Serum leptin level across different phases of menstrual cycle in normal weight and
overweight / obese Saudi females
‫مقارنة مستوى هرمون اللبتين خالل المراحل المختلفة للدورة الشهرية ( الطمثية ) بين االناث السعوديات ذوات الوزن‬
‫سمنة‬/ ‫الطبيعي واالناث الالتي لديهن زيادة في الوزن‬
Nazish Rafique (FCPS): ‫نازك رفيق‬
Corresponding author :Ayad M Salem (PhD), ‫إياد محمد سالم‬
Rabia Latif (PhD): ‫رابعة لطيف‬
Running title : leptin across menstrual cycle
1
‫‪Nazish Rafique (FCPS): Assistant professor, department of physiology, College of Medicine,‬‬
‫‪University of Dammam, Dammam, Kingdome of Saudi Arabia E mail: [email protected]‬‬
‫نازك رفيق‪ :‬استاذ مساعد –قسم وظائف االعضاء‪-‬كلية الطب‪-‬جامعة الدمام‪ -‬المملكة العربية السعودية‬
‫‪Corresponding author: Ayad Mohammed Salem (PhD), Assistant professor, department of‬‬
‫‪physiology, College of Medicine, University of Dammam, Dammam, Kingdome of Saudi‬‬
‫‪Arabia, Tel: 00966559801273, Fax: 0096638578048 , E mail: [email protected]‬‬
‫إياد محمد سالم ‪ :‬استاذ مساعد –قسم وظائف االعضاء‪-‬كلية الطب‪-‬جامعة الدمام‪ -‬المملكة العربية السعودية‬
‫‪Rabia Latif (PhD): Assistant professor, department of physiology, College of Medicine,‬‬
‫‪University of Dammam, Dammam, Kingdome of Saudi Arabia, E mail: [email protected]‬‬
‫رابعة لطيف ‪ :‬استاذ مساعد –قسم وظائف االعضاء‪-‬كلية الطب‪-‬جامعة الدمام‪ -‬المملكة العربية السعودية‬
‫الخالصة‬
‫االهداف‪ :‬مقارنة مستوى هرمون اللبتين في الدم وعالقته بمستوى هرمون األستراديول اثناء مراحل الدورة الشهرية (‬
‫الطمثية) المختلفة بين االناث ذوات الوزن الطبيعي واالناث ذوات الوزن الزائد و السمنة ‪.‬‬
‫الطريقة اجريت هذه الدراسة بكلية الطب‪-‬جامعة الدمام‪-‬المملكة العربية السعودية في الفترة ما بين مارس ‪ 2014‬ومارس‬
‫‪ , 2015‬وقد شملت الدراسة ‪ 57‬طالبة ممن ليهن دورة شهرية ( طمثية ) منتظمة وتم تقسيمهن الى مجموعتين ‪ :‬مجموعة‬
‫الوزن الطبيعي (‪ 27‬طالبة) ومجموعة الوزن الزائد والسمنة (‪ 30‬طالبة) وقد تم قياس مستويات هرمون الليبتين و‬
‫األستراديول في مصل الدم خالل وقت مبكر من المرحلة الجرابية (‪ ، )follicular phase‬مرحلة ما قبل التبويض(‪pre-‬‬
‫‪ )ovulatory‬ومرحلة الطور األصفر (‪ )luteal phases‬من الدورة الشهرية باستخدام تقنية ‪.ELISA‬‬
‫النتائج‪ :‬اظهرت مستويات هرمون الليبتين في الدم زيادة مطردة خالل مراحل الدورة الشهرية المختلفة‪ ،‬ابتداءا من المرحلة‬
‫الجرابية )‪ (9.97 ± 5.48 ng/dl‬مرورا بمرحلة ما قبل التبويض )‪ (11.58 ± 6.49 ng/dl‬ثم بلوغه اعلى مستوى في‬
‫مرحلة الطور األصفر‪ .(12.52 ± 6.39 ng/dl, p < 0.001).‬وقد لوحظ نفس النمط من التغيير خالل مراحل الدورة‬
‫الشهرية عند تحليل مجموعة الوزن الطبيعي و مجموعة زيادة الوزن‪ /‬السمنة بشكل منفصل‪ .‬كما أظهرت النتائج ارتفاع‬
‫مستويات اللبتين في الدم في مجموعة زيادة الوزن ‪ /‬السمنة مقارنة بمجموعة الوزن الطبيعي‪، .‬بينما لم يكن هناك ارتباط بين‬
‫مستوى هرمون الليبتين و مستوى هرمون األستراديول خالل مراحل الدورة الشهرية في كلتا المجموعتين‪.‬‬
‫الخالصة‪ :‬هناك زيادة في مستويات هرمون الليبتين في الدم خالل مرحلتي الطور األصفر وما قبل التبويض من الدورة‬
‫الشهرية مقارنة مع المرحلة الجرابية‪ ،‬مما يدل على أن هذا الهرمون الدهني قد يلعب دورا في وظيفة اإلنجاب عند اإلناث‬
‫وخاصة في عملية التبويض وما بعد اإلباضة ‪.‬‬
‫‪2‬‬
Abstract
Objectives: To compare serum leptin levels during various phases of menstrual cycle and its
correlation with serum oestradiol between normal weight and overweight/obese young
females.
Methods: This study was conducted in college of medicine, University of Dammam, KSA.
Fifty seven young females with normal menstrual cycle were grouped into 27 normal weight
and 30 overweight /obese subjects. Serum leptin and oestradiol levels were measured during
early follicular, pre-ovulatory and luteal phases of menstrual cycle using ELISA technique.
Results: Serum leptin levels were significantly different across different phases of menstrual
cycle, it showed a steady increment from follicular phase (9.97 ± 5.48 ng/dl) through preovulatory phase (11.58 ± 6.49 ng/dl) with their peaks in luteal phase (12.52 ± 6.39 ng/dl, p <
0.001). Same pattern of change during menstrual phases was observed when the normal
weight and overweight/obese group were analyzed separately. Serum leptin levels were
significantly higher in overweight/obese group compared to normal weight subjects. In any of
the study groups, leptin levels were not found to be correlated with oestradiol level during
different phases of menstrual cycle.
Conclusion: There is an increase in serum leptin levels during the luteal and pre-ovulatory
phases of menstrual cycle compared to the follicular phase, indicating that this adipocytokine
may play a role in the reproductive function of the females especially in the process of
ovulation and lutenization.
Keywords: leptin, menstrual cycle, oestradiol
3
Introduction:
Leptin is a multifunctional adipose tissue hormone that is produced by the LEP (leptin)
gene1 , it has emerged as potential regulator of both energy homeostasis and reproductive
function with increasing evidence for its roles in the complex interplay between nutrition and
reproduction. Indeed, it has been well described that under nutrition or obesity, both can lead
to subfertility or infertility in human2.
Leptin has been recognized to play a role in human reproduction as early as 1949
when leptin deficient female mice were found to be not only obese but also infertile 3. A
more recent study found that women with hypothalamic amenorrhea have significantly lower
levels of circulating leptin when compared with healthy female subjects, administration of
recombinant leptin to these women showed restored menstrual cycles and fertility4.
Furthermore, a number of studies reported a higher level of mean circulating leptin in women
two to three times than in men5. These findings lies behind the development of the hypothesis
for leptin as an important player in the female reproduction via its stimulatory effect on the
hypothalamic-pituitary-gonadal axis6, leptin accelerates GnRH secretion from hypothalamous
indirectly through interneurons upstream of GnRH neurons. GnRH neurons are not affected by
leptin directly but other neuropeptides such as NPY, kisspeptin and proopiomelanocortin
(POMC) could mediate this action. In addition, leptin has direct effects on the anterior
pituitary and ovaries as well5.
The role of leptin in regulation of menstrual cycle and female reproduction had been
firstly suggested by Riad-Gabril et al, when they found a variation of serum leptin during
female menstrual cycle, but this variation was absent in men and postmenopausal women
over a period of 28 days 7. Subsequently, number of studies evaluated the levels of leptin
during the menstrual cycle, most of them showed an increase in leptin levels from the
follicular phase to reach a peak in luteal phase8-11, some reported a peak during the preovulatory phase12 while other showed no trend across menstruation13.
Current evidences therefore suggest endogenous leptin signaling is required for female
reproductive capacity. But, the mechanism of its action and its relation to sex hormones, is not
fully elucidated. The literature regarding leptin variation during menstrual cycle is
inconsistent, at the same time, the relationship between leptin and sex hormones is complex
and remains an area of controversy . Furthermore, only a few studies evaluated the effect of
body weight on serum leptin levels across different phases of the menstrual cycle in human
subjects. So the primary aim of this study was to find out the serum leptin levels in different
phases of menstrual cycle among young females, and to compare its levels between normal
weight and overweight/obese participants. Our secondary objective was to examine the
correlation between this adipocytokine and the oestradiol level. The results of our study can be
helpful in understanding the role of leptin in reproduction and fertility .
4
Method
This study was a prospective cohort study carried out at Department of Physiology,
College of Medicine, University of Dammam in the period from March 2014 to March 2015.
Fifty seven, regularly menstruating, healthy female students (18-25 years) from University of
Dammam were selected using convenience sampling method. Female students were excluded
from the study if they were pregnant, breast feeding within the past six months, had been
diagnosed with menstrual irregularities or ovulatory disorders, were using oral contraceptives
or any medication for chronic illness.
The subjects were categorized into two groups: normal weight group (BMI = 18.524.99), and overweight/obese group (BMI ≥ 25), depending upon their body mass index.
Weight and height of the subjects were measured in light clothing without shoes using Sicca
digital scale and stadiometer respectively. BMI was calculated as weight in kilograms divided
by the square of the height in meters (kg/m2); waist circumference (WC) and hip
circumference were measured with a non-stretchable plastic tape. The subjects were briefed
about the project in a familiarization session in which they were instructed about how to make
a basal body temperature chart.
An informed written consent was taken from all subjects and the study was approved by
Institutional Review Board in University of Dammam, KSA (IRB-2014-01-173).
All participants were followed over one menstrual cycle. Three blood samples per
subject were collected at three different times of menstrual cycle as following: 1) Early
Follicular Phase: During days 2-5 from onset of menstrual cycle 2) Pre ovulatory Phase:
During 11-16days before the onset of the next menstrual cycle 3) Luteal Phase: 3-5 days
before onset of next menstrual cycle. Determination of the menstrual cycle phase was done
using basal body temperature chart and serum oestradiol level changes14 .
Blood samples were obtained by venipuncture after an overnight fast between 8-10
AM (in order to minimize the effects of diet and circadian rhythm on leptin and estrogen
levels). All blood samples were allowed to clot and centrifuged within 30 minutes after vein
puncture. The obtained serum was frozen at -80 C till further analysis.
All samples from each participant’s cycle were run together in one batch to control for
inter-assay differences. Serum leptin was measured using Human Leptin, EMD Millipore kits
with inter and intra assay coefficient of variation (CV) of (2.6- 6.2 %) and (2.6-4.6 %)
respectively. Serum oestradiol levels were determined using human oestradiol Eliza kits
Sigma Aldrich, with inter-assay and intra-assay CV less than 10 %. .
Statistical analysis:
Data was expressed as arithmetic means ± standard deviation, the differences in the
level of study variables within the same group at different phases of menstrual cycle were
5
compared using one way repeated measure ANOVA , in case of data violation of the
assumption of sphericity, we used Greenhouse-Geisser values, whereas post hoc multiple
comparisons was performed using Bonferroni’s correction.
Comparison of study variables between the normal weight and overweight/obese
groups were estimated using unpaired t test. In addition, the correlation between the levels of
leptin with oestradiol (E2) was tested using Pearson correlation coefficients. Statistical
analysis was performed using the SPSS software package (Version 16.0 for Windows; SPSS
Chicago, IL, USA). All standard tests were two tailed, P < 0.05 was regarded as statistically
significant.
Results
The mean duration of the menstrual cycle in all study subjects was 29 ±1 (mean ±SD)
days (range = 27-31 days). The duration of the menstruation (bleeding) was 6± 1 day (mean
±SD).The participants’ characteristics in the two study groups are listed in (table 1).
Serum leptin levels showed a significant steady increment throughout the different
menstrual phases with their peaks in luteal phase. Serum leptin levels during luteal phase (L)
and pre-ovulatory phase (PO) were significantly higher than during early follicular phase (F) (
L = 12.52 ± 6.39, PO = 11.58 ± 6.49 vs F = 9.97 ± 5.48 ng/ml, P < 0.001). In contrast no
significant difference in serum leptin was found between pre-ovulatory and luteal phases
(table 2). When analyzing each study group individually, similar pattern of leptin variation
during menstrual cycle was observed in overweight / obese groups (L = 14.15 ± 7.10, PO =
13.32 ± 7.25 vs F = 11.37 ± 5.74 ng/ml, P = 0.001). However, in normal weight group, leptin
level during luteal phase was significantly higher than during follicular phase (10.17± 4.37
and 7.98± 4.50 respectively, P = 0.008), but no significant difference was observed in leptin
levels between pre-ovulatory and both follicular and luteal phases levels (table 3). Serum
leptin levels were higher in overweight-obese group compared to normal weight subjects
during all phases of menstrual cycle (P < 0.05) (table 3).
Similarly serum oestradiol differed significantly across various stages of menstrual
cycle, post hoc multiple comparison showed a significant increase in serum oestradiol level
from early follicular to pre-ovulatory phase (44.69± 22.41 vs76.47 ±52.32,pg/ml respectively
P = 0.004) but insignificant decrease from pre-ovulatory to the luteal phase (76.47
±52.32vs67.72 ± 36.41 pg./ml respectively)(table 2).The same pattern of change in oestradiol
level during menstrual phases was observed in each study group separately (table 3). No
significant difference was found in serum oestradiol level between normal weight and
overweight /obese groups across all phases of menstrual cycle (table 3).
There was a direct correlation between serum leptin level with BMI, waist
circumference and hip circumference during luteal phase (data not shown). But no significant
correlation was found between leptin and oestradiol E2 level during all phases of menstrual
cycle (follicular, pre-ovulatory and luteal phase) in any of study groups (table 4).
6
Table 1: baseline anthropometric measurements of the participants
Variables (mean ± SD)
Overweight–obese
group (n= 30)
18.96 ± 0.17
76.79 ± 12.55
P value
Age (year)
Weight (kg)
Normal weight
group (n= 27)
19 .08 ± 0.28
52.39 ± 6.7
Height (cm)
154.79 ± 5.7
157.35± 5.7
0.101
BMI (kg/m2)
21.8 ± 1.89
30.9 ± 3.7
0.000*
Waist circumference (cm)
74.58 ± 5.88
86.7727 ±14.08
0.000*
Hip circumference (cm)
Waist / hip (W/H) ratio
97.45 ± 6.33
0.77± 0.06
110.93 ±15.96
0.78 ± 0.07
0.000*
0.671
*Significant level at P < 0.001
BMI = body mass index
7
0.506
0.000*
Table 2: Serum leptin and estradiol levels in different phases of menstrual cycle in all
subjects of the study
Hormones
(mean ± SD)
Leptin (ng/ml)
Estradiol
(pg./ml)
Phases of menstrual cycle
Follicular phase (F) Pre-Ovulation (PO) Luteal phase (L)
(n=57)
(n=57)
(n=57)
9.97 ± 5.48
11.58 ± 6.49
12.52 ± 6.39
44.69± 22.41
76.47 ±52.32
67.72 ± 36.41
* Significant level for F vs both PO & L using repeated measure ANOVA
8
P value
0.000*
0.001*
Table 3: Comparisons of serum leptin and estradiol (E2) levels within and between
groups at different phases of menstrual cycle
hormones (mean ± SD)
Leptin
(ng/ml)
Estradiol
(pg/ ml)
Follicular phase (F)
Preovulatory phase (PO)
Luteal phase (L)
P value (within group)
Follicular phase (F)
Pre-ovulatory phase(PO)
Luteal phase (L)
P value (within group)
Normal weight
group
(n= 27)
7.98 ± 4.49
9.09± 4.21
10.20 ± 4.37
0.004 ¥
48.94± 23.18
78.42 ±45.02
67.83±41.19
0.045†
Overweight –
obese group
(n= 30)
11.37 ± 5.74
13.32 ± 7.25
14.15 ± 7.1
0.001†
41.04±21.69
74.79±58.64
67.63±32.51
0.017 †
*Significant level using unpaired t test
† Significant level for F vs both PO & L using repeated measure ANOVA
¥ Significant level for F vs L using repeated measure ANOVA
9
P value
(between groups)
0.022*
0.015*
0.021*
0.209
0.806
0.985
Table 4: Correlation between serum leptin and estradiol E2 in various phases of
menstrual cycle:
Serum estradiol E2
Normal weight group (n=27)
Serum leptin
F
F
PO
L
Pearson
correlation
P value
Pearson
correlation
P value
PO
Overweight/obese group (n=30)
L
-0.120
F
PO
L
0.299
0.577
0.122
-0.176
0.118
0.410
0.550
Pearson
correlation
P value
0.095
0.137
0.659
0.487
F= follicular phase, PO= pre-ovulatory phase, L= luteal phase
10
Discussion:
In this study we observed that in regularly menstruating females, leptin levels showed
a steady increment across the menstrual cycle with significant higher concentration during the
pre-ovulatory and luteal phases compared to the follicular phase.
These results are in accordance with a number of previous studies which have shown
considerable variation in leptin levels throughout the menstrual cycles with peak levels in the
luteal rather than the follicular phase8-11 . In another study, a pre-ovulatory peak of leptin level
was also observed (concurrent with LH surge)12, but this peak was less clearly defined from
the high leptin during the luteal phase reported in that study. In contrast, only a few early
studies reported a small non-significant variation in leptin level across menstruation 13, 15.
By dividing the subjects in this study according to the BMI, both lean and overweightobese females showed the same significant pattern of leptin variation during menstrual cycle
with high leptin concentration during luteal phase, this is in agreement to Al-Harithy et al16 ,
who found a physiological fluctuation in leptin concentration with higher level during luteal
phase both in lean and overweight females. This study also confirmed the strong correlation
between serum leptin and adiposity indices (body mass index, waist circumference and hip
circumference), as has been mentioned in many previous researches 9, 16. In addition, higher
leptin levels were recorded in overweight –obese group compared to normal weight group
across all menstrual phases, which is in agreement with many studies that reveal higher leptin
concentration in overweight-obese compared to lean subjects16-18 .
We controlled for adiposity by our study design to be sure that variation in leptin levels
during menstruation was not affected by BMI. Interestingly, our findings of significant leptin
fluctuation during different phases of menstruation both in normal weight group and
overweight-obese group proved that factors other than obesity are responsible for leptin
changes during menstruation. One of the sources for high leptin level during luteal phase
could be the corpus luteum, a study on human 19 and animal models 20 showed possible leptin
production from corpus luteum. Further support of this idea came from a recent study on a
cohort of 259 women where anovulatory cycles (i.e. no lutinization in these cycles was
presumed) showed a decreased level of serum leptin during luteal phase compared with
corresponding higher luteal level during the ovulatory cycles (corpus luteum active cycles)12.
Another possible explanation for higher leptin during luteal phase of ovulatory cycles lies in
the fact that ovulation is considered as inflammatory reaction, many inflammatory mediators
within the ovarian follicles were found to be stimulated by the LH surge21 . Since leptin has a
pro-inflammatory activity 22, 23. Hence, the increasing serum leptin during the luteal phase
might be a response to inflammatory process related to ovulation.
Food intake has been suggested by some groups to be the cause of increased serum
leptin during luteal phase7, In a more recent study, no association between pattern of food
intake and the changes in leptin level during menstruation was reported 24. However to
exclude the nutritional and circadian influences on serum leptin , blood samples were
collected in this study after an overnight fast between 8-10 AM. The increased luteal leptin
11
might have many physiological benefits. Leptin is a mediator of cell proliferation23, 25 and with
respect to the presence of leptin receptors in the endometrium5, 26, it is plausible that the luteal
phase of the menstrual cycle is accompanied by increased leptin levels to prepare the
endometrium for implantation. Furthermore, the body energy regulating function of leptin
might plays an important role in preparation for a high energy demanding pregnancy27.
In addition, Leptin have been suggested to induce ovulation during menstrual cycle.
Experimentally, leptin was found to induce LH secretion either directly from anterior pituitary
28, 29
or through the effect on hypothalamic receptors4, 28. As further proof, administration of
recombinant leptin was also found to restore menstruation and fertility in women with
hypothalamic amenorrhea, 4, 30. Though in our study we didn’t observer a pre-ovulatory peak
of leptin , our finding of steady increment of leptin level from follicular phase through preovulatory to reach a peak in luteal phase doesn’t contradict with the suggested leptin’s role in
ovulation since the pre-ovulatory leptin level recorded by our study was very close to the
luteal phase peak.
The literature on relationship between leptin and oestradiol during menstrual cycle is
inconsistent, In the present study, no correlation was found between leptin levels and
oestradiol during any menstrual phase in any study group. Similarly many studies showed that
the changes in plasma leptin during the menstrual cycle were not related to changes in sex
hormones7, 10, 31. In contrast, other studies reported a positive correlation between the level of
leptin and that of oestradiol during menstrual cycle 12, 16. These controversial results might
highlight a complex feedback loop controlling leptin-oeastradiol inter-relation instead of just
simple unidirectional relation. Hence, the absence of correlation between leptin and oestradiol
doesn’t mean absence of leptin’s role in female reproduction.
The small sample size and the frequency of sampling in this study limited our ability to
draw inferences regarding the exact role of leptin in female reproduction. However, our data
clearly reports a significant variation of leptin during menstrual cycle, reflecting a
reproductive role of leptin in female that is not clearly defined.
Conclusion
In our cohort of healthy, regularly menstruating females, leptin levels increased across
the menstrual cycle, with a luteal peak both overall and when dividing the subjects according
to the BMI. Leptin was not associated with changes in oestradiol level during the menstrual
cycle. The physiological significance of higher leptin level during the luteal phase are not fully
understood, but taking into consideration previous data, are likely related to preparing the
body for highly energy demanding pregnancy and enhancing the fertility. Future researches on
leptin’s effect on menstrual cycle physiology in females is needed, particularly comparisons
between fertile and infertile women of different body weights to elucidate the exact role of
leptin in female reproduction.
12
Acknowledgement: This work was supported by Deanship of Scientific Research at the
University of Dammam. KSA [grant number 2014293]. We are thankful to Lavina De Costa
and Maha Al-Hamdan for their technical assistance
Conflict of interest: The authors declared that they have no conflict of interest
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