Levonorgestrel-IUS system and endometrial manipulation.

Progesterone is the established hormone to treat anovulatory conditions. It is known that continuous administration of progesterone both orally or parenterally corrects menstrual irregularity, decreases the menstrual blood loss and can also act as a contraceptive. This versatility in its action is due to the ability of the hormone to act on the reproductive tract, primarily the uterus. Various progestogens have been synthetically prepared in order to reduce the side-effects and to be effective.[12] Levonorgestrel (LNG) is a second generation 19-nortestosterone derivative which was isolated in the 60’s from its parent progestin norgestrel and started being used effectively in many indications.[3] With the discovery of the uterine first pass mechanism[4] progesterone started to being used successfully through the vaginal route. This enhanced delivery of the drug was found to be a good method to manipulate the endometrium towards implantation or contraception whenever required. It was presumed that delivering progesterone locally within the uterine cavity could further remove the problem of hormonal side-effects as well as could be more effective in contraception as well. This led to the development of a progesterone loaded intra uterine device called Progestasert[5] in order to quieten the uterus and decrease the expulsion rate that was seen in the Cu intrauterine device (IUD's). Although this was a good contraceptive, it had to be replaced each year. Soon Luukkainen developed a device which could deliver progesterone continuously into the uterus in low doses over years. This was the birth of the Levonorgestrel -Intrauterine system (LNG – IUS) that was taken up by Bayer Schering and popularized and named Mirena.[6]

The IUD resembles the Cu IUD in shape but contains a mixture of 52 g of LNG and polydimethyl siloxane (PDMS) surrounded by a rate controlling PDMS capsule.[6] This allows a steady delivery of 20 μg of LNG/day with very few systemic side-effects. There is a rapid absorption of the drug from the uterine cavity via the capillaries in the basal layer of the endometrium into the circulation. LNG can be detected in the plasma within a few hours of insertion. However, these levels plateau within a month and fall to 11 μg/day at the end of 5 years. The levels of LNG in the endometrium are 1000 times higher than what are seen in progesterone implants and this is what is responsible for the unique effects of the device.[7]

LNG is a very potent 19-nortestosterone derivative that functions well at low doses. This makes it the perfect choice for a small IUD and the highly progestogenic features of this molecule make it a good contraceptive and therapeutic agent. It causes changes within the uterine milieu effectively. Hence, this system is used effectively in many other conditions where manipulation of the endometrium is required and where fertility is not an immediate issue. The changes in the endometrium are dose related and time bound. Elaborate studies on the endometrium using LNG for a period of 1-6 months[8] have shown a strong suppression and atrophy of the glandular endometrium with the stroma becoming swollen and decidualized the mucosa thins out and the epithelium becomes inactive. In the 1st month itself following LNG-IUS insertion steroid receptor content is significantly decreased in all cells,[9] resulting in the altered expression of many locally acting mediators.[10] The vascular system[11] is also affected leading to absence of spiral artery formation and presence of large dilated blood vessels. Scanning electron microscope studies have shown complete absence of microstructures like the pinapodes[12] thus rendering the endometrium bald. This transformation of the endometruim is incompatible with pregnancy and this is what makes the system effective as a contraceptive. Prolonged use over years reverses the hyperestrogenic state and this effect is utilized in treating hyperplasias of the endometrium. However, the exact dose and duration of treatment are still not known for this indication.[13] Moreover, a complete regression can only be seen if the entire uterus is examined histologically on hysterectomy, but then the purpose of non-surgical treatment is no doubt defeated. However, in a study where patients underwent hysterectomy due to failure of response, it was seen that the uterus did contain lesions like polyps, fibroids or hyperplasia even after IUD insertion.[14]

There are some perplexing areas as far as the action of this system is concerned. One of the most vexing problems is break through bleeding (BTB) and a common reason for discontinuation of LNG-IUS use. Although no single factor has been identified to account for this breakthrough bleeding, it has been hypothesized that it may be due to the intense modulation of the endometrium by high levels of progesterone[15] locally within the endometrium and as a treatment, anti-progestins have been suggested to be given intermittently, which may correct the relative deficiency of estradiol in these patients.

Yet another area where LNG-IUS is effective is the reduction of pain in endometriosis. But why does LNG reduce the pain of endometriosis? It is known that the device leads to atrophy in the uterine endometrium but what of the ectopic endometrium?[16] This could only happen if there was either suppression of ovulation (which does not happen) or high levels of LNG in the peritoneal cavity to bring this about. A small study reported high peritoneal levels of LNG after 6 months of use in patients of endometriosis.[17] A Cochrane review of 2006 also suggested that LNG reduces the postoperative recurrent dysmenorrohoea in patients of endometriosis[16] due to a similar reason but the exact pathway of action still eludes us.

The device is therefore ideal for most of the conditions of estrogen excess. It is also comfortable to the patient who wants contraception but wishes her fertility to return soon after its removal. Fertility is known not only to return but also enhanced when it is used to treat conditions like hyperplasia. LNG-IUS has been effectively used in ART patients with abnormal endometium before taking them up for IVF.[1819]

LNG-IUS is no doubt a very efficient tool for treating many disorders where endometrial manipulation is required but much still needs to be discovered regarding the mechanisms involved in suppression of the menstruation, BTB episodes and the local endometrial environment with uterine LNG administration.