Comparison of ovarian follicular activity during treatment with a monthly injectable contraceptive and a low-dose oral contraceptive.

Ovarian follicular development occurs during treatment with combined and progestin-only oral contraceptive (OC) pills and progestin-containing subdermal implants, and can be associated with the development of persistent functional cysts that may require surgical removal. Lunelle is a once-a-month injectable contraceptive containing estradiol cypionate 5 mg and medroxyprogesterone acetate 25 mg. A randomized, comparative study was undertaken to compare the effect on ovarian follicular activity associated with use of Lunelle and a low-dose OC. A total of 30 ovulatory subjects were randomly assigned to receive two cycles of treatment with either an OC containing ethinyl estradiol 20 microg and 0.1 mg levonorgestrel or Lunelle. During the second cycle of treatment, pelvic sonography was performed every 4 days, at which time the maximum follicle diameter was measured. Study end points were the presence of follicles >/=10, 20, and 30 mm. In all, 13 of 15 subjects in the OC group and 14 of 15 in the Lunelle group completed the study. Follicles measuring >/=10 mm were present in 11 of 13 (84.6%) in the OC users and in four of 14 (28.6%) in the Lunelle users (p <0.05). In the OC group, six of 13 subjects (46.1%) developed follicles >/=20 mm, and one of 13 (7.7%) developed follicles >/=30 mm. No subjects in the Lunelle group developed a follicle >/=20 mm in diameter. This study indicates that Lunelle is associated with a significantly lower incidence of ovarian follicular development compared to that of an OC containing 20 microg ethinyl estradiol and 0.1 mg levonorgestrel.

Does anovulation induced by oral contraceptives favor pregnancy during the following two menstrual cycles?

OBJECTIVE: To compare IVF and pregnancy outcomes before and after anovulation induced by oral contraceptives. DESIGN: Observational clinical study. SETTING: Infertility clinic. PATIENT(S): Forty women with two intact ovaries (32 of 40 couples with male factor infertility and 8 with unknown causes of infertility) underwent 190 IVF treatment cycles (55 natural cycles and 135 clomiphene citrate-stimulated cycles). INTERVENTION(S): If the women failed to conceive after 2-4 IVF treatment cycles, oral contraceptives were used to induce anovulation for 1 month before IVF was performed in two consecutive cycles. MAIN OUTCOME MEASURE(S): Rates of oocyte retrieval, fertilization, cleavage, preembryo formation, pregnancy, and implantation were compared before and after a period of anovulation. RESULT(S): The pregnancy rate per cycle of the first and second cycle combined (23%) and that of the second cycle alone (30%) after a period of anovulation were significantly higher than that observed before a period of anovulation (9%). CONCLUSION(S): Anovulation induced by oral contraceptives, showing bilateral ovarian quiescence, enhances pregnancy rates in the following two menstrual cycles of IVF treatment.

PIP: This observational clinical study compared the in vitro fertilization (IVF) and pregnancy outcomes before and after anovulation induced by oral contraceptives. A total of 40 patients from the Fukuda Ladies Clinic, Japan, with two intact ovaries who underwent 190 IVF treatment cycles were enrolled in the study. If the women failed to conceive after 2-4 IVF treatment cycles, oral contraceptives were used to induce anovulation for 1 month before IVF was performed in two consecutive cycles. Rates of oocyte retrieval, fertilization, cleavage, pre-embryo formation, pregnancy, and implantation were compared before and after a period of anovulation. Results revealed that the pregnancy rate per cycle of the first and second cycle combined (23%) and that of the second cycle alone (30%) after a period of anovulation were significantly higher than that observed before a period of anovulation (9%). Based on this finding, it is concluded that anovulation induced by oral contraceptives, showing bilateral ovarian quiescence, enhances pregnancy rates in the following two menstrual cycles of IVF treatment.

Efficacy, bleeding patterns, and side effects of a 1-year contraceptive vaginal ring.

A combined contraceptive vaginal ring designed to last 12 months was tested at three clinic sites. This ring released approximately 1 mg of norethindrone acetate (NET-Ac) and 20 micrograms of ethinyl estradiol (EE) daily. A total of 60 women were enrolled to use the ring in a schedule of 3 weeks in/1 week out. Serum norethindrone (NET) and ethinyl estradiol (EE) levels were assayed twice weekly in cycles 6, 9, and 13. Mean NET concentrations between cycles 6 and 9 were relatively stable between 13 and 19 nmol/L but showed a 10%-21% decrease in all centers between cycles 9 and 13. Mean EE concentrations ranged from 75 to 103 pmol/L, but did not have the same decrease as NET between cycles 9 and 13. Cycles with progesterone peaks (> 9.6 nmol/L) compatible with some luteal activity occurred in 4% of cycles sampled in Sydney, 3% in Santo Domingo, and 26% in Los Angeles. Half of these cycles exhibited at least one progesterone value > 32 nmol/L with three of 18 occurring in noncompliant cycles. Heavier body weight was associated with increased probability of luteal activity. Based on serum estradiol peaks > 400 pmol/L, eight of 81 cycles appeared to have marked follicular activity with no luteal activity. No pregnancies occurred. Nausea was reported by about half the subjects in approximately 10% of the visits (mainly in the first 1-2 days in the first cycle immediately after ring insertion). Vomiting was reported by 20% of subjects early in the first cycle only. Headache was reported on occasion by nearly 50% of the women, but the relationship to ring use was uncertain. Vaginal discharge was reported by 17 women (82% of these were from one clinic). Of 60 women, 14 discontinued before completing the study, but only two discontinuations were for medical reasons. Small but statistically significant changes occurred in lipid levels in two of the three centers. All changes remained within normal limits and were similar to those seen with many oral contraceptives. It appears that this ring may perform slightly differently in different populations, but is a highly satisfactory method of contraception for many women. Minor modifications in design could provide higher levels of steroid release and in the later months of the ring life span would assure continuing high levels of contraceptive protection for heavier women.

PIP: This study determines the ovarian effects, contraceptive efficacy, and effects on serum levels of norethindrone acetate (NET-Ac) and ethinyl estradiol (EE) among women using a single contraceptive vaginal ring (CVR) cyclically over a period of 1 year. A total of 60 women were enrolled and used the ring according to a schedule of 3 weeks "in" and 1 week "out." Assays of serum norethindrone acetate (NET-Ac) ethinyl estradiol (EE) levels were taken twice weekly in cycles 6, 9, and 13. Despite luteal activity in some cycles, no pregnancies were noted within the 12-month study period. Heavier body weight was associated with increased probability of luteal activity. Mean serum levels decreased over the last 3 months of CVR use, accounting for the increase in luteal activity and possible ovulations in cycle 13. Among women in Sydney, by contrast with women in the other centers, a difference in the effect on lipids was seen. However, the changes in lipid levels were very small. The side effects were a little different from those experienced by women using a combined pill. Nausea and vomiting were largely confined to early cycles and most common in the first days of the first cycle. Weight gain was also not a problem, although there was a small mean increase in body weight over the 12-month treatment period. This study indicates that use of a single CVR releasing EE and NET-Ac over a period of 12 months constitutes an acceptable, safe and effective contraceptive method.

Activity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives.

This study was performed to evaluate pituitary-ovarian recovery in the pill-free interval during use of three low-dose combined oral contraceptives (COC). Either the estrogen component or the progestin component was comparable in the study groups, to evaluate their relative influence. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) levels were measured and follicle number and size estimated by transvaginal sonography daily during the 7-day pill-free interval in 44 healthy volunteers using three different low-dose oral contraceptives. Healthy volunteers were enrolled using 20 micrograms ethinyl estradiol (EE) + 75 micrograms gestodene (GSD) (Harmonet, Wyeth-Lederle; n = 15), 20 micrograms EE + 150 micrograms desogestrel (DSG) (Mercilon, Organon n = 17), or 30 micrograms EE + 150 micrograms DSG (Marvelon, Organon, n = 12) given according to the usual regimen of one tablet daily during 3 weeks and 1 week pill-free interval. No ovulations were observed. Pituitary hormones were not statistically significantly different at the beginning of the pill-free interval between the study groups. FSH concentrations were significantly higher at the end of the pill-free interval in the 30 micrograms EE group compared with both 20 micrograms EE groups (7.0 [0.6-12.4] IU/L vs 4.9 [1.4-6.1] IU/L and 4.5 [2.4-7.4] IU/L; p = 0.001). In both 20 micrograms EE groups, a single persistent follicle (24 and 28 mm) was present in one subject. Follicle diameters were statistically significantly smaller at the beginning and at the end of the pill-free period in the 30 micrograms EE group compared with both 20 micrograms EE study groups. Dominant follicles (defined as follicle diameter > or = 10 mm) were observed at the end of the pill-free interval in both 20 micrograms EE groups (in 27% and 18% of women, respectively) but not in the 30 micrograms EE group. Finally, the area-under-the-curve for E2 was statistically significantly lower in the 30 micrograms EE group compared with both 20 micrograms EE groups. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval. Dominant follicles were encountered only in the 20 micrograms EE study groups.

PIP: This article reports on a study that evaluated pituitary-ovarian recovery in the pill-free interval during a period of use of one of three low-dose combined oral contraceptives (COC). 44 female volunteers using low-dose oral contraception were subdivided into three groups in this comparative study: 15 women used 20 mcg ethinyl estradiol (EE) + 75 mcg gestodene; 17 used 20 mcg EE + 150 mcg desogestrel; 12 used 30 mcg EE + 150 mcg desogestrel. No ovulations were observed. Pituitary hormone levels between the study groups were not significantly different at the beginning of the pill-free interval. Follicle-stimulating hormone (FSH) concentrations were significantly higher at the end of the pill-free interval in the 30 mcg EE group than in both 20 mcg EE groups. In each of the 20 mcg EE groups, a single persistent follicle (24 mm and 28 mm, respectively) was found in 1 subject. In conclusion, the EE content rather than the progestin component in the studied COC determined the extent of residual ovarian activity at the beginning of the pill-free interval.

Pregnancies in women with Turner's syndrome.

Ovarian failure is a typical feature in Turner's syndrome. Therefore, hormone replacement therapy (HRT) is necessary to achieve the development of normal female sexual characteristics and to prevent cardiovascular complications and osteoporosis. Spontaneous puberty occurs in 5-10% of women with Turner's syndrome, and 2-5% of them become pregnant spontaneously. Sexually active young women with Turner's syndrome need contraception. It can be administered as contraceptive pills, which also serve as HRT. Oocyte donation is now a treatment option for infertility of these women. Excellent results have been obtained with 46% of embryo transfers resulting in pregnancy. The pregnancies carry high risks and have to be followed up carefully. The children born following oocyte donation have no additional risks. Risks can be reduced by transferring only one embryo at a time to the uterus, thus avoiding twin pregnancies. Ovarian tissue from young girls with Turner's syndrome could be cryopreserved for infertility treatment in the future, but the optimal age of ovarian biopsy has to be studied, and methods of replantation and maturation of oocytes in vitro have still to be developed. Fertility counselling has become important in the treatment of girls with Turner's syndrome.

PIP: Ovarian failure and amenorrhea are the typical features in Turner's syndrome resulting from an accelerated loss of oocytes from the ovaries after the 18th week of fetal life or over a few postnatal months or years. The cause and mechanism of this loss are unknown. About 5-10% of girls with Turner's Syndrome have spontaneous pubertal development and 5% having menstrual periods. Therefore, hormone replacement therapy (HRT) is necessary to achieve the development of normal female sexual characteristics and to prevent cardiovascular complications and osteoporosis. Spontaneous puberty occurs in 5-10% of women with Turner's syndrome, and 2-5% of them have become pregnant spontaneously. Sexually active young women with Turner's syndrome need contraception. It can be administered as contraceptive pills, which also serve as HRT. Oocyte donation is now a treatment option for infertility of these women. Excellent results have been obtained with 46% of embryo transfers resulting in pregnancy. The pregnancies carry high risks and have to be followed up carefully. The children born following oocyte donation have no additional risks. Risks can be reduced by transferring only one embryo at a time to the uterus, thus avoiding twin pregnancies. Ovarian tissue from young girls with Turner's syndrome could be cryopreserved for infertility treatment in the future, but the optimal age of ovarian biopsy has to be studied, and methods of replantation and maturation of oocytes in vitro have still to be developed. Fertility counseling has become important in the treatment of girls with Turner's syndrome.

Tubo-ovarian abscess after tubal ligation.

Tubo-ovarian abscess usually results from ascending infection of the lower genital tract. In a few cases it can occur as a result of direct contamination at the time of tubal sterilization. We describe a case that presented seven years after post partum tubal sterilization, showing both acute and chronic components.

PIP: This paper presents the case of a 32-year-old woman who developed a tubo-ovarian abscess 7 years following tubal ligation via minilaparotomy. Symptoms experienced included pain, which was exacerbated by walking, and mild deep dyspareunia. Abdominal and pelvic examinations revealed pain in the left iliac fossa, cervical excitation tenderness, and an ill-defined left adnexal mass. Sonographic evaluation of the pelvis showed an irregularly shaped, cystic mass (8.0 x 4.5 x 5.3 cm) with thickened internal septations and solid parts. A left tubo-ovarian multilobulated complex mass adherent to the omentum and the pelvic side was found upon laparotomy. There was pus in the Pouch of Douglas, and the uterus was 10 weeks in size with symmetrical enlargement. The previously ligated right fallopian tube and the ovary were unremarkable. Management includes left adnexectomy, omental biopsy, and 5-day course of antibiotics against Staphylococcus aureus, which was cultured from the purulent material in the Pouch of Douglas. Tubo-ovarian abscess should be considered in diagnosing patients presenting symptoms of pelvic inflammatory disease.

Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates.

OBJECTIVE: To assess the effect of pretreatment with an oral contraceptive (OC) on ovarian cyst formation during pituitary suppression with buserelin acetate. DESIGN: Prospective randomized trial. SETTING: Academic medical center. PATIENT(S): Eighty-three patients who were undergoing IVF-ET treatment. INTERVENTION(S): Patients in the study group were pretreated with an OC for 14 days starting on the first day of menstruation. The administration of SC buserelin acetate was initiated on the last day of OC administration. Patients in the control group began to receive buserelin acetate on day 2 of menstruation. Hormonal assays and ultrasound scans were performed on the first day of menstruation, and 7, 11, and 14 days after the commencement of buserelin acetate administration. Thereafter, these tests were performed weekly until pituitary suppression was achieved. MAIN OUTCOME MEASURE(S): Incidence of cyst formation. RESULT(S): A cyst developed in 27 patients in the control group (52.9%) and no patients in the study group (odds ratio [OR]=115; 95% confidence interval [CI]=10-617). Patients in the study group achieved pituitary suppression faster (median difference [MD]=7 days; 95% CI=4-14) and required fewer ampules of gonadotropin (MD=10; 95% CI=6-14). They recruited more follicles (MD=3; 95% CI=0-5) and had higher pregnancy rates (37.2% versus 33.3%). CONCLUSION(S): Pretreatment with an OC abolishes ovarian cyst formation, shortens the time required to achieve pituitary suppression, and decreases gonadotropin requirements without having a negative effect on pregnancy rates.

PIP: Administration of a gonadotropin-releasing hormone analog (GnRH-a) before ovarian stimulation with gonadotropins in women undergoing in vitro fertilization (IVF) treatment produces higher pregnancy and live birth rates, but also results in formation of ovarian cysts that must be treated before stimulation can commence. The effect of pretreatment with an oral contraceptive (OC) on ovarian cyst formation during pituitary suppression with the GnRH-a buserelin acetate was investigated in a prospective randomized trial of women undergoing IVF at Royal Victoria Hospital (Montreal, Quebec, Canada). 51 women were pretreated with an OC for 14 days, starting on the first day of menstruation, and began buserelin acetate (500 mcg/day) on the last day of OC administration. The 51 women in the control group were treated with the standard protocol of 500 mcg/day of buserelin acetate starting on the second day of menstruation. A cyst developed in 27 controls (52.9%) but in no women pretreated with OCs (odds ratio, 115; 95% confidence interval, 10.7-617.5). 49 pretreated women (96.1%) compared with 22 controls (43.1%) achieved pituitary suppression after 7 days of GnRH-a administration. Pretreated women also required a median of 10 fewer ampules of gonadotropin than controls, recruited a median of 3 more follicles than their non-pretreated counterparts, and had higher pregnancy rates (37.2% and 33.3%, respectively). OCs are assumed to prevent the formation of ovarian cysts during GnRH-a administration through a dual effect of pituitary suppression and ovarian protection. OC pretreatment enables a significant simplification of the long standard protocol of GnRH-a administration.

Timing of onset of contraceptive effectiveness in Depo-Provera users. II. Effects on ovarian function.

OBJECTIVE: To determine the timing of onset of contraceptive effectiveness after the first injection of 150 mg of depot medroxyprogesterone acetate (DMPA) administered between days 8 and 13 of the menstrual cycle. DESIGN: Descriptive, prospective study. SETTING: A tertiary university referral center. PATIENT(S): Thirty healthy women between 18 and 40 years of age. INTERVENTION: Volunteers were injected with DMPA between days 8 and 13 (5 women on each day) of the menstrual cycle. MAIN OUTCOME MEASURE(S): Ovarian function determined by serum levels of E2 and progesterone and follicular development evaluated by vaginal ultrasound. RESULT(S): In nine (30%) of 30 women studied, DMPA did not prevent ovulation. All ovulations occurred in women receiving DMPA between days 10 and 13 of the cycle. No woman who received injections on day 8 or 9 ovulated. Ovulation suppression was more effective in women with low ovarian activity. All ovulation occurred within 3 days after the injection. CONCLUSION: A back-up contraceptive method, used after the 7th day of the menstrual cycle, is recommended for up to 7 days after the first injection of DMPA.

PIP: To ensure ovulation does not occur, it is recommended that Depo-Provera injections be administered within the first 7 days of the menstrual cycle. In some settings, this requirement acts as a barrier to women's free access to injectable contraception. Thus, the present study investigated the timing of onset of contraceptive effectiveness when the first injection of depot medroxyprogesterone acetate is administered between days 8-13 of the menstrual cycle. 30 women 18-40 years of age attending a university referral center in Campinas, Brazil, in 1995-96, were enrolled. Ovulation, detected through serum progesterone and estradiol assays and confirmed by follicle rupture at vaginal ultrasound, occurred in 9 cases (30%). No ovulations occurred when injection was administered on day 8 (n = 5) or day 9 (n = 5) of the menstrual cycle; only 1 of the 5 women treated on day 10 ovulated. On the other hand, 4 of the 10 women treated on days 11 and 12 and 4 of the 5 injected on day 13 showed evidence of ovulation. All ovulation occurred within 3 days after injection. Ovulation occurred only among women who had serum estradiol levels of 100 pg/ml and above and a leading follicle diameter greater than 13 mm at the time of injection. Ovulation suppression was more effective in women with low ovarian activity. A back-up contraceptive method used for 4 days after Depo-Provera injection should provide sufficient protection when the method is administered after day 7 of the menstrual cycle. However, given the uncertainty of the assumption of short viability of the human oocyte, it is safer to recommend 1 week's use of a back-up method or abstinence.

A randomized cross-over study on various hormonal parameters of two triphasic oral contraceptives.

The effect of two triphasic oral contraceptives (Triquilar [TRQ] and Trisiston [TRS]) containing ethinyl estradiol (EE) and levonorgestrel (LNG) on various hormonal parameters was investigated in 26 women during a cross-over study. TRS consisted of 0.03 mg EE + 0.05 mg LNG (six tablets), 0.04 mg EE + 0.075 mg LNG (six tablets), and 0.03 mg EE + 0.15 mg LNG (nine tablets), whereas TRQ was different in the second phase (five tablets) and third phase (10 tablets). Blood samples were taken on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. Both formulations inhibited ovulation reliably and decreased the serum levels of gonadotropins, free testosterone, and dehydroepiandosterone sulfate in a time-dependent manner, whereas estradiol and testosterone were already suppressed on day 6, indicating a direct suppressive effect on ovarian steroid synthesis. Prolactin, which rose sporadically in some women, was not significantly changed. In contrast, the levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the hormone-free interval of 7 days, all parameters returned at least partly to baseline. There was no significant difference between the effects of both formulations. The results suggest the possibility of a direct inhibitory effect of contraceptive steroids on ovarian steroid synthesis.

PIP: A randomized crossover study involving 26 women in Germany investigated the effect of two triphasic oral contraceptives (OCs) on selected hormonal parameters. The first triphasic, Trisiston, contained 0.03 mg of ethinyl estradiol (EE) and 0.05 mg of levonorgestrel (LNG) (6 tablets), 0.04 mg EE and 0.075 mg LNG (6 tablets), and 0.03 mg EE and 0.15 mg LNG (9 tablets). The second, Triquilar, differed from the first in the second (5 tablets) and third (10 tablets) phases. Serum samples were collected on days 6, 11, 21, and 28 of the control and washout cycles and the third treatment cycle. There were no significant differences in the hormonal effects of the two formulations. Both triphasics inhibited ovulation reliably and decreased serum levels of gonadotropins, free testosterone, and dehydroepiandrosterone sulfate in a time-dependent manner. Estradiol and testosterone were already suppressed on day 6. Prolactin rose sporadically in some women, but was not significantly changed. In contrast, levels of sex hormone binding globulin, corticosteroid binding globulin, and cortisol were significantly elevated by 100%. During the 7-day hormone-free interval, all parameters returned at least partly to baseline. These findings suggest a direct inhibitory effect of OC steroids on ovarian steroid synthesis.

Effects of long-term low-dose mifepristone on reproductive function in women.

Low-dose antiprogestin administration has been proposed as a new contraceptive modality to interference with endometrial receptivity without disturbing ovarian function. The effects of 1 mg/day mifepristone for 150 days on the menstrual cycle were assessed in 21 surgically sterilized women. The aim was to study each woman for one control cycle and during months 1, 3 and 5 of treatment. Ovulation, endometrial thickness, serum oestradiol and progesterone, urinary luteinizing hormone, endometrial morphology and cervical mucus were assessed. Luteal phase progesterone concentrations were observed in 36 of the 60 treated months assessed and less frequently as treatment progressed. The bleeding pattern was regular in most biphasic cycles, while prolonged interbleeding intervals or no bleeding were associated with monophasic cycles. Altered endometrial morphology was found in all cases irrespective of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were observed in 25 and 34% respectively of the monophasic cycles. Mifepristone, 1 mg/day, interferes with endometrial development while allowing the occurrence of biphasic ovarian cycles and regular bleeding. However, it also prevents ovarian cyclicity in a high proportion of treated months, and this is associated with increased endometrial growth in some women, which may be of concern.

PIP: Low-dose antiprogestin administration has been proposed as a new contraceptive modality that interferes with endometrial receptivity without disturbing ovarian function. To explore this potential, the effects on the menstrual cycle of 1 mg/day of mifepristone for 150 days were assessed in 21 surgically sterilized women from Santiago, Chile. Control cycles were biphasic in all 21 women and ovulatory in 20 women. Luteal phase progesterone concentrations were observed in 36 of the 60 treatment months (1, 3, and 5) assessed. The proportion of ovulatory cycles was highest during month 1 and decreased progressively with treatment. 40% of treatment cycles were monophasic and bleeding cyclicity was altered in 57%. Prolonged inter-bleeding intervals or no bleeding occurred in monophasic cycles. Endometrial morphology was altered in all cases, regardless of the occurrence of luteal activity. Increased endometrial thickness and dilated glands were recorded in 25% and 34%, respectively, of the monophasic cycles. These findings suggest that 1 mg of mifepristone interferes with endometrial development while allowing biphasic ovarian cycles and regular bleeding. Whether these endometrial alterations are sufficient to prevent implantation remains to be established. The long-term effect of prevention of ovarian cyclicity and the associated increased endometrial growth recorded in some women require further investigation.

Low-malignant potential epithelial tumors of the ovary: a clinicopathological study.

Low-malignant potential (LMP) epithelial tumors of the ovary are a group which occupy an intermediate position between the benign and those of the frankly malignant ovarian neoplasms. The actual incidence, present age and treatment are still being discussed. During the period 1991-1996, from the 650 ovarian tumors which were diagnosed and treated in our institution, 401 were epithelial tumors. The LMP serous epithelial tumors consisted of 4.36% of all serous tumors while LMP mucinous tumors were 9.70% of all mucinous tumors. The LMP serous tumors had an 8 cm diameter on average, 83% were unilocular and 76.5% unilateral. The LMP mucinous tumors had a 17 cm diameter on average, 95% were multilocular and 95% unilateral. The mean age at diagnosis was 39 years for LMP serous tumors and 48 years for LMP mucinous tumors.

PIP: The incidence and clinical features of low-malignant potential (LMP) epithelial tumors of the ovary were investigated in a review of the 650 ovarian tumor cases diagnosed and treated at the University of Crete (Greece) Department of Obstetrics and Gynecology in 1991-96. 401 of these cases were epithelial tumors. Of these, 282 (70.32%) were benign, 96 (23.94%) were malignant, and 23 (5.74%) were LMP. LMP serous epithelial tumors accounted for 4.36% of all serous tumors while LMP mucinous tumors contributed 9.70% of the mucinous tumors. LMP serous tumors averaged 8 cm in diameter; 83% were unilocular and 76.5% were unilateral. LMP mucinous tumors averaged 17 cm in diameter; 95% were multilocular and 95% were unilateral. The primary presenting symptoms were pelvic pain (35%), palpable mass (30%), and menstrual aberrations (15%). Only 1 case of extra-ovarian metastasis was reported. The mean age at diagnosis was 39 years for LMP serous tumors and 48 years for LMP mucinous tumors. Prognosis for women with stage I ovarian tumors of LMP is excellent, with a 99% survival rate.

Borderline ovarian tumours: retrospective analysis of twenty-one cases.

Twenty-one borderline ovarian tumour cases, diagnosed and treated in our oncology section between 1986 and 1996, were retrospectively analysed. Thirty-three percent of the cases had serous tumours and the rest (66.6%) were mucinous, 57.1% of the mucinous tumours were the intestinal type and the remaining 42.9% were the endocervical type. When all the cases were analysed, the average age was 45.4+/-18.6 years, the average follow-up period was 5.5+/-2.6 years. The preoperative average CA125 level was 55.1+/-51.9 U/mL, and for CA19.9 it was 48.2+/-47.8 U/mL. Of the patients 85.7% were stage I and 14.3% state III. There were not any significant differences between the serous, intestinal-type mucinous and endometroid-type mucinous tumours regarding tumour volumes (p>0.05). When serous and mucinous tumours were compared according to the tumour markers, CA125 levels were significantly higher in the serous tumours (p=0.04) and CA19.9 levels were significantly higher in the mucinous tumours (p=0.02). All of the patients are under our follow-up and are in remission, except one, who died in the third year of the treatment because of chronic renal failure unrelated to the ovarian pathology.

PIP: Tumors of low malignant potential represent approximately 15% of epithelial ovarian tumors and tend to occur at a younger age than malignant neoplasia. This paper presents a retrospective analysis of the 21 borderline ovarian tumors diagnosed and treated at Dokuz Eylul University in Izmir, Turkey, in 1986-96. The average age at presentation was 45.4 +or- 18.6 years. The diagnosis was made by exploratory laparotomy and frozen section. 7 tumors (33.3%) were serous and 14 (66.6%) were mucinous. 8 borderline mucinous tumors (57.1%) were intestinal type and 6 (42.9%) were endocervical. The average preoperative cancer marker level was 55.1 +or- 51.9 U/ml for CA125 and 48.2 +or- 47.8 U/ml for CA19.9. CA125 levels were significantly higher in serous tumors (p = 0.04) while CA19.9 measurements were significantly higher in mucinous tumors (p = 0.02). 18 tumors (85.7%) were stage I and 3 (14.3%) were stage III. There were no significant differences in tumor volume between serous, intestinal-type mucinous, and endometroid-type mucinous tumors. Women with stage I tumors who wanted to preserve their fertility underwent unilateral salpingo-oophorectomy; total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed in the remaining cases. Women with stage III tumors received 6 rounds of first-line adjuvant chemotherapy followed by second-look laparotomy. 1 patient died in the third year of treatment as a result of chronic renal failure unrelated to the ovarian pathology; the remaining women, who have been followed an average of 5.5 +or- 2.6 years, are in remission.

Dimeric inhibin serum values as markers of ovarian activity in pill-free intervals.

Levels of inhibin A and B as well as other hormones in serum samples obtained during the pill-free interval in women taking combined oral contraceptives (OC) were measured to asses the extent of ovarian activity during that period. Type of pill and day of pill-free interval were recorded during routine gynecologic check-ups, if patients were in the pill-free period and had taken their pills regularly in the previous cycle. In addition to inhibin A and B, serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), and progesterone were also quantified. Inhibin B levels rise significantly in parallel with rising levels of FSH, LH, and E2. Progesterone levels were completely suppressed and inhibin A levels rose slightly but insignificantly. Inhibins are sensitive biochemical markers of ovarian activity in pill-free intervals.

PIP: Serum values of dimeric inhibin A and B were measured to assess the restoration of pituitary and ovarian activity during the pill-free interval in women taking combined oral contraceptives. 175 healthy women 18-35 years of age from five areas in Belgium were enrolled and monitored during routine gynecologic examinations. During the 7 day pill-free interval, inhibin B levels rose significantly in parallel with rising levels of follicle-stimulating hormone, luteinizing hormone, and estradiol. Progesterone levels were completely suppressed. Inhibin A levels rose slightly but insignificantly, reflecting an absence of development of preovulatory follicles. These findings indicate that inhibins are sensitive biochemical markers of ovarian activity in pill-free intervals. Inhibin B appears to be predominantly a product of the cohort of developing primary and subsequent early antral follicles, while inhibin A secretion is more indicative of dominant follicular and corpus luteum function.

[Late effects of sterilization in women]. / Naisen sterilisaation myöhäisvaikutukset.

Sterilization affects measurably the circulation and the functioning of the ovaries, but further studies are required to estimate the clinical meaning of the change.

PIP: In Finland, every year a total of 11,000 female sterilizations are carried out, whereas worldwide 400 million such procedures are expected to be performed by the year 2000. In the past decade, major changes have occurred in the technical aspects of the procedure. Unilateral and bilateral endocoagulation of the Fallopian tube used to be standard procedure, but at the present time, when using the method of choice, laparoscopy, a clip ties the tube. Post-sterilization symptoms include pain (10-26% of cases), pain irrespective of menstrual cycle (6-40%), dyspareunia (4%), premenstrual tension (6-40%), and prolonged menstruation. Arterial blood flow between the uterus and Fallopian tube may be disturbed and tissue damage may result infrequently. Earlier methods of female sterilization produced more tissue damage, as clips affect blood circulation. In one study, lower abdominal circulation was measured by Doppler ultrasound and compared with nonsterilized subjects 2 days before sterilization, 2 days after, and 3 months later. The results indicated that patients whose uterine blood flow had decreased subsequently returned to the previous normal value, but in the ovaries the change was greater and return to the previous value did not occur. The author's own study used salivary samples 1 month before sterilization, 3 months after sterilization, and 1 year afterwards during a whole menstrual cycle. Total progesterone values slowly decreased 1 year after sterilization. Within the menstrual cycle, the peak of the progesterone level was the lowest 3 months after sterilization and it did not reach the pre-sterilization level. Sterilization exerts a measurable effect on the ovaries, but more investigations are needed to confirm this finding.

Case studies in contraception.

Choosing the appropriate type of contraception should be decided by the healthcare professional and the patient. The author presents three unique and different cases, including insightful discussions, that should provide insight and possibly some creative solutions to some of today's contraceptive questions.

PIP: Presented and discussed are 3 cases illustrating the need for individualized decision-making in contraceptive prescription. In the 1st case, a 34-year-old woman with multiple sclerosis requested a contraceptive method with a lower failure rate than that associated with barrier methods. After discussion about potential risks and side effects, an IUD was inserted. The 2nd case involved a 17-year-old woman who presented for routine gynecologic care. She was satisfied with condom use, but admitted to episodes of unprotected intercourse--including one in the preceding 24 hours. After a negative pregnancy test, the woman was provided with emergency contraceptive pills and advised to return in 3 weeks to discuss a more reliable method of contraception. In the 3rd case, a 42-year-old woman presented with complaints of heavy and irregular menstrual periods, a 30-pound weight gain in the past year, and acne; she was not using any contraceptive method. Biopsy revealed a disorganized proliferative endometrium consistent with polycystic ovarian syndrome. The patient was placed on a weight reduction diet and given a triphasic norgestimate oral contraceptive.

Effect of once weekly administration of mifepristone on ovarian function in normal women.

The effects of mifepristone on ovarian function during a once weekly oral administration regimen were studied in nine healthy women. Each received 25 mg mifepristone on cycle days 3, 10, 17, and 24. Ovulation, as documented by hormonal measurements and ultrasonography, was inhibited during treatment in five subjects, with a midcycle surge of luteinizing hormone and ovulation occurring 6-18 days after the last pill was administered in four of the five subjects. These five treatment cycles were prolonged 9-26 days. The other four subjects had normal cycles as judged by serum hormone levels, ultrasonography, and cycle length. All nine subjects had delayed endometrial growth as indicated by ultrasonography. There was a significant correlation between concentrations of serum mifepristone (10 h and 58 h) and alpha 1-acid glycoprotein, the protein to which mifepristone binds in circulation. Response to mifepristone did not depend on its circulating levels. We conclude that once weekly administration of 25 mg mifepristone can interfere with normal follicular development and function, but the inhibition of ovulation was inconsistent.

Modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest.

Twenty-two healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.3 +/- 4.1), were included in a single-center, noncomparative study to investigate the modulation of ovarian function by an oral contraceptive containing 30 micrograms ethinyl estradiol in combination with 2.00 mg dienogest. At baseline, during three treatment cycles and post-treatment, serum levels of luteinizing hormone, follicle-stimulating hormone, 17 beta-estradiol, and progesterone were assayed and ultrasonography was used to measure follicular size and the thickness of the endometrium. The primary efficacy variable was inhibition of ovulation as measured by ovarian activity grading. All volunteers ovulated during the pretreatment cycle. During treatment, none of the subjects had ovulatory cycles, although there was still some ovarian activity in several subjects. During the first treatment cycle, only 4% (1 subject) of cycles showed active follicle-like structures. The frequency of follicle-like structures increased to 33% and 35% during treatment cycles 2 and 3. The frequency of presumptive luteinized unruptured follicle-like structures was 5% (1 subject) and 15% (3 subjects) in treatment cycles 2 and 3. The serum hormone concentrations were effectively suppressed in comparison to baseline. The ovarian activity returned to baseline during the post-treatment period. One subject was excluded from further study because of a medical problem believed unrelated to use of the oral contraceptive. No serious adverse events were recorded during the course of the study. The results of the present investigation indicate that the modulatory effects on ovarian function of the monophasic oral-contraceptive containing 30 micrograms ethinyl estradiol combined with 2.00 mg dienogest lead to adequate suppression of ovarian activity and effective inhibition of ovulation.

Ovarian volume in gynecologically healthy women using no contraception, or using IUD or oral contraception.

OBJECTIVE: The aim of this study was to determine the ovarian volume by transvaginal ultrasonography in a gynecologically healthy population of women using no contraception, using intrauterine contraceptive device, or using oral contraceptive. MATERIALS AND METHOD: The study had a cross-sectional design. The ovaries of 428 women aged 1445 who contacted the family planning clinic in the county of Funen were examined. Most of the statistical analyses were carried out using standard techniques. However polynominal regression analysis was used to model ovarian volumes as a function of the day of cycle. RESULTS: No differences between the volumes of the right and the left ovary were found in any of the groups. Significant differences were found between the ovarian volumes of the three groups. The ovarian volumes were found to be largest in women using intrauterine contraceptive device, lesser in women using no contraception and smallest in women using oral contraception. A significant difference was found of the ovarian volumes throughout the menstrual cycle in women who were not using oral contraception. The ovarian volumes did not change throughout the menstrual cycle in women using oral contraception. In women not using oral contraception the largest ovary increased in volume from the start of the cycle to day 19, thereafter the volume declined. No evidence of any change of volume over the menstrual cycle was found in the smallest ovary and, for women using oral contraception, both ovaries. There was no correlation between age, height, weight, parity, and ovarian volume in any of the groups. CONCLUSION: The ovarian volumes, in gynecologically healthy women using intrauterine contraceptive device, are larger than in women using no contraception. It appears that oral contraception reduces the volumes of both ovaries in all phases of the menstrual cycle to equal levels.

PIP: The aim of this cross-sectional study was to determine the ovarian volume by transvaginal ultrasonography in a gynecologically healthy population of women using no contraception, using IUDs, or using oral contraceptives (OCs). The ovaries of 428 women aged 14-45 who contacted the family planning clinic in the county of Funen were examined. Most of the statistical analyses were carried out using standard techniques. However, polynominal regression analysis was used to model ovarian volumes as a function of the day of cycle. No differences between the volumes of the right and the left ovary were found in any of the groups. Significant differences were found between the ovarian volumes of the three groups. The ovarian volumes were found to be largest in women using IUDs, lesser in women using no contraception, and smallest in women using OCs. A significant difference was found of the ovarian volumes throughout the menstrual cycle in women who were not using OCs. The ovarian volumes did not change throughout the menstrual cycle in women using OCs. In women not using OCs the largest ovary increased in volume from the start of the cycle to day 19; thereafter the volume declined. No evidence of any change of volume over the menstrual cycle was found in the smallest ovary and, for women using OCs, in both ovaries. There was no correlation between age, height, weight, parity, and ovarian volume in any of the groups. The ovarian volumes in gynecologically healthy women using IUDs are larger than in women using no contraception. It appears that OC use reduces the volumes of both ovaries in all phases of the menstrual cycle to equal levels.

The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women.

Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, glucose intolerance, and obesity. High levels of the lipostatic hormone, leptin, have also been reported in this condition. The purpose of the present study was to examine the effect of an oral contraceptive (OC) of low androgenicity containing desogestrel on glucose tolerance in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on leptin concentrations. Sixteen nondiabetic hyperandrogenic women, aged 29 +/- 1 yr with a body mass index (BMI) of 36.8 +/- 1.8 kg/m2, underwent an oral glucose tolerance test before and after 6 months of therapy with the OC. Free testosterone decreased and sex hormone-binding globulin increased after therapy (P < 0.001). Glucose tolerance deteriorated significantly, and two women developed diabetes. Body weight, BMI, and leptin did not change significantly. Leptin correlated with BMI before (r = 0.56; P = 0.02) and after (r = 0.51; P = 0.04) treatment, but not with glucose, insulin, total and free testosterone, or sex hormone-binding globulin before or after treatment. In conclusion, 1) glucose tolerance should be monitored in hyperandrogenic women using OC, even those of low androgenicity; and 2) changes in androgenic/estrogenic status had no effect on the leptin concentration, suggesting that its sexual dimorphism is not related to sex steroids.

PIP: Ovarian hyperandrogenism can be associated with insulin resistance, hyperinsulinemia, and glucose intolerance--all of which, in turn, have been linked to high levels of the lipostatic hormone, leptin. This study investigated the effect of an oral contraceptive (OC) containing a progestin of low androgenicity on glucose tolerance and insulinemia in hyperandrogenic women and the impact of changes in androgenic/estrogenic status on plasma leptin levels. 16 nondiabetic hyperandrogenic US women (mean age, 29 years) with a mean body mass index of 36.8 kg/sq. m underwent oral glucose tolerance testing before and after 6 months of treatment with an OC containing 30 mcg of ethinyl estradiol and 150 mcg of desogestrel. Treatment was associated with significant decreases in free testosterone and increased sex hormone-binding globulin (p 0.001). Glucose tolerance deteriorated moderately but significantly. After 6 months of treatment, 5 women had normal glucose tolerance, 9 had impaired glucose tolerance, and 2 developed non-insulin-dependent diabetes mellitus. There were no significant changes in serum insulin concentrations, body weight, body mass index, or leptin, but leptin levels were highly correlated with body mass index both before and after treatment. The data suggest that the sexual dimorphism of leptin is not caused by differences in sex hormones. Even when OCs containing low androgenic progestins are prescribed, women at high risk for diabetes should receive regular glucose tolerance tests.

Intracervical and fundal administration of levonorgestrel for contraception: endometrial thickness, patterns of bleeding, and persisting ovarian follicles.

OBJECTIVE(S): To study the prevalence of persisting ovarian follicles and to assess the endometrial changes and patterns of vaginal bleeding over 1 year of use of a 20 micrograms/24 h levonorgestrel-releasing intracervical contraceptive device. DESIGN: Prospective, randomized study. SETTING: Two family planning clinics in Helsinki, Finland. PATIENT(S): Women requesting intrauterine hormonal contraception. INTERVENTION(S): Insertion of a levonorgestrel-releasing intracervical contraceptive device into the cervical canal (group 1, n = 151) or fundally into the uterine cavity (group 2, n = 147) for contraception. MAIN OUTCOME MEASURE(S): Transvaginal ultrasonography of the ovaries and endometrium at insertion and 3, 6, and 12 months after insertion. Data on bleeding were collected using menstrual diary cards. RESULTS: Persisting ovarian follicles were found in < 8% of women. In both groups, the amount of endometrial tissue decreased significantly in 3 months. The incidence of amenorrhea during the 1st year was higher in the fundal insertion group. CONCLUSION(S): The number of persisting follicles was low. Follicles resolved within 6 to 8 weeks. No association was found between persisting follicles and problems of bleeding. Compared with intracervical insertion, fundal insertion resulted in more uniform endometrial suppression and fewer days of bleeding and spotting.

PIP: The prevalence of persisting ovarian follicles as well as endometrial changes and vaginal bleeding patterns associated with the levonorgestrel-releasing intracervical contraceptive device were investigated in a 12-month prospective study involving 398 women recruited from 2 family planning clinics in Helsinki, Finland. The device, which released 20 mcg of levonorgestrel per 24 hours, was inserted into the cervical canal in 151 women and fundally into the uterine cavity in the remaining 147 women. Transvaginal ultrasonography of the endometrium and ovaries was performed at insertion and at 3, 6, and 12 months post-insertion. The prevalence of persisting ovarian follicles was 6.5% at 3 months, 7.7% at 6 months, and 3.2% at 12 months, with no significant differences between the 2 study groups. All but 1 follicular structure resolved spontaneously within 6-8 weeks of follow-up. In both groups, endometrial tissue thickness decreased significantly by 3 months and remained thin for the duration of the study. The number of days of bleeding, documented through menstrual diaries, decreased slowly in the cervical group, from 4.0 in the first month to 2.0 in the sixth month and 1.0 in the 12th month; however, a very steep decrease occurred in the fundal insertion group, from 5.0 in the first month to 1.0 in the sixth month and 0.0 in the 12th month. 11% of women in the intracervical insertion group compared with 24% in the fundal insertion group experienced at least 1 continuous 90-day amenorrhea episode. There was no correlation between functional ovarian cysts and bleeding patterns. Although fundal insertion of an intracervical contraceptive device results in more uniform suppression of the endometrium, women who consider amenorrhea undesirable should have the device inserted cervically.