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• October, 2009 •

Endometrial progesterone receptors and Levonorgestrel as emergency contraceptive

Alberto Palomino M.D. and Luigi Devoto M.D.
Institute for Maternal and Child Research, University of Chile, School of Medicine, Santiago Chile.

Levonorgestrel as an emergency contraceptive (LNG-EC) is used world –wide with clinical success. For maximal effectiveness it should be administered within 72 hrs after unprotected intercourse. A single dose of 1.5 mg of Levonorgestrel or divided 12 hrs apart effectively prevents an undesired pregnancy. Investigations on the mechanisms of action have clearly revealed that LNG-EC administration during early-mid proliferative phase inhibits or delays the ovulation process, while none endometrial morphological alterations are observed if the drug is administered during the periovulatory stage or early luteal phase.

Since the maximal fertility period encompasses a narrow period including the five days before ovulation and the day of ovulation itself, it is interesting to elucidate whether the administration of LNG-EC during the LH surge is capable to inhibit  ovulation, the corpus luteum  production of steroids or endometrial morphology and molecular features of the receptive endometrium.

The endometrium is receptive to embryo attachment during the implantation window, a defined period of luteal phase that encompasses days 20-24 of the menstrual cycle. In preparation for the maternal-embryo dialogue and subsequent successful implantation, the endometrium undergoes morphological, biochemical and molecular changes driven by ovarian steroids and local factors.

Progesterone, the main hormone produced by the corpus luteum, regulates the expression of endometrial genes and proteins,  that are associated to endometrial receptivity including cytokines, grow factors and cell attachment molecules.

It is thought that progesterone has an effect on endometrium mainly through its cognate receptor signaling acting on genes bearing DNA response elements to progesterone or on stromal compartment through local factors like cytokines and grow factors.
The expression of endometrial progesterone receptor is regulated by estradiol and progesterone and is localized in epithelial and stroma endometrial cells and appears to be critical for the establishment of endometrial receptiveness. The down-regulation of epithelial endometrial progesterone receptor and its persistence in the stroma compartment  is a characteristic of all mammalian endometrium during the implantation period.

Levonorgestrel is a synthetic progestin  used in gynecologic clinical practice with different forms of administration including contraceptive pills, IUD-delivering Levonorgestrel and long-acting subdermal implants. A common side effect reported is the unscheduled vaginal bleeding that is associated with atrophic endometrium, changes of VEGF expression and disruption of progesterone receptor expression.

To test the hypothesis that LNG-EC administered on the day of LH surge may alter the expression of endometrial progesterone receptor and endometrial receptivity biomarkers, we conducted a randomized prospective trial to compare the effect of LNG-EC in treated and non-treated subjects previously sterilized by tubal ligation.

Our study demonstrated that neither ovulation nor progesterone production by the corpus luteum and endometrial progesterone receptor expression were effected by LNG-EC.

Moreover, the critical epithelial endometrial progesterone receptor  down-regulation as well as the expression of selected endometrial receptivity biomarkers, including Glycodelin-A avb3 integrin and L-selectin ligand, were not different between control subjects than those treated with LNGEC.

The effect of Levonorgestrel on endometrial progesterone receptor appears to be related to the pharmacokinetics of different modes of administration. Indeed, we  demonstrated that tissue concentration of Levonorgestrel in LNG-EC is 100 times lower than in IUD-delivering LNG.
It is thought that failures of LNG-EC in preventing  pregnancy occur primarily when the unprotected intercourse takes place in the peri-ovulatory period.

Thus the contraceptive mechanism of LNG-EC during the peri-ovulatory stage remains elusive. However, our recent in-vivo investigation demonstrated that it does not  affect the corpus luteum function or the alteration of progesterone receptor or endometrial receptivity biomarkers, indicating that the molecules involved in embryo implantation are not impaired.

References

  1. Hansen LB, Sassen JJ, Teal SB. Levonorgestrel-only dosing strategies for emergency contraception. Pharmacotherapy 2007 27 (2): 278
  2. Croxatto HB, Ortiz ME, Müller AL. Mechanisms of action of emergency contraception Steroids. 2003; 68 (10-13): 1095-8.
  3. Durand M, Del Carmen Cravioto M, Raymond EG, Durán-Sánchez O, De Cruz-Hinojosa M, Castell-Rodríguez A, Schiavon R, Larrea F. On the mechanisms of action of short-term Levonorgestrel administration in emergency contraception. Contraception 2001; 64(4): 227- 34.
  4. Lessey BA. The role of endometrium during embryo implantation. Human Reproduction 2000 15;6:39-50
  5. Giudice L Potential biochemical markers of uterine receptivity Human Reproduction 1999 14; 2: 3-16
  6. Lessey BA. Two pathways of progesterone action in the human endometrium: implications for implantation and contraception. Steroids. 2003; 68(10-13): 809-15.
  7. Lessey BA, Yeh I, Castelbaum AJ, Fritz MA, Ilesanmi AO, Korzeniowski P, Sun J, Chwalisz K. Endometrial progesterone receptors and markers of uterine receptivity in the window of implantation. Fertil Steril 1996; 65(3): 477-83.
  8. Guttinger A, Critchley HO. Endometrial effects of intrauterine Levonorgestrel. Contraception 2007; 75(6): S93-8.
  9. PalominoWA, Kohen P, Devoto L. Levonorgestrel as an emergency contraceptive does not disrupt the expression of the L-selectin ligand or molecular markers of endometrial receptivity. Fertility and Sterility 2009 In process of publication.
  10. Devoto L, Fuentes A, Palomino A, Espinoza A, Kohen P, Ranta S, von Hertzen H. Pharmacokinetics and endometrial tissue levels of Levonorgestrel after administration of a single 1.5-mg dose by the oral and vaginal route. Fertil Steril. 2005; 84(1): 46-51

Three questions to the editorial’s Authors

  1. What is the effectiveness of steroids as emergency contraception?

    The effectiveness of emergency contraception depends on the pharmacological regimen used. Clinical effectiveness trials have found that LNG-EC is more effective than the Yuzpe regimen ( Contraceptive pills of Ethinyl estradiol (100ug) and LNG (0.5 mg) with additional minor effects . The present effectiveness of LNG has been estimated between 59% and 95% under different delays of administration. However, it is important to note that its effectiveness is probably overestimated due to the absence of clinical trials with a placebo control group ( ethical reasons prevent such study).

  2. What is the mechanism of action of LNG-EC?

    Animals and human studies have found effects on ovulatory processes but not significant effects after ovulation. In human, physiological studies have consistently demonstrated that LNG-EC inhibits, delays, or modifies hormone profiles associated with ovulation resulting in ovulation disruption. The luteal phase studies do not support luteal phase defects and our recent investigations have not found modifications in endometrial progesterone receptor and endometrial receptivity biomarkers. Deleterious effects on human spermatozoa were not demonstrated in vivo or in vitro for LNG concentrations as used in EC.

  3. What is the indication for LNG-EC to be effective?

    It should be administered within 72 hrs of unprotected intercourse. Its effectiveness is related to the time of intercourse within the menstrual cycle and to the interval of pill administration after the unprotected intercourse. In general it is effective only in ~85% of the cases.

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