Diane-35 and metformin therapy in rats with endometrial lesions induced by dihydrotestosterone exposure

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Abstract

Background

Cotreatment with metformin and Diane-35 is conventionally used in the clinic to ameliorate ovulatory dysfunction and insulin resistance in women with polycystic ovary syndrome (PCOS). We previously showed that this combination treatment could reverse endometrial hyperplasia and endometrial cancer (EC) in patients with PCOS. Here, we aimed to investigate the influence of dihydrotestosterone (DHT) and this cotreatment on the endometrium, along with the related mechanisms.

Methods

We treated a DHT-exposed rat model with Diane-35 or metformin alone or their combination and investigated the 3-dimensional (3D) endometrial structure to determine the role of these treatments in reversing endometrial lesions and to clarify the underlying mechanisms. Uterine segments were made transparent with clear, unobstructed brain/body imaging cocktails and a computational analysis protocol and then labeled with 4',6-diamidino-2-phenylindole (DAPI), antiandrogen receptor (AR) antibody, and antiglucose transportation protein 4 (GLUT4) antibody. We visualized and analyzed the endometrial structure, AR expression, and GLUT4 expression under 3D conditions using light sheet microscopy and Imaris software (Bitplane, Zurich, Switzerland).

Results

Long-term DHT treatment contributed to hyperandrogenism and insulin resistance in female Wistar rats. After DHT treatment, rats exhibited other PCOS-like characteristics, such as polycystic ovary morphology, hypothalamic-pituitary-ovarian axis disorder, and relative endometrial hyperplasia. After metformin and Diane-35 treatment, the PCOS-like characteristics and endometrial hyperplasia were alleviated.

Conclusions

Hyperandrogenism and insulin resistance likely play important roles in the pathophysiological changes of PCOS and lead to PCOS-like characteristics as well as endometrial lesions. Hypoandrogenic and insulin sensitization therapy can alleviate DHT-induced endometrial hyperplasia by regulating AR and GLUT4 expression.

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Most cited references 62

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iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging.

Nicolas Renier, Zhuhao Wu, David J Simon … (2014)

The visualization of molecularly labeled structures within large intact tissues in three dimensions is an area of intense focus. We describe a simple, rapid, and inexpensive method, iDISCO, that permits whole-mount immunolabeling with volume imaging of large cleared samples ranging from perinatal mouse embryos to adult organs, such as brains or kidneys. iDISCO is modeled on classical histology techniques, facilitating translation of section staining assays to intact tissues, as evidenced by compatibility with 28 antibodies to both endogenous antigens and transgenic reporters like GFP. When applied to degenerating neurons, iDISCO revealed unexpected variability in number of apoptotic neurons within individual sensory ganglia despite tight control of total number in all ganglia. It also permitted imaging of single degenerating axons in adult brain and the first visualization of cleaved Caspase-3 in degenerating embryonic sensory axons in vivo, even single axons. iDISCO enables facile volume imaging of immunolabeled structures in complex tissues. PAPERCLIP:

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Endometrial cancer.

Philippe Morice, Alexandra Leary, Carien Creutzberg … (2016)

Endometrial cancer is the most common gynaecological tumour in developed countries, and its incidence is increasing. The most frequently occurring histological subtype is endometrioid adenocarcinoma. Patients are often diagnosed when the disease is still confined to the uterus. Standard treatment consists of primary hysterectomy and bilateral salpingo-oophorectomy, often using minimally invasive approaches (laparoscopic or robotic). Lymph node surgical strategy is contingent on histological factors (subtype, tumour grade, involvement of lymphovascular space), disease stage (including myometrial invasion), patients' characteristics (age and comorbidities), and national and international guidelines. Adjuvant treatment is tailored according to histology and stage. Various classifications are used to assess the risks of recurrence and to determine optimum postoperative management. 5 year overall survival ranges from 74% to 91% in patients without metastatic disease. Trials are ongoing in patients at high risk of recurrence (including chemotherapy, chemoradiation therapy, and molecular targeted therapies) to assess the modalities that best balance optimisation of survival with the lowest adverse effects on quality of life.

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Is Open Access

Mouse Estrous Cycle Identification Tool and Images

Shannon L. Byers, Michael Wiles, Sadie Dunn … (2012)

The efficiency of producing timed pregnant or pseudopregnant mice can be increased by identifying those in proestrus or estrus. Visual observation of the vagina is the quickest method, requires no special equipment, and is best used when only proestrus or estrus stages need to be identified. Strain to strain differences, especially in coat color can make it difficult to determine the stage of the estrous cycle accurately by visual observation. Presented here are a series of images of the vaginal opening at each stage of the estrous cycle for 3 mouse strains of different coat colors: black (C57BL/6J), agouti (CByB6F1/J) and albino (BALB/cByJ). When all 4 stages (proestrus, estrus, metestrus, and diestrus) need to be identified, vaginal cytology is regarded as the most accurate method. An identification tool is presented to aid the user in determining the stage of estrous when using vaginal cytology. These images and descriptions are an excellent resource for learning how to determine the stage of the estrous cycle by visual observation or vaginal cytology.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Transl Med

Journal ID (iso-abbrev): Ann Transl Med

Journal ID (publisher-id): ATM

Title: Annals of Translational Medicine

Publisher: AME Publishing Company

ISSN (Print): 2305-5839

ISSN (Electronic): 2305-5847

Publication date (Electronic): 02 February 2023

Publication date (Print): 31 March 2023

Volume: 11

Issue: 6

Electronic Location Identifier: 247

Affiliations

[1 ]deptDepartment of Obstetrics and Gynecology, Shanghai Medical School , Fudan University , Shanghai, China;

[2 ]deptShanghai Key Laboratory of Female Reproductive Endocrine Related Diseases , Fudan University , Shanghai, China;

[3 ]deptDepartment of Gynecology , Obstetrics and Gynecology Hospital of Fudan University , Shanghai, China;

[4 ]deptDepartment of Cardiovascular Surgery, Shanghai Chest Hospital , Shanghai Jiao Tong University , Shanghai, China;

[5 ]deptDepartment of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, State Key Laboratory of Medical Neurobiology, Institute of Acupuncture and Moxibustion, Fudan Institutes of Integrative Medicine , Fudan University , Shanghai, China;

[6 ]deptDepartment of Anesthesiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine , Shanghai University of Traditional Chinese Medicine , Shanghai, China;

[7 ]deptDepartment of Breast Surgery , Obstetrics and Gynecology Hospital of Fudan University , Shanghai, China

Author notes

Contributions: (I) Conception and design: Y Liu, X Li, Y Feng; (II) Administrative support: R Xu, Y Liu, Y Zhou, Y Wang, F Zhang; (III) Provision of study materials or patients: X Li; (IV) Collection and assembly of data: Y Liu, R Xu, X Li, Y Feng, J Sun, X Tong, P Cui, T Ma; (V) Data analysis and interpretation: Y Liu, R Xu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Yi Feng. State Key Laboratory of Medical Neurobiology, Institute of Acupuncture and Moxibustion, Fudan Institutes of Integrative Medicine, Fudan University, No. 138, Medical College Road, Xuhui District, Shanghai 200032, China. Email: fengyi17@ 123456fudan.edu.cn ; Xin Li. Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, No. 419, Fangxie Road, Huangpu District, Shanghai 200032, China. Email: lxsure1501@ 123456163.com .

Article

Publisher ID: atm-11-06-247

DOI: 10.21037/atm-21-2441

PMC ID: 10113095

PubMed ID: 37082665

SO-VID: f709fa6d-4377-466a-8513-1e89cfefc102

License:

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.

Diane-35 and metformin therapy in rats with endometrial lesions induced by dihydrotestosterone exposure

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Abstract

Background

Methods

Results

Conclusions

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Most cited references 62

iDISCO: a simple, rapid method to immunolabel large tissue samples for volume imaging.

Endometrial cancer.

Mouse Estrous Cycle Identification Tool and Images

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