Intrauterine hormonal system

• Contraception
• Menorrhagia (heavy menstruation), endometriosis, chronic pain in the lower abdomen, dysmenorrhea and anemia. In some cases, HCV allows a woman to avoid a hysterectomy - removal of the uterus. ^{[1] [2] [3]}

An IUD can only be installed by a specially trained doctor. The device must be inserted into the uterine cavity according to all manufacturer's instructions, under aseptic conditions, to avoid bacteria from entering the uterine cavity. With a high risk of endometritis (inflammation of the inner lining of the uterus), antibiotics should be prescribed before the introduction of the IUD, but it is better not to use an IUD in such women. ^[four]

The technique for introducing an IUD is somewhat different from that for conventional IUDs because of the larger diameter of the device, which is due to the presence of a reservoir with LNG. Therefore, cervical canal expansion and local anesthesia are sometimes required. This IUD can be entered at any time of the menstrual cycle (MC), after artificial abortion in the first trimester (immediately after surgery) in the absence of infection. After birth, the IUD is recommended to be administered no earlier than 6 weeks later. The first control inspection is carried out after 1 month, then after 3 months and then 1 time per year.

The period of use of the IUD, according to the recommendations, is 5 years, after which the IUD is recommended to be removed and replaced with a new one. According to Sivin J. et al. (1991), LNG-IUD can be used for 7 years, since its effectiveness and safety are maintained during this period.

The pronounced contraceptive effect of LNG-IUD is determined by several mechanisms:

• a change in the structure of the endometrium;
• impaired sperm function;
• changes in the viscosity and chemical properties of cervical mucus ;
• violation of the peristalsis of the fallopian tubes;
• a decrease in the hypothalamic-pituitary function (mild inhibition of the secretion of luteinizing hormone, changes in the ovulation process and the function of the corpus luteum).

LNG-IUD has a multifaceted effect on the endometrium, including:

• inhibition of proliferative processes;
• suppression of mitotic activity of endometrial and myometrial cells;
• decidual stroma reaction;
• thickening and fibrosis of the walls of blood vessels;
• capillary thrombosis;
• decrease in vascularization and the number of vessels;
• development of atrophic processes and amenorrhea.

The endometrial glands are reduced in size, atrophy, the stroma becomes edematous. Sometimes an inflammatory reaction occurs, leukocyte infiltration, endometrial stroma necrosis. Critchley N. et al. (1998) 12 months after the administration of LNG-IUDs, a significant decrease in the concentration of estrogen and progesterone receptors was found in the endometrium. This, according to Zhu P. et al. (1999), confirming this effect, and explains the contraceptive effect of Mirena, as well as the onset of amenorrhea. One of the factors mediating the mitotic effect of estrogens on the endometrium is an insulin-like growth factor - 1. In an experimental study, Pekonen F. et al. (1992) showed that against the background of the use of LNG-IUS in the endometrium, the production of a protein that binds the indicated growth factor increases, which helps to suppress the stimulating effect of estrogens on the mitotic activity of the endometrium.

The role of changes in cervical mucus in the contraceptive effect of LNG-IUD is still under discussion. Some researchers note that with the use of LNG-IUDs, mucus production in the cervical canal is reduced. Ortiz ME et al. (1987) noted an increase in the viscosity of cervical mucus due to an increase in its density, which complicates the passage of not only sperm, but also pathogenic microorganisms into the uterine cavity. However, it is assumed that the effect of LNG on cervical mucus is not its main contraceptive effect, although a decrease in its number and structural changes may well impede the passage of sperm into the uterine cavity.

There are indications in the literature that LNG and its derivatives can have a direct effect on spermatozoa by suppressing their functional activity. Significant suppression of endometrial function can also contribute to impaired sperm migration into the fallopian tubes.

A large number of studies have been devoted to the effect of LNG-IUD on ovulation processes. Many researchers believe that ovulatory ovarian function is not suppressed against the background of LNG-IUD. According to Coleman M. et al. (1997), during the first year of application of LNG-IUDs, up to 78.5% of MCs were ovulatory, and only a small percentage of cases showed inhibition of ovulation processes with the subsequent development of an inferior luteal phase. Apparently, amenorrhea resulting from the use of LNG-IUD is not due to suppression of ovarian function, but to the reaction of the endometrium to the local effect of LNG. Changes in the hypothalamic-pituitary system were minor. According to Barbosa J. et al. (1990), the cyclic function of the ovaries is preserved when using LNG-IUD, regardless of the presence or absence of menstrual bleeding, amenorrhea is due to the local effect of LNG on the endometrium. Thus, the main role in preventing pregnancy with the use of LNG-IUDs is not played by suppressing ovulation, but by changing the morphology and function of the endometrium as a result of local exposure to LNG.

Usually, removal of the IUD is easiest if performed at the end of the menstrual cycle and is performed by a doctor or a specially trained nurse. At the same time, tweezers grasp the threads of the spiral and gently pulling at them, remove the spiral.

“Loss of a spiral” is a situation when a woman herself cannot find the spiral threads during a routine checkup and the doctor does not see them during the examination. ^[5] In this situation, the spiral is removed either using a special device, or they try to hook it with tweezers through the cervix. ^{[6] [7]} In rare cases, such attempts are unsuccessful, ultrasound is required and the perforation of the spiral into the abdominal cavity, or its invisible loss, is eliminated. Very rarely hysteroscopy is required.

After the removal of Mirena, the woman’s fertility is restored quite quickly: during the year, the frequency of planned pregnancies reaches 79.1–96.4%. The condition of the endometrium is restored 1-3 months after the removal of LNG-IUD, MC normalizes within 30 days.

WHO publication Contraceptive use criteria and the Royal Family of Obstetrics and Gynecologists UK publication on family planning and contraception have a list of contraindications for the use of levonorgestrel-containing spirals if this is associated with a health risk.

Conditions that are proven or theoretically can be dangerous when using HCV with levonorgestrel:

• Postpartum period - 48 hours - 4 weeks (high risk of HCV expulsion)
• Deep vein thrombosis or pulmonary thromboembolism
• Benign trophoblastic disease (cystic drift)
• A history of breast cancer for at least 5 years after treatment
• Ovarian cancer
• A very high probability of gonorrhea or other diseases transmitted through the hollow, for example, chlamydia.
• AIDS AIDS (except for successful antiretroviral therapy)
• Active liver disease (acute viral hepatitis, severe decompensated cirrhosis, benign or malignant liver tumors)

Absolute contraindications for the use of HCV with levonorgestrel:

• Pregnancy
• Postpartum sepsis
• Immediately after septic abortion
• Vaginal bleeding of unknown nature prior to examination
• Chorionepithelioma
• Cervical Cancer (before treatment)
• Active liver disease (acute viral hepatitis, severe decompensated cirrhosis, benign or malignant liver tumors)
• Active or recent breast cancer (hormone-sensitive tumor)
• Endometrial cancer
• Deformation of the uterine cavity with fibroids, or anatomical anomalies of the structure
• Current pelvic inflammatory disease
• Current purulent cervicitis, chlamydial infection, or gonorrhea.
• Female reproductive system tuberculosis

The most common side effect of LNG-IUDs that develops for the first 3 months of use is acyclic meager spotting and irregular MC. It is characteristic that, when comparing LNG-IUD with IUD Nova-T, these phenomena in the first 2 months were significantly more pronounced when using LNG-IUD, at 3-4 months the differences between IUDs disappeared, and after 5 months the number of days of menstrual and acyclic bleeding in the LNG-IUD group became significantly smaller than when using Nova-T.

According to Sturridge F. et al. (1997), more than 10% of women 5 months after the introduction of LNG-IUD have amenorrhea due to endometrial atrophy due to local exposure to LNG, but not ovarian dysfunction. It is noteworthy that many authors consider the term “amenorrhea" to be unacceptable to denote the absence of menstruation while using LNG-IUD, since in this case it is not a pathological phenomenon and can be regarded as a therapeutic effect of this method of contraception.

Sometimes, during the first months after the introduction of LNG-IUD, patients experience symptoms of depression, which may be associated with a low concentration of estradiol in the blood plasma.

Headache with the use of LNG-IUD is observed in 5-10% of women. As a rule, it disappears after 2-3 months and does not require special treatment. Engorgement of the mammary glands is sometimes noted, mainly in patients with a high concentration of estradiol in the blood plasma or in the presence of an neovulated follicle.

Against the background of the use of LNG-IUD, functional ovarian cysts may occur, however, they usually undergo reverse development without treatment and are not an indication for the removal of IUDs.

The incidence of inflammatory diseases of the pelvic organs when using LNG-IUD is low. According to Toivonen J. (1991), LNG-IUDs even have a protective effect against this pathology, which expands the indications for the use of LNG-IUDs.

The severity of side effects decreases with increasing duration of use of LNG-IUD.

According to Prilepskaya V.N. et al. (2000), the most common adverse reactions with the use of LNG-IUD are acyclic intermenstrual spotting (50.8%), breast engorgement (15.4%) and acne (15.4%), which appear in the first 2 –3 months of contraception and subsequently disappear without prescribing any therapy.

Menstrual Changes

The most common side effect of LNG-IUD in the first 3 months is acyclic meager spotting and an irregular menstrual cycle. When comparing the nature of menstrual cycles in women with LNG-IUD and Nova-T, it was found that in the first 2 months. the duration of menstrual bleeding and acyclic scanty spotting is much higher with the use of LNG-IUD, but by the 3rd and 4th month these differences disappeared, and after 5 months. the number of days of menstrual and acyclic bleeding in the group with LNG-IUD decreased sharply compared with the group using Nova-T. According to F. Sturridge et al. (1997), more than 10% of women, 5 months after the administration of LNG-IUD, amenorrhea occurs due to endometrial atrophy due to local exposure to levonorgestrel, but not ovarian dysfunction. It is noteworthy that many authors consider the use of the term "amenorrhea" to mean the absence of menstruation during the use of LNG-IUD due to the fact that amenorrhea in this case is a symptom, not a disease, and can be regarded as a therapeutic effect of this method of contraception.

CSNilsson et al. (1984) revealed a significant decrease in the volume of menstrual blood loss due to the use of LNG-IUD in comparison with the nature of menstruation before the introduction of IUDs or in comparison with menstruation against the background of copper-containing agents. The average blood loss over 3 cycles for LNG-IUD was 72 ml in this study, and 112 ml for copper-containing ones.

Sometimes patients experience symptoms of depression during the first months after the introduction of LNG-IUD, which experts explain as low plasma concentrations of estradiol.

Headache with the use of LNG-IUD is observed in 5-10% of women. As a rule, it disappears after 2-3 months and does not require special treatment. Sometimes engorgement of the mammary glands is observed mainly in patients with a high concentration of estradiol in blood plasma or in the presence of an neovulated follicle. Against the background of the use of LNG-IUDs, functional ovarian cysts may occur, but usually they underwent reverse development without treatment and are not an indication for the removal of IUDs.

Pelvic inflammatory diseases

The incidence of inflammatory diseases of the pelvic organs when using LNG-IUD is low. The total score was 0.5 compared to 2 when using TCu200Ag (J. Toivonen, 1991), which allowed the authors to conclude that the protective effect of LNG-IUDs against inflammatory diseases of the genital organs. According to A. Kubba (1998), the occurrence of infectious complications is possible on the 20th day after the introduction of any IUD, more often as a result of infection of the genital tract with chlamydia and other microorganisms before the introduction of the IUD. Therefore, to prevent this complication, a preliminary examination for STIs is necessary, especially for women under 25 years of age and those who have recently changed their partner.

The severity of side effects decreases with increasing duration of use of LNG-IUD.

Nursing Mothers

Contraceptives containing only progesterone, such as IUDs, do not affect lactation or the growth of the child. ^[eight]

Levonorgestrel is found in the blood of children who are breastfed, the concentration in this case is 7% of the concentration in the mother’s blood. ^{[9] A} six-year study of children whose mothers used levnorgestrel-containing contraception and breastfeeding showed that children had a higher risk of eye and respiratory infections, but lower the risk of various neurological complications compared to those children whose mothers used the usual IUD ^[10] . Long-term studies on the effect of levonorgestrel on breast-fed children have not been conducted.

The World Health Organization is opposed to the introduction of an IUD immediately after childbirth, since in this case there is a higher risk of a spiral falling out. Also, experts have doubts about the effect of hormones on the development of the liver and brain of the baby within 6 weeks after birth. However, WHO recommends that even lactating women be advised to Mirena as a possible contraceptive measure 6 weeks after delivery. ^{[11] The} British Family Planning Organization offers Mirena as a means of contraception for lactating women, starting four weeks after giving birth. ^[12]

Impact on the incidence of cancer

The FDA concluded that Mirena’s ability to cause cancer is very low. ^[13] According to a 1999 study by the International Agency for Research on Cancer Diseases, birth control pills containing progestin alone reduce the risk of endometrial cancer. The authors concluded that these methods do not increase the risk of cancer, although a small sample does not allow final conclusions. ^[14] The use of progestin alone in menopause doubles the risk of breast cancer compared to those who did not use anything. ^[15]

Because breast cancer cells are often sensitive to hormones, Mirena and other hormonal methods of contraception are not recommended for women who have cancer, now have cancer, or suggest that they may have cancer.

Bone Mineral Density

There is no evidence that LNG-IUD can somehow affect bone mineral density. ^[16] The only published study showed that with prolonged use (more than 7 years), the bone mineral density of the radius and ulna was exactly the same as those who did not use Mirena. In addition, all measurements were the same as expected values ​​for women from the same age group. The authors of the study argue that such results were predictable, since it is well known that the main factor responsible for bone loss in women is hypoestrogenism, and, according to previous studies, the level of estradiol in women using Mirena was normal . ^[17]

According to numerous studies, the high contraceptive effectiveness of LNG-IUD (Pearl Index is 0–0.3) is comparable to that of surgical sterilization, but the contraceptive effect of Mirena is completely reversible. According to Prilepskaya V.N. et al. (2000), when using LNG-IUDs, pregnancy was not achieved in any of the 65 women participating in the study.

Andersson, K. et al. (1994) showed that LNG-IUD is significantly more protective against ectopic pregnancy than other IUDs. According to a European multicenter study, the ectopic pregnancy rate per 100 women-years was 0.2 for Mirena and 2.5 for Nova-T.

After removal of LNG-IUD, the woman’s fertility is restored quite quickly: during the year, the frequency of planned pregnancies reaches 79.1-96.4%. The condition of the endometrium is restored 1-3 months after the removal of LNG-IUD, the menstrual cycle normalizes within 30 days, fertility - on average after 12 months.

According to large-scale studies, with control periods of 5 years, LNG-IUD does not adversely affect blood coagulation. The content of fibrinogen, prothrombin complex factors, platelets and their aggregation activity remain stable against the background of the use of LNG-IUDs. Fluctuations in the blood lipid spectrum (total cholesterol - cholesterol, cholesterol high density cholesterol - HDL cholesterol, low density lipoprotein cholesterol - LDL cholesterol, very low density lipoprotein cholesterol - cholesterol, TG, CA) did not exceed standard values, i.e. its atherogenic effect on the parameters of the lipid spectrum of the blood, as well as the activity of liver enzymes, was not found. The results of clinical studies, which lasted for 5 years, showed that LNG-IUD does not adversely affect blood pressure and body weight.

The authors explained the LNG-IUDs by a direct effect on the foci of adenomyosis: a decrease in the level of prostaglandins and factors of fibrinolytic activity in the endometrium, a decrease in the degree of vascularization, inhibition of proliferative processes and hypotrophy of the ectopic endometrium. Fedele L. et al. 11 LNG-IUDs were administered to treat rectovaginal endometriosis. After 3 months, the manifestations of dysmenorrhea disappeared and the severity of dyspareunia decreased. According to transrectal ultrasonography, by the 12th month of treatment, the sizes of foci of endometriosis in the rectovaginal septum area slightly decreased. The authors associated this effect with the direct effect of LNG at the receptor level.

Various medications are used to treat PMS. Barrington J. et al. (1997) used for this purpose subcutaneous implantation of estradiol in combination with LNG-IUD. Estradiol suppressed ovarian function and stopped the symptoms of PMS, and LNG-IUD prevented the development of hyperplastic processes in the endometrium.

According to our data (2001), the clinical manifestations of PMS (irritability, decreased ability to work, weakness, bloating, swelling of the lower extremities, etc.) disappeared in 21.5% of women by the 6th month, and in 36.9% by 12 month of application of LNG-IUD. The disappearance or significant weakening of pain was noted in 20.0% of patients with primary dysmenorrhea by the 6th month of contraception and in 35.4% by the 12th month.

Scholten, R. et al. (1989) evaluated in 52 women with PMS the efficacy of LNG-IUD and copper-containing IUD. It was demonstrated that, against the background of LNG-IUD, the severity of PMS symptoms significantly decreased, while on the background of a copper-containing IUD, on the contrary, it intensified.

For patients with hormone-dependent breast cancer (breast cancer), tamoxifen is often prescribed as adjuvant therapy. Unfortunately, as a result of the estrogen-like action of the drug, endometrial polyps, myoma, hyperplasia, and even endometrial cancer can develop. A randomized control study was conducted in postmenopausal women who had been receiving adjuvant tamoxifen therapy for breast cancer for at least a year. Parts of women were given LNG-IUD for a year. Based on the results of studying endometrial biopsies, it was concluded that LNG-IUD has a protective effect on it. However, to confirm these data, a larger randomized study should be carried out, and LNG-IUDs should be administered before starting treatment with tamoxifen.

It is possible to use LNG-IUD as a microdosed hormonal progestogen component of hormone replacement therapy (HRT), in combination with estrogens. Such use of LNG-IUDs was first reported by Andersson K. et al. in 1992, HRT with LNG-IUS contributes to a significant reduction in the severity of symptoms of menopausal syndrome and regression of hyperplastic processes in the endometrium and mammary glands. According to our data (2001), a significant weakening of vegetovascular (92%) and neuropsychiatric (85%) disorders was noted in women with menopausal syndrome in premenopause after 6 months of using HRT with Mirena as a progestational component. The use of LNG-IUD in addition to estrogen as a part of HRT in perimenopausal patients suppresses endometrial proliferation, promotes the development of amenorrhea and avoids side vasomotor symptoms. In a study by Hampton NRE et al. (2005) after 60 months of using LNG-IUD in perimenopausal women, endometrial hyperplasia was not detected. After 12 months, amenorrhea developed in 54.4% of patients, and by the end of the study - in 92.7%.

According to large-scale studies with a 5-year follow-up, LNG-IUS does not adversely affect the lipid spectrum, blood pressure, and body weight. According to our data, the use of LNG-IUDs does not impair metabolic control and does not cause insulin resistance. A small amount of LNG entering the blood from the IUD does not affect glucose metabolism.

So, an analysis of the literature data indicates that LNG-IUD is not only an effective method for preventing unwanted pregnancy in women of reproductive age and fertile women with an ovulatory menstrual cycle in premenopause, but also an effective treatment for a number of common gynecological diseases.

The most appropriate use of LNG-IUD in patients with hyperplastic processes in the endometrium and mammary glands, with endometriosis, uterine fibroids, as well as with dysmenorrhea and PMS. The results of the studies indicate that LNG-IUD is an effective, cost-effective treatment method that reduces menstrual blood loss, improves hemoglobin and serum iron.

Thus, hormonal contraception and hormonal therapy using an IUD containing LNG are links in the same chain. LNG-IUD is not only a highly effective and reversible method of contraception for women of all age groups, but also has a number of therapeutic properties in many gynecological diseases.

Progestasert была первой внутриматочной гормональной системой, разработанной в 1976 году, производилась до 2001 года. ^[18] Система содержала прогестерон со скоростью высвобождения в 65 микрограммов в сутки ^[18] . В большинстве стран её заменяли раз в год, во Франции – раз в 18 месяцев, процент неудач составлял 2% в течение года. ^[nineteen]

Разработка и исследования Мирены начались ещё в семидесятых годах. ^[20] Мирена впервые появилась на рынке в Финляндии в 1990 году, но до 2000 года не было получено одобрения FDA. Из системы выделяется 20 микрограммов левоноргестрела в сутки, и она может оставаться на месте в течение 5 лет.

Contrel, бельгийская компании, которая разработала GyneFix в настоящее время работает над исследованием новой, низкодозовой Т-образной спирали Femilis (14 микрограммов в сутки). Femilis будет выпускаться и в меньшем размере (Femilis Slim) для нерожавших женщин. Ещё можно будет вводить через специальный шприц, и считается, что эффективность введения в этом случае будет меньше зависеть от опыта врача.

Также получены положительные результаты по применению нового мягкого внутриматочного устройства FibroPlant-LNG (также от фирмы Contrel). Закрепляется на дне матки, а не фиксируется самой пластиковой конструкцией. Она выделяет 14 микрограммов левоноргестрела в сутки и может использоваться по крайней мере 3 года. До 2005 года эти устройства не продавались. ^[21]

• "IUDs—An Update". Population Information Program, the Johns Hopkins School of Public Health Volume XXIII (Number 5). December 1995.
• FDA (2000). "Medical review".
• A.V. Тагиева, В.Н. Прилепская. "Гормональная внутриматочная рилизинг-система "мирена" и гормональная терапия – звенья одной цепи". ФГУ "Научный Центр акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова", Москва

• Intrauterine system (IUS)