The corrective role of superparamagnetic iron oxide nanoparticles for the genes controlling hypothalamus-pituitary-testis-axis in male obesity-associated secondary hypogonadism.

Background: Obesity is one of the most prevalent and perilous health affairs. Male obesity-associated secondary hypogonadism (MOSH) is one of many of its complexities, which is mounting in parallel with the aggravation of obesity. Magnetic nanoparticles seem to be an advanced favorable trend in multiple biomedical fields. Aim: In this study, we explore the therapeutic effects of superparamagnetic iron oxide nanoparticles (SPIONs) coated with carboxymethyl cellulose (CMC) on an obese male rat model with MOSH syndrome, comparing their impacts with a well-known anti-obesity medication (Orlistat). Methods: 42 male albino rats split into 7 equal groups: 1-negative control: nonobese, untreated; 35 rats fed the high fat-high fructose (HFHF) diet for a period of 12 weeks. Obese rats splitted into 6 equal groups; 2-positive control: obese untreated; 3-obese given Orlistat (30 mg/kg); 4-obese given CMC-SPIONs (25 mgFe/kg); 5-obese given CMC-SPIONs (50 mgFe/kg); 6-obese given CMC-SPIONs(25 mgFe/kg) + Orlistat (30 mg/kg), 7-obese given CMC-SPIONs (50 mgFe/kg) + Orlistat (30 mg/kg); all treatments given orally for 4 weeks. During sacrifice, blood serum and sectioned hypothalamic, pituitary, testicular, and adipose tissues were collected for biochemical and biomolecular assessments. Results: The HFHF diet for 12 weeks resulted in a significant upsurge in body weight, body mass index, serum fasting glucose, insulin resistance, TAG, total cholesterol, and LDL-c; HDL-c was dropped. Serum FSH, LH, and testosterone values declined. A significant disorder in expression levels of genes regulating the hypothalamic-pituitary-testicular-axis pathway. Hypothalamic GnRH, Kisspeptin-1, Kisspeptin-r1, and Adipo-R1 values declined. GnIH and Leptin-R1 values raised up. Pituitary GnRH-R values declined. Testicular tissue STAR, HSD17B3, and CYP19A1 values declined. Adipose tissue adiponectin declined, while leptin raised up. CMC-SPIONs 25-50 mg could modulate the deranged biochemical parameters and correct the deranged expression levels of all previous genes. Co-treatments revealed highly synergistic effects on all parameters. Overall, CMC-SPIONs have significant efficiency whether alone or with Orlisat in limiting obesity and consequence subfertility. Conclusion: CMC-SPIONs act as an incoming promising contender for obesity and MOSH disorders management, and need more studies on their mechanisms.

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

INTRODUCTION: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility. METHODS AND ANALYSIS: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores. ETHICS AND DISSEMINATION: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial. TRIAL REGISTRATION NUMBER: NCT05364008.

Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

Does vitamin D have a potential role in precocious puberty? A meta-analysis.

Background: Precocious puberty, one of the common pediatric endocrine system diseases, has been related to reduced adult height, adverse psychological outcomes and long-term health consequences. Previous findings have found that low levels of vitamin D appear to be associated with the characteristics of precocious puberty such as early menarche. However, the effect of vitamin D on precocious puberty remains controversial. Methods: The published literature was searched from PubMed, Web of Science, Cochrane Library, MEDLINE, EMBASE, CNKI, Wan Fang and VIP databases up to October 2022. A randomized effect model was used to perform a meta-analysis to evaluate differences in vitamin D concentration between precocious puberty subjects and normal subjects, the risk of precocious puberty in subjects with low vitamin D levels, and the effect of supplementation of vitamin D on subjects with precocious puberty on medication. Results: Our study found that precocious puberty subjects had lower serum vitamin D levels than the normal population (standardized mean difference (SMD) = -1.16 ng ml-1 and 95% confidence interval (CI) = -1.41 and -0.91 ng ml-1). Meanwhile, the lower level of vitamin D was associated with the risk of precocious puberty (odd ratio (OR) = 2.25 and 95% CI = 1.66 and 3.04). Moreover, compared with gonadotropin-releasing hormone analogue (GnRHa) intervention alone, subjects receiving GnRHa + vitamin D intervention had significantly lower luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels and bone age, and higher predicted adult height (PAH). Conclusions: Vitamin D may have a potential role in precocious puberty and more data from large clinical trials are needed to confirm the findings.

Effects of Zishen Yutai Pills on in vitro Fertilization-Embryo Transfer Outcomes in Patients with Diminished Ovarian Reserve: A Prospective, Open-Labeled, Randomized and Controlled Study.

OBJECTIVE: To explore the effects of Zishen Yutai Pills (ZYPs) on the quality of oocytes and embryos, as well as pregnancy outcomes in patients with diminished ovarian reserve (DOR) receiving in vitro fertilization-embryo transfer (IVF-ET). The possible mechanisms, involving the regulation of bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), were also investigated. METHODS: A total of 120 patients with DOR who underwent their IVF-ET cycle were randomly allocated to 2 groups in a 1:1 ratio. The patients in the treatment group (60 cases) received ZYPs from the mid-luteal phase of the former menstrual cycle by using gonadotropin-releasing hormone (GnRH) antagonist protocol. The patients in the control group (60 cases) received the same protocol but without ZYPs. The primary outcomes were the number of oocytes retrieved and high-quality embryos. Secondary outcomes included other oocyte or embryo indices as well as pregnancy outcomes. Adverse events were assessed by comparison of the incidence of ectopic pregnancy, pregnancy complications, pregnancy loss, and preterm birth. Contents of BMP15 and GDF9 in the follicle fluids (FF) were also quantified with enzyme-linked immunosorbent assay. RESULTS: Compared with the control group, the numbers of oocytes retrieved and high-quality embryos were significantly increased in the ZYPs group (both P<0.05). After treatment with ZYPs, a significant regulation of serum sex hormones was observed, including progesterone and estradiol. Both hormones were up-regulated compared with the control group (P=0.014 and 0.008), respectively. No significant differences were observed with regard to pregnancy outcomes including implantation rates, biochemical pregnancy rates, clinical pregnancy rates, live birth rates, and pregnancy loss rates (all P>0.05). The administration of ZYPs did not increase the incidence of adverse events. The expressions of BMP15 and GDF9 in the ZYPs group were significantly up-regulated compared with the control group (both P<0.05). CONCLUSIONS: ZYPs exhibited beneficial effects in DOR patients undergoing IVF-ET, resulting in increments of oocytes and embryos, and up-regulation of BMP15 and GDF9 expressions in the FF. However, the effects of ZYPs on pregnancy outcomes should be assessed in clinical trials with larger sample sizes (Trial reqistration No. ChiCTR2100048441).

Advances in the medical treatment of adolescent endometriosis.

Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus. Adolescent endometriosis is often confined to the pelvic cavity and is a common cause of secondary dysmenorrhea in adolescents. Adolescent endometriosis is often with delayed diagnosis. Early diagnosis and intervention can prevent the damage of pelvic structure and ovarian tissue and reduce the incidence of adhesion and infertility. Adolescent endometriosis can be diagnosed and treated by laparoscopic biopsy. There are many kinds of drugs to treat endometriosis, such as NSAIDs, progesterone, selective progesterone receptor antagonists, GnRH-a, gonadotropin-releasing hormone antagonists, aromatase inhibitors, dopamine agonists, angiogenesis inhibitors, vegetable drugs, traditional Chinese medicine prescriptions. Future treatment options, including Future treatment options include CTZ, vitamin D3, oxytocin receptor inhibitors, melatonin, doxycycline, bevacizumab, curcumin, isotretinoin, and rosiglitazone, etc., can inhibit ectopic lesions. This article mainly summarizes advances in medical treatment underlying adolescent endometriosis and provides guidance for the early clinical diagnosis and intervention of adolescent endometriosis, to improve the quality of life of patients and reduce adverse outcomes.

GnRH replacement rescues cognition in Down syndrome.

At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis.

BACKGROUND: Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. OBJECTIVE AND RATIONALE: The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included. SEARCH METHODS: Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217). OUTCOMES: Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls). WIDER IMPLICATIONS: For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.

Preventing ovarian failure associated with chemotherapy.

Alkylating chemotherapy is often used to treat pre-menopausal women for various malignancies and autoimmune diseases. Chemotherapy-associated ovarian failure is a potential consequence of this treatment which can cause infertility, and increases the risk of other long term adverse health sequelae. Randomised trials, predominantly of women undergoing alkylating chemotherapy for breast cancer, have shown evidence for the efficacy of gonadotropin-releasing hormone agonists (GnRHa) in preventing chemotherapy-associated ovarian failure. The European St Gallen and United States National Comprehensive Cancer Network guidelines recommend the use of concurrent GnRHa to reduce the risk of ovarian failure for pre-menopausal women undergoing chemotherapy for breast cancer. The GnRHa goserelin, a monthly 3.6 mg depot subcutaneous injection, has recently been listed on the Australian Pharmaceutical Benefits Scheme to reduce risk of ovarian failure for pre-menopausal women receiving alkylating therapies for malignancy or autoimmune disease. The first dose of goserelin should ideally be administered at least 1 week before commencement of alkylating treatment and continued 4-weekly during chemotherapy. Concurrent goserelin use should now be considered for all pre-menopausal women due to commence alkylating chemotherapy (except those with incurable cancer), regardless of their childbearing status, in an effort to preserve their ovarian function. For women who have not completed childbearing, consideration of other fertility preservation options, such as cryopreservation of embryos or oocytes, is also important.

Bone health during endocrine therapy for cancer.

Preservation of bone health remains a long-term clinical challenge in patients with breast and prostate cancer. Osteoporosis, defined by a loss of bone mass and microarchitecture, often results in fragility fractures that are typically associated with a high socioeconomic burden. Endocrine therapy, a mainstay treatment in the management of patients with hormone-sensitive breast and prostate cancer in the adjuvant setting, commonly exerts adverse effects on the musculoskeletal system and is associated with an increased risk of osteoporosis and fractures. Adjuvant use of gonadotropin-releasing hormone analogues, which can also be used in metastatic disease, in combination with tamoxifen in premenopausal women, and aromatase inhibitors in postmenopausal women with hormone-sensitive breast cancer, causes rapid bone loss and fragility fractures. By contrast, selective oestrogen receptor modulators, such as tamoxifen, have bone-protective effects in postmenopausal women. In men with castration-sensitive prostate cancer, androgen deprivation is achieved with drugs that lower gonadotropin levels, and these drugs can be combined with androgen receptor antagonists. These therapies induce a high bone turnover with rapid bone loss that is reminiscent of the changes occurring in early menopause and result in an increased risk of fracture. In this Review, we describe how adjuvant endocrine therapies of breast and prostate cancer impair bone health and outline evidence from randomised controlled trials of strategies to reduce risk of fracture.

Pulsatile GnRH Therapy May Restore Hypothalamus-Pituitary-Testis Axis Function in Patients With Congenital Combined Pituitary Hormone Deficiency: A Prospective, Self-Controlled Trial.

Context: The effectiveness of pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with congenital combined pituitary hormone deficiency (CCPHD) has not been investigated because of the limited number of patients, as well as these patients' presumed pituitary hypoplasia, poor gonadotrophic cell reserve, and impaired gonadotrophic response to GnRH. Objective: To assess the pituitary response to pulsatile GnRH therapy in men with CCPHD. Design: Prospective, self-controlled, 3-month clinical trial. Settings: University endocrine clinic. Patients: Men with hypogonadotropic hypogonadism caused by CCPHD. Intervention: Pulsatile GnRH was administered subcutaneously for 3 months. Main outcome measures: Primary endpoints were total serum testosterone, testicular volume, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. Secondary endpoints included occurrence of spermatogenesis. Results: A total of 40 men with CCPHD completed the study. Of these, 60% (24 of 40) showed a good response to pulsatile GnRH treatment (response group). At 3 months, their LH and FSH levels increased to within the normal range and their testosterone levels increased to 8.67 ± 4.83 nmol/L. Of the patients in the response group, 33.3% (8 of 24) of them achieved spermatogenesis. The remaining 40% (16 of 40) of patients had a poor response to pulsatile GnRH treatment. Magnetic resonance imaging (MRI) did not reveal any correlation between pituitary response and pituitary height and/or integrity of the pituitary stalk. Conclusions: This study suggests that gonadotrophs in patients with CCPHD can exist and be functional-even with MRI evidence of pituitary hypoplasia or dysplasia. Pulsatile GnRH therapy restored pituitary-testis axis function in 60% of patients with CCPHD. These results may directly guide the clinical therapeutic choice.

Effects of pomegranate extract in supplementing gonadotropin-releasing hormone therapy on idiopathic central precocious puberty in Chinese girls: a randomized, placebo-controlled, double-blind clinical trial.

Central precocious puberty (CPP) without organic abnormality is called idiopathic CPP (ICPP). The objective of this trial was to evaluate the effects of pomegranate extract in supplementing gonadotropin-releasing hormone (GnRH) analog therapy on ICPP-affected girls in the Chinese population. 286 girls, diagnosed with ICPP were initially enrolled into this trial, and among them 225 eligible patients were randomized to receive a combinational GnRH analog treatment supplemented with either a placebo or pomegranate extract on a daily basis for a period of 3 months. Their demographics, secondary sexual characteristics and hormone profiles were analyzed at baseline and end of trial. After 3 months of treatment, demographic profiles including bone age, growth velocity and height standard deviation score for bone age, and secondary sexual characteristics including uterus and ovary volume, as well as serum hormone profiles including estradiol, peak luteinizing hormone and insulin-like growth factor 1 were all significantly improved in girls receiving a combinational treatment of both GnRH analog and pomegranate extract. Daily consumption of pomegranate extract was able to supplement and improve the treatment outcomes of the GnRH analog therapy for ICPP in Chinese girls.

Very High-Risk Localized Prostate Cancer: Outcomes Following Definitive Radiation.

PURPOSE: Existing definitions of high-risk prostate cancer consist of men who experience significant heterogeneity in outcomes. As such, criteria that identify a subpopulation of National Comprehensive Cancer Network (NCCN) high-risk prostate cancer patients who are at very high risk (VHR) for poor survival outcomes following prostatectomy were recently developed at our institution and include the presence of any of the following disease characteristics: multiple NCCN high-risk factors, primary Gleason pattern 5 disease and/or ≥5 biopsy cores with Gleason sums of 8 to 10. Whether these criteria also apply to men undergoing definitive radiation is unclear, as is the optimal treatment regimen in these patients. METHODS AND MATERIALS: All men consecutively treated with definitive radiation by a single provider from 1993 to 2006 and who fulfilled criteria for NCCN high-risk disease were identified (n=288), including 99 patients (34%) with VHR disease. Multivariate-adjusted competing risk regression models were constructed to assess associations between the VHR definition and biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Multivariate-adjusted Cox regression analysis assessed the association of the VHR definition with overall mortality (OM). Cumulative incidences of failure endpoints were compared between VHR men and other NCCN high-risk men. RESULTS: Men with VHR disease compared to other NCCN high-risk men experienced a higher 10-year incidence of BF (54.0% vs 35.4%, respectively, P<.001), DM (34.9% vs 13.4%, respectively, P<.001), PCSM (18.5% vs 5.9%, respectively, P<.001), and OM (36.4% vs 27.0%, respectively, P=.04). VHR men with a detectable prostate-specific antigen (PSA) concentration at the end of radiation (EOR) remained at high risk of 10-year PCSM compared to VHR men with an undetectable EOR PSA (31.0% vs 13.7%, respectively, P=.05). CONCLUSIONS: NCCN high-risk prostate cancer patients who meet VHR criteria experience distinctly worse outcomes following definitive radiation and long-term androgen deprivation therapy, particularly if an EOR PSA is detectable. Optimal use of local therapies for VHR patients should be explored further, as should novel agents.

Premenstrual syndrome: A mini review.

Premenstrual syndrome (PMS) is characterized by recurrent, moderate-to-severe affective, physical, and behavioral symptoms that develop during the luteal menstrual cycle and disappear within a few days of menstruation. Premenstrual dysphoric disorder (PMDD) is a severe and disabling condition that can affect personal relationships and occupational activities. PMS occurs in 30-40% of reproductive-age females; PMDD affects 3-8% of this population. Although the etiology of PMS is unclear, several theories suggest increased sensitivity to normal hormonal changes and neurotransmitter abnormalities. The diagnostic method of PMS is the Daily Record of Severity of Problems, which women with PMS can use to self-report several symptoms and their severity. Although combined oral contraceptives and serotonergic antidepressants are effective drugs, each is a different option for treating PMS/PMDD. Serotonergic antidepressants are the drugs of choice for improving both physical and mood symptoms. Combined oral contraceptives appear to primarily improve physical symptoms. Clinicians should consider each patient's situation individually. Other treatment options include lifestyle modification, cognitive behavioral therapy, and herbal medicine (e.g., chasteberry).

Efficacy and safety of remifemin on peri-menopausal symptoms induced by post-operative GnRH-a therapy for endometriosis: a randomized study versus tibolone.

BACKGROUND: The aim of this study was to investigate clinical efficacy and safety of Remifemin on peri-menopausal symptoms in endometriosis patients with a post-operative GnRH-a therapy. MATERIAL AND METHODS: We treated 116 women who had endometriosis with either Remifemin (n=56) 20 mg bid po or Tibolone (n=60) 2.5 mg qd po for 12 weeks after GnRH-a injection. The efficacy was evaluated by Kupperman menopausal index (KMI), and hot flash/sweating scores. The safety parameters such as liver and renal functions, lipid profile, endometrial thickness, and serum sex hormone level, as well as the incidence of adverse events were recorded. RESULTS: (1) After GnRH-a therapy, KMI and hot flash/sweating scores in both groups increased significantly (P<0.05) but we found no significant difference for KMI (2.87±1.40 for Remifemin and 2.70±1.26 for Tibolone) and hot flash/sweating scores (0.94±1.72 for Remifemin and 1.06±1.78 for Tibolone) between the 2 groups (P>0.05). (2) No statistical change was observed in liver or renal functions and lipid profile in both groups before and after the treatment (P>0.05). The post-therapeutic serum FSH, LH, and E2 level and endometrial thickness decreased remarkably in both groups (P<0.05). E2 level in the Remifemin group was obviously lower than that in the Tibolone group (P<0.05), and FSH and LH levels were strongly higher (P<0.05). No significant difference in thickness were found in either group (P>0.05). The Remifemin group had far fewer adverse events than the Tibolone group (P<0. 05). CONCLUSIONS: Compared with Tibolone, Remifemin had a similar clinical efficacy and was safer for the peri-menopausal symptoms induced by GnRH-a in endometriosis patients.

Gonadal suppressive and cross-sex hormone therapy for gender dysphoria in adolescents and adults.

Individuals with gender dysphoria experience distress associated with incongruence between their biologic sex and their identified gender. Gender dysphoric natal males receive treatment with antiandrogens and estrogens to become feminized (transsexual females), whereas natal females with gender dysphoria receive treatment with androgens to become masculinized (transsexual males). Because of the permanence associated with cross-sex hormone therapy (CSHT), adolescents diagnosed with gender dysphoria receive gonadotropin-releasing hormone analogs to suppress puberty. High rates of depression and suicide are linked to social marginalization and barriers to care. Behavior, emotional problems, depressive symptoms, and global functioning improve in adolescents receiving puberty suppression therapy. Gender dysphoria, psychological symptoms, quality of life, and sexual function improve in adults who receive CSHT. Within the first 6 months of CSHT, changes in transsexual females include breast growth, decreased testicular volume, and decreased spontaneous erections, and changes in transsexual males include cessation of menses, breast atrophy, clitoral enlargement, and voice deepening. Both transsexual females and males experience changes in body fat redistribution, muscle mass, and hair growth. Desired effects from CSHT can take between 3 and 5 years; however, effects that occur during puberty, such as voice deepening and skeletal structure changes, cannot be reversed with CSHT. Decreased sexual desire is a greater concern in transsexual females than in transsexual males, with testosterone concentrations linked to sexual desire in both. Regarding CSHT safety, bone mineral density is preserved with adequate hormone supplementation, but long-term fracture risk has not been studied. The transition away from high-dose traditional regimens is tied to a lower risk of venous thromboembolism and cardiovascular disease, but data quality is poor. Breast cancer has been reported in both transsexual males and females, but preliminary data suggest that CSHT does not increase the risk. Cancer screenings for individuals of both natal and transitioned sexes should occur as recommended. More long-term studies are needed to ensure that CSHT regimens with the best outcomes can continue to be prescribed for the transsexual population.

[Adjunctive treatment of GnRHa combined wenshen xiaozheng decoction in treating endometriosis after laparoscopy: a clinical observation].

OBJECTIVE: To observe the therapeutic efficacy and safety of gonadotropin-releasing hormone agonist (GnRHa) combined Wenshen Xiaozheng Decoction (WXD) in auxiliary treating endometriosis after laparoscopy. METHODS: One hundred and thirty-four endometriosis patients with confirmative pathological diagnosis were assigned to three groups depending on whether they would receive adjuvant therapy or Chinese medicine treatment, i.e., the control group, the observation 1 group, and the observation 2 group. The 22 patients in the control group received no adjuvant therapy after laparoscopy. The 42 patients in the observation 1 group were treated with GnRHa 3.6 mg by subcutaneous injection starting from the 1st day to the 5th day of menstruation, once per 28 days. The 70 patients in the observation 2 group were treated with GnRHa 3.6 mg by subcutaneous injection in combination with WXD starting from the 1st day to the 5th day of menstruation, once per 28 days. They also took WXD for 7 doses, one cycle per every 28 days. The treatment lasted for three to six months. Serum levels of estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and cancer antigen 125 (CA125), as well as clinical efficacy, and adverse drug reactions were observed before and after treatment. RESULTS: There was statistical difference in serum levels of E2, FSH, or LH between the control group and the observation 1 and 2 groups (P < 0.05). There was no statistical difference in serum levels of E2, FSH, or LH between the observation 1 group and the observation 2 group (P > 0.05). There was statistical difference in the clinical efficiency among the 3 groups (P < 0.05). There was statistical difference in the pre-post difference of CA125 levels among the three groups (P < 0.01). Compared with the control group, there was no statistical difference in the pre-post difference of CA125 levels between the observation 1 group and the observation 2 group (P > 0.05). No obvious adverse reaction occurred during the treatment. CONCLUSIONS: GnRHa combined WXD showed confirmative clinical efficacy in treating endometriosis after laparoscopy. It also could lower serum levels of E2, FSH, and LH levels. So it was an ideal solution for treatment of endometriosis.

Maternal exposure to dioxin imprints sexual immaturity of the pups through fixing the status of the reduced expression of hypothalamic gonadotropin-releasing hormone.

Our previous studies have shown that treatment of pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 1 µg/kg) at gestational day (GD) 15 reduces the pituitary synthesis of luteinizing hormone (LH) during the late fetal and early postnatal period, leading to the imprinting of defects in sexual behaviors at adulthood. However, it remains unclear how the attenuation of pituitary LH is linked to sexual immaturity. To address this issue, we performed a DNA microarray analysis to identify the gene(s) responsible for dioxin-induced sexual immaturity on the pituitary and hypothalamus of male pups, born of TCDD-treated dams, at the age of postnatal day (PND) 70. Among the reduced genes, we focused on gonadotropin-releasing hormone (GnRH) in the hypothalamus because of published evidence that it has a role in sexual behaviors. An attenuation by TCDD of GnRH expression emerged at PND4, and no subsequent return to the control level was seen. A change in neither DNA methylation nor histone acetylation accounted for the reduced expression of GnRH. Intracerebroventricular infusion of GnRH to the TCDD-exposed pups after reaching maturity restored the impairment of sexual behaviors. Supplying equine chorionic gonadotropin, an LH-mimicking hormone, to the TCDD-exposed fetuses at GD15 resulted in a recovery from the reduced expression of GnRH, as well as from the defects in sexual behavior. These results strongly suggest that maternal exposure to TCDD fixes the status of the lowered expression of GnRH in the offspring by reducing the LH-assisted steroidogenesis at the perinatal stage, and this mechanism imprints defects in sexual behaviors at adulthood.

Herbal preparations for uterine fibroids.

BACKGROUND: Uterine fibroids are the most common non-malignant growths in women of childbearing age. They are associated with heavy menstrual bleeding and subfertility. Herbal preparations are commonly used as alternatives to surgical procedures. OBJECTIVES: To evaluate the effectiveness and safety of Chinese herbal medicine for treatment of uterine fibroids. SEARCH METHODS: The authors with the guidance of the Trials Search Coordinator searched the following electronic databases: the Trials Registers of the Cochrane Menstrual Disorders and Subfertility Group and the Cochrane Complementary Medicine Field, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), MEDLINE, EMBASE, the Chinese Biomedical Database, the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), AMED, and LILACS. The searches were up to 11 September 2012. SELECTION CRITERIA: Randomised controlled trials comparing herbal preparations with no intervention, placebo, medical treatment, or surgical procedures in women with uterine fibroids. We included trials of herbal preparations with or without conventional therapy. DATA COLLECTION AND ANALYSIS: Two review authors collected data independently. We assessed trial risk of bias according to our methodological criteria. We presented dichotomous data as risk ratios (RR) and continuous outcomes as mean differences (MD), both with 95% confidence intervals (CI). MAIN RESULTS: We included 21 randomised trials (involving 2222 women) and the majority of them had unclear or high risk of bias. There were several different herbal preparations used within the included trials. The average treatment duration was three to six months. The primary outcome of uterine fibroid related symptoms was not reported in any of the included trials. The majority of the trials reported fibroid volume and size of the uterus.Compared with mifepristone, Tripterygium wilfordii extract was associated with a greater reduction in the fibroid volume (MD -23.03 cm(3), 95% CI -28.39 to -17.67; 2 trials) and in uterine size (MD -51.25 cm(3), 95% CI -77.70 to -24.80; 2 trials). There was no evidence of a significant difference between Nona Roguy herbal product and gonadotropin-releasing hormone (GnRH) agonist on the average fibroid volume or the uterine size. The combination of Guizhi Fuling formula and mifepristone was associated with a greater reduction in the fibroid volume (-1.72 [-2.42, -1.02] 7 trials) and in uterine size (MD -31.63 [95% CI -54.58, -8.68] 3 trials)) compared with mifepristone alone. Only 13/21 trials reported on adverse events and no serious adverse effects from herbal preparations were reported. AUTHORS' CONCLUSIONS: Current evidence does not support or refute the use of herbal preparations for treatment of uterine fibroids due to insufficient studies with large sample sizes and of high quality. Further high quality trials evaluating clinically relevant outcomes are warranted.