Pharmacokinetics of altrenogest in gilts.

Altrenogest, a synthetic progestogen, is characterized by its estrus synchronization in mares, ewes, sows, and gilts. To investigate the pharmacokinetic profile and evaluate its accumulation in gilts, 18 oral doses of 20 mg altrenogest/gilt/day were given to eight healthy gilts at an interval of 24 hr. Plasma samples were collected, and altrenogest was determined by ultra-high-performance liquid chromatography with mass spectrometry. WinNonlin 6.4 software was used to calculate the pharmacokinetic parameters through noncompartmental model analysis. After the first administration (D 1), the pharmacokinetic parameters, including Tmax , Cmax , and the elimination half-life (T1/2λz ), were similar to those observed after the final administration (D 18). However, the mean residence time at D 1 was significantly lower than D 18. As a whole, the mean steady-state plasma concentration (Css ), degree fluctuation (DF), accumulation factor (Rac ), and area under the plasma concentration-time curve in steady state (AUCss ) were 22.69 ± 6.15 ng/ml, 270.64 ± 42.51%, 1.53 ± 0.23, and 544.63 ± 147.49 ng hr/ml, respectively. These results showed that after 18 consecutive days of oral administration of altrenogest, plasma concentrations of altrenogest had a certain degree of fluctuation, without significant accumulations.

PI3K, AKT, and P-AKT levels in thin endometrium.

The aim of this study was to explore the expression of PI3K, AKT, and P-AKT, and to investigate the role of PI3K/AKT signaling pathway in thin endometrium. We included 40 women treated in affiliated Shenzhen Nanshan People's Hospital of Guangdong Medical University for endometrial conditions between August 2013 and January 2015, 20 with a normal endometrium, and 20 with thin endometrium. The expression of PI3K, AKT, and P-AKT was evaluated by the immunohistochemical S-P method. The expression of PI3K, AKT, and P-AKT proteins was significantly lower in the thin endometrium group than in the normal endometrium group (P < 0.05). The expression of PI3K and AKT was positively correlated with the expression of P-AKT. The expression of PI3K, AKT, and P-AKT proteins in the thin endometrium decreases during the proliferative phase, and this process could be associated with PI3K/AKT signaling.

Simultaneous online SPE-LC-MS/MS quantification of six widely used synthetic progestins in human plasma.

Co-administration of synthetic progestin containing hormonal contraceptives (HCs) and antiepileptic drugs (AEDs) is a common clinical situation which needs specific considerations due to drug interactions. Several studies have demonstrated that lamotrigine plasma levels are significantly decreased during co-medication with HCs, and that this interaction is associated with increased seizure frequency in most of the cases. Additionally, an increase in contraceptive failure and unintended pregnancy could be observed during co-medication. Hence, monitoring of progestin plasma levels in patients with AED co-medication is of interest. A rapid and reliable online solid-phase extraction-high performance liquid chromatography-tandem mass spectrometry (online SPE-LC-MS/MS) method using gradient elution in the LC domain was established and validated for the simultaneous quantitative determination of gestodene, dienogest, drospirenone, etonogestrel, cyproterone acetate, and levonorgestrel in human plasma. The online SPE-LC-MS/MS method covered a quantification concentration range of 5-100 ng/ml for dienogest, 1-100 ng/ml for etonogestrel and 2-100 ng/ml for all other analytes. Stable isotope-labeled internal standards were used for analyte quantification based on selected reaction monitoring experiments. Inter- and intra-assay precision and accuracy were determined from quality control (QC) samples at the lower limits of quantification and at low, medium, and high concentration levels within the calibration range. Inter-assay reproducibility at the QC levels was better than 10% (relative standard deviation, RSD), accuracy at these levels ranged from -3.7% to 11.3%. Total extraction efficiency, tested at three concentrations, ranged from 92.5% to 106.4%. Matrix interferences were excluded by post-column infusion experiments. To prove the applicability of the assay in clinical cohorts, a sample set (n = 298) stemming from study patients under AED/oral HC co-medication was screened for progestin plasma levels. This method has to be considered a research-use-only assay and must not be used for diagnostic or therapeutic purposes, since it did not undergo formal performance evaluation in the sense of the IVD directive (98/79/EG) of the European Community.

Single- and Multiple-Dose Pharmacokinetics and Safety of Vilaprisan in Healthy Postmenopausal Japanese Women: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: As the prevalence of some gynecological conditions depends on patient characteristics such as race/ethnicity, it is important to study therapies for these conditions in diverse populations. The study described in this article was conducted to investigate the safety, tolerability, and pharmacokinetics of vilaprisan, a selective progesterone receptor modulator, in Japanese women in Japan. It supplements two comparable studies that were conducted in healthy postmenopausal European and Chinese women, respectively. METHODS: In this exploratory randomized, placebo-controlled, double-blind, ascending-dose study, five groups of healthy postmenopausal Japanese women received vilaprisan as immediate-release tablets (1, 5, or 15 mg as a single dose or 1 or 5 mg/day for 28 days) or placebo tablets (single dosing: 8 subjects/dose step, thereof 2 subjects randomized to placebo; multiple dosing: 12 subjects/dose step, thereof 4 subjects randomized to placebo). Blood samples for pharmacokinetic profiles were collected over 14-19 days. Safety assessments were based on adverse event data, vital signs, electrocardiograms, clinical laboratory tests, and transvaginal ultrasound examinations. RESULTS: 48 participants were randomized, treated, and analyzed. Vilaprisan was rapidly absorbed, reaching maximum plasma concentrations (Cmax) between 1 and 3 h post dose. Post maximum, plasma concentrations rapidly declined, indicating pronounced distribution into tissues. The exposure of vilaprisan increased roughly dose-proportionally: The geometric mean (geometric coefficients of variation) areas under the concentration time curves from time zero to infinity (AUC∞) after single administration of 1, 5, or 15 mg vilaprisan were 67 µg·h/l (34%), 249 µg·h/l (15%), and 788 µg·h/l (37%), respectively. The AUC in the dosing interval after multiple administrations (AUC24,md) of 1 mg/day was 76 µg·h/l (59%), and the AUC24,md after 5 mg/day was 311 µg·h/l (20%). Geometric mean Cmax values also increased roughly dose-proportionally: They amounted to 6 µg/l (22%), 16 µg/l (33%), and 52 µg/l (27%) after single administration and to 8 µg/l (28%) and 31 µg/l (22%) after multiple administrations of the above doses. Mild adverse events were observed, similar to those observed in other clinical studies of vilaprisan. CONCLUSIONS: Overall, vilaprisan was safe and well tolerated. The exposure in Japanese women was similar to that observed in European and Chinese women in separate studies. TRIAL REGISTRATION: 15 Nov 2011 (no registration number assigned).

Female sexual function and dysfunction in the reproductive years: the influence of endogenous and exogenous sex hormones.

INTRODUCTION: Sexual function in women in the reproductive age years is under psychological, sociocultural, and relationship influences, as well as the influence of sex hormones. AIM: To examine the data relating to sexual function in women in the reproductive age group, particularly the influence of sex hormones. To examine, in particular, the influence of the menstrual cycle, pregnancy, the oral contraceptive pill and endogenous and exogenous testosterone. METHODS: Review of the literature on female sexual function, confining the search to the reproductive age range. RESULTS: Population studies of sexual function identify sexual disinterest as being the most common sexual complaint in premenopausal women. Most studies of menstrual cyclicity identify a periovulatory increase in sexual desire or activity. All prospective studies of sexuality in pregnancy document a decline in sexual function with progression of pregnancy. Studies of the influence of the oral contraceptive pill on sexual function are contradictory with most prospective controlled studies showing no deleterious effect. Studies of the influence of endogenous androgens on sexuality are also contradictory with one large cross-sectional study showing no correlation, but some case-controlled studies show low androgens in women with sexual dysfunction. Studies of testosterone therapy in premenopausal women are ambiguous, with no clear dose-response effect. CONCLUSIONS: Sexual disinterest is prevalent in premenopausal woman despite being hormone replete. The assessment of androgen contribution is hampered by the unreliability of the testosterone assay in the female range. Large cross-sectional and longitudinal studies have not identified a correlation between testosterone and sexual function in women. Sexual dysfunction in the premenopausal age range is common. Sex hormones have a modifying effect on sexual function but social influences and learned responses are as important. The role of testosterone requires further study.

The metabolic clearance rate, the brain extraction and distribution and the uterine extraction and retention of progesterone and R 5020 in estrogen-treated ovariectomized rabbits.

The metabolic clearance rate (MCR), uterine extraction, uterine retention and brain distribution of the synthetic progestin R 5020 and progesterone were studied in estrogen-treated ovariectomized rabbits. The MCR of R 5020 was 163+/-15 (SE) 1/day and was lower than that of progesterone. The uterine extraction of R 5020 (51.4+/-3.9 (SE)%) was greater than that of progesterone (33.7+/-7.7%) as was the uterine tissue:arterial blood ratio (28.1+/-4 vs. 7.3). The brain and pituitary retention and distribution of R 5020 and progesterone were the same and provided no evidence for a selective accumulation of a progestin in the pituitary or hypothalamus.

Measurement of serum clogestone acetate (AY-11,440) by a radioreceptor assay: a practical approach to the quantitative determination of synthetic progestins.

A novel method is described for the measurement of nanogram quantities of clogestone acetate (3beta, 17alpha-dihydroxy-6-chloropregna-4,6-dien-20-one 3,17-diacetate) in serum:clogestone acetate (CgAc) is converted to chlormadinone acetate in the presence of wheat germ lipase and hydroxysteroid dehydrogenase. The ketonic steroid formed is then incubated with rat uterine cytosol and 3-H-progesterone. The concentration of 3CgAc is estimated from a standard curve derived by incubating cytosol with 3-H-progesterone and varying amounts of chlormadinone acetate. The statistically validated method has been used for the estimation of serum CgAc in humans and dogs given an oral dose of the steroid. The radioreceptor assay (RRA), has practical advantages over related techniques such as radioimmunoassay (RIA) especially with respect to the developmental work. This is the first time that a quantitative assay of a progestin by the tissue receptor approach has been described.

The binding of a synthetic progestin, R5020 to transcortin and serum albumin.

R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione), a synthetic progestin, was tested for its binding to purified human transcortin, albumin and human serum. Scatchard analysis showed that R5020 bound relatively weakly to transcortin (Kass = 8 X 10(6)M-1); in 20% human serum or albumin greater than 90% was bound with low Kass and an indeterminate number of binding sites.

Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone.

OBJECTIVE: To evaluate the effect of thalidomide on the plasma pharmacokinetics of ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Ten women who had undergone surgical sterilization were enrolled in an open-label crossover study conducted in the Georgetown University Clinical Research Center. The pharmacokinetics of single doses of 0.07 mg ethinyl estradiol and 2 mg norethindrone were measured at baseline and after 3 weeks of 200 mg thalidomide. Compliance with the thalidomide regimen was assessed with use of Medication Event Monitoring System (MEMS) caps. RESULTS: No changes were observed in the pharmacokinetics of ethinyl estradiol or norethindrone with thalidomide therapy. The mean +/- SD area under the plasma concentration-time curve (AUC0-infinity) for ethinyl estradiol was 6580 +/- 1100 ng.h/L at baseline and 5970 +/- 1560 ng.h/L after the thalidomide regimen (paired t test, P > .05). The values for norethindrone were 103 +/- 54 micrograms.h/L and 107 +/- 58 micrograms.h/L (paired t test, P > .05). No changes were observed for other pharmacokinetic parameters assessed for either ethinyl estradiol or norethindrone. No accumulation of thalidomide was seen after 21 days of therapy: day 1 AUC0-infinity 41.1 +/- 13.9 micrograms.h/mL; day 21 AUC0-infinity 59.6 +/- 27.3 micrograms.h/mL (paired t test, P > .05). No changes were observed for other pharmacokinetic parameters assessed for thalidomide between days 1 and 21. Thalidomide was well tolerated but caused variable degrees of sedation. The average thalidomide compliance rate was 97%. CONCLUSIONS: The pharmacokinetics of thalidomide do not change with 3 weeks of daily dosing. Thalidomide does not alter the pharmacokinetics of ethinyl estradiol or norethindrone. Therefore there is no drug interaction between thalidomide and these 2 drugs. The efficacy of oral contraceptives containing ethinyl estradiol and norethindrone should not be affected by concomitant thalidomide therapy.

PIP: An open-label crossover study was conducted to evaluate the effect of thalidomide on the plasma pharmacokinetics of ethinyl estradiol (INN, ethinyl estradiol) and norethindrone (INN, norethisterone) among 10 women who had undergone surgical sterilization at Georgetown University Clinical Research Center. The pharmacokinetics of single doses of 0.07 mg ethinyl estradiol and 2 mg norethindrone were measured at baseline and after 3 weeks of 200 mg thalidomide. Compliance with the thalidomide regimen was assessed with the use of Medication Event Monitoring System caps. The results showed that there were no changes in the pharmacokinetics of ethinyl estradiol or norethindrone with thalidomide therapy. Furthermore, no changes were seen for other pharmacokinetic parameters assessed for thalidomide between days 1 and 21. Thalidomide was well tolerated, but caused variable degrees of sedation. The average compliance rate of thalidomide was 97%. This study concluded that there was no drug interaction between thalidomide and the other two drugs (ethinyl estradiol and norethindrone). The efficacy of oral contraceptives containing ethinyl estradiol and norethindrone should not be affected by concomitant thalidomide therapy.

Effects of two progestin-only contraceptives, Depo-Provera and Norplant-II, on the vaginal epithelium of rhesus monkeys.

The objective of this study was to determine whether progestin-only contraceptives induce thinning of the vaginal epithelium in nonhuman primates. Eight intact rhesus monkeys (four per group) were treated with either a single intramuscular injection of 30 mg of Depo-Provera or a subcutaneous insertion of Norplant-II (2 x 75 mg rods; day 0). Norplant-II rods were removed 90 days after insertion. Vaginal biopsies were obtained during a pretreatment menstrual cycle and following treatment on days 10, 30, 60, 118, and 146. Formalin-fixed vaginal biopsies were evaluated for epithelial thickness and the degree of keratinization. The circulating levels of estradiol, progesterone, medroxyprogesterone acetate (MPA), or levonorgestrel (LNG) were monitored throughout the study by specific radioimmunoassays. Circulating levels of estradiol and progesterone confirmed the stage of the menstrual cycle in which pretreatment biopsies were obtained. Following treatment with Depo-Provera, serum levels of MPA increased to 2.3 +/- 0.6 ng/ml (x +/- SE, n = 4) within 24 hr. Serum levels of MPA were maximal on day 14 (5.5 +/- 0.9 ng/ml), dropped below 1 ng/ml by day 50, and were nondetectable by day 70. Circulating levels of LNG were elevated 24 hr after insertion of Norplant-II (5.8 +/- 3.0 ng/ml), peaked on day 2 (7.6 +/- 4.2 ng/ml), remained between 1.4 and 6.2 ng/ml from days 14 to 90, and were nondetectable by day 118, the first serum sample after removal of Norplant-II. There were no significant differences (p > 0.05) in the epithelial thickness (microm), number of epithelial cell layers, or type of epithelium present in vaginal biopsies obtained during the follicular or luteal phases of the pretreatment menstrual cycle. Conversely, a pronounced effect of progestin treatment was observed on the vaginal epithelium. There were no significant differences (p > 0.05) between the two progestin treatment groups, but a significant effect (p < 0.05) over time was observed (two-way ANOVA). Compared with pretreatment menstrual cycle controls, the vaginal epithelial thickness was decreased (p < 0.05) by day 30 or 60 following Norplant-II insertion or Depo-Provera injection, respectively. The number of epithelial cell layers was also decreased (p < 0.05) on days 30 and/or 60 in progestin-treated monkeys compared with pretreatment control cycles. Following removal of Norplant-II or metabolic excretion of MPA, the vaginal epithellium regenerated and the thickness was no longer different (p > 0.05) from the pretreatment control cycle. These data demonstrate that progestin-only contraceptives induced thinning of the vaginal epithelium in rhesus monkeys, and this effect was rapidly reversible following physical or metabolic removal of the progestin.

Enzyme immunoassay for nomegestrol acetate in human plasma.

Currently available chromatographic assays of the progestative drug nomegestrol acetate in human plasma are not suitable for monitoring drug kinetics more than 24 h after clinical dosage. A specific and sensitive enzyme immunoassay was therefore developed. A 3(O-carboxymethyl)oxime derivative of nomegestrol acetate was synthesized and coupled to bovine serum albumin in order to raise polyclonal antibodies in rabbits. The enzymatic tracer was obtained by coupling the 3(O-carboxymethyl)oxime derivative to acetylcholinesterase (E.C.3.1.1.7.). HPLC fractionation of human plasma samples followed by enzyme immunoassay revealed the presence of cross-reacting metabolites. An automated procedure of metabolite separation was developed using silica bonded with diol groups (Diol Bakerbond column). This procedure ensured assay specificity. The quantification limit in human plasma was 0.1 ng/ml. Mean repeatability (intra-assay variation) and reproducibility (inter-assay variation) were 9 and 15%, respectively. The enzyme immunoassay allowed monitoring of the kinetics of nomegestrol acetate 144 h after oral administration of a single 5 mg dose. Values for human samples were in excellent agreement with those assayable by HPLC followed by u.v. detection.

Relationship of estradiol levels to breakthrough bleeding during continuous combined hormone replacement therapy.

OBJECTIVE: To determine whether serum estradiol and dydrogesterone concentrations are associated with the occurrence of breakthrough bleeding. METHODS: In a prospective, double-blind study, 194 postmenopausal women were allocated randomly to receive one of four doses of dydrogesterone (2.5 mg, 5 mg, 10 mg, 15 mg) continuously combined with 2 mg of micronized 17beta-estradiol. All medication was taken orally for a total of 168 days. Vaginal bleeding was recorded on a daily basis. Serum estradiol (E2) and dihydrodydrogesterone (the main metabolite of dydrogesterone) trough levels were measured at day 85 and at the end of the study (day 168). Bleeding pattern analysis was done according to the reference period method. RESULTS: One hundred fifty-two of 177 women who completed the study supplied valid data on drug compliance, smoking habits, bleeding episodes, and serum hormone concentrations, which were used to assess the impact of serum E2 and dihydrodydrogesterone concentrations on the occurrence of breakthrough bleeding. Logistic regression analysis identified only the serum E2 concentration as having an independent, statistically significant effect (P = .003) on the occurrence of breakthrough bleeding; no such effect was associated with dihydrodydrogesterone levels (P = .118). The relative risk for the occurrence of breakthrough bleeding was 2.7 (95% confidence interval [CI] 1.454, 5.609) for serum E2 concentrations greater than 40 pg/mL. CONCLUSION: The occurrence of breakthrough bleeding during continuous combined hormone replacement therapy with estradiol and dydrogesterone in postmenopausal women was related to serum estradiol levels and not to dydrogesterone levels. Further studies are needed to test the hypothesis that estrogen is a major factor in the incidence of bleeding during postmenopausal hormone replacement therapy.

Therapeutic effects of the levonorgestrel-releasing intrauterine system in the treatment of idiopathic menorrhagia.

OBJECTIVE: To investigate the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of idiopathic menorrhagia. DESIGN: Measurements of menstrual blood loss (MBL), hemoglobin, and serum ferritin before and after LNG-IUS insertion. SETTING: National Research Institute for Family Planning and Beijing Gynecology and Obstetrics Hospital, Beijing, People's Republic of China. PATIENT(S): Thirty-four patients with MBL over 80 mL. INTERVENTION(S): Insertion of the LNG-IUS on cycle days 5-7 and follow-up at 3-month intervals for 3 years. MAIN OUTCOME MEASURE(S): Measurement of MBL, serum ferritin, and hemoglobin for evaluation of efficacy of treatment. RESULT(S): A significant reduction of MBL to 23.4 mL (78.7% decrease), 26.4 mL (83.8% decrease), 2.7 mL (97.7% decrease), and 13.7 mL (85.0% decrease) at 6, 12, 24, and 36 months, respectively. After 6 months, one-third of the patients experienced amenorrhea, and one-fourth, spotting. Hemoglobin increased significantly from 121.5 g/L preinsertion to 135.5 g/L after 36 months, while serum ferritin levels increased significantly from 21.9 ng/mL before insertion to 92.8 ng/mL after 36 months. In women using the LNG-IUS for 3-4 years, the E2 levels in 20 samples were 239.4 pmol/L, P levels were 11.1 nmol/L, and serum LNG levels were maintained at an average of 511 pmol/L. CONCLUSION(S): The significant reduction of MBL and the increase in hemoglobin and serum ferritin levels in the treatment of menorrhagia with the LNG-IUS has great implications for women's reproductive health, particularly in developing countries.

Development of a new sensitive and specific time-resolved fluoroimmunoassay (TR-FIA) of chlormadinone acetate in the serum of treated menopausal women.

We describe the development of a serum chlormadinone acetate (CMA) time-resolved fluoroimmunoassay (TR-FIA). We prepared haptens (3-CMO-chlormadinone acetate and 6-chloropregna-4,6-dien-17,20-diol-3-one-20-hemisuccinate), biotinylated tracers (3(biotinylaminopropylamido) 3-CMO-chlormadinone acetate and 3-(6-chloropregna-4,6-dien-17,20-diol-3-one-20-hemisuccinylamino)1-biotinylaminopropane), and immunogens necessary for eliciting two antibodies (anti-chlormadinone acetate 3-CMO/BSA and anti-chlormadinone 20-hemisuccinate/BSA). The specificity of the assay was rigorously studied to eliminate possible interference by polar metabolites of CMA, particularly 17 alpha-acetoxy-6-chloro-3beta-hydroxypregna-4,6-diene-20-one (3beta-hydroxy metabolite), employing an easy-to-use ethylene glycol chromatographic step prior to immunoassay, so as to separate the polar metabolites, in particular the 3beta-hydroxy-CMA metabolite, from the intact CMA. The choice of the anti-CMA antibody was guided by the high assay sensitivity obtained with the anti-CMA 3-CMO/BSA antibody. The detection limit was 51pg/ml. Interassay reproducibility CVs were between 2.6 and 4.5%. This TR-FIA thus appeared to be a sensitive, specific, precise, and consequently well-suited method for measurement of serum CMA during a pharmacokinetic study in women.

Serum levels of 3-keto-desogestrel after oral administration of desogestrel and 3-keto-desogestrel.

In a cross-over study with orally administered desogestrel (0.150 mg) plus ethinyloestradiol (0.030 mg) and 3-keto-desogestrel (0.150 mg) plus ethinyloestradiol (0.030 mg) in ten women under steady-state conditions, the serum levels of 3-keto-desogestrel were monitored by radioimmunoassay. No statistically significant differences between treatment groups were found with respect to the areas under the curve of the serum levels versus time (AUC), peak heights and peak times. The individual AUCs for 3-keto-desogestrel after dosing with desogestrel (plus EE) or 3-keto-desogestrel (plus EE) show a similar degree of variation. The biotransformation of desogestrel into 3-keto-desogestrel is rapid and appears not to be limited by the metabolic capacity of the normal liver.

Intravaginal contraception with the synthetic progestin, R2323.

PIP: A Silastic intravaginal ring (IVR) containing R2323 (17 alpha-ethinyl-17 beta-hydroxy-18-methyl-4,9,11-estrien-3-one) in its center core was tested in vitro and in 4 women for 1 cycle each. Initially 330 mg of drug was released/day from the IVR in vitro, and after 150 days the value had declined to about 230 mg. Ovulation was inhibited in the 4 subjects due to the constant release of R2323 as evidenced by the steroid blood levels of 1-3 ng/ml. When the IVR was removed, R2323 blood levels quickly fell to zero. All the women had normal withdrawal bleeding, and 2 subjects followed during a recovery cycle had ovulatory levels of progesterone.^ieng

Progestin implants for female contraception.

Four different implants, in the form of capsules or covered rods, that release one of the synthetic progestins levonorgestrel, etonogestrel, Nestorone, or Elcometrine and nomegestrol acetate were reviewed. Biocompatible polymers or copolymers of polydimethyl/polymethylvinyl-siloxanes or ethylvinylacetate are used to hold the steroid crystals and to control the rate of release. Once inserted under the skin, these implants release the corresponding steroid continuously over prolonged periods, a process that can be readily interrupted by implant removal. During long-term use of the implant, the released steroid circulates in blood at a fairly stable level. The physical characteristics of the implants, including drug contents and rate of release, serum levels of the progestin during use, and the duration of their effective life are described. Total steroid loads vary in the range of 50 mg to 216 mg; average release rates are in the range of 30-100 ug/day, and effective lives from 6 months to 7 years.

Release kinetics of 3-keto-desogestrel from contraceptive implants (Implanon) in dogs: comparison with in vitro data.

Ethylene-vinyl acetate (EVA) polymeric contraceptive implants (Implanon) containing 3-keto-desogestrel have been prepared aiming at an in vitro initial release rate of 60 micrograms 3-keto-desogestrel/day. These implants are designed to have an intended life-time of 2 years. During a 3-year period, the release of these implants was studied in 4 dogs after subdermal insertion, using plasma clearance of 3-keto-desogestrel assessed after intravenous administration of 3-keto-desogestrel and steady state plasma levels of 3-keto-desogestrel. The mean plasma level of 3-keto-desogestrel decreased gradually during the first year of the study, viz. from 1.64 nmol/1 at 7 days after implantation to 0.69 nmol/l after one year. At the end of the second year, the level had decreased further to 0.45 nmol/l while after 3 years, the mean 3-keto-desogestrel plasma level was 0.42 nmol/l. The calculated mean daily release of 3-keto-desogestrel decreased during the first year from 70 micrograms/day to 30 micrograms/day. During the second and third year, the decrease in release rate was much less, viz. going from 30 micrograms/day to 28 micrograms/day and from 28 micrograms/day to 25 micrograms/day, respectively. This indicates a much more constant release during the second and third year of the study. The calculated cumulative amount of 3-keto-desogestrel released from the implant during the dog study was 34.0 mg. Based on the initial amount of 3-keto-desogestrel in the implant of 68.3 mg, the remaining amount in the implants at termination of the study should be approximately 34.3 mg. Actually, the mean remaining amount of 3-keto-desogestrel was 33.8 mg, which is in very close agreement with the calculated value. Implants from the same batch as used in the in vivo study were also analyzed for the in vitro release at regular times during the 3-year study period. After one year, the in vitro release rate was about 43 micrograms/day whereas this release rate was 33 and 27 micrograms/day after 2 and 3 years, respectively. Although the in vitro set-up constantly gave a somewhat higher release in comparison with the in vivo release, it is apparent that the in vitro procedure is valuable for prediction of the in vivo release characteristics of the implant. There were no indications for 3-keto-desogestrel accumulation at the implantation site. No local irritations were seen and the animals had no discomfort at all.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of Implanon. An integrated analysis.

The aims of this paper were to present data on the pharmacokinetics, clearance, bioavailability, and in vivo absorption of etonogestrel (ENG); to present the results of a longitudinal analysis of the plasma concentration-time curves of ENG; and to present the results of a cross-sectional analysis on the association of body weight with serum ENG concentrations. Implanon had an absorption rate of almost 60 micrograms/day after 3 months, which slowly decreased to 30 micrograms/day at the end of 2 years. The bioavailability over this period of time was constant and close to 100%. The clearance remained around 7.5 L/h. With a bioavailability and clearance that remained constant, it was concluded that accumulation of ENG does not occur. After Implanon insertion, serum concentrations increased within 8 h to concentrations associated with ovulation inhibition. Maximum mean serum concentrations (Cmax) amounted to 813 pg/mL and the time (tmax) to reach Cmax was 4 days. After reaching Cmax, ENG serum concentrations declined to about 196 pg/mL at the end of the first year, followed by a slow decline to 156 pg/mL at the end of the third year. After removal of Implanon, serum ENG concentrations declined to levels less than the detection limit of the assay (20 pg/mL) within 1 week. Lower body weight was associated with higher serum ENG concentrations.

In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women.

Previous studies with postmenopausal women receiving oral doses of norethisterone-containing preparations have shown that a small fraction of the dose is converted metabolically to ethinyl estradiol and may be detected in the peripheral blood. To investigate the extent and the dose dependence of this conversion in more detail, we performed a study with 24 postmenopausal women who received single oral doses of 5 mg norethisterone as well as 5 and 10 mg norethisterone acetate with a washout phase of 2 weeks between each treatment. After each treatment, blood was collected at regular intervals and the concentrations of norethisterone and ethinyl estradiol were analyzed in the serum samples by a specific radioimmunoassay and by gas chromatography/mass spectrometry, respectively. Ethinyl estradiol was present in the serum samples of all women following treatment with norethisterone acetate and, except for four cases, also after treatment with norethisterone. The conversion ratio of norethisterone acetate to ethinyl estradiol was 0.7 +/- 0.2% and 1.0 +/- 0.4% at doses of 5 and 10 mg, respectively. This corresponded to an oral dose equivalent of about 6 micrograms ethinyl estradiol per milligram of norethisterone acetate. For norethisterone, a conversion ratio of 0.4 +/- 0.4% was found at a dose of 5 mg, which corresponded to an oral dose equivalent of about 4 micrograms ethinyl estradiol per milligram of norethisterone. Although it cannot be excluded that in individual cases, even higher doses of ethinyl estradiol may be produced by conversion, it is concluded that at therapeutic doses of the progestogens, the exposure to metabolically derived ethinyl estradiol is probably of little clinical significance not only in fertile women using oral contraceptive combination preparations containing norethisterone and ethinyl estradiol, but also in postmenopausal women who receive oral doses of estradiol for estrogen replacement. The estrogenic effects of metabolically derived ethinyl estradiol on the liver (eg. synthesis of transport proteins) are very likely more than compensated due to the androgenic activity of norethisterone.