Recombinant-luteinzing hormone supplementation in women during IVF/ICSI cycles with GNRH-antagonist protocol: A systematic review and meta-analysis.

The objective of this meta-analysis is to determine the beneficial effect of recombinant-luteinizing Hormone (r-LH) addition in women undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) with gonadotropin-releasing hormone (GnRH) antagonist protocol and whether an optimal time of Recombinant-Luteinizing Hormone (r-LH) supplementation exist during the controlled of stimulation (COS). The primary outcomes are clinical Pregnancy rate and the number of oocytes retrieved. Secondary outcomes are the number of metaphase II oocytes, miscarriage rate and live birth rate. Results show that supplementation of LH generated a greater number of oocytes retrieved than patients who did not receive LH supplementation, but it did not help with other pregnancy outcomes. Furthermore, the result of the subgroup analysis revealed no significant difference in the outcomes with different LH addition times.

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.

Comparison of blastocyst euploidy rates following luteal versus follicular phase stimulation in a GnRH antagonist protocol: a prospective study with repeated ovarian stimulation cycles.

STUDY QUESTION: Is there any difference in the mean number of euploid embryos following luteal phase start (LS) and follicular phase start (FS) of ovarian stimulation? SUMMARY ANSWER: The mean number of euploid blastocysts is equivalent independent of whether the inseminated oocytes are derived from FS or LS. WHAT IS KNOWN ALREADY: Starting ovarian stimulation at any time of the cycle ('random-start') is commonly used for emergency fertility preservation in cancer patients. A few retrospective studies have been published evaluating LS in women undergoing ovarian stimulation in the context of IVF, but there is a lack of robust data on the comparative efficacy of LS versus FS.Although 'random start' is commonly used in cancer survivors, few retrospective and uncontrolled studies have been published evaluating luteal phase stimulation in women undergoing ovarian stimulation in the context of IVF. Owing to this evident lack of robust data on the efficacy of LS, guidelines typically recommend the LS approach only for medical reasons and not in the context of IVF. STUDY DESIGN, SIZE, DURATION: This is a prospective, equivalence study, with repeated stimulation cycles, conducted between May 2018 and December 2021. Overall, 44 oocyte donors underwent two identical consecutive ovarian stimulation cycles, one initiated in the FS and the other in the LS. The primary outcome of the study was to evaluate whether FS and LS in the same patient would result in equivalent numbers of euploid embryos following fertilization of oocytes with the same sperm sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 44 oocyte donors underwent two consecutive ovarian stimulation protocols with 150 µg corifollitropin alpha followed by 200 IU recombinant FSH (rFSH) in a fixed GnRH antagonist protocol. The only difference between the two cycles was the day of initiation of ovarian stimulation, which was in the early follicular phase (FS) in one cycle, and in the luteal phase (LS) in the other. Forty-four oocyte recipients participated in the study receiving a mean of six metaphase II (MII) oocytes from each stimulation cycle (FS and LS). All MIIs were inseminated with the corresponding recipient's partner sperm (which had been previously frozen) or donor sperm, in order to safeguard the use of the same sample for either the FS or LS. Following fertilization and blastocyst culture, all generated embryos underwent genetic analysis for aneuploidy screening (preimplantation genetic testing for aneuploidy). MAIN RESULTS AND THE ROLE OF CHANCE: FS resulted in a significantly shorter duration of ovarian stimulation (difference between means (DBM) -1.05 (95% CI -1.89; -0.20)) and a lower total additional dose of daily rFSH was needed (DBM -196.02 (95% CI -319.92; -72.12)) compared with LS. The donors' hormonal profile on the day of trigger was comparable between the two stimulation cycles, as well as the mean number of oocytes (23.70 ± 10.79 versus 23.70 ± 8.81) (DBM 0.00 (95% CI -3.03; 3.03)) and MII oocytes (20.27 ± 9.60 versus 20.73 ± 8.65) (DBM -0.45 (95% CI -2.82; 1.91)) between FS and LS cycles, respectively. Following fertilization, the overall blastocyst formation rate was 60.70% with a euploid rate of 57.1%. Comparisons between the two stimulation cycles did not reveal any significance differences in terms of fertilization rates (71.9% versus 71.4%), blastocyst formation rates (59.4% versus 62%) and embryo euploidy rates (56.9 versus 57.3%) for the comparison of FS versus LS, respectively. The mean number of euploid blastocysts was equivalent between the FS (1.59 ± 1.30) and the LS (1.61 ± 1.17), (DBM -0.02 (90%CI -0.48; 0.44)). LIMITATIONS, REASONS FOR CAUTION: The study was performed in young, potentially fertile oocyte donors who are patients with high blastocyst euploidy rates. Although results may be extrapolated to young infertile women with good ovarian reserve, caution is needed prior to generalizing the results to infertile women of older age. WIDER IMPLICATIONS OF THE FINDINGS: The current study provides evidence that initiation of ovarian stimulation in the luteal phase in young potentially fertile women may result in a comparable number of oocytes and comparable blastocyst euploidy rates compared with follicular phase stimulation. This may imply that in case of a freeze-all protocol in young patients with good ovarian reserve, clinicians may safely consider initiation of ovarian stimulation during the luteal phase. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by an unrestricted grant from MSD/Organon. N.P.P. has received Research grants and honoraria for lectures from: Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins Intenational, Roche Diagnostics, IBSA, Theramex, Gedeon Richter. F.M., E.C., M.R. and S.G. declared no conflict of interests. TRIAL REGISTRATION NUMBER: The study was registered at Clinical Trials Gov (NCT03555942).

A retrospective, matched case-control study of recombinant LH versus hMG supplementation on FSH during controlled ovarian hyperstimulation in the GnRH-antagonist protocol.

Background: The role of luteinizing hormone (LH) in controlled ovarian hyperstimulation (COH) requires more evidence for its efficacy. Several studies compared recombinant human LH (r-hLH) or human menopausal gonadotropin (hMG) in combination with recombinant human follicle-stimulating hormone (r-hFSH) but lack the results with GnRH-antagonist protocol and in Asians. Methods: This is a retrospective, single-center study inspecting women receiving GnRH antagonist protocol and r-hFSH+hMG or r-hFSH+r-hLH regimen for over five days for COH in the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle in Taiwan from 2013 to 2018. The outcomes of IVF/ICSI cycles were analyzed after propensity score matching between the two groups. A subgroup analysis was conducted in cycles in which women underwent their first embryo transfer (ET), including fresh ET and frozen ET (FET). Results: With a total of 503 cycles, the results revealed that the r-hFSH+r-hLH group performed better in terms of numbers of oocytes retrieved (r-hFSH+hMG vs. r-hFSH+r-hLH, 11.7 vs. 13.7, p=0.014), mature oocytes (8.7 vs. 10.9, p=0.001), and fertilized oocytes (8.3 vs. 9.8, p=0.022), while other outcomes were comparable. The analysis of first ET cycles also showed similar trends. Although the implantation rate (39% vs. 43%, p=0.37), pregnancy rate (52% vs. 53%, p=0.90), and live birth rate (39% vs. 45%, p=0.19) were not significantly different, the miscarriage rate was higher in the r-hFSH+hMG group than the r-hFSH+r-hLH group (26% vs. 15%, p<0.05) in first ET cycles. The cumulative pregnancy rate was significantly higher in the r-hFSH+r-hLH group (53% vs. 64%, p=0.02). No significant difference in rates of ovarian hyperstimulation syndrome (OHSS) was observed. Conclusion: The results support the hypothesis that the treatment of r-hLH+r-hFSH improves COH clinical outcomes in the IVF/ICSI cycle.

Recombinant LH supplementation improves cumulative live birth rates in the GnRH antagonist protocol: a multicenter retrospective study using a propensity score-matching analysis.

BACKGROUND: Luteinizing hormone (LH) is critical in follicle growth and oocyte maturation. However, the value of recombinant LH (r-LH) supplementation to recombinant follicle stimulating hormone (r-FSH) during controlled ovarian stimulation in the gonadotrophin releasing hormone (GnRH) antagonist regimen is controversial. METHODS: This multicenter retrospective cohort study recruited 899 GnRH antagonist cycles stimulated with r-LH and r-FSH in 3 reproductive centers and matched them to 2652 r-FSH stimulating cycles using propensity score matching (PSM) for potential confounders in a 1:3 ratio. The primary outcome was the cumulative live birth rate (CLBR) per complete cycle. RESULTS: The baseline characteristics were comparable in the r-FSH/r-LH and r-FSH groups after PSM. The r-FSH/r-LH group achieved a higher CLBR than the r-FSH group (66.95% vs. 61.16%, p = 0.006). R-LH supplementation also resulted in a higher 2-pronuclear embryo rate, usable embryo rate, and live birth rate in both fresh embryo transfer cycles and frozen-thawed embryo transfer (FET) cycles. No significant differences were found in the rate of moderate and severe ovarian hyperstimulation syndrome (OHSS), or cycle cancellation rate in the prevention of OHSS. CONCLUSIONS: R-LH supplementation to r-FSH in the GnRH antagonist protocol was significantly associated with a higher CLBR and live birth rate in fresh and FET cycles, and improved embryo quality without increasing the OHSS rate and cycle cancellation rate.

Network meta-analysis of 6 kinds of Chinese patent medicines combined with mifepristone in the treatment of uterine fibroids: A protocol for systematic review and network meta-analysis.

BACKGROUND: Uterine fibroids are benign. They belong to the category of "abdominal mass" in traditional Chinese medicine, and pathogenesis is mainly caused by weakness of the body, qi stagnation, and blood stasis. Drug therapy is the preferred treatment of uterine fibroids in clinical practice, and mifepristone is the most commonly used drug. In the past decade, a large number of clinical randomized controlled trials have proven that Chinese patent medicine combined with mifepristone in the treatment of uterine fibroids has a better curative effect, fewer adverse reactions, and higher safety than mifepristone alone. However, there is a lack of evidence-based research. This study aims to integrate clinical data through network meta-analysis to provide more evidence-based medical evidence for clinical medication. METHODS: The comprehensive search included Chinese and other-language databases, such as MEDLINE (PubMed), Web of Science, The Cochrane Library, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China Scientific Journal Database, and China Biomedical Literature Database. Clinical randomized controlled trials of 6 Chinese patent medicines combined with mifepristone for the treatment of uterine fibroids, including Guizhi Fuling Capsule, Gongliuxiao Capsule, Gongliuqing Capsule, Danbie Capsule, Gongliuning Capsule, and Xiaojiean Capsule were retrieved. The search period was from January 2010 to April 2021. Two researchers screened the literature through EndNote and used Excel to extract data. RevMan 5.3 was used to evaluate the quality of the literature. Treatment measures were analyzed in R language, and a forest map and probability ranking map of various interventions were drawn. The network evidence map and correction comparison funnel map of various interventions were drawn by STATA 14.0 software. RESULTS: This study provides the clinical efficacy and safety of network meta-analysis of 6 kinds of Chinese patent medicines combined with mifepristone in the treatment of uterine fibroids will be systematically evaluated or descriptively analyzed. CONCLUSION: This study's purpose is to provide a reference for the clinical treatment of uterine fibroids to choose more effective intervention therapies.

The efficacy and safety of Xuefu Zhuyu Decoction combined Mifepristone in the treatment of Uterine leiomyoma: A protocol systematic review and meta-analysis.

BACKGROUND: Uterine leiomyoma (UL) is a common severe gynecological issue. In China, Xuefu Zhuyu Decoction (XFZYD), combined with Mifepristone, is widely used in the treatment of UL. However, their combined effectiveness and safety for this purpose have not yet been explored. OBJECTIVE: This systematic review aims to evaluate the effectiveness and safety of XFZYD combined with Mifepristone as a method of treatment for UL. METHODS: We searched the following 7 databases: 3 English medical databases (PubMed, EMBASE, Cochrane Library), and 4 Chinese medical databases (Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and the Wanfang database). The primary outcome was the effect of XFZYD combined with Mifepristone on the effective rate, uterine leiomyoma volume (ULV), and uterine volume (UV) of uterine leiomyoma. Bias risk was assessed using the Cochrane risk of bias tool. The software RevMan5 was used to evaluate the quality of the included studies and process the data. RESULTS: This study will evaluate the efficacy and safety of XFZYD combined with Mifepristone in the treatment of uterine fibroids by evaluating the effective rate, Uterine Leiomyoma volume, and uterine volume, the incidence of estradiol, luteinizing hormone, and other indicators. CONCLUSION: This study will provide reliable evidence-based evidence for Xuefu Zhuyu Decoction Combined with Mifepristone in the treatment of uterine fibroids. ETHICS AND DISSEMINATION: Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/YADN3.

Pharmacological Modulation of Steroid Activity in Hormone-Dependent Breast and Prostate Cancers: Effect of Some Plant Extract Derivatives.

: The great majority of breast and prostate tumors are hormone-dependent cancers; hence, estrogens and androgens can, respectively, drive their developments, making it possible to use pharmacological therapies in their hormone-dependent phases by targeting the levels of steroid or modulating their physiological activity through their respective nuclear receptors when the tumors relapse. Unfortunately, at some stage, both breast and prostate cancers become resistant to pharmacological treatments that aim to block their receptors, estrogen (ER) or androgen (AR) receptors, respectively. So far, antiestrogens and antiandrogens used in clinics have been designed based on their structural analogies with natural hormones, 17-ß estradiol and dihydrotestosterone. Plants are a potential source of drug discovery and the development of new pharmacological compounds. The aim of this review article is to highlight the recent advances in the pharmacological modulation of androgen or estrogen levels, and their activity through their cognate nuclear receptors in prostate or breast cancer and the effects of some plants extracts.

[Dienogest usefulness in pelvic pain due to endometriosis. A meta-analysis of its effectiveness]. / Evaluación de dienogest en el tratamiento del dolor pélvico asociado a la endometriosis. Un metaanálisis de su efectividad.

BACKGROUND: Endometriosis is the presence of functional endometrial tissue in the pelvic peritoneum and it affects several age groups. That is why the impact of endometriosis in quality of life is considerable. The objective of this study was to evaluate the effectiveness of dienogest in patients with pelvic pain associated to endometriosis (PPAE). METHODS: The evaluation of the effectiveness was carried out through a systematic review using the Cochrane methodology. It was used Markov model, which considers two states of health (with and without PPAE), with the possibility of weekly transition. Women between 18 and 45 years with PPAE were included, in a temporary horizon of 26 weeks. A level of statistical significance of 95% was used for a p < 0.05, with a multivariate probabilistic analysis of sensibility, as well as a univariate analysis of sensibility in several scenarios. RESULTS: The probability that the female patient did not experience PPAE with the initial treatment was 87.91% with dienogest, 80.07% with danazol, 84.93% with medroxyprogesterone (injectable and oral) and 89.17% with gosereline. The probability that the female patient abandoned her initial treatment was 9% with dienogest, 12.07% with danazol, 9.6 and 6.75% with medroxyprogesterone injectable and oral, respectively, and 10.8 and 3.6% 3-monthly and monthly with gosereline. CONCLUSION: Compared to danazol, medroxiprogesterone and gosereline, dienogest is the most efficient alternative to treat PPAE.

Introducción: La endometriosis es la presencia de tejido endometrial funcional en el peritoneo pélvico y afecta a varios grupos de edad, por lo que su impacto en la calidad de vida es considerable. El objetivo fue evaluar la efectividad del dienogest en pacientes con dolor pélvico asociado a endometriosis (DPAE), al compararlo con danazol, medroxiprogesterona y goserelina. Métodos: se hizo una revisión sistemática de la literatura con la metodología Cochrane. Se usó el modelo de Markov, que considera dos estados de salud: con y sin DPAE, con posibilidad de transición semanal. Se consideraron mujeres entre 18 y 45 años con DPAE, en un horizonte de 26 semanas; se utilizó un nivel de significación estadística de 95% (p < 0.05), con un análisis probabilístico multivariante de sensibilidad y uno univariante de sensibilidad en varios escenarios. Resultados: la probabilidad de que la mujer se encontrara sin DPAE con el tratamiento inicial fue de 87.91% para dienogest, 80.07% para danazol, 84.93% para medroxiprogesterona inyectable y oral y 89.17% para goserelina; la probabilidad de que la mujer abandonara su tratamiento inicial fue de 9% para dienogest, 12.07% para danazol, 9.6 y 6.75% para medroxiprogesterona inyectable y oral, respectivamente, y 10.8 y 3.6% para goserelina trimestral y mensual, respectivamente. Conclusiones: Comparado con el danazol, la medroxiprogesterona y la goserelina, el dienogest es la alternativa más eficiente para el DPAE.

Diurnal Variation of the Peripheral Cholinergic Antiinflammatory Function in Mice.

AIMS: Cholinergic antiinflammatory (CAI) pathway functions importantly in inflammation via α7 nicotinic acetylcholine receptors (α7nAChR). The present work tested circadian rhythm in peripheral CAI activity and validities of CAI activity and glucocorticoids in chronotherapy for lipopolysaccharide (LPS)-induced shock. METHODS: Vesicular acetylcholine transporter (VAChT) expressed in liver and kidney was examined every 3 h in C57BL/6 mice. Proinflammatory cytokines in serum and survival time in shock were monitored after LPS injection every 3 h. Mifepristone, antagonist of glucocorticoid receptors, and methyllycaconitine (MLA), antagonist of α7nAChR, were administrated before LPS to block antiinflammatory function of endogenous glucocorticoids and acetylcholine. RESULTS: Both levels of tumor necrosis factor α, interleukin 1ß, and interleukin 6 and mortality exhibited diurnal variations with prominent peaks when LPS was given at 15:00, and the minimum mortality occurred at 00:00. Expression of VAChT increased during resting period. MLA increased serum proinflammatory cytokines slightly, but not affected survival rate. Both differences in cytokines and in survival times between LPS injection at 15:00 and 00:00 were eliminated by mifepristone, but not by MLA. CONCLUSION: Peripheral CAI pathway exerts more powerful antiinflammatory effect during resting period. Glucocorticoids appear to be efficient in chronotherapy for septic shock.

Ovarian Stimulation Protocol in IVF: An Up-to-Date Review of the Literature.

The Assisted Reproductive Technology (ART) was born in order to help couples with infertility issues in having a baby. The first treatments of IVF used the spontaneous cycle of the women, with the retrieval of only one oocyte. Further studies have shown that it is possible to induce ovulation by administrating gonadotropins during the menstrual cycle, in order to obtain a higher number of oocytes. Many stimulation protocols have been introduced for controlled ovarian hyperstimulation of patients undergoing in vitro fertilization treatment. This review describe the different stimulation protocols using follicle-stimulating hormone (FSH) in combination with Gonadotropin releasing hormone (GnRH) either agonist or antagonist, oral supplementations and ovarian triggering. Using GnRH antagonist protocols have been demonstrated to improve significantly the clinical pregnancy rates for expected poor and high-responders, and in those women at high risk of developing ovarian hyperstimulation syndrome (OHSS). Two meta-analyses showed a better outcome in terms of the live birth rate when highly purified human menopausal gonadotropin (HMG) was used for ovarian stimulation compared with recombinant follicle stimulating hormone (rFSH) in the GnRH agonist long protocol. One of the most efficient stimulation protocol is the use of a combined protocol of human derived urinary FSH (uFSH) and rFSH. Combined protocol has resulted in a significant increase in the proportion of mature metaphase II oocytes and grade 1 embryos when compared to either rFSH or uFSH alone. A significantly higher delivery rate was achieved in rFSH+uFSH compared to the other protocols in poor and normal responders. Studying the combination of melatonin with myo-inositol and folic acid has also showed a higher percentage of mature oocytes in the melatonin group and a higher percentage of G1 embryos as well. However, It remains a crucial step to confirm the efficacy of such protocols for clinical application and it is still needs to comparison studies on larger scale with more focused on the differences in patients' response criteria and additional confounding variables, in order to draw more defined conclusions.

An Evidence-based Approach to the Medical Management of Fibroids: A Systematic Review.

Fibroids are the most common tumor of the female reproductive tract, but approved medical treatments are limited. Patients demand uterine-sparing treatments which preserve fertility and avoid surgery. We systematically reviewed PubMed and Cochrane databases from January 1985 to November 2015 for evidence-based medical therapies for fibroids in the context of disease prevention, treatment of early disease, treatment of symptomatic disease, and preoperative management. We identified 2182 studies, of which 52 studies met inclusion and exclusion criteria. Published data affirm the efficacy of multiple agents, which are promising avenues for the development of medical alternatives to surgery.

Blockade of glucocorticoid receptors with RU486 attenuates cardiac damage and adipose tissue inflammation in a rat model of metabolic syndrome.

Glucocorticoids are stress hormones that modulate metabolic, inflammatory and cardiovascular processes. We recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive (DS) and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated the effects of glucocorticoid receptor (GR) blockade on cardiac and adipose tissue pathology and gene expression, as well as on glucose metabolism in this model. DS/obese rats were treated with the GR blocker RU486 (2 mg kg(-1) per day, subcutaneous) for 4 weeks beginning at 9 weeks of age. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+), or DS/lean) littermates of DS/obese rats served as controls. Treatment of DS/obese rats with RU486 attenuated left ventricular (LV) fibrosis and diastolic dysfunction, as well as cardiac oxidative stress and inflammation, without affecting hypertension or LV hypertrophy. Administration of RU486 to DS/obese rats also inhibited the upregulation of GR and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) expression at the mRNA and protein levels in the heart; it attenuated adiposity and adipose tissue inflammation, as well as the upregulation of GR and 11ß-HSD1 mRNA and protein expression in adipose tissue; it ameliorated fasting hyperinsulinemia as well as insulin resistance and glucose intolerance. Our results thus implicate the glucocorticoid-GR axis in the pathophysiology of MetS, and they suggest that GR blockade has therapeutic potential for the treatment of this condition.

Dienogest. A possible conservative approach in bladder endometriosis. Results of a pilot study.

Deep endometriosis involvement of the bladder is uncommon but it is symptomatic in most of the cases. Although laparoscopic excision is very effective, some patients with no pregnancy desire require a medical approach. We performed a pilot study on the effect of a new progestin dienogest on bladder endometriosis. Six patients were treated for 12 months with dienogest 2 mg/daily. Pain, urinary symptoms, quality of life, nodule volume and side effects were recorded. During treatment, symptoms improved very quickly and the nodules exhibit a remarkable reduction in size. Dienogest may be an alternative approach to bladder endometriosis.

Hidradenitis suppurativa: A practical review of possible medical treatments based on over 350 hidradenitis patients.

Hidradenitis suppurativa (HS), a pathological follicular disease, impacts patients' lives profoundly. HS most commonly involves cutaneous intertriginous areas, such as the axilla, inner thighs, groin and buttocks, and pendulous breasts, but can appear on any follicular skin. Protean, HS manifests with variations of abscesses, folliculitis, pyogenic granulomas, scars (oval honeycombed), comedones, tracts, fistulas, and keloids. The pathophysiology might involve both defects of the innate follicular immunity and overreaction to coagulase negative Staphylococcus. Treatment depends on the morphology, extent, severity, and duration. Topical clindamycin and dapsone are often adequate for treating mild HS. For Stage 1 and 2 HS, first line treatment combines rifampin with either oral clindamycin or minocycline. Other HS treatments include: fluoroquinolones with metronidazole and rifampin, oral dapsone, zinc, acitretin, hormone blockers (oral contraceptive pills, spironolactone, finasteride, and dutasteride), and oral prednisone. For severe HS, cyclosporine, adalimumab, or infliximab (used at double psoriatic doses) and intravenous carbapenems or cephalosporins are often required. Isotretinoin, etanercept, isoniazid, lymecycline, sulfasalazine, methotrexate, metformin, colchicine, clarithromycin, IVIG, and thalidomide are less favored treatments. The role of botulinum toxin is uncertain. The most important life style modification is weight loss. De-roofing fluctuant nodules and injection of intralesional corticosteroids ameliorates the disease and perhaps, if done at regular intervals, improves HS more permanently. Surgical excision and CO2 laser ablation are more definitive treatments. The 1064 nm laser for hair removal aids in the treatment of HS. This article centers on medical therapies and will only passingly mention surgical and laser treatments. This article summarizes my treatment experience with over 350 HS patients.

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.

Mifepristone pretreatment reduces ethanol withdrawal severity in vivo.

BACKGROUND: Prolonged ethanol (EtOH) intake may perturb function of the hypothalamic-pituitary-adrenal axis in a manner that promotes dependence and influences EtOH withdrawal severity. Prior in vivo and in vitro studies suggest that corticosteroids, in particular, may be elevated during EtOH intoxication and withdrawal, suggesting that intracellular glucocorticoid receptors (GRs) may promote the development of EtOH dependence. METHODS: Adult male Sprague-Dawley rats were subjected to a 4-day binge-like EtOH administration regimen (3 to 5 g/kg/i.g. every 8 hours designed to produce peak blood EtOH levels (BELs) of <300 mg/dl). Subgroups of animals received s.c. injection of the GR antagonist mifepristone (20 or 40 mg/kg in peanut oil at 0800 hours on each of the 4 days prior to withdrawal). BELs were assessed at 0900 and 1500 hours on Days 2 (D2) and 4 (D4) of the regimen. BEL, blood corticosterone levels (BCLs), and EtOH withdrawal-associated behavioral abnormalities were assessed 10 to 12 hours after the final EtOH administration. RESULTS: Daily mean EtOH doses for D1 to D4 of the regimen were 14.4, 9.9, 7.1, and 8.6 g/kg, respectively. The EtOH gavage regimen produced mean BELs of 255 mg/dl at 0900 on D2 and 156.2 mg/dl at 0900 on D4 of the regimen. Withdrawal from the EtOH exposure regimen, beginning 10 hours after the last EtOH administration, produced significant elevations in BCL and behavioral abnormalities including tremors, stereotypy, and "wet dog shakes." Mifepristone administration did not alter food intake or weight during the 4-day regimen, nor were there drug-dependent differences in BEL or BCL on withdrawal day. Although mifepristone produced no significant changes in behavior of EtOH-naïve animals, pretreatment with mifepristone (40 mg/kg) significantly reduced the severity of EtOH withdrawal. CONCLUSIONS: Findings suggest that activation of GRs promotes neuroadaptation to binge-like EtOH exposure, contributing to the development of EtOH dependence. Further, GRs may represent therapeutic targets to be exploited in reducing the severity of EtOH withdrawal.

An elderly patient with chronic hyponatremia.

Hyponatremia is the most common electrolyte disorder. With the aging of the population and the greater propensity of the elderly to develop hyponatremia, this electrolyte disorder is of increasing importance to the practicing nephrologist. In this Attending Rounds, an illustrative patient with hyponatremia is presented. The reasons for the increased incidence and prevalence of hyponatremia in the elderly are discussed, with emphasis on the effects of aging on urinary dilution, the frequently multifactorial nature of hyponatremia in this population, and the absence of a definite cause for inappropriate and persistent vasopressin release in many such patients. The rationale for treating the hyponatremia, even when apparently asymptomatic, is discussed, with attention to cognitive function, gait, and bone structure disturbances that increase the risk for fractures. The various available treatment approaches, including water restriction, demeclocycline, loop diuretics with NaCl supplementation, urea, and vasopressin antagonists are summarized, with emphasis on the efficacy and limitations of each of these therapies.

GnRH receptors in cancer: from cell biology to novel targeted therapeutic strategies.

The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH agonists (through receptor desensitization) and antagonists (through receptor blockade) for the treatment of steroid-dependent pathologies, including hormone-dependent tumors. It has also become increasingly clear that GnRH-R are expressed in cancer tissues, either related (i.e. prostate, breast, endometrial, and ovarian cancers) or unrelated (i.e. melanoma, glioblastoma, lung, and pancreatic cancers) to the reproductive system. In hormone-related tumors, GnRH-R appear to be expressed even when the tumor has escaped steroid dependence (such as castration-resistant prostate cancer). These receptors are coupled to a G(αi)-mediated intracellular signaling pathway. Activation of tumor GnRH-R by means of GnRH agonists elicits a strong antiproliferative, antimetastatic, and antiangiogenic (more recently demonstrated) activity. Interestingly, GnRH antagonists have also been shown to elicit a direct antitumor effect; thus, these compounds behave as antagonists of GnRH-R at the pituitary level and as agonists of the same receptors expressed in tumors. According to the ligand-induced selective-signaling theory, GnRH-R might assume various conformations, endowed with different activities for GnRH analogs and with different intracellular signaling pathways, according to the cell context. Based on these consistent experimental observations, tumor GnRH-R are now considered a very interesting candidate for novel molecular, GnRH analog-based, targeted strategies for the treatment of tumors expressing these receptors. These agents include GnRH agonists and antagonists, GnRH analog-based cytotoxic (i.e. doxorubicin) or nutraceutic (i.e. curcumin) hybrids, and GnRH-R-targeted nanoparticles delivering anticancer compounds.

Post-exposure sleep deprivation facilitates correctly timed interactions between glucocorticoid and adrenergic systems, which attenuate traumatic stress responses.

Reliable evidence supports the role of sleep in learning and memory processes. In rodents, sleep deprivation (SD) negatively affects consolidation of hippocampus-dependent memories. As memory is integral to post-traumatic stress symptoms, the effects of post-exposure SD on various aspect of the response to stress in a controlled, prospective animal model of post-traumatic stress disorder (PTSD) were evaluated. Rats were deprived of sleep for 6 h throughout the first resting phase after predator scent stress exposure. Behaviors in the elevated plus-maze and acoustic startle response tests were assessed 7 days later, and served for classification into behavioral response groups. Freezing response to a trauma reminder was assessed on day 8. Urine samples were collected daily for corticosterone levels, and heart rate (HR) was also measured. Finally, the impact of manipulating the hypothalamus-pituitary-adrenal axis and adrenergic activity before SD was assessed. Mifepristone (MIFE) and epinephrine (EPI) were administered systemically 10-min post-stress exposure and behavioral responses and response to trauma reminder were measured on days 7-8. Hippocampal expression of glucocorticoid receptors (GRs) and morphological assessment of arborization and dendritic spines were subsequently evaluated. Post-exposure SD effectively ameliorated long-term, stress-induced, PTSD-like behavioral disruptions, reduced trauma reminder freezing responses, and decreased hippocampal expression of GR compared with exposed-untreated controls. Although urine corticosterone levels were significantly elevated 1 h after SD and the HR was attenuated, antagonizing GRs with MIFE or stimulation of adrenergic activity with EPI effectively abolished the effect of SD. MIFE- and EPI-treated animals clearly demonstrated significantly lower total dendritic length, fewer branches and lower spine density along dentate gyrus dendrites with increased levels of GR expression 8 days after exposure, as compared with exposed-SD animals. Intentional prevention of sleep in the early aftermath of stress exposure may well be beneficial in attenuating traumatic stress-related sequelae. Post-exposure SD may disrupt the consolidation of aversive or fearful memories by facilitating correctly timed interactions between glucocorticoid and adrenergic systems.