Mechanisms that explain the contraceptive action of progestin implants for women
Abstract
Four different contraceptive implants for women, in the form of capsules or covered rods, that release either one of the synthetic progestins levonorgestrel, etonogestrel, Nestorone, or Elcometrine and nomegestrol acetate were considered. These progestins act by binding to their receptors located in diverse target cells, which are distributed along the hypothalamic-pituitary-gonadal-genital tract axis. These implants differ in the extent to which each one interferes with various steps of the reproductive process and in the intensity with which each one affects the same process along its effective life, but they have in common the ability to interfere with several key processes required for gamete encounter and fertilization. The steps they interfere with most are the ovulatory process, through partial or complete inhibition of the gonadotropin surge, and by changing the quality of cervical mucus; they restrict or suppress the access of fertile spermatozoa to the site of fertilization. Changes in endometrial development also occur, but this contribution to the contraceptive action is difficult to determine at the present time.
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Progesterone-only hormonal birth control methods do induce contraceptive states.
“From a biological perspective, we know that progesterone-only hormonal birth control methods do induce contraceptive states [35]”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [35]
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“, Whitehouse Station, NJ, USA) contains 68 mg etonogestrel embedded in one ethylene-vinyl-acetate rod [5].”
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Rocha, A. L. L., Campos, R. R., Miranda, M. M. S., Raspante, L. B. D. P., Carneiro, M. M., Vieira, C. S., & dos Reis, F. M. (2017) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2018.1389893 · Cited by 17 · see citing works
Hohmann, H. L. (2009) · Patient Preference and Adherence · doi:10.2147/ppa.s4299 · Cited by 17 · see citing works
Maijer, A. M., & Semple, S. (2015) · Journal of Applied Animal Welfare Science · doi:10.1080/10888705.2015.1083432 · Cited by 16 · see citing works
“Implanon releases the progestin etonogestrel (Bennink, 2000; Croxatto, 2002).”
BackgroundTodd, C. S., Deese, J., Wang, M., Hubacher, D., Steiner, M. J., Otunga, S., & Damme, L. V. (2014) · Contraception · doi:10.1016/j.contraception.2014.10.008 · Cited by 15 · see citing works
“The hypothesized contraceptive mechanism of action of the LNG implant is through thickening of cervical mucus and, to a lesser degree, suppression of or dysfunctional ovulation [4,5].”
BackgroundLong‐acting contraception in adolescents and young women with type 1 and type 2 diabetes
Salinas, A., Merino, P. M., Giraudo, F., & Ethel Codner, D. (2020) · Pediatric Diabetes · doi:10.1111/pedi.13069 · Cited by 17 · see citing works
“Half of all users may exhibit diminished ovulation rates.(33)”
BackgroundContraceptive methods in adolescence: a narrative review of guidelines
Margaritis, K., Margioula‐Siarkou, G., Margioula‐Siarkou, C., Petousis, S., & Galli‐Τsinopoulou, A. (2023) · The European Journal of Contraception & Reproductive Health Care · doi:10.1080/13625187.2022.2162336 · Cited by 14 · see citing works
Contraceptive Implants: An Overview and Update
Isley, M. M., & Edelman, A. B. (2007) · Obstetrics and Gynecology Clinics of North America · doi:10.1016/j.ogc.2007.01.002 · Cited by 14 · see citing works
Contraceptive implants: A review and current perspective in southwest Nigeria
Kolawole, O., Sowemimo, O., Ojo, O., & Fasubaa, O. B. (2018) · Tropical Journal of Obstetrics and Gynaecology · doi:10.4103/tjog.tjog_6_18 · Cited by 14 · see citing works
“[26] Although ovulation is occasionally observed in the 3rd year of use,[27] the implant remains a highly effective contraceptive throughout this time because of the secondary modes of action.”
BackgroundMishell, J., & Shoupe, D. (2015) · Springer eBooks · doi:10.1007/978-3-319-20185-6 · Cited by 14 · see citing works
Stabile, G., Foti, C., Mordeglia, D., Santo, D. D., Mangino, F. P., Laganà, A. S., & Ricci, G. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11113226 · Cited by 13 · see citing works
“The contraceptive effect is obtained through two complementary mechanisms: the progestin inhibits the gonadotropin secretion and ovulation, and it causes changes in cervical mucus and tubal motility that are unfavorable to sperm migration [12].”
BackgroundPatient-Centered Contraceptive Counseling
Yecies, E. B., & Borrero, S. B. (2020) · Springer eBooks · doi:10.1007/978-3-030-50695-7_4 · Cited by 13 · see citing works
A rodent model of human dose-equivalent progestin-only implantable contraception
Allaway, H. C. M., Pierson, R. A., Invik, J., & Bloomfield, S. A. (2021) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-021-00729-w · Cited by 12 · see citing works
Vaisbuch, E., Erez, O., & Romero, R. J. (2021) · Springer eBooks · doi:10.1007/978-3-030-52508-8_1 · Cited by 11 · see citing works
Hou, Z., Xu, W., Chen, S., Guo, J., Li, P., Hu, J., Yang, L., & Chen, J. (2023) · Journal of Material Science and Technology · doi:10.1016/j.jmst.2023.01.040 · Cited by 10 · see citing works
Ballantyne, K., Anderson, S. T., Pyne, M. J., Nicolson, V. N., Mucci, A., Lisle, A. T., & Johnston, S. D. (2015) · Reproduction Fertility and Development · doi:10.1071/rd14387 · Cited by 10 · see citing works
“This observation provided indirect evidence that follicular development was possibly not suppressed by LNG treatment, as is the case in women (Croxatto 2002).”
BackgroundResultHernández‐Juárez, J., Garcı́a-Latorre, E., Moreno‐Hernández, M., Moran-Perez, J. F., Rodriguez-Escobedo, M. A., Cogque-Hernandez, G., Julián-Nacer, R., Hernandez-Giron, X., Palafox-Gomez, R., Isordia‐Salas, I., et al. (2014) · Reproductive Health · doi:10.1186/1742-4755-11-33 · Cited by 10 · see citing works
“Each SCI has ENG (68 mg) the active metabolite of desogestrel (DSG) [9].”
BackgroundFailure of Implanon® on antituberculous therapy
Gbolade, B. A. (2010) · Open Access Journal of Contraception · doi:10.2147/oajc.s12194 · Cited by 10 · see citing works
“Its main mechanism of action is ovulation suppression, augmented by increased cervical mucus viscosity that hinders the passage of spermatozoa and alters the endometrial lining, 7 and it is independent of user compliance.”
Vaisbuch, E., Erez, O., & Romero, R. J. (2015) · Springer eBooks · doi:10.1007/978-3-319-14385-9_1 · Cited by 10 · see citing works
Unintended pregnancy and the role of long-acting reversible contraception
Modi, M. N., Heitmann, R. J., & Armstrong, A. Y. (2013) · Expert Review of Obstetrics & Gynecology · doi:10.1586/17474108.2013.848596 · Cited by 9 · see citing works
Khalid, S., Hanif, R., Jabeen, I., Mansoor, Q., & Ismail, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0196312 · Cited by 9 · see citing works
A 5-year clinical evaluation of subdermal implants among Abakaliki acceptors
Nwali, M. I., Nnamdi, E., & Jude, A. (2016) · Journal of Basic and Clinical Reproductive Sciences · doi:10.4103/2278-960x.175730 · Cited by 8 · see citing works
“The modes of action include interference with cervical mucus making it thick and difficult for sperm penetration hence preventing fertilization,[7,8] prevention of ovulation by altering the hypothalamo-pituitary-ovarian axis,[9,10] and may also interfere with endometrial development.”
BackgroundHormonal contraceptive use in HIV-infected women using antiretroviral therapy: a systematic review
Womack, J. A., Novick, G., & Goulet, J. L. (2015) · Open Access Journal of Contraception · doi:10.2147/oajc.s55038 · Cited by 8 · see citing works
The oestrogen ‘sparing’ effect of implanon: A case report and review
Ogbonmwan, S. E. O., Briggs, P., & Amu, O. (2006) · The European Journal of Contraception & Reproductive Health Care · doi:10.1080/13625180500520174 · Cited by 8 · see citing works
Nanoparticle Technology for Respiratory Tract Mucosal Vaccine Delivery
Johnson, L. M., Mecham, J. B., Quinn, F. D., & Hickey, A. J. (2019) · KONA Powder and Particle Journal · doi:10.14356/kona.2020013 · Cited by 8 · see citing works
Systemic and barrier contraceptives for the dermatologist: a review
Chan, C. S., Harting, M. S., & Rosén, T. (2009) · International Journal of Dermatology · doi:10.1111/j.1365-4632.2009.04148.x · Cited by 7 · see citing works
The Structure, Function, and Evaluation of the Female Reproductive Tract
Lessey, B. A., & Young, S. L. (2013) · Elsevier eBooks · doi:10.1016/b978-1-4557-2758-2.00010-x · Cited by 8 · see citing works
Grossesse sous Implanon® : une « enquête » à propos de trois cas
Boucoiran, I., Trastour, C., Faraj, L., Delotte, J., & Bongain, A. (2011) · Gynécologie Obstétrique & Fertilité · doi:10.1016/j.gyobfe.2010.08.025 · Cited by 6 · see citing works
Etonogestrel contraceptive implant failure in a woman taking rifampin: a case report
Tufa, T. H., Sium, A. F., & Abubeker, F. A. (2022) · Contraception and Reproductive Medicine · doi:10.1186/s40834-022-00172-1 · Cited by 5 · see citing works
“The mechanism of action is mainly through suppression of ovulation augmented by increased cervical mucus viscosity that hinders the passage of spermatozoa [3].”
BackgroundDMPA: battered and bruised but still needed and used in the USA
Nelson, A. L. (2010) · Expert Review of Obstetrics & Gynecology · doi:10.1586/eog.10.60 · Cited by 5 · see citing works
Contraceptive Devices for Women: Implants, Intrauterine Devices and Other Products
Craik, J., & Rowlands, S. (2014) · Springer eBooks · doi:10.1007/978-3-319-12406-3_8 · Cited by 5 · see citing works
Kailasam, C., Akande, V., & Gordon, U. D. (2005) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-005-4889-3 · Cited by 5 · see citing works
“(15) concluded that follicular growth and the ovulatory process is disrupted with all of them.”
BackgroundBreast Cancer Risk with Progestin Subdermal Implants: A Challenge in Patients Counseling
Mohammed, G., Mousa, N. A., Talaat, I. M., Ibrahim, H., & Saber-Ayad, M. M. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.781066 · Cited by 4 · see citing works
“In this review, we focus on these two implants, both shown to have comparable effectiveness, release characteristics and pharmacokinetics (6).”
BackgroundOliveira-Ribeiro, M., Petta, C. A., Andrade, L. A. L. D. A., Hidalgo, M., Peloggia, A., & Bahamondes, L. G. (2006) · Contraception · doi:10.1016/j.contraception.2005.10.013 · Cited by 4 · see citing works
Black, A., Guilbert, É., Costescu, D., Dunn, S., Fisher, W. A., Kives, S. L., Mirosh, M., Norman, W. V., Pymar, H. C., Reid, R. L., et al. (2016) · Journal of Obstetrics and Gynaecology Canada · doi:10.1016/j.jogc.2016.03.005 · Cited by 4 · see citing works
The Structure, Function, and Evaluation of the Female Reproductive Tract
Strauss, J. F., & Lessey, B. A. (2009) · Elsevier eBooks · doi:10.1016/b978-1-4160-4907-4.00009-7 · Cited by 4 · see citing works
Contraception for the Cardiac Patient: a Cardiologist’s Primer
Florio, K. L., Kao, M., Johnson, T., Tuttle, H. A., White, D., Nelson, L., Patel, N. B., Ramaeker, D. M., Kendig, S., Schmidt, L. M., et al. (2020) · Current Treatment Options in Cardiovascular Medicine · doi:10.1007/s11936-020-00853-7 · Cited by 4 · see citing works
“Similar to the progestin-containing IUD, it also thins the endometrial lining and thickens the cervical mucus [30,46].”
BackgroundThe Contraceptive Implant: An Updated Review of the Evidence
Amico, J., Kumar, B., Rosenstein, H., & Gold, M. (2015) · Current Obstetrics and Gynecology Reports · doi:10.1007/s13669-014-0110-y · Cited by 3 · see citing works
“Cardiovascular and Metabolic Effects The CDC US MEC considers use of progestin-only contraceptives as a Category 1 (no restriction) or Category 2 (advantages generally outweigh the risk) for conditions which increase a woman’s risk of a cardiovascular event, with additional restrictions for DMPA [5].”
BackgroundInfluential[Reversible long-duration contraceptives: an efficient strategy to reduce non-planned pregnancies].
Lira-Plascencia, J., Velázquez-Ramírez, N., Ibargüengoitia-Ochoa, F., Montoya-Romero, J. D. J., Castelazo‐Morales, E., & Castro, E. V. (2013) · PubMed · Cited by 3 · see citing works
Phillips, S. J., Steyn, P. S., & Curtis, K. M. (2016) · Contraception · doi:10.1016/j.contraception.2016.05.004 · Cited by 3 · see citing works
“LNG causes changes in the cervical mucus that prevent penetration by sperm and also inhibits ovulation and leads to altered endometrial development and ovulatory dysfunction in most women [8,9].”
BackgroundDepot Medroxyprogesterone Acetate
McCullough, D. C., Eraso, K. M., & Kaunitz, A. M. (2020) · Springer eBooks · doi:10.1007/978-3-030-46391-5_6 · Cited by 3 · see citing works
Filho, E. S. F., Bahamondes, L. G., Duarte, D. C., Guimarães, A. L. M., de Almeida, P. G., Soares, J. M., Baracat, E. C., & Sorpreso, I. C. E. (2021) · Gynecological Endocrinology · doi:10.1080/09513590.2021.1974380 · Cited by 3 · see citing works
Contraceptive Counseling in Obese Women
McNicholas, C. P., Zigler, R. E., & Madden, T. E. (2015) · Springer eBooks · doi:10.1007/978-1-4939-2611-4_9 · Cited by 3 · see citing works
Monoplant® the Indonesian Implant: The Overview of Implant and Its Development
Gunardi, E. R., Affandi, B., & Muchtar, A. (2011) · Indonesian Journal of Obstetrics and Gynecology · Cited by 3 · see citing works
Progestin Injectable Contraceptives
Allen, R. H., Cwiak, C. A., & Kaunitz, A. M. (2015) · Springer eBooks · doi:10.1007/978-3-319-20185-6_8 · Cited by 3 · see citing works
Menstrual Pattern and Characteristics of One-Rod and Two-Rod Levonorgestrel Implant Users
Gunardi, E. R., & Susilo, S. A. (2021) · Obstetrics and Gynecology International · doi:10.1155/2021/2904542 · Cited by 3 · see citing works
“Etonogestrel implant works by inhibiting ovulation [24, 25].”
BackgroundThuwanut, P., Brown, J. L., Comizzoli, P., & Crosier, A. E. (2019) · Theriogenology · doi:10.1016/j.theriogenology.2019.07.001 · Cited by 3 · see citing works
A New Progestin Implant (Implanon) for Long-Term Contraception
(2007) · Obstetrics and Gynecology · doi:10.1097/01.aog.0000258239.10143.ff · Cited by 3 · see citing works
Hidalgo, A., & Palau, A. A. (2004) · FMC - Formación Médica Continuada en Atención Primaria · doi:10.1016/s1134-2072(04)76131-9 · Cited by 3 · see citing works
Sonographic imaging in progestin users and future directions
Varma, R., & Mascarenhas, L. (2002) · Ultrasound in Obstetrics and Gynecology · doi:10.1046/j.1469-0705.2002.00824.x · Cited by 3 · see citing works
“Widespread mechanisms have been proposed to explain the menstrual irregularities that complicate progestin therapy, but a unifying hypothesis remains elusive, thereby hindering development of effective therapeutic strategies 2–5 .”
BackgroundA Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle
Zhao, L., Kim, R., Oremland, L. S., Chowkwale, M., Pillis, L. G. D., & Brooks, H. Z. (2024) · The IMA volumes in mathematics and its applications · doi:10.1007/978-3-031-58516-6_3 · Cited by 2 · see citing works
Meriç, İ., Yapıcı, M., & Koc, D. G. (2025) · Toxics · doi:10.3390/toxics13090764 · Cited by 2 · see citing works
“…pharmaceutical class in aquatic systems after ethinylestradiol [16] and therefore, motivating our focus on LNG. LNG—a 19-nortestosterone-derived synthetic progestin—has garnered particular scrutiny owing to its high receptor affinity, physicochemical stability, and environmental ubiquity [8,17].”
Progesterone Receptors and Opportunities for Contraception
Croxatto, H. B. (2006) · Springer eBooks · doi:10.1007/3-540-27147-3_1 · Cited by 2 · see citing works
Self-citationContraception par progestatifs
Duranteau, L. (2008) · EMC - Gynécologie · doi:10.1016/s0246-1064(08)44372-4 · Cited by 2 · see citing works
Moutchia, J., Mouemba, D.-K. M., & Ngwasiri, C. A. (2018) · Journal of Medical Case Reports · doi:10.1186/s13256-018-1675-2 · Cited by 2 · see citing works
“restricting the access of spermatozoa to the site of fertilization; and suppression of endometrial maturation thereby impairing implantation of the blastocyst [5, 6, 9].”
BackgroundRushing, J. S., Appiah, L. A., Polotsky, A. J., Murray, S. C., Foust, E., Hassell, K. L., & Roeca, C. M. (2021) · Journal of Assisted Reproduction and Genetics · doi:10.1007/s10815-020-02057-1 · Cited by 2 · see citing works
Prevention of Adolescent Pregnancies
Creatsas, G. K. (2014) · ISGE series · doi:10.1007/978-3-319-09662-9_5 · Cited by 1 · see citing works
Long-Acting Progestin Injectables
Jurow, R., & Shoupe, D. (2006) · Humana Press eBooks · doi:10.1007/978-1-59745-150-5_7 · Cited by 1 · see citing works
- Authors
- Croxatto, H. B.
- Affiliations
- Instituto Chileno de Medicina Reproductiva (CL)
- Corresponding author
- Croxatto, Horacio B.
- Venue
- Contraception
- Publisher
- Elsevier BV
- Published
- 2002-01
- Volume
- 65
- Issue
- 1
- Pages
- 21-27
- ISSN
- 0010-7824 (ISSN-L)
- OpenAlex
- W2044424478
- Cited by
- 117
- References
- 54
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 3 · 2021: 10 · 2020: 10 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 10 · 2014: 6 · 2013: 3 · 2012: 6
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Contraception (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- contraceptive implants, progestins, levonorgestrel, etonogestrel, norethisterone, norethisterone acetate, hypothalamic-pituitary-gonadal axis, ovulation inhibition, luteinizing hormone surge, cervical mucus, sperm transport, endometrium, female contraception
- MeSH terms
- Cervix Mucus, Contraceptive Devices, Female, Drug Implants, Endometrium, Female, Humans, Ovary, Progesterone Congeners
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