Levonorgestrel-releasing intrauterine system effects on metabolic variables in PCOS

Abstract

Background

We aimed to determine and compare the reproductive hormone level and metabolic of patients with polycystic ovary syndrome (PCOS) when treated with a levonorgestrel-releasing intrauterine system (LNG-IUS).

Objectives

Sixty-four women with PCOS (Group A) and sixty-six healthy women inserted with a LNG-IUS for conception (Group B) were recruited from the Department of Obstetrics and Gynecology in Jinhua Hospital Zhejiang University School of Medicine.

Method

We compared the general characteristics of the cases between the two groups, including age, body mass index (BMI), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), abdominal circumference (AC) and waist circumference (WC). Each patient was evaluated by transvaginal ultrasonography (TVS) to determine the number of oocytes and ovarian volume, and the intima-media thickness (IMT) of the common carotid artery was measured on an ECG image from the left common carotid artery before and six months, 12 months and 24 months after patients were inserted with the LNG-IUS. Hormone levels (follicle stimulating hormone, luteinizing hormone, serum estradiol and total testosterone), serum insulin, sex hormone binding globulin (SHBG), total cholesterol (TC), high density lipoprotein (HDL), and triglyceride (TG), were evaluated before and six months, 12 months and 24 months after patients were inserted with an LNG-IUS. The levels of testosterone (T) in the non-HA (hyperandrogenemia) group and HA group in PCOS group were compared with the baseline. We also compared cases without insulin resistance in the PCOS group with their baseline.

Results

Prior to LNG-IUS insertion, the PCOS group had significantly higher total testosterone levels (p < 0.05), lower HDL levels (p < 0.05), and a greater ovarian volume (p < 0.05) than the control group. Compared to baseline values, there was a significant increase in fasting glycemia at six months after LNG-IUS insertion (p < 0.05). Mean ovarian volume was significantly smaller than the volume prior to LNG-IUS insertion (p < 0.05); LDL and TC were significantly reduced when compared to baseline evaluation in the PCOS group. The remaining variables did not differ significantly during the 24 months follow-up period. The control group did not show any significant changes when compared to the period before LNG-IUS insertion. When the groups were compared after the 24-month follow-up, WC, AC, FSH, LH, T, SHBG, HDL, FINs, FAI and ovarian volume were significantly different when compared between the two groups (p < 0.05) .

Conclusion

The LNG-IUS is an effective and safe non-surgical device and the use of this system for 24 months did not result in significant changes in the clinical and metabolic variables in women with PCOS and healthy control females.

Keywords:

• Polycystic ovary syndrome
• levonorgestrel-releasing intrauterine system
• contraception
• progestogen

Introduction

Polycystic ovary syndrome (PCOS) is a heterogenous endocrine disorder among women of reproductive age, presenting in at least 5–10% of women worldwide [1]. The current recommended diagnostic criteria for PCOS are characterized by HA (hyperandrogenemia), menstrual irregularity, as well as polycystic ovarian (PCO) morphology [2]. The diagnosis of PCOS is based on endocrinological and reproductive abnormalities; associated metabolic features of the condition have become more recognized as key features of PCOS, including disorders of glucose metabolism and lipid metabolism, thus increasing the risk of developing type 2 diabetes and cardiovascular disease [3,4]. In PCOS patients, the increased GnRH pulse frequency can promote LH secretion, thus leading to ovarian dysfunction and the abnormal synthesis of sex steroids. In addition, peripheral sex steroid hormones can modulate the action of GnRH neurons through a feedback effect that is impaired in PCOS, thus forming a vicious cycle. A previous study by Glueck et al. demonstrated that the incidence of early spontaneous abortion in patients with PCOS is 20–41% [5, 6]. The optimal interventions for appropriate target metabolic PCOS traits should favorably influence androgen synthesis, sex hormone binding globulin (SHBG) production, insulin sensitivity, and clinical symptoms, including irregular menstrual cycle, acne and hirsutism. These requirements are difficult to meet with a single form of treatment.

The most widely used option for long-term treatment is combined oral contraceptives (COC).

Morin-Papunen et al. showed that COC treatment caused a significant reduction in total androgen levels and a highly significant increase in SHBG, but no changes in insulin sensitivity or fasting insulin [7]. COC may improve clinical symptoms temporarily, however, many patients cannot use this treatment over long periods due to the increased risk of COC on deep vein thrombosis, weight gain, breast tenderness and mood changes.

Any effective treatment that delivers a hormone locally and is associated with a lower systemic level is likely to be more acceptable to the patient as the side effects would be more tolerable. The Mirena intrauterine system (Schering Health, Berlin, Germany) delivers levonorgestrel (Lng) locally at a steady rate of 20 mg/24 h and offers the added advantage of a single administration for a possible duration of 5 years. Thus far, only one study [8] has evaluated the performance of the Mirena intrauterine system was not associated with relevant changes in clinical or metabolic markers in women without comorbidities with PCOS; however, the follow-up period was short. The aim of our study was to evaluate the effect of the Mirena intrauterine system in women with PCOS followed up over a period of 24 months by comparing the levels of various reproductive hormones and metabolic indices from baseline and to women without PCOS.

Materials and methods

Patient selection

This single-center study involved the retrospective analysis of 64 PCOS patients (Group A) treated at the Outpatient Department of Jinhua Hospital Zhejiang University School of Medicine from July 2017 to July 2019. PCOS was diagnosed according to the Rotterdam criteria [9]. Each woman with PCOS requested placement of the LNG-IUS (Mirena®, Bayer Schering Pharma Oy, Turku, Finland). The LNG-IUS was not inserted on the same day as the invitation to participate in the study. We also included 66 healthy women as a control (Group B); these women were healthy volunteers and all wished to use the LNG-IUS as their method of contraception over the same period. All control women had ultrasound-proven normal ovarian morphology and regular menstrual cycles (24–35 days). None of the patients had hirsutism or acne. None of the patients received COC or other forms of medicine that could interfere with hormonal or metabolic states. The exclusion criteria for both groups of patients were as follows: the current presence or a history of venous or arterial thrombosis; chronic and/or acute inflammatory processes; smoking; the use of a COC or other medicine during a six-month period before the beginning of our study; in the PCOS group, we excluded patients with irregular menstruation that was not caused by PCOS, while in the control group, we excluded patients with irregular menstruation. The Outpatient Department is the sector responsible for the follow-up of all women. This study was approved by the institutional review board, and all women signed an informed consent form prior to admission (ethical approval number: 2019-195).

Variables and measurements

Age, BMI, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), abdominal circumference (AC) and waist circumference (WC) were evaluated. During two years of follow-up, we assessed hormone levels, fasting insulin, SHBG, TC, HDL, LDL and TG at six months, 12 months, and 24 months after the LNG-IUS was inserted. Each patient was evaluated by vaginal sonography to assess the ovarian volume; and the IMT of the common carotid artery was measured on an ECG image of the left common carotid artery (Vieira et al. 2012) before and after the LNG-IUS was inserted. The IMT of the distal wall of the common carotid artery was measured four times on this image, approximately 10 to 20 mm proximal to the carotid bulb and then averaged. The serum samples were separated and stored at −80 °C until processing. Serum was obtained after the blood was centrifuged at 3,000 r/min at 4 °C for 5 min, aliquoted, and stored at −80 °C until serum tests were performed. Hormone levels were evaluated by liquid chromatography/tandem mass spectrometry. Serum insulin and SHBG levels were determined by chemiluminescence and TC, HDL, LDL, and TG were measured by immunoenzymatic methods.

Statistical analysis

SPSS 17.0 (SPSS, Inc., IBM, Chicago, IL) was used for statistical analysis. Data are presented as mean ± standard deviation (SD), median (range), or absolute number (%). Differences in means between the two groups were evaluated by t-tests. All P - values were two-tailed and a p < 0.05 was considered statistically significant.

Results

In total, 130 patients were recruited at the beginning of the study. However, over the two years of follow-up, two patients in group A and one patient in group B were lost to follow up. In addition, one patient in group B expulsed the device three months after insertion, and one patient in group B removed the LNG-IUS four months after implantation due to persistent bleeding. The remaining patients (62 in group A and 63 in group B) were all followed-up in an appropriate manner.

Clinical characteristics, serum hormone levels, and biochemical characteristics of the two groups of subjects are shown in Tables 1 and 2. Age, IMT, SAP, DAP, and the serum levels of FPG, TG, TC, and LDL did not differ significantly between the two groups during the 24-month follow-up period (p > 0.05). However, the PCOS patients had significantly higher levels of BMI, AC, WC, LH, FSH, FAI, T, FIN, HOMA-IR and ovarian volumes than those in the control group during the 24-month follow-up period (p < 0.05) (Tables 1 and 2). During the 24-month follow-up period, the women with PCOS were associated with some modifications, including a 8.71% reduction in TC levels, a 2.51% reduction in LDL levels, a 5.23% reduction in ovarian volume, and a 4.06% increase in fasting glycemia). These variations were less than 10% compared to the basal period and did not have any significant clinical impact. The control group did not show any significant changes during the 24-month follow-up period when compared to the period before LNG-IUS insertion.

Table 1. The baseline measurements women with PCOS and controls.

Characteristics	Group	Baseline
Age, year	Group A	32.18 ± 6.06
	Group B	31.61 ± 5.75
BMI, kg/m^2	Group A	22.88 ± 1.94^a
	Group B	21.10 ± 1.07^a
WC, kg/m^2	Group A	77.01 ± 8.42^a
	Group B	70.87 ± 6.33^a
AC, cm	Group A	81.53 ± 7.59^a
	Group B	77.45 ± 5.74^a
IMT, cm	Group A	0.46 ± 0.04
	Group B	0.45 ± 0.04
SAP, mmHg	Group A	115.50 ± 14.23
	Group B	111.27 ± 10.67
DAP, mmHg	Group A	76.06 ± 9.03
	Group B	73.41 ± 7.52
FSH, IU/L	Group A	6.23 ± 0.81^a
	Group B	5.20 ± 0.98^a
LH, IU/L	Group A	11.85 ± 2.26^a
	Group B	6.14 ± 0.91^a
T, nmol/L	Group A	2.39 ± 0.50^a
	Group B	1.30 ± 0.27^a
SHBG, nmol/L	Group A	46.52 ± 12.84^a
	Group B	72.08 ± 12.72^a
FAI	Group A	5.48 ± 1.63^a
	Group B	1.86 ± 0.52^a
FPG, mmol/L	Group A	5.17 ± 0.70
	Group B	4.93 ± 0.67
FINs, mIU/L	Group A	12.32 ± 3.16^a
	Group B	7.82 ± 2.15^a
HOMA-IR	Group A	2.81 ± 0.72^a
	Group B	1.72 ± 0.59^a
TC, mg/dL	Group A	176.98 ± 31.93
	Group B	170.05 ± 27.99
TG, mg/dL	Group A	84.95 ± 19.03
	Group B	79.34 ± 19.93
HDL, mg/dL	Group A	47.82 ± 8.89^a
	Group B	52.20 ± 10.87^a
LDL, mg/dL	Group A	105.10 ± 33.67
	Group B	113.82 ± 18.54
Ovarian volumes, cm^3	Group A	10.13 ± 3.09^a
	Group B	6.16 ± 1.44^a

Abbreviations: BMI, body mass index; WC, waist circumference; AC, abdominal circumference; IMT, intima-media thickness of the carotid artery; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; FSH, Follicle-Stimulating Hormone; LH, luteinizing hormone; T, testosterone; SHBG, sex hormone-binding globulin; FAI, free androgen index; FPG, fasting plasma glucose; FIN, Fasting insulin; HOMA-IR, homeostasis model assessment of insulin resistance; TC, total cholesterol; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

^ap < 0.05 compared with two groups (standard deviation).

Table 2. The age, IMT, SAP, DAP, AC, WC serum levels of FPG, TG, TC, LDL,LH, FSH, T, FIN and ovarian volumes in two groups during the 24-month following-up.

Characteristics	Group	6 month	12 month	24 month
Age, year	Group A	--	--	--
	Group B	--	--	--
BMI, kg/m^2	Group A	23.07 ± 1.90^a	22.93 ± 1.73^a	22.90 ± 1.67^a
	Group B	21.24 ± 0.87^a	21.20 ± 0.95^a	21.14 ± 0.84^a
WC, cm	Group A	78.02 ± 8.18^a	76.90 ± 7.62^a	77.24 ± 7.61^a
	Group B	71.50 ± 7.38^a	71.16 ± 7.15^a	70.42 ± 7.46^a
AC, cm	Group A	81.76 ± 6.65^a	81.59 ± 6.02^a	81.62 ± 5.85^a
	Group B	78.52 ± 5.47^a	77.81 ± 5.07^a	77.75 ± 4.69^a
IMT, cm	Group A	0.47 ± 0.03	0.48 ± 0.03	0.47 ± 0.02
	Group B	0.46 ± 0.03	0.46 ± 0.05	0.46 ± 0.03
SAP, mmHg	Group A	114.23 ± 13.81	112.10 ± 12.21	116.11 ± 11.40
	Group B	110.37 ± 10.79	110.03 ± 8.20	112.68 ± 9.20
DAP, mmHg	Group A	77.10 ± 9.10	75.40 ± 8.66	74.34 ± 6.89
	Group B	74.22 ± 7.36	72.90 ± 5.98	71.84 ± 5.53
FSH, IU/L	Group A	5.98 ± 1.13^a	5.89 ± 0.79^a	6.15 ± 0.94^a
	Group B	5.34 ± 0.97^a	5.25 ± 0.65^a	5.42 ± 0.89^a
LH, IU/L	Group A	11.62 ± 2.0^a	11.43 ± 2.18^a	12.03 ± 1.94^a
	Group B	6.20 ± 0.86^a	6.02 ± 0.63^a	5.91 ± 0.64^a
T, nmol/L	Group A	2.36 ± 0.33^a	2.45 ± 0.45^a	2.50 ± 0.48^a
	Group B	1.35 ± 0.23^a	1.32 ± 0.20^a	1.28 ± 0.19^a
SHBG, nmol/L	Group A	48.70 ± 8.0^a	51.0 ± 12.11^a	48.85 ± 10.79^a
	Group B	69.44 ± 13.43^a	70.84 ± 12.08^a	74.01 ± 15.33^a
FAI	Group A	4.99 ± 1.10^ab	5.06 ± 1.47^a	5.37 ± 1.80^a
	Group B	2.03 ± 0.58^a	1.92 ± 0.49^a	1.84 ± 0.62^a
FPG, mmol/L	Group A	5.38 ± 0.98^b	5.11 ± 0.72	5.20 ± 0.58
	Group B	4.88 ± 0.60	4.85 ± 0.55	5.01 ± 0.56
FINs, mIU/L	Group A	11.98 ± 2.73^a	12.08 ± 2.57^a	12.28 ± 2.44^a
	Group B	7.56 ± 2.03^a	7.75 ± 2.08^a	8.15 ± 2.16^a
HOMA-IR	Group A	2.69 ± 0.68^ab	2.63 ± 0.65^a	2.84 ± 0.63^a
	Group B	1.65 ± 0.55^a	1.69 ± 0.66^a	1.81 ± 0.52^a
TC, mg/dL	Group A	168.43 ± 28.57^b	164.24 ± 29.63^b	161.57 ± 26.75^b
	Group B	167.11 ± 30.16	168.12 ± 29.96	171.13 ± 28.19
TG, mg/dL	Group A	82.86 ± 18.34	82.70 ± 16.03	86.10 ± 17.66
	Group B	80.12 ± 19.06	78.37 ± 17.22	81.45 ± 18.69
HDL, mg/dL	Group A	46.84 ± 7.20^a	46.64 ± 5.78^a	48.84 ± 5.79^a
	Group B	50.90 ± 8.03^a	51.26 ± 8.92^a	51.82 ± 9.07^a
LDL, mg/dL	Group A	101.84 ± 30.93^b	103.14 ± 29.49	102.46 ± 28.64^b
	Group B	111.15 ± 22.57	112.09 ± 20.46	111.24 ± 21.91
Ovarian volumes, cm^3	Group A	9.74 ± 2.81^ab	9.66 ± 2.75^ab	9.60 ± 2.59^ab
	Group B	6.12 ± 1.30^a	6.11 ± 1.26^a	6.09 ± 1.27^a

Abbreviations: BMI, body mass index; WC, waist circumference; AC, abdominal circumference; IMT, intima-media thickness of the carotid artery; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; FSH, Follicle-Stimulating Hormone; LH, luteinizing hormone; T, testosterone; SHBG, sex hormone-binding globulin; FAI, free androgen index; FPG, fasting plasma glucose; FIN, Fasting insulin; HOMA-IR, homeostasis model assessment of insulin resistance; TC, total cholesterol; TG, triglycerides; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

^ap < 0.05 compared with two groups (standard deviation).

^bp < 0.05 compared to baseline value (intragroup comparison).

In the PCOS group, we compared the non-HA group and HA group; there were no statistically significant differences in T level during the two years of follow-up (Table 3). In the PCOS group, there were 59 cases without insulin resistance; we compared the progress of these patients over the next two years. There were statistically significant differences in the six months after inserting the LNG-IUS but there were no statistically significant differences over the 12 and 24 months after inserting the LNG-IUS (Table 4).

Table 3. The comparision between non-HA group and HA group in PCOS group with the baseline.

PCOS group	Group	improved	Not improved	P value
	HA Group	13	7	0.584
	Non-HA Group	23	19

Table 4. The comparision of HOMA-IR level between cases without insulin resistance in PCOS group with their baseline.

PCOS group	Baseline	6 month	12 month	24 month
	2.73 ± 0.64	2.56 ± 0.58^b	2.62 ± 0.59^a	2.78 ± 0.58^a

^ap > 0.05 compared to baseline value.

^bp < 0.05 compared to baseline value.

Discussion

In the past, COC was considered an appropriate choice of treatment, regardless of whether PCOS patients had symptoms of obesity, hirsutism, acne, and ovulation disorders. However, many PCOS patients, especially women who did not experience major symptoms do not like to use long-term oral drugs because of their side effects such as weight gain, breast tenderness and mood changes.

Considering the pioneering development and disadvantages of COC, we introduced am LNG-IUS that could be inserted into the uterus. The LNG-IUD releases 20 mg of levonorgestrel each day and the serum levels of Lng are similar to those in patients who want to use the device for contraception; this is consistent with a previous report [10]. Due to poor ovulation and estrogen stimulation in the absence of progesterone, women with PCOS may develop simple endometrial hyperplasia, followed by complex or atypical hyperplasia, and even endometrial cancer [11]. The core concept of the LNG-IUS in our study is the efficient local administration of Lng. Levonorgestrel is known to down-regulate the Progesterone and estrogen receptors in the endometrium and to inhibit the endometrial production of E2-induced growth factors or the production of growth factor-binding protein from the endometrium [12]. The LNG-IUS works locally in the uterine cavity and compared with COC this device has fewer side effects on the whole body. This is supported by the high concentration gradient between the endometrium and the serum (>1000) [13], thus suggesting that the sub-endometrial vascular and lymphatic network quickly take up Lng for rapid transfer to the endometrium. According to long-term clinical observation, most cases of endometrial hyperplasia are reversible or maintain a continued healthy state. Only a few atypical cases would evolve into endometrial cancer after a long period of time [14]. Thus, early interventional treatment in PCOS is very important. In our study, the Lng released by the device helped to protect the endometrium but did not have negative impact on reproductive hormone levels and metabolic indices. According to the 24-month following period, the use of the LNG-IUS by women with PCOS was associated with some favorable modifications, including an 8.71% reduction in TC levels, a 2.51% reduction in LDL levels, and a 5.23% reduction in ovarian volume. However, some factors did not show any significant changes, for example, there was a 4.06% increase in fasting glycemia. However, these variations were less than 10% when compared to the basal period, a fact that probably had no relevant clinical impact. This finding is consistent with those reported by Lang et al. [15]. In the PCOS group, we compared the non-HA group and HA group; there was no statistically significant difference in T level over the subsequent two-year period. Use of the LNG-IUS for 24 months did not result in any significant changes in T level in the non-HA group and HA group. There were 59 cases without insulin resistance in the PCOS group and there were no statistically significant differences in the 12 and 24 months after inserting the LNG-IUS. In the long term, the use of the LNG-IUS did not result in any significant changes in the HOMA-IR level in cases without insulin resistance.

There were some limitations associated with our current research that should be taken into consideration. The follow-up period was short, and the sample size was relatively small. Future studies should incorporate a larger number of cases and a longer follow-up period.

In conclusion, the LNG-IUS is an effective and safe non-surgical device and the use of the LNG-IUS for 24 months did not result in any significant changes in the clinical and metabolic variables of women with PCOS and healthy control females.

Statement of ethics

The study was approved by the Ethics Committee of Jinhua Municipal Central Hospital (ethics approval number: 2019-195).

Acknowledgments

Thanks are due to Lanying Jin for valuable discussion.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.