胰岛素样生长因子I及其结合蛋白1对超排卵周期卵泡发育的影响

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Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 in premature rupture of membranes

BACKGROUND: The aim of the study was to evaluate whether the circulating levels of insulin-like growth factor-I (IGF-I) and its major circulating binding protein, IGFBP-3, are affected in premature rupture of membranes (PROM) and preterm delivery. METHODS: The levels of IGF-I and IGFBP-3 were measured in 32 pregnant women with PROM and in 27 healthy gestational age-matched pregnant women. Statistical analyzes were performed by analysis of variance. RESULTS: All the patients with PROM had preterm delivery, at a gestational age of 31.9 +/- 0.4 weeks (mean +/- SEM). In the control subjects, pregnancy proceeded to term. In the PROM patients, the serum IGF-I and IGFBP-3 levels (289 +/- 21 ng/ml and 8248 +/- 407 ng/ml, respectively) were not statistically different from those in the control subjects (275 +/- 22 ng/ml and 7579 +/- 488 ng/ml). Seventeen patients with PROM showed a rise in serum C-reactive protein, indicating subclinical intrauterine infection. Also in this subgroup of patients the levels of serum IGF-I (281 +/- 27 ng/ml) and IGFBP-3 (9010 +/- 633 ng/ml) were not different from those in the control subjects. Before delivery, serial serum samples were available from 22 patients with PROM. No consistent changes in IGF-I or IGFBP-3 concentrations were seen during the mean follow-up period of 9 days. CONCLUSIONS: IGF-I and IGFBP-3 do not appear to play any significant role in the maintenance of pregnancy in PROM patients with preterm delivery, whether or not associated with emerging intrauterine infection.     

Progesterone and estradiol in the saliva and plasma during the menstrual cycle

Plasma and salivary progesterone and estradiol were measured throughout nine menstrual cycles and before and after intramuscular injection of progesterone in four women. Mean +/- standard error of the mean (SE) salivary progesterone increased significantly from 238.7 +/- 14.3 pg/ml in the proliferative phase to 475.3 +/- 39.8 pg/ml in the secretory phase (p less than 0.001). There was a highly significant correlation between plasma and salivary progesterone levels throughout the menstrual cycle (r = 0.5841, p = 0.001). The ratio of plasma to salivary progesterone was 6.4 during the proliferative phase and increased to 26.7 during the secretory phase. Free unbound progesterone as determined by equilibrium dialysis gave a mean +/- SE level of 126.8 +/- 6.9 pg/ml during the proliferative phase and increased significantly to 196.8 +/- 18.8 pg/ml during the secretory phase (p less than 0.001). The corresponding levels in the plasma were 88.5 +/- 11.2 pg/ml, which increased significantly to 332.2 +/- 39.2 pg/ml (p less than 0.001). Free progesterone constituted 53.7% and 41.4% of salivary progesterone during the proliferative and secretory phases, respectively, whereas the corresponding percentages in the plasma were 5.8% and 2.6%. Both plasma and salivary progesterone levels increased in a dose-dependent manner after an intramuscular injection of progesterone, with peak levels being attained from 2 to 3 hours after the injection. Salivary estradiol levels were 5 to 18 and 8 to 35 pg/ml in the proliferative and secretory phases, respectively, but showed no correlation with plasma estradiol levels. The findings are discussed in relationship to the origin of salivary progesterone and the potential use of it as an index of ovulation.     

The evidence for an etiological relationship between oral contraceptive use and dysplastic change in cervical tissue.

A case-control study of 112 patients with cervical intraepithelial neoplasia (CIN) and 131 control subjects was conducted. Estradiol receptor levels were determined in the total (cytosolic-nucleosolic) fraction of the neoplastic cervical specimens taken during the late proliferative phase of their cycle from 58 premenopausal patients who had been oral contraceptive (OC) users for at least 2 years and from 54 premenopausal women who had not been OC users. All specimens contained variable amount of estradiol receptor (from 7.6 to 53.0 fmol estradiol/mg protein and 7.2 to 29.3 fmol estradiol/mg protein in patients who were OC users and non-users, respectively). A significant correlation was found between estradiol receptor concentration and histological grading in both groups, likewise higher levels of estradiol receptor were observed in the low-grade CIN group tissue from patients who were OC users (p < 0.05). At the same time 17 beta-estradiol and progesterone levels were also determined in the serum of all women who had not used an OC for at least 12 months. The mean +/- SD estradiol serum levels in non-users of OC with CIN (0.189 +/- 0.08 ng/ml, follicular phase) were greater than the mean +/- SD (1.163 +/- 0.33 ng/ml, luteal phase) progesterone serum concentration. Serum estradiol levels were significantly higher (p < 0.05) in OC users, whereas progesterone levels were not (p > 0.05). OC users had an increased risk (odds ratio = 1.31, 95% CI 1.0-2.3) of cervical neoplasia.     

Changes in serum sex hormone-binding globulin, free estradiol, and testosterone during gonadotropin treatment

Sex hormone-binding globulin (SHBG), estradiol (E2), percent free E2, percent of E2 bound to SHBG, and testosterone (T) were evaluated in 28 ovulatory women during human menopausal gonadotropin-stimulated cycles for in vitro fertilization. Patients were divided into two categories: low responders, in whom serum E2 concentration reached levels less than 1000 pg/ml (mean, 638 +/- 93), and high responders, with serum E2 levels greater than 1000 pg/ml (mean, 2219 +/- 330). A significant increase in SHBG can occur within a short time in high responders (from 62.8 to 103.9 nmol/l) but not in low responders. This increase is accompanied by a significant decrease in the percent free (bioavailable) E2, but the distribution of E2 between the fraction bound to SHBG or albumin did not vary. Despite the increase in the levels of SHBG, the concentration of bioavailable (free) E2 in hyperstimulated women is higher than in normal cycles. The significant increase in T in high responders, by virtue of its higher affinity for SHBG, probably contributes to the increased levels of bioavailable E2.     

Absorption of oral progesterone is influenced by vehicle and particle size

The oral route of progesterone administration has long been considered impractical because of poor absorption and short biologic half-life. Recent reports suggest that micronization of progesterone enhances absorption and increases serum and tissue levels of progesterone. This study checks serum progesterone levels before and 0.5, 1, 2, 3, 4, and 6 hours after oral administration of 200 mg of progesterone in seven subjects. Progesterone was plain milled, micronized, plain milled in oil, micronized in oil, or micronized in enteric-coated capsules. All patients exhibited a significant increase in serum progesterone levels after oral progesterone administration. Mean peak progesterone levels (30.3 +/- 7.0 ng/ml) (p less than 0.005) were achieved with micronized progesterone in oil at 2.0 +/- 0.3 (p less than 0.05) hours after administration. Four types of oral progesterone had equivalent mean peak elevations and mean times to peak: plain milled, 9.6 +/- 2.5 ng/ml at 4.0 +/- 0.5 hours; micronized 13.2 +/- 2.4 ng/ml at 3.2 +/- 0.4 hours; plain milled in oil, 11.3 +/- 3.0 ng/ml at 4.0 +/- 0.5 hours; and micronized in enteric-coated capsules, 11.2 +/- 3.0 ng/ml at 4.1 +/- 0.7 hours. Contrary to traditional teaching, these data show that significant serum progesterone levels can be achieved by oral administration. Absorption can be significantly improved by the physical characteristics of the progesterone and the vehicle used with oral administration.     

胰岛素样生长因子及胰岛素样生长因子结合蛋白-3与胎儿生长受限的关系

目的　探讨胰岛素样生长因子 (IGF) Ⅰ、IGF Ⅱ和IGF结合蛋白 3(IGFBP 3)与胎儿生长的关系 ,以及IGF在胎儿生长受限 (FGR)发病中的作用。方法　选取 2 0例分娩FGR胎儿 (FGR组 )、10例分娩巨大儿 (巨大儿组 )及 2 0例分娩正常儿 (对照组 )的产妇 ,抽取 3组产妇分娩后肘静脉血及其新生儿脐静脉血 ,分离血清。采用放射免疫法和免疫放射法测定 3组产妇及其新生儿血清中IGF Ⅰ、IGF Ⅱ及IGFBP 3的水平。结果　 (1)FGR组产妇血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为(130 5± 2 6 0 ) μg/L、(2 40± 0 42 ) μg/L及(5 5 79± 848) μg/L ;新生儿脐血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (6 6± 1 7) μg/L、(1 5 4± 0 31) μg/L及 (86 9± 183) μg/L。 (2 )巨大儿组产妇血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (30 9 7± 44 6 ) μg/L、(2 43± 0 2 5 ) μg/L及(5 5 6 2± 742 ) μg/L ;新生儿脐血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (6 9 6± 2 3 9) μg/L、(2 19± 0 2 9) μg/L及(16 82± 130 )μg/L。(3)对照组产妇血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (30 7 9± 70 7) μg/L、(2 41± 0 36 )μg/L及 (5 5 86± 6 78) μg/L ;新生儿脐血清IGF Ⅰ、IGF Ⅱ及IGFBP 3水平分别为 (6 8 9     

Gap junctions and myometrial steroid hormone receptors in pregnant and postpartum rats: a possible cellular basis for the progesterone withdrawal hypothesis

Myometrial gap junctions, levels of cytosol and nuclear estradiol and progesterone receptors, and serum estradiol and progesterone levels were determined simultaneously in pregnant and postpartum rats. Between days 15 to 20 after conception, levels of progesterone nuclear receptors decreased (776.8 +/- 88.5 versus 241.1 +/- 56.5 fmol/mg of DNA, p less than 0.05). The mean serum progesterone also fell by about 50% during this period, but variation in individual levels between days 15 to 20 did not allow for this group to achieve statistical significance until day 21. As the progesterone nuclear receptors decreased, estradiol remained stable, but estradiol nuclear receptors increased (day 21 versus 22: 1710.6 +/- 61.1 versus 3254.8 +/- 203.8 fmol/mg of DNA, p less than 0.05), preceding the increase in gap junctions observed at parturition (day 21 versus 22: 2.0 +/- 0.2 versus 8.0 +/- 3.2 [per 1000 micron plasma membrane], p less than 0.05). Gap junctions fell to prepartum levels by 12 hours, when progesterone nuclear receptors were markedly increasing (6 versus 12 hours post partum: 637.7 +/- 324.8 versus 1509.6 +/- 283.2 fmol/mg of DNA, p less than 0.05). Relationships between gap junctions and cellular estradiol and progesterone nuclear receptors are clearer than could be forecast by circulating hormone measurements alone, and may offer a cellular basis for the role of progesterone in controlling labor.     

Oral contraceptives increase insulin-like growth factor binding protein-1 concentration in women with polycystic ovarian disease.

Insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits IGF actions in vitro. OBJECTIVE: To investigate the effect of oral contraceptive (OC) pills, given for 3 months, on serum gonadotropin, androgen, IGF-I, and IGFBP-1 concentrations, and glucose tolerance in seven women with polycystic ovarian disease (PCOD) and in five healthy control subjects. PATIENTS: Seven women with PCOD and five healthy control subjects. INTERVENTIONS: An oral glucose tolerance test (OGTT) was performed before and after treatment with OC. RESULTS: After treatment with OC, serum luteinizing hormone, androstenedione, and free testosterone levels decreased, and sex hormone-binding globulin concentration increased in the women with PCOD as well as in the control subjects. The cumulative response of serum insulin to OGTT was larger in the women with PCOD than in the control subjects both before and after treatment. Serum IGF-I concentration, which was unchanged during OGTT, decreased from basal level of 326 +/- 70 micrograms/L to 199 +/- 28 micrograms/L after treatment with OC in the women with PCOD, whereas no change was found in the control subjects (from 235 +/- 11 micrograms/L to 226 +/- 11 micrograms/L). Treatment with OC caused an increase of the mean basal IGFBP-1 concentration from 24 +/- 7 micrograms/L to 73 +/- 14 micrograms/L in the women with PCOD. This increase was constant during the OGTT. In the control subjects, treatment with OC did not result in any significant change in IGFBP-1 concentrations (from 44 +/- 11 micrograms/L to 61 +/- 9 micrograms/L). CONCLUSION: The combination of decreased total IGF-I concentration and increased IGFBP-1 concentration induced by OC may decrease ovarian androgen production in PCOD.     

Cyclic changes in serum levels of insulin-like growth factor binding protein-1 in women treated with clomiphene citrate and tamoxifen.

In order to investigate the cyclic changes of serum insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1) and IGFBP-3 levels in menstrual cycles treated with or without antiestrogens (clomiphene citrate and tamoxifen), we treated 24 young women having irregular menstrual cycles with either clomiphene citrate (100 mg/day) (n = 12) or tamoxifen (60 mg/day) (n = 12) from the 5th to the 9th day of the menstrual cycle. Without antiestrogens, 12 women with regular menstrual cycles were recruited as controls. There was a preovulatory (day 13) peak of circulating IGFBP-1 in women treated with or without antiestrogens. A significant concomitant increase in serum estradiol was also observed on day 13 of the menstrual cycle in subjects treated with clomiphene citrate and in controls. However, no significant elevation in preovulatory estradiol was detected in women treated with tamoxifen. In clomiphene citrate and control groups, a significant positive correlation was found between circulating IGFBP-1 and estradiol, and between serum levels of IGFBP-1 and inhibin A at the preovulatory stage (on day 13). In contrast, no such association was observed in the tamoxifen group. Unlike cyclic changes in circulating IGFBP-1, serum concentrations of IGF-I and IGFBP-3 remained unchanged throughout the menstrual cycle in all groups. In conclusion, the preovulatory peak of circulating IGFBP-1 can be induced in cycles treated with both clomiphene citrate and tamoxifen. In addition, a significant positive correlation between estradiol, inhibin A and IGFBP-1 at the preovulatory stage indicates that IGFBP-1 may also reflect follicular development and may further be used as an additional indicator to monitor folliculogenesis under clomiphene citrate treatment.     

Cyclic changes in serum levels of insulin-like growth factor binding protein-1 in women treated with clomiphene citrate and tamoxifen

In order to investigate the cyclic changes of serum insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1) and IGFBP-3 levels in menstrual cycles treated with or without antiestrogens (clomiphene citrate and tamoxifen), we treated 24 young women having irregular menstrual cycles with either clomiphene citrate (100 mg/day) (n = 12) or tamoxifen (60 mg/day) (n = 12) from the 5th to the 9th day of the menstrual cycle. Without antiestrogens, 12 women with regular menstrual cycles were recruited as controls. There was a preovulatory (day 13) peak of circulating IGFBP-1 in women treated with or without antiestrogens. A significant concomitant increase in serum estradiol was also observed on day 13 of the menstrual cycle in subjects treated with clomiphene citrate and in controls. However, no significant elevation in preovulatory estradiol was detected in women treated with tamoxifen. In clomiphene citrate and control groups, a significant positive correlation was found between circulating IGFBP-1 and estradiol, and between serum levels of IGFBP-1 and inhibin A at the preovulatory stage (on day 13). In contrast, no such association was observed in the tamoxifen group. Unlike cyclic changes in circulating IGFBP-1, serum concentrations of IGF-I and IGFBP-3 remained unchanged throughout the menstrual cycle in all groups. In conclusion, the preovulatory peak of circulating IGFBP-1 can be induced in cycles treated with both clomiphene citrate and tamoxifen. In addition, a significant positive correlation between estradiol, inhibin A and IGFBP-1 at the preovulatory stage indicates that IGFBP-1 may also reflect follicular development and may further be used as an additional indicator to monitor folliculogenesis under clomiphene citrate treatment.     

Peritoneal fluid prostaglandins in endometriosis, tubal disorders, and unexplained infertility

To elucidate the roles of prostaglandins in peritoneal fluid and sex steroids in patients with endometriosis (N = 29), tubal disorders (N = 15), and unexplained infertility (N = 13), assays were performed using 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) (a metabolite of prostacyclin), thromboxane B2 (a metabolite of thromboxane A2), estradiol, and progesterone. Women with normal pelvic anatomy (N = 25) served as controls. Peritoneal fluid 6-keto-PGF1 alpha concentrations in patients with endometriosis (742 +/- 104 pg/ml, mean +/- SE), tubal disorders (987 +/- 211 pg/ml), and unexplained infertility (1659 +/- 770 pg/ml) were higher than those in the control women (515 +/- 77 pg/ml). The thromboxane B2 levels in the peritoneal fluid in endometriosis (554 +/- 73 pg/ml), tubal disorders (614 +/- 107 pg/ml), and unexplained infertility (668 +/- 161 pg/ml) were higher than the levels in the control subjects (333 +/- 23 pg/ml). There was no relationship between 6-keto-PGF1 alpha/thromboxane B2 in peritoneal fluid and day of menstrual cycle. The concentrations of estradiol and progesterone were normal in all patient groups and were not related to the 6-keto-PGF1 alpha and thromboxane B2 levels. The authors suggest that these prostanoids, which may contribute to infertility, may originate mainly from the peritoneum as a result of irritation by endometriotic implants, tubal adhesions, and scarring.     

Metformin therapy increases insulin-like growth factor binding protein-1 in hyperinsulinemic women with polycystic ovary syndrome

OBJECTIVES: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism, insulin resistance, compensatory hyperinsulinemia, and increased levels of free insulin-like growth factor-I (IGF-I), presumably due to a decline in IGF binding protein 1 (IGFBP-1). This study was designed to evaluate effects of metformin therapy on serum levels of IGFBP-1 and IGF-I. STUDY DESIGN: Twenty-seven obese, hyperandrogenic PCOS women with elevated fasting insulin were treated for 12 weeks with metformin (500 mg p.o., t.i.d.). Serum levels of insulin, testosterone, sex hormone binding globulin (SHBG), IGF-I, and IGFBP-1 were measured before and after treatment. Body mass index (BMI) and waist-to-hip ratio (WHR) were assessed at baseline and at the end of therapy. RESULTS: Metformin therapy significantly increased IGFBP-1 concentration by 38% (P = 0.05) but had no demonstrable effect on the total IGF-I levels. Fasting insulin levels declined by 38% (P = 0.0001) while the glucose/insulin ratio increased by 72% (P = 0.0001) and quantitative insulin sensitivity check index (QUICKI) increased by 8% (P = 0.0001). Metformin treatment also significantly decreased testosterone (by 37%, P = 0.0001) and increased SHBG concentration (by 16%, P = 0.04). Multiple linear regression analysis revealed that baseline IGFBP-1 levels correlated inversely and independently with two baseline parameters: WHR (P = 0.003) and free testosterone index (P = 0.04). CONCLUSIONS: The present study shows that metformin therapy not only restores normal levels of insulin and testosterone, but also decreases the pool of free-bioactive IGF-I by increasing the levels of circulating IGFBP-1. We provide further arguments in favor of metformin therapy in hyperinsulinemic women with PCOS.     

Synergistic effect of relaxin and progesterone on cyclic adenosine 3',5'-monophosphate levels in the rat uterus

Cyclic adenosine 3',5'-monophosphate is known to modulate smooth muscle contractility. Because both relaxin and progesterone have been demonstrated to affect myometrial cyclic adenosine monophosphate activity, we questioned whether the previously observed synergism of these two hormones in inhibiting uterine contractility is mediated via cyclic adenosine monophosphate. Immature rats were treated with estradiol benzoate (n = 7) or a combination of estradiol benzoate and progesterone (n = 7). Uterine horns were isolated, each horn was divided into two segments, and these horn segments were incubated in Ringer-Locke solution, either alone (control) or with 3-isobutyl-1-methylxanthine (MIX) 0.5 mM, MIX 0.5 mM + relaxin 10 ng/ml, or MIX 0.5 mM + relaxin 50 ng/ml. When compared with uterine segments incubated in MIX alone, treatment with MIX + relaxin 50 ng/ml significantly increased cyclic adenosine monophosphate levels in animals treated with estradiol benzoate alone or in combination with progesterone. Relaxin 10 ng/ml was sufficient to significantly elevate mean (+/- SEM) uterine cyclic adenosine monophosphate levels above that of control MIX-treated uteri in animals receiving both estradiol benzoate and progesterone (2.49 +/- 0.39 pm/micrograms deoxyribonucleic acid [DNA] versus 1.08 +/- 0.16 pm/microgram DNA, p less than 0.05) but not in animals receiving estradiol benzoate alone (2.08 +/- 0.32 pm/micrograms DNA versus 1.28 +/- 0.16 pm/micrograms DNA, NS). Compared with treatment with MIX only, MIX + relaxin 10 ng/ml and MIX + relaxin 50 ng/ml produced greater increases in uterine cyclic adenosine monophosphate in the steroid combination group than in the estradiol benzoate controls (144.8% and 233.7% versus 71.7% and 156.6%, respectively). These results suggest that the synergism of relaxin and progesterone in inhibiting uterine contractility may be mediated by intracellular cyclic adenosine monophosphate.     

瘦素调节人卵巢黄素化颗粒细胞功能的体外研究

目的　探讨瘦素、促卵泡激素 (FSH)和胰岛素样生长因子Ⅰ (IGF Ⅰ )对人卵巢黄素化颗粒细胞雌二醇 (E2 )、孕酮 (P)生成的影响及可能的作用机制。方法　培养人黄素化颗粒细胞 ,分别以瘦素 (3 0ng/ml)、FSH (1 0ng/ml)、IGF Ⅰ (30 0ng/ml)以及相同终浓度的瘦素 +FSH、瘦素 +IGF Ⅰ、FSH +IGF Ⅰ、瘦素 +FSH +IGF Ⅰ对其刺激 2 4h ,对照组不加任何药物。对药物作用后的黄素化颗粒细胞行形态学观察、细胞计数 ;用放射免疫法检测培养液中E2 和P水平 ;同时用逆转录聚合酶链反应法对黄素化颗粒细胞行瘦素受体mRNA检测。结果　瘦素、FSH和IGF Ⅰ对黄素化颗粒细胞生长无影响。瘦素对黄素化颗粒细胞E2 生成量无影响 ,对FSH刺激E2 的生成也无影响 ,E2 水平作用前分别为 (0 10 3± 0 0 36 )pmol/10 0 0细胞、(0 32 3± 0 0 4 2 )pmol/10 0 0细胞 ,作用后分别为 (0 12 0± 0 0 0 8)pmol/10 0 0细胞、(0 343± 0 0 34)pmol/10 0 0细胞 ;而对IGF Ⅰ、FSH +IGF Ⅰ刺激黄素化颗粒细胞生成E2 有显著的抑制作用 ,E2 水平作用前后分别为 (0 318± 0 0 37)pmol/10 0 0细胞与 (0 4 93± 0 0 36 )pmol/10 0 0细胞、(0 193± 0 0 2 5 )pmol/10 0 0细胞与 (0 2 5 1± 0 0 33)pmol/10 0 0细胞 (P <0 0 5 ,<0     

Serum levels and molecular sizes of growth hormone during pregnancy in relation to levels of lactogens, insulin-like growth factor I and insulin-like growth factor binding protein-1.

Growth hormone (GH), placental lactogen (PL), prolactin (PRL), insulin-like growth factor I (IGF-I) and IGF binding protein-1 (IGFBP-1) were determined in serum by radioimmunoassays (RIAs) in 12 women during pregnancy. GH and PL were analyzed by two monoclonal antibodies (Mab 3 and Mab 1) raised against pituitary GH. Serum IGFBP-1 had reached maximum levels at midpregnancy while PRL, PL and IGF-I increased continuously during pregnancy. Mab 1, which cross-reacts with PL, measured consistently higher levels of PL in serum than a commercial PL RIA (p less than 0.01) due to interference of cross-reacting serum proteins in the Mab 1 RIA. The GH-specific Mab 3 showed decreasing GH levels in unfractionated serum throughout gestation, but detected GH-immunoreactive proteins of approximately 40-200 kD after molecular sieve chromatography of pooled serum from late pregnancy. It is suggested that the formation of GH complexes of large molecular mass account for the successive disappearance of monomeric GH during pregnancy.     

Effect of clomiphene citrate treatment on endometrial estrogen and progesterone receptor induction in women

A direct adverse effect of clomiphene citrate on the endometrium has been presumed, and interference with estrogen receptor-mediated endometrial estrogen receptor and progesterone receptor induction has been implicated as the mechanism responsible for an increased incidence of luteal phase deficiency in association with clomiphene citrate treatment. To clarify the net influence of clomiphene administration on endometrial steroid receptor induction, we studied five normal ovulatory women, in both a spontaneous and clomiphene-induced (150 mg/day, cycle days 5 to 9) ovulatory cycle. From cycle day 11 blood samples were obtained daily and urinary luteinizing hormone determinations were performed twice daily. Endometrial biopsy was performed on the day of the urinary luteinizing hormone surge and again 13 days after the surge. Serum levels of follicle-stimulating hormone and luteinizing hormone were determined by immunoradiometric assay, estradiol and progesterone by radioimmunoassay, and clomiphene citrate isomer concentrations in treatment cycles by reversed-phase high-performance liquid chromatography and fluorescence detection. Total, cytosolic, and salt-extracted nuclear endometrial estrogen receptor and progesterone receptor concentrations were determined by enzyme-linked immunoassay. Serum estradiol was threefold to fivefold higher (p less than 0.05) in clomiphene-induced than in spontaneous cycles 8 and 10 days before the luteinizing hormone surge, and progesterone was increased (p less than 0.05) from the day of the surge to end of the cycle. Serum enclomiphene rose to plateau between 12 and 6 days before the luteinizing hormone surge (4.1 +/- 0.8 ng/ml, mean +/- SE, n = 19) and fell thereafter to less than 1.0 ng/ml. Zuclomiphene levels increased rapidly between 14 and 8 days before the surge (53.9 +/- 2.8 ng/ml, mean +/- SE, n = 5) and then decreased gradually but remained elevated throughout the luteal phase (29.0 +/- 1.2 ng/ml, mean +/- SE, n = 33). Late luteal endometrial histology was abnormal in one of four available treatment cycle specimens, but the endocrine characteristics and number and subcellular distribution of estrogen receptor and progesterone receptor in the abnormal cycle were not different from those of normal, in-phase cycles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fasting serum growth hormone and insulin-like growth factor-I and -II concentrations in women with leiomyomata uteri treated with leuprolide acetate or placebo

Eighteen patients with leiomyomata uteri were randomized to receive either leuprolide acetate depot (n = 9) 3.75 mg intramuscularly (IM) or placebo (n = 9) IM every 4 weeks for four injections. Leuprolide acetate treated patients demonstrated a reduction in mean uterine volume of 34% and a decrease in serum estradiol (E2) concentrations from 120 +/- 21 pg/mL (mean +/- standard error) to 16 +/- 9 pg/mL. Leuprolide acetate treated patients also demonstrated significant decreases in serum growth hormone (GH) (3.0 +/- 0.4 ng/mL versus 1.4 +/- 0.4 ng/mL) and insulin-like growth factor-I (IGF-I) concentrations (3.3 +/- 0.4 U/mL versus 1.3 +/- 0.2 U/mL) over the 12 week treatment period. Serum IGF-II levels did not change. Mean uterine volume and serum E2, GH, IGF-I, and IGF-II concentrations did not change in placebo-treated patients. These data suggest that hypoestrogenism is associated with decreases in circulating GH and IGF-I.     

Ovulation induction increases serum levels of insulin-like growth factor binding protein 1.

The effect of ovulation induction on serum insulin-like growth factor binding protein 1 (IGFBP-1) level in relation to sex hormone binding globulin (SHBG) levels was evaluated. Serum samples were collected 8 to 12 days after ovulation from 26 women undergoing ovulation induction with clomiphene citrate (CC), and from 58 women treated with CC in combination with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). In addition, serum samples were obtained from 63 spontaneously ovulating women and from 12 women during an anovulatory cycle. Luteal phase serum IGFBP-1 levels were 4.22 +/- 2.95 micrograms/L (P less than .05) in the CC group and 7.31 +/- 6.13 micrograms/L (P less than .001) in the CC/hMG/hCG group as compared to unstimulated ovulatory cycles (2.64 +/- 2.52 micrograms/L). No significant difference in IGFBP-1 levels was seen between spontaneously ovulatory and anovulatory cycles. The serum IGFBP-1 levels correlated positively to SHBG levels (r = .52, P less than .001). The data show that ovulation induction increases serum IGFBP-1 levels in parallel to SHBG levels, indicating that ovarian stimulation, which results in increased steroid hormone production, also induces changes in other factors known to modulate steroid hormone actions.     

Maternal zinc and cord blood zinc, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 levels in small-for-gestational-age newborns

PURPOSE: To determine the relationship between maternal serum zinc (Zn) levels and birth weight of the offspring and their correlation with cord blood Zn, insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) levels. METHOD: 22 term small-for-gestational-age (SGA) and 34 term appropriate-for-gestational-age (AGA) infants and their mothers were included. Maternal and cord blood Zn levels and cord blood IGF-1 and IGFBP-3 levels were measured. RESULTS: Eighteen percent of mothers had Zn deficiency (< 75 mcg/dl). No significant difference between IGF-1 and IGFBP-3 levels and birth weight of infants of the mothers with and without Zn deficiency was found. Maternal and neonatal Zn levels correlated (r = 0.38, p < 0.01). Mean IGF-1 and IGFBP-3 levels were significantly lower in the SGA group compared to the AGA group (42.3 +/- 16.8 ng/ml, 1.2 +/- 0.2 mcg/ml, and 62.4 +/- 22.7 ng/ml, 1.5 +/- 0.4 mcg/ml, p < 0.001). A correlation was found between birth weight, IGF-1 and IGFBP-3 levels, and weight gain of the mother during pregnancy (p < 0.01). CONCLUSIONS: Zn deficiency was not observed to be a risk factor for low birth weight. The significant difference between the SGA and AGA babies' IGF-1 and IGFBP-3 levels emphasizes function of the IGF system in intrauterine growth.