Alterations in the insulin-like growth factor system during the menstrual cycle in normal women
Introduction
The insulin-like growth factors (IGF-I and IGF-II) are important stimulators of cell growth and differentiation [1]. The majority of circulating IGF-I has a hepatic origin 2, 3. While growth hormone (GH) is the most important stimulator of hepatic synthesis of IGF-I [3], steroidal hormones are known to influence its plasma levels. While estrogens given by the oral route are known to suppress plasma levels of IGF-I 4, 5, this effect may be due to exposure of estrogens in supra physiological concentrations to the liver, as only about 10% of estradiol administered by the oral route reaches systemic circulation unmetabolized due to extensive first pass metabolism [6]. On the other hand, the influence of physiological plasma estrogen and progestin concentrations on plasma IGF-I levels is less clear.
In a previous study we found no correlation between plasma estrogens and IGF-I levels in postmenopausal women [7]. While some authors have reported estrogen replacement therapy by the cutaneous route to influence plasma levels of IGF-I [4], others could not find such an effect [8]. Regarding alterations in plasma IGF-I during the menstrual cycle, some authors reported plasma IGF-I to be highest during the luteal phase [9], while others could not detect any difference between the different phases 10, 11.
Bioavailability of IGF-I to the tissues may be influenced by alterations in plasma levels of IGF-binding proteins (IGFBPs). In addition, the major IGF-binding protein in plasma, IGFBP-3, exists not only in an intact but also a proteolytically modified (‘clipped’) form with reduced ligand binding activity [12]. Increased IGFBP-3 protease activity may be an important physiological mechanism to increase IGF-I delivery to the tissues [13]. Thus, it is necessary to measure total levels of IGF-binding proteins and in addition the functional status of IGFBP-3 to fully evaluate the IGF-system.
We have recently shown the progestin megestrol acetate to influence IGFBP-3 fragmentation in breast cancer patients [13]which may indicate a role of sex steroids in the regulation of this parameter.
This study was conducted to evaluate alterations in total IGF-I, IGF-II, IGFBP-1, IGFBP-3 and also IGFBP-3 fragmentation in relation to the different phases during the normal menstrual cycle in healthy women. To our knowledge, possible alterations in IGFBP-3 fragmentation during the menstrual cycle have not been evaluated in previous studies.
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Patients and methods
Ten premenopausal women belonging to the hospital staff gave their informed consent to take part in the study. Before inclusion, all subjects reported regular menstrual cycles with a duration varying between 28 and 30 days. One subject was later excluded from the analysis due to an abnormal cycle during the test period (lasting for more than 6 weeks exceeding the time schedule of blood sampling). Eight women were between 28 and 36 years old, while the last subject was 48 years (median 30, range
Results
Mean plasma levels of total IGF-I, IGF-II, IGFBP-1 and IGFBP-3 together with estradiol and progesterone at different phases during the menstrual cycle are shown in Table 1. While no difference in plasma IGF-II levels between the different phases was noted, a modest but significant difference in plasma IGF-I (P<0.01) and IGFBP-3 (P<0.05) was observed. Excluding the women from the analysis who were 48 years old did not influence the level of significance. The lowest level of IGF-I was found
Discussion
Plasma levels of IGF-I seen in our patients were in the same range as previously reported for subjects of their age [21].
Previous studies on plasma IGF-I levels during the menstrual cycle in humans have provided conflicting results 9, 10, 11. Some early studies included a limited number of patients while others analyzed IGF-I levels in unextracted serum, in which case results may be confounded by binding protein interactions in the assays. Two recent studies have reported no day to day
Acknowledgements
This work was supported by the Norwegian Cancer Society.
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