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SummaryThe intraindividual variability in terms of coagulation analyses was explored in 10-16 samples collected from each of 15 women during one menstrual cycle. For comparison, six men were sampled six times during a period of 30 days. The following variables were analysed: FVII, FVIII, FX, vWF:Ag, vWF: ristocetin cofactor, fibrinogen, antithrombin, plasminogen and antiplasmin.The results demonstrated mean coefficients of variation ranging between 4.5 (plasminogen) and 20.7 (vWF:Ag). In certain individuals, the intraindividual variability amounted to nearly 40%, in particular in the assays of FVIII and vWF: Ag. No direct relation between these two factors and oestradiol, progesterone or testosterone levels could be observed in our individuals.The implications of these variations are discussed in terms of disease prediction and diagnosis of coagulation disorders.

Vaginal rings releasing levonorgestrel (L-NOG) at an initial rate of 27 micrograms/24h were studied in a group of 24 normally menstruating women during three months (i.e., during three four-week segments). Each segment consisted of three weeks with the vaginal rings in situ followed by a treatment-free period of one week. The women were divided into three groups (8 subjects each). The first group received vaginal rings only, the second and third groups were treated, in addition, with transdermal systems (patches) releasing estradiol at a rate of 50 and 100 micrograms/24h, respectively. Peripheral blood samples were withdrawn three times weekly (Monday, Wednesday and Friday) during a pretreatment cycle and during the following three months of treatment. The levels of L-NOG, estradiol and progesterone were analyzed by radioimmunoassay techniques. In all subjects, endometrial biopsies were taken in a control cycle and during the last days with vaginal rings in situ in segments II and III. The treatment with estradiol did not significantly influence L-NOG levels. Considerable differences in the L-NOG levels between the subjects of the same group were observed. Fluctuation in ovarian reaction within groups was also large. Nevertheless, estradiol noticeably increased the proportion of anovulatory cycles; the total number of anovulatory segments was 5, 9 and 19 (out of 24) in the groups "No estradiol", "50 micrograms/24h estradiol" and "100 micrograms/24h estradiol", respectively. A morphometric study of the endometrium indicated a significant decrease in the diameter of glands. This change was due to L-NOG alone, but it seemed to be accentuated by the exogenous estradiol. The occurrence of glandular mitoses increased in both groups receiving estradiol in a dose-dependent manner, indicating an increased endometrial proliferation. The treatment with estradiol did not significantly alter the bleeding pattern.

The pharmacokinetic and pharmacodynamic effects of vaginal rings releasing levonorgestrel (L-NOG) at an initial rate of 27 μg/24 h were studied in a group of 12 normally menstruating women during 90 days of continuous use (i.e., during three 30-day treatment segments). Blood samples were drawn immediately before insertion, 15 and 30 min, as well as 1, 2, 4, 8, 12 and 24 h after insertion of the rings, and thereafter three times weekly throughout the study for the analysis of L-NOG, estradiol, progesterone and sex hormone-binding globulin (SHBG). Endometrial biopsies were obtained for a morpho-metric analysis in a pre-treatment (control) cycle and in the 6th and 10th weeks of treatment. The peak of average L-NOG levels was reached within two hours after the insertion of rings. Until 24 h after insertion, the levels did not change significantly. Thereafter, a decrease at a rate of 0.2% per day was initiated. The L-NOG and SHBG levels were highly correlated. This was seen for both the pre-treatment SHBG vs L-NOG (r = 0.96) and the treatment SHBG vs L-NOG levels (r = 0.92). There was a significant (p < 0.001) decrease of SHBG levels due to treatment. During the total of 36 treatment segments, a normal ovarian function was seen in 47% of the segments. The women were anovulatory and had an inadequate lutal function in 28% and 25% of segments, respectively. No correlation between the L-NOG levels and ovarian reaction to treatment was found. The use of L-NOG induced significant changes in the endometrium; the number of glands/mm2 decreased after 6 (p < 0.02) and 10 weeks of use (p

Twenty normally menstruating women volunteered for a study in which plasma samples were collected daily during an entire menstrual cycle. On the same days, samples of morning urine were also collected, as well as random samples of urine voided at the visit to the Outpatient Clinic. Progesterone (P), estradiol (E2) and lutropin (LH) were assayed in plasma, and pregnanediol-3-glucuronide (PdG), estrone-glucuronide (E1G), estriol-16-glucuronide (E3G), P, and E2 were measured in urine using radioimmunoassays. Progesterone in urine was assayed both with and without preceding chromatography. All urinary glucuronides and progesterone exhibited cyclic patterns similar to those of E2 or P in plasma. Seven-fold increases from early follicular to luteal phase values (for PdG and urinary P; the latter both with and without chromatography), or to peak levels (for E1G and E3G) were observed. The difference between the baseline and peak levels was less distinct (approximately 5-fold) for E2 in urine. The day-to-day coefficient of variation of early follicular phase values decreased from 40% to 25% by calculating the ratios of the glucuronides or P to creatinine (C). The peaks of estrogen glucuronides were delayed mostly by 1 day in comparison to the peaks of E2 in plasma. The urinary peaks of estrogens were in most cases more closely clustered around the day of the LH-peak when the measurements were corrected for C. For the determination of the first significant rise of steroid levels in a cycle, the calculation of a sustained rise (leading to a significant cumulative sum - CUSUM) was found superior when compared to other recommended indices, such as a 50% increase over the mean of 3 preceding values, or the increase over the baseline level plus 2 standard deviations. Sustained rises were calculated for all indices studied (including the ratio of urinary E1G to PdG). The ratio of E1G to C in morning urine gave consistently the most compact distribution of sustained rises. It is concluded that daily measurements of urinary PdG (or P) and E1G (or, possibly, E2) could substitute the serial assays of P and E2 in peripheral blood in the retrospective assessment of the ovarian functionn. The day-to-day variation can be significantly reduced, if results are expressed per concentration of C. For the prediction of ovulation or fertile period, the best index of urinary steroids appears to be the sustained rise in the ratio of E1G to C. However, this "best" method is still not good enough in terms of overall reliability and practicability.

We used histochemical methods specific for carbohydrates on accurately timed endometrial biopsies to examine changes in quantity or electronegativity of the endometrium's luminal glycocalyx through the menstrual cycle in normal fertile women. Electronegative glycocalyx was detectable light-microscopically throughout the menstrual cycle. On the third day after the luteinizing hormone peak, a significant increase (P = 0.005) in endometrial surface glycocalyx was evident along with the appearance, in endometrial glands, of material having the staining properties of acid mucus glycoprotein (MGP), which implies that after this material's production by the glands or by the surface epithelium, it becomes adsorbed onto the surface glycocalyx. This phenomenon was accompanied by an apparent decrease in glycocalyceal electronegativity as indicated by a shift from high iron diamine (pH 1.0) to alcian blue (pH 2.5) staining reactivity. Because the timing of the appearance of endometrial moderately acid MGP coincides with or precedes the time that the early fertilized embryo enters the endometrial cavity, a role for the MGP in embryo nutrition or in implantation is suggested.

The pharmacokinetic and pharmacodynamic effects of norethisterone (17 α-ethinyl-17β-hydroxy-4-estren-3-one; NET) released continuously from vaginal devices at a rate of 50 μg/24 h and 200 μg/24 h, respectively, were investigated during a 90-day period in two groups of seven women each with regular menstrual periods. Blood samples were taken three times weekly (mondays, Wednesdays, and fridays) during a control cycle and during the entire study period for the estimation of estradiol, progesterone, and NET levels, and hourly blood samples were collected throughout a 24-hour period after 6 weeks of exposure to assess the short term variation in NET levels. In addition, an endometrial biopsy was taken on days 21–23 of the control cycle and after 6 and 10 weeks with the device in situ.