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• W2005118768 abstract "Unexplained infertility is estimated to occur in 10%–15% of couples seeking fertility treatment (1Crosignani P.G. Collins J. Cooke I.D. Diczfalusy E. Rubin B. Recommendations of the ESHRE workshop on “unexplained infertility.” Anacapri, August 28–9, 1992.Hum Reprod. 1993; 8: 977-980PubMed Google Scholar) and is a diagnosis by exclusion. We propose that a genetic mutation in the progesterone receptor (PROGINS), long known to be essential for reproduction, may have an etiologic role in some couples with heretofore-unexplained infertility. This mutation results in an amino acid substitution in the hinge region of the progesterone receptor and alters the function of the receptor (2Kieback D.G. Tong X.W. Wiegel N.L. Agoulnick I.U. A genetic mutation in the progesterone receptor (PROGINS) leads to an increased risk of nonfamilial breast and ovarian cancer causing inadequate control of estrogen receptor driven proliferation [Abstract no. 6].Gynecologic Investigation. 1998; : 40aGoogle Scholar). This functional alteration and the significance of the progesterone receptor in reproduction led us to evaluate this mutated allele in a female population with unexplained infertility. Twenty-six Caucasian women with the diagnosis of unexplained infertility were included in this study. This study was approved by the Institutional Review Board. Criteria for the diagnosis of unexplained infertility and inclusion consisted of the following: [1] infertility for >1 year duration; [2] females 23 to 40 years of age; [3] 25- to 34-day ovulatory cycles confirmed by urinary ovulation testing; [4] normal luteal phase endometrial biopsy; [5] normal day 3 FSH; [6] normal serum TSH; [7] normal serum prolactin; [8] normal intrauterine cavity evaluated by either hysterosalpingogram or hysteroscopy; and [9] normal pelvic peritoneum and fallopian tubes evaluated by laparoscopy. Eleven subjects with minimal or mild endometriosis were included. Male partners had [1] normal semen analysis (3World Health Organization. Laboratory manual for the examination of human semen and semen-cervical mucus interaction. 3rd ed. 2–19. Cambridge University Press: New York, 1992.Google Scholar) and [2] absence of anti-sperm antibodies detected by immunobead testing in the seminal plasma. The 28 Caucasian controls consisted of fertile women with at least one full-term birth and no history of infertility. Subjects underwent up to four cycles of controlled ovarian hyperstimulation and intrauterine insemination. Patients received either FSH (Metrodin [Serono Laboratories, Norwell, MA] or Fertinex [urofollitropin, Serono]) or hMG (Pergonal [Serono] or Humagon [Organon, West Orange, NJ]). In addition to controlled ovarian hyperstimulation and insemination, four women underwent one cycle of IVF. Genomic DNA was isolated from the buffy coat as described elsewhere (4McKenna N.J. Kieback D.G. Carney D.N. Fanning M. McLinden J. Headon D.R. A germline TaqI restriction fragment length polymorphism in the progesterone receptor gene in ovarian carcinoma.Br J Cancer. 1995; 71: 451-455Crossref PubMed Scopus (75) Google Scholar). A 10-μL polymerase chain reaction (PCR) mixture was prepared containing 4 μM of each intron G primer, sense: 5′-TGAAGTTGTTTGACAAGCTGTTGG-3′ and antisense: 5′-GCCTCTAAAATGAAAGGCAGAAAGC-3′; 250 μM of each dNTP; 100 ng of genomic DNA; 0.2 units of Taq polymerase; 5 mM KCl; 1 mM Tris-HCl (pH 8.3); and 0.15 mM of MgCl2. The cycling profile consisted of denaturation at 94°C for 1 minute, annealing at 60°C for 1 minute, and extension at 72°C for 1 minute, with an initial denaturation step at 94°C for 3 minutes. This was run for a total of 34 cycles. After PCR, 10 μL of amplified product was subjected to electrophoresis on a 1.5% agarose gel stained with ethidium bromide. The 320–base pair (bp) Alu insertion in Intron G produces a 494-bp fragment compared with a 174-bp fragment present in wild types (Fig. 1A). Because all three mutations occur simultaneously (2Kieback D.G. Tong X.W. Wiegel N.L. Agoulnick I.U. A genetic mutation in the progesterone receptor (PROGINS) leads to an increased risk of nonfamilial breast and ovarian cancer causing inadequate control of estrogen receptor driven proliferation [Abstract no. 6].Gynecologic Investigation. 1998; : 40aGoogle Scholar), restriction fragment length polymorphism analysis was carried out on exon 5 for confirmation. A 10-μL PCR mixture was prepared in the same fashion as for intron G, except primers for exon 5 were used, sense: 5′-GTTTTCGAAACTTACATATTG-3′ and antisense: 5′-TCATTTAGTATTAGATCAGGT-3′, and the annealing temperature was decreased to 54°C. The PCR product was subject to digestion with the restriction enzyme NlaIII (New England Biolabs, Beverly, MA) according to the manufacturers’ recommendation. Ten microliters of the digested product was subjected to electrophoresis on a 1.5% agarose gel stained with ethidium bromide. The C to T mutation creates an additional enzyme recognition site for NlaIII (CATG). Compared with wild type with a single 159-bp fragment, homozygous mutants contain 2 fragments: 106 and 53 bp. Subjects heterozygous for the allele contain all three fragments: 159, 106, and 53 bp (Fig. 1B). Fisher’s exact test was used to compare the prevalence of the PROGINS allele between the infertile group and controls. Student’s t test was used to compare age of conception and weight at first pregnancy. Fisher’s exact test was used to compare family history of ovarian or breast cancer and pregnancy rates. The Kruskal-Wallis test was used to compare the subjects’ ages, cycle 1 peak estradiol levels, cycle 1 estradiol per follicle, number of mature follicles, number of ampules of medication used, and day of hCG administration. Eleven of 26 (42%) women with unexplained infertility were heterozygous for PROGINS. This was significantly increased over controls, among whom only 4 of 28 (14%) women were heterozygous for PROGINS. There were no homozygous mutants in either group. Infertility patients were older than controls (31.8 ± 5.62 years of age vs. 24.2 ± 5.62 years of age). Although there was a statistically significant difference in the age of our cases vs. that of the controls, the overall ages were young when considering age as a factor in infertility. There was no statistically significant difference in weight at conception, family history of ovarian cancer, or family history of breast cancer. In the group of women with unexplained infertility, clinical parameters of the stimulation cycle and outcomes were compared in women who carry PROGINS and in those women with unexplained infertility who do not carry the allele. There was no statistically significant difference in the subjects’ ages, cycle 1 peak estradiol levels, cycle 1 estradiol per follicle, number of mature follicles, number of ampules of medication used, and day of hCG administration. There was also no statistically significant difference in pregnancy rates. A progesterone receptor mutation, PROGINS, is significantly more prevalent in women with unexplained infertility than in fertile controls. In this study, 42% of women with unexplained infertility carried the mutant allele compared with 14% of fertile controls, a statistically significant increase. To our knowledge, this is the first report describing a human progesterone receptor mutation in association with infertility. This mutated allele consists of an Alu insertion at intron G, a G to T point mutation in the first nucleotide of codon 660 within exon 4 resulting in a valine to leucine substitution, and a C to T point mutation in the third nucleotide of codon 770 within exon 5 resulting in a silent base pair change (2Kieback D.G. Tong X.W. Wiegel N.L. Agoulnick I.U. A genetic mutation in the progesterone receptor (PROGINS) leads to an increased risk of nonfamilial breast and ovarian cancer causing inadequate control of estrogen receptor driven proliferation [Abstract no. 6].Gynecologic Investigation. 1998; : 40aGoogle Scholar). This amino acid substitution in exon 4, a region encoding the hinge region, is an area involved in receptor dimerization (5Tetel M.J. Jung S. Carbajo P. Ladtkow T. Skafar D.F. Edwards D.P. Hinge and amino terminal sequences contribute to solution dimerization of human progesterone receptor.Mol Endocrinol. 1997; 11: 1114-1128Crossref PubMed Scopus (62) Google Scholar), transcriptional activation (6Tsai M. O’Malley B.W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.Annu Rev Biochem. 1994; 63: 451-486Crossref PubMed Scopus (2666) Google Scholar), nuclear localization (7Guiochon-Mantel A. Loosfelt H. Lescop P. Sar S. Atger M. et al.Mechanisim of nuclear localization of the progesterone receptor evidence for interaction between monomers.Cell. 1989; 57: 1147-1154Abstract Full Text PDF PubMed Scopus (240) Google Scholar), ligand binding (5Tetel M.J. Jung S. Carbajo P. Ladtkow T. Skafar D.F. Edwards D.P. Hinge and amino terminal sequences contribute to solution dimerization of human progesterone receptor.Mol Endocrinol. 1997; 11: 1114-1128Crossref PubMed Scopus (62) Google Scholar), and interactions with co-repressors (8Jackson T.A. Richer J.K. Bain D.L. Takimoto G.S. Tung L. Horwitz K.B. The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT.Mol Endocrinol. 1997; 11: 693-705Crossref PubMed Scopus (383) Google Scholar). Thus, a mutation in this region might alter overall function. Preliminary data reveal that the PROGINS allele produces a progesterone receptor that has increased transcriptional activity and stability (2Kieback D.G. Tong X.W. Wiegel N.L. Agoulnick I.U. A genetic mutation in the progesterone receptor (PROGINS) leads to an increased risk of nonfamilial breast and ovarian cancer causing inadequate control of estrogen receptor driven proliferation [Abstract no. 6].Gynecologic Investigation. 1998; : 40aGoogle Scholar). Increased receptor stability and transcriptional activity may account for the patients’ infertility. Normally, the progesterone receptor is down-regulated in endometrial epithelium during the luteal phase, at a time when embryo implantation takes place (9Lessey B.A. Killiam A.P. Metzger D.A. Haney A.F. Greene G.L. McCartry Jr, K.S. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle.J Clin Endocrinol Metab. 1988; 67: 334-340Crossref PubMed Scopus (587) Google Scholar). With increased stability and transcriptional activity of the PROGINS receptor, the normal down-regulation of the progesterone receptor at a critical time during implantation may be delayed. Lessey et al. (10Lessey B.A. Yeh I. Castelbaum A.J. Fritz M.A. Ilesanmi A.O. Korzeniowski P. et al.Endometrial progesterone receptors and markers of uterine receptivity in the window of implantation.Fertil Steril. 1996; 65: 477-483PubMed Google Scholar) demonstrated that the elevation of epithelial progesterone receptor is associated with absent expression of the integrin αυβ3 vitronectin receptor, a marker of endometrial receptivity. This can occur despite a histologically normal endometrium, referred to as a type II defect, seen in 39% of women with unexplained infertility and an in-phase endometrium (11Lessey B.A. Castelbaum A.J. Sawin S.W. Sun J. Integrins as markers of uterine receptivity in women with primary unexplained infertility.Fertil Steril. 1995; 63: 535-542Abstract Full Text PDF PubMed Google Scholar), statistics similar to the prevalence of the mutated allele in our infertile patient population. Another marker of implantation, pinopode formation, is also dependent on the downregulation of the progesterone receptor (12Stavreus-Evers A. Nikas G. Sahlin L. Eriksson H. Landgren B. Formation of pinopodes in human endometrium is associated with the concentrations of progesterone and progesterone receptors.Fertil Steril. 2001; 76: 782-791Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). Thus, the increased stability of the mutated receptor may lead to altered expression of the integrin αυβ3 vitronectin receptor and pinopode formation despite a normal luteal phase biopsy. Hence, an associated implantation defect in these women with the PROGINS allele may exist. Further investigation of the endometrium of these women is warranted." @default.
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