1 Academic Department of Obstetrics and Gynaecology, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH and 2 Department of Chemical Pathology, Imperial College School of Medicine, Charing Cross Hospital, Fulham Palace Road, London W6 8RX, UK
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Abstract |
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Key words: leptin/neuro-endocrine/neurosteroids/premenstrual syndrome
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Introduction |
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Although leptin receptors are expressed on ovarian granulosa cells (Cioffi et al., 1997), and leptin treatment of bovine granulosa cell culture inhibits oestradiol production (Spicer and Francisco, 1997
, 1998
), the major effects of leptin on reproduction appear to be centrally mediated. Evidence from animal studies has shown that the neuro-endocrine effects of leptin are more marked when administered centrally than peripherally, suggesting that some of its effects are mediated by direct action on central receptors (Campfield et al., 1995
; Stephens et al., 1995
). Leptin appears to have a permissive role in the onset of puberty by reactivation of the hypothalamic-pituitary-gonadal axis (Clarke and Henry, 1999
; Quinton et al., 1999
). Furthermore, leptin deficiency results in hypogonadotrophic hypogonadism, impaired sexual maturation and infertility, which are corrected by leptin replacement (Ahima et al., 1996
, 1997
; Chehab et al., 1996
).
Premenstrual syndrome (PMS) is a group of menstrually related chronic, cyclical disorders manifested by psychological and physical symptoms in the second half of the menstrual cycle. It has been suggested that the psychological symptoms of the disease may be due to abnormal neuro-endocrine response to normal ovarian function in susceptible women. Since the hypothalamus controls emotional behaviour, and the metabolic and neuro-endocrine effects of leptin are mediated by its receptors in the hypothalamus, we postulated that circulating leptin concentrations were increased in PMS, and that contributes to the disease by stimulation of its hypothalamic receptors. In this study, we have compared circulating leptin concentrations in the follicular and luteal phases of the menstrual cycle in PMS and symptom-free controls.
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Materials and methods |
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None of the women used hormonal contraception or had history of hypertension, metabolic or endocrine disease, or used any drugs that may have effects on circulating leptin concentrations. Venous blood was obtained from the antecubital vein, spun immediately and plasma stored at 70°C until assayed for leptin, oestradiol and progesterone. Total circulating leptin concentrations (expressed as ng/l) were measured in duplicates by radioimmunoassay (Linco Research, Inc., St Louis, MO, USA). The assay employed a polyclonal (rabbit) antibody raised against recombinant human leptin. Standards and 125I tracer were also made from recombinant human leptin (Ma et al., 1996). All samples were run in duplicate and the average intra- and inter-assay coefficients of variation were 3 and 8% respectively. The local ethics committee approved the study, and informed consent was obtained from all subjects.
Statistical analysis
Data for the clinical characteristics and plasma progesterone values were normally distributed and the values are expressed as mean ± SD. Plasma leptin and oestradiol values showed a non-gaussian distribution and were expressed as median (interquartile range). Statistical significance between the variables was analysed using paired t-test or Wilcoxon signed-rank paired test for the appropriate data. The strength of association between plasma leptin, oestradiol and progesterone was tested using Spearman's correlation coefficient. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS), version 4. P < 0.05 was considered statistically significant.
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Results |
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No significant correlation was observed between leptin concentrations and age, BMI, oestradiol, and progesterone concentrations in both menstrual phases, in the control and PMS groups, and the ovulatory subgroups.
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Discussion |
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The aetiology of PMS is unknown, and the diagnosis is based on the timing and symptom pattern observed in daily symptom records maintained by the patient. The disorder is not universally acknowledged as a disease, and no medical speciality has accepted responsibility for its treatment, although it is recognized by the legal profession as a disease of the mind. Presently there is little evidence that absolute concentrations (deficiency or excess) of hormones cause PMS or that women with PMS have different hormonal patterns from those without. It has been suggested that the disease may result from an abnormal central nervous response to normal gonadal steroids or their metabolites (Berga, 1998). Such central effects may be direct on the brain or indirect by modulating neurotransmitter receptor responses such as
-aminobutyric acid A (GABA-A) receptor complex. Metabolites of progesterone (allopregnanolone and pregnenolone) can alter neuronal excitability by interaction with the GABA-A receptors (Rupprecht, 1997
) in susceptible women. Genetic predisposition may also contribute to the development of the disease (Freeman and Halbreich, 1998
).
Although it is not clear from our data whether the raised leptin concentrations are a cause or a consequence of the disease, there are several possible explanations. Leptin may contribute to the pathophysiology of PMS by direct action on receptors in the hypothalamic neurones (Mercer et al., 1996). The hypothalamus is one of the most important centres of the motor output pathways of the limbic system, controlling food intake and many of the endocrine functions of the body, including emotional behaviour. Although the functional leptin receptors OB-Rb are located in nearly all parts of the brain (Mercer et al., 1996
; Guan et al., 1997
), they are highly expressed in the hypothalamus. Hypothalamic OB-Rb is expressed in its paraventricular, ventromedial and arcuate nuclei, areas known to be involved in satiety and reproduction (Bray et al., 1981
; Menedez et al., 1991).
In this study, although the pattern of change of leptin in PMS was similar to that reported in normal cycles (Raid-Gabriel et al., 1998), the difference between the luteal and follicular leptin was greater in the PMS group. Furthermore, the concentrations were also higher during the follicular phase of PMS cycles compared with the controls, suggesting the increase may not be limited to the luteal phase. Although our data cannot explain this observation, high follicular leptin concentrations may have a priming effect on the central nervous system in those women prone to PMS. It may also explain why some women develop symptoms very early during the luteal phase. Further studies will be required to establish precisely when during PMS cycles circulating leptin begins to rise, by daily measurements of plasma leptin concentrations in PMS women.
Although previous observations have suggested that leptin inhibits gonadotrophin-stimulated human luteinized granulosa cell progesterone production (Brannian et al., 1999), there was no clear relationship between leptin and oestradiol or progesterone in this study. The relationship between leptin and insulin-induced oestradiol, LH or FSH were not investigated in this study. This suggests that any possible role played by leptin in the pathophysiology of PMS may be by direct stimulation of the hypothalamus, and not mediated by ovarian steroids.
Another possible mechanism for leptin in PMS is augmentation of central response to neurosteroids and their metabolites, such as allopregnanolone and pregnenolone. Evidence from animal studies suggest that leptin down-regulates neuropeptide-Y (NP-Y) activity via its receptors located on NP-Y neurones in the hypothalamus (Williams et al., 1999). Neuropeptide-Y is a powerful orexetic factor, which plays an important role in feeding (White, 1993
), and reproduction (Kalra, 1993
). Leptin may play a role in PMS by influencing the NP-Y transmission pathway. Furthermore, it has recently been reported that central serotonin activity is reduced in PMS and plasma concentrations of its metabolites increased during the luteal phase of the PMS cycles. Reduced serotonin activity in PMS may be responsible for the depressive mood experienced by some women with the disease (Freeman et al., 1998). It is also the pharmacological basis for the use of selective serotonin re-uptake inhibitors for the treatment of PMS (Freeman et al., 1999
). Leptin induces brain serotonin metabolism through the L-arginine-nitric oxide pathway (Calapai et al., 1999
). Increased serotonin metabolism or uptake will reduce its concentrations and may provide a possible mechanism for leptin in the development of PMS. Leptin concentrations are altered in women with eating disorders (Nakai et al., 1999
). Although food craving is a common symptom in PMS, we are unable to explain the relationship between food craving and increased leptin concentrations in PMS, as leptin stimulates the satiety centre. It is not clear whether this phenomenon represents a state of temporary leptin resistance similar to that described in obesity (Lee et al., 1996
). However, obese women and those with insulin resistance do not necessarily exhibit PMS. We are currently carrying out studies to investigate whether a relationship exists between insulin resistance and leptin concentrations in women with PMS.
In summary, we have shown that plasma leptin concentrations are higher in PMS compared with asymptomatic menstrual cycles, independent of plasma oestradiol and progesterone concentrations. Although robust conclusions cannot be drawn from these data, as the number of women in the study is small, the probability of such a difference as that observed between the two groups occurring by chance was so small that the findings are likely to represent a true biological difference. The clinical utility of plasma leptin as a tool for the diagnosis of PMS should await independent confirmation of our findings. Further work is required to define the precise role played by leptin in the pathophysiology of PMS, as circulating concentrations may not reflect tissue activity.
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Notes |
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References |
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Submitted on April 27, 2000; accepted on July 21, 2000.