echinomycin enhanced the levels of cytoplasmic cytochrome c and cell apoptosis in the nascent corpus luteum. These findings revealed that HIF-1α/BNIP3-mediated autophagy enabled the process of granulosa cell luteinization and protected the granulosa-lutein cells from further apoptosis under hypoxia niche. To our knowledge, the present study firstly clarified that HIF-1α/BNIP3-mediated autophagy contributes to the luteinization of granulosa cells during the formation of pregnant corpus luteum, which will help us further understanding the luteal biology and provide us new clues for the treatment of luteal insufficiency.

Progestogens in luteal support

Progestational agents are often prescribed to increase the clinical pregnancy rate in assisted reproduction. Progestogens affect implantation, cytokine balance, natural killer cell activity, arachidonic acid release and myometrial contractility. Progesterone production from the corpus luteum is essential for reproduction, but assisted reproductive technologies (ART) can impair luteal function. ART cycles can be classified into three, fresh cycles in which there may or may not be luteal insufficiency, agonist or antagonist cycles in which there is luteal insufficiency, and luteal support is essential, and donor cycles, in which there is no corpus luteum, and a luteal phase has to be created. However, there is no adequate diagnostic test for luteal insufficiency. This article summarises the effect of various progestogens, progesterone itself whether administered vaginally, intra-muscularly, rectally or subcutaneously, and the effect of the progestogen, dydrogesterone. The time of commencement and cessation of therapy are also discussed. Progestogens are also often used to treat threatened and recurrent miscarriage. In these patients progestogen supplementation may need to be prolonged. In threatened miscarriage, until after all bleeding stops, and in recurrent miscarriage, at least as long as the luteo-placental shift.

OR31-05 Emergence of Ovarian Hyperandrogenism and Luteal Insufficiency Following ESR1 Knockdown in the Mediobasal Hypothalamus of Adult Female Rhesus Monkeys

Diminished estradiol (E2) negative feedback action by neuronal ESR1 in the arcuate nucleus (ARC) of the mediobasal hypothalamus (MBH) is hypothesized to cause gonadotropin-releasing hormone (GnRH) hypersecretion, and thus LH excess, contributing to ovarian hyperandrogenism in polycystic ovary syndrome (PCOS). In primates, including humans, however, the mediating estrogen receptor is unknown. Thus, to test the hypothesis that diminished E2 action on ARC ESR1 contributes to female primate ovarian hyperandrogenism, eleven, ovary intact, adult female rhesus macaques, pair housed with female peers, received five 12µl MRI-guided MBH infusions into the rostral-to-caudal extent of both right and left ARC. Each infusion comprised gadolinium contrast agent and ~3-4 x 1010 adeno-associated virus 8 (AAV8) particles containing either a shRNA specific for ESR1 (n=6, ERaKD) or scrambled shRNA (n=5, control). Mid-surgery MRI scans identified targeting accuracy. 2-2.5 years following AAV8 infusion, EIA-determined P4 values were obtained from twice weekly serum samples; samples obtained during the follicular phase of menstrual cycles or anovulatory periods were submitted to liquid chromatography, tandem mass spectrometry (LCMS) for additional steroid hormones. LCMS-determined values were also obtained 0 hours (h) and 24 h following an IM injection of 200IU hCG. Both ERaKD (28.5 ± 1.3 days, mean ± SEM) and control (34.0 ± 3.3 days) female groups exhibited comparably regular menstrual cycles. ERaKD exhibited higher circulating levels of LH (2.8 ± 0.2 ng/ml, p=0.03), androstenedione (A4, 0.43 ± 0.03 ng/ml, p=0.03) and testosterone (T, 0.23 ± 0.03 ng/ml, p=0.09), and LH/FSH ratio (1.7 ± 0.2, p=0.05) compared to controls (LH, 2.1 ± 0.4; A4, 0.30 ± 0.05; T, 0.18 ± 0.01 ng/ml; LH/FSH 1.3 ± 0.2). Following an ovarian androgen-stimulating hCG injection, ERaKD 24-h peak levels for T (0.28 ± 0.01 ng/ml) were higher (p=0.03) compared to controls (0.21 ± 0.01 ng/ml). In addition, luteal insufficiency emerged in ERaKD females, with mean (2.4 ± 0.3 ng/ml), peak (3.6 ± 0.4 ng/ml) and area-under-the-curve (AUC, 23.2 ± 4.2 ng/ml/days) P4 values diminished compared to controls (mean, 3.6 ± 0.1, p=0.01; peak 5.7 ± 0.1 ng/ml, p=0.01; AUC, 43.7 ± 6.7 ng/ml/days, p=0.03). Taken together, these results suggest that knockdown of ARC ESR1 disrupts Gn stimulation of ovarian function, contributing to female monkey ovarian hyperandrogenism and menstrual cycle impairment emulating PCOS in women.

Gender characteristics of autoimmune hypogonadism

Autoimmune gonadal lesions represent a highly heterogenous conditions affecting men and women of reproductive age and resulting in loss of endocrine function and, eventually, infertility. Well-known and well-documented risk factors exist, and the presence or suspicion of autoimmune disorder should be regarded as an important one. For the purpose of the present study, ELISA kits according to the proprietary technology for detection of antitesticular and antiovarian antibodies were developed. Among men with autoimmune orchitis an increased level of antibodies to steroid-producing testicular cells, decreased serum total and free testosterone and altered semen parameters were found. Combined autoimmune diseases were present (autoimmune thyroiditis, vitiligo, type 1 diabetes) in 13.5 % of cases. In women with autoimmune oophoritis the main finding was anovulation with preserved serum FSH and LH levels (91.6 %) and luteal insufficiency (8.4 %). In total, 19.4 % of patients had other autoimmune diseases (autoimmune thyroiditis, vitiligo, chronic autoimmune hepatitis, rheumatoid arthritis, systemic lupus erythematosus).