Fenofibrate for Endometriosis, Part Two

by Jeffrey Dach MD

A 29 year old real estate agent arrived in my office and told me her story.  She had been suffering with pelvic pain, recurrent urinary tract infections and severe PMS for many years now.  Her many previous doctors could do little to help.  Finally, she underwent an exploratory laparoscopic procedure which showed extensive endometriosis.  The examining doctor found scattered  endometrial implants throughout the peritoneal cavity which in retrospect had been causing all the pain.  Although the symptoms improved from the laparoscopic surgery which removed most of the implants, the patient still had considerable abdominal discomfort and pain around the monthly menstrual cycles.  Above image : Endometriosis in lymph node courtesy of wikimedia commons.

This article is part two.  For part one, Click here.

Endometriosis, What is It?

Endometriosis is implantation of endometrial tissue outside the uterine cavity in the peritoneal space. In part on of this series, we discussed how these peritoneal implants originate from retrograde flow of endometrial cells out of the fallopian tubes.  Although they are not cancerous, these endometrial implants may share many features common to cancer cells , such as activation of inflammatory pathways (NF-kB Nuclear Factor Kappa-B, and IL-6), with stimulation of angiogenesis, upregulation of VEG-F , (Vascular Endothelial Growth Factor), and PDGF (platelet derived growth factor).  In addition, the implants stimulate neuro-genesis, the growth of new nerve fibers accounting for increased pain sensations.

Dr Bedaiwy summarizes new treatments in 2017:(1-3)

“The current treatments are surgical and hormonal but have limitations….New treatments include gonadotropin-releasing hormone analogues, selective progesterone (or estrogen) receptor modulators, aromatase inhibitors, immunomodulators, and anti-angiogenic agents.”(1-3)

Angiogeneisis Inhibitors as Novel Treatment for Endometriosis

Blocking NF-KB Activation with HCG

Since NFKB activation is a key feature of endometriosis, one might think that blocking this activation might be useful in treating the disease. That is exactly what Dr. Huber found using HCG (human chorionic gonadotropin) in a series of studies from 2004 and 2007.  In a 2004 clinical study, Dr Huber found that weekly  injections of HCG was effective for reducing endometriosis pain.(5)  Further studies show HCG is anti-inflammatory with blockade of Nuclear factor K-B activation.(6-7)

“HCG suppressed TNF-alpha- or IL-1beta-induced NF-kappaB DNA-binding activity” (7)

The HCG Protocol developed by Dr Wright includes nightly melatonin and gluten free diet.(4)

Statin Drugs Block NF-KB Activation

The statin drugs are another class of drugs with potent blockage of Nuclear factor Kappa Beta Activation.(9)  In the first study of its kind, in 2013, Dr Fariba Almassinokiani used simvastatin 20 mg daily to successfully treat endometriosis pain after laparoscopic surgery.(10) Sixty women were treated with either simvastatin or a Gonadotropin Inhibitor (Decapeptyl which blocks secretion of LH,FSH) for 16 weeks, finding both groups had equal and highly significant reduction in pain symptoms.

Statin drugs are potent inhibitors of NFKB activation, and have even been suggested as repurposed anti-cancer drugs.

Fenofibrate Novel Treatment for Endometrisosis

Fenofibrate is an old drug used to control lipids which has been repurposed as an anti-cancer drug.  Fenobrate down regulates both NFK-B and VEGF, both key targets for endometriosis treatment.(20)  Based on our concept that endometriosis has “cancer-like” biological properties, repurposed anti-cancer-agdrugs such as fenofibrate might be useful.  As one might expect, Fenofibrate was effective for regression of endometrial implants in an animal model.  in a 2009 study, Dr Onalan found “Fenofibrate causes regression of endometriotic implants: a mouse model” in a dose dependent manner.(18)

Notes: Rapamycin and Itraconazole, Dipyridimole Inhibits Platelet Derived growth factor

Articles with Related Interest:

Endometriosis Natural Treatments Part One

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
954-792-4663

Links and references:

1) free pdf  Bedaiwy, Mohamed A., et al. “New developments in the medical treatment of endometriosis.” Fertility and sterility 107.3 (2017): 555-565.

Endometriosis affects 1 in 10 women of reproductive-age. The current treatments are surgical and hormonal but have limitations, including the risk of recurrence, side effects, contraceptive action for women who desire pregnancy, and cost. New treatments include gonadotropin-releasing hormone analogues, selective progesterone (or estrogen) receptor modulators, aromatase inhibitors, immunomodulators, and antiangiogenic agents. Further research is needed into central sensitization, local neurogenesis, and the genetics of endometriosis to identify additional treatment targets. A wider range of medical options allows for the possibility of precision health and a more personalized treatment approach for women with endometriosis.

Aromatase Inhibitorsmfor endometriosis

2) Agarwal, Sanjay K., and Warren G. Foster. “Reduction in Endometrioma Size with Three Months of Aromatase Inhibition and Progestin Add-Back.” BioMed Research International 2015 (2015).

The purpose of this study was to assess the impact of 3 months of aromatase inhibition together with progestin add-back on ovarian endometrioma size. This prospective cohort study was performed at University Medical Center (UC San Diego). Women trying to conceive were excluded. After informed consent, all women were treated with the aromatase inhibitor letrozole (5 mg/d) with norethindrone acetate (5 mg/d) add-back for 3 months. Pre- and posttreatment assessments of endometrioma sizes were performed by ultrasound. The impact of treatment on pain was determined using the patient assessed endpoints of the Biberoglu and Behrman scale. These included assessing dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain each on a scale from 0 to 3. The primary endpoint of this study was the change in ultrasound documented endometrioma size. Fourteen endometriomas in 8 consecutive women were treated for 3 m. Mean endometrioma diameter decreased 50% from 4.6 ± 1.6 cm to 2.3 ± 1.6 cm (mean ± SD). This represents a 75% decrease in endometrioma volume. Endometriosis symptoms of dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain also improved with treatment. In conclusion, a 3-month course of high dose aromatase inhibition with progestin add-back significantly reduces ovarian endometrioma size and warrants further investigation.

Pathogenesis

3)  Suardika, Anom, and Tjokorda Gede Astawa Pemayun. “New insights on the pathogenesis of endometriosis and novel non-surgical therapies.” Journal of the Turkish German Gynecological Association 19.3 (2018): 158.

Dienogest (DNG) is an oral progestin that has been recognized as single-drug therapy for endometriosis in Europe, Japan, Australia and Singapore (26,27). DNG is a 19-nortestosterone derivative with the advantage of short plasma half-life, strong progestin effect on endometrium, high bioavailability, anti-androgenic activity, and moderate gonadotropin secretion inhibition

The most important factor in the pathophysiology of endometriosis is the estrogen hormonal dysregulation and progesterone resistance.

DNG 2 mg/day has been shown to significantly inhibit the expression of genes and proteins associated with aromatase and cyclooxygenase (COX)-2, as well as prostaglandin E2 (PGE2) production (30,31).

Provision of long-term DNG has been proven to be effective, safe, tolerable, as well as low incidence of adverse events and drop-out rates (26,33). DNG administration, when compared to GnRH agonists, provides a similar improvement in the intensity of complaints, but lower decrease in estrogen level or negative impact on bone mass (26). DNG can be tolerated in long-term administration due to negligible antiestrogenic, glucocorticoid, and mineralocorticoids effects (26,29). The most frequent side effects are breast pain (4.2%), nausea (3.0%), and irritability (2,4%) (27,34).

AIs when combined with progestogen, COC, or GnRH agonist significantly decrease endometriotic pain intensity, thereby improving patient’s quality of life. AI is superior in preventing postoperative recurrence when compared to GnRH or Danazol, within 6 months period (40,41).

The recommended daily dose is 1 mg for anastrozole, 2.5 mg for letrozole and 25 mg for exemestane, with the lowest decrease in E2 levels caused by exemestane (52-72%) (39).

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Gluten Free !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Going gluten-free significantly slashed endometriosis pain!

HCG- 1 to 2 intramuscular injections of 1500 to 5000 IU HCG per week for a period of 3-12 months.

4)  The Hidden HCG breakthrough — totally eliminate or control excruciating endometriosis!  Oct 13, 2014 | Dr. Jonathan V. Wright’s Articles

5)  Wien Klin Wochenschr. 2004 Dec 30;116(24):839-43.
Systemic HCG treatment in patients with endometriosis: a new perspective for a painful disease.  Huber AV1, Huber JC, Kolbus A, Imhof M, Nagele F, Loizou D, Kaufmann U, Singer CF.

Endometriosis is characterized by the presence of endometrium-like tissue outside the uterus. This condition causes painful periods, chronic pelvic pain, subfertility and a profound reduction in quality of life, especially during women’s reproductive years. Currently available medical therapies offer comparatively little therapeutic benefit and are often burdened by considerable side effects. However, since clinical evidence shows that pregnancy leads to alleviation of endometriotic symptoms, we have for the first time examined the effect of human chorionic gonadotrophin (HCG) injections on symptoms such as dysmenorrhea and pelvic pain.
PATIENTS AND METHODS:Thirty-one patients with histologically verified endometriosis refractory to therapy received 1 to 2 intramuscular injections of 1500 to 5000 IU HCG per week for a period of 3-12 months. A QoL questionnaire and the visual analog pain intensity scale (VAS) were used to evaluate quality of life and pain intensity, respectively, before and after three months of treatment.
RESULTS:Three months of HCG therapy led to a highly significant reduction of endometriosis-related pain (p<0.001, Wilcoxon test) and to improvement of disease-related parameters such as sleeplessness (p<0.001), irritability (p<0.001), overall discomfort (p<0.001), depressive moods (p<0.001) and painful defecation (p=0.01). Dyspareunia and dysmenorrhea also clearly improved (both p<0.001), though HCG did not lead to significant reduction of dysuria (p=0.66). Prolonged therapy with HCG for up to 12 months (mean: 4.42 months) did not lead to reduction of the beneficial effect.
CONCLUSIONS:HCG injections lead to significant and clinically relevant reduction in pain intensity and to greatly improved quality of life in women with therapy-refractory endometriosis. The remarkable clinical effect of parenteral HCG in our study will have to be confirmed in additional trials but clearly indicates an extremely promising new perspective in the treatment of endometriosis.

6)  Fertil Steril. 2007 Oct;88(4 Suppl):1232-9. Epub 2007 Jun 11.
Effect of highly purified human chorionic gonadotropin preparations on the gene expression signature of stromal cells derived from endometriotic lesions: potential mechanisms for the therapeutic effect of human chorionic gonadotropin in vivo.
Huber A1, Hudelist G, Knöfler M, Saleh L, Huber JC, Singer CF.
To investigate alterations in the overall gene expression profile of endometriosis-derived stroma with increasing concentrations of hCG by using the Affymetrix GeneChip U133 Set.
DESIGN:In vitro study.
SETTING:Academic research institution.
PATIENT(S):Women undergoing diagnostic laparoscopic surgery for endometriosis.
INTERVENTION(S):Increasing concentrations of hCG, added to fibroblast monocultures from endometriotic lesions.
RESULT(S):We have found that hCG concentrations of 0.1 U/mL and higher lead to a dose-dependent increase in the expression of 68 genes. Most of the up-regulated genes encoded proteins that are involved in cell adhesion, intercellular communication, extracellular matrix (ECM) remodeling, apoptosis, and inflammation. We then incubated stromal monocultures from nine patients treated with and without 50 U/mL of hCG and performed reverse transcriptase-polymerase chain reaction (RT-PCR) for selected, highly up-regulated genes to validate our DNA array findings and to confirm that the alterations in the gene expression signature are exemplary of patients with endometriosis.
CONCLUSION(S):We have shown that hCG induces dose-dependent alterations in the gene expression profile of stromal cells obtained from endometriotic lesions and have, for the first time, identified potential mechanisms by which hCG might exert its therapeutic effect on endometriotic lesions.

7) free pdf

Huber, A. V., et al. “Human chorionic gonadotrophin attenuates NF-κ B activation and cytokine expression of endometriotic stromal cells.” MHR: Basic science of reproductive medicine 13.8 (2007): 595-604.

Recently, a clinical study provided evidence that treatment of endometriotic women with human chorionic gonadotrophin (hCG) alleviates disease-related pain and sleeplessness suggesting therapeutic effects of the hormone. Since endometriosis is associated with aberrant concentrations of inflammatory mediators in the peritoneal fluid, we investigated whether hCG may affect cytokine-dependent activation of the key-regulatory transcription factor NF-kappaB and expression of two nuclear factor kappa B (NF-kappaB)-inducible genes, tumour necrosing factor (TNF-alpha) and interleukin (IL)-1beta, in stromal cells isolated from ectopic endometriotic tissues. Electrophoretic mobility shift assay revealed that treatment of these cultures with the urinary preparation hCG-A suppressed TNF-alpha- or IL-1beta-induced NF-kappaB DNA-binding activity, whereas another urinary hCG preparation (hCG-B) was less effective. Recombinant alpha-hCG or epidermal growth factor (EGF), a contaminant of some urinary hCG preparations, did not alter cytokine-dependent NF-kappaB activation. Immunofluorescene of its p65 subunit revealed that pre-incubation with hCG-A strongly decreased TNF-alpha-dependent nuclear expression of NF-kappaB. Accordingly, hCG-A diminished IL-1beta-induced TNF-alpha transcript levels and protein release measured by quantitative real-time PCR and enzyme-linked immunosorbent assay. The hormone also attenuated TNF-alpha-dependent mRNA expression of IL-1beta. Western blot analyses revealed that hCG-A impaired TNF-alpha-mediated phosphorylation and degradation of the inhibitor I kappa B alpha suggesting that the hormone may reduce nuclear import of NF-kappaB by stabilizing its inhibitor. The data suggest that hCG attenuates inflammation-dependent NF-kappaB activation and cytokine expression that could provide one explanation for the beneficial role of the hormone in endometriotic patients.

8) Rahman, Nafis A., and C. V. Rao. “Recent progress in luteinizing hormone/human chorionic gonadotrophin hormone research.” Molecular human reproduction 15.11 (2009): 703-711. Recent progress in luteinizing hormone human chorionic gonadotrophin Rahman Nafis Hum Mol Repro 2009

statins for endometriosis

9)  Biol Reprod. 2006 Jul;75(1):107-11. Epub 2006 Mar 29.
Statins inhibit growth of human endometrial stromal cells independently of cholesterol availability. Piotrowski PC1, Kwintkiewicz J, Rzepczynska IJ, Seval Y, Cakmak H, Arici A, Duleba AJ.

Endometriosis is characterized by ectopic growth of endometrial tissues. Statins, inhibitors of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMGCR), have been shown to decrease proliferation of several mesenchymal tissues. Actions of statins may be related to decreased availability of cholesterol as well as intermediate metabolites of the mevalonate pathway downstream of HMGCR. This study was designed to evaluate effects of statins on growth of endometrial stromal cells and to investigate mechanisms of these effects. Human endometrial stromal cells were cultured in the absence and in the presence of serum and with or without mevastatin and simvastatin. DNA synthesis and viable cell numbers were determined. Effects of statins were also evaluated in the presence of mevalonate and squalene. Furthermore, effects on phosphorylation of mitogen-activated protein kinase 3/1 (MAPK3/1) (also known as extracellular signal-regulated kinase [ERK1/2]) were determined. Mevastatin and simvastatin induced a concentration-dependent inhibition of DNA synthesis and viable cell count in chemically defined media and in the presence of serum. Mevalonate, but not squalene, abrogated inhibitory effects of statins on cell proliferation. Statins inhibited MAPK3/1 phosphorylation. This is the first study demonstrating that statins inhibit growth of endometrial stromal cells. This effect is also demonstrable in the presence of a supply of cholesterol and may be related to decreased activation of MAPK3/1. The present observations may be relevant to potential therapeutic use of statins in conditions such as endometriosis.

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this study is that it is the first to evaluate use of simvastatin to relieve endometriotic pains.

10) Almassinokiani, Fariba, et al. “Effects of simvastatin in prevention of pain recurrences after surgery for endometriosis.” Medical science monitor: international medical journal of experimental and clinical research 19 (2013): 534.

prescribed simvastatin (film-coated tablet simvaHEXAL, 20 mg daily for 4 months)

Statin affects the growth of endometriotic tissues by inhibiting angiogenesis [8,16].  The severity of dyspareunia, dysmenorrhea, and pelvic pain before and after treatment were not significantly different between the 2 groups (Table 4). However, after treatment, the severity of dyspareunia, dysmenorrhea, and pelvic pain in the 2 groups was significantly reduced and the difference between before and after treatment in 3 parameters in each group was significant (Table 5). None of the patients showed adverse effects of simvastatin and all continued medical treatment for 4 months. Three of the patients in the simvastatin group became pregnant 4 months after surgery. All of them had mild endometriosis.  To compare efficacy of simvastatin with GnRHa (Decapeptyl 3.75 mg) on endometriosis-related pains following surgery for endometriosis.
Material/Methods:  Sixty women with pelvic endometriosis, after laparoscopic diagnosis and conservative laparoscopic surgery, were treated with either simvastatin (n=30) for 16 weeks or Decapeptyl (n=30) every 4 weeks for 4 doses.
Results:  Using VAS, the score of dyspareunia, dysmenorrhea, and pelvic pain 6 months after laparoscopic surgery declined significantly in both groups (p=0.001), but the difference between results of the 2 groups was not significant (p>0.05).
Conclusions:  Both treatment modalities showed comparable effectiveness in the treatment of pains related to endometriosis.

11)   Nasu, Kaei, et al. “Simvastatin inhibits the proliferation and the contractility of human endometriotic stromal cells: a promising agent for the treatment of endometriosis.” Fertility and sterility 92.6 (2009): 2097-2099.

12)  Yilmaz, Bulent, et al. “Atorvastatin causes regression of endometriotic implants in a rat model.” Reproductive biomedicine online 20.2 (2010): 291-299.

13)  Gynecol Endocrinol. 2017 Dec;33(12):923-927. Efficacy comparison of oral rosuvastatin versus oral progesterone and bevacizumab on regression of surgically endometriotic implants in rats.
Kebapcilar AG1, Ilhan TT1, Dursunoglu D2, Kebapcilar L3, Ipekci SH3, Baldane S3, Ucar MG1, Kirac CO3, Kurt K1, Celik C1.

This study hypothesizes that oral rosuvastatin, oral dienogest and intraperitoneal bevacizumab might improve endometriosis in randomly selected female Wistar albino rats with surgically endometriotic implants. Thirty female Wistar albino rats with surgically endometriotic implants were randomized into three treatment groups: oral rosuvastatin (20 mg kg/day; oral rosuvastatin group 1; n = 10), oral progesterone (dienogest group 2; n = 10) and intraperitoneal bevacizumab (2.5 mg/kg of single intraperitoneal injection of bevacizumab; bevacizumab group 3; n = 10), for 10 days. Post-treatment variables were compared. The oral rosuvastatin group showed higher reduction for the glandular epithelium and uterine vessels of histopathological scores values than the oral progesterone group (both, p < 0.017, respectively). The median glandular epithelium and uterine vessels and histopathological scores values did not show a statistically significant difference between group 1 and group 3 (p > 0.017). Endometrial thickness values and uterine volume values were more significantly reduced in the oral rosuvastatin group than the oral progesterone group (both, p < 0.017, respectively). Moreover, endometrial thickness and uterine volume values were not different in groups we compared with group 3 (p > 0.017). In conclusion, oral rosuvastatin and intraperitoneal injection of bevacizumab may cause more significant regression of surgically endometriotic implants in rats than oral progesterone medications.

14) Patel, Tushar R., and Siobhan A. Corbett. “Simvastatin suppresses LPS-induced Akt-phosphorylation in the human monocyte cell line THP-1.” Journal of Surgical Research 116.1 (2004): 116-120.

15) Hölschermann, Hans, et al. “Statins prevent NF-κB transactivation independently of the IKK-pathway in human endothelial cells.” Atherosclerosis 185.2 (2006): 240-245

16) Ahn, Kwang Seok, Gautam Sethi, and Bharat B. Aggarwal. “Simvastatin potentiates TNF-α-induced apoptosis through the down-regulation of NF-κB-dependent antiapoptotic gene products: role of IκBα kinase and TGF-β-activated kinase-1.” The Journal of Immunology 178.4 (2007): 2507-2516.

17)  Chae, Young Kwang, et al. “Statins as anti-cancer therapy; Can we translate preclinical and epidemiologic data into clinical benefit?.” Discovery medicine 20.112 (2015): 413-427.

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Fenofibrate

18) Fertil Steril. 2009 Dec;92(6):2100-2.  Fenofibrate causes regression of endometriotic implants: a rat model. Onalan G1, Zeyneloglu HB, Bayraktar N.

Fenofibrate -a peroxisome proliferator-activated receptor-a agonist- is an angiostatic agent that is commonly used in human liver diseases, therefore it may interfere with the angiogenetic process required for endometriosis. In a rat endometriosis model, we demonstrated that peritoneal implant areas and vascular endothelial growth factor levels in the peritoneal fluid were significantly decreased in high dose or low dose finofibrate and luprolide acetate treated groups compared to control.

19) Herington, Jennifer L., et al. “Development and Prevention of Postsurgical Adhesions in a Chimeric Mouse Model of Experimental Endometriosis.” Fertility and sterility 95.4 (2011): 1295.
To examine the impact of a recent surgery on development of endometriosis-related adhesions in a chimeric model and to determine the therapeutic efficacy of pioglitazone (PIO).
Design  Human endometrial biopsies were maintained in estradiol (E) with or without PIO for 24 hrs prior to intraperitoneal injection into immunocompromised mice at multiple timepoints following peritoneal surgery. The presence and extent of adhesions was examined in animals relative to the initial establishment of experimental endometriosis.
Endometrial biopsies for experimental studies described herein were provided by normally cycling women without a medical history indicative of endometriosis or adhesions.
Examination of the development of endometriosis-related adhesions in an experimental model.
Results  Without therapeutic intervention, injection of E-treated human endometrial tissue into mice near the time of peritoneal surgery resulted in multiple adhesions and extensive endometriotic-like disease. In contrast, PIO treatment reduced adhesive disease and experimental endometriosis related to surgical injury.
Conclusions  The presence of human endometrial tissue fragments in the peritoneal cavity of mice with a recent surgical injury promoted development of both adhesive disease and experimental endometriosis. Targeting inflammation and angiogenesis with PIO therapy limited the development of postsurgical adhesions associated with ectopic endometrial growth.

20) Koltai, Tomas. “Fenofibrate in cancer: mechanisms involved in anticancer activity.” F1000 Research 4 (2015).

The main mechanisms of anti-cancer activity:

1) Anti-angiogenesis through down-regulation of Vascular Endothelial Growth Factor (VEGF), Vascular Endothelial Growth Factor Receptor (VEGFR) and Hypoxia Inducible factor-1 a (HIF-1a),

2) inhibition of endothelial cell migration

Apoptosis and cell cycle arrest mechanism include:

1) down-regulation of Nuclear Factor Kappa B (NF-kB) and Protein kinase B (Akt)
2) Decrease of cellular energy by impairing mitochondrial function
3) Growth impairment from down-regulation of Phospho-Inositol 3 Kinase (PI3K)/Akt axis and down-regulation of the p38 map kinase (MAPK) cascade.

Anti-metastatic activities of Fenofibrate:

1) Down-regulation of MCP-1 (monocyte chemotactic protein-1),
2) decreased Metalloprotease-9 (MMP-9) production,
3) weak down-regulation of adhesion molecules like E selectin, intercellular adhesion molecules (ICAM) and Vascular Endothelial Adhesion Molecules (VCAM)

4) decreased secretion of chemokines like Interleukin-6 (IL-6), and down-regulation of cyclin D-1.

21) video Kirk hamilton  –  Endometriosis…HCG, Melatonin and Gluten-Free Diet Help!

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22) https://www.ncbi.nlm.nih.gov/pubmed/27503693
Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:61-66. doi: 10.1016/j.ejogrb.2016.05.032. Epub 2016 May 27.
Hormonal therapy for endometriosis: from molecular research to bedside.
Tosti C1, Biscione A1, Morgante G1, Bifulco G2, Luisi S1, Petraglia F3.
Author information
Abstract

Endometriotic lesions are associated with hormonal imbalance, including increased estrogen synthesis, metabolism and progesterone resistance. These hormonal changes cause increased proliferation, inflammation, pain and infertility. Hormonal imbalances are targets for treatment. Therapeutic strategies and innovations of hormonal drugs for endometriosis are increasing. Acting on estrogen receptors are hormonal drugs decreasing systemic and local estrogen synthesis (GnRH analogs, GnRH antagonists, Aromatase inhibitors) or estrogen activity (selective estrogen receptor modulators). The progesterone resistance is counteracted by progestins (Medroxyprogesterone acetate, Dienogest, Danazol, Levonorgestrel) or by Selective progesterone receptor modulators, a class of drugs under development. The future trend will be to define new drugs to use for prolonged period of time and with poor side effects considering endometriosis a chronic disease.

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23) Br J Pharmacol. 2006 Sep; 149(2): 137–144.
Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation M W Laschke,1,* A Elitzsch,1 C Scheuer,1 J H Holstein,1 B Vollmar,2 and M D Menger1

Rapamycin is a widely used drug with antifungal, immunosuppressant and antiangiogenic effects. Herein, we studied whether immunosuppressive doses of rapamycin are capable of influencing endometriotic lesions.
Experimental approach:  We tested in vitro the potential of rapamycin to inhibit endothelial cell sprouting using the aortic ring assay and we further studied its effect on the expression of proliferating cell nuclear antigen (PCNA), apoptotic cell death-associated activated caspase-3 and vascular endothelial growth factor (VEGF) in cultured endometrial tissue fragments. In addition, we analyzed the drug in vivo after induction of endometriotic lesions by transplanting isolated endometrial fragments into the dorsal skinfold chamber of Syrian golden hamsters. Using intravital fluorescence microscopy, we repetitively analyzed angiogenesis, neovascularization and microcirculatory parameters over a time period of 14 days in rapamycin-treated animals and DMSO-treated controls.

24) Head, Sarah A., et al. “Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells.” Proceedings of the National Academy of Sciences 112.52 (2015): E7276-E7285.

Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.

==========================

pioglitazone (PIO

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3038191/
Herington, Jennifer L., et al. “Development and Prevention of Postsurgical Adhesions in a Chimeric Mouse Model of Experimental Endometriosis.” Fertility and sterility 95.4 (2011): 1295.
To examine the impact of a recent surgery on development of endometriosis-related adhesions in a chimeric model and to determine the therapeutic efficacy of pioglitazone (PIO).
Design

Human endometrial biopsies were maintained in estradiol (E) with or without PIO for 24 hrs prior to intraperitoneal injection into immunocompromised mice at multiple timepoints following peritoneal surgery. The presence and extent of adhesions was examined in animals relative to the initial establishment of experimental endometriosis.
Setting

Medical School Research Center
Patients   Endometrial biopsies for experimental studies described herein were provided by normally cycling women without a medical history indicative of endometriosis or adhesions.

Examination of the development of endometriosis-related adhesions in an experimental model.
Results  without therapeutic intervention, injection of E-treated human endometrial tissue into mice near the time of peritoneal surgery resulted in multiple adhesions and extensive endometriotic-like disease. In contrast, PIO treatment reduced adhesive disease and experimental endometriosis related to surgical injury.
Conclusions    The presence of human endometrial tissue fragments in the peritoneal cavity of mice with a recent surgical injury promoted development of both adhesive disease and experimental endometriosis. Targeting inflammation and angiogenesis with PIO therapy limited the development of postsurgical adhesions associated with ectopic endometrial growth.

 

===================================================

https://www.ncbi.nlm.nih.gov/pubmed/27503693
Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:61-66. doi: 10.1016/j.ejogrb.2016.05.032. Epub 2016 May 27.
Hormonal therapy for endometriosis: from molecular research to bedside.
Tosti C1, Biscione A1, Morgante G1, Bifulco G2, Luisi S1, Petraglia F3.

Endometriotic lesions are associated with hormonal imbalance, including increased estrogen synthesis, metabolism and progesterone resistance. These hormonal changes cause increased proliferation, inflammation, pain and infertility. Hormonal imbalances are targets for treatment. Therapeutic strategies and innovations of hormonal drugs for endometriosis are increasing. Acting on estrogen receptors are hormonal drugs decreasing systemic and local estrogen synthesis (GnRH analogs, GnRH antagonists, Aromatase inhibitors) or estrogen activity (selective estrogen receptor modulators). The progesterone resistance is counteracted by progestins (Medroxyprogesterone acetate, Dienogest, Danazol, Levonorgestrel) or by Selective progesterone receptor modulators, a class of drugs under development. The future trend will be to define new drugs to use for prolonged period of time and with poor side effects considering endometriosis a chronic disease.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Rapamycin – Itraconazole ?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2013796/
Br J Pharmacol. 2006 Sep; 149(2): 137–144.
Rapamycin induces regression of endometriotic lesions by inhibiting neovascularization and cell proliferation M W Laschke,1,* A Elitzsch,1 C Scheuer,1 J H Holstein,1 B Vollmar,2 and M D Menger1

Rapamycin is a widely used drug with antifungal, immunosuppressant and antiangiogenic effects. Herein, we studied whether immunosuppressive doses of rapamycin are capable of influencing endometriotic lesions.
Experimental approach:  We tested in vitro the potential of rapamycin to inhibit endothelial cell sprouting using the aortic ring assay and we further studied its effect on the expression of proliferating cell nuclear antigen (PCNA), apoptotic cell death-associated activated caspase-3 and vascular endothelial growth factor (VEGF) in cultured endometrial tissue fragments. In addition, we analyzed the drug in vivo after induction of endometriotic lesions by transplanting isolated endometrial fragments into the dorsal skinfold chamber of Syrian golden hamsters. Using intravital fluorescence microscopy, we repetitively analyzed angiogenesis, neovascularization and microcirculatory parameters over a time period of 14 days in rapamycin-treated animals and DMSO-treated controls.

Itraconazole

https://www.pnas.org/content/112/52/E7276
Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.

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Anti-angiogenic treatment

free pdf
https://academic.oup.com/humupd/article/18/6/682/627018

Laschke, M. W., and M. D. Menger. “Anti-angiogenic treatment strategies for the therapy of endometriosis.” Human reproduction update 18.6 (2012): 682-702.

initiation of the disease by retrograde menstruation of highly angiogenic endometrial fragments into the peritoneal cavity. Based on these findings, endometriosis has been classified as a typical angiogenic disease, such as cancer, psoriasis or diabetic retinopathy (Healy et al., 1998).

Several studies report that COX-2 is also crucially involved in the pathogenesis of endometriosis. COX-2 over-expression is found in both endometriotic lesions and eutopic endometrium of patients with endometriosis when compared with controls

treatment with COX-2 inhibitors prevents the implantation of endometrium to ectopic sites and induces the regression of established endometriotic lesions

Dopamine agonists

A decade ago, Basu et al. (2001) made the interesting discovery that the neurotransmitter dopamine selectively inhibits the vascular permeabilizing and angiogenic activity of VEGF at non-toxic levels, revealing a new link between the nervous system and angiogenesis. This led to the idea to use dopamine agonists for anti-angiogenic therapy. In gynaecology, dopamine agonists, such as cabergoline, are currently used for the suppression of breast-feeding and treatment of hyperprolactinaemia (Gillam et al., 2006; Colao et al., 2007; Buhendwa et al., 2008). Importantly, cabergoline treatment during pregnancy does not increase the risk of spontaneous miscarriage, premature delivery or congenital abnormalities (Robert et al., 1996; Ricci et al., 2002).

cabergoline

Based on these reports, the Pellicer research group analysed the effect of cabergoline on growth and vascularization of endometriotic lesions in the nude mouse model (Novella-Maestre et al., 2009). They found that daily oral treatment with cabergoline over 14 days causes the regression of endometriotic lesions by suppression of cell proliferation and VEGF-mediated angiogenesis. They could further demonstrate that cabergoline treatment results in a significantly lower expression of VEGF and VEGFR-2 in endometriotic lesions (Novella-Maestre et al., 2010). Thus, they concluded that dopamine agonists may be successful in the treatment of peritoneal endometriosis. However, chronic cabergoline treatment is known to be associated with an increased incidence of cardiac valve regurgitation (Schade et al., 2007). Therefore, in an additional study they compared the efficacy of the non-ergot-derived dopamine agonist quinagolide with that of cabergoline in inhibiting angiogenesis and vascularization of endometriotic lesions (Delgado-Rosas et al., 2011). Because both compounds were equally effective, they decided to perform a clinical pilot study with quinagolide in hyperprolactinemic patients with endometriosis, who required a first surgical intervention and underwent a second-look laparoscopy (Gómez et al., 2011). Of interest, treatment with the dopamine agonist quinagolide induced a 70% reduction of endometriotic lesions, with 35% of lesions vanishing completely. Further histological analyses revealed that this was associated with a down-regulation of VEGF/VEGFR-2, pro-angiogenic cytokines and plasminogen activator inhibitor-1 within the lesions. These highly promising results and the beneficial side effect profile of quinagolide suggest that this compound should now be tested in larger clinical multicenter trials for its applicability in patients with endometriosis.

fenofibrate

PPAR agonists have been developed for the treatment of hypertrigliceridemia and type 2 diabetes mellitus in the form of fibrates and thiazolidinediones (Lalloyer and Staels, 2010).

Onalan et al. (2009) demonstrated for the first time in a rat model that treatment with the PPAR-α agonist fenofibrate causes regression of endometriotic lesions, which is associated with reduced VEGF levels in the peritoneal fluid.

Lebovic et al. (2007) demonstrated in the baboon endometriosis model that the size and overall number of endometriotic lesions is significantly reduced in animals treated with rosiglitazone and pioglitazone (Lebovic et al., 2010) when compared with placebo-treated controls.

celecoxib

https://www.ncbi.nlm.nih.gov/pubmed/21683949
Fertil Steril. 2011 Aug;96(2):428-33. The inhibitory effect of celecoxib and rosiglitazone on experimental endometriosis.  Olivares C1, Ricci A, Bilotas M, Barañao RI, Meresman G.

To evaluate the effects of celecoxib and rosiglitazone on the implantation and growth of endometriotic-like lesions in a murine model of endometriosis.
DESIGN:Prospective experimental study.
SETTING:Animal research and laboratory facility.
ANIMAL(S):Two-month-old female BALB/c mice.
INTERVENTION(S):Surgically induced endometriosis in female BALB/C mice; 28 days of treatment with celecoxib, rosiglitazone, or their combination; counting, measuring, excising, and fixing lesions.
MAIN OUTCOME MEASURE(S):Immunohistochemical examination for proliferating cell nuclear antigen (PCNA), CD31, and CD34 to assess cell proliferation and vascularization, with the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) technique for apoptosis evaluation.
RESULT(S):Celecoxib and the combined treatment (celecoxib and rosiglitazone) statistically significantly reduced the mean number of lesions established per mouse, and all treatments diminished the implant volume. In addition, cell proliferation within the implants was statistically significantly reduced, and apoptosis was statistically significantly enhanced by all treatments. Also, we found that all treatments diminished the vascularized area in the lesion.
CONCLUSION(S):These results are promising and reveal that celecoxib and rosiglitazone, combined or separately, have a beneficial effect on overall endometriotic growth.

curcumin

https://www.ncbi.nlm.nih.gov/pubmed/21069258
Int J Mol Med. 2011 Jan;27(1):87-94. doi: 10.3892/ijmm.2010.552. Epub 2010 Nov 8.
Inhibitory effect of curcumin on angiogenesis in ectopic endometrium of rats with experimental endometriosis.Zhang Y1, Cao H, Hu YY, Wang H, Zhang CJ.
The aim of this study was to observe the inhibitory effect of curcumin on endometriosis (EMS) and to determine its influence on vascular endothelial growth factor (VEGF) and microvessel density (MVD) in eutopic and ectopic endometrium of experimental rats, thus exploring the pathogenesis of EMS offering more experimental evidence for the clinical use of curcumin. Forty-eight female virgin rats were subjected to autotransplantation of endometrium during the estrus stage. After four weeks, 8 rats were randomly sacrificed to confirm that the rat model was successful. The remaining rats were randomly divided into four groups. Three groups were intragastrically administered curcumin (50, 100 and 150 mg/kg), and the model group was intragastrically administered vehicle alone. All rats were treated daily for four continuous weeks and examined by histology and immunohistochemical staining for MVD of eutopic and ectopic endometrium. Our results revealed that the cubic capacity of focal tissue in gross appearance was high in the model group and dose-dependently diminished after treatment with curcumin (P<0.05). There was an increase in MVD and VEGF in the ectopic endometrium, which was decreased significantly after treatment with curcumin (P<0.05); the effects being dose-dependent. The correlation between MVD and VEGF was positive. In conclusion, heterogeneity was found to exist between eutopic and ectopic endometrium due to differences noted in MVD and the expression of VEGF between the eutopic and ectopic endometrium in the model group. Curcumin decreased the quantity of microvessels and VEGF protein expression in the heterotopic endometrium of rats with EMS.

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Dipyridimole

Pathophysiology- platelet-derived endothelial growth factor 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836682/
Fertil Steril. 2012 Sep; 98(3): 10.1016/j.fertnstert.2012.06.029.
Pathogenesis and Pathophysiology of Endometriosis
Richard O. Burney, M.D., M.Sc.a and Linda C. Giudice, M.D., Ph.D.b
Evidence for VEGF as the prominent angiogenic factor is compelling. Other angiogenic factors implicated in disease pathophysiology include angiogenin (70), platelet-derived endothelial growth factor (71), and macrophage migration inhibitory factor (72).

dipyridimole – antiplatelet agents

https://academic.oup.com/jcem/article/84/1/359/2866270
https://www.ncbi.nlm.nih.gov/pubmed/9920107/
J Clin Endocrinol Metab. 1999 Jan;84(1):359-62.
Expression of platelet-derived endothelial cell growth factor (PD-ECGF) related to angiogenesis in ovarian endometriosis.
Fujimoto J1, Sakaguchi H, Hirose R, Tamaya T.
Platelet-derived endothelial cell growth factor (PD-ECGF) is expressed in the lining epithelial cells of ovarian endometriomas, and in interstitial cells of the subepithelial area with angiogenesis. The expression of PD-ECGF persists in endometriotic endometrium during the menstrual cycle. This might suggest that PD-ECGF contributes to the growth of ovarian endometriomas via subepithelial angiogenesis independently of the sex steroidal milieu.

 

Published on May 19th, 2019 by
Jeffrey Dach MD

The post Fenofibrate for Endometriosis, Part Two appeared first on Jeffrey Dach MD.