Hormonal intrauterine device

This article is about hormone-based IUDs. For copper-based, see Copper IUDs.

A hormonal intrauterine device (IUD), also known as an intrauterine system (IUS) with progestogen and sold under the brand name Mirena among others, is an intrauterine device that releases a progestogenic hormonal agent such as levonorgestrel into the uterus.^[2] It is used for birth control, heavy menstrual periods, and to prevent excessive build of the lining of the uterus in those on estrogen replacement therapy.^[2] It is one of the most effective forms of birth control with a one-year failure rate around 0.2%.^[1] The device is placed in the uterus and lasts three to eight years.^[3][4] Fertility often returns quickly following removal.^[2]

IUD with progestogen
Correctly inserted IUD
Background
Type	Intrauterine
First use	1990 (Mirena—currently available) 1976 (Progestasert—discontinued in 2001)
Synonyms	intrauterine system (IUS), levonorgestrel intrauterine system
Trade names	Mirena, Skyla, Liletta, others
AHFS/Drugs.com	Professional Drug Facts
Failure rates (first year)
Perfect use	0.1–0.2%^[1]
Typical use	0.1–0.2%^[1]
Usage
Duration effect	3–8 years
Reversibility	2–6 months
User reminders	Check thread position monthly
Clinic review	One month after insertion, then annually
Advantages and disadvantages
STI protection	No
Periods	Menstrual irregularity, periods usually lighter or none at all
Weight	Potential side effect
Benefits	No need to remember to take daily action
Risks	benign ovarian cysts, transient risk of PID, uterine perforation (rare)

Side effects include irregular periods, benign ovarian cysts, pelvic pain, and depression.^[2] Rarely uterine perforation may occur.^[2] Use is not recommended during pregnancy but is safe with breastfeeding.^[2] The IUD with progestogen is a type of long-acting reversible birth control.^[5] It works by thickening the mucus at the opening of the cervix, stopping the buildup of the lining of the uterus, and occasionally preventing ovulation.^[2]

The IUD with levonorgestrel was first approved for medical use in 1990 in Finland and in the United States in 2000.^[6] It is on the World Health Organization's List of Essential Medicines.^[7][8]

Medical uses

Hormonal intrauterine device

Clinical data
ATC code	None
Legal status
Legal status	CA: ℞-only^[9] US: ℞-only^[10]^[11]^[12]^[13] In general: ℞ (Prescription only)

The hormonal IUD is an extremely effective method of birth control, and a 2021 study demonstrated that it may be used for emergency contraception.^[14] In addition to birth control, the hormonal IUD is used for prevention and treatment of:

• Heavy menstrual periods^[15]
• Endometriosis and chronic pelvic pain^[15][16]
• Adenomyosis and dysmenorrhea^[15][17]
• Anemia^[18]
• Endometrial hyperplasia (especially in pre-menopausal women who wish to maintain fertility in the treatment of endometrial hyperplasia)^[19][20]
• In some cases, use of a hormonal IUD may prevent a need for a hysterectomy.^[21]

Advantages:

• Considered one of the most effective forms of reversible birth control^[22]
• Can be used while breastfeeding^[23] (see also nursing mothers)
• No preparations needed before sex,^[24] though routine checking of the device strings by patient and physician is advised to ensure proper placement remains intact^[25]
• 90% of users who wish to become pregnant do so within 24 months of removal.^[26]
• May experience lighter periods (some women stop having periods completely, see also amenorrhea)^[27]
• Effective for up to three to eight years (depending on the IUD)^[4]

Disadvantages:

• Irregular periods and spotting between periods often occurs after insertion^[27] This usually improves after three to six months.^[4]
• Moderate to severe discomfort may be experienced during insertion procedure, including uterine cramping and back pain.
• Other potential adverse effects and risks

Effectiveness

After insertion, Mirena is effective at preventing pregnancy for up to eight years.^[28] Kyleena is approved for five years and Skyla is approved for three years.^[29][30]

The hormonal IUD is a long-acting reversible contraceptive, and is considered one of the most effective forms of birth control. The first year failure rate for the hormonal IUD is 0.1-0.2% and the five-year failure rate is 0.7-0.9%.^[31][28][32] These rates are comparable to tubal sterilization, but unlike sterilization the effects of the hormonal IUD are reversible.

The hormonal IUD is considered to be more effective than other common forms of reversible contraception, such as the birth control pill, because it requires little action by the user after insertion.^[22] The effectiveness of other forms of birth control is mitigated (decreased) by the users themselves. If medication regimens for contraception are not followed precisely, the method becomes less effective. IUDs require no daily, weekly, or monthly regimen, so their typical use failure rate is therefore the same as their perfect use failure rate.^[22]

In a 10-year study, the levonorgestrel coil was found to be as effective as oral medicines (tranexamic acid, mefenamic acid, combined oestrogen–progestogen or progesterone alone) for heavy periods; the same proportion of women had not had surgery for heavy bleeding and had similar improvements in their quality of life.^[33][34]

In women with bicornuate uterus and in need of contraception, two IUDs are generally applied (one in each horn) due to lack of evidence of efficacy with only one IUD.^[35] Evidence is lacking regarding progestogen IUD usage for menorrhagia in bicornuate uterus, but a case report showed good effect with a single IUD for this purpose.^[36]

Breastfeeding

Progestogen-only contraceptives such as an IUD are not believed to affect milk supply or infant growth.^[37] However, a study in the Mirena application for FDA approval found a lower continuation of breastfeeding at 75 days in hormonal IUD users (44%) versus copper IUD users (79%).^[38]: 37

When using Mirena, about 0.1% of the maternal dose of levonorgestrel can be transferred via milk to the nursed infant.^[39] A six-year study of breastfed infants whose mothers used a levonorgestrel-only method of birth control found the infants had increased risk of respiratory infections and eye infections, though a lower risk of neurological conditions, compared to infants whose mothers used a copper IUD.^[40] No longer-term studies have been performed to assess the long-term effects on infants of levonorgestrel in breast milk.

There are conflicting recommendations about use of Mirena while breastfeeding. The U.S. CDC does not recommend any hormonal method as a first choice of contraceptive for nursing mothers, although progestin-only methods, such as Mirena, may be used with close follow-up or when the benefits outweigh the risks.^[41] The World Health Organization recommends against immediate postpartum insertion, citing increased expulsion rates. It also reports concerns about potential effects on the infant's liver and brain development in the first six weeks postpartum. However, it recommends offering Mirena as a contraceptive option beginning at six weeks postpartum even to nursing women.^[42][43] Planned Parenthood offers Mirena as a contraceptive option for breastfeeding women beginning at four weeks postpartum.^[44]

Contraindications

A hormonal IUD should not be used by people who:

• Are, or think they may be, pregnant^[23]
• Have abnormal vaginal bleeding that has not been explained^[23] (controversial)^[45]
• Have untreated cervical or uterine cancer^[23]
• Have, or may have, breast cancer^[23]
• Have abnormalities of the cervix or uterus^[46] (controversial)^[45]
• Have had pelvic inflammatory disease within the past three months^[23]
• Have had an STI such as chlamydia or gonorrhea within the past three months^[23]
• Have liver disease or tumor^[46]
• Have an allergy to levonorgestrel or any of the inactive ingredients included in the device^[46]

Insertion of an IUD is acceptable after a dilation and evacuation (D&E) abortion (second-trimester abortion), but may be associated with a higher expulsion rate.^[47] To reduce the risk of infection, insertion of an IUD is not recommended for women that have had a medical abortion but have not yet had an ultrasound to confirm that the abortion was complete, or that have not yet had their first menstruation following the medical abortion.^[44]

A full list of contraindications can be found in the WHO Medical Eligibility Criteria for Contraceptive Use and the CDC United States Medical Eligibility Criteria for Contraceptive Use.^[23][48]

Side effects

Further information: Progestogen (medication) § Side effects

• Irregular menstrual pattern: irregular bleeding and spotting is common in the first three to six months of use. After that time periods become shorter and lighter, and 20% of women stop having periods after one year of use.^[49] The average user reports 16 days of bleeding or spotting in the first month of use, but this diminishes to about four days at 12 months.^[50][51]
• Cramping and pain: many women feel discomfort or pain during and immediately after insertion. Some women may have cramping for the first 1–2 weeks after insertion.^[52]
• Expulsion: Sometimes the IUD can slip out of the uterus. This is termed expulsion. Around 5% of IUD users experience expulsion. If this happens a woman is not protected from pregnancy.^[52][53] Expulsion is more common in younger women, women who have not had children, and when an IUD is inserted immediately after childbirth or abortion.^[54][55][56]

• Perforation: Very rarely, the IUD can be pushed through the wall of the uterus during insertion. Risk of perforation is mostly determined by the skill of the practitioner performing the insertion. For experienced medical practitioners, the risk of perforation is one per 1,000 insertions or less.^[57] With postpartum insertions, perforation of the uterus is more likely to occur when uterine involution is incomplete; involution usually completes by 4–6 weeks postpartum.^[55] Special considerations apply to women who plan to breastfeed. If perforation does occur it can damage the internal organs, and in some cases surgery is needed to remove the IUD.
• Pregnancy complications: Although the risk of pregnancy with an IUD is very small, if one does occur there is an increased risk of serious problems. These include ectopic pregnancy, infection, miscarriage, and early labor and delivery. As many as half the pregnancies that occur in Mirena users may be ectopic. The incidence rate of ectopic pregnancies is approximately one per 1000 users per year.^{[38]: 3–4} Immediate removal of the IUD is recommended in the case of pregnancy.^[52][53] No pattern of birth defects was found in the 35 babies for whom birth outcomes were available at the time of FDA approval.^{[38]: 5, 41}
• Infection: The insertion of the IUD does have a small risk of pelvic inflammatory disease (PID). Concurrent infection with gonorrhea or chlamydia at the time of insertion increases the risk of pelvic inflammatory disease.^[58] If PID does occur, it will most likely happen within 21 days of insertion. The device itself does not increase the risk of infection.^[52]
• Ovarian cysts: Enlarged follicles (ovarian cysts) have been diagnosed in about 12% of the subjects using a hormonal IUD in studies that use ultrasound to look for cysts, even if asymptomatic. In studies that only evaluate symptomatic cysts, only 4.5% of women complain of any ovarian cysts over 5 or more years of use, and only 0.3% require IUD removal for ovarian cysts.^[59] Thus, any issues with ovarian cysts are not of a clinically relevant nature. Most of these follicles are asymptomatic, although some may be accompanied by pelvic pain or dyspareunia. In most cases the enlarged follicles disappear spontaneously after two to three months. Surgical intervention is not usually required.^[60]
• Mental health changes including: nervousness, depressed mood, mood swings^[46]
  Further information: Progestogen (medication) § Mood changes
• Weight gain^[46]
• Headache, migraine^[46]
• Nausea^[46]
• Acne^[46]
• Excessive hairiness^[46]
• Lower abdominal or back pain^[46]
• Decreased libido^[46]
• Itching, redness or swelling of the vagina^[46]
• Vaginal discharge^[61]
• Breast pain, tenderness^[61]
• Edema^[61]
• Abdominal distension^[61]
• Cervicitis^[61]
• Bacterial vaginosis^[62]
• May affect glucose tolerance^[61]
• May experience a change in vision or contact lens tolerance^[26]
• May deplete vitamin B1 which can affect energy, mood, and nervous system functioning^[26]
• A "lost coil" occurs when the thread cannot be felt by a woman on routine checking and is not seen on speculum examination.^[63] Various thread collector devices or simple forceps may then be used to try to grasp the device through the cervix.^[64] In the rare cases when this is unsuccessful, an ultrasound scan may be arranged to check the position of the coil and exclude its perforation through into the abdominal cavity or its unrecognised previous expulsion.

Cancer

According to a 1999 evaluation of the studies performed on progestin-only birth control by the International Agency for Research on Cancer, there is some evidence that progestin-only birth control reduces the risk of endometrial cancer. The IARC in 1999 concluded that there is no evidence progestin-only birth control increases the risk of any cancer, though the available studies were too small to be definitively conclusive.^[65]

Progesterone is a hormone in the endometrium that counteracts estrogen driven growth.^[66] Very low levels of progesterone will cause estrogen to act more, leading to endometrial hyperplasia and adenocarcinoma.^[66] These effects can be minimized if treated with progestin, but not in very many cases.

Estrogen and progesterone have an antagonistic relationship. Estrogen promotes the growing of endometrial lining, while progesterone limits it.^[66] In the case of endometrial cancer, progesterone can negatively regulate estrogen driven growth. Tumors formed are correlated with insufficient progesterone and excess estrogen.^[66] In patients with endometrial cancer who use progestin releasing IUDs concluded mixed results.

A 2020 meta-analysis by Livia Conz et al. estimated that users of levonorgestrel-releasing systems had an increased breast cancer risk in general (with an odds ratio of 1.16) and higher risk for those over age 50 (odds ratio 1.52), and suggested balancing this risk against the known benefits of long-term use.^[67] Researchers cautioned against causal interpretation from this study, citing confounding effects, methodological concerns and a 2020 meta-analysis of randomized controlled trials which showed no increased risk.^[68][69][70]

Bone density

No evidence has been identified to suggest Mirena affects bone mineral density (BMD).^[71] Two small studies, limited to studying BMD in the forearm, show no decrease in BMD.^[72][73] One of the studies showed at seven years of use, similar BMD at the midshaft of the ulna and at the distal radius as nonusers matched by age and BMI.^[72] In addition, BMD measurements were similar to the expected values for women in the same age group as the participants. The authors of the study said their results were predictable, since it is well established that the main factor responsible for bone loss in women is hypoestrogenism, and, in agreement with previous reports, they found estradiol levels in Mirena users to be normal.^[72]

Composition and hormonal release

 

Mirena IUD visible on pelvic radiograph.

The hormonal IUD is a small T-shaped piece of plastic, which contains levonorgestrel, a type of progestin.^[28] The cylinder of the device is coated with a membrane that regulates the release of the drug.^[74] Bayer markets Skyla as Jaydess in the United Kingdom.^[75] Jaydess releases six micrograms per day and lasts for three years.^[76] In comparison, oral contraceptives can contain 150 micrograms of levonorgestrel.^[52] The hormonal IUD releases the levonorgestrel directly into the uterus, as such its effects are mostly paracrine rather than systemic. Most of the drug stays inside the uterus, and only a small amount is absorbed into the rest of the body.^[52]

Insertion and removal

 

Schematic depiction of vaginal ultrasonography of a Mirena.

 

Vaginal ultrasonography showing a Mirena in optimal place in the uterus, as viewed from angle shown in schematic depiction.

The hormonal IUD is inserted in a similar procedure to the nonhormonal copper IUD, and can only be inserted by a qualified medical practitioner.^[52] Before insertion, a pelvic exam is performed to examine the shape and position of the uterus. A current STI at the time of insertion can increase the risk of pelvic infection.^[77] However, routine screening for gonorrhea and chlamydia prior to insertion is not recommended.^[78] If a person needs screening and there is no evidence of infection on examination or has been previously screened, insertion of the IUD does not need to be delayed.^[79]

Insertion

During the insertion, the vagina is held open with a speculum, the same device used during a pap smear.^[52] A grasping instrument is used to steady the cervix, the length of the uterus is measured for proper insertion with a uterine sound for decreasing chance of uterine perforation with the IUD, and the IUD is placed using a narrow tube through the opening of the cervix into the uterus.^[52] A short length of monofilament plastic/nylon string hangs down from the cervix into the vagina. The string allows physicians and patients to check to ensure the IUD is still in place and enables easy removal of the device.^[52] Moderate to severe cramping can occur during the procedure, which generally takes five minutes or less. Insertion can be performed immediately postpartum and post-abortion if no infection has occurred.^[23]

Misoprostol is not effective in reducing pain in IUD insertion.^[80]

Removal

Removal of the device should also be performed by a qualified medical practitioner. After removal, fertility will return to previous levels relatively quickly.^[81] One study found that the majority of participants returned to fertility within three months.^[82]

Mechanisms of action

Levonorgestrel is a progestogen, i.e. a progesterone receptor agonist. The hormonal IUD's primary mechanism of action is to prevent fertilization.^{[52][83][84][85][86]} The levonorgestrel intrauterine system has several contraceptive effects, although thickening of the cervical mucus appears to be the primary effect.^[87] Other effects include making the inside of the uterus become fatal to sperm^[85][88] and thinning of the endometrial lining, but this is not the usual function.^[89][90]

Ovulation is not inhibited in all cases.^[85][91]

Numerous studies have demonstrated that IUDs primarily prevent fertilization, not implantation.^[52] In one experiment involving tubal flushing, fertilized eggs were found in half of women not using contraception, but no fertilized eggs were found in women using IUDs.^[92] IUDs also decrease the risk of ectopic pregnancy, which further implies that IUDs prevent fertilization.^[52]

History

Hormonal IUDs were developed in the 1970s following the development of the copper IUD in the 1960s and 1970s.^[93] Dr. Antonio Scommenga, working at the Michael Reese Hospital in Chicago, discovered that administering progesterone inside the uterus could have contraceptive benefits.^[93] With knowledge of Scommegna's work, a Finnish doctor, Jouni Valter Tapani Luukkainen, created the T-shaped IUD that released progesterone, marketed as the Progestasert System in 1976. This IUD had a short, 1-year lifespan and never achieved widespread popularity. Following this relative lack of success, Dr. Luukkainen replaced the progesterone with the hormone levonorgestrel to be released over a five-year period, creating what is now Mirena.^[94]

The Mirena IUD was studied for safety and efficacy in two clinical trials in Finland and Sweden involving 1,169 women who were all between 18 and 35 years of age at the beginning of the trials. The trials included predominantly Caucasian women who had been previously pregnant with no history of ectopic pregnancy or pelvic inflammatory disease within the previous year. Over 70% of the participants had previously used IUDs.^[10]

In 2013 Skyla, a lower dose levonorgestrel IUD effective for up to three years, was approved by the FDA.^[95] Skyla has a different bleeding pattern than Mirena, with only 6% of women in clinical trials becoming amenorrheic (compared to approximately 20% with Mirena).

The city of Turku, Finland, is currently the only production site for the Mirena contraceptive family.^[96]

Controversies

In 2009, Bayer, the maker of Mirena, was issued an FDA Warning Letter by the United States Food and Drug Administration for overstating the efficacy, minimizing the risks of use, and making "false or misleading presentations" about the device.^[97][98] From 2000 to 2013, the federal agency received over 70,072 complaints about the device and related adverse effects.^[99][100] As of April 2014, over 1,200 lawsuits have been filed in the United States.^{[98][101][102][103]}

References

1. Trussell J (2011). "Contraceptive efficacy". In Hatcher RA, Trussell J, Nelson AL, Cates Jr W, Kowal D, Policar MS (eds.). Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 779–863. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734. Table 26–1 = (PDF). Archived from the original (PDF) on 15 February 2017.
2. British National Formulary: BNF 69 (69th ed.). British Medical Association. 2015. p. 556. ISBN 978-0-85711-156-2.
3. "Levonorgestrel intrauterine system medical facts from Drugs.com". drugs.com. from the original on 1 January 2017. Retrieved 1 January 2017.
4. "Hormonal IUDs". www.plannedparenthood.org. from the original on 24 April 2019. Retrieved 20 April 2019.
5. Wipf J (2015). Women's Health, An Issue of Medical Clinics of North America. Elsevier Health Sciences. p. 507. ISBN 978-0-323-37608-2. from the original on 10 January 2023. Retrieved 1 September 2017.
6. Bradley LD, Falcone T (2008). Hysteroscopy: Office Evaluation and Management of the Uterine Cavity. Elsevier Health Sciences. p. 171. ISBN 978-0-323-04101-0. from the original on 12 January 2023. Retrieved 1 September 2017.
7. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
8. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
9. "Mirena Product information". Health Canada. 22 November 2007. from the original on 19 April 2024. Retrieved 19 April 2024.
10. . Bayer Health Pharmaceuticals. May 2009. Archived from the original on 18 June 2015. Retrieved 18 June 2015.
11. "Kyleena- levonorgestrel intrauterine device". DailyMed. 13 March 2023. from the original on 22 September 2023. Retrieved 19 April 2024.
12. "Skyla- levonorgestrel intrauterine device". DailyMed. 31 January 2023. from the original on 9 December 2023. Retrieved 19 April 2024.
13. "Liletta- levonorgestrel intrauterine device". DailyMed. 29 June 2023. from the original on 29 November 2021. Retrieved 19 April 2024.
14. "Science Update: Hormonal IUD as effective as a copper IUD at emergency contraception and with less discomfort, NICHD-funded study suggests". 4 February 2021. from the original on 26 July 2021. Retrieved 26 July 2021.
15. Bahamondes L, Bahamondes MV, Monteiro I (July 2008). "Levonorgestrel-releasing intrauterine system: uses and controversies". Expert Review of Medical Devices. 5 (4): 437–445. doi:10.1586/17434440.5.4.437. PMID 18573044. S2CID 659602.
16. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa E, Silva JC, et al. (July 2005). "Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis". Human Reproduction. 20 (7): 1993–1998. doi:10.1093/humrep/deh869. PMID 15790607.
17. Sheng J, Zhang WY, Zhang JP, Lu D (March 2009). "The LNG-IUS study on adenomyosis: a 3-year follow-up study on the efficacy and side effects of the use of levonorgestrel intrauterine system for the treatment of dysmenorrhea associated with adenomyosis". Contraception. 79 (3): 189–193. doi:10.1016/j.contraception.2008.11.004. PMID 19185671.
18. Faundes A, Alvarez F, Brache V, Tejada AS (June 1988). "The role of the levonorgestrel intrauterine device in the prevention and treatment of iron deficiency anemia during fertility regulation". International Journal of Gynaecology and Obstetrics. 26 (3): 429–433. doi:10.1016/0020-7292(88)90341-4. PMID 2900174. S2CID 34592937.
19. "The American College of Obstetricians and Gynecologists Committee Opinion no. 631. Endometrial intraepithelial neoplasia". Obstetrics and Gynecology. 125 (5): 1272–1278. May 2015. doi:10.1097/01.AOG.0000465189.50026.20. PMID 25932867. S2CID 46508283.
20. Mittermeier T, Farrant C, Wise MR (September 2020). "Levonorgestrel-releasing intrauterine system for endometrial hyperplasia". The Cochrane Database of Systematic Reviews. 2020 (9): CD012658. doi:10.1002/14651858.CD012658.pub2. PMC 8200645. PMID 32909630.
21. Marjoribanks J, Lethaby A, Farquhar C (January 2016). "Surgery versus medical therapy for heavy menstrual bleeding". The Cochrane Database of Systematic Reviews. 2016 (1): CD003855. doi:10.1002/14651858.CD003855.pub3. PMC 7104515. PMID 26820670.
22. Winner B, Peipert JF, Zhao Q, Buckel C, Madden T, Allsworth JE, et al. (May 2012). "Effectiveness of long-acting reversible contraception". The New England Journal of Medicine. 366 (21): 1998–2007. doi:10.1056/NEJMoa1110855. PMID 22621627. S2CID 16812353. from the original on 11 June 2020. Retrieved 30 June 2019.
23. Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, et al. (July 2016). "U.S. Medical Eligibility Criteria for Contraceptive Use, 2016" (PDF). MMWR. Recommendations and Reports. 65 (3): 1–103. doi:10.15585/mmwr.rr6503a1. PMID 27467196. (PDF) from the original on 16 October 2020. Retrieved 3 February 2020.
24. "IUD". Planned Parenthood. from the original on 18 June 2015. Retrieved 18 June 2015.
25. . Let's Talk About Mirena. Bayer. Archived from the original on 18 June 2015. Retrieved 18 June 2015.
26. "Mirena". MediResource Inc. from the original on 3 July 2015. Retrieved 18 June 2015.
27. Hidalgo M, Bahamondes L, Perrotti M, Diaz J, Dantas-Monteiro C, Petta C (February 2002). "Bleeding patterns and clinical performance of the levonorgestrel-releasing intrauterine system (Mirena) up to two years". Contraception. 65 (2): 129–132. doi:10.1016/s0010-7824(01)00302-x. PMID 11927115.
28. "Mirena IUD Homepage | Official Website". from the original on 31 July 2012. Retrieved 19 July 2012., Bayer Pharmaceuticals.
29. Highlights of Prescribing Information (Report). 9 January 2013. from the original on 6 May 2016.
30. "What are hormonal IUDs?". Planned Parenthood. from the original on 24 April 2019. Retrieved 19 April 2019.
31. Westhoff CL, Keder LM, Gangestad A, Teal SB, Olariu AI, Creinin MD (March 2020). "Six-year contraceptive efficacy and continued safety of a levonorgestrel 52 mg intrauterine system". Contraception. 101 (3): 159–161. doi:10.1016/j.contraception.2019.10.010. PMID 31786203. S2CID 208535090. from the original on 10 June 2020. Retrieved 2 January 2020.
32. Jensen JT, Creinin MD, Speroff L, eds. (2019). Speroff & Darney's clinical guide for contraception (Sixth ed.). Philadelphia, PA: Wolters Kluwer. p. 15. ISBN 978-1-9751-0728-4. OCLC 1121081247.
33. Kai J, Dutton B, Vinogradova Y, Hilken N, Gupta J, Daniels J (October 2023). "Rates of medical or surgical treatment for women with heavy menstrual bleeding: the ECLIPSE trial 10-year observational follow-up study". Health Technology Assessment. 27 (17): 1–50. doi:10.3310/JHSW0174. PMC 10641716. PMID 37924269. from the original on 6 November 2023. Retrieved 12 April 2024.
34. "The coil and medicines are both effective long-term treatments for heavy periods". NIHR Evidence. 8 March 2024. doi:10.3310/nihrevidence_62335. from the original on 18 March 2024. Retrieved 12 April 2024.
35. Oelschlager AM, Debiec K, Micks E, Prager S (2013). "Use of the Levonorgestrel Intrauterine System in Adolescents With Known Uterine Didelphys or Unicornuate Uterus". Journal of Pediatric and Adolescent Gynecology. 26 (2): e58. doi:10.1016/j.jpag.2013.01.029. ISSN 1083-3188.
36. Acharya GP, Mills AM (July 1998). "Successful management of intractable menorrhagia with a levonorgestrel-releasing intrauterine device, in a woman with a bicornuate uterus". Journal of Obstetrics and Gynaecology. 18 (4): 392–393. doi:10.1080/01443619867263. PMID 15512123.
37. Truitt ST, Fraser AB, Grimes DA, Gallo MF, Schulz KF (2003). Lopez LM (ed.). "Combined hormonal versus nonhormonal versus progestin-only contraception in lactation". The Cochrane Database of Systematic Reviews (2): CD003988. doi:10.1002/14651858.CD003988. PMID 12804497.
38. (PDF). Center for Drug Evaluation and Research. U.S. Food and Drug Administration. December 2000. Archived from the original (PDF) on 27 February 2008.
39. (PDF). Bayer NZ. 11 December 2009. Archived from the original (PDF) on 6 July 2011. Retrieved 10 February 2011.
40. Schiappacasse V, Díaz S, Zepeda A, Alvarado R, Herreros C (July 2002). "Health and growth of infants breastfed by Norplant contraceptive implants users: a six-year follow-up study". Contraception. 66 (1): 57–65. doi:10.1016/S0010-7824(02)00319-0. PMID 12169382.
41. "Classifications for Intrauterine Devices | CDC". www.cdc.gov. 9 April 2020. from the original on 15 July 2020. Retrieved 7 July 2020.
42. World Health Organization (2015). Medical eligibility criteria for contraceptive use (5th ed.). Geneva: World Health Organization. hdl:10665/181468. ISBN 978-92-4-154915-8.
43. World Health Organization (2015). "Medical eligibility criteria for contraceptive use, fifth edition 2015: executive summary". World Health Organization. hdl:10665/172915. from the original on 28 August 2021. Retrieved 3 February 2020.
44. . Planned Parenthood. July 2005. Archived from the original on 12 October 2006. Retrieved 8 October 2006.
45. Heavy menstrual bleeding (update). National Institute for Health and Care Excellence. 2018.
46. "Mirena: Consumer Medicine Information" (PDF). Bayer. March 2014. (PDF) from the original on 27 April 2014. Retrieved 27 April 2014.
47. Roe AH, Bartz D (January 2019). "Society of Family Planning clinical recommendations: contraception after surgical abortion". Contraception. 99 (1): 2–9. doi:10.1016/j.contraception.2018.08.016. PMID 30195718.
48. WHO (2010). . Medical Eligibility Criteria for Contraceptive Use (4th ed.). Geneva: Reproductive Health and Research, WHO. ISBN 978-92-4-156388-8. Archived from the original on 10 July 2012.
49. Hidalgo M, Bahamondes L, Perrotti M, Diaz J, Dantas-Monteiro C, Petta C (February 2002). "Bleeding patterns and clinical performance of the levonorgestrel-releasing intrauterine system (Mirena) up to two years". Contraception. 65 (2): 129–132. doi:10.1016/S0010-7824(01)00302-X. PMID 11927115.
50. McCarthy L (May 2006). "Levonorgestrel-Releasing Intrauterine System (Mirena) for Contraception". Am Fam Physician. 73 (10): 1799–. from the original on 26 September 2007. Retrieved 4 May 2007.
51. Rönnerdag M, Odlind V (September 1999). "Health effects of long-term use of the intrauterine levonorgestrel-releasing system. A follow-up study over 12 years of continuous use". Acta Obstetricia et Gynecologica Scandinavica. 78 (8): 716–721. doi:10.1034/j.1600-0412.1999.780810.x. PMID 10468065.
52. Dean G, Schwarz EB (2011). "Intrauterine contraceptives (IUCs)". In Hatcher RA, Trussell J, Nelson AL, Cates Jr W, Kowal D, Policar MS (eds.). Contraceptive technology (20th revised ed.). New York: Ardent Media. pp. 147–191. ISBN 978-1-59708-004-0. ISSN 0091-9721. OCLC 781956734. p.150:

    Mechanism of action
    Although the precise mechanism of action is not known, currently available IUCs work primarily by preventing sperm from fertilizing ova.²⁶ IUCs are not abortifacients: they do not interrupt an implanted pregnancy.²⁷ Pregnancy is prevented by a combination of the "foreign body effect" of the plastic or metal frame and the specific action of the medication (copper or levonorgestrel) that is released. Exposure to a foreign body causes a sterile inflammatory reaction in the intrauterine environment that is toxic to sperm and ova and impairs implantation.^28,29 The production of cytotoxic peptides and activation of enzymes lead to inhibition of sperm motility, reduced sperm capacite journal and survival, and increased phagocytosis of sperm.^30,31… The progestin in the LNg IUC enhances the contraceptive action of the device by thickening cervical mucus, suppressing the endometrium, and impairing sperm function. In addition, ovulation is often impaired as a result of systemic absorption of levonorgestrel.²³
    p. 162:
    Table 7-1. Myths and misconceptions about IUCs
    Myth: IUCs are abortifacients. Fact: IUCs prevent fertilization and are true contraceptives.

53. "IUDs—An Update". Population Reports. XXII (5). Population Information Program, Johns Hopkins School of Public Health. December 1995.
54. . Population Reports. XXII (5). Population Information Program, Johns Hopkins School of Public Health. December 1995. Archived from the original on 5 September 2006.
55. . Population Reports. XXII (5). Population Information Program, Johns Hopkins School of Public Health. December 1995. Archived from the original on 29 April 2006.
56. . Population Reports. XXII (5). Population Information Program, Johns Hopkins School of Public Health. December 1995. Archived from the original on 11 August 2006.
57. WHO Scientific Group on the Mechanism of Action Safety and Efficacy of Intrauterine Devices, World Health Organization (1987). Mechanism of action, safety and efficacy of intrauterine devices. Geneva: World Health Organization. hdl:10665/38182. ISBN 92-4-120753-1. World Health Organization technical report series; no. 753.
58. Grimes DA (September 2000). "Intrauterine device and upper-genital-tract infection". Lancet. 356 (9234): 1013–1019. doi:10.1016/S0140-6736(00)02699-4. PMID 11041414. S2CID 7760222.
59. Teal SB, Turok DK, Chen BA, Kimble T, Olariu AI, Creinin MD (January 2019). "Five-Year Contraceptive Efficacy and Safety of a Levonorgestrel 52-mg Intrauterine System". Obstetrics and Gynecology. 133 (1): 63–70. doi:10.1097/AOG.0000000000003034. PMC 6319579. PMID 30531565.
60. Bahamondes L, Hidalgo M, Petta CA, Diaz J, Espejo-Arce X, Monteiro-Dantas C (August 2003). "Enlarged ovarian follicles in users of a levonorgestrel-releasing intrauterine system and contraceptive implant". The Journal of Reproductive Medicine. 48 (8): 637–640. PMID 12971147.
61. "Mirena". Bayer UK. 11 June 2013. from the original on 18 June 2015. Retrieved 18 June 2015.
62. Donders GG, Bellen G, Ruban K, Van Bulck B (March 2018). "Short- and long-term influence of the levonorgestrel-releasing intrauterine system (Mirena®) on vaginal microbiota and Candida". Journal of Medical Microbiology. 67 (3): 308–313. doi:10.1099/jmm.0.000657. PMID 29458551.
63. Nijhuis JG, Schijf CP, Eskes TK (July 1985). "[The lost IUD: don't look too far for it]". Nederlands Tijdschrift voor Geneeskunde. 129 (30): 1409–1410. PMID 3900746.
64. Kaplan NR (April 1976). "Letter: Lost IUD". Obstetrics and Gynecology. 47 (4): 508–509. PMID 1256735.
65. . International Programme on Chemical Safety. 1999. Archived from the original on 28 September 2006. Retrieved 8 October 2006.
66. Kim JJ, Chapman-Davis E (January 2010). "Role of progesterone in endometrial cancer". Seminars in Reproductive Medicine. 28 (1): 81–90. doi:10.1055/s-0029-1242998. PMC 4767501. PMID 20104432.
67. Conz L, Mota BS, Bahamondes L, Teixeira Dória M, Françoise Mauricette Derchain S, Rieira R, et al. (August 2020). "Levonorgestrel-releasing intrauterine system and breast cancer risk: A systematic review and meta-analysis". Acta Obstetricia et Gynecologica Scandinavica. 99 (8). Wiley: 970–982. doi:10.1111/aogs.13817. PMID 31990981. S2CID 210946832.
68. Al Kiyumi MH, Al Battashi K, Al-Riyami HA (September 2021). "Levonorgestrel-releasing intrauterine system and breast cancer; Is there an association?". Acta Obstetricia et Gynecologica Scandinavica. 100 (9). Wiley: 1749. doi:10.1111/aogs.14188. PMID 34021506. S2CID 235094824.
69. Silva FR, Grande AJ, Da Rosa MI (February 2021). "Is the levonorgestrel-releasing intrauterine system a risk factor for breast cancer?". Acta Obstetricia et Gynecologica Scandinavica. 100 (2). Wiley: 363–364. doi:10.1111/aogs.13966. PMID 32740910. S2CID 220942002.
70. Romero SA, Young K, Hickey M, Su HI (December 2020). "Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen". The Cochrane Database of Systematic Reviews. 12 (12): CD007245. doi:10.1002/14651858.CD007245.pub4. PMC 8092675. PMID 33348436.
71. Faculty of Family Planning and Reproductive Health Care Clinical Effectiveness Unit (April 2004). "FFPRHC Guidance (April 2004). The levonorgestrel-releasing intrauterine system (LNG-IUS) in contraception and reproductive health". The Journal of Family Planning and Reproductive Health Care. 30 (2): 99–108, quiz 109. doi:10.1783/147118904322995474. PMID 15086994. S2CID 31281104.
72. Wong AY, Tang LC, Chin RK (June 2010). "Levonorgestrel-releasing intrauterine system (Mirena) and Depot medroxyprogesterone acetate (Depoprovera) as long-term maintenance therapy for patients with moderate and severe endometriosis: a randomised controlled trial". The Australian & New Zealand Journal of Obstetrics & Gynaecology. 50 (3): 273–279. doi:10.1111/j.1479-828X.2010.01152.x. PMID 20618247. S2CID 22050651.
73. Bahamondes MV, Monteiro I, Castro S, Espejo-Arce X, Bahamondes L (May 2010). "Prospective study of the forearm bone mineral density of long-term users of the levonorgestrel-releasing intrauterine system". Human Reproduction. 25 (5): 1158–1164. doi:10.1093/humrep/deq043. PMID 20185512.
74. Luukkainen T (1991). "Levonorgestrel-releasing intrauterine device". Annals of the New York Academy of Sciences. 626 (1): 43–49. Bibcode:1991NYASA.626...43L. doi:10.1111/j.1749-6632.1991.tb37898.x. PMID 1905510. S2CID 39610456.
75. Bayer Group. . Jaydess. Bayer PLC. Archived from the original on 17 November 2016. Retrieved 16 November 2016.
76. Römer T, Bühling KJ (2013). "Intrauterine hormonelle Kontrazeption". Gynäkologische Endokrinologie. 11 (3): 188–196. doi:10.1007/s10304-012-0532-4. S2CID 20088018.
77. Mohllajee AP, Curtis KM, Peterson HB (February 2006). "Does insertion and use of an intrauterine device increase the risk of pelvic inflammatory disease among women with sexually transmitted infection? A systematic review". Contraception. 73 (2): 145–153. doi:10.1016/j.contraception.2005.08.007. PMID 16413845. from the original on 6 February 2020. Retrieved 6 February 2020.
78. Curtis KM, Tepper NK, Jatlaoui TC, Berry-Bibee E, Horton LG, Zapata LB, et al. (July 2016). "U.S. Medical Eligibility Criteria for Contraceptive Use, 2016". MMWR. Recommendations and Reports. 65 (3): 1–103. doi:10.15585/mmwr.rr6503a1. PMID 27467196.
79. "CDC - Summary - US SPR - Reproductive Health". www.cdc.gov. 21 June 2017. from the original on 13 September 2017. Retrieved 13 September 2017.
80. Lopez LM, Bernholc A, Zeng Y, Allen RH, Bartz D, O'Brien PA, et al. (July 2015). "Interventions for pain with intrauterine device insertion". The Cochrane Database of Systematic Reviews. 2015 (7): CD007373. doi:10.1002/14651858.CD007373.pub3. PMC 9580985. PMID 26222246.
81. Mansour D, Gemzell-Danielsson K, Inki P, Jensen JT (November 2011). "Fertility after discontinuation of contraception: a comprehensive review of the literature". Contraception. 84 (5): 465–477. doi:10.1016/j.contraception.2011.04.002. PMID 22018120.
82. Randic L, Vlasic S, Matrljan I, Waszak CS (September 1985). "Return to fertility after IUD removal for planned pregnancy". Contraception. 32 (3): 253–259. doi:10.1016/0010-7824(85)90048-4. PMID 4085244.
83. Ortiz ME, Croxatto HB (June 2007). "Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action". Contraception. 75 (6 Suppl): S16–S30. doi:10.1016/j.contraception.2007.01.020. PMID 17531610. p. S28:

    Conclusions
    Active substances released from the IUD or IUS, together with products derived from the inflammatory reaction present in the luminal fluids of the genital tract, are toxic for spermatozoa and oocytes, preventing the encounter of healthy gametes and the formation of viable embryos. The current data do not indicate that embryos are formed in IUD users at a rate comparable to that of nonusers. The common belief that the usual mechanism of action of IUDs in women is destruction of embryos in the uterus is not supported by empirical evidence. The bulk of the data indicate that interference with the reproductive process after fertilization has taken place is exceptional in the presence of a T-Cu or LNG-IUD and that the usual mechanism by which they prevent pregnancy in women is by preventing fertilization.

84. ESHRE Capri Workshop Group (May–June 2008). "Intrauterine devices and intrauterine systems". Human Reproduction Update. 14 (3): 197–208. doi:10.1093/humupd/dmn003. PMID 18400840. p. 199:

    Mechanisms of action
    Thus, both clinical and experimental evidence suggests that IUDs can prevent and disrupt implantation. It is unlikely, however, that this is the main IUD mode of action, … The best evidence indicates that in IUD users it is unusual for embryos to reach the uterus.
    In conclusion, IUDs may exert their contraceptive action at different levels. Potentially, they interfere with sperm function and transport within the uterus and tubes. It is difficult to determine whether fertilization of the oocyte is impaired by these compromised sperm. There is sufficient evidence to suggest that IUDs can prevent and disrupt implantation. The extent to which this interference contributes to its contraceptive action is unknown. The data are scanty and the political consequences of resolving this issue interfere with comprehensive research.
    p. 205:
    Summary
    IUDs that release copper or levonorgestrel are extremely effective contraceptives... Both copper IUDs and levonorgestrel releasing IUSs may interfere with implantation, although this may not be the primary mechanism of action. The devices also create barriers to sperm transport and fertilization, and sensitive assays detect hCG in less than 1% of cycles, indicating that significant prevention must occur before the stage of implantation.

85. Speroff L, Darney PD (2011). "Intrauterine contraception". A clinical guide for contraception (5th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 239–280. ISBN 978-1-60831-610-6. pp. 246–247:

    Mechanism of action
    The contraceptive action of all IUDs is mainly in the intrauterine cavity. Ovulation is not affected, and the IUD is not an abortifacient.^58–60 It is currently believed that the mechanism of action for IUDs is the production of an intrauterine environment that is spermicidal.
    Nonmedicated IUDs depend for contraception on the general reaction of the uterus to a foreign body. It is believed that this reaction, a sterile inflammatory response, produces tissue injury of a minor degree but sufficient enough to be spermicidal. Very few, if any, sperm reach the ovum in the fallopian tube.
    The progestin-releasing IUD adds the endometrial action of the progestin to the foreign body reaction. The endometrium becomes decidualized with atrophy of the glands.⁶⁵ The progestin IUD probably has two mechanisms of action: inhibition of implantation and inhibition of sperm capacite journal, penetration, and survival.

86. Jensen JT, Mishell Jr DR (2012). "Family planning: contraception, sterilization, and pregnancy termination.". In Lentz GM, Lobo RA, Gershenson DM, Katz VL (eds.). Comprehensive gynecology. Philadelphia: Mosby Elsevier. pp. 215–272. ISBN 978-0-323-06986-1. p. 259:

    Intrauterine devices
    Mechanisms of action
    The common belief that the usual mechanism of action of IUDs in women is destruction of embryos in the uterus is not supported by empirical evidence... Because concern over mechanism of action represents a barrier to acceptance of this important and highly effective method for some women and some clinicians, it is important to point out that there is no evidence to suggest that the mechanism of action of IUDs is abortifacient.
    The LNG-IUS, like the copper device, has a very low ectopic pregnancy rate. Therefore, fertilization does not occur and its main mechanism of action is also preconceptual. Less inflammation occurs within the uterus of LNG-IUS users, but the potent progestin effect thickens cervical mucus to impede sperm penetration and access to the upper genital track.

87. Sivin I, Stern J, Coutinho E, Mattos CE, el Mahgoub S, Diaz S, et al. (November 1991). "Prolonged intrauterine contraception: a seven-year randomized study of the levonorgestrel 20 mcg/day (LNg 20) and the Copper T380 Ag IUDS" (PDF). Contraception. 44 (5): 473–480. doi:10.1016/0010-7824(91)90149-a. PMID 1797462. (PDF) from the original on 22 November 2023. Retrieved 28 December 2023.
88. Guttinger A, Critchley HO (June 2007). "Endometrial effects of intrauterine levonorgestrel". Contraception. 75 (6 Suppl): S93–S98. doi:10.1016/j.contraception.2007.01.015. PMID 17531624.
89. ESHRE Capri Workshop Group (2008). "Intrauterine devices and intrauterine systems". Human Reproduction Update. 14 (3): 197–208. doi:10.1093/humupd/dmn003. PMID 18400840. Both copper IUDs and levonorgestrel releasing IUSs may interfere with implantation
90. Hatcher RA (2011). Contraceptive technology (20th rev. ed.). [New York, N.Y.]: Ardent Media. p. 162. ISBN 978-1-59708-004-0. Although the precise mechanism of action is not known, currently available IUCs work primarily by preventing sperm from fertilizing ova.26 IUCs are not abortifacients: they do not interrupt an implanted pregnancy.27 Pregnancy is prevented by a combination of the "foreign body effect" of the plastic or metal frame and the specific action of the medication (copper or levonorgestrel) that is released. Exposure to a foreign body causes a sterile inflammatory reaction in the intrauterine environment that is toxic to sperm and ova and impairs implantation.28,29 The production of cytotoxic peptides and activation of enzymes lead to inhibition of sperm motility, reduced sperm capacite journal and survival, and increased phagocytosis of sperm.30,31… The progestin in the LNg IUC enhances the contraceptive action of the device by thickening cervical mucus, suppressing the endometrium, and impairing sperm function. In addition, ovulation is often impaired as a result of systemic absorption of levonorgestrel
91. Malik S (January 2013). "Levonorgestrel-IUS system and endometrial manipulation". Journal of Mid-Life Health. 4 (1): 6–7. doi:10.4103/0976-7800.109625. PMC 3702070. PMID 23833526.
92. Alvarez F, Brache V, Fernandez E, Guerrero B, Guiloff E, Hess R, et al. (May 1988). "New insights on the mode of action of intrauterine contraceptive devices in women". Fertility and Sterility. 49 (5): 768–773. doi:10.1016/S0015-0282(16)59881-1. PMID 3360166.
93. Thiery M (March 1997). "Pioneers of the intrauterine device". The European Journal of Contraception & Reproductive Health Care. 2 (1): 15–23. doi:10.1080/13625189709049930. PMID 9678105.
94. Thiery M (June 2000). "Intrauterine contraception: from silver ring to intrauterine contraceptive implant". European Journal of Obstetrics, Gynecology, and Reproductive Biology. 90 (2): 145–152. doi:10.1016/s0301-2115(00)00262-1. PMID 10825633.
95. . Archived from the original on 13 August 2014.
96. Laitinen K. . businessfinland.fi. Archived from the original on 21 September 2021. Retrieved 21 September 2021.
97. "2009 Warning Letters and Untitled Letters to Pharmaceutical Companies". U.S. Food and Drug Administration. from the original on 18 June 2015. Retrieved 18 June 2015.
98. Bekiempis V (24 April 2014). "The Courtroom Controversy Behind Popular Contraceptive Mirena". Newsweek. from the original on 18 June 2015. Retrieved 18 June 2015.
99. Budusun S. . ABC Cleveland. Archived from the original on 18 June 2015. Retrieved 18 June 2015.
100. Colla C (21 May 2013). . ABC 15 Arizona. Archived from the original on 18 June 2015. Retrieved 18 June 2015.
101. Bekiempis V (24 April 2014). "The Courtroom Controversy Behind Popular Contraceptive Mirena". Newsweek. from the original on 15 November 2016. Retrieved 16 November 2016.
102. "Popular contraceptive device Mirena target of lawsuits in Canada, U.S". CTV. 21 May 2014. from the original on 26 October 2016. Retrieved 16 November 2016.
103. Blackstone H (31 May 2016). "When IUDs Go Terribly Wrong". Vice. from the original on 17 November 2016. Retrieved 16 November 2016.