A systematic review and meta-analysis of clinical trials implementing aromatase inhibitors to treat male infertility

Aromatase activity has commonly been associated with male infertility characterized by testicular dysfunction with low serum testosterone and/or testosterone to estradiol ratio.In this subset of patients,and particularly in those with hypogonadism,elevated levels of circulating estradiol may establish a negative feedback on the hypothalamic–pituitary–testicular axis by suppressing follicle-stimulating hormone(FSH)and luteinizing hormone(LH)production and impaired spermatogenesis.Hormonal manipulation via different agents such as selective estrogen modulators or aromatase inhibitors to increase endogenous testosterone production and improve spermatogenesis in the setting of infertility is an off-label option for treatment.We carried out a systematic review and meta-analysis of the literature of the past 30 years in order to evaluate the benefits of the use of aromatase inhibitors in the medical management of infertile/hypoandrogenic males.Overall,eight original articles were included and critically evaluated.Either steroidal(Testolactone)or nonsteroidal(Anastrozole and Letrozole)aromatase inhibitors were found to statistically improve all the evaluated hormonal and seminal outcomes with a safe tolerability profile.While the evidence is promising,future prospective randomized placebo-controlled multicenter trials are necessary to better define the efficacy of these medications.

Chinese Medicine Yishen Jiangu Granules(益肾健骨颗粒)on Aromatase Inhibitor-Associated Musculoskeletal Symptoms

Objective： To assess the effectiveness of Yishen Jiangu Granules（益肾健骨颗粒, YSJGG） on aromatase inhibitor-associated musculoskeletal symptoms（AIMSS）. Methods： A single-arm, open-label study was conducted in 34 postmenopausal women with breast cancer who experienced AIMSS. Patients were treated with YSJGG for 12 weeks（12.4 g orally twice daily）. The primary outcome was a change in the mean worst pain score of Brief Pain Inventory-Short Form（BPI-SF） over 12 weeks, and the second outcomes included changes in pain severity and pain-related interference of BPI-SF and Western Ontario and McMaster Universities Osteoarthritis Index（WOMAC）, Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands（M-SACRAH）, the Functional Assessment of Cancer Therapy-Breast（FACT-B）, bone mineral density（BMD） and blood indices such as calcium（Ca）, phosphate（P）, and alkaline phosphatase（ALP）. Results： Of 37 women recruited, 30 initiated the therapy and 24 were evaluable at 12 weeks. The primary outcome（BPI-SF worst pain scores） achieved a 2.17-point reduction compared with baseline（5.75±1.87 vs 3.58±2.15, P〈0.01）. There were reductions in pain severity（decreased 1.65, P〈0.01） and pain-related interference（decreased 2.55, P〈0.01）. The changes in WOMAC and M-SACRAH scores were similar to BPI-SF（P〈0.05）. In the FACT-B, only physical wel-being and functional wel-being were improved compared with baseline（P〈0.05）. No clinical differences were found in BMD, Ca, P and ALP. Conclusion： YSJGG is an effective and wel-tolerated agent to reduce AIMSS.

Molecular Docking Studies of Estrone-Coumarin Derivatives as Aromatase and 17β-HSD1 Inhibitors Related to Hormone Receptor Positive (HR+) Breast Cancer

Hormone Receptor positive (HR+) breast cancer is the most common malignancy in women. New strategies in the treatments have targeted the estrogen biosynthesis pathways including the inhibition of the aromatase and 17β-HSD1 enzymes. The present work, describes the study of a new family of 9 hybrid compounds derived from estrone attached to a coumarin fragment, linked through different lengths of hydrocarbon chains. The activity of these compounds was evaluated by molecular docking with two relevant enzymes in breast cancer (HR+). It has been proposed nine compounds as 17β-HSD1 inhibitors and six as aromatase inhibitors. We found important interactions with key amino acids at the orthosteric site of each enzyme and their score values compared to the crystallographic ligand. The in silico analysis showed good score values in the proposed compounds, where the steroidal portion presented important interactions with Met374 and Tyr155 in aromatase and in 17β-HSD1 respectively. Highlighting Compounds 2, 5 and 8 with an aromatic ring at the C4 position of the coumarin moiety, which favored arene-H type interactions essential for protein-ligand recognition. In addition, the results related to the 17β-HSD1 enzyme demonstrated how the length of the linker influences the interaction;the best score was found for derivative 8 with a chain of 8 methylenes.

抗黄体酮联合Aromatase抑制剂或iNOS终止恒河猴妊娠

[目的]评价抗黄体酮(mifepristone)联合Aromatase抑制剂(letrozole或aminoglutethimide)或iNOS抑制剂(aminoguandine)是否能有效终止恒河猴早期妊娠。[方法]将30只猴子随机分为5组(治疗组每组6只,对照组6只),并在妊娠30,31和32天进行如下处理:对照组,每只动物1ml安慰剂;A组,Mifepristone(1mg/kg,sc.);B组,Mifepristone(sc.)+Letrozole(2.5mg/只sc.);C组,Mifepristone(1mg/kg,sc.)+aminoglute-chimide(50mg/kgsc.,bid);D组,Mifepristone(1mg/kg,sc.)+aminoguanidine(150mg/kg,sc.,bid)。所有妊娠猴在妊娠29天通过超声波确认。[结果]在B、C、D组,所有的动物的妊娠都在妊娠早期被终止(6/6)。A组和对照组的妊娠终止率分别为3/6和2/6。同时,联合用药能够有效排空子宫腔和减少出血。[结论]该处理能有效地终止恒河猴早期妊娠。联合用药比用于女人的妊娠治疗更有效,并减少了流血时间,或许可以代替目前的终止妊娠的医疗方法。

Steroid Sulfatase Inhibitor Reduces Proliferation of Ishikawa Endometrial Cancer Cells in Co-Culture Systems

Objectives: Estrogens significantly contribute toward the growth and development of endometrial cancers. Two principal pathways have been implicated in the final steps of estrogen synthesis: the steroid sulfatase (STS) and aromatase pathways. In this study, we aimed to evaluate the possible effects of tumor-stromal interactions on local estrogen biosynthesis in endometrial cancer. We also assessed the biological effects of inhibitors of steroid sulfatase and aromatase in the co-culture system compared with usual monocultures. Methods/Materials: We isolated stromal cells from endometrial cancer patients to examine local biosynthesis of estrogens and tumor-stromal interactions. Next we examined the effects of steroid sulfatase inhibitor and aromatase inhibitor in monoculture of endometrial cancer cell line (Ishikawa) and in a co-culture system involving an Ishikawa cells and stromal cells. Results: Estrogen receptor and steroid sulfatase mRNA levels in cancer cells were significantly higher in the co-cultures compared with the monocultures of endometrial cancer cells. Estradiol and androstenediol concentrations were also significantly higher in the co-cultured cells. Proliferation of the cancer cells was significantly increased through the steroid sulfatase pathway, which metabolizes androgens, estrone sulfate, and estradiol sulfate as its substrates. However, its proliferation was significantly decreased by the treatment of steroid sulfatase or aromatase inhibitors. The significant growth inhibition by the steroid sulfatase and aromatase inhibitors were also observed in the co-culture system. Conclusions: We evaluated the effects of STS inhibitor and aromatase inhibitors on the proliferation of estrogen-dependent endometrial cancer cells. Considering that intratumoral estrogen metabolism plays an important role, our co-culture systems provide an environment similar to that of the tumor in living patients in terms of metabolism and synthesis of intratumoral estrogens. The results of this study may aid in achieving improved clinical responses from patients treated with STS inhibitors.

Management of genitourinary syndrome of menopause in breast cancer survivors:An update

There is increasing attention about managing the adverse effects of adjuvant therapy(Chemotherapy and anti-estrogen treatment)for breast cancer survivors(BCSs).Vulvovaginal atrophy(VVA),caused by decreased levels of circulating estrogen to urogenital receptors,is commonly experienced by this patients.Women receiving antiestrogen therapy,specifically aromatase inhibitors,often suffer from vaginal dryness,itching,irritation,dyspareunia,and dysuria,collectively known as genitourinary syndrome of menopause(GSM),that it can in turn lead to pain,discomfort,impairment of sexual function and negatively impact on multiple domains of quality of life(QoL).The worsening of QoL in these patients due to GSM symptoms can lead to discontinuation of hormone adjuvant therapies and therefore must be addressed properly.The diagnosis of VVA is confirmed through patient-reported symptoms and gynecological examination of external structures,introitus,and vaginal mucosa.Systemic estrogen treatment is contraindicated in BCSs.In these patients,GSM may be prevented,reduced and managed in most cases but this requires early recognition and appropriate treatment,but it is normally undertreated by oncologists because of fear of cancer recurrence,specifically when considering treatment with vaginal estrogen therapy(VET)because of unknown levels of systemic absorption of estradiol.Lifestyle modifications and nonhormonal treatments(vaginal moisturizers,lubricants,and gels)are the first-line treatment for GSM both in healthy women as BCSs,but when these are not effective for symptom relief,other options can be considered,such as VET,ospemifene,local androgens,intravaginal dehydroepiandrosterone(prasterone),or laser therapy(erbium or CO2 Laser).The present data suggest that these therapies are effective for VVA in BCSs;however,safety remains controversial and a there is a major concern with all of these treatments.We review current evidence for various nonpharmacologic and pharmacologic therapeutic modalities for GSM in BCSs and highlight the substantial gaps in the evidence for safe and effective therapies and the need for future research.We include recommendations for an approach to the management of GSM in women at high risk for breast cancer,women with estrogen-receptor positive breast cancers,women with triplenegative breast cancers,and women with metastatic disease.

The effect of anastrozole on mRNA expression of oestrogen related gene in MCF-7 breast cancer cells

Objective: To look for additional markers of molecular biology response to anastrozole, a new aromatase inhibitor, on the growth and mRNA expression level of MCF-7 cell. Methods: We investigated the effect of anastrzole on growth and gene expression in the human breast cancer cell line MCF-7 and compared with the most widely used antiestrogen tamoxifen. We chose 4 genes to examine regulation of gene expression of estrogen regulated genes: PR A, PR B, ErbB-2 and cyclin D1. Results: Compared with the tamoxifen, a statistically significant growth inhibition was observed with anastrozole. The PR A, PR B and cyclin D1 mRNA level in anastrozole treated cells was sigificantly below the level in tamoxifen treated cells (P<0. 05). They had agonistic effect on ErbB gene (P>0. 05). Conclusion: The third generation of aromatase inhibitors anastrozole exert more inhibit function in some expression of estrogen regulated genes than tomoxifen in MCF-7 cell line.

Medical treatments of endometriosis: a review

Endometriosis is a chronic gynecological disorder that affects approximately 10%of women of reproductive age.Most medical treatments used today for endometriosis pain are hormonal therapies,which are not an option for those trying to conceive and are not tolerated by a subset of patients due to side effects.In this article,we offer a comprehensive review of current and investigational medical therapeutic options used to treat endometriosis pain,as well as a symptom-based systematic approach for patients with painful endometriosis.We have also included recommendations for research to enhance the evolution of novel therapeutic options.A thorough literature search was carried out,and the data were synthesized using a synthesis matrix that classifies and categorizes various arguments.

Inhibition of oestrogen biosynthesis induces mild anxiety in C57BL/6J ovariectomized female mice

Objective Letrozole, a next-generation aromatase inhibitor, has become a favored drug for the treatment of breast cancer in postmenopausal women. Although letrozolc is generally well tolerated, its adverse effects on the central nervous system have been reported. The present study aimed to assess the behavioural outcomes of letrozole administra- tion in mice to determine its side effects. Methods C57BL/6J female ovariectomized mice received administration of letrozole （2.5 mg/kg per day） or vehicle by gavage for 3 weeks. Behavioural tasks were used to assess anxiety, depression, as well as learning and memory in mice. Results Letrozole-treated mice showed an increased latency to enter the inner area of the chamber on the third day of the open field test, and traveled a shorter distance in the open arms of the elevated plus maze. No significant difference was found in the light-dark box or forced swimming task between letrozole-treated and vehicle-treated mice. Besides, letrozole did not change the spontaneous alternation behaviour of mice in the Y-maze. In the Morris water maze, mice administered with letrozole exhibited an improvement in spatial learning and memory compared with the vehicle-treated mice. Conclusion Our results indicate that the inhibition of oestrogen biosynthesis results in mild anxious behaviour, which may be a consideration in the treatment of breast cancer in postmenopausal women using aromatase inhibitors.

Alternatives to testosterone replacement： testosterone restoration

The European Male Aging Study has demonstrated that the hypogonadism of male aging is predominantly secondary. Theoretically with appropriate stimulation from the pituitary, the aging testis should be able to produce eugonadal levels of testosterone. The strategies for the treatment of late onset hypogonadism （LOH） have focused on replacement with exogenous testosterone versus restoration of endogenous production. The purpose of this article is to review existing peer-reviewed literature supporting the concept of restoration of endogenous testosterone in the treatment of LOH.

Target-based anticancer indole derivatives and insight into structure-activity relationship:A mechanistic review update(2018—2021)

Cancer,which is the uncontrolled growth of cells,is the second leading cause of death after heart disease.Targeting drugs,especially to specific genes and proteins involved in growth and survival of cancer cells,is the prime need of research world-wide.Indole moiety,which is a combination of aromatic-heterocyclic compounds,is a constructive scaffold for the development of novel leads.Owing to its bioavailability,high unique chemical properties and significant pharmacological behaviours,indole is considered as the most inquisitive scaffold for anticancer drug research.This is illustrated by the fact that the U.S.Food and Drug Administration(FDA)has recently approved several indole-based anticancer agents such as panobinostat,alectinib,sunitinib,osimertinib,anlotinib and nintedanib for clinical use.Furthermore,hundreds of studies on the synthesis and activity of the indole ring have been published in the last three years.Taking into account the facts stated above,we have presented the most recent advances in medicinal chemistry of indole derivatives,encompassing hot articles published between 2018and 2021 in anticancer drug research.The recent advances made towards the synthesis of promising indole-based anticancer compounds that may act via various targets such as topoisomerase,tubulin,apoptosis,aromatase,kinases,etc.,have been discussed.This review also summarizes some of the recent efficient green chemical synthesis for indole rings using various catalysts for the period during 2018—2021.The review also covers the synthesis,structure-activity relationship,and mechanism by which these leads have demonstrated improved and promising anticancer activity.Indole molecules under clinical and preclinical stages are classified into groups based on their cancer targets and presented in tabular form,along with their mechanism of action.The goal of this review article is to point the way for medicinal chemists to design and develop effective indole-based anticancer agents.