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Biomedical subjects

R F Williams

Publications and source records attributed to R F Williams.

At least 19 recordsLinked to original sources
PubMed2000

Variations in plasma levels of substance P and effects of a specific substance P antagonist of the NK(1) receptor on preovulatory LH and FSH surges and progesterone secretion in the cycling cynomolgus monkey.

These studies investigated the role of substance P (SP) in the regulation of the hypothalamic-pituitary-ovarian axis in cynomolgus monkeys with normal menstrual cycles. Plasma concentrations of SP were determined in blood samples taken every morning in normally menstruating cynomolgus monkeys throughout the menstrual cycle. There was a significant decreasing linear trend of SP during the follicular phase (cycle day -13 to day 0) and a significant inverse relationship between SP plasma values and plasma 17beta-estradiol (E(2)) values from day -13 to day 0 of the adjusted cycle. Correspondingly, SP area under the curve was significantly greater during the follicular phase than the luteal phase. In a second experiment, plasma concentrations of E(2), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone and length of cycles were measured after five daily intragastric administrations (10 mg/kg) of an NK(1) receptor (SP receptor) antagonist (RPR 100893; 10 mg/kg) initiated after serum E(2) concentrations had exceeded 125 pg/ml. There was a statistically significant reduction in the amplitude (41% of control) and the area under the curve (37% of control) of the preovulatory LH surge. In addition, there was a reduction of the duration of the LH surge (3 +/- 0.1 days in controls vs. 2.1 +/- 0.2 days in treated animals). The present results show for the first time that there are significant variations in plasma levels of SP, with a strong negative correlation with serum levels of E(2) during the follicular phase of the cynomolgus monkey, and that endogenous SP has a potentiating role in the interactive hypothalamo-anterior-pituitary mechanisms which lead to the preovulatory LH and FSH surges during the menstrual cycle in the monkey.

Animals↗
PubMed1999

Evaluation of gadopentetate dimeglumine magnetic resonance cisternography in an animal model: preliminary report.

RATIONALE AND OBJECTIVES: To evaluate magnetic resonance (MR) imaging characteristics of the cisternal administration of gadopentetate dimeglumine (gadolinium) in a small experimental animal. METHODS: Four female New Zealand White rabbits were used for this experiment. Each rabbit received a single dose of intrathecal gadolinium (doses ranged from 75-100 micromol) via a cisternal puncture. Immediate and delayed sagittal and axial T1-weighted images of the brain and cervical spinal cord were acquired on a 2 Tesla CSI magnet. RESULTS: All the rabbits tolerated the experiment well, without significant alterations in behavior or seizure activity. During the early phase of imaging, subarachnoid space enhancement was observed over the surface of the brain parenchyma and spinal cord on T1-weighted images. Gradual diffusion of the gadolinium into the cranial parenchyma was seen on the delayed MR studies (45 minutes-6 hours), as revealed by progressive generalized enhancement of the brain. Sustained enhancement of gray matter of the spinal cord was observed. CONCLUSION: This study illustrates that there is no barrier between the cerebrospinal fluid (CSF) and the brain-spinal cord with regard to gadolinium. Possible practical applications for gadolinium-enhanced MR myelography or cisternography include the assessment of communication or obstruction of CSF pathways, subarachnoid space CSF flow pattern analysis, spontaneous or acquired CSF fistula evaluation, evaluation of the intercommunication of central nervous system cystic structures bordering on CSF pathways, and the study of the dynamics of gadolinium diffusion in the central nervous system parenchyma.

Animals↗
PubMed1998

Screening for antiproliferative actions of mifepristone. Differential endometrial responses of primates versus rats.

This laboratory has previously shown the capability of the antiprogestin, mifepristone, to noncompetitively inhibit estrogen-induced endometrial proliferation in nonhuman primates. In the following study, use of the rat uterine weight bioassay was compared against a primate (Macaca fascicularis) uterine bioassay to identify the noncompetitive/antiproliferative effects of mifepristone. These uterine bioassays were contrasted for reasons of identifying a comparative laboratory rodent model that could substitute for the need to use primate models in the screening of potential antiprogestins, thereby saving time, cost, and primate resources. Results of the primate experiment showed that mifepristone decreased endometrial proliferation in a dose-dependent manner; importantly, this decrease occurred in the presence of sustained physiologic serum 17 beta-estradiol (E2) levels. However, in the rat model, results showed that mifepristone altered uterine wet weight and blotted weight values only in those animals receiving pharmacological doses of E2 (p < 0.05). Based on the results summarized herein, use of this rat uterine weight bioassay as a substitute for primate models is not recommended for screening and identification of "interesting" antiprogestins. Apparently, the endometrial noncompetitive antiestrogenic/antiproliferative effects of mifepristone, observed repeatedly in these laboratory primates, do not operate in the rat uterine tissue.

Animals↗
PubMed1998

Chronic antiprogestin therapy produces a stable atrophic endometrium with decreased fibroblast growth factor: a 1-year primate study on contraception and amenorrhea.

OBJECTIVE: To describe the efficacy of mifepristone in the prevention of menstrual bleeding and ovulation, with similar observations in comparison groups. DESIGN: Prospective experimental study. Thirty-two cynomolgus monkeys were divided equally into four treatment groups (n = 8). Treatment lasted for 1 year. INTERVENTION(S): Group I received GnRH-agonist (GnRH-a) and in-sequence mifepristone, group II received mifepristone only, group III received GnRH-a only, and group IV received vehicle control. MAIN OUTCOME MEASURE(S): Serum estradiol and progesterone, menstrual bleeding, endometrial thickness, and endometrial expression of basic fibroblast growth factor (bFGF) as determined by immunohistochemistry. RESULT(S): Weekly progesterone determinations showed that mifepristone-treated monkeys seldom ovulated (6 ovulations in 8 years), compared with the controls (100 ovulations in 8 years), while maintaining early to midfollicular levels of circulating serum estradiol. The GnRH-a-only group also rarely ovulated, but was chronically and severely hypoestrogenic. The mifepristone-only group showed scant menstrual bleeding (5 days in 8 years) as compared with the menstrual frequency in control animals (422 days in 8 years). Endometrial proliferation, as determined by biopsy, was similarly minimal for both the GnRH-a and mifepristone groups, and statistically less than in control monkeys. Both the mifepristone and GnRH-a treatments suppressed endometrial gland expression of the angiogenesis polypeptide bFGF. CONCLUSION(S): Chronic mifepristone induced anovulation along with virtual amenorrhea, which suggests the worth of this novel hormonal contraceptive.

Amenorrhea↗
PubMed1998

Once weekly azithromycin therapy for prevention of Mycobacterium avium complex infection in patients with AIDS: a randomized, double-blind, placebo-controlled multicenter trial.

We conducted a randomized, double-blind, placebo-controlled multicenter trial of azithromycin (1,200 mg once weekly) for the prevention of Mycobacterium avium complex (MAC) infection in patients with AIDS and a CD4 cell count of < 100/mm3. In an intent-to-treat analysis through the end of therapy plus 30 days, nine (10.6%) of 85 azithromycin recipients and 22 (24.7%) of 89 placebo recipients developed MAC infection (hazard ratio, 0.34; P = .004). There was no difference in the ranges of minimal inhibitory concentrations of either clarithromycin or azithromycin for the five breakthrough (first) MAC isolates from the azithromycin group and the 18 breakthrough MAC isolates from the placebo group. Of the 76 patients who died during the study, four (10.5%) of 38 azithromycin recipients and 12 (31.6%) of 38 placebo recipients had a MAC infection followed by death (P = .025). For deaths due to all causes, there was no difference in time to death or number of deaths between the two groups. Episodes of non-MAC bacterial infection per 100 patient years occurred in 43 azithromycin recipients and 88 placebo recipients (relative risk, 0.49; 95% confidence interval, 0.33-0.73). The most common toxic effect noted during the study was gastrointestinal, reported by 78.9% of azithromycin recipients and 27.5% of placebo recipients. Azithromycin given once weekly is safe and effective in preventing disseminated MAC infection, death due to MAC infection, and respiratory tract infections in patients with AIDS and CD4 cell counts of < 100/mm3.

AIDS-Related Opportunistic Infections↗
PubMed1997

Substrate and substrate analog binding to endothelial nitric oxide synthase: electron paramagnetic resonance as an isoform-specific probe of the binding mode of substrate analogs.

The binding of arginine analogs to endothelial nitric oxide synthase (eNOS, NOSIII) perturbs the environment of the high-spin ferriheme in a highly ligand-specific manner. Using electron paramagnetic resonance as a probe of heme ligation geometry, four categories of high-spin complex could be distinguished. These are analogous to the four classes of high-spin complexes, stabilized individually by the binding of L-arginine, N-hydroxy-L-arginine (NHA), N-methyl-L-arginine (NMA), and N-nitro-L-arginine (NNA), which we have previously reported for the other two isoforms. Each of these species is five-coordinate and retains the axial thiolate ligand but each differs in its ligation geometry. N-Methyl-L-arginine is a relatively poor inhibitor of eNOS, and the NMA complex of eNOS differs from the N-methyl-L-arginine complexes of inducible nitric oxide synthase (iNOS, NOSII) and neuronal nitric oxide synthase (nNOS, NOSI) in that it is of lower rhombicity. We previously showed that inducible nitric oxide synthase, which binds NNA less tightly than eNOS and nNOS, could not form the lower rhombicity NNA complex characteristic of nNOS. Endothelial nitric oxide synthase readily forms such lower rhombicity complexes, which correlates with the tight binding of NNA to this isoform. Arginine and tetrahydrobiopterin promote loss of the flavin free radical EPR signal, while arginine analog inhibitors stabilize the radical; this suggests that the residual flavin radicals can serve as a source of reducing equivalents for slow turnover in the absence of endogenous reductant.

Animals↗
PubMed1997

Pharmaceutical services in the United States Army.

The status of pharmaceutical services in the United States Army is described. The Army Medical Department (AMEDD) has 157 commissioned pharmacy officers and 399 civilian pharmacists working in the United States and overseas. Pharmaceutical services are provided from fixed medical treatment facilities on Army installations and, during war and other field operations, field hospitals. Reductions in personnel and facility closures have helped align the AMEDD with the size of the Army's activeduty force, but there has been only a 15% reduction in the number of eligible beneficiaries. Measures such as the interservice TRICARE program have been implemented to help meet the continued high demand for pharmaceutical services cost-effectively. Army pharmacy is similar to civilian pharmacy, except that Army hospitals often include high-volume outpatient pharmacies not usually found in civilian institutions. Pharmacists are being given direct patient care roles on multidisciplinary teams. Army pharmacists participate in field exercises so that they will be prepared to provide services under combat conditions. The AMEDD trains its own pharmacy technicians in a highly structured 18-week course. A triservice Pharmacoeconomic Center (PEC) has been established with the goal of providing prescribers with the tools for making cost-effective decisions about drug therapy, including a formulary. Army pharmacy officers have broad opportunities to further their education and training. In preparing for the next century, Army pharmacists need to continue to prove their value to the AMEDD, the Army, and the Department of Defense.

Delivery of Health Care↗
PubMed1997

Longitudinal relaxation and diffusion measurements using magnetic resonance signals from laser-hyperpolarized 129Xe nuclei.

Methods for T1 relaxation and diffusion measurements based on magnetic resonance signals from laser-hyperpolarized 129Xe nuclei are introduced. The methods involve optimum use of the perishable hyperpolarized magnetization of 129Xe. The necessary theoretical framework for the methods is developed, and then the methods are applied to measure the longitudinal relaxation constant, T1, and the self-diffusion constant, D, of hyperpolarized 129Xe. In a cell containing natural abundance 129Xe at 790 Torr, the T1 value was determined to be 155 +/- 5 min at 20 degrees C and at 2.0 T field. For a second cell at 896 Torr, at the same field and temperature, the T1 value was determined to be 66 +/- 2 min. At a higher field of 7.05 T, the T1 values for the two cells were found to be 185 +/- 10 and 88 +/- 5 min, respectively. The 129Xe self-diffusion constant for the first cell was measured to be 0.057 cm2/ s and for the second cell it was 0.044 cm2/s. The methods were applied to 129Xe in the gas phase, in vitro; however, they are, in principle, applicable for in vivo or ex vivo studies. The potential role of these methods in the development of newly emerging hyper-polarized 129Xe MRI applications is discussed.

Animals↗
PubMed1997

Vascular endothelial growth factor in primate endometrium is regulated by oestrogen-receptor and progesterone-receptor ligands in vivo.

We investigated hormonal regulation of endometrial angiogenesis in menstruating primates. This study was designed to demonstrate: (i) that cell-specific vascular endothelial growth factor (VEGF) production and expression in monkey endometrium are regulated by steroid receptor ligands; and (ii) mifepristone (RU 486) alters VEGF production even in the absence of a progestin agonist. Endometrial VEGF production was compared by computer-assisted immunohistochemical analysis during induced hypoestrogenism and after oestradiol, progestin, or antiprogestin (mifepristone) treatment. VEGF gene expression was estimated by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in endometrial samples from castrate cynomolgus monkeys, from intact monkeys in the luteal phase, and from monkeys treated for 20 days with levonorgestrel (LNG) or mifepristone. VEGF staining intensities in glandular epithelium and VEGF mRNA expression were highest in hypoestrogenic monkeys. Progestin treatment induced intense VEGF staining in the stroma. Gene expression of VEGF-189, but not other isoforms, was higher in progesterone- and progestin (LNG)-exposed endometria compared to mifepristone-exposed endometria or endometria from anovulatory cycles (P < 0.04). Mifepristone abolished VEGF staining in glandular epithelium almost completely. We conclude that VEGF protein and VEGF mRNA expression levels in primate endometrium depend on the steroidal milieu. Anti-angiogenic effects of mifepristone via suppression of VEGF production might represent a mechanism for its quelling effects on endometrium.

Animals↗
PubMed1996

Multiple transcription start sites for the GnRH gene in rhesus and cynomolgus monkeys: a non-human primate model for studying GnRH gene regulation.

In humans, transcription of the gonadotropin-releasing hormone (GnRH) gene can be initiated at two transcription start sites to produce different GnRH mRNAs. The upstream transcription start site is used only in reproductive tissues and tumors. To determine if a similar pattern of GnRH gene expression exists in non-human primates, we cloned GnRH cDNA from rhesus monkey hypothalamic RNA using reverse transcriptase-polymerase chain reaction (RT-PCR) and the 5' flanking region of the monkey GnRH gene by PCR. A 96% similarity between monkey and human GnRH cDNA was found with 94% similarity in the upstream promoter region. An upstream transcriptional start site, was identified in cynomolgus monkey testicular mRNA, 504 base pairs upstream from the hypothalamic site, which was different from that identified in the human GnRH gene. Various cynomolgus monkey reproductive tissues were found to utilize this upstream transcriptional start site. In contrast, no evidence was found for the use of upstream transcriptional start sites in rat testis or placenta, suggesting that the reproductive tissue specificity of the upstream transcription start site may be a primate specific feature.

Amino Acid Sequence↗
PubMed1996

Inhibition of ovulation by progestin analogs (agonists vs antagonists): preliminary evidence for different sites and mechanisms of actions.

Continuous administration of the antiprogesterone RU486 inhibits ovulation in women and in monkeys; in this regard RU486 may act as a progestin agonist rather than as an antagonist. We compared the site(s) and mechanism(s) of RU486-induced ovulation inhibition with those of levonorgestrel (LNG). Six regularly menstruating cynomolgus monkeys each received placebo, RU486 (1 mg/kg/d) or LNG (2 g/kg/d) i.m. between days (cd) 2-22 of three separate menstrual cycles. Serum levels of estradiol (E2), progesterone (P4), androstenedione, LH and FSH were analyzed by RIAs in daily blood samples. Basal and GnRH-stimulated (1 and 50 g of GnRH i.v. 2 h apart) secretion of LH and FSH was assessed using serial blood samples collected for 12 h on cd 10. Mean cycle length was prolonged by RU486 and LNG treatments from 32 d to 70 d and 52 d, respectively (p < 0.02). Ovulation was inhibited in five of the six primates during RU486, and in all six during LNG treatment. During RU486 treatment, serum E2 levels were similar to those of the control cycle; despite peaks of E2 secretion, no LH peaks were seen. In contrast, E2 concentrations were profoundly suppressed during LNG treatment (p < 0.005). The reduction in serum E2 was accompanied by lower levels of androstenedione, and suppressed ratio of E2/androstenedione (p < 0.02) suggesting both reduced synthesis and aromatization of androgen precursors during administration of LNG. Consequently, LNG treatment was associated with higher levels of serum FSH and LH (p < 0.001; 1-way ANOVA). Similarly, as during the luteal phase of the menstrual cycle, the amplitude of basal LH-pulses was increased during LNG treatment (p < 0.05), whereas RU486 treatment did not affect basal LH secretion. The GnRH-stimulated release of LH was similar during the placebo, RU486 and LNG cycles; enhanced release of FSH was seen during administration of LNG. Thus, in the present model system, RU486 seems to inhibit ovulation mainly at the level of hypothalamus, possibly by interfering with the steroidal positive feedback signals from the ovary. However, LNG inhibits ovulation differently, most likely via direct progesterone-like effects on folliculogenesis and the hypothalamus. The pituitary does not appear to be the major site of action(s) of RU486 or LNG. Thus, the differential mechanisms of ovulation inhibition by RU486 and LNG seem to result from lesser intraovarian impact of RU486 as well as dissimilar influences on tonic gonadotropin secretory levels. We conclude that when inhibiting ovulation, RU486 does not act as a progestin agonist, but rather, functions through a hypothalamic mechanism(s), which might be unique to RU486 as a progesterone antagonist.

Analysis of Variance↗
PubMed1996

Combined carotid endarterectomy, innominate artery reconstruction, and coronary artery bypass grafting: case report.

Neurologic injury is one of the most devastating complications of combined carotid and cardiac procedures. Although the cause of the deficit is usually embolic, the exact cause is often not apparent at the time of surgery. We present a complex case of combined carotid endarterectomy, innominate artery reconstruction, and coronary artery bypass procedures in which intraoperative monitoring with somatosensory evoked potentials and transcranial Doppler ultrasonography combined with postoperative acetazolamide single photon emission computed tomographic scans was used to correlate intraoperative events with cerebral activity and functional results. Although computed tomographic scan, magnetic resonance imaging, and clinical evaluation were negative for any evidence of stroke, the patient exhibited subtle postoperative changes in neuropsychologic function. These changes were correlated with intraoperative microemboli detected by transcranial Doppler monitoring, and postoperative acetazolamide single photon emission computed tomographic scanning, which revealed bilateral cortical defects.

Acetazolamide↗
PubMed1996

Endometrial effects of RU486 in primates--antiproliferative action despite signs of estrogen action and increased cyclin-B expression.

Continuous antiprogestin administration to hormone replaced, castrate monkeys inhibits estrogen-induced endometrial proliferation through mechanisms which remains unclear. To elucidate the molecular mechanisms of RU486-induced endometrial suppression, we treated six intact female cynomolgus monkeys on cycle days 2-22 sequentially with placebo, RU486 (1 mg/kg/day) and levonorgestrel (LNG) (2 microg/kg/day) intramuscularly (i.m.), with uterine wedge sections and endometrial biopsies collected on day 22 of each cycle. The uterine sections were evaluated for morphology, mitosis and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Changes in the mRNA levels of ER, PR, cyclin-B and tumour suppressor gene p21 were assessed using co-amplification with beta-actin by reverse transcriptase-polymerase chain reaction (RT-PCR). Administration of RU486 uniformly resulted in characteristic suppression of endometrium with few mitosis, dense stroma and simple glands, whereas the effects of LNG were less uniform. Following RU486 administration, the levels of endometrial ER and PR mRNA were comparable to proliferative phase endometrium, and significantly higher than those seen in the secretory endometrium, indicating that some of the biological actions of E2 were not inhibited during RU486 treatment. Despite scarce mitosis, PCNA was readily detectable in all samples. Curiously, in comparison to secretory phase controls, the levels of cyclin-B, but not p21, mRNA were markedly increased following RU486. The effects of LNG on the levels of these mRNA species varied, with mean levels falling between those of the secretory phase controls, and RU486-treated specimens. The increase in cyclin-B mRNA and lack of mitosis suggests that anti-proliferative actions of RU486 in the primate endometrium might be associated with a cell-cycle block at the G2-M interphase. Whether mechanisms similar to these are associated with the beneficial clinical effects of RU486 seen in the treatment of various hormone dependent maladies remains to be determined.

Animals↗
PubMed1996

Antiinflammatory C-glucosyl chromone from Aloe barbadensis.

A new antiinflammatory agent identified as 8-[C-beta-D-[2-O-(E)-cinnamoyl]glucopyranosyl]-2- [(R)-2-hydroxypropyl]-7-methoxy-5-methylchromone (1) has been isolated from Aloe barbadensis Miller. At a dose of 200 microg/mouse ear, 1 exhibited topical antiinflammatory activity equivalent to 200 microg/ear of hydrocortisone. There was no reduction in thymus weight caused by treatment with 1 for any of the doses tested, while 200 microg/ear of hydrocortisone resulted in a 50% decrease in thymus weight.

Aloe↗
PubMed1996

Non-competitive anti-oestrogenic actions of progesterone antagonists in primate endometrium: enhancement of oestrogen and progesterone receptors with blockade of post-receptor proliferative mechanisms.

Previous studies have shown that the progesterone antagonists (antiprogestins) inhibit oestrogen-dependent endometrial proliferation in ovariectomized monkeys, without having affinity to the oestrogen receptor (ER). This study was designed to investigate the effect of the antiprogestins mifepristone (RU 486) and onapristone (ZK 98,299), on the concentration of ER and progesterone receptor (PR) in the endometrium of long-term ovariectomized cynomolgus monkeys (Macaca fascicularis). In untreated monkeys, tissue preparations bound in total 228 +/- 68 pmol [3H]-oestradiol/g protein (ER), and 119 +/- 42 pmol [3H]-R5020/g protein (PR). These values were not significantly different from the total binding capacities of tissues from monkeys treated with RU 486 alone or primates treated with oestradiol plus progesterone. Treatment with oestradiol alone almost doubled the ER and PR concentrations. Combined treatment with oestradiol and RU 486 enhanced the ER and PR concentrations in a dose-dependent manner: 1 mg/kg body weight (bw) RU 486/kg increased both ER and PR contents about 3-fold. The dose of 5mg/kg bw RU 486 or onapristone increased the ER and PR concentrations almost 6- and 5-fold respectively, compared with the oestradiol-treated controls. Our results demonstrate that RU 486 and onapristone increased the endometrial ER and PR concentrations far beyond the physiological level in ovariectomized, oestradiol-treated monkeys. Whether the over-expression of ER and PR in the presence of antiprogestins is causally related to the antiproliferative impact of antiprogestins in the endometrium (non-competitive anti-oestrogenic effects) or is an independent action in unknown.

Animals↗
PubMed1996

Antiprogestin and/or gonadotropin-releasing hormone agonist for endometriosis treatment and bone maintenance: a 1-year primate study.

The fact that RU 486 curtailed estrogen-induced endometrial proliferation in primates and relieved pelvic pain in women with endometriosis is the reason for continuing research on antiprogestins. Thirty-two adult female cynomolgus monkeys demonstrating menstrual regularity had surgery for the induction of endometriosis. After lesion staging, four treatment groups (n = 8), each of 1-yr duration, were made. Group I received combination/sequential therapy with depot GnRH agonist (GnRH-a) for 3 months, followed by weekly RU 486 for 9 months. Group II received weekly RU 486, group III received monthly GnRH-a, and group IV served as a vehicle control. A staging laparotomy was performed every 3 months to assess the area of peritoneal endometriosis (square centimeters) and the thickness of in situ endometrium. Bone density was measured serially by dual x-ray absorptiometry. Serum was collection weekly. Mean (+/- SE) serum estradiol levels were lower after GnRH-a (77.1 +/- 2.6 pmol/L) than after RU 486 (231 +/- 12 pmol/L) treatment and lower than those in untreated cycling controls (231 +/- 13 pmol/L). GnRH-a produced significant atrophy of endometriotic plaques within 3 months of therapy; this lesion reduction was sustained with RU 486. Both GnRH-a and RU 486 alone produced profound thinning of ectopic and eutopic endometrium throughout 1 yr of continuous therapy. Bone density decreased significantly after 6 months of GnRH-a alone (P < 0.05), without significant changes in the other groups. After RU 486 treatment, there were no significant changes in testosterone, androstenedione, sex hormone-binding globulin, or cortisol. Like GnRH-a, long term antiprogestin therapy produced a reduction in the volume of pelvic endometriotic lesions as well as atrophy of in situ endometrium; however, RU 486 allowed maintenance of tonic ovarian estradiol secretion, suggesting that efficacious endometriosis therapy can be sustained long term without the sequelae of hypoestrogenism, specifically bone density loss.

Animals↗