Clinical characteristics of endometrioma with and without dysmenorrhea diagnosed by laparoscopy: A retrospective cohort study in a tertiary center.

OBJECTIVE: Clinical characteristics of patients with endometrioma without dysmenorrhea have not been well delineated; our goal was to remedy this issue by performing a retrospective cohort study. METHODS: A total of 379 patients who underwent laparoscopic surgery for endometrioma ≥4 cm at a tertiary hospital were included in this retrospective study. Patients were divided into two groups based on the presence of dysmenorrhea at the time of hospital visit; with dysmenorrhea group and without dysmenorrhea group. RESULTS: Patients without dysmenorrhea comprised 9.5% of all surgically confirmed endometriomas. Significant differences were found in the revised American Society for Reproductive Medicine (rASRM) stage, age at surgery, and bilaterality. Patients with rASRM stage IV were more likely to have dysmenorrhea than were subjects with rASRM stage III (odds ratio (OR), 10.58; 95% confidence interval (CI), 4.63-24.21; P < 0.001). Older patients were less likely to have dysmenorrhea (OR, 0.94; 95% CI, 0.88-1.00; P = 0.045), as were patients with bilateral rather than unilateral endometrioma (OR, 0.36; 95% CI, 0.15-0.82; P = 0.015). No significant differences in cyst size, age at menarche, body mass index (BMI), parity, or history of previous ovarian surgery were found between the two groups. CONCLUSION: Patients without dysmenorrhea comprised 9.5% of endometrioma cases and had less advanced rASRM stage, were older at surgery, and had a higher probability of bilateral than unilateral endometrioma than patients with dysmenorrhea.

Dienogest attenuates STAT3 activation in ovarian endometriotic cysts.

OBJECTIVE: Recent studies have suggested that endometriosis could be the result of excessive activation of signal transducer and activator of transcription 3 (STAT3), which is associated with the regulation of essential cellular mechanisms such as proliferation, invasion, and apoptosis. That finding implies that regulating STAT3 activation could play a key role in treating endometriosis. In the present study, we aimed to evaluate whether the anti-endometriotic effects of dienogest is mediated by the regulation of STAT3 activation. STUDY DESIGN: STAT3 activation was evaluated in normal endometrial and ovarian endometriotic tissues obtained from patients with/without preoperative dienogest treatment. A subsequent in vitro analysis with endometriotic cyst stromal cells (ECSCs) was used to confirm the direct influence of dienogest in STAT3 activation. RESULT: STAT3 activation is significantly higher in endometriotic tissues from non-treated patients than in normal endometrial tissues, and that difference is reversed by preoperative administration of dienogest. Similarly, the inhibitory effects of dienogest on STAT3 activation are demonstrated by in vitro results showing that dienogest treatment significantly inhibits IL-6-stimulated STAT3 activation in cultured ECSCs. That inhibition was accompanied by decreased expression of proliferative (PCNA), invasive (MMP-2), and anti-apoptotic (BCL-2) proteins. Furthermore, downregulating STAT3 activity with siRNA decreased PCNA, MMP-2, and BCL-2 expression in IL-6-treated ECSCs. CONCLUSION: Dienogest inhibits STAT3 activation in ECSCs, which affects their proliferation, invasiveness, and apoptosis.

Different effects of menopausal hormone therapy on non-alcoholic fatty liver disease based on the route of estrogen administration.

The effects of menopausal hormone therapy (MHT) on non-alcoholic fatty liver disease (NAFLD) were compared based on the route of estrogen administration. The study included 368 postmenopausal women who received MHT for 12 months. Patients were divided into transdermal (n = 75) and oral (n = 293) groups based on the estrogen route. Changes in the prevalence of NAFLD were compared between the two groups before and after 12 months of MHT. In addition, differences in the progression of NAFLD after MHT based on the dose of estrogen and type of progestogen were evaluated in the oral group. After MHT, the prevalence of NAFLD decreased from 24 to 17.3% in the transdermal group but increased from 25.3 to 29.4% in the oral group. Little or no change was found in clinical characteristics and laboratory tests in the transdermal group during MHT. However, serum levels of total cholesterol and low-density lipoprotein cholesterol decreased and triglycerides and high-density lipoprotein cholesterol increased significantly in the oral group. Furthermore, changes in the prevalence of NAFLD were not significantly different based on the dose of estrogen or type of progestogen. Our findings indicate that transdermal estrogen can be beneficial in terms of NAFLD progression.

Clinical Characteristics of Gynecologic Problems During Childhood in the Korean Population.

BACKGROUND: This study analyzed common gynecologic problems among Korean patients younger than ten years. METHODS: We performed a retrospective analysis of medical records of patients younger than ten years who visited the Pediatric and Adolescent Gynecology Clinic at Samsung Medical Center between 1995 and 2020. RESULTS: Among the 6,605 patients who visited the Pediatric and Adolescent Gynecology Clinic, data from 642 patients younger than ten years were analyzed in this study. The most common chief complaint was genital anomalies, followed by increased vaginal discharge and abnormal findings on clinical examinations. The most common disease entity was agglutination of the labia minora, which was commonly discovered incidentally during routine screenings. Vulvovaginitis, the second most common disease, was identified by symptoms of vaginal discharge, pruritus, and vaginal spotting. Neoplasm, issues with vaginal bleeding, and "other causes" were additional categories of gynecologic problems. 245 patients (38.2%) were referred from primary care sources, 175 patients (27.4%) sought care directly at the clinic, 169 patients (26.3%) were referrals from the institution's pediatric department, and the remainder were referrals from other departments. CONCLUSION: This study provides information about the gynecologic problems most frequently encountered in pediatric patients. The study provides helpful insight for primary care physicians into the proper management and timing of referrals for these gynecologic problems of pediatric patients.

Comparison of goserelin and leuprorelin for ovarian protection during chemotherapy in young patients with breast cancer.

PURPOSE: Although different gonadotropin-releasing hormone (GnRH) agonists may have different effects, their effect of ovarian protection during chemotherapy for breast cancer has not been compared. This study aimed to compare the effects of goserelin and leuprorelin for ovarian protection during chemotherapy in young patients with breast cancer. METHODS: This prospective study analyzed 193 patients with breast cancer aged ≤ 40 years who had regular menstruation and serum anti-Müllerian hormone (AMH) levels ≥ 1 ng/mL before treatment. Patients received either goserelin or leuprorelin for ovarian protection during doxorubicin/cyclophosphamide-based chemotherapy. Resumption of menstruation and changes in serum levels of AMH were compared between the two groups at 12 months after completion of chemotherapy. RESULTS: The mean age and the pretreatment serum AMH level were 33.2 years and 4.4 ng/mL in goserelin group and 34.2 years and 4.0 ng/mL in leuprorelin group. The proportion of patients who resumed menstruation was not different between the goserelin (94.4%) and leuprorelin (95.3%) groups at 12 months after chemotherapy completion. Serum AMH levels decreased significantly in both the goserelin (from 4.4 to 1.2 ng/mL) and leuprorelin (from 4.0 to 1.2 ng/mL) groups, with no statistical significance. In addition, no difference was found in the proportion of patients with serum AMH levels ≥ 1 ng/mL between the goserelin (49.5%) and leuprorelin (44.2%) groups at 12 months after chemotherapy. CONCLUSION: Goserelin and leuprorelin were comparable in terms of ovarian protection during doxorubicin/cyclophosphamide-based chemotherapy in young patients with breast cancer.

Efficacy of Post-Operative Medication to Prevent Recurrence of Endometrioma: Cyclic Oral Contraceptive (OC) After Gonadotropin-Releasing Hormone (GnRH) Agonist Versus Dienogest.

BACKGROUND: There are several medical treatment options for endometrioma. Progestin, especially dienogest, is an effective drug for preventing recurrence of endometrioma after surgery. Additionally, oral contraceptive (OC) use after conservative surgery has been reported to reduce significantly the risk of endometrioma recurrence. The aim of this study was to compare the long-term effects of gonadotropin-releasing hormone (GnRH) agonist followed by OC to those of dienogest alone to prevent recurrence of endometrioma after laparoscopic surgery. METHODS: A retrospective cohort study was performed on patients who underwent conservative laparoscopic surgery for endometrioma between January 2000 and December 2020, in the Endometriosis Clinic, Department of Gynecology, Samsung Medical Center. A total of 624 patients who received medical treatment at least six months after laparoscopic conservative surgery for endometrioma was included. Among them, 372 patients used OC after GnRH agonist therapy, and 252 patients used dienogest. Within the OC group, 148 used a 21/7 regiment and 224 used a 24/4 regimen. A cumulative endometrioma recurrence curve was presented using the Kaplan-Meier method to compare the recurrence of those groups. RESULTS: The cumulative recurrence rate of endometrioma for 60 months was 2.08% (n = 4) in the OC after GnRH agonist group and 0.40% (n = 1) in the dienogest group. There was no statistical difference in cumulative recurrence of endometrioma between the two groups. In subgroup analysis, the cumulative recurrence rate of endometrioma over 60 months was 4.21% (n = 2) in the 21/7 OC group and 1.09% (n = 2) in the 24/4 OC group and showed no significant difference. CONCLUSION: Long-term use of OC after GnRH agonist as well as that of dienogest treatment are effective postoperative medical therapies for preventing endometrioma recurrence. Thus, the choice of regimen can be individualized or used interchangeably depending on patient condition, need for contraception, and compliance with drug therapy.

Early menopause is associated with increased risk of retinal vascular occlusions: a nationwide cohort study.

This nationwide population-based cohort study evaluated the association between female reproductive factors and the incidence of retinal vein occlusion (RVO) and retinal artery occlusion (RAO) using data provided by the Korea National Health Insurance Service. A total of 2,289,347 postmenopausal women over 50 years of age who participated in both national health screening and cancer screening in 2013 or 2014 were included. Data on female reproductive factors, including age at menarche, age at menopause, parity, history of hormone replacement therapy, and oral contraceptive pill usage, were collected. Patients were followed up until December 2018, and incident cases of RVO and RAO were identified using registered diagnostic codes from claim data. During an average follow-up period of 4.90 years, 7461 and 1603 patients were newly diagnosed with RVO and RAO, respectively. In the multivariable-adjusted Cox proportional hazard model, patients who experienced menopause after 55 years of age had a lower risk of RVO and RAO development compared to those who had menopause before 45 years of age, with a hazard ratio (95% confidence interval) of 0.83 (0.76-0.95) for RVO and 0.80 (0.66‒0.98) for RAO. In conclusion, early menopause was an independent risk factor for future development of RVO and RAO.

Inhibition of the NLRP3 inflammasome by progesterone is attenuated by abnormal autophagy induction in endometriotic cyst stromal cells: implications for endometriosis.

The NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a cytosolic multi-protein complex that induces inflammation and is known to be regulated negatively by autophagy. Previous studies reported an abnormal induction of autophagy linked to progesterone resistance in human endometriotic cells. Therefore, an aberrant autophagy induction response to progesterone might contribute to the altered inflammatory response observed in endometriotic tissues. To evaluate this hypothesis, we elucidate whether regulation of the NLRP3 inflammasome by ovarian steroids is mediated by autophagy in human endometrial stromal cells (normal endometrial stromal cells (NESCs)) from patients with uterine leiomyoma (presumed normal) and whether abnormal autophagy induction in endometriotic cyst stromal cells (ECSCs) affects NLRP3 inflammasome-induced interleukin-1ß (IL-1ß) production. Our results show that estrogen enhanced NLRP3 inflammasome activation in NESCs, resulting in increased IL-1ß production. Progesterone decreased NLRP3 inflammasome activity with an increase in autophagy induction in estrogen-treated NESCs. Inhibition of NLRP3 inflammasome activity by progesterone was blocked by autophagy inhibition. However, progesterone failed to change NLRP3 inflammasome activity and autophagy induction in estrogen-treated ECSCs. In contrast, dienogest, a specific progesterone receptor agonist, reduced NLRP3 inflammasome-mediated IL-1ß production through autophagy induction in ECSCs. Furthermore, autophagy induction was decreased and NLRP3 inflammasome activity was increased in endometriotic tissues, which was reversed by preoperative administration of dienogest. In conclusion, our results suggest that progesterone inhibits NLRP3 inflammasome activation through autophagy in endometrial stromal cells. However, this inhibitory effect is attenuated in endometriotic stromal cells due to an aberrant autophagic response to progesterone, which could lead to an altered inflammatory response in endometriosis.

Appropriate Age for Height Control Treatment in Patients With Marfan Syndrome.

Objective: This study aimed to determine the most appropriate age for height control treatment in patients with Marfan syndrome (MFS). Materials and Methods: This retrospective study included patients with MFS who underwent height control treatment with estradiol valerate. The estrogen dose was increased according to the height change. The cut-off age for the maximum difference between the expected height and actual final height was evaluated. Results: Seventeen patients were included in this study. The difference between the height predicted by the growth curve and the final height (gcHtD) and that predicted by the bone age and the final height (baHtD) was the largest in the 10.5 years age group (p=0.0045 and p=0.0237, respectively). The gcHtD was 10.6 (10.2, 13.5) cm for patients aged ≤10.5 years, whereas it was 0.6 (-3.65, 5.85) cm for patients aged >10.5 years. The baHtD was 10.1 (7.31, 11.42) cm for patients aged ≤10.5 years, while it was 3.83 (0.84, 6.4) cm for patients aged >10.5 years. When height change was observed for a minimum of 6 months after completion of estrogen treatment, the average growth was 0.6 (0.2, 2.1) cm. Conclusion: Initiating height control treatment before the age of 10.5 years is effective in female patients with MFS.

Effect of Tissue-Selective Estrogen Complex on Hip Structural Geometry in Postmenopausal Women: A 12-Month Study.

Background: Hip structural analysis (HSA) is a method for evaluating bone geometry reflecting bone structural and biomechanical properties. However, tissue-selective estrogen complex (TSEC) treatment effects on HSA have not been investigated. Objective: This study was performed to evaluate the effect of TSEC treatment on hip geometry in postmenopausal Korean women. The treatment was given for 12 months, and hip geometry was measured by HSA. Materials and Methods: A total of 40 postmenopausal women who received TSEC containing conjugated estrogen 0.45 mg and bazedoxifene 20 mg for treating vasomotor symptoms were included in this retrospective cohort study. The changes in bone mineral density and parameters of HSA including the outer diameter, cross-sectional area, cross-sectional moment of inertia, cortical thickness, section modulus, and buckling ratio as determined by dual-energy X-ray absorptiometry were compared before and after 12 months of TSEC treatment. Results: Mean age and years since menopause were 55.1 and 4.5 years, respectively. Total hip bone mineral density significantly increased by 0.74% after treatment (P=0.011). The changes in HSA were mainly demonstrated in the narrow femoral neck: cross-sectional area (P=0.003) and cortical thickness (P<0.001) increased significantly. For the shaft region, only SM decreased significantly after treatment (P=0.009). However, most parameters did not change significantly with TSEC treatment in the intertrochanteric and shaft regions. Conclusions: Our findings demonstrate that 12 months of TSEC treatment could improve bone geometry as measured by HSA. The findings suggest that TSEC might be an interesting option for the prevention of fracture as well as osteoporosis in postmenopausal women.

Serum estradiol level according to dose and formulation of oral estrogens in postmenopausal women.

This study was performed to evaluate serum estradiol level in postmenopausal women using oral menopausal hormone therapy (MHT) with different doses and formulations of estrogens. A total of 344 postmenopausal women who received oral MHT was included in this cross-sectional study. Serum estradiol level was compared according to formulation (estradiol hemihydrate [EH] or valerate [EV], conjugated estrogen [CE]) and dose (estradiol 1 or 2 mg, CE 0.45 or 0.625 mg) of the estrogens. Mean age and years since menopause were 56.9 and 7.9 years, respectively. Mean duration of MHT was 27.4 months. Since serum estradiol levels were not significantly different at either dose, EH and EV at the same dose were combined for comparisons: estradiol 1 mg and 2 mg. The serum estradiol level with estradiol 2 mg (107.6 pg/mL) was significantly higher by 60% than with estradiol 1 mg (65.8 pg/mL) or CE 0.45 mg (60.1 pg/mL), and it was also significantly higher than with CE 0.625 mg (76.8 pg/mL). Our findings suggest that serum estradiol level is not directly proportional to estrogen dose. In terms of serum concentration, CE 0.45 mg is equivalent to estradiol 1 mg.

Nuclear factor-kappa B signaling in endometriotic stromal cells is not inhibited by progesterone owing to an aberrant endoplasmic reticulum stress response: a possible role for an altered inflammatory process in endometriosis.

Endoplasmic reticulum (ER) stress serves as a key modulator of the inflammatory response by controlling nuclear factor-kappaB (NF-κB) signaling. Previous studies from our laboratory have reported an abnormal induction of ER stress linked to progesterone resistance in human endometriotic cells. Therefore, an aberrant ER stress response to progesterone might contribute to the altered inflammatory response observed in endometriotic tissues. To evaluate this hypothesis, we investigated whether ER stress is involved in regulation of NF-κB in endometrial stromal cells and whether induction of aberrant ER stress in endometriotic stromal cells affects pro-inflammatory cytokine production. We found that tunicamycin-induced ER stress inhibited NF-κB activation and pro-inflammatory cytokine (IL-6 and COX2) production in TNF-α- or IL-1ß-treated normal endometrial stromal cells (NECSs). Tunicamycin increased the expression of A20 and C/EBPß, which are negative regulators of NF-κB, and this increase inhibited NF-κB activity in NESCs incubated with TNF-α or IL-1ß. Similarly, progesterone increased A20 and C/EBPß expression through upregulation of ER stress in NESCs, resulting in inhibition of NF-κB activity and IL-6 and COX2 production. However, progesterone had no significant effects on induction of ER stress, A20 or C/EBPß expression, NF-κB activity or IL-6 or COX2 production in ovarian endometriotic cyst stromal cells (ECSCs). In contrast, upregulation of ER stress by tunicamycin significantly reduced IL-6 and COX2 production by inhibiting NF-κB activity in ECSCs. In conclusion, our results suggest that NF-κB activity in endometriotic stromal cells was not inhibited because of an aberrant ER stress response to progesterone, resulting in an increase in pro-inflammatory cytokine production.

The Long-Term Effect of Dienogest on Bone Mineral Density After Surgical Treatment of Endometrioma.

The aim of this study was to evaluate the changing pattern of bone mineral density (BMD) levels after 3 years of dienogest use post endometrioma surgery and investigate the possible predictive factors for BMD reduction. This retrospective study included 44 reproductive-aged women who took dienogest (2 mg/day) and followed up BMD for 3 years after laparoscopic endometrioma surgery from July 2013 to December 2018. In addition, to investigate the predictive factors in the group with decreased BMD, analysis was added for patients with decreased BMD after taking dienogest for 1 year post laparoscopic endometrioma surgery. After 3 years of treatment with dienogest, BMD of both the lumbar spine (- 4.4%) and femur neck (- 3.6%) decreased significantly compared to the baseline levels. Bone loss predominantly occurred during the first year of treatment in the lumbar spine (- 2.4%) and gradually decreased with time during the treatment period. The predictive factors for BMD reduction after dienogest use were evaluated based on a 1-year change in BMD levels of 160 women, but no associated factors were found. This study demonstrated that dienogest use for 3 years was associated with a significant and gradual decrease in BMD and no predictive factors for BMD reduction during the first year of treatment with dienogest were found. These results may be useful in counseling patients regarding long-term effects of dienogest use on reducing BMD levels so that appropriate preventive measures can be taken.

Factors associated with endometrial pathology during tamoxifen therapy in women with breast cancer: a retrospective analysis of 821 biopsies.

PURPOSE: This study evaluated the factors associated with endometrial pathologies during tamoxifen use in women with breast cancer. METHODS: This study analyzed 821 endometrial biopsies from women who received tamoxifen for breast cancer. Clinical characteristics were compared according to the presence of endometrial pathology (atypical hyperplasia and cancer). In addition, patients with endometrial polyps were compared with women with normal histology. RESULTS: Among 821 biopsies, atypical endometrial hyperplasia and cancer were diagnosed in 7 women each. Endometrial polyps were found in 173 women, and 634 women presented normal histology. In comparing women with endometrial pathology (atypical hyperplasia and cancer, n = 14) and those without pathology, parity was significantly lower (P = 0.014) and endometrial thickness was significantly higher (P < 0.001) in women with pathology. In addition, abnormal uterine bleeding was more common in the pathology group (P < 0.001). However, age, body mass index, menopausal status, intrauterine device use, history of diabetes mellitus, and duration of tamoxifen use did not differ according to the presence of pathology. In comparing women with endometrial polyps and those with normal endometrium, significant differences were found in parity (P < 0.001), duration of tamoxifen use (P = 0.003), and endometrial thickness (P < 0.001), but not in the presence of abnormal vaginal bleeding. CONCLUSION: Parity, endometrial thickness, and the presence of abnormal vaginal bleeding, but not age, body mass index, and menopausal status, may be associated with endometrial pathology during tamoxifen use in women with breast cancer. This finding might provide useful information for gynecological surveillance and counseling during tamoxifen treatment.

Dienogest regulates apoptosis, proliferation, and invasiveness of endometriotic cyst stromal cells via endoplasmic reticulum stress induction.

Dienogest, a specific progesterone receptor agonist, is used in the treatment of endometriosis. However, it is still unclear as to the mechanisms of therapeutic effects on endometriosis. Our recent study showed that endometriosis may be the result of aberrant endoplasmic reticulum (ER) stress induction due to progesterone resistance. This finding suggests that the regulation of ER stress induction may play a key role in treatment of endometriosis. Therefore, the anti-endometriotic effects of dienogest may be mediated by regulation of ER stress. To test this hypothesis, we elucidate whether dienogest affects endometriotic stromal cell apoptosis, proliferation and invasiveness by modulating ER stress-induced CCAAT/enhancer-binding protein homologous protein (CHOP) expression. Specifically, PRKR-like ER kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4), inositol-requiring kinase 1 (IRE1)/TNF receptor-associated factor 2 (TRAF2)/apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) signaling, and downstream CHOP were evaluated to determine the involved ER stress-mediated regulation mechanism of CHOP expression. Our results show that progesterone treatment did not have any significant effects on ER stress, apoptosis, proliferation, and invasion in estrogen-treated endometriotic cyst stromal cells (ECSCs). However, dienogest treatment upregulated the induction of ER stress. It also led to increased apoptosis, and decreased proliferation and invasiveness. These dienogest-induced changes in apoptosis, proliferation and invasiveness were reversed by the ER stress inhibitor salubrinal. Furthermore, dienogest-induced ER stress increased CHOP expression through activation of both PERK/elf2α/ATF4 and IRE1/TRAF2/ASK1/JNK signaling. This upregulation was blocked by transfection with PERK and IRE1 siRNA, which decreased apoptosis and increased the proliferation and invasiveness of dienogest-treated ECSCs. Taken together, our findings indicate that dienogest enhances ER stress induction in endometriotic stromal cells, which affects apoptosis, proliferation and invasiveness via CHOP upregulation.

The Efficacy of Long-Term Estrogen Replacement Therapy in Turner Syndrome Women with Premature Ovarian Insufficiency.

STUDY OBJECTIVE: To evaluate the efficacy of long-term estrogen replacement therapy (ERT) in uterine development and bone mineral density (BMD) of Turner syndrome (TS) women with premature ovarian insufficiency (POI). DESIGN AND SETTING: Retrospective study. PARTICIPANTS AND INTERVENTIONS: Thirty-seven TS women grouped according to ovarian function status: TS women with POI (n = 32), aged 11-26 years, and those with intact ovarian function (IOF; n = 5), aged 13-17 years. TS women with POI underwent ERT. MAIN OUTCOME MEASURES: Changes in uterine length, anterior-posterior (AP) fundal diameter of the uterus, and BMD were assessed. Statistical methods included Mann-Whitney U test and paired t test. RESULTS: In TS women with POI, uterine length, AP fundal diameter, and BMD significantly increased after ERT (P < .001). TS women with POI were subdivided into classic (n = 11) and variant (n = 21) types, and there were no significant differences in uterine development and BMD according to types of chromosome. After receiving ERT, AP fundal diameter was significantly longer in classic TS women (P = .034) compared with those with variant type. CONCLUSION: Long-term ERT increased uterine length (before: 4.4 cm; after: 7.2 cm) and AP fundal diameter (before: 0.9 cm; after: 2.4 cm), and improved BMD in TS women with POI. After ERT, in TS women with POI, uterine length, BMD at lumbar 2-4 and femoral neck were similar to those of TS women with IOF. Therefore, TS women with POI can catch up to those with IOF by receiving ERT.

Association of BRCA Mutations and Anti-müllerian Hormone Level in Young Breast Cancer Patients.

Background: Several preclinical and clinical studies have suggested that BRCA-mutation carriers may have decreased ovarian reserve. However, data in this area are limited and inconsistent, especially in young breast cancer patients. Objective: This study evaluated the association between BRCA mutation status and serum anti-Müllerian hormone (AMH) level in young, reproductive-aged patients with breast cancer. Materials and Methods: Patients ≤ 40 years of age with breast cancer and who had known BRCA status and baseline serum AMH level at Samsung Medical Center, Seoul, Korea, were considered for inclusion. A total of 52 BRCA mutation carriers (27 BRCA1 and 25 BRCA2) and 264 non-carriers were selected for analyses. The serum level of AMH was compared according to presence of a BRCA mutation, and linear and logistic regression analyses were performed to evaluate the association between BRCA mutation and serum AMH level. Results: No difference was found in clinical characteristics between BRCA-mutation carriers and non-carriers. Subjects with any BRCA mutation had a significantly lower median AMH than those without a mutation (2.60 vs. 3.85 ng/mL, 32% reduction, P = 0.004). Linear regression analysis showed a significant negative association between BRCA mutation and AMH level. In addition, logistic regression demonstrated non-significantly increased odds of mutation carriers having AMH < 1.2 ng/mL. However, no difference was found between BRCA1/2 mutations. Conclusions: Breast cancer patients with BRCA mutation have significantly lower serum AMH level. Fertility preservation should be considered more aggressively in young breast cancer patients with BRCA mutation.

Comparison of long-term use of combined oral contraceptive after gonadotropin-releasing hormone agonist plus add-back therapy versus dienogest to prevent recurrence of ovarian endometrioma after surgery.

OBJECTIVE: The aim of this study was to compare long-term use of combined oral contraceptive (COC) after gonadotropin-releasing hormone (GnRH) agonist plus add-back therapy with dienogest (DNG) treatment as medical treatments after surgery for ovarian endometrioma. METHODS: This prospective cohort study analyzed 52 reproductive-aged women who underwent surgery for ovarian endometrioma and received postoperative medical treatment with either COC after GnRH agonist (n = 20) or DNG (n = 32) for 24 months. Changes in quality-of-life (QOL) and bone mineral density (BMD) were compared according to treatment. In addition, recurrence of pain and lesions were compared. RESULTS: Baseline characteristics did not differ in demographic profiles and factors associated with endometriosis or QOL. During 24 months of treatment, no differences in any component of QOL were found between the two groups. BMD at the lumbar spine significantly decreased after the first 6 months of treatment in both COC after GnRH agonist (-3.5%) and DNG (-2.3%) groups, but the groups did not differ statistically. After 6 months, further decrease in BMD was not observed until 24 months in both groups. In addition, no cases of pain or endometrioma recurrence were found. CONCLUSION: Our results suggest that long-term use of COC after GnRH agonist plus add-back therapy is comparable to dienogest as a long-term postoperative medical treatment for endometriosis.

Involvement of endoplasmic reticulum stress in regulation of endometrial stromal cell invasiveness: possible role in pathogenesis of endometriosis.

Endoplasmic reticulum (ER) stress is known to reduce invasiveness in some cancer cells by inhibiting the AKT/mTOR pathway. A previous study from our laboratory suggested that ER stress is promoted by progesterone in human endometrial cells, which suggests that progesterone may inhibit endometrial cell invasiveness by up-regulating ER stress. Therefore, aberrant ER stress in response to progesterone may contribute to the altered invasiveness found in endometriotic tissues. To test this hypothesis, we elucidate whether ER stress is involved in regulation of human endometrial cell invasiveness through the AKT/mTOR pathway and if this involvement is associated with altered invasiveness in endometriotic cells. Specifically, we sought to determine the effects of ER stress on AKT/mTOR pathway by evaluating ER stress-mediated CHOP/TRIB3 signaling, a negative regulator of AKT. We found that ER stress marker GRP78 expression increased with CHOP and TRIB3 expression in normal endometrial stromal cells (NESCs) treated with tunicamycin, and this increase was accompanied by decreased AKT and mTOR activity and cellular invasiveness. Similarly, progesterone increased GRP78, CHOP and TRIB3 expression in NESCs. Subsequently, inhibition of AKT and mTOR activity decreased cellular invasiveness. This progesterone-induced decrease in cellular invasiveness was reversed by inhibition of ER stress. In contrast, progesterone did not change CHOP, TRIB3, AKT, mTOR or invasiveness in endometriotic cyst stromal cells. In contrast to normal endometrium, endometriotic tissues showed no changes in CHOP, TRIB3 and invasion-related proteins (MMP2 and MMP9) expression throughout the menstrual cycle. Taken together, our findings indicate that abnormal ER stress response to progesterone increased endometriotic stromal cell invasiveness via the AKT/mTOR pathway.

Tissue-selective estrogen complex for women who experience breast discomfort or vaginal bleeding when on hormone therapy.

OBJECTIVE: The objective of this study was to evaluate the effects of switching from hormone therapy to tissue-selective estrogen complex (TSEC) in women who experience vaginal bleeding or breast discomfort. METHODS: This retrospective cohort study included 82 postmenopausal women who received TSEC after switching from another hormone therapy due to adverse events. Changes in symptoms and imaging after switching to TSEC were evaluated. RESULTS: The mean age was 56.9 years. The women were switched to TSEC due to vaginal bleeding in 56.1% and breast discomfort in 47.6% (multiple choices were allowed). After the switch, almost all women (97.6%) experienced an improvement in adverse events. However, 27% of the women had worsening of vasomotor symptoms, which was more common when hormone therapy was changed from 2 mg of estradiol (41.7%) compared with 1 mg of estradiol (16.7%), 0.625 mg of conjugated estrogen (30%), or tibolone (12.5%). Images of breast lesions and fibroids before the switch were assessed, showing no change in most women. CONCLUSIONS: This study suggests that TSEC is a good option for women who have breast discomfort or persistent bleeding during other hormone therapy when taking into account the differences in estrogen dose.