Abstract
Progestin-only (p-only) contraceptives often cause breakthrough bleeding for unknown reasons. In this study, we aimed to evaluate the long-term effects of p-only contraceptives to gain a better understanding of breakthrough bleeding mechanism. Wistar rats were divided into etonorgesterel implant (Group 1, n = 25), depot medroxyprogesterone acetate injectable (Group 2, n = 25), and control groups (n = 5). Five rats each from groups 1 and 2 were examined every 10 days for up to 50 days after the medication. Uteri and ovaries were removed and prepared for immunohistochemisty and scanning electron microscopy. The tissue nitric oxide (NO) levels were determined by Griess reaction. Dynamic changes of endometrial estrogen and progesterone receptor immunoreactivity were observed in a time-dependent manner in groups 1 and 2. The number of endometrial pinopodes, which are small endometrial protrusions, increased in both groups. There was no difference between groups for the estrogen receptor in the surface epithelium of the ovary. Estrogen-alpha and progesterone receptor in follicular cells decreased in a time-dependent manner. The granulosa cells underwent atrophic and were disorganized. Decreased levels of uterine tissue NO were determined in groups 1 and 2. The effect of some p-only contraceptives make some dynamic changes in the endometrium, ovaries, steroid hormone receptors, cell morphology, and biochemical features of the tissues during their use.
Similar content being viewed by others
References
Gallo MF, Grimes DA, Schulz KF, d’Arcangues C, Lopez LM (2005) Combination injectable contraceptives for contraception. Cochrane Database Syst Rev 20:CD004568
Sereepapong W, Chotnopparatpattara P, Taneepanichskul S, Markham R, Russell P, Fraser IS (2004) Endometrial progesterone and estrogen receptors and bleeding disturbances in depot medroxyprogesterone acetate users. Hum Reprod 19:547–552
Hickey M, Fraser IS (2000) A functional model for progestogen-induced breakthrough bleeding. Hum Reprod 15:1–6
Oborná I, Novotný R, Brezinová J, Petrová P, Lichnovský V, Fingerová H (2004) Changes in the development of uterine pinopodes in steroid hormone supplemented cycles. Physiol Res 53:423–429
Taguchi M, Alfer J, Chwalisz K, Beier HM, Classen-Linke I (2000) Endothelial nitric oxide synthase is differently expressed in human endometrial vessels during the menstrual cycle. Mol Hum Reprod 6:185–190
Norman EJ, Cameron LT (1996) Nıtrıc oxide in human uterus. Rev Reprod 1:61–68
Khorram O, Garthwaite M, Magness RR (1999) Endometrial and myometrial expression of nitric oxide synthase isoforms in pre- and postmenopausal women. J Clin Endocrinol Metab 84:2226–2232
Bennink HJ (2000) The pharmacokinetics and pharmacodynamics of Implanon, a single-rod etonogestrel contraceptive implant. Eur J Contracept Reprod Health Care 5:12–20
Mäkäräinen L, van Beek A, Tuomivaara L, Asplund B, Coelingh Bennink H (1998) Ovarian function during the use of a single contraceptive implant: Implanon compared with Norplant. Fertil Steril 69:714–721
Hidalgo MM, Lisondo C, Juliato CT, Espejo-Arce X, Monteiro I, Bahamondes L (2006) Ovarian cysts in users of Implanon and Jadelle subdermal contraceptive implants. Contraception 73:532–536
Miranda KM, Espey MG, Wink DA (2001) Nitric oxide. Biol and Chem 5:62–71
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Anal Biochem 126:131–138
Morison NB, Zhang J, Kaitu’u-Lino TJ, Fraser IS, Salamonsen LA (2007) The long-term actions of etonogestrel and levonorgestrel on decidualized and non-decidualized endometrium in a mouse model mimic some effects of progestogen-only contraceptives in women. Reproduction 133:309–321
Critchley HO, Bailey DA, Au CL, Affandi B (1993) Rogers. Immunohistochemical sex steroid receptor distribution in endometrium from long-term subdermal levonorgestrel users and during the normal menstrual cycle. Hum Reprod 8:1632–1639
Macpherson AM, Archer DF, Leslie S, Charnock-Jones DS, Makkink WK, Smith SK (1999) The effect of etonogestrel on VEGF, oestrogen and progesterone receptor immunoreactivity and endothelial cell number in human endometrium. Hum Reprod 14:3080–3087
Zhu P, Liu X, Luo H, Gu Z, Cheng J, Xu R, Lian S, Wu S, Wang J (1999) The effect of a levonorgestrel-releasing intrauterine device on human endometrial oestrogen and progesterone receptors after one year of use. Hum Reprod 14(4):970–975
Charnock-Jones DS, Macpherson AM, Archer DF, Leslie S, Makkink WK, Sharkey AM, Smith SK (2000) The effect of progestins on vascular endothelial growth factor, oestrogen receptor and progesterone receptor immunoreactivity and endothelial cell density in human endometrium. Hum Reprod 3:85–95
Creus M, Ordi J, Fábregues F, Casamitjana R, Carmona F, Cardesa A, Vanrell JA, Balasch J (2003) The effect of different hormone therapies on integrin expression and pinopode formation in the human endometrium: a controlled study. Hum Reprod 18:683–693
Stavreus-Evers A, Nikas G, Sahlin L, Eriksson H, Landgren BM (2001) Formation of pinopodes in human endometrium is associated with the concentrations of progesterone and progesterone receptors. Fertil Steril 76:782–791
Alvarez-Sanchez F, Brache V, de Oca VM, Cochon L, Faúndes A (2000) Prevalence of enlarged ovarian follicles among users of levonorgestrel subdermal contraceptive implants (Norplant). Am J Obstet Gynecol 182:535–539
Bahamondes L, Hidalgo M, Petta CA, Diaz J, Espejo-Arce X, Monteiro-Dantas C (2003) Enlarged ovarian follicles in users of a levonorgestrel-releasing intrauterine system and contraceptive implant. J Reprod Med 48:637–640
Bjersing L, Cajander S (1975) Ovulation and the role of the ovarian surface epithelium. Experientia 15:605–608
Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC (2001) Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev 22:255–288
Katabuchi H, Okamura H (2003) Cell biology of human ovarian surface epithelial cells and ovarian carcinogenesis. Med Electron Microsc 36:74–86
Brandenberger AN, Tee MK, Jaffe RB (1998) Estrogen receptor a (ER-a) and b (ER-b) mRNAs in normal ovary, ovarian serous cystadenocarcinoma and ovarian cancer cell lines: down-depletion of ER-b in neoplastic tissues. J Clin Endocrinol Metab 83:1025–1028
Lau KM, Mok SC, Ho SM (1999) Expression of human estrogen receptor-a and -b, progesterone receptor, and androgen receptor mRNA in normal and malignant ovarian epithelial cells. Proc Natl Acad Sci USA 96:5722–5727
Vermeirsch H, Simoens P, Coryn M, Van den Broeck W (2001) Immunolocalization of progesterone receptors in the canine ovary and their relation to sex steroid hormone concentrations. Reproduction 122:73–83
Ho SM (2003) Estrogen, progesterone and epithelial ovarian cancer. Reprod Biol Endocrinol 1:73
Cunat S, Hoffman P, Pujol P (2004) Estrogens and epithelial ovarian cancer. Gynecol Oncol 94:25–32
Rodgers RJ, Irving-Rodgers HF, van Wezel IL, Krupa M, Lavranos TC (2001) Dynamics of the membrana granulosa during expansion of the ovarian follicular antrum. Mol Cell Endocrinol 22(171):41–48
Hafez ES, Makabe S, Motta PM (1980) Surface ultrastructure of functional and nonfunctional human ovaries. Int J Fertil 25:94–99
Chwalisz K, Garfield RE (2000) Role of nitric oxide in implantation and menstruation. Hum Reprod 15:96–111
Zervou S, Klentzeris LD, Old RW (1999) Nitric oxide synthase expression and steroid regulation in the uterus of women with menorrhagia. Mol Hum Reprod 5:1048–1054
Telfer JF, Irvine GA, Kohnen G, Campbell S, Cameron IT (1997) Expression of endothelial and inducible nitric oxide synthase in non-pregnant and decidualized human endometrium. Mol Hum Reprod 3:69–75
Bulbul A, Yağci A, Altunbaş K, Sevimli A, Celik HA, Karadeniz A, Akdağ E (2007) The role of nitric oxide in the effects of ovarian steroids on spontaneous myometrial contractility in rats. Theriogenology 68:1156–1168
Shaamash AH, Zakhari MM (2005) Increased serum levels of nitric oxide metabolites among users of levonorgestrel-releasing implants [corrected] a possible role in progestin-induced bleeding. Hum Reprod 20:302–306
Conflict of interest statement
There is no actual or potential conflict of interest in relation to this article.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lortlar, N., Kilic, S., Peker, T. et al. The long-term effects of progesterone-only contraceptives on endometrium and ovary in rats. Arch Gynecol Obstet 281, 1051–1059 (2010). https://doi.org/10.1007/s00404-010-1356-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00404-010-1356-x