Ben-Shian Huang

Oestrogen‐induced angiogenesis promotes adenomyosis by activating the Slug‐VEGF axis in endometrial epithelial cells

Adenomyosis is an oestrogen‐dependent disease characterized by the invasion of endometrial epithelial cells into the myometrium of uterus, and angiogenesis is thought to be required for the implantation of endometrial glandular tissues during the adenomyotic pathogenesis. In this study, we demonstrate that compared with eutopic endometria, adenomyotic lesions exhibited increased vascularity as detected by sonography. Microscopically, the lesions also exhibited an oestrogen‐associated elevation of microvascular density and VEGF expression in endometrial epithelial cells. We previously reported that oestrogen‐induced Slug expression was critical for endometrial epithelial–mesenchymal transition and development of adenomyosis. Our present studies demonstrated that estradiol (E2) elicited a Slug‐VEGF axis in endometrial epithelial cells, and also induced pro‐angiogenic activity in vascular endothelial cells. The antagonizing agents against E2 or VEGF suppressed endothelial cells migration and tubal formation. Animal experiments furthermore confirmed that blockage of E2 or VEGF was efficient to attenuate the implantation of adenomyotic lesions. These results highlight the importance of oestrogen‐induced angiogenesis in adenomyosis development and provide a potential strategy for treating adenomyosis through intercepting the E2‐Slug‐VEGF pathway.

Effects of dehydroepiandrosterone supplementation on women with poor ovarian response: A preliminary report and review.

OBJECTIVE To investigate the effect of dehydroepiandrosterone (DHEA) supplementation on women with poor ovarian response (POR). MATERIALS AND METHODS Women with POR treated with flexible daily gonadotropin-releasing hormone antagonist in vitro fertilization (IVF) cycles at The Reproductive Center in Kaohsiung Veterans General Hospital between January 2013 and October 2013, were enrolled for this prospective study. When patients failed to become pregnant during the first IVF cycle, they were treated with DHEA supplementation (30 mg, 3 times a day, orally) for 3 months (mean 12.2 weeks) before the next IVF cycle. Parameters of biochemical, ultrasound and treatment outcomes were compared before and after DHEA supplementation. RESULTS Ten patients with a mean age of 36.6 ± 4.2 years were identified. After DHEA treatment, there was a significant increase in antral follicle count, from 2.8 ± 1.0 to 4.1 ± 1.2 (p < 0.05), and anti-Müllerian hormone, from 0.4 ± 0.2 ng/mL to 0.84 ± 0.2 ng/mL (p < 0.001). A significant decrease of Day 3 follicle-stimulating hormone and estradiol, from 14.4 ± 1.7 mIU/mL to 10.1 ± 0.7 mIU/mL and from 51.2 ± 6.3 pg/mL to 35.2 ± 4.2 pg/mL, respectively (both p < 0.001), was noted. Increased numbers of retrieved oocytes (from 2.4 ± 1.1 to 4.2 ± 1.2; p < 0.01), fertilized oocytes (from 1.7 ± 0.5 to 3.8 ± 1.1; p < 0.001), Day 3 embryos (from 1.7 ± 0.5 to 3.7 ± 1.1; p < 0.001) and transferred embryos (from 1.7 ± 0.8 to 2.8 ± 0.8; p < 0.01) were also seen in these women with POR after DHEA treatment. Three women became pregnant after DHEA treatment. CONCLUSION The potential benefits of DHEA supplementation in women with POR were suggested by the biochemical parameters and IVF outcomes.

Clinical presentation and outcome of adult-type granulosa cell tumors: A retrospective study of 30 patients in a single institute

Background: Ovarian adult‐type granulosa cell tumors (GCTs) are characterized as low‐malignant and late‐recurrent ovarian tumors. Although some clinical and pathological prognostic factors have been reported, other factors have yet to be sufficiently investigated for necessary confirmation. The aim of this study was to test the correlation between clinical factors and outcome, based on patients seen in a single institute. Methods: Thirty patients with pathologically confirmed adult‐type GCTs between 1984 and 2010 were reviewed retrospectively. Among them, eight (26.7%) had recurrence, which subsequently contributed to two mortalities. Results: In a comparison of the clinical characteristics of the premenopausal and postmenopausal women with GCT, all of the postmenopausal women had symptoms (100% vs. 63.6%, p = 0.01). With regard to disease recurrence, only abnormal preoperative serum cancer antigen 125 level (≥35 U/mL) was significant (50% vs. 11%, p = 0.03), and residual tumor showed a borderline trend (100% vs. 21.4%, p = 0.06). Other factors, including International Federation of Gynecology and Obstetrics stage, tumor size, tumor rupture prior to or during operation, body mass index, parity, serum estrogen level, and adjuvant therapy, were not statistically significant. Conclusion: Physicians should be alert to the difference in the symptom presentation of GCTs between pre‐ and postmenopausal women, giving particular attention to the usefulness of the preoperative serum level of cancer antigen 125 in patients with GCTs. More evidence is needed to confirm this observation.

Ruptured ovarian endometrioma

We read the report by Huang et al entitled “Long-term follow-up of patients surgically treated for ruptured ovarian endometriotic cysts” [1] with interest. The authors retrospectively reviewed 11 patients with ruptured endometrioma and a history of dysmenorrhea who underwent surgical intervention and followed-up examination for more than 3 years, and the authors concluded that emergency surgical intervention may lead to a better prognosis, particularly in patients without a history of previous endometrioma surgery [1]. Although the authors’ conclusion suggesting that emergent surgical intervention may lead to a better prognosis might be correct, authors did not provide enough data to support their conclusion. For example, the authors failed to define the term “emergency surgical intervention”. In addition, the term of “prognosis” is also unclear. Based on our understanding of this article [1], prognosis might include pain score, sonographic findings, serum CA-125 levels, further surgery (e.g., cyst aspiration), and pregnancy, but the above mentioned prognosis is not consistent in the article [1]. Of course, we should emphasize that this should not be construed as an argument against the authors’ excellent work. Only one patient underwent surgery 48 hours later after the sudden onset of acute abdomen, and the majority of the patients (64%; n 1⁄4 7) were surgically treated within 6 hours [1]. Did the authors suggest to each patient that they should be treated within 6 hours? If the abovementioned definition is acceptable, based on our understanding, three patients in this report had a future successful pregnancy [1] and all underwent surgical intervention within the first 6 hours (1 laparotomy and the other 2 laparoscopies). In addition, all of these patients did not have a history of endometrioma surgery, which may be the reason why the authors reached their conclusion: emergency surgical intervention may lead to a better prognosis if the outcome is evaluated in terms of the pregnancy. In contrast, if the need for further procedures was also included in the evaluation of the clinical outcomes, this would include two of seven patients (29%) in the emergency surgical intervention group who underwent cystic aspiration in comparison with one of four patients (25%) who was diagnosed by cystic aspiration on a follow-up examination. The need for further procedures seems to be similar between both groups, suggesting that no advantage was gained by patients who were surgically treated

Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan.

Abstract Endometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long‐term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities.

Low-dose add-back therapy during postoperative GnRH agonist treatment

OBJECTIVE Low-dose add-back therapy during postoperative GnRH agonist treatment could lower the risk of add-back-induced endometriosis recurrence and reduce treatment dropout compared with a regular dose. However, the effect of low-dose add-back therapy is still unknown. The aim of this study was to determine whether low-dose add-back therapy can also effectively relieve the hypoestrogenic side effects and simultaneously maintain a therapeutic response of GnRH agonist treatment. MATERIALS AND METHODS This analysis was a prospective cohort study. During postoperative GnRH agonist treatment, a total of 107 women were prescribed add-back therapy [oral combination tablet; estradiol valerate (1 mg) and medroxyprogesterone acetate (2.5 mg)] (Indivina; Orion, Espoo, Finland) for 20 weeks. Patients in the low dose add-back therapy group were prescribed the tablet once a day, and patients in the regular dose group were given the tablet twice a day. Hypoestrogenic side effects, such as hot flashes and insomnia, were recorded. Patients were also questioned regarding their pelvic symptoms and pain to evaluate the possibility of endometriosis recurrence. Lumbar spine (L2-L4) bone mineral density was measured using dual X-ray absorptiometry. The dropout rates in both groups were also evaluated. RESULTS The incidence of hypoestrogenic side effects was lower in the low dose group compared with the regular dose group, including hot flashes (19.2% vs. 21.8%, p = 0.741) and insomnia (15.4% vs. 18.2%, p = 0.699), although there were no significant difference between the groups. In addition, a higher number of patients in the regular dose group dropped out of treatment compared to the low dose group (14.5% and 9.6%, respectively, p = 0.435). The patients in both groups had a significant loss of mean bone mineral density during therapy (p < 0.001 and p = 0.018 for the low dose and regular dose groups, respectively). CONCLUSION Low dose add-back therapy could effectively ameliorate hypoestrogenic side effects and simultaneously maintain the therapeutic response of GnRH agonist treatment. The treatment dropout was lower compared with a regular dose. Therefore, low dose add-back therapy can be considered a treatment choice during postoperative GnRH agonist treatment.

Oestrogen-induced angiogenesis and implantation contribute to the development of parasitic myomas after laparoscopic morcellation

BackgroundIatrogenic parasitic myomas (PMs), caused by intra-corporeal power morcellation during laparoscopy is gradually increasing. However, the pathogenesis and medical treatment of PMs remain largely unelucidated.MethodsLaparoscopically-induced PM xenografted mouse model was conducted by xenografting human uterine myoma fragments into the abdominal cavity of SCID mice and hormonal manipulation was performed using this mouse model to demonstrate the role of oestrogen in the development of implanted PMs. Immunohistochemistry of oestrogen receptor α (ERα), progesterone receptor (PR), vimentin, vascular endothelial growth factor (VEGF), microvessel density (MVD) and Ki-67 index was performed and compared.ResultsIn the patient with PMs, ERα, PR, angiogenesis and proliferative property expression were upregulated in PM lesions compared to uterine myomas. In the laparoscopically-induced PM mouse model, implanted myomas had more steroid receptor expressions, angiogenesis and proliferative property compared with pre-xenografted or non-implanted myoma. Depletion of oestrogen in the ovariectomized (OVX) mice decreased laparoscopically-induced PM implantations. In comparison, the implantations of PMs were increased with additional E2 supplement. Hormonal manipulation in the PM mouse model, including AI, GnRHa and SERM groups, were compared and AI significantly decreased the implantations, steroid receptor, angiogenesis, cell density, and proliferative index of PMs compared with control group. Furthermore, GnRHa significantly decreased VEGF and MVD expressions compared with control group.ConclusionsThese data highlight the crucial role of oestrogen in the development of laparoscopically-induced PMs and suggest that hormone manipulation may be a potential therapeutic agent.Trial registrationThis protocol was approved by the Human and Animal Institutional Review Board of Taipei Veterans General Hospital (VGHIRB No 2014-10-002C on Nov. 17th, 2014; IACUC 2014-119 on Aug. 22nd, 2014).

Endometriosis Might Be Inversely Associated with Developing Chronic Kidney Disease: A Population-Based Cohort Study in Taiwan

This study was conducted to determine the risk of chronic kidney disease (CKD) among women with endometriosis in Taiwan. We conducted a retrospective cohort study using the National Health Insurance Research Database of Taiwan. A total of 27,973 women with a diagnosis of endometriosis and 27,973 multivariable-matched controls (1:1) from 2000 to 2010 were selected. Cox regression and computed hazard ratios (HR) with 95% confidence intervals (95% CI) were used to determine the risk of CKD among women with endometriosis. The incidence rates (IR, per 10,000 person-years) of CKD among women with and without endometriosis were 4.64 and 7.01, respectively, with a significantly decreased risk of CKD (crude HR 0.65, 95% CI 0.53–0.81; adjusted HR 0.69, 95% CI 0.56–0.86) among women with endometriosis. The IR of CKD progressively increased with age, but the trend of lower CKD risk among women with endometriosis was consistent. However, the lower risk of CKD in women with endometriosis was no longer statistically significant after adjusting for menopausal status (adjusted HR 0.85, 95% CI 0.65–1.10). The results suggest that endometriosis is inversely associated with CKD, but this effect was mediated by menopause. The possible mechanism of this association is worthy of further evaluation.

Estrogen Effects on Wound Healing

Wound healing is a physiological process, involving three successive and overlapping phases—hemostasis/inflammation, proliferation, and remodeling—to maintain the integrity of skin after trauma, either by accident or by procedure. Any disruption or unbalanced distribution of these processes might result in abnormal wound healing. Many molecular and clinical data support the effects of estrogen on normal skin homeostasis and wound healing. Estrogen deficiency, for example in postmenopausal women, is detrimental to wound healing processes, notably inflammation and re-granulation, while exogenous estrogen treatment may reverse these effects. Understanding the role of estrogen on skin might provide further opportunities to develop estrogen-related therapy for assistance in wound healing.

Uterine sarcoma part III—Targeted therapy: The Taiwan Association of Gynecology (TAG) systematic review

Uterine sarcoma is a very aggressive and highly lethal disease. Even after a comprehensive staging surgery or en block cytoreduction surgery followed by multimodality therapy (often chemotherapy and/or radiation therapy), many patients relapse or present with distant metastases, and finally die of diseases. The worst outcome of uterine sarcomas is partly because of their rarity, unknown etiology, and highly divergent genetic aberration. Uterine sarcomas are often classified into four distinct subtypes, including uterine leiomyosarcoma, low-grade uterine endometrial stromal sarcoma, high-grade uterine endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Currently, evidence from tumor biology found that these tumors showed alternation and/or mutation of genomes and the intracellular signal pathway. In addition, some preclinical studies showed promising results for targeting receptor tyrosine kinase signaling, phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway, various kinds of growth factor pathways, Wnt/beta-catenin signaling pathway, transforming growth factor β/bone morphogenetic protein signal pathway, aurora kinase A, MDM2 proto-oncogene, histone deacetylases, sex hormone receptors, certain types of oncoproteins, and/or loss of tumor suppressor genes. The current review is attempted to summarize the recurrent advance of targeted therapy for uterine sarcomas.