Amaury Teixeira Leite Andrade

Quantitative studies on menstrual blood loss in IUD users.

Despite the introduction of new intrauterine devices (IUDs), the most important complication involving their use continues to be excessive menstrual bleeding. IUD use in developing countries with women who are already depleted in body iron stores may prove to be deleterious to their health. Mean amounts of menstrual blood loss (MBL) for women not using contraception in the western world is about 32 ml. This mean is increased to 52-72 ml with use of the Lippes loop and other non-medicated devices up to 24 months after insertion. For the Copper-7 and Copper-T-200 devices this mean increase is to 37-40 ml in the first month, decreasing to 30-38 ml at 12 months after IUD insertion. In the users of the Multiload-250 IUD at one month post-insertion the MBL is from 56 to 63 ml and from 36 to 39 ml at 24 months of use. The mean Multiload-375 device users at one month after insertion lose a mean of 45-73 ml at 24 months, 35-50 ml. With the progestogen-releasing IUD mean MBL is 27-36 ml at 1 month and 9-13 ml at 12 months post-insertion. Intermenstrual blood loss is significant only in the first month of use for all IUDs. Discontinuation rates for pain and bleeding with non-medicated IUDs are from 11.0-19.6 per 100 women per year, and for the copper IUDs 4.4 to 6.8 per 100 women in the first year of use. The main problem with prolonged menstrual bleeding is depletion of the body iron stores; this is highly significant with non-medicated devices, less important with copper devices and conversely, iron stores are increased in users of progestogen-releasing devices. This is based on serum ferritin measured up to 24 months after insertion. The ferritin values correlated well with the volumes of MBL. It is suggested, especially for women with low body iron stores, that there is an order of preference for IUDs to be used. This should be: firstly, the progestogen-releasing devices; secondly, the Copper-T and Copper-7 IUDs; thirdly the larger surface copper devices (Cu-T-220C, Multiload 250 and 375, Cu-T-380). Non-medicated devices are not to be recommended for these women.

Consequences of uterine blood loss caused by various intrauterine contraceptive devices in South American women

Increased menstrual blood loss (MBL) associated with intrauterine device (IUD) use may precipitate or aggravate iron deficiency anaemia, adversely affecting the health of women particularly those from developing countries. Studies were conducted to define the association of MBL and iron status in South American women; to determine the level of MBL induced by IUD use which would result in iron depletion, the length of time for this depletion to occur and, comparing various IUDS, to determine if any currently tested IUDs are suited to long-term use in South American women. A total of 395 women received one of 5 types of IUDs in Santiago, Chile, and Juiz de Fora, Brazil: Lippes Loop, Multiload-250 and Multiload-375 were used in both centres; in Santiago some subjects received the Copper-7 or ProgestasertR devices and in Juiz de Fora, the TCu 200 and the T-Chloroquin IUDs were also tested. MBL and haemoglobin (HGB) were measured for 3 menstrual cycles before insertion, and following insertion, at one, two, four, six, nine, twelve, eighteen and twenty-four months in the majority of cases. Serum ferritin was measured before insertion and at intervals of six months. Mean values of MBL prior to IUD insertion in both centres varied from 21-30 ml. As with previous publications, the use of the Lippes Loop was associated with the greatest increase in MBL which was sustained throughout the 24 months of observation. Women who had one of the two types of Multiload devices inserted also had increased MBL and reduced ferritin for at least 12 months of use. TCu 200 and Copper-7 IUD users had an initial increase in MBL of 1 to 17 ml in the first six months of observation returning to normal levels beyond six months. Serum ferritin levels were lower for one year and then returned to admission values. ProgestasertR users confirmed previous reports of a reduction of 40-50% in MBL and an increase in serum ferritin. Few significant changes in haemoglobin (HGB) concentrations were found. Serum ferritin levels on admission ranged from 7.1 to 16.4 ng/ml in Santiago and from 15.8 to 23.2 ng/ml in Juiz de Fora. Many women were in a marginal state of iron balance as evidenced by lower serum ferritin values. Changes in serum ferritin were very closely related to those in MBL.(ABSTRACT TRUNCATED AT 400 WORDS)

Contraceptive effects of native plants in rats

Abstract To study the effects of Gossypium herbaceum L. and Ruta graveolens upon implantation, extracts of these plants were administered to pregnant rats at different doses and routes. The results show that both extracts produce inhibitory effects on implantation, with an important loss of eggs.

Menstrual blood loss in women using the frameless FibroPlant® LNG-IUS

BACKGROUND This study was conducted to report on a menstrual blood loss (MBL) study and iron stores in women with and without heavy menstrual bleeding using the frameless FibroPlant levonorgestrel-releasing intrauterine system (LNG-IUS) for contraception. STUDY DESIGN An open, prospective, noncomparative MBL study, using FibroPlant releasing 14 mcg of LNG/day for contraception. MBL was assessed by the quantitative alkaline hematin (QAH) technique. RESULTS The MBL study was conducted in 40 heavy and normally menstruating Brazilian women seeking contraception. MBL was reduced from a mean baseline menstrual volume of 29.7 mL to a mean volume of 1.5 mL after 24 months, while ferritin values increased from a mean value of 31.1 ng/mL (at baseline) to a mean level of 72.5 ng/mL (after 24 months of use). Differences were highly significant (p<.0005). There were no significant differences between those who had normal menstrual bleeding and the heavy bleeders. The heavy bleeders had comparable MBL to the normal bleeders 3 months after insertion, and by 24 months post-insertion, their ferritin levels were comparable to those of the normal bleeders. Amenorrhea occurred in 80% of women out of 40 after 24 months of use. No pregnancies were recorded. CONCLUSION The LNG-IUS is effective in reducing MBL in normally menstruating women as well as in women with heavy menstrual bleeding. The authors agree with the recommendations by the UK National Institute for Clinical Effectiveness and the new Finnish guidelines for heavy menstrual bleeding that the LNG-IUS should be positioned as first-line treatment prior to endometrial ablation or hysterectomy.

Quantitative menstrual and intermenstrual blood loss in women using Lippes Loop and Copper T intrauterine devices

127 women were studied during 3 consecutive menstrual cycles preceding, and 6 non-consecutive menstrual cycles during the 1st year following insertion of either Lippes Loop C or Copper T. Both (MBL) menstrual blood loss and (IMBL) intermenstrual blood loss were quantified during these cycles. When postinsertion MBL was averaged and compared to mean preinsertion MBL, the Lippes Loop and Copper T devices increased the volume of menstrual bleeding by 99 and 42% respectively. In spite of this, mean hemoglobin levels did not change significantly during the period of study. Quantifiable MBL was experienced primarily during the 1st cycle postinsertion. The incidence was 90% in women inserted with the Lippes Loop C and 48% in those women inserted with the Copper T during this cycle. The volume of IMBL was extremely variable among the women studied (0.7 - 398 ml). In several cases the volume nearly equalled or even exceeded the MBL of the 1st cycle. Incidence of IMBL fell to 6.5% and 5.0% in the 2nd postinsertion cycle for women with loops and copper devices, respectively. Thereafter the incidence was neglibible. This marked decrease in incidence was not due to closures for bleeding. Less than 10% of the total blood loss experienced during the 1st year postinsertion was the result of IMBL and following the 1st postinsertion cycle, it contributed less than 2% of the total blood loss. The conclusion is that IMBL, while contributory to IUD discontinuation rates, does not contribute significantly to total blood loss and thus to iron loss following IUD insertion.

Pinealectomy and blindness during pregnancy in the rat

Little alludes to the possibility of transplacental transmission of herpes simplex, and there is a paucity of data regarding the efficacy of abdominal delivery.? Amstey’ reviewed the neonatal outcome of infants delivered abdominally of mothers with genital herpetic lesions. He cites a case wherein a term infant died from herpes infection after abdominal delivery although the membranes were intact. This case is interesting from several standpoints. Advanced and marked scarring lesions at birth suggest intrauterine infection of a minimum of one to two weeks’ duration. Positive Immunoglobulin M antibodies to herpes suggest further an infection of at least two weeks’ duration prior to delivery. Since the infant was delivered within 24 hours of membrane rupture, an ascending and contact mode of transmission may be excluded. The foregoing presents the likelihood of transplacental dissemination, which may influence clinical judgment regarding abdominal delivery in selected cases.

Effects of a continuous-combined regimen of low-dose hormone therapy (oestradiol and norethindrone acetate) and tibolone on the quality of life in symptomatic postmenopausal women: A double-blind, randomised study

OBJECTIVE This study compared the effects of a continuous-combined regimen of low-dose hormone therapy (LD-HT) versus tibolone and supplemental calcium/vitamin D3 (control) on quality of life (QoL) in symptomatic postmenopausal women. DESIGN This study was a prospective, randomised, double-blind, comparative trial with a control group. SETTING The study was conducted in a climacteric outpatient clinic in the University Hospital of Federal University of Juiz de Fora, Brazil. POPULATION A total of 174 postmenopausal women under 60 years of age who attended the climacteric outpatient clinic between June 2009 and June 2011 were recruited. These women complained of moderate or intense vasomotor symptoms and exhibited no contraindications for the use of hormone therapy. INTERVENTIONS The patients were randomised into three groups: (1) daily treatment with 2.5mg tibolone (n=64), (2) 50mg calcium carbonate+200 IU vitamin D3 (Ca/Vit D3, n=54) or (3) 1mg oestradiol+0.5mg norethindrone acetate (E2/NETA, n=56) for 12 weeks. PRIMARY OUTCOME MEASURES The primary outcome was the evaluation of QoL using the Womens Health Questionnaire (WHQ) in all subjects at baseline and after 4, 8 and 12 weeks of treatment. RESULTS A total of 130 women in the following groups completed the study: tibolone (n=42), Ca/Vit D3 (n=44) and E2/NETA (n=44). An improved QoL based on the WHQ was observed at T0 (80.12±14.04, 77.73±15.3, 77.45±15.4) and T12 (57.0±15.5, 55.7±16.7, 58.4±12.6) for the tibolone, E2+NETA and Ca/Vit D3 groups, respectively (p values <0.05). The three groups exhibited significantly different scores at T12 for sexual behaviour and vasomotor symptoms. The tibolone group exhibited better sexual function compared with the E2/NETA and Ca/Vit D3 groups (4.2±26, 5.6±2.8, 5.4±2.8, respectively, p values <0.05). LD-HT was superior to tibolone and Ca/Vit D3 treatment for improvements in vasomotor symptoms (3.2±1.5, 4.0±1.8, 4.3±2.0, respectively, p values <0.05). Adverse effects were few and mild. CONCLUSIONS An improved QoL was observed in the three study groups. Tibolone primarily improved sexual function, and E2/NETA exhibited a superior response for vasomotor symptoms.

Femilis® 60 Levonorgestrel-Releasing Intrauterine System—A Review of 10 Years of Clinical Experience

Objective The aim of this study was to update the clinical experience with the Femilis® 60 levonorgestrel-releasing intrauterine system (LNG-IUS), now up to 10 years in parous and nulliparous women, particularly with regard to ease and safety of insertion, contraceptive performance, retention, acceptability, continuation of use, impact on menstrual blood loss (MBL), and duration of action. Study Design Using the Femilis® 60 LNG-IUS releasing 20 μg of levonorgestrel/day, the following studies were conducted: an open, prospective noncomparative contraceptive study, an MBL study, a perimenopausal study, a study for the treatment of endometrial hyperplasia, and early cancer of the uterus, a residue study. Results A total of 599 Femilis LNG-IUS were inserted in various clinical trials, the majority for contraceptive purposes. The total exposure in the first and second contraceptive studies, covering 558 parous and nulliparous women, was 32,717 woman-months. Femilis has high contraceptive effectiveness as only one pregnancy occurred. Expulsion of the LNG-IUS was rare with only two total and no partial expulsions (stem protruding through the cervical canal) occurred. Femilis was well tolerated, with continuation rates remaining high. Several MBL studies were conducted, totaling 80 heavy and normal menstrual bleeders, using the pictorial bleeding assessment chart method or the quantitative alkaline hematin technique. Virtually all women responded well with strongly reduced menstrual bleeding. Amenorrhea rates were high, up to 80% after three months, and ferritin levels simultaneously increased significantly. The Femilis LNG-IUS was tested in 104 symptomatic perimenopausal women for seamless transition to and through menopause, adding estrogen therapy when required. Patient tolerability appeared high as >80% requested a second and a third LNG-IUS. Twenty women presenting with nonatypical and atypical hyperplasia and one woman presenting with early endometrial carcinoma were treated with Femilis LNG-IUS. All histology specimens showed full regression, and patients remained in remission without signs of hyperplasia or cancer at yearly and ongoing follow-up examinations up to 10 years. Residual content of LNG was measured in 37 women having the Femilis LNG-IUS for up to 10 years. In 10 of the 102 women who had the Femilis 60 in situ for 10 years between 20% and 30% of the original 60 mg was recovered confirming the long duration of action of the Femilis 60 LNG-IUS. Conclusion These studies suggest that the Femilis 60 LNG-IUS releasing 20 μg of LNG/day is an effective, well-tolerated, and well-retained contraceptive both in parous and in nulliparous women. The design of the LNG-IUS, with flexible transverse arm(s) length of 28 mm, allows for a simplification of the insertion technique and training requirements facilitating the use by nonspecialist providers in either developed or developing countries. For nulliparous women, additional evaluation of devices with a 24 mm transverse arm(s), as it relates to tolerability, retention, and continuation of use, still needs to be undertaken.

Commentary--A historical note on the development of the frameless IUD.

To the Editor: We would like to make a comment on the article which was published recently: “The frameless copper IUD (GyneFix) and the TCu380A IUD: results of an 8-year multicenter randomized comparative trial” [1]. When investigators meetings and training sessions were organized prior to the start of the study, it was apparent that the inserter, called FlexiGard® (not GyneFix® as the title wrongly indicates), had several important shortcomings and could not be used as such in clinical trials. The manufacturer (and licensing partner) at that time made some improvements, but when the WHO randomized comparative study started in 22 centers, the FlexiGard® inserter still had some shortcomings (Fig. 1). As a consequence, the device was recalled twice, each time for a period of approximately 6 months. Following assessment and correction of some of the shortcomings, the studies resumed, without conducting new training sessions. The number of failed insertions due to no or incorrect anchoring was high and resulted in too many early expulsions, as demonstrated in the published paper [1]. It was clear that the inserter should be further improved and that proper training should be conducted. The following comment was made in the 3-year interim publication, published in this journal: “Because of the shortcomings of the FlexiGard® inserter, the complexity of the insertion technique, and the failure to correct the inserter problems during the study, the value of the new concept could not be fully appreciated” [2]. In the meantime, the licensing partner also prepared multicenter clinical trials in Europe and the US. When these studies started, with the same FlexiGard® inserter, it was not surprising that similar, or even worse, problems due to the shortcomings of the inserter occurred. Amazingly, some investigators had no failed insertions, while others had failed insertions and expulsions in up to 20% as some investigators were not properly trained. The results of these studies were reported and published, but the title of the paper mentioned wrongly the comparison between TCu380A IUD with the Cu-Fix IUD, instead of the FlexiGard® IUD [3]. This was clarified in a letter of 8 August 1996 to the authors of the article [4]. The least we can say is that the problems created by the shortcomings of the FlexiGard® inserter, and which were not corrected either during the WHO or during the EU–US randomized comparative trials, created an important bias. This was confirmed in clinical trials with the optimized inserter, later called GyneFix® (Fig. 2). The results of these trials, conducted in Europe, Latin America and China, were reviewed and published in 2003 [5]. It was concluded from these studies that the implantation technology is very effective and that the improved inserter allows reliable insertion and secure anchoring. As the technique of anchoring is completely new, insertion training is essential. This was unfortunately not Contraception 81 (2010) 172–176

Intrauterine levonorgestrel delivery with frameless fibrous delivery system: review of clinical experience.

The concept of using a frameless intrauterine device (IUD) instead of the conventional plastic framed IUD is not new. Frameless copper IUDs have been available since the late 1990s. They rely on an anchoring system to retain in the uterine cavity. The clinical experience with these IUDs suggests that frameless IUDs fit better as they are thin and, therefore, do not disturb or irritate the uterus. High tolerance and continuation rates have been achieved as complaints of pain are virtually nonexistent and the impact on menstrual blood loss is minimal. Conventional levonorgestrel-releasing intrauterine systems (LNG-IUSs) are very popular as they significantly reduce menstrual bleeding and provide highly effective contraception. However, continuation of use remains problematic, particularly in young users. Total or partial expulsion and displacement of the LNG-IUS also occur too often due to spatial incompatibility within a small uterine cavity, as strong uterine contractions originate, attempting to get rid of the bothersome IUD/IUS. If not expelled, embedment ensues, often leading to chronic pain and early removal of the IUD/IUS. Several studies conducted recently have requested attention to the relationship between the LNG-IUS and the endometrial cavity. Some authors have proposed to measure the cavity width prior to inserting an IUD, as many uterine cavities are much smaller than the currently existing LNG-IUSs. A frameless fibrous drug delivery system fits, in principle, in all uterine cavities and may therefore be preferable to framed drug delivery systems. This review examines the clinical performance, acceptability, and potential of the frameless LNG-IUS (FibroPlant®) when used for contraception, treatment of heavy menstrual bleeding, dysmenorrhea, and endometrial suppression in women using estrogen replacement therapy, endometrial hyperplasia, and other gynecological conditions. The review concludes that FibroPlant LNG-IUS offers unique advantages in reducing side effects.