Continuous Combined Oral Contraceptives Research Articles

Autoimmune progesterone dermatitis: a retrospective case series.

Background:Autoimmune progesterone dermatitis (APD) is a rare hypersensitivity disorder characterized by recurring dermatologic manifestations during the luteal phase of the menstrual cycle in women. Well-defined clinical and diagnostic criteria, outcomes measurements, and standard treatments are lacking.Methods:We performed a single-institution retrospective review of adult patients (older than 20 years at the time of diagnosis) with APD.Results:Fourteen patients were included with mean age of clinical onset of 34.3 ± 7.7 (range 24-54) years. There was a delay of 3.9 ± 5.5 (range 0.4-20) years between the onset of disease symptoms and diagnosis. The onset of APD was after exposure to exogenous progesterone in 9 of 14 patients. Progesterone skin test was performed in 9 patients and 6 were positive. Patients frequently presented with urticaria (9/14, 64.3%) and dermatitis (4/14, 28.6%). Continuous combined oral contraceptives (4/14, 28.6%), gonadotropin-releasing hormone agonist (3/14, 21.4%), and hysterectomy with bilateral salpingo-oophorectomy (2/14, 14.3%) were the most common attempted treatments with reliable outcomes.Conclusions:APD is a rare disorder which lacks universal diagnostic measures and criteria, contributing to a significant delay in diagnosis. Large-scale multicenter studies are needed to develop accurate tests, establish diagnostic criteria, and define treatment outcomes.

Dienogest versus continuous oral levonorgestrel/EE in patients with endometriosis: what’s the best choice?

Objective Combined oral contraceptives (COC) and progestogens are widely used for the treatment of endometriosis. The objective of the study is to compare the efficacy of dienogest 2 mg vs continuous oral levonorgestrel/EE (levonorgestrel 0.1 mg/ethinyl estradiol 0.02 mg) on ovarian endometriomas, deep infiltrating endometriosis (DIE), chronic pelvic pain (CPP), dyspareunia, analgesic use, quality of life (QoL), compliance and side effects. Methods Prospective cohort study. Two cohorts of patients with endometriosis, 50 taking dienogest (group A) and 50 taking continuous levonorgestrel/EE (group B), were evaluated at the beginning of therapy (t0), after 3 (t3) and 6 months (t6). Size of endometriomas, DIE, QoL, pain symptoms, and side effects were assessed. Results Dienogest was significantly effective on CPP (p = .002), dyspareunia (p = .021) ovarian endometriomas (p = .015) and DIE lesions reduction (p = .014). Levonorgestrel/EE was significantly effective on dyspareunia (p = .023). Analgesics consumption significantly decreased in both groups (p < .001). Both treatments significantly improved the QoL. Over 6 months a significant improvement was found, more frequently in patients taking dienogest. The only side effect that both groups complained about was vaginal bleeding, present in the first 3 months of treatment (p < .001). Conclusions Both treatments are effective and safe for patients with endometriosis. Patients compliance and side effects are similar in both groups, however, there was a significantly higher reduction in endometriotic lesions, pain symptoms, and improvement of the QoL in women taking dienogest than in women taking continuous COC.

Autoimmune progesterone dermatitis in the adolescent population.

Autoimmune progesterone dermatitis (APD) is a rare autoimmune hypersensitivity reaction that occurs cyclically at the peak of endogenous progesterone production during the menstrual cycle in women. No study characterizing APD in the adolescent population is found; it appears likely to be underdiagnosed and undertreated. A retrospective, single-center, review of all adolescent and pediatric patients (<20years old at onset) with documented diagnosis of APD. Seventeen adolescent APD patients were included (mean age at diagnosis: 14.4±2years, mean interval of 13.6±11.1months between symptom onset and diagnosis). Twelve patients presented with urticaria, two with fixed drug eruption. Erythema multiforme, eczema, and recurrent aphthous stomatitis were present in one patient each. Exposure to exogenous progestin was present in two patients prior to disease onset. Progesterone skin test was performed in six patients with positive results in two. Fourteen patients received antihistamines and/or a topical corticosteroid. Combined oral contraceptives (COCs) were given to eleven patients, in seven via continuous daily dosing. Gonadotropin-releasing hormone agonist (GnRHa) was used in five, progesterone desensitization in four, omalizumab in two, and danazol in one patient. Adolescent APD is associated with a significant delay in diagnosis. The most common manifestation is urticaria. Exogenous exposure to progestins is uncommon in adolescent APD. Continuous COC, GnRHa, and progesterone desensitization have been used to control symptoms. Large, multicenter studies are required to better define, diagnose, and treat this under recognized condition among adolescent patients.

Bone mass in women with premature ovarian insufficiency: a comparative study between hormone therapy and combined oral contraceptives.

The aim of the study was to evaluate whether combined oral contraceptives (COCs) can be used as hormone therapy (HT) to preserve bone mineral density (BMD) in women with premature ovarian insufficiency (POI). An observational study of women with POI comparing the use of COC (ethinylestradiol 30 μg + levonorgestrel, continuously) with: low-dose HT (continuous conjugated estrogen 0.625 mg plus medroxyprogesterone or continuous estradiol [E2] 1 mg + norethisterone), high-dose HT (continuous conjugated estrogen 1.25 mg + medroxyprogesterone or continuous E2 2 mg + norethisterone), tibolone 2.5 mg, or no treatment. Bone density scans were performed every 2 ± 1 years. The difference between final and initial (delta) BMD values was calculated for the lumbar spine, total femur, and femoral neck. Generalized estimating equations were used to analyze the effect of treatment over time. Variables without normal distribution were transformed into ranks. Overall, 420 scans (210 deltas) of 119 women were analyzed. The women were 30.3 ± 9.2 years old (mean ± SD). BMD deltas at the lumbar spine and total femur were grater in the COC and high-dose HT groups. At the lumbar spine, the differences between two scans were greater in the COC group when compared to low-dose HT group: -0.043 (95% CI -0.062 to -0.024), untreated: -0.056 (-0.080 to -0.032), and tibolone: -0.050 (-0.094 to -0.006) groups. Total femur BMD decreases and the delta were lower in the low-dose HT group -0.038 (-0.052 to -0.024) when compared to COC. Continuous COC was associated with increased BMD in women with POI compared to low-dose HT, with similar improvement in the COC and high-dose HT groups. : Video Summary:http://links.lww.com/MENO/A620.

Patterns in the Management of Endometriosis Among Physicians: A Cross-Sectional Survey [28A

INTRODUCTION: Management of endometriosis is complex and varies among providers. This study investigates patterns in the management of endometriosis among Obstetrics and Gynecology physicians in the United States. METHODS: The Institutional Review Board reviewed and approved this study. A national online survey was sent to 5000 members of the American College of Obstetrics and Gynecology. It included 22 questions designed to assess the medical, surgical, and pain management of endometriosis. Variations in management were assessed using Fisher exact test and Mann-Whitney test. RESULTS: The adjusted response rate was 24.5%. The most common initial treatment for pelvic pain and suspected endometriosis was continuous combined oral contraceptives (COCs) (58%). When medical management fails, 52% of respondents opt for surgical management; 45% of respondents treat with excision while 42% treat with cautery ablation. Most indicated they offer postoperative hormone suppression, including continuous COCs (45%) or gonadotropin-releasing hormone agonists with add-back therapy (27%). The majority prescribe nonsteroidal anti-inflammatory drugs to treat endometriosis-related pain while a minority opt for alternative treatments such as opioids, acupuncture, and psychological support. 82% of physicians believe there is a need for women with endometriosis to have psychosocial care; however, only 15% routinely refer patients for psychological counseling. Importantly, 72% of respondents indicated they do not feel adequately trained to provide care for psychosocial aspects of endometriosis. CONCLUSION: The majority of responding providers are practicing evidence-based care for the treatment of endometriosis. Although most physicians recognize the need for a multidisciplinary approach to the treatment of endometriosis-related pain, only a minority recommend alternative treatments.

Premenstrual Dysphoric Disorder: Contemporary Diagnosis and Management

Most ovulatory women experience premenstrual symptoms (premenstrual syndrome, molimina) which indicate impending menstruation and are of little clinical relevance because they do not affect quality of life. A few women, however, experience significant physical and/or psychological symptoms before menstruation that, if left untreated, would result in deterioration in functioning and relationships. The precise etiology remains elusive, although new theories are gaining support in pre-clinical and early clinical trials. Refined diagnostic criteria allow better discrimination of this condition from other psychiatric diagnoses and the selection of symptom appropriate therapies that afford relief for most women. Pharmacotherapies (particularly selective serotonin reuptake inhibitors and SNRIs) represent the first-line treatment for premenstrual dysphoric disorder and severe, mood-related premenstrual syndrome. Continuous combined oral contraceptives have limited evidence for usefulness in premenstrual dysphoric disorder, whereas medical ovarian suppression is often recommended for patients who fail to respond or cannot tolerate first-line treatments (e.g., selective serotonin reuptake inhibitors). The use of cognitive behavioural therapies is promising, but it remains limited by sparse data and restricted access to trained professionals. A proper diagnosis (particularly the distinction from other underlying psychiatric conditions) is crucial for the implementation of effective therapy and alleviation of this impairing condition.

Treatment of premenstrual dysphoria with continuous versus intermittent dosing of oral contraceptives: Results of a three-arm randomized controlled trial.

Although traditionally dosed combined oral contraceptives (COCs) (21 days of active pills, 7 days of inactive pills) have not been demonstrated as superior to placebo for the treatment of premenstrual dysphoria (PMD), some randomized controlled trials (RCTs) indicate that oral contraceptives administered with a shortened or eliminated hormone-free interval are superior to placebo. However, results of such trials are mixed, and no existing studies have directly compared continuous and intermittent dosing schedules of the same oral contraceptive. The present study compared placebo, intermittent dosing of oral contraceptives, and continuous dosing of contraceptives for the treatment of PMD. Fifty-five women with prospectively confirmed PMD completed a three-arm, RCT in which they were randomized to 3 months of placebo (n = 22), intermittent drospirenone/ethinyl estradiol dosed on a 21-7 schedule (n = 17), or continuous drospirenone/estradiol (n = 16) following a baseline assessment month. All three groups demonstrated similar, robust reductions in premenstrual symptoms over time. A marked placebo response was observed. The study fails to replicate a uniquely beneficial effect of continuous COC on PMD. Additional work is needed to understand the psychosocial context bolstering the placebo response in women with PMD.

Endometriosis, an everlasting challenge.

Endometriosis, an everlasting challenge.

A survey of bonobo (Pan paniscus) oral contraceptive pill use in North American zoos.

Contraception is an essential tool in reproductive management of captive species. The Association of Zoos and Aquariums (AZA) Reproductive Management Center (RMC) gathers data on contraception use and provides recommendations. Although apes have been given oral contraceptive pills (OCPs) for at least 30 years, there have been no published reports with basic information on why the pill is administered, formulations and brands used, and effects on physiology and behavior. Here, we report survey results characterizing OCP use in bonobos (Pan paniscus) housed in North American zoos, as well as information accumulated in the RMC's Contraception Database. Of 26 females treated, there have been no failures and nine reversals. The most commonly administered OCP formulation in bonobos contained ethinyl estradiol (EE) 35 μg/norethindrone 1 mg. Few females on combined oral contraceptives (COCs) were given a continuous active pill regimen; a hormone-free interval of at least 5 days was allowed in most. Crushing the pill and mixing with juice or food was common. Females on COCs seldom experienced breakthrough estrus or bleeding, while these conditions were sometimes observed for females on continuous COCs. All females on COCs exhibited some degree of perineal swelling, with a mean score of 3 or 3+ most commonly reported. Behavioral changes included less sexual behavior, dominant females becoming subordinate, and a negative effect on mood. No appreciable change in weight was noted. Taken together, these results indicate that OCPs are an effective and reversible contraceptive option for bonobos that can be used by zoos and sanctuaries to limit reproduction. Zoo Biol. 35:444-453, 2016. © Wiley Periodicals, Inc.

Combined oral contraceptive treatment for bleeding complaints with the etonogestrel contraceptive implant: a randomised controlled trial

Objective: Estimate symptom improvement rate of women with bleeding complaints using the etonogestrel contraceptive implant when started on continuous combined oral contraceptives (COC).Methods: We conducted a double-blinded randomised controlled trial of women reporting troublesome bleeding related to their etonogestrel contraceptive implant and desiring intervention. Participants received continuous COCs or placebo for four weeks to evaluate self-reported bleeding improvement at four weeks. Participants could continue study treatment or prescribed COCs for another eight weeks if desired. We planned to enroll 130 participants between two sites (80% power to detect a 20% effect size at a 0.05 significance level, with 10% loss to follow up).Results: We closed the study after enrolling 26 participants due to recruitment futility. All women on COCs and 75% of placebo users reported bleeding improvement at four weeks (p = 0.09), with 92% and 42%, respectively, reporting significant improvement (p = 0.03). The median number of days until bleeding stopped for at least four days in COC and placebo users was 1 day (range 1–9) and 4.5 days (range 1–28), respectively (p = 0.63). Eight (75%) COC and five (42%) placebo users opted to continue study treatment (p = 0.41). Despite bleeding improvement, women who desired implant removal at enrollment were more likely to re-request removal than those who initially considered other interventions (3 of 5 [60%] vs 1 of 17 [6%], p = 0.03).Conclusion: Although women who have troublesome bleeding while using the contraceptive implant may experience improvement with no treatment over 4 weeks, women using COCs are more likely to report significant improvement.Clinicaltrials.gov registration number: NCT01963403.

Effect of oral contraceptives and doxycycline on endometrial MMP-2 and MMP-9 activity

ObjectivesTo describe the effect of combined oral contraceptives (COCs) on matrix metalloproteinases MMP-2 and MMP-9 activity and compare MMP activity in women taking a COC with or without doxycycline. Study designSubjects (n=20) underwent endometrial biopsies (1) in the late luteal phase of a baseline cycle prior to initiating COCs, (2) on days 19–21 while taking COCs in a standard 28-day cycle (7-day hormone-free interval) and (3) on days 26–28 while taking active COCs continuously for a 28-day cycle. During the continuous COC cycle, they were randomized to receive daily subantimicrobial dose doxycycline 40mg or placebo. ResultsCompared to baseline, COC treatment increased MMP-2 (p<.001) and MMP-9 (p<.001). MMP activity was lower in subjects taking a COC with doxycycline compared to those receiving placebo although only significantly lower for MMP-2 latent form (p=.002). ConclusionsUnscheduled bleeding with COCs may be the result of increased endometrial MMPs. Sample size limitations prevent us from determining how doxycycline affects MMP activity in COC users.

Menstrual suppression for adolescents.

The purpose of this review is to highlight the recent literature and emerging data describing clinical situations in which menstrual suppression may improve symptoms and quality of life for adolescents. A variety of conditions occurring frequently in adolescents and young adults, including heavy menstrual bleeding, and dysmenorrhea as well as gynecologic conditions such as endometriosis and pelvic pain, can safely be improved or alleviated with appropriate menstrual management. Recent publications have highlighted the efficacy and benefit of extended cycle or continuous combined oral contraceptives, the levonorgestrel intrauterine device, and progestin therapies for a variety of medical conditions. This review places menstrual suppression in an historical context, summarizes methods of hormonal therapy that can suppress menses, and reviews clinical conditions for which menstrual suppression may be helpful.

Abstract 5575: Effects of continuous combined oral contraceptives on mouse mammary gland structure and tumor progression

Abstract The breast goes through cycles of cell growth, differentiation and regression with every estrous/menstrual cycle, driven by hormonal stimulation followed by hormone withdrawal. The number of cycles over a lifetime is positively associated with breast cancer risk. This increased risk may be the result of hormone-stimulated epithelial growth, inflammatory tissue remodeling processes during hormone withdrawal, or both. The use of cyclic combined oral contraceptives (cyclic COC), which incorporates a hormone withdrawal period in each cycle, has been associated with an increased risk of breast cancer, particularly in African American women, current COC users, and women who initiated COC use early in life. In contrast, the effect of extended-use (i.e., continuous) COC on breast cancer risk has not been evaluated. The purpose of the current study was to test the hypothesis that continuous exposure to COC is not associated with the increased risk observed with cyclic COC, and may even provide protection against breast cancer, by removal of the hormone withdrawal phase. Starting at day 50 of age (to mimic COC exposure in young women), BALB/C mice were fed liquid diets +/- supplementation with 0.0041 mg/kg ethinyl estradiol and 0.0185 mg/kg levonorgestrel (dose calculated by surface area conversion from the human COC dose of 20 µg ethinyl estradiol and 90 µg levonorgestrel). After 28 days, 10 mice per group were sacrificed and mammary glands dissected for whole mount and histologic analysis. An additional 20 mice per group were injected orthotopically with 10e5 syngeneic TM2H mammary epithelial tumor cells, and tracked for tumor latency, growth and tumor burden. The extended COC group showed 65% increase in mammary gland epithelial density compared to control. However, this increased epithelial density was associated with an increased alveolar branching and a decrease in carcinogen-sensitive terminal end buds. These results suggest that short term exposure to continuous COC can induce a more differentiated state in nonparous mouse mammary glands. In mice transplanted with tumor cells, the continuous COC group showed significantly increased tumor latency and decreased tumor burden, compared to controls. These results demonstrate that continuous COC administration, despite the higher levels of hormone exposure, can render the mouse mammary gland less susceptible to the growth of transplanted tumor cells. Mechanistic studies are ongoing. Citation Format: Evelyn Esteves, Sherin David, Dawn Bowers, Brian MacQueen, Melanie Ruszczyk, Dhruv Chachad, Rajani Marthappa Shenoy, Patricia A. Masso-Welch. Effects of continuous combined oral contraceptives on mouse mammary gland structure and tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5575. doi:10.1158/1538-7445.AM2014-5575

Severe Hyperandrogenemia and Insulin Resistance in a 12-Year-Old Girl

BackgroundSigns of androgen excess are common complaints of adolescents and young adults. Rapid onset/progression of hyperandrogenism or virilization should prompt further investigation to exclude an androgen-secreting tumor. CaseWe report the case of an obese young adolescent girl who presented with hirsutism, deepened voice, oligomenorrhea, marked acanthosis nigricans, and rapidly increasing testosterone and insulin levels. Imaging studies were negative for both ovarian and adrenal masses. She was successfully treated with continuous combined oral contraceptives. Investigation, treatment, and outcome are reviewed. Summary and ConclusionThis case demonstrates that patients with PCOS may present with a testosterone > 200 ng/dL and that severe hyperinsulinemia can be associated with rapid progression of hyperandrogenism.

Oral contraceptives in migraine therapy

Even if sometimes combined oral contraceptives (COCs) can initiate or aggravate headaches, in particular migraine, the headaches generally tend to improve after the first months of COC use. If migraine persists, in many patients the attacks are more likely to occur during the pill-free week, and an oral contraceptive-induced menstrual migraine (OCMM) occurs. In case of OCMM, some hormonal manipulations are available, by eliminating or reducing the hormone-free interval (HFI), in order to prevent this estrogen-withdrawal headache. It is possible to use a continuous COCs regimen, to shorten the HFI to less than the traditional 7days, to use a low-dose estrogen supplementation after the 21days of COCs or to prescribe a progestogen-only pill (POP). Interestingly, the use of a POP is a safe option also for women suffering from migraine with aura (in which COCs are absolutely contraindicated) and a recent trial suggests that its use can reduce the frequency of migraine attacks and the duration of aura symptoms too.

Evaluation of extended and continuous use oral contraceptives.

Oral contraceptives are classically given in a cyclic manner with 21 days of active pills followed by 7 days of placebo. In the past 4 years, new oral contraceptives have been introduced which either shorten the placebo time, lengthen the active pills (extended cycle), or provide active pills every day (continuous). These concepts are not new; extended and continuous pills were first studied in the 1960s and 1970s and have been provided in an off-label manner by gynecologists to treat menstrual disorders, such as menorrhagia and dysmenorrhea, and gynecologic disorders, such as endometriosis. Now that extended and continuous combined oral contraceptives are available for all patients, it is critical for providers to understand the physiology, dosing, side effects, and benefits of this form of oral contraceptive. This article reviews the history and the potential uses of the new continuous combined oral contraceptive.

Puberty menorrhagia secondary to inherited bleeding disorders

The first patient, an 18-year-old girl suffering from Fechtner syndrome with macrothrombocytopenia, deafness and end-stage renal failure, required peritoneal dialysis and long-term steroid therapy. Her platelet count remained below 50 × 109/L despite splenectomy. She developed irregular and prolonged menstrual bleeding 1 year after her menarche, which was initially controlled with combined oral contraceptives (COC). At age 16, her periods became heavy and prolonged, resulting in severe anemia despite repeated transfusion. As her condition could not be controlled, total abdominal hysterectomy was eventually performed. The operation was complicated by subrectus hematoma, which subsided spontaneously. The second patient was a 14-year-old girl who developed prolonged and heavy menstrual flow 2 years after menarche. She had intracranial hemorrhage secondary to factor VII deficiency soon after birth, resulting in right hemiparesis, complex partial seizures and mild mental deficiency. She had severe bleeding from the mucous membrane requiring frequent and repeated hospitalization, plasma transfusion and recombinant factor VIIa infusion. Her menstruation was very heavy and difficult to control, and a 6-month course of subcutaneous injection of gonadotropin-releasing hormone analog (GnRH-a) had to be given to suppress menstruation. Her subsequent menstruation was still uncontrollable despite repeated intravenous injection of conjugated estrogen and transfusion of clotting factors. She finally underwent a hysterectomy and the operation was uneventful. Both Fechtner syndrome and factor VII deficiency are rare types of inherited coagulation disorders with intractable spontaneous mucous membrane type of bleeding. Fechtner syndrome is characterized by macrothrombocytopenia while factor VII deficiency is paradoxically associated with thrombosis. There is no effective curative treatment and the control of bleeding requires the replenishment of the deficient coagulation factors. These factors have a very short half-life, requiring repeated and frequent infusion. Bleeding disorder is a relatively common cause of menorrhagia in adolescent girls and management is difficult as the underlying coagulation problem can only be temporarily and partially corrected (1,2). Medical treatment is unlikely to work unless long-term amenorrhea can be achieved. Although amenorrhea can be achieved with continuous COC, breakthrough bleeding is common and can be heavy. The presence of epilepsy and the increased risk of thrombosis in the second patient further complicated its use. Depo-Provera should not be used as it requires intramuscular injection. Danazol carries significant androgenic side-effects, and is not tolerated by adolescent girls. GnRH-a therapy is effective in producing amenorrhea. However, suppression of sex hormone production hinders secondary sexual development and causes exaggerated osteoporosis in adolescent girls. Although “add-back” therapy may minimize the risk of osteoporosis, its effect on secondary sexual development is unknown, especially when the ideal dosage for adolescents has not been delineated (3). Although the levonorgestrel intrauterine system (LNG-IUS) can induce amenorrhea, the initial prolonged breakthrough bleeding can be heavy in patients with coagulation disorder. The relatively large size of the device also makes it inappropriate for the small uterus in adolescents. Its use is not advisable in patients on long-term steroid therapy as in our first patient. Endometrial ablation is also not an ideal treatment option as complete amenorrhea occurs in only 60% of cases, and the rate tends to decrease with time and recurrence rate is high in young girls (4). Moreover, pregnancy is contraindicated after the procedure and is associated with significant risk of postabortal or postpartum hemorrhage. Despite the immediate surgical risk, hysterectomy appears to be the only effective treatment of choice in this situation. Increased risk of bleeding is the major concern (5), but this can be minimized by perioperative transfusion of platelet concentrates, fresh frozen plasma and clotting factor as indicated. The operation should be performed by experienced surgeons with meticulous control of bleeding. Although laparoscopic surgery is reported to be associated with minimal bleeding, it is not clear whether the use of electrosurgery can control bleeding adequately in a patient with coagulation defect. We chose to perform the operation by the conventional method as it allows suture ligation to ensure adequate hemostasis. The management of severe menorrhagia in adolescents secondary to coagulation disorder carries a therapeutic dilemma. Both clinicians and patients are reluctant to resort to hysterectomy at this young age despite the lack of effective long-term treatment. When curative therapy for the underlying disorder is unavailable, hysterectomy should be considered early to avoid the risk of bleeding and to improve the quality of life.

Continuous combined oral contraceptives: results of a randomized controlled trial.

Objective: Administration of continuous combined estrogen/progestin oral contraceptives (OC) has the potential to improve contraceptive efficacy while eliminating the inconvenience of menstruation and minimizing the development or progression of certain gynecologic disorders. The purpose of this pilot study was to compare patient acceptability and side effects of OC administered in an intermittent versus continuous fashion.