Levonorgestrel and estradiol release from an improved contraceptive vaginal ring.
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Contraceptive Devices, Female↗
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Comparison of the metabolic effects of two hormonal contraceptive methods: an oral formulation and a vaginal ring. II. Serum lipoproteins and apolipoproteins.
In a long-term, prospective study the effects on lipoprotein lipids and apolipoproteins (apo) of a combined oral contraceptive (OC) (30 micro gram ethinylestradiol and 150 micro gram levonorgestrel) and a contraceptive vaginal ring (CVR) releasing estradiol (about 180 micro gram per day) and levonorgestrel (about 290 micro gram per day) were compared. The two treatments induced significantly different effects. In the OC group the lipoprotein-lipid concentrations showed only minor changes, but apolipoproteins (apo) B and A-I increased by about 15%. In contrast, during treatment with the CVR there was a 25% decrement of cholesterol in high density lipoprotein (HDL) and at most 10% in low density lipoprotein (LDL) cholesterol, with only minor effects on apo B and A-I. The ratio of LDL and HDL cholesterol increased in the CVR group but not in the OC group. The results also indicate a change in the composition of the LDL and HDL particles, with an altered lipid/protein ratio, during both contraceptive treatments. Despite the impressive relative increase in LDL:HDL ratio in the contraceptive ring group, the average absolute value of this ratio did not reach the mena for healthy men.
Adolescent↗
The effect of levonorgestrel and estrone rods on male reproductive function.
The effect on spermatogenesis of the implantation of six rods containing levonorgestrel and three estrone rods was studied in seven volunteers aged 32-40, with normal pre-treatment spermiogram. None of the subjects achieved azoospermia. The lowest sperm count was below 1 million/ml in three subjects and below 12 million/ml in the other four. Plasma FSH and testosterone were severely depressed during the study, but LH was only transiently depressed for the first two months. Four subjects recovered pre-treatment sperm counts in spite of the FSH levels below 1.5 mIU/ml and testosterone levels below 1 ng/ml, which is contradictory to the current concept on hormonal regulation of spermatogenesis.
Adult↗
The effect of ethinyl estradiol 20 mcg and levonorgestrel 250 mcg on the pituitary-ovarian function during normal tablet-taking and when tablets are missed.
A new combined pill containing 20 micrograms of ethinyl estradiol and 250 micrograms of levonorgestrel has been developed. The safety margin of this type of low-dose preparation needed to be assessed and this was done by evaluating daily levels of LH, FSH, estradiol, progesterone, 1-NG and EE2 as well as cervical mucus characteristics in six patients when one and then two consecutive pills were deliberately omitted mid-way through the cycle. Results demonstrated that there was no evidence of breakthrough ovulation, although there was some continued ovarian steroidogenesis, a feature consistent with previous studies using combined preparations. Existing instructions to patients regarding missed pills should continue in order to ensure maximal contraceptive safety.
Adolescent↗
Hormonal consequences of "missing the pill".
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Adolescent↗
Pharmacokinetic and pharmacodynamic investigations with vaginal devices releasing levonorgestrel at a constant, near zero order rate.
The pharmacokinetic and pharmacodynamic effects of vaginal devices releasing levonorgestrel (L-NOG) at a constant rate (in vitro release: approximately 20 micrograms/day) were studied in a group of 20 normally menstruating women during a period of 90 days of continuous use. Peripheral blood samples were withdrawn two or three times (in the great majority of subjects, on Mondays, Wednesdays and Fridays) during a pretreatment (control) cycle, during 90 days of exposure and during the first week following the removal of the device, and the levels of L-NOG, estradiol and progesterone were analyzed by radioimmunoassay techniques. In 8 of these subjects, endometrial biopsies were also taken during days 23 to 25 of the control cycle, and then 6 and 10 weeks following the insertion of the devices. In addition, the initial absorption rate and removal half-life of L-NOG were assessed in 7 subjects using the devices for a period of 8 days only. Following insertion of the devices, the levels of L-NOG rose very rapidly, and reached the final "plateau" in some 30 minutes' time. This was followed by a limited period of "burst" with doubling the levels for a few hours, after which the levels remained stable and diminished very slowly in a linear fashion with an average decline of 23-26% during 90 days, corresponding to a daily decrease of 0.2 to 0.3 per cent. The removal half-life (first compartment) after 90 days of exposure in 19 subjects was 16.1 (13.7-18.6) hours. Sixty-nine treatment segments of 30 days were studied with frequent hormone assays; of these, 20 (or 29%) were anovulatory, 13 (19%) exhibited inadequate luteal function, and 32 (52%) had normal ovulatory-like cycles. All endometrial biopsies obtained during the pretreatment cycle were normal secretory; of the 16 biopsies obtained during treatment, 4 were suppressed, 2 proliferative, 6 secretory, and 4 could not be dated because of bleeding. An assessment of the bleeding profiles during exposure to L-NOG revealed almost a doubling of the number of days with bleeding and spotting (35% compared to 18% during the pretreatment cycle). However, significantly more frequent bleeding was found in the 20 anovulatory segments (37.3%) than in the 36 normal ovulatory-like ones (27.7%). It is concluded that differences in the frequency of bleeding and spotting with low-dose progestogens may reflect differences in the frequency of ovulation inhibition just as much as differences in the hormonal profiles of the compounds administered.
Adult↗
Release rates of levonorgestrel from Silastic capsules, homogeneous rods and covered rods in humans.
Three forms of subdermal implants containing levonorgestrel are described. These are: capsules, in which the powdered drug is sealed inside of lengths of Medical Grade Silastic tubing; homogeneous rods, in which the drug is uniformly dispersed in Silastic 382 Medical Grade Elastomer; and covered rods, in which a core rod of drug and filler-free polydimethylsiloxane polymer (50:50, Wt:Wt) are sealed inside thin-walled Silastic tubing. Long-term in vivo release rates from human subjects are presented; 6.5 years for capsules, 3.6 years for homogeneous rods and 4 years for covered rods. Sets of six capsules release a decreasing amount of drug through the first few hundred days in situ and after 500 days a fairly constant rate of about 35 micrograms per day is released (2 micrograms/cm). Homogeneous rods deliver a continuously declining amount of drug during the entire time studied. In the first 100 days the release averages 136 micrograms per day from a set of three 3-cm rods (15 micrograms/cm), gradually declining to 30 micrograms per day (3.3 micrograms/cm) from day 800 to day 1300. The covered rods deliver at a constant rate of 17.5 micrograms per day for a 3-cm rod (5.83 micrograms/cm) through 4 years.
Capsules↗
Hormonal consequences of missing the pill during the first two days of three consecutive artificial cycles.
The hormonal effects of the deliberate omission of a low-dose combined oral contraceptive pill (30 micrograms ethinyl estradiol + 150 micrograms levonorgestrel) during the first two days of three consecutive artificial cycles were studied in 10 women. The plasma levels of estradiol, progesterone, levonorgestrel and--whenever justified--of LH were measured three times weekly (Mondays, Wednesdays and Fridays) throughout a 90-day period, and the ovarian reaction to the prolongation of the pill-free period from 7 to 9 days was assessed. One subject (with a premature LH surge) showed a marked follicular and an inadequate luteal activity in 2 of 3 cycles. The remaining cycles were characterized by a varying degree of follicular activity associated with the absence of any luteal function. None of the subjects exhibited peripheral steroid levels indicating a normal ovulatory cycle. The results are interpreted as suggesting that repeated prolongation of the pill-free period from 7 to 9 days might result in a gradual increase in ovarian activity.
Adult↗
The interaction between sex hormone binding globulin and levonorgestrel released from vaginal rings in women.
The levels of levonorgestrel (L-NOG), progesterone and estradiol were measured in plasma samples of 17 normally menstruating women during a control cycle and during a subsequent period (90 days) with a L-NOG-releasing vaginal ring. During days 38-66 after the insertion of the vaginal ring the concentrations of sex hormone binding globulin binding sites (hereafter: SHBG levels) were also assayed. Significant correlations were found not only between the corresponding levels of SHBG and L-NOG during exposure to the latter compound (r = 0.44; P less than 0.05), but also between the levels of SHBG in the control cycle and the levels of L-NOG measured during exposure (r = 0.60; P less than 0.01). Furthermore, the decrease in SHBG levels during the vaginal administration of L-NOG was directly proportional to the levels of SHBG in the pretreatment cycle (r = 0.64; P less than 0.01). A significant relationship was found between the levels of L-NOG (and, hence - indirectly - the levels of SHBG) and the degree of suppression of ovarian function. Thus the levels of L-NOG were lower (P less than 0.01) in the subjects (n = 8) with an apparently normal or partially suppressed ovulatory-like pattern of progesterone than in those subjects (n = 9) in whom progesterone levels were completely suppressed.
Adult↗
Enhanced metabolism of levonorgestrel during phenytoin treatment in a woman with Norplant implants.
A 26-year-old woman, treated with phenytoin for 10 years because of epilepsy, had Norplant subdermal implants inserted after a legal abortion. She became pregnant again after nine months of Norplant use. Her plasma levonorgestrel (LNG) levels were followed during one month during phenytoin treatment and then later during one month after discontinuation of phenytoin. During phenytoin treatment, plasma LNG levels were markedly below the levels found in healthy women with Norplant. There was a pronounced, statistically significant increase in plasma LNG levels after discontinuation of phenytoin. The plasma levels of sex hormone binding globulin were markedly above those found in normal healthy women during treatment with phenytoin and decreased significantly after cessation of phenytoin. The effects on the pharmacokinetics of LNG were reflected by effects on the menstrual cycle. During phenytoin treatment, the woman had regular ovulatory menstrual cycles. After cessation of phenytoin, her cycles became irregular and during the study period of one month, no signs of ovulation were found. It is concluded that treatment with phenytoin during use of Norplant subdermal implants enhances the metabolism of LNG to an extent where the contraceptive efficacy is endangered.
Adult↗
The bioavailability of ethinyloestradiol and levonorgestrel in patients with an ileostomy.
The bioavailability of ethinyloestradiol and levonorgestrel has been studied in 5 young women with an ileostomy following surgery for ulcerative colitis and compared to that in 5 control subjects. Single i.v. and oral doses of both drugs were administered and the bioavailability calculated from the ratio of the two areas under the plasma concentration versus time curve for the two drugs. The mean bioavailability of ethinyloestradiol in the patients with an ileostomy was 55.4 +/- 10.9% (+/- S.D.) compared to a control value of 45.0 +/- 6.1% (p greater than or equal to 0.1). The mean bioavailability of levonorgestrel in the ileostomy patients was 85.2 +/- 13.1% compared to 104.6 +/- 22.3% in the controls (p greater than or equal to 0.1). Women who have an ileostomy following lower bowel surgery can rely on their oral contraceptive preparations being absorbed in the normal way.
Adult↗
Pharmacokinetics of oral contraceptive steroids in Egyptian women: studies with Ovral, Nordette and Norminest.
Plasma concentration profiles and pharmacokinetic parameters have been obtained following single dose administration of three commonly used oral contraceptive steroid preparations, Ovral, Nordette and Norminest to Egyptian women. The constituents of the preparations are as follows: Ovral (50 micrograms ethinyloestradiol, EE2 and 500 micrograms levonorgestrel, LNG); Nordette (30 micrograms EE2 and 150 micrograms LNG); and Norminest (35 micrograms EE2 and 500 micrograms norethisterone, NOR). Peak plasma concentrations of EE2 ranged between 116-160 pg ml-1 for Ovral, 55-78 pg ml-1 for Norminest and 30-70 pg ml-1 for Nordette. There was no significant difference in half-life (t1/2), oral clearance (CL) or apparent volume of distribution (Vd). The relative values of the area under the plasma concentration-time curve (AUC) reflected well the different amounts of oestrogen in each preparation. There was no significant difference in t1/2, CL or Vd for LNG in the 2 preparations containing this progestogen. The mean AUC following Nordette (150 micrograms LNG) was 40% of that following Ovral (500 micrograms LNG; p less than 0.001). Comparing pharmacokinetic parameters for the same dose of LNG (Ovral) and NOR (Norminest) showed the AUC to be decreased and CL and Vd increased in the latter group. The study indicates that the kinetic profile of the OCS in healthy Egyptian women are similar to other ethnic populations.
Adult↗
Estradiol plasma levels during long-term treatment with Norplant subdermal implants.
Estradiol-(E2) plasma levels were assessed in forty-seven women treated for one through seven years with the same set of Norplant implants. Each woman was subjected to one (n = 34), two (n = 11) or three (n = 2) sampling runs. At each sampling run, blood samples were drawn every third or fourth day during 5 or 6 consecutive weeks. Sampling runs were classified as ovulatory (n = 11), anovulatory (n = 49) or uncertain (n = 1) according to progesterone levels. Controls were Copper T users (n = 8), all classified as ovulatory. No significant differences were found for the mean E2 levels between Norplant users and Copper T users and between ovulatory and anovulatory cases. The mean of the peak E2 value found in each sampling run was significantly higher in anovulatory Norplant subjects than in the control group. The mean of the minimum E2 level observed was significantly lower in Norplant cases than in Copper T users. A single woman from the Norplant group and none from the Copper T group had all E2 values below 370 pmol/l. The inhibition of the reproductive function induced by Norplant implants is associated with a wider range of E2 circulating levels. None of the values observed at the extremes should cause serious concerns. High peaks are transitory and opposed by the antiestrogenic effect of levonorgestrel. Persistent low levels which could be associated with a hypoestrogenic state were observed in a single case.
Adult↗
Selectivity in progesterone and androgen receptor binding of progestagens used in oral contraceptives.
The relative binding affinities (RBAs) of four progestational compounds (norethisterone, levonorgestrel, 3-keto-desogestrel and gestodene) for the human progesterone and androgen receptors were measured in MCF-7 cytosol and intact MCF-7 cells. For the binding to the progesterone receptor, both Org 2058 and Org 3236 (or 3-keto-desogestrel) were used as labelled ligands. The following ranking (low to high) for the RBA of the nuclear (intact cells) progesterone receptor irrespective of the ligand used is found: norethisterone much less than levonorgestrel less than 3-keto-destogestrel less than gestodene. The difference between the various progestagens is significant with the exception of that between 3-keto-desogestrel and gestodene, when Org 2058 is used as ligand. For the cytosolic progesterone receptor, the same order is found with the exception that similar RBAs are found for gestodene and 3-keto-desogestrel. The four progestagens clearly differ with respect to binding to the androgen receptor using dihydrotestosterone as labelled ligand in intact cells; the ranking (low to high) is: norethisterone less than 3 keto-desogestrel less than levonorgestrel and gestodene. The difference between 3-keto-desogestrel and levonorgestrel or gestodene is significant. The selectivity indices (ratio of the mean RBA for the progesterone receptor to that of androgen receptor) in intact cells are significantly higher for 3-keto-desogestrel and gestodene than for levonorgestrel and norethisterone. From these results we conclude that the introduction of the 18-methyl in norethisterone (levonorgestel) increases both the binding to the progesterone and androgen receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Cell Line↗
Pharmacokinetic study of levonorgestrel used as a postcoital agent.
The pharmacokinetics and pharmacodynamics of levonorgestrel (LNG) were studied in six women given 0.75 mg LNG orally for seven days during the periovulatory phase of the menstrual cycle. Steady-state concentrations of LNG were reached within three days and serum LNG concentrations at various times on day 7 were generally lower than on day 1, presumably due to a reduced serum level of SHBG. On day 7 the volume of distribution was significantly increased and Co significantly decreased and both the clearance and elimination half-life were higher on day 7 than on day 1. Half-lives varied from 5.6 to 25.1 hours. The day-to-day intra-subject variations in serum LNG concentrations ranged from 23% to 80%. Serum concentrations of pituitary and ovarian hormones suggested that ovulation was not inhibited in four of the six subjects and was delayed in the remaining two. No significant changes in serum prolactin levels were observed.
Absorption↗
Clearance of levonorgestrel from the circulation following removal of NORPLANT subdermal implants.
The disappearance of levonorgestrel from plasma after the removal of NORPLANT subdermal implants was studied in 12 women who had been treated from 5.5 to 78 months. The existence of one or two half-lives for the rate of disappearance was assessed. The influence of body weight, body fat and length of treatment upon levonorgestrel clearance was studied through stepwise regression analysis. It was found that the levonorgestrel decay rate after implant removal can be entirely accounted assuming one half-life of 42 +/- 16 h (mean +/- SD; range 13 to 62 h). Stepwise regression analysis showed that levonorgestrel half-life is positively correlated with body weight and not significantly correlated with the length of treatment or body fat. It is concluded that, after long-term administration of levonorgestrel via subdermal implants, the major part of the steroid is cleared from plasma within 96 h and that only trace amounts are detected in the following days.
Adult↗
Ovarian function during use of a levonorgestrel-releasing IUD.
Ovarian function was studied for two complete menstrual cycles in 9 regularly menstruating women and for 8 weeks in three amenorrhoeic women who had used levonorgestrel-releasing IUDs (LNG-IUD) for more than four years. Nine patients using copper IUDs (Nova-T) were studied for two complete menstrual cycles as controls. According to progesterone levels, 15/17 cycles in women using LNG-IUDs were ovulatory, whereas only 8/17 cycles showed normal follicular growth and rupture as judged by ultrasound. In ovulatory cycles, the peak progesterone levels were lower than in the controls. The preovulatory estradiol and LH peak levels were also lower than in control subjects. SHBG levels were lower in LNG-IUD users than in copper IUD users. It is concluded that, although the dose of levonorgestrel released from the IUD is very low, it probably exerts an effect on the gonadotrophin secretion, which disturbs follicular development in many of the women studied, which in addition to the local effect on the endometrium, contributes to its high contraceptive efficacy.
Adult↗
Morphometric study of the human endometrium following continuous exposure to levonorgestrel released from vaginal rings during 90 days.
The effects of vaginal devices releasing levonorgestrel (LNG) at a constant rate of approximately 20 micrograms/24 hrs on the human endometrium were studied in a group of 69 normally menstruating women during a period of 90 days of continuous use. Peripheral blood samples were withdrawn three times weekly starting at day 10 of a pretreatment (control) cycle and then three times weekly from day 60 to 90 of the treatment period. The levels of LNG, estradiol, progesterone and sex hormone binding globulin (SHBG) were analyzed by radioimmunoassay techniques. Endometrial biopsies were obtained in the luteal phase of the pretreatment cycle and on day 84-87 of the treatment period. Increased bleeding occurred in most subjects exposed to the LNG-releasing device; the mean number of bleeding and spotting days was 26.4 +/- 8.9 S.D. which exceeded that found in their control cycle. Morphometric analyses of the endometrial biopsies using 9 quantitative indices, revealed highly significant changes in glands and stroma following the use of the LNG-releasing vaginal device. Irrespective of the circulating steroid levels, the administration of LNG significantly diminished the glandular diameter (p less than 0.001), reduced the volume density of the glands (p less than 0.001) and of the glandular epithelium (p less than 0.001). and modified the ratio glandular epithelium: glands (p less than 0.001). It is concluded that levonorgestrel released at a rate of 20 micrograms/24 hrs, induces characteristic changes in the histologic structure of the human endometrium. Although no simple correlation has been found between any of the endometrial indices and the numbers of bleeding/spotting days or bleeding days, the changes as such may represent biochemical alterations which could be predisposing factors for intermenstrual bleeding and spotting. To prove a causal relationship between morphological and biochemical changes and changes in bleeding patterns, further in-depth studies may be required.
Contraceptive Agents, Female↗