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Clinical Experience with Vaginal Gestrinone in Pentravan® in the Treatment of Endometriosis Pain

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Clinical Experience with Vaginal Gestrinone in Pentravan® in the Treatment of Endometriosis Pain Open Access Austin Journal of Reproductive Medicine & Infertility Research Article Clinical Experience with Vaginal Gestrinone in Pentravan® in the Treatment of Endometriosis Pain Maia H Jr1*, Haddad C1, dos Santos Junior WSD2, Abstract Pinheiro N3, Silva Santos A4 and Coutinho A1 1Instituto da Mulher, Itaigara Memorial Day Hospital, An open clinical trial was conducted with 47 patients with endometriosis and Brazil pain, previously treated unsuccessfully with progestin alone or continuous oral 2Department of Life Sciences, Universidade do Estado da contraceptives. The patients were treated with vaginal gestrinone in Pentravan® Bahia (UNEB), Brazil (5mg/ml) (Fagron, the Netherlands) together with oral pinus pinaster extract 3ImagePat, Pathology Institute, Brazil and resveratrol daily. Pain scores were evaluated at baseline and 1, 2, 3 and 4Undergraduate Student of Biomedicine, Mauricio Nassau 6 months after beginning treatment. Vaginal ultrasonography was performed University, Brazil after 2 months. In twenty patients, both aromatase and VEGF expression were *Corresponding author: Hugo Maia Jr, Instituto da investigated by immunohistochemistry in the endometrium prior to and 3 months Mulher, Itaigara Memorial Day Hospital, Salvador Bahia, after the initiation of treatment. Blood was drawn at baseline and after 2 months Brazil RIWUHDWPHQW0HDQSDLQVFRUHEHIRUHWUHDWPHQWZDVUHGXFLQJVLJQL¿FDQWO\WR 0.4 (p=0.0001) in the second month of treatment. After three months all patients Received: July 30, 2015; Accepted: August 10, 2015; were pain-free. Amenorrhea rates were 80% in the second month, reaching Published: August 13, 2015 100% for the remainder of the treatment. Uterine and ovarian cyst volume GHFUHDVHG GXULQJ WUHDWPHQW 7KHUH ZHUH QR VWDWLVWLFDOO\ VLJQL¿FDQW FKDQJHV in total cholesterol, baseline FSH or LH. HDL-cholesterol, triglycerides, total WHVWRVWHURQH DQG HVWUDGLRO OHYHOV GHFUHDVHG VLJQL¿FDQWO\ +HPRJORELQ OHYHOV LQFUHDVHGVLJQL¿FDQWO\IURPWRJUDPV S /LYHUHQ]\PHVUHPDLQHG XQFKDQJHG6+%*OHYHOVGHFUHDVHGVLJQL¿FDQWO\GXULQJWUHDWPHQW%RWK9(*) DQGDURPDWDVHH[SUHVVLRQLQWKHHQGRPHWULXPGHFUHDVHGVLJQL¿FDQWO\DIWHU months of treatment. These preliminary results show that the association of vaginal gestrinone with oral resveratrol and pinus pinaster extract is an effective treatment for endometriosis-related pain, inducing amenorrhea in patients in whom previous treatment with progestin alone or oral contraceptives had failed. Keywords: Gestrinone; progesterone resistance; testosterone; endometriosis; NF-Kappa.b Introduction receptor beta (ER-β) causes an imbalance in the ERβ-to-ERα ratio in stromal cells, which further suppresses progesterone receptor Endometriosis is an in#ammatory pathology in which estrogens synthesis. Excessive estrogenic action thus results in an increase are produced in both the eutopic endometrium and in the lesions. in cyclooxygenase-2 expression, greater progesterone resistance %e synthesis of estrogens is the result of epigenetic changes leading and in#ammation [4]. One promising approach to overcome this to activation of the aromatase gene, thus stimulating local estrogen problem would be to use hormones that counteract this estrogenic production, which will sustain and enhance the in#ammatory dominance and the ensuing excessive in#ammation by activating the milieu in both the eutopic endometrium and in the endometriotic androgen receptor instead of the progesterone receptor. Testosterone lesions. %ese molecular changes lead to an overproduction of local is a steroid hormone that exerts anti in#ammatory e$ects by blocking prostaglandins and the ensuing excessive in#ammation will result in the activation and translocation of NF-Kappa.b transcription factor the suppression of progesterone receptors, thus leading to progesterone to cell nuclei, thus halting the in#ammatory cascade [5]. Since this resistance and treatment failure [1]. Progesterone receptor de&ciency transcription factor is constitutively activated in endometriosis, associated with the enhanced local estrogen production will lead to its inhibition by testosterone will halt in#ammation and decrease an imbalance between the e$ects of estrogen and progesterone, which pain [6]. Testosterone receptors are expressed in the endometrial will decrease the normal luteal-phase progesterone dominance and stroma [7], thus rendering this tissue responsive to androgenic replace it with estrogen supremacy [2]. If endometriosis is viewed hormones. %is provides a plausible biological explanation for the as a hyper-estrogenic, progesterone-resistant pathology a$ecting use of androgenic hormones in the treatment of endometriosis. not only the endometrium but also the peritoneal milieu, this may One drug that appears promising is gestrinone, which has been suggest that novel therapeutic approaches are needed to overcome used for the treatment of endometriosis and myomas for more than this obstacle. %is will bene&t patients in whom standard medical three decades [8]. It is highly e$ective when administered by the treatments, either with a continuous regimen of oral contraceptives oral route; however, its androgenic side e$ects precluded its wider or with progestins, have failed, without the need to rely on the use acceptance. Nonoral routes for the administration of gestrinone GNRH analogs to induce a hypoestrogenic menopausal-like state [3]. have been developed in Brazil, particularly in the form of sub dermal In endometriosis, the abnormal elevated expression of the estrogen implants [8]. Despite the lower incidence of androgenic side e$ects Austin J Reprod Med Infertil - Volume 2 Issue 4 - 2015 Citation: Maia H Jr, Haddad C, dos Santos Junior WSD, Pinheiro N, Silva Santos A and Coutinho A. Clinical Submit your Manuscript | www.austinpublishinggroup.com Experience with Vaginal Gestrinone in Pentravan® in the Treatment of Endometriosis Pain. Austin J Reprod Med Maia et al. © All rights are reserved Infertil. 2015; 2(4): 1021. Maia H Jr Austin Publishing Group with the implants compared to the oral administration, sub dermal pain associated with irregular bleeding. Prior to initiating treatment implants have the disadvantage that their insertion and removal with vaginal gestrinone, all the patients were evaluated clinically. involve invasive procedures and doses cannot easily be adjusted by Global pain scores, applied to both dysmenorrhea and dyspareunia, the patient once the implants are inserted [8,9]. %e development of were rated by the patient at baseline and 1, 2, 3 and 6 months following simple, non-invasive and self-administered, non oral routes through treatment using a visual analogic scale in which 0 was indicative of which to deliver gestrinone may o$er certain advantages over the use no pain and 10 re#ected the worst pain imaginable. %e patients of implants for the treatment of endometriosis and myomas. One were treated with a combination of 5 mg of vaginal gestrinone in promising route for the administration of hormones is the vaginal Pentravan® (Fagron, the Netherlands) three times a week with 100 mg mucosa. Previous studies in the 1980s showed that the insertion of a of oral pinus pinaster extract (Fagron, the Netherlands) and 30 mg of 2.5 mg pill containing gestrinone into the vagina two or three times a resveratrol (Fagron, the Netherlands) daily. %ese medications were week e$ectively managed pain in endometriosis patients and induced prepared by a licensed compounding pharmacy. %e pinus pinaster amenorrhea in almost 50% of patients, with fewer side e$ects when extract (100mg) and resveratrol (30 mg) were prepared and placed compared to either the oral or sub dermal routes [9]. %ese initial in the same capsule at a local compounding pharmacy supervised results identi&ed the vaginal mucosa as a promising route for the by the same pharmacist (WSDS). All the resveratrol, pinus pinaster delivery of gestrinone for the treatment of pelvic pathologies because extract and gestrinone used in this study were obtained from the of the &rst uterine pass e$ect. %is mechanism is a very e$ective same supplier (Fagron, the Netherlands), and all were submitted to means of concentrating hormones and other pharmacologically a quality control analysis conducted at Fagron’s plant in Anapolis, active agents in the pelvic region before they are distributed into Goias, Brazil to ensure the purity of the preparation. Gestrinone is the systemic circulation. %is is accomplished through an active licensed by the Brazilian drug regulatory authority (ANVISA) for use transport mechanism which acts locally and is greatly helped by as an oral medication for the treatment of endometriosis; however, the the close proximity of the vaginal vein and artery. %is creates a drug is also widely used o$ label in the form of sub dermal implants concentration gradient in the pelvic organs that enables vaginally for the same indication, since the oral route of administration is administered hormones to reach high tissue levels despite rather associated with a higher incidence of side e$ects [9]. %e patients were low systemic blood levels [10]. Recently, the development of better instructed to insert the gestrinone/Pentravan® preparation into the permeation excipients such as Pentravan®, which proved e$ective for vagina at bedtime using a disposable plastic applicator. %e resveratrol the vaginal delivery of danazol to treat deep endometriosis-related and pinus pinaster extract were given together in the same capsule pain, prompted us to investigate its use with gestrinone in association (Vcaps®, Fagron,
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