Variation of Leptin During Menstrual Cycle and Its Relation to the Hypothalamic–Pituitary–Gonadal (HPG) Axis: A Systematic Review

Figures & data

Figure 1 Flow chart of the literature search and selection process.

Table 1 Summary of 18 Studies That Showed Significant Variation of Leptin During Different Phases of the Menstrual Cycle

Studies	Location	Mean Age	Subjects Studied	Study Design	Duration	Frequency of Sampling	Main Conclusion	Limitation	Quality Score
Ahrens et al (2014)—The Bio Cycle Study (2005–2007)^Citation37	USA	27±8.2 years	259 healthy premenopausal women with regular menstruation BMI=18–35	Prospective cohort study	One cycle (n=9) two cycles (n=250)	Eight samples per cycle during the following phases: menses, early and late follicular phase, LH surge, ovulation, early, mid, and late luteal phases	Serum leptin increased from menstruation to the late luteal phase with a mid-cycle peak. Leptin was positively correlated with estradiol, progesterone, testosterone, LH, and negatively with FSH	Involved women of BMI between 18 and 35 which limits the generalization of the findings due to leptin insensitivity that develops in obese subjects	6
Geisthovel et al (2004)^Citation32	Germany	29±4.25 years	30 regular menstruating women (BMI=20±1.3),	Prospective observational study	Three consecutive menstrual cycles	Measurement were performed twice throughout all phases of the menstrual cycle II (early and mid-follicular phase, preovulatory phase and early and late luteal phase), additional two measurements were done on cycle III during early and mid-follicular phase, preovulatory phase	Significant variation of leptin was observed with a steady increment from early follicular phase to reaches its peak at late luteal phase	Small sample size	5
Riad-Gabrirel et al (1998)^Citation20	USA	28±2 years	Nine regular menstruating women (BMI=23.9±1.8)	Prospective observational study	One complete cycle	Every 1–2 days throughout the menstrual cycle	Leptin concentration was significantly higher during mid-luteal phase compared to follicular phase. No correlations between leptin with estrogen, progesterone, LH, and FSH were detected	Small sample size	5
Cella et al (2000)^Citation39	Italy	29.7±4.8 years	Eight women with normal cycle (BMI=22±1.3)	Clinical longitudinal study	One complete cycle	Daily during complete cycle	Leptin varied significantly with higher level during luteal phase compared to follicular phase, with a transient peak in the late follicular phase. Leptin was positively correlated with estradiol and progesterone. No correlation with LH and FSH	Small sample size	5
Wyskida et al (2017)^Citation31	Poland	18–30 years	52 healthy women with normal menstrual cycle BMI (18-5-24)	Prospective observational study	One menstrual cycle	Three samples between days 2 and 4, 12 and 14, and 24 and 26 of each subject’s menstrual cycle	Leptin was significantly higher in both mid-cycle and luteal phase. Leptin significantly related to total testosterone	Less frequent sampling. Determination of menstrual phases based on menstrual rhythm only	4.5
Fernández-Real et al (2000)^Citation38	Spain	Lean women =35.8 2±2 years Overweight women=37.7 2.1 years	Nineteen normal menstruating women divided into two groups: nine lean women (BMI <25) and 10 overweight women (BMI >25)	Comparative prospective study	One complete cycle	Three times; early follicular (3–4 days from menstruation), mid-cycle (days 12–15) and mid-luteal (days 17–22)	Leptin changed significantly in lean women with higher levels during preovulatory and luteal phase, while overweight women showed stable unaltered leptin level. Leptin were correlated to LH but not with estrogen nor with progesterone	Small sample size less frequent sampling. Determination of phases based on menstrual rhythm only	4.5
Rafique et al, (2018)^Citation36	Saudi Arabia	19–25 years	Fifty-six females with normal menstrual cycel divided into two groups: 26 normal weight (BMI=18.5–24.99) and 30 overweight/obese (BMI ≥25)	Comparative prospective study	One complete cycle	Three times: follicular phase (2–3 days from the onset of menstruation), preovulatory (11–16 days before the onset of the next menstrual cycle) and luteal phase (3–5 days before the onset of the next cycle)	Leptin was significantly increase during luteal phase compared to follicular phase in normal weight group. However, in overweight obese group, leptin was significantly higher during both preovulatory and luteal phase compared to follicular phase. No association between leptin with serum estradiol was detected in both groups	Less frequent sampling. Determination of menstrual phases based on menstrual rhythm only	4.5
Ludwig et al (2000)^Citation34	Germany	Not mentioned	Sixteen normal menstruating women (BMI 18–25)	Prospective observational study	One cycle	Each alternate day during complete cycle starting after day 3 of menstrual cycle.	Leptin showed higher level during luteal phase compared to the follicular phase. No correlation with estrogen and progesterone	Small sample size. Determination of phases based on menstrual rhythm only	4.5
Stock et al (1999)^Citation43	Sweden	30±5 years	Thirteen women (BMI=22.2±2.5	Prospective observational study	One complete cycle	Four times during menstrual cycle: days 1–3, 6–8,13–15 and 22–25	Small overall significant variation during the menstrual cycle,	Small sample size. Less frequent sampling	4.5
Wunder et al (2006)^Citation23	Switzerland	25.5±5.5 20–32 years	36 healthy women with normal BMI (18.5–25)	Prospective observational study	One full cycle	Every 1–2 during one complete cycle (14–19 samples per participant)	Leptin was significantly higher during the mid-luteal phase compared to early follicular and ovulatory phases. Leptin was positively correlated with prolactin and testosterone, no correlations with progesterone and estrogen were detected	Small sample size	4.5
Geisthovel et al (1998)^Citation16	Germany	22–38 years	Nineteen normal weight women (BMI:18–24)	Clinical study with control group of 19 regularly menstruating women	Three menstrual cycles	Five samples, mid-follicular phase around days 7–9, preovulatory phase, twice during mid-luteal phase (4 days and 6 days after ovulation), and on the mid-follicular phase of the next cycle	Significant cyclic changes were observed with high concentration at preovulatory and mid-luteal phases compared with the two mid-follicular phases	Small sample size	4.5
Al-Harithy et al (2006)^Citation35	Saudi Arabia	19–39 years	Sixty-five regular menstruating women divided into two groups: 32 normal weight (BMI <25), and 33 overweight/obese group (BMI >25)	Comparative prospective study	One menstrual cycle	Four samples on day 3, 10, 17 and 24 from the beginning of the menstruation	Leptin varied significantly with lower level during the early follicular phase and the highest during the luteal phase in the two groups. Leptin was significantly correlated with estrogen in both group, and with progesterone in normal weight group, no correlation with testosterone, FSH and LH was found in both groups	Less frequent sampling. Determination of phases based on menstrual rhythm only	4
Asimakopoulos et al (2009)^Citation24	Greece	19–30 years	Sixteen regular menstruating women (BMI=19.46–24.90)	Prospective observational study	One menstrual cycle	Every alternate day throughout the cycle	Leptin varied significantly with higher values during the luteal phase and mid-cycle phases compared to the follicular phase. Leptin was positively correlated to estrogen, progesterone and negatively with FSH	Small sample size	4
Hardie et al (1997)^Citation17	UK	31.5±3 years	Six healthy normal menstruating women (BMI=21.6± 0.5)	Longitudinal observational study	One complete cycle	Serial sampling start from one day after menstruation then every third day, apart from days 11–17 during which daily sampling was done.	Leptin was significantly higher during periovulatory and luteal phases compared to follicular phase. Leptin was correlated with the progesterone level during luteal phase.	Small sample size	4
Faustman et al (2016)^Citation41	Austria	34.2±6.5 years	Twenty-eight women, BMI 22.4±3.44	Prospective longitudinal study	One complete cycle	Four times early (T1) and late (T2) follicular phase, mid (T3) and late (T4) luteal phase	Leptin was higher during mid-luteal phase compared to the early follicular phase. Progesterone was inversely related to leptin during late follicular and early luteal phase	Small sample size. Determination of phases based only on menstrual rhythm and body basal temperature changes	3.5
Mannucci et al (1998)^Citation18	Italy	18–35 years	Eighteen normal menstruating women (BMI <27)	Prospective observational study	One full cycle	Four times during the menstrual cycle (day 3,10,17, and 24 from the beginning of menstruation)	Leptin during day 10, 17, and 24 was higher compared to day 3 of the menstrual cycle. No correlation with estradiol, progesterone, testosterone, DHEAS, androstenedione, LH, and FSH	Small sample size and less frequent sampling. Determination of phases based on menstrual rhythm only	3.5
Paolisso et al (1999)^Citation19	Italy	26.1±0.8 years	Sixteen women with normal menstrual cycle (BMI=21.1±0.3)	Prospective observational study	One complete cycle	Three times: follicular phase (days 4–7), periovulatory phase (day of luteinizing hormone (LH) surge ±1 day], luteal phase (days 23–27).	Leptin was significantly changed during menstrual cycle. A positive correlation between leptin concentration and progesterone level was detected throughout all menstrual phases.	Small sample size and less frequent sampling	3.5
Gröschl et al (2002)^Citation33	Germany	19–22 years	Ten healthy normal women with normal menstrual cycle (BMI=19.5–22.2)	Observational prospective study	One complete cycle	Daily during one complete menstrual cycle	Salivary leptin showed significantly higher level during luteal phase compared to follicular phase. Leptin was positively correlated with progesterone	Small sample size. Determination of phases based on menstrual rhythm only	3.5

Table 2 Summary of Four Studies That Showed Stable Leptin Level During Different Phases of the Menstrual Cycle

Studies	Location	Mean Age	Subjects Studied	Study Design	Duration	Frequency of Sampling	Main Conclusion	Limitation	Quality Score
Šrámková et al (2015)^Citation28	Czech republic	31.8±3.56 years	Twenty-seven women with normal menstrual cycle (BMI 22.9±2.8)	Prospective observational study	One full cycle	Every three days for a total of 10 samples starting from the first or second day after menstruation	Leptin showed nonsignificant increase during ovulation	Small sample size. Determination of the menstrual phases based on menstrual rhythm only	3
Capobianco et al (2010)^Citation27	Italy	21–44 years	Eighteen normal menstruating women (BMI=18.4–25.4) divided into two groups. Ovulatory (N=10) and anovulatory group (N=8)	Prospective observational study	One full cycle	Three times: at menstrual phase (days 2–3), preovulatory (days 12–13), and luteal phase (days 23–24)	No significant change in leptin in both ovulatory and nonovulatory cycles. Leptin was significantly higher in ovulatory group compared to nonovulatory cycle. Leptin was positively correlated with FSH, no associations with estrogen, progesterone, and LH	Small sample size less frequent sampling. Determination of phases based on menstrual rhythm only	4.5
Maruyama et al (2001)^Citation42	Japan	Normal weight (35.1±4 years) obese (34.2± 2 years)	Ten healthy women divided into two groups: 5 normal weight group (n=5, BMI=22.4±0.3) obese group (n=5, BMI=28.2±0.9)	Comparative prospective study	One full cycle	Three blood samples, early follicular (between days 2 and 5 after the onset of menses, ovulatory phase (first and third day after LH surge, and luteal phase (seventh day after LH surge	Normal group showed no change in serum leptin, Leptin was significantly higher during luteal phase in obese group, leptin was significantly correlated with estrogen both in normal weight and obese groups,	Small sample size less frequent sampling	4
Teirmaa et al (1998)^Citation44	Finland	23.5±2.1 years	Eight women with normal menstrual cycle (BMI 21.2±1.6)	Prospective observational study	One full cycle	Three blood samples: between the second and fifth days, the 14th or 15th day, and between the 24th and 26th days of the cycle	There was no significant change in leptin during the different phase of menstrual cycle. Leptin was positively correlate with LH but not with estrogen and progesterone.	Small sample size less frequent sampling. Determination of phases based on menstrual rhythm only	3.5

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