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Original Studies |
Departments of Obstetrics and Gynecology and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520
Address all correspondence and requests for reprints to: Hugh S. Taylor, M.D., Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520. E-mail: Hugh.Taylor{at}Yale.edu
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Abstract |
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Introduction |
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Attractive candidates for molecular mediators of endometrial development are the HOX genes. HOX genes are the vertebrate homologs of the Drosophila homeotic selector genes. These genes give identity to developing body segments in the fly (7). The homeotic genes encode homeodomain proteins that act as transcription factors (8, 9, 10). The highly conserved homeobox sequences can be detected in a diverse array of metazoans including humans and represent a universal molecular mechanism of developmental control (7, 11, 12, 13). Targeted disruption of Hox genes in mice have confirmed that they are required for proper embryonic development and play a similar role to their Drosophila counterparts (14). These genes are clustered on the chromosome and are expressed along the body axis in a colinear fashion with their order within the cluster (11). Therefore, those genes at the 5' end of the cluster are expressed more caudally and involved in reproductive system (15, 16).
Targeted mutation of the Hoxa11 gene in mice results in axial skeletal defects, limb deformities, and females with uterine factor infertility (17, 18). Mutant mice ovulate normally and produce embryos that are viable when transferred to a wild-type surrogate uterus. However, the Hoxa11 mutant mice have a uterus that does not allow implantation. Normal embryos transferred to the uterus of mutant mice fail to implant. Additionally, heterozygotes showed decreased implantation rates. The mutant uterus is unable to support embryonic development.
Although originally the implantation defect was thought to result from a defect in uterine development, it has recently been demonstrated that Hoxa11/HOXA11 expression persists in the adult endometrium of mice (18, 19) and humans (19). We hypothesize that regulation of this gene in the adult may mediate the development of the human endometrium. In the present study, we have examined HOXA11 gene expression in the human endometrium at phases across the menstrual cycle and in early pregnancy. We have also examined the role of sex steroids as novel modulators of HOX gene expression.
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Materials and Methods |
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Endometrium was collected from normal cycling women by endometrial biopsy with informed consent, under an approved institutional Human Investigations Committee protocol Endometrium was also obtained from four women using depomedroxyprogeterone acetate for contraception. Decidua was obtained from four normal first trimester elective terminations of pregnancy after obtaining informed consent. Half of the tissue was immediately frozen in the liquid nitrogen and stored at -72 C. The other half of the tissue sample was fixed in formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Menstrual cycle dating was determined by menstrual history and confirmed by histological examination using the criteria of Noyes et al. (2).
Northern blot analysis
Tissues or cultured cells were homogenized in 4 M guanidinium thiocyanate, 25 mM sodium citrate (pH 7.0), 0.5% sarkosyl, and 0.1 M 2-mercaptoethanol. Total RNA was size-fractionated on a 1% agarose-0.66 M formaldehyde gel with a [32P] labeled riboprobe as described below. Hybridization was performed overnight at 60 C in 50% formamide, 1 x SSC, 5 x Denhardt’s reagent, 0.2% transfer RNA, and [32P]-labeled riboprobe at 2(106) cpm/mL. The filter was washed twice at 68 C for 30 min in 0.1 x SSC and 0.1% SDS. Kodak (Eastman Kodak, Rochester, NY) X-Omat AR film was exposed overnight at -70 C.
Probe preparation
Plasmids used for probe preparation were a generous gift from E. Boncinnelli and their use established by Boncinelli, ourselves and others (19, 20, 21). pGEM plasmids containing sequence from the 3' untranslated region of human HOXA11 were linearized with EcoRI or HindIII (New England Biolabs, Inc., Beverly, MA), ethanol precipitated and used as template for generation of riboprobes. Radiolabeled RNA probes were generated by in vitro transcription using the Promega Corp. riboprobe kit (Madison, WI). Sense and antisense probes were generated using the appropriate RNA polymerase (T7 or SP6) and labeled with alpha-[33P] or [32P] UTP (Amersham, Arlington Heights, IL).
In situ hybridization
In situ hybridization was performed with both sense and antisense [33P]-labeled riboprobes. Endometrium was fixed in 4% paraformaldehyde, cryoprotected in 30% sucrose, and embedded in OCT compound (Miles, Elkhart, IN). Ten micrometer frozen sections were obtained and mounted on Vectabond-coated slides (Vector Laboratories, Inc., Burlingame, CA). Before use, sections were treated with 0.2 M HCl, Pronase (0.16 mg/mL), and 0.026 M acetic anhydride, then dehydrated. Tissue sections were hybridized overnight with 3(106) cpm of each probe in 0.25 M NaCl, 0.01 M Tris-HCl (pH 7.5), 0.01 M NaPO4 (pH 6.8), 5 mM EDTA, Ficoll 400 (0.02%), polyvinylpyrrolidone (0.02%), BSA fraction V (0.02%), 50% formamide, 12.5% dextran sulfate, yeast transfer RNA (tRNA) (1.25 mg/mL), and 10 mM dithiothreitol. Hybridization was performed in a humidified chamber for 16 h at 50 C. Slides were treated with RNase A at 37 C and then washed 16 h in 0.25 M NaCl, 0.01 M Tris-Cl (pH 7.5), 0.01 M NaPO4 (pH 6.8), 5 mM EDTA, Ficoll 400 (0.02%), polyvinylpyrrolidone (0.02%), BSA fraction V (0.02%) and 50% formamide. Slides were dehydrated, dried and dipped in Ilford K5D (Mobberley, UK) emulsion. Exposure was carried out at 4 C for 7 to 12 days, and slides were developed with Kodak D-19 film. Slides were counterstained with hematoxylin and eosin. Representative darkfield and brightfield photomicrographs were taken at 20x magnification on an Olympus Corp. (Lake Success, NY) microscope with Kodak Ektrachrome film.
Cell culture
Endometrial samples were obtained from four different normal cycling women in the proliferative phase. Endometrial epithelium and stromal cells were separated as described previously. Briefly, the tissue was finely minced and cells were dispersed by incubation in HBSS containing HEPES (25 mM), penicillin (200 U/mL), streptomycin (200 micrograms/mL), collagenase (1 mg/mL, 15 U/mg), and DNase (0.1 mg/mL, 1500 U/mg) for 20–30 min at 37 C with agitation. The cells were separated by filtration through a wire sieve with 73-µm diameter pores. The stromal cells were found in the filtrate whereas the endometrial glands are retained by the sieve. The stromal cells were pelleted, washed, and suspended in phenol red-free Ham’s F12:DMEM (1:1) containing antibiotics and 10% charcoal-stripped FCS. The cells were passaged once and grown to confluence. Confluent monolayers were maintained in phenol red-free, serum-free media for 48 h and subsequently treated with 17ß estradiol (5 x 10-8 M) or medroxyprogesterone acetate (10-7 M) for 4 h. Immunocytochemical analysis of endometrial cells was conducted after the first passage. Factor VIII (22), cytokeratin (23), 3C10 (24, 25) and vimentin (26, 27) were used as markers of endothelial cells, epithelial cells, macrophages and stromal cells respectively. Ninety-seven percent of the cells were endometrial stromal cells. Epithelial cells and macrophages accounted for approximately 3% and 0.2% of the cells; endothelial cells were absent. (Ishikawa cells were grown in the same medium and treated identically as the primary stromal cells.)
Ishikawa cells were a generous gift of Richard Hochberg and well characterized by his laboratory (28, 29, 30, 31, 32, 33). Estrogen and progesterone receptor status was verified by ELISA according to the manufacturer’s instructions (Abbott Laboratories, Weisbaden, Germany). Cells were grown in 70–80% confluence.
Statistical analysis
The autoradiographic bands were quantified using a laser densitometer (Molecular Dynamics, Inc., Sunnyvale, CA). Each HOXA11 band was normalized to the value obtained from the same lane hybridized to G3PDH. Data were analyzed using ANOVA. Statistical significance was defined as P < 0.05.
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Results |
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To examine the role of HOXA11 in endometrial development, the
menstrual cycle stage-specific expression pattern was characterized.
Total RNA was extracted from human endometrium across the menstrual
cycle and during early pregnancy. Thirty specimens were divided into
approximately equal groups corresponding to early and late
proliferative stage, and to early, mid, and late secretory stage
according to the criteria of Noyes et al. (2). Northern blot
analysis were performed with antisense [32P] labeled
riboprobes that hybridizes to the 3' untranslated region of HOXA11.
Representative samples are demonstrated in Fig. 1A
. Moderate levels of HOXA11 expression
are seen throughout the menstrual cycle. Of note was the markedly
increased levels of HOXA11 messenger RNA (mRNA) in the mid-secretory
phase, compared with the proliferative and early-secretory phase.
Hybridization to a control probe (G3PDH) shows that approximately equal
amounts of RNA were loaded in each well. Densinometric analysis
revealed a greater than 2-fold increase in the average abundance of
HOXA11 during the mid and late luteal phase when normalized to G3PDH
(Fig. 1B). The difference between mid and late secretory stage was
statistically different from that of earlier phases. There was no
statistical difference between levels of expression throughout the
proliferative phase or the early secretory phase.
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Endometrium from post-menopausal patients which demonstrated atrophy,
expressed low levels of HOXA11 (not shown). In patients treated with
long-term progestins (i.e. depot medroxyprogesterone acetate
[MPA]) levels of HOXA11 expression were similar to that in the
proliferative phase (Fig. 3). Taken
together, the results indicate that HOXA11 expression varies throughout
the menstrual cycle and increases markedly in the mid-secretory phase,
which corresponds to the time of implantation. Expression of HOXA11
persists into pregnancy, but not with long-term exposure to exogenous
progestins.
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The cellular distribution of HOXA11 was localized within the
endometrium using in situ hybridization. Fig. 4, A and B, shows brightfield and
darkfield illumination of a representative section of secretory
endometrium after hybridization using a [33P] labeled
antisense probe containing the 3' untranslated region of HOXA11.
Stromal and glandular cells both express HOXA11, although at higher
levels in the stromal cells. Confirming the results of northern blot
analysis, levels of expression were higher in the mid and late
secretory phase (data not shown). Control skeletal muscle showed no
hybridization nor did uterus hybridized to a sense control probe (data
not shown).
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The differential HOXA11 expression observed in the endometrium
coincided with developmental changes that are under the control of
sex-steroid hormones. To determine whether sex steroids regulate HOXA11
expression, cultured cells were treated with estrogen and progesterone.
Primary stromal cells were grown to confluence in steroid-free medium
and serum starved for 24 h before treatment with physiologic
concentration of 17-ß estradiol (5 x 10-8
M), MPA (10-7 M) or both. Northern
blot analysis shown in Fig. 5A
demonstrates that either estrogen or progesterone stimulated HOXA11
expression approximately 2- to 3-fold. Progesterone produced greater
stimulation than estrogen and combination of the two gave maximal
expression. Four cultures from different women were subject to steroid
treatment and average densitometric readings are displayed in Fig. 5B.
A statistically significant difference (P < 0.05)
exists between each lane.
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. A similar response
was seen using either MPA acetate or progesterone. Peak levels of
expression were reached within 1 h and persisted at 24 h
after treatment with progesterone. Prolonged treatment with
progesterone results sustained HOXA11 mRNA levels for 24 h, but a
gradual return to pretreatment levels by 4 days. These findings are
consistent with the observed increased in expression of HOXA11 in the
secretory endometrium when estrogen is present and progesterone levels
increase.
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). A similar response was seen after
treatment with progesterone. These results confirm a regulatory role
for sex steroids on HOXA11 expression.
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, pretreatment with
cycloheximide had no effect on the estrogen induced HOXA11 expression,
suggesting that protein synthesis was not required. Similarly,
cycloheximide had no effect on the progesterone induced HOXA11
expression (data not shown). |
Discussion |
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Human endometrium undergoes a menstrual cycle-dependent differentiation under the influence of sex steroids. During the proliferative phase, under the influence of estrogen, the endometrium thickens by 2- to 3-fold, due to the proliferation and differentiation of surface epithelium, glands, stroma, and blood vessels (1). With the onset of progesterone production, the endometrium undergoes a differentiation process that renders it receptive to implantation. Numerous changes in both histologic features and molecular markers have been described (1, 2, 36). Disorders of the endometrial maturation are common and lead to infertility, dysfunctional bleeding, hyperplasia, and cancers; disruption of the development of endometrium is also an important component of contraception. The molecular regulators of this differentiation process are still unknown.
Attractive candidates for molecular regulators of endometrial differentiation are homeobox genes. Homeobox genes encode DNA-binding proteins, which are highly conserved throughout evolution and functional as transcriptional regulators (7, 11, 37). Homeobox genes were first identified in Drosophila melanogaster, where they impart a developmental identity to segmental body units of the fly (7). In vertebrates, including humans, HOX genes correspond to both structurally and functionally to Drosophila homeotic genes (38, 39). The unique combination of HOX gene expression in embryonic development imparts tissue identity. Recently we have described the role of HOX genes of the A axis in the development of the murine reproductive system (19). HOXA11 is expressed in the developing uterus. Persistent expression is noted in the adult uterus (18, 19). This adult expression pattern observed in mice is conserved in the human endometrium (19). The HOXA11 gene, which is involved in directing embryonic development of the endometrium may later regulate development of the endometrium in the menstrual cycle. In this report, we demonstrate that HOXA11 is expressed in a menstrual cycle phase-dependent manner. One way in which differential tissue identity is obtained is through selective activation of HOX genes. HOXA11 expression is noted in the proliferative phase of the menstrual cycle when estrogen is the predominant steroid hormone affecting the uterus. HOXA11 mRNA levels significantly increase in the mid-secretory phase at the time when progesterone levels rise rapidly. A parallel increase in the expression is noted in cell culture experiments in which both primary stromal cells and Ishikawa endometrial adenocarcinoma cells increase HOXA11 expression in response to estrogen and progesterone. Under the influence of sex steroids, changing levels of HOXA11 may lead to the growth and differentiation of human endometrium. Analogous to the role of HOXA11 in embryonic development, this gene may regulate transcription of downstream genes, altering cell fate and leading to the coordinated differentiation of this tissue.
Sex steroid regulation of HOXA11
In this report, we demonstrate that estrogen and progesterone are novel regulators of HOX gene expression. Few molecular regulators of HOX gene expression are known. One, retinoic acid, imparts differential regulation of HOX genes at the 3' end of the HOX cluster (40, 41, 42). Here we describe regulation of a gene at the 5' end of the HOX cluster, HOXA11, by another nuclear hormone receptor transcription factor. Estrogen and progesterone both increase expression of HOXA11. Physiologic concentrations of progesterone induces a dose-responsive increase in HOXA11 expression. HOXA11 is induced rapidly in response to treatment with sex steroids. Pretreatment with cycloheximide does not alter the sex steroid induced expression. Taken together, these data suggest that the sex steroid-sex steroid receptor complex directly binds to regulatory elements of HOXA11 altering the expression of this gene. It will be interesting to determine whether other nuclear hormone receptors regulate HOX gene expression.
Role of HOXA11 in Implantation
Essential for successful implantation of the human blastocyst is a receptive uterine endometrium with synchronously developed components (4). The endometrium undergoes characteristic cyclic changes in response to circulating sex steroids, and, as described above, HOXA11 may mediate this response to sex steroids by directing the development of the endometrium in the menstrual cycle.
HOXA11 is essential for implantation in the mouse. Targeted mutation of the HOXA11 gene results in uterine factor infertility (17, 18). Despite being anatomically and histologically normal, the uterus does not support the development or allow the implantation of preembryos including wild-type embryos. The Hoxa11 (-/-) embryos are viable when placed in a wild-type surrogate uterus. The spatially and temporally regulated expression pattern of HOXA11 is suggestive of an essential role in the human implantation. HOXA11 is differentially expressed in the uterine endometrium throughout the menstrual cycle. A dramatic increase in levels of expression accompanies endometrial differentiation at the mid-secretory phase, which is the time of implantation in the human. The HOXA11 (-/-) mutations likely act as an adult phenotype altering cyclic endometrial development rather than through a developmental defect of the uterus in the embryonic period. Heterozygote Hoxall mutant mice displayed reduced implantation rates. This heterozygous effect is likely attributable to the reduced levels of HOXA11 transcripts. This indicates that expression levels play an important role in regulating implantation and further support an essential role for the increasing levels of HOXA11 at the time of implantation in the human. Furthermore, continued progesterone treatment does not maintain HOXA11 levels seen in the secretory phase. HOXA11 expression is progesterone dependent only in the context of stage appropriate endometrial development. The data suggest that, in human endometrium, sex steroid modulation of HOXA11 expression directs sequential differentiation of the endometrium and leads to implantation receptivity. Furthermore, the persistent expression in decidua suggested a continued role in pregnancy.
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Footnotes |
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Received July 20, 1998.
Revised December 4, 1998.
Accepted December 22, 1998.
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5 adrenal steroids. Endocrinology. 127:2757–2762.
activity in the Ishikawa human endometrial
adenocarcinoma cell line. J Clin Endocrinol Metab. 63:356–359.This article has been cited by other articles:
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  K. A. Connell, M. K. Guess, H. W. Chen, T. Lynch, R. Bercik, and H. S. Taylor HOXA11 Promotes Fibroblast Proliferation and Regulates p53 in Uterosacral Ligaments Reproductive Sciences, July 1, 2009; 16(7): 694 - 700. [Abstract] [PDF]
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 J. Sarno, F. Schatz, S. J. Huang, C. Lockwood, and H. S. Taylor Thrombin and interleukin-1{beta} decrease HOX gene expression in human first trimester decidual cells: implications for pregnancy loss Mol. Hum. Reprod., July 1, 2009; 15(7): 451 - 457. [Abstract] [Full Text] [PDF]
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G. Weiss, L. T. Goldsmith, R. N. Taylor, D. Bellet, and H. S. Taylor Inflammation in Reproductive Disorders Reproductive Sciences, February 1, 2009; 16(2): 216 - 229. [Abstract] [PDF]
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 B. Lee, H. Du, and H. S. Taylor Experimental Murine Endometriosis Induces DNA Methylation and Altered Gene Expression in Eutopic Endometrium Biol Reprod, January 1, 2009; 80(1): 79 - 85. [Abstract] [Full Text] [PDF]
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D. Vitiello, R. Pinard, and H. S. Taylor Gene Expression Profiling Reveals Putative HOXA10 Downstream Targets in the Periimplantation Mouse Uterus Reproductive Sciences, May 1, 2008; 15(5): 529 - 535. [Abstract] [PDF]
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 R. Martin, M. B. Taylor, G. Krikun, C. Lockwood, G. E. Akbas, and H. S. Taylor Differential Cell-Specific Modulation of HOXA10 by Estrogen and Specificity Protein 1 Response Elements J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1920 - 1926. [Abstract] [Full Text] [PDF]
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 G. E. Akbas, X. Fei, and H. S. Taylor Regulation of HOXA10 expression by phytoestrogens Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E435 - E442. [Abstract] [Full Text] [PDF]
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 C. C. Smith and H. S. Taylor Xenoestrogen exposure imprints expression of genes (Hoxa10) required for normal uterine development FASEB J, January 1, 2007; 21(1): 239 - 246. [Abstract] [Full Text] [PDF]
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 G. S. Daftary and H. S. Taylor Endocrine Regulation of HOX Genes Endocr. Rev., June 1, 2006; 27(4): 331 - 355. [Abstract] [Full Text] [PDF]
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J. L. Sarno, F. Schatz, C. J. Lockwood, S.-T. J. Huang, and H. S. Taylor Thrombin and Interleukin-1{beta} Regulate HOXA10 Expression in Human Term Decidual Cells: Implications for Preterm Labor J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2366 - 2372. [Abstract] [Full Text] [PDF]
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 B. Zhao, D. Koon, and K. E Bethin Identification of transcription factors at the site of implantation in the later stages of murine pregnancy. Reproduction, March 1, 2006; 131(3): 561 - 571. [Abstract] [Full Text] [PDF]
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 H. Yoshida, R. Broaddus, W. Cheng, S. Xie, and H. Naora Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition Cancer Res., January 15, 2006; 66(2): 889 - 897. [Abstract] [Full Text] [PDF]
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 H. S. Taylor and X. Fei Emx2 Regulates Mammalian Reproduction by Altering Endometrial Cell Proliferation Mol. Endocrinol., November 1, 2005; 19(11): 2839 - 2846. [Abstract] [Full Text] [PDF]
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 A.K. Bang, E. Carlsen, M. Holm, J.H. Petersen, N.E. Skakkebaek, and N. Jorgensen A study of finger lengths, semen quality and sex hormones in 360 young men from the general Danish population Hum. Reprod., November 1, 2005; 20(11): 3109 - 3113. [Abstract] [Full Text] [PDF]
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H. Du, G. S. Daftary, S. I. Lalwani, and H. S. Taylor Direct Regulation of HOXA10 by 1,25-(OH)2D3 in Human Myelomonocytic Cells and Human Endometrial Stromal Cells Mol. Endocrinol., September 1, 2005; 19(9): 2222 - 2233. [Abstract] [Full Text] [PDF]
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 X. Fei, H. Chung, and H. S. Taylor Methoxychlor Disrupts Uterine Hoxa10 Gene Expression Endocrinology, August 1, 2005; 146(8): 3445 - 3451. [Abstract] [Full Text] [PDF]
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M. Tang, H. S. Taylor, and S. Tabibzadeh In vivo gene transfer of lefty leads to implantation failure in mice Hum. Reprod., July 1, 2005; 20(7): 1772 - 1778. [Abstract] [Full Text] [PDF]
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G. E. Akbas and H. S. Taylor HOXC and HOXD Gene Expression in Human Endometrium: Lack of Redundancy with HOXA Paralogs Biol Reprod, January 1, 2004; 70(1): 39 - 45. [Abstract] [Full Text] [PDF]
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S. Tulac, N. R. Nayak, L. C. Kao, M. van Waes, J. Huang, S. Lobo, A. Germeyer, B. A. Lessey, R. N. Taylor, E. Suchanek, et al. Identification, Characterization, and Regulation of the Canonical Wnt Signaling Pathway in Human Endometrium J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3860 - 3866. [Abstract] [Full Text] [PDF]
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 B. P. Whitcomb, D. G. Mutch, T. J. Herzog, J. S. Rader, R. K. Gibb, and P. J. Goodfellow Frequent HOXA11 and THBS2 Promoter Methylation, and a Methylator Phenotype in Endometrial Adenocarcinoma Clin. Cancer Res., June 1, 2003; 9(6): 2277 - 2287. [Abstract] [Full Text] [PDF]
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J.J. Buck, R.M. Williams, I.A. Hughes, and C.L. Acerini In-utero androgen exposure and 2nd to 4th digit length ratio--comparisons between healthy controls and females with classical congenital adrenal hyperplasia Hum. Reprod., May 1, 2003; 18(5): 976 - 979. [Abstract] [Full Text] [PDF]
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M. W. M. Yao, H. Lim, D. J. Schust, S. E. Choe, A. Farago, Y. Ding, S. Michaud, G. M. Church, and R. L. Maas Gene Expression Profiling Reveals Progesterone-Mediated Cell Cycle and Immunoregulatory Roles of Hoxa-10 in the Preimplantation Uterus Mol. Endocrinol., April 1, 2003; 17(4): 610 - 627. [Abstract] [Full Text] [PDF]
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D. Cermik, B. Selam, and H. S. Taylor Regulation of HOXA-10 Expression by Testosterone in Vitro and in the Endometrium of Patients with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 238 - 243. [Abstract] [Full Text] [PDF]
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Y. M. Chau, S. Pando, and H. S. Taylor HOXA11 Silencing and Endogenous HOXA11 Antisense Ribonucleic Acid in the Uterine Endometrium J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2674 - 2680. [Abstract] [Full Text] [PDF]
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G. S. Daftary, P. J. Troy, C. N. Bagot, S. L. Young, and H. S. Taylor Direct Regulation of {beta}3-Integrin Subunit Gene Expression by HOXA10 in Endometrial Cells Mol. Endocrinol., March 1, 2002; 16(3): 571 - 579. [Abstract] [Full Text] [PDF]
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K. BLOCK, A. KARDANA, P. IGARASHI, and H. S. TAYLOR In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mullerian system FASEB J, June 1, 2000; 14(9): 1101 - 1108. [Abstract] [Full Text]
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H. S. Taylor, C. Bagot, A. Kardana, D. Olive, and A. Arici HOX gene expression is altered in the endometrium of women with endometriosis Hum. Reprod., May 1, 1999; 14(5): 1328 - 1331. [Abstract] [Full Text] [PDF]
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