- Open Access
Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs)
© Chwalisz et al; licensee BioMed Central Ltd. 2006
- Published: 9 October 2006
Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied. The SPRM asoprisnil is being studied in women with symptomatic uterine leiomyomata and endometriosis. Asoprisnil shows a high degree of uterine selectivity as compared to effects on ovulation or ovarian hormone secretion in humans. It induces amenorrhea and decreases leiomyoma volume in a dose-dependent manner in the presence of follicular phase estrogen concentrations. It also has endometrial antiproliferative effects. In pregnant animals, the myometrial, i.e. labor-inducing, effects of asoprisnil are blunted or absent. Studies in non-human primates played a key role during the preclinical development of selective progesterone receptor modulators. These studies provided the first evidence of uterus-selective effects of asoprisnil and structurally related compounds, and the rationale for clinical development of asoprisnil.
- Cynomolgus Monkey
- Endometrial Thickness
- Human Endometrium
- Spiral Artery
- Endometrial Gland
Progesterone plays a crucial role in controlling various reproductive functions. It is the natural ligand of the progesterone receptor (PR), which is expressed in various tissues in the body, predominantly in the reproductive tract. The isolation of progesterone in 1934 [1–3] led to the search for synthetic, orally active progestins (PR agonists) that have found broad applications in fertility control and hormone therapy. Since the discovery of mifepristone in 1981 by the scientists of Roussel Uclaf , several progesterone antagonists (PAs) became available for preclinical and clinical evaluation . More recently, selective progesterone receptor modulators (SPRMs) have been synthesized and biologically characterized. SPRMs represent a new class of PR ligands that exert clinically relevant tissue-selective progesterone agonist, antagonist, partial, or mixed agonist/antagonist effects on various progesterone target tissues in an in vivo situation depending on the biological action studied . Asoprisnil (J867), a novel steroidal compound that belongs to the class of 11β-benzaldoxime-substituted estratrienes [7, 8], is being studied in women with symptomatic uterine leiomyomata and endometriosis. It shows high PR specificity, mixed PR agonist/antagonist activity, and high degree of uterine selectivity in animal models and humans . Unlike PAs, asoprisnil does not induce labor in relevant models of pregnancy and parturition.
Studies in cynomolgus monkeys provided the first evidence that the 11β-benzaldoxime-substituted SPRMs may induce amenorrhea by directly targeting the endometrium and have direct endometrial antiproliferative effects, irrespective of ongoing ovulatory cycles . The endometrial effects of SPRMs and PAs are specific to menstruating primates (Old World monkeys, humans) since variable effects were observed in non-menstruating species (rodents, rabbits, tree shrews, and New World monkeys) . The endometrial antiproliferative effects and the endometrium specific vascular effects were subsequently confirmed in women treated with asoprisnil . Human studies also showed that asoprisnil improved the symptoms of leiomyomata, reduced leiomyoma volume , and reduced pain associated with endometriosis . In this brief review, we discuss the discovery and early clinical development of asoprisnil and related SPRMs, focusing on the effects of these compounds on the primate uterus.
The primate endometrium is a highly specialized tissue composed of different cell components, including luminal and glandular epithelium, endometrial stroma, lymphoid and non-lymphoid cells, and blood vessels . The endometrium is probably the most dynamic tissue in the human body. In humans and menstruating ("old-world") non-human primates the endometrium undergoes cyclic changes characterized by regeneration and proliferation during the follicular phase of the ovarian cycle, secretory differentiation during the luteal phase, and menstruation accompanied by vasoconstriction of spiral arteries and changes in extracellullar matrix that occur after the physiologic decline in progesterone concentrations that occur at the end of the luteal phase. Spiral arteries are key vessels that control menstruation . These vessels are unique to the primate endometrium and are highly sensitive to progesterone. They seem to be controlled by perivascular stromal cells (pericytes), which show very high PR density .
Estrogen is the primary mitogen in the endometrium, acting primarily on the epithelium. "Unopposed" estrogen treatment (without a progestin phase) leads to proliferation of glandular and stromal cells and may lead to endometrial hyperplasia and possibly endometrial cancer. Endometrial hyperplasia is characterized by increased proliferation of the endometrial glandular epithelium, resulting in an increase of the gland/stroma ratio. Progesterone and synthetic progestins oppose the effects of estrogen on the epithelium, and thereby protect the endometrium from the development of hyperplasia. The specific mechanisms that have been proposed to explain the antiproliferative action of progesterone on the uterine epithelium include: (i) down-regulation of estrogen receptors (ER) in target tissues, (ii) induction of the endometrial enzyme 17β-hydroxysteroid dehydrogenase Type 2 that catalyzes the conversion of estradiol to the less active estrone, (iii) reduction in estrogen-induced specific protein expression, and (iv) inhibition of estrogen-induced proto-oncogenes (cjun, cfos), which act as growth factors in the endometrium (reviewed by ). Although all the mechanisms seem to be involved, the down-regulation of ER in target tissues most likely plays the primary role in this respect.
During the drug discovery program, we conducted studies in cynomolgus monkeys to determine the effects of selected SPRMs in the primate endometrium . One of our initial studies compared the endometrial effects of a "model" SPRM with high agonist activity (J1042) with those of PAs (ZK 137 316 and ZK 230 211). This study showed that all three compounds have a profound antiproliferative effect on the endometrium characterized by a decrease in endometrial thickness and reduction in mitotic activity in both endometrial epithelium and stroma. Endometrial stroma appeared compact in all treatment groups, which suggested a progesterone antagonist effect of J1042 and the reference PAs [9, 18]. However, J1042, but not the reference PAs, induced secretory activity of the endometrial glands characterized by glandular sacculation with subnuclear vacuolization and secretion, suggesting a weak progesterone agonistic effect. In contrast, both PAs produced degenerative changes in endometrial glands without any secretory changes. In addition, morphometric studies revealed that J1042 reduced intraluminal diameter of spiral arteries in the basalis to a higher degree than the PAs, but did not cause hyalinizing degeneration of spiral arteries as had previously been observed in animals treated with PAs. This study, which showed for the first time the presence of partial secretory effects of a SPRM in the primate endometrium, played a key role in the conceptualization and discovery of tissue selectivity of SPRMs.
The effect of asoprisnil on endometrial morphology was consequently studied in more detail in cynomolgus monkeys treated with lower doses of asoprisnil for a shorter period of time . A total of 24 ovarian-intact, cycling animals were administered either saline (n = 6) or vehicle (n = 4) as controls, or three doses of asoprisnil (10 mg/kg [n = 4], 30 mg/kg [n = 4] and 90 mg/kg [n = 6]) orally, once daily for 90 days. Four animals from each group were sacrificed at the end of treatment and two animals from each of the saline and 90 mg/kg groups were held without treatment for a recovery period of 28 days after which they were also sacrificed. In this study, asoprisnil was suspended in a vehicle containing 10% ethanol, 35% PEG (polyethylene glycol) 300 and 55% Cremophor-EL (polyoxyethylenglyceroltriricinoleat 35, polyoxyl 35 castor oil) to enhance its oral absorption. The AUCs at these dosages in female monkeys were 368, 2495 and 13422 ng•hr/mL, respectively. The entire reproductive tract was removed from all animals and assessed for general histological changes, including spiral artery development, endometrial thickness, and stromal compaction. Endometrial thickness was assessed by measuring the distance from the luminal surface to the myometrial border, and stromal compaction was quantified by computerized assessment of the number of stromal cells per unit area. The effects on proliferative state were quantified by assessing two markers of proliferation, Ki-67 and phosphorylated histone 3 (Phospho H3). Ki-67 is a nuclear protein expressed during all stages of the cell cycle except G0 and is a standard index of overall cellular proliferation. Because histone 3 is phosphorylated only during mitosis and is expressed only in mitotic chromosomes, Phospho H3 staining provides a direct indication of mitotic activity. The effects of asoprisnil on ovarian, cervical and vaginal histology were also assessed.
In this study, the ovaries in the saline and vehicle controls were all normal in appearance, marked by either antral follicles or functional corpora lutea. The endometria in all control animals were either in the proliferative or secretory phases. However, in the asoprisnil-treated animals, the two higher doses suppressed ovulation and progesterone secretion. The previous 39-week toxicological study showed that estradiol was maintained at follicular phase levels, and in the current study, the vagina was in an estrogenized state (assessed by degree of cornification) in all asoprisnil-treated animals, indicating that (i) estradiol levels were physiologically adequate, and (ii) asoprisnil did not block estrogen action in the vagina.
In sum, asoprisnil had reversible antiovulatory and endometrial antiproliferative effects, but did not suppress estrogen action in other parts of the reproductive tract of ovarian-intact cynomolgus macaques.
Phase I and Phase II trials confirmed tissue-selective effects of asoprisnil in the human uterus. Some of the clinical studies with asoprisnil have been published , or reported in abstract form ; ; .
In a Phase I study, the effects of asoprisnil versus placebo were evaluated in 60 healthy regularly cycling premenopausal women during treatment for 28 days at daily oral doses ranging from 5 mg to 100 mg/day, starting during the first two days of the menstrual cycle . Asoprisnil consistently prolonged the menstrual cycle at doses ≥ 10 mg/day. However, the effects on luteal phase progesterone indicative of luteinization were inconsistent and lacked dose dependency. The estradiol levels of women treated with asoprisnil were within the range of the follicular phase. This study demonstrated that asoprisnil suppresses menstruation by primarily targeting the endometrium.
In a Phase II setting, the effects of asoprisnil 5 mg, 10 mg, and 25 mg on bleeding patterns and various leiomyoma endpoints were evaluated in a double-blind, placebo-controlled study of patients with uterine leiomyomata . The patients were treated for 3 months. Asoprisnil significantly suppressed both the duration and intensity of uterine bleeding in a dose-dependent manner as evidenced by bleeding diaries, and high amenorrhea rates (0%, 28.1%, 64.3%, and 83.3% at placebo, 5 mg, 10 mg and 25 mg, respectively). There was a significant increase in hemoglobin concentrations by week 12 in all asoprisnil groups compared to placebo. Asoprisnil also significantly reduced menorrhagia scores in patients with leiomyomata . The suppressive effects of asoprisnil on endometrial bleeding were evident within the first month and maintained throughout the entire treatment period. These effects were accompanied by a dose-dependent reduction in the volumes of the largest leiomyoma as measured by ultrasound. Asoprisnil had no statistically significant effects on ovarian estrogens (estradiol and estrone). Consistent with the absence of antiglucocorticoid activity in humans at clinically relevant doses, there were no increases in serum concentrations of cortisol or dehydroepiandrosterone sulphate (DHEA-S) with asoprisnil [11, 22].
In summary, asoprisnil demonstrated antiproliferative effects on the endometrium in the presence of follicular phase estradiol concentrations in both humans and monkeys. However, these studies also revealed some differences between the non-human primate models and humans with respect to endometrial effects. In the human endometrium, asoprisnil treatment for up to 3 months was associated with non-physiologic secretory effects in the glandular epithelium and presence of unusual "thick-walled" arterial vessels in the stroma . In cynomolgus monkeys neither secretory changes in endometrial glands, nor formation of thick-walled endometrial spiral arteries were observed, pointing out to some important differences in the steroid receptor pharmacology of the monkey and human endometrium. The reason for these differences is unclear. However, our studies with asoprisnil and previous experience with PAs suggest that the macaque endometrium might be more sensitive to PR-ligands than the human endometrium, which would explain more dramatic effects of SPRMs and PAs in these animals. Therefore, in spite of many similiarities between monkey and human endometrium, caution is warranted in extrapolating the data generated in nonhuman primates to humans.
The potential effects of SPRMs on the breast tissue are of special interest. In primates, mammary gland development is controlled by a complex interplay between the reproductive hormones (estradiol, progesterone, and prolactin), and local growth factors . There is growing evidence that progesterone is an important mitogen in epithelial breast cells . On the one hand, PAs suppress mammary gland proliferation and inhibit growth of PR-positive mammary gland tumors in animal models . On the other hand, mitotic activity in normal breast tissue peaks during the luteal phase, and synthetic progestins consistently increase mammographic breast density, which is a surrogate parameter of breast proliferation [28, 29], as well as upregulate the expression of proliferation markers in the mammary gland .
Inhibitory effects of asoprisnil on mammary gland development were consistently observed in a 39-week toxicological study in intact female cynomolgus monkeys . Although these effects are consistent with antiproliferative effects of asoprisnil on mammary gland proliferation, they should be interpreted with caution because of high doses used in toxicological studies, and potential differences between macaques and humans regarding hormonal regulation of breast proliferation and differentiation.
Our studies in non-human primates and humans reviewed above revealed that asoprisnil and other 11β-benzaldoxime-substituted SPRMs exert tissue-selective effects on the uterus in the presence of follicular phase estrogen concentrations and no antiglucocorticoid effects. These compounds can abolish endometrial bleeding and suppress endometrial proliferation in both macaques and humans. Inhibitory effects of leiomyoma growth were observed in human studies with asoprisnil. Our studies show that asoprisnil exhibits inhibitory effects on (i) endometrial bleeding, (ii) endometrial proliferation, and (iii) leiomyoma volume in humans, predominantly via tissue-specific (uterine) mechanisms. These effects, discussed in more detail below, are likely to reflect target tissue specific manifestation of PR modulation that affects downstream pathways of PR, ER AR and most likely other, still unidentified pathways.
Control of endometrial bleeding
Amenorrhea was consistently observed in asoprisnil-treated cynomolgus monkeys . In women, amenorrhea was already observed within 30 days of commencement of asoprisnil treatment, irrespective of the effect of luteinization suggestive of ovulation. This effect is sustained during longer treatment, with minimal bleeding abnormalities such as spotting and breakthrough bleeding [10, 11]. These observations suggest that the endometrial arteries are stable during treatment with asoprisnil.
Although the mechanism of asoprisnil-induced amenorrhea is still not completely understood, the current evidence suggests that asoprisnil may have a direct or indirect inhibitory effect on endometrial spiral arteries. Interestingly, asoprisnil-induced morphological changes in spiral arteries, characterized by thickening of the wall, clearly differ from those commonly observed in women using long-acting progestins or levonorgestrel-containing intrauterine systems. These treatments are associated with the formation of "thin-walled" microvessels that are very fragile, and frequently lead to breakthrough bleeding [32–34]. Our working hypothesis is that asoprisnil controls endometrial bleeding by targeting the perivascular cells in the endometrium, which are characterized by a high density of PRs . This hypothesis, which is currently under investigation, would explain tissue-specific effects of asoprisnil on endometrial vasculature.
Endometrial antiproliferative effect
Asoprisnil and structurally related SPRMs have endometrial antiproliferative effects in macaques and humans. The exact mechanism of this effect is still not fully understood. The effects of asoprisnil on the human endometrium are currently being investigated using various morphological, immunohistochemical and molecular endpoints. These studies should provide more insight into the molecular mechanisms underlying this effect, in particular the role of the partial progesterone agonist and antagonist activities of asoprisnil in the endometrium. Based on experiments conducted in cynomolgus monkeys, we previously proposed that the endometrial antiproliferative effect of SPRM and PAs might be due to the reduction in endometrial blood flow as consequence of vascular changes in the endometrium . However, this hypothesis has not yet been confirmed in humans. More recently the role of endometrial AR has been emphasized as a potential mechanism of the endometrial antiproliferative effects of PAs [35–38]. Androgens are known to inhibit estrogen effects in the primate endometrium . The AR hypothesis was proposed based on the observation of greatly enhanced expression of AR in the endometrial glands of macaques treated with various PAs and in women treated with mifepristone . Furthermore, the AR antagonist flutamide reversed the endometrial antiproliferative effect of the PA as evidenced by changes in mitotic index, endometrial height and weight . Since up-regulation of AR was observed in the endometrial stroma of cynomolgus monkeys treated with asoprisnil, its antiproliferative effect on endometrial glandular epithelium might be mediated by AR-mediated stromal growth factors . In addition, asoprisnil has weak androgenic properties, which may play a role in this respect .
Reduction in leiomyoma volume
Several mechanisms, which are under investigation, might be involved in asoprisnil-induced reduction in leiomyoma volume, including a direct, PR-mediated antiproliferative and pro-apoptotic effects on leiomyoma cells, inhibition of growth factors, modulation of extracellullar matrix synthesis, reduction in uterine blood flow, etc.
The results of an in vitro study with leiomyoma and myometrial primary cell cultures showed that asoprisnil inhibits proliferation and induces apoptosis of leiomyoma cells without having any effects on the normal myometrial cells . In this study, the proliferation marker PCNA was used to quantify the effects on proliferation, whereas TUNEL assay was used to determine the effects on apoptosis. In a second study, asoprisnil also inhibited the expression of EGF, IGF-I, TGFβ3 and their receptors in cultured leiomyoma cells without affecting their expression in matching myometrial cells . In addition, a decrease in uterine blood flow following treatment with asoprisnil may contribute to this effect. This hypothesis is currently under evaluation in clinical studies.
Molecular basis for tissue-selective effect of SPRMs
The molecular mechanism of tissue selectivity of steroid receptor modulators has been recently proposed based on the ability of a liganded PR to interact with different coregulators depending on the specific ligand [42–45]. Coregulators (coactivators and corepressors) are nuclear proteins that form multiple complexes with nuclear receptors and modulate their transcriptional activity [46–49]. Coactivators enhance transcriptional activity of nuclear receptors, whereas corepressors elicit inhibitory effects on nuclear receptors. The PAs either favor interaction of PR with corepressors or inhibit interactions with coactivators, whereas "pure" PR agonists promote the interaction of the nuclear receptor with coactivators [50, 51]. SPRMs with partial PR agonist activity induce an intermediate state of interaction between nuclear receptors and coactivators [45, 50, 52]. Since the availability of both coactivators and corepressors is dependent on tissue and hormonal milieu, the cell type- and promoter-specific differences in coregulator recruitment determine the tissue selectivity of SPRMs [6, 45]. More recent molecular studies show that asoprisnil-liganded PR promotes the recruitment of the coactivator SRC-1 in an in vitro model  which could explain the partial agonist effects observed in animal models and humans. Molecular studies of coregulator expression in human tissues exposed to asoprisnil are ongoing. These studies should provide more insight into the molecular mechanism of tissue selectivity of asoprisnil in the uterus.
Studies in non-human primates played a key role in the conceptualization and discovery of tissue selectivity of SPRMs. They provided the first evidence of the endometrial antiproliferative effects of asoprisnil and other 11β-benzaldoxime substituted SPRMs in the primate model, as characterized by a decrease in mitotic counts, Phospho H3 expression and endometrial thickness. These models also showed that PR modulation results in a complex interaction with ER- and AR-mediated responses. Uterus-selective effects of asoprisnil have been confirmed in clinical studies in humans. Clinical studies in healthy volunteers (Phase I) and patients with leiomyomata showed that asoprisnil induces dose-dependent inhibition of uterine bleeding predominantly due to an endometrial effect. Furthermore, our Phase II studies showed that asoprisnil reduces the volume of uterine leiomyomata in a dose-dependent manner. Although the mechanism of this effect is not fully explored, the in vitro studies with leiomyoma primary cell cultures, as well as morphological investigations of leiomyoma tissue suggest a increase in apoptosis accompanied by a decrease in proliferation after treatment with asoprisnil. These effects seem to be cell-specific, since no such changes were observed in myometrial cells.
Asoprisnil induces "non-physiologic secretory effects" on the human endometrium during treatment for up to 3 months. These effects are consistent with endometrial antiproliferative effects of asoprisnil, without evidence of hyperplastic changes. However, long-term studies with asoprisnil will be necessary to fully assess the endometrial effects of asoprisnil.
Figure 1 is a courtesy of Alexander Hillisch (TnTec GmbH, Jena, Germany). We also thank Gretchen Bodum for editing the manuscripts and expert comments.
This work was supported by TAP Pharmaceutical Products Inc, Lake Forest, IL 60045, USA.
This work was presented in part during the Annual Meeting of the Society for Gynecologic Investigation (SGI), March 2005, Los Angeles, CA.
This article has been published as part of Reproductive Biology and Endocrinology Volume 4, Supplement 1, 2006: Basic and applied biology of the primate reproductive tract: in honor of the career of Dr Robert M Brenner. The full contents of the supplement are available online at http://www.rbej.com/supplements/4/S1.
- Allen WM, Wintersteiner O: Crystalline progesterone. Science. 1934, 80: 190-191. 10.1126/science.80.2069.190-a.View ArticlePubMedGoogle Scholar
- Slotta KH, Rushig H, Fels E: Reindarstellung des Hormons aus dem Corpus luteum. Ber Chem Ges. 1934, 67: 1270-1273.View ArticleGoogle Scholar
- Butenandt A, Westphal U, Hohlweg W: Uber das Hormon des Corpus luteum. Hopper-Seyler's Z Physiol Chem. 1934, 227: 84-98.View ArticleGoogle Scholar
- Philibert D, Deraedt R, Teutsch G: RU 38486: a potent antiglucocorticoid in vivo. The VII International Congress of Pharmacology: 1981; Tokyo, Japan. 1981Google Scholar
- Spitz IM: Progesterone antagonists and progesterone receptor modulators: an overview. Steroids. 2003, 68 (10–13): 981-993. 10.1016/j.steroids.2003.08.007.View ArticlePubMedGoogle Scholar
- Chwalisz K, Perez MC, DeManno D, Winkel C, Schubert G, Elger W: Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis [published erratum appears in Endocr Rev. 2005;26:703]. Endocr Rev. 2005, 26 (3): 423-438. 10.1210/er.2005-0001.View ArticlePubMedGoogle Scholar
- Elger W, Bartley J, Schneider B, Kaufmann G, Schubert G, Chwalisz K: Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity. Steroids. 2000, 65: 713-723. 10.1016/S0039-128X(00)00178-1.View ArticlePubMedGoogle Scholar
- DeManno D, Elger W, Garg R, Lee R, Schneider B, Hess-Stumpp H, Schubert G, Chwalisz K: Asoprisnil (J867): a selective progesterone receptor modulator for gynecological therapy. Steroids. 2003, 68 (10–13): 1019-1032. 10.1016/j.steroids.2003.09.008.View ArticlePubMedGoogle Scholar
- Chwalisz K, Brenner RM, Fuhrmann UU, Hess-Stumpp H, Elger W: Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium. Steroids. 2000, 65 (10–11): 741-751. 10.1016/S0039-128X(00)00190-2.View ArticlePubMedGoogle Scholar
- Chwalisz K, Elger W, Stickler T, Mattia-Goldberg C, Larsen L: The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women. Hum Reprod. 2005, 20: 1090-1099. 10.1093/humrep/deh738.View ArticlePubMedGoogle Scholar
- Chwalisz K, Parker RL, Williamson S, Larsen L, McCrary K, Elger W: Treatment of uterine leiomyomas with the novel selective progesterone receptor modulator (SPRM) J867 [abstract]. J Soc Gynecol Invest. 2003, 10 (Suppl 2): 636-Google Scholar
- Chwalisz K, Mattia-Goldberg C, Lee M, Elger W, Edmonds A: Treatment of endometriosis with the novel selective progesterone receptor modulator (SPRM) asoprisnil [abstract]. Fertil Steril. 2004, 82 (Suppl 2): S83-S84.Google Scholar
- Schubert G, Ring S, Erhardt B: Method for the production of 4-[17a-substituted-3-oxoestra-4,9-dien-11β-yl]benzaldehyde (1E or 1Z)-oximes. In. US. 2004Google Scholar
- Brenner RM, Rudolph L, Matrisian L, Slayden OD: Non-human primate models; artificial menstrual cycles, endometrial matrix metalloproteinases and s.c. endometrial grafts. Hum Reprod. 1996, 11 (Suppl 2): 150-164.View ArticlePubMedGoogle Scholar
- Brenner RM, Nayak NR, Slayden OD, Critchley HO, Kelly RW: Premenstrual and menstrual changes in the macaque and human endometrium: relevance to endometriosis. Ann N Y Acad Sci. 2002, 955: 60-74. discussion 86–68, 396–406View ArticlePubMedGoogle Scholar
- Padykula HA: Regeneration in the primate uterus: the role of stem cells. Ann N Y Acad Sci. 1991, 622: 47-56.View ArticlePubMedGoogle Scholar
- Kelly RW, King AE, Critchley HO: Inflammatory mediators and endometrial function--focus on the perivascular cell. J Reprod Immunol. 2002, 57 (1–2): 81-93. 10.1016/S0165-0378(02)00008-6.View ArticlePubMedGoogle Scholar
- Chwalisz K, Brenner R, Nayak N, Joskowiak D, Elger W: A comparison of the endometrial antiproliferative effects of a mesoprogestin (J1042) with the antiprogestins ZK 137 316 and ZK 230 211 in cynomolgus monkeys [Abstract]. J Soc Gynecol Invest. 2000, 7: 21A-10.1016/S1071-5576(99)00050-7.View ArticleGoogle Scholar
- Brenner RM, Slayden OD, Garg R, Chwalisz K: Asoprisnil suppresses endometrial proliferation in cynomolgus macaques [abstract]. J Soc Gynecol Invest. 2005, 12 (Suppl): 208A-Google Scholar
- Brenner RM, Slayden OD, Rodgers WH, Critchley HO, Carroll R, Nie XJ, Mah K: Immunocytochemical assessment of mitotic activity with an antibody to phosphorylated histone H3 in the macaque and human endometrium. Hum Reprod. 2003, 18 (6): 1185-1193. 10.1093/humrep/deg255.View ArticlePubMedGoogle Scholar
- Chwalisz K, Larsen L, McCrary K, Edmonds A: Effects of the novel selective progesterone receptor modulator (SPRM) asoprisnil on bleeding patterns in subjects with leiomyomata. J Soc Gynecol Invest. 2004, 11 (Suppl 2(2)): 320A-321A.Google Scholar
- Chwalisz K, Larsen L, McCrary K, Edmonds A: Effects of the novel selective progesterone receptor modulator (SPRM) asoprisnil on selected hormonal parameters in subjects with leiomyomata. Fertil Steril. 2004, 82 (Suppl 2): S306-10.1016/j.fertnstert.2004.07.825. abstract P-483View ArticleGoogle Scholar
- Noyes R, Hertig AT, Rock J: Dating the endometrial biopsy. Fertil Steril. 1950, 1: 3-25.Google Scholar
- Williams AR, Critchley HO, Osei JHC, Chwalisz K: The selective progesterone receptor modulator asoprisnil inhibits glandular proliferation and induces consistent morphological effects in human endometrium [abstract]. J Soc Gynecol Investig. 2006, 13 (Suppl 2): 261A-262A.Google Scholar
- Clarke RB: Steroid receptors and proliferation in the human breast. Steroids. 2003, 68 (10–13): 789-794. 10.1016/S0039-128X(03)00122-3.View ArticlePubMedGoogle Scholar
- Pike MC, Spicer DV: Hormonal contraception and chemoprevention of female cancers. Endocr Relat Cancer. 2000, 7 (2): 73-83. 10.1677/erc.0.0070073.View ArticlePubMedGoogle Scholar
- Hoffmann J, Lichtner RB, Fuhrmann U, Michna H, Parczyk K, Neef G, Chwalisz K, Schneider MR: Effects of progesterone receptor antagonists on breast cancer. 2002, London: Martin Dunitz LtdView ArticleGoogle Scholar
- Lundstrom E, Wilczek B, von Palffy Z, Soderqvist G, von Schoultz B: Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens. Climacteric. 2001, 4 (1): 42-48.View ArticlePubMedGoogle Scholar
- Conner P, Svane G, Azavedo E, Soderqvist G, Carlstrom K, Graser T, Walter F, von Schoultz B: Mammographic breast density, hormones, and growth factors during continuous combined hormone therapy. Fertil Steril. 2004, 81 (6): 1617-1623. 10.1016/j.fertnstert.2004.02.096.View ArticlePubMedGoogle Scholar
- Hofseth LJ, Raafat AM, Osuch JR, Pathak DR, Slomski CA, Haslam SZ: Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab. 1999, 84 (12): 4559-4565. 10.1210/jc.84.12.4559.PubMedGoogle Scholar
- Chwalisz K, Garg R, Brenner RM, Schubert G, Elger W: Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis. Ann NY Acad Sci. 2002, 955: 373-388. discussion 389–393, 396–406View ArticlePubMedGoogle Scholar
- Hickey M, Dwarte D, Fraser IS: Superficial endometrial vascular fragility in Norplant users and in women with ovulatory dysfunctional uterine bleeding. Hum Reprod. 2000, 15 (7): 1509-1514. 10.1093/humrep/15.7.1509.View ArticlePubMedGoogle Scholar
- Hickey M, Fraser IS: The structure of endometrial microvessels. Hum Reprod. 2000, 15 (Suppl 3): 57-66.View ArticlePubMedGoogle Scholar
- Simbar M, Manconi F, Markham R, Hickey M, Fraser IS: A three-dimensional study of endometrial microvessels in women using the contraceptive subdermal levonorgestrel implant system, norplant. Micron. 2004, 35 (7): 589-595. 10.1016/j.micron.2004.01.005.View ArticlePubMedGoogle Scholar
- Slayden OD, Nayak NR, Burton KA, Chwalisz K, Cameron ST, Critchley HO, Baird DT, Brenner RM: Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium. J Clin Endocrinol Metab. 2001, 86 (6): 2668-2679. 10.1210/jc.86.6.2668.PubMedGoogle Scholar
- Brenner RM, Slayden OD, Critchley HO: Anti-proliferative effects of progesterone antagonists in the primate endometrium: a potential role for the androgen receptor. Reproduction. 2002, 124 (2): 167-172. 10.1530/rep.0.1240167.View ArticlePubMedGoogle Scholar
- Brenner RM, Slayden OD, Nayak NR, Baird DT, Critchley HO: A role for the androgen receptor in the endometrial antiproliferative effects of progesterone antagonists. Steroids. 2003, 68 (10–13): 1033-1039. 10.1016/S0039-128X(03)00120-X.View ArticlePubMedGoogle Scholar
- Brenner RM, Slayden OD: Progesterone receptor antagonists and the endometrial antiproliferative effect. Semin Reprod Med. 2005, 23 (1): 74-81. 10.1055/s-2005-864035.View ArticlePubMedGoogle Scholar
- Slayden OD, Brenner RM: Flutamide counteracts the antiproliferative effects of antiprogestins in the primate endometrium. J Clin Endocrinol Metab. 2003, 88 (2): 946-949. 10.1210/jc.2002-021763.View ArticlePubMedGoogle Scholar
- Chen W, Wang J, Ohara J, DeManno D, Chwalisz K, Maruo T: Selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured uterine leiomyoma cells but not in cultured normal myometrial cells [abstract]. Fertil Steril. 2005, 84 (Suppl 1): S152-10.1016/j.fertnstert.2005.07.368.View ArticleGoogle Scholar
- A novel selective progesterone receptor modulator asoprisnil (J867) down-regulates the expression of EGF, IGF-I, TGFβ and their receptors in cultured uterine leiomyoma cells. [http://humrep.oxfordjournals.org/cgi/reprint/del035v1?maxtoshow=HITS=10hits=10RESULTFORMAT=fulltext=Maruosearchid=1FIRSTINDEX=0resourcetype=HWCIT]
- Bagchi MK, Tsai SY, Tsai MJ, O'Malley BW: Progesterone enhances target gene transcription by receptor free of heat shock proteins hsp90, hsp56, and hsp70. Mol Cell Biol. 1991, 11 (10): 4998-5004.PubMed CentralView ArticlePubMedGoogle Scholar
- Vegeto E, Allan GF, Schrader WT, Tsai MJ, McDonnell DP, O'Malley BW: The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell. 1992, 69 (4): 703-713. 10.1016/0092-8674(92)90234-4.View ArticlePubMedGoogle Scholar
- Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O'Malley BW, McDonnell DP: Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol. 1993, 7 (10): 1244-1255. 10.1210/me.7.10.1244.PubMedGoogle Scholar
- Smith CL, O'Malley BW: Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004, 25 (1): 45-71. 10.1210/er.2003-0023.View ArticlePubMedGoogle Scholar
- Horwitz KB, Jackson TA, Bain DL, Richer JK, Takimoto GS, Tung L: Nuclear receptor coactivators and corepressors. Mol Endocrinol. 1996, 10 (10): 1167-1177. 10.1210/me.10.10.1167.PubMedGoogle Scholar
- Hull ML, Prentice A, Wang DY, Butt RP, Phillips SC, Smith SK, Charnock-Jones DS: Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis. Hum Reprod. 2004Google Scholar
- Chen JD, Evans RM: A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature. 1995, 377 (6548): 454-457. 10.1038/377454a0.View ArticlePubMedGoogle Scholar
- Onate SA, Tsai SY, Tsai MJ, O'Malley BW: Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995, 270 (5240): 1354-1357.View ArticlePubMedGoogle Scholar
- Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, Horwitz KB: 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 (6): 693-705. 10.1210/me.11.6.693.View ArticlePubMedGoogle Scholar
- Wagner BL, Norris JD, Knotts TA, Weigel NL, McDonnell DP: The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor. Mol Cell Biol. 1998, 18 (3): 1369-1378.PubMed CentralView ArticlePubMedGoogle Scholar
- Wagner BL, Pollio G, Leonhardt S, Wani MC, Lee DY, Imhof MO, Edwards DP, Cook CE, McDonnell DP: 16 alpha-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity. Proc Natl Acad Sci USA. 1996, 93 (16): 8739-8744. 10.1073/pnas.93.16.8739.PubMed CentralView ArticlePubMedGoogle Scholar
- Melvin V, Perez M, Chwalisz K, Edwards D: Mechanism of action of the selective progesterone receptor modulator asoprisnil [abstract]. The Endocrine Society's 87th Annual Meeting: 4–7 June 2005. 2005, San Diego, CA: The Endocrine Society, 613-Abstract P613-284Google Scholar
- Schubert G, Elger W, Kaufmann G, Schneider B, Reddersen G, Chwalisz K: Discovery, chemistry, and reproductive pharmacology of asoprisnil and related 11beta-benzaldoxime substituted selective progesterone receptor modulators (SPRMs). Semin Reprod Med. 2005, 23 (1): 58-73. 10.1055/s-2005-864034.View ArticlePubMedGoogle Scholar
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