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Continual administration of low doses of the antiprogestin ZK 137 316 was previously reported to permit ovarian/menstrual cyclicity, but disrupt endometrial growth in macaques. The contraceptive efficacy of this regimen was tested in female rhesus monkeys (10 per group) treated daily with vehicle (controls), 0.01 or 0.03 mg ZK 137 316 per kg body weight for 30 days before and during continual co-habitation with males of proven fertility. Treatment continued until confirmation of pregnancy or for 5 months after pair-housing with males. Mating and vaginal sperm were evident in all females. A cumulative pregnancy rate of 90% (9/10) was observed in the controls. Of the 10 animals receiving 0.01 mg/kg, four conceived during the first 2 months of pairing (P = 0.06) with no further conceptions. No pregnancies were observed in the 0.03 mg/kg group (P < 0.01). Timely, overt menses occurred at a higher frequency in the 0.01 mg/kg group than the 0.03 mg/kg group. However, corpora lutea were present in ovaries from both groups during the last treatment cycle, indicating that ovarian cycles occurred. Thus, chronic administration of low-dose ZK 137 316 that permits continued ovarian cyclicity and a high incidence of timely menses, prevents pregnancy in non-human primates. This regimen may provide a novel method of contraception for women. [ABSTRACT FROM AUTHOR]

Large doses of antiprogestin typically disrupt menstrual cyclicity. A chronic low-dose regimen of the potent new antiprogestin ZK 137 316, which permits continued menstrual cyclicity but alters gonadal-reproductive tract activity, was established. Rhesus monkeys received a vehicle (n = 6) or 0.01 (n = 8), 0.03 (n = 8) or 0.1 (n = 5) mg ZK 137 316/kg body weight daily for five menstrual cycles (C-1 to C-5). Oestradiol, progesterone and gonadotrophin profiles were normal during cycles involving vehicle and 0.01 and 0.03 mg ZK 137 316/kg body weight. In the 0.1 mg/kg group, mid-cycle oestradiol and gonadotrophin surges, and subsequent progesterone production, were absent in C-3 and C-5. Ovarian cyclicity was accompanied by timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3, half the animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg group were amenorrhoeic. A corpus luteum was noted during the mid-luteal phase of C-5 in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral and cystic follicles were evident in the 0.1 mg/kg group. Thus, a daily treatment with 0.01 mg/kg ZK 136 317 permitted normal menstrual cyclicity in macaques. While the daily administration of 0.03 mg/kg ZK 136 317 allowed ovarian cyclicity, menstruation was disrupted in some animals. Increasing the dose to 0.1 mg./kg antagonized pituitary function and resulted in anovulation and amenorrhoea. A chronic low-dose regimen of the antiprogestin ZK 137 316, which permits normal ovarian/menstrual cyclicity, has potential as a contraceptive in women. [ABSTRACT FROM PUBLISHER]

The long-term effects of the antiprogestin ZK 137 316 on reproductive tract morphology in rhesus macaques were investigated. The monkeys were injected daily (i.m.) for five menstrual cycles with vehicle or 0.01, 0.03 or 0.1 mg ZK 137 316/kg body weight. Reproductive tracts (n = 3/group) were collected during the mid-luteal phase (day 8) of the fifth cycle in the control, 0.01 and 0.03 mg/kg groups, or 6-7 days after the oestradiol peak in the 0.1 mg/kg group. ZK 137 316 treatment resulted in a dose-dependent atrophy of the endometrium, marked by a reduced mitotic activity in the glands, compaction of the stroma, degradation of spiral arteries and dilation of veins. There was no effect of ZK 137 316 on myometrial or oviductal weight. Treatment with 0.1 and 0.03 mg/kg, but not 0.01 mg/kg resulted in fully ciliated and secretory oviducts, indicating a dose-dependent blockade of progesterone antagonism of oestrogen-dependent oviductal differentiation. In the endometrium, the suppressive action of progesterone on oestrogen and progestin receptors was also blocked by ZK 137 316 in a dose-dependent manner. However, endometrial atrophy appeared due to inhibition of progesterone action together with a blockade of oestrogen-dependent proliferation. The profoundly suppressed endometrium produced by chronic low-dose ZK 137 316 treatment is unlikely to support implantation. Such treatment may therefore provide a novel contraceptive modality. [ABSTRACT FROM PUBLISHER]

The purpose of this research is to identify how decision-makers within anchor institutions, using the context of higher education, determine the course of action in response to an improbable disaster event, such as the recent coronavirus disease 2019 (COVID-19) pandemic. A survey was conducted among higher education decision-makers during spring 2020 at the moment they were adapting to COVID-19. The survey aimed to identify policies and planning measures that may help Institutions of Higher Education learn from this experience to maintain continuity of operations should similar or unanticipated events occur in the future. With this knowledge, both assets and detriments contributing to community vulnerability can be better balanced to inform decision-making. The outcomes of the analysis and shared reflections inform the development of future policy and strengthen existing processes for preparedness and mitigation planning for unexpected events.

In the United States, most floodplain relocation (or buyout) programs focus on moving homeowners, then deal separately with what happens with the land afterward. These programs typically divide processes for relocation planning, engagement, funding, and implementation from those related to post-buyout land management and restoration. The structural and operational conditions that lead to this separation of roles and responsibilities miss out on opportunities to create more synergistic socio-ecological strategies that may produce healthier outcomes for both people and the environment. In other domains, research shows that healthy people and healthy environments can co-create each other through more virtuous cycles. In this perspective essay, we argue that we can better create such virtuous cycles in floodplain relocation programs by integrally considering social and ecological components. Such efforts can encourage more people to decide to relocate, thereby creating more contiguous places to restore. They can also empower more residents to help steward these sites, an action that in turn helps heal and strengthen flood-affected communities. These arguments, while particular to the United States, have resonance for floodplain management and land use planning worldwide., Competing Interests: Conflict of interest Linda Shi is an editorial board member of Socio-Ecological Practice Research. She was not involved in the peer-review or handling of the manuscript, and has no other competing interests to disclose. All coauthors have no conflict of interests to declare that are relevant to the content of this article., (© The Author(s) 2023.)

Climate change-exacerbated flooding has renewed interest in property buyouts as a pillar of managed retreat from coastal zones and floodplains in the United States. However, federal buyout programs are widely critiqued for being inaccessible and inequitable. To learn whether and how subnational buyout programs overcome these limitations, we examined five leading US state, county, and local buyout programs to see what they teach us about redesigning future federal policies. Our mixed-methods research used interviews and document analysis to develop case studies, juxtaposed subnational strategies against a review of critiques of federal buyouts, and focus group discussions with subnational buyout managers and experts to identify limitations of their programs. We find that subnational programs can be more inclusive and better respond to resident needs as compared to existing federal programs due to their access to dedicated, non-federal funding and their standing institutional status, which allows them to learn and evolve over time. Nevertheless, these programs lack coordination with and control over agencies that permit development and produce affordable housing. This gives buyout programs limited power in shaping the overall equity of who lives in floodplains and who has access to affordable, resilient housing after a buyout. Their experiences suggest federal programs can support managed retreat nationwide by increasing support for institutional and staff capacity at state and county levels, encouraging efforts to bridge institutional silos at subnational levels, and holistically mainstream climate considerations into regional floodplain development, affordable housing production, and flood risk mitigation., (© The Author(s) 2022.)

High-grade dysplastic spondylolisthesis (HGDS) is a subset of L5-S1 spondylolisthesis that occurs due to dysmorphic anatomy at the lumbosacral junction, often resulting in sagittal imbalance. Enhanced understanding of global sagittal alignment has led many to preferentially treat HGDS with reduction and fusion to restore sagittal balance. The purpose of this article is to review published surgical techniques for obtaining sagittal correction in HGDS and to evaluate the current evidence regarding the associated surgical complications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

AKI after cardiac surgery remains strongly associated with mortality and lacks effective treatment or prevention. Preclinical studies suggest that cell-based interventions may influence functional recovery. We conducted a phase 2, randomized, double-blind, placebo-controlled trial in 27 centers across North America to determine the safety and efficacy of allogeneic human mesenchymal stem cells (MSCs) in reducing the time to recovery from AKI after cardiac surgery. We randomized 156 adult subjects undergoing cardiac surgery with evidence of early AKI to receive intra-aortic MSCs (AC607; n =67) or placebo ( n =68). The primary outcome was the time to recovery of kidney function defined as return of postintervention creatinine level to baseline. The median time to recovery of kidney function was 15 days with AC607 and 12 days with placebo (25th, 75th percentile range, 10-29 versus 6-21, respectively; hazard ratio, 0.81; 95% confidence interval, 0.53 to 1.24; P =0.32). We did not detect a significant difference between groups in 30-day all-cause mortality (16.7% with AC607; 11.8% with placebo) or dialysis (10.6% with AC607; 7.4% with placebo). At follow-up, 12 patients who received AC607 and six patients who received placebo had died. Rates of other adverse events did not differ between groups. In these patients with AKI after cardiac surgery, administration of allogeneic MSCs did not decrease the time to recovery of kidney function. Our results contrast with those in preclinical studies and provide important information regarding the potential effects of MSCs in this setting., (Copyright © 2018 by the American Society of Nephrology.)

Background: Data on differences in toxicity and efficacy of chemotherapy and radiotherapy among different ethnic groups is limited. We evaluated differences in toxicity, tolerability and clinical outcome of Ashkenazi and non-Ashkenazi Jews receiving postoperative chemoradiation for locally advanced gastric cancer (LAGC)., Patients and Methods: Between 6/2000-12/2007, 84 Ashkenazi patients and 60 non-Ashkenazi patients underwent chemoradiation following resection of LAGC (INT-116 trial)., Results: Patients' and tumor characteristics were comparable. Ashkenazi patients experienced significantly higher rates of fatigue, anorexia, and grade 3-4 dysphagia, as well as a trend for a higher rate of diarrhea. The incidence of other toxicities, dose adjustments of chemotherapy and radiotherapy and patient prognosis did not differ., Conclusion: This study shows higher rates of various toxicities among Ashkenazi patients receiving postoperative chemoradiation for LAGC compared to non-Ashkenazi patients. To our knowledge, this is the first study comparing treatment toxicity, tolerability and outcome between these two groups.

The spinal cord is particularly susceptible to ischaemic injury following repair of extensive descending thoracic and thoracoabdominal aortic aneurysms (TAAA). For the past decade, the Mount Sinai group in New York has intensively studied the anatomy of the extensive vascular network surrounding the spinal cord, as well as its dynamic morphology in response to decreased blood pressure and flow. Along with clinical data, experimental findings gave rise to the Collateral Network Concept, by which spinal cord injury in open TAAA repair can be significantly reduced. With the more recent widespread use of endovascular repair, strategies to prevent ischaemic spinal cord damage after extensive segmental artery sacrifice/occlusion are still evolving. The hypothesis that dividing extensive aneurysm repair into two steps may mitigate the impact of diminished blood flow to the collateral network has led to a recently conducted series of staged repair experiments. By exploiting the resources of the collateral network, spinal cord injury could be minimised in staged open, as well as in staged hybrid repair and seems equally adoptable for endovascular procedures. The contribution presented herein provides an overview of clinical and experimental studies on the staged approach. Furthermore, it briefly assesses the anatomic rationale for the collateral network concept., (Georg Thieme Verlag KG Stuttgart · New York.)

Much of our understanding of the molecular control of menstruation arises from laboratory models that experimentally recapitulate some, but not all, aspects of uterine bleeding observed in women. These models include: in vitro culture of endometrial explants or isolated endometrial cells, transplantation of human endometrial tissue into immunodeficient mice and the induction of endometrial breakdown in appropriately pretreated mice. Each of these models has contributed to our understanding of molecular and cellular mechanisms of menstruation, but nonhuman primates, especially macaques, are the animal model of choice for evaluating therapies for menstrual disorders. In this chapter we review some basic aspects of menstruation, with special emphasis on the macaque model and its relevance to the clinical issues of irregular and heavy menstrual bleeding (HMB).

Purpose: To describe the histological findings in the aortic wall 5 days after thoracic endovascular aortic repair (TEVAR) in a porcine model., Methods: Two overlapping stent-grafts were implanted in each of 6 juvenile pigs, covering the entire descending thoracic aorta (DTA). On the 5(th) postoperative day, tissue samples were taken from the DTA in each animal. Medial thickness and medial necrosis were quantified and compared to measurements from the aortas of 6 control animals., Results: Significant medial thinning was observed in stent-covered regions in the test animals. At the proximal landing zone, aortic wall thickness changed from 1387±68 to 782±74 µm within the covered aortic segment (p = 0.028); at the distal landing site, the wall thickness was 365±67 µm within the stent and 501±57 µm distally (p = 0.028). In the overlap zone, the aortic wall measured 524±122 vs. 1053±77 µm in native controls (p = 0.004). Aortic thickness proximal to the graft did not differ from the proximal region of native aortas (1468±96 vs. 1513±80 µm, p = 0.423), but the aorta was significantly thinner distal to the stent (707±38 vs. 815±52 µm, p = 0.004). Laminar necrosis constituted 38%±7% of the media in the proximal landing zone, 54%±4% in the overlap zone, and 46%±13% in the distal landing zone., Conclusion: In this porcine model, significant medial thinning and necrosis of the stented aorta was observed. The findings suggest an early phase of vulnerability of the aortic wall, before scarring and adaptive changes have strengthened the residual aorta.

Despite the vital physiological role of endometrial regeneration during the menstrual cycle and the various pathological implications of abnormal growth of endometrial epithelial cells, the local factors and regulatory mechanisms involved in endometrial regeneration and growth have not been well characterized. Here, we examine the pattern, hormone dependence, and potential functions of Wnt7a (wingless-type MMTV integration site family member 7a), which is known to play a critical role in the formation of the mouse endometrial epithelium during embryonic development, in both human and artificially cycling rhesus macaque endometrium, and using a potent Wnt-antagonist in a mouse model of endometrial regeneration. Wnt7a transcript levels were examined using quantitative real-time PCR and in situ hybridization, and immunohistochemistry was performed to detect Ki-67 and 3,5-bromodeoxyuridine. Stringent, fully conditional Wnt inhibition was achieved by adenoviral expression of Dickkopf-1 during artificial endometrial regeneration in mice. In macaques, Wnt7a expression was confined to the newly formed luminal epithelium (LE) and upper glands during the postmenstrual repair phase. The signal increased in the LE during the proliferative phase but decreased in the upper glands and was undetectable in the glands by the late proliferative phase. Interestingly, Wnt7a was completely suppressed in the LE and remained undetectable in other cell types after 7 d of progesterone treatment. The pattern of Wnt7a expression in the human endometrium was similar to that in macaques. Blockade of Wnt signaling during endometrial regeneration in mice resulted in a dramatic delay in reepithelialization and degeneration of glands and LE. These results strongly suggest, for the first time, a role for Wnt7a in postmenstrual regeneration and proliferation of endometrial glands and LE in primates, and its dramatic suppression by progesterone is likely essential for secretory transformation of the epithelium.

Background: In a porcine model, we investigated the impact of sudden stent graft occlusion of thoracic intercostal arteries after open lumbar segmental artery (SA) ligation., Methods: After randomization into two groups, 20 juvenile Yorkshire pigs (27.1±0.6 kg) underwent open lumbar SA sacrifice (T13-L5) followed by endovascular coverage of all thoracic SAs (T4-T12) at 32°C, either in a single operation (group 1) or in two stages separated by seven days (group 2). Collateral network pressure (CNP) was monitored by catheterization of the SA L1, and postoperative hind limb function was assessed using a modified Tarlov score., Results: The CNP in group 1 decreased to 34% of baseline, whereas CNP after lumbar SA ligation in group 2 fell to 55% of baseline (74±2.4 to 25±3.6 mm Hg vs 74±4.5 to 41±5.5 mm Hg; p<0.0001). Subsequent thoracic stenting (group 2) led to another significant but milder drop (p=0.002 versus stage 1) from the restored CNP (71±4.2 to 54±4.9 mm Hg). Five of ten pigs in group 1 suffered paraplegia, in contrast to none in group 2 (median Tarlov score 6, vs 9; p=0.0031). Histopathologic analysis showed more severe ischemic damage to the lower thoracic (p=0.05) and lumbar spinal cord (p=0.002) in group 1., Conclusions: These results underline the potential of the staged approach in hybrid procedures. Furthermore they highlight the need for established adjuncts for preventing paraplegia in hybrid and pure stent-graft protocols in which sudden occlusion of multiple SAs occurs., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Prevention of paraplegia after repair of thoracoabdominal aortic aneurysm requires understanding the anatomy and physiology of the spinal cord blood supply. Recent laboratory studies and clinical observations suggest that a robust collateral network must exist to explain preservation of spinal cord perfusion when segmental vessels are interrupted. An anatomic study was undertaken., Methods: Twelve juvenile Yorkshire pigs underwent aortic cannulation and infusion of a low-viscosity acrylic resin at physiologic pressures. After curing of the resin and digestion of all organic tissue, the anatomy of the blood supply to the spinal cord was studied grossly and with light and electron microscopy., Results: All vascular structures at least 8 μm in diameter were preserved. Thoracic and lumbar segmental arteries give rise not only to the anterior spinal artery but to an extensive paraspinous network feeding the erector spinae, iliopsoas, and associated muscles. The anterior spinal artery, mean diameter 134 ± 20 μm, is connected at multiple points to repetitive circular epidural arteries with mean diameters of 150 ± 26 μm. The capacity of the paraspinous muscular network is 25-fold the capacity of the circular epidural arterial network and anterior spinal artery combined. Extensive arterial collateralization is apparent between the intraspinal and paraspinous networks, and within each network. Only 75% of all segmental arteries provide direct anterior spinal artery-supplying branches., Conclusions: The anterior spinal artery is only one component of an extensive paraspinous and intraspinal collateral vascular network. This network provides an anatomic explanation of the physiological resiliency of spinal cord perfusion when segmental arteries are sacrificed during thoracoabdominal aortic aneurysm repair., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: A comprehensive strategy to prevent paraplegia after open surgical or endovascular repair of thoracoabdominal aortic aneurysms requires a thorough understanding of the response of the collateral network to extensive segmental artery sacrifice., Methods: Ten Yorkshire pigs underwent perfusion with a low-viscosity acrylic resin. With the use of cardiopulmonary bypass, 2 animals each were perfused in the native state and immediately, 6 hours, 24 hours, and 5 days after sacrifice of all segmental arteries (T4-L5). After digestion of surrounding tissue, the vascular cast of the collateral network underwent analysis of arterial and arteriolar diameters and the density and spatial orientation of the vasculature using light and scanning electron microscopy., Results: Within 24 hours, the diameter of the anterior spinal artery had increased significantly, and within 5 days the anterior spinal artery and the epidural arterial network had enlarged in diameter by 80% to 100% (P < .0001). By 5 days, the density of the intramuscular paraspinous vessels had increased (P < .0001), a shift of size distribution from small to larger arterioles was seen (P = .0002), and a significant realignment of arterioles parallel to the spinal cord had occurred (P = .0005)., Conclusions: Within 5 days after segmental artery occlusion, profound anatomic alterations in the intraspinal and paraspinous arteries and arterioles occurred, providing the anatomic substrate for preservation of spinal cord blood flow via collateral pathways., (Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: We describe the long-term results of aortic arch replacement using a trifurcated graft, including an assessment of survival, neurologic complications, and graft patency., Methods: A retrospective review was conducted on data from 206 consecutive patients (125 male; median age, 67 years; range, 20-87 years) who had a trifurcated graft used for aortic arch replacement between September 1999 and September 2009. Seventy-four patients (35.9%) had chronic dissection, 68 patients (33.0%) had atherosclerotic aneurysms, and 39 patients (18.9%) had degenerative disease. Ninety-one patients (44.2%) had undergone previous cardiac surgery., Results: An elephant trunk was placed in 190 patients (92.2%) and completed in 101 patients (53.1%), with an interval of less than 365 days between stages in 94 of 101 patients. Hospital mortality was 6.8% (14/206). Adverse outcome (death/stroke within the first year postoperatively) occurred in 27.7% of patients (57/206; 50 deaths/7 strokes). Among 152 1-year survivors, the annual rates of transient ischemic attack and stroke were 0.85% and 1.1%, respectively. At 6 years, 75% of patients were still alive, compared with 92% in a matched New York State control population (P < .001). Follow-up computed tomography scans (189 studies in 176/206 patients [85.4%]) revealed 100% patency of the trifurcated graft limbs at a mean of 2.3 years., Conclusions: Aortic arch replacement using a trifurcated graft is highly durable, with excellent patency in the branch grafts, and is associated with a low incidence of cerebral embolization. However, the long-term outcome in these patients is compromised by extensive comorbidities., (Copyright © 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Endovascular repair of descending thoracic and thoracoabdominal aortic aneurysms is an appealing alternative to the standard surgical approach, but precludes revascularization of segmental arteries (SAs). For safer surgical and endovascular repairs, an accurate prediction of the risk of paraplegia in relation to the extent of SA sacrifice is needed., Methods: From January 1994 to October 2008, 609 patients (mean age, 63 ± 14 years) underwent surgical descending thoracic or thoracoabdominal aortic aneurysm repair without SA reimplantation. Three hundred seventy-six patients (62%) were male; 159 (26%) had urgent or emergent operation; 199 (33%) had previous aortic surgery. Somatosensory- or motor-evoked potential monitoring and cerebrospinal fluid drainage were routinely performed., Results: Hospital mortality was 10.7% (65 patients). Spinal cord injury (SCI) occurred in 3.4% (21 patients). The extent of resection-expressed as the number of SAs sacrificed (p = 0.007)-and the need for visceral artery reimplantation (p = 0.03) were independent risk factors for paraplegia. Further analysis identified four risk groups (p < 0.0001): fewer than 8 SAs sacrificed (group A, SCI = 1.2%); sacrifice of 8 to 12 SAs with proximal origin in the upper thorax (group B, SCI = 3.7%); 8 to 12 SAs sacrificed beginning in the lower thorax (group C, SCI = 15.4%); and 13 or more SAs sacrificed (group D, SCI = 12.5%). This four-group model more accurately predicts SCI risk than the Crawford classification (goodness of fit c statistic: 0.748 versus 0.640)., Conclusions: The extent of SA sacrifice is the most powerful predictor of paraplegia risk. For aneurysms of moderate extent, a more distal location involving the abdominal aorta increases the risk of spinal cord injury. Sacrifice of fewer than 8 SAs is associated with a very low paraplegia risk regardless of location., (Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: In a pig model, we compared spinal cord injury after extensive segmental artery (SA) sacrifice in a single stage with recovery after a two-stage procedure: lumbar artery followed by thoracic SA sacrifice., Methods: Twenty juvenile Yorkshire pigs were randomly assigned to undergo extensive SA sacrifice at 32 degrees C in a single operation (group 1, n = 10), or thoracic SA ligation 7 days after lumbar artery sacrifice (group 2, n = 10). Spinal cord perfusion pressure (SCPP) was monitored using a catheter placed in the distal stump of L1. Hind limb function was evaluated intraoperatively using motor-evoked potentials and for 5 days postoperatively using a modified Tarlov score., Results: Motor-evoked potentials were intact in all pigs until 1 hour after surgery. All pigs in group 2 fully recovered hind limb function, whereas 40% in group 1 experienced paraplegia (median Tarlov scores 9 versus 7; p = 0.004). Group 1 SCPP fell to 28 +/- 6 mm Hg after SA sacrifice, compared with 44 +/- 8 mm Hg in group 2 (p < 0.0001). After sacrifice of all residual SAs, SCPP in group 2 remained consistently greater than 85% of baseline, significantly higher than group 1 SCPP from end clamping until 72 hours (p = 0.0002). Histopathologic analysis showed more severe ischemic damage to the lower thoracic (p < 0.001) and lumbar spinal cord (p = 0.01) in group 1., Conclusions: In contrast with the single-stage approach, a two-stage procedure, starting with ligation of six or fewer lumbar SAs, leads to only a mild drop in SCPP and stimulates vascular remodeling, minimizing the impact of subsequent SA sacrifice on spinal cord function. The greater safety of extensive SA sacrifice when undertaken in two stages has important implications for endovascular and hybrid aneurysm repair., (2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The optimal treatment of chronic distal aortic dissection remains controversial, with endovascular stent-graft techniques challenging traditional surgery., Methods: From January 1994 to April 2007, 104 patients (82 male, median age 60.5 years) with chronic distal aortic dissection underwent surgical repair, 0 to 21 years after initial diagnosis of acute type A or B dissection (median 2.1 years). Twenty-three (22%) patients underwent urgent-emergent surgery. Mean aortic diameter was 6.9 +/- 1.4 cm. Indications for surgery, other than aortic expansion, were pain in 6 (6%) patients, malperfusion in 6 (6%), and rupture in 11 (11%). Forty-nine (47%) had previous cardioaortic surgery (29% dissection-related), 21 (20%) had coronary artery disease, 12 (12%) had Marfan syndrome, and 4 (4%) were on chronic dialysis. Twenty-six (25%) had a thrombosed false lumen. Thirty (29%) patients required reimplantation of visceral arteries; 8.3 +/- 2.7 segmental artery pairs were sacrificed., Results: Hospital mortality was 9.6% (10 patients). Paraplegia occurred in 5 (4.8%). Twenty-seven patients (26%) experienced adverse outcome (death within one year, paraplegia, stroke, or dialysis). Adverse outcome was associated with atheroma (p = 0.04, odds ratio = 4.3). Survival was 78% at 1, 68% at 5, and 59% at 10 years (average follow-up, 7.7 +/- 4.1 years). Freedom from distal aortic reoperation was 99% at 1, 93% at 5, and 83% at 10 years. After one year, patients enjoyed longevity equivalent to a normal age-sex matched population (standardized mortality ratio = 1.38, p = 0.23). By multivariate analysis, atheroma (p = 0.0005, relative risk = 9.32) and age (p = 0.0003, relative risk = 1.15/year) were risk factors for long-term survival., Conclusions: The efficacy of open repair for distal chronic dissection is highlighted by normal survival after the first year, and a low reoperation-reintervention rate., (Copyright (c) 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Ulipristal (UPA; CDB-2914) is a progesterone receptor modulator with contraceptive potential. To test its effects when delivered by an intrauterine system (IUS), we prepared control and UPA-filled IUS and evaluated their effects in rhesus macaques., Study Design: Short lengths of Silastic tubing either empty (n=3) or containing UPA (n=5) were inserted into the uteri of 8 ovariectomized macaques. Animals were cycled by sequential treatment with estradiol and progesterone. After 3.5 cycles, the uterus was removed., Results: During treatment, animals with an empty IUS menstruated for a mean total of 11.66+/-0.88 days, while UPA-IUS treated animals bled for only 1+/-0.45 days. Indices of endometrial proliferation were significantly reduced by UPA-IUS treatment. The UPA exposed endometria were atrophied with some glandular cysts while the blank controls displayed a proliferative morphology without cysts. Androgen receptors were more intensely stained in the glands of the UPA-IUS treated endometria than in the blank-IUS treated controls., Conclusions: In rhesus macaques, a UPA-IUS induced endometrial atrophy and amenorrhea. The work provides proof of principle that an IUS can deliver effective intrauterine concentrations of Ulipristal., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: The levonorgestrel-releasing intrauterine system (LNG-IUS) is a highly effective contraceptive. However, during early months of use unscheduled vaginal bleeding is common, sometimes leading to discontinuation. This study aimed to determine whether intermittent administration of progesterone receptor modulator CDB-2914 would suppress unscheduled bleeding during the first 4 months after insertion of the LNG-IUS., Methods: CDB-2914 150 mg, in divided doses, or placebo tablets, were administered over three consecutive days starting on Days 21, 49 and 77 after LNG-IUS insertion, in a double-blind randomized controlled trial of women aged 19-49 years, newly starting use of LNG-IUS. Daily bleeding diaries were completed for 6 months, and summarized across blocks as percentage days bleeding/spotting (BS%)., Results: Of 69 women randomized to receive CDB-2914, and 67 placebo, 61 and 55, respectively, completed the trial. BS% decreased with time in both arms, but showed a much steeper treatment-phase gradient in the placebo arm (P < 0.0001), so that a benefit of CDB-2914 in the 28 days after first treatment (-11% points, 95% CI -19 to -2), converted to a disadvantage by 64 days after the third treatment (+10% points, 95% CI 1-18)., Conclusions: The effect of CDB-2914 on BS% was initially beneficial but then by third treatment was disadvantageous. Nevertheless, only 3% (4/136) of all women discontinued LNG-IUS. These findings give insight into possible mechanisms and suggest future research directions. ISRCTN Trial no. ISRCTN58283041; EudraCT no. 2006-006511-72.

Despite extensive literature on vascular endothelial growth factor (VEGF) expression and regulation by steroid hormones, the lack of clear understanding of the mechanisms of angiogenesis in the endometrium is a major limitation for use of antiangiogenic therapy targeting endometrial vessels. In the current work, we used the rhesus macaque as a primate model and the decidualized mouse uterus as a murine model to examine angiogenesis during endometrial breakdown and regeneration. We found that blockade of VEGF action with VEGF Trap, a potent VEGF blocker, completely inhibited neovascularization during endometrial regeneration in both models but had no marked effect on preexisting or newly formed vessels, suggesting that VEGF is essential for neoangiogenesis but not survival of mature vessels in this vascular bed. Blockade of VEGF also blocked reepithelialization in both the postmenstrual endometrium and the mouse uterus after decidual breakdown, evidence that VEGF has pleiotropic effects in the endometrium. In vitro studies with a scratch wound assay showed that the migration of luminal epithelial cells during repair involved signaling through VEGF receptor 2-neuropilin 1 (VEGFR2-NP1) receptors on endometrial stromal cells. The leading front of tissue growth during endometrial repair was strongly hypoxic, and this hypoxia was the local stimulus for VEGF expression and angiogenesis in this tissue. In summary, we provide novel experimental data indicating that VEGF is essential for endometrial neoangiogenesis during postmenstrual/postpartum repair.

Background: Chronic kidney disease (CKD) is recognized as an independent cardiovascular disease (CVD) risk state, particularly in the elderly, and has been defined by levels of estimated glomerular filtration rate (eGFR) and markers of kidney damage. The relationship between CKD and CVD in younger and middle-aged adults has not been fully explored., Methods: Community volunteers completed surveys regarding past medical events and underwent blood pressure and laboratory testing. Chronic kidney disease was defined as an eGFR <60 mL x min(-1) x 1.73 m(-2) or urine albumin-creatinine ratio (ACR) > or =30 mg/g. Premature CVD was defined as self-reported myocardial infarction or stroke at <55 years of age in men and <65 years of age in women. Mortality was ascertained by linkage to national data systems., Results: Of 31 417 participants, the mean age was 45.1 +/- 11.2 years, 75.5% were female, 36.8% African American, and 21.6% had diabetes. A total of 20.6% were found to have CKD, with the ACR and eGFR being the dominant positive screening tests in the younger and older age deciles, respectively. The prevalences of premature myocardial infarction (MI), stroke, or death, and the composite were 5.3%, 4.7%, 0.8%, 9.2%, and 2.5%, 2.2%, 0.2%, 4.2% for those with and without CKD, respectively (P < .0001 for composite). Multivariable analysis found CKD (OR 1.44, 95% CI 1.27-1.63), age (OR 1.05 [per year], 95% CI 1.04-1.06), hypertension (OR 1.61, 95% CI 1.40-1.84), diabetes (OR 2.03, 95% CI 1.79-2.29), smoking (OR 1.91, 95% CI 1.66-2.21), and less than high school education (OR 1.59, 95% CI 1.37-1.85) as the most significantly associated factors for premature CVD or death (all P < .0001). Survival analysis found those with premature MI or stroke and CKD had the poorest short-term survival over the next 3 years after screening., Conclusions: Chronic kidney disease is an independent predictor of MI, stroke, and death among men and women younger than age 55 and 65 years, respectively. These data suggest the biologic changes that occur with kidney failure promote CVD at an accelerated rate that cannot be fully explained by conventional risk factors or older age. Screening for CKD by using both the ACR and eGFR can identify younger and middle-aged individuals at high risk for premature CVD and near-term death.

Background: Fibronectin (FN) is a component of the extracellular matrix that participates in wound healing in various tissues as an adhesive ligand for integrins (Itgs). To determine whether these molecules play similar roles during menstrual repair, we evaluated the expression and localization of FN and specific Itgs in the primate endometrium under hormonally controlled conditions., Methods: Ovariectomized rhesus macaques were treated for 2 weeks with estradiol (E(2)) followed by E(2) with progesterone for 2 weeks. On day 28, progesterone was withdrawn and uteri were collected during menstruation, postmenstrual repair, and the proliferative and secretory phases. Analysis was by focused microarray, real time PCR, in situ hybridization and immunocytochemistry., Results: Progesterone withdrawal induced significant elevations of FN, Itg alpha5 and Itg beta1 transcripts during menstruation as compared to day 28 (FN: P < 0.01; Itg alpha5: P < 0.05; Itg beta1: P < 0.05; real time PCR). These increases were concentrated in the glandular epithelium (FN) and stroma (Itg alpha5beta1) of the uppermost zones. Cyclic changes in Itg alpha3 occurred in the glandular epithelium., Conclusions: Spatially and temporally restricted peaks of expression of FN and its Itg receptors are closely correllated with menstruation and postmenstrual repair in the primate endometrium.

Vervet monkeys (Chlorocebus aethiops) are Old World nonhumans that display attenuated menstruation that requires detection by vaginal swab. The physiology underlying attenuated menstruation in this species has not been previously studied. To fill this gap, we evaluated endometrial cell proliferation, steroid receptor localization and expression of menstruation-associated matrix metalloproteinase (MMP) enzymes in vervets during natural and artificial menstrual cycles. The artificial cycles were induced by sequentially treating ovariectomized animals with estradiol (E(2)) and progesterone (P). Because menstrual flow is exceptionally light in this species, menses was detected by vaginal swab. We found that both natural and artificially cycled animals menstruated 3-5 days after the decline of P at the end of the cycle. As in other primates, P withdrawal at the end of artificial cycles triggered endometrial expression of MMPs, including MMP-1, 2, 3, 7, 10, 11, 13 and 26 transcripts. In both the natural and artificial menstrual cycle, menstrual sloughing was restricted to the upper one-fourth of the endometrium, and MMP-1 and 2 were strongly expressed by the stroma of the sloughing zone. MMP-7 was localized in the endometrial glands during late menses. As in macaques, epithelial cell proliferation was localized to the functionalis zone during the estrogen-dominated proliferative phase and to the basalis zone glands during the P-dominated secretory phase. Regulation of estrogen and progestin (or estradiol and progesterone) receptors was similar to that reported for macaques. Because strong similarities exist between the endometrium of vervets, macaques and women, we conclude that vervets can provide a useful animal model for studies on hormone regulation of menstruation.

Intrauterine devices (IUDs) that release progestins are highly effective contraceptives, but they induce breakthrough bleeding that some women find unacceptable. Because progesterone (P) antagonists [antiprogestins (APs)] are known to suppress the endometrium, induce amenorrhea and inhibit fertility, AP-releasing IUDs (AP-IUDs) may provide an effective contraceptive that also controls endometrial bleeding. Here, we assessed the effects of empty (blank) vs. AP-IUDs (ZK 230 211) on bleeding patterns and endometrial growth in ovariectomized, artificially cycled macaques. The AP-IUDs (but not the blank controls) induced extended, frank menstruation when inserted during the late luteal phase, an indication of local AP action. Over time, endometrial glandular and arterial proliferation were inhibited, steroid receptors were elevated, spiral arteries showed degenerative changes, P withdrawal bleeding was prevented, and estradiol (E(2))-dependent proliferation was suppressed by the AP-IUDs. In sum, AP-IUDs suppressed the effects of P on endometrial progestational development and blocked the effects of E(2) on endometrial proliferation, as previously shown for systemic treatment with APs. Therefore, AP IUDs may provide novel contraceptive devices with minimal breakthrough bleeding.

Background: Clinicians routinely prescribe progestins along with estrogens during menopausal hormone therapy (HT) to block estrogen-dependent endometrial proliferation. Breakthrough bleeding (BTB) can negate the utility of this treatment. Because progestin antagonists also inhibit estrogen-dependent endometrial proliferation in women and macaques, we used a menopausal macaque model to determine whether a potent progestin antagonist (ZK 230 211, Schering AG; ZK) combined with estrogen would provide a novel mode of HT., Method: Ovariectomized rhesus macaques were treated for 5 months with either estradiol (E(2)) alone, E(2) + progesterone (two doses) or E(2) + ZK (0.01, 0.05 or 0.25 mg/kg)., Results: In the E(2) + progesterone groups, progesterone suppressed endometrial proliferation and induced a thick decidualized endometrium. In the E(2) + ZK 230 211 groups, all doses of ZK blocked endometrial proliferation and induced endometrial atrophy. In all ZK-treated groups, the atrophied endometrium contained some dilated glands lined by an inactive, flattened, non-mitotic epithelium. BTB was much lower in the E(2) + ZK groups (17 days of spotting, all groups) than in the E(2) and E(2) + progesterone groups (155 bleeding days, all groups). ZK suppressed E(2) effects in the cervix, but not in the vagina, oviduct or mammary glands. All serum chemistry and lipid profiles were normal., Conclusion: The ability of ZK to block estrogen-dependent endometrial proliferation, induce endometrial atrophy and suppress BTB in a menopausal macaque model indicates that progestin antagonists may provide a novel mode of HT.

Macaques are menstruating nonhuman primates that provide important animal models for studies of hormonal regulation in the uterus. In women and macaques the decline of progesterone (P) at the end of the cycle triggers endometrial expression of a variety of matrix metalloproteinase (MMP) enzymes that participate in tissue breakdown and menstrual sloughing. To determine the minimal duration of P withdrawal required to induce menses, we assessed the effects of adding P back at various time points after P withdrawal on both frank bleeding patterns and endometrial MMP expression. Artificial menstrual cycles were induced by treating the animals sequentially with implants releasing estradiol (E2) and progesterone (P). To assess bleeding patterns, P implants were removed at the end of a cycle and then added back at 12, 24, 30, 36, 40, 48, 60, or 72 hours (h) after the initial P withdrawal. Observational analysis of frank bleeding patterns showed that P replacement at 12 and 24 h blocked menses, replacement at 36 h reduced menses but replacement after 36 h failed to block menses. These data indicate that in macaques, a critical period of P withdrawal exists and lasts approximately 36 h. In other similarly cycled animals, we withdrew P and then added P back either during (12-24 h) or after (48 h) the critical period, removed the uterus 24 h after P add back and evaluated endometrial MMP expression. Immunocytochemistry showed that replacement of P during the critical period suppressed MMP-1, -2 and -3 expression along with menses, but replacement of P at 48 h, which failed to suppress mense, suppressed MMP-1 and MMP-3 but did not block MMP-2. We concluded that upregulation of MMPs is essential to menses induction, but that after the critical period, menses will occur even if some MMPs are experimentally blocked.

This review focuses on the complex events that occur in the endometrium after progesterone is withdrawn (or blocked) and menstrual bleeding ensues. A detailed understanding of these local mechanisms will enhance our knowledge of disturbed endometrial/uterine function--including problems with excessively heavy menstrual bleeding, endometriosis and breakthrough bleeding with progestin only contraception. The development of novel strategies to manage these clinically significant problems depends on such new understanding as does the development of new contraceptives which avoid the endometrial side effect of breakthrough bleeding.

Angiopoietin-1 (Ang-1) is an important angiogenic factor that has not been thoroughly studied in the primate endometrium. We evaluated the endometrial expression of Ang-1 and its receptor, Tie2, during induced menstrual cycles in rhesus macaques. Tie2 expression was confined to the vascular endothelium without marked change during the cycle. However, Ang-1 expression varied considerably during the cycle. In the proliferative phase, Ang-1 was only expressed in the basal zone glands, and this expression was estradiol (E2) dependent. In the early- to mid-secretory phase, Ang-1 expression spread to the upper glands, luminal epithelium and the vascular smooth muscle cells (VSMC) of spiral arteries. In the late secretory phase, the signal disappeared from the glands but remained elevated in the VSMC of spiral arteries. Notably, there was a significant correlation between VSMC proliferation and Ang-1 expression in the VSMC of the spiral arteries. Progesterone (P) withdrawal in the early secretory phase induced a decline in Ang-1 expression in the glands and VSMC of spiral arteries along with a complete suppression of VSMC proliferation. These data suggest, for the first time, that Ang-1 may play a key role in the P-dependent growth of the unique spiral arteries in the primate endometrium.

Background: It is unknown to what degree physicians adjust erythropoietin doses to achieve hemoglobin levels (11.0 to 12.0 g/dL [110 to 120 g/L]) recommended by the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) for patients with end-stage renal disease receiving hemodialysis. Our objective is to examine epoetin alfa prescribing patterns for achieving the target hemoglobin level range in this population., Methods: Monthly hemoglobin levels and epoetin alfa doses from 2 large databases were retrospectively analyzed. One data set comprised 31,267 patients from the Fresenius Medical Care-North America (FMC-NA) database, and the other comprised 128,761 patients based on claims for Medicare services., Results: Longitudinal evaluation of the FMC-NA data set showed that hemoglobin levels in patients administered epoetin alfa cycled in and out of the NKF-K/DOQI hemoglobin target range, and doses were decreased in 98.8% of patients with persistent hemoglobin levels greater than 12.0 g/dL (> 120 g/L). Hemoglobin levels in patients from the Medicare data set that initially were outside the target range migrated into the range with epoetin alfa dose titration. FMC-NA patients with a 3-month average hemoglobin level less than 11.0 g/dL (< 110 g/L) were administered significantly greater epoetin alfa doses than those with average hemoglobin levels greater than 12.0 g/dL (> 120 g/L; 21,838 versus 13,503 U/wk; P < 0.0001). Less than 0.4% of patients administered epoetin alfa were persistently anemic (hemoglobin < 11.0 g/dL [< 110 g/L]) and were administered persistently high doses (> 30,000 U/wk), but failed to respond with a 0.5-g/dL or greater (> or = 5-g/L) increase in hemoglobin levels., Conclusion: In these analyses, few hemodialysis patients experienced persistent anemia while being administered high epoetin alfa doses. Physicians appeared to appropriately adjust doses to achieve hemoglobin levels recommended by the NKF-K/DOQI guidelines.

Objective: Our aim was to study the effect of estradiol and raloxifene on collagen synthesis, by measuring the expression collagen I and III mRNA., Study Design: Nineteen nulliparous young adult rhesus macaques underwent oophorectomy and were treated for 5 months with estradiol alone, raloxifene, or no hormone. Tissue samples were acquired from the lateral vaginal wall, and included the paravaginal attachment and levator ani muscle. Expression of mRNA for collagen I and III was measured by in situ hybridization., Results: Estradiol increased mRNA for collagen I and III compared with no hormone and raloxifene treatment (ANOVA, P < .05). Collagen mRNA was localized to fibroblasts in the vaginal connective tissue and the connective tissue investments of striated muscle. Collagen mRNA was not expressed in epithelial, smooth, and striated muscle cells., Conclusion: Estrogen, but not raloxifene, increases collagen gene transcription and indicates stimulation of collagen synthesis in pelvic floor connective tissues.

Background: Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data., Study Design: The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

Although much is known about the biology of vascular endothelial growth factor (VEGF) and its cognate receptors (VEGFRs), VEGFR1 and VEGFR2, little is known about the roles of the VEGFRs neuropilin (NP)-1 and NP-2 in the primate endometrium. In this study, we investigated the cellular localization and hormonal regulation of NP-1 and NP-2 mRNA by in situ hybridization in the endometrium of ovariectomized, hormonally cycled rhesus macaques and women during the natural menstrual cycle. NP-1 mRNA was highly expressed in vascular endothelium and in stromal cells, but in these cells, NP-1 expression did not change during the menstrual cycle. However, NP-1 mRNA was also expressed in the luminal epithelium (not the glands), and its expression in these cells was elevated during the mid- to late proliferative phase and completely suppressed during the secretory phase. The increase in NP-1 level in the luminal epithelium was estradiol dependent because such expression was not detectable in the absence of estradiol in ovariectomized, hormone-deprived animals. Moreover, NP-1 expression in the luminal epithelium was highly correlated with the degree of proliferation in these cells. A recent study showed that blockade of VEGF action can inhibit luminal epithelial cell proliferation, but there is no evidence of VEGFR1 and VEGFR2 expression in these cells. Therefore, NP-1 may be the relevant VEGFR that mediates proliferation in this epithelium. NP-2 mRNA, unlike NP-1, was expressed only by the endothelium of veins, and in these cells, its expression was hormonally regulated in the converse manner: it was very low during the proliferative phase and high during the secretory phase. The increased permeability and edema observed during the secretory phase in the primate endometrium may be mediated in part by VEGF-NP-2 interaction. In the human endometrium, the pattern of expression and cellular localization of both NP-1 and NP-2 during the menstrual cycle were essentially identical with that seen in the rhesus macaque endometrium. These are the first data to specify the hormonal regulation and cell-specific expression of NP-1 and NP-2 mRNA in the endometrium of both women and nonhuman primates. The findings extend our understanding of VEGF action in the primate endometrium.

Progesterone receptors (PR) mediate multiple aspects of female reproduction and are important targets for reagents that can modulate progesterone-dependent events. Many such reagents have been developed, and they range from full PR antagonists (PAs) to compounds with mixed agonist/antagonist actions, currently known as selective progesterone receptor modulators (SPRMs). In women and nonhuman primates, many PR antagonists suppress estrogen-dependent mitotic activity in the endometrial glands as well as block progestational development of the endometrium. These latter effects are tissue- and species-specific, are most dramatic in women and nonhuman primates, and are referred to as endometrial antiproliferative effects. Recent evidence suggests that the endometrial androgen receptor plays an important role in these effects. For example, endometrial androgen receptors are increased by treatment with PAs, and combination treatment with estrogen, a PA, and an antiandrogen (flutamide) prevents the endometrial antiproliferative effect. Various PR modulators have great promise as gynecological therapeutics, but additional research is needed to improve our understanding of their endometrial effects.

This article reviews the effects of estradiol (E(2)), progesterone (P) and P receptor antagonists (PA) on the rhesus macaque endometrium. Ovariectomized macaques can be treated with implants of estradiol (E(2)) and P to induce precisely controlled, artificial menstrual cycles. During these cycles, treatment with E(2) alone induces an artificial proliferative phase marked by extensive endometrial epithelial cell proliferation and increased expression of stromal and epithelial estrogen receptor (ER) and P receptor (PR). Androgen receptor (AR) is also upregulated by E(2) but is expressed only by the endometrial stroma. Progesterone acts on the E(2) primed endometrium to induce secretory differentiation and causes suppression of epithelial and stromal ER, epithelial PR, and stromal AR in the functionalis zone. However, epithelial ER and PR are retained in the basalis zone during the secretory phase. When potent P antagonists (PA) are administered acutely at the end of an E(2) + P induced cycle, menses typically ensues similar to P withdrawal at the end of the menstrual cycle. When PAs are administered chronically there is significant blockage of all P- dependent effects including upregulation of ER, PR and AR and suppression of glandular secretory function. However, chronic PA administration also inhibits estrogen-dependent endometrial cell proliferation and growth. This endometrial antiproliferative effect is the basis of the clinical use of PA to control various diseases such as endometriosis.