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Levonorgestrel (LNG) is the most frequently used form of emergency contraception (EC) globally.[1] In its oral form, it is commonly taken within 120 hours of unprotected sex, and can be taken as a single dosage of 1.5 mg or as two doses of 0.75 mg taken 12 hours apart, although the former is recommended.[1] Under these conditions, levonorgestrel is estimated to decrease the chances of pregnancy by 57-93%.[1]


Method

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Production

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Levonorgestrel is produced directly from the compound methoxydienone [2]. Acetylene gas is passed through a saturated solution of potassium hydroxide creating a tetrahydrofuran solution[2]. Methoxydienone is dissolved in acetone then added drop-wise to the tetrahydrofuran solution and stirred to completion of the reaction[2]. Water is added to separate the organic layer that is formed, which is then removed and mixed with hydrochloric acid[2]. When the pH reaches 1, the solution is warmed and the levonorgestrel is obtained[2].

Functionality in the body

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The similar structure of Levonorgestrel (LNG) to progesterone allows LNG to mimics the effects of progesterone. LNG inhibits two main processes in the body: ovulation and fertilization.

  • LNG uses a negative feedback loop to inhibit ovulation, using the same feedback loop as progesterone. It does this by delaying or inhibiting the release of the hormone gonadotrophin, which is one of the main hormones responsible for regulating ovulation during the menstrual cycle[3]. The pituitary gland in the brain detects high levels of levonorgestrel, mimicking progesterone, and signals the hypothalamus to stop producing gonadotrophin, thus stopping ovulation[3]. During pregnancy, progesterone is naturally produced by the ovaries to inhibit ovulation. Increased concentrations of either LNG or progesterone signals the hypothalamus to inhibit signaling to the ovary to release an egg.
  • LNG thickens the cervical mucus to prevent sperm cells from entering the uterus. Progesterone thickens the cervical mucus to trap sperm cells in the uterus to increase the probability of fertilization.[4]

Varying studies find debatable evidence regarding if LNG can also prevent implantation. The Steroid Research Laboratory states that the administration of intrauterine LNG suppressed endometrial development. [5] The contribution of natural lack of implantation should not be excluded when considering if LNG directly correlates to the inhibition of implantation. [6]

Medical uses

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***Emergency birth control **Jasmine look over this and delete/edit if necessary**

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As part of the medication Plan B, levonorgestrel functions by preventing pregnancy at various points in the fertilization process. Levonorgestrel firstly stops ovulation from occurring, halting the release of an egg from the ovary that could potentially meet a sperm cell after intercourse.[7] If the drug is taken after ovulation has occurred, it can prevent fertilization.[7] If fertilization has already taken place, it can block implantation.[7] If Plan B is successful, each point in this process would effectively halt a pregnancy. However, if implantation occurs successfully, pregnancy may not be avoided.[7]

Controversy

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As a synthesized version of progesterone, levonorgestrel has been proven to work if taken like a standard birth control pill; small doses over a long period of time. It also has been proven to thicken the cervical mucus after several days, enough to prevent the sperm from penetrating the uterus. However, as Plan B is a one time, high dose meant for the morning after intercourse, there is little evidence for its effect in preventing pregnancy, as it is too late to prevent sperm from entering[8]. It is hard to determine if statistics of the Plan B pill and its ability to prevent pregnancy are simply due to personal biological reasons of the individual test subjects or the effectiveness of the drug[8].

Available Forms

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As a type of emergency contraception, levonorgestrel is used after unprotected intercourse to reduce the risk of pregnancy.[9] However, it can serve different hormonal purposes in its different methods of delivery. It is available for use in a variety of forms:

Pill

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Levonorgestrel can be taken orally in the form of an emergency contraceptive pill. The typical dosage is either 1.5 mg taken once, as suggested by the American College of Obstetricians and Gynecologists, or 0.75 mg taken 12-24 hours apart, as approved by the FDA.[10] The effectiveness of the drug is not affected by choosing one regimen over the other.[10] The most widely used form of oral emergency contraception is the progestin-only pill, which contains a 1.5 mg dosage of levonorgestrel.[9] Levonorgestrel-only emergency contraceptive pills are reported to have an 89% effectiveness rate if taken within the recommended 72 hours after sex.[11] The efficacy of the drug decreases by 50% for each 12 hour delay in taking the dose once the emergency contraceptive regimen has been started.[11]

Patch

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Levonorgestrel in the form of a patch is generally used for hormone replacement therapy in post-menstrual women, treating symptoms such as osteoporosis or hot flashes.[12] It is commonly paired with the hormone estradiol in a estradiol/levonorgestrel transdermal system.[12] These patches typically release about 0.045 mg of estradiol and 0.015 mg of levonorgestrel in a 24-hour period.[13] While studies have shown that increasing the proportion of levonorgestrel does not affect the amount or advantages of estradiol release, the simultaneous delivery of a progestogen such as levonorgestrel is necessary for the protection of the endometrium.[13][14][15] The estradiol/levonorgestrel transdermal patch has been found to be effective in combating symptoms of menopause, namely decreasing vasomotor symptoms and increasing bone mineral density.[14][16]

Intrauterine Device

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The levonorgestrel intrauterine system (LNG-IUS) is a type of long-term birth control that releases the progestin into the uterine cavity.[17][18] Levonorgestrel is released at a constant, gradual rate of 0.02 mg per day by the polydimethylsiloxane membrane of the device, which renders it effective for up to 5 years.[17] The mechanism of LNG-IUD is primarily preconceptual—it inhibits sperm transport, uterine lining development, and implantation.[19] Because it is inserted directly into the uterus, levonorgestrel is present in the endometrium in much higher concentrations that would result from a LNG-containing oral pill; the LNG-IUS delivers 391 ng of levonorgestrel to the inner uterine region while a comparable oral contraceptive delivers only 1.35 ng.[17] This high level of levonorgestrel impedes the function of the endometrium, making it hostile for sperm transport, fertilization, and implantation of an ovum.[17] The LNG-IUS also triggers the activity of glycodelin A (GdA), a glycoprotein found in the uterus that has natural contraceptive behavior, as it interferes with the bonding of the egg and sperm.[19]

Implant

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Levonorgestrel is used in silastic implants as a long-term contraceptive regimen. It releases a constant 0.03 mg of levonorgestrel per day, and sustains a large amount of the original drug content years after the implant is first inserted.[20] Users of this type of implant report irregularities and aggravated symptoms of their menstrual cycle more then users of the levonorgestrel oral pills, however, these effects are mostly characteristic of the first year of implant use.[20][21] The LNG implant is notably effective due to prolonged compliance by users, and fertility is promptly restored following the removal of the implant.[20][22]

Chemistry

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See also: List of progestogens, List of androgens/anabolic steroids, and Norgestrel

** Levonorgestrel, also known as 17α-ethynyl-18-methyl-19-nortestosterone or as 17α-ethynyl-18-methylestr-4-en-17β-ol-3-one, is a syntheticestrane steroid and a derivative of testosterone.[42][43] It is the C13β or levorotatory stereoisomer and enantiopure form of norgestrel, the C13α or dextrorotatory isomer being inactive.[44][45] Levonorgestrel is more specifically a derivative of norethisterone (17α-ethynyl-19-nortestosterone) and is the parent compound of the gonane (18-methylestrane) subgroup of the 19-nortestosterone family of progestins.[46] Levonorgestrel acetate and levonorgestrel butanoate are C17β esters of levonorgestrel.[47][48] It has a molecular weight of 312.45 g/mol and LogP=3.8. **

Reaction Mechanism

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  1. ^ a b c "ScienceDirect". www.sciencedirect.com. Retrieved 2019-05-13.
  2. ^ a b c d e Wong, Fung Fuh; et al. "Synthesis process of levonorgestrel by methoxydienone". Google Patents (in Chinese). Retrieved 15 May 2019.
  3. ^ a b Shaw, N. D.; Histed, S. N.; Srouji, S. S.; Yang, J.; Lee, H.; Hall, J. E. (2010-4). "Estrogen Negative Feedback on Gonadotropin Secretion: Evidence for a Direct Pituitary Effect in Women". The Journal of Clinical Endocrinology and Metabolism. 95 (4): 1955–1961. doi:10.1210/jc.2009-2108. ISSN 0021-972X. PMC 2853991. PMID 20133465. {{cite journal}}: Check date values in: |date= (help)
  4. ^ Peck, Rebecca; Rella, Walter; Tudela, Julio; Aznar, Justo; Mozzanega, Bruno (2016-2). "Does levonorgestrel emergency contraceptive have a post-fertilization effect? A review of its mechanism of action". The Linacre Quarterly. 83 (1): 35–51. doi:10.1179/2050854915Y.0000000011. ISSN 0024-3639. PMC 5102184. PMID 27833181. {{cite journal}}: Check date values in: |date= (help)
  5. ^ Reima, I.; Lehtonen, E.; Lähteenmäki, P.; Pakarinen, P. I. (1998-07-01). "The ultrastructure of human endometrium is altered by administration of intrauterine levonorgestrel". Human Reproduction. 13 (7): 1846–1853. doi:10.1093/humrep/13.7.1846. ISSN 0268-1161. PMID 9740437.
  6. ^ Trussel, James (2006). "Mechanism of action of emergency contraceptive pills" (PDF). Elsevier. 74: 87–89.
  7. ^ a b c d Research, Center for Drug Evaluation and (2018-11-03). "FDA's Decision Regarding Plan B: Questions and Answers". FDA.
  8. ^ a b Kahlenborn, Chris; Peck, Rebecca; Severs, Walter B. (2015-2). "Mechanism of action of levonorgestrel emergency contraception". The Linacre Quarterly. 82 (1): 18–33. doi:10.1179/2050854914Y.0000000026. ISSN 0024-3639. PMC 4313438. PMID 25698840. {{cite journal}}: Check date values in: |date= (help)
  9. ^ a b "Emergency Contraception - ACOG". www.acog.org. Retrieved 2019-05-13.
  10. ^ a b Hansen, Laura B.; Saseen, Joseph J.; Teal, Stephanie B. (2007-2). "Levonorgestrel-only dosing strategies for emergency contraception". Pharmacotherapy. 27 (2): 278–284. doi:10.1592/phco.27.2.278. ISSN 0277-0008. PMID 17253917. S2CID 24229915. {{cite journal}}: Check date values in: |date= (help)
  11. ^ a b Shohel, Mohammad; Rahman, Mohammad Mahfuzur; Zaman, Asif; Uddin, Mir Muhammad Nasir; Al-Amin, Md Mamun; Reza, Hasan Mahmud (2014-04-04). "A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception". BMC Women's Health. 14: 54. doi:10.1186/1472-6874-14-54. ISSN 1472-6874. PMC 3977662. PMID 24708837.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ a b "Estradiol And Levonorgestrel (Transdermal Route) Description and Brand Names - Mayo Clinic". www.mayoclinic.org. Retrieved 2019-05-31.
  13. ^ a b "Climara Pro® (Estradiol/Levonorgestrel Transdermal System)" (PDF). Food and Drug Administration.
  14. ^ a b von Holst, Thomas; Salbach, Birgitt (2002-03-25). "Efficacy of a new 7-day transdermal sequential estradiol/levonorgestrel patch in women". Maturitas. 41 (3): 231–242. doi:10.1016/S0378-5122(01)00297-3. ISSN 0378-5122. PMID 11886769.
  15. ^ Mueck, Alfred O.; Römer, Thomas (2018-07-31). "Choice of progestogen for endometrial protection in combination with transdermal estradiol in menopausal women". Hormone Molecular Biology and Clinical Investigation. 37 (2). doi:10.1515/hmbci-2018-0033. ISSN 1868-1891. PMID 30063464. S2CID 51886877.
  16. ^ Warming, L.; Ravn, P.; Christiansen, C. (2005-02-14). "Levonorgestrel and 17β-estradiol given transdermally for the prevention of postmenopausal osteoporosis". Maturitas. 50 (2): 78–85. doi:10.1016/j.maturitas.2004.03.016. ISSN 0378-5122. PMID 15653003.
  17. ^ a b c d Jensen, Jeffrey T. (2005-9). "Contraceptive and Therapeutic Effects of the Levonorgestrel Intrauterine System: An Overview". Obstetrical & Gynecological Survey. 60 (9): 604–612. doi:10.1097/01.ogx.0000175805.90122.af. ISSN 0029-7828. PMID 16121115. S2CID 43177026. {{cite journal}}: Check date values in: |date= (help)
  18. ^ Bao, Quanying; Gu, Bing; Price, Claire F.; Zou, Yuan; Wang, Yan; Kozak, Darby; Choi, Stephanie; Burgess, Diane J. (2018-10-25). "Manufacturing and characterization of long-acting levonorgestrel intrauterine systems". International Journal of Pharmaceutics. 550 (1): 447–454. doi:10.1016/j.ijpharm.2018.09.004. ISSN 0378-5173. PMC 6622171. PMID 30195080.
  19. ^ a b Seppälä, M.; Affandi, B.; Koistinen, R.; Koistinen, H.; Mandelin, E. (1997-12-01). "Levonorgestrel-releasing intrauterine device-wearing women express contraceptive glycodelin A in endometrium during midcycle: another contraceptive mechanism?". Human Reproduction. 12 (12): 2671–2675. doi:10.1093/humrep/12.12.2671. ISSN 0268-1161. PMID 9455833.
  20. ^ a b c Diaz, S.; Pavez, M.; Miranda, P.; Robertson, D. N.; Sivin, I.; Croxatto, H. B. (1982-05-01). "A five-year clinical trial of levonorgestrel silastic implants (Norplant™)". Contraception. 25 (5): 447–456. doi:10.1016/0010-7824(82)90033-6. ISSN 0010-7824. PMID 6809423.
  21. ^ Berenson, Abbey B.; Wiemann, Constance M. (1995-04-01). "Use of levonorgestrel implants versus oral contraceptives in adolescence: A case-control study". American Journal of Obstetrics and Gynecology. 172 (4, Part 1): 1128–1137. doi:10.1016/0002-9378(95)91471-4. ISSN 0002-9378. PMID 7726249.
  22. ^ Polaneczky, Margaret; Slap, Gail; Forke, Christine; Rappaport, Aviva; Sondheimer, Steven (1994-11-03). "The Use of Levonorgestrel Implants (Norplant) for Contraception in Adolescent Mothers". New England Journal of Medicine. 331 (18): 1201–1206. doi:10.1056/NEJM199411033311806. ISSN 0028-4793. PMID 7935659.
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