Neurodevelopmental disorders in children exposed in utero to synthetic progestins: analysis from the national cohort of the Hhorages Association.

The medical and scientific communities have not yet fully acknowledged the undesirable effects of the synthetic hormones that have been administered to pregnant women for decades. The somatic effects of in utero exposure to diethylstilbestrol (DES), such as genital malformations, infertility, and cancer, have long been recognized but this has not been the case concerning psychiatric disorders. The progestins used in contraception and hormone replacement therapy are known to affect the adult brain, but no data exist on their effects due to in utero exposure of children. The Hhorages Association, a national patient support group, has assembled a cohort of 1200 women who took synthetic hormones during pregnancy. These women had a combined 1934 children. We obtained full questionnaire responses from 46 women treated with progestins only - and not an estrogenic cocktail - who gave birth to 115 children. Three groups were observed: Group 1 (n = 18): firstborn unexposed children, Group 2 (n = 62): children exposed in utero to synthetic progestins, and Group 3 (n = 35): children born after a previous pregnancy treated with progestins. No psychiatric disorders were reported in Group 1 and the incidence of psychiatric disorders was drastically elevated in Group 2. Our work shows a striking increase in psychiatric disorders among children exposed in utero to progestins and strongly suggests that prenatal exposure is associated with a high risk of psychiatric disorders in adolescence and adulthood, whether accompanied or not by disorders of sex development.

Progestin-associated shift of meningioma mutational landscape.

Background: Meningiomas are the most common primary tumor of the central nervous system. The relationship between meningioma and progestins is frequently mentioned but has not been elucidated. Patients and methods: We identified 40 female patients operated for a meningioma after long-term progestin therapy and performed targeted next generation sequencing to decipher the mutational landscape of hormone-related meningiomas. A published cohort of 530 meningiomas in women was used as a reference population. Results: Compared with the control population of meningiomas in women, progestin-associated meningiomas were more frequently multiple meningiomas [19/40 (48%) versus 25/530 (5%), P < 10-12] and located at the skull base [46/72 (64%) versus 241/481 (50%), P = 0.03]. We found a higher frequency of PIK3CA mutations [14/40 (35%) versus 18/530 (3%), P < 10-8] and TRAF7 mutations [16/40 (40%) versus 140/530 (26%), P < 0.001] and a lower frequency of NF2-related tumors compared with the control population of meningiomas [3/40 (7.5%) versus 169/530 (32%), P < 0.001]. Conclusion: This shift in mutational landscape indicates the vulnerability of certain meningeal cells and mutations to hormone-induced tumorigenesis. While the relationship between PIK3CA mutation frequency and hormone-related cancers such as breast and endometrial cancer is well-known, this hormonally induced mutational shift is a unique feature in molecular oncology.

Ongoing or previous mental disorders predispose to adverse mood reporting during combined oral contraceptive use.

PURPOSE: Previous studies have emphasised that women with pre-existing mood disorders are more inclined to discontinue hormonal contraceptive use. However, few studies have examined the effects of combined oral contraceptives (COC) on mood in women with previous or ongoing mental disorders. MATERIALS AND METHODS: This is a supplementary analysis of an investigator-initiated, double-blinded, randomised clinical trial during which 202 women were treated with either a COC (1.5 mg estradiol and 2.5 mg nomegestrolacetate) or placebo during three treatment cycles. The Mini International Neuropsychiatric Interview was used to collect information on previous or ongoing mental disorders. The primary outcome measure was the total change score in five mood symptoms on the Daily Record of Severity of Problems (DRSP) scale in the intermenstrual phase of the treatment cycle. RESULTS: Women with ongoing or previous mood, anxiety or eating disorders allocated to COC had higher total DRSP Δ-scores during the intermenstrual phase of the treatment cycle in comparison with corresponding women randomised to placebo, mean difference 1.3 (95% CI 0.3-2.3). In contrast, among women without mental health problems, no difference in total DRSP Δ-scores between COC- and placebo users was noted. Women with a risk use of alcohol who were randomised to the COC had higher total DRSP Δ-scores than women randomised to placebo, mean difference 2.1 (CI 95% 1.0-3.2). CONCLUSIONS: Women with ongoing or previous mental disorders or risk use of alcohol have greater risk of COC-induced mood symptoms. This may be worth noting during family planning and contraceptive counselling.

In Defense of Progesterone: A Review of the Literature.

Context • The medical literature on the use of progesterone in postmenopausal women is often confusing and contradictory. Some physicians implicate natural progesterone in an increase in the risk of breast cancer. The chemical structure of natural progesterone (P4) is quite different from chemically altered, synthetic chemicals called progestins, which results in different actions at the cell level. Objective • The research team intended to review the literature to examine the benefits and safety of natural progesterone and determine whether it can cause an increase or decrease in breast cancer risk. Design • A review of the medical literature to examine the benefits and safety of natural progesterone as compared with synthetic progestins. Intervention • Studies examined compared controls not receiving hormone therapy with women receiving estrogen alone and in combination with natural progesterone and with various synthetic progestins, such as medroxyprogesterone acetate-the most commonly used synthetic progestin. Outcome Measures • Outcome measures included factors such as progression and survival of breast and other cancers and other epidemiological and laboratory data. Results • A meta-analysis of 3 studies involving 86 881 postmenopausal women reported that the use of natural progesterone was associated with a significantly lower risk of breast cancer compared with synthetic progestins. Anovulation and low levels of serum progesterone have been associated with a significantly higher risk of breast cancer in premenopausal women. Use of progesterone has been linked to lower rates of uterine and colon cancers and may also be useful in treating other cancers such as ovarian, melanoma, mesothelioma, and prostate. Progesterone may also be helpful in preventing cardiovascular disease and preventing and treating neurodegenerative conditions such a stroke and traumatic brain injury. Conclusions • Physicians should have no hesitation prescribing natural progesterone. The evidence is clear that progesterone does not cause breast cancer. Indeed, progesterone is protective and preventative of breast cancer.

Effect of Progesterone and Synthetic Progestins on Whole Blood Clot Formation and Erythrocyte Structure.

Combined oral contraceptive (COC) use is a risk factor for venous thrombosis (VT) and related to the specific type of progestin used. VT is accompanied by inflammation and pathophysiological clot formation, that includes aberrant erythrocytes and fibrin(ogen) interactions. In this paper, we aim to determine the influence of progesterone and different synthetic progestins found in COCs on the viscoelasticity of whole blood clots, as well as erythrocyte morphology and membrane ultrastructure, in an in vitro laboratory study. Thromboelastography (TEG), light microscopy, and scanning electron microscopy were our chosen methods. Our results point out that progestins influence the rate of whole blood clot formation. Alterations to erythrocyte morphology and membrane ultrastructure suggest the presence of eryptosis. We also note increased rouleaux formation, erythrocyte aggregation, and spontaneous fibrin formation in whole blood which may explain the increased risk of VT associated with COC use. Although not all COC users will experience a thrombotic event, individuals with a thrombotic predisposition, due to inflammatory or hematological illness, should be closely monitored to prevent pathological thrombosis.

Efficacy of dienogest in the treatment of symptomatic adenomyosis: a pilot study.

Adenomyosis is a common disorder in premenopausal women that causes dysmenorrhea, pelvic pain and menorrhagia. Considering that adenomyosis is an estrogen-dependent disease, the medical treatment is based on this hormone. Effective and well-tolerated medical treatments for symptomatic adenomyosis are needed. Dienogest, an oral progestin, has been extensively investigated in the treatment of endometriosis. In this report, we present the results on the efficacy and safety of dienogest in the treatment of symptomatic adenomyosis. Seventeen patients with symptomatic adenomyosis were included in this study, of which 15 continued dienogest for up to 24 weeks. Dienogest significantly reduced adenomyosis-associated pelvic pain as well as serum CA-125 and CA19-9 levels. It also demonstrated a modest suppression of estradiol (>50 pg/ mL), which is consistent with the findings of other reports. During treatment, five patients experienced worsening anemia because of metrorrhagia, which is the most frequent adverse effect associated with dienogest. This report suggests that dienogest is an effective and well-tolerated therapy for symptomatic adenomyosis.

Possible role of PGRMC1 in breast cancer development.

Hormone therapy may increase the risk of breast cancer. Thus, especially the addition of synthetic progestins may play a decisive role according to the results of clinical studies. Overexpression of a special receptor, i.e. the progesterone receptor membrane component-1 (PGRMC1), may offer a potential new pathway to explain the observed increase in breast cancer risk in the combined arm of the Women's Health Initiative. PGRMC1 is expressed in breast cancer tissue and may be important in tumorigenesis. The expression of PGRMC1 in breast cancer tissue is significantly different from that in normal mammary glands. Certain synthetic progestins can increase the proliferation of PGRMC1-overexpressing breast cancer cells and may thus be involved in tumorigenesis, while progesterone and certain synthetic progestins such as nomegestrol or chlormadinone acetate react neutrally. Our investigations point towards an important role of estrogen receptor-α in the signaling cascade, resulting in the proliferative effect induced by progestins. Thus, activation of PGRMC1 may explain the increased breast cancer risk observed during treatment with certain progestins. Very recently, PGRMC1 was investigated in serum samples of lung cancer patients and matched healthy patients; significantly higher concentrations were shown in the cancer patients. Therefore, PGRMC1 might be a predictor for other cancers as well but, according to clinical trials, its importance for a possible screening tool, particularly for breast cancer risk during hormone therapy, seems of interest.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies. Part 4: the Million Women Study.

BACKGROUND: Based principally on findings in three studies, the collaborative reanalysis (CR), the Women's Health Initiative (WHI) and the Million Women Study (MWS), it is claimed that hormone replacement therapy (HRT) with estrogen plus progestogen (E+P) is now an established cause of breast cancer; the CR and MWS investigators claim that unopposed estrogen therapy (ET) also increases the risk, but to a lesser degree than does E+P. The authors have previously reviewed the findings in the CR and WHI (Parts 1-3). OBJECTIVE: To evaluate the evidence for causality in the MWS. METHODS: Using generally accepted causal criteria, in this article (Part 4) the authors evaluate the findings in the MWS for E+P and for ET. RESULTS: Despite the massive size of the MWS the findings for E+P and for ET did not adequately satisfy the criteria of time order, information bias, detection bias, confounding, statistical stability and strength of association, duration-response, internal consistency, external consistency or biological plausibility. Had detection bias resulted in the identification in women aged 50-55 years of 0.3 additional cases of breast cancer in ET users per 1000 per year, or 1.2 in E+P users, it would have nullified the apparent risks reported. CONCLUSION: HRT may or may not increase the risk of breast cancer, but the MWS did not establish that it does.

Upregulation of an estrogen receptor-regulated gene by first generation progestins requires both the progesterone receptor and estrogen receptor alpha.

Progestins, synthetic compounds designed to mimic the activity of natural progesterone (P4), are used globally in menopausal hormone therapy. Although the older progestins medroxyprogesterone acetate (MPA) and norethisterone (NET) have been implicated in increased breast cancer risk, little is known regarding newer progestins, and no significant risk has been associated with P4. Considering that breast cancer is the leading cause of mortality in women, establishing which progestins increase breast cancer incidence and elucidating the underlying mechanisms is a global priority. We showed for the first time that the newer-generation progestin drospirenone (DRSP) is the least potent progestin in terms of proliferation of the estrogen-responsive MCF-7 BUS breast cancer cell line, while NET and P4 have similar potencies to estradiol (E2), the known driver of breast cancer cell proliferation. Notably, MPA, the progestin most frequently associated with increased breast cancer risk, was significantly more potent than E2. While all the progestogens enhanced the anchorage-independent growth of the MCF-7 BUS cell line, MPA promoted a greater number of colonies than P4, NET or DRSP. None of the progestogens inhibited E2-induced proliferation and anchorage-independent growth. We also showed that under non-estrogenic conditions, MPA and NET, unlike P4 and DRSP, increased the expression of the estrogen receptor (ER) target gene, cathepsin D, via a mechanism requiring the co-recruitment of ERα and the progesterone receptor (PR) to the promoter region. In contrast, all progestogens promoted the association of the PR and ERα on the promoter of the PR target gene, MYC, thereby increasing its expression under non-estrogenic and estrogenic conditions. These results suggest that progestins differentially regulate the way the PR and ER converge to modulate the expression of PR and ER-regulated genes. Our novel findings indicating similarities and differences between P4 and the progestins, emphasize the importance of comparatively investigating effects of individual progestins rather than grouping them as a class. Further studies are required to underpin the clinical relevance of PR/ERα crosstalk in response to different progestins in both normal and malignant breast tissue, to either confirm or refute their suitability in combination therapy for ER-positive breast cancer.

Use of the levonorgestrel releasing-intrauterine system in nulliparous women--a non-interventional study in Sweden.

OBJECTIVES: To evaluate the insertion procedure and continuation rates of the levonorgestrel releasing-intrauterine system (LNG-IUS) in nulliparous women who, due to fear of complications, are often denied this very effective contraceptive method. METHODS: A non-interventional study of 224 nulliparous women attending family planning services for insertion of a LNG-IUS. RESULTS: There were only six unsuccessful insertions. The insertions, mostly carried out by midwives, were regarded as easy by 72% of the inserters. Nineteen women (9%) considered the procedure to have been painless, 162 (72%) moderately painful, and 39 (17%), severely painful. At follow-up, 12-16 weeks post-insertion, 76% (165/216) of the women were satisfied with their method. Women in the youngest age group were more satisfied than women in the oldest age group (75% and 59%, respectively). Only 5% were dissatisfied. Neither perforations nor pregnancies were reported during the whole study period. CONCLUSION: Our results support the current practice in Sweden of offering LNG-IUS routinely to nulliparous women.

[Weight gain and progestin-only contraceptives: more concern than evidence]. / Prise de poids et contraceptifs à progestatifs seuls: plus d'inquiétude que de preuves scientifiques.

Weight gain is a side effect often associated with progestin-only contraceptives. A recently published Cochrane review focuses on this issue that has been addressed in only few studies of good quality. Here we discuss the results of this review in the context of three clinical cases. With progestin-only contraceptives the weight gain is less than often thought, especially after six or twelve months of treatment. Some results are rather reassuring, especially those in obese women and during the post-partum period. This should help improve the compliance of women who fear gaining weight with this type of hormonal contraception.

Breast Cancer Risk with Progestin Subdermal Implants: A Challenge in Patients Counseling.

There is a steady global rise in the use of progestin subdermal implants, where use has increased by more than 20 times in the past two decades. BC risk has been reported with the older progestin only methods such as oral pills, injectables, and intrauterine devices, however, little is known about the risk with subdermal implants. In this review, we aim to update clinicians and researchers on the current evidence to support patient counseling and to inform future research directions. The available evidence of the association between the use of progestin subdermal implants and BC risk is discussed. We provide an overview of the potential role of endogenous progesterone in BC development. The chemical structure and molecular targets of synthetic progestins of relevance are summarized together with the preclinical and clinical evidence on their association with BC risk. We review all studies that investigated the action of the specific progestins included in subdermal implants. As well, we discuss the potential effect of the use of subdermal implants in women at increased BC risk, including carriers of BC susceptibility genetic mutations.

A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins.

BACKGROUND: In singleton gestations, 17 alpha-hydroxyprogesterone caproate (17P) has been shown to reduce the rate of recurrent preterm birth. This study was undertaken to evaluate whether 17P would reduce the rate of preterm birth in twin gestations. METHODS: We performed a randomized, double-blind, placebo-controlled trial in 14 centers. Healthy women with twin gestations were assigned to weekly intramuscular injections of 250 mg of 17P or matching placebo, starting at 16 to 20 weeks of gestation and ending at 35 weeks. The primary study outcome was delivery or fetal death before 35 weeks of gestation. RESULTS: Six hundred sixty-one women were randomly assigned to treatment. Baseline demographic data were similar in the two study groups. Six women were lost to follow-up; data from 655 were analyzed (325 in the 17P group and 330 in the placebo group). Delivery or fetal death before 35 weeks occurred in 41.5% of pregnancies in the 17P group and 37.3% of those in the placebo group (relative risk, 1.1; 95% confidence interval [CI], 0.9 to 1.3). The rate of the prespecified composite outcome of serious adverse fetal or neonatal events was 20.2% in the 17P group and 18.0% in the placebo group (relative risk, 1.1; 95% CI, 0.9 to 1.5). Side effects of the injections were frequent in both groups, occurring in 65.9% and 64.4% of subjects, respectively (P=0.69), but were generally mild and limited to the injection site. CONCLUSIONS: Treatment with 17 alpha-hydroxyprogesterone caproate did not reduce the rate of preterm birth in women with twin gestations. (ClinicalTrials.gov number, NCT00099164 [ClinicalTrials.gov].).

Certain progestins prevent the enhancing effect of 17beta-estradiol on NO-mediated inhibition of platelet aggregation by endothelial cells.

OBJECTIVE: Estro-progestin treatments have been associated with an increased risk of thromboembolic events in postmenopausal women. This study examined whether progestins affect the stimulatory effect of estrogens on the endothelial formation of nitric oxide (NO), a potent antithrombotic factor. METHODS AND RESULTS: Experiments were performed with human endothelial cells. Endothelial NO synthase (eNOS) and GTP cyclohydrolase I (GTPCH I) mRNA expression was assessed by RT-PCR, eNOS protein by Western blotting, NO formation by electron spin resonance spectroscopy, and platelet aggregation by an aggregometer. Medroxyprogesterone acetate (MPA), progesterone, levonorgestrel, and nomegestrol acetate prevented the 17beta-estradiol (17beta-E)-induced expression of eNOS mRNA and protein. MPA and progesterone reduced the 17beta-E-induced formation of NO and potentiation of the inhibitory effect of endothelial cells on platelet aggregation whereas levonorgestrel and nomegestrol acetate were without effect. Moreover, MPA and progesterone prevented the 17beta-E-induced expression of GTPCH I mRNA. Mifepristone, a glucocorticoid and progesterone receptor antagonist, and L-sepiapterin prevented the inhibitory effect of MPA and progesterone on platelet aggregation. CONCLUSIONS: Certain progestins, including MPA, attenuate the 17beta-E-induced NO-mediated inhibition of platelet aggregation by endothelial cells through preventing both eNOS and GTPCH I expression most likely via activation of glucocorticoid receptors.

Risk of venous thromboembolism with drospirenone in combined oral contraceptive products.

OBJECTIVE: To review primary literature regarding the risk of venous thromboembolism (VTE) in users of combined oral contraceptives (COCs) containing drospirenone compared to COCs containing other progestins. DATA SOURCES: A literature search of MEDLINE and EMBASE (1950-January 2010) was conducted using the following search terms: VTE, thrombosis, thromboembolism, COC, combined hormonal contraceptives, drospirenone, Yasmin, and Yaz. Additional references were retrieved from reference citations. STUDY SELECTION AND DATA EXTRACTION: All English-language primary literature studies were evaluated for relevance. Five studies were identified for evaluation: 1 prescription event monitoring study, 2 prospective postmarketing cohort studies, 1 validation study, and 1 retrospective cohort study. DATA SYNTHESIS: Use of a COC is associated with a 3- to 6-fold increase in VTE risk compared to nonuse. This risk may vary among different oral contraceptives due to the progestin component. Studies evaluated showed that women utilizing a drospirenone-containing COC did not have a higher risk of VTE when compared to women utilizing other progestins. The crude incidence rate ratio for VTE in women taking a COC containing drospirenone compared to a COC containing other progestins ranged from 0.9 to 1.7 (95% CI 0.5 to 2.4). While the studies evaluating VTE risk were mostly large and long term, most failed to consider important risk factors for VTE such as prolonged immobility, obesity, smoking history, and family history of VTE (which could suggest a genetic predisposition to thrombotic events). It was also unclear with some of the studies whether equivalent estrogen doses were used in the comparisons. CONCLUSIONS: Several studies have evaluated the risk of VTE in users of COC-containing drospirenone compared with other progestins, and none were able to show a significantly increased risk of VTE with drospirenone. The recent media attention regarding VTE risk and drospirenone-containing COCs does not seem to be well supported by the research currently available.

Hormone therapy and fatal breast cancer.

PURPOSE: Among unanswered questions is whether menopausal use of estrogen therapy (ET) or estrogen-plus-progestin therapy (CHT) increases risk of developing fatal breast cancer i.e., developing and dying of breast cancer. Using a population-based case-control design, we estimated incidence rate ratios of fatal breast cancer in postmenopausal hormone therapy (HT) users compared to non-users by type, duration, and recency of HT use. METHODS: HT use prior to breast cancer diagnosis in 278 women who died of breast cancer within 6 years of diagnosis (cases) was compared with use in 2224 controls never diagnosed with breast cancer using conditional logistic regression. Measures taken to address potential bias and confounding inherent in case-control studies included collecting and adjusting for detailed data on demographic and other factors potentially associated both with HT use and breast cancer. RESULTS: Fifty-six per cent of cases and 68% of controls reported HT use. Among current 3+ year HT users, odds ratios and 95% confidence intervals for death were 0.83 (0.50, 1.38) and 0.69 (0.44, 1.09), respectively, for exclusive use of CHT or of ET, and were 0.94 (0.59, 1.48) and 0.70 (0.45, 1.07) for any use of CHT or of ET regardless of other hormone use. CONCLUSION: Point estimates suggest no increased risk of fatal breast cancer with HT use, although 50% increases in risk in longer-term current CHT users cannot be ruled out.

Hypertension in women: the role of progesterone and aldosterone.

The age-related course of blood pressure and its gender-related difference, as well as the incidence of hypertension, have been the subject of multiple experimental, clinical and epidemiological studies over the past decades. The role of the sex hormones estradiol and testosterone within this gender dimorphism has been investigated without conclusive results. In this review, we provide background information on the gender difference in blood pressure, describe the impact of progesterone and aldosterone, and discuss the pathophysiology of aldosteronism as well as the potential role of drospirenone as a gender-specific agent for the prevention and treatment of hypertension and for cardiovascular protection.

Different cardiovascular effects of progestins according to structure and activity.

Following the publication of the Women's Health Initiative study, the controversy was raised regarding the role of progestins in hormonal replacement therapy (HRT). Some of the most prescribed molecules, with partial androgenic or glucocorticoid activity, have been shown to oppose partially the beneficial effect of estrogens on surrogate markers of cardiovascular disease risk. Unfortunately, this concern has been directed towards progestins as a class effect, although striking differences exist among the types of molecules used. The synthetic progestins used in HRT have varying pharmacologic properties depending on the molecules from which they are derived, either testosterone or progesterone. Very small structural changes in these molecules may induce considerable difference in their effects on various targets and especially on the surrogate markers of cardiovascular disease risk, where some molecules may reverse the beneficial effects of estrogen. Natural progesterone and some of its derivatives such as the 19-norprogesterone molecules or the new molecules drospirenone, a potent antimineralocorticoid agent with a beneficial effect on blood pressure, and dienogest do not exert any androgenic effect and have no negative effect on the lipids or on the endothelial cells. Although it is likely that the new progestins may be neutral on the coronary disease risk, when administered to the younger postmenopausal woman, this has not as yet been documented by large, randomized, controlled trials.

[Low dose oral contraceptives: 30 microg are still used?]. / Contraccettivi a basso dosaggio: quelli contenenti 30 microg sono ancora da prescrivere?

The choice between oral contraceptives (OC) containing 30 or 20 microg of ethinylestradiol (EE) is founded on clinical sign and medical history of the women. Not always a lower dose of EE cause less side effects than an higher dose. Often 20-microg-EE OC induces menstrual cycle alterations and sexual dysfunctions, inducing the women to stop the treatment. Low estrogens concentration have a negative effect on external genital tract, with a consequent vaginal dryness and dispareunia. It is known that OC with 20-microg of EE determine a lower increase of sex hormone binding globulin compared to 30 mg EE and the consequence can be a reduction in antiandrogen effect of OC. OC containing 30 microg of EE have a positive effect on peak in young women, particularly in lean subjects. Moreover, 30 microg of EE induce a better ovarian suppression associated with a lower steroidal production during the week of interruption. Besides, 30-microg-EE OC works well in blocking ovarian cysts formation in women with endocrine dysfunctions like polycystic ovary syndrome or with previous luteal cysts. In conclusion, an OC with 30 microg of EE and an antiandrogen progestin is better than another with 20 microg of EE with the same progestin, because 30 microg of EE have a more powerful antiandrogenic action and guarantee very good cosmetics and endocrine results.

The Femilis LNG-IUS: contraceptive performance-an interim analysis.

OBJECTIVE: To provide an update on the experience with the Femilis levonorgestrel-releasing intrauterine system (LNG-IUS) used for up to five years by parous and nulliparous women, particularly with regard to its contraceptive performance. STUDY DESIGN: An interim, open, prospective non-comparative study of the Femilis LNG-IUS releasing 20 microg of levonorgestrel/day. RESULTS: Two-hundred and eighty insertions were carried out in women with a mean age of 35.7 years (range 17-48), 60% of whom were parous and 40% nulliparous. Twenty-four women with uterine pathology (e.g., fibroids, menorrhagia) were included in the study. The cumulative gross discontinuation life table rates were determined. The total observation period was 8,028 woman-months. The LNG-IUS was easy to insert in 95.7% of the cases, and no perforations occurred. No pregnancies were observed and only one expulsion took place (rate 0.4/100 women at five years). The cumulative total use-related discontinuation rate was 14.7/100 at five years. There were nine removals because of pain, six of which were in nulliparous women. Four women requested removal of the IUS for bleeding problems. Fourteen removals were done for 'other' medical reasons among which mood disturbances (five cases) were the most frequent, and 12 for non-medical reasons. Fifteen removals were requested for pregnancy wish. Twelve of these women became pregnant within one year and all had uneventful pregnancies. The Femilis LNG-IUS was equally well accepted by nulliparous as by parous women. Most women with heavy menstrual bleeding prior to insertion, whether associated with fibroids or not, reported much less bleeding, scanty bleeding or even no bleeding at all after insertion. CONCLUSION: This study suggests that the Femilis LNG-IUS, which releases 20 microg LNG/d, is a highly effective, well tolerated and well retained contraceptive both in parous and nulliparous women. The shorter crossarm of the LNG-IUS has simplified its insertion technique, which may contribute to its safety. This could promote use by non specialist providers and enhance the application of the method.