Premenstrual Dysphoric Disorder Symptoms Following Ovarian Suppression: Triggered by Change in Ovarian Steroid Levels But Not Continuous Stable Levels.

OBJECTIVE: Premenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression and stimulated by administration of ovarian steroids, yet they appear with ovarian steroid levels indistinguishable from those in women without PMDD. Thus, symptoms could be precipitated either by an acute change in ovarian steroid levels or by stable levels above a critical threshold playing a permissive role in expression of an underlying infradian affective "pacemaker." The authors attempted to determine which condition triggers PMDD symptoms. METHOD: The study included 22 women with PMDD, ages 30 to 50 years. Twelve women who experienced symptom remission after 2-3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received 1 month of single-blind (participant only) placebo and then 3 months of continuous combined estradiol/progesterone. Primary outcome measures were the Rating for Premenstrual Tension observer and self-ratings completed every 2 weeks during clinic visits. Multivariate repeated-measure ANOVA for mixed models was employed. RESULTS: Both self- and observer-rated scores on the Rating for Premenstrual Tension were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with the last month of leuprolide alone, the placebo month, and the second and third months of estradiol/progesterone. There were no significant differences in symptom severity between the last month of leuprolide alone, placebo month, or second and third months of estradiol/progesterone. Finally, the Rating for Premenstrual Tension scores in the second and third estradiol/progesterone months did not significantly differ. CONCLUSIONS: The findings demonstrate that the change in estradiol/progesterone levels from low to high, and not the steady-state level, was associated with onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

Depression during the menopause transition: impact on quality of life, social adjustment, and disability.

The impact of depression on quality of life (QOL) and social support has neither been well characterized in clinical samples of women with perimenopausal depression (PMD) nor have the relative contributions of depression and other menopausal symptoms (e.g., hot flushes) to declining QOL been clarified. In this study, we compared QOL measures, social support, and functional disability in PMD and non-depressed perimenopausal women. We evaluated women aged 40-60 years who presented with menstrual cycle irregularity, elevated plasma FSH levels, and met criteria for perimenopause. A structured clinical interview was administered to determine the presence or absence of major and minor depression. Outcome measures included the Quality of Life Enjoyment Scale Questionnaire, the Sheehan Disability Scale, the Global Assessment of Functioning, the Social Adjustment Scale, and the Duke Social Support Index. Kruskal-Wallis tests and ANOVAs were used to compare outcome measures. Ninety women with PMD and 51 control women participated in this study. Women with PMD reported significantly decreased QOL, social support, and adjustment and increased disability compared with non-depressed perimenopausal women. Neither perimenopausal reproductive status alone nor the presence of hot flushes had a significant negative impact on QOL measures. PMD is accompanied by significant reductions in QOL, social support, and disability similar to depression in women at other stages of life. PMD may also contribute to decreased QOL in community- or clinic-based samples of perimenopausal women. It remains unclear whether the clinical characteristics we identified reflect pre-existing risk factors for depression during the perimenopause or the effects of a current depression. Future clinical and treatment studies in perimenopausal women should distinguish depressed women when outcome measures include QOL.

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder.

Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, double-blind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. Analyses were performed with SAS PROC MIXED. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the low-dose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.

Effects of Estradiol Withdrawal on Mood in Women With Past Perimenopausal Depression: A Randomized Clinical Trial.

IMPORTANCE: Perimenopause is accompanied by an increased risk of new and recurrent depression. The coincidence of declining ovarian function with the onset of depression led to the inference that "withdrawal" from physiologic estradiol levels underpinned depression in perimenopause. To our knowledge, this is the first controlled systematic study to directly test the estrogen withdrawal theory of perimenopausal depression (PMD). OBJECTIVE: To examine the role of estradiol withdrawal in PMD. DESIGN, SETTING, AND PARTICIPANTS: Initial open-label treatment with estradiol followed by randomized, double-blind, placebo-controlled, parallel-design evaluation of continued estradiol treatment was evaluated at an outpatient research facility at the National Institutes of Health Clinical Center. An intent-to-treat analysis was performed between October 2003 and July 2012. Participants included asymptomatic postmenopausal women with past PMD responsive to hormone therapy (n = 26) and asymptomatic postmenopausal women with no history of depression (n = 30) matched for age, body mass index, and reproductive status who served as controls. Data were analyzed between November 2012 and October 2013 by repeated-measures analysis of variance. INTERVENTIONS: After 3 weeks of open-label administration of transdermal estradiol (100 µg/d), participants were randomized to a parallel design to receive either estradiol (100 µg/d; 27 participants) or matched placebo skin patches (29 participants) for 3 additional weeks under double-blind conditions. MAIN OUTCOMES AND MEASURES: Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale (completed by raters blind to diagnosis and randomization status), self-administered visual analog symptom ratings, and blood hormone levels obtained at weekly clinic visits. RESULTS: None of the women reported depressive symptoms during open-label use of estradiol. Women with past PMD who were crossed over from estradiol to placebo experienced a significant increase in depression symptom severity demonstrated using the Center for Epidemiologic Studies-Depression Scale and 17-item Hamilton Depression Rating Scale, with mean (SD) scores increasing from estradiol (ie, 2.4 [2.0] and 3.0 [2.5]) to placebo (8.8 [4.9] and 6.6 [4.5], respectively [P = .0004 for both]). Women with past PMD who continued estradiol therapy and all women in the control group remained asymptomatic. Women in both groups had similar hot-flush severity and plasma estradiol levels during use of placebo. CONCLUSIONS AND RELEVANCE: In women with past PMD that was previously responsive to hormone therapy, the recurrence of depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian estradiol secretion can trigger an abnormal behavioral state in these susceptible women. Women with a history of PMD should be alert to the risk of recurrent depression when discontinuing hormone therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00060736.

Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency.

OBJECTIVE: Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI. METHODS: One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests. RESULTS: No differences in baseline characteristics, including serum hormone levels (P > 0.05), were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively (P = 0.35). After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo (P < 0.001). Baseline testosterone levels were not associated with either adverse or beneficial clinical effects. CONCLUSIONS: A 150-µg testosterone patch achieves physiologic hormone levels in women with POI. Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder.

Effects of pharmacologically induced hypogonadism on mood and behavior in healthy young women.

OBJECTIVE: The relationship between depression and estrogen withdrawal remains controversial. The authors examined the effects of gonadotropin-releasing hormone agonist-induced ovarian suppression on mood, sleep, sexual function, and nighttime hot flushes. They focused on whether participating women experienced clinically significant depressive symptoms and whether specific symptoms associated with hypogonadism (nighttime hot flushes and disturbed sleep) increased susceptibility to depression. METHOD: Participants were 72 healthy premenopausal women, ages 19-52 years, with no current or past axis I psychiatric diagnosis or gynecological or other medical illness. After 2 months of baseline screening, women received monthly injections of leuprolide acetate (3.75 mg) for 2-3 months. Outcomes were measured using the Beck depression inventory (BDI) and a daily rating scale measuring the severity of several affective and behavioral symptoms. Data were analyzed by repeated-measures analysis of variance using PROC MIXED (for mixed models). RESULTS: BDI scores ≥10 were reported in four of the 72 women (5.6%). Relative to baseline, induced hypogonadism was associated with significantly decreased sexual interest, disturbed sleep, and more severe nighttime hot flushes, but no significant change in any mood-related symptom score. Hot flush severity was significantly correlated with disturbed sleep. CONCLUSIONS: These data demonstrate that clinically significant depressive symptoms were rare accompaniments of short-term estradiol withdrawal and induced hypogonadism in healthy premenopausal women. Additionally, neither nighttime hot flushes nor disturbed sleep were sufficient to cause depressive symptoms in hypogonadal women.

A comparison of clinicians' access to online knowledge resources using two types of information retrieval applications in an academic hospital setting.

OBJECTIVE: The research studied whether a clinician's preference for online health knowledge resources varied with the use of two applications that were designed for information retrieval in an academic hospital setting. METHODS: The researchers analyzed a year's worth of computer log files to study differences in the ways that four clinician groups (attending physicians, housestaff physicians, nurse practitioners, and nurses) sought information using two types of information retrieval applications (health resource links or Infobutton icons) across nine resources while they reviewed patients' laboratory results. RESULTS: From a set of 14,979 observations, the authors found statistically significant differences among the 4 clinician groups for accessing resources using the health resources application (P<0.001) but not for the Infobuttons application (P = 0.31). For the health resources application, the preferences of the 4 clinical groups varied according to the specific resources examined (all P≤0.02). CONCLUSION: The information-seeking behavior of clinicians may vary in relation to their role and the way in which the information is presented. Studying these behaviors can provide valuable insights to those tasked with maintaining information retrieval systems' links to appropriate online knowledge resources.

Depression in women with spontaneous 46, XX primary ovarian insufficiency.

CONTEXT: A high prevalence of depressive symptoms is observed in women with primary ovarian insufficiency (POI) compared with women in whom the menopause is normally timed. Indeed, studies suggest that depression and/or its pharmacological treatment contribute to the onset of POI. OBJECTIVES: We characterize the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of POI and the onset of menstrual irregularity in women with POI. DESIGN AND SETTING: We conducted a cross-sectional clinic-based study at the National Institutes of Health Clinical Research Center. PATIENTS: A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study. MAIN OUTCOME MEASURES: The structured clinical interview for DSM-IV was performed. RESULTS: Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P < 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events. CONCLUSIONS: POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship.

The psychosocial transition associated with spontaneous 46,XX primary ovarian insufficiency: illness uncertainty, stigma, goal flexibility, and purpose in life as factors in emotional health.

OBJECTIVE: To examine factors associated with emotional well-being in women with spontaneous primary ovarian insufficiency. DESIGN: Cross-sectional and case-control study. SETTING: Clinical research center, national U.S. health research facility. PATIENT(S): Women diagnosed with spontaneous 46,XX primary ovarian insufficiency (n = 100) at a mean age of 32.4 years and healthy control women of similar age (n = 60). INTERVENTION(S): Administration of validated self-reporting instruments. MAIN OUTCOME MEASURE(S): Illness uncertainty, stigma, goal disengagement/re-engagement, purpose in life, Positive and Negative Affect Schedule, Center of Epidemiologic Studies Depression Scale, State-Trait Anxiety Inventory. RESULT(S): Compared with controls, women with spontaneous primary ovarian insufficiency scored adversely on all measures of affect. Illness uncertainty and purpose in life were significant independent factors associated with anxiety (R(2) = 0.47), stigma and purpose in life were the significant independent factors associated with depression (R(2) = 0.51), and goal re-engagement and purpose in life were significantly and independently associated with positive affect (R(2) = 0.43). CONCLUSION(S): This evidence supports the need for prospective studies. Our findings are consistent with the hypothesis that clinicians could improve the emotional well-being of their patients with primary ovarian insufficiency by [1] informing them better about their condition, [2] helping them to feel less stigmatized by the disorder, and [3] assisting them in developing alternative goals with regard to family planning as well as other goals.

Association of interleukin-15-induced peripheral immune activation with hepatic stellate cell activation in persons coinfected with hepatitis C virus and HIV.

Hepatic stellate cells (HSCs) mediate hepatitis C virus (HCV)-related liver fibrosis, and increased HSC activation in human immunodeficiency virus (HIV)/HCV coinfection may be associated with accelerated fibrosis. We examined the level of HSC activation in HIV/HCV-coinfected and HCV-monoinfected subjects and its relationship to the level of activation and gene expression of peripheral immune cells in coinfected subjects. HSC activation levels positively correlated with peripheral CD4+ and CD8+ T cell immune activation and were associated with enhanced interleukin-15 (IL-15) gene expression, suggesting a pathogenic role for IL-15-driven immunomediated hepatic fibrosis. Future strategies that reduce immune activation and HSC activation may delay progression of liver fibrosis.

Functional well-being is positively correlated with spiritual well-being in women who have spontaneous premature ovarian failure.

OBJECTIVE: To examine the relationship between spiritual well-being and functional well-being in women who have spontaneous premature ovarian failure. DESIGN: Cross-sectional. SETTING: The Mark O. Hatfield Clinical Research Center at the US National Institutes of Health. PATIENT(S): Women diagnosed with spontaneous premature ovarian failure (N = 138) at a median age of 28 years. INTERVENTION(S): Administration of validated self-reporting instruments. MAIN OUTCOME MEASURE(S): Functional Well-Being, Spiritual Well-Being, Meaning/Peace, and Faith scores. RESULT(S): We found a significant positive correlation between overall spiritual well-being and functional well-being scores. The Meaning/Peace subscale strongly correlated with functional well-being, explaining approximately 62% of the variance. In contrast, the Faith subscale was less strongly correlated with functional well-being, explaining only 7% of the variance. In multiple regression analysis evaluating the relative subscale contributions to functional well-being, only Meaning/Peace remained statistically significant. We found no significant associations between either spiritual well-being or functional well-being and age; age at diagnosis; time since diagnosis; or partner, children, or racial status. CONCLUSION(S): This study provides cross-sectional data supporting the need for prospective controlled studies. Strategies to improve spiritual well-being in the domains of meaning, purpose, and inner peace may provide a therapeutic approach to reduce the emotional suffering that accompanies the life-altering diagnosis of premature ovarian failure.

CD10 immunohistochemical staining enhances the histological detection of endometriosis.

OBJECTIVE: To determine whether the use of CD10 immunohistochemistry in addition to hematoxylin and eosin (H&E) staining would increase the sensitivity of surgically suspected endometriosis lesions. DESIGN: Retrospective cohort study. SETTING: Tertiary care government research hospital. PATIENT(S): Thirty-one women with chronic pelvic pain. INTERVENTION(S): Immunohistochemical analysis for CD10 was performed on 108 possible endometriotic lesions and in the corresponding endometrial biopsy samples obtained during laparoscopy. When CD10 immunohistochemistry results were positive, the corresponding H&E section was reviewed to determine if the initial diagnosis should be revised. MAIN OUTCOME MEASURE(S): Histologic diagnosis of endometriosis by adjunctive use of CD10 immunohistochemistry in conjunction with H&E-stained specimens. RESULT(S): In endometrial stroma, CD10 was consistently present. Of the 70 specimens judged negative initially by H&E staining, CD10 staining led to the diagnosis of endometriosis in 11. The addition of CD10 immunohistochemistry detected more positive endometriosis lesions than H&E staining alone (45% vs. 35%). In three women with minimal endometriosis at surgery but initially negative histopathology, CD10 immunohistochemistry changed the histologic diagnosis to endometriosis. CONCLUSION(S): The adjunctive use of CD10 immunohistochemistry improves diagnostic sensitivity for endometriosis, especially for women with minimal disease.

Walking ability and its relationship to lower-extremity muscle strength in children with idiopathic inflammatory myopathies.

OBJECTIVE: To describe gait deficits and their association with lower-extremity muscle strength in children with juvenile idiopathic inflammatory myopathies (IIM). DESIGN: Cross-sectional, descriptive study. SETTING: Clinical research center. PARTICIPANTS: Consecutive sample of 25 ambulatory children diagnosed with juvenile IIM. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Manual muscle test (MMT) of bilateral hip flexor, extensor, and abductor; knee extensor; and ankle plantarflexor strength, all measured on a 0- to 10-point scale and summary strength measures. Video-based movement analysis to determine walking speed; gait cycle time; right and left step time; stride length; right and left step length; and stance, swing, and double-limb support phase durations. RESULTS: Walking speed (1.03+/-0.27 m/s) was reduced because of shortened stride lengths (1.03+/-0.21 m) more than prolonged gait cycle times (1.05+/-0.22s). Walking speed highly correlated with the number of muscle groups weaker than grade 7 out of 10 (r=-.89) and the strength of the hip flexors (r=.85). CONCLUSIONS: Lower-extremity strength measures, including MMT scores of individual muscle groups and the number of weak muscle groups, were predictive of gait limitations in children with juvenile IIM.

Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C.

BACKGROUND & AIMS: CCR5Delta32, a 32-base pair deletion of the CC chemokine receptor (CCR) 5 gene, is associated with slowed human immunodeficiency virus disease progression in heterozygotes and protection against infection in homozygotes. A recent study found a higher than expected frequency of CCR5Delta32/Delta32 in patients with hepatitis C virus infection. The roles of other disease-associated chemokine system polymorphisms have not been evaluated in hepatitis C virus infection. METHODS: Six chemokine system polymorphisms (CCR5Delta32, CCR5 promoter 59029-G/A, CCR2 -64I, RANTES [regulated upon activation, normal T cells expressed and secreted] -403 -G/A, and -28 -C/G and stromal derived factor 1 -3'A) were studied in 417 patients with liver diseases (339 with hepatitis C) and 2380 blood donors. The clinical parameters of hepatitis C virus infection were compared between carriers and noncarriers of each genetic variant. RESULTS: The frequency of CCR5Delta32 homozygosity was 0.8% in whites with hepatitis C virus and 1.1% in controls (P = 0.75). The CCR5Delta32 allele was not associated with any of the clinical parameters of hepatitis C virus infection. Hepatitis C virus-seropositive whites with the RANTES -403-A allele were less likely to have severe hepatic inflammation compared with those without (odds ratio, 0.34; P = 0.03). In multivariate analysis, the CCR5 promoter 59029 -A allele was marginally associated with a sustained response to interferon therapy (odds ratio, 3.07; P = 0.048). CONCLUSIONS: In this cohort, the frequency of CCR5Delta32 homozygosity in patients with hepatitis C was similar to controls. The high prevalence of CCR5Delta32 homozygosity in the hepatitis C virus patients of the earlier study likely reflects resistance to human immunodeficiency virus infection in hemophiliacs rather than a susceptibility to hepatitis C virus infection. Expression of CCR5 and RANTES may be important in the modulation of hepatic inflammation and response to interferon therapy in chronic hepatitis C.

Ethnicity greatly influences cytokine gene polymorphism distribution.

Polymorphisms in the regulatory regions of cytokine genes are associated with high and low cytokine production and may modulate the magnitude of alloimmune responses following transplantation. Ethnicity influences allograft half-life and the incidence of acute and chronic rejection. We have questioned whether ethnic-based differences in renal allograft survival could be due in part to inheritance of cytokine polymorphisms. To address that question, we studied the inheritance patterns for polymorphisms in several cytokine genes (IL-2, IL-6, IL-10, TNF-alpha, TGF-beta, and IFN-gamma) within an ethnically diverse study population comprised of 216 Whites, 58 Blacks, 25 Hispanics, and 31 Asians. Polymorphisms were determined by allele-specific polymerase chain reaction and restriction fragment length analysis. We found striking differences in the distribution of cytokine polymorphisms among ethnic populations. Specifically, significant differences existed between Blacks and both Whites and Asians in the distribution of the polymorphic alleles for IL-2. Blacks, Hispanics and Asians demonstrated marked differences in the inheritance of IL-6 alleles and IL-10 genotypes that result in high expression when compared with Whites. Those of Asian descent exhibited an increase in IFN-gamma genotypes that result in low expression as compared to Whites. In contrast, we did not find significant ethnic-based differences in the inheritance of polymorphic alleles for TNF-alpha. Our results show that the inheritance of certain cytokine gene polymorphisms is strongly associated with ethnicity. These differences may contribute to the apparent influence of ethnicity on allograft outcome.

Diagnosis of avascular necrosis of the hip in asymptomatic HIV-infected patients: Clinical correlation of physical examination with magnetic resonance imaging.

OBJECTIVE: To determine if physical examination can identify avascular necrosis of the hip (AVN) in asymptomatic HIV-infected patients. DESIGN: Prospective, blinded population studyResults: Ten of the 176 patients were positive for AVN by MRI. Four subjects had unilateral disease and six had bilateral disease. Five hips (1.4%) in four patients were indeterminate. We evaluated physical examination maneuvers both singly and in combination. Tests done singly generally provided a higher degree of specificity (67-92%) but sensitivities were lower (0-50%) with all p-values ≥0.08. Positive predictive values based on physical exam, were <17% and negative predictive values were >90% for any single test. Combining all tests gave a high sensitivity (88%) and negative predictive value (98%), but low specificity (34%) and positive predictive value (6%) with p = 0.10. Only two of 16 hips with positive MRI findings showed no abnormalities when all tests were combinedConclusions: This study establishes the limited usefulness of a detailed physical examination of the hip early in the course of AVN. Patients who test negative on physical exam are unlikely to have AVN positive by MRI. Positive findings on physical examination of the hip may help identify patients who need further evaluation by MRI based on overall clinical suspicion.