Effect of Timing of Gonadotropin-Releasing Hormone Agonist Administration for Ovarian Protection in Patients with Breast Cancer.

PURPOSE: This study was performed to investigate the effect of the interval between the start of gonadotropin-releasing hormone agonist (GnRHa) and the start of chemotherapy on ovarian protection in patients with breast cancer. METHODS: This was a prospective observational cohort study that included 136 patients with breast cancer below 40 years who received GnRHa during chemotherapy for fertility preservation. Plasma anti-Müllerian hormone (AMH) levels were measured before chemotherapy (baseline) and after chemotherapy. Subjects were divided into 3 groups according to the interval between the start of GnRHa and the start of chemotherapy for analysis: 1-6 days, 7-13 days, and ≥ 14 days. The ratio of the post-chemotherapy AMH value to the baseline AMH (pcAMH) at each time point were compared among the 3 groups. Ranked analysis of covariance was used for statistical analysis, adjusted for age, body mass index (BMI), and the existence of polycystic ovaries (PCOs). In addition, recovery of ovarian function (AMH ≥ 1 ng/mL) at 12 months was evaluated. RESULTS: The median age of the patients was 32 years. There was no difference in the baseline AMH levels among the 3 groups (mean ± standard error: 5.0 ± 0.4 ng/mL [1-6 days], 5.3 ± 0.7 ng/mL [7-13 days], and 8.1 ± 1.3 ng/mL [≥ 14 days]; p = 0.250). The pcAMH at 3, 6, 12, 24, and 36 months were not significantly different among the 3 groups (p-values were 0.332, 0.732, 0.830, 0.148, and 0.393, respectively). In multivariate analysis, young age (p = 0.024), low BMI (p = 0.013), and the existence of PCO (p = 0.015) were predictors for AMH ≥ 1 ng/mL at 12 months. CONCLUSION: There was no difference in the ovarian protective effect according to the difference in the timing of administration of GnRHa.

Amenorrhea and Menopause in Patients with Breast Cancer after Chemotherapy.

PURPOSE: The probability of ovarian failure after cytotoxic chemotherapy in patients with breast cancer has not been well established in Korea. This study aimed to assess the rate of ovarian failure in a large cohort of Korean premenopausal patients with breast cancer 12 months after chemotherapy. METHODS: This retrospective cohort study included premenopausal women (aged 20-44 years) with breast cancer who underwent chemotherapy after surgery. The rates of treatment-related amenorrhea (TRA) and chemotherapy-induced menopause (CIM) at 12 months after chemotherapy were analyzed. RESULTS: A total of 237 patients met the inclusion criteria. The rate of TRA was 61.6% and that of CIM was 13.1% at 12 months after chemotherapy. The rates of TRA and CIM were 28.0% and 4.0%, respectively, in women aged 25-34 years, and they gradually increased up to 75.9% (TRA) and 15.8% (CIM), respectively, in women aged 40-44 years. The frequency of CIM was significantly lower than that of TRA in both age groups. In multivariate analyses, only tamoxifen use was significantly associated with a decreased risk of CIM (p < 0.001). Age of 40 years or higher and the regimens of doxorubicin plus cyclophosphamide followed by docetaxel or paclitaxel were associated with increased risk of TRA (p = 0.001 and p = 0.002, respectively). CONCLUSION: Marked discrepancy in the rates of CIM and TRA was observed in this study. Further, the age-specific frequency of CIM and TRA observed in this study is a reliable and practical estimate of the risks of CIM and TRA in the absence of gonadal protection.

Early gonadotropin-releasing hormone antagonist protocol in women with polycystic ovary syndrome: A preliminary randomized trial.

OBJECTIVE: To prospectively evaluate the efficacy and safety of a fixed early gonadotropin-releasing hormone (GnRH) antagonist protocol compared to a conventional midfollicular GnRH antagonist protocol and a long GnRH agonist protocol for in vitro fertilization (IVF) in patients with polycystic ovary syndrome (PCOS). METHODS: Randomized patients in all three groups (early antagonist, n=14; conventional antagonist, n=11; long agonist, n=11) received 21 days of oral contraceptive pill treatment prior to stimulation. The GnRH antagonist was initiated on the 1st day of stimulation in the early antagonist group and on the 6th day in the conventional antagonist group. The GnRH agonist was initiated on the 18th day of the preceding cycle. The primary endpoint was the number of oocytes retrieved, and the secondary endpoints included the rate of moderate-to-severe ovarian hyperstimulation syndrome (OHSS) and the clinical pregnancy rate. RESULTS: The median total number of oocytes was similar among the three groups (early, 16; conventional, 12; agonist, 19; p=0.111). The early GnRH antagonist protocol showed statistically non-significant associations with a higher clinical pregnancy rate (early, 50.0%; conventional, 11.1%; agonist, 22.2%; p=0.180) and lower incidence of moderate-to-severe OHSS (early, 7.7%; conventional, 18.2%; agonist, 27.3%; p=0.463), especially among subjects at high risk for OHSS (early, 12.5%; conventional, 40.0%; agonist, 50.0%; p=0.324). CONCLUSION: In PCOS patients undergoing IVF, early administration of a GnRH antagonist may possibly lead to benefits due to a reduced incidence of moderate-to-severe OHSS in high-risk subjects with a better clinical pregnancy rate per embryo transfer. Further studies with more subjects are required.

Cadaver skin allograft may improve mortality rate for burns involving over 30% of total body surface area: a propensity score analysis of data from four burn centers.

Cadaver skin is used for temporary wound covering, but there is insufficient evidence regarding its clinical usefulness in patients with major burns. We aimed to analyze the effect of cadaveric skin allograft on mortality rates in patients with burns involving > 30% of total body surface area (TBSA). Our study included 1282 patients with > 30% of TBSA burned admitted to four hospitals in Korea between June 1, 2008 and December 31, 2016. Of these, 698 patients underwent cadaver skin allograft (cadaver group), and 584 were treated with conventional treatment (non-cadaver group). We corrected the differences between the two groups using propensity score matching, and generated 474 propensity score-matched pairs. Overall 90-day in-hospital mortality rate among all patients was 35.3% (453/1282). There was a significant difference in 90-day in-hospital mortality between the two groups for both unmatched [cadaver vs. conventional, 31.7 vs. 39.7%; difference, 8.0; 95% confidence interval (CI) 2.8-13.3] and propensity-matched groups (37.8 vs. 47.3%; difference, 9.5; 95% CI 3.2-15.8). Logistic regression analyses showed a significant association between cadaver skin allograft and lower 90-day in-hospital mortality in the propensity-matched groups (odds ratio, 0.42; 95% CI 0.29-0.62). Patients with major burns who underwent cadaver skin allograft had a lower mortality rate compared to those who did not. Cadaver skin allograft may improve the survival of patients with major burns, especially in the early phase of injury.

Clinical outcomes of frozen embryo transfer cycles after freeze-all policy to prevent ovarian hyperstimulation syndrome.

OBJECTIVE: To compare the clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR) in frozen embryo transfers (FETs) following either freeze-all policy to prevent ovarian hyperstimulation syndrome (OHSS; freeze-all group) or excess embryo cryopreservation after fresh embryo transfer (surplus group). METHODS: The freeze-all group comprised 44 FET cycles performed in 25 women between 2010 and 2016. The surplus group comprised 53 FET cycles performed in 47 women during the same period. The cumulative CPR and OPR according to duration of cryopreservation (interval between cryopreservation and FET) was estimated using Kaplan-Meier plots. Cox regression analysis was used for identifying factor to affect to cryopreservation duration in cycles with pregnancy. RESULTS: In day 2-4 transfer cycles, the crude CPR (40% vs. 18.2%) and OPR (20% vs. 4.5%) were similar between the 2 groups. In day 5 transfer, the crude CPR (33.3% vs. 38.7%) and OPR (33.3% vs. 29%) were also similar between the 2 groups. The cumulative CPR (100% vs. 47.5%) and OPR (100% vs. 33.3%) in day 2-4 transfer as well as the cumulative CPR (46.7% vs. 100%) and OPR (46.7% and 74.8%) in day 5 transfer were also similar between the 2 groups. The median duration of cryopreservation was significantly shorter in the freeze-all group than in the surplus group (19.8 vs. 36.9 weeks, P=0.04). Previous history of delivery was the only factor associated with a shorter cryopreservation duration in cycles with pregnancy (hazard ratio, 0.18; 95% confidence interval, 0.05-0.65; P=0.01). CONCLUSION: Freezing embryos to prevent OHSS and transferring the frozen embryos later may guarantee an acceptable reproductive outcome.

Androgen receptor cytosine, adenine, and guanine trinucleotide repeat polymorphism in Korean patients with endometriosis: A case-control study.

STUDY OBJECTIVE: To investigate the association between the androgen receptor (AR) cytosine, adenine, and guanine (CAG) repeat polymorphisms and endometriosis. STUDY DESIGN: A prospective case-control, genetic association study was performed on women with surgically proven endometriosis (n=421) and controls free of endometriosis (n=349). AR CAG repeat lengths were determined from peripheral blood samples. The difference in the frequency of each alleles were compared in patients with endometriosis and controls using Chi-square test. MAIN RESULTS: No significant difference in biallelic length mean between patients and controls was observed. Alleles containing 24 CAG repeats were significantly more frequent in stage I-II (mild) endometriosis than in the control samples (19.8% and 13.3%, respectively; OR 1.60, 95% CI 1.04-2.47). Additionally, a higher frequency of both alleles with 24 or more CAG repeats was observed in individuals with mild endometriosis, in comparison with the controls (25.6% and 15.2%, respectively; OR 1.92, 95% CI 1.09-3.38). CONCLUSIONS: AR gene CAG repeat polymorphisms are associated with the increased risk of mild endometriosis.

Ospemifene: A Novel Option for the Treatment of Vulvovaginal Atrophy.

Ospemifene-a third-generation selective estrogen receptor modulator approved by the Food and Drug Administration in 2013-is an oral medication for the treatment of dyspareunia. In postmenopausal women with vulvovaginal atrophy, ospemifene significantly improves the structure and pH levels of the vagina, reducing dyspareunia. It is available as a 60-mg tablet; hence, women who may have had prior difficulty with vaginal administration or on-demand use of nonprescription lubricants and moisturizers would likely prefer this form of treatment. Preclinical studies demonstrated that ospemifene has an estrogen agonist action on the bone, reducing the cell proliferation of ductal carcinoma in an in situ model. Studies evaluating the safety of treatment for up to 52 weeks have shown that ospemifene is a safe medication with minimal impact on the endometrium. Further studies with larger number of subjects are necessary to better conclude its effects and long-term safety.

Major Disease Prevalence and Menstrual Characteristics in Infertile Female Korean Smokers.

We investigated the prevalence of smoking and factors associated with smoking in infertile Korean women. Smoking status, education, occupation, personal habits, past medical history, current illness, stress level, and menstrual characteristics were collected from self-report questionnaires. The Beck Depression Inventory (BDI) was used to assess the degree of depression. Data on the causes of infertility and levels of six reproductive hormones were collected from medical records. Among 785 women less than 42 years of age, the prevalence of current, secondhand, past, and never smokers were 12.7%, 45.7%, 0.9%, and 40.6%, respectively. Primary infertility was more frequent in secondhand smokers. Causes of infertility were similar among current, secondhand, and never smokers. Current smokers were less educated (P < 0.001) and more likely to consume alcohol than secondhand or never smokers (P < 0.001). Secondhand smokers slept less than current smokers (P = 0.041). Among several major diseases, only the prevalence of diabetes mellitus (4.0%) was significantly higher in current smokers than in secondhand smokers (0.0%, P = 0.002) or never smokers (0.6%, P = 0.031). The self-reported prevalence of depression, and the degree of depression were similar among women with different smoking statuses. There were no differences in menstrual characteristics or serum levels of six reproductive hormones between current, secondhand, and never smokers, even after excluding women with polycystic ovary syndrome. In conclusion, education/employment status, alcohol drinking, and the prevalence of primary infertility and diabetes mellitus were significantly different according to smoking status among infertile women.

Analysis of falsely elevated risk of ovarian malignancy algorithm in women with ovarian endometrioma.

OBJECTIVE: To estimate the incidence of falsely elevated risk of ovarian malignancy algorithm (ROMA) in a group of women with pathologically confirmed endometrioma and to investigate the associated factors. METHODS: One hundred premenopausal women surgically diagnosed with ovarian endometrioma were selected. Preoperative clinical, laboratory, and surgical characteristics were compared between the elevated-risk group (ROMA-premenopausal value, ≥7.4%) and normal-risk group (ROMA-premenopausal value, <7.4%). RESULTS: Elevated ROMA was observed in 15 women (false positive rate, 15%). Excluding one woman with known chronic renal failure, we compared the characteristics of 99 women between the elevated-risk group (n=14) and the normalrisk group (n=85). None of the clinical and surgical variables distinguished the two groups. Serum level of CA 125 >82.3 U/mL and serum level of human epididymis protein 4 (HE4) >46 pmol/L could predict an elevated ROMA test with a statistical significance. When serum level of HE4 ≤46 pmol/L, none of the women showed an elevated ROMA test, regardless of serum level of CA 125; however, 55.6% of the women showed an elevated ROMA test when serum level of HE4 >46 pmol/L and CA 125 ≤82.3 U/mL and all women showed an elevated ROMA test when serum level of HE4 >46 pmol/L and CA 125 >82.3 U/mL. CONCLUSION: The incidence of falsely elevated ROMA was 15% in the group of women with pathologically confirmed endometrioma. Interpretation of the ROMA results should be cautious when serum level of HE4 >46 pmol/L and CA 125 >82.3 U/mL in women with suspicious ovarian endometrioma.

A revised risk analysis of stress ulcers in burn patients receiving ulcer prophylaxis.

OBJECTIVE: Most of the literature about Curling's ulcer was published from 1960 through 1980. Therefore, an updated study of Curling's ulcer is needed. We analyzed the risk factors affecting ulcer incidence in burn patients. METHODS: We retrospectively analyzed the medical records of burn patients who were admitted to two burn centers. We collected information about the general characteristics of patients, burn area size, abbreviated burn severity index, whether surgery was performed, endoscopy results, and the total body surface area (TBSA). We performed a multivariate regression analysis predicting development of Curling's ulcer. RESULTS: In total, 135 patients (mean age, 49.5±13.5 years) underwent endoscopy. Endoscopy revealed ulcer in 51 patients: 36 (70.6%) with gastric ulcers, 9 (17.6%) with duodenal ulcers, and 6 (11.8%) with both ulcer types. Burn area, burn depth, epigastric pain, melena, intensive care unit admission, burn area >20% of TBSA, and undergoing surgery for the burn were significantly different between the ulcer and non-ulcer groups. Multivariate analysis showed two independent factors significantly associated with ulcer: epigastric pain (odds ratio [OR]: 4.55, 95% confidence interval [CI]: 1.74 to 11.90), major burn (TBSA > 20%)(OR: 4.31 ,95% CI: 1.34 to 13.85). CONCLUSION: For burn patients, presence of epigastric pain and major burn with TBSA > 20% showed significant association with ulcer development.

Association of epidermal growth factor receptor gene polymorphisms with advanced endometriosis in a Korean population.

OBJECTIVES: To determine if specific single nucleotide polymorphisms (SNPs) in the Epidermal Growth Factor Receptor (EGFR) gene were meaningful markers for the risk of advanced stage endometriosis in a Korean population. STUDY DESIGN: Case-control study in a collective of 299 women with endometriosis and 285 controls. Three polymorphisms (151904 A>T [T628T] on exon 16 [rs 17337023], 162093 G>A [Q787Q] on exon 20 [rs 10251977], and 181946 C>T [D994D] on exon 25 [rs 2293347]) were assessed by a Minor Groove Binder (MGB) primer/probe Taqman assay. In-silico haplotypes were deduced using the Haploview (version 3.32) software package. RESULTS: There were no statistically significant differences in the genotype or haplotype frequencies of the three EGFR polymorphisms between subjects with endometriosis versus the control group. Even when the endometriosis cases were subdivided into stage III and IV based on the ASRM criteria, no statistically significant differences in genotype distribution or haplotype frequencies were observed between the three groups. CONCLUSIONS: Our results suggest that the 151904 A>T, 162093 G>A, and 181946 C>T polymorphisms in the EGFR gene are not associated with advanced stage endometriosis in a Korean population. Our results are in agreement with the results reported by Inagaki et al.