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Francesco J Demayo - One of the best experts on this subject based on the ideXlab platform.
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deletion of rhoa in progesterone receptor expressing cells leads to Luteal Insufficiency and infertility in female mice
Endocrinology, 2017Co-Authors: Ahmed El E Zowalaty, John P Lydon, Yi Zheng, Francesco J DemayoAbstract:Ras homolog gene family, member A (RhoA) is widely expressed throughout the female reproductive system. To assess its role in progesterone receptor-expressing cells, we generated RhoA conditional knockout mice RhoAd/d (RhoAf/f-Pgr-Cre+/-). RhoAd/d female mice had comparable mating activity, serum luteinizing hormone, prolactin, and estradiol levels and ovulation with control but were infertile with progesterone Insufficiency, indicating impaired steroidogenesis in RhoAd/d corpus luteum (CL). RhoA was highly expressed in wild-type Luteal cells and conditionally deleted in RhoAd/d CL. Gestation day 3.5 (D3.5) RhoAd/d ovaries had reduced numbers of CL, less defined corpus Luteal cord formation, and disorganized CL collagen IV staining. RhoAd/d CL had lipid droplet and free cholesterol accumulation, indicating the availability of cholesterol for steroidogenesis, but disorganized β-actin and vimentin staining, indicating disrupted cytoskeleton integrity. Cytoskeleton is important for cytoplasmic cholesterol movement to mitochondria and for regulating mitochondria. Dramatically reduced expression of mitochondrial markers heat shock protein 60 (HSP60), voltage-dependent anion channel, and StAR was detected in RhoAd/d CL. StAR carries out the rate-limiting step of steroidogenesis. StAR messenger RNA expression was reduced in RU486-treated D3.5 wild-type CL and tended to be induced in progesterone-treated D3.5 RhoAd/d CL, with parallel changes of HSP60 expression. These data demonstrated the in vivo function of RhoA in CL Luteal cell cytoskeleton integrity, cholesterol transport, StAR expression, and progesterone synthesis, and a positive feedback on StAR expression in CL by progesterone signaling. These findings provide insights into mechanisms of progesterone Insufficiency.
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Liver receptor homolog-1 is essential for pregnancy
2016Co-Authors: Cong Zhang, Francesco J Demayo, Michael J. Large, Raj Duggavathi, John P, Kristina Schoonjans, Ertug Kovanci, Bruce D. MurphyAbstract:Successful pregnancy requires coordination of an array of signals and factors from multiple tissues. One such element, the liver receptor homolog-1 (Lrh-1, NR5A2), is an orphan nuclear receptor that regulates metabolism and hormone synthesis1. It is strongly expressed in granulosa cells of ovarian follicles and in the corpus luteum of rodents2 and humans. Germline ablation of the Lrh-1 gene in mice is embryo-lethal at gastrulation3. Depletion of Lrh-1 in the ovarian follicle demonstrates that it regulates genes required for both steroid synthesis and ovulation4. To study the effects of Lrh-1 on mouse gestation, we disrupted its expression in the corpus luteum, resulting in Luteal Insufficiency. Hormone replacement permitted embryo implantation but was followed by gestational failure with impaired endometrial decidualization, compromised placental formation, fetal growth retardation, and fetal death. Lrh-1 is expressed in the mouse and human endometrium. In a human model of primary culture of endometrial stromal cells, depletion of Lrh-1 by siRNA abrogated decidualization. These findings demonstrate that Lrh-1 is necessary for maintenance of the corpus luteum, for promotion of decidualization and for placental formation. It therefore plays multiple, indispensible roles in establishing and sustaining pregnancy
G Siklósi - One of the best experts on this subject based on the ideXlab platform.
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aetiology and pathomechanism of folliculo Luteal Insufficiency
2016Co-Authors: G SiklósiAbstract:To investigate the causes and pathogenesis of folliculo-Luteal Insufficiency (FLI), we compared the different clinical and hormonal features of cycles with physiological or deficient folliculo-Luteal function. The weight and body mass index (BMI) (kg/m2) of patients with FLI were significantly (p < 0.001) higher, and serum cortisol and prolactin levels were also significantly (p < 0.001) increased when compared to physiological cycles. Serum androgen levels (testosterone, free testosterone, androstenedione, DS) were elevated significantly (p < 0.001) compared to the physiological level only when FLI was associated with hirsutism (12.2 %).
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treatment of folliculo Luteal Insufficiency
2016Co-Authors: G SiklósiAbstract:There are two possible treatments for folliculo-Luteal Insufficiency (FLI), namely, stimulation of the insufficient function and/or suppression of the increased hypothalamic-pituitary-adrenal (HPA) axis activity that causes FLI. In this chapter, we summarise our experiences regarding clomiphene citrate (CC) and low-dosage corticoid treatment (LDCT) of FLI.
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the role of folliculo Luteal Insufficiency in the emergence of random chromosomal abnormalities
2016Co-Authors: G SiklósiAbstract:It is a proven fact that about 50 % of pregnancy losses are caused by randomly occurring, mainly numerical chromosomal abnormalities (CA) that emerge during oogenesis (sometimes during spermiogenesis). Based on this, the normalisation of folliculo-Luteal function (FLF) and placentation – if this did not influence the emergence of CAs – would be able to decrease the prevalence of miscarriage by half at most, while the actual miscarriage rate is only a fraction of this number.
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Luteal Insufficiency as the primary cause of habitual abortion--its successful treatment
Acta bio-medica de L'Ateneo parmense : organo della Societa di medicina e scienze naturali di Parma, 1992Co-Authors: G SiklósiAbstract:In order to assess Luteal Insufficiency as a causative factor in habitual abortion, serial progesterone determinations were accomplished. Luteal Insufficiency was proved on the basis of progesterone values by criteria elaborated by the author in 151 of 160 unselected patients with a history of 2-6 (mean 3.3) unsuccessful pregnancies. Normalization of Luteal function before conception resulted in birth in case of 148 (92.5%) and first or second trimester abortion in case of 12 women (7.5%). 148 women with physiological Luteal function delivered 205 newborns from 192 pregnancies (in 44 patients two, in 11 patients twin pregnancies and in one case a trigeminal pregnancy). Out of 12 twin pregnancies 10 terminated with mature, one with immature (complicated with uterus bicornis) births and one terminated with spontaneous abortion. One from the two trigeminal pregnancies resulted in immature birth and one in a spontaneous abortion in the second trimester. Fifteen pregnancies conceived in the group of 13 women with uterus bicornis or septus resulted in 13 mature and one premature births and the sole twin pregnancy case ended with immature birth. Based on the results achieved so far, the author regard the treatment of Luteal Insufficiency--beside the proving the aetiology--as the most successful therapy for habitual abortion.
Kohji Miyazaki - One of the best experts on this subject based on the ideXlab platform.
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a case of a pregnant woman with Luteal Insufficiency and a mutation in the beta subunit of luteinizing hormone
International journal of fertility and women's medicine, 2000Co-Authors: Kentaro Takahashi, Hiroko Kurioka, Harukiko Kanasaki, Masako Okada, Tomoya Ozaki, Kohji MiyazakiAbstract:We report a case of a pregnant woman with Luteal Insufficiency and infertility associated with a variant luteinizing hormone (LH) β-subunit and normal follicle-stimulating hormone (FSH) concentration. A 29-year-old woman presented to our hospital with infertility. Given the presence of low mid-Luteal serum progesterone concentration and out-of-phase endometrial biopsy, Luteal Insufficiency was suspected. Several forms of treatment (clomiphene citrate therapy and human menopausal gonadotrophin therapy) were administered, but did not improve the patient's Luteal Insufficiency. However, administration of hCG during the Luteal phase could distinctly improve the Luteal Insufficiency. She became pregnant after Luteal support with progesterone. Sequence analysis of the patient's LH β-subunit gene indicated heterozygosity for the point mutations Trp 8 to Arg 8 and Ilel 5 to Thrl 5 in the coding sequence. LH hypersecretion resembling that seen in polycystic ovary syndrome was observed. Serum concentrations of variant LH showed a more rapid increase in response to gonadotrophin-releasing hormone and reached a higher apparent value than did those of normal LH. Therefore, abnormal bioactivity and mistimed secretion of variant LH at mid-cycle may have a deleterious effect on the completion of oocyte maturation, ovulation, and subsequent corpus luteum function.
M Y Dawood - One of the best experts on this subject based on the ideXlab platform.
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corpus Luteal Insufficiency
Current Opinion in Obstetrics & Gynecology, 1994Co-Authors: M Y DawoodAbstract:The corpus luteum is controlled by luteinizing hormone (LH) and intra-ovarian morphofunctional specialization and autocrine/paracrine mechanisms. Corpus Luteal Insufficiency produces Luteal phase defects (LPD). The poor precision and validation of endometrial histologic dating and single or random multiple serum progesterone measurements produce widely variable diagnoses. The true prevalence rate of LPD may be only 3–5% similar to that due to chance. The role of LPD in causing infertility can be challenged because the diagnosis is not predictive of recurrence in subsequent cycles, and other causes of infertility are not controlled for. Intraobserver and interobserver variability, uterine site of biopsy, Luteal phase length, time of ovulation, and Luteal phase timing of biopsy have been examined and have confirmed the imprecision of dating as a sensitive and reliable assessment of Luteal Insufficiency. There is support for either early or late Luteal phase biopsy. Endometrial dating using LH timing as a reference point is relatively more reliable. Integrated Luteal progesterone is the only currently accurate assessment of Luteal sufficiency. Clomiphene does not increase LPD but increases serum progesterone, integrated progesterone, corpus luteum LH/human chorionic gonadotropin (hCG), and insulin-like growth factor-1 (IGF-1) receptors, all of which promote increased progesterone production and do not affect endometrial estrogen and progesterone receptors. hCG is more likely to stimulate progesterone production if given at the mid rather than early Luteal phase corresponding to the phase with highest total and available (unoccupied) corpus Luteal LH receptors. Careful analysis of published studies on treatment of LPD revealed only one randomized controlled study, and, statistically, all studies revealed no better outcome with progesterone treatment.
John P Lydon - One of the best experts on this subject based on the ideXlab platform.
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deletion of rhoa in progesterone receptor expressing cells leads to Luteal Insufficiency and infertility in female mice
Endocrinology, 2017Co-Authors: Ahmed El E Zowalaty, John P Lydon, Yi Zheng, Francesco J DemayoAbstract:Ras homolog gene family, member A (RhoA) is widely expressed throughout the female reproductive system. To assess its role in progesterone receptor-expressing cells, we generated RhoA conditional knockout mice RhoAd/d (RhoAf/f-Pgr-Cre+/-). RhoAd/d female mice had comparable mating activity, serum luteinizing hormone, prolactin, and estradiol levels and ovulation with control but were infertile with progesterone Insufficiency, indicating impaired steroidogenesis in RhoAd/d corpus luteum (CL). RhoA was highly expressed in wild-type Luteal cells and conditionally deleted in RhoAd/d CL. Gestation day 3.5 (D3.5) RhoAd/d ovaries had reduced numbers of CL, less defined corpus Luteal cord formation, and disorganized CL collagen IV staining. RhoAd/d CL had lipid droplet and free cholesterol accumulation, indicating the availability of cholesterol for steroidogenesis, but disorganized β-actin and vimentin staining, indicating disrupted cytoskeleton integrity. Cytoskeleton is important for cytoplasmic cholesterol movement to mitochondria and for regulating mitochondria. Dramatically reduced expression of mitochondrial markers heat shock protein 60 (HSP60), voltage-dependent anion channel, and StAR was detected in RhoAd/d CL. StAR carries out the rate-limiting step of steroidogenesis. StAR messenger RNA expression was reduced in RU486-treated D3.5 wild-type CL and tended to be induced in progesterone-treated D3.5 RhoAd/d CL, with parallel changes of HSP60 expression. These data demonstrated the in vivo function of RhoA in CL Luteal cell cytoskeleton integrity, cholesterol transport, StAR expression, and progesterone synthesis, and a positive feedback on StAR expression in CL by progesterone signaling. These findings provide insights into mechanisms of progesterone Insufficiency.
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conditional ablation of progesterone receptor membrane component 2 causes female premature reproductive senescence
Endocrinology, 2016Co-Authors: Nicole C Clark, John J Peluso, John P Lydon, Cindy A Pru, Siupok Yee, James K PruAbstract:The nonclassical progesterone receptors progesterone receptor membrane component (PGRMC) 1 and PGRMC2 have been implicated in regulating cell survival of endometrial and ovarian cells in vitro and are abundantly expressed in these cell types. The objective of this study was to determine if Pgrmc1 and Pgrmc2 are essential for normal female reproduction. To accomplish this objective, Pgrmc1 and/or Pgrmc2 floxed mice (Pgrmc2fl/fl and Pgrmc1/2fl/fl) were crossed with Pgr-cre mice, which resulted in the conditional ablation of Pgrmc1 and/or Pgrmc2 from female reproductive tissues (i.e.,Pgrmc2d/d and Pgrmc1/2d/d mice). A breeding trial revealed that conditional ablation of Pgrmc2 initially led to subfertility, with Pgrmc2d/d female mice producing 47% fewer pups/litter than Pgrmc2fl/fl mice (P = 0.001). Pgrmc2d/d mice subsequently underwent premature reproductive senescence by parities 2 to 5, producing 37.8% fewer litters overall during the trial compared with Pgrmc2fl/fl mice (P = 0.020). Similar results were observed with Pgrmc1/2d/d mice. Based on ovarian morphology and serum P4, the subfertility/infertility was not due to faulty ovulation or Luteal Insufficiency. Rather an analysis of midgestation implantation sites revealed that postimplantation embryonic death was the major cause of the subfertility/infertility. As with our previous report of Pgrmc1d/d mice, Pgrmc2d/d and Pgrmc1/2d/d mice developed endometrial cysts consistent with accelerated aging of this tissue. Given the timing of postimplantation embryonic demise, uterine decidualization may be disrupted in mice deficient in PGRMC2 or PGRMC1/2. Overall, this study revealed that Pgrmc1 and/or Pgrmc2 are required for the maintenance of uterine histoarchitecture and normal female reproductive lifespan.
