Sonographic evaluation of bladder wall thickness in women with lower urinary tract dysfunction

OBJECTIVE: To investigate the correlation between bladder wall thickness (BWT) measured by ultrasonography and lower urinary tract dysfunction (LUTD) in patients with lower urinary tract symptoms (LUTS). METHODS: Forty-eight women with LUTS who underwent urodynamic study and BWT by ultrasonography as outpatients were studied. We assessed LUTS during a medical examination by interview. The thinnest part of the bladder wall was measured by a transabdominal ultrasonography. We excluded patients who had visited another hospital previously because we did not know what treatment they had received, including medications, behavioral therapy, or other treatments. We constructed receiver operating characteristic (ROC) curves for diagnosis of LUTD and also determined reliable BWT criteria by calculating the area under the curve. Statistical analyses were performed using the Kolmogorov-Smirnov method and Student's t-test. RESULTS: The mean age, body mass index, and duration of symptoms were 59.9±9.7 years, 26.06±3.4 kg/m², and 53.4±38.2 months, respectively. Urodynamic study parameters (Valsalva leak point pressure, maximal urethral closure pressure, functional length, and postvoid residual volume) were lower in patients with BWT < 3 mm; however, these differences were not significant. Patients with BWT ≥3 mm developed a hypoactive bladder (P=0.009) and intrinsic sphincter deficiency (ISD) (P=0.001) at a significantly higher rate. According to the ROC analysis, the best BWT cut-off value was 3 mm for overactive bladder diagnosis. CONCLUSIONS: Women with LUTD showed higher BWT values (≥3 mm), especially patients with hypoactive bladder and ISD. Sonographic evaluation of BWT is an easy, fast, and noninvasive method for possible diagnostic tool for LUTD.

Human chorionic gonadotropin-administered natural cycle versus spontaneous ovulatory cycle in patients undergoing two pronuclear zygote frozen-thawed embryo transfer

OBJECTIVE: To compare human chorionic gonadotropin (HCG)-administered natural cycle with spontaneous ovulatory cycle in patients undergoing frozen-thawed embryo transfer (FTET) in natural cycles. METHODS: In this retrospective cohort study, we analyzed the clinical outcome of a total of 166 consecutive FTET cycles that were performed in either natural cycle controlled by HCG for ovulation triggering (HCG group, n=110) or natural cycle with spontaneous ovulation (control group, n=56) in 166 infertile patients between January 2009 and November 2013. RESULTS: There were no differences in patients' characteristics between the 2 groups. The numbers of oocytes retrieved, mature oocytes, fertilized oocytes, grade I or II embryos and frozen embryos in the previous in vitro fertilization (IVF) cycle in which embryos were frozen were comparable between the HCG and control groups. Significant differences were not also observed between the 2 groups in clinical pregnancy rate (CPR), embryo implantation rate, miscarriage rate, live birth rate and multiple CPR. However, the number of hospital visits for follicular monitoring was significantly fewer in the HCG group than in the control group (P < 0.001). CONCLUSION: Our results demonstrated that HCG administration for ovulation triggering in natural cycle reduces the number of hospital visits for follicular monitoring without any detrimental effect on FTET outcome when compared with spontaneous ovulatory cycles in infertile patients undergoing FTET in natural ovulatory cycles.

Pelvic artery embolization in the management of pelvic arterial bleeding following midurethral sling surgery for stress urinary incontinence

The transobturator tape (TOT) method is the recent minimally invasive midurethral sling surgery. The TOT method was invented to reduce complication rate of surgical technique for female stress urinary incontinence. Pelvic bleeding following TOT procedure, although extremely rare, could be occurred. We presented three cases which treat pelvic arterial bleeding after midurethral sling (TOT and tension-free vaginal tape Secur) surgery via pelvic artery embolization. Therefore we report our cases with brief review of the literature.

Efficacy and safety of dienogest in patients with endometriosis: A single-center observational study over 12 months / 대한생식의학회지

OBJECTIVE: To evaluate the efficacy and safety of dienogest treatment in patients who had received dienogest for 12 months or more to treat endometriosis. METHODS: We analyzed the clinical data of 188 women with endometriosis who had been treated with 2 mg of dienogest once a day for 12 months or more at a single institute. We evaluated changes in endometriosis-associated pain and endometrioma size, recurrence rate, and adverse events following dienogest administration. Bone mineral density (BMD) was measured in patients who were prescribed dienogest for more than 18 months. RESULTS: Pain was significantly reduced at 12 months after dienogest medication. In those treated with dienogest due to recurrent endometrioma, the size of the endometrioma was significantly decreased at the 12-month and 18-month follow-ups. We found only one case of sonographic recurrence during dienogest administration among those who were treated postoperatively to prevent recurrence (1 of 114, 0.9%). The most common adverse drug reaction was uterine bleeding (3.2%), and other adverse events were generally tolerable and associated with low discontinuation rates (5.2%). Among the 50 patients in whom BMD was measured, 10 patients (20%) had a Z-score below the expected range for age. CONCLUSION: The administration of dienogest for a year or more seems to be highly effective in preventing recurrence after surgery, reducing endometriosis-associated pain, and decreasing the size of recurrent endometrioma, with a favorable safety and tolerability profile. However, BMD should be checked in patients on long-term medication due to possible bone loss in some women.

Increased expression of nuclear factor kappa-B p65 subunit in adenomyosis

OBJECTIVE: Nuclear factor kappa-B (NF-κB) is a critical proinflammatory regulator that has been suggested to play a pivotal role in the pathogenesis and pathophysiology of endometriosis. In the present study, we aimed to evaluate whether the expression of NF-κB p65 subunit is increased in the eutopic endometrium and/or in the adenomyosis nodule of women with adenomyosis. METHODS: Thirty-three women with histologically confirmed adenomyosis after laparoscopic or transabdominal hysterectomy were recruited. Women with carcinoma in situ of uterine cervix without evidence of adenomyosis or endometriosis (n=32) served as controls. Formalin-fixed, paraffin-embedded archival tissues were sectioned and immunostained utilizing a monoclonal anti-human NF-κB p65 subunit antibody, and the immunoreactivity of NF-κB p65 subunit was compared between women with and without adenomyosis. RESULTS: The immunoreactivities of both the nuclear and the cytoplasmic NF-κB p65 subunit were significantly increased in the stromal cells in the eutopic endometrium as well as in the adenomyosis nodule of women with adenomyosis compared with controls, respectively. The nuclear expression of NF-κB p65 subunit was significantly higher in the glandular cells in the eutopic endometrium as well as the adenomyosis nodule of women with adenomyosis compared with controls, respectively. CONCLUSION: The expression of NF-κB p65 is increased in the eutopic endometrium and adenomyosis nodule of women with adenomyosis, which strongly suggest that NF-κB plays a critical role in the pathogenesis and/or pathophysiology of adenomyosis.

Decreased Progesterone Receptor B/A Ratio in Endometrial Cells by Tumor Necrosis Factor-Alpha and Peritoneal Fluid from Patients with Endometriosis

PURPOSE: Progesterone resistance is thought to be a major factor that contributes to progression of endometriosis. However, it is not clear what causes progesterone resistance in endometriosis. This study aimed to assess whether cytokines or peritoneal fluid can affect progesterone receptor (PR) expression in endometrial cells and to verify whether PR expression is reduced in endometriosis. MATERIALS AND METHODS: The PR-B/A ratio was measured via real-time polymerase chain reaction after in vitro culture, in which endometrial cells were treated with either tumor necrosis factor-alpha (TNF-α), interleukin-1 beta, or peritoneal fluid obtained from women with advanced-stage endometriosis. Immunohistochemistry was performed to compare PR-B expression between eutopic and ectopic endometrial tissues from women with and without advanced-stage endometriosis. RESULTS: The PR-B/A ratio was significantly decreased by treatment with either TNF-α (p=0.011) or peritoneal fluid from women with advanced-stage endometriosis (p=0.027). Immunoreactivity of PR-B expression was significantly lower during the secretory phase than during the proliferative phase in endometrial tissues from control subjects (p<0.001). PR-B expression was significantly reduced in the eutopic endometrium (p=0.031) and ovarian endometrioma (p=0.036) from women with advanced-stage endometriosis compared with eutopic endometrium tissues from control subjects. CONCLUSION: Progesterone resistance in endometriosis may be caused by proinflammatory conditions in the pelvic peritoneal microenvironment.

Decreased Progesterone Receptor B/A Ratio in Endometrial Cells by Tumor Necrosis Factor-Alpha and Peritoneal Fluid from Patients with Endometriosis

PURPOSE: Progesterone resistance is thought to be a major factor that contributes to progression of endometriosis. However, it is not clear what causes progesterone resistance in endometriosis. This study aimed to assess whether cytokines or peritoneal fluid can affect progesterone receptor (PR) expression in endometrial cells and to verify whether PR expression is reduced in endometriosis. MATERIALS AND METHODS: The PR-B/A ratio was measured via real-time polymerase chain reaction after in vitro culture, in which endometrial cells were treated with either tumor necrosis factor-alpha (TNF-α), interleukin-1 beta, or peritoneal fluid obtained from women with advanced-stage endometriosis. Immunohistochemistry was performed to compare PR-B expression between eutopic and ectopic endometrial tissues from women with and without advanced-stage endometriosis. RESULTS: The PR-B/A ratio was significantly decreased by treatment with either TNF-α (p=0.011) or peritoneal fluid from women with advanced-stage endometriosis (p=0.027). Immunoreactivity of PR-B expression was significantly lower during the secretory phase than during the proliferative phase in endometrial tissues from control subjects (p<0.001). PR-B expression was significantly reduced in the eutopic endometrium (p=0.031) and ovarian endometrioma (p=0.036) from women with advanced-stage endometriosis compared with eutopic endometrium tissues from control subjects. CONCLUSION: Progesterone resistance in endometriosis may be caused by proinflammatory conditions in the pelvic peritoneal microenvironment.

Effect of second-line surgery on in vitro fertilization outcome in infertile women with ovarian endometrioma recurrence after primary conservative surgery for moderate to severe endometriosis

OBJECTIVE: To evaluate the effect of second-line conservative surgery on in vitro fertilization (IVF) outcome in comparison with IVF without second-line surgery in infertile women with ovarian endometrioma recurrence after primary conservative surgery. METHODS: In this retrospective cohort study, 121 consecutive IVF/intracytoplasmic sperm injection cycles that were performed after second-line surgery (n=53) or without second-line surgery (control group, n=68) between January 2006 and December 2011 in 121 infertile women with ovarian endometrioma(s) recurrence after primary conservative surgery for moderate to severe endometriosis were included. The two groups were compared in terms of controlled ovarian stimulation and IVF outcomes. RESULTS: There were no differences in patients' characteristics between the two groups. Total dose and days of gonadotropins administered were significantly higher in the second-line surgery group than in the control group (P<0.001, P=0.008). The numbers of oocytes retrieved, mature oocytes and grade 1 or 2 embryos were significantly lower in the second-line surgery group (P=0.007, P=0.001, P<0.001, respectively). Clinical pregnancy rate per cycle and embryo implantation rate were also significantly lower in the second-line surgery group of 24.5% and 11.8% compared with 48.5% and 25.3% in the control group (P=0.008, P=0.005, respectively). CONCLUSION: Ovarian response to controlled ovarian stimulation and IVF outcome after second-line surgery is worse than those in IVF cycles without second-line surgery in infertile women with ovarian endometrioma recurrence after primary surgery for moderate or severe endometriosis.

Impact of glycosylation on the unimpaired functions of the sperm / 대한생식의학회지

One of the key factors of early development is the specification of competence between the oocyte and the sperm, which occurs during gametogenesis. However, the starting point, growth, and maturation for acquiring competence during spermatogenesis and oogenesis in mammals are very different. Spermatogenesis includes spermiogenesis, but such a metamorphosis is not observed during oogenesis. Glycosylation, a ubiquitous modification, is a preliminary requisite for distribution of the structural and functional components of spermatids for metamorphosis. In addition, glycosylation using epididymal or female genital secretory glycans is an important process for the sperm maturation, the acquisition of the potential for fertilization, and the acceleration of early embryo development. However, nonemzymatic unexpected covalent bonding of a carbohydrate and malglycosylation can result in falling fertility rates as shown in the diabetic male. So far, glycosylation during spermatogenesis and the dynamics of the plasma membrane in the process of capacitation and fertilization have been evaluated, and a powerful role of glycosylation in spermatogenesis and early development is also suggested by structural bioinformatics, functional genomics, and functional proteomics. Further understanding of glycosylation is needed to provide a better understanding of fertilization and embryo development and for the development of new diagnostic and therapeutic tools for infertility.

Polycystic ovary syndrome woman with heterozygous androgen receptor gene mutation who gave birth to a child with androgen insensitivity syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, and it is a multifactorial polygenic disorder with a broad spectrum of clinical manifestations. Although pathogenesis is still unclear, androgen receptor (AR) gene polymorphism may be one of the etiologic factors of PCOS. AR gene polymorphism has been also associated with other forms of androgen pattern diseases. We report a PCOS woman with heterozygous AR gene mutation who gave birth to a baby with andorgen insensitivity syndrome.

Alterations in uterine hemodynamics caused by uterine fibroids and their impact on in vitro fertilization outcomes / 대한생식의학회지

OBJECTIVE: To investigate the impact of fibroids on the blood flow of the uterine and subendometrial arteries and in vitro fertilization (IVF) outcomes. METHODS: In this study, we analyzed 86 IVF/intracytoplasmic sperm injection (ICSI) cycles in which a gonadotropin-releasing hormone antagonist protocol was used for controlled ovarian stimulation between January 2008 and March 2009. The subjects comprised 86 infertile women with (fibroid group, n=43) or without (control group, n=43) uterine fibroids. RESULTS: Patient characteristics were similar between the fibroid and control groups. The IVF/ICSI outcomes in patients with fibroids were similar to those of patients in the control group. The resistance index (RI) and pulsatile index (PI) of the uterine and subendometrial arteries on the day of embryo transfer were also comparable between the two groups. IVF outcomes and uterine hemodynamics in patients with multiple (> or =2) fibroids were similar to those of patients with a single fibroid. However, clinical pregnancy and implantation rates were significantly lower in patients with fibroids who experienced uterine cavity distortion than in patients with fibroids who had a normal uterine cavity (both p<0.05). The RI and PI of the subendometrial artery were significantly higher on the day of embryo transfer in patients with fibroids who experienced uterine cavity distortion than in patients with fibroids who had a normal uterine cavity (both p<0.05). CONCLUSION: Fibroids which distorting the uterine cavity might impair the subendometrial artery blood flow clinical pregnancy rate and embryo implantation rate in infertile patients undergoing IVF. Otherwise, IVF outcomes were not influenced by the presence of uterine fibroids.

Subclinical hypothyroidism diagnosed by thyrotropin-releasing hormone stimulation test in infertile women with basal thyroid-stimulating hormone levels of 2.5 to 5.0 mIU/L

OBJECTIVE: To investigate the prevalence of subclinical hypothyroidism (SH) diagnosed by thyrotropin-releasing hormone (TRH) stimulating test in infertile women with basal thyroid-stimulating hormone (TSH) levels of 2.5 to 5.0 mIU/L. METHODS: This study was performed in 39 infertile women with ovulatory disorders (group 1) and 27 infertile women with male infertility only (group 2, controls) who had basal serum TSH levels of 2.5 to 5.0 mIU/L and a TRH stimulating test. Serum TSH levels were measured before TRH injection (TSH0) and also measured at 20 minutes (TSH1) and 40 minutes (TSH2) following intravenous injection of 400 microg TRH. Exaggerated TSH response above 30 mIU/L following TRH injection was diagnosed as SH. Group 1 was composed of poor responders (subgroup A), patients with polycystic ovary syndrome (subgroup B) and patients with WHO group II anovulation except poor responder or polycystic ovary syndrome (subgroup C). RESULTS: The prevalence of SH was significantly higher in group 1 of 46.2% (18/39) compared with 7.4% (2/27) in group 2 (P=0.001). TSH0, TSH1, and TSH2 levels were significantly higher in group 1 than the corresponding values in group 2 (P<0.001, P<0.001, P<0.001). In group 1, TSH1 and TSH2 levels were significantly lower in subgroup C compared with those in subgroup A and B (P=0.008, P=0.006, respectively). CONCLUSION: TRH stimulation test had better be performed in infertile women with ovulatory disorders who have TSH levels between 2.5 and 5.0 mIU/L for early detection and appropriate treatment of SH.

The effect of aromatase inhibitor letrozole incorporated in gonadotrophin-releasing hormone antagonist multiple dose protocol in poor responders undergoing in vitro fertilization

OBJECTIVE: To evaluate whether letrozole incorporated in a gonadotrophin-releasing hormone (GnRH) antagonist multiple dose protocol (MDP) improved controlled ovarian stimulation (COS) and in vitro fertilization (IVF) results in poor responders who underwent IVF treatment. METHODS: In this retrospective cohort study, a total of 103 consecutive IVF cycles that were performed during either the letrozole/GnRH antagonist MDP cycles (letrozole group, n=46) or the standard GnRH antagonist MDP cycles (control group, n=57) were included in 103 poor responders. COS results and IVF outcomes were compared between the two groups. RESULTS: Total dose and days of recombinant human follicle stimulating hormone (rhFSH) administered were significantly fewer in the letrozole group than in the control group. Duration of GnRH antagonist administered was also shorter in the letrozole group. The number of oocytes retrieved was significantly higher in the letrozole group. However, clinical pregnancy rate per cycle initiated, clinical pregnancy rate per embryo transfer, embryo implantation rate and miscarriage rate were similar in the two groups. CONCLUSION: The letrozole incorporated in GnRH antagonist MDP may be more effective because it results comparable pregnancy outcomes with shorter duration and smaller dose of rhFSH, when compared with the standard GnRH antagonist MDP.

The first successful live birth following preimplantation genetic diagnosis using PCR for type 1 citrullinemia

Type 1 citrullinemia (CTLN1) is an autosomal recessive inherited metabolic disorder caused by anargininosuccinicnate synthetase deficiency. The patient was a 38-year-old Korean woman who is a carrier for CTLN1 and her first baby was diagnosed with CTLN1. Preimplantation genetic diagnosis (PGD) for CTLN1 in day 3 embryos using polymerase chain reaction was performed for live birth of healthy baby who is no affected with CTLN1. One unaffected blastocyst was transferred. This resulted in a clinical pregnancy and the live birth of healthy male twin. They were confirmed to be unaffected with CTNL1 by post natal diagnosis. This is the first case report of the use of PGD for CTNL1.

Causes of amenorrhea in Korea: Experience of a single large center / 대한생식의학회지

OBJECTIVE: To investigate the causes of amenorrhea in Korean women. METHODS: Medical records from 1,212 women with amenorrhea who visited the Department of Obstetrics and Gynecology, Asan Medical Center, between January 1989 and December 2011 were retrospectively reviewed. Amenorrhea was categorized as either primary or secondary. RESULTS: Primary amenorrhea was identified in 132 of the patients (10.9%) and secondary amenorrhea in 1,080 (89.1%). The most frequent causes of primary amenorrhea were gonadal dysgenesis (28.0%, 37/132); Mayer-Rokitansky-Kuster-Hauser syndrome (20.0%, 27/132); and constitutional delay and androgen insensitivity syndrome (8.3%, 11/132; 8.3%, 11/132, respectively). Secondary amenorrhea was due to polycystic ovary syndrome (48.4%, 523/1,080); premature ovarian insufficiency (14.0%, 151/1,080); and nutrition-related hypogonadotropic hypogonadism (8.3%, 90/1,080). CONCLUSION: In this retrospective study, gonadal dysgenesis was the most common cause of primary amenorrhea and polycystic ovary syndrome was the most common cause of secondary amenorrhea in Korean women.

The effect of luteal phase progesterone supplementation on natural frozen-thawed embryo transfer cycles

OBJECTIVE: To evaluate the effect of progesterone supplementation during the luteal phase on pregnancy outcome in natural frozen-thawed embyo transfer (FTET) cycles. METHODS: In this retrospective cohort study, 228 consecutive patients who underwent FTET cycles between January 2009 and September 2012 were included. One hundred forty-five patients received luteal progesterone support (P group) but 83 patients did not receive any progesterone supplementation during luteal phase (control group). RESULTS: There were no differences in patients' characteristics between the two groups. The two groups were similar with respect to the characteristics of previous fresh in vitro fertilization cycle in which embryos were cryopreserved including the numbers of oocytes retrieved, mature oocytes, fertilized oocytes, grade 1 or 2 embryos and frozen embryos. Also, significant differences were not observed between the P and control groups in clinical pregnancy rate, embryo implantation rate and multiple pregnancy rate. However, miscarriage rate was significantly lower in the P group and live birth rate was significantly higher in the P group than in the control group (P<0.05, P<0.05). CONCLUSION: Our results suggest that luteal phase progesterone supplementation decreases miscarriage rate and improves live birth rate in natural FTET cycles.

Surgical resection or aspiration with ethanol sclerotherapy of endometrioma before in vitro fertilization in infertilie women with endometrioma

OBJECTIVE: To evaluate whether the surgical resection or aspiration with ethanol sclerotherapy (AEST) of endometrioma before in vitro fertilization (IVF) affect controlled ovarian stimulation (COS) and IVF outcome in the infertilie women with endometroma undergoing IVF. METHODS: In this retrospective cohort study, 101 consecutive IVF/intracytoplasmic sperm injection cycles that were performed in 101 patients with endometrioma(s) between January 2008 and December 2012 were included. Before IVF, 36 patients underwent surgical resection of endometrioma (resection group), 29 patients had transvaginal endometrioma AEST (aspiration group), and 36 patients did not take any surgical intervention (control group). The three groups were compared in terms of COS and IVF outcomes. RESULTS: Total antral follicle count was significantly lower in the resection group than in the aspiration or control group. The numbers of follicles with a diameter of 14 to 17 mm on the human chorionic gonadotropin day, retrieved oocytes, mature oocytes, and fertilized oocytes were significantly lower in the resection group than in two other groups. However, three groups were similar in terms of clinical pregnancy rate (CPR) per initiated cycle, CPR per embryo transfer, embryo implantation rate, and miscarriage rate. CONCLUSION: Neither of surgical resection and AEST of endometrioma before IVF treatment can give any beneficial effect on IVF outcomes. Moreover, surgical resection of endometrioma can affect the ovarian reserve and ovarian response during COS.

Successful pregnancy by direct intraperitoneal insemination in an infertile patient with failure of recanalization of isthmic stenosis after laparoscopic radical trachelectomy

Radical trachelectomy is a promising fertility-sparing treatment for patients with early stage cervical cancer who want to preserve their fertility. However, isthmic stenosis occurs frequently in patients who received radical trachelectomy and it is one of the causes of infertility following radical trachelectomy. Moreover, despite the treatment for recanalization of isthmic stenosis, recanalization can fail or isthmic stenosis can recur. Herein we report a successful pregnancy and birth by direct intraperitoneal insemination in an infertile woman with failure of recanalization of isthmic stenosis after laparoscopic radical trachelectomy.

A 6-year-old girl with vaginal spotting who was diagnosed with perivascular epithelioid cell neoplasm after vaginoscopic resection

Perivascular epithelioid cell neoplasm (PEComa) is a rare tumor with unknown malignant potential. We report a case of a 6-year-old child with history of brain tumor (pineoblastoma), who presented with intermittent vaginal spotting for 6 months. A vaginoscopy revealed a 1.5x1.0-cm mass on the vaginal wall. Pathological examination demonstrated that the tumor was composed of clear cells with organoid patterns, which were immunohistochemically positive for HMB-45 and TFE3, and negative for CK, HNF1-B, SOX10, Melan A, and S-100 protein. These findings were consistent with PEComa arising from the vagina. Regular follow-up with magnetic resonance imaging has shown no signs of recurrence. This case shows that early detection of PEComa and subsequent regular follow-ups are important because of the neoplasm's unknown malignant potential.

Update on the treatment of endometriosis / 대한생식의학회지

Endometriosis is defined as the presence of functional endometrial tissue outside the uterus, causing diverse progressive symptoms such as infertility, pelvic pain, and dysmenorrhea. Although endometriosis has been described since the 1800s, the mechanisms responsible for its pathogenesis and progression remain poorly understood. It is well established that endometriosis grows and regresses in an estrogen-dependent fashion and the disease can be effectively cured by definitive surgery. However, prolonged medical therapy may be needed in most of the cases since conservative surgery is usually performed especially in young women. This treatment modality is often associated with only partial relief and/or recurrence of the disease. In the present review, up-to-date findings on the treatment of endometriosis will be briefly summarized. The outcomes of surgery in patients with endometriosis will be reviewed in terms of pelvic pain relief as well as infertility treatment largely based on recent Cochrane reviews and clinical reports. The efficacy of newer drugs including aromatase inhibitor, anti-tumor necrosis factor-alpha, and dienogest will be also reviewed based on recent clinical studies.