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PubMed2002

The effects of levonorgestrel on various sperm functions.

Two doses of 750-microg levonorgestrel at 12 h apart is one of the regimens for emergency contraception. The mechanism of action of this regimen is not fully known. We investigated whether levonorgestrel influences sperm functions and thereby, exerts contraceptive activity. The motility, acrosome reaction, zona binding capacity, and oocyte fusion capacity of human spermatozoa treated with 1, 10, and 100 ng/mL levonorgestrel for 3 h were evaluated. Levonorgestrel decreased the curvilinear velocity of the treated spermatozoa in a dose-dependent manner. A significant decrease in straight-line velocity, average path velocity and linearity were also found with 100 ng/mL levonorgestrel treatment. This concentration of levonorgestrel, but not others, also marginally decreased (p = 0.045) the zona binding capacity of the treated spermatozoa. The steroid had no effect on acrosome reaction but had a dose-dependent inhibition on spermatozoa-oocyte fusion. These data show that levonorgestrel affects sperm function only at high concentration and the contribution of these effects to emergency contraception is unlikely to be significant.

Acrosome Reaction↗

PubMed2003

Levonorgestrel and mifepristone in emergency contraception.

Research on new technologies by the Special Programme of Research, Development and Research Training in Human Reproduction at WHO has led to the development of two new methods for emergency contraception, the levonorgestrel regimen and a low-dose mifepristone regimen. In 4 years, the levonorgestrel regimen has already been approved in some 95 countries. We review this research and present combined data from our multinational trials and combined estimates of efficacy for mifepristone and for levonorgestrel separately. Data were available for 6283 women in 10 mg mifepristone groups and 4098 women in levonorgestrel groups. One of these studies compared the two methods, namely a randomized, double-blind trial in which we also investigated a single dose of 1.5 mg of levonorgestrel. Both levonorgestrel and mifepristone are effective for emergency contraception and prevent a high percentage of pregnancies when used within a few days after coitus. Mifepristone is associated with later return of menses compared to levonorgestrel.

Clinical Trials as Topic↗

PubMed1997

A comparative study of two levonorgestrel-containing hormone replacement therapy regimens of efficacy and tolerability variables.

OBJECTIVE: To compare the effect of two sequential hormone replacement regimens differing in the dose of levonorgestrel on climacteric symptoms, bleeding pattern and lipid metabolism in postmenopausal women. STUDY DESIGN: In a multicentre, randomized, double-blind, active-treatment-controlled study, 210 postmenopausal women were assessed at the end of treatment cycles 3 and 6. The high-levonorgestrel group was treated with 2 mg estradiol valerate (days 1-21) sequentially combined with 0.25 mg levonorgestrel (days 12-21). The low-levonorgestrel group received the same estrogen regimen (2 mg estradiol valerate, days 1-21), but levonorgestrel was administered sequentially in a dose of 0.15 mg during the last 12 days of the cycle (days 10-21). Statistical analysis by Student's t-test for dependent variables (measured values versus baseline) and independent variables (differences between groups), and the composite t-test method for comparison of both regimens with respect to efficacy, was performed. RESULTS: Both groups were statistically comparable. The trial was completed by 137 subjects. Protocol violations occurred in 38 cases. Thirty-five subjects dropped out during the study, 21 of them because of adverse events. Both treatments were equally effective in the treatment of climacteric complaints. There were no clinically significant changes in body weight, blood pressure, haematological tests, and parameters of clinical chemistry. There was a tendency towards a reduction in bleeding intensity in both groups in the second half of the treatment period. The treatment for six cycles with both regimens significantly (P < 0.05) decreased plasma concentrations of triglycerides (significant in the low-levonorgestrel group only), high-density lipoprotein cholesterol, high-density lipoprotein-3-cholesterol, lipoprotein(a) and apolipoprotein A1. In parallel, the serum concentration of total cholesterol increased significantly in both treatment groups, whereas low-density lipoprotein cholesterol increased significantly in the high-levonorgestrel group only. The changes in high-density lipoprotein-2-cholesterol, and apolipoprotein B did not reach statistical significance. CONCLUSIONS: It can be concluded that both sequential combined oral hormone replacement therapy (HRT) regimens were equivalent with respect to efficacy and tolerability in the treatment of women with climacteric complaints. The preparation with the lower dose of progestin showed a tendency towards a less unfavourable influence on the lipid profile.

Cohort Studies↗

PubMed2000

Contraception with a novel 'frameless' intrauterine levonorgestrel-releasing drug delivery system: a pilot study.

OBJECTIVE: To evaluate the contraceptive performance, acceptability, side-effects and adverse events of a novel 'frameless' intrauterine drug delivery system, the FibroPlant levonorgestrel intrauterine system, releasing 14 microg of levonorgestrel/day. An ancillary objective was to evaluate the effect of the new intrauterine system on menstrual blood loss. STUDY DESIGN: This was an open-label, non-comparative, ongoing pilot study. Fifty-four insertions were performed by the first author in fertile women between 16 and 51 years of age for contraception. Eighteen of these women were fitted with the FibroPlant levonorgestrel intrauterine system for the treatment of excessive bleeding as well as for contraceptive purposes. Of these women, 12 had medium-to-large-sized uterine fibroids in addition to heavy menstrual flow. The follow-up period of the trial was between 6 and 16 months. RESULTS: At the time of study analysis the total number of woman-months was 464 and 21 women had had the FibroPlant levonorgestrel intrauterine system in place for more than 1 year. No pregnancies occurred. All women reported greatly reduced bleeding; however, no cases of amenorrhea resulting from endometrial suppression were encountered. Significant spotting was rare after the first 3 months following insertion. No complications (e.g. infection, expulsion or perforation) occurred. The FibroPlant levonorgestrel intrauterine system was well tolerated by all women involved in the study and no systemic hormonal side-effects were reported. CONCLUSIONS: Although the average age of the study subjects was 40 years, this preliminary study suggests that the FibroPlant levonorgestrel intrauterine system is an effective contraceptive. The FibroPlant levonorgestrel intrauterine system is also highly efficacious in controlling bleeding in women presenting with excessive menstrual flow. Effective endometrial suppression is the principal mechanism underlying both the contraceptive effect and the effect on menstrual blood loss. The low release rate oflevonorgestrel results in an absence of hormonal side-effects. The unique 'frameless' design characteristics of the intrauterine system facilitate insertion and minimize pain and discomfort. These factors, together with the low incidence of amenorrhea, appear to be a significant step forward from the 'framed' Nova-T levonorgestrel intrauterine system (Mirena).

Adolescent↗

PubMed1995

The effect of local intrauterine levonorgestrel administration on endometrial thickness and uterine blood circulation.

To evaluate non-invasively the role of levonorgestrel releasing devices in direct contact with the endometrium on menstrual spotting and endometrium inactivation, we inserted levonorgestrel releasing devices (20 micrograms/24 h) either into the cervical canal or the uterine cavity of 30 fertile women. Both before insertion and over the following 3 months, we used transvaginal sonography to measure the endometrial thickness in 20 of the women and Doppler flow to measure the uterine blood flow in the remaining 10 women. The women were asked to keep records of menstrual bleeding and they gave blood samples for the measurement of serum oestradiol, progesterone and levonorgestrel. By 10 weeks after insertion there was a significant decrease in endometrial thickness in both groups. Intracervical levonorgestrel release allowed the endometrium to maintain cyclic changes, whereas direct intrauterine levonorgestrel release eliminated the cyclical changes. The total number of spotting days was significantly less (P = 0.0249) in the intracervical release group at 3 months; 1.2 +/- 0.6 versus 8.1 +/- 1.8 (mean +/- SE). There were no significant differences in hormone concentrations between the groups. The pulsatility index did not change significantly during the study. We concluded that the inactivation process of the endometrium can be monitored by transvaginal sonography and that locally administered levonorgestrel does not change circulatory conditions detectable by Doppler flow. Our results also suggest that the inactivation process of the endometrium is different between intracervical and intrauterine levonorgestrel administration and may explain the difference in the number of spotting days.

Adult↗

PubMed2005

The role of the levonorgestrel-releasing intrauterine device in the management of symptomatic endometriosis.

PURPOSE OF REVIEW: The aim of this article is to evaluate the biological rationale for the use of an intrauterine device releasing 20 mug/day of levonorgestrel in women with endometriosis, and to assess its efficacy in relieving pelvic pain symptoms. RECENT FINDINGS: Levonorgestrel induces endometrial glandular atrophy and extensive decidual transformation of the stroma, downregulates endometrial cell proliferation, increases apoptotic activity, and has antiinflammatory and immunomodulatory effects. Up to 85% of patients wearing the device have anovulatory cycles during the first 3 months of use, but the proportion falls to below 35% by 12 months. After the first year of use, a 70-90% reduction in monthly blood loss is observed; few women report intermenstrual bleeding and about 20-30% amenorrhea. This is advantageous in patients experiencing dysmenorrhea. Although it is maintained that the hormonal activity of the levonorgestrel intrauterine device is local, a systemic effect secondary to uterine absorption of levonorgestrel is probable. The levonorgestrel intrauterine device has proven effective in relieving pelvic pain symptoms caused by peritoneal and rectovaginal endometriosis and in reducing the risk of recurrence of dysmenorrhea after conservative surgery. SUMMARY: Intrauterine administration of levonorgestrel with direct distribution to pelvic tissues would imply a local concentration greater than plasma levels. This could result in a superior effectiveness with limited adverse effects and increased patient compliance during long-term treatment. Further trials are needed, however, to verify whether the good results observed are maintained during an entire 5-year period, to confirm the efficacy on dyspareunia and dyschezia, and to compare the effects of the levonorgestrel intrauterine device with those of other treatment options.

Contraceptive Agents, Female↗

PubMed1996

The role of triphasic levonorgestrel in oral contraception: a review of metabolic and hemostatic effects.

Epidemiological studies suggesting a possible association between the use of combined oral contraceptives and an increased risk of cardiovascular disease have led to extensive investigations into the effect of oral contraceptives on lipid and carbohydrate metabolism, and on hemostasis. Since this association was originally suggested, the steroid dose in oral contraceptives has been significantly reduced and new progestogens have been developed. Also, triphasic formulations have been introduced which offer a well-balanced estrogen/progestogen ratio, allowing a further reduction in the progestogen dose per cycle, and thus helping to minimize unwanted metabolic and hemostatic effects. The metabolic interactions of triphasic levonorgestrel, the first triphasic formulation to be introduced, have received particular attention. Lipid metabolism appears to be largely unaffected by triphasic levonorgestrel, most studies reporting no significant change in high- (HDL-C) or low-density lipoprotein-cholesterol (LDL-C) levels. Several studies have reported a decrease in the lipoprotein subfraction HDL2-C levels, but in most cases measurements of the LDL-C/HDL-C and apolipoprotein A-1/B ratios reveal no clinically significant effects. Concerning lipids, most studies suggest that triphasic levonorgestrel has less metabolic impact than the monophasic formulation. In common with all currently available oral contraceptives, triphasic levonorgestrel appears to have some effect on carbohydrate metabolism. The study results vary, however; some investigators have found an impairment of glucose tolerance, whereas others have not detected any significant effect. Compared with lipid and carbohydrate metabolism, fewer studies have investigated the effect of triphasic levonorgestrel on hemostasis. In common with all estrogen-containing oral contraceptives, levonorgestrel appears to stimulate some procoagulant activity, elevating the levels of factors VII and X, and fibrinogen. However, the effect of triphasic levonorgestrel appears to be balanced, with most studies reporting a corresponding increase in anti-coagulant-fibrinolytic activity. Although most of the studies reviewed here reported some statistically significant metabolic interactions, many authors comment that the changes are probably not clinically relevant in terms of an altered risk of cardiovascular disease. The true risk of vascular disease associated with modern low-dose oral contraceptives remains to be confirmed when sufficient epidemiological data eventually become available.

Carbohydrate Metabolism↗

PubMed1998

A double-blind study comparing the contraceptive efficacy, acceptability and safety of two progestogen-only pills containing desogestrel 75 micrograms/day or levonorgestrel 30 micrograms/day. Collaborative Study Group on the Desogestrel-containing Progestogen-only Pill.

OBJECTIVE: To compare the contraceptive efficacy, bleeding pattern, acceptability and safety of desogestrel 75 micrograms/day (Cerazette) as a progestogen-only formulation to levonorgestrel 30 micrograms/day in healthy female subjects. METHODS: In a double-blind, randomized, group-comparative, multicenter trial, 989 subjects were randomized to desogestrel 75 micrograms/day and 331 to levonorgestrel 30 micrograms/day. The women were observed during 13 consecutive treatment periods of 28 days. RESULTS: The Pearl indices for in-treatment pregnancies, excluding gross non-compliance, were 0.14 (one pregnancy in 727 woman-years) in the desogestrel group and 1.17 (three pregnancies in 257 woman-years) in the levonorgestrel group. Using the 90-day reference period for assessing the bleeding pattern, desogestrel users had a higher incidence of amenorrhea and infrequent bleeding on the one hand, and of frequent bleeding and prolonged bleeding on the other hand, at the beginning of the study period. In contrast to the levonorgestrel group, a tendency towards less bleeding over time was observed in the desogestrel group. The frequency and pattern of adverse experiences were comparable for desogestrel 75 micrograms/day and levonorgestrel 30 micrograms/day. CONCLUSIONS: Desogestrel 75 micrograms/day is a reliable and safe progestogen-only pill with a contraceptive efficacy superior to levonorgestrel 30 micrograms/day. These was a similar overall acceptability of desogestrel 75 micrograms/day and levonorgestrel 30 micrograms/day.

Adolescent↗

PubMed2001

Treatment of menorrhagia with a novel 'frameless' intrauterine levonorgestrel-releasing drug delivery system: a pilot study.

OBJECTIVE: To evaluate the effect on menstrual blood loss of a novel 'frameless' intrauterine drug delivery system, the FibroPlant levonorgestrel intrauterine system (IUS), releasing 14 microg of levonorgestrel/day. An ancillary objective was to evaluate the contraceptive performance. STUDY DESIGN: This was an open-label, non-comparative ongoing pilot study. Thirty-two insertions were performed in fertile women aged between 31 and 51 years for the treatment of menorrhagia, as well as for contraceptive purposes. Fifteen women who developed excessive bleeding were fitted with the FibroPlant levonorgestrel IUS immediately following the removal of a copper-bearing intrauterine device (IUD), the GyneFix IUD. To discriminate between menorrhagia and normal menstrual blood loss, women were evaluated using a simple visual assessment technique. The trial covered a period from a minimum of 1 month up to 23 months. RESULTS: At the time of study analysis, the total number of woman-months was 361. Fourteen of the women had had the FibroPlant levonorgestrel IUS in place for more than 1 year, and 29 women for 6 months or more. All women reported greatly reduced bleeding. However, no cases of amenorrhea resulting from endometrial suppression were encountered. The reduction of bleeding was substantial after 1 month of treatment and decreased further over the next months to remain stable thereafter. The mean bleeding score before treatment was 338 (range 185-740) in the group who had had no prior use of an IUD and 368 (range 185-890) in the group with prior IUD use. The mean bleeding score dropped to a mean score of 70 (range 5-210) in the 'no prior IUD use' group and to a mean score of 52 (range 3-150) in the 'prior IUD use' group, after 1-23 months of follow-up. This result is highly statistically significant (p < 0.001). There were no statistical differences in bleeding scores before and during treatment between the two groups of women, with or without prior use of the copper IUD. Significant spotting was rare after the first 3 months following insertion. No complications (e.g. infection, expulsion or perforation) or pregnancies occurred. The FibroPlant levonorgestrel IUS was well tolerated by all women involved in the study and no systemic hormonal side-effects were reported. CONCLUSION: The FibroPlant levonorgestrel IUS is effective in significantly reducing the amount of menstrual blood loss in women with menorrhagia. Strong endometrial suppression is the principal mechanism explaining both the effect on menstrual blood loss and the contraceptive performance of the IUS. There were no differences in bleeding scores before and during treatment between the two groups of women with or without prior use of the copper IUD, suggesting that the development of heavy bleeding was not related to the use ofthe IUD. The therapeutic effect of this contraceptive method is highly desirable, particularly in women with heavy bleeding or anemia in developing countries, as other treatment modalities are less effective, more costly, more invasive or inaccessible. The low daily release rate of levonorgestrel from the FibroPlant levonorgestrel IUS results in a low incidence of hormonal side-effects and reduces the likelihood of amenorrhea. The simple design characteristics and revolutionary anchoring system minimize the occurrence of complaints of pain and the incidence of expulsion.

Adult↗

PubMed2000

Evaluation of the ability of levonorgestrel butanoate alone, or in combination with testosterone buciclate, to suppress spermatogenesis in the bonnet monkey (Macaca radiata).

Levonorgestrel butanoate, 0.25, 1.0 and 2.5 mg/kg, administered as two injections 60 days apart (groups II, III, IV), failed to suppress spermatogenesis consistently and uniformly in adult bonnet monkeys (group size, n=6) compared to controls (group I). Levonorgestrel butanoate at the same doses combined with two simultaneous injections of 40 mg testosterone buciclate (groups V, VI, VII), consistently suppressed spermatogenesis in the period 60-240 days and in most animals to azoospermia or severe oligozoospermia (<5 x 106/mL) during days 90-210. The degree and duration of suppression were greatest in group VI. Sperm motility declined in all treated animals and spermatozoa in the semen of animals from groups V and VI lost all progressive motility in the period 60-150 and 60-210 days, respectively. The changes in testosterone levels were similar in groups V and VI, increasing within 24 h after the combined injection to reach a peak by day 28 followed by a sharp decrease until day 67. The second injection increased testosterone levels by a lesser degree to peak levels on day 81. In group VII, testosterone levels decreased until day 59 after the first injection but increased to a maximum on day 81 after the second injection followed by a gradual decrease until day 150 to below baseline values. Peak levels of serum levonorgestrel were observed 1-7 days after injection of levonorgestrel butanoate alone. Clearance of the drug was slow, being detectable in the circulation until day 330 of the 360 day study period in the high dose group. Dose-response increases to peak levels of levonorgestrel were attained on day 7 in groups V, VI and VII, after the first injection. After the second injection, peak levels were seen on day 61 in groups V and VI and on day 81 in group VII. Levonorgestrel was no longer detectable in blood in groups V and VI by days 210 and 300, respectively, but small circulating amounts remained in group VII at the conclusion of the study on day 360. This study indicates that when levonorgestrel butanoate is combined with a long-acting androgen and injected at two-monthly intervals, effective and reversible suppression of spermatogenesis is achieved.

Animals↗

PubMed1998

Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia.

OBJECTIVE: To compare the efficacy and acceptability of the levonorgestrel intrauterine system and norethisterone for the treatment of idiopathic menorrhagia. DESIGN: A randomised comparative parallel group study. SETTING: Gynaecology outpatient clinic in a teaching hospital. PARTICIPANTS: Forty-four women with heavy regular periods and a measured menstrual blood loss exceeding 80 ml. METHODS: Twenty-two women had a levonorgestrel intrauterine system inserted within the first seven days of menses, and 22 women received norethisterone (5 mg three times daily) from day 5 to day 26 of the cycle for three cycles. MAIN OUTCOME MEASURES: The main outcome measure was the change in objectively assessed menstrual blood loss after three months of treatment. RESULTS: When menstrual blood loss at three months was expressed as a percentage of the control, the levonorgestrel intrauterine system reduced menstrual blood loss by 94% (median reduction 103 ml; range 70 to 733 ml), and oral norethisterone by 87% (median reduction 95 ml; range 56 to 212 ml). After three cycles of treatment 76% of the women in the levonorgestrel intrauterine system group wished to continue with the treatment, compared with only 22% of the norethisterone group. CONCLUSIONS: Both the levonorgestrel intrauterine system and oral norethisterone in this regimen provided an effective treatment for menorrhagia in terms of reducing menstrual blood loss to within normal limits. The levonorgestrel intrauterine system was associated with higher rates of satisfaction and continuation with treatment, and thus offers an effective alternative to currently available medical and surgical treatments for menorrhagia.

Adult↗

PubMed1980

Clinical and endocrinologic study of continuous levonorgestrel administration from subcutaneous solid polydimethylsiloxane rods.

Three solid polydimethylsiloxane (Silastic) rods containing levonorgestrel were inserted into the subcutaneous tissue of the volar aspect of the forearm of 8 women. Serum samples were drawn three times a week for 2 months and weekly thereafter for 2 years in 3 of the subjects. The other subjects had serum drawn during the twelfth and last treatment months. Levonorgestrel, estradiol and progesterone were measured in all samples. The subject kept a bleeding record. In comparison to an earlier clinical trial in which 6 hollow capsules of Silastic filled with levonorgestrel were used, the 3 solid levonorgestrel-containing rods provided higher serum levels of levonorgestrel, fewer serum estradiol peaks, only a single episode of ovulation and better bleeding performance.

Adult↗

PubMed1982

Clinical performance of a new levonorgestrel-releasing intrauterine device. A randomized comparison with a nova-T-copper device.

The clinical performance of two levonorgestrel-releasing intrauterine devices (IUDs) with different release rates was studied and compared with a copper-releasing Nova-T device in a randomized partly double-blind multiclinical trial. Special attention was given to patterns of bleeding, hormonal side-effects, blood pressure and body weight. The clinical acceptability of the levonorgestrel IUDs was as good as that of the copper-releasing IUD. A highly significant decrease in the amount of menstrual blood loss was seen with the levonorgestrel-IUDs, the users of which experienced fewer days of bleeding than prior to insertion. Patients suffering from dysmenorrhea experienced relief from this symptom after insertion of a levonorgestrel-IUD. Some side-effects, usually referred to as hormonal, increased during the levonorgestrel-IUD use, but did not result in higher termination rates than with the Nova-T device. No changes in body weight were recorded for the levonorgestrel-IUDs and a slight decrease in both systolic and diastolic blood pressure was found after one year of use. No infections were recorded.

Adolescent↗

PubMed1983

Levonorgestrel plasma levels during continuous administration with different models of subdermal implants.

Plasma concentrations of levonorgestrel were determined in women using subdermal levonorgestrel implants. One group had 6 Silastic capsules (NORPLANT), one group had 4 and one group had 6 covered Silastic rods for variable lengths of time. Levonorgestrel concentrations remained constant around 0.4 ng/ml up until 6 years of use in the Norplant group. The observation period was shorter for the covered rods; plasma concentrations were, however, constant around 0.55 ng/ml and 0.70 ng/ml for 3.5 years with the 4 rods and 6 covered rods, respectively. The difference in mean levonorgestrel concentrations between the three groups were statistically significant (p less than 0.0005). Plasma levels of levonorgestrel were twice to three times higher in blood obtained from the arm with the implants compared to the levels found in the other arm. The application of a tourniquet for variable periods before blood sampling did not influence the plasma concentrations of levonorgestrel.

Blood Specimen Collection↗

PubMed1990

Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids.

There is limited information on the metabolism of levonorgestrel, norethindrone and structurally related contraceptive steroids. Both levonorgestrel and norethindrone undergo extensive reduction of the alpha, beta-unsaturated ketone in ring A. Levonorgestrel also undergoes hydroxylation at carbons 2 and 16. The metabolites of both compounds circulate predominantly as sulfates. In urine, levonorgestrel metabolites are found primarily in the glucuronide form, whereas norethindrone metabolites are present in approximately equal amounts as sulfates and glucuronides. Of the progestogens structurally related to norethindrone, norethindrone acetate, ethynodiol diacetate, norethindrone enanthate, and perhaps lynestrenol, undergo rapid hydrolysis and are converted to the parent compound and its metabolites. There is no convincing evidence that norethynodrel is converted to norethindrone. Of the progestogens structurally related to levonorgestrel, it appears that neither desogestrel nor gestodene are transformed to the parent compound. However, there is evidence that norgestimate can be, at least partly, converted to levonorgestrel. Further studies on the metabolism of these progestogens are required before we can understand their mechanism of action.

Animals↗

PubMed1993

A clinical comparison of two triphasic oral contraceptives with levonorgestrel or norethindrone: a prospective, randomized, single-blind study.

Menstrual bleeding patterns were investigated in young women taking either a levonorgestrel triphasic, Triquilar, or a norethindrone triphasic, Ortho 7/7/7, two commonly prescribed low-dose oral contraceptives. The levonorgestrel triphasic contains ethinyl estradiol (EE) 30 micrograms + levonorgestrel (LNG) 50 micrograms for the first six days, EE 40 micrograms + LNG 75 micrograms for the following five days, and EE 30 micrograms + LNG 125 micrograms for the last ten days. The norethindrone triphasic contains EE 35 micrograms + norethindrone (NET) 0.5 mg for the first seven days, EE 35 micrograms + NET 0.75 mg for the following seven days and EE 35 micrograms + NET 1.0 mg for the last seven days. Three hundred women from 16 to 25 years of age were randomized to the levonorgestrel triphasic (n = 150) or the norethindrone triphasic (n = 150) groups. Assessments were made from daily diary cards and from bimonthly investigator interviews over 6 pill cycles. The results showed a higher incidence of intermenstrual bleeding (breakthrough bleeding and/or spotting) in the norethindrone triphasic group (NET group) than in the levonorgestrel triphasic group (LNG group): 44.9% of patients (66/147) randomized to the LNG group reported intermenstrual bleeding one or more times during the study compared with 61.9% (91/147) randomized to the NET group (p = 0.0036). Furthermore, in subjects who did not miss any pills, the proportion of patients with intermenstrual bleeding in each cycle was significantly greater (p < 0.02, cycles 1-4, 6; p > 0.05, cycle 5) and was experienced for more days per cycle (p < 0.05, cycle 1) and for more cycles per patient (p < 0.05, 5 cycles) in the NET group compared with the LNG group. Intermenstrual bleeding was also less frequently observed in the LNG group than in the NET group in patients who missed pills (p < 0.05, cycles 3, 5 and 6). In addition, early withdrawal bleeding occurred more often in the NET group than in the LNG group (p < 0.05, cycles 1, 3 and 4). The incidence of amenorrhea was similar in both groups. These results demonstrate a significantly lower incidence of intermenstrual bleeding and therefore better cycle control with the levonorgestrel triphasic Triquilar, compared with the norethindrone triphasic Ortho 7/7/7.

Adolescent↗

PubMed1995

Effects of levonorgestrel on capacity of mouse oocytes for fertilization and development.

This study utilized a mouse model to examine whether levonorgestrel implants, such as Norplant, may exert their contraceptive effects in part by adversely affecting oocyte quality. Time-release pellets and silastic capsules containing levonorgestrel were implanted subdermally in mice and left in situ for periods of two or three months. After that time, mice were given injections of gonadotropins to stimulate ovulation and oocytes were obtained from the oviducts of the animals, inseminated, and subsequently cultured for 96 hrs, some in medium supplemented with levonorgestrel. The numbers of oocytes that were fertilized and the numbers that developed at least to the morula stage were determined. Levonorgestrel was not found to have an adverse effect on either fertilization or preimplantation development but instead was found in some cases to increase the proportion of oocytes fertilized and the proportion of embryos that developed to morulae. Results indicate that the contraceptive effect of levonorgestrel implants should be attributed to effects other than diminished oocyte quality and they further substantiate the safety of levonorgestrel, suggesting that it will not adversely affect early embryonic development in the event that a pregnancy should be initiated during its use.

Animals↗

PubMed2006

Cerebral venous sinus thrombosis in users of four hormonal contraceptives: levonorgestrel-containing oral contraceptives, norgestimate-containing oral contraceptives, desogestrel-containing oral contraceptives and the contraceptive patch.

BACKGROUND: It has been suggested that the risk for cerebral venous sinus thrombosis (CVST) may be greater among users of the contraceptive patch than among users of oral contraceptives (OCs). METHODS: From the PharMetrics database, we identified women aged 15-44 years who filled at least one prescription for either the contraceptive patch or desogestrel-containing, norgestimate-containing or levonorgestrel-containing OCs to assess the risk of CVST. The person-time of current exposure to each study drug, as well as the incidence rates (IRs) and incidence rate ratios (IRRs) of CVST, was calculated. RESULTS: We identified over 1 million users of the four study drugs. There were five cases of CVST among current users of desogestrel, seven cases among current users of norgestimate, two cases among current users of levonorgestrel and none among current users of the contraceptive patch. The IRs per 100,000 woman-years were 2.7 [95% confidence interval (95% CI)=0.9-6.3], 1.6 (95% CI=0.7-3.3), 0.7 (95% CI=0.1-2.4) and 0.0 (95% CI=0.0-4.8), respectively, in users of desogestrel, norgestimate, levonorgestrel and the contraceptive patch. There were two women who had CVST while not currently taking a hormonal contraceptive (IR=0.4 per 100,000 woman-years; 95% CI=0.1-1.3). The IRRs were 4.0 (95% CI=0.7-42.4) for desogestrel-containing versus levonorgestrel-containing OCs, and 2.4 (95% CI=0.5-24.0) for norgestimate-containing versus levonorgestrel-containing OCs. The IRR for the patch could not be calculated. CONCLUSIONS: There is no evidence of an increased risk of CVST in users of the contraceptive patch compared to users of levonorgestrel-containing OCs.

Administration, Cutaneous↗