The addition of dydrogesterone improves the outcomes of pregnant women with low progesterone levels when receiving vaginal progesterone alone as luteal support in HRT-FET cycles.

Purpose: Vaginal progesterone (VP) alone has been used as luteal support (LS) in HRT-FET cycles without measuring serum progesterone concentrations (SPC) because it can achieve adequate intrauterine progesterone levels. However, several reports showed that the co-administration of progestin produced better outcomes than VP alone. We tried to address this discrepancy, focusing on SPC. Methods: VP was given to 180 women undergoing HRT-FET. We measured SPC when pregnancy was diagnosed on day 14 of LS. We compared assisted reproductive technology outcomes between VP alone versus VP + dydrogesterone (D). Results: When using VP alone, average SPC in the miscarriage cases (9.6 ng/mL) were significantly lower compared with the ongoing pregnancy (OP) cases (14.7 ng/mL). The cut-off value for progesterone, 10.7 ng/mL, was a good predictor for the subsequent course of the pregnancy. Of 76 women receiving D ± VP from the start of LS and achieving a pregnancy, the numbers of OP were 44 (84.6%) in SPC ≥ 10.7 ng/mL and 20 (83.3%) in SPC ≤ 10.7 ng/mL with no significant difference. Conclusion: VP alone resulted in lower SPC in some pregnant women in HRT-FET cycles and exhibited a lower OP rate. The co-administration of D improved an OP rate of low progesterone cases to the level comparable with non-low progesterone cases.

A novel orally active gonadotropin-releasing hormone antagonist, relugolix, is a potential substitute for injectable GnRH antagonists in controlled ovarian stimulation in assisted reproductive technology.

PURPOSE: To evaluate the efficacy of an oral gonadotropin-releasing hormone antagonist (GnRH Ant), relugolix (R), for assisted reproductive technology (ART). METHODS: We enrolled women undergoing ART using a GnRH Ant for controlled ovarian stimulation. We compared R; 20 mg/day with cetrorelix acetate (C); 0.125 mg. C was administered to 88 women in 2019, and R to 93 women in 2020. Clinical outcomes associated with ART were assessed in both groups. RESULTS: The luteinizing hormone levels on the day of human chorionic gonadotropin injection in the R group (1.26 ± 0.93 IU/L) were significantly lower than those in the C group (2.85 ± 3.02 IU/L). There were no cases in which egg retrieval was canceled in both groups. The total doses of gonadotropins administered were greater in the R group compared with the C group. The number of days of GnRH Ant administration in the R group (1.71 ± 0.57 days) was significantly longer compared with the C group (1.48 ± 0.58 days). The number of oocytes collected, fertilization rates, and pregnancy rates (R; 47.1% vs C; 45.8%) did not differ between the two groups. CONCLUSION: An orally active GnRH Ant, relugolix, when used in controlled ovarian stimulation for ART, showed comparable clinical outcomes with cetrorelix.

Different anti-Mullerian hormone (AMH) levels respond to distinct ovarian stimulation methods in assisted reproductive technology (ART): Clues to better ART outcomes.

PURPOSE: We asked whether the relationship between anti-Mullerian hormone (AMH) value and the response to ovarian stimulation (OS) might be AMH value-related and differ for each regimen, aiming at getting clues as to how to choose OS protocols according to AMH levels. We further addressed how AMH value connects with ART outcome. METHODS: A total of 1112 women undergoing egg retrieval in ART were included. We adopted four OS protocols, that is, clomiphene, clomiphene + low-dose gonadotropins (Gns), GnRH (Gn-releasing hormone) + Gns (short), and GnRH antagonist. RESULTS: Anti-Mullerian hormone showed a stronger correlation with egg number compared with age over a wide age range. When patients were stratified into four groups by AMH value (<1, 1-2, 2-3, and 3≦ ng/mL), the relationship between AMH and egg number differed among differential OS regimes. The number of eggs rose as AMH and total doses of Gn increased. When analyzed for each AMH group, egg number, but not AMH, was associated with pregnancy rate. CONCLUSION: Different AMH levels exhibit characteristic responses to distinct OS regimens. To improve ART outcomes, personalized OS should be selected so as to maximize egg number, which seems to be a more precise variable than AMH for predicting pregnancy.

Proteomic analysis of the heart in normal aging mice.

Aging induces pathological cardiovascular changes such as cardiac dysfunction and arteriosclerosis. With aging, heart cells, especially, become more susceptible to lethal damage. In this report, we tried to understand the precise mechanism of myocardial change resulting from aging by examining the heart proteome in aging mice using two-dimensional gel electrophoresis (2DE). The proteins were stained with fluorescence dyes (SYPRO Ruby and Pro-Q Diamond) and identified by subsequent MALDI-TOF-MS / MS. As a result, markedly altered levels of 14 proteins and 7 phosphoproteins were detected in the hearts of 3-, 7-, 11-, and 20-month-old mice. The functions of these identified proteins and phosphoproteins were energy metabolism, muscle contraction, glycolysis, and cytoskeletal support. Additionally, the results of Western blotting confirmed changes in the expression of FTH, CPNE5, and SUCLA2. These findings showed that aging modified the expression of proteins and phosphoproteins in the heart. We suggest that changes in the expression of these proteins are critical to the development of cardiac dysfunction resulting from aging. J. Med. Invest. 69 : 217-223, August, 2022.

Nuclear localization of bradykinin B(2) receptors reflects binding to the nuclear envelope protein lamin C.

The mechanism of action of bradykinin (BK), a pro-inflammatory mediator, is thought to be mediated by specific cell surface membrane bradykinin B2 receptors. Some evidence suggests that there are both intracellular and nuclear bradykinin B2 receptors. This study identified proteins that interact with the C-terminus of the bradykinin B2 receptor (in particular, the nuclear membrane protein lamin C), using the yeast two-hybrid system. The motif of the C-terminal domain (CT) mutant 303-320 in bradykinin B2 receptor was identified as a lamin C protein binding motif. Immunohistochemistry revealed colocalization of FLAG- bradykinin B2 receptor with HA-lamin C in the nucleus of HEK 293T cells. In situ proximity ligation assay (PLA) showed that FLAG-bradykinin B2 receptor formed heterodimers with HA-lamin C in the nucleus. In addition, live cell fluorescence imaging showed that bradykinin B2 receptor-EGFP was located in the nucleus and co-localized with HcRed-lamin C. Interestingly, neither BK addition nor bradykinin B2 receptor CT mutation reduced the binding to lamin C or changed the distribution of bradykinin B2 receptor. Taken together, these findings demonstrate that bradykinin B2 receptor-lamin C heterodimers form in the nucleus independent of BK stimulation and CT mutation. We propose that heterodimerization of bradykinin B2 receptor with lamin C is essential to nuclear localization of bradykinin B2 receptor and plays an important role in cell signaling and function.