{"paper_id":"803eb526-f59c-4063-9bf3-085cffc30eb9","body_text":"Page 1 of  3\nThe Mechanism of Single Progesterone as Add-Back \nTherapy to GnRH-a Administration\nJiming Chen, Junling Liu, Weiwei Wei, Ying Cao, Yilin Sun, Huichao Xiao, Yafeng Zheng, Yunfen Jiang and \nRuxia Shi*\nDepartment of Obstetrics and Gynecology, The Affiliated Changzhou NO. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213000, China\nOpinion\nEndometriosis (EMS) is a common estrogen-dependent \ngynecological disorder, which affects quality of life and fertility of \nproductive-aged women [1]. Current treatment of EMS is mainly \nbased on surgery and post-operative maintenance treatment of \novarian suppressive agents. A major challenge for women with EMS \nis the post-operative recurrence [2-3]. Some medical treatments \nhave been suggested for EMS, such as oral contraceptive pills, and \ngonadotropin-releasing hormone agonists (GnRH-a). GnRH-a is an \nimportant treatment modality for EMS, significantly reducing EMS-\nrelated symptoms [4-6]. \nHowever, the employment of GnRH-a could reduce the estrogen \nlevel, leading to severe peri-menopausal symptoms such as hot \nflash, colpoxerosis, sexual hypoactivity, and bone loss, which \nhinders its long-term and extensive application [7]. The peri-\nmenopausal symptoms could be solved by the hormone based “add-\nback therapy” [8-10]. As for add-back therapy, three regimens were \nrecommended by Obstetrics and Gynecology Branch of Chinese \nMedical Association [11]. \nEstrogen and progesterone regimen:  continuous \ncombination of estrogen and progesterone. Estradiol valerate 0.5-\n1.5mg/d, or conjugated estrogen0.3~0.45mg/d or estradiol patch \nreleasing 25~50μg daily, or estradiol gel 1.25g/d via percutaneous \ndaub; for progesterone, 5mg/d dydrogesterone or 2~4mg/d \nmedroxyprogesterone is often used. Compound preparation \nestradiol spironolone tablets can also be used, 1 tablet per day.\nSingle progesterone: 1.25~2.5mg norethindrone acetate daily.\nContinuous use of tibolone, 1.25~2.5mg/d is recommended.\nAccording to the conventional understanding, the purpose \nof add-back to GnRH-a is to supplement estrogen to alleviate the  \nseries of problems caused by low estrogen. So why should we  \n \ndiscuss this single progesterone regimen (In fact, this regimen has \nnot been used too much clinically)? Many clinical teachers have \nasked this question in the gynecologic endocrine conference, this \nwas a brief state of my personal understanding. \nBefore answering this question, let me briefly review the \nmechanism of add-back therapy to GnRH-a administration. The use \nof GnRH-a, which will inhibit the gonadal axis, is bound to result \nin patients’ low estrogen status. In order to alleviate the series \nof problems caused by this low estrogen status, meanwhile to \nprolong patients’ GnRH-a application time and compliance, based \non the theory of “estrogen dosage window” (Different tissues \nhave different sensitivity to estrogen), some scholars put forward \na therapeutic regimen (Add-back) to keep estrogen at a normal \nlevel in the body so that it will not stimulate ectopic endometrial \ngrowth without causing perimenopausal symptoms and bone loss \n[E2:146~183 pmol/L (40~50 pg/ml)]. Such estrogen level does \nnot affect curative effect and can reduce side effects [12]. \nSince it is to solve the problem of low estrogen, it is easy \nto understand the other two estrogen regimens: estrogen plus \nprogesterone combination regimen (why to add progesterone \ndydrogesterone 5mg or MPA 2-4mg? EMS is an estrogen-dependent \ndisease, the combination regimen is more conducive to endometrial \natrophy, but there are also reports on single estrogen regimen); \nUse tibolone continuously with a recommended dose of 1.25~2.5 \nmg/d (tibolone component: 7-methylenethinolone, its metabolites \nhave three kinds of activities: estrogen, progesterone and androgen \neffects respectively, as a result, the compound effect is equivalent to \nthe combination regimen.).\nSome Gynecologists often feel confused regarding the single \nprogesterone regimen (norethindrone acetate 1.25-2.5mg, qd) \ntogether with its mechanism.\n*Corresponding author: Ruxia Shi, Department of Obstetrics and Gynecology, The \nAffiliated Changzhou NO. 2 People’s Hospital of Nanjing Medical University, No.68 \nGehu Road, Wujin District, Changzhou, 213000, China.\nReceived Date: January 02, 2019\nPublished Date: January 04, 2019\nISSN: 2641-6247                                                                                                                           DOI: 10.33552/WJGWH.2019.01.000521\nWorld Journal of \nGynecology & Women’s Health\nOpinion Copyright © All rights are reserved by Ruxia Shi\nThis work is licensed under Creative Commons Attribution 4.0 License  WJGWH.MS.ID.000521.\n\n\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 1-Issue 5\nCitation: Ruxia Shi, Jiming Chen, Junling Liu, Weiwei Wei, Ying Cao, et al. The Mechanism of Single Progesterone as Add-Back Therapy to \nGnRH-a Administration. W J Gynecol Women’s Health. 1(5): 2018. WJGWH.MS.ID.000521. DOI: 10.33552/WJGWH.2019.01.000521.\nPage 2 of  3\nBefore understanding this issue, we should first review the \nclassification, function and characteristics of progesterone.\nProgesterone is mainly divided into three categories:\n1. Natural progesterone\n2. Dydrogesterone: which is close to the natural progesterone\n3. Synthetic progesterone: mostly progesterone derivatives \nor testosterone derivatives.\nSynthetic progesterone is divided into four sub-categories:\n1. 17 ἀ hydroxyprogesterone derivatives (representative \ndrugs: medroxyprogesterone MPA, megestrol MA, cyproterone \nCPA)\n2. 19-gestonorone derivatives (representative drug: \nnomegestrol)\n3. spironolactone derivatives (drospirenone)\n4. 19- nortestosterone derivatives (mainly including: \nnorethindrone (NET) with estrane structure and norgestrel \n(LNG) with sterane structure).\nAs a derivative of 19-nortestosterone, norethindrone has \nan estrange structure. This derivative has high progesterone \nactivity after metabolism, as well as androgen activity and partial \nestrogen activity. This characteristic determines that it has a good \nhemostatic effect on abnormal uterine bleeding (AUB) clinically. As \nwe all know, synthetic progesterone has a very efficient and precise \nhemostatic effect, however, besides an effective progestogen \neffect, norethindrone has a synergistic effect to progestogen with \nits partial estrogen activity (via upregulation the activity of PR), \nmoreover, the androgen activity of its metabolite at the same time, \ncan reduce pelvic congestion effectively and the amount of uterine \nbleeding (Based on this principle, when progesterone injection \nis clinically used to treat AUB, 25-50mg testosterone propionate \ninjection (androgen) via intramuscular injection qd is often given \nabout 3-4 days before drug withdrawal to reduce withdrawal \nbleeding).\nBased on the above statement and analysis, norethindrone \nselected in the single progesterone regimen of the add-back therapy \nshould be obtained by taking the estrogen of its metabolites.\nAppendix\nDigression on synthetic progesterone from 19- nortestosterone \nderivatives.\nSynthetic progesterone from 19- nortestosterone derivatives \ninclude: norethindrone (NET) which has an estrane structure and \nnorgestrel (LNG) which has a sterane structure.\nNorethindrone has been described previously and were briefly \nintroduced here. (Note: As a synthetic progesterone preparation, \nnorethindrone has an estrane structure, and it is a derivative of the \nsynthetic 19-nortestosterone. It has weak estrogen activity, anti-\nestrogen activity, together with mild androgen activity and protein \nassimilation effect, and its androgen activity is about 1/6 of that of \ntestosterone).\nLevonorgestrel (LNG), which has a sterane structure, is the \nmain component of the familiar Mirena intrauterine device and \nprogesterone emergency contraception pills and is currently the \nmost efficient progesterone. What is levonorgestrel (LNG)? LNG \nis a fully synthetic and highly effective progesterone (synthetic \nprogesterone preparation which has a sterane structure). AS the \noptical active agent of racemic norgestrel, the progesterone activity \nof levonorgestrel is 1 time stronger than that of norgestrel and \nabout 100 times that of norethindrone. Therefore, the dose can \nbe halved compared with norgestrel, and the adverse reactions \ncan be reduced correspondingly. Levonorgestrel mainly acts on \nhypothalamus and pituitary gland, thereby the peak levels of FSH \nand LH in the middle menstrual period will be significantly reduced \nor just disappear, and the ovulation ceases. Levonorgestrel has \nobvious anti-estrogen activity, which is about 10 times stronger \nthan norethindrone. However, LNG has almost no estrogen activity, \nwhich can thicken cervical mucus and prevent sperm penetration. It \nshows strong progesterone activity on endometrial transformation, \nwhich can thin endometrium. Endometrium epithelial cells present \nlow columnar shape and have poor secretion, which is not conducive \nto implantation of pregnant eggs (The contraceptive effect is \naccurate!). LNG also has certain androgen activity and protein \nassimilation effect, and both oral and subcutaneous injection can \ninhibit ovulation.\nAcknowledgement\nThis work was supported by a grant from Major Science and \nTechnology Project of Changzhou Health and Family Planning \nCommission(ZD201812).\nConflict of Interest\nNo conflict of interest.\nReferences\n1. Nirgianakis K, Bersinger NA, McKinnon B, Kostov P , Imboden S, et \nal. (2013) Regression of the inflammatory microenvironment of the \nperitoneal cavity in women with endometriosis by GnRHa treatment. \nEur J Obstet Gynecol Reprod Biol 170(2): 550-554.\n2. Almassinokiani F, Mehdizadeh A, Sariri E, Rezaei M, Almasi A, et al. \n(2013) Effects of simvastatin in prevention of pain recurrences after \nsurgery for endometriosis. Med Sci Monit 19: 534-539.\n3. The Chinese medical association branch of obstetrics and gynecology \nendometriosis group (2007) The diagnosis and treatment of \nendometriosis. Chin J Obstet Gynecol 42 (9): 645-647.\n4. Leng JH, Lang JH, Yang JX (2000) Progress of diagnosis and treatment of \nendometriosis. Chin J Obstet Gynecol 35 (1): 53-55.\n5. Liu DY, Gu MJ, Shu JZ, Shi YX, Wang CY, et al. (2006) Effect of triptorelin \nand an extended-interval dosing regimen in the treatment of patients \nwith endometriosis and adenomyoma. Chin J Obstet Gynecol 41 (10): \n657-659.\n6. Yang DZ and Wang MY (2010) Proceedings of the third national meeting \non endometriosis and chronic pelvic pain. Chin J Obstet Gynecol 45 (4): \n243-245.\n7. Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima M, et al. (2010) \nCell proliferation effect of GnRH agonist on pathological lesions of \nwomen with endometriosis, adenomyosis and uterine myoma. Hum \nReprod 25 (11): 2878–2890.\n8. Wang YQ, Zhang SF, Chen X, Zhu J, Hua KQ, et al. (2009) Effects and safety \nof gonadotrophin-releasing hormone agonist combined with estradiol \n\nCitation: Ruxia Shi, Jiming Chen, Junling Liu, Weiwei Wei, Ying Cao, et al. The Mechanism of Single Progesterone as Add-Back Therapy to \nGnRH-a Administration. W J Gynecol Women’s Health. 1(5): 2018. WJGWH.MS.ID.000521. DOI: 10.33552/WJGWH.2019.01.000521.\nWorld Journal of Gynecology & Women’s Health                                                                                                             Volume 1-Issue 5 \nPage 3 of  3\npatch and oral medroxyprogesterone acetate on endometriosis. Chinese \nJ Obstet Gynecol 44 (7): 7-9.\n9. Liu PS, Li X, Liu Y, Hong-luan M, Yu-lan S (2008) Ximingting tablets in \nthe treatment of women with climacteric syndrome. J Shandong Univ \n46(8): 791-794.\n10. Zhou L and Liu YJ (2011) Progress of black cohosh treatment for peri-\nmenopausal syndrome. Res Integ Tradit Chin West Med 3(3): 150-152.\n11. Endometriosis Collaboration Group, Obstetrics and Gynecology Branch, \nChinese Medical Association (2015). Chin J Obstet Gynecol 50(3): 161-\n169. \n12. Barbieri RL (1992) Hormone treatment of endometriosis: the estrogen \nthreshold hypothesis. Am J Obster Gynecol 166(2): 740-745.","source_license":"CC0","license_restricted":false}