{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T15:49:13Z","timestamp":1775058553129,"version":"3.50.1"},"reference-count":31,"publisher":"BMJ","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Fam Plann Reprod Health Care"],"accepted":{"date-parts":[[2007,8,13]]},"published-print":{"date-parts":[[2007,10]]},"abstract":"<jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>The most common reason for discontinuation of long-acting progestogen-only contraceptives is irregular bleeding following local endometrial vascular changes. To reduce unpredictable bleeding episodes among depot medroxyprogesterone acetate (DMPA) users, the combined injectable contraceptive, Cyclofem\u00ae, was offered as an alternative. However, there is a gap in our knowledge about the effects of Cyclofem on the endometrial vasculature and patterns of bleeding. This study aimed to compare the effects of Cyclofem and DMPA on endometrial vascular density, endometrial histology and pattern of bleeding.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Sixty-eight healthy women with regular menstrual bleeding and seeking injectable long-acting contraceptives were recruited. Two endometrial samples (before and 3 to 6 months after initial exposure to DMPA or Cyclofem) were collected from each participant. The samples were stained using an immunohistochemical method and anti-CD34 to visualise the endometrial vasculature. Endometrial vascular density was assessed using standard techniques.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Sixty-eight women were randomly assigned to Cyclofem (38 women) or DMPA (30 women). Endometrial vascular density was 149.3 \u00b1 6.7 (mean \u00b1 SD)\/mm<jats:sup>2<\/jats:sup> before injection. This significantly decreased to 132.4 \u00b1 12.2 after DMPA use, and from 151.9 \u00b1 5.8 to 131.8 \u00b1 12.8 vessels\/mm<jats:sup>2<\/jats:sup> following Cyclofem use (paired <jats:italic>t<\/jats:italic>-test, <jats:italic>p<\/jats:italic> &lt;0.05). However, there was no significant difference between endometrial vascular density during treatment with Cyclofem or DMPA. Total bleeding days in the first and second 3-month time intervals were 28 \u00b1 23 and 18 \u00b1 12 days in DMPA users and 22 \u00b1 14 and 16 \u00b1 9 days in Cyclofem users, respectively, Spotting was the most common type of bleeding experienced, and atrophic endometrium was the most common histological pattern observed in both groups.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study demonstrated that both Cyclofem and DMPA use are associated with decreased endometrial vascular density and atrophic endometrium, in addition to irregular bleeding, mainly spotting. There was no significant difference in bleeding patterns or endometrial findings observed for these two injectable contraceptives in Iranian women.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1783\/147118907782101887","type":"journal-article","created":{"date-parts":[[2008,1,23]],"date-time":"2008-01-23T19:08:23Z","timestamp":1201115303000},"page":"271-276","source":"Crossref","is-referenced-by-count":11,"title":["A comparative study of Cyclofem\u00ae and depot medroxyprogesterone acetate (DMPA) effects on endometrial vasculature"],"prefix":"10.1136","volume":"33","author":[{"given":"Masoumeh","family":"Simbar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hananeh","family":"Zham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fahimeh Ramezani","family":"Tehrani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeinab","family":"Hashemi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian S","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2007,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s10456-005-9003-z","article-title":"Progestogen-only contraception and endometrial break-through bleeding","volume":"8","author":"Smith, O.P.; Critchley, H.O.","year":"2005","unstructured":"Smith OP, Critchley HO. Progestogen-only contraception and endometrial break-through bleeding. Angiogenesis 2005; 8: 117\u2013126.","journal-title":"Angiogenesis"},{"key":"ref_2","first-page":"381","article-title":"Pharmacokinetics of depot medroxyprogesterone acetate contraception","volume":"41","author":"Mishell, DR","year":"1996","unstructured":"Mishell DR. Pharmacokinetics of depot medroxyprogesterone acetate contraception. J Reprod Med 1996; 41: 381\u2013390.","journal-title":"J Reprod Med"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0029-7844(96)00194-9","article-title":"Experiences of injectable contraceptive users in an urban setting","volume":"88","author":"Sangi-Haghpeykar, H.; Poindexter, A.N.; Bateman, L.; Ditmore, JR","year":"1996","unstructured":"Sangi-Haghpeykar H, Poindexter AN, Bateman L, Ditmore JR. Experiences of injectable contraceptive users in an urban setting. Obstet Gynecol 1996; 88: 227\u2013233.","journal-title":"Obstet Gynecol"},{"key":"ref_4","first-page":"439","article-title":"Vaginal bleeding patterns in women using once-amonth injectable contraceptives","volume":"14","author":"Fraser, I.S.","year":"1994","unstructured":"Fraser IS. Vaginal bleeding patterns in women using once-amonth injectable contraceptives. Contraception 1994; 49: 399\u2013420. 5 d\u2019Arcangues C. Once-a-month injectable contraceptives. World Health Forum 1993; 14: 439\u2013440.","journal-title":"Contraception; 49: 399\u2013420. 5 d\u2019Arcangues C. Once-a-month injectable contraceptives"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0010-7824(99)00064-5","article-title":"Once-a-month injectable contraceptives, Cyclofem and Mesigyna, in Egypt. Efficacy, causes of discontinuation, and side effects","volume":"60","author":"Hassan, E.O.; el-Nahal, N.; el-Hussinie, M.","year":"1999","unstructured":"Hassan EO, el-Nahal N, el-Hussinie M. Once-a-month injectable contraceptives, Cyclofem and Mesigyna, in Egypt. Efficacy, causes of discontinuation, and side effects. Contraception 1999; 60: 87\u201392. 7 d\u2019Arcangues C. Once-a-month estrogen\/progestogen injectables. Entre Nous Cph Den 1991; 15.","journal-title":"Contraception; estrogen\/progestogen injectables"},{"key":"ref_6","first-page":"2","article-title":"Mechanisms of menstrual bleeding: dysfunctional uterine bleeding and breakthrough bleeding","volume":"11","author":"Fraser, I.S.; Hickey, M.; Song, J.Y.","year":"1996","unstructured":"Fraser IS, Hickey M, Song JY. Mechanisms of menstrual bleeding: dysfunctional uterine bleeding and breakthrough bleeding. Hum Reprod 1996; 11(Suppl. 2): 156\u2013178.","journal-title":"Hum Reprod"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1016\/S0010-7824(86)80016-6","article-title":"A morphometric study of the effects of oral norethisterone and levonorgestrel and endometrial blood vessels","volume":"34","author":"Hourihan, H.M.; Sheppard, B.L.; Bonnar, J.","year":"1986","unstructured":"Hourihan HM, Sheppard BL, Bonnar J. A morphometric study of the effects of oral norethisterone and levonorgestrel and endometrial blood vessels. Contraception 1986; 34: 603\u2013612.","journal-title":"Contraception"},{"key":"ref_8","first-page":"53","article-title":"Endometrial morphology during the normal cycle and under the influence of contraceptive steroids","volume-title":"Contraception and Mechanisms of Endometrial Bleeding","author":"Johannisson, E.","year":"1990","unstructured":"Johannisson E. Endometrial morphology during the normal cycle and under the influence of contraceptive steroids. In: d\u2019Arcangues C, Fraser IS, Newton JR, Odlind V (eds), Contraception and Mechanisms of Endometrial Bleeding. Cambridge, UK: Cambridge University Press, 1990; 53\u201381."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0010-7824(99)00012-8","article-title":"A longitudinal study of changes in endometrial microvascular density in Norplant implant users","volume":"59","year":"1999","unstructured":"A longitudinal study of changes in endometrial microvascular density in Norplant implant users. Contraception 1999; 59: 123\u2013129.","journal-title":"Contraception"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1093\/oxfordjournals.humrep.a138268","article-title":"Endometrial microvascular density during the normal menstrual cycle and following exposure to long-term levonorgestrel","volume":"8","author":"Rogers, P.A.W.; Au, C.L.; Affandi, B.","year":"1993","unstructured":"Rogers PAW, Au CL, Affandi B. Endometrial microvascular density during the normal menstrual cycle and following exposure to long-term levonorgestrel. 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The endometrial vascular appearance in Norplant users: preliminary results from a hysteroscopic study. Hum Reprod 1996; 11(Suppl. 2): 35\u201344.","journal-title":"Hum Reprod"},{"key":"ref_13","first-page":"253","article-title":"The analysis of vaginal bleeding patterns induced by fertility regulating methods","volume":"4","author":"Belsey, E.M.; Machin, D.; d\u2019Arcangues, C.","year":"1986","unstructured":"Belsey EM, Machin D, d\u2019Arcangues C. The analysis of vaginal bleeding patterns induced by fertility regulating methods. Contraception 1986; 4: 253\u2013260.","journal-title":"Contraception"},{"key":"ref_14","first-page":"3","article-title":"Dating the endometrial biopsy","volume-title":"Fertil Steril","volume":"1","author":"Noyes, R.W.; Hertig, A.T.; Rock, J.","year":"1950","unstructured":"Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril 1950; 1: 3\u201325."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/0002-9378(79)90344-2","article-title":"Vessel density in endometrium of women with and without intrauterine contraceptive devices: a morphometric evaluation","volume":"135","author":"ST, Jr, Shaw; LK, Macaulay; WR, Hohman","year":"1979","unstructured":"Shaw ST Jr, Macaulay LK, Hohman WR. Vessel density in endometrium of women with and without intrauterine contraceptive devices: a morphometric evaluation. 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Am J Obstet Gynecol 1981; 141: 821\u2013827.","journal-title":"Am J Obstet Gynecol"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.contraception.2004.07.002","article-title":"Endometrial vascularization in levonorgestrel intrauterine device users; computerized microvessel measurement study","volume":"71","author":"Jondet, M.; Letellier, B.; Verdys, M.T.","year":"2005","unstructured":"Jondet M, Letellier B, Verdys MT. Endometrial vascularization in levonorgestrel intrauterine device users; computerized microvessel measurement study. Contraception 2005; 71: 60\u201364.","journal-title":"Contraception"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.contraception.2004.04.006","article-title":"Effect of long-term progestin treatment on endometrial vasculature in normal cycling mice","volume":"70","author":"Girling, J.E.; Heryanto, B.; Patel, N.; Rogers, P.A.","year":"2004","unstructured":"Girling JE, Heryanto B, Patel N, Rogers PA. Effect of long-term progestin treatment on endometrial vasculature in normal cycling mice. Contraception 2004; 70: 343\u2013350.","journal-title":"Contraception"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.micron.2004.01.005","article-title":"A threedimensional study of endometrial microvessels in women using the contraceptive subdermal levonorgestrel implant system, Norplant","volume":"35","author":"Simbar, M.; Manconi, F.; Markham, R.; Hickey, M.; Fraser, I.S.","year":"2004","unstructured":"Simbar M, Manconi F, Markham R, Hickey M, Fraser IS. A threedimensional study of endometrial microvessels in women using the contraceptive subdermal levonorgestrel implant system, Norplant. Micron 2004; 35: 589\u2013595.","journal-title":"Micron"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1093\/humrep\/14.3.716","article-title":"Changes in vascular basement membrane in the endometrium of Norplant users","volume":"14","author":"Hickey, M.; Simbar, M.; Markham, R.; Young, L.; Manconi, F.; Russell, P.","year":"1999","unstructured":"Hickey M, Simbar M, Markham R, Young L, Manconi F, Russell P, et al. Changes in vascular basement membrane in the endometrium of Norplant users. Hum Reprod 1999; 14: 716\u2013721.","journal-title":"Hum Reprod"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1093\/humrep\/deg023","article-title":"Hormonally mediated disturbance of angiogenesis in the human endometrium after exposure to intrauterine levonorgestrel","volume":"18","author":"McGavigan, C.J.; Dockery, P.; Metaxa-Mariatou, V.; Campbell, D.; Stewart, C.J.; Cameron, I.T.","year":"2003","unstructured":"McGavigan CJ, Dockery P, Metaxa-Mariatou V, Campbell D, Stewart CJ, Cameron IT, et al. Hormonally mediated disturbance of angiogenesis in the human endometrium after exposure to intrauterine levonorgestrel. Hum Reprod 2003; 18: 77\u201384.","journal-title":"Hum Reprod"},{"issue":"3","key":"ref_22","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/humrep\/15.suppl_3.57","article-title":"The structure of endometrial microvessels","volume":"15","author":"Hickey, M.; Fraser, I.S.","year":"2000","unstructured":"Hickey M, Fraser IS. The structure of endometrial microvessels. Hum Reprod 2000; 15(Suppl. 3): 57\u201366.","journal-title":"Hum Reprod"},{"issue":"3","key":"ref_23","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/humrep\/15.suppl_3.135","article-title":"The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin-only contraceptives","volume":"15","author":"Vincent, A.J.; Salamonsen, L.A.","year":"2000","unstructured":"Vincent AJ, Salamonsen LA. The role of matrix metalloproteinases and leukocytes in abnormal uterine bleeding associated with progestin-only contraceptives. Hum Reprod 2000; 15(Suppl. 3): 135\u2013143.","journal-title":"Hum Reprod"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1093\/humrep\/17.5.1189","article-title":"Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase\/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding","volume":"17","author":"Vincent, A.J.; Zhang, J.; Ostor, A.; Rogers, P.A.; Affandi, B.; Kovacs, G.","year":"2002","unstructured":"Vincent AJ, Zhang J, Ostor A, Rogers PA, Affandi B, Kovacs G, et al. Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase\/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding. Hum Reprod 2002; 17: 1189\u20131198.","journal-title":"Hum Reprod"},{"key":"ref_25","first-page":"4822","article-title":"Temporal and spatial association of matrix metalloproteinases with focal endometrial breakdown and bleeding upon progestin-only contraception","volume":"85","author":"Galant, C.; Vekemans, M.; Lemoine, P.; Kokorine, I.; Twagirayezu, P.; Henriet, P.","year":"2000","unstructured":"Galant C, Vekemans M, Lemoine P, Kokorine I, Twagirayezu P, Henriet P, et al. Temporal and spatial association of matrix metalloproteinases with focal endometrial breakdown and bleeding upon progestin-only contraception. J Clin Endocrinol Metab 2000; 85: 4822\u20134834.","journal-title":"J Clin Endocrinol Metab"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1210\/jc.2005-2748","article-title":"Mechanism of irregular bleeding with hormone therapy: the role of matrix metalloproteinases and their tissue inhibitors","volume":"91","author":"Hickey, M.; Crewe, J.; Mahoney, L.A.; Doherty, D.A.; Fraser, I.S.; Salamonsen, L.A.","year":"2006","unstructured":"Hickey M, Crewe J, Mahoney LA, Doherty DA, Fraser IS, Salamonsen LA. Mechanism of irregular bleeding with hormone therapy: the role of matrix metalloproteinases and their tissue inhibitors. 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Endocrinology 1998; 139: 4607\u20134013.","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1006621809825","article-title":"Endometrial histology in long-term users of the once-a-month injectable contraceptive Cyclofem","volume":"15","author":"Bahamondes, L.; Maradiegue, E.; Diaz, J.; Trelles, J.; Escanhoela, C.; Petta, C.","year":"1999","unstructured":"Bahamondes L, Maradiegue E, Diaz J, Trelles J, Escanhoela C, Petta C, et al. Endometrial histology in long-term users of the once-a-month injectable contraceptive Cyclofem. Adv Contracept 1999; 15: 1\u20137.","journal-title":"Adv Contracept"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0010-7824(96)00173-4","article-title":"My Huong NT. 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Fam Plann Perspect 1999; 31: 64\u201372, 93."}],"container-title":["Journal of Family Planning and Reproductive Health Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1783\/147118907782101887","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T17:08:28Z","timestamp":1757092108000},"score":1,"resource":{"primary":{"URL":"https:\/\/jfprhc.bmj.com\/lookup\/doi\/10.1783\/147118907782101887"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,10]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2007,10,1]]},"published-print":{"date-parts":[[2007,10]]}},"alternative-id":["10.1783\/147118907782101887"],"URL":"https:\/\/doi.org\/10.1783\/147118907782101887","relation":{},"ISSN":["1471-1893","2045-2098"],"issn-type":[{"value":"1471-1893","type":"print"},{"value":"2045-2098","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,10]]}}}