Positive intervention effect of mobile health application based on mindfulness and social support theory on postpartum depression symptoms of puerperae.

OBJECTIVE: This study investigated the effects of mobile health application designed based on mindfulness and social support theory on parenting self-efficacy and postpartum depression symptoms of puerperae. METHODS: We recruited 130 puerperae from a hospital in China and randomized them to an App use group (n = 65) and a waiting control group (n = 65). The App group underwent an 8-week app use intervention while the control group underwent no intervention. We measured four main variables (mindfulness, perceived social support, maternal parental self-efficacy and postpartum depressive symptoms) before and after the App use intervention. RESULTS: In the App group, perceived social support, maternal parental self-efficacy were significantly higher and postpartum depressive symptoms was significantly lower. In the control group, there were no significant differences in any of the four variables between the pre-test and post-test. CONCLUSIONS: Our findings indicated that the mobile health application may help to improve perceived social support, maternal self-efficacy and reduce postpartum depressive symptoms. The finding of the mobile health application's effect extends our understanding of integrative effects of mindfulness and perceived social support on reduction of postpartum depressive symptoms and suggests clinical potentials in the treatment of postpartum depressive symptoms.

Early maternal separation accelerates the progression of endometriosis in adult mice.

BACKGROUND: A large body of research highlights the importance of early-life environmental impact on the health outcome in adulthood. However, whether early-life adversity (ELA) has any impact on the development of endometriosis is completely unclear. In this study, we tested the hypothesis that ELA, as manifested by neonatal separation, can accelerate the progression of endometriosis in mouse through activation of the adrenergic receptor ß2 (ADRB2) signaling pathway, leading to increased angiogenesis and progression of endometriotic lesions. METHODS: Eight female Balb/C mice, in late pregnancy, were used used for this study, which later gave birth to 22 female newborn pubs. Eleven additional female Balb/C mice were also used as donors of uterine tissues. The 22 newborn pubs were randomly divided into 2 equal-sized groups, maternal separation (MS) and no separation (NS). Pubs in the MS group were separated from their dams for 3 h/day from postnatal day (PND) 1 to 21, while those in the NS control remained in the home cage with their dams. In adulthood (8-week old), 3 mice in each group were randomly selected to undergo a battery of behavior tests. The remaining 8 mice in each group were induced with endometriosis by intraperitoneal injection of uterine fragments from donor mice. Four weeks after the induction, all mice were sacrificed and their endometriotic lesions were excised for quantification and then prepared for immunohistochemistry analysis. RESULTS: We confirmed that MS during infancy resulted in anxiety and depression-like behaviors as previously reported. We also found that in MS mice the lesion weight was increased by over 2 folds and generalized hyperalgesia was also significantly increased as compared with NS mice. Immunostaining analysis demonstrated that MS accelerated the development of endometriosis likely through decreased dopamine receptor D2 (DRD2) expression and activation of the ADRB2/cAMP-response element binding protein (CREB) signaling pathway, leading to increased angiogenesis and progression of endometriotic lesions. CONCLUSIONS: Exposure of female mouse pups to ELA such as MS during their infancy period accelerates the progression of endometriosis, possibly through altered neuronal wiring and hyperactivity of the hypothalamic-pituitary-adrenal axis.

Perioperative Intervention by ß-Blockade and NF-κB Suppression Reduces the Recurrence Risk of Endometriosis in Mice Due to Incomplete Excision.

Despite the demonstrated efficacy of surgical treatment of endometriosis, recurrence after surgery still remains a formidable challenge. Surgery, especially when performed repeatedly, decreases ovarian reserve. Clearly, control of recurrence is an unmet medical need. So far nearly all efforts to control recurrence have been devoted to the identification of risk factors, biomarkers, and postoperative medication. One area that has been completely overlooked is the possibility of perioperative intervention. In this study, we tested the hypothesis that perioperative use of a nonspecific ß-blocker and/or a nuclear factor-κB (NF-κB) inhibitor can retard the growth of residual endometriotic lesions that are left intact in the primary surgery. We established a mouse model of recurrence due to incomplete lesion removal by deliberately leaving residual lesions intact in the primary excision surgery. One hour before and 24 hours after the surgery, mice were either untreated or treated with andrographolide, propranolol, or both. Two weeks after the primary surgery, all mice were sacrificed and all lesions were excised and evaluated for immunohistochemistry analysis. We found that perioperative use of andrographolide and/or propranolol significantly decelerated the growth of residual lesions that were intentionally left out during the primary surgery. The perioperative intervention also significantly attenuated the generalized hyperalgesia resulting from the presence of residual lesions. It also inhibited the activation of the adrenergic receptor ß2 signaling, resulting in reduced angiogenesis, epithelial-mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation as well as NF-κB suppression and progesterone receptor isoform B induction. These data strongly suggest that perioperative use of ß-blockers and/or NF-κB inhibitors may reduce the risk of recurrence in endometriosis.

Chronic stress accelerates the development of endometriosis in mouse through adrenergic receptor ß2.

STUDY QUESTION: Does chronic stress in mice accelerate the development of endometriosis, and, if so, through what mechanism? SUMMARY ANSWER: Exposure to chronic stress accelerates the development of endometriosis and exacerbates the endometriosis-associated generalized hyperalgesia, most likely through activation of the adrenoceptor ß2 (ADRB2) and cAMP responsive element-binding protein (CREB). WHAT IS KNOWN ALREADY: Women with endometriosis tend to have higher levels of psychological stress, which is known to impact negatively on health in general and to promote tumor growth and metastasis in particular. Exposure to chronic stress before and after the induction of endometriosis is reported to increase lesion sizes in rodents, but it is unclear whether adrenoceptors are involved or not in the stress-promoted development of endometriosis. STUDY DESIGN, SIZE, DURATION: Three independent, prospective, randomized mouse experimentations. A total of 184 virgin female Balb/C mice were used. PARTICIPANTS/MATERIALS, SETTING, METHODS: In Experiment 1, the mice were randomly divided into four groups: the control group, which received no stress; the before, after and both groups, which received immobilization stress before, after and both before and after the induction of endometriosis, respectively. In Experiment 2, mice were randomly divided into four groups one day after the induction of endometriosis: phosphate buffer saline (PBS) and propranolol (PROP) groups, which received the mini-pump containing, respectively, PBS only and propranolol (a non-selective ADRB antagonist) but no stress, STR+PROP and STR+PBS groups, which received stress and the mini-pump containing, respectively, propranolol and PBS. The immobilization stress started after the insertion of mini-pumps. In Experiment 3, mice were induced with endometriosis. Three days after the induction, they were randomly divided into four groups: control, ADRAa, ADRB2a, and ADRBa, which received the mini-pump containing solution only, metaraminol (a non-specific α adrenoceptor agonist), tebutaline (a specific ADRB2 agonist), or isoproterenol (a non-specific ADRB agonist), respectively. In all three experiments, the bodyweight and hotplate latency were evaluated before sacrifice 14 days after the induction. In all experimentations, the lesion weight was evaluated and the harvested ectopic endometrial tissue samples were subjected to immunohistochemistry analysis of vascular endothelial growth factor (VEGF), CD31-positive microvessels, proliferating cell nuclear antigen (PCNA), phosphorylated CREB, ADRB1, ADRB2, ADRB3, adrenergic receptor α1 (ADRA1) and ADRA2. MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to chronic stress accelerated the development of endometriosis and exacerbated the endometriosis-associated generalized hyperalgesia. This promotional effect is likely to be mediated through the systemic activation of the sympatho-adreno-medullary (SAM) axis, which results in subsequent release of catecholamines. The surging catecholamines may activate ADRB2 and CREB, yielding increased angiogenesis and cellular proliferation in ectopic endometrium in mice with induced endometriosis. In addition, ß adrenergic receptor blockade completely abolished the promotional effect of chronic stress, likely through suppression of ADRB2 and CREB activation, thus suppressing angiogenesis and proliferation. Moreover, a non-specific adrenergic ß agonist and a specific adrenergic ß2 agonist, but not non-specific adrenergic α agonist, acted similarly to chronic stress, accelerating the development of endometriosis and exacerbating the generalized hyperalgesia in mice with pre-existing endometriosis. LARGE SCALE DATA: NA. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the use of immunohistochemistry analyses only and the lack of molecular data. WIDER IMPLICATIONS OF THE FINDINGS: The present study provides the experimental evidence that chronic stress can promote the development of endometriosis through the activation of ADRB2. Given ADRB2 is also expressed in human endometriosis and appears to be functional, and in light of recent awareness that adrenergic signaling plays critical roles in tumorigenesis, it is likely that adrenergic signaling may play important roles in the development of endometriosis and is potentially a target for intervention. STUDY FUNDING/COMPETING INTERESTS: This research was supported in part by grants (81270676,  81471434 and 81530040  to S.W.G.;  81370695 and 81671436  to X.S.L.) from the National Natural Science Foundation of China, and grant (2013ZYJB0019 to X.S.L.) from Shanghai Municipal Commission of Health and Family Planning. None of the authors has anything to disclose.

Surgery accelerates the development of endometriosis in mice.

BACKGROUND: Surgery is currently the mainstay treatment for solid tumors and many benign diseases, including endometriosis, and women tend to receive substantially more surgeries than men mainly because of gynecological and cosmetic surgeries. Despite its cosmetic, therapeutic, or even life-saving benefits, surgery is reported to increase the cancer risk and promotes cancer metastasis. Surgery activates adrenergic signaling, which in turn suppresses cell-mediated immunity and promotes angiogenesis and metastasis. Because immunity, angiogenesis, and invasiveness are all involved in the pathophysiology of endometriosis, it is unclear whether surgery may accelerate the development of endometriosis. OBJECTIVE: The objective of the study was to test the hypothesis that surgery activates adrenergic signaling, increases angiogenesis, and accelerates the growth of endometriotic lesions. STUDY DESIGN: This was a prospective, randomized experimentation. The first experiment used 42 female adult Balb/C mice, and the second used 90 female adult Balb/C mice. In experiment 1, 3 days after the induction of endometriosis, mice were randomly divided into 3 groups of approximately equal sizes, control, laparotomy, and mastectomy. In experiment 2, propranolol infusion via Alzet pumps was used to forestall the effect of sympathetic nervous system activation by surgery. In both experiments, mice were evaluated 2 weeks after surgery. Lesion size, hotplate latency, and immunohistochemistry analysis of vascular endothelial growth factor, CD31-positive microvessels, proliferating cell nuclear antigen, phosphorylated cyclic adenosine monophosphate-responsive element-binding protein, ß2-adrenergic receptor (ADRB)-2, ADRB1, ADRB3, ADRA1, and ADRA2 in ectopic implants. RESULTS: Both mastectomy and laparotomy increased lesion weight and exacerbated hyperalgesia, increased microvessel density and elevated the immunoreactivity against ADRB2, phosphorylated cyclic adenosine monophosphate-responsive element-binding protein, vascular endothelial growth factor, and proliferating cell nuclear antigen but not ADRB1, ADRB3, ADRA1, and ADRA2, suggesting activated adrenergic signaling, increased angiogenesis, and accelerated growth of endometriotic lesions. ß-Blockade completely abrogated the facilitory effect of surgery, further underscoring the critical role of ß-adrenergic signaling in mediating the effect of surgery. CONCLUSION: Surgery activates adrenergic signaling, increases angiogenesis, and accelerates the growth of endometriotic lesions in the mouse, but such a facilitory effect of surgery can be completely abrogated by ß-blockade. Whether surgery can promote the development of endometriosis in humans warrants further investigation.

Surgical History and the Risk of Endometriosis: A Hospital-Based Case-Control Study.

Women tend to receive more surgical procedures than men. Our mouse study shows that surgical stress promotes the development of endometriosis. This study was undertaken to test the hypothesis that surgery increases the risk of endometriosis. We recruited 208 patients with ovarian endometrioma and 212 age-matched patients with ovarian teratoma and retrieved information on the history of any surgical procedures after menarche, grouped by laparotomy, laparoscopy, gynecologically related procedures, cesarean section, and surgeries performed on torso and extremities was recorded. We then evaluated the association, if any, between endometriosis and history of surgical procedures. Cases and controls were comparable with respect to age, marital status, education level, and occupation. Eleven (5.3%) cases had laparotomy before the index surgery while 4 (1.9%) controls did. Sixty-six (31.7%) cases had Cesarean section while 53 (25.0%) controls did. Multivariate analysis identified age, at the index surgery laparotomy, and cesarean section as 3 factors positively associated with the risk of endometriosis while parity was found to be negatively associated with the risk. Laparotomy was associated with increased risk of endometriosis (odds ratio [OR] = 3.64, 95% confidence interval [CI] = 1.08-12.31), while cesarean section was associated with 2-fold increase in risk (OR = 2.16, 95% CI = 1.31-3.55). Both laparotomy and cesarean section may increase the risk of endometriosis probably by activation of adrenergic signaling, thus facilitating angiogenesis and accelerating the growth of endometriotic lesions that are already in existence. This finding may have important ramifications for the perioperative management of patients with increased risk or recurrence risk of endometriosis.

Initiation of GnRH agonist treatment on 3-5 days postoperatively in endometriosis patients: a randomized controlled trial.

Seventy patients with stage III or IV endometriosis were randomly assigned to 2 groups after conservative surgery. Group O (n = 35) received 3 cycles of a 28-day gonadotropin-releasing hormone agonist (GnRH-a) treatment (goserelin, 3.6 mg) starting 3-5 days postoperatively. Group M (n = 35) received the same treatment starting on days 1-5 of menstruation. Groups were further subdivided according to add-back treatment. Pre- and posttreated levels of estradiol (E2 ), follicle stimulating hormone (FSH), and luteinizing hormone (LH) and visual analog scale (VAS), Kupperman menopausal index (KMI), and bone mineral density (BMD) scores were recorded. The incidence of uterine bleeding was assessed. In both groups, serum levels of E2 , FSH, and LH and VAS scores decreased significantly after treatment. Spotting was the most frequent bleeding pattern. During cycle 1, the bleeding time in group M was much longer that than that in group O (P =.001), and the bleeding rate in group M was significantly higher than that in group O (P =.024, RR = 1.185). In patients with stage III or IV endometriosis, the efficacy of GnRH-a initiated 3-5 days postoperatively was equivalent to that of GnRH-a initiated on days 1-5 of menstruation. Female patients who initiated GnRH-a treatment 3-5 days postoperatively experienced less uterine bleeding during the first cycle of treatment.

The incidence and characteristics of uterine bleeding during postoperative GnRH agonist treatment combined with estrogen-progestogen add-back therapy in endometriosis patients of reproductive age.

To evaluate the incidence and characteristics of uterine bleeding during postoperative gonadotropin-releasing hormone agonist (GnRHa) treatment combined with the lowest effective dose of estrogen-progestogen add-back therapy in Chinese women of reproductive age with endometriosis. Seventy Chinese women aged 18 to 50 years with stage III or IV endometriosis and treated with postoperative GnRHa after conservative surgery for endometriosis were eligible for this study. Patients were randomly divided into two equal groups, G and A. Group G (n = 35) received three 28-day cycles of postoperative GnRHa treatment by subcutaneous injection (goserelin, 3.6 mg). Group A (n = 35) received the same GnRHa treatment in addition to daily estradiol valerate (0.5 mg) and dydrogesterone (5 mg) add-back therapy. Serum E2 and FSH levels were assessed at the end of each treatment cycle, as well as incidence and patterns of uterine bleeding. After the last GnRHa treatment cycle, endometrial thickness was evaluated by ultrasonography and the recovery of menstruation was recorded. Uterine bleeding incidence was above 90% in both groups during the first treatment cycle (group G: 90.6%; group A: 93.8%), but decreased markedly in the second treatment cycle (group G: 15.6%; group A: 21.9%), and continued to decline until the end of the third treatment cycle (group G: 6.3%; group A: 12.5%). For each cycle, the incidence of uterine bleeding in group A was slightly but not statistically higher. Irregular spotting was the most common uterine bleeding pattern observed in each of the three treatment cycle. The addition of estrogen and progestogen therapy to a postoperative GnRHa regimen does not lead to an increase in the duration or amount of treatment-induced uterine bleeding.

Marker gene screening for human mesenchymal stem cells in early osteogenic response to bone morphogenetic protein 6 with DNA microarray.

AIMS: Microarray data were analyzed using bioinformatic tools to screen marker genes of human mesenchymal stem cells (hMSC) in response to bone morphogenetic protein 6 (BMP6). RESULTS: A total of 190 differentially expressed genes were identified. The interaction network was divided into three functional modules. These genes were connected with BMP signaling pathways and regulation of cell processes, while NOG and BMPR2 participated in the transforming growth factor-beta signal pathway. Besides, several related small molecules were acquired. CONCLUSION: Marker genes in osteogenic responses to BMP6 treatment for hMSC were screened with microarray data along with elaborate function analysis by bioinformatics. NOG and BMPR2 showed potential to become indicators to monitor the directed differentiation of hMSC into osteoblasts, which can be used for bone disease treatment. Moreover, small molecules such as W-13 were retrieved and provided directions for future drug design.

Oral continuous combined 0.5 mg estradiol valerate and 5 mg dydrogesterone as daily add-back therapy during post-operative GnRH agonist treatment for endometriosis in Chinese women.

OBJECTIVE: To evaluate the lowest effective dose of combined estrogen and progestogen (E(2)+P) add-back therapy during post-operative gonadotropin-releasing hormone agonist (GnRHa) treatment for endometriosis in Chinese women. STUDY DESIGN: The study enrolled 81 patients aged 18 to 50 years with stage III or IV endometriosis, as diagnosed by surgery. All patients were given GnRHa 3.6 mg by subcutaneous injection once every 28 days for a total of three times. Patients were divided into three groups: the first (n = 35; GnRHa only group) received GnRHa only without add-back therapy, the second (n = 35; 0.5 mg E(2)+P add-back group) received GnRHa plus 0.5 mg estradiol valerate and 5 mg dydrogesterone orally every day, and the third (n = 11; 1 mg E(2)+P add-back group) received GnRHa plus 1 mg estradiol valerate and 10 mg dydrogesterone orally every day for the duration of treatment. All patients were required to follow up at our hospital at 4, 8 and 12 weeks after treatment initiation to assess efficacy and levels of serum reproductive hormones. RESULTS: Compared with baseline levels, serum levels of the four reproductive hormones assessed (E(2), LH, P(4) and FSH) were significantly decreased in both the GnRHa only and the 0.5 mg E(2)+P add-back groups at 4, 8, and 12 weeks after treatment; and levels reached a stable state at 4 weeks of treatment. In the 1 mg E(2)+P add-back group, LH and FSH serum levels were significantly decreased, while those of E(2) and P were not significantly different at any of the time points assessed. In the 0.5 mg E(2)+P add-back group, E(2) serum levels decreased drastically at first, then gradually over the course of the study. In contrast, pre- and post-treatment E(2) serum levels in the 1 mg E(2)+P add-back group were not significantly different, and these levels were over 45 pg/mL for the entire study duration. Comparison among groups showed that E(2) levels in both add-back groups were significantly higher than in the GnRHa only group at 12 weeks after treatment. Furthermore, E(2) serum levels in the two add-back groups at 8 and 12 weeks after treatment were significantly different. CONCLUSION: Oral continuous combined 0.5 mg/d estradiol valerate and 5 mg/d dydrogesterone as immediate add-back therapy during post-operative GnRH agonist treatment for severe endometriosis may be the most suitable regimen for Chinese women.

[Clinical efficacy and safety of gonadotropin releasing hormone agonist combined with estrogen-dydrogesteronea in treatment of endometriosis].

OBJECTIVE: To compare clinical effect of gonadotropin releasing hormone agonist (GnRH-a) alone and GnRH-a combined with low-dose dydrogesteronea and estradiol valerate on sex hormone, hypoestrogenic symptoms, quality of life and bone mineral density (BMD) in treatment of endometriosis. METHODS: Seventy patients with moderate or severe endometriosis, who were diagnosed by laparotomy or laparoscopic surgery within two months, were randomly assigned into two groups. 35 patients in GnRH-a group were treated by goserelin (3.6 mg) for three months, and 35 patients in add-back group were treated by goserelin (3.6 mg) combined with estradiol valerate 0.5 mg and dydrogesteronea 5 mg daily. Before and after the treatment, clinical parameters were recorded and analyzed, including visual analog scale (VAS), medical outcomes survey short form 36 (SF-36), Kupperman menopausal index (KMI), BMD, the serum level of follicle stimulating hormone (FSH), estradiol (E2) and bone gla-protein (BGP). The first menstruation and VAS were also followed up after treatment. RESULTS: Every 3 cases in two groups lost follow-up. (1) Reproductive hormone: the level of E2 in add-back group [(94+/-71) pmol/L] was significantly higher than (54+/-52) pmol/L in GnRH-a group (P<0.01). The level of FSH in add-back group [(3.0+/-1.9) U/L] was significantly lower than (5.7+/-2.9) U/L in GnRH-a group (P<0.05). (2) VAS: after treatment, VAS in both group decreased significantly when compared with that before treatment (P<0.05), and remained until menstruated. (3) KMI: KMI in add back-group (10+/-8)was significantly lower than (14+/-6) in GnRH-a group (P<0.05). (4) BMD: compared with that before treatment, BMD decreased significantly after treatment in GnRH-a group (P<0.05), no remarkable difference of BMD was observed before and after treatment in add-back group. Before treatment, serum BGP in both groups did not show statistical difference. After treatment, the level of BGP in GnRH-a group [(7932+/-5206) ng/L] was significantly higher than (5419+/-2917) ng/L in add-back group (P<0.05). CONCLUSIONS: GnRH-a combined with estrogen-progesterone regimen could relieve pain from endometriosis as effectively as GnRH-a alone and reduce hypoestrogenic symptoms and bone loss. Therefore, it is a safe and effective treatment.