Faculty Bibliography

Abnormal uterine bleeding in women older than age 40 years, and certainly in menopausal patients, mandates evaluation, mainly to exclude cancer and hyperplasia, but also to better diagnose the source of the bleeding to appropriately manage the patient. In the past, dilation and curettage was the mainstay of diagnosis. This gave way to in-office suction pump-generated biopsies. Most recently, disposable biopsy instruments with their own internal piston to generate suction have become the standard of care. Rarely has such a technique received such widespread acceptance with such limited validation. Transvaginal ultrasonography, when technically feasible, is a noninvasive way to image the endometrial cavity. Saline-infusion sonohysterography is a subset of transvaginal ultrasonography reserved for patients in whom an adequate endometrial echo is not seen or when an endometrial echo is seen but not sufficiently thin. Appropriate understanding and use of transvaginal ultrasonography and addition of sonohysterography when necessary can allow a clinical algorithm that can triage patients with abnormal uterine bleeding to (1)no anatomic pathology best treated expectantly; (2)a global endometrial process, in which case random blind endometrial sampling is appropriate; or (3)a focal endometrial abnormality in which case endometrial sampling should be done with the visualization offered by hysteroscopy. Newer disposable office hysteroscopes finally allow office hysteroscopy to be done as a truly "point-of-care option." Finally, the incidence of thick endometrial echo found incidentally in postmenopausal women with no bleeding is extremely high (10-17%)and should not trigger automatic invasive endometrial evaluation.

BACKGROUND:The Surveillance, Epidemiology, and End Result (SEER) database shows a variable increase in endometrial cancer incidence over time. The objective of this review was to examine published endometrial cancer rates and potential etiologies. METHODS:Endometrial cancer incidence was obtained from the SEER Program database from 1975 through 2014, and a test for trend in incidence was calculated. Changes in risk factors thought to be associated with endometrial cancer, including age, obesity, diabetes, diet and exercise, reproductive factors, and medications (hormone therapy [HT] including Food and Drug Administration [FDA]-approved and non-FDA-approved [compounded] estrogens and progestogens, tamoxifen, and hormonal contraceptives) were found through PubMed searches. Temporal trends of risk factors were compared with endometrial cancer trends from SEER. RESULTS:Although endometrial cancer rates were constant from 1992 to 2002 (women 50-74 years of age), they increased 2.5% annually with a 10% increase from 2006 to 2012 (trend test 0.82). Use of approved prescription estrogen-progestogen combination products decreased after the publication of the Women's Health Initiative (WHI) data, whereas other risk factors either remained constant or decreased during the same time; however, compounded bioidentical HT (CBHT) use increased coincident with the endometrial cancer increase. CONCLUSION/CONCLUSIONS:Endometrial cancer rate increases after the first publication of WHI data in 2002 may be associated with the decreased use of approved estrogen-progestogen therapy, the increase in CBHT use, and the prevalence of obesity and diabetes; potential relationships require further evaluation.

OBJECTIVE:To evaluate the safety and efficacy of ospemifene for the treatment of moderate to severe vaginal dryness in postmenopausal women with vulvovaginal atrophy (VVA). METHODS:This 12-week, multicenter, double-blind phase 3 study randomized postmenopausal women (aged 40-80 years) with VVA and moderate to severe vaginal dryness as their most bothersome symptom to daily oral ospemifene 60 mg or placebo. Coprimary efficacy endpoints included changes from baseline to week 12 in percentages of vaginal parabasal and superficial cells, vaginal pH, and vaginal dryness severity with ospemifene versus placebo; other secondary endpoints were evaluated (weeks 4, 8, and 12). Safety was assessed by treatment-emergent adverse events (TEAEs) and endometrial biopsies. RESULTS:Women (n = 631; ospemifene [n = 316], placebo [n = 315]) had a mean age of 59.8 years, a mean body mass index of 27.2 kg/m, and most were white. Ospemifene significantly improved (P < 0.0001) the percentages of parabasal and superficial cells, vaginal pH, and severity of vaginal dryness severity compared with placebo at week 12; significant between-group differences were noted by week 4. Secondary endpoints of dyspareunia (P < 0.001), maturation value (P < 0.0001), and the Female Sexual Function Index (P < 0.05) also significantly improved with ospemifene versus placebo at week 12. Significantly more women responded (31.5% vs 6.0%; P < 0.0001) or were satisfied (49.2% vs 33.8%; P = 0.0007) with ospemifene versus placebo at week 12. No unexpected TEAEs, treatment-related serious TEAEs, thrombotic events, or endometrial hyperplasia or carcinoma were observed. CONCLUSIONS:Ospemifene was effective and well tolerated for the treatment of moderate-to-severe vaginal dryness in postmenopausal women with VVA.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

Background/UNASSIGNED:Endometrial adenocarcinoma is the most prevalent type of endometrial cancer. Diagnostic codes to identify endometrial adenocarcinoma in administrative databases, however, have not been validated. Objective/UNASSIGNED:To develop and validate an algorithm for identifying the occurrence of endometrial adenocarcinoma in a health insurance claims database. Methods/UNASSIGNED:To identify potential cases among women in the HealthCore Integrated Research Database (HIRD), published literature and medical consultation were used to develop an algorithm. The algorithm criteria were at least one inpatient diagnosis or at least two outpatient diagnoses of uterine cancer (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) 182.xx) between 1 January 2010 and 31 August 2014. Among women fulfilling these criteria, we obtained medical records and two clinical experts reviewed and adjudicated case status to determine a diagnosis. We then estimated the positive predictive value (PPV) of the algorithm. Results/UNASSIGNED:The PPV estimate was 90.8% (95% CI 86.9-93.6), based on 330 potential cases of endometrial adenocarcinoma. Women who fulfilled the algorithm but who, after review of medical records, were found not to have endometrial adenocarcinoma, had diagnoses such as uterine sarcoma, rhabdomyosarcoma of the uterus, endometrial stromal sarcoma, ovarian cancer, fallopian tube cancer, endometrial hyperplasia, leiomyosarcoma, or colon cancer. Conclusions/UNASSIGNED:An algorithm comprising one inpatient or two outpatient ICD-9-CM diagnosis codes for endometrial adenocarcinoma had a high PPV. The results indicate that claims databases can be used to reliably identify cases of endometrial adenocarcinoma in studies seeking a high PPV.

The loss of sex steroids (e.g. estradiol, dehydroepiandrosterone [DHEA], progesterone) that causes menopause commonly affects a woman's general health and produces bothersome physical changes that may interfere with normal sexual and genitourinary functioning. Although both over-the-counter and prescription treatments are available, there remains a large unmet need, as less than 10% of women are treated. Adrenal DHEA and its sulfate are the most abundant steroids in humans. Here we review the development of intravaginal prasterone, the synthetic equivalent to endogenous DHEA. Prasterone is approved by the US Food and Drug Administration for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. Prasterone has been shown to decrease the pain associated with dyspareunia, and to improve vaginal pH, as well as superficial and parabasal cell counts, while maintaining serum hormone levels within the range of those seen in normal postmenopausal women. Unlike other menopausal prescription therapies, intravaginal prasterone does not carry a boxed warning, thus allowing the clinician and patient to engage in meaningful and reassuring discussion around a new approach that treats this common, debilitating condition.

: In clinical practice, although only 3% to 7% of women with postmenopausal bleeding (PMB) will ultimately be found to have cancer, it is the clinician's responsibility to ensure that endometrial cancer is not present. The diagnostic evaluation of PMB has evolved greatly. This Practice Pearl addresses the appropriate evaluation of women with PMB.

Objective: Genitourinary syndrome of menopause (GMS), comprising vulvovaginal atrophy (VVA), impacts the health and quality of life of postmenopausal women. Genital symptoms of VVA include vaginal dryness as a most bothersome symptom (MBS) which over time leads to sexual dysfunction and emotional distress and remains a condition of unmet need. The objective of the study was to evaluate the safety and efficacy of ospemifene, an oral, selective estrogen receptor modulator and nonhormonal option, for the treatment of vaginal dryness as the MBS of postmenopausal women with VVA.
Design(s): This Phase 3, multicenter, randomized, double-blind, placebo-controlled study assessed the efficacy and safety of ospemifene in menopausal women with vaginal dryness as MBS of VVA. Eligible subjects were postmenopausal, age 40-80 with moderate to severe vaginal dryness as a self-reported MBS of VVA. Subjects were randomized dryness) and female sexual function index (FSFI).
Result(s): 631 subjects were enrolled into the study and included in the intention-to-treat (ITT) population (ospemifene=316; placebo=315). The differences between treatment groups in change from baseline to Week 12 for each of the co-primary efficacy endpoints were statistically significant (p < 0.0001). These differences between treatment groups for co-primary endpoints were change from baseline at Week 4, 8, and 12 were the response variable. Other endpoints evaluated included vaginal pain associated with sexual activity, percentage of responders (a composite of increase from baseline of >= 10 in maturation value, decrease of >= 0.5 in vaginal pH, and decrease of >= 1 in categorical score for severity of MBS of vaginal dryness) and female sexual function index (FSFI).
Result(s): 631 subjects were enrolled into the study and included in the intention-to-treat (ITT) population (ospemifene=316; placebo=315). The differences between treatment groups in change from baseline to Week 12 for each of the co-primary efficacy endpoints were statistically significant (p < 0.0001). These differences between treatment groups for co-primary endpoints were observed as early as Week 4 and continued through Weeks 8 and 12. The severity of vaginal pain associated with sexual activity, among the other VVA symptoms assessed, also showed a significantly greater reduction from baseline in the ospemifene group compared to placebo by week 12. The percentage of responders significantly increased in the ospemifene group compared to placebo at weeks 4 and continued through weeks 8 and 12 with a statistically significant increase in the FSFI score in the ospemifene group at week 12. In the safety population, overall treatment-emergent AEs (TEAE) were reported within Week 12 for 35.3% of subjects in the ospemifene group and 33.3% of subjects in the placebo group. There were no TEAEs of deep vein thrombosis or breast cancer, and no deaths. Consistent with previous trials, subjects with intact uteri showed a slight mean endometrial thickening with ospemifene treatment; a mean increase of 0.63 mm in the ospemifene group compared to a mean decrease of 0.23 mm in the placebo group. No cases of endometrial hyperplasia or carcinoma were observed.
Conclusion(s): The results of this double-blind, randomized, placebo-controlled Phase 3 trial support that ospemifene 60 mg daily may be efficacious and safe in the treatment of moderate or severe vaginal dryness as the MBS of VVA. Ospemifene demonstrated statistically significant superiority over placebo for all co-primary efficacy endpoints by Week 12. The effectiveness of ospemifene was evident at week 4 and maintained through the study at Weeks 8 and 12. Endometrial findings at 12 weeks showed slight increase in endometrial thickness and no cases of hyperplasia or carcinoma

Ultrasound is the most commonly used imaging technique for the evaluation of ovarian and other adnexal lesions. The interpretation of sonographic findings is variable because of inconsistency in descriptor terminology used among reporting clinicians. The use of vague terms that are inconsistently applied can lead to significant differences in interpretation and subsequent management strategies. A committee was formed under the direction of the ACR initially to create a standardized lexicon for ovarian lesions with the goal of improving the quality and communication of imaging reports between ultrasound examiners and referring clinicians. The ultimate objective will be to apply the lexicon to a risk stratification classification for consistent follow-up and management in clinical practice. This white paper describes the consensus process in the creation of a standardized lexicon for ovarian and adnexal lesions and the resultant lexicon.

Challenges intrinsic to the accurate diagnosis of endometriosis contribute to an extended delay between the onset of symptoms and clinical confirmation. Intraoperative visualization, preferably with histologic verification, is considered by many professional organizations to be the gold standard by which endometriosis is diagnosed. Clinical diagnosis of symptomatic endometriosis via patient history, physical examination, and noninvasive tests is easy to perform but generally viewed as less accurate than surgical diagnosis. Technological advances and increased understanding of the pathophysiology of endometriosis warrant continuing reevaluation of the standard method for diagnosing symptomatic disease. A review of the published literature was therefore performed with the goal of comparing the accuracy of clinical diagnostic measures with that of surgical diagnosis. The current body of evidence suggests that clinical diagnosis of symptomatic endometriosis is more reliable than previously recognized and that surgical diagnosis has limitations that could be underappreciated. Regardless of the methodology used, women with suspected symptomatic endometriosis would be well served by a diagnostic paradigm that is reliable, conveys minimal risk of under-diagnosis or over-diagnosis, lessens the time from symptom development to diagnosis, and guides the appropriate use of medical and surgical management strategies.