**3. Types of IUDs: copper and hormonal**

The two main types of IUDs are the copper non-hormonal device and the hormonal device.

There are a few types of *copper devices* as well. The most frequent copper device series are the *T380* devices that also consist of the original *T380A*, the *T380Ag* available in Finland, and the *T380S* available in Canada and UK [12]. This IUD has a small plastic "T" frame with a stem wrapped with copper wire and also copper collars on the two arms of the frame, of about 380 mm2 of copper. T380A has been approved around the world for up to 10 years [13], with no uterine perforation reported, but a high rate of medical removal due to bleeding, pain, and pelvic infection [12].

Other types of copper IUDs include the *Multiload* series of devices that consists of *ML250* for a 3 years' use and the *ML375* with more copper to enhance a longer use, up to 5 years. The device has additional plastic fins on the lateral, and curved arms to avoid spontaneous expulsion [12].

**2. History of IUDs**

258 Family Planning

bleeding and dysmenorrhea [7].

**3. Types of IUDs: copper and hormonal**

practitioners [3].

380 mm2

pelvic infection [12].

Intrauterine contraception with various devices seems to have a long history, from the ancient Arabs who placed round smooth stones in the camels' uteri to prevent conception during long journeys. In the late nineteenth century, intracervical devices have been used to prevent pregnancy or to induce abortion [3]. Still, the first medical communication on medical IUD was published in Germany, at the beginning of the twentieth century by Richter [4], who reported the results of intrauterine insertion of a metallic ring with catgut tied around it. In the 1920s, Ernest Graefenberg attached a silver wire to the ring for Roentgen visualization, but silver rings were rapidly abandoned as they led to gingival argyrosis. An alloy of copper, nickel, and zinc was used instead [5]. In 1959, the first paper was published who condemned the IUDs as dangerous because of the ineffectiveness, risk of infection, and carcinogenic potential [5]. The modern IUDs evolved from 1960 with a T-shaped product that configured better to the natural shape of the uterus [6]. By the mid-1960s, IUDs became a widely used method with fewer potential cardiovascular risks when compared to oral contraceptives [7]. In 1970, nearly 10% of women were using the Dalkon Shield IUD as a contraceptive method. Since then, the use of IUDs dropped because of the severe septic cases reported, along with the increased risk of pelvic inflammatory disease (PID) and infertility

[8]. IUDs were even withdrawn from the US market between 1986 and 1988.

Since the introduction of the levonorgestrel 52 mg IUD in 2001, this intervention achieved a new, therapeutic, dimension—because of significant benefits in treating heavy menstrual

Today, IUDs are an important component of family planning, as they are used by one in 10 women in the USA and 9–24% of all contraceptives in European countries [9]. The highest rates of IUD use are recorded in Asia: 40% of women in China, 50% in Korea, and 56% in Uzbekistan [10], while the lowest rates are recorded in Africa. The trend of contraceptive method is declining as the use of injectable products is increasing [11]. From the beginning, the gynecologists were preferred for a safe insertion of the IUD, instead of general

The two main types of IUDs are the copper non-hormonal device and the hormonal device. There are a few types of *copper devices* as well. The most frequent copper device series are the *T380* devices that also consist of the original *T380A*, the *T380Ag* available in Finland, and the *T380S* available in Canada and UK [12]. This IUD has a small plastic "T" frame with a stem wrapped with copper wire and also copper collars on the two arms of the frame, of about

of copper. T380A has been approved around the world for up to 10 years [13], with

no uterine perforation reported, but a high rate of medical removal due to bleeding, pain, and

The *GyneFix* device has been introduced in 1997 as a frameless copper-bearing device designed especially for nulliparous women. However, it associates an increased risk of expulsion in the first 3 months. Both *GyneFix* and *T380A* are reported to have high efficiency in women contraception [14].

Besides pure copper devices, there is also a gold IUD called *Eurogine Gold T*, *Goldlily,* or *GoldringMedusa*, with a gold core that prevents the copper from fragmenting or corroding [15].

Silver was also being added on a copper device, to reduce fragmentation, and to prolong the lifespan of the device. The production of the initial *NovaT200* was ceased, because of poorer performance and *NovaT 380* was developed [12].

To reduce side effects of IUDs such as bleeding, pain, and expulsion, *Flexi-T300* was introduced, with a smaller and more flexible frame and thinner side arms that are bent back on themselves. *Flexi-T300* is also preferred for emergency contraception, as it is cheap and easily inserted and removed [12].

Since 1976, medicated or *hormonal IUDs* were developed. *Mirena* was produced in 2001 as a hormonal IUD releasing 52 mg of levonorgestrel during a 5 years' period of approved use [7]. Mirena releases approximately 20 μg of levonorgestrel daily in the first few weeks with a decrease to 18 μg/day by the end of 1 year and 10 μg/day after 5 years [16]. Other hormonal IUDs, as *Skyla* or *Jaydess,* have a shorter period of use (3 years) because of the lower levonorgestrel content (13.5 mg), that is released 14 μg daily after the first few weeks and with a rapid decrease to 10 μg/day by 2 months and 5 μg/day by the end of 3 years [17]. Besides contraception, the hormonal IUDs reduce the blood flow with amenorrhea in about 20% of cases within 1 year [18]. *FibroPlant* is a frameless levonorgestrel-releasing IUD with a nonresorbable thread through the center and with similar effects on uterine-bleeding patterns as Mirena [12].

Other IUDs include the *copper indomethacin* type, available in China, with a silicone elastomer beads containing 25 mg of indomethacin that does not interfere with the copper release and reduces the menstrual cramping [12].

In Austria and Israel, a *copper intrauterine ball* is available, which once inserted takes the shape of a sphere. The rationale of the ball shape is to reduce the irritating effect of classic copper IUD. It is also easy to insert with no uterine perforation reported and highly accepted by patients [19].

New IUDs, such as flexible VeraCept—that utilize a low-dose copper configuration of 175 mm<sup>2</sup> surface area on a shape memory Nitinol frame—need clinical trials for validation of efficacy and tolerability [20] (**Figures 1** and **2**).

endometrium. Therefore, the endometrial and myometrial function is disturbed by cellular and humoral immune-inflammatory reaction. Intrauterine foreign bodies are known to interfere with reproduction in all species [21]. Other mechanisms of action for *copper IUDs* are related to copper ions' effect on the *sperm motility and viability* and also to *changes of the cervical mucus* [7]. However, recent studies demonstrated no significant increase in inflammatory reaction, so the effect of copper on the sperm or oocyte remains as the main mechanism of action [22]. The mechanism of inhibiting fertilization or sperm viability impairment may be responsible for the high efficacy of copper IUDs as emergency contraception [23]. The reported failure rate for copper IUD placement for emergency contraception within 5 days of intercourse or ovulation is less than 1‰, significantly more effective than any hormonal emergency contraceptive [24, 25]. Even if copper IUDs do not usually influence the menstrual frequency or quantity, 10–13% of women have their IUD removed

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in the first year due to increase of menstrual flow and cramping-type abdominal pain [26].

tory disease (PID) and tubal infertility is considered false [31, 32].

Foreign body reaction with toxic changes to sperm + +

Thickened cervical mucus affecting sperm motility +

Decreased number of fertilized ova in fallopian tubes + +

Altered cytotoxic cytokine and integrin profile + + Endometrial atrophy, decreased thickness, and secretions +

**Table 1.** Mechanisms of action of the main types of IUDs. Modified, Schulman et al. [35].

Copper ions spermicidal or cytotoxic +

Immune-inflammatory reaction with increased leukocytes +

**Effects on sperm**

**Effects on fertilization**

**Effects on the endometrium**

Besides the foreign body reaction, another mechanism of the *hormonal IUD* is represented by the release of small amount of progestin hormones, respectively, levonorgestrel. The hormonal effects induce an unfriendly and even *fatal environment to sperm* inside the uterus, with inhibition of capacitation, penetration, and survival [27]. Hormonal IUDs interfere with sperm motility by *thickening cervical mucus*, thus preventing the sperm to travel up into the uterus [28], while copper IUDs rather impair the sperm viability, with various effects as head-tail disruption [29]. A *thinner endometrium* develops under the progesterone influence and egg implantation is affected. Also, menstrual blood flow is reduced, thus hormonal IUDs are frequently used to treat menorrhagia [30]. We underline that IUDs, whether hormonal or non-hormonal, do not provide protection against sexually transmitted diseases. Still, the historical association with pelvic inflamma-

The indomethacin-releasing copper IUD contains a nonsteroidal anti-inflammatory agent, indomethacin, that do not interfere with copper ions [33, 34], aimed to reduce the menstrual

**Copper IUD Hormonal levonorgestrel IUD**

blood flow and cramping that are frequently related by IUDs users [33] (**Table 1**).

**Mechanisms of action Type of intrauterine device**

**Figure 1.** Various types of IUD. Copper devices presented in the upper row, from left to right: T Safe Cu380A®, Nova T380®, Flexi-T300®, Multiload Cu375®, GyneFix®, Ocon® Cooper intrauterine ball. In the middle row—hormonal IUDs: Mirena®, Skyla®, FibroPlant® frameless levonorgestrel-releasing device. In the lower row, other IUD types are presented, as the indomethacin-releasing cooper device AiMu® and the flexible, low copper dose VeraCept®.

**Figure 2.** General structure with stems, arms, and strings of the IUD. Normal location after proper IUD insertion in the middle of the endometrial cavity with no extension in the myometrium, both arms spread toward the uterine horns and the inferior part of the vertical body stem just above the isthmus.
