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Fulltext Kelulut Honey Improves Folliculogenesis, Steroidogenic, and Aromatase Enzyme Profiles and Ovarian Histomorphology in Letrozole-Induced Polycystic Ovary Syndrome Rats

Kamal DAM, Ibrahim SF, Ugusman A, Zaid SSM, Mokhtar MH

Nutrients, 2022 Oct 18;14(20).
PMID: 36297046 DOI: 10.3390/nu14204364

Polycystic ovary syndrome (PCOS) has been linked to aberrant folliculogenesis and abnormalities in the aromatase enzyme (Cyp19a1) and the steroidogenic enzyme, 17-alpha-hydroxylase (Cyp17a1) expression. It has been demonstrated that Kelulut honey (KH) improves both female and male reproductive system anomalies in animal studies. Here, we examined the effects of isolated and combined KH, metformin, and clomiphene in improving folliculogenesis, aromatase, and steroidogenic enzyme profiles and ovarian histomorphology in letrozole-induced PCOS rats. Letrozole (1 mg/kg/day) was administered to female Sprague-Dawley (SD) rats for 21 days to induce PCOS. PCOS rats were subsequently divided into six experimental groups: untreated, treatment with metformin (500 mg/kg/day), clomiphene (2 mg/kg/day), KH (1 g/kg/day), combined KH (1 g/kg/day) and metformin (500 mg/kg/day), and combined KH (1 g/kg/day) and clomiphene (2 mg/kg/day). All treatments were given orally for 35 days. We found that KH was comparable with clomiphene and metformin in improving the expression of Cyp17a1 and Cyp19a1, apart from enhancing folliculogenesis both histologically and through the expression of folliculogenesis-related genes. Besides, the combination of KH with clomiphene was the most effective treatment in improving the ovarian histomorphology of PCOS rats. The effectiveness of KH in restoring altered folliculogenesis, steroidogenic, and aromatase enzyme profiles in PCOS warrants a future clinical trial to validate its therapeutic effect clinically.

Matched MeSH terms: Aromatase/genetics; Aromatase/metabolism
Effect of Traditional Chinese Medicine on Musculoskeletal Symptoms in Breast Cancer: A Systematic Review and Meta-Analysis

Poo CL, Dewadas HD, Ng FL, Foo CN, Lim YM

J Pain Symptom Manage, 2021 07;62(1):159-173.
PMID: 33278502 DOI: 10.1016/j.jpainsymman.2020.11.024

CONTEXT: Traditional Chinese Medicine (TCM) has been widely used as a complementary medical treatment for arthralgia and other types of pain. The available literature on the effectiveness of TCM on breast cancer patients with musculoskeletal symptoms reports controversial results.
OBJECTIVES: The objective of this review is to assess the effectiveness of TCM as a treatment option for musculoskeletal symptoms in patients with breast cancer who were treated with aromatase inhibitors (AIs).
METHODS: A comprehensive literature search was conducted using PubMed, the Cochrane Library, SAGE journals, Scopus, EMBASE, Web of Science, Medline, Cumulated Index to Nursing and Allied Health Literature (CINAHL), Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), Wanfang, and Chinese Medical Journal Database (CMJ) from May 2020 to November 2020. The literature review included randomized controlled trials (RCTs) of TCM for AI-related musculoskeletal symptoms.
RESULTS: Four RCTs incorporating TCM were assessed by meta-analysis and reported favorable effects in reducing worst pain score (n = 284, mean difference [MD]: 2.31; 95% CI, 1.74 to 2.88; P

Matched MeSH terms: Aromatase Inhibitors/therapeutic use
Oncofertility Treatment Among Breast Cancer Women: A Paradigm Shift of Practice After a Decade of Service

Ahmad MF, Sugishita Y, Suzuki-Takahashi Y, Sawada S, Iwahata H, Shiraishi E, et al.

J Adolesc Young Adult Oncol, 2020 08;9(4):496-501.
PMID: 32283045 DOI: 10.1089/jayao.2019.0177

Purpose:
Our center is known as a pioneer center initiating oncofertility service since 2010 in Japan. We demonstrate our transition of this service in regional university hospitals ingenuously.
Methods:
We compared two phases of service: initial phase (2011 and 2012) and current phase (2019). The comparison included the number of women attending the oncofertility unit, diversity of breast cancer cases, the acceptability of preservation service, and the type of fertility preservation (FP) option offered in between these phases.
Results:
A total of 58 women were seen during the initial phase as compared with 41 women in the later phase. The mean age at diagnosis was not significantly different between the two periods. The majority of them were married and diagnosed with stage II luminar type. The current phase had a tendency to have a higher anti-Müllerian hormone level although not reaching significance. At least 50% of them declined FP and 84.5% never received ovarian control stimulation in the initial phase. Otherwise, 61% used aromatase inhibitor in the current phase. Only 15.5% in the initial phase received control ovarian stimulation whereas 63.4% in the current phase received it. The ovarian tissue cryopreservation was highly chosen during the initial phase (25.9%), whereas embryo cryopreservation (39%) was highly opted for during the current phase. All of our parameters are comparable between these two phases (p > 0.05).
Conclusion:
The significant changes of oncofertility practice were observed mainly due to the understanding of the oncofertility concept among reproductive physicians and the acceptance environment, including standard guidelines, supportive society, as well as advancements in cryobiology technique.

Matched MeSH terms: Aromatase; Aromatase Inhibitors
Fulltext Cytotoxicity anticancer activities of anastrozole against breast, liver hepatocellular, and prostate cancer cells

Hassan F, El-Hiti GA, Abd-Allateef M, Yousif E

Saudi Med J, 2017 Apr;38(4):359-365.
PMID: 28397941 DOI: 10.15537/smj.2017.4.17061

OBJECTIVES: To investigate the cytotoxic effect of anastrozole on breast (MCF7), liver hepatocellular (HepG2), and prostate (PC3) cancer cells. Methods: This is a prospective study. Anastrozole's mechanism of apoptosis in living cells was also determined by high content screening (HCS) assay. Methylthiazol tetrazolium (MTT) assay was carried out at the Centre of Biotechnology Research's, Al-Nahrain University, Baghdad, Iraq between July 2015 and October 2015. The HCS assay was performed at the Centre for Natural Product Research and Drug Discovery, Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia between November 2015 and February 2016. Results: The most significant cytotoxic effect of anastrozole towards 3 cancer cell lines was obtained when its concentration was 400 µg/mL. The MCF7 cells were more sensitive to anastrozole compared with the HepG2 and PC-3 cells. There was a significant increase in membrane permeability, cytochrome c and nuclear intensity when anastrozole (200 µg/mL) was used compared with doxorubicin (20 µg/mL) as a standard. Also, there was a significant decrease in cell viability and mitochondrial membrane permeability when anastrozole (200 µg/mL) was used compared with positive control. Conclusion: Anastrozole showed cytotoxic effects against the MCF7, HepG2, and PC3 cell lines as determined in-vitro by the MTT assay. The HCS technique also showed toxic effect towards MCF7. It is evident that anastrozole inhibits the aromatase enzyme preventing the aromatization mechanism; however, it has a toxic effect.

Matched MeSH terms: Aromatase/metabolism; Aromatase Inhibitors/pharmacology*
Eurycomanone, the major quassinoid in Eurycoma longifolia root extract increases spermatogenesis by inhibiting the activity of phosphodiesterase and aromatase in steroidogenesis

Low BS, Choi SB, Abdul Wahab H, Das PK, Chan KL

J Ethnopharmacol, 2013 Aug 26;149(1):201-7.
PMID: 23810842 DOI: 10.1016/j.jep.2013.06.023

Eurycoma longifolia Jack (Simaroubaceae family), known locally as 'Tongkat Ali' by the ethnic population, is popularly taken as a traditional remedy to improve the male libido, sexual prowess and fertility. Presently, many tea, coffee and carbonated beverages, pre-mixed with the root extract are available commercially for the improvement of general health and labido. Eurycomanone, the highest concentrated quassinoid in the root extract of E. longifolia improved fertility by increasing testosterone and spermatogenesis of rats through the hypothalamus-pituitary-gonadal axis, but the mechanisms underlying the effects are not totally clear.

Matched MeSH terms: Aromatase/metabolism; Aromatase Inhibitors/isolation & purification; Aromatase Inhibitors/pharmacology*
Reproductive viability of paradoxically masculinised Gambusia holbrooki generated following diethylstilbestrol (DES) treatment

Patil JG, Norazmi-Lokman NH, Kwan TN

Comp Biochem Physiol B Biochem Mol Biol, 2020 07 22;248-249:110468.
PMID: 32710933 DOI: 10.1016/j.cbpb.2020.110468

Hormonal sex reversal can produce monosex fish stocks and provide insights into their gamity and reproductive physiology. However, paradoxical effects have been reported in several fish species that remain largely ignored as anomalies, particularly those of masculinisation. As a first step, this study examined reproductive viability of paradoxically masculinised Gambusia holbrooki produced following oral administration (20-100 mg/kg feed) of a feminizing hormone diethylstilbestrol (DES). Contrary to expectation, all treatment groups produced 100% male populations. Survival, mating behaviour, gamete production, breeding output as well as expression of anti-Mullerian hormone (amh), ovarian (cyp19a1a) and brain (cyp19a1b) aromatase of masculinised fish were also examined. Survival (≤ 54.1 ± 7.3%) at termination of DES treatment was significantly lower compared with controls (88.6 ± 4.3%) but remained unaffected post treatment. Gonopodium thrusting frequency (33 ± 9.8 per 10 min) was not significantly different to untreated males just as sperm abundance (3.9 ± 1.5 × 108/male) and their motility (88.6 ± 29.1%). Importantly, paradoxically masculinised fish mated with virgin females and produced clutch sizes (22 ± 4) and progeny survival (87.0 ± %) that were comparable to that of untreated males. Masculinised testes showed high amh and low cyp19a1a expression, a pattern resembling those of untreated males. Production of paradoxically sex-reversed males with a capability to produce viable offspring has not been reported previously in this or other fish species. The outcomes support a feed-back regulation of oestrogenic pathways in this viviparous fish and could be useful for ecological applications such as controlling invasive fish populations.

Matched MeSH terms: Aromatase
Fulltext Dual Actions of Mammalian and Piscine Gonadotropin-Inhibitory Hormones, RFamide-Related Peptides and LPXRFamide Peptides, in the Hypothalamic-Pituitary-Gonadal Axis

Ubuka T, Parhar I

Front Endocrinol (Lausanne), 2017;8:377.
PMID: 29375482 DOI: 10.3389/fendo.2017.00377

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that decreases gonadotropin synthesis and release by directly acting on the gonadotrope or by decreasing the activity of gonadotropin-releasing hormone (GnRH) neurons. GnIH is also called RFamide-related peptide in mammals or LPXRFamide peptide in fishes due to its characteristic C-terminal structure. The primary receptor for GnIH is GPR147 that inhibits cAMP production in target cells. Although most of the studies in mammals, birds, and fish have shown the inhibitory action of GnIH in the hypothalamic-pituitary-gonadal (HPG) axis, several in vivo studies in mammals and many in vivo and in vitro studies in fish have shown its stimulatory action. In mouse, although the firing rate of the majority of GnRH neurons is decreased, a small population of GnRH neurons is stimulated by GnIH. In hamsters, GnIH inhibits luteinizing hormone (LH) release in the breeding season when their endogenous LH level is high but stimulates LH release in non-breeding season when their LH level is basal. Besides different effects of GnIH on the HPG axis depending on the reproductive stages in fish, higher concentration or longer duration of GnIH administration can stimulate their HPG axis. These results suggest that GnIH action in the HPG axis is modulated by sex-steroid concentration, the action of neuroestrogen synthesized by the activity of aromatase stimulated by GnIH, estrogen membrane receptor, heteromerization and internalization of GnIH, GnRH, and estrogen membrane receptors. The inhibitory and stimulatory action of GnIH in the HPG axis may have a physiological role to maintain reproductive homeostasis according to developmental and reproductive stages.

Matched MeSH terms: Aromatase
Fulltext Andrographolide is an Alternative Treatment to Overcome Resistance in ER-Positive Breast Cancer via Cholesterol Biosynthesis Pathway

Rajaratinam H, Nafi SNM

Malays J Med Sci, 2019 Sep;26(5):6-20.
PMID: 31728115 MyJurnal DOI: 10.21315/mjms2019.26.5.2

Oestrogen receptor (ER)-positive breast cancer is one of the common forms of breast cancer affecting women worldwide. ER-positive breast cancer patients are subjected to anti-oestrogen therapy such as selective oestrogen receptor modulator (SERM) and aromatase inhibitors (AIs). Recently, the emergence of resistance to anti-oestrogen treatment is under intensive focus. The different mechanisms postulated to explain the occurrence of resistance in ER-positive breast cancer treatment include the loss of ER function and the crosstalk between signalling pathways in cancer cells. Recent literature highlighted that the cholesterol biosynthesis pathway acts as a novel mechanism underlying resistance to oestrogen deprivation. The present study aimed to highlight the role of cholesterol biosynthesis in anti-oestrogen treatment resistance, putatively suggesting an alternative plant-based treatment using andrographolide from Andrographis paniculata. The hypolipidaemic effect of andrographolide can be utilised to prevent the resistance in the treatment of ER-positive breast cancer contributed by cholesterol biosynthesis.

Matched MeSH terms: Aromatase Inhibitors
The influence of genetic polymorphisms on the efficacy and side effects of anastrozole in postmenopausal breast cancer patients

Abubakar MB, Wei K, Gan SH

Pharmacogenet Genomics, 2014 Dec;24(12):575-81.
PMID: 25203739 DOI: 10.1097/FPC.0000000000000092

Breast cancer is a common cause of cancer mortality among women. Several genetic factors have been implicated in its development. Current treatment guidelines for estrogen receptor-positive breast cancer recommend that anastrozole [or any of the other two aromatase inhibitors (letrozole and exemestane)] is used as an alternative to tamoxifen or following several years of tamoxifen treatment. Nevertheless, this approach is still associated with many challenges, ranging from the recurrence of breast cancer to considerable interindividual variability in the tolerability of anastrozole, which may cause adverse effects, such as musculoskeletal symptoms, and lead to the withdrawal of many patients from treatment. Variabilities in the genes encoding the drug target (aromatase) or its metabolizing enzymes (CYP3A and UGT1A) contribute toward the interindividual variability in anastrozole's pharmacokinetics and/or pharmacodynamics. This paper reviews the role of genetic polymorphisms of CYP19A1, CYP3A4, and UGT1A4 in the responses of female hormone receptor-positive postmenopausal breast cancer patients to anastrozole. Many reviews in the literature have suggested that the study of functional polymorphisms and investigation of relevant genetic markers may provide valuable information in predicting responses to anastrozole in terms of its therapeutic and adverse effects. Nevertheless, more studies are required before the knowledge of its pharmacogenomics can be applied to the individualization of treatment to ensure that patients receive the maximum benefits. Therefore, future analyses, including but not limited to genome-wide association studies, are encouraged to address some of the gray areas in the pharmacogenomics of anastrozole therapy in postmenopausal breast cancer cases; this will help in providing guidance for future pharmacogenomics protocols when anastrozole is utilized in patients' management.

Matched MeSH terms: Aromatase/genetics*
The expression of sex steroid receptors and sex steroid-synthesizing/metabolizing enzymes in metastasized lymph nodes of prostate cancer

Nakamura Y, Ise K, McNamara KM, Azmahani A, Sato S, Fujishima F, et al.

Hum Pathol, 2019 02;84:124-132.
PMID: 30290162 DOI: 10.1016/j.humpath.2018.09.011

The expression statuses of sex steroid receptors and sex steroid-synthesizing/metabolizing enzymes have been reported in primary prostate cancer lesions, but that in metastatic lymph nodes has remained unknown. Therefore, in this study, we immunolocalized these proteins in primary tumors and paired metastatic lymph nodes of prostate cancer and correlated the findings with clinicopathological factors of individual patients. The expression statuses of AR and ER β was significantly increased in metastatic lymph nodes compared with primary lesions, whereas that of 17βHSD1, 17βHSD2, 17βHSD5, and STS immunoreactivity was decreased in metastatic lymph nodes. In metastatic lymph nodes, the status of 5α2 was significantly correlated with that of AR. In addition, 17βHSD5-, 5α1-, STS-, and EST-positive cases were significantly associated with Gleason score (GS) status (GS > 8 versus GS < 7) in metastatic lymph nodes. Results of our present study did demonstrate that in situ androgen and estrogen metabolism and action play roles in pathophysiology of prostate cancer in metastatic lymph nodes, but these steroidogenic effects could be different from those in primary lesions.

Matched MeSH terms: Aromatase/metabolism
Adjuvant endocrine therapy side-effects among postmenopausal breast cancer patients in Malaysia

Choo SB, Saifulbahri A, Zullkifli SN, Fadzil ML, Redzuan AM, Abdullah N, et al.

Climacteric, 2019 04;22(2):175-181.
PMID: 30556740 DOI: 10.1080/13697137.2018.1540563

OBJECTIVE: This study was conducted to determine the prevalence and severity of menopausal symptoms and their associated risk factors among postmenopausal breast cancer patients receiving adjuvant endocrine therapy.
METHODS: Postmenopausal breast cancer patients on endocrine therapy were recruited at three hospitals in Malaysia. Presence and severity of menopausal symptoms were determined using the Menopause Rating Scale. Sociodemographic and clinical data were collected from medical records.
RESULTS: A total of 192 patients participated in this study. Commonly reported symptoms were musculoskeletal pain (59.9%), physical and mental exhaustion (59.4%), and hot flushes (41.1%). Multivariate analyses indicated that increasing number of years after menopause until the start of endocrine therapy was significantly associated with less likelihood of reporting menopausal symptoms and musculoskeletal pain. Patients with primary or secondary education levels reported significantly less menopausal urogenital symptoms compared to patients with a tertiary education level. Patients using aromatase inhibitors were twice as likely to experience musculoskeletal pain compared to patients using tamoxifen (odds ratio, 2.18; 95% confidence interval, 1.06-4.50; p

Matched MeSH terms: Aromatase Inhibitors/adverse effects
Treatment of the Hypogonadal Infertile Male-A Review

Ho CC, Tan HM

Sex Med Rev, 2013 May;1(1):42-49.
PMID: 27784559 DOI: 10.1002/smrj.4

INTRODUCTION: Testosterone treatment for hypogonadism is detrimental for men in reproductive age as it impairs spermatogenesis, and therefore affects fertility. It is, therefore, not indicated in men with hypogonadism and infertility.
AIM: The aim of this review is to analyze current data regarding options of treatment for men with hypogonadism and infertility.
MAIN OUTCOMES MEASURES: A comprehensive review of the current literature on management of infertility among hypogonadal men.
METHODS: A literature search using PubMed from 1980 to 2012 was done on articles published in the English language. The following medical subject heading terms were used: "infertility," "infertile," "hypogonadism;" "testosterone deficiency" and "men" or "male;" and "treatment" or "management."
RESULTS: The options for hypogonadal testicular failure are limited. Hormonal treatment is by and large ineffective. For secondary hypogonadism (hypogonadotropic/normogonadotropic hypogonadism), the options include gonadotropin-releasing hormone, human chorionic gonadotropin (hCG), human menopausal gonadotropin (hMG), follicle-stimulating hormone (FSH), and anti-estrogens and aromatase inhibitors. Dopamine antagonist is indicated for prolactinoma. Artificial reproductive technique is indicated for primary testicular failure and also when medical therapy fails.
CONCLUSION: The most suitable option with the current data available is hCG with or without hMG/FSH. Testosterone supplementation should be avoided, but if they are already on it, it is still possible for a return of normal sperm production within 1 year after discontinuing testosterone. Ho CCK and Tan HM. Treatment of the hypogonadal infertile male-A review. Sex Med Rev 2013;1:42-49.

Matched MeSH terms: Aromatase Inhibitors

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