• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

The Acceptability of a Small Intrauterine Progestogen-Releasing System for Continuous Combined Hormone Therapy in Early Postmenopausal Women

Posted on: Sunday, 27 February 2005, 03:00 CST

ABSTRACT

Objective To assess the acceptability, ease of insertion, tolerance and associated bleeding of a novel intrauterine progestogen-releasing system, combined with transdermal estradiol, in postmenopausal women.

Design An open non-comparative study of 294 postmenopausal women with an intact uterus at 27 centers in six countries.

Method All subjects had requested treatment for menopausal symptoms and had received transdermal estradiol 50 g/day by patch and an experimental intrauterine system (MLS) releasing levonorgestrel 10 g/day. Details of the insertion were recorded and subsequent bleeding, side-effects and adverse events were documented on a daily diary. Endometrial thickness was measured by transvaginal ultrasound scan prior to insertion of the MLS and after 12 months. The study is of 3 years duration. This report summarizes the results after the first year.

Results The median age of the subjects was 52.6 years (range 41.7- 59.6 years), 90% were within 3-5 years of menopause and 78% had previously used hormone therapy (HT). The MLS was inserted at the first attempt in 297/294 (94%) subjects and was facilitated by dilatation of the cervical canal in 65 (22%) subjects. Local anesthesia was given to 30 (10%) subjects. Of the 17 with a failed first insertion, two subjects did not want a second attempt, in 14 a second attempt succeeded, facilitated by cervical dilatation in seven and local anesthetic in three subjects. There was one failed insertion. Investigators rated 80% of first insertions as easy, 14% as slightly difficult and 6% as very difficult. The second insertion was easy in 9/15 subjects, slightly difficult in 4/15 and very difficult in one (data from one subject missing). During insertion, 34% subjects had no pain, 49% said it was mild, in 15% it was moderate and in 2% the pain was severe. At 12 months, one MLS had been expelled. Spotting was the most common form of bleeding and this decreased from a median of 9 to 0 days at 4 months, although 10% of subjects continued to report spotting up to 12 months. Bleeding days were few and mainly in the first 2 months. At the end of month 11, 66.8% were amenorrheic and 87% non-bleeding. Only nine subjects discontinued because of bleeding. There was no correlation between the bleeding profiles and number of years since menopause, previous HT use or body mass index. The median endometrial thickness at entry to the study (without HT) was 2.6 mm and 3.4 mm at 12 months. Of the adverse events, after the pain associated with insertion, headache was the next most common at 13.3% and mastalgia was experienced by 7.8% of subjects. Overall, the dropout rate was low at 28 subjects (9.5%). There were favorable changes in the serum lipid profile consistent with the effects of estradiol and suggesting minimal attenuation by the intrauterine progestogen.

Conclusion This interim report of a 3-year study has confirmed that the menopausal levonorgestrel intrauterine system is easy to insert and is well tolerated by postmenopausal women.

Key words: INTRAUTERINE PROGESTOGEN, CONTINUOUS COMBINED HORMONE THERAPY, BLEEDING, POSTMENOPAUSE

INTRODUCTION

Progestogen is added to hormone therapy (HT) in postmenopausal women to prevent endometrial hyperplasia and carcinoma. There is no evidence that progestogen has any other benefits, so it is logical to deliver the progestogen directly to the endometrial cavity. The intrauterine delivery of progestogen by means of a levonorgestrel intrauterine system (LNG-IUS, Mirena, Schering Oy, Finland) has already been introduced in both perimenopausal and postmenopausal women, together with oral or transdermal estrogen therapy. These combinations have been shown to be equally effective in controlling climacteric symptoms as longer established cyclic or continuous combined estrogen and progestogen regimens, and to result in an atrophie endometrium after the first few months of treatment, during which breakthrough bleeding and spotting are common. The LNG-IUS delivers levonorgestrel at a rate of 20 g/24 h initially directly into the endometrial cavity, and has been licensed for contraception and control of menorrhagia in many countries for several years. After the menopause, the uterus and cervix tend to shrink so that cannulation of the cervix and insertion of an intrauterine device can be more difficult. A smaller version of the LNG-IUS, the menopause levonorgestrel system (MLS), has been developed which releases 10 g levonorgestrel per 24 h initially, with the intention that this will be more suitable for providing the progestogen component of combined continuous estrogen and progestogen therapy (CCEPT). A preliminary study, which compared the LNG-IUS and MLS in postmenopausal women has reported similar and complete protection of the endometrium over 1 year^sup 2^. This present study was designed to assess the acceptability, ease of insertion and tolerance of the MLS and associated bleeding during the first year of use. In addition, the effects on the serum lipid profile were assessed as a surrogate marker of the systemic effects of levonorgestrel. Both oral levonorgestrel combined with oral estrogen therapy3,4 and intrauterine levonorgestrel (LNG-IUS) combined with transdermal estrogen therapy are known to reduce the high density lipoprotein (HDL) cholesterol concentration in postmenopausal women. This may be eliminated with the smaller release rate of levonorgestrel from the MLS when compared with that of the LNG-IUS.

If recent concerns about the effects of progestogen in combined HT regimens on mammographie breast density6,7, breast cancer8 and cardiovascular disease risk are valid, there would be potential advantages in these respects in reducing the systemic levels of progestogen by low-dose intrauterine administration. This is an interim report of a 3-year study.

SUBJECTS AND METHODS

Subjects

A total of 294 healthy postmenopausal women with an intact uterus were included in an open non-comparative study by clinical investigators at 27 centers in Austria, Finland, France, Germany, Ireland and the United Kingdom. Subject recruitment started in May 2000 and was completed in May 2001. This report presents results obtained after 1 year, while the study was ongoing until May 2004.

Prior to the study, permission was obtained from the appropriate Independent Ethics Committees and the Regulatory Authorities in the countries and centers involved. All subjects sought treatment for menopause-related complaints and provided written informed consent.

The criteria for inclusion were postmenopause for at least 1 year, with a maximum of 5 years since last menstrual period, confirmed by a serum follicle stimulating hormone level of more than 25 IU, intact uterus, and an appropriate washout period of previous HT or an intrauterine system for 4 weeks (6 months for unopposed estrogens).

The criteria for exclusion were known contraindications for HT, use of drugs known to interact with hormone treatments, body mass index ≥ 31 kg/m^sup 2^, systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 95 mmHg, not responding to treatment, total fasting serum cholesterol of ≥ 7.8 mmol/1 (lipid-lowering medication not allowed). Gynecological criteria for exclusion were undiagnosed abnormal vaginal bleeding, (history of) endometrial hyperplasia, current endometrial polyp, distorted uterine cavity, current or recent (< 6 months) pelvic infection or cervicitis, (suspected) tumor of breast, uterus or ovary, abnormal cervical smear, absence of histologically evaluable endometrial tissue at screening (assessment of the endometrial response is a primary objective of the study).

Methods

Medical and gynecological history, previous use of HT, general physical and gynecological examination, transvaginal ultrasonography (including endometrial thickness measurement), mammography (if not performed within previous 12 months), cervical smear, blood (for serum lipid levels and other parameters) and urine samples and endometrial biopsy were recorded or performed at screening.

At the entry visit, the gynecological examination was repeated and treatment was assigned. All patients received uninterrupted transdermal estradiol 50 g per day (Climara /Progynova TS/ Cutanum, Schering AG, Germany) and, as the progestogen component, the MLS (Schering Oy, Finland), an experimental intrauterine system with an initial in vitro release of 10 g of levonorgestrel per day. The MLS consists of a T-shaped body of 28 mm, measured both horizontally and vertically, and a poly-dimethyl siloxane cylinder containing 12 mg of levonorgestrel and covered with a release-controlling membrane. The maximum diameter of the device is 2.8 mm (the LNG-IUS has maximum diameter of 3.8 mm and length of 32 mm). The MLS is inserted into the uterine cavity by use of a custom-made inserter (diameter of 3.8 mm, compared to the LNG-IUS inserter diameter of 4.8 mm) and has an active lifespan of 3 years.

Two insertion attempts were allowed and insertion experiences, such as ease, pain and facilitating interventions (e.g. cervical canal dilatation and the use of local anesthesia or oral analgesics) were recorded. There were no specific crit\eria for the assessments of ease of insertion by the doctor or pain experienced by the woman. Following insertion, transvaginal ultrasonography was performed to assess proper fundal position of the system.

Study participants were issued with diaries for daily recording of bleeding events and estradiol patches. Bleeding events were classified as 'none', 'spotting' (not requiring sanitary protection except panty liners), and 'bleeding'; the latter class was subdivided into 'light' (less than normal menstrual blood loss), 'normal' or 'heavy' (more than normal menstrual blood loss), all relative to the subject's experience. In this report, bleeding profiles based on 30-day reference periods are presented.

During the year covered by this report, the investigators saw the subjects at 3, 6 and 12 months. At these visits, a gynecological examination was performed, the diaries were collected and reviewed, ultrasonography was performed to monitor the position of the MLS and, at 12 months, the endometrial thickness was assessed by traiisvaginal ultrasound. At 12 months, a blood sample was taken for analysis of serum lipids and hemoglobin. All laboratory tests were performed at Interlab GmbH, Germany. At all patient visits, adverse events were recorded. The study protocol contained several other assessments that are not covered here, but which will be reported after this 3-year study has been completed.

In the present report, insertion and bleeding experiences, endometrial thickness, serum lipid changes and general and specific safety will be presented.

Statistical methods

Simple descriptive statistical methods have been used. For the correlation between endometrial thickness and bleeding events, a non- parametric Spearman coefficient (values between - 1 and 1) has been calculated.

RESULTS

The total number of subjects screened for eligibility was 372. Of these, 78 (21%) did not meet with one or more of the eligibility criteria. The most frequent reasons for exclusion were, in descending order: no confirmed menopause, no endometrial tissue available for assessment, severe hypertension, elevated serum cholesterol, body mass index ≥ 31 kg/m^sup 2^, and inadequate washout of previous HT.

All the subjects were Caucasian. Their median age was 52.6 years (range 41.7-59.6 years) and all were within 5 years and 90% within 3 years since the menopause. Previous hormone therapy had been used by 77.6%, and 18% were current smokers.

Twenty-eight subjects (9.5%) discontinued the study in the course of the year. The reasons for discontinuation were adverse events for 21 subjects and other reasons for seven subjects. The adverse events reported as a reason for stopping were bleeding problems in nine subjects, painful breasts, weight gain, skin irritation in three subjects each, and bloating, mood changes and lack of efficacy in one subject each. As a result, a total of 266 patients completed the first year of this study.

Insertion and retention of the MLS

The first insertion attempt succeeded in 277/294 (94%) subjects. This attempt was facilitated by dilatation of the cervical canal in 65 (22%) of subjects. Most of these dilatations (41) took place before the insertion was tried, while the others were performed during the procedure.

Local anesthesia (paracervical block or similar) was given to 30 subjects (10%), 24 prior to attempted insertion and six during the procedure. Oral analgesics were given to 52 (18%) before, three (1%) during and 31 (11%) subjects after the insertion.

The investigators rated 80% of the first insertions as easy, 14% as slightly difficult and 6% as very difficult. The subjects reported pain during insertion as follows: none 34%, mild 49%, moderate 15% and severe 2%.

Of the 17 with failed first insertion attempts (two subjects did not want a second attempt), 14 succeeded at the second attempt, facilitated in seven subjects by cervical canal dilatation (six before and one during the procedure); local anesthesia was given in three subjects before the second attempt and oral analgesics were given to four subjects. Investigators rated this second insertion as easy in 9/15 subjects, slightly difficult in 4/15 and very difficult in one (data for one patient missing). No pain was reported by 4/15 subjects, mild pain by 4/15, moderate pain by 6/ 15 and severe pain by 1/15.

At 12 months, one MLS was found to have been expelled. There was one failed insertion.

Bleeding profiles

The bleeding experiences of the subjects are presented as median number of days per subject during each 30-day reference period, over the first 11 months of the study. Figure 1 shows all bleeding and/ or spotting days, and Figure 2 the median number of days when only bleeding was reported. Bleeding-only days were few and limited to the first 2 months of use (decreasing from 2 to O and staying at O throughout the year of observation); the most common experience was spotting, and these episodes were longest during the first month after insertion. The median number of days with spotting decreased from 9 to 0 days at 4 months, but 30 (10%) subjects continued to report spotting until the end of the observation period.

Figure 1 Median number of bleeding and/or spotting days

Figure 2 Median number of bleeding-only days

The percentages of subjects who experienced 'no bleeding', that is they may have spotted but not bled, and those who had amenorrhea are given in Figure 3. At the end of month 11, 66.8% of subjects were amenorrhcic and 87% were non-bleeding. The data for the 12th reference period were not included as not all had been verified by the cut-off date for reporting.

Since a low number of subjects (nine) discontinued because of bleeding problems, and reporting was fairly accurate, the percentages found can be considered representative for this treatment combination in this population. The subjects reported compliance of 99% with the use of the estrogcn patches at 6 and 12 months.

The bleeding profiles were further analyzed together with a number of covariates: number of years since menopause, previous use of HT, body mass index 25 kg/m^sup 2^, and current smoking. None of these analyses showed a significant difference. However, the numbers of subjects who were more than 2 years postmenopause, had not used HT before the study and who did smoke were low.

The median cndometrial thickness at screening was 2.6 mm (Q 1, 1.8 mm and Q 3, 3.6 mm) and 3.4 mm at 12 months (Q 1, 2.7 mm and Q 3, 4.1 mm). The 12-month value of the endometrial thickness was analyzed together with the number of reported bleeding and/or spotting days during months 6-11. The non-parametric correlation coefficient (Spearman) was 0.08. As the range of the Spearman coefficient was from - 1 to + 1, the outcome, close to , indicates the absence of a correlation.

Figure 3 Percentage of subjects with 'no bleeding' (may have had some spotting) and those with complete amenorrhea

Serum lipids

The scrum lipid results at screening and 12 months are shown in Table 1, and the percentage change in Figure 4. The changes reflect a favorable shift and suggest little attenuation of the effects of estrogen by the intrauterine administration of the low dose of levonorgestrel.

Safety and side-effects

Some degree of pain during insertion of the MLS was reported by 257/291 (88.3%), and 26 women (8.9%) rated this pain as severe. Post- insertion pain was of short duration in almost all subjects. Removal of the MLS caused pain in five of the 28 subjects who discontinued.

Table 1 Serum lipid concentrations (mmol/l) given as median values (upper and lower quartiles shown in parentheses)

Figure 4 Fasting serum lipids; percentage change from screening to 12 months (median and 95% confidence intervals). Total, total cholesterol; HDL, high density cholesterol; LDL, low density cholesterol; TG, triglycerides

Other side-effects classified as related to the study treatment were headache in 39% of subjects, breast tension in 7.8% and skin irritation due to the patches in 18%. There was no significant change in body weight or blood pressure recordings during the study.

Of the total of 915 reported adverse events, 844 (92%) were considered mild or moderate and 71 (8%) as severe. Ten serious adverse events were reported. In two of the subjects, treatment was not started because of benign breast disease in one and a metastasized carcinoma of unknown primary site discovered at screening in another. Of the remaining eight subjects, five had elective surgical procedures for conditions unrelated to the study treatment; one (a nurse) had HIV infection, possibly resulting from an infected syringe needle accident at work, and one patient was hospitalized because of diarrhea.

One subject developed a rapidly growing endometrial cancer when 5 months into the study. The tumor was poorly differentiated and had metastasized. She had a strong family history of gastrointestinal cancer and had never used HT. Genetic examination revealed a microsatellite instability similar to the one found in the human non- polyposis colorectal cancer (HNPCC) syndrome. Females with this syndrome are known to have an increased incidence of endometrial cancer. Based on these findings, a causal relationship with the study treatment was considered unlikely.

DISCUSSION

The investigators considered that the small MLS was easy to use in 80% of cases and insertion was achieved in 94% of women at the first attempt. There was only one failure in 15 women who had a second attempt (two women declined the second attempt). A previous study comparing the MLS with the larger LNG-IUS has reported easier insertion with the smaller device . In only 6% of insertions did the investigators consider the procedure to be very difficult, and, although the majority of subjects experienced some pain after insertion, in only 2% was this considered to be severe. In the comparative study2, insertion of the MLS was difficult in 3.7% compar\ed with 21.4% with the LNG-IUS, and severe pain was experienced by 1.9% and 10.7%, respectively. The diameter of the inserter for the MLS is 3.8 mm, which is only 1 mm less than the inserter for the LNG-IUS, but the cervix in postmenopausal women is often less easily cannulated than in younger women, so that this difference can be critical. In addition, 78% of women in this study had used HT previously which could also have helped to reduce insertion difficulties and discomfort. Insertion of an MLS into the uterine cavity carries some risk of infection and traumatic perforation, as is common to all intrauterine applications. However, if the correct insertion technique is used, the risk for uterine perforation should be very low10. There were no recorded perforations or evidence of pelvic infections in our study. In fertile women, the risk of pelvic infection over 3-5 years of use of the LNG-IUS has been found to be less than 1%11,12.

Only nine women withdrew during the first 12 months because of bleeding, and the amenorrhea rates after 11 months of 66.8% and 'no- bleeding' of 87% are as good as any other reported for CCEPT regimens13-15. Spotting was the most common form of bleeding and the higher incidence in the first month would have been partly resulting from the endometrial biopsy and the insertion of the MLS. The overall drop-out rate was also low at 9% and compares very favorably with other studies. The endometrial thickness increased slightly from a median of 2.6 mm at screening (without HT), to 3.4 mm after 12 months of the combined estradiol and levonorgestrel therapy. Endometrial histology was not performed after 1 year but will be reported on completion of the full 3-year study. Previous studies of both the LNG-IUS and MLS devices in combination with various routes and doses of estrogcn therapy have shown consistent suppression and usually a progestogen-induced atrophy of the endometrium and no cases of hyperplasia2,10. The one case with endometrial adenocarcinoma would seem to be due to a genetic predisposition to adenocarcinomata and is most unlikely to have been related to the therapy.

There were changes in all the serum lipid concentrations from screening to 12 months, but all of these were in a favorable direction, and were consistent with what would be expected from unopposed transdcrmal estradiol therapy16; they suggest little attenuation of the effects of estrogen by the intrauterine administration of the low dose of levonorgestrel.

In the circulation, levonorgestrel is bound mainly to sex hormone binding globulin (SHBG) and there is a positive correlation between the concentrations of plasma levonorgestrel and SHBG. In the comparative study of the LNG-IUS and MLS in postmenopausal women, the mean serum concentration of levonorgestrel reached a steady level of approximately 470 pg/ml (1499.3 pmol/l). This is about a quarter of the concentration found in postmenopausal women who received oral cyclical Icvonorgestrel at a daily dose of 250 g in combination with an oral daily dose of estradiol valerate 2 mg17. The MLS with a smaller daily release rate of levonorgestrel induced significantly smaller serum concentrations of levonorgestrel. This could be partly explained by a small induction of SHBG by transdermal estradiol in comparison with oral estrogen18. A future report of this present study will include measurements of circulating levonorgestrel. The recent reports from the Women's Health Initiative (WHI) and the Million Women Study (MWS) have implied that the progestogen component of continuous combined therapy may be the more important factor associated with an increased risk of breast cancer, such that some doubts have been raised about the relative benefits of adding progestogen to protect the endometrium8. The direct application of progestogen to the endometrium with the MLS and the lower dose in the circulation may provide a more favorable route for progestogen administration.

This interim report of a 3-year study has confirmed that the menopausal levonorgestrel intrauterine system (MLS) is easy to insert and is well tolerated by postmenopausal women.

References

1. Andersson K, Mattsson L-, Rybo G, Stadberg E. Intrauterine release of levonorgestrel: a new way of adding progestogen in hormone replacement therapy. Am J Obstet Gynecol 1992;79: 963-7

2. Raudaskoski T, Tapanaincn J, Toms E, et al. Intrauterine 10 g and 20 g levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response. Br J Obstet Gynaecol 2002;109:136-44

3. Hirvonen E, Mlknen M, Manninen V. Clinical and lipid metabolic effects of unopposed oestrogen and two oestrogen-progestogen regimens in post-menopausal women. Maturitas 1987;9:69-79

4. Graff-Iversen S, Stensvold I, Lind-Larsen PG, Nodarse EO, Tverdal A, Urdal P. Serum lipids in postmenopausal or perimenopausal women using estrogen alone, estrogen with levonorgestrel, or estrogen with norcthisterone, compared with nonusers: results from a cross sectional study in two Norwegian countries, 1985-1988. J Clin Epidemiol 1998;51:1311-16

5. Raudaskoski T, Eahti E, Kauppila A, Apaja-Sarkkinen M, Eaatikainen T. Transdermal estrogen with a levonorgestrel-releasing device for climacteric complaints: clinical and endometrial responses. Am J Obstet Gynecol 1995;172:114-19

6. Lundstrom E, Wilczek B, von Palffy Z, Soderqvist G, von Schoultz B. Mammographic breast density during hormone replacement therapy: effects of continuous combination, unopposed transdermal and low-potency estrogen regimens. Climacteric 2001;4:42-8

7. Chlebowski RT, Hendrix SL, Langer RD, et al. for the WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2003;289:3243- 53

8. Million Women Study Collaborators. Breast cancer and hormone replacement therapy in the Million Women Study. Lancet 2003;362:419- 27

9. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. J Am Med Assoc 2002;288:321- 33

10. Riphagen FR. Intrauterinc application of progestins in hormone replacement therapy: a review. Climacteric 2000;3:199-212

11. Toivonen J, Lukkainen T, Allonen H. Protective effect of intrauterine release of levonorgestrol on pelvic infection: three years comparative experience of levonorgestrol and copper-releasing intrauterine devices. Obstet Gynecol 1991;77: 261-4

12. Lukkainen T, Allonen H, Haukkamaa M, Lhteenmki P, Nilsson CJ, Toivonen J. Five years experience with a levonorgestrol-releasing IUCD. Contraception 1986;33:139-48

13. Hillard T. Continuous combined oestrogen and progestogen. In Sturdee DW, Olah K, Keane D, eds. The yearbook of Obstetrics and Gynaecology, vol 9. London: RCOG Press, 2002

14. MacLennan AH, MacLennan A, Wenzel S, Chambers HM, Eckert K. Continuous low-dose oestrogen and progestogen replacement therapy: a randomised trial. Med J Aust 1993;159: 102-6

15. Pickar JH, Bottiglioni F, Archer DF, for the Menopause Study Group. Amenorrhea frequency with continuous combined hormone replacement therapy: a retrospective analysis. Climacteric 1998;1:130-6

16. Godsland IF. Effects of postmenopausal hormone replacement therapy on lipid, lipoprotein and apolipoprotein (a) concentrations: analysis of studies published from 1974-2000. Fertil Steril 2001;75:898-915

17. Suhonen S, Holmstrm T, Allonen HO, Lhteenmki P. Intrauterine and subdermal progestin administration in postmenopausal hormone replacement therapy. Fertil Steril 1995;63:336-42

18. Raudaskoski T, Laatikainen T, Kauppila A. Sex hormone binding globulin as an indicator of the hepatic impacts of continuous combined hormone replacement regimens. Maturitas 1998;29: 87-92

D. W. Sturdee, M. L. Rantala*, J. C. Colau[dagger], H-P. Zahradnik[double dagger] and F. E. Kipbagen** for the multicenter MLS Investigators

Department of Obstetrics & Gynaecology, Solihull Hospital, Solihull, UK; * Gynekologikeskus Adina, Lnsituulentie, Espoo, Finland; [dagger] Hpital Foch, S Uresnes, France; [double dagger] Universitt Frauenklinik, Endokrinologie Reproduktionsmedizin, Freiburg, Germany; ** Clinical Development, Schering Oy, Helsinki, Finland

Correspondence: Dr D. W. Sturdee, Department of Obstetrics & Gynaecology, Solihuil Hospital, Solihull B9I 2JL, UK

ORIGINAL ARTICLE

2004 International Menopause Society

DOI: 10.1080/13697130400012270

Received 5-05-04

Revised 7-07-04

Accepted 8-07-04

Conflict of interest F.E.R. is Director of Clinical Development for Schering Oy. D.W.S. has received honoraria for lecturing at Schering-sponsored symposia.

Source of funding The study was conceived, designed and sponsored by Schering Oy, Finland.

Copyright CRC Press Dec 2004

Source: Climacteric

More News in this Category