Accepted Manuscript Title: The late-luteal leptin level, caloric intake and eating behaviors among women with premenstrual dysphoric disorder Author: Chih-Hung Ko Cheng-Fang Yen Cheng-Yu Long Yu-Ting Kuo Cheng-Sheng Chen Ju-Yu Yen PII: DOI: Reference:
S0306-4530(15)00089-X http://dx.doi.org/doi:10.1016/j.psyneuen.2015.03.002 PNEC 2941
To appear in: Received date: Revised date: Accepted date:
19-10-2014 28-2-2015 1-3-2015
Please cite this article as: http://dx.doi.org/10.1016/j.psyneuen.2015.03.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highlights
3.
Ac ce p
te
d
M
an
us
4. 5.
ip t
2.
Late-luteal leptin negatively correlated to caloric intake in normal-weight women. Normal-weight PMDD women had a lower late-luteal leptin level than normal-weight controls. Normal-weight PMDD women had a higher late-luteal caloric intake than normal-weight controls. Overweight PMDD women had hyperleptinemia in the late-luteal phase. Overweight PMDD women had a higher late-luteal sweet caloric intake than overweight controls.
cr
1.
1
Page 1 of 38
The late-luteal leptin level, caloric intake and eating behaviors among women with premenstrual dysphoric disorder. Running title: Leptin in PMDD
us
1
cr
Cheng-Sheng Chen,2,3 Ju-Yu Yen 2,3,6
Department of Psychiatry, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung
an
Medical University, Kaohsiung, Taiwan 2
ip t
Chih-Hung Ko,1,2,3 Cheng-Fang Yen,2,3 Cheng-Yu Long,4 Yu-Ting Kuo,5
Department of Psychiatry, Faculty of Medicine, College of Medicine, Kaohsiung
3
M
Medical University, Kaohsiung City, Taiwan
Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung,
Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital,
te
4
d
Taiwan
Kaohsiung, Taiwan
Department of Radiology, Chi-Mei Medical Center, Tainan, Taiwan
6
Department of Psychiatry, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung,
Ac ce p
5
Taiwan
Corresponding Author:
Ju-Yu Yen M.D., Ph.D.
Department of Psychiatry, Kaohsiung Medical University Hospital 100, Tzyou 1st Road, Kaohsiung 80708, Taiwan. Telephone: +886-7-3121101 ext. 6822 E-mail: [email protected] 2
Page 2 of 38
Abstract Objectives: A marked increased in food intake in the late-luteal phase is a characteristic symptom of premenstrual dysphoric disorder (PMDD). The aim of the
ip t
study was to evaluate the leptin level, caloric intake, and eating behaviors of women with PMDD across the menstrual cycle among normal-weight and overweight
cr
subjects, respectively.
Methods: A total of 62 women with PMDD and 69 controls were recruited following
us
psychiatric interviewing and underwent prospective investigation. The leptin level,
an
caloric intake, and three factors related to eating behavior were assessed in both the late-luteal and follicular phases.
M
Results: The women with PMDD had greater increases in caloric intake, sweet caloric intake, and uncontrolled eating in the late-luteal phase than the controls. Among the
d
normal-weight women, the leptin level was negatively correlated with caloric intake.
te
The normal-weight women with PMDD had a lower leptin level, a lower leptin/body fat percentage (BFP), a higher caloric intake, and higher uncontrolled eating and
Ac ce p
emotional eating in the late-luteal phase than the normal-weight controls. Their leptin level was correlated negatively with sweet caloric intake. On the other hand, the overweight women with PMDD had a higher leptin level than the normal-weight women with PMDD and no decline was observed in their leptin level in the late-luteal phase. There were no differences in the leptin level between the overweight women with PMDD and the overweight controls. They also had a higher sweet caloric intake and higher uncontrolled eating and emotional eating than the overweight controls. Conclusions: A decline in the leptin level is associated with late-luteal overeating among normal-weight women with PMDD. Hyperleptinemia and a high sweet caloric intake of overweight women with PMDD should be monitored and addressed in order 3
Page 3 of 38
to attenuate the risk of leptin resistance. The detailed roles of leptin and other psycho-neuro-endocrinology factors in the mechanism of overeating among women
ip t
with PMDD should be evaluated in future study.
Key words: Premenstrual dysphoric disorder (PMDD), caloric intake, leptin,
Ac ce p
te
d
M
an
us
cr
uncontrolled eating.
4
Page 4 of 38
1. Introduction Premenstrual dysphoric disorder (PMDD) was included as an official diagnostic criteria in the DSM 5 in 2012 (American Psychiatric Association, 2012) based on
ip t
adequate evidence (Epperson et al., 2012). It is defined as having predictable, cyclic, and functional-impairing psychological and somatic symptoms, such as depression,
cr
irritability, lethargy or hypersomnia. These symptoms are aggravated in the late-luteal
phase of the menstrual cycle and resolved by menstruation (Rapkin and Winer, 2009).
us
Marked changes in appetite and overeating are typical concomitant PMDD symptoms
an
(American Psychiatric Association, 2012) and are affected by the menstrual cycle among women with PMDD (Yen et al., 2010). Evaluation of hormones that fluctuate
M
during the menstrual cycle and affect eating behavior, such as leptin, may provide
d
insight into the mechanism of overeating symptoms among women with PMDD.
te
1.1. The caloric intake of women with PMDD Food intake is reduced in the periovulatory phase and increased during the luteal
Ac ce p
phase among women (Buffenstein et al., 1995; Dye and Blundell, 1997; Van Vugt, 2010), particularly among those with PMDD (Evans et al., 1999; McNeil and Doucet, 2012). Women with PMDD have been reported to eat more calories in the late-luteal phase than in the follicular phase as compared with control women (Reed et al., 2008). Further, sweet food craving is exacerbated in the late-luteal phase among women with PMDD (Yen et al., 2010). These results indicated that women with PMDD increase their food intake in the late-luteal phase. However, whether women with PMDD have an increased caloric intake and an increased sweet caloric intake in the late-luteal phase as compared with healthy women has not been empirically evaluated throughout the menstrual cycle. Additionally, the underlying factors 5
Page 5 of 38
contributing to the changes in caloric intake among women with PMDD are not well-understood (McNeil and Doucet, 2012).
ip t
1.2. The role of leptin in the appetite of women with PMDD Leptin, a hormone secreted by adipocytes, acts on the hypothalamus to regulate
cr
appetite and neuroendocrine function (Cohen, 2006). Leptin has a role in ovulation
through its stimulation of the pituitary to secrete luteinizing hormone (LH) (Fenichel
us
et al., 2008). The administration of recombinant leptin has been shown to restore
an
menses and fertility in women with hypothalamic or leptin deficiency amenorrhea (Chou et al., 2011; von Schnurbein et al., 2012). Recent studies have demonstrated
M
that the leptin level is increased over the menstrual cycle, with a mid-cycle peak concurrent with the LH surge (Ahrens et al., 2014). These studies all indicated that
d
leptin is related to not only eating behavior, but also to the menstrual cycle
te
(Goumenou et al., 2003). One study revealed a significant decline in leptin among women with PMDD in comparison with controls (Akturk et al., 2013). As leptin plays
Ac ce p
key roles in the menstrual cycle and appetite and has been found to be altered among women with PMDD, further study is necessary to evaluate the alterations in the leptin level and their effects on the caloric intake of women with PMDD (Akturk et al., 2013).
Further, leptin is transported across the blood-brain-barrier by a saturable
transporter system and exerts its anorectic effect via the hypothalamic arcuate nucleus. It results in a reduced food intake and an increased energy expenditure (Suzuki et al., 2012). However, obese individuals often have high leptin levels, which result in a failure to respond to exogenous leptin (Suzuki et al., 2012). Obesity has been reported to be associated with PMDD (Masho et al., 2005). The moderating effect of being 6
Page 6 of 38
overweight should be considered when evaluating the association between leptin and caloric intake. Further, there exist complex associations between the menstrual cycle, leptin level, eating behavior, obesity, and PMDD (McNeil and Doucet, 2012), and
ip t
evaluation of these factors across the menstrual cycle with analysis separately in overweight and normal-weight women may provide insight into the effect of leptin on
cr
the late-luteal caloric intake among women with PMDD.
us
1.3. The role of PMDD symptoms and associated factors in caloric intake in the
an
late-luteal phase
Aside from hormone levels, mood, stress, and rewarding characteristics contribute to
M
overeating behavior (Jauch-Chara and Oltmanns, 2014). Depression and irritability are the cardinal symptoms of PMDD (Ko et al., 2013; Yen et al., 2011). Emotional
d
eating is an eating behavior motivated by multiple negative emotions (Chesler, 2012)
te
and moderate stress-induced food intake in females (van Strien et al., 2014). Further, women with PMDD have a higher impulsivity (Yen et al., 2011). Impulsivity is
Ac ce p
associated with uncontrolled eating (Leitch et al., 2013), a tendency to eat more than usual due to a loss of control over intake (Karlsson et al., 2000), and contributes to caloric intake (Kronick et al., 2011). Women with PMDD also have impaired inhibitory control (Yen et al., 2013). The inhibitory control function is associated with cognitive restraint, conscious restriction of food intake in order to control body weight or to promote weight loss (Leitch et al., 2013). Cognitive restraint has been reported to associate with caloric intake among women with PMDD (Evans et al., 1999). Thus, whether three factors related to eating behavior, including cognitive restraint, uncontrolled eating and emotional eating, contribute to caloric intake should be evaluated among women with PMDD. 7
Page 7 of 38
1.4. The aims of the study Thus, the aims of the study were to evaluate: 1) whether the menstrual cycle
ip t
(late-luteal phase versus follicular phase) or PMDD (PMDD group versus controls) have impacts on the leptin level, caloric intake, and eating behaviors; 2) whether
cr
being overweight moderates the association between leptin level and caloric intake; 3) the differences in leptin level, caloric intake and eating behaviors between women
us
with PMDD and controls among overweight and normal-weight subjects; 4) whether
an
eating behaviors are associated with late-luteal caloric intake among normal-weight or
Ac ce p
te
d
M
overweight women with PMDD.
8
Page 8 of 38
2. Methods 2.1. Participants Subjects were recruited using an advertisement posted specifically to attract a PMDD
ip t
group without treatment and a control group on a university campus from 08/2011 to 10/2012. Volunteers in the PMDD group had a positive response to five or more
cr
premenstrual symptoms of the eleven DSM-IV-TR criteria of PMDD (American
Psychiatric Association, 2000). The control group had positive responses to fewer
us
than 2 of those criteria or had no functional impairment under mild symptoms.
an
Subjects currently taking psychotropic or hormone medication, such as contraceptive medication, were excluded from the study. A total of 169 (90 PMDD candidate
M
subjects and 79 candidate control subjects) women with a college or higher educational level were screened using the self-reported Premenstrual Symptoms
d
Screening Tool (PSST) after informed consent was obtained. Eighty-six participants
te
of the PMDD candidates were screened and were found to have moderate to severe premenstrual symptoms and entered the next steps of analysis. In addition, 75 women
Ac ce p
of the candidate controls were screened and found not to have premenstrual symptoms and entered the next steps of analysis. The other subjects were excluded. The women were then interviewed by one of two psychiatrists to exclude psychotic disorder and bipolar I disorder using the Mini-International Neuropsychiatric Interview (MINI), and to make the diagnosis of PMDD based on the DSMIV-TR criteria (American Psychiatric Association, 2000). Eighty-three PMDD candidate subjects and 75 candidate controls were diagnosed as having PMDD and not having PMDD, respectively. All of the subjects participated in a prospective investigation to confirm their premenstrual symptoms exacerbation. The study was approved by the Institutional Review Board (IRB) of Kaohsiung Medical University Hospital. 9
Page 9 of 38
2.2. Measures The Premenstrual Symptoms Screening Tool (PSST): The tool was developed by
ip t
Steiner and colleagues (Steiner et al., 2003). We utilized the scale to screen women with moderate to severe premenstrual symptoms (Steiner et al., 2003). They had to
cr
have 1) at least 1 of the first 4 items of the 14 symptoms; 2) four or more items of the 14 items assessing PMDD symptoms; and 3) at least 1 of the 5 items assessing
us
functional impairments that were classified as of a moderate to severe level, with a
an
score of 3 or 4.
The Premenstrual Dysphoric Disorder (PMDD) Severity Questionnaire (PMDDSQ):
M
The PMDDSQ was developed to evaluate the severity of PMDD symptoms across the menstrual cycle (Yen et al., 2013). The questionnaire is an 11-point Likert
d
questionnaire rating the severity of the 11 criteria of PMDD in the DSM IV-TR. Every
te
symptom was rated on a scale ranging from 0 to 10 to represent none at all to an extreme severity. The total score of the 11 items was used to represent the PMDD
Ac ce p
severity. The questionnaire had a Cronbach’s alpha of 0.98 and the four-week test-retest reliability was 0.92.
The mean caloric intake: The subjects recorded their dietary intake for three days
(the two last weekdays and one last holiday in the week before menstruation and in the week after menstruation). They recorded all food and drink consumed, except water. The eating time, name of the food (including trade mark), estimated volume or weight, method of cooking and sugar levels of drinks were noted. The caloric values of the foods were calculated according to information from the Food and Drug Administration, Ministry of Health and Welfare, Taiwan. The total caloric intake was then divided by three to determine the mean caloric intake per day. Sweet-tasting 10
Page 10 of 38
foods, such as cake, ice cream, candy, doughnuts, waffles, cookies or chocolate, and sugary beverages were classified as sweet food. The sweet food caloric intake was calculated in the same way.
ip t
18-item Three-Factor Eating Questionnaire (TFEQ): The self-assessed four-point response scale measures cognitive and behavioral components of eating. It contains
cr
three subscales, cognitive restraint (6 items), uncontrolled eating (9 items), and
emotional eating (3 items) (Karlsson et al., 2000). The Cronbach’s α values of the 3
us
subscales of the TFEQ were 0.77, 0.83, and 0.86, respectively.
Body mass index (BMI) is a measure of weight adjusted for height, calculated as
an
weight in kilograms divided by the square of height in meters (kg/m2). Subjects with a
M
BMI higher than 24 were classified as overweight based on the definition of the Health Promotion Administration, Ministry of Health and Welfare, Taiwan. Further,
te
(@Omron).
d
body fat percentage (BFP in %) was assessed using a body composition monitor
The levels of estrogen and progesterone: Blood samples were obtained directly from
Ac ce p
all subjects from a cannulated vein after testing in the late-luteal phase and the follicular phase. The serum was separated by centrifugation and stored at -20°C until further analysis. Estrogen and progesterone were measured using a Coat-A-count radioimmunoassay kit (Siemens Medical Solutions Diagnostics, Los Angeles, CA, USA).
The level of leptin: Serum and plasma samples were stored at -20°C until analysis.
Serum leptin levels were measured using an RIA kit from Linco Research, a division of Millipore Inc. (Cat# HL-81K, St Charles, MO, USA). The intra-assay CV ranged from 3.4 to 8.35% and the inter-assay CV ranged from 3.0 to 6.2%. The sensitivity was 0.5 ng/mL. The assays were run on a Cobra II series auto-gamma counting 11
Page 11 of 38
system (Packard Instrument Company; Meriden, CT, USA). The serum leptin level was standardized for BFP (dividing the serum leptin level by BFP; leptin/BFP) to
ip t
control the effect of body fat percentage.
2.3. Procedures
cr
All participants were evaluated in both the late-luteal phase (within one week before menstruation as predicted by the last menstruation cycle) and the follicular phase
us
(within one week after the end of menstruation and before ovulating). All subjects
an
were prohibited from eating or drinking, with the exception of water in a volume lower than 300 cc, in the three hours before entering the laboratory. After 1.5 hours of
M
questionnaire completion and cognitive assessment, blood was obtained to assess the estrogen, progesterone, and leptin levels. The participants were allowed to eat after
d
the blood test. Half of the subjects (39 in the PMDD group and 39 in the control group)
te
were assessed first in the late-luteal phase and then again in the follicular phase. The other subjects were assessed in reverse. After the investigation in the first menstrual
Ac ce p
cycle, all participants were followed-up and completed the PMDDSQ once a week for 2 menstrual cycles.
2.4. Data analysis
The differences in age, educational level, BMI, BFP, estrogen, and progesterone between the PMDD and control group were evaluated by the t test.
Repeated-measures two-factor analysis of variance (ANOVA) was used to evaluate the leptin level, caloric intake, and eating behaviors as a function of the menstrual cycle phase (late-luteal phase versus follicular phase) and PMDD diagnosis (PMDD group versus control group), controlling for age and educational level, to demonstrate 12
Page 12 of 38
the late-luteal changes in PMDD. As leptin and leptin/BFP were not of a normal distribution, non-parametric analysis was used to evaluate the leptin level data. We also evaluated the difference in leptin level between the overweight group and the
ip t
normal-weight group using the Mann-Whitney Test. Two-factor ANOVA was used to evaluate the leptin level as a function of PMDD diagnosis (PMDD group versus
cr
control group) and weight (overweight group versus normal-weight group). Then, the association between the leptin level and PMDD was evaluated separately in the
us
overweight and normal-weight groups. A p-value lower than 0.05 was considered
an
statistically significant for the above analyses. The correlations between leptin level and caloric intake were evaluated by Spearman’s analysis. A p-value lower than
M
0.0125 was considered statistically significant for Spearman’s analysis after
Ac ce p
te
d
Bonferroni correction in multiple tests.
13
Page 13 of 38
3. Results According to the definition of a symptomatic cycle in PMDD, women with PMDD should have a PMDDSQ score in the late-luteal phase that is 30% higher than the
ip t
individual minimal score in the menstrual cycle (Smith et al., 2003). Further, the score on the PMDDSQ in the late-luteal phase among women with PMDD should be higher
cr
than the mean plus two standard deviations of that in the control group. A total of 16 PMDD candidates were excluded from the PMDD group because they did not meet
us
the criteria for two consecutive symptomatic cycles (Smith et al., 2003). Five women
an
with PMDD and 6 controls did not complete the caloric intake assessment. A total of 62 women with PMDD and 69 controls were entered into the final analysis. There
M
were no differences in age, educational level, estrogen level or progesterone level between the women with PMDD and the controls (Table 1). There were also no
te
PMDD and the controls.
d
significant differences in BMI or body fat percentage between the women with
Ac ce p
3.1. The late-luteal changes in leptin level, caloric intake and eating behaviors (Figure 1)
Repeated-measures two-factor ANOVA demonstrated significant late-luteal
increases in caloric intake (F = 6.21, p = 0.01; Fig. 1A), sweet caloric intake (F = 4.96, p = 0.03; Fig. 1B), and uncontrolled eating (F = 27.78, p < 0.001; Fig. 1F), and
significant late-luteal declines in leptin level (F = 4.09, p = 0.045; Fig. 1C) and
leptin/BFP (F = 7.14, p = 0.008; Fig, 1D) among the women with PMDD in comparison with the control group. The interaction effect was not significant for emotional eating (F = 3.46, p = 0.065) or cognitive restraint (F = 3.34, p = 0.07). There were no significant correlations between estrogen or progesterone levels and 14
Page 14 of 38
caloric intake or eating behaviors.
3.2. The correlation between leptin level and caloric intake among the overweight and
ip t
normal-weight subjects A total of 25 women (19.1%) were classified as overweight. The women who were
cr
overweight had a significantly higher leptin level (late-luteal phase: Z = 5.98, p
500 ml per day of sugar-sweetened beverages (Lin et al., 2013). A heavy fructose intake contributes not
Ac ce p
only to obesity (Bray, 2010), but also to leptin resistance (Vasselli et al., 2013). Thus, the higher late-luteal sweet caloric intake in overweight women with PMDD should be assessed and addressed. Moreover, they also had higher emotional eating behaviors than the overweight controls. Thus, intervention for emotional symptoms, dietary control, particularly control of high-fructose corn syrup-containing food, and a healthy lifestyle, such as exercise, should be promoted for overweight women with PMDD to attenuate the risk of leptin resistance.
4.6. Limitations Nonetheless, several limitations should be noted in this study. First, the number of 21
Page 21 of 38
subjects was limited in this study because many candidates were excluded according to the criteria for a symptomatic cycle (Smith et al., 2003) in the prospective investigation. Second, the leptin level was assessed during starvation, but not during
ip t
satiation. Evaluation of the response of the leptin level to eating food might allow more in-depth evaluation of the leptin level. Third, the causal relationships could not
us
cr
be confirmed owing to the cross-sectional design of this study.
4.7. Conclusion
an
The women with PMDD had greater increases in caloric intake, sweet caloric intake, and uncontrolled eating in the late-luteal phase than the controls. Among the
M
normal-weight women, the leptin level was negatively correlated with caloric intake. The leptin level of the women with PMDD declined in the late-luteal phase and was
d
negatively associated with sweet caloric intake. These results indicated that the
te
late-luteal decline in the leptin level, integrated with uncontrolled eating and emotional eating, is involved in overeating among normal-weight women with PMDD.
Ac ce p
On the other hand, the overweight women with PMDD had hyperleptinemia in the late-luteal phase. The hyperleptinemia could be a possible promotor of increased caloric intake among overweight women with PMDD, as well as overweight women without PMDD. The detailed roles of leptin and other psycho-neuro-endocrinology factors in the mechanism of eating behaviors among normal-weight or overweight women with PMDD should be studied in the future.
22
Page 22 of 38
Funding and Disclosure
ip t
The authors declare no conflicts of interest.
Acknowledgments
cr
This study was supported by grants from the National Science Council (NSC
us
100-2629-B-037-001-MY2), and the Kaohsiung Medical University Hospital
Ac ce p
te
d
M
an
(KMUH100-0R51).
23
Page 23 of 38
References
Ac ce p
te
d
M
an
us
cr
ip t
Ahrens, K., Mumford, S.L., Schliep, K.C., Kissell, K.A., Perkins, N.J., Wactawski-Wende, J., Schisterman, E.F., 2014. Serum leptin levels and reproductive function during the menstrual cycle. Am. J. Obstet. Gynecol. 210, 248 e241-249. Akturk, M., Toruner, F., Aslan, S., Altinova, A.E., Cakir, N., Elbeg, S., Arslan, M., 2013. Circulating insulin and leptin in women with and without premenstrual disphoric disorder in the menstrual cycle. Gynecol. Endocrinol. 29, 465-469. American Psychiatric Association, 2012. the draft fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). American Psychiatric Association, Arlington. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). American Psychiatric Association, Arlington. Banks, W.A., Kastin, A.J., Huang, W., Jaspan, J.B., Maness, L.M., 1996. Leptin enters the brain by a saturable system independent of insulin. Peptides 17, 305-311. Both-Orthman, B., Rubinow, D.R., Hoban, M.C., Malley, J., Grover, G.N., 1988. Menstrual cycle phase-related changes in appetite in patients with premenstrual syndrome and in control subjects. Am. J. Psychiatry 145, 628-631. Bray, G.A., 2010. Soft drink consumption and obesity: it is all about fructose. Curr. Opin. Lipidol. 21, 51-57. Buffenstein, R., Poppitt, S.D., McDevitt, R.M., Prentice, A.M., 1995. Food intake and the menstrual cycle: a retrospective analysis, with implications for appetite research. Physiol. Behav. 58, 1067-1077. Chesler, B.E., 2012. Emotional eating: a virtually untreated risk factor for outcome following bariatric surgery. ScientificWorldJournal 2012, 365961. Chien, C.P., Cheng, T.A., 1985. Depression in Taiwan: epidemiological survey utilizing CES-D. Seishin Shinkeigaku Zasshi 87, 335-338. Chou, S.H., Chamberland, J.P., Liu, X., Matarese, G., Gao, C., Stefanakis, R., Brinkoetter, M.T., Gong, H., Arampatzi, K., Mantzoros, C.S., 2011. Leptin is an effective treatment for hypothalamic amenorrhea. Proc. Natl. Acad. Sci. U. S. A. 108, 6585-6590. Cohen, M.M.Jr., 2006. Role of leptin in regulating appetite, neuroendocrine function, and bone remodeling. Am. J. Med. Genet. A 140, 515-524. Dye, L., Blundell, J.E., 1997. Menstrual cycle and appetite control: implications for weight regulation. Hum. Reprod. 12, 1142-1151. 24
Page 24 of 38
Ac ce p
te
d
M
an
us
cr
ip t
Epperson, C.N., Steiner, M., Hartlage, S.A., Eriksson, E., Schmidt, P.J., Jones, I., Yonkers, K.A., 2012. Premenstrual dysphoric disorder: evidence for a new category for DSM-5. Am. J. Psychiatry 169, 465-475. Evans, S. M., Foltin, R. W., & Fischman, M. W., 1999. Food "cravings" and the acute effects of alprazolam on food intake in women with premenstrual dysphoric disorder. Appetite 32, 331-349. Feng, H., Zheng, L., Feng, Z., Zhao, Y., Zhang, N., 2013. The role of leptin in obesity and the potential for leptin replacement therapy. Endocrine 44, 33-39. Fenichel, R.M., Dominguez, J.E., Mayer, L., Walsh, B.T., Boozer, C., Warren, M.P., 2008. Leptin levels and luteinizing hormone pulsatility in normal cycling women and their relationship to daily changes in metabolic rate. Fertil. Steril. 90, 1161-1168. Geisthovel, F., Jochmann, N., Widjaja, A., Horn, R., Brabant, G., 2004. Serum pattern of circulating free leptin, bound leptin, and soluble leptin receptor in the physiological menstrual cycle. Fertil. Steril. 81, 398-402. Giannini, A.J., Price, W.A., Loiselle, R.H., Giannini, M.C., 1985. Hyperphagia in premenstrual tension syndrome. J. Clin. Psychiatry 46, 436-438. Goumenou, A.G., Matalliotakis, I.M., Koumantakis, G.E., Panidis, D.K., 2003. The role of leptin in fertility. Eur. J. Obstet. Gynecol. Reprod. Biol. 106(2), 118-124. Hsiao, M.C., Liu, C.Y., Hsu, S.C., Hsiao, C.C., Lin, Y.H., Hsieh, T.T., 2011. Elevated serum cholesterol levels in women with premenstrual dysphoric disorder. Int. J. Psychiatry Med. 42, 85-92. Jauch-Chara, K., Oltmanns, K.M., 2014. Obesity--a neuropsychological disease? Systematic review and neuropsychological model. Prog. Neurobiol. 114, 84-101. Karlsson, J., Persson, L.O., Sjostrom, L., Sullivan, M., 2000. Psychometric properties and factor structure of the Three-Factor Eating Questionnaire (TFEQ) in obese men and women. Results from the Swedish Obese Subjects (SOS) study. Int. J. Obes. Relat. Metab. Disord. 24, 1715-1725. Klok, M.D., Jakobsdottir, S., Drent, M.L., 2007. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes. Rev. 8, 21-34. Knight, Z.A., Hannan, K.S., Greenberg, M.L., Friedman, J.M., 2010. Hyperleptinemia is required for the development of leptin resistance. PLoS One 5, e11376. Ko, C.H., Long, C.Y., Chen, S.Y., Chen, I.J., Huang, T.H., Yen, J.Y., 2013. Depression, irritability, and anxiety in women with premenstrual dysphoric disorder. Int. J. Psychiatry Med. 46, 39-55. 25
Page 25 of 38
Ac ce p
te
d
M
an
us
cr
ip t
Ko, C.H., Long, C.Y., Yen, C.F., Chen, C.S., Wang, P.W., Yen, J.Y., 2014. Gonadotrophic hormone and reinforcement sensitivity systems in women with premenstrual dysphoric disorder. Psychiatry Clin. Neurosci. 68, 785-794. Kronick, I., Auerbach, R.P., Stich, C., Knauper, B., 2011. Compensatory beliefs and intentions contribute to the prediction of caloric intake in dieters. Appetite 57, 435-438. Leitch, M.A., Morgan, M.J., Yeomans, M.R., 2013. Different subtypes of impulsivity differentiate uncontrolled eating and dietary restraint. Appetite 69, 54-63. Lin, T.K., Weng, C.Y., Wang, W.C., Chen, C.C., Lin, I.M., Lin, C.L., 2008. Hostility trait and vascular dilatory functions in healthy Taiwanese. J. Behav. Med. 31, 517-524. Lin, W.T., Huang, H.L., Huang, M.C., Chan, T.F., Ciou, S.Y., Lee, C.Y., Chiu Y.W., Duh, T.H., Lin, P.L., Wang, T.N., Liu, T.Y., Lee, C.H., 2013. Effects on uric acid, body mass index and blood pressure in adolescents of consuming beverages sweetened with high-fructose corn syrup. Int. J. Obes. (Lond) 37, 532-539. Macht, M., Mueller, J., 2007. Immediate effects of chocolate on experimentally induced mood states. Appetite. 31, 667-674. Masho, S.W., Adera, T., South-Paul, J., 2005. Obesity as a risk factor for premenstrual syndrome. J. Psychosom. Obstet. Gynaecol. 26, 33-39. McNeil, J., Doucet, E., 2012. Possible factors for altered energy balance across the menstrual cycle: a closer look at the severity of PMS, reward driven behaviors and leptin variations. Eur. J. Obstet. Gynecol. Reprod. Biol. 163, 5-10. Minocci, A., Savia, G., Lucantoni, R., Berselli, M.E., Tagliaferri, M., Calò, G., Petroni, M.L., de Medici, C., Viberti, G.C., Liuzzi, A., 2000. Leptin plasma concentrations are dependent on body fat distribution in obese patients. Int. J. Obes. Relat. Metab. Disord. 24, 1139-1144. Myers, M.G.Jr., Heymsfield, S.B., Haft, C., Kahn, B.B., Laughlin, M., Leibel, R.L., Tschöp, M.H., Yanovski, J.A., 2012. Challenges and opportunities of defining clinical leptin resistance. Cell Metab. 15, 150-156. Ninomiya, Y., Shigemura, N., Yasumatsu, K., Ohta, R., Sugimoto, K., Nakashima, K., Lindemann, B., 2002. Leptin and sweet taste. Vitam. Horm. 64, 221-248. Radloff, L.S., 1977. The CES-D Scale: A self-report depression scale for research in the general population. Appl. Psychol. Meas. 1, 16. Raman, J., Smith, E., Hay, P., 2013. The clinical obesity maintenance model: an integration of psychological constructs including mood, emotional regulation, disordered overeating, habitual cluster behaviours, health literacy and cognitive function. J. Obes. 2013, 240128. 26
Page 26 of 38
Ac ce p
te
d
M
an
us
cr
ip t
Rapkin, A.J., Winer, S.A., 2009. Premenstrual syndrome and premenstrual dysphoric disorder: quality of life and burden of illness. Expert. Rev. Pharmacoecon. Outcomes Res. 9, 157-170. Rasheed, P., Al-Sowielem, L.S., 2003. Prevalence and predictors of premenstrual syndrome among college-aged women in Saudi Arabia. Ann. Saudi. Med. 23, 381-387. Reed, S.C., Levin, F.R., Evans, S.M., 2008. Changes in mood, cognitive performance and appetite in the late luteal and follicular phases of the menstrual cycle in women with and without PMDD (premenstrual dysphoric disorder). Horm. Behav. 54, 185-193. Schulz, C., Paulus, K., Johren, O., Lehnert, H., 2012. Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO). Endocrinology 153, 143-153. Smith, M.J., Schmidt, P.J., Rubinow, D.R., 2003. Operationalizing DSM-IV criteria for PMDD: selecting symptomatic and asymptomatic cycles for research. J. Psychiatr. Res. 37, 75-83. Solomon, S.J., Kurzer, M.S., Calloway, D.H., 1982. Menstrual cycle and basal metabolic rate in women. Am. J. Clin. Nutr. 36, 611-616. Steiner, M., Macdougall, M., Brown, E., 2003. The premenstrual symptoms screening tool (PSST) for clinicians. Arch. Womens Ment. Health 6, 203-209. Suzuki, K., Jayasena, C.N., Bloom, S.R., 2012. Obesity and appetite control. Exp. Diabetes Res. 2012, 824305. Tessier, D.R., Ferraro, Z.M., Gruslin, A., 2013. Role of leptin in pregnancy: consequences of maternal obesity. Placenta 34, 205-211. Turner, S.A., Luszczynska, A., Warner, L., Schwarzer, R., 2010. Emotional and uncontrolled eating styles and chocolate chip cookie consumption. A controlled trial of the effects of positive mood enhancement. Appetite 54, 143-149. van Strien, T., Ouwens, M.A., Engel, C., de Weerth, C., 2014. Hunger, inhibitory control and distress-induced emotional eating. Appetite 79, 124-133. Van Vugt, D.A., 2010. Brain imaging studies of appetite in the context of obesity and the menstrual cycle. Hum. Reprod. Update 16, 276-292. Vasselli, J.R., Scarpace, P.J., Harris, R.B., Banks, W.A., 2013. Dietary components in the development of leptin resistance. Adv. Nutr. 4, 164-175. Volkow, N.D., Wang, G.J., Baler, R.D., 2011. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn. Sci. 15, 37-46. von Schnurbein, J., Moss, A., Nagel, S.A., Muehleder, H., Debatin, K.M., Farooqi, I. S., Wabitsch, M., 2012. Leptin substitution results in the induction of 27
Page 27 of 38
Ac ce p
te
d
M
an
us
cr
ip t
menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism. Horm. Res. Paediatr. 77, 127-133. Willner, J.P., 1998. Reproductive genetics and today's patient options: prenatal diagnosis. Mt. Sinai. J. Med. 65, 173-177. Yen, J.Y., Chang, S.J., Ko, C.H., Yen, C.F., Chen, C.S., Yeh, Y.C., Chen, C.C., 2010. The high-sweet-fat food craving among women with premenstrual dysphoric disorder: emotional response, implicit attitude and rewards sensitivity. Psychoneuroendocrinology 35, 1203-1212. Yen, J.Y., Chen, C.C., Chang, S.J., Ko, C.H., Chen, C.S., Yen, C.F., 2011. Hostility, Impulsivity, and Behavior Inhibition Among Women with PMDD. CNS Spectr. 16, 205-213. Yen, J.Y., Tu, H.P., Chen, C.S., Yen, C.F., Long, C.Y., Ko, C.H., 2013. The effect of serotonin 1A receptor polymorphism on the cognitive function of premenstrual dysphoric disorder. Eur. Arch. Psychiatry Clin. Neurosci. 264, 729-739. Zheng, H., Lenard, N.R., Shin, A.C., Berthoud, H.R., 2009. Appetite control and energy balance regulation in the modern world: reward-driven brain overrides repletion signals. Int. J. Obes. (Lond) 33 Suppl 2, S8-13. Zysberg, L., Rubanov, A., 2010. Emotional intelligence and emotional eating patterns: a new insight into the antecedents of eating disorders? J. Nutr. Educ. Behav. 42, 345-348.
28
Page 28 of 38
Table 1. Comparisons of demographic data, body mass index (BMI), body fat percentage (BFP), estrogen, and progesterone between the women with premenstrual dysphoric disorder (PMDD) and the controls. Independent t-test
23.58 ± 3.51 16.25 ± 1.76
21.75 ± 3.48 21.86 ± 3.83
21.87 ± 3.59 21.75 ± 3.49
-0.193 0.171
26.80 ± 5.33 26.27 ± 4.94
27.63 ± 4.45 27.89 ± 4.49
-0.969 -1.970
77.05 ± 6.40 67.86 ± 6.57
-1.005 -1.098
9.07 ± 8.53 1.13 ± 1.95
-0.550 -1.725
us
M
82.74 ± 6.27 51.66 ± 3.60 9.88 ± 8.99 0.82 ± 1.23
-0.389 -0.446
cr
23.35 ± 3.07 16.13 ± 1.15
d
Age Educational level BMI Late-luteal Follicular Body fat percentage (BFP) Late-luteal Follicular Estrogen Late-luteal Follicular Progesterone Late-luteal Follicular
an
Variables (Missing N)
Control group N = 69 (Mean ± SD)
ip t
PMDD group N = 62 (Mean ± SD)
Ac ce p
te
† Non-parametric analysis: Z values of the Mann-Whitney Test
29
Page 29 of 38
Table 2. The correlations between serum leptin level and caloric intake in late-luteal phase among women with PMDD, controls and all subjects. All subjects
Control group
CI
SCI
CI
-0.32**
-0.08
-0.16
-0.32
-0.41**
0.22
-0.34***
-0.12
-0.14
-0.36*
-0.45**
0.17
-0.05 -0.01
-0.04 0.16
-0.11 0.04
0.19 -0.10
-0.37 -0.30
Normal-weight subjects Leptin/BFP
a
Overweight subjects Leptin a Leptin/BFP a
b
0.06 -0.06
us
Leptin a
SCI
ip t
SCI
cr
CI
PMDD group
Ac ce p
te
d
M
an
*: p
S0306-4530(15)00089-X http://dx.doi.org/doi:10.1016/j.psyneuen.2015.03.002 PNEC 2941
To appear in: Received date: Revised date: Accepted date:
19-10-2014 28-2-2015 1-3-2015
Please cite this article as: http://dx.doi.org/10.1016/j.psyneuen.2015.03.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highlights
3.
Ac ce p
te
d
M
an
us
4. 5.
ip t
2.
Late-luteal leptin negatively correlated to caloric intake in normal-weight women. Normal-weight PMDD women had a lower late-luteal leptin level than normal-weight controls. Normal-weight PMDD women had a higher late-luteal caloric intake than normal-weight controls. Overweight PMDD women had hyperleptinemia in the late-luteal phase. Overweight PMDD women had a higher late-luteal sweet caloric intake than overweight controls.
cr
1.
1
Page 1 of 38
The late-luteal leptin level, caloric intake and eating behaviors among women with premenstrual dysphoric disorder. Running title: Leptin in PMDD
us
1
cr
Cheng-Sheng Chen,2,3 Ju-Yu Yen 2,3,6
Department of Psychiatry, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung
an
Medical University, Kaohsiung, Taiwan 2
ip t
Chih-Hung Ko,1,2,3 Cheng-Fang Yen,2,3 Cheng-Yu Long,4 Yu-Ting Kuo,5
Department of Psychiatry, Faculty of Medicine, College of Medicine, Kaohsiung
3
M
Medical University, Kaohsiung City, Taiwan
Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung,
Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital,
te
4
d
Taiwan
Kaohsiung, Taiwan
Department of Radiology, Chi-Mei Medical Center, Tainan, Taiwan
6
Department of Psychiatry, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung,
Ac ce p
5
Taiwan
Corresponding Author:
Ju-Yu Yen M.D., Ph.D.
Department of Psychiatry, Kaohsiung Medical University Hospital 100, Tzyou 1st Road, Kaohsiung 80708, Taiwan. Telephone: +886-7-3121101 ext. 6822 E-mail: [email protected] 2
Page 2 of 38
Abstract Objectives: A marked increased in food intake in the late-luteal phase is a characteristic symptom of premenstrual dysphoric disorder (PMDD). The aim of the
ip t
study was to evaluate the leptin level, caloric intake, and eating behaviors of women with PMDD across the menstrual cycle among normal-weight and overweight
cr
subjects, respectively.
Methods: A total of 62 women with PMDD and 69 controls were recruited following
us
psychiatric interviewing and underwent prospective investigation. The leptin level,
an
caloric intake, and three factors related to eating behavior were assessed in both the late-luteal and follicular phases.
M
Results: The women with PMDD had greater increases in caloric intake, sweet caloric intake, and uncontrolled eating in the late-luteal phase than the controls. Among the
d
normal-weight women, the leptin level was negatively correlated with caloric intake.
te
The normal-weight women with PMDD had a lower leptin level, a lower leptin/body fat percentage (BFP), a higher caloric intake, and higher uncontrolled eating and
Ac ce p
emotional eating in the late-luteal phase than the normal-weight controls. Their leptin level was correlated negatively with sweet caloric intake. On the other hand, the overweight women with PMDD had a higher leptin level than the normal-weight women with PMDD and no decline was observed in their leptin level in the late-luteal phase. There were no differences in the leptin level between the overweight women with PMDD and the overweight controls. They also had a higher sweet caloric intake and higher uncontrolled eating and emotional eating than the overweight controls. Conclusions: A decline in the leptin level is associated with late-luteal overeating among normal-weight women with PMDD. Hyperleptinemia and a high sweet caloric intake of overweight women with PMDD should be monitored and addressed in order 3
Page 3 of 38
to attenuate the risk of leptin resistance. The detailed roles of leptin and other psycho-neuro-endocrinology factors in the mechanism of overeating among women
ip t
with PMDD should be evaluated in future study.
Key words: Premenstrual dysphoric disorder (PMDD), caloric intake, leptin,
Ac ce p
te
d
M
an
us
cr
uncontrolled eating.
4
Page 4 of 38
1. Introduction Premenstrual dysphoric disorder (PMDD) was included as an official diagnostic criteria in the DSM 5 in 2012 (American Psychiatric Association, 2012) based on
ip t
adequate evidence (Epperson et al., 2012). It is defined as having predictable, cyclic, and functional-impairing psychological and somatic symptoms, such as depression,
cr
irritability, lethargy or hypersomnia. These symptoms are aggravated in the late-luteal
phase of the menstrual cycle and resolved by menstruation (Rapkin and Winer, 2009).
us
Marked changes in appetite and overeating are typical concomitant PMDD symptoms
an
(American Psychiatric Association, 2012) and are affected by the menstrual cycle among women with PMDD (Yen et al., 2010). Evaluation of hormones that fluctuate
M
during the menstrual cycle and affect eating behavior, such as leptin, may provide
d
insight into the mechanism of overeating symptoms among women with PMDD.
te
1.1. The caloric intake of women with PMDD Food intake is reduced in the periovulatory phase and increased during the luteal
Ac ce p
phase among women (Buffenstein et al., 1995; Dye and Blundell, 1997; Van Vugt, 2010), particularly among those with PMDD (Evans et al., 1999; McNeil and Doucet, 2012). Women with PMDD have been reported to eat more calories in the late-luteal phase than in the follicular phase as compared with control women (Reed et al., 2008). Further, sweet food craving is exacerbated in the late-luteal phase among women with PMDD (Yen et al., 2010). These results indicated that women with PMDD increase their food intake in the late-luteal phase. However, whether women with PMDD have an increased caloric intake and an increased sweet caloric intake in the late-luteal phase as compared with healthy women has not been empirically evaluated throughout the menstrual cycle. Additionally, the underlying factors 5
Page 5 of 38
contributing to the changes in caloric intake among women with PMDD are not well-understood (McNeil and Doucet, 2012).
ip t
1.2. The role of leptin in the appetite of women with PMDD Leptin, a hormone secreted by adipocytes, acts on the hypothalamus to regulate
cr
appetite and neuroendocrine function (Cohen, 2006). Leptin has a role in ovulation
through its stimulation of the pituitary to secrete luteinizing hormone (LH) (Fenichel
us
et al., 2008). The administration of recombinant leptin has been shown to restore
an
menses and fertility in women with hypothalamic or leptin deficiency amenorrhea (Chou et al., 2011; von Schnurbein et al., 2012). Recent studies have demonstrated
M
that the leptin level is increased over the menstrual cycle, with a mid-cycle peak concurrent with the LH surge (Ahrens et al., 2014). These studies all indicated that
d
leptin is related to not only eating behavior, but also to the menstrual cycle
te
(Goumenou et al., 2003). One study revealed a significant decline in leptin among women with PMDD in comparison with controls (Akturk et al., 2013). As leptin plays
Ac ce p
key roles in the menstrual cycle and appetite and has been found to be altered among women with PMDD, further study is necessary to evaluate the alterations in the leptin level and their effects on the caloric intake of women with PMDD (Akturk et al., 2013).
Further, leptin is transported across the blood-brain-barrier by a saturable
transporter system and exerts its anorectic effect via the hypothalamic arcuate nucleus. It results in a reduced food intake and an increased energy expenditure (Suzuki et al., 2012). However, obese individuals often have high leptin levels, which result in a failure to respond to exogenous leptin (Suzuki et al., 2012). Obesity has been reported to be associated with PMDD (Masho et al., 2005). The moderating effect of being 6
Page 6 of 38
overweight should be considered when evaluating the association between leptin and caloric intake. Further, there exist complex associations between the menstrual cycle, leptin level, eating behavior, obesity, and PMDD (McNeil and Doucet, 2012), and
ip t
evaluation of these factors across the menstrual cycle with analysis separately in overweight and normal-weight women may provide insight into the effect of leptin on
cr
the late-luteal caloric intake among women with PMDD.
us
1.3. The role of PMDD symptoms and associated factors in caloric intake in the
an
late-luteal phase
Aside from hormone levels, mood, stress, and rewarding characteristics contribute to
M
overeating behavior (Jauch-Chara and Oltmanns, 2014). Depression and irritability are the cardinal symptoms of PMDD (Ko et al., 2013; Yen et al., 2011). Emotional
d
eating is an eating behavior motivated by multiple negative emotions (Chesler, 2012)
te
and moderate stress-induced food intake in females (van Strien et al., 2014). Further, women with PMDD have a higher impulsivity (Yen et al., 2011). Impulsivity is
Ac ce p
associated with uncontrolled eating (Leitch et al., 2013), a tendency to eat more than usual due to a loss of control over intake (Karlsson et al., 2000), and contributes to caloric intake (Kronick et al., 2011). Women with PMDD also have impaired inhibitory control (Yen et al., 2013). The inhibitory control function is associated with cognitive restraint, conscious restriction of food intake in order to control body weight or to promote weight loss (Leitch et al., 2013). Cognitive restraint has been reported to associate with caloric intake among women with PMDD (Evans et al., 1999). Thus, whether three factors related to eating behavior, including cognitive restraint, uncontrolled eating and emotional eating, contribute to caloric intake should be evaluated among women with PMDD. 7
Page 7 of 38
1.4. The aims of the study Thus, the aims of the study were to evaluate: 1) whether the menstrual cycle
ip t
(late-luteal phase versus follicular phase) or PMDD (PMDD group versus controls) have impacts on the leptin level, caloric intake, and eating behaviors; 2) whether
cr
being overweight moderates the association between leptin level and caloric intake; 3) the differences in leptin level, caloric intake and eating behaviors between women
us
with PMDD and controls among overweight and normal-weight subjects; 4) whether
an
eating behaviors are associated with late-luteal caloric intake among normal-weight or
Ac ce p
te
d
M
overweight women with PMDD.
8
Page 8 of 38
2. Methods 2.1. Participants Subjects were recruited using an advertisement posted specifically to attract a PMDD
ip t
group without treatment and a control group on a university campus from 08/2011 to 10/2012. Volunteers in the PMDD group had a positive response to five or more
cr
premenstrual symptoms of the eleven DSM-IV-TR criteria of PMDD (American
Psychiatric Association, 2000). The control group had positive responses to fewer
us
than 2 of those criteria or had no functional impairment under mild symptoms.
an
Subjects currently taking psychotropic or hormone medication, such as contraceptive medication, were excluded from the study. A total of 169 (90 PMDD candidate
M
subjects and 79 candidate control subjects) women with a college or higher educational level were screened using the self-reported Premenstrual Symptoms
d
Screening Tool (PSST) after informed consent was obtained. Eighty-six participants
te
of the PMDD candidates were screened and were found to have moderate to severe premenstrual symptoms and entered the next steps of analysis. In addition, 75 women
Ac ce p
of the candidate controls were screened and found not to have premenstrual symptoms and entered the next steps of analysis. The other subjects were excluded. The women were then interviewed by one of two psychiatrists to exclude psychotic disorder and bipolar I disorder using the Mini-International Neuropsychiatric Interview (MINI), and to make the diagnosis of PMDD based on the DSMIV-TR criteria (American Psychiatric Association, 2000). Eighty-three PMDD candidate subjects and 75 candidate controls were diagnosed as having PMDD and not having PMDD, respectively. All of the subjects participated in a prospective investigation to confirm their premenstrual symptoms exacerbation. The study was approved by the Institutional Review Board (IRB) of Kaohsiung Medical University Hospital. 9
Page 9 of 38
2.2. Measures The Premenstrual Symptoms Screening Tool (PSST): The tool was developed by
ip t
Steiner and colleagues (Steiner et al., 2003). We utilized the scale to screen women with moderate to severe premenstrual symptoms (Steiner et al., 2003). They had to
cr
have 1) at least 1 of the first 4 items of the 14 symptoms; 2) four or more items of the 14 items assessing PMDD symptoms; and 3) at least 1 of the 5 items assessing
us
functional impairments that were classified as of a moderate to severe level, with a
an
score of 3 or 4.
The Premenstrual Dysphoric Disorder (PMDD) Severity Questionnaire (PMDDSQ):
M
The PMDDSQ was developed to evaluate the severity of PMDD symptoms across the menstrual cycle (Yen et al., 2013). The questionnaire is an 11-point Likert
d
questionnaire rating the severity of the 11 criteria of PMDD in the DSM IV-TR. Every
te
symptom was rated on a scale ranging from 0 to 10 to represent none at all to an extreme severity. The total score of the 11 items was used to represent the PMDD
Ac ce p
severity. The questionnaire had a Cronbach’s alpha of 0.98 and the four-week test-retest reliability was 0.92.
The mean caloric intake: The subjects recorded their dietary intake for three days
(the two last weekdays and one last holiday in the week before menstruation and in the week after menstruation). They recorded all food and drink consumed, except water. The eating time, name of the food (including trade mark), estimated volume or weight, method of cooking and sugar levels of drinks were noted. The caloric values of the foods were calculated according to information from the Food and Drug Administration, Ministry of Health and Welfare, Taiwan. The total caloric intake was then divided by three to determine the mean caloric intake per day. Sweet-tasting 10
Page 10 of 38
foods, such as cake, ice cream, candy, doughnuts, waffles, cookies or chocolate, and sugary beverages were classified as sweet food. The sweet food caloric intake was calculated in the same way.
ip t
18-item Three-Factor Eating Questionnaire (TFEQ): The self-assessed four-point response scale measures cognitive and behavioral components of eating. It contains
cr
three subscales, cognitive restraint (6 items), uncontrolled eating (9 items), and
emotional eating (3 items) (Karlsson et al., 2000). The Cronbach’s α values of the 3
us
subscales of the TFEQ were 0.77, 0.83, and 0.86, respectively.
Body mass index (BMI) is a measure of weight adjusted for height, calculated as
an
weight in kilograms divided by the square of height in meters (kg/m2). Subjects with a
M
BMI higher than 24 were classified as overweight based on the definition of the Health Promotion Administration, Ministry of Health and Welfare, Taiwan. Further,
te
(@Omron).
d
body fat percentage (BFP in %) was assessed using a body composition monitor
The levels of estrogen and progesterone: Blood samples were obtained directly from
Ac ce p
all subjects from a cannulated vein after testing in the late-luteal phase and the follicular phase. The serum was separated by centrifugation and stored at -20°C until further analysis. Estrogen and progesterone were measured using a Coat-A-count radioimmunoassay kit (Siemens Medical Solutions Diagnostics, Los Angeles, CA, USA).
The level of leptin: Serum and plasma samples were stored at -20°C until analysis.
Serum leptin levels were measured using an RIA kit from Linco Research, a division of Millipore Inc. (Cat# HL-81K, St Charles, MO, USA). The intra-assay CV ranged from 3.4 to 8.35% and the inter-assay CV ranged from 3.0 to 6.2%. The sensitivity was 0.5 ng/mL. The assays were run on a Cobra II series auto-gamma counting 11
Page 11 of 38
system (Packard Instrument Company; Meriden, CT, USA). The serum leptin level was standardized for BFP (dividing the serum leptin level by BFP; leptin/BFP) to
ip t
control the effect of body fat percentage.
2.3. Procedures
cr
All participants were evaluated in both the late-luteal phase (within one week before menstruation as predicted by the last menstruation cycle) and the follicular phase
us
(within one week after the end of menstruation and before ovulating). All subjects
an
were prohibited from eating or drinking, with the exception of water in a volume lower than 300 cc, in the three hours before entering the laboratory. After 1.5 hours of
M
questionnaire completion and cognitive assessment, blood was obtained to assess the estrogen, progesterone, and leptin levels. The participants were allowed to eat after
d
the blood test. Half of the subjects (39 in the PMDD group and 39 in the control group)
te
were assessed first in the late-luteal phase and then again in the follicular phase. The other subjects were assessed in reverse. After the investigation in the first menstrual
Ac ce p
cycle, all participants were followed-up and completed the PMDDSQ once a week for 2 menstrual cycles.
2.4. Data analysis
The differences in age, educational level, BMI, BFP, estrogen, and progesterone between the PMDD and control group were evaluated by the t test.
Repeated-measures two-factor analysis of variance (ANOVA) was used to evaluate the leptin level, caloric intake, and eating behaviors as a function of the menstrual cycle phase (late-luteal phase versus follicular phase) and PMDD diagnosis (PMDD group versus control group), controlling for age and educational level, to demonstrate 12
Page 12 of 38
the late-luteal changes in PMDD. As leptin and leptin/BFP were not of a normal distribution, non-parametric analysis was used to evaluate the leptin level data. We also evaluated the difference in leptin level between the overweight group and the
ip t
normal-weight group using the Mann-Whitney Test. Two-factor ANOVA was used to evaluate the leptin level as a function of PMDD diagnosis (PMDD group versus
cr
control group) and weight (overweight group versus normal-weight group). Then, the association between the leptin level and PMDD was evaluated separately in the
us
overweight and normal-weight groups. A p-value lower than 0.05 was considered
an
statistically significant for the above analyses. The correlations between leptin level and caloric intake were evaluated by Spearman’s analysis. A p-value lower than
M
0.0125 was considered statistically significant for Spearman’s analysis after
Ac ce p
te
d
Bonferroni correction in multiple tests.
13
Page 13 of 38
3. Results According to the definition of a symptomatic cycle in PMDD, women with PMDD should have a PMDDSQ score in the late-luteal phase that is 30% higher than the
ip t
individual minimal score in the menstrual cycle (Smith et al., 2003). Further, the score on the PMDDSQ in the late-luteal phase among women with PMDD should be higher
cr
than the mean plus two standard deviations of that in the control group. A total of 16 PMDD candidates were excluded from the PMDD group because they did not meet
us
the criteria for two consecutive symptomatic cycles (Smith et al., 2003). Five women
an
with PMDD and 6 controls did not complete the caloric intake assessment. A total of 62 women with PMDD and 69 controls were entered into the final analysis. There
M
were no differences in age, educational level, estrogen level or progesterone level between the women with PMDD and the controls (Table 1). There were also no
te
PMDD and the controls.
d
significant differences in BMI or body fat percentage between the women with
Ac ce p
3.1. The late-luteal changes in leptin level, caloric intake and eating behaviors (Figure 1)
Repeated-measures two-factor ANOVA demonstrated significant late-luteal
increases in caloric intake (F = 6.21, p = 0.01; Fig. 1A), sweet caloric intake (F = 4.96, p = 0.03; Fig. 1B), and uncontrolled eating (F = 27.78, p < 0.001; Fig. 1F), and
significant late-luteal declines in leptin level (F = 4.09, p = 0.045; Fig. 1C) and
leptin/BFP (F = 7.14, p = 0.008; Fig, 1D) among the women with PMDD in comparison with the control group. The interaction effect was not significant for emotional eating (F = 3.46, p = 0.065) or cognitive restraint (F = 3.34, p = 0.07). There were no significant correlations between estrogen or progesterone levels and 14
Page 14 of 38
caloric intake or eating behaviors.
3.2. The correlation between leptin level and caloric intake among the overweight and
ip t
normal-weight subjects A total of 25 women (19.1%) were classified as overweight. The women who were
cr
overweight had a significantly higher leptin level (late-luteal phase: Z = 5.98, p
500 ml per day of sugar-sweetened beverages (Lin et al., 2013). A heavy fructose intake contributes not
Ac ce p
only to obesity (Bray, 2010), but also to leptin resistance (Vasselli et al., 2013). Thus, the higher late-luteal sweet caloric intake in overweight women with PMDD should be assessed and addressed. Moreover, they also had higher emotional eating behaviors than the overweight controls. Thus, intervention for emotional symptoms, dietary control, particularly control of high-fructose corn syrup-containing food, and a healthy lifestyle, such as exercise, should be promoted for overweight women with PMDD to attenuate the risk of leptin resistance.
4.6. Limitations Nonetheless, several limitations should be noted in this study. First, the number of 21
Page 21 of 38
subjects was limited in this study because many candidates were excluded according to the criteria for a symptomatic cycle (Smith et al., 2003) in the prospective investigation. Second, the leptin level was assessed during starvation, but not during
ip t
satiation. Evaluation of the response of the leptin level to eating food might allow more in-depth evaluation of the leptin level. Third, the causal relationships could not
us
cr
be confirmed owing to the cross-sectional design of this study.
4.7. Conclusion
an
The women with PMDD had greater increases in caloric intake, sweet caloric intake, and uncontrolled eating in the late-luteal phase than the controls. Among the
M
normal-weight women, the leptin level was negatively correlated with caloric intake. The leptin level of the women with PMDD declined in the late-luteal phase and was
d
negatively associated with sweet caloric intake. These results indicated that the
te
late-luteal decline in the leptin level, integrated with uncontrolled eating and emotional eating, is involved in overeating among normal-weight women with PMDD.
Ac ce p
On the other hand, the overweight women with PMDD had hyperleptinemia in the late-luteal phase. The hyperleptinemia could be a possible promotor of increased caloric intake among overweight women with PMDD, as well as overweight women without PMDD. The detailed roles of leptin and other psycho-neuro-endocrinology factors in the mechanism of eating behaviors among normal-weight or overweight women with PMDD should be studied in the future.
22
Page 22 of 38
Funding and Disclosure
ip t
The authors declare no conflicts of interest.
Acknowledgments
cr
This study was supported by grants from the National Science Council (NSC
us
100-2629-B-037-001-MY2), and the Kaohsiung Medical University Hospital
Ac ce p
te
d
M
an
(KMUH100-0R51).
23
Page 23 of 38
References
Ac ce p
te
d
M
an
us
cr
ip t
Ahrens, K., Mumford, S.L., Schliep, K.C., Kissell, K.A., Perkins, N.J., Wactawski-Wende, J., Schisterman, E.F., 2014. Serum leptin levels and reproductive function during the menstrual cycle. Am. J. Obstet. Gynecol. 210, 248 e241-249. Akturk, M., Toruner, F., Aslan, S., Altinova, A.E., Cakir, N., Elbeg, S., Arslan, M., 2013. Circulating insulin and leptin in women with and without premenstrual disphoric disorder in the menstrual cycle. Gynecol. Endocrinol. 29, 465-469. American Psychiatric Association, 2012. the draft fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). American Psychiatric Association, Arlington. American Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). American Psychiatric Association, Arlington. Banks, W.A., Kastin, A.J., Huang, W., Jaspan, J.B., Maness, L.M., 1996. Leptin enters the brain by a saturable system independent of insulin. Peptides 17, 305-311. Both-Orthman, B., Rubinow, D.R., Hoban, M.C., Malley, J., Grover, G.N., 1988. Menstrual cycle phase-related changes in appetite in patients with premenstrual syndrome and in control subjects. Am. J. Psychiatry 145, 628-631. Bray, G.A., 2010. Soft drink consumption and obesity: it is all about fructose. Curr. Opin. Lipidol. 21, 51-57. Buffenstein, R., Poppitt, S.D., McDevitt, R.M., Prentice, A.M., 1995. Food intake and the menstrual cycle: a retrospective analysis, with implications for appetite research. Physiol. Behav. 58, 1067-1077. Chesler, B.E., 2012. Emotional eating: a virtually untreated risk factor for outcome following bariatric surgery. ScientificWorldJournal 2012, 365961. Chien, C.P., Cheng, T.A., 1985. Depression in Taiwan: epidemiological survey utilizing CES-D. Seishin Shinkeigaku Zasshi 87, 335-338. Chou, S.H., Chamberland, J.P., Liu, X., Matarese, G., Gao, C., Stefanakis, R., Brinkoetter, M.T., Gong, H., Arampatzi, K., Mantzoros, C.S., 2011. Leptin is an effective treatment for hypothalamic amenorrhea. Proc. Natl. Acad. Sci. U. S. A. 108, 6585-6590. Cohen, M.M.Jr., 2006. Role of leptin in regulating appetite, neuroendocrine function, and bone remodeling. Am. J. Med. Genet. A 140, 515-524. Dye, L., Blundell, J.E., 1997. Menstrual cycle and appetite control: implications for weight regulation. Hum. Reprod. 12, 1142-1151. 24
Page 24 of 38
Ac ce p
te
d
M
an
us
cr
ip t
Epperson, C.N., Steiner, M., Hartlage, S.A., Eriksson, E., Schmidt, P.J., Jones, I., Yonkers, K.A., 2012. Premenstrual dysphoric disorder: evidence for a new category for DSM-5. Am. J. Psychiatry 169, 465-475. Evans, S. M., Foltin, R. W., & Fischman, M. W., 1999. Food "cravings" and the acute effects of alprazolam on food intake in women with premenstrual dysphoric disorder. Appetite 32, 331-349. Feng, H., Zheng, L., Feng, Z., Zhao, Y., Zhang, N., 2013. The role of leptin in obesity and the potential for leptin replacement therapy. Endocrine 44, 33-39. Fenichel, R.M., Dominguez, J.E., Mayer, L., Walsh, B.T., Boozer, C., Warren, M.P., 2008. Leptin levels and luteinizing hormone pulsatility in normal cycling women and their relationship to daily changes in metabolic rate. Fertil. Steril. 90, 1161-1168. Geisthovel, F., Jochmann, N., Widjaja, A., Horn, R., Brabant, G., 2004. Serum pattern of circulating free leptin, bound leptin, and soluble leptin receptor in the physiological menstrual cycle. Fertil. Steril. 81, 398-402. Giannini, A.J., Price, W.A., Loiselle, R.H., Giannini, M.C., 1985. Hyperphagia in premenstrual tension syndrome. J. Clin. Psychiatry 46, 436-438. Goumenou, A.G., Matalliotakis, I.M., Koumantakis, G.E., Panidis, D.K., 2003. The role of leptin in fertility. Eur. J. Obstet. Gynecol. Reprod. Biol. 106(2), 118-124. Hsiao, M.C., Liu, C.Y., Hsu, S.C., Hsiao, C.C., Lin, Y.H., Hsieh, T.T., 2011. Elevated serum cholesterol levels in women with premenstrual dysphoric disorder. Int. J. Psychiatry Med. 42, 85-92. Jauch-Chara, K., Oltmanns, K.M., 2014. Obesity--a neuropsychological disease? Systematic review and neuropsychological model. Prog. Neurobiol. 114, 84-101. Karlsson, J., Persson, L.O., Sjostrom, L., Sullivan, M., 2000. Psychometric properties and factor structure of the Three-Factor Eating Questionnaire (TFEQ) in obese men and women. Results from the Swedish Obese Subjects (SOS) study. Int. J. Obes. Relat. Metab. Disord. 24, 1715-1725. Klok, M.D., Jakobsdottir, S., Drent, M.L., 2007. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes. Rev. 8, 21-34. Knight, Z.A., Hannan, K.S., Greenberg, M.L., Friedman, J.M., 2010. Hyperleptinemia is required for the development of leptin resistance. PLoS One 5, e11376. Ko, C.H., Long, C.Y., Chen, S.Y., Chen, I.J., Huang, T.H., Yen, J.Y., 2013. Depression, irritability, and anxiety in women with premenstrual dysphoric disorder. Int. J. Psychiatry Med. 46, 39-55. 25
Page 25 of 38
Ac ce p
te
d
M
an
us
cr
ip t
Ko, C.H., Long, C.Y., Yen, C.F., Chen, C.S., Wang, P.W., Yen, J.Y., 2014. Gonadotrophic hormone and reinforcement sensitivity systems in women with premenstrual dysphoric disorder. Psychiatry Clin. Neurosci. 68, 785-794. Kronick, I., Auerbach, R.P., Stich, C., Knauper, B., 2011. Compensatory beliefs and intentions contribute to the prediction of caloric intake in dieters. Appetite 57, 435-438. Leitch, M.A., Morgan, M.J., Yeomans, M.R., 2013. Different subtypes of impulsivity differentiate uncontrolled eating and dietary restraint. Appetite 69, 54-63. Lin, T.K., Weng, C.Y., Wang, W.C., Chen, C.C., Lin, I.M., Lin, C.L., 2008. Hostility trait and vascular dilatory functions in healthy Taiwanese. J. Behav. Med. 31, 517-524. Lin, W.T., Huang, H.L., Huang, M.C., Chan, T.F., Ciou, S.Y., Lee, C.Y., Chiu Y.W., Duh, T.H., Lin, P.L., Wang, T.N., Liu, T.Y., Lee, C.H., 2013. Effects on uric acid, body mass index and blood pressure in adolescents of consuming beverages sweetened with high-fructose corn syrup. Int. J. Obes. (Lond) 37, 532-539. Macht, M., Mueller, J., 2007. Immediate effects of chocolate on experimentally induced mood states. Appetite. 31, 667-674. Masho, S.W., Adera, T., South-Paul, J., 2005. Obesity as a risk factor for premenstrual syndrome. J. Psychosom. Obstet. Gynaecol. 26, 33-39. McNeil, J., Doucet, E., 2012. Possible factors for altered energy balance across the menstrual cycle: a closer look at the severity of PMS, reward driven behaviors and leptin variations. Eur. J. Obstet. Gynecol. Reprod. Biol. 163, 5-10. Minocci, A., Savia, G., Lucantoni, R., Berselli, M.E., Tagliaferri, M., Calò, G., Petroni, M.L., de Medici, C., Viberti, G.C., Liuzzi, A., 2000. Leptin plasma concentrations are dependent on body fat distribution in obese patients. Int. J. Obes. Relat. Metab. Disord. 24, 1139-1144. Myers, M.G.Jr., Heymsfield, S.B., Haft, C., Kahn, B.B., Laughlin, M., Leibel, R.L., Tschöp, M.H., Yanovski, J.A., 2012. Challenges and opportunities of defining clinical leptin resistance. Cell Metab. 15, 150-156. Ninomiya, Y., Shigemura, N., Yasumatsu, K., Ohta, R., Sugimoto, K., Nakashima, K., Lindemann, B., 2002. Leptin and sweet taste. Vitam. Horm. 64, 221-248. Radloff, L.S., 1977. The CES-D Scale: A self-report depression scale for research in the general population. Appl. Psychol. Meas. 1, 16. Raman, J., Smith, E., Hay, P., 2013. The clinical obesity maintenance model: an integration of psychological constructs including mood, emotional regulation, disordered overeating, habitual cluster behaviours, health literacy and cognitive function. J. Obes. 2013, 240128. 26
Page 26 of 38
Ac ce p
te
d
M
an
us
cr
ip t
Rapkin, A.J., Winer, S.A., 2009. Premenstrual syndrome and premenstrual dysphoric disorder: quality of life and burden of illness. Expert. Rev. Pharmacoecon. Outcomes Res. 9, 157-170. Rasheed, P., Al-Sowielem, L.S., 2003. Prevalence and predictors of premenstrual syndrome among college-aged women in Saudi Arabia. Ann. Saudi. Med. 23, 381-387. Reed, S.C., Levin, F.R., Evans, S.M., 2008. Changes in mood, cognitive performance and appetite in the late luteal and follicular phases of the menstrual cycle in women with and without PMDD (premenstrual dysphoric disorder). Horm. Behav. 54, 185-193. Schulz, C., Paulus, K., Johren, O., Lehnert, H., 2012. Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO). Endocrinology 153, 143-153. Smith, M.J., Schmidt, P.J., Rubinow, D.R., 2003. Operationalizing DSM-IV criteria for PMDD: selecting symptomatic and asymptomatic cycles for research. J. Psychiatr. Res. 37, 75-83. Solomon, S.J., Kurzer, M.S., Calloway, D.H., 1982. Menstrual cycle and basal metabolic rate in women. Am. J. Clin. Nutr. 36, 611-616. Steiner, M., Macdougall, M., Brown, E., 2003. The premenstrual symptoms screening tool (PSST) for clinicians. Arch. Womens Ment. Health 6, 203-209. Suzuki, K., Jayasena, C.N., Bloom, S.R., 2012. Obesity and appetite control. Exp. Diabetes Res. 2012, 824305. Tessier, D.R., Ferraro, Z.M., Gruslin, A., 2013. Role of leptin in pregnancy: consequences of maternal obesity. Placenta 34, 205-211. Turner, S.A., Luszczynska, A., Warner, L., Schwarzer, R., 2010. Emotional and uncontrolled eating styles and chocolate chip cookie consumption. A controlled trial of the effects of positive mood enhancement. Appetite 54, 143-149. van Strien, T., Ouwens, M.A., Engel, C., de Weerth, C., 2014. Hunger, inhibitory control and distress-induced emotional eating. Appetite 79, 124-133. Van Vugt, D.A., 2010. Brain imaging studies of appetite in the context of obesity and the menstrual cycle. Hum. Reprod. Update 16, 276-292. Vasselli, J.R., Scarpace, P.J., Harris, R.B., Banks, W.A., 2013. Dietary components in the development of leptin resistance. Adv. Nutr. 4, 164-175. Volkow, N.D., Wang, G.J., Baler, R.D., 2011. Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn. Sci. 15, 37-46. von Schnurbein, J., Moss, A., Nagel, S.A., Muehleder, H., Debatin, K.M., Farooqi, I. S., Wabitsch, M., 2012. Leptin substitution results in the induction of 27
Page 27 of 38
Ac ce p
te
d
M
an
us
cr
ip t
menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism. Horm. Res. Paediatr. 77, 127-133. Willner, J.P., 1998. Reproductive genetics and today's patient options: prenatal diagnosis. Mt. Sinai. J. Med. 65, 173-177. Yen, J.Y., Chang, S.J., Ko, C.H., Yen, C.F., Chen, C.S., Yeh, Y.C., Chen, C.C., 2010. The high-sweet-fat food craving among women with premenstrual dysphoric disorder: emotional response, implicit attitude and rewards sensitivity. Psychoneuroendocrinology 35, 1203-1212. Yen, J.Y., Chen, C.C., Chang, S.J., Ko, C.H., Chen, C.S., Yen, C.F., 2011. Hostility, Impulsivity, and Behavior Inhibition Among Women with PMDD. CNS Spectr. 16, 205-213. Yen, J.Y., Tu, H.P., Chen, C.S., Yen, C.F., Long, C.Y., Ko, C.H., 2013. The effect of serotonin 1A receptor polymorphism on the cognitive function of premenstrual dysphoric disorder. Eur. Arch. Psychiatry Clin. Neurosci. 264, 729-739. Zheng, H., Lenard, N.R., Shin, A.C., Berthoud, H.R., 2009. Appetite control and energy balance regulation in the modern world: reward-driven brain overrides repletion signals. Int. J. Obes. (Lond) 33 Suppl 2, S8-13. Zysberg, L., Rubanov, A., 2010. Emotional intelligence and emotional eating patterns: a new insight into the antecedents of eating disorders? J. Nutr. Educ. Behav. 42, 345-348.
28
Page 28 of 38
Table 1. Comparisons of demographic data, body mass index (BMI), body fat percentage (BFP), estrogen, and progesterone between the women with premenstrual dysphoric disorder (PMDD) and the controls. Independent t-test
23.58 ± 3.51 16.25 ± 1.76
21.75 ± 3.48 21.86 ± 3.83
21.87 ± 3.59 21.75 ± 3.49
-0.193 0.171
26.80 ± 5.33 26.27 ± 4.94
27.63 ± 4.45 27.89 ± 4.49
-0.969 -1.970
77.05 ± 6.40 67.86 ± 6.57
-1.005 -1.098
9.07 ± 8.53 1.13 ± 1.95
-0.550 -1.725
us
M
82.74 ± 6.27 51.66 ± 3.60 9.88 ± 8.99 0.82 ± 1.23
-0.389 -0.446
cr
23.35 ± 3.07 16.13 ± 1.15
d
Age Educational level BMI Late-luteal Follicular Body fat percentage (BFP) Late-luteal Follicular Estrogen Late-luteal Follicular Progesterone Late-luteal Follicular
an
Variables (Missing N)
Control group N = 69 (Mean ± SD)
ip t
PMDD group N = 62 (Mean ± SD)
Ac ce p
te
† Non-parametric analysis: Z values of the Mann-Whitney Test
29
Page 29 of 38
Table 2. The correlations between serum leptin level and caloric intake in late-luteal phase among women with PMDD, controls and all subjects. All subjects
Control group
CI
SCI
CI
-0.32**
-0.08
-0.16
-0.32
-0.41**
0.22
-0.34***
-0.12
-0.14
-0.36*
-0.45**
0.17
-0.05 -0.01
-0.04 0.16
-0.11 0.04
0.19 -0.10
-0.37 -0.30
Normal-weight subjects Leptin/BFP
a
Overweight subjects Leptin a Leptin/BFP a
b
0.06 -0.06
us
Leptin a
SCI
ip t
SCI
cr
CI
PMDD group
Ac ce p
te
d
M
an
*: p
