The HMG-domain containing transcription factor Sox10 plays a crucial role in regulating Schwann cell survival and differentiation and is expressed throughout the entire Schwann cell lineage. While its importance in peripheral myelination is well established, little is known about its role in the early stages of Schwann cell development. In a search for direct target genes of Sox10 in Schwann cell precursors, the transcriptional co-repressor Tle4 was identified. At least two regions upstream of the Tle4 gene appear involved in mediating the Sox10-dependent activation. Once induced, Tle4 works in tandem with the bHLH transcriptional repressor Hes1 and exerts a dual inhibitory effect on Sox10 by preventing the Sox10 protein from transcriptionally activating maturation genes and by suppressing Sox10 expression through known enhancers of the gene. This mechanism establishes a regulatory barrier that prevents premature activation of factors involved in differentiation and myelin formation by Sox10 in immature Schwann cells. The identification of Tle4 as a critical downstream target of Sox10 sheds light on the gene regulatory network in the early phases of Schwann cell development. It unravels an elaborate regulatory circuitry that fine-tunes the timing and extent of Schwann cell differentiation and myelin gene expression.

This study investigated the effect of human menopausal gonadotropin (hMG) on reproductive efficiency of synchronized ewes with the sponge and progesterone (P4) injection-based protocols. In study 1, anoestrous ewes (n = 120) were used. Sixty ewes were treated with sponge (S) for 12 days. The injection of eCG (SeCG group, n = 30) or hMG (ShMG, n = 30) was given at the time of sponge removal. Thirty ewes received IM injection of P4, three times every 48 h and the injection of hMG was given 24 h after the third P4 injection (3PhMG group, n = 30), and 30 ewes were used as control group. Pregnancy was diagnosed on day 50 after the release of ram. In study 2, 60 ewes were randomly divided into two equal groups. In the treated group with antibiotics (n = 30), before inserting, the sponges were impregnated with the antibiotic penicillin G sodium (5,000,000 IU) and in the control group (n = 30), there was no added antibiotics. Before inserting and after removing sponges, a vaginal cytology sample was taken with a sterile cotton swab. The number of neutrophils in each sample was counted and analysed. The rate of oestrus and total pregnancy was greater in SeCG (96.7, 93.3%), ShMG (82.8, 93.1%) and 3PhMG (67.9, 89.3%) groups compared with the control group (13.8, 41.4%) (p < .05). No significant difference was found in single, twin and total lambing and pregnancy rates after injection of eCG and hMG during the non-breeding season (p > .05). A higher percentage of control ewes had the vaginal smear with neutrophils more than 50% (96.7% vs. 76.7%; p < .05). In conclusion, a single dose of hMG can induce fertile oestrus in synchronized ewes with P4 administered by either injection or intravaginally. Purulent discharge and percentage of neutrophils were significantly reduced in the synchronized ewes by the impregnated sponges with the antibiotic penicillin.

OBJECTIVE: Does ovarian stimulation with highly purified (hp)-HMG protect from elevated progesterone in the follicular phase compared to recombinant FSH (r-FSH) cycles through a different regulation of follicular steroidogenesis?
CONCLUSIONS: hp-HMG enhanced the Δ4 pathway from pregnenolone to androstenodione leading to lower serum progesterone at the end of the cycle, while r-FSH promoted the conversion of pregnenolone to progesterone causing higher follicular phase progesterone levels.
BACKGROUND: Elevated progesterone in the follicular phase has been related to lower clinical outcome in fresh IVF cycles. Progesterone levels are positively correlated to ovarian response, and some studies have shown that when r-FSH alone is used for ovarian stimulation serum progesterone levels on the day of triggering are higher than when hp-HMG is given. Whether this is caused by a lower ovarian response in hp-HMG cycles or to a difference in follicular steroidogenesis in the two ovarian stimulation regimens has not been well characterized.
METHODS: A randomized controlled trial including 112 oocyte donors undergoing ovarian stimulation with GnRH antagonists and 225 IU/day of r-FSH (n = 56) or hp-HMG (n = 56) was carried out in a university-affiliated private infertility clinic. Subjects were recruited between October 2016 and June 2018.
METHODS: The women were aged 18-35 years with a regular menstrual cycle (25-35 days) and normal ovarian reserve (serum anti-Müllerian hormone (AMH) = 10-30 pMol/l) undergoing ovarian stimulation for oocyte donation. FSH, LH, estradiol (E2), estrone, progesterone, pregnenolone, 17-OH-progesterone, androstenodione, dehidroepiandrostenodione, and testosterone were determined on stimulation Days 1, 4, 6, and 8 and on day of triggering in serum and in follicular fluid. Samples were frozen at -20°C until assay. Total exposures across the follicular phase were compared by polynomic extrapolation.
RESULTS: Subjects in both groups were comparable in terms of age, BMI, and AMH levels. Ovarian response was also similar: 17.5 ± 7.9 (mean ± SD) versus 16.5 ± 7.5 oocytes with r-FSH and hp-HMG, respectively (P = 0.49). Serum progesterone (ng/ml) on day of trigger was 0.46 ± 0.27 in the hp-HMG group versus 0.68 ± 0.50 in the r-FSH group (P = 0.010). Differences for progesterone were also significant on stimulation days 6 and 8. The pregnenolone: progesterone ratio was significantly increased in the r-FSH group from stimulation day 8 to the day of trigger (P = 0.019). Serum androstenodione (ng/ml) on day of trigger was 3.0 ± 1.4 in the hp-HMG group versus 2.4 ± 1.1 in the r-FSH group (P = 0.015). Differences in adrostenodione were also significant on stimulation Day 8. The pregnenolone:androstenodione ratio was significantly higher in the hp-HMG group (P = 0.012) on Days 6 and 8 and trigger. There were no other significant differences between groups. Follicular fluid E2, FSH, LH, dehidroepioandrostenodione, androstenodione, and testosterone were significantly higher in the hp-HMG than r-FSH group. No differences were observed for progesterone, estrone, 17-OH-progesterone, and pregnenolone in follicular fluid.
CONCLUSIONS: All women included in the study were young, not infertile, and had a normal BMI and a good ovarian reserve. The findings might be different in other patient subpopulations. Hormone analyses with immunoassays are subject to intra-assay variations that may influence the results.
CONCLUSIONS: Stimulation with hp-HMG may prevent progesterone elevation at the end of the follicular phase because of a different follicular steroidogenesis pathway, regardless of ovarian response. This should be considered, particularly in patients at risk of having high progesterone levels at the end of the follicular phase when a fresh embryo transfer is planned.
BACKGROUND: Roche Diagnostics provided unrestricted funding for all serum and follicular fluid hormone determinations. J.L.R., M.M., and A.P. have nothing to declare. E.B. has received consulting fees from Ferring, Merck, Gedeon Richter, and Roche and has participated in a research cooperation with Gedeon-Richter. In addition, the author has participated in speakers\' bureau and received fees from Ferring, Gedeon Richter, Merck, and Roche. P.A. has received consulting fees from MSD and has participated in speakers\' bureau and received fees from Ferring. P.A. also declares travel/meeting support from MSD. E.L. has received consulting fees from Ferring and MSD. In addition, the author has participated in a research cooperation with Gedeon-Richter. Also, the author has participated in speakers\' bureau and received fees from Ferring and IBSA, as well as travel/meeting support from IBSA and Gedeon Richter. E.B., P.A., and E.L. also own stocks in IVIRMA Valencia.
BACKGROUND: NCT: NCT02738580.
UNASSIGNED: 19 February 2016.
UNASSIGNED: 03 October 2016.

Fine needle aspiration cytology (FNAC) is an established diagnostic modality today, but its utilization in skin tumors is limited by the fact that most of these lesions are small and easily accessible for clinicians to perform an excision biopsy. As a result, our knowledge of the cytological features of some of the uncommonly encountered skin tumors is still lacking. The aim of this study was to correlate the cytological features of cutaneous mixed tumors (CMTs) with histological and immunohistochemical findings in four cases of CMT in commonly and uncommonly encountered locations. We also review the recent updates highlighting the various genetic rearrangements and newer more specific immunohistochemical markers described so far. This was a retrospective study, and all the slides were taken from our departmental archives. Case 1 was a 25-year-old male who presented with a gradually increasing painless swelling over the right angle of the mouth of 1.5 years duration. Case 2 was a 45-year-old male with swelling on the right forearm for the last three years. Case 3 was a 35-year-old female with a forehead swelling of one year duration. Case 4 was a 55-year-old female with left cheek swelling for two years. On clinical examination, all four nodular swellings were predominantly in the skin/subcutaneous tissue. On cytology, all cases showed abundant chondromyxoid material with clusters of benign epithelial cells and a fair number of predominantly singly scattered myoepithelial cells. The diagnosis of all four cases was further confirmed on histopathology and immunohistochemistry, and the findings correlated well with cytology. The cytological features of CMT closely correlate with their histopathological and immunohistochemical features. Newer immunohistochemistry (IHC) marker pleomorphic adenoma gene 1 (PLAG1) may be helpful in making a definitive diagnosis of CMT on cytology and cell block preparation along with a good clinical correlation. Complete surgical excision is the treatment of choice, and recurrence is rare.

UNASSIGNED: Idiopathic hypogonadotropic hypogonadism (IHH) is a prevalent congenital genetic disorder with multiple inheritance patterns. IHH can manifest as normal hypogonadotrophic sexual hypofunction (nIHH) or with an abnormal sense of smell, known as Kallmann. It primarily affects the production and effectiveness of gonadotropin-releasing-hormone (GnRh), leading to reduced follicle-stimulating hormone and luteinizing hormone levels. This results in infertility and underdeveloped secondary sexual characteristics.
UNASSIGNED: A 29-year-old female presented with infertility.
UNASSIGNED: IHH diagnosis was confirmed through magnetic resonance (MR) scan, endocrine tests, physical examination, and B ultrasonic inspection. Additionally, genetic studies, including chromosome analysis, were conducted for the patient. The results confirmed no genetic abnormalities or concerns.
UNASSIGNED: The patient underwent multiple ovulation induction programs.
UNASSIGNED: After several ovulation induction cycles, the patient conceived and delivered a live baby.
UNASSIGNED: For IHH patients, a tailored human menopausal gonadotropin (HMG) dose is recommended. High-dose HMG can benefit those with poor follicular response. The addition of letrozole (5-7.5mg) may enhance follicular response during stimulation. Our approach, which emphasizes the combined use of high-dose HMG, letrozole, and the adjustment of FSH and LH ratios, offers a unique perspective compared to traditional treatments. If HMG treatment is ineffective, alternative ovulation induction methods, such as r-fsh combined with r-lh or HMG combined with rLH, can be considered. Adjusting the FSH and LH ratio and varying rFSH and rLH additions might help achieve dominant follicles and live birth in resistant cases. This case report underscores the potential benefits of our regimen, suggesting its consideration for future research and clinical applications.

To evaluate the outcomes of a long GnRH agonist protocol with corifollitropin alfa followed by hMG in low responders.
Retrospective cohort study. Patients with a suboptimal previous ovarian response (<9 oocytes) and a normal ovarian reserve (Poseidon groups 1 and 2) were classified in 1) Group 1 (n=88), submitted to a second cycle with a GnRH antagonist protocol using rFSH/hMG; 2) Group 2 (n=66), submitted to a long GnRH agonist protocol with corifollitropin alfa followed by hMG (named as simplified long protocol). Clinical outcomes were compared between groups and between the first/second cycle of each group.
Clinical outcomes were similar between groups. There were no differences in the number of oocytes [7(5-11.75) versus 7(5-10), p=0.802], clinical pregnancy (19.3% versus 18.2%, p=0.858) and live birth rates (18.2% versus 15.2%, p=0.619). However, baseline characteristics were different, decoding a poor prognosis among women in group 2. Both groups (1 and 2) had significantly higher number of oocytes, pregnancy, and live birth rates in the second cycle. In group 2, there was a higher rate of embryo transfer (56.1% versus 27.3%, p<0.001). In group 1, despite the similar rate of embryo transfer, there was a higher positive hCG (23.9% versus 8.0%, p=0.004).
Both simplified long protocol and GnRH antagonist protocol are suitable for low responders. The best second cycle clinical outcomes experienced in a population with worse prognosis (group 2) suggests that the simplified long protocol may be a better option, although prospective well-conducted studies must explore this hypothesis.

Isolated follicle-stimulating hormone (FSH) deficiency is a rare cause of infertility in both sexes, and only a few cases have been reported in Japan. This is a case report of a young male patient with isolated FSH deficiency and azoospermia who was successfully treated with human menopausal gonadotropin (hMG). A 28-year-old male patient was referred for azoospermia. The delivery at his birth was uneventful and a family history of infertility or hypogonadism was not observed. The testes volume was 22/24 mL (right/left). No varicocele was observed in the ultrasound, and no sign or symptom of hypogonadism was found. In the semen analysis, however, the sperm concentration was as low as 2.5×106/mL and the motility was less than 1%. The endocrine panel revealed luteinizing hormone (LH) (2.1 mUI/mL, normal values 0.8-5.7 mUI/mL) and testosterone (6.57 ng/ml, normal values 1.42-9.23 ng/mL) were normal, while the FSH level was very low (0.6 mUI/mL, normal values 2.0-8.3 mIU/mL). The odor and the karyotype 46, XY, were normal. The brain MRI scans showed no abnormal findings. Genitalia and potency were normal. The diagnosis was made of isolated FSH with severe oligoastenozoospermia clinically.  FSH replacement therapy was employed. The patient self-injected 150 units of hMG three times a week. After 3 months of the treatment, the sperm concentration and motility went up to 264×106/mL and 12%, respectively. At 5 months, the patient\'s spouse conceived naturally, and at 7 months the treatment was terminated. During the treatment, FSH rose to the normal range, while other test items showed no change. The patient\'s health condition was uneventful. The spouse delivered a healthy boy. In conclusion, for isolated FSH with severe oligoastenozoospermia, hMG can be as effective as recombinant human FSH (rh-FSH), although the dosage remains a matter of discussion.

The high-mobility-group domain-containing transcription factor Sox9 confers glial competence to neuroepithelial precursors in the developing central nervous system and is an important determinant of astroglial and oligodendroglial specification. In oligodendroglial cells, it remains expressed in oligodendrocyte progenitor cells (OPCs) of the developing nervous system, but is shut off in differentiating oligodendrocytes as well as in OPCs that persist in the adult nervous system. To better understand the role of Sox9 in OPCs, we generated mouse models that allowed oligodendroglial expression of a Sox9 transgene during development or in the adult. With transgene expression beginning in the last trimester of pregnancy, the number of OPCs increased dramatically, followed by comparable gains in the number of pre-myelinating and myelinating oligodendrocytes as assessed by marker gene expression. This argues that Sox9 boosts oligodendrogenesis during ontogenetic development at all stages, including terminal oligodendrocyte differentiation. When Sox9 transgene expression started in the adult, many transgene-expressing OPCs failed to maintain their progenitor cell identity and instead converted into myelinating oligodendrocytes. As infrequent and inefficient differentiation of adult OPCs is one of the main obstacles to effective remyelination in demyelinating diseases such as Multiple Sclerosis, increased Sox9 levels in adult OPCs may substantially increase their remyelination capacity.

Human menopausal gonadotrophin (hMG) has been reported to produce a comparable superovulatory response to that of follicle stimulating hormone (FSH). Furthermore, hMG has a long half-life as compared with FSH. The present study was designed to compare hMG administered once daily and FSH administered twice daily over a 4 - day period on superovulatory response of Suffolk ewes. During the mid-luteal phase, twenty-four Suffolk donor ewes received intravaginal sponges at day 0 for 12 days. The superovulatory regimens in the Control group (n = 12) and the Treatment group (n = 12) consisted of eight injections of FSH given at twice daily and four injections of hMG given at once daily, respectively. At day 13, the donor ewes were subjected to laparoscopic insemination. Embryos were recovered, classified, and transferred to recipient ewes at day 19. Pregnancy status was determined by ultrasound examination 40 days after transfer. Lambing rate was calculated after all the ewes had delivered. No significant differences were observed between the two groups in terms of the structures recovered, transferable embryos, degenerated embryos, unfertilized oocytes, pregnancy rate and lambing rate. The results showed that once daily injection of hMG can produce a comparable superovulatory response and embryo transfer outcomes to those obtained by twice daily injection of FSH over a 4 - day period. It is feasible that hMG is used to replace FSH and reduce the number of injection treatments in ovine superovulatory regimens.

Superovulation of high-producing dairy cows is a challenging subject in dairy farms with respect to the cost, dose and type of gonadotropin. The objectives of this study were to compare three gonadotropin products: Folltropin-V® (highly purified FSH with porcine origin), Cinnal-f® (recombinant human FSH) and Menotropins® (hMG) for superovulation in high-producing Holstein lactating dairy cows and to investigate the pregnancy outcomes achieved following transferring embryos recovered from donors treated with different gonadotropins. Healthy high-producing Holstein lactating dairy cows (n = 30; milk production: 46.35 ± 8.78 kg; parity: 2-4; days in milk: 80-130 days) without any puerperal problems were selected as donors. On Day 10 after estrus (Day 0 of superovulation), donors (10 cows in each experimental groups) received Folltropin-V® (400 mg NIH, dissolved in 20 ml), Cinnal-f® (20 vials; each vial of 1 ml contains 75 IU Follitropin alfa) and Menotropins ® (20 ampules; each ampule of 1 ml contains 75 IU FSH and 75 IU LH), administered twice daily, in decreasing doses (4,4; 3,3; 2,2; 1,1 ml), over 4 days. On Day 2 of superovulation, donors received 3 doses of prostaglandin F2α analogue, 6 h apart. They were inseminated twice with a frozen semen at 12 and 24 h after standing estrus. Concurrent with the second insemination, donors received 2500 IU hCG (Karma Pharmatech GmbH, Germany). On Day 7 after standing estrus, superovulatory responses (number of CLs, total ova/embryos and transferable embryos) were recorded and Code 1 embryos, recovered from each treated donors, were transferred to synchronized heifers. Pregnancy was detected on Day 30 and 60 after AI. Gestation length, the number and weight of live births were recorded. Data were analyzed using Proc GLM, Proc Mixed and Proc Genmod of SAS. The respective number of corpora lutea, total number of ova/embryos and transferable embryos were not different among donors received Cinnal-f (25.5 ± 3.01, 11.2 ± 2.77, 5.1 ± 0.86), Menotropins (24.0 ± 3.21, 9.0 ± 2.04, 6.3 ± 1.74) and Folltropin-V (20.3 ± 3.21, 8.9 ± 1.90, 5.1 ± 1.16; P > 0.05). Pregnancy rates on Day 30 was similar among treatment groups (P > 0.05). However, pregnancy rates on Day 60 and the number of calves born healthy was less in heifers that received embryos from Cinnal-f treated donors (P < 0.05). In conclusion, Cinnal-f and Menotropins could provide similar superovulatory response to Folltropin-V for superovulation of high-producing Holstein lactating dairy cows.