Contraception in perimenopausal women with

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ceptive Novinet® (Gedeon Richter, Hungary), containing 20 μg ethinylestradiol and 150 μg desogestrel (20EE/DSG). (2) Group 2 was composed of 10 type 1 ...

Gynecological Endocrinology, April 2006; 22(4): 198–206

CONTRACEPTION

Contraception in perimenopausal women with diabetes mellitus

OLGA R. GRIGORYAN, ELENA E. GRODNITSKAYA, ELENA N. ANDREEVA, MARINA V. SHESTAKOVA, GALINA A. MELNICHENKO, & IVAN I. DEDOV

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Federal Facility Endocrinological Research Centre under the Russian Academy of Medical Sciences, Moscow, Russia (Received 18 June 2005; revised 23 January 2006; accepted 6 February 2006)

Abstract Aim. To assess the effect of combined oral contraceptives (COCs) and intrauterine devices (IUDs) on carbohydrate and lipid metabolism and hemostasis in perimenopausal diabetic women. Methods. The open randomized study included a total of 113 diabetic women using COCs with different estrogen/ progestogen profiles – ethinylestradiol (EE) 20 mg/desogestrel 150 mg, EE 30 mg/desogestrel 150 mg and EE 30 mg/gestodene 75 mg – and levonorgestrel-releasing or copper IUDs. Average daily insulin requirements, levels of glycosylated hemoglobin, total cholesterol, triglycerides, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, the state of coagulation hemostatis and fibrinolytic activity were determined at baseline and after 3, 6, 9 and 12 months of contraception. The control group was composed of 40 age-matched diabetic women who did not use any methods of contraception. Results. Neither COCs nor IUDs influenced glycosylated hemoglobin and had little or no influence on the elevation in the requirements for insulin preparations. The majority of the preparations did not exert any unfavorable effect on the blood lipid profile. Taking COCs was accompanied by increased intravascular activation of blood platelets and to a lesser degree by alterations in parameters of hemostatic homeostasis. The use of IUDs had a neutral effect on blood coagulation and fibrinolysis systems. Conclusion. Comparing lipid levels and hemostatic variables as a function of glycosylated hemoglobin level, we conclude that diabetes control has greater influence on these parameters than the type and dose of steroids involved in the contraceptive devices.

Keywords: Diabetes mellitus, perimenopause, contraception, combined oral contraceptives, intrauterine devices

Introduction Fertility is known to decrease during the perimenopause in both healthy and diabetic women. However, up to 30% of 45- to 54-year-old apparently healthy women do have regular menstrual cycles and are capable of conceiving. Fertility in women suffering from diabetes mellitus (DM) does not differ substantially from that in their non-diabetic contemporaries; in the presence of the regular rhythm of menstruations the frequency of ovulatory cycles can reach 90% or 34% in oligomenorrhea [1]. None the less, physiological pregnancy in DM women is a stress factor associated with progressing vascular complications of the disease, frequently encountered ketoacidosis and development of hypoglycemic states, as well as with complications of the pregnancy itself (e.g. miscarriage, late gestosis, hydramnios and fetal contamination).

Currently, in order to provide reliable contraception in diabetic women, particular emphasis is placed on highly efficient modern methods aimed at correcting fertility; these include combined oral contraceptives (COCs), intrauterine devices (IUDs) and surgical sterilization. Diabetic women during the perimenopause period are considered to be at especially high risk if being prescribed a contraceptive, for it is this age period that is accompanied and followed by nearly a 100% rate of manifestations of varying severity arising from remote complications of the primary disease, i.e. diabetic neuropathy, retinopathy, nephropathy and macrovascular complications. Diabetes is associated with accelerated rates of thrombosis, circulation dysfunction and atherosclerosis. Patients with diabetes have two lipid disorders. One is low-density lipoprotein cholesterol (LDL-C) level higher than optimal, which contributes to atherogenesis and coronary plaque rupture. The other

Correspondence: O. R. Grigoryan, Leninsky prospect 41/2–48, Moscow 119 334, Russian Federation. Tel: 7 095 135 75 63. Fax: 7 095 126 75 44. E-mail: [email protected] ISSN 0951-3590 print/ISSN 1473-0766 online ª 2006 Taylor & Francis DOI: 10.1080/09513590600624317

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Contraception in women with DM is a condition called atherogenic dyslipidemia, which is characterized by a triad of lipid disorders: elevated triglycerides (TG), small LDL particles and low high-density lipoprotein cholesterol (HDL-C). Atherogenic dyslipidemia in diabetic patients often is called diabetic dyslipidemia. Both LDL-C and atherogenic dyslipidemia deserve attention [2]. Vascular endothelium, the primary defense against thrombosis, is abnormal in diabetes. Endothelial abnormalities undoubtedly play a role in the enhanced activation of platelets and clotting factors seen in diabetes. Coagulation activation markers, such as prothrombin activation fragment 1 þ 2 and thrombin– anti-thrombin complexes, are elevated in diabetes. The plasma levels of many clotting factors including fibrinogen, factor VII, factor VIII, factor XI, factor XII, kallikrein and von Willebrand factor are also elevated. Conversely, the level of the anticoagulant protein C is decreased. The fibrinolytic system, the primary means of removing clots, is relatively inhibited in diabetes due to abnormal clot structures that are more resistant to degradation and an increase in plasminogen activator inhibitor type 1. Increased circulating platelet aggregates, increased platelet aggregation in response to platelet agonists, increased platelet contractile force and the presence of higher plasma levels of platelet release products, such as b-thromboglobulin, platelet factor 4 and thromboxane B(2), demonstrate platelet hyperactivity in diabetes. This constellation of findings supports the clinical observation that diabetes is a hypercoagulable state [3]. However, even against a background of taking COCs in diabetic women, researchers have not revealed any correlation between the level of glycosylated hemoglobin (HbA1c), daily insulin requirements, and the negative dynamics of retinopathy, nephropathy, onset and/or progression of arterial hypertension [4,5]. Moreover, the World Health Organization (WHO) guidelines on family planning do not preclude the use of low-dose COCs in nonsmoking diabetic women during the perimenopause if they have no macrovascular complications of their primary disease or other cardiovascular diseases [6]. Several prospective studies found no differences in the incidence rate of pelvic inflammatory disease (PID) in apparently healthy versus diabetic women using copper-containing IUDs. Nor were reliably significant differences revealed in the indications for IUD extraction, with similar incidence of PID in both groups [7,8]. However, abnormal uterine bleeding, such as menorrhagia and intermenstrual bleeding, is one of the most undesirable side-effects of the use of IUDs. Currently, a promising method of contraception for this cohort of patients is the Mirena1 levonorgestrel (LNG)-releasing intrauterine system (IUS), compar-

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able in contraceptive reliability to sterilization. The LNG-IUS has several non-contraceptive benefits, including a decrease in the volume of blood loss and dysmenorrhea. In addition, it can be used to treat heavy menstrual bleeding (idiopathic or associated with adenomyosis or leiomyoma). The use of this method during perimenopause has considerable advantages related to inhibition of proliferative processes in the endometrium in the presence of a constant concentration of estrogens in blood plasma. Women who suffer from climacteric symptoms while they are using the LNG-IUS can be given estrogen to relieve their symptoms [9]. According to the WHO guidelines, the use of copper-containing IUDs in women with DM has no restrictions, and while using the LNG-IUS, the advantages of this method dominate over a hypothetical risk [6]. The aim of the present study was to assess the effect of current COCs and IUDs on carbohydrate and lipid metabolism and the hemocoagulation and fibrinolysis systems in perimenopausal women with DM over a 1-year period. Methods We conducted this open randomized controlled trial at the Federal Facility Endocrinological Research Centre under the Russian Academy of Medical Sciences (Moscow, Russia). The study protocol and informed consent documents were approved by the local ethics committee. The enrollment period was November 2002 to July 2003. The study included a total of 153 women (mean age 44.3 + 5.2 years) suffering from DM without evidence of proliferative retinopathy, nephropathy and macrovascular complications. All gave signed informed consent before participating in the study. The average age of onset of type 1 DM was 24.6 + 4.9 years and duration of the disease 14.3 + 3.8 years; for type 2 DM, these indices were 38.1 + 2.8 years and 5.3 + 4.7 years, respectively. The daily average dose of insulin preparations for type 1 DM women amounted to 64.6 + 12.2 U. Of the type 2 DM women, 27 (82%) were on oral hypoglycemic therapy; six (18%) women were on therapy with insulin agents, with the average daily insulin requirements amounting to 47.8 + 11.9 U. Of microvascular complications of DM, nonproliferative retinopathy was revealed in 15 (26%) type 1 DM women and in 39 (71%) type 2 DM women; pre-proliferative retinopathy was found in 43 (74%) type 1 DM women and in 16 (29%) type 2 DM women. Before commencement of the trial, the women were randomized using a computer-generated scheme to five treatment groups and the control group.

200 (1)

(2)

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(3)

(4)

(5)

(6)

O. R. Grigoryan et al. Group 1 comprised 14 type 1 DM women (subgroup A) and 14 type 2 DM women (subgroup B) taking the microdose oral contraceptive Novinet1 (Gedeon Richter, Hungary), containing 20 mg ethinylestradiol and 150 mg desogestrel (20EE/DSG). Group 2 was composed of 10 type 1 DM women (subgroup A) and 10 type 2 DM women (subgroup B) taking Marvelon1 (Organon, The Netherlands), containing 30 mg ethinylestradiol and 150 mg desogestrel (30EE/DSG). Group 3 consisted of 12 type 1 DM women (subgroup A) and nine type 2 DM women (subgroup B) taking Femoden1 (Schering, Germany), containing 30 mg ethinylestradiol and 75 mg gestodene (30EE/GSD). Group 4 comprised 11 type 1 DM women and 11 type 2 DM women using a T-shaped copper-containing IUD. Group 5 comprised 11 type 1 DM women and 11 type 2 DM women using the Mirena1 (Schering, Germany) LNG-IUS. The control group was composed of 40 agematched women who did not use any methods of contraception.

Exclusion criteria were: type 1 and type 2 DM women in the state of decompensation of the primary disease; ketoacidosis; a history of myocardial infarction and/or thromboembolism during the year prior to commencement of the study; elevated blood creatinine and urea; nodular form of fibrous-cystic mastopathy; the presence of any oncological diseases at the time of the study; lack of self-control skills; and smoking. All of the women enrolled completed the study (women who eliminated the IUD were not excluded from the statistical analyses). All women underwent a general clinical examination consisting of studying the case history, general and gynecological examinations. The gynecological examination included examination and palpation of the mammary glands; bimanual gynecological examination; speculum-assisted visual inspection of the cervix uteri; a Papanicolaou smear; and a vaginal smear for microflora. Biochemical parameters assessed during the study were HbA1c level, average daily insulin requirements, and total cholesterol (TC), TG, LDL-C and HDL-C levels. Biochemical evaluation was performed by enzymatic methods using a Hitachi Modular-P system (Roche/Hitachi 912; Roche Diagnostics, Basel, Switzerland). The state of coagulation hemostatis was judged on the basis of the following parameters: activated partial thromboplastin time (aPTT), amount of factors VII and VIII, prothrombin index, amount of fibrinogen in blood plasma, thrombin time (TT) and progressive activity of

antithrombin III, on an STA Compact analyzer using kits (Roche Diagnostics). The state of fibrinolytic activity was assessed by spontaneous lysis of blood plasma euglobulins and Hageman-factor-dependent fibrinolysis. Platelet aggregations were induced by thrombin (Sigma, St. Louis, MO, USA) and performed in a Chronolog dual-channel aggregometer (Coulter, Margency, France) according to the turbidimetric method of Born. The clinical and laboratory examinations were carried out at baseline and after 3, 6, 9 and 12 months of receiving contraception. Statistical analyses Statistical analysis was performed by means of the software package Statistica for Windows 5.5 (StatSoft Inc., USA, 1999). Values of quantitative parameters are presented as mean + standard deviation. To study the relationship between quantitative parameters, we used Spearman’s rank correlation method. The quantitative parameters in various groups were compared using the Kruskal–Wallis test (for three and more groups) or the Mann–Whitney test (for two groups). The changes in quantitative indices at various times of treatment were evaluated by means of the Friedman test (for three and more time points) or the Wilcoxon paired test (for two time points). If significant differences were revealed, multiple comparisons were carried out using the Newman–Keuls test. The qualitative parameters were compared by means of the w2 test. The obtained findings were regarded as significant if p 5 0.05. Results Comparative analysis of HbA1c levels in type 1 and type 2 DM women receiving oral and intrauterine contraception revealed that its changes were statistically insignificant in all subgroups studied, with no differences between the treatment and the control groups (Table I). Figure 1 shows the dynamics of the average daily insulin requirements in type 1 DM women receiving COCs. The group of patients taking 30EE/GSD showed a statistically significant increase in insulin requirements (compared with baseline), amounting on average to 7.6% after 3 months, 16.8% after 6 months, 27.4% after 9 months and 21.2% after 12 months of contraception (p 5 0.001, Friedman’s test). Of the 33 women with type 2 DM from the therapeutic group receiving COC, after 12 months of contraception one (3%) woman taking 30EE/GSD, due to decompensation of her primary disease, was switched to insulin therapy with average daily insulin requirements amounting to 46.4 + 8.4 U. Figure 2 shows the dynamics of the average daily insulin requirements in type 1 DM women receiving intrauterine contraception, where no statistically

Contraception in women with DM

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Table I. Glycosylated hemoglobin levels (%) at baseline and follow-up. Group Oral contraception 30EE/DSG 20EE/DSG 30EE/GSD Intrauterine contraception T-shaped copper IUD LNG-IUS

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Control group

Baseline

3 months

6 months

9 months

12 months

Type Type Type Type Type Type

1 2 1 2 1 2

DM DM DM DM DM DM

7.5 + 0.3 7.6 + 0.5 7.5 + 0.3 7.7 + 0.4 7.5 + 0.3 7.3 + 0.4

7.6 + 0.5 7.5 + 0.6 7.6 + 0.2 7.8 + 0.5 7.6 + 0.2 7.4 + 0.6

7.4 + 0.4 7.7 + 0.3 7.4 + 0.4 7.6 + 0.7 7.4 + 0.4 7.5 + 0.5

7.6 + 0.3 7.4 + 0.5 7.6 + 0.6 7.5 + 0.4 7.6 + 0.6 7.6 + 0.3

7.5 + 0.6 7.5 + 0.7 7.5 + 0.4 7.6 + 0.3 7.5 + 0.4 7.4 + 0.7

Type Type Type Type

1 2 1 2

DM DM DM DM

7.8 + 0.3 7.5 + 0.7 7.6 + 0.5 7.4 + 0.6

7.7 + 0.8 7.7 + 0.4 7.5 + 0.6 7.5 + 0.2

7.9 + 0.2 7.5 + 0.7 7.6 + 0.9 7.7 + 0.3

7.5 + 0.6 7.6 + 0.4 7.6 + 0.2 7.5 + 0.7

7.8 + 0.7 7.4 + 0.3 7.7 + 0.3 7.6 + 0.6

7.7 + 0.6

7.5 + 0.3

7.7 + 0.5

7.6 + 0.7

7.5 + 0.2

EE, ethinylestradiol; DSG, desogestrel; GSD, gestodene; IUD, intrauterine device; LNG, levonorgestrel; IUS, intrauterine system, DM, diabetes mellitus.

Figure 1. Effect of oral contraception in perimenopausal women with diabetes mellitus on average daily insulin requirement. 20EE/ DSG, 20 mg ethinylestradiol and 150 mg desogestrel; 30EE/DSG, 30 mg ethinylestradiol and 150 mg desogestrel; 30EE/GSD, 30 mg ethinylestradiol and 75 mg gestodene.

significant changes in the average daily dose of insulin preparations were revealed (Friedman’s test). Of the 22 women with type 2 DM receiving intrauterine contraception, 18 subjects (82%) had prior to contraception been on therapy with oral hypoglycemic agents. The remaining four (18%) women had been on therapy with insulin preparations, with average daily insulin requirements of 46.7 + 10.7 U. None of the women was switched to insulin preparations during the course of the present study. Analyzing the effect of oral and intrauterine contraception on blood lipid profile revealed the following findings. Among the women taking 20EE/DSG, the subgroup of type 1 DM patients showed a statistically

Figure 2. Effect of intrauterine contraception in perimenopausal women with diabetes mellitus on average daily insulin requirement. Copper IUD, copper-containing intrauterine device; LNGIUS, levonorgestrel-releasing intrauterine system.

significant elevation of TC level after 3 and 6 months that amounted to 12.2% and 9.2%, respectively; corresponding values in the subgroup of type 2 DM women were 10.4% and 6.6% (compared with baseline, Newman–Keuls test). In the subgroup of type 2 DM women, LDL-C level increased significantly by 3.3% after 6 months of therapy (compared with baseline) (Table II). Use of 30EE/DSG resulted in a statistically significant increase in HDL-C level after 12 months of contraception, amounting to 5.4% in the type 1 DM women and 11.3% in the type 2 DM women (Table III). Among the women taking 30EE/GSD, 6 months’ use of the drug resulted in statistically significant

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decreases in TC and LDL-C levels – 12.1% and 12.2%, respectively, in the type 1 DM subgroup and 9.9% and 16.3%, respectively, in the type 2 DM subgroup – and did not have any considerable effect of the concentrations of TG and HDL-C (Table IV). Hence, 3EE/DSG and 30EE/GSD formulations exerted a favorable effect on blood lipid profile. No significant differences in lipid concentrations from baseline to follow-up were seen in the control group. We analyzed the impact of the COCs on lipid metabolism as a function of the state of DM compensation. In type 1 and type 2 DM women with good compensation of carbohydrate metabolism

(HbA1c 5 7%), blood lipid profile indices were virtually unchanged by the use of oral contraception. However, in women with poor control of type 1 DM (HbA1c  7 to 5 9%), oral contraception resulted in statistically significant increases in LDL-C and TG levels by 4.7% and 31.0% after 3 months, 8.4% and 28.8% after 6 months, 3.6% and 27.7% after 9 months and 4.2% and 31.0% after 12 months, respectively (compared with baseline). Among the type 2 DM patients with poor control of their diabetes we found statistically significant elevations in TC level (2.3% and 2.5% after 9 and 12 months, respectively) and LDL-C level (by 18.0% after

Table II. Lipids levels at baseline and follow-up: group receiving oral contraception with 20 mg ethinylestradiol and 150 mg desogestrel. Parameter (mmol/l) TC TG HDL-C LDL-C

Group Type Type Type Type Type Type Type Type

1 2 1 2 1 2 1 2

DM DM DM DM DM DM DM DM

Baseline

3 months

6 months

9 months

12 months

6.88 + 0.95 7.14 + 0.93 0.88 + 0.75 0.91 + 1.14 1.68 + 0.68 1.58 + 0.82 2.75 + 0.85 2.76 + 0.63

7.72 + 0.49* 7.88 + 1.11* 0.90 + 1.15 0.90 + 1.35 1.69 + 0.92 1.59 + 0.75 2.81 + 1.35 2.78 + 0.73

7.51 + 1.05* 7.61 + 0.83* 0.82 + 1.16* 0.89 + 0.93 1.71 + 0.85 1.57 + 1.15 2.76 + 0.14 2.85 + 0.75*

6.98 + 0.98 7.15 + 0.55 0.83 + 0.51* 0.86 + 1.74* 1.87 + 0.92* 1.62 + 0.93* 2.81 + 1.45 2.72 + 0.91

7.02 + 1.25 7.28 + 1.14 0.81 + 0.55* 0.88 + 0.51* 1.89 + 1.12* 1.62 + 0.91* 2.84 + 1.13 2.72 + 0.45

TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; DM, diabetes mellitus; *significantly different from baseline (p 5 0.05, Newman–Keuls test).

Table III. Lipids levels at baseline and follow-up: group receiving oral contraception with 20 mg ethinylestradiol and 150 mg desogestrel. Parameter (mmol/l) TC TG HDL-C LDL-C

Group Type Type Type Type Type Type Type Type

1 2 1 2 1 2 1 2

DM DM DM DM DM DM DM DM

Baseline

3 months

6 months

9 months

12 months

7.78 + 1.45 7.84 + 1.32 0.86 + 0.37 0.87 + 0.54 1.66 + 0.68 1.51 + 0.83 2.75 + 0.75 2.86 + 0.63

7.79 + 1.39 7.91 + 1.51 0.84 + 0.75 0.88 + 0.75 1.69 + 0.92 1.53 + 0.95 2.79 + 0.85 2.84 + 1.03

7.67 + 1.15 7.68 + 1.84 0.89 + 1.16 0.89 + 1.33 1.68 + 0.46 1.55 + 0.73 2.80 + 1.14 2.81 + 1.71

7.77 + 1.91 7.60 + 1.57 0.87 + 1.58 0.90 + 0.71 1.67 + 0.81 1.57 + 0.37 2.81 + 0.45 2.78 + 1.95

7.72 + 1.23 7.64 + 0.84 0.88 + 0.57 0.87 + 1.21 1.75 + 0.50* 1.68 + 0.64* 2.83 + 0.76 2.80 + 1.45

TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; DM, diabetes mellitus; *significantly different from baseline (p 5 0.05, Newman–Keuls test).

Table IV. Lipids levels at baseline and follow-up: group receiving oral contraception with 30 mg ethinylestradiol and 75 mg gestodene. Parameter (mmol/l) TC TG HDL-C LDL-C

Group Type Type Type Type Type Type Type Type

1 2 1 2 1 2 1 2

DM DM DM DM DM DM DM DM

Baseline

3 months

6 months

9 months

12 months

7.87 + 1.75 7.74 + 1.82 0.76 + 0.37 0.72 + 1.53 1.68 + 0.68 1.56 + 0.83 2.95 + 0.55 3.13 + 0.63

7.73 + 1.39 7.68 + 1.85 0.74 + 0.55 0.75 + 1.72 1.69 + 0.95 1.55 + 0.95 2.91 + 1.34 2.99 + 1.03

6.92 + 0.93* 7.88 + 1.14 0.75 + 1.16 0.74 + 1.73 1.70 + 0.83 1.59 + 0.19 2.59 + 0.54* 2.62 + 1.19*

7.91 + 1.11 7.61 + 1.07 0.74 + 1.57 0.71 + 1.78 1.69 + 0.72 1.58 + 1.23 2.93 + 0.65 3.02 + 1.95

7.65 + 0.29 7.64 + 1.84 0.78 + 1.57 0.72 + 1.81 1.70 + 1.63 1.57 + 1.92 2.89 + 0.66 2.93 + 1.45

TC, total cholesterol; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; DM, diabetes mellitus; *significantly different from baseline (p 5 0.05, Newman–Keuls test).

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Contraception in women with DM 6 months), as well as a statistically significant decrease in HDL-C concentration (12.5% after 6 months of taking the COCs). Analyzing blood lipid profile indices in those women receiving contraception with the coppercontaining IUD revealed an inconsiderable (albeit statistically significant) decrease in TC level by 8.6% after 12 months of use. Use of the LNG-IUS resulted in little or no influence on blood lipid profile (with the exception of a transient elevation in TC level at 6 to 12 months, amounting to 5.7% and 7.3%, respectively, which was not accompanied by any alterations in the dynamics of LDL-C and HDL-C concentrations). A comparative analysis of hemostasis system parameters in all women prior to the use of oral and intrauterine contraceptives revealed disorders in its functional state towards elevated indices of intravascular coagulation. Thirty-four (94%) type 1 DM women and twenty-nine (88%) type 2 DM women were observed to have an increased amount of factor VII: for type 1 DM, 153.7 + 22.8%; for type 2 DM, 149.85 + 46.9%. Correlation analysis revealed a moderately manifest relationship between HbA1c level and factor VII content in the group of type 1 DM women (r ¼ 0.46; p 5 0.05). The group of DM women receiving oral contraception demonstrated statistically significant decreases in aPTT and TT after 12 months of use, amounting to 7.6% and 6.1%, respectively (compared with baseline). In the group of women on intrauterine contraception, only the aPTT index decreased significantly by 4.6% after 12 months of contraception (Table V). No significant differences in hemostatic variables from baseline to follow-up were seen in the control group. Studying plasma fibrinolytic activity by means of traditional tests for clinical practice revealed no signs of its altered activity in DM women. The time of lysis

203

of the euglobulin fraction and Hageman-factordependent lysis did not differ from the norm, being clinically insignificant. Comparing hemostatic variables as a function of HbA1c level in type 1 DM women revealed statistically significant increases in the level of factor VIII ( p 5 0.05) and factor VII (p 5 0.001) with HcA1c  9%, as compared with the same indices in patients with HbA1c 5 9%. Against the background of taking 30EE/DSG, the type 1 DM women demonstrated a statistically significant change in the intravascular activation of blood platelets as the elevated sum of the active form of blood platelets: 9.4 + 0.9% at baseline versus 10.9 + 1.3% after 6 months, an increase of 13.8% compared with baseline (p 5 0.05). The combination 30EE/GSD was also associated with an elevation in the sum of the active forms of blood platelets, which amounted to 8.7% after 6 months of taking the COC. Among the women taking 20EE/DSG, the elevation in the sum of the active forms of blood platelets after 6 months’ COC usage averaged 5.4% (p 5 0.05). Hence, the elevated intravascular activation of blood platelets (increased sum of the platelet active forms) in diabetic women taking COCs was noted to depend on both the type of the progestogenic component and the dose of the estrogenic component, being a constituent part thereof. On the other hand, the use of intrauterine contraceptives, i.e. the copper-containing IUD and the LNG-IUS, had a neutral effect on the hemocoagulation and fibrinolysis systems, and did not depend on the degree of DM compensation. Amongst the women using a T-shaped copper IUD (n ¼ 22), the main complications and adverse reactions of intrauterine contraception were menstrual cycle disturbances (polymenorrhea, menoand/or metrorrhagia), which developed within the first 2–6 months of using it, and pain syndrome

Table V. Hemostatic variables at baseline and follow-up. Prothrombin index (%)

Fibrinogen (mg/dl)

Thrombin time (s)

Activated partial thromboplastin time (s)

Progressive activity of antithrombin III (%)

98 + 4.47 98 + 5.51 97 + 6.43 98 + 4.34 98 + 3.61

345 + 18 349 + 21 342 + 17 347 + 15 345 + 20

18.5 + 2.9 18.4 + 3.1 18.5 + 2.9 18.3 + 2 .7 17.1 + 3.0*

34.4 + 1.92 33.7 + 2.30 34.1 + 2.56 33.9 + 2.09 32.3 + 2.12*

97 + 11 99 + 14 93 + 9 95 + 12 97 + 8

Intrauterine contraception Baseline 98 + 4.37 3 months 97 + 5.43 6 months 98 + 4.61 9 months 98 + 3.39 12 months 97 + 4.58

338 + 15 343 + 22 346 + 25 339 + 17 336 + 19

18.1 + 2.4 17.8 + 3.6 17.7 + 2.3 17.6 + 3.7 17.7 + 2.6

34.7 + 1.82 33.9 + 2.11 34.1 + 1.56 34.3 + 2.09 33.1 + 2.12*

99 + 12 101 + 14 97 + 10 95 + 7 99 + 9

Oral contraception Baseline 3 months 6 months 9 months 12 months

*Significantly different from baseline (p 5 0.05, Newman–Keuls test).

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(Table VI). The IUD was removed in four (18%) type 1 DM women and in two (9%) type 2 DM women after 6 months due to persistent, frequent intermenstrual bloody discharge. Incomplete expulsion of the IUD, occurring after 5.6 + 3.7 months, was diagnosed in two (9%) type 1 DM women. Over the follow-up period, vaginal and cervical smears revealed fungi of the Candida genus in 16 (73%) type 1 DM women and eight (36%) type 2 DM women; in five (31%) and six (75%) of these women, respectively, with no clinical manifestations. In four and one cases, the mycotic lesion had been the cause of erosive vulvovaginitis with secondary infection. However, this did not result in dissemination of the inflammatory process to the small-pelvis organs. In all cases, comprehensive pathogenetic therapy (fungicidal) combined with anti-relapsing courses yielded a positive outcome. We did not consider mycotic vulvovaginitis a complication of intrauterine contraception because its incidence did not differ reliably from that prior to prescribing the contraception. There were no inflammatory diseases of the smallpelvis organs over the whole follow-up period, despite the fact that eight (36%) type 1 DM women and two (9%) type 2 DM women were known to have endured them previously. Comparative analysis of the complications and side-effects in the 22 diabetic women using the LNG-IUS as a means of contraception revealed the following: of the 11 women with type 1 DM, four (36%) cases posed difficulties of a mechanical nature at the time of insertion and five (45%) women appeared to develop pain syndrome. Polymenorrheatype menstrual cycle disturbances with a single episode of menorrhagia were observed in one woman (9%) only. Eight (73%) women demonstrated normalization of their menstrual cycle to occur on average after 31 + 3.2 days with the duration of blood loss amounting to 4.6 + 1.7 days. No cases of expulsion were registered in any women with type 1 DM. However, two (9%) women using the

Table VI. Side-effects of various methods of contraception in perimenopausal women with diabetes mellitus (DM). Side-effect Oral contraception None Intermenstrual bloody discharge Breast enlargement and tenderness Gnawing pain in the lower limbs Pain in the dextral hypochondrium Allergic reactions Vaginal discharge Intrauterine contraception Menstrual cycle disorders Pain syndrome Data are expressed as n (%).

Type 1 DM

Type 2 DM

(n ¼ 36) 11 (30.5) 7 (19.4) 16 (44.4) 5 (13.9) 2 (5.6) 0 27 (75.0)

(n ¼ 33) 2 (6.1) 3 (9.1) 10 (30.3) 5 (15.2) 4 (12.1) 0 15 (45.5)

(n ¼ 22) 5 (22.7) 3 (13.6)

(n ¼ 22) 4 (18.2) 3 (13.6)

LNG-IUS reported to have developed acne vulgaris on the back and face during the first month of contraception, which resolved spontaneously 24 + 13 days later. Our results revealed virtually no difference between the type 1 DM women (n ¼ 11) and type 2 DM women (n ¼ 11) using the T-shaped copper IUD in either the pattern or the incidence of complications and adverse events. The rate of expulsion of the LNG-IUS was considerably lower than that of the T-shaped copper IUD in type 2 DM women, but however was higher than that of the type 1 DM patients on the LNG-IUS. Discussion The findings obtained in the present study indicate that neither COCs nor IUDs influence carbohydrate metabolism in diabetic women. In addition, both IUDs and present-day COCs have little or no influence on the elevation in the requirements for insulin preparations. The only exception was the combination 30 mg EE/75 mg GSD, which considerably increased the insulin requirements in type 1 DM women. The comparative analysis of lipid metabolism revealed that the majority of the preparations did not exert any unfavorable effect on blood lipid profile. However, use of the combination 20 mg EE/ 150 mg DSG in perimenopausal women with type 1 DM was noted to induce a clinically significant deterioration in blood lipid profile as soon as within 6 months of usage, to be followed by stabilization of the studied parameters after 12 months of contraception, at a somewhat higher level than initially. Analysis of the blood lipid profile in women on intrauterine contraception revealed that the main clinical indices did not change significantly in the patients with fair-to-moderate compensation of DM. Poor compensation of the primary disease (HbA1c  9%) was accompanied and followed by statistically significant elevations in TC and LDL-C levels, as well as elevated TG level and a lowered level of HDL-C. Hence, the blood lipid profile did not deteriorate in diabetic women using IUDs on the background of satisfactory compensation of the primary disease (HbA1c  7 to 5 9%); however, blood lipid profile worsened in those female patients with poor compensation of carbohydrate metabolism owing to elevated levels of TC and LDL-C and a decrease in HDL-C. Analysis of the dynamics of the blood lipid profile in women with good and poor compensation of DM showed that it is the degree of carbohydrate metabolism compensation that mainly determines the elevated concentration of atherogenic fractions of lipids in blood plasma, rather than the dose, composition and route of administration of the contraceptive device involved.

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Contraception in women with DM Among women with various degrees of carbohydrate metabolism compensation, the taking of COCs was accompanied by increased intravascular activation of blood platelets and to a lesser degree by changes in parameters of hemostatic homeostasis. The decreased aPTT and TT while taking oral contraceptives turned out to be clinically insignificant, because they were within the limits of physiological fluctuations, albeit statistically significant compared with baseline. Comparing hemostatis system parameters as a function of HbA1c level in type 1 DM women, patients with HbA1c  9% exhibited a statistically significant elevation in the level of factors VII and VIII, compared with patients having HbA1c in the range from 7 to 59%. Hence, the relationship between HbA1c level and factor VII content was detected only in type 1 DM women. Administration of 30 mg EE/150 mg DSG was accompanied and followed by an alteration in the intravascular activation of blood platelets as the increased sum of active forms of blood platelets, but only in type 1 DM women. The combination 30 mg EE/75 mg GSD was also associated with an elevation in the sum of the active forms of blood platelets as soon as 6 months after commencing usage; while when taking 20 mg EE/150 mg DSG, the elevation in the sum of the active forms of blood platelets after 6 months’ use amounted to 5.4%. The use of IUDs exerted a neutral effect on the system of hemocoagulation and fibrinolysis, and did not depend on the degree of DM compensation and/or the presence of hyperlipidemia. The incidence of side-effects of COCs and IUDs did not differ from that in apparently healthy women, which has been confirmed by the findings of other researchers [7,8]. Moreover, during our study we did not observe a single case of PID. Studying use of the LNG-IUS in type 1 and type 2 DM perimenopausal women revealed a neutral effect of this contraceptive device on carbohydrate and lipid metabolism indices, blood coagulation and fibrinolysis in the cohort of the patients concerned. One of the factors which would explain our finding of no systemic alterations while using the LNG-IUS is the low dose of LNG released during 24 h (20 mg), sufficient for producing a contraceptive effect without negatively influencing either lipid/carbohydrate metabolism or the hemostatis system, which does not contradict the findings obtained in other studies. Rogovskaya and colleagues found no differences between type 1 DM reproductive women making use of the LNG-IUS and a copper-containing IUD [10]. However, the effect of LNG on blood lipid profile while taking LNG-releasing preparations was studied mainly in trials involving apparently healthy women. According to Andersson and associates, the only significant alteration in lipid profile in postmenopausal

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women using the LNG-IUS in combination with estrogen was a temporal decrease in HDL-C by month 6 of contraception [11]. Raudaskoski and collaborators and Wollter-Svensson and co-workers reported that the HDL-C fraction increased and the LDL-C fraction decreased in non-diabetic perimenopausal women who for a year used the LNG-IUS releasing 5 or 10 mg LNG/24 h in combination with orally administered estradiol [12,13]. Hence, as highly effective methods aimed at correcting female fertility, women with DM during the perimenopausal period should be recommended to receive preparations containing 20 mg EE, which leads to a less pronounced elevation in the intravascular activation of blood platelets as compared with preparations containing 30 mg EE. The use of lowdose COCs, copper and LNG-releasing IUDs in diabetic women during the perimenopausal period exerts no clinically significant effect on indices of carbohydrate and lipid metabolism against the background of sustained and satisfactory compensation of carbohydrate metabolism (i.e. HbA1c level  7.5%). The copper and LNG-releasing IUDs have a neutral effect on the blood coagulation system and fibrinolysis, and do not depend on the degree of DM compensation.

References 1. Schwallie PC. Experience with Depo-provera as an injectable contraceptive. J Reprod Med 1974;13:113–117. 2. Grundy SM, Garber A, Goldberg R, Havas S, Holman R, Lamendola C, Howard WJ, Savage P, Sowers J, Vega GL. Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group IV: lifestyle and medical management of risk factors. Circulation 2002;105:e153–e158. 3. Carr ME. Diabetes mellitus: a hypercoagulable state. J Diabetes Complications 2001;15:44–54. 4. Garg SK, Chase HP, Marshall G, Hoops SL, Holmes DL, Jackson WE. Oral contraceptives and renal and retinal complications in young women with insulin-dependent diabetes mellitus. J Am Med Assoc 1994;271:1099–1102. 5. Klein BEK, Moss SE, Klein R. Oral contraceptives in women with diabetes. Diabetes Care 1990;13:895–898. 6. Family and Reproductive Health Programme. Improving access to quality care in family planning. Medical eligibility criteria for contraceptive use. 2nd ed. Geneva: World Health Organization; 2000. 7. Kimmerle R, Weiss R, Berger M, Kurz KH. Effectiveness, safety, and acceptability of a copper intrauterine device (CU Safe 300) in type I diabetic women. Diabetes Care 1990;16: 1227–1230. 8. Skouby SO, Molsted-Pedersen L, Kosonen A. Consequences of intrauterine contraception in diabetic women. Fertil Steril 1984;42:568–572. 9. Andersson K. The levonorgestrel intrauterine system: more than a contraceptive. Eur J Contracept Reprod Health Care 2001;6:15–22. 10. Rogovskaya S, Rivera R, Grimes DA, Chen PL, Pierre-Louis B, Prilepskaya V, Kulakov V. Effect of a levonorgestrel intrauterine system on women with type 1 diabetes: a randomized trial. Obstet Gynecol 2005;105: 811–815.

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11. Andersson K, Stadberg E, Mattsson LA, Rybo G, Samsioe G. Intrauterine or oral administration of levonorgestrel in combination with estradiol to perimenopausal women – effects on lipid metabolism during 12 months of treatment. Int J Fertil Menopausal Stud 1996;41:476–483. 12. Raudaskoski T, Tapanainen J, Tomas E, Luotola H, Pekonen F, Ronni-Sivula H, Timonen H, Riphagen F, Laatikainen T. Intrauterine 10 mg and 20 mg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response. Br J Obstet Gynaecol 2002;109:136–144.

13. Wollter-Svensson LO, Stadberg E, Andersson K, Mattsson LA, Odlind V, Persson I. Intrauterine administration of levonorgestrel in two low doses in HRT. A randomized clinical trial during one year: effects on lipid and lipoprotein metabolism. Maturitas 1995;22:199–205.