Adrenomedullin and nitric oxide in menstrual and in vitro fertilization cycles. Relationship to estradiol.

BACKGROUND: Estradiol has marked systemic vasodilator effects which may be partially mediated by nitric oxide. Recently, a new vasodilator peptide, adrenomedullin, having potent vasodilatory action which is mediated at least in part by nitric oxide, has been isolated. This study investigated whether a relationship exists between circulating levels of estradiol, adrenomedullin, and nitrite/nitrate (the two stable oxidation products of NO metabolism) both in the spontaneous menstrual cycle and IVF cycles. METHODS: Ten normal ovulatory infertile patients were included in this prospective longitudinal study. Circulating levels of estradiol, adrenomedullin, and nitrite/nitrate were investigated. Follicular fluid concentrations of adrenomedullin and nitrite/nitrate, as well as estradiol, were also determined in IVF cycles. RESULTS: Serum nitrite/nitrate levels were significantly elevated in the late follicular phase compared to cycle day 3 of the spontaneous menstrual cycle thus paralleling plasma estradiol. However, no significant change in serum nitrite/nitrate concentration was found associated to multifollicular development and supraphysiological levels of estradiol in IVF cycles. Adrenomedullin plasma levels did not show significant variation either in menstrual or IVF cycles. No correlation was found between plasma estradiol levels and nitrite/nitrate serum concentrations or adrenomedullin plasma levels nor between circulating adrenomedullin and nitrite/nitrate both in menstrual and IVF cycles. Follicular fluid concentrations of estradiol and adrenomedullin but not nitrite/nitrate were significantly higher than those found in plasma or serum. Neither estradiol follicular fluid concentration correlated with those of adrenomedullin or nitrite/nitrate nor a relationship was observed between adrenomedullin and nitrite/nitrate. CONCLUSIONS: Circulating levels of nitrite/nitrate show a significant increase during the late follicular phase in the normal menstrual cycle which is unrelated to adrenomedullin. In addition, this does not necessarily indicate a cause and effect relationship between nitrite/nitrate and estradiol levels given that no increase in nitrite/nitrate was observed from a hypoestrogenic to a hyperestrogenic state during IVF cycles. Further studies are necessary to clarify this subject. Also, the biological and clinical significance of the presence of adrenomedullin in the human follicular fluid remains to be elucidated.     

The utility of serum leptin and follicular fluid leptin, estradiol, and progesterone levels during an in vitro fertilization cycle

PURPOSE: To prospectively evaluate serum and follicular fluid leptin, estradiol, and progesterone levels during in vitro fertilization. METHODS: Prospective observational study measuring serum levels at six points during the IVF cycle and follicular fluid at the time of retrieval. RESULTS: Serum leptin and estradiol levels both significantly increased for the individual patients during the IVF stimulation process. None of the leptin levels differed based on pregnancy outcome. BMI significantly correlated with all leptin levels. Follicular fluid estradiol correlated with serum estradiol only in pregnant patients (r = 0.97, p<0.01) and was unrelated in non-pregnant patients (r=-0.15, p=0.81). CONCLUSION: Serum and follicular leptin levels are highly correlated. Leptin levels increase during the IVF cycle and vary between patients based on maternal BMI, but do not correlate with other serum hormone levels or pregnancy outcome. Pregnancy outcome success was reflected in the relationship between follicular fluid and serum levels of estradiol, independent of leptin levels.     

Plasma androgen levels during the menstrual cycle.

Utilizing RIA methods, T, DHT, delta 4, and DHEA levels were determined daily during a complete cycle in 15 normal young women with apparently normal ovulatory cycles. T, DHT, and delta 4 levels showed statistically significant cyclical variations, with highest values in the periovulatory period and lowest values in early follicular and late luteal phase. DHEA levels showed random variations during the cycle. The failure to detect these variations by some authors may be related to the relatively large interindividual variation in plasma levels.     

Changes in the in vitro metabolism of estradiol by human endometrium during the menstrual cycle

Slices of human endometrial curettings were superfused with buffer solutions of labeled steroids, and concentrations of labeled precursors and products were measured in perfusate and tissue. Significant differences were found among various types of endometria when labeled estradiol (E₂) was perfused. The tissue to medium ratio (T/M), the ratio of intracellular concentrations of labeled estrone (E₂), and E₂ (E₁/E₂), and intracellular clearance (IC) were 1.2 ± 0.7, 14 ± 5.5, and 18 ± 6.2 respectively, in secretory endometrium and 9.5 ± 4.7, 2.0 ± 0.9, and 2.9 ± 1.7, respectively, in proliferative endometrium. Measurements of rates of entry and interconversion of E₁ and E₂ by a two-tracer technique indicated that these results cannot be attributed to permeability changes but may be due to increasing interconversions of E₂ and E₁ throughout the menstrual cycle. T/M values were independent of concentrations of E₁ in the perfusion medium (0.1 to 5,000 ng. per milliliter) when corrected for the amount of hormone tightly bound to nuclei. No significant differences in these parameters between proliferative and secretory endometria were observed when labeled E₁ or progesterone were perfused.     

Antioxidant protection during the menstrual cycle: the effects of estradiol on ascorbic-dehydroascorbic acid plasma levels and total antioxidant plasma status in eumenorrhoic women during the menstrual cycle

BACKGROUND: Estrogens, apart from their classic role as steroid hormones, also possess significant antioxidant properties. The present study was undertaken to assess the antioxidant potential of the female during the various menstrual phases and to investigate the correlation between ascorbic acid, dehydroascorbic acid plasma levels, total antioxidant plasma status, and estradiol levels. DESIGN AND METHODS: Thirteen eumenorrhoic women were studied. Ascorbic acid and dehydroascorbic acid plasma levels, total antioxidant plasma status, estradiol, progesterone, luteinizing hormone, and follicle-stimulating hormone during time of menstruation, midfollicular phase, time of ovulation, and midluteal phase were determined. Ascorbic-dehydroascorbic acid ratio was also calculated. RESULTS: A progressive significant rise in ascorbic acid plasma levels (p < 0.01), ascorbic-dehydroascorbic acid ratio (p < 0.001), and total antioxidant plasma status (p < 0.05) from menstruation to ovulation was observed. Moreover, a significant decrease in dehydroascorbic acid was found at the same phases (p < 0.05). Changes of estradiol levels during the menstrual cycle correlated positively with the changes of ascorbic acid levels and total antioxidant plasma status (p < 0.05). Furthermore, estradiol levels correlated positively with ascorbic acid levels (p < 0.05, r < 0.5), ascorbic-dehydroascorbic acid ratio (p < 0.05, r < 0.5), and total antioxidant plasma status (p < 0.05, r < 0.8) in all menstrual phases. CONCLUSIONS: An elevated antioxidant protection during ovulation and the midluteal phase appears to be present in eumenorrhoic women. Moreover we observed a cyclic variation in the antioxidant parameters we assayed in the females in the present study, which could be due to cyclic changes in estradiol levels.     

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.     

Histology of the baboon endometrium during the menstrual cycle and pregnancy.

The histologic characteristics of baboon endometrium during the menstrual cycle and pregnancy were studied and compared with those of human endometrium. Eight phases of endometrial change during the menstrual cycle are described. The samples were dated on the basis of sex skin changes. The basic histology of the baboon endometrium is similar to that of human endometrium, but some differences were observed. The growth of baboon endometrium is more sluggish, secretion is less intense, and many of the changes, especially in the stroma, are localized, less diffuse than they are in human endometrium. During pregnancy, decidual transformation in the baboon is much less intense than that in the human. No differences were observed between endometrium in association with preimplantation embryos and that from nonpregnant animals at comparable times following ovulation.     

Comparison of the patterns of androstenedione, progesterone, and estradiol during the human menstrual cycle

The pattern of androstenedione (A), serum estradiol (E2), and progesterone was measured during the menstrual cycle. No clear-cut pattern was observed for A such as was observed for E2 and progesterone. The mean levels of A tended to increase from Day 1 of menses to midcycle in all women, following the luteinizing hormone (LH) peak, but with marked fluctuation. A significant decline (p.05) in mean A levels from the LH peak to the day prior to menses was noted in all subjects. The ovaries secreted A throughout the menstrual cycle, with the lowest rate just prior to menses. The marked daily variation in A was most likely caused by the adrenal gland. Whether or not A has a luteal origin has not been resolved.     

Salivary estradiol and progesterone during the normal ovulatory menstrual cycle in Chinese women

Salivary and serum levels of estradiol and progesterone were measured by radioimmunoassay in 10 Chinese women during their normal menstrual cycles. Changes in salivary estradiol and progesterone levels followed a similar pattern to that in the serum. Significant correlation was found between salivary and serum levels of estradiol and progesterone (p less than 0.001). Measurements of these salivary steroids may be used to assess follicular dynamics. Moreover, salivary sampling is simple, convenient and stress free.