Abstract
Objective. To evaluate the acceptability and endometrial safety of a novel intrauterine drug delivery system, FibroPlant- levonorgestrel (LNG), combined with estrogen therapy (ET) in 150 peri- and postmenopausal women, followed-up for at least 3 years.
Design. This was a prospective, non-comparative study in peri- and postmenopausal women. In the majority of women, treatment with the FibroPlant-LNG intrauterine system (IUS), combined with ET, was initiated during the perimenopausal transitional phase to establish a smooth transition to menopause and suppress the endometrium to prevent endometrial proliferation and bleeding. A 3.5-cm long coaxial fibrous delivery system, delivering approximately 14 g LNG/ day, was used. The calculated duration of release of the system is at least 3 years. The majority of women received percutaneous 17 β-estradiol (Oestrogel), 1.5 mg daily on a continuous basis, which provides sufficient blood levels of estrogen in most women to suppress climacteric symptoms and protect against bone loss.
Outcome measures. To measure acceptability, women were asked, after they had the IUS in place for a minimum of 3 years, if they would like to continue the combined regimen and if they would accept renewal of the IUS. Endometrial safety was evaluated by transvaginal ultrasound examination and endometrial biopsy in a subset of 101 women prior to replacement of the IUS.
Results. Ninety-four insertions were done in perimenopausal and 56 in postmenopausal women aged between 33 and 78 years. Of the total group of 150 women, 132 women (88.0%) accepted replacement of the IUS and ten are waiting for replacement. This group includes nine women who will receive a second replacement. The number of women continuing the method is 142 (94.6%). Histological examinations conducted on endometrial biopsies from 101 postmenopausal women prior to replacement, after an average period of use of the regimen of 40 months (range 25-50 months), showed predominantly inactive endometrium characterized by pseudodecidual reaction of the endometrial stroma with endometrial atrophia, which is in keeping with the effects seen with a progestogenic compound. There were no specimens showing signs of proliferation.
Conclusions. Results suggest that the frameless FibroPlant-LNG IUS is safe, well tolerated, well accepted and effective in suppressing the endometrium during ET. Intrauterine progestogen administration in postmenopausal women can be regarded as fundamentally advantageous compared with systemically applied progestogens, which may have potentially inherent ill side-effects, especially on the breast and cardiovascular system, as reported in the recent literature.
Keywords: Intrauterine drug delivery system, progestogens, progestins, levonorgestrel, hormone therapy, perimenopause, postmenopause
Introduction
The primary role of progestogen in peri- and postmenopausal hormone therapy is endometrial protection to prevent hyperplasia [1]. Prior to the widespread use of combined estrogen-progestogen therapy (EPT), the risk of developing hyperplasia due to unopposed estrogen stimulation was substantial. Endometrial hyperplasia in postmenopausal women with an intact uterus, treated with unopposed oral estrogen, was found in 20% of women during the first year and in 62% after 3 years of estrogen therapy (ET), compared with untreated controls [2]. Hyperplasia is characterized by a proliferation of the endometrial glands. In non-atypical (simple) hyperplasia, the glands are normal but, in atypical hyperplasia, glandular abnormality is present both structurally and at cellular level [3]. Non-atypical hyperplasia rarely progresses to more severe conditions. Atypical adenomatous hyperplasia, on the other hand, has been observed to progress to adenocarcinoma of the uterus in 29% of cases [4]. Progestogens should therefore be added to ET in all postmenopausal women with an intact uterus.
Since the mid-1980s, EPT has increasingly been prescribed. The North American Menopause Society recently reviewed the types of EPT regimen used in the USA and concluded that standard regimens provide adequate endometrial protection [I]. A Cochrane review devoted to this subject also came to the conclusion that the addition of an oral progestin to ET, administered either continuous cyclic or continuous combined, is associated with reduced rates of hyperplasia [5].
An important drawback of postmenopausal EPT is the occurrence of withdrawal or breakthrough bleeding. Withdrawal uterine bleeding occurs in 80% of women using cyclic EPT. Continuous-combined regimens avoid withdrawal bleeding, but breakthrough bleeding has been observed in up to 40% of women during the first 6 months. Most postmenopausal women dislike breakthrough bleeding and this is the commonest reason for discontinuation and non-adherence to the treatment regimen. With EPT, therefore, irregular bleeding should be kept to a minimum.
Depending on the EPT type, dose and route of administration, progestogens may have adverse effects on the cardiovascular system and breast tissue. The Women’s Health Initiative (WHI) reported an increased risk of heart disease, stroke and breast cancer [6]. Since these adverse effect were not observed with ET alone, it is speculated that adding progestogens may diminish the beneficial effects on atherosclerosis, vasodilatation and plasma lipids and may contribute to the increased risk of breast cancer.
Indeed, the WHI suggests that EPT may stimulate breast cancer growth and hinder breast cancer diagnosis due to increased mammographie density when a progestogen is added to ET [7,8]. This was recently confirmed in the Million Women Study and other studies, in particular the Swedish cohort study [9,11].
Intrauterine-administered progestogen, such as levonorgestrel (LNG), delivered to the target cells of the endometrium, has a profound suppressive effect on endometrial growth rendering the endometrium inactive and simultaneously eliminating uterine bleeding [12-14]. Pharmacokinetic studies with an intrauterine system (IUS) releasing 20 g LNG (Mirena; Schering AG, Germany) have shown substantially lower plasma concentrations than those seen with a subdermal LNG implant (Norplant; Wyeth PHARMACEUTICALS Inc, USA), the combined oral contraceptive pill and the mini-pill; moreover, unlike with oral contraceptives, LNG levels with the Mirena IUS do not display peaks and troughs [15]. This is important because the low plasma levels may have a significantly lower impact on organ tissues such as the breast and cardiovascular tissue.
The present study reports the interim results of a continuous- combined estrogen plus low-dose LNGreleasing IUS after more than 3 years of use in periand postmenopausal women, and provides data on the endometrial morphology during use of the IUS to evaluate endometrial safety.
Methods
Description of the FibroPlant-levonorgestrel intrauterine system
The FibroPlant-LNG IUS is an anchored LNG-releasing device. It is a multicomponent system consisting of a non-resorbable thread of which the proximal end is provided with a single knot. Attached thereto is a 3.5-cm long and approximately 1-2-mm wide fibrous delivery system, releasing approximately 14 g LNG/day. The fiber is fixed to the anchoring thread by means of a metal clip 1 cm from the anchoring knot. The anchoring knot is implanted into the myometrium of the uterine fundus using an insertion instrument, so permanently securing the implant in the uterine cavity (Figure 1). The metal clip allows visibility of the system on ultrasound and X-ray, allowing proper location of the IUS in the uterine cavity at insertion and on follow-up (Figure 2). The anchoring knot is also visible on ultrasound. Measuring the distance between the surface of the uterus and the metal clip (S-S distance) indicates whether the FibroPlant system has been properly anchored. In contrast with framed drug delivery systems, such as the T-shaped, LNG-releasing Mirena’ IUS, the FibroPlant-LNG IUS has no frame and so is completely flexible, adapting to cavities of every size and shape.
Based on in vitro study, the rate of LNG release is constant over several years. The duration of release, calculated by extrapolation, is more than 3 years. The fibrous delivery system was developed in cooperation with the Polymer Research Group, Department of Chemistry, University of Ghent, Ghent, Belgium.
Figure 1. The FibroPlant-levonorgestrel intrauterine system after insertion in a uterine model.
Figure 2. Ultrasound visualization of the endometrium in the presence of the FibroPlant- levonorgestrel intrauterine system (Aloka SS3500 with high-resolution, 7-10 MHz broadband vaginal sound).
Admission
Perimenopausal (the perimenopause is defined as the period immediately prior to menopause and the first year after the menopause) and postmenopausal (the postmenopause is the period following the final menstrual period) women who consulted with climacteric symptoms or menstrual problems were enrolled in the study. To minimize the dropout rate, great attention was paid to explaining the advantages and possible disadvantages of the replacement therapy. Women were told they could expect scanty interme\nstrual bleeding during the first weeks or months but that this is a normal side-effect which usually disappears in time and should not be a cause of concern. Use of the study product was approved by the Ethics Committee of the University of Ghent, Belgium and written informed consent was obtained. Prior to the insertion procedure, a medical history was taken and a pelvic examination was carried out, and the patient was checked for any clinical signs of sexually transmitted diseases (STDs). Since women included in the study were at low risk for STDs, no routine chlamydia tests were done. All women were screened for their clinical suitability for insertion of an intrauterine device and compliance with World Health Organization eligibility criteria [16]. Women with the following conditions were excluded: clinical cervicitis or vaginitis (infection should be ruled out); sound length greater than 10 cm; history of pelvic inflammatory disease, genital actinomycosis or chronic pelvic pain; blood clotting disorder and/or undiagnosed genital tract bleeding; known or suspected uterine or cervical malignancy including unresolved, abnormal PAP smear; congenital malformation of the vagina, cervix or uterus; postpartum endometritis or history of infected abortion; leukemia; currently receiving corticosteroid or immunosuppressive therapy; and congenital valvular heart disease. Uterine status was evaluated by transvaginal ultrasound examination prior to insertion of the implant system to exclude uterine abnormalities. In the event that basal and parabasal cells were found on a wet vaginal smear, indicating an atrophie status of the uterus, ET was started immediately and insertion of the FibroPlant system was postponed until the uterus was sufficiently primed and a wet smear showed the absence of parabasal cells (usually 1 month later). All insertions were performed in the majority of women without local or intracervical anesthesia. Following insertion, a transvaginal ultrasound was performed to locate the device in the uterus.
Estrogen was administered as either a percutaneous estrogen- containing gel (Oestrogel; Besins Intern, Belgium) in a dosage of 0.75-1.5 mg/day or a transdermal matrix system (Systen; Janssen- Cilag, Belgium), in a dosage of 50 g/day.
Follow-up and device replacement
Women were followed-up at 1, 3, 6 and 12 months following insertion of the IUS and every 6 months thereafter. They were asked about their bleeding pattern and any side-effects or adverse reactions. A gynecological examination was performed as well as a transvaginal ultrasound to locate the implant and to evaluate the thickness of the endometrium according to Fleischer and colleagues [17].
To measure acceptability, women were asked, after they had the IUS in place for a minimum of 3 years, if they would like to continue estrogen replacement therapy and if they would accept renewal of the IUS. If they accepted, an appointment was scheduled to remove the FibroPlant-LNG IUS and insert a new device immediately.
Endometrial biopsy
To assess the impact of the regimen on the endometrium, an endometrium biopsy was taken with a suction curette (Probet; Gyntics, Belgium) prior to device replacement in at least 100 consecutive women reporting for follow-up, to confirm the transvaginal ultrasound findings. This number was considered sufficient because the effects of LNG on endometrial morphology are well known. The samples were drawn from all parts of the uterus to get a representative picture. The biopsies were placed in phosphate- buffered formaldehyde 4% immediately upon collection and stained with hematoxylin and eosin for examination. They were examined by two pathologists according to the diagnostic categories of Hendrickson and Kempson [18].
Data collection, monitoring and analysis
Data were recorded on standard pre-coded forms at admission, at each scheduled and unscheduled follow-up visit, and upon discontinuation from the study. The cut-off date was 31 August 2003. All data were sent to the data-coordinating center at the Department of Medical Informatics and Statistics, University Hospital Ghent, Belgium, for providing statistical data analysis for the study. The rates of discontinuation for individual reasons and groups of reasons were analyzed using the S-PLUS statistical software package (MathSoft Corp., Cambridge, MA, USA) [19] and the cumulative discontinuation rates were computed using survival analysis methods [20,21].
Results
Between 21 April 1997 and 19 June 2000, the FibroPlant-LNG implant system was inserted in 150 perimenopausal and postmenopausal women. Ninety-four insertions were done in perimenopausal and 56 in postmenopausal women aged between 33 and 78 years (Table I). Insertion was difficult in two postmenopausal women due to cervical stenosis, necessitating sounding and dilatation of the cervical canal. In four perimenopausal women fibroids were present, classified as single or multiple intramural and subserosal fibroids ( > 6 cm) with no evidence of submucosal fibroids.
The events and cumulative gross discontinuation rates are presented in Table II. Of the total group of 150 women, 132 (88.0%) accepted replacement of the IUS and ten are waiting for replacement. This group includes nine women who will receive a second replacement. The total number of women continuing with the method is 142 (94.6%). There were five (3.3%) removals for medical reasons (one for abnormal bleeding, one for pain complaints, one for ‘suspicion’ of pelvic infection by a colleague, one prior to surgery for a para-ovarian tumor and one for weight gain). One woman was released from follow-up due to non-compliance with the study requirements. She had ambiguous feelings about the benefits and risks of EPT although she was symptom-free and had a normal gynecological examination at the time of her last visit.
Table I. Characteristics of the 150 users of the FibroPlant- levonorgestrel intrauterine system: age distribution.
Table II. Events and cumulative gross continuation and discontinuation rates (with standard error in parentheses, expect specified otherwise) per 100 women in 150 users of the FibroPlant- levonorgestrel intrauterine system (IUS).
There were no expulsions of the anchored FibroPlant-LNG IUS. The study, with total number of women-months of use of 6063, was well followed-up. The average number of months with the device in situ was 40 (range 4-70). Only two women (1.3%) were lost from the final analysis.
Histological examinations conducted on endometrial biopsies from 101 postmenopausal women prior to IUS replacement, after an average period of use of the method of 40 months (range 25-50 months), showed predominantly inactive endometrium characterized by pseudodecidual reaction of the endometrial stroma with endometrial atrophy. There were no specimens showing signs of proliferation (Figure 3).
A thin endometrium (
No side-effects of the progestogen (breast tenderness, bloating, headaches, acne, mood swings, depression) were reported. Slight scanty and infrequent bloody discharge requiring no protection, or a small panty liner, occurred in some women during use of the regimen, usually for a very short duration in postmenopausal women and those close to menopause. In a minority of women, this erratic blood- stained discharge lasted longer. However, only one woman requested removal of the IUS for this reason. No serious adverse effects were observed (e.g., pelvic inflammatory disease, perforation). One patient complained of abdominal pain each time she replaced a transdermal patch. There were no expulsions of the IUS recorded.
Figure 3. Photomicrograph showing endometrial atrophy and decidualization of the stroma in a woman using combined estrogen therapy with a low-dose intrauterine levonorgestrel-releasing system (hematoxylin and eosin staining, 20).
Discussion
In 1995, Sarrel described the cardiovascular benefits of ET and how progestins compromise the cardioprotective effect of estrogens [22]. The survey provided evidence that progestins have an anti- estrogenic effect and can potentially counteract the beneficial effects of co-administered estrogens, this effect being dose- and duration-dependent. More recently, several reports on the cardiovascular effects of various types of progestogens, combined with ET, have been published. Following publication of the WHI [6] and Heart and Estrogen/progestin Replacement Study (HERS) [23] reporting significant risks with EPT, it was recommended not to initiate any ET or EPT for primary or secondary prevention of coronary heart disease. The conclusions from the WHI and HERS are in contradiction with earlier observational studies and experiments conducted in humans and animals as reported by Sarrel and others. The approach followed by our group is in line with the recommendations by Sarrel to develop intrauterine systems that deliver a progestin directly to the target structure, the endometrium, to avoid reversal of the potential beneficial effect of systemic ET and to minimize adverse effects. Endometrial studies showed that even 5 g LNG/day is sufficient to suppress the endometrium [24,25].
Previous studies with a FibroPlant-LNG system releasing 14 g/day for the treatment of endometrial hyperplasia suggested that it is an effective method for suppressing the endometrium in women with non- atypical and atypical hyperplasia, indicating the strong anti- proliferative effect on the endometrium of this low-dose, locally applied, potent progestin [26]. In 101 consecutive women in the present study, an endometrial biopsy was performed during treatment. No hyperplasia was detected. A similar low incidence (0%) of hyperplasia in postmenopausal women receiving ET and a low-dose LNG IUS has been observed in other studies [2]. Intrauterine proges\togen delivery, particularly LNG, is probably more effective in postmenopausal women in preventing endometrial proliferation than oral treatment because of the uniform suppression of the endometrium throughout the whole thickness of the mucosa caused by the high tissue concentrations when the hormone is administered locally [24,27,28]. With sequential therapy, however, there may be a higher rate of hyperplasia, including complex and atypical hyperplasia [29,3O]. The duration of the progestogen administration seems more important than the daily dose as far as prevention of endometrial hyperplasia is concerned [31]. Continuous, intrauterine progestin delivery could, therefore, be ideal as the promising results obtained in this study suggest.
The thin endometrium (
The majority of women take hormone therapy to obtain relief from climacteric symptoms rather than for prevention of cardiovascular disease or osteoporosis. Climacteric symptoms are most distressing during the perimenopausal years and, therefore, the uptake of hormone therapy (HT) is highest during the transition to menopause. A large number of women, however, will not continue HT and as many as 60% or more of women taking oral HT will discontinue it after a year [34,36]. Re-initiation of withdrawal bleeding, breakthrough bleeding and hormonal side-effects, caused by systemic progestogen absorption, are the main reasons for discontinuing therapy. With continuous-combined ET plus intrauterine LNG delivery, most women in the perimenopause experience breakthrough bleeding during the first 3 months, which gradually disappears during the months thereafter [37,38]. However, postmenopausal women with absent ovarian function develop an atrophie endometrium and amenorrhea soon after ET combined with insertion of the IUS because the local progestogen reduces the concentration of estrogen receptors and, hence, the local estrogen bioactivity [31,39]. In the present study, virtually all women were bleed-free (occasional infrequent spotting) or had amenorrhea at the end of the first year of EPT, as reported earlier [14], and a high rate of adherence to the treatment regimen was observed that can be ascribed to the absence of bleeding and progestogen-like side-effects.
The results of a recently published cohort study in 29 508 Swedish women, which concluded that both combined systemic estrogen/ progestogen and combined sequential EPT regimens are associated with increased breast cancer risk, is alarming. However, it is reassuring that the study did not find a higher breast cancer risk with estrogen-only therapy, even for longer periods (more than 48 months) [U]. Therefore the authors suggested that estrogen used in combination with a low-dose progestin-releasing IUS could be an attractive option to minimize the impact of the hormone on breast tissue, confirming the viewpoint of the authors of the present study. This opinion is further confirmed by the recently published arm of the WHI that evaluated the long-term benefits of estrogen alone and showed no adverse cardiovascular effects and increase in breast cancer risk. On the contrary, a reduced risk of breast cancer of 23% was found. The risk of myocardial infarction was also reduced (by 9%) but the number of cerebrovascular incidents increased slightly [4O].
Conclusions
The main objective of the present clinical trial was to evaluate an alternative route of progestin administration in peri- and postmenopausal women using ET. The study suggests that continuous- combined ET with intrauterine delivery of a progestogen was highly accepted by the women in the study. The rationale of the development of the FibroPlant-LNG IUS is to minimize the potential adverse effects on cardiovascular and other organ systems. As progestogens are required only to oppose the stimulating effects of estrogens on the endometrium, locally acting progestogens, by definition, could avoid the metabolic effects, as well as effects on other tissues, observed with systemically applied progestogens. Intrauterine LNG delivery with low-dose systems, even though minimal absorption may occur, should be regarded as essentially locally acting.
This regimen also offers important additional benefits that could be exploited, such as high adherence to treatment and the low discontinuation rate because of bleeding problems and progestogen- like side-effects.
In addition, an IUS that adapts to volume changes of the uterus, which reduces in size gradually due to the suppressive effect of the LNG and the falling endogenous estrogen levels, will be optimally tolerated by women.
Acknowledgement
The authors are grateful to Professor Dr G. Van Maele, of the Department of Medical Informatics and Statistics, University Hospital Ghent, Belgium, for analyzing statistical data for the study and Dr Patrick Rowe, Reproductive Health Consultant, Vesancy, France, for reviewing this paper.
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DIRK WILDEMEERSCH1, DIRK JANSSENS2, ETIENNE SCHACHT3, KRIS PYLYSER4, & NATHALIE DE WEVER4
1 Contrel Research, Technology Park Zwijnaarde, Ghent, Belgium, 2 Gynecologische Dienst, Tumhout, Belgium, 3 Polymer Research Group, University of Ghent, Department of Chemistry, Ghent, Belgium, and 4 Dienst Anatomo-pathologie, St. Augustinus Hospital, Veurne, Belgium
Correspondence: D. Wildemeersch, Piers de Raveschootlaan 125, 8300 Knokke, Belgium. Tel: 32 50600900. Fax: 32 50622429. E-mail: [email protected]
Copyright CRC Press Jun 2005
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