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ABSTRACT: Leptin, which is the product of the obese gene, is believed to play important roles in pubertal development and reproductive function in females. In a study using adult male rats, it was found that leptin stimulated secretion of gonadotropin from the pituitary in a dose-related manner. However, there has been no such study in female rats.
To investigate the effects of leptin on the production of LH and FSH from the pituitary in female rats, using primary cultured pituitary cells.
In this study, we determined body weight, serum leptin concentration and serum estradiol (E(2)) concentration in female Wistar rats at 3, 5, 6, 7, 9 and 11 weeks of age, and cultured pituitary cells from 6-week-old female Wistar rats with leptin (0--10(-7) mol/l) and GnRH (0 or 10(-8) mol/l). Then basal and GnRH-stimulated extra- and intracellular LH and FSH were assayed by RIA.
Serum leptin concentration increased with increases in body weight and E(2) concentration. The pubertal serum leptin concentration was about 10(-10) mol/l. At a lower or moderate concentration, leptin produced dose-related increases in both basal and GnRH-stimulated extra- and intracellular LH and FSH in pituitary cells. At a concentration of 10 mol/l, leptin significantly (P<0.05) stimulated both basal and GnRH-stimulated extra- and intracellular LH and FSH. However, at greater concentrations, these effects diminished.
These results indicated that leptin induced pituitary cells to produce and secrete both LH and FSH, with or without GnRH. The concentration of leptin that induced the greatest production of gonadotropins by pituitary cells was 10(-10) mol/l, which was the same as the physiological pubertal concentration. Leptin may be involved in the onset of puberty. It is also conceivable that leptin may be a cause of ovulatory failure, not only in weight loss but also in weight gain.
European Journal of Endocrinology 06/2001; 144(6):653-8. · 3.42 Impact Factor
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ABSTRACT: We performed a randomized controlled study to determine the efficacy of add-backed therapy by every-other-day administration of 0.625 mg conjugated equine estrogen (CEE) and 2.5 mg medroxyprogesterone acetate (MPA) on GnRH agonists (GnRH-a) treatment in Japanese women with symptomatic endometriosis. At the end of treatment, serum estrone and estradiol levels in the add-back group (n = 11) were significantly higher than those in the control group (n = 10). The assessment of Beecham classification by bimanual examination, serum CA-125 levels, and the frequency of genital bleeding revealed no significant differences between the two groups. The add-back group showed reduced Kupperman indices relative to those of the control group, and could prevent the loss of bone density. These findings led to a conclusion that GnRH-a therapy added back by every-other-day administration of 0.625 mg CEE and 2.5 mg MPA was a safe and effective treatment for Japanese women with endometriosis.
Gynecologic and Obstetric Investigation 02/2001; 52(4):217-22. · 1.28 Impact Factor
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ABSTRACT: Tissues in various parts of the body have different sensitivities to estradiol. However, it is very difficult to measure the serum estradiol levels precisely in women receiving oral conjugated equine estrogen, which is a mixture of estrogens. In the present study, we precisely measured the serum levels of estradiol in postmenopausal women undergoing hormone replacement therapy (HRT), and we clarified the relationships between serum estradiol levels and the effects of HRT on the Kupperman index, bone mineral density (BMD), serum gonadotropin, lipid metabolism and unscheduled bleeding as the clinical endpoints.
Sixty-eight postmenopausal or bilaterally ovariectomized women, aged 30-64 years, who had been suffering from vasomotor symptoms such as hot flush or atrophy of the vagina were randomly assigned to two groups: one group of 34 patients who received oral administration of 0.625 mg conjugated equine estrogen (CEE, Premarin, Wyeth) and 2.5 mg medroxyprogesterone acetate (MPA, Provera, Upjohn) every other day, and another group of 34 patients who received oral administration of 0.625 mg CEE and 2.5 mg MPA every day. All subjects were re-classified into three groups according to the serum estradiol level after 12 months of treatment: (1) low estradiol group (<15 pg/ml, n = 25); (2) middle estradiol group (> or =15 and <25 pg/ml, n = 27), and (3) high estradiol group (> or =25 pg/ml, n = 16). We examined the relationships between serum estradiol level and the effects of estradiol on the Kupperman index, BMD, serum gonadotropin levels, lipid profile and unscheduled bleeding in these three groups. Results: Results obtained by using our newly developed high-performance liquid chromatography (HPLC)-radioimmunoassay (RIA) system clearly showed that the effects on each tissue in postmenopausal women receiving oral CEE and MPA is closely related to estradiol level. The effects of HRT on BMD, serum gonadotropin levels and lipid profile were shown to be clearly dependent on the serum estradiol levels, while the effect of HRT on the Kupperman index was independent of the serum estradiol level. Furthermore, it was also found that a very low concentration of estradiol (<15 pg/ml) was sufficient to suppress the serum LH and FSH levels and to relieve vasomotor symptoms, and that the minimum concentration of estradiol required to increase BMD was 15 pg/ml. On the other hand, the level of estradiol required to reduce total cholesterol, low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (Apo B) was found to be more than 25 pg/ml, while the level required to increase high density lipoprotein-cholesterol (HDL-C) and apolipoprotein A1 (Apo A1) was at least 15 pg/ml. The incidence of unscheduled bleeding was also lower in the low estradiol group than in the other estradiol level groups.
These results suggest that the different clinical endpoints have different response thresholds and thus reflect tissue sensitivity to estradiol levels achieved by HRT.
Hormone Research 01/2001; 56(1-2):38-44. · 2.48 Impact Factor
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M Kamada,
M Irahara,
M Maegawa,
T Yasui,
S Yamano,
M Yamada, M Tezuka,
Y Kasai,
K Deguchi,
Y Ohmoto,
T Aono
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ABSTRACT: In elderly subjects the capacity for antibody production is depressed. This immunosenescence state of humoral immunity is associated with the occurrence of autoimmune disorders involving CD5+ B (B-1) cells. Since estrogen is capable of stimulating the production of autoantibodies, this sex steroid hormone may be a contributing cause of the higher incidence of autoimmune diseases in women. In the present study, B cell subsets in women during the postmenopausal period was determined. The effect of hormone replacement therapy (HRT) on B cell subsets was examined to establish whether the administration of gonadal hormones influence humoral immunity in postmenopausal women.
Forty six untreated pre- and postmenopausal women and 39 women on HRT were studied. The proportion of B-1 (CD5+) and conventional CD5- B (B-2) lymphocytes was determined by two-color flow cytometry. Serum autoantibodies to a nuclear antigen and to interleukin (IL)-1alpha were measured by immunofluorescence and by radioimmunoassay, respectively. Thirteen women were examined prospectively before and during HRT.
In late postmenopausal women (> or = 30 years postmenopausal period), the proportion of B-2 cells was significantly reduced (p<0.01) compared to those of premenopausal and perimenopausal women. HRT induced a significant (p<0.01) increase in the percentage of B-2 cells, while that of B-1 cells remained unchanged. HRT did not affect autoantibody production.
HRT may retard the progress of immunosenescence by increasing the production of B-2 cells. Moreover, HRT appears not to increase the risk of autoimmune diseases developing in postmenopausal women.
Maturitas 01/2001; 37(3):173-9. · 2.77 Impact Factor
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ABSTRACT: We investigated the effects of Toki-shakuyaku-san and its crude ingredients in relation to the secretion of a cytokine-induced neutrophil chemoattractant, CINC/gro, interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) in the ovulatory process. Toki-shakuyaku-san significantly (p < 0.01) stimulated the secretion of 17 beta-estradiol but did not stimulate the secretion of progesterone in cultured whole ovarian dispersates. Toki-shakuyaku-san enhanced the secretion of CINC/gro in a dose-dependent manner and the production of CINC/gro at concentrations of 10 and 100 micrograms/ml of Toki-shakuyaku-san increased significantly (p < 0.01). Toki-shakuyaku-san also enhanced secretions of both IL-1 beta and TNF alpha, which are known to stimulate the secretion of CINC/gro in the ovulatory process. The production of TNF alpha increased significantly (p < 0.05) with 10 and 100 micrograms/ml of Toki-shakuyaku-san. Atractylodis Lanceae Rhizoma, Cnidii Rhizoma, Angelicae Radix, Paeoniae Radix and Alismatis Rhizoma, which are crude ingredients of Toki-shakuyaku-san, significantly (p < 0.01) enhanced the secretion of CINC/gro at concentrations of 100 micrograms/ml. The results of this study show that Toki-shakuyaku-san can stimulate the secretion of 17 beta-estradiol and stimulate the ovulatory process by stimulating the production of CINC/gro, IL-1 beta and TNF alpha in vitro. As a treatment for ovulatory disorders, Toki-shakuyaku-san may have stimulatory effects on both steroidogenesis and the ovulatory process.
Methods and Findings in Experimental and Clinical Pharmacology 12/2000; 22(10):725-30. · 0.93 Impact Factor
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ABSTRACT: Immunosenescence is associated with the occurrence of lethal diseases, such as infection and malignancy. Since endocrinosenescence occurs simultaneously with immunosenescence, we determined whether or not lymphocytes and T cell subsets were altered in post-menopausal women. The ability of hormone replacement therapy (HRT) to reverse or modify the aberrations of the cell populations observed in elderly women was also examined. Thirty-nine untreated post-menopausal women and 39 women on HRT were studied. The proportions of lymphocytes and T cell subsets (helper, cytotoxic and immature T cells, and naive and memory/activated T cells) were determined by two color flow cytometry. Thirteen women were examined before and during HRT. At late post-menopause (> or = 30 years post-menopausal period), the proportion of peripheral blood lymphocytes showed a tendency to decline (p=0.06) compared with that at early (< or = 10 years) post-menopause. Significant (p<0.05) decrease in naive T cells and an increase in memory/activated T cells occurred at late post-menopause compared to those at early post-menopause. The percentage of lymphocytes in women on HRT was significantly (p<0.05) higher than that in untreated women at late post-menopausal stage. Furthermore, in a prospective study, HRT induced a significant (p<0.02) increase in the percentage of lymphocytes but showed no effect on the aberrations of naive and memory/activated T cells. HRT prevents the decline in the lymphocytes observed in post-menopausal women. However, HRT appears not to influence the observed alteration in T cell subsets.
Journal of endocrinological investigation 07/2000; 23(6):376-82. · 1.57 Impact Factor
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ABSTRACT: Circulating levels of leptin, estradiol (E(2)) and progesterone (P(4)) throughout normal menstrual cycles (n = 13), and controlled, stimulated cycles (n = 33) were examined using sensitive specific radioimmunoassays in order to investigate the relationships between sex hormones (E(2), P(4)). Serum leptin levels during the normal menstrual cycle remained constant. However, in the ovulation induction cycle, E(2) levels and circulating leptin levels increased in parallel with the process of stimulation. In addition, leptin/body mass index ratios for all samples were significantly correlated with log(10)E(2). We conclude that particularly high levels of E(2) may have an effect on the secretion of leptin from adipose tissue.
Gynecologic and Obstetric Investigation 02/2000; 49(2):119-23. · 1.28 Impact Factor
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ABSTRACT: It is well known that feeding disorders are deeply related to reproductive dysfunction, and some feeding regulatory factors may modulate the reproductive function. We examined the effect of orexins, the newly discovered orexigenic hypothalamic neuropeptides, on the pulsatile secretion of LH to clarify their influence on the reproductive function. We administered orexins or saline into the third ventricle of bilaterally ovariectomized (OVX) rats, and measured the serum LH concentration by RIA in blood samples drawn every 6 min for 2 hours to analyze the pulsatile secretion. In the orexin-treated groups, the mean LH concentration and the pulse frequency were significantly reduced (p < 0.01), but the pulse amplitude did not differ significantly. These data indicate that orexins suppress the pulsatile secretion of LH by influencing GnRH neurons at the hypothalamic level.
Biochemical and Biophysical Research Communications 11/1999; 264(3):759-62. · 2.48 Impact Factor
