Human chorionic gonadotropin reduces aromatizable androgens and aromatase activity in women stimulated by clomiphene citrate and human menopausal gonadotropin

Periovulatory steroidal dynamics in women undergoing ovulation induction with clomiphene citrate and human menopausal gonadotropin were studied in 31 women with tubal blockage. Serum estradiol levels were significantly reduced 36 hours after human chorionic gonadotropin administration (from 1792 +/- 162 to 926 +/- 132 pg/ml, p less than 0.001). Peripheral levels of testosterone and androstenedione did not change during this periovulatory time. Progesterone and 17 alpha-hydroxyprogesterone, as anticipated, significantly increased with an early rise noted within the first 8 hours of human chorionic gonadotropin administration (p less than 0.001). A significant reduction of the ratios of the steroidal pairs 17 alpha-hydroxyprogesterone-progesterone (17 alpha-hydroxylase) and androstenedione-17 alpha-hydroxyprogesterone (17,20-desmolase) was observed after human chorionic gonadotropin injection (p less than 0.001). Aromatase activity appeared to be inhibited because of a significant reduction in the estradiol/testosterone ratio 34 to 36 hours after human chorionic gonadotropin administration. Thus human chorionic gonadotropin, which triggers ovulation in women treated by clomiphene citrate-human menopausal gonadotropin, appears to partially reduce aromatizable substrate as well as inhibit aromatase activity.     

Accelerated starvation in late pregnancy: a comparison between obese women with and without gestational diabetes mellitus

We compared the glucose, insulin, free fatty acid, and 3-hydroxybutyrate responses to a briefly extended overnight fast during the third trimester of pregnancy between two groups: obese women with normal glucose tolerance (n = 10) and age- and weight-matched women with gestational diabetes mellitus (n = 10). After a 12-hour overnight fast, plasma glucose (95 +/- 4 vs. 78 +/- 2 mg/dl; p less than 0.01), insulin (32 +/- 5 vs. 17 +/- 2 microU/ml; p less than 0.02), and free fatty acid (860 +/- 63 vs. 639 +/- 79 mmol/L; p less than 0.05) levels were higher in the patients with gestational diabetes mellitus. 3-Hydroxybutyrate levels were similar in the two groups at that time (0.23 +/- 0.04 vs. 0.18 +/- 0.03 mmol/L; p greater than 0.3). When the fast was extended to 18 hours by having the patients skip breakfast, glucose levels fell more rapidly in the group with gestational diabetes mellitus but remained elevated compared with the nondiabetic women. Insulin levels declined at a similar rate in the two groups. Free fatty acid levels did not increase significantly in the group with gestational diabetes mellitus during the extended fast. In contrast, free fatty acid levels increased by 44% in the normal pregnant women, reaching the level observed in the group with gestational diabetes mellitus after 18 hours. 3-Hydroxybutyrate levels remained virtually identical in the two groups throughout the brief fast. Thus, compared with that of normal pregnant women, the response of obese women with gestational diabetes mellitus to brief caloric deprivation during late pregnancy was characterized by a greater fall in plasma glucose values without a greater propensity to ketosis. Our findings may have important implications for the dietary management of obese patients with gestational diabetes mellitus.     

Hyperinsulinemia in hyperthecosis of the ovaries

Fasting insulin concentrations and the insulin response to an oral glucose tolerance test were measured in six virilized women with ovarian hyperthecosis and six weight-matched normal women. For comparison, six women with polycystic ovarian disease were also studied. The diagnosis of hyperthecosis was confirmed in all six virilized women by histologic examination of the ovaries. The fasting insulin concentrations were increased in all of the hyperthecosis patients (84 +/- 32 microU/ml). Insulin response to an oral glucose tolerance test was greatly increased (p less than 0.01) in comparison to normal women and women with polycystic ovarian disease. Significant positive correlations were found between peripheral insulin concentrations and ovarian vein testosterone (r = 0.879, p less than 0.02), dihydrotestosterone (r = 0.866, p less than 0.03), and androstenedione (r = 0.992, p less than 0.01) levels. Insulin resistance persisted after removal of the ovaries even though androgen levels returned to normal. These results suggest that a significant degree of insulin resistance exists in women with hyperthecosis and that insulin stimulates ovarian stromal androgen synthesis and thus may play a role in the pathogenesis of ovarian hyperthecosis.     

Clinical, immunologic, and genetic definitions of primary and secondary recurrent spontaneous abortions

Follicular fluid was obtained from anovulatory patients (n = 12), stimulated with human menopausal gonadotropin, clomiphene, and human chorionic gonadotropin to evaluate the relative responses of inhibin, follicle regulatory protein, and steroid levels in follicles from ovaries requiring exogenous stimulation for follicular development. Follicular fluid concentrations of estradiol, progesterone, androstenedione, testosterone, dihydrotestosterone, and 3 alpha-androstenediol were determined by radioimmunoassay. Follicular fluid inhibin activity was determined by suppression of rat pituicyte follicle-stimulating hormone, and follicle regulatory protein activity was determined by suppression of porcine granulosa cell aromatase. The mean level of steroids were progesterone (7529 +/- 1601 ng/ml), estradiol (1082 +/- 158 ng/ml), androstenedione (15.2 +/- 3.17 ng/ml), 3 alpha-androstenediol (0.90 +/- 0.13 ng/ml), testosterone (2.23 +/- 33 ng/ml), and dihydrotestosterone (0.77 +/- 0.11 ng/ml). Follicle regulatory protein activity was 16.6% +/- 4.3% and mean inhibin level was 62.9 +/- 7.52 U. These results are in contrast to reports of follicular fluid steroid levels from normal ovulatory patients treated with exogenous gonadotropin. Although altered levels of hormones were present within these follicles, they clearly were not atretic, as evidenced by elevated estradiol levels and estradiol/androstenedione ratios. Alterations in the normal follicular response to pharmacologic gonadotropin stimulation in the follicles of anovulatory women suggest the presence of granulosa cell dysynchrony .     

Acute modulation of the hypothalamic-pituitary axis by intravenous testosterone in normal women

Intravenous testosterone was infused for 6 hours in 23 ovulatory women, divided into five groups according to dose, to assess the effects of testosterone on gonadotropin secretion. Serum testosterone increased from 0.24 +/- 0.08 to steady-state levels of 1.63 +/- 0.18 ng/ml in the lowest-dose group (1) and to 42.1 +/- 3.3 ng/ml in the highest-dose group (4). In another group (5), patients were pretreated with testolactone, which prevented the estradiol rise associated with testosterone infusion. All groups except group 1 exhibited significant reductions in the delta maximum responses of luteinizing hormone to gonadotropin-releasing hormone during testosterone infusion compared with pretreatment levels (p less than 0.01). This was also evident for the testolactone group (5). There were no observed changes in serum follicle-stimulating hormone. Luteinizing hormone pulse frequency was decreased (p less than 0.05) with testosterone concentrations of 27.2 +/- 0.77 and 42.1 +/- 3.3 ng/ml (groups 3 and 4), but only in the highest group (4) was there a decrease in pulse amplitude (p less than 0.05). No luteinizing hormone pulse changes were observed with lower concentrations of testosterone. Plasma immunoreactive gonadotropin-releasing hormone levels remained undetectable or low in some of the groups sampled. These data suggest that short-term infusions of testosterone inhibit hypothalamic-pituitary function of normal women when high doses are used, and this effect may be independent of aromatization to estrogen.     

Chorionic gonadotropin receptors and immunoreactive chorionic gonadotropin in implantation of the rabbit blastocyst

To determine the temporal relationship between immunoreactive chorionic gonadotropin, chorionic gonadotropin receptors, and implantation of the rabbit blastocyst, (1) immunoreactive chorionic gonadotropin in plasma, uterine flushings and blastocysts; (2) chorionic gonadotropin receptors on blastocysts (day 5 and 6) and embryonic and interembryonic segments of the uterus (day 7); and (3) chorionic gonadotropin receptors on the endometrium and myometrium (day 1 through 6) were measured. Binding of I125-labeled beta-subunit of human chorionic gonadotropin (hCG) by cell membranes from blastocysts increased significantly from 6.0 +/- 1.1 fmol/mg of protein (mean +/- SE) on day 5 (N = 6) to 16.1 +/- 1.3 fmol/mg of protein on day 6 (n = 6) (P less than 0.001). Immunoreactive chorionic gonadotropin levels in blastocyst fluid increased from 0.3 ng/ml of day 5 to 0.65 ng/ml on day 6. Specific binding of I125-labeled hCG was absent in endometrial and myometrial cell membranes before implantation (days 1 to 6) but was found in decidual cells from embryonic segments on day 7. Plasma immunoreactive chorionic gonadotropin or chorionic gonadotropin--like material increased from 6 ng/ml of day 1 to 52 ng/ml on day 7. Uterine flushings had chorionic gonadotropin levels of 0.4 ng/ml of day 2, which increased slowly to 1.0 ng/ml on day 7. Intrauterine instillation of hCG into nonpregnant uterine horns demonstrated transuterine absorption of hCG with plasma hCG levels showing a dose-related response. Our findings demonstrate that (1) immunoreactive chorionic gonadotropin or chorionic gonadotropin--like material is detectable in plasma, uterine flushings, and blastocyst fluid before implantation, (2) chorionic gonadotropin receptors are present on the blastocyst cells before implantation, and (3) the uterus can absorb chorionic gonadotropin from its lumen.     

Sonographic parameters and hormonal status in lean and obese women with polycystic ovary syndrome

A total of 34 patients with the diagnosis of polycystic ovary syndrome (PCOS) were recruited for this study. Weight distribution in lean PCOS women (n = 17) was 93.5% to 110.5% of normal weight for height and age. In obese women (n = 17) this distribution was 119.5 to 146.5%. Serum testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), delta 4-androstendione (delta 4-A), sex hormone binding globulin, (SHBG), 17-hydroxyprogesterone (17-OH PRG), 17b oestradiol (17b-E2), cortisol (CORT), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) and insulin (INS) were measured. Serum SHBG levels were lower in obese PCOS women (72.9 +/- 16.2 nmol/l) than in lean PCOS women (99.6 +/- 10.5) (p < 0.001). Fasting insulin levels were higher in obese PCOS women (30.4 +/- 4.5 mUI/ml) than in lean PCOS women (14.2 +/- 7.6 mUI/ml) (p < 0.001). Mean ovarian volume did not differ significantly between lean and obese PCOS women (12.5 +/- 3.7 ml vs 16.1 +/- 5.3, p > 0.5). Endometrial thickness was roughly similar between the two groups. Endometrial surface area in lean PCOS women (7.6 +/- 2.2 cm2) was lower than in obese PCOS women (10.1 +/- 1.9 cm2) and the difference was significant (p < 0.01).     

Differing concentrations of human chorionic gonadotropin and prolactin in the cyst fluid of hydatidiform mole and in amniotic fluid

The concentrations of human chorionic gonadotropin and prolactin in the cyst fluid of molar tissue were compared with that of normal amniotic fluid. Molar fluid was aspirated from the vesicles of molar tissue in eight women (duration of amenorrhea 14.1 +/- 1 week, mean +/- SEM). Amniotic fluid was obtained at amniocentesis in 24 women (mean duration of amenorrhea 15.9 +/- 0.2 week). Hormones were measured by specific radioimmunoassay. The concentrations (mean +/- SEM) of human chorionic gonadotropin in molar fluid and amniotic fluid were 581,829 +/- 112,581 and 3187 +/- 505 mlU/ml (p less than 0.001), respectively. For prolactin the levels in molar fluid and amniotic fluid were 44 +/- 24 and 1962 +/- 313 ng/ml (p less than 0.001), respectively. These data demonstrate that molar fluid contains 182-fold higher levels of human chorionic gonadotropin and 45-fold lower levels of prolactin than amniotic fluid obtained from normal pregnant women with a similar duration of amenorrhea. In addition to altered endocrine function of the trophoblast, there may be altered prolactin secretion from the decidua in molar pregnancy as compared with normal pregnancy. Further research is required to evaluate prolactin production from decidua of molar pregnancy.     

C-peptide and insulin levels at 24-30 weeks' gestation: an increased risk of adverse pregnancy outcomes?

OBJECTIVE: The hypothesis was that fasting C-peptide and insulin values, during an oral glucose tolerance test (OGTT), might allow an estimation of the increased risk for gestational hypertension (GH) and fetal macrosomia. STUDY DESIGN: Two-hundred and six consecutive patients were submitted to an OGTT. Thirty-five developed gestational hypertension and 29 delivered large-for-gestational-age (LGA) newborns. Plasma glucose levels (mg/dl) and insulin levels (microU/ml) were measured fasting and after 60, 120 and 180 min C-peptide fasting levels (ng/ml) were also measured. RESULTS: Twenty-five patients were excluded, 181 were enrolled. According to the OGTT, 143 patients were classified as normal, 26 were found affected by gestational diabetes (GD) mellitus, and 12 had impaired gestational glucose tolerance (IGGT). Hypertensive women exhibited higher 60 and 120 min insulin values than the normotensive group (128.3+/-69.9 microU/ml versus 86.2+/-58.3 microU/ml, P<0.05; 104.9+/-66.4 microU/ml versus 78.7+/-56.5 microU/ml, P<0.05).C-peptide cut-off at 2.9 ng/ml resulted predictive for patients delivering large-for-gestational-age newborns (OR=3.42, 95% CI=1.59-7.39). CONCLUSIONS: C-peptide and insulin may be used as indicators of risk for the development of complications in late pregnancy.     

Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin

OBJECTIVE: To determine the clinical, hormonal, and biochemical effects of metformin therapy in obese and nonobese patients with polycystic ovary syndrome (PCOS). DESIGN: Controlled clinical study. SETTING: Department of Gynecology of Federal University of S?o Paulo, S?o Paulo, Brazil. PATIENT(S): Twenty-nine patients with PCOS. INTERVENTION(S): Patients were treated with 500 mg of p.o. metformin t.i.d. for 6 months. MAIN OUTCOME MEASURE(S): Clinical data as well as serum concentrations of sex steroids, sex hormone-binding globulin (SHBG), gonadotropins, leptin, GH, lipids, insulin, and glucose levels were assessed before and after treatment. RESULT(S): In the metformin group of nonobese patients, the mean fasting serum insulin concentration decreased from a pretreatment value of 12.1 +/- 2.4 to 6.3 +/- 0.6 microU/mL after treatment, and the area under the curve of insulin decreased from 5,189.1 +/- 517.4 to 3,035.6 +/- 208.9 microU/mL per minute. Also in the metformin group of nonobese patients, the mean basal serum total testosterone, free testosterone, and androstenedione concentrations decreased by 38%, 58%, and 30%, respectively. In the obese patients treated with metformin, only free testosterone showed a statistically significant decrease (1.7 +/- 0.2). CONCLUSION(S): Our data suggest that nonobese patients respond better than obese patients to a 1.5 g/day metformin regimen.     

Menstrual cyclicity has a profound effect on glucose homeostasis

Results from oral glucose tolerance tests have frequently demonstrated a deterioration in glucose metabolism during the luteal phase of the menstrual cycle. To examine this issue further, eight women underwent both midfollicular (days 3 to 10) and midluteal (days 20 to 25) phase hyperglycemic clamp studies (+125 mg glucose/dl) after an overnight fast. Glucose levels rose from 83 +/- 1 to 207 +/- 2 and 87 +/- 1 to 207 +/- 2 mg/dl, respectively, during the follicular and luteal phases. The basal (6 +/- 1 versus 7 +/- 1 microU/ml) and glucose-stimulated (42 +/- 5 versus 43 +/- 6 microU/ml) insulin responses were similar in the follicular and luteal studies. However, glucose uptake was significantly higher during the follicular versus the luteal phase (10.99 +/- 0.97 versus 6.93 +/- 0.37 mg/kg-min; P less than 0.01), as was the ratio of glucose uptake to insulin concentration (30.0 +/- 5.5 versus 19.7 +/- 3.7, P less than 0.01). The authors conclude that: (1) Glucose metabolism is impaired in the luteal phase of the menstrual cycle; (2) This defect cannot be explained by differences in the plasma insulin response; and (3) This impairment in the ability to promote glucose uptake under hyperglycemic conditions suggests a defect in the mass action effect of glucose per se.     

Dynamics of human chorionic gonadotropin, prolactin, and growth hormone in serum and amniotic fluid throughout normal human pregnancy

This study was performed to establish the dynamics of human chorionic gonadotropin, prolactin, and growth hormone throughout pregnancy in serum and amniotic fluid. Two hundred fifty healthy women at 8 to 42 weeks' gestation were studied. The highest serum human chorionic gonadotropin level was measured between weeks 8 to 12 (53,715 +/- 3574 mIU/ml, mean +/- SEM), with a decline to a mean plateau of 11,806 +/- 1250 mIU/ml from week 18. Amniotic fluid human chorionic gonadotropin had a similar pattern with a mean of 68,100 +/- 8422 mIU/ml at weeks 8 to 10, declining from week 18 to a plateau of 2005 +/- 260 mIU/ml. Human chorionic gonadotropin showed a significant correlation (r = 0.85, p less than 0.001) between levels of both compartments demonstrating an even distribution. Prolactin levels showed a dichotomy of patterns and levels. Serum prolactin showed a continuous rise from 45.3 +/- 14 ng/ml at week 8 to 224 +/- 20 ng/ml at week 36. In contrast, amniotic fluid prolactin remained low until week 14 (33.1 +/- 0.8 ng/ml), followed by a sharp and significant (p less than 0.001) increase to a plateau of 3750 +/- 200 ng/ml between weeks 18 to 26, declining to a second plateau of 500 +/- 50 ng/ml at week 36. Serum growth hormone increased from a mean of 3.5 +/- 1.4 ng/ml seen at weeks 8 to 10 to a mean of 14 +/- 2.0 ng/ml at weeks 28 to 30, followed by a plateau of similar levels. The pattern of growth hormone secretion in amniotic fluid demonstrated a sharp increase during the 14-16 interval with a maximum mean level of 15.5 +/- 1.5 ng/ml and a slow steady decline thereafter. In conclusion, the similar pattern and concentration of human chorionic gonadotropin throughout pregnancy in both maternal and amniotic fluid are probably the result of direct human chorionic gonadotropin diffusion from the placenta. The dissimilar pattern and concentration of prolactin are the result of two different sources of prolactin secretion during pregnancy. Serum prolactin originates from the pituitary and amniotic fluid prolactin from the decidua. Since the pattern of growth hormone secretion resembles that of prolactin, it is possible that growth hormone, like prolactin, is secreted by the same sources.     

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.     

Vasopressin levels during pregnancy and labor

Baseline plasma vasopressin concentrations were measured in 10 healthy women during a normal menstrual cycle, 97 normal women during pregnancy and 43 pregnant women hospitalized during the third trimester because of pregnancy-induced hypertension (PIH). Plasma vasopressin levels were also measured in 44 normal pregnant women in early labor and in 30 parturients at delivery. The random plasma vasopressin concentrations did not vary significantly between the nonpregnant women during the follicular phase (2.3 +/- 0.2 microU/ml) and luteal phase (2.2 +/- 0.3 microU/ml) or during the third trimester in normal pregnant women (2.0 +/- 0.2 microU/ml) or those with PIH (2.0 +/- 0.1 microU/ml). There was a significant reduction (p less than 0.01) in plasma vasopressin levels in the pregnant women during the first trimester (1.5 +/- 0.1 microU/ml) and second trimester (1.5 +/- 0.1 microU/ml) as compared to levels in nonpregnant and pregnant women in the third trimester. The mean plasma vasopressin levels in the pregnant women complaining of nausea were similar to those in the pregnant women without nausea. Plasma vasopressin levels in women during labor did not increase significantly over third-trimester-pregnancy concentrations during the first stage of labor (1.9 +/- 0.1 microU/ml) or at delivery (1.8 +/- 0.1 microU/ml). These cross-sectional measurements of maternal plasma vasopressin levels do not support a role for vasopressin in the development of PIH or in the initiation or maintenance of labor.     

Androgenic response in anovulatory women during menotropins stimulation

Menotropins (human menopausal gonadotropin [hMG]) are used to induce follicular maturation and ovulation in anovulatory infertile women. To determine how hMG stimulation affected ovarian androgen production during such therapy, plasma androstenedione (A) and testosterone (T) levels were measured at the beginning and end of hMG therapy in 5 patients with anovulatory hypogonadotropism (group 1) and 15 patients with anovulatory polycystic ovary syndrome (group 2). Mean pretreatment levels of plasma estradiol (E2), T, and A were significantly higher in group 2 compared with group 1. Stimulation with hMG caused E2 levels to reach the same maximum value in both groups. Testosterone levels increased from 0.2 +/- 0.03 ng/ml (mean /+- SE) to 0.4 %/- 0.038 ng/ml for group 1 patients, and from 0.53 +/- 0.06 ng/ml to 0.8 +/- 0.1 ng/ml for group 2 patients. Androstenedione levels increased from 1.5 +/- 0.47 ng/ml to 2.1 +/- 0.4 ng/ml and from 4.37 +/- 0.77 ng/ml to 5.8 +/- 1.1 ng/ml in groups 1 and 2, respectively. The influence of hMG on plasma androgen levels was studied in women who received several treatment cycles before they became pregnant. In these women plasma androgen levels reached the same values in all cycles, including the final cycle in which the patient became pregnant. The data indicate that patients treated with hMG become pregnant despite marked gonadal androgen production. These observations suggest that hMG therapy promotes steroidogenesis in both the granulosa and theca cells of the follicle.     

Body weight, hyperinsulinemia, and gonadotropin levels in the polycystic ovarian syndrome: evidence of two distinct populations.

OBJECTIVE: To investigate the impact of body weight (BW) and insulin levels on gonadotropin and androgen levels in women with the polycystic ovarian syndrome (PCOS). DESIGN: Comparative study of endocrinologic parameters in PCOS women. SETTING: University Hospital Reproductive Endocrinology Unit. PATIENTS: Thirty obese and 19 nonobese women with PCOS. Seven obese and 7 nonobese normal women. MAIN OUTCOME MEASURES: Serum concentrations of insulin, testosterone, androstenedione, luteinizing hormone (LH), follicle-stimulating hormone. Serum LH response to gonadotropin-releasing hormone (GnRH) administration and assessment of insulin resistance by the continuous infusion of glucose with model assessment (CIGMA) test. RESULTS: Fasting insulin levels correlated with body mass index (BMI). Basal LH levels correlated inversely with BMI. Nonobese women with PCOS had a higher LH response to GnRH than obese women with PCOS. Only obese women with PCOS showed insulin resistance and fasting hyperinsulinemia. CONCLUSIONS: The data suggest that women with PCOS may be divided into two subgroups: those with obesity, insulin resistance, hyperinsulinemia, and normal/minimally elevated LH levels and those with normal BW, elevated LH levels, and normoinsulinemia.     

Influence of obesity and menopausal status on serum leptin, cholecystokinin, galanin and neuropeptide Y levels.

Obesity occurs in 60% of women after menopause and is characterized by an excess of adipose tissue that depends on several orexigenic (neuropeptide Y (NPY) stimulates carbohydrate ingestion, galanin stimulates fat intake) and anorectic (leptin, cholecystokinin (CCK)) factors. Both leptin and insulin can reduce hypothalamic NPY production and secretion. Behavior related to the consumption of food is probably attributed to the NPY-galanin signalling route. We investigated basal levels of serum leptin, CCK, galanin and NPY in 16 non-obese premenopausal women, in 15 obese premenopausal women (body mass index (BMI) 34.6 +/- 1.3 SD) and in ten obese postmenopausal women (BMI 34.7 +/- 1.5 SD) to determine the relationship between obesity, menopause and these neuropeptides. Obese premenopausal women had three-fold elevations of serum leptin (32.1 +/- 3.2 ng/ml) in comparison to non-obese premenopausal women (10.3 +/- 1.5 ng/ml), but similar levels to those in obese postmenopausal women (35.3 +/- 4.1 ng/ml). In all 44 patients and in both sub-groups of premenopausal and postmenopausal women, serum leptin exhibited a strong positive correlation with BMI (r = 0.8692, p < 0.0001; r = 0.8803, p = 0.0001; r = 0.8184, p = 0.0001, respectively). Serum galanin values showed a statistically significant increment in the obese postmenopausal group (51.1 +/- 8.1 pg/ml) compared to both premenopausal groups: the non-obese (34.9 +/- 5.8 pg/ml) and the obese (36.0 +/- 5.5 pg/ml). Non-obese menstruating women demonstrated NPY levels (175.0 +/- 12.8 pg/ml) significantly higher than those of obese premenopausal women (126.0 +/- 12.1 pg/ml) and obese postmenopausal women (138.1 +/- 15.4 pg/ml). CCK values showed no differences between non-obese and obese pre- and postmenopausal groups. Basal insulin values were elevated in both obese groups compared to non-obese premenopausal women. Significantly increased leptin and galanin levels in postmenopausal obese women coupled with decreased NPY levels revealed some changes in the neuropeptides regulating eating behavior, which may be the reason for the onset of postmenopausal obesity.     

Successful induction of ovulation and conception with pulsatile intravenous administration of human menopausal gonadotropins in anovulatory infertile women resistant to clomiphene and pulsatile gonadotropin-releasing hormone therapy

Gonadotropins are released in a pulsatile fashion at a frequency of between 1 and 2 hours in the follicular phase of the menstrual cycle. Human menopausal gonadotropins are usually administered intramuscularly. We evaluated the gonadal response to intravenous human menopausal gonadotropins administered in a pulsatile fashion over nine treatment cycles in three anovulatory infertile women. Human menopausal gonadotropin pulses in doses up to 12 IU follicle-stimulating hormone at frequencies between 2 to 3 hours over 3 to 17 days resulted in ovulation in five cycles with one pregnancy being conceived. In the ovulatory cycles (5,000 to 10,000 IU of human chorionic gonadotropin was used to induce ovulation), the 17 beta-plasma estradiol level was 961 +/- 128 versus 326 +/- 95 pg/ml (mean +/- SEM) in the anovulatory cycles (p = 0.015). The dose of human menopausal gonadotropins (in ampules of Pergonal, 75 IU of follicle-stimulating hormone and 75 IU of luteinizing hormone) in the intravenous cycles needed to induce ovulation was 12.3 +/- 1.4 versus 20.4 +/- 0.9 for intramuscular cycles (n = 80 in 23 women, p = 0.008). Treatment was well tolerated and without complications. We are continuing to explore the use of this apparently more efficient mode of administering human menopausal gonadotropins to anovulatory patients resistant to other techniques of ovulation induction therapy.     

Randomized trial of human versus animal species insulin in diabetic pregnant women: improved glycemic control, not fewer antibodies to insulin, influences birth weight.

OBJECTIVE: Macrosomia occurs in infants of diabetic mothers in spite of "nearly normal maternal blood glucose levels" with insulin treatment. Insulin antibodies may carry bound insulin into the fetal blood and thus may be associated with fetal hyperinsulinemia and macrosomia in these infants. Our objective was to test the hypothesis that human insulin is associated with lower insulin antibody levels and less macrosomia than is animal species insulin. STUDY DESIGN: Forty-three insulin-requiring pregnant (< 20 weeks' gestation) women, previously treated with animal insulin, were randomized to human and animal insulins and studied at weeks 10 through 20, 24, 28, 32, 36, and 38, at delivery, and at 3 months post partum. Infant blood was drawn at delivery (cord) and at 1 day and 3 months post partum 1 hour after a glucose-amino acid challenge. RESULTS: Women receiving human insulin required significantly less insulin per kilogram of body weight and showed significant dampening of glucose excursions (p < 0.05 for each comparison). Infants born to mothers receiving human insulin weighed 2880 +/- 877 gm compared with 3340 +/- 598 gm for infants of women treated with animal insulin (p < 0.05). There was no difference in insulin antibody levels between groups for either mothers or infants. Infants born to mothers receiving human insulin had a 1 hour C-peptide level after the glucose-amino acid challenge at 3 months of age of 0.21 +/- 0.13 pmol/ml compared with 0.32 +/- 0.13 pmol/ml (p = 0.01). CONCLUSION: Administration of human insulin to pregnant diabetic women has a therapeutic advantage over animal insulin, with less maternal hyperglycemia or hypoglycemia, fewer larger-for-gestational-age infants, and less neonatal hyperinsulinemia. Our data do not support the hypothesis that maternal antibodies to insulin influence infant birth weight.     

Salivary and plasma bound and "free" testosterone in men and women

Paired samples of blood and saliva from 37 men and nine women throughout the menstrual cycle were measured for testosterone by radioimmunoassay and free testosterone by equilibrium dialysis. There was a highly significant correlation between plasma and salivary testosterone, with a correlation coefficient r = 0.71 (p = less than 0.001). In men, free testosterone constituted 78% of salivary testosterone but only 4% of plasma testosterone; mean +/- SE salivary testosterone was 193.7 +/- 6.7 pg/ml compared to plasma testosterone of 5,140 +/- 298.0 pg/ml. Salivary testosterone decreased significantly from a morning (0800 hours) level of 208 +/- 7.5 to an evening (1800 hours) level of 174 +/- 8.4 pg/ml (p = less than 0.001) (n = 23). Similarly, plasma testosterone was significantly higher in the morning (6,584 +/- 472 pg/ml) than in the evening (5,571 +/- 357 pg/ml) (p = less than 0.005) (n = 25). Free testosterone in saliva and plasma also showed significantly higher morning than evening levels. The coefficients of variability for hourly changes (0900 to 1800 hours) in salivary testosterone and free testosterone were 13.6% and 16.7% compared to 12.7% and 20.9% for plasma testosterone and free testosterone, respectively. In women, salivary testosterone during the proliferative phase of the menstrual cycle was 108.3 +/- 5.8 pg/ml, and it increased significantly to 130.5 +/- 6.0 pg/ml in the secretory phase (p = less than 0.02). Our findings indicate that measurements of salivary testosterone reflect plasma testosterone and may be a useful noninvasive method of assessing levels of testosterone.