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Effect of oral versus intrauterine progestins on weight in women undergoing fertility preserving therapy for complex atypical hyperplasia or endometrial cancer
Gynecologic Oncology 140 (2016) 234–238
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Effect of oral versus intrauterine progestins on weight in women undergoing fertility preserving therapy for complex atypical hyperplasia or endometrial cancer☆ Diana Cholakian a, Kari Hacker b, Amanda N. Fader a, Paola A. Gehrig b, Edward J. Tanner III a,⁎ a b
The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Medicine, Baltimore, MD, United States Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
H I G H L I G H T S • LNG-IUD was associated with less weight gain than megestrol acetate during therapy. • Obese women gained less weight with progestin therapy for endometrial cancer. • Obese women gained less weight with LNG-IUD than megestrol acetate during therapy.
a r t i c l e
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Article history: Received 17 September 2015 Received in revised form 2 December 2015 Accepted 13 December 2015 Available online 17 December 2015 Keywords: Endometrial cancer Fertility preservation Progestin therapy
a b s t r a c t Objective. The objective of this analysis was to evaluate weight changes associated with oral progestin therapies versus the levonorgestrel-containing intrauterine device (LNG-IUD) in women undergoing fertilitypreserving therapy for complex atypical hyperplasia (CAH) and endometrial cancer (EMC). Methods. All patients diagnosed with CAH or EMC managed with fertility-preserving progestin therapy at two institutions from 1998 to 2012 were identified. Those with serial weight measurements before, during and after therapy were included. Patients were categorized according to the type of progestin therapy administered. The rate of weight change over time of patients treated with oral versus intrauterine progestins was compared using the Mann Whitney U test. Results. Sixty patients with EMC (35) or CAH (25) were treated during the study period, with 12 patients receiving multiple regimens. These included megestrol acetate (MA, n = 42), LNG-IUD (n = 22), and other oral progestins (n = 11). The median age at diagnosis was 32 and median pre-progestin body mass index (BMI) was 40.4 kg/m2. The median therapy duration was 11.7 months [range: 2.3–118.5]. Median weight change during therapy was greater with MA versus LNG-IUD (+ 2.95 vs. + 0.05 kg, P = 0.03). Patients with a BMI b 35 gained more weight during therapy versus patients with BMI ≥ 35 (+2.30 vs. −0.70 kg/month, P = 0.04); however, in patients with BMI ≥ 35, MA was still associated with more weight gain than LNG-IUD (+2.2 vs.-5.40 kg, P = 0.05). Conclusion. Oral progestin therapy for conservative treatment of young EMC/CAH survivors is associated with increased weight gain, especially when megestrol acetate is utilized. Utilization of LNG-IUD may result in less weight gain. © 2015 Elsevier Inc. All rights reserved.
1. Introduction With rising obesity rates in the United States, it is postulated that the incidence of complex atypical endometrial hyperplasia (CAH) and
☆ Disclosure statement: The authors report no conflicts of interest. No industry or pharmaceutical support was obtained to conduct this research or produce this manuscript. ⁎ Corresponding author at: 600 N Wolfe Street, Phipps 281, Baltimore, MD 21287, United States. E-mail address: [email protected] (E.J. Tanner).
http://dx.doi.org/10.1016/j.ygyno.2015.12.010 0090-8258/© 2015 Elsevier Inc. All rights reserved.
endometrial adenocarcinoma (EMC) in premenopausal women will also increase [1]. Even now, up to 14% of women with endometrial cancer are diagnosed at 40 years of age or younger [2,3]. While the standard of care for the management of CAH or EMC includes hysterectomy, this recommendation may conflict with the fertility plans of younger women, especially in a society where the age of first delivery is delayed to later in life [4]. In recent years, progestin therapy has been successfully used to treat select women with endometrial cancer and hyperplasia who desire to preserve fertility. The efficacy of progestin therapy on treatment of
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CAH or grade 1 EMC has been studied widely; however, most reports are retrospective [5–11]. The most common progestin regimens include megestrol acetate (MA) and the levonorgestrel intrauterine system (LNG-IUD). These modalities may be equally effective [12], with a recent meta-analysis showing a pooled regression rate of 66–76.2% and relapse rate of 40.6% for both regimens [13,14]. In fact, women with endometrial hyperplasia were more likely to show regression with an LNG-IUD compared to oral progestins [36], prospective head-to-head comparisons of these treatment modalities are lacking. It is well established that use of progestins in women for contraception or treatment of benign gynecologic conditions leads to weight gain, especially in women who are obese at baseline [15–17]. Progestins can even be used to help patients gain weight in some circumstances. A recent Cochrane Review of MA used for anorexia-cachexia syndrome showed an 8% weight gain in MA-treated patients versus control patients [7]. Given that obesity is one of the strongest risk factors for CAH and EMC, use of progestin therapy in this setting is problematic — and potentially counterproductive. Additionally, numerous reports demonstrate decreased disease-specific and overall survival with increasing BMI in patients with EMC [13,18–20]. Importantly, obesity appears to be a modifiable risk factor for mortality from disease [21]. In theory, the LNG-IUD system should offer the same advantages for the treatment of CAH and EMC without the degree of weight gain associated with systemic absorption of oral progestins. Although response rates and pregnancy outcomes are frequently evaluated in studies of patients treated conservatively for CAH and EMC, the role of potential weight gain with progestin therapies during gynecologic cancer treatment has not yet been well evaluated [12]. It is, therefore, important to define whether any of the progestin therapies used in the conservative management of women with CAH or EMC are more likely to result in weight gain. 2. Methods After obtaining Institutional Review Board approval at both institutions, we identified all women 45 years of age or younger treated with progestin therapy for at least two months for complex atypical endometrial hyperplasia (CAH) or grade 1–2 endometrioid adenocarcinoma of the endometrium (EMC) at one of two institutions (Johns Hopkins Hospital, Baltimore, MD and University of North Carolina School of Medicine, Chapel Hill, NC) from 1998 to 2012. Women were excluded from the analysis if they were treated with progestin therapy for reasons other than fertility preservation or did not have serial weight measurements available pre, during and post-progestin therapy. Demographic data was collected including age at diagnosis, ethnicity, BMI and other comorbidities. Patients were categorized according to the type and number of progestin therapies received. For purposes of comparison, patients that received both oral progestins and LNG-IUD were categorized in the LNG-IUD group. The date that progestin therapy started and ended was collected as well as the starting and ending patient weights. Using this data, we were able to calculate the total weight change and the rate of weight change over time (kg/month) for each progestin therapy. Using patient heights collected at time of diagnosis, we calculated the body mass index (BMI) at diagnosis and change in BMI over time (kg/m2/month) during therapy. If dates or weights were missing for a regimen, we excluded data for that regimen from analysis. SPSS version 22 was used to calculate differences in weight change for oral progestin regimens versus LNG-IUD. Testing for normality of the data was performed using the Shapiro–Wilk test. To compare demographic data between treatment groups, categorical data were assessed using the Chi Square test while continuous variables were assessed using the Student T test for variables with normal distribution. Comparisons of weight changes during therapy and weight change over time during therapy were performed using the Mann Whitney U test due to non-normal distribution of the data.
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3. Results We identified 60 eligible patients treated at two institutions, Johns Hopkins Hospital (n = 34) and the University of North Carolina Medical Center (n = 26) from 1998 to 2012. Twenty-five patients were initially treated for CAH and 35 were initially treated for EMC. Demographic data is found in Table 1. The median age at diagnosis was 32.0 years (range: 22–45) with 13 patients (19%) having concurrent diabetes mellitus. Seven of these 13 diabetic patients were taking metformin during progestin therapy. The median starting weight for the entire cohort was 110.4 kg (range: 45.4–198.6) and the median starting BMI was 40.4 kg/m2 (range: 18.3–70.7). Most patients were treated with just one progestin-containing regimen (n = 48, 80.0%), although 11 (18.3%) were treated with two and one (1.7%) was treated with three consecutive regimens (Table 2). Three patients were treated with both LNG-IUD and oral progestins and were categorized in the LNG-IUD group for comparison purposes. Results were not significantly altered by including the three patients treated with both regimens in the oral progestin group or by including them in a separate third group. Megestrol acetate (MA) was the most commonly prescribed regimen (n = 40, 55.6%), followed by LNG-IUD (n = 22, 30.6%), medroxyprogesterone acetate (MPA, n = 5, 6.9%), and other oral progestin-containing regimens (n = 5, 6.9%). The dosing regimen for patients receiving oral therapy varied. For patients receiving MA, doses ranged between MA 40 mg twice daily to 160 mg twice daily. For MPA, the average dose varied between 10 mg daily and 40 mg daily. In many patients, the progestin doses were changed throughout the course of their treatment, making assessment of any dose-related impact on weight change infeasible to assess. LNG-IUD was used as first line therapy in 28.3% of patients. LNG-IUD was more likely to be used as first line therapy in patients with diabetes (53.8% versus 25.4%, P = 0.04) and increased BMI (48.4 kg/m2 versus 39.0 kg/m2, P = 0.03) but was not influenced by patient age or ethnicity. Patients were treated with an individual progestin regimen for a median of 11.7 months (range: 2.3–118.6). The median overall weight change during therapy was + 0.9 kg (range: − 53.0–+24.5) with a median weight change over time of + 0.08 kg/month (range: − 4.5–+ 2.0). The median duration of progestin therapy for first, second, and third line regimens were 11.7, 10.8, and 47 months, respectively. Twentysix patients (43.3%) eventually underwent hysterectomy due to persistent disease (13), patient preference (3), inability to tolerate progesterone (3), or disease progression (1). There was no correlation between weight gain during progestin therapy and risk of persistent/progressive disease (P = 0.989). The median weight change during therapy in patients treated with any oral progestin regimen was not statistically different versus patients treated with LNG-IUD (+1.40 versus +0.05 kg, P = 0.09). The median weight change during therapy with MPA was not different from LNGIUD (−1.60 versus +0.05 kg, P = 0.60); however, the median weight Table 1 Demographics of patients with endometrial hyperplasia or carcinoma treated with fertility preserving progestin therapy. Characteristic
All cases (%)
Median age at diagnosis, years (range) Ethnicity Caucasian African-American Asian Hispanic Other/unknown Diabetes mellitus Median starting weight per regimen, kg (range) Median starting BMI per regimen, kg/m2 (range) BMI ≥ 35 at diagnosis
32 (22–45) 33 (56.9) 16 (27.6) 4 (6.9) 3 (5.2) 2 (3.4) 11 (19.0) 110.4 (45.4–198.6) 40.4 (18.3–70.7) 35 (60.3)
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Table 2 Progestin-containing regimen characteristics. Variable
Cases (%)
# of regimens received per patient One regimen Two regimens Three regimens Progestin-containing regimens Megestrol acetate LNG-IUD Medroxyprogesterone acetate Other oral progestins Median duration of therapy, months (range) All regimens First progestin regimen Second progestin regimen Third progestin regimen Median weight change during therapy, kg All regimens First progestin regimen Second progestin regimen Third progestin regimen Median weight change over time during therapy, kg/month All regimens First progestin regimen Second progestin regimen Third progestin regimen Patients undergoing hysterectomy Reason for hysterectomy Persistence or progression of disease Patient preference Inability to tolerate progesterone Uncertain
48 (80.0) 11 (18.3) 1 (1.7) 40 (55.6) 22 (30.6) 5 (6.9) 5 (6.9) 11.7 (2.3–118.6) 11.7 (2.3–118.6) 10.8 (5.0–61.4) 47 +0.9 (−53.0–+24.5) +1.0 (−53.0–+24.5) +1.0 (−16–+10.9) −20.9
+0.08 (−4.5–+2.0) +0.10 (−4.5–+2.0) +0.06 (−1.8–+1.2) −0.4 27 (45) 13 (48.1) 6 (22.2) 4 (14.8) 4 (14.8)
change during therapy with MA was significantly greater versus LNGIUD (+2.95 versus +0.05 kg, P = 0.03). Similarly, the median weight change over time in patients treated with any oral progestin regimen was not statistically different from patients treated with LNG-IUD (+0.12 versus +0.01 kg/month, P = 0.11). The median weight change over time during therapy with MPA was not different from LNG-IUD (− 0.13 versus + 0.01 kg/month, P = 0.49); however, the median weight change over time during therapy with MA was significant as compared to LNG-IUD (+ 0.19 versus + 0.01 kg/month, P = 0.03; Table 3). Several other factors had a positive correlation with increased weight gain during progestin therapy with univariate analysis including BMI ≥ 35.0 and a history of diabetes mellitus. Patients with a BMI b 35 demonstrated more weight gain during therapy compared to patients with a BMI ≥ 35 (+ 2.30 kg versus − 0.70 kg, P = 0.04) as well as more weight gain per month during therapy (+0.18 kg/month versus − 0.01 kg/month, P = 0.01). Interestingly, in the subset of patients with a BMI ≥ 35, the use of LNG-IUD continued to retain its association with decreased weight gain during therapy versus MA (−5.40 kg versus +2.20 kg, P = 0.05) and weight gain over time during therapy versus MA (−0.35 kg/month versus +0.10 kg/month, P = 0.05). A similar association between the presence of diabetes mellitus and weight gain
during progestin therapy was also identified, likely due to the strong correlation between obesity and diabetes in our cohort. We did not identify any other covariates associated with increased risk of weight gain during progestin therapy including age, presence of CAH versus EMC, use of metformin in diabetic patients, or the sequencing of therapies. We were also unable to identify reliable documentation about lifestyle modifications or their outcomes in medical records and therefore could not correlate these interventions on weight changes either.
4. Discussion The treatment of endometrial cancer in young women is highlighted by the conflict between eradicating malignancy and the cancer survivor's pursuit of important life goals, including fertility. If fertilitypreserving therapies continue to “fuel the fire” of excess adiposity, insulin resistance, and anovulation, patients may not only be unable to achieve their pregnancy goals, but may be in a worse overall health position than when diagnosed [22,23]. Our data are among the first to demonstrate what many who have treated young endometrial cancer survivors with conservative therapy have long suspected: high dose systemic progestin therapies, particularly megestrol acetate, may be associated with an increased risk of weight gain compared to locallyacting therapy with the levonorgestrel intrauterine device [24,25]. Data regarding the impact of intrauterine versus systemic progestin therapies on weight gain in the contraceptive literature is variable and likely dependent on the patient population studied and the dose of progestin administered [17,25–28]. In our cohort, increased weight gain was only seen in the subgroup of oral progestin patients treated with megestrol acetate. It is unclear whether this effect is a particular concern of megestrol acetate or, as we suspect is more likely, a reflection of the small proportion (14%) of patients treated with other oral progestin agents. Interestingly, it appeared that patients who were already morbidly obese (BMI ≥ 35.0) experienced less weight gain during conservative management of endometrial cancer and hyperplasia than those who were less overweight. It is possible that weight gain is a more significant problem than perhaps previously realized for patients that are not already morbidly obese. Given that increased weight gain after diagnosis correlates with decreased survival in patients with endometrial cancer, this concern is relevant regardless of starting weight [29]. It is unclear whether the increased weight gain seen in less obese patients reflects a physiologic difference in the response to progestin therapy in these patients or whether other factors are at play. We suspect that practitioners are more acutely aware of the risks of weight gain in patients that are already morbidly obese and therefore more likely to aggressively counsel these patients about the risks of further weight gain. We attempted to determine whether lifestyle interventions were recommended differently in obese versus non-obese patients but found inadequate documentation about whether or not these interventions were being offered and, if offered, whether patients were compliant with these recommendations. As there is little downside to doing so, these results should prompt clinicians to focus counseling efforts on all patients – including those who are not obese – so that patients do not gain weight
Table 3 Weight changes according to progestin regimens and demographic characteristics. Comparison groups
Median starting weight, kg
Median ending weight, kg
Median duration of therapy, months
Median weight change during therapy, kg
P
Median weight change over time during progestin therapy, kg/month
P
LNG-IUD versus OP LNG-IUD versus MPA LNG-IUD versus MA BMI b 35 versus ≥35 DM, yes versus no
126.0 vs. 97.3 126.2 vs. 98.0 126.2 vs. 96.4 79.8 vs. 136.5 126.8 vs. 106.1
127.0 vs. 98.0 127.0 vs. 91.6 127.0 vs. 98.0 80.3 vs. 136.0 107.3 vs. 110.5
11.2 vs. 11.7 11.2 vs. 10.8 11.2 vs. 12.0 15.3 vs. 10.8 9.6 vs. 12.4
+0.05 vs. +1.40 +0.05 vs. −1.60 +0.05 vs. +2.95 +2.30 vs. −0.70 −5.00 vs. +1.80
0.09 0.60 0.03 0.04 0.002
+0.01 vs. +0.12 +0.01 vs. −0.13 +0.01 vs. +0.19 +0.18 vs. −0.01 −0.17 vs. +0.17
0.11 0.49 0.05 0.01 0.003
BMI: body mass index, DM: diabetes mellitus, LNG-IUD: levonorgestrel intrauterine system, MA: megestrol acetate, MPA: medroxyprogesterone acetate, OP: all oral progestin regimens.
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during fertility preserving therapy, especially if oral progestins are administered. Beyond the risks of weight gain seen in less obese patients, it appears that the association between decreased weight gains with LNG-IUD appears to hold true even in the morbidly obese. In fact, there was a striking disparity in weight change (7.6 kg) during the course of treatment with LNG-IUD versus MA in morbidly obese patients. These results support the consideration of LNG-IUD in all patients – but especially in the morbidly obese – given data supporting equivalent efficacy in comparison to oral progestins from an oncologic perspective [13]. There are currently no randomized trials comparing the efficacy and side effects of various progestin therapies in the fertility preservation setting. With so many options available, how should we base our management decisions? Oncologic outcomes appear to be equivalent between oral progestins and LNG-IUD and appear to be independent of BMI [13,30,31]. Given the potential for detrimental systemic effects with oral progestins, we prefer to initiate therapy with a LNG-IUD whenever feasible. If patients do not have a response at 3–6 months, an oral progestin may be added for increased dose intensity. Metformin, which has also demonstrated efficacy both for the treatment of endometrial cancer and weight loss, has further potential to counteract the underlying causes of EMC in young women [32,33]. It is unclear whether the addition of metformin could counter the detrimental effects of oral progestins. Until this has been further studied, we believe that any fertility preserving strategy that includes metformin should also still consider LNG-IUD as the first line option whenever feasible. The current investigation has a number of limitations. Foremost, the small cohort, retrospective design and that choice of individual progestin regimens were largely a matter of physician preference. A variety of confounding factors could have been present including performance status and patient/physician bias regarding treatment choices and lifestyle interventions during therapy. Furthermore, although compliance is assumed to be 100% with the LNG-IUD system, adherence to oral progestin therapy could not be assumed or determined in our data set. Some studies have attempted to assess compliance by assessing serum progestin levels, however this can also be difficult given various doses of progestin therapy [34]. If anything, non-compliance with oral progestin regimens would result in less weight gain, and therefore, less likely to be a major source of bias. Ultimately, our data likely represent a real world application of progestin administration and perhaps are more generalizable than what might be expected in the setting of a prospective trial. For this question in particular, evaluating data outside the setting of clinical trial is enlightening given the barriers that exist for implementation of both treatment strategies. As mentioned previously, oral progestin efficacy is dependent upon patient compliance. On the other hand, the LNG-IUD must be placed in a controlled setting. While this can often be done in the office in most cases, insertion may occasionally need to be done in an operating room – an issue that is particularly salient in patients that are frequently morbidly obese with other medical comorbidities. Another barrier to patient compliance that also has been understudied in the literature is cost of fertility-preserving treatment. Based on a comparison of wholesale costs and 100% compliance, six months of medroxyprogesterone acetate 40 mg given twice daily would cost $443 while 80 mg given twice daily would cost $886. In contrast, the market price of the LNG-IUD system (20 mcg/24 h) is $308. These calculations suggest the potential for cost savings with the LNG-IUD although a more detailed analysis would be useful. These results clearly demonstrate the need for higher quality prospective data. With a larger sample size, questions about the value of alternative regimens such as medroxyprogesterone acetate and the addition of metformin may be more definitively answered. An ongoing trial evaluating the addition of metformin to the LNG-IUD will hopefully answer at least this final question [35]. We must continue to seek other conservative therapies that effectively treat endometrial pathology while safeguarding patient priorities whenever safe and feasible.
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Conflict of interest statement The authors declare that there are no conflicts of interest.
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Effect of oral versus intrauterine progestins on weight in women undergoing fertility preserving therapy for complex atypical hyperplasia or endometrial cancer☆ Diana Cholakian a, Kari Hacker b, Amanda N. Fader a, Paola A. Gehrig b, Edward J. Tanner III a,⁎ a b
The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, Johns Hopkins Medicine, Baltimore, MD, United States Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC, United States
H I G H L I G H T S • LNG-IUD was associated with less weight gain than megestrol acetate during therapy. • Obese women gained less weight with progestin therapy for endometrial cancer. • Obese women gained less weight with LNG-IUD than megestrol acetate during therapy.
a r t i c l e
i n f o
Article history: Received 17 September 2015 Received in revised form 2 December 2015 Accepted 13 December 2015 Available online 17 December 2015 Keywords: Endometrial cancer Fertility preservation Progestin therapy
a b s t r a c t Objective. The objective of this analysis was to evaluate weight changes associated with oral progestin therapies versus the levonorgestrel-containing intrauterine device (LNG-IUD) in women undergoing fertilitypreserving therapy for complex atypical hyperplasia (CAH) and endometrial cancer (EMC). Methods. All patients diagnosed with CAH or EMC managed with fertility-preserving progestin therapy at two institutions from 1998 to 2012 were identified. Those with serial weight measurements before, during and after therapy were included. Patients were categorized according to the type of progestin therapy administered. The rate of weight change over time of patients treated with oral versus intrauterine progestins was compared using the Mann Whitney U test. Results. Sixty patients with EMC (35) or CAH (25) were treated during the study period, with 12 patients receiving multiple regimens. These included megestrol acetate (MA, n = 42), LNG-IUD (n = 22), and other oral progestins (n = 11). The median age at diagnosis was 32 and median pre-progestin body mass index (BMI) was 40.4 kg/m2. The median therapy duration was 11.7 months [range: 2.3–118.5]. Median weight change during therapy was greater with MA versus LNG-IUD (+ 2.95 vs. + 0.05 kg, P = 0.03). Patients with a BMI b 35 gained more weight during therapy versus patients with BMI ≥ 35 (+2.30 vs. −0.70 kg/month, P = 0.04); however, in patients with BMI ≥ 35, MA was still associated with more weight gain than LNG-IUD (+2.2 vs.-5.40 kg, P = 0.05). Conclusion. Oral progestin therapy for conservative treatment of young EMC/CAH survivors is associated with increased weight gain, especially when megestrol acetate is utilized. Utilization of LNG-IUD may result in less weight gain. © 2015 Elsevier Inc. All rights reserved.
1. Introduction With rising obesity rates in the United States, it is postulated that the incidence of complex atypical endometrial hyperplasia (CAH) and
☆ Disclosure statement: The authors report no conflicts of interest. No industry or pharmaceutical support was obtained to conduct this research or produce this manuscript. ⁎ Corresponding author at: 600 N Wolfe Street, Phipps 281, Baltimore, MD 21287, United States. E-mail address: [email protected] (E.J. Tanner).
http://dx.doi.org/10.1016/j.ygyno.2015.12.010 0090-8258/© 2015 Elsevier Inc. All rights reserved.
endometrial adenocarcinoma (EMC) in premenopausal women will also increase [1]. Even now, up to 14% of women with endometrial cancer are diagnosed at 40 years of age or younger [2,3]. While the standard of care for the management of CAH or EMC includes hysterectomy, this recommendation may conflict with the fertility plans of younger women, especially in a society where the age of first delivery is delayed to later in life [4]. In recent years, progestin therapy has been successfully used to treat select women with endometrial cancer and hyperplasia who desire to preserve fertility. The efficacy of progestin therapy on treatment of
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CAH or grade 1 EMC has been studied widely; however, most reports are retrospective [5–11]. The most common progestin regimens include megestrol acetate (MA) and the levonorgestrel intrauterine system (LNG-IUD). These modalities may be equally effective [12], with a recent meta-analysis showing a pooled regression rate of 66–76.2% and relapse rate of 40.6% for both regimens [13,14]. In fact, women with endometrial hyperplasia were more likely to show regression with an LNG-IUD compared to oral progestins [36], prospective head-to-head comparisons of these treatment modalities are lacking. It is well established that use of progestins in women for contraception or treatment of benign gynecologic conditions leads to weight gain, especially in women who are obese at baseline [15–17]. Progestins can even be used to help patients gain weight in some circumstances. A recent Cochrane Review of MA used for anorexia-cachexia syndrome showed an 8% weight gain in MA-treated patients versus control patients [7]. Given that obesity is one of the strongest risk factors for CAH and EMC, use of progestin therapy in this setting is problematic — and potentially counterproductive. Additionally, numerous reports demonstrate decreased disease-specific and overall survival with increasing BMI in patients with EMC [13,18–20]. Importantly, obesity appears to be a modifiable risk factor for mortality from disease [21]. In theory, the LNG-IUD system should offer the same advantages for the treatment of CAH and EMC without the degree of weight gain associated with systemic absorption of oral progestins. Although response rates and pregnancy outcomes are frequently evaluated in studies of patients treated conservatively for CAH and EMC, the role of potential weight gain with progestin therapies during gynecologic cancer treatment has not yet been well evaluated [12]. It is, therefore, important to define whether any of the progestin therapies used in the conservative management of women with CAH or EMC are more likely to result in weight gain. 2. Methods After obtaining Institutional Review Board approval at both institutions, we identified all women 45 years of age or younger treated with progestin therapy for at least two months for complex atypical endometrial hyperplasia (CAH) or grade 1–2 endometrioid adenocarcinoma of the endometrium (EMC) at one of two institutions (Johns Hopkins Hospital, Baltimore, MD and University of North Carolina School of Medicine, Chapel Hill, NC) from 1998 to 2012. Women were excluded from the analysis if they were treated with progestin therapy for reasons other than fertility preservation or did not have serial weight measurements available pre, during and post-progestin therapy. Demographic data was collected including age at diagnosis, ethnicity, BMI and other comorbidities. Patients were categorized according to the type and number of progestin therapies received. For purposes of comparison, patients that received both oral progestins and LNG-IUD were categorized in the LNG-IUD group. The date that progestin therapy started and ended was collected as well as the starting and ending patient weights. Using this data, we were able to calculate the total weight change and the rate of weight change over time (kg/month) for each progestin therapy. Using patient heights collected at time of diagnosis, we calculated the body mass index (BMI) at diagnosis and change in BMI over time (kg/m2/month) during therapy. If dates or weights were missing for a regimen, we excluded data for that regimen from analysis. SPSS version 22 was used to calculate differences in weight change for oral progestin regimens versus LNG-IUD. Testing for normality of the data was performed using the Shapiro–Wilk test. To compare demographic data between treatment groups, categorical data were assessed using the Chi Square test while continuous variables were assessed using the Student T test for variables with normal distribution. Comparisons of weight changes during therapy and weight change over time during therapy were performed using the Mann Whitney U test due to non-normal distribution of the data.
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3. Results We identified 60 eligible patients treated at two institutions, Johns Hopkins Hospital (n = 34) and the University of North Carolina Medical Center (n = 26) from 1998 to 2012. Twenty-five patients were initially treated for CAH and 35 were initially treated for EMC. Demographic data is found in Table 1. The median age at diagnosis was 32.0 years (range: 22–45) with 13 patients (19%) having concurrent diabetes mellitus. Seven of these 13 diabetic patients were taking metformin during progestin therapy. The median starting weight for the entire cohort was 110.4 kg (range: 45.4–198.6) and the median starting BMI was 40.4 kg/m2 (range: 18.3–70.7). Most patients were treated with just one progestin-containing regimen (n = 48, 80.0%), although 11 (18.3%) were treated with two and one (1.7%) was treated with three consecutive regimens (Table 2). Three patients were treated with both LNG-IUD and oral progestins and were categorized in the LNG-IUD group for comparison purposes. Results were not significantly altered by including the three patients treated with both regimens in the oral progestin group or by including them in a separate third group. Megestrol acetate (MA) was the most commonly prescribed regimen (n = 40, 55.6%), followed by LNG-IUD (n = 22, 30.6%), medroxyprogesterone acetate (MPA, n = 5, 6.9%), and other oral progestin-containing regimens (n = 5, 6.9%). The dosing regimen for patients receiving oral therapy varied. For patients receiving MA, doses ranged between MA 40 mg twice daily to 160 mg twice daily. For MPA, the average dose varied between 10 mg daily and 40 mg daily. In many patients, the progestin doses were changed throughout the course of their treatment, making assessment of any dose-related impact on weight change infeasible to assess. LNG-IUD was used as first line therapy in 28.3% of patients. LNG-IUD was more likely to be used as first line therapy in patients with diabetes (53.8% versus 25.4%, P = 0.04) and increased BMI (48.4 kg/m2 versus 39.0 kg/m2, P = 0.03) but was not influenced by patient age or ethnicity. Patients were treated with an individual progestin regimen for a median of 11.7 months (range: 2.3–118.6). The median overall weight change during therapy was + 0.9 kg (range: − 53.0–+24.5) with a median weight change over time of + 0.08 kg/month (range: − 4.5–+ 2.0). The median duration of progestin therapy for first, second, and third line regimens were 11.7, 10.8, and 47 months, respectively. Twentysix patients (43.3%) eventually underwent hysterectomy due to persistent disease (13), patient preference (3), inability to tolerate progesterone (3), or disease progression (1). There was no correlation between weight gain during progestin therapy and risk of persistent/progressive disease (P = 0.989). The median weight change during therapy in patients treated with any oral progestin regimen was not statistically different versus patients treated with LNG-IUD (+1.40 versus +0.05 kg, P = 0.09). The median weight change during therapy with MPA was not different from LNGIUD (−1.60 versus +0.05 kg, P = 0.60); however, the median weight Table 1 Demographics of patients with endometrial hyperplasia or carcinoma treated with fertility preserving progestin therapy. Characteristic
All cases (%)
Median age at diagnosis, years (range) Ethnicity Caucasian African-American Asian Hispanic Other/unknown Diabetes mellitus Median starting weight per regimen, kg (range) Median starting BMI per regimen, kg/m2 (range) BMI ≥ 35 at diagnosis
32 (22–45) 33 (56.9) 16 (27.6) 4 (6.9) 3 (5.2) 2 (3.4) 11 (19.0) 110.4 (45.4–198.6) 40.4 (18.3–70.7) 35 (60.3)
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Table 2 Progestin-containing regimen characteristics. Variable
Cases (%)
# of regimens received per patient One regimen Two regimens Three regimens Progestin-containing regimens Megestrol acetate LNG-IUD Medroxyprogesterone acetate Other oral progestins Median duration of therapy, months (range) All regimens First progestin regimen Second progestin regimen Third progestin regimen Median weight change during therapy, kg All regimens First progestin regimen Second progestin regimen Third progestin regimen Median weight change over time during therapy, kg/month All regimens First progestin regimen Second progestin regimen Third progestin regimen Patients undergoing hysterectomy Reason for hysterectomy Persistence or progression of disease Patient preference Inability to tolerate progesterone Uncertain
48 (80.0) 11 (18.3) 1 (1.7) 40 (55.6) 22 (30.6) 5 (6.9) 5 (6.9) 11.7 (2.3–118.6) 11.7 (2.3–118.6) 10.8 (5.0–61.4) 47 +0.9 (−53.0–+24.5) +1.0 (−53.0–+24.5) +1.0 (−16–+10.9) −20.9
+0.08 (−4.5–+2.0) +0.10 (−4.5–+2.0) +0.06 (−1.8–+1.2) −0.4 27 (45) 13 (48.1) 6 (22.2) 4 (14.8) 4 (14.8)
change during therapy with MA was significantly greater versus LNGIUD (+2.95 versus +0.05 kg, P = 0.03). Similarly, the median weight change over time in patients treated with any oral progestin regimen was not statistically different from patients treated with LNG-IUD (+0.12 versus +0.01 kg/month, P = 0.11). The median weight change over time during therapy with MPA was not different from LNG-IUD (− 0.13 versus + 0.01 kg/month, P = 0.49); however, the median weight change over time during therapy with MA was significant as compared to LNG-IUD (+ 0.19 versus + 0.01 kg/month, P = 0.03; Table 3). Several other factors had a positive correlation with increased weight gain during progestin therapy with univariate analysis including BMI ≥ 35.0 and a history of diabetes mellitus. Patients with a BMI b 35 demonstrated more weight gain during therapy compared to patients with a BMI ≥ 35 (+ 2.30 kg versus − 0.70 kg, P = 0.04) as well as more weight gain per month during therapy (+0.18 kg/month versus − 0.01 kg/month, P = 0.01). Interestingly, in the subset of patients with a BMI ≥ 35, the use of LNG-IUD continued to retain its association with decreased weight gain during therapy versus MA (−5.40 kg versus +2.20 kg, P = 0.05) and weight gain over time during therapy versus MA (−0.35 kg/month versus +0.10 kg/month, P = 0.05). A similar association between the presence of diabetes mellitus and weight gain
during progestin therapy was also identified, likely due to the strong correlation between obesity and diabetes in our cohort. We did not identify any other covariates associated with increased risk of weight gain during progestin therapy including age, presence of CAH versus EMC, use of metformin in diabetic patients, or the sequencing of therapies. We were also unable to identify reliable documentation about lifestyle modifications or their outcomes in medical records and therefore could not correlate these interventions on weight changes either.
4. Discussion The treatment of endometrial cancer in young women is highlighted by the conflict between eradicating malignancy and the cancer survivor's pursuit of important life goals, including fertility. If fertilitypreserving therapies continue to “fuel the fire” of excess adiposity, insulin resistance, and anovulation, patients may not only be unable to achieve their pregnancy goals, but may be in a worse overall health position than when diagnosed [22,23]. Our data are among the first to demonstrate what many who have treated young endometrial cancer survivors with conservative therapy have long suspected: high dose systemic progestin therapies, particularly megestrol acetate, may be associated with an increased risk of weight gain compared to locallyacting therapy with the levonorgestrel intrauterine device [24,25]. Data regarding the impact of intrauterine versus systemic progestin therapies on weight gain in the contraceptive literature is variable and likely dependent on the patient population studied and the dose of progestin administered [17,25–28]. In our cohort, increased weight gain was only seen in the subgroup of oral progestin patients treated with megestrol acetate. It is unclear whether this effect is a particular concern of megestrol acetate or, as we suspect is more likely, a reflection of the small proportion (14%) of patients treated with other oral progestin agents. Interestingly, it appeared that patients who were already morbidly obese (BMI ≥ 35.0) experienced less weight gain during conservative management of endometrial cancer and hyperplasia than those who were less overweight. It is possible that weight gain is a more significant problem than perhaps previously realized for patients that are not already morbidly obese. Given that increased weight gain after diagnosis correlates with decreased survival in patients with endometrial cancer, this concern is relevant regardless of starting weight [29]. It is unclear whether the increased weight gain seen in less obese patients reflects a physiologic difference in the response to progestin therapy in these patients or whether other factors are at play. We suspect that practitioners are more acutely aware of the risks of weight gain in patients that are already morbidly obese and therefore more likely to aggressively counsel these patients about the risks of further weight gain. We attempted to determine whether lifestyle interventions were recommended differently in obese versus non-obese patients but found inadequate documentation about whether or not these interventions were being offered and, if offered, whether patients were compliant with these recommendations. As there is little downside to doing so, these results should prompt clinicians to focus counseling efforts on all patients – including those who are not obese – so that patients do not gain weight
Table 3 Weight changes according to progestin regimens and demographic characteristics. Comparison groups
Median starting weight, kg
Median ending weight, kg
Median duration of therapy, months
Median weight change during therapy, kg
P
Median weight change over time during progestin therapy, kg/month
P
LNG-IUD versus OP LNG-IUD versus MPA LNG-IUD versus MA BMI b 35 versus ≥35 DM, yes versus no
126.0 vs. 97.3 126.2 vs. 98.0 126.2 vs. 96.4 79.8 vs. 136.5 126.8 vs. 106.1
127.0 vs. 98.0 127.0 vs. 91.6 127.0 vs. 98.0 80.3 vs. 136.0 107.3 vs. 110.5
11.2 vs. 11.7 11.2 vs. 10.8 11.2 vs. 12.0 15.3 vs. 10.8 9.6 vs. 12.4
+0.05 vs. +1.40 +0.05 vs. −1.60 +0.05 vs. +2.95 +2.30 vs. −0.70 −5.00 vs. +1.80
0.09 0.60 0.03 0.04 0.002
+0.01 vs. +0.12 +0.01 vs. −0.13 +0.01 vs. +0.19 +0.18 vs. −0.01 −0.17 vs. +0.17
0.11 0.49 0.05 0.01 0.003
BMI: body mass index, DM: diabetes mellitus, LNG-IUD: levonorgestrel intrauterine system, MA: megestrol acetate, MPA: medroxyprogesterone acetate, OP: all oral progestin regimens.
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during fertility preserving therapy, especially if oral progestins are administered. Beyond the risks of weight gain seen in less obese patients, it appears that the association between decreased weight gains with LNG-IUD appears to hold true even in the morbidly obese. In fact, there was a striking disparity in weight change (7.6 kg) during the course of treatment with LNG-IUD versus MA in morbidly obese patients. These results support the consideration of LNG-IUD in all patients – but especially in the morbidly obese – given data supporting equivalent efficacy in comparison to oral progestins from an oncologic perspective [13]. There are currently no randomized trials comparing the efficacy and side effects of various progestin therapies in the fertility preservation setting. With so many options available, how should we base our management decisions? Oncologic outcomes appear to be equivalent between oral progestins and LNG-IUD and appear to be independent of BMI [13,30,31]. Given the potential for detrimental systemic effects with oral progestins, we prefer to initiate therapy with a LNG-IUD whenever feasible. If patients do not have a response at 3–6 months, an oral progestin may be added for increased dose intensity. Metformin, which has also demonstrated efficacy both for the treatment of endometrial cancer and weight loss, has further potential to counteract the underlying causes of EMC in young women [32,33]. It is unclear whether the addition of metformin could counter the detrimental effects of oral progestins. Until this has been further studied, we believe that any fertility preserving strategy that includes metformin should also still consider LNG-IUD as the first line option whenever feasible. The current investigation has a number of limitations. Foremost, the small cohort, retrospective design and that choice of individual progestin regimens were largely a matter of physician preference. A variety of confounding factors could have been present including performance status and patient/physician bias regarding treatment choices and lifestyle interventions during therapy. Furthermore, although compliance is assumed to be 100% with the LNG-IUD system, adherence to oral progestin therapy could not be assumed or determined in our data set. Some studies have attempted to assess compliance by assessing serum progestin levels, however this can also be difficult given various doses of progestin therapy [34]. If anything, non-compliance with oral progestin regimens would result in less weight gain, and therefore, less likely to be a major source of bias. Ultimately, our data likely represent a real world application of progestin administration and perhaps are more generalizable than what might be expected in the setting of a prospective trial. For this question in particular, evaluating data outside the setting of clinical trial is enlightening given the barriers that exist for implementation of both treatment strategies. As mentioned previously, oral progestin efficacy is dependent upon patient compliance. On the other hand, the LNG-IUD must be placed in a controlled setting. While this can often be done in the office in most cases, insertion may occasionally need to be done in an operating room – an issue that is particularly salient in patients that are frequently morbidly obese with other medical comorbidities. Another barrier to patient compliance that also has been understudied in the literature is cost of fertility-preserving treatment. Based on a comparison of wholesale costs and 100% compliance, six months of medroxyprogesterone acetate 40 mg given twice daily would cost $443 while 80 mg given twice daily would cost $886. In contrast, the market price of the LNG-IUD system (20 mcg/24 h) is $308. These calculations suggest the potential for cost savings with the LNG-IUD although a more detailed analysis would be useful. These results clearly demonstrate the need for higher quality prospective data. With a larger sample size, questions about the value of alternative regimens such as medroxyprogesterone acetate and the addition of metformin may be more definitively answered. An ongoing trial evaluating the addition of metformin to the LNG-IUD will hopefully answer at least this final question [35]. We must continue to seek other conservative therapies that effectively treat endometrial pathology while safeguarding patient priorities whenever safe and feasible.
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Conflict of interest statement The authors declare that there are no conflicts of interest.
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