Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:

1. Explain the mechanism of action of the levonorgestrel intrauterine device to noncontraceptive clinical situations.

2. Identify the noncontraceptive indications for which the levonorgestrel intrauterine device can be used.

3. Summarize evidence-based recommendations for counseling patients on the effectiveness of the levonorgestrel intrauterine device in noncontraceptive indications.

Before the 20th century, there were no clear data with regard to use of intrauterine devices (IUDs) for contraception or for other indications in humans. Dr. Richard Richter from Germany first documented the use of silk worm gut rings in the uterus to prevent pregnancy in 1909. After this, Dr. Ernst Grafenberg developed the "silver ring," a spiral wound circular nonhormonal IUD made of silk suture and wrapped in silver wire in 1928. Development of the contraceptive copper IUD in the 1960s occurred after copper was found to have spermicidal effects. The levonorgestrel IUD (LNG-IUD) was developed in the 1970s after research by Dr. Antonio Scommegna demonstrated intrauterine progesterone could induce endometrial atrophy. This concept was used by Dr. Jouni Valter Tapani Luukkainen to develop Progestasert, the first hormone-containing IUD, marketed in 1976, which was effective for 1 year. Progestasert resembled modern-day IUDs; it was T-shaped and made with polydimethylsiloxane (PDMS) coated with progesterone to allow for slow/controlled release of hormone. The natural hormone progesterone was later replaced with levonorgestrel (LNG), a synthetic progestin with more potent progesterone receptor (PR) agonistic effects that lasted for 5 years. This device is now known as Mirena (LNG-20).1

At the time of writing, there are 4 types of LNG-IUDs currently available in the United States: Mirena (LNG-20) and Liletta (LNG-18.6) both containing 52 mg of LNG and releasing 20 and 18.6 [mu]g of LNG per day, respectively, Kyleena (LNG-19.5) containing 19.5 mg of LNG and releasing 17.5 [mu]g per day, and Skyla (LNG-13.5) releasing 14 [mu]g of LNG per day. Different amounts of LNG release per day (14-20 [mu]g) correspond to duration effectiveness for contraception (3-8 years).

According to 2019 UN data, the IUD is the second most used form of contraceptive in the world (17%) after female sterilization (24%). The use of IUDs varies by region and type of IUDs. In Eastern and Southeast Asia, the IUD is the most common form of contraceptive used.2 In Europe and North America, the IUD is less commonly used for contraception, with oral contraceptives and condoms the most used. Copper IUDs are more commonly used globally compared with LNG-IUDs for contraception.3 The use of LNG-IUDs for noncontraceptive purposes is less well understood.

Mechanism of Action

The LNG-IUD is made of PDMS coated with LNG to allow for a controlled release of LNG. There are 2 major mechanisms by which LNG-IUDs provide contraceptive action: (1) alteration of the consistency of cervical mucus and (2) alteration of the endometrium. The primary hormone, LNG, is a type of synthetic progestin and acts as a PR agonist in the endometrium. Activation of the PR in the endometrium induces atrophy of the endometrial lining. Furthermore, progestin acts to change cervical mucus to become thicker and less penetrable to sperm.

Estrogen-containing contraceptives have been widely used to treat many noncontraceptive gynecologic conditions that affect people with uteri; however, many patients may be ineligible for estrogen-containing therapy secondary to its contraindications. In addition, the efficacy of estrogen-containing therapies is often user-dependent. The LNG-IUD presents a non-estrogen-containing option for treatment of gynecologic conditions that is long-acting and user-independent after initial insertion.

Noncontraceptive Uses of the LNG-IUD

Abnormal Uterine Bleeding

Abnormal uterine bleeding (AUB) refers to variations in amount and frequency of uterine bleeding patterns beyond the average 5 to 7 days of menstrual flow occurring every 21 to 35 days in nonpregnant uterus-bearing individuals who have passed menarche. The Federation of Gynecology and Obstetrics (FIGO) developed the acronym PALM-COEIN to refer to the most common structural and nonstructural causes of AUB including polyps, adenomyosis, leiomyomas, malignancy, coagulopathy, ovulatory dysfunction, endometrial, iatrogenic, and otherwise not classified. The LNG-IUD is commonly used as a treatment option for AUB; however, its use specifically for each cause varies. This section reviews the use of LNG-IUDs in PALM-COEIN categories.

Polyps

Endometrial polyps are hyperplastic growths of endometrial glands and stroma. The majority of endometrial polyps are benign, although in certain patient populations such as postmenopausal patients, tamoxifen users, and patients with hereditary cancer syndromes, the incidence of malignancy is slightly higher. Endometrial polyps can be found incidentally or can be symptomatic. AUB, especially intermenstrual bleeding, is the most common presentation of symptomatic endometrial polyps. Some patients with endometrial polyps can experience heavier bleeding at regular menstrual intervals. Evidence of the use of the LNG-IUD for treatment of endometrial polyps is very limited. On review of the literature there was 1 case-control study of 39 patients comparing the LNG-IUD to expectant management for endometrial polyps diagnosed via hysteroscopy.4 The study demonstrated the potential for regression of endometrial polyps in participants who had the LNG-IUD inserted, hence suggesting the potential for the LNG-IUD in treatment of AUB caused by endometrial polyps.

Adenomyosis

Adenomyosis is a condition where endometrial glands and stroma are present within the myometrium. Adenomyosis can cause heavy menstruation, dysmenorrhea, and uterine enlargement. A systematic review and meta-analysis of 10 prospective studies demonstrated that the LNG-IUD has the potential to improve pain scores, bleeding volume, and uterine size for people with adenomyosis.5 A randomized controlled trial (RCT) of 62 patients compared the effectiveness of the LNG-IUD to a low-dose combined oral contraceptive (COC) in treatment of adenomyosis-related pain and bleeding. The study demonstrated that participants in both groups experienced a decrease in pain and bleeding, but the reduction was greater in the LNG-IUD group compared with the COC group.6

Hysterectomy has long been considered the definitive treatment for adenomyosis. However, in another RCT comparing the LNG-IUD and hysterectomy, participants in both groups demonstrated comparable improvement in hemoglobin levels at 6 months and 1 year after treatment.7 In addition, although both groups demonstrated overall improvement in quality of life, the LNG-IUD group seemed to perform better in the psychological and social aspects of quality of life measures. Another study that followed patients with adenomyosis who had the LNG-IUD for at least 5 years demonstrated the positive effects of the LNG-IUD in decreasing dysmenorrhea and menorrhagia. This proved to be a persistent benefit that only started to plateau after 6 years.8 Overall, the available data do suggest that the LNG-IUD is a promising option for treating adenomyosis, although the data on effectiveness are still limited.

Leiomyomata

Leiomyomata, or uterine fibroids, are the most common type of uterine tumor, with prevalence in about 70% of people with uteri worldwide. Fibroids can be associated with heavy menstrual bleeding and bulk symptoms, and thus have a significant impact on quality of life, particularly for people of color and/or of lower socioeconomic status.9 In addition to surgical management, fibroids have typically been managed with medical or interventional therapy such as uterine artery embolization. A Cochrane review of 4 studies in 2020 evaluated the effectiveness of progesterone or progestin-releasing IUDs in treatment of fibroids. Results were limited to the available studies and demonstrated comparable effects of the LNG-IUD on bleeding pattern and fibroid size as compared with COCs.10 When compared with oral progestins, the LNG-IUD was demonstrated to reduce bleeding at 6 months among people with fibroids.11 Based on the data available, LNG-IUDs are likely effective for AUB as it relates to fibroids; however, its impact on fibroid size and bulk-related symptoms is not as clear.

Malignancy

Endometrial cancer and endometrial hyperplasia are malignant and malignancy precursor causes of AUB in people with uteri. The mainstay of treatment for endometrial cancer is surgical management with total hysterectomy and surgical staging. For endometrial hyperplasia, hysterectomy is a definitive surgical management, although nonsurgical options can be acceptable if close follow-up can be guaranteed. For some patients, surgical management might not be the most desired option for various reasons, such as patients who are not optimal surgical candidates or who desire future fertility. For those patients, nonsurgical options, mainly with progesterone therapies have been explored, although guidelines and evidence are clearer for endometrial hyperplasia compared with endometrial cancer. Oral high-dose medroxyprogesterone acetate and megestrol acetate are the most common progestin therapies used. The LNG-IUD seems to be an emerging option for progesterone delivery, with increasing evidence to demonstrate its effectiveness, especially in causing regression of endometrial hyperplasia. Additionally, long-term use of the LNG-IUD generally seems better tolerated than oral progestin use for similar periods. A systematic review and meta-analysis of 24 observation studies and 1001 people with uteri demonstrated that the LNG-IUD achieved a higher pooled regression rate compared with oral progestins for complex (92% vs 66%, P < 0.01) and atypical hyperplasia (90% vs. 69%, P = 0.03).12 Another study of current evidence of fertility-sparing treatment for endometrial cancer and endometrial hyperplasia demonstrated a complete response of 79% for the LNG-IUD compared with 75% for oral progestins, and recurrence rate actually lower in the LNG-IUD of 11% compared with 33% for oral progestins.13

Coagulopathy and Iatrogenic

Several types of coagulopathies including von Willebrand disease, immune thrombocytopenia (ITP), and iatrogenic medically indicated anticoagulated patients can predispose to AUB. The LNG-IUD has been demonstrated to be effective in reducing uterine bleeding among these patients as well; however, limited data are available. A cross-sectional study among people with uteri with ITP who used LNG-IUDs and those who did not found LNG-IUD users to have a significantly lower bleeding score and fatigue on the pictorial bleeding assessment calendar score and the menorrhagia multiattribute scale.14 A prospective observational case series by Vilos et al15 in 2009 demonstrated that in a population of obese premenopausal people with AUB receiving warfarin therapy, the LNG-IUD was effective at improving the bleeding profile in 70% of those patients. However, large systematic reviews have not been carried out to assess the effectiveness of LNG-IUDs on various types of coagulopathies.

Ovulatory Dysfunction

There is a scarcity of data regarding the impacts of the LNG-IUD on ovulatory dysfunction including polycystic ovarian syndrome (PCOS). Research on the systemic hormonal impact of LNG-IUDs has demonstrated that they can suppress ovulation in some individuals, but this is not their primary mechanism of action. A small study of 7 individuals using the LNG-IUD assessed plasma hormone levels of follicle-stimulating hormone, luteinizing hormone, and LNG and whether ovulation occurred. This revealed that during the first 3 months of IUD use, 2 out of 7 people ovulated, and the plasma level of LNG was elevated. After 1 year however, plasma LNG levels decreased, and 5 out of 7 ovulated.16 More research is needed to understand whether LNG-IUDs can regulate ovulation. However, given that many people with PCOS suffer from irregular and heavy menstrual bleeding, the menstrual effects of ovulatory dysfunction may be mitigated with the use of IUDs due to its effect on the endometrium.

Endometriosis

Endometriosis is caused by endometrial glands and stroma that grow outside of the endometrial cavity. Endometriosis can cause chronic pelvic pain (CPP), fertility problems, and increased risk of psychologic diseases due to the burden of its symptoms. Endometriotic lesions are mostly found in the pelvis; however, they can also be found in distant sites such as the bowel, diaphragm, or pleural cavity. Endometriotic lesions are thought to be estrogen-dependent. Overall, use of the LNG-IUD demonstrates comparable symptomatic control effects for endometriosis when compared with gonadotropin-releasing hormone (GnRH) analogs, nonsteroidal anti-inflammatories such as naproxen, or progestins such as depot medroxyprogesterone acetate.

A Cochrane review included 2 RCTs comparing the LNG-IUD and expectant management and demonstrated moderate evidence that the LNG-IUD brought improvement in pain symptoms in patients with endometriosis.17 Another RCT compared the effectiveness of the LNG-IUD versus naproxen acetate for treatment of pain. Participants in both groups experienced decrease in pain symptoms. LNG-IUD users continued to experience decrease in mean pain scores between the first and sixth months of use, whereas the mean pain scores among naproxen users did not change.18 An RCT comparing the LNG-IUD and a GnRH analog demonstrated no improvement in CPP symptoms in both groups and no significant difference between the groups, although the IUD group reported a higher bleeding score.19 Regardless, there was no difference in quality-of-life assessment between the groups at 6 months. A 3-year follow-up of this study demonstrated encouraging continuation of IUD use at 3 years (59%) and, of those patients, 82.6% had pain scores between 0 and 3.19 The main treatment for endometriosis has been ovarian suppression; however, this is not a main mechanism of action of the LNG-IUD. It is theorized that the presence of LNG in the peritoneal fluid could directly suppress the endometriosis implants.20

Primary Dysmenorrhea

Primary dysmenorrhea is the presence of cramping lower abdominopelvic pain that occurs during menses without evidence of a specific cause such as those described. The pathophysiology of primary dysmenorrhea is thought to be secondary to increased amounts of prostaglandins during menses as a result of endometrial sloughing, causing rhythmic uterine contractions. Theoretically, the LNG-IUD would be a good option for managing primary dysmenorrhea, as its mechanism of action includes endometrial atrophy, resulting in less endometrial sloughing, and therefore less prostaglandin production and dysmenorrhea. Primary dysmenorrhea is a diagnosis of exclusion. As a result, there are not many studies that directly look at treatment options for primary dysmenorrhea.

Other Pelvic Pain

There is no consensus on the definition of CPP. It is generally described as constant or intermittent, noncyclic pain in the pelvic area that has persisted for 3 to 6 months. The use of the LNG-IUD in CPP caused by identifiable causes such as leiomyomata or endometriosis is addressed in other sections in this article. The nature of CPP is complicated; as such, it is understandably challenging to assess the effectiveness of the LNG-IUD in treatment of CPP.21 There is currently no available data on the use of the LNG-IUD for treatment of CPP without identifiable cause.

Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder (PMDD) is a constellation of cyclic behavioral, psychological, and physical symptoms that are associated with the menstrual cycle, causing significant interference with a patient's life. These symptoms usually start in the luteal phase of the menstrual cycle and ease once menstruation begins. The symptoms of PMDD are thought to be caused by hormonal changes during the menstrual cycle. As such, patients diagnosed with PMDD who desire contraception are usually offered combined contraceptives as the first-line treatment, as combined estrogen-progestin formulations suppress the cyclic variation of ovarian hormones.

There are limited data on the effectiveness of the LNG-IUD as a treatment for PMDD. Because the LNG-IUD's main mechanism of action is not ovarian suppression, theoretically it would not be expected to reliably alleviate cyclic variation of ovarian hormones and is not recommended as a treatment option. Indeed, some studies have raised concerns of the LNG-IUD's potential to negatively affect mood, as a small level of LNG (although very low) does appear in the bloodstream. Overall, the existing data do not demonstrate that the LNG-IUD has a negative impact on mood for users.22 A limited systematic review of 6 studies demonstrated that use of the LNG-IUD did not correlate with worsening clinical outcomes of patients with existing diagnosis of major depressive disorder or bipolar disorder.23

Hirsutism and Acne

The LNG-IUD has not been well studied in hirsutism. Given that it is a locally acting progestin, many think it would produce lower androgenic side effects than systemic progestins. A survey-based study of LNG-IUD users demonstrated that 35% of respondents had increased acne, compared with 4% with improved acne, and 61% with no change. In this study, 41% of participants described excess facial hair after placement of the IUD, although this finding was not significant.24 A retrospective cohort study of a total of 1224 people who used hormonal and nonhormonal IUDs demonstrated a positive correlation between hormonal IUD use and acne vulgaris (odds ratio [OR] 2.514, P < 0.001) and a negative correlation between the hormonal IUD use and hirsutism (OR 0.446, P = 0.0025) and androgenic alopecia (OR 0.109, P = 0.0017).25

Hormone Replacement Therapy

Between 50% and 82% of people in the United States reported experiencing vasomotor symptoms in the perimenopausal period. Vasomotor symptoms are a sudden sensation of extreme heat affecting the upper body, lasting for 1 to 5 minutes, and sometimes causing significant disruption to a patient's day or sleep at night. The most effective therapy for vasomotor symptoms of menopause is hormone replacement therapy with estrogen. For people who have a uterus, progestin add-back is the standard treatment for endometrial protection. There are various options for progestin delivery, including the LNG-IUD. A systematic review of 7 RCTs and 4 prospective studies investigating the effectiveness of the LNG-IUD versus other routes of progestin delivery such as oral or transdermal demonstrated the LNG-IUD was equally effective at endometrial protection.26 No patient receiving either the LNG-IUD or alternative routes of progestin developed endometrial hyperplasia. Similar endometrial protective effect of the LNG-IUD has been demonstrated in other studies.27-29 The LNG-IUD has also been demonstrated to have comparable acceptability to other progestin delivery routes. A systematic review of 6 RCTs demonstrated that although vaginal spotting was common in the LNG-IUD groups in the first 3 to 6 months of use, there was no difference in discontinuation rates.30 Overall evidence seems to suggest that the LNG-IUD is a good option for progestin add-back therapy for patients on estrogen replacement therapy.

Cancer Prevention

Endometrial Cancer

As mentioned earlier, the LNG-IUD is a potential option for treatment of endometrial hyperplasia. Because endometrial hyperplasia is a precursor to endometrial adenocarcinoma, especially for endometrial hyperplasia with atypia where the risk of progression to endometrial carcinoma is up to 40%, the LNG-IUD has the potential to prevent endometrial cancer for patients diagnosed with endometrial hyperplasia. This effect is also seen in LNG-IUD users without the diagnosis of endometrial hyperplasia. A cohort study of 104,318 people identified through the National Women and Cancer Study of Norway demonstrated a risk ratio (RR) of 0.22 (95% confidence interval [CI] 0.13-0.40) for endometrial cancer when compared between ever users and never users of the LNG-IUD.31 Another cohort study in Finland looked at cancer risk in people aged 30 to 49 years who used the LNG-IUD for menorrhagia between 1994 and 2007 and noted a lower incidence than expected of endometrial adenocarcinoma, with a standardized incidence ratio of 0.50 (95% CI 0.35-0.70).32 A single-arm feasibility study screened 104 people with a body mass index of 40 or greater for eligibility of using an LNG-IUD as a primary prevention against endometrial cancer.33 Of those, 25 people qualified and received the LNG-IUD. At the 6-month post-insertion follow-up, it was found Ki-67 and PR expressions were significantly lower than at the time of IUD insertion. Ki-67 is only expressed in proliferating cells, and in fact differentiates benign from malignant endometrium. These observations demonstrate the potential for the use of the LNG-IUD in preventing cancer, although at present there are insufficient data to conclude that the LNG-IUD effectively prevents cancer and could therefore be recommended as a primary prevention strategy.

Ovarian Cancer

There is no study that directly looks at the effectiveness of the LNG-IUD as a primary prevention strategy for ovarian cancer; however, retrospective studies have noticed a lower rate of ovarian cancer in LNG-IUD users.31,32 A cohort study of 104,318 people in Norway demonstrated an RR of 0.53 (0.32-0.88) for ovarian cancer compared between ever users and never users of the LNG-IUD.31 Another cohort study in Finland demonstrated a standardized incidence ratio for ovarian cancer of 0.60 (0.45-0.76) between users and nonusers of the LNG-IUD for menorrhagia.32 A systematic review and meta-analysis of 15 case-control and cohort studies demonstrated that IUD use of any type is associated with a reduced incidence of ovarian cancer, with the overall OR of 0.68 (95% CI 0.55-0.85) for those with ever use of an IUD.34

Cervical Cancer

Limited data are available on the effectiveness of the use of the LNG-IUD in cervical cancer prevention. A systematic review and meta-analysis demonstrated the incidence of invasive cervical cancer to be 30% lower in people who have used an IUD compared with those who have never used.35 Of note, this study was inclusive of all types of IUDs and not just the LNG-IUD. In addition, some studies included in this meta-analysis were conducted before the human papillomavirus vaccine became widely available so may not be as applicable in populations with high vaccination rate.

Breast Cancer

Again, limited data are available on the effectiveness of the LNG-IUD in breast cancer prevention. Available data on any relationship between LNG-IUD use and breast cancer are retrospective and are from the Finnish National Health Registry. The data are inconsistent regarding the relationship between LNG-IUD use and incidence of breast cancer. A Finnish observational nationwide cohort study demonstrated a standardized incidence ratio of 1.19 (95% CI 1.13-1.25) for breast cancer among patients who had the LNG-IUD placed for menorrhagia treatment.32 Another postmarketing epidemiologic study among Finnish LNG-IUD users demonstrated no significant difference in the breast cancer risk between users and nonusers of the LNG-IUD.36

Conclusion

The LNG-IUD has been proven effective for many noncontraceptive indications, such as treatment for different causes of AUB and dysmenorrhea, and is an effective progestin add-back therapy for patients with uteri using hormone replacement therapy. The LNG-IUD also has the potential to treat endometrial hyperplasia and prevent endometrial cancer, although more data are needed to support these and similar clinical indications.

Practice Pearls

* There are 2 major mechanisms of action of the LNG-IUD: 1) alteration of the endometrium causing endometrial atrophy; and 2) cervical mucus thickening.

* The LNG-IUD has potential to treat AUB caused by endometrial polyps.

* In treatment of adenomyosis, the LNG-IUD can have comparable effectiveness in decreasing bleeding and pain compared with COCs and can have comparable improvement in quality of life compared with hysterectomy.

* The LNG-IUD can potentially improve AUB caused by uterine leiomyoma, although its effect on bulk symptoms is unclear.

* The LNG-IUD offers comparable effectiveness as oral progestins in management of endometrial hyperplasia and endometrial carcinoma in patients who are not surgical candidates.

* There is evidence to demonstrate that the LNG-IUD can improve the bleeding profile in patients with AUB due to coagulopathies and iatrogenic causes.

* The LNG-IUD has the potential to improve CPP associated with endometriosis and primary dysmenorrhea.

* The LNG-IUD has not been demonstrated to be beneficial in the treatment of PMDD.

* There is no clear link between LNG-IUD use and hirsutism.

* The LNG-IUD is an effective progestin add-back therapy for endometrial protection in patients on hormone replacement therapy.

* The LNG-IUD is currently not used as primary prevention for any gynecologic cancer. However, there is evidence that the LNG-IUD is associated with lower incidence of endometrial, ovarian, and cervical cancer. There are inconclusive data regarding LNG-IUD use and breast cancer.

References