Further progress of the etiology,diagnosis and treatment of peripheral precocious puberty / 中华预防医学杂志

Peripheral precocious puberty(PPP),also known as puberty independent from hypothalamic-pituitary axis activation,is stimulated by hormones from other sources, with only partial sexual characteristics development but without mature sexual function. The secondary sexual characteristics development occurs before 7.5 years of age in girls and before 9 years of age in boys. Clinical manifestations are diverse, and PPP has varied etiology including congenital adrenal hyperplasia, McCune-Albright syndrome, ovarian cyst, adrenal tumor, ovarian tumor, testicular tumor, human chorionic gonadotropin producing tumor, familial male precocious puberty, aromatase excess syndrome, and environmental estrogen. Early identification of etiology, accurate differential diagnosis and prenatal gene screening play a significant role in the prevention, diagnosis and treatment of the disease.

Aromatase deficiency caused by mutation of CYP19A1 gene: A case report / 中南大学学报(医学版)

Aromatase deficiency (AD) is a rare autosomal recessive genetic disease caused by loss-of-function mutations in aromatase gene (CYP19A1), leading to congenital estrogen deficiency syndrome. Both mothers of AD patients during pregnancy and female AD fetus show virilization, while male patients are usually diagnosed in adulthood due to continued height increase and metabolic abnormalities. In 2019, a patient with AD was admitted in the Second Xiangya Hospital. The patient was a 37-year-old adult male who continued to grow linearly after adulthood. His estradiol was below the measurable line, the follicle-stimulating hormone (FSH) increased, bone age delayed, epiphysis unfused, and the bone mass reduced. CYP19A1 gene detection showed that c.1093C>T, p.R365W was homozygous mutation. This disease is rare in clinic. Clinicians need to raise awareness of the disease for early diagnosis and treatment to improve the long-term prognosis of patients.

Influence of CYP19A1 gene expression levels in women with breast cancer: a systematic review of the literature

Breast cancer is the most frequently diagnosed malignant neoplasm in women and is considered a multifactorial disease of unknown etiology. One of the major risk factors is genetic alteration. Changes in CYP19A1 gene expression levels have been associated with increased risk and increased aggressiveness of breast cancer. Increased CYP19A1 gene expression and/or aromatase activity are among the major regulatory events for intratumoral production of estrogens in breast malignant tissues. This systematic review aimed to investigate the influence of CYP19A1 gene expression levels in women with breast cancer. The research was carried out using the PubMed, Scopus, and Web of Science databases. Searches were conducted between February 2 and May 15, 2019. Inclusion criteria were studies published between 2009 and 2019, English language publications, and human studies addressing the gene expression of CYP19A1 in breast cancer. A total of 6.068 studies were identified through PubMed (n=773), Scopus (n=2,927), and the Web of Science (n=2,368). After selecting and applying the inclusion and exclusion criteria, six articles were included in this systematic review. This systematic review provides evidence that increased or decreased levels of CYP19A1 gene expression may be related to pathological clinical factors of disease, MFS, OS, DFS, WATi, markers of metabolic function, concentrations of E1, FSH, and in the use of multiple exons 1 of the CYP19A1 gene in breast cancer.

Predicting the Benefit of Adjuvant Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer Patients with Phosphorylated S6K1 Expression Status / 한국유방암학회지

PURPOSE: Phosphorylated ribosomal S6 kinase 1 (pS6K1) is a major downstream regulator of the mammalian target of rapamycin (mTOR) pathway. Recent studies have addressed the role of S6K1 in adipogenesis. pS6K1 may affect the outcome of estrogen depletion therapy in patients with hormone-sensitive breast cancer due to its association with adipogenesis and increased local estrogen levels. This study aimed to investigate the potential of pS6K1 as a predictive marker of adjuvant aromatase inhibitor (AI) therapy outcome in postmenopausal or ovarian function-suppressed patients with hormone-sensitive breast cancer.METHODS: Medical records were retrospectively reviewed in postmenopausal or ovarian function-suppressed patients with estrogen receptor-positive and node-positive primary breast cancer. pS6K1 expression status was scored on a scale from 0 (negative) to 3+ (positive) based on immunohistochemical analysis.RESULTS: A total of 428 patients were eligible. The median follow-up duration was 44 months (range, 1–90). In patients with positive pS6K1 expression, AIs significantly improved disease-free survival (DFS) compared to selective estrogen receptor modulators (SERMs) (5 year-DFS: 83.5% vs. 50.7%, p = 0.016). However, there was no benefit of AIs on DFS in the pS6K1 negative group (5 year-DFS 87.6% vs. 91.4%, p = 0.630). On multivariate analysis, AI therapy remained a significant predictor for DFS in the pS6K1 positive group (hazard ratio, 0.39; 95% confidence interval, 0.16–0.96; p = 0.041). pS6K1 was more effective in predicting the benefit of AI therapy in patients with ages < 50 (p = 0.021) compared to those with ages ≥ 50 (p = 0.188).CONCLUSION: pS6K1 expression may predict AI therapy outcomes and serve as a potential predictive marker for adjuvant endocrine therapy in postmenopausal and ovarian function-suppressed patients with hormone-sensitive breast cancer. AIs may be more effective in patients with pS6K1 positive tumors, while SERM could be considered an alternative option for patients with pS6K1 negative tumors.

PARAGON (ANZGOG-0903): a phase 2 study of anastrozole in asymptomatic patients with estrogen and progesterone receptor-positive recurrent ovarian cancer and CA125 progression / 부인종양

OBJECTIVE: A subset of patients with recurrent ovarian cancer (ROC) may benefit from antiestrogen therapy with higher response rates reported in tumors that are strongly estrogen receptor (ER)-positive (ER+). PARAGON is a basket trial that incorporates 7 phase 2 trials investigating the activity of anastrozole in patients with ER+ and/or progesterone receptor (PR)-positive (PR+) recurrent/metastatic gynecological cancers. METHODS: Postmenopausal women with ER+ and/or PR+ ROC, who were asymptomatic and had cancer antigen 125 (CA125) progression after response to first line chemotherapy, where chemotherapy was not clinically indicated. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. RESULTS: Fifty-four patients were enrolled (52 evaluable). Clinical benefit at three months (primary endpoint) was observed in 18 patients (34.6%; 95% confidence interval [CI]=23%–48%). Median progression-free survival (PFS) was 2.7 months (95% CI=2.1–3.1). The median duration of clinical benefit was 6.5 months (95% CI=2.8–11.7). Most patients progressed within 6 months of starting anastrozole but 12 (22%) continued treatment for longer than 6 months. Anastrozole was well tolerated. In the exploratory analysis, ER histoscores and the intensity of ER staining did not correlate with clinical benefit rate or PFS. CONCLUSION: A subset of asymptomatic patients with ER+ and/or PR+ ROC and CA125 progression had durable clinical benefit on anastrozole, with acceptable toxicity. Anastrozole may delay symptomatic progression and the time to subsequent chemotherapy. The future challenge is to identify the subset of patients most likely to benefit from an aromatase inhibitor and whether the clinical benefit could be increased by the addition of other agents.

Aromatase inhibition in ovarian cancer: repeated signals of efficacy but tools for patient selection remain elusive / 부인종양

No abstract available.

A pilot study of gonadotropin-releasing hormone agonist combined with aromatase inhibitor as fertility-sparing treatment in obese patients with endometrial cancer / 부인종양

OBJECTIVE: This study aims to evaluate the effects and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH agonist) combined with aromatase inhibitor (AI) in preserving the fertility of obese women with grade 1 endometrial cancer (EC). METHODS: This study recruited obese EC patients who wished to preserve their fertility. The treatment regimen consisted of intramuscular GnRH agonist 3.75 mg every 4 weeks and oral AI 2.5 mg daily. The maintenance regimen was the same as the initial treatment regimen. Primary outcomes included response rate, time to complete response (CR), and time to recurrence; pregnancy outcomes included the time to pregnancy, pregnancy rate and live birth rate. RESULTS: Six obese patients with EC were included in this study, with the age (mean±standard deviation [SD]) of 30.5±3.3 years and body mass index (mean±SD) of 35.0±1.4 kg/m2. CR rate was 100%, and time to CR was 3–6 months. None of the patients had recurrence after a median follow-up of 4.0 years (range, 1.3–7.0 years). The most common side effects were menopause-like symptoms. Among these patients, no weight gain was observed during treatment. The pregnancy rate and live birth rate was 50.0% and 75.0%, respectively, with a median time to pregnancy of 2.4 years (range, 1.0–5.5 years). CONCLUSION: The combination of GnRH agonist and AI demonstrated promising long-term effect in young obese EC patients who wished to preserve their fertility. No weight gain side effects were observed. Further studies with a larger sample size are needed to fully evaluate this novel treatment regimen.

Effect of Tripterygium Glycosides Tablets on reproductive toxicity in female rats with Ⅱ type collagen induced arthritis / 中国中药杂志

The aim of this paper was to observe the toxic effect of Tripterygium Glycosides Tablets( TG) on the reproductive system of Ⅱ type collagen induced arthritis( CIA) male rats,and to explore the toxic mechanism preliminarily. Fifty SD rats were randomly divided into normal control group( Con),model group( CIA),Tripterygium Glycosides Tablets clinical equivalent dose groups of 1,2,4 times( 9,18,36 mg·kg-1),10 rats in each group,and were given by gavage once a day for 42 days after the first immunization.The organ indexes of uterine and ovarian were calculated on days 21 and 42. Histopathological and morphological changes of uterine and ovarian were observed under optical microscope. The concentration of estradiol( E2),follicle-stimulating hormone( FSH),luteinizing hormone( LH),17α-hydroxylase( CYP17 A1) and cytochrome P450 19 A1( CYP19 A1) in serum were detected by ELISA. Immunohistochemistry was used to observe the expression of Bax and Bcl-2 related proteins in the apoptosis pathway of uterus and ovary. The results showed that compared with the Con group,CIA group could reduce the number of uterine glands( P<0.05),but no significant changes were observed in other groups. Compared with the CIA group,there were no significant changes in the coefficients of uterus and ovary in the Tripterygium Glycosides Tablets groups. The number of uterine glands,total follicles in the ovary,mature follicles and corpus luteum,the distribution of blood vessels and mitochondria had a certain inhibitory trend,and also slightly increased the number of atresia follicles,but the histopathological quantitative indicators were not statistically different. Except that 2 times clinical dose of Tripterygium Glycosides Tablets could significantly reduce the content of CYP19 A1( P<0. 05) after 42 d administration,there were no significant changes in serum estrogen E2,FSH,LH and estrogen synthesis key enzymes CYP17 A1 in each administration group. Medium and high doses of Tripterygium Glycosides Tablets could increase the expression of apoptotic protein Bax in uterine and ovarian tissues( P<0. 05,P<0. 01),and all the administration groups could inhibit the expression of apoptotic inhibiting protein Bcl-2( P <0. 05,P<0. 01,P<0.001),42 d was more obvious than 21 d. In conclusion,4 times and less than 4 times Tripterygium Glycosides Tablets did not cause obvious toxicity and histopathological changes in the reproductive organs of CIA rats,but it could reduce the level of serum estrogen synthesis key enzyme CYP19 A1 and affect the content of apoptosis-related proteins Bax and Bcl-2 in uterus and ovary tissues. The relevant mechanism needs further study.

Pretentious genomic selection signatures in CYP19A1 gene associated with silent estrous behavior in water buffalo in Pakistan

Background: Poor reproductive efficiency of river buffalos hampers the production capabilities of animals. Buffalos are mainly considered poor breeders owing to the constrained expression of estrus behavior. Failure to display heat signs is an indication of improper functionality of signaling peptides to trigger on a series of behavioral changes, which can be detectable by breeders for timely insemination of females. This might cause an animal to be a repeat breeder. Genomic variations underlying synthesis of signaling peptides can be a useful marker to select superior animals with better reproductive efficiency. In this context, the current study was designed to analyze the CYP19A1 gene in Nili-Ravi buffalo. Results: A total of 97 animals were selected and were divided into two groups on the basis of their heat score. PCR amplification and sequencing of the amplicons were performed using the specific sets of primer, and then, sequences were analyzed for novel variants. A total of 11 polymorphic sites were identified illustrating phenotypic variation in the heat score. Most of the loci were found homologous. Single Nucleotide Polymorphisms (SNPs) were analyzed for association with silent estrus. A three-dimensional protein model was also generated to locate the position of exonic SNPs. Conclusion: This study illustrated that polymorphic sites in the CYP19A1 gene provided potential markers for selection of buffalos with better estrus behavior.

Gonadotropin-releasing Hormone Agonist Plus Aromatase Inhibitor in the Treatment of Uterine Leiomyoma in Near Menopause Patient: A Case Series Study

OBJECTIVES: There are many drugs for of symptomatic fibroids. Gonadotropin-releasing hormone (GnRH) agonists are the well known drugs. Also, aromatase inhibitors are effective. All published studies surveyed the effect of one of these two drugs. In this study as the first study decided to evaluate the effectiveness of the combination of GnRH agonists + aromatise inhibitor on the uterine fibroids. METHODS: A cross-sectional prospective case series study was performed on 10 known cases of uterine fibroids late perimenopause, at least 3 myomas >5 cm, abnormal uterine bleeding and anemia due to fibroids, candidate for hysterectomy, no tendency to surgery. A single dose of Diphereline 11.25 mg, SR plus 2.5 mg of Letrozole daily for 4 weeks with add-back therapy + calcium carbonate were used. The second dose of Diphereline 11.25 mg, SR was used 3 months after the first injection. The patients were followed until 3 years. RESULTS: The mean age of the study group was 49.90 ± 1.66. The mean fibroid size reduced from 15.05 ± 57.20 cm to 13.56 ± 39.39 cm (P = 0.012) and fibroid volume reduced from 72.78 ± 110.6 to 50.96 ± 64.2 (P = 0.116). There was no signification changes in the serum level of hormones at the end of six months. Eight cases were menopause at the end of the study and hypoestrogenism symptoms did not happened in none of the cases until the end of 24 months. Except in one case, there was no need to do surgery on others. CONCLUSIONS: Combination of Diphereline + Letrozole probably could prevent surgery in cases that have multiple fibroids, perimenopause, anemic and candidate for surgery.

Porcine intestinal lymphoid tissues synthesize estradiol

Estradiol (17β-estradiol) is synthesized primarily in the gonads of both sexes and regulates the development and function of reproductive organs. Recently, we reported that intestinal lymphocyte homeostasis is regulated by estradiol synthesized de novo in the endothelial cells of the high endothelial venules (HEVs) of mesenteric lymph nodes and Peyer's patches in mice. This observation prompted us to hypothesize that HEVs of intestinal lymphoid tissues are sites of estradiol synthesis across species. In this study, we examined whether estradiol is synthesized in the intestinal lymphoid tissues of adolescent piglets. Comparisons of estradiol levels in blood and tissue showed that estradiol concentrations in mesenteric lymph nodes and Peyer's patches were significantly higher than the level in serum. Reverse transcription polymerase chain reaction showed that porcine intestinal lymphoid tissues express mRNAs for steroidogenic enzymes (StAR, 17β-Hsd, 3β-Hsd, Cyp17a1, and Cyp19a1), and immunohistochemical results in ilial tissue showed expression of aromatase (CYP19) in Peyer's patch-localized endothelial cells of HEVs. When mesenteric lymph node and Peyer's patch tissues were cultured in vitro, they produced estradiol. Taken together, the results indicate that mesenteric lymph nodes and Peyer's patches are sites of estradiol synthesis in adolescent piglets.

Effectiveness of bisphosphonate combined with activated vitamin D in patients with aromatase inhibitor-induced osteoporosis after breast cancer operation

OBJECTIVES: We compared the effectiveness of bisphosphonates combined with activated vitamin D administered for therapy of aromatase inhibitor-induced osteoporosis after a breast cancer operation and primary postmenopausal osteoporosis through propensity score matching. METHODS: Forty-eight postmenopausal patients with estrogen receptor-positive early breast cancer, who had postoperative adjuvant treatment with aromatase inhibitors and whose T-score of bone mineral density (BMD) decreased below −2.5 (AI group), and 48 patients of primary postmenopausal osteoporosis (PO group) enrolled in this retrospective observational study. They were administered monthly risedronate or minodronate, and daily alfacalcitol or eldecalcitol were combined. Their BMD (L2–4, L-BMD), serum-corrected calcium, serum phosphate, tartrate-resistant acid phosphatase 5b (TRACP-5b), bone alkaline phosphatase (BAP), estimated glomerular filtration rate, urine calcium/creatinine ratio, intact-parathyroid hormone, and 25-hydroxy vitamin D were measured before treatment and until 24 months. RESULTS: L-BMD values increased with time compared with the baseline values in each group, and there was no significant difference in the groups. Percentage value of TRACP-5b decreased rapidly after 6 months and maintained low level until 24 months in both groups. Percentage value of BAP in the AI group decreased continuously until 24 months. In contrast, the percentage change in the PO group plateaued after 6 months. CONCLUSIONS: It is suggested that monthly oral bisphosphonate combined with activated Vitamin D is an effective therapy to increase BMD in the aromatase inhibitor-induced osteoporosis after breast cancer operation. Monitoring of kidney function and concentration of Ca in blood and urine may be necessary.

Efficacy of Combined Aromatase Inhibitor and Luteinizing Hormone-Releasing Hormone Agonist in Premenopausal Metastatic Breast Cancer

PURPOSE: Endocrine therapy is the preferred treatment for hormone receptor (HR)-positive metastatic breast cancer (MBC). We investigated the efficacy of combined aromatase inhibitor (AI) and luteinizing hormone-releasing hormone (LHRH) agonist in premenopausal patients with HR-positive MBC. METHODS: We retrospectively analyzed the medical records of 21 HR-positive premenopausal MBC patients treated with combined AI and LHRH agonist therapy. RESULTS: The median follow-up period was 32.9 months. The overall response rate was 47.6%, with three complete responses (14.3%) and seven partial responses (33.3%). Nine patients (42.9%) achieved stable disease lasting more than 6 months; thus, the clinical benefit rate was 90.4%. The median time to progression was 45.4 months. No patients experienced grade 3 or 4 toxicity. CONCLUSION: Combined AI and LHRH agonist treatment safely and effectively induced remission or prolonged disease stabilization, suggesting that this could be a promising treatment option for HR-positive premenopausal patients with MBC.

Recent Update on RANKL Inhibitor / 대한내과학회지

The prevalence of osteoporosis is continuing to increase with growing elderly population. A variety of anti-osteoporotic agents have been used for the prevention and treatment of osteoporosis and osteoporotic fractures. Novel therapeutic agents based on the newly discovered mechanisms in bone biology have been recently introduced. Denosmab, a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand, is a new therapeutic agent that inhibits osteoclast differentiation, activity, and survival. In the fracture reduction evaluation of denosumab in osteoporosis every 6 months (FREEDOM) trial, denosumab treatment for 36 months significantly increased bone mineral density at all skeletal sites evaluated, thereby resulting in a significant reduction in the risk of vertebral, nonvertebral, and hip fractures. In the FREEDOM Extension study, in which denosumab treatment was continued for up to 10 years, denosumab showed a continued improvement in bone mineral density and a consistently low fracture risk similar to rates observed in the denosumab group during the FREEDOM trial. Denosumab also offered a favorable safety profile with generally low and stable adverse event rates. Denosumab was indicated for treatment of postmenopausal women with osteoporosis at high risk for fracture, treatment to increase bone mass in men with osteoporosis, treatment of bone loss in men receiving androgen deprivation therapy for prostate cancer, and treatment of bone loss in women receiving adjuvant aromatase inhibitor therapy for breast cancer. For these patients, denosumab is an important option for the prevention and treatment of osteoporosis and osteoporotic fractures.

Assessment of Quality of Life and Safety in Postmenopausal Breast Cancer Patients Receiving Letrozole as an Early Adjuvant Treatment / 한국유방암학회지

PURPOSE: There are few reports from Asian countries about the long-term results of aromatase inhibitor adjuvant treatment for breast cancer. This observational study aimed to evaluate the long-term effects of letrozole in postmenopausal Korean women with operable breast cancer. METHODS: Self-reported quality of life (QoL) scores were serially assessed for 3 years during adjuvant letrozole treatment using the Korean version of the Functional Assessment of Cancer Therapy-Breast questionnaires (version 3). Changes in bone mineral density (BMD) and serum cholesterol levels were also examined. RESULTS: All 897 patients received the documented informed consent form and completed a baseline questionnaire before treatment. Adjuvant chemotherapy was administered to 684 (76.3%) subjects, and 410 (45.7%) and 396 (44.1%) patients had stage I and II breast cancer, respectively. Each patient completed questionnaires at 3, 6, 12, 18, 24, 30, and 36 months after enrollment. Of 897 patients, 749 (83.5%) completed the study. The dropout rate was 16.5%. The serial trial outcome index, the sum of the physical and functional well-being subscales, increased gradually and significantly from baseline during letrozole treatment (p<0.001). The mean serum cholesterol level increased significantly from 199 to 205 after 36 months (p=0.042). The mean BMD significantly decreased from −0.39 at baseline to −0.87 after 36 months (p<0.001). CONCLUSION: QoL gradually improved during letrozole treatment. BMD and serum cholesterol level changes were similar to those in Western countries, indicating that adjuvant letrozole treatment is well tolerated in Korean women, with minimal ethnic variation.

Impact of hormonal therapy and other adjuvant therapies on contralateral breast volume change after implant-based breast reconstruction

BACKGROUND: Adjuvant therapy after breast surgery, including tamoxifen or aromatase inhibitors, improves the postoperative outcomes and long-term survival of breast cancer patients. The aim of this study was to determine whether volume changes occurred in the contralateral breast during hormonal or other adjuvant therapies. METHODS: This study reviewed 90 patients who underwent unilateral breast reconstruction between September 2012 and April 2018 using tissue expanders and a permanent implant after the surgical removal of breast cancer. The volume of the contralateral breast was measured using a cast before the first (tissue expander insertion) and second (permanent implant change) stages of surgery. Changes in breast volume were evaluated to determine whether adjuvant therapy such as hormonal therapy, chemotherapy, and radiation therapy influenced the volume of the contralateral breast. RESULTS: The group receiving tamoxifen therapy demonstrated a significant decrease in volume compared with the group without tamoxifen (−7.8% vs. 1.0%; P=0.028). The aromatase inhibitor–treated group showed a significant increase in volume compared with those who did not receive therapy (−6.2% vs. 4.5%; P=0.023). There were no significant differences between groups treated with other hormonal therapy, chemotherapy, or radiation therapy. CONCLUSIONS: Patients who received tamoxifen therapy showed a significant decrease in volume in the contralateral breast, while no significant change in weight or body mass index was found. Our findings suggest that we should choose smaller implants for premenopausal patients, who have a high likelihood of receiving tamoxifen therapy.

Combined Effect of the PGR + 331C > T, CYP17A1 -34A > G and CYP19A1 1531G > A Polymorphisms on the Risk of Developing Endometriosis / Efeito combinado dos polimorfismos PGR + 331C > T, CYP17A1 -34A > G e CYP19A1 1531G > A no risco de desenvolvimento da endometriose

Abstract Purpose To evaluate the magnitude of the association of the polymorphisms of the genes PGR, CYP17A1 and CYP19A1 in the development of endometriosis. Methods This is a retrospective case-control study involving 161 women with endometriosis (cases) and 179 controls. The polymorphisms were genotyped by real-time polymerase chain reaction using the TaqMan system. The association of the polymorphisms with endometriosis was evaluated using the multivariate logistic regression. Results The endometriosis patients were significantly younger than the controls (36.0±7.3 versus 38.0±8.5 respectively, p = 0.023), and they had a lower body mass index (26.3±4.8 versus 27.9±5.7 respectively, p = 0.006), higher average duration of the menstrual flow (7.4±4.9 versus 6.1±4.4 days respectively, p = 0.03), and lower average time intervals between menstrual periods (25.2±9.6 versus 27.5±11.1 days respectively, p = 0.05). A higher prevalence of symptoms of dysmenorrhea, dyspareunia, chronic pelvic pain, infertility and intestinal or urinary changes was observed in the case group when compared with the control group. The interval between the onset of symptoms and the definitive diagnosis of endometriosis was 5.2±6.9 years. When comparing both groups, significant differences were not observed in the allelic and genotypic frequencies of the polymorphisms PGR + 331C > T, CYP17A1 -34A > G and CYP19A1 1531G > A, even when considering the symptoms, classification and stage of the endometriosis. The combined genotype PGR + 331TT/CYP17A1 -34AA/CYP19A11531AA is positively associated with endometriosis (odds ratio [OR] = 1.72; 95% confidence interval [95%CI] = 1.09-2.72). Conclusions The combined analysis of the polymorphisms PGR-CYP17A1-CYP19A1 suggests a gene-gene interaction in the susceptibility to endometriosis. These results may contribute to the identification of biomarkers for the diagnosis and/or prognosis of the disease and of possible molecular targets for individualized treatments.

Resumo Objetivo Avaliar a magnitude de associação de polimorfismos nos genes PGR, CYP17A1 e CYP19A1 no desenvolvimento da endometriose. Métodos Este é um estudo retrospectivo do tipo caso-controle, envolvendo 161 mulheres com endometriose (casos) e 179 controles. Os polimorfismos foram genotipados pela reação em cadeia da polimerase em tempo real utilizando o sistema TaqMan. A associação dos polimorfismos estudados com a endometriose foi avaliada pela regressão logística multivariada. Resultados As pacientes com endometriose eram significativamente mais jovens do que os controles (36,0±7,3 versus 38,0±8,5, respectivamente, p = 0,023), apresentaram um índice de massa corporal menor (26,3±4,8 versus 27,9±5,7, respectivamente, p = 0,006), maior tempo médio de duração do fluxo menstrual (7,4±4,9 versus 6,1±4,4 dias, respectivamente, p = 0,03) e menor tempo médio do intervalo entre as menstruações (25,2±9,6 versus 27,5±11,1 dias, respectivamente, p = 0,05). Uma maior prevalência dos sintomas de dismenorreia, dispareunia, dor pélvica crônica, infertilidade, alterações intestinais e urinárias foi observada no grupo casos comparado ao grupo controle. O tempo médio entre o início dos sintomas e o diagnóstico definitivo de endometriose foi de 5,2±6,9 anos. Comparando os dois grupos, não foram observadas diferenças significativas nas frequências alélicas e genotípicas dos polimorfismos PGR + 331C > T, CYP17A1 -34A > G e CYP19A1 1531G > A, e nem considerando os sintomas, a classificação e o estadiamento da endometriose. O genótipo combinado PGR + 331TT/CYP17A1 -34AA/CYP19A11531AA está associado positivamente com a endometriose (razão de possibilidades [RP] = 1,72; intervalo de confiança de 95% [IC95%] = 1,09-2,72). Conclusões A análise combinada dos polimorfismos PGR-CYP17A1-CYP19A1 sugere uma interação gene-gene na susceptibilidade à endometriose. Estes resultados podem contribuir para a identificação de biomarcadores para o diagnóstico e/ou prognóstico da doença, assim como de possíveis alvos moleculares para um tratamento individualizado.

Androgênios e mama / Androgens and breast

O câncer de mama (BCA) é uma das neoplasias mais frequentes em mulheres de vários países, a exposição excessiva aos estrogênios é um dos principais fatores de risco. Os ovários são as principais fontes de produção estrogênica endógena; porém, na menopausa essa produção cessa e a síntese extragonadal, sobretudo nas células mesenquimais do tecido adiposo, passa a ser a principal fonte de produção estrogênica, pois essas células apresentam aromatase, enzima que converte androgênios em estrogênios. Apoiada por fortes evidências clínicas, a reposição androgênica tem sido recomendada para o alívio de sintomas decorrentes da síndrome da insuficiência androgênica feminina, tais como fadiga, alterações do humor e quadros de depressão; além disso, estudos experimentais têm sugerido a possibilidade de uma plausível proteção da reposição androgênica contra o BCA. Nesses estudos, em que atuou por meio de seus receptores, a testosterona apresentou efeitos antiproliferativos, pró­apoptóticos e inibiu a atividade dos receptores estrogênicos e do crescimento de tumores mamários; evidências clínicas também apoiam o papel protetor dos androgênios na mama. Entretanto, outros estudos indicam que esse papel protetor depende do nível de atividade da aromatase; assim, a testosterona pode exercer um efeito inibidor direto no crescimento tumoral ao ligar­se ao seu receptor, porém ter um efeito estimulador indireto através de sua conversão para estrogênios pela aromatase. A obesidade e a insulina, além de múltiplos outros fatores, alguns dos quais são fatores de risco independentes para BCA, podem resultar na superexpressão da aromatase e ter como resultado aumento na produção localizada de estrogênios, os quais são fatores estimulantes do BCA. Estudos sobre a administração de testosterona em mulheres são escassos e controversos e não existem estudos que forneçam dados em termos de segurança desse uso em longo prazo. Assim, nesta revisão pretendemos mostrar como os androgênios atuam na mama. Frente às evidências atuais, o uso de androgênios em mulheres com fatores de risco para câncer de mama não é recomendado.(AU)

Breast cancer (BCAA) is one of the most frequent malignancies in women in several countries, which excessive exposure to oestrogens is one of the main risk factors. The ovaries are the main source of endogenous estrogen production; however, at menopause this production sessate and extra­gonadal synthesis, especially in ectomesenchymal cells from adipose tissue, turns the main source of estrogen production, since these cells express aromatase, an enzyme that converts androgens to estrogens. Supported by strong clinical evidence androgen replacement has been recommended for the relief of symptoms caused by female syndrome of androgen insufficiency, such as fatigue, mood swings and depression; Furthermore, experimental studies have suggested the possibility of protection of androgen replacement against BCA. In these studies, acting through their receptors, testosterone showed antiproliferative, proapoptotic and inhibited the activity of estrogen receptors and growth of mammary tumors; Clinical evidence also support the protective role of androgens in the breast. However, studies indicate that this protective role depends on the level of aromatase activity; for instance, testosterone can exert a direct inhibitory effect on tumor growth by binding to its receptor, but have an indirect effect by stimulating its conversion to oestrogens by aromatase. Obesity and insulin, as well as multiple other factors, some of which are independent risk factors for BCA, may result in overexpression of aromatase, resulting in increased localized production of estrogens, which are inducible factors of BCA. Studies on the administration of testosterone in women are scarce and controversial, and there are no studies that provide data in terms of long­term use of safety. Thus, in this review we intend to show how androgens act in the breast. Given the current evidence, the use of androgens in women with risk factors for breast cancer is not recommended.(AU)

Bilateral Salpingo-oophorectomy Compared to Gonadotropin-Releasing Hormone Agonists in Premenopausal Hormone Receptor?Positive Metastatic Breast Cancer Patients Treated with Aromatase Inhibitors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Although combining aromatase inhibitors (AI) with gonadotropin-releasing hormone agonists (GnRHa) is becoming more common, it is still not clear if GnRHa is as effective as bilateral salpingo-oophorectomy (BSO). MATERIALS AND METHODS: We retrospectively analyzed data of 66 premenopausal patients with hormone receptor– positive, human epidermal growth factor receptor 2–negative recurrent and metastatic breast cancer who had been treated with AIs in combination with GnRHa or BSO between 2002 and 2015. RESULTS: The median patient age was 44 years. Overall, 24 (36%) received BSO and 42 (64%) received GnRHa. The clinical benefit rate was higher in the BSO group than in the GnRHa group (88% vs. 69%, p=0.092). Median progression-free survival (PFS) was longer in the BSO group, although statistical significance was not reached (17.2 months vs. 13.3 months, p=0.245). When propensity score matching was performed, the median PFS was 17.2 months for the BSO group and 8.2 months for the GnRHa group (p=0.137). Multivariate analyses revealed that the luminal B subtype (hazard ratio, 1.67; 95% confidence interval [CI], 1.08 to 2.60; p=0.022) and later-line treatment (≥ third line vs. first line; hazard ratio, 3.24; 95% CI, 1.59 to 6.59; p=0.001) were independent predictive factors for a shorter PFS. Incomplete ovarian suppression was observed in a subset of GnRHa-treated patients whose disease showed progression, with E2 levels higher than 21 pg/mL. CONCLUSION: Both BSO and GnRHa were found to be effective in our AI-treated premenopausal metastatic breast cancer patient cohort. However, further studies in larger populations are needed to determine if BSO is superior to GnRHa.

The Examination of Ovarian Reserve in Premenopausal Patients with Hormone Receptor Positive Breast Cancer / 이화의대지

The evaluation of menopausal status is an important subject in the field of treatment of hormone receptor positive breast cancer. According to the menopausal status, endocrine therapy should be categorized by individual patient. However, the gonadal injury caused by various therapeutic drugs and its recovery would confuse the interpretation of clinical and biological markers for ovarian reserve. There are some methods to examine the functional ovarian reserve indirectly. Ultrasonography for counting follicles is a relatively reliable procedure, although it is not feasible because of time-labor consumption and high cost. Biological marker from blood samples such as serum follicle stimulating hormone (FSH), serum estradiol (E2), serum inhibin, or anti-Müllerian hormone (AMH) would be a better choice. The examination of serum FSH and E2 is already recommended as biomarkers for measuring functional ovarian reserve in many guidelines. However, there are limitation of serum FSH and E2 in patients with chemotherapy-induced amenorrhea and treated by tamoxifen. AMH is promising biomarker in the field of infertility treatment even in the patients treated by chemotherapy. It might be a possible biomarker to determine the menopausal status for decision-making whether aromatase inhibitor could be applicable or not in hormone positive breast cancer patients with chemotherapy induced amenorrhea or treated by tamoxifen.