Screening for activated protein C resistance before oral contraceptive treatment: a pilot study.

The feasibility and cost-effectiveness of screening women for congenital thrombophilic alterations before oral contraceptive (OC) treatment was investigated. A total of 525 women (mean age 21.9 years, 73% aged < 25 years) were examined before their first OC course. At first screening, completely normal results were recorded in 485 (92.4%) women, the remaining showing single (n = 34) or multiple (n = 6) alterations. At second examination (possible in 37 of 40), activated protein C resistance (APCR) was confirmed in 21 cases (4.0%, 18 with factor V Leiden), protein C, or protein S reduction in 8 (1.5%) and 2 (0.4%) cases, respectively. No cases with antithrombin III deficiency were detected. The global estimated cost ($US) to detect one altered case was: $7795 for protein S, $2696 for antithrombin III (no case found), $1374 for protein C and $433 for APCR. The present study confirms that extensive thrombophilic screening before OC treatment is not currently advisable. APCR assessment, however, seems to have a favorable cost-effectiveness ratio: the alteration is frequent and has a synergistic effect with OC; sensibility and specificity of some methods are good; family history is unreliable to single out possible carriers; finally, carriers can be fully informed of their increased thrombotic risk if treated with OC and can receive thromboprophylaxis during life situations associated with high thrombotic risk (e.g., pregnancy and puerperium).

PIP: This article investigates the feasibility and cost effectiveness of screening women for congenital thrombophilic changes before oral contraceptive (OC) treatment. The study population included 525 women who were examined before their first OC course between September 1995 and May 1997 in Bologna, Italy. A completely normal result was seen in 92.4% women during the first screening, which was conducted before the first OC course. The second examination showed that activated protein C resistance (APCR) was confirmed in 21 cases (4.0%, 18 with factor V Leiden), and protein C and protein S reduction in 8 (1.5%) and 2 (0.4%) cases, respectively. Antithrombin III deficiency cases were not detected. The detection of one altered case is estimated to cost $7795 for protein S, $2696 for antithrombin III, $1374 for protein C, and $433 for APCR. The study confirmed that extensive thrombophilic screening before OC treatment was not advisable. However, APCR assessment was found to be cost-effective. The alteration was frequent and APCR had a synergistic effect with OC, and the sensibility and specificity of some methods for detection of APCR are good. Family history is not reliable for identifying possible carriers for the thrombophilic trait. Carriers can be fully informed of their high risk if treated with OC and can receive thromboprophylaxis in conditions where thrombotic risk is high.

Longitudinal evaluation of the different gonadotropin pulsatile patterns in anovulatory cycles of young girls.

We studied 13 adolescents (mean gynecological age 29.2 +/- 14.1 months) with anovulatory cycles and 7 women with ovulatory cycles (mean gynecological age 33.1 +/- 15.3 months) as a control group. Adolescents with anovulatory cycles were grouped on the basis of mean plasma LH values: group 1 (n = 7) with high LH values, and group 2 (n = 6) with normal LH values. In all women plasma gonadotropin concentrations were measured at 10-min intervals for 8 h on day 4 of the cycle. Pulsatile gonadotropin secretion was also studied in each subject a second time 40 months later, to establish the outcome of the different pulsatile patterns. Group 1 had more frequent and greater LH pulses than the other two groups (which were similar) and had the highest plasma 17 beta estradiol, testosterone, androstenedione, and 17 hydroxyprogesterone concentrations. Longitudinal control showed that: in group 1, three subjects out of seven acquired ovulatory cycles and there was a fall in mean LH plasma levels (30 +/- 5 vs. 9 +/- 4 IU/L; P less than 0.01), number of pulses (8.3 +/- 1.5 vs. 5 +/- 0; P less than 0.025), mean amplitude (13 +/- 3 vs. 5 +/- 2 IU/L; P less than 0.02) and an increase in interpulse interval (56 +/- 10 vs. 91 +/- 6 min; P less than 0.01). In four subjects anovulatory cycles persisted and the LH pulsatile profile remained unchanged. In group 2, five subjects out of six acquired ovulatory cycles, but there were no significant changes in the number of pulses (6 +/- 1 vs. 6 +/- 2; P = NS), interpulse interval (97 +/- 30 vs. 85 +/- 30 min; P = NS), or amplitude (5 +/- 2 vs. 4 +/- 2 IU/L; P = NS). The results indicate that: 1) anovulatory young women with early normal plasma LH values have an adequate GnRh pulsatile pattern which will easily lead to ovulation; 2) anovulatory young women with high LH plasma values may have a reproductive system blocked in a pathological condition, similar to that observed in polycystic ovary syndrome; 3) only few subjects with high plasma LH values are able to achieve ovulation and normalize LH pulsatile pattern as a consequence of a new mode of GnRh release.

The effects of desogestrel and ethinylestradiol combination in normal and hyperandrogenic young girls: speculations on contraception in adolescence.

Hormone profile and ovarian morphology were studied in two groups of adolescents (group 1:19 girls with slight signs of hyperandrogenism; group 2: 14 normal adolescents) in basal conditions and during a contraceptive combination of 30 micrograms ethinyl estradiol (EE) and 150 micrograms desogestrel (D). Treatment was associated with a low incidence of side effects in both groups. In group 1, acne generally improved within 12 months while hirsutism was only reduced in some subjects (58%) after 12 months of therapy (basal hair score 8.50 +/- 1.60 vs 5.81 +/- 1.53 p less than 0.001). Significant falls in plasma levels of LH, total and free testosterone and an increase in sex-hormone-binding globulin levels were observed during treatment especially in group 1. High percentage of multifollicular ovaries (75%) characterized hyperandrogenic subjects. Ovarian volume and number of follicles, higher in group 1 than 2 in basal conditions, showed a significant reduction in both groups and normal ovarian morphology was restored in hyperandrogenic subjects. Considering the high incidence of hyperandrogenemia in adolescence and its implications, our data suggest that the EE.D combination suits adolescent biological condition and is one of the suitable contraceptive methods in adolescents which also has therapeutic effects.

PIP: 33 young females requesting oral contraception (OC) agreed to be part of a study to determine the effects of desogestrel and ethinyl estradiol combination on hyperandrogenemia. Group I included 19 adolescents between 15-19 years old with varying menstrual cycles. 36.8% had acne, all had excess body hair (hirsutism), and 79% were anovulatory. Group II which consisted of 14 normal ovulating adolescents between 17-20 years old with no signs of hyperandrogenemia served as controls. Physicians treated all subjects with an estroprogestin OC (30 ug ethinyl estradiol and 150 ug desogestrel). The combined OC caused very few side effects. Acne essentially vanished in all but 2 subjects. In The hair score of 58% of the subjects decreased significantly after 12 months of treatment (p .001), while there was no significant change in the 1st 3 months. Plasma levels of luteinizing hormone and total and free testosterone fell, especially in Group I. An increase in sex hormone binding globulin levels occurred as well, particularly in Group I. In basal conditions, hyperandrogenic subjects had more multifollicular ovaries (55%) than did the controls (25%) and ovarian volume was higher for Group I than for Group II. During treatment, the number of ovarian cysts decreased substantially in Group I and ovarian size and morphological characteristics were restored. These results suggest that, due to the high occurrence of hyperandrogenemia in adolescents, the desogestrel-ethinyl estradiol combination is appropriate to the adolescent biological condition and has beneficial effects, therefore it is a safe and suitable contraceptive method for adolescents.

Episodic pulsatile secretion of FSH, LH, prolactin, oestradiol, oestrone, and LH circadian variations in polycystic ovary syndrome.

Pulsatile secretion of LH, FSH, PRL, oestradiol and oestrone was studied in a group of 16 patients with micropolycystic ovary syndrome (PCOS) and compared with that of normal ovulatory women in the fifth to sixth day of the cycle. Hormone concentrations were measured at 10 min intervals for 8 h starting at 0930 h. In seven subjects, the study was prolonged for 24 h, with 20 min interval samples, in an attempt to evaluate the circadian rhythm of LH by cosinor analysis. Significant fluctuations occurred in the concentration of each hormone. Values shown are mean +/- SD. PCOS subjects had high LH mean values (27.9 +/- 5.9 IU/l) (P less than 0.005). LH pulse amplitude was higher than controls (11.6 +/- 3.7 IU/l versus 5.2 +/- 1.8 IU/l; P less than 0.005) while no consistent changes in frequency or interpulse interval (62.0 +/- 10.7 min versus 65.8 +/- 19.2 min; P = NS) were found. A mean of 4.8 +/- 1.2 pulses of FSH occurred in 8 h and the mean pulse amplitude was 2.68 +/- 1.11 with no differences from controls. All patients were normoprolactinaemic. A mean of 5.5 +/- 1.9 pulses occurred in 8 h, the interpulse interval was 76.1 +/- 14.4 min and the amplitude was 2.87 +/- 0.76 ng/ml and there were no significant differences from controls; 75% of PRL pulses showed a temporal relationship with LH pulses. Oestrone mean basal values were higher in PCOS (47.2 +/- 12.5 pg/ml) than controls (32.0 +/- 9.9 pg/ml; P less than 0.02), while no differences were observed as regards oestradiol. Oestradiol pulse amplitude was nearly the same as oestrone (43.6 +/- 18.8 pg/ml and 37.7 +/- 16.1 pg/ml, respectively); 6.0 +/- 2.2 pulses and 6.0 +/- 1.6 pulses occurred in 8 h with an interpulse interval of 81.1 +/- 27.1 min and 71.8 +/- 11.1 min, respectively. Sixty-five per cent of LH pulses were followed by an oestradiol and oestrone peak. The mean time of the appearance was 17 +/- 15 min and 25 +/- 23 min, respectively. In the PCOS group a consistent 24 h rhythm in mean plasma LH levels was found with the highest hormone values at 1720 h (P less than 0.05) unrelated to apparent sleep and different from that of adult women. Pulse frequency showed a significant slowing during the night with the longest interpulse interval at 0327 h (P less than 0.03) while no significant periodicity was observed in LH pulse amplitude.(ABSTRACT TRUNCATED AT 400 WORDS)

Different gonadotropin pulsatile fashions in anovulatory cycles of young girls indicate different maturational pathways in adolescence.

To characterize the spectrum of pulsatile gonadotropin secretion during the postmenarchal period, we studied 24 adolescents whose gynecological age was 1-4 yr. Six women with ovulatory cycles formed a control group. Eighteen women with anovulatory cycles were grouped on the basis of mean plasma LH values: group 1 (n = 8) with high LH values and group 2 (n = 10) with normal LH values. In all women, plasma gonadotropin concentrations were measured at 10-min intervals for 8 h on day 4 of the cycle. Pulsatile gonadotropin secretion was also studied a second time in 7 women from group 1 and 7 from group 2 after 5 days of progesterone (P) in oil treatment to assess the role of P in regulating gonadotropin secretion in the postmenarchal period. Group 1 had more frequent and greater LH pulses than the other two groups (which were very similar) and had the highest plasma 17 beta-estradiol, testosterone (T), androstenedione (A), and 17-hydroxyprogesterone concentrations. In all anovulatory women, basal LH values were correlated with the LH interpulse interval (r = -0.65; P less than 0.01) and pulse amplitude (r = 0.86; P less than 0.001). LH pulse amplitude was correlated with basal 17 beta-estradiol values (r = 0.74; P less than 0.001), and LH interpulse interval with basal T (r = -0.83; P less than 0.001), A (r = -0.51; P less than 0.05), and 17-hydroxyprogesterone (r = -0.79; P less than 0.001) values. P administration decreased LH pulse frequency and increased LH pulse amplitude more in group 2 than in group 1 with high LH values; a clear reduction was also found in A, T, and 5 alpha-dihydrotestosterone values. These results indicate that 1) anovulatory young women with high plasma LH values have an alternative maturational pathway, different from that of anovulatory women with normal plasma LH values, who are similar to ovulatory adolescents; 2) the pulsatile pattern of gonadotropin secretion has specific roles linked separately to amplitude and frequency in controlling ovarian steroidogenesis, which accounts for the endocrine differences between groups; and 3) in the postmenarchal period, by modulating LH and FSH pulsatility and thus reducing androgen levels and their atretic action on follicles, P may be a basic regulatory factor in enhancing functional cyclicity.

Postmenarchal evolution of endocrine pattern and ovarian aspects in adolescents with menstrual irregularities.

Ninety-five adolescents with menstrual irregularities persisting since menarche were studied and the data analyzed in relation to gynecologic age. In each year, in the premenstrual phase, luteinizing hormone (LH), testosterone (T), and androstenedione (delta 4A) values were higher than those of adults. Estrone (E1), estradiol (E2), 17-hydroxyprogesterone (17-OHP), progesterone (P), and dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) gradually increased up to adult values correlating with gynecologic age. By ultrasound, nearly half the ovaries were multicystic and ovarian volume was greater than that of adults in each gynecologic year. When the data were classified as ovulatory or anovulatory, ovulation appeared to be a dynamic process characterized by ovaries similar to those of adults and by increasing hormonal levels correlated to gynecologic age. By contrast, in anovulatory cycles, mean T, delta 4A, and LH values were stable in each year and constantly higher than in ovulatory cycles and adult controls. These findings suggest that, despite persistent irregular cycles, some adolescents normalize all endocrine and ovarian parameters toward maturity, while subjects with persistent irregular anovulatory cycles maintain marked hyperandrogenism, increasingly high LH values, and enlarged multicystic ovaries.

Ovarian multifollicularity, high LH and androgen plasma levels, and anovulation are frequent and strongly linked in adolescent irregular cycles.

Ninety-seven adolescents (0.5-6.0 years in gynaecological age) suffering from various kinds of menstrual irregularities were studied and compared with 20 adults by performing ovarian ultrasonography and plasma hormonal determinations. High percentages of multifollicularity (57.7%) and enlarged ovaries (46.3%) were found in the entire group of adolescents. Adolescents with multifollicular ovaries (more than 4 cystic areas) showed higher percentages of luteinizing hormone (LH: 32%), testosterone (T: 34%), and androstenedione (A: 43%) levels exceeding the upper normal adult range than subjects with homogeneous (less than 4 cystic areas) ovaries (LH: 12%, T: 10%, A: 19%, respectively). Ovulation can further discriminate the adolescents: in fact, adolescents with homogeneous ovaries and ovulatory cycles have a hormonal pattern almost identical to that of adults. On the contrary, subjects with multifollicular ovaries and anovulatory cycles show low values of follicle-stimulating hormone (FSH) and high values of LH, T and A, significantly different from those in ovulatory subjects with homogeneous ovaries (P less than 0.005) and from those in adults (P less than 0.005).