RESUMEN
STUDY QUESTION: Is there a pharmacodynamic interaction between ulipristal acetate (UPA) 30 mg for emergency contraception and a daily progestin-only contraceptive pill, desogestrel (DSG) 0.75 mg, when initiated the next day? SUMMARY ANSWER: In this study, DSG impaired the ability of UPA to delay ovulation, but UPA had little impact on the onset of contraceptive effects due to DSG. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator used for emergency contraceptive (EC) at the dose of 30 mg. UPA delays ovulation by at least 5 days when administered in the mid to late follicular phase. In theory, potent progestins could reactivate progesterone signaling that leads to follicle rupture, thereby impacting the effectiveness of UPA as EC. In addition, UPA could alter the onset of the contraceptive effect of progestin-containing contraceptives started immediately after UPA. STUDY DESIGN, SIZE, DURATION: A single-blind (for observer), placebo-controlled, partial crossover study was conducted in two sites [Dominican Republic (DR) and the Netherlands (NDL)] over 11 months from October 2012 to September 2013. Healthy female volunteers participated in two of the three treatment cycles separated by a washout cycle. Treatment combinations studied were as follows: (i) a single 30 mg dose of UPA followed by 75 µg per day DSG for 20 days, (ii) a single 30 mg dose of UPA followed by 20 days of placebo matching that of DSG (PLB2) or (iii) one tablet of placebo-matching UPA (PLB1) followed by 75 µg per day DSG for 20 days. Participants were randomized to one of the three treatment sequences (UPA + DSG/UPA + PLB2, PLB1 + DSG/UPA + DSG and UPA + PLB2/PLB1 + DSG) when a lead follicle was ≥ 14 to <16 mm diameter on transvaginal ultrasound imaging (TVU). PARTICIPANTS/MATERIAL, SETTING, METHODS: A total of 71 women were included, and 49 were randomized to a first treatment combination of the three period sequences (20 in the DR and 29 in the NDL); 41 of the 49 continued and completed two treatment combinations (20 in the DR and 21 in the NDL). MAIN RESULTS AND THE ROLE OF CHANCE: Initiating DSG treatment the day after UPA significantly reduced the ovulation delaying effect of UPA (P = 0.0054). While ovulation occurred in only one of the 29 UPA-only cycles (3%) in the first 5 days, it occurred in 13 of the 29 (45%) UPA + DSG cycles. LIMITATIONS, REASONS FOR CAUTION: This was a small, descriptive, pharmacodynamic study in which some findings differed by study site. Distinguishing between a cystic corpus luteum and a luteinized unruptured follicle (LUF) by TVU was difficult in some cases; however, the investigators reached consensus, when the study was still blinded, regarding ovulation based on hormone levels and careful review of daily TVU images. WIDER IMPLICATIONS OF THE FINDINGS: Initiating the use of a DSG progestin-only pill (POP) immediately after UPA reduces the ability of UPA to delay ovulation and thus may decrease its efficacy as EC. If starting a DSG POP after using UPA for EC, and possibly any progestin-only method, consideration should be given to delaying for at least 5 days after UPA intake in order to preserve the ovulation delaying effects of UPA.
Asunto(s)
Anticoncepción Postcoital/métodos , Anticonceptivos Sintéticos Orales/administración & dosificación , Desogestrel/administración & dosificación , Norpregnadienos/uso terapéutico , Ovulación/efectos de los fármacos , Adolescente , Adulto , Anticonceptivos Sintéticos Orales/uso terapéutico , Estudios Cruzados , Desogestrel/uso terapéutico , República Dominicana , Femenino , Humanos , Países Bajos , Estudios Prospectivos , Método Simple Ciego , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Current methods of hormonal emergency contraception (EC) are ineffective in preventing follicular rupture when administered in the advanced pre-ovulatory phase. This study was designed to determine the capacity of ulipristal acetate (UPA), a selective progesterone receptor modulator developed for EC, to block follicular rupture when administered with a follicle of >or=18 mm. METHODS: This was a double-blind, crossover, randomized, placebo-controlled study. Thirty-five women contributed with UPA (30 mg. oral) and a placebo cycle. Serial blood sampling for luteinizing hormone (LH), estradiol and progesterone measurements and follicular monitoring by ultrasound were performed before and for 5 days following treatment. Follicular rupture inhibition was assessed in the overall study population and in subgroups of women stratified by when treatment was administered in relation to LH levels (before the onset of the LH surge, after the onset of the surge but before the LH peak or after the LH peak). RESULTS: Follicular rupture failed to occur for at least 5 days following UPA administration in 20/34 cycles [59%; 95% confidence interval (CI) (40.7-75.4%)], whereas rupture took place in all cycles within 5 days of placebo intake. When UPA was administered before the onset of the LH surge, or after the onset but before the LH peak, follicle rupture had not occurred within 5 days in 8/8 (100%) and 11/14 [78.6%; 95% CI (49.2-95.3)] cycles, respectively. In contrast, when UPA was given after the LH peak, follicle rupture inhibition was only observed in 1/12 [8.3%; 95% CI (0.2-38.5)] cycles. CONCLUSIONS: This study demonstrates that UPA can significantly delay follicular rupture when given immediately before ovulation. This new generation EC compound could possibly prevent pregnancy when administered in the advanced follicular phase, even if LH levels have already begun to rise, a time when levonorgestrel EC is no longer effective in inhibiting ovulation.
Asunto(s)
Anticoncepción Postcoital/métodos , Anticonceptivos Sintéticos Poscoito/uso terapéutico , Fase Folicular/efectos de los fármacos , Norpregnadienos/administración & dosificación , Norpregnadienos/uso terapéutico , Folículo Ovárico/efectos de los fármacos , Inhibición de la Ovulación/efectos de los fármacos , Adulto , Anticoncepción Postcoital/efectos adversos , Anticonceptivos Sintéticos Poscoito/administración & dosificación , Anticonceptivos Sintéticos Poscoito/efectos adversos , Estudios Cruzados , Método Doble Ciego , Estradiol/sangre , Femenino , Fase Folicular/sangre , Humanos , Hormona Luteinizante/sangre , Norpregnadienos/efectos adversos , Tamaño de los Órganos , Folículo Ovárico/anatomía & histología , Folículo Ovárico/diagnóstico por imagen , Progesterona/sangre , Receptores de Progesterona/antagonistas & inhibidores , Estadística como Asunto , Factores de Tiempo , Ultrasonografía , Adulto JovenRESUMEN
We assessed to what extent the standard dose of levonorgestrel (LNG), used for emergency contraception, or a single dose (half dose), given in the follicular phase, affects the ovulatory process during the ensuing 5-day period. Fifty-eight women were divided into three groups according to timing of treatment. Each woman contributed with three treatment cycles separated by resting cycles. All received placebo in one cycle, and standard or single dose in two other cycles, in a randomized order. The diameter of the dominant follicle determined the time of treatment. Each woman had the same diameter assigned for all her treatments. Diameters were grouped into 33 categories: 12-14, 15-17 or 18-20 mm. Follicular rupture failed to occur during the 5-day period in 44%, 50% and 36% of cycles with the standard, half dose and placebo, respectively. Ovulatory dysfunction, characterized by follicular rupture associated with absent, blunted or mistimed gonadotropin surge, occurred in 35%, 36% and 5% of standard, single dose or placebo cycles, respectively. In conclusion, LNG can disrupt the ovulatory process in 93% of cycles treated when the diameter of the dominant follicle is between 12 and 17 mm. It is highly probable that this mode of action fully accounts for the contraceptive efficacy as well as the failure rate of this method. The present data suggest that half the dose may be as effective as the standard dose.
Asunto(s)
Anticonceptivos Sintéticos Orales/farmacología , Anticonceptivos Sintéticos Poscoito/farmacología , Levonorgestrel/farmacología , Folículo Ovárico/efectos de los fármacos , Ovulación/efectos de los fármacos , Adolescente , Adulto , Chile , Anticonceptivos Sintéticos Orales/administración & dosificación , Anticonceptivos Sintéticos Poscoito/administración & dosificación , República Dominicana , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Levonorgestrel/administración & dosificación , Hormona Luteinizante/sangre , Ciclo Menstrual/sangre , Ciclo Menstrual/efectos de los fármacos , Folículo Ovárico/diagnóstico por imagen , Ovulación/sangre , UltrasonografíaRESUMEN
This study was conducted to assess to what extent the Yuzpe regimen, or half the dose, given in the follicular phase, prevents ovulation during the ensuing 5 days. Sixty women were divided into six groups. All groups received placebo in one cycle and drug in another, in a randomized order. Groups differed by the dose and size of the leading follicle at the time of treatment (12-14, 15-17, or 18-20 mm). Ovulation was absent during the ensuing 5 days in 13 of 20 participants (65%) and in 8 of 20 participants (40%) who received the full and the half dose, respectively, when follicles were 12-17 mm. No ovulation occurred, within the critical period, in 7 of 39 placebo cycles (18%). When follicles were 18-20 mm, treatment did not prevent ovulation. In most drug-treated cycles, plasma gonadotropin and sex steroid levels were significantly depressed within the 5-day period, even when follicular rupture occurred within that period. In conclusion, the Yuzpe regimen can suppress or postpone ovulation to an extent that exceeds the fertile life of spermatozoa. Lack of ovulation within the critical period and dysfunction of the ovulatory process probably account for the contraceptive effect of this method in most cases. The present data do not warrant the use of half the dose of the Yuzpe regimen.
Asunto(s)
Anticonceptivos Poscoito , Etinilestradiol/administración & dosificación , Fase Folicular , Levonorgestrel/administración & dosificación , Ovario/efectos de los fármacos , Ovario/fisiología , Anticonceptivos Poscoito/efectos adversos , Método Doble Ciego , Estradiol/sangre , Etinilestradiol/efectos adversos , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Levonorgestrel/efectos adversos , Hormona Luteinizante/sangre , Folículo Ovárico/anatomía & histología , Ovulación , PlacebosRESUMEN
Contraceptive methods, including implants, do not prevent common symptoms and adverse health events that most people experience. It is difficult, therefore, to decide whether or not the occurrence of symptoms or adverse events that are common can be attributed to use of a contraceptive method or to determine if a given method changes the likelihood of their occurrence. Based on the review of the literature, no apparent differences in the frequency of adverse events are evident between the six-implant or two-rod levonorgestrel systems and the single implant etonogestrel and nomegestrol acetate systems. The most frequent adverse events reported in clinical trials that are probably related to implant use are headaches and acne. Weight gain, dizziness, and mood changes are also frequently mentioned adverse events and are possibly steroid-related. Other possibly related adverse events, although much less frequently reported, are loss of libido, fatigue, hair loss, and other skin conditions. Persistent ovarian follicles that spontaneously disappear are a common event during use of progestin-only contraceptives, and providers should be aware of this condition to avoid unnecessary interventions. Overall, the vast experience reported in the clinical studies reviewed here show that all existing implantable contraceptives are equally safe. This can probably be attributed to the low-hormonal dose delivered by progestin-implant systems.
Asunto(s)
Anticonceptivos Femeninos/efectos adversos , Congéneres de la Progesterona/efectos adversos , Dolor Abdominal/inducido químicamente , Acné Vulgar/inducido químicamente , Mama/efectos de los fármacos , Mareo/inducido químicamente , Implantes de Medicamentos , Fatiga/inducido químicamente , Femenino , Enfermedades del Cabello/inducido químicamente , Cefalea/inducido químicamente , Humanos , Libido/efectos de los fármacos , Náusea/inducido químicamente , Quistes Ováricos/inducido químicamente , Aumento de Peso/efectos de los fármacosRESUMEN
Nestorone(R) progestin (NES) is a potent 19-nor-progesterone derivative which is biologically inactive when administered orally; however, it is an excellent option for implant contraception. The objective of this study was to evaluate ovarian function during use of either one 4-cm or two 3-cm NES implants for 24 months. A total of 60 volunteers were enrolled in each dose group. Vaginal ultrasound (VUS) and blood sampling for determinations of estradiol (E(2)), progesterone (P) and NES serum levels were carried out twice a week for 6 consecutive weeks, beginning in months 1, 6, 12, 18, and 24 of implant use. Serum levels of NES declined with time, with a more pronounced decrease during the first 18 months of implant use; thereafter, NES levels remained stable until the end of the study at 24 months. Luteal activity was very infrequent during the first year of use (<3%) but increased during the second year, occurring in 27% and 35% of the sampling periods in the 1-implant group, and 2% and 16% of the sampling periods in the 2-implant group, at months 18 and 24 of use, respectively. No luteal activity was observed with NES levels above 80 pmol/L. Serum P levels in periods of luteal activity were significantly lower than those of controls. Persistent anovulatory follicles were the most common VUS finding and this was associated with E(2) levels that remained within the normal range (101-1500 pmol/L) in the majority of the sampling periods studied. Considering that a single implant offers advantage for insertion and removal, a new single NES implant is being developed with a slightly higher release rate, to reduce effectively the incidence of ovulation and provide a greater margin of safety beyond 2 years.
Asunto(s)
Anticonceptivos Femeninos/administración & dosificación , Norprogesteronas/administración & dosificación , Ovario/efectos de los fármacos , Ovario/fisiología , Adolescente , Adulto , Anticonceptivos Femeninos/sangre , Relación Dosis-Respuesta a Droga , Implantes de Medicamentos , Estradiol/sangre , Femenino , Humanos , Norprogesteronas/sangre , Folículo Ovárico/diagnóstico por imagen , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/fisiología , Ovario/diagnóstico por imagen , Ovulación/efectos de los fármacos , Progesterona/sangre , UltrasonografíaRESUMEN
The relationship between ovarian hormones and bleeding patterns during continuous progestin contraception was studied in 29 women who used Nestorone (NES) releasing implants. Oestradiol and progesterone were measured in blood samples taken twice a week for 6 consecutive weeks, during months 6, 12, 18 and 24 of implant use. Retrospectively, the association between hormonal concentrations and bleeding patterns was evaluated. Twenty-four short (
Asunto(s)
Anticonceptivos Femeninos/administración & dosificación , Glándulas Endocrinas/efectos de los fármacos , Menstruación/efectos de los fármacos , Norprogesteronas/administración & dosificación , Adolescente , Adulto , Amenorrea/sangre , Anticonceptivos Femeninos/farmacología , Implantes de Medicamentos , Glándulas Endocrinas/fisiología , Estradiol/sangre , Femenino , Humanos , Ciclo Menstrual/sangre , Menstruación/sangre , Norprogesteronas/farmacología , Concentración Osmolar , Progesterona/sangre , Estudios Retrospectivos , Factores de TiempoRESUMEN
The objective of this study was to time the onset of contraceptive effectiveness in Norplant implant users, when the capsules were inserted beyond the first 7 days of the cycle, based on the immediate effect on the ovarian activity. A total of 42 healthy women requesting Norplant implant contraception were enrolled at clinics in Santo Domingo, Dominican Republic, and in Baltimore, Maryland. Implants were inserted on days 8-13 of the menstrual cycle. Blood samples for estradiol (E2), progesterone (P), luteinizing hormone (LH) (in a subset of 12 women), and levonogestrel (LNG) assay, were taken at 0 h and at 6, 12, 24, 72, and 168 h postinsertion. Ovulation, as defined by P > 2.5 ng/mL, occurred in 40% of subjects. A short lasting, frequently blunted, LH peak occurred within 12 h postinsertion, in all these subjects. The remaining subjects had anovulatory cycles with two distinct E2 profiles: continuously increasing E2 levels to a high mean of 414.3 pg/mL (28%), or no sustained increase in E2 (32%). Most cycles (86%) in which Norplant was inserted with high E2 levels (> 175 pg/mL) were ovulatory, whereas none were ovulatory with low E2 (< 100 pg/mL) at insertion. Based on the endocrine effects of Norplant implant insertion in the midadvanced follicular phase, in which ovulation will either occur within 48 h of insertion or will be impaired, additional contraceptive protection is necessary only for 3 days.
Asunto(s)
Anticoncepción , Anticonceptivos Femeninos/administración & dosificación , Levonorgestrel/administración & dosificación , Adolescente , Adulto , Implantes de Medicamentos , Estradiol/sangre , Femenino , Humanos , Cinética , Levonorgestrel/sangre , Hormona Luteinizante/sangre , Ciclo Menstrual , Progesterona/sangre , Factores de TiempoRESUMEN
Levonorgestrel has an inhibitory effect on sex hormone binding globulin (SHBG). This decrease in SHBG leads to an increase in the free levonorgestrel index (FLI), which has a stronger biological effect. The interaction between serum levels of levonorgestrel and SHBG in long-term users of Norplant implants has been described. This study was designed to understand the same interaction immediately after the insertion of the implants, in a group of 16 women, sampled at 0 and 6 h and at 1, 3, and 7 days after Norplant implant insertion. Peak serum levonorgestrel levels were achieved at 24 h after insertion, remaining stable on day 3 and decreasing by > 10% by day 7. SHBG did not change during the first 24 h, but decreased by 19% and 60% on days 3 and 7, respectively. FLI more than doubled from day 1 to day 7 after insertion. The large decrease in SHBG and doubling of FLI is not followed by a similar reduction in levonorgestrel, which is hard to explain without an increase in the release rate of the steroid from the capsule.
PIP: It has been documented that levonorgestrel (LNG) administration by any route induces a significant reduction in circulating levels of sex hormone binding globulin (SHBG), which, in turn, leads to an increase in the free LNG index (FLI). A previous study found a pronounced reduction in SHBG levels as early as 7 days after insertion of the LNG-releasing Norplant contraceptive implants. The present study investigated the same interaction 1-7 days after Norplant insertion in 16 women recruited from a family planning clinic in Santo Domingo, Dominican Republic. Mean SHBG level at insertion was 75.9 nmol/l and was essentially unchanged 24 hours later. On postinsertion day 3, however, a 19% reduction over baseline was recorded. This decrease in SHBG was even more marked between days 3 and 7. By day 7, the mean SHBG serum level was only 40% of that found at the time of implant insertion. 6 hours after implant insertion, LNG levels were already above 700 pg/ml and peaked at over 1000 pg/ml at 24 hours, remained stable at this level until day 3, and then showed a moderate and nonsignificant decline of about 10%. The FLI was 5.1 at 24 hours postinsertion, remained at this level until day 3, and reached 11.9 by day 7. The lack of a significant reduction in LNG between postinsertion days 1 and 7 was unexpected given the 60% drop in SHBG and the doubling in the FLI. Two possible explanations for this finding are an increase in the amount of LNG entering the circulation or a large cross-reaction of the LNG assay with LNG metabolites in serum.
Asunto(s)
Anticonceptivos Femeninos , Levonorgestrel/efectos adversos , Levonorgestrel/sangre , Globulina de Unión a Hormona Sexual/metabolismo , Implantes de Medicamentos , Femenino , Humanos , Cinética , Levonorgestrel/administración & dosificación , Estudios ProspectivosRESUMEN
The objective of this study was to measure oestradiol, progesterone and endometrial development among Norplant implant users with bleeding complaints. Seventy-six volunteers complaining of prolonged/frequent bleeding were enrolled. Oestradiol, progesterone and endometrial thickness (assessed by vaginal ultrasound) were determined at that visit. Two thirds of the women had low oestradiol (< 50 pg/ml) and all except one had low progesterone concentrations (< 3 ng/ml). A total of 68% had a very thin endometrium (< 3 mm). A subgroup of 21 women were followed twice a week for 8 consecutive weeks. Oestradiol and progesterone concentrations remained low during the continuous bleeding episodes or short bleeding-free intervals (< or = 15 days), yet increased five- to sixfold (253.4 +/- 142.2 pg/ml) in long bleeding-free intervals. Endometrial thickness remained thin irrespective of the differences in bleeding patterns and oestradiol. We conclude that Norplant implant users with bleeding complaints are usually characterized by low oestradiol concentrations, absence of luteal activity and thin endometrium. A good correlation exists with increasing oestradiol concentrations and longer bleeding-free intervals, but this is not manifested by increased endometrial thickness. However, few subjects bleed with relatively high oestradiol concentrations, therefore a better understanding of the intimate disturbances related to endometrial bleeding in users of long-acting progestins is still pending.
Asunto(s)
Anticonceptivos Femeninos/efectos adversos , Endometrio/efectos de los fármacos , Estradiol/metabolismo , Levonorgestrel/efectos adversos , Congéneres de la Progesterona/efectos adversos , Hemorragia Uterina/inducido químicamente , Implantes de Medicamentos , Endometrio/patología , Femenino , Humanos , Hemorragia Uterina/patologíaRESUMEN
OBJECTIVE: To determine whether the process of ovulation could be interrupted by the insertion of Norplant implants (Leiras Pharmaceuticals, Turku, Finland) in the advanced preovulatory phase. DESIGN: Prospective study. SETTING: The Department of Biomedical Research at the Family Planning Clinic of PROFAMILIA, Santo Domingo, Dominican Republic. PATIENTS: Healthy women of reproductive age, requesting Norplant implants contraception. Thirteen of 15 women volunteers who were admitted completed the study. INTERVENTIONS: Norplant implants were inserted when the dominant follicle reached a mean diameter of 16 mm, based on serial vaginal ultrasounds (US) beginning on day 10 of the cycle. Blood samples for determination of E2, P, LH, and levonorgestrel, were taken and vaginal US performed at 0, 4, 24, 48, and 72 hours after insertion. If follicle rupture had not occurred at 72 hours after insertion, blood sampling and US were done three times per week during 2 additional weeks. RESULTS: Follicle rupture occurred in 11 of 13 subjects within 72 hours after insertion, with the exception of 1 subject in whom rupture occurred between 72 and 192 hours. Two women already had an LH peak at the time of insertion. In 9 of the remaining 11 women, a shortlasting, blunted LH surge was observed at 4 hours postinsertion. In the remaining two women, who had the lowest E2 levels, ovulation was inhibited, and a persistent follicle developed without luteinization. CONCLUSIONS: The insertion of Norplant implants in the advanced follicular phase will not inhibit ovulation if sufficient E2 priming has occurred. On the contrary, the exogenous progestin may rapidly foster ovulation shortly after.
PIP: 15 healthy women of reproductive age requesting Norplant were admitted into this prospective study conducted to determine whether the ovulation process can be interrupted by the insertion of Norplant implants during the advanced preovulatory phase. The implants were inserted when the dominant follicle reached a mean diameter of 16 mm, based upon serial vaginal ultrasounds (US) beginning day 10 into the cycle. Blood samples to determine levels of E(2), P, LH, and levonorgestrel were taken and vaginal US performed at 0, 4, 24, 48, and 72 hours after insertion. If follicle rupture had not occurred by 72 hours after insertion, blood sampling and US were done three times per week for two additional weeks. Follicle rupture occurred in 11 of the 13 subjects who completed the study within 72 hours after insertion, except for one subject who experienced rupture at 72-192 hours. Overall, it was determined that the insertion of Norplant implants during the advanced follicular phase will not inhibit ovulation if sufficient E(2) priming has occurred. The exogenous progestin, however, may rapidly foster ovulation shortly thereafter.
Asunto(s)
Levonorgestrel/administración & dosificación , Hormona Luteinizante/metabolismo , Folículo Ovárico/fisiología , Ovulación , Implantes de Medicamentos , Estradiol/sangre , Femenino , Humanos , Cinética , Levonorgestrel/sangre , Levonorgestrel/farmacología , Hormona Luteinizante/sangre , Folículo Ovárico/anatomía & histología , Folículo Ovárico/diagnóstico por imagen , Progesterona/sangre , Estudios Prospectivos , Ultrasonografía , Vagina/diagnóstico por imagenRESUMEN
OBJECTIVE: Our purpose was to evaluate whether prolonged or irregular bleeding during Norplant implant use could be alleviated with the use of oral hormonal medication. STUDY DESIGN: One hundred fifty users of the Norplant levonorgestrel contraceptive implant with prolonged or frequent bleeding were enrolled in this prospective, randomized, comparative study and assigned to one of three treatment groups for 20 days: ethinyl estradiol 50 microg, an oral contraceptive (50 microg ethinyl estradiol and 250 microg levonogestrel), and placebo. Total days of bleeding during treatment and length of the bleeding-free interval were analyzed. RESULTS: Women treated with the levonorgestrel-ethinyl estradiol pill bled an average of 2.6 days during treatment compared with 5.4 and 12.3 days in the ethinyl estradiol and placebo groups, respectively. Differences between both hormonal groups and placebo were significant (p <0.00001); moreover, the combined pill was more effective than ethinyl estradiol along (p <0.0001). CONCLUSION: The combined pill proved to be an excellent palliative treatment and is a more practical approach because of availability at all clinic sites.
PIP: In the Dominican Republic, clinical researchers randomly assigned 150 users of the contraceptive implant Norplant who came to Profamilia's Family Planning Clinic in Santo Domingo complaining of bleeding irregularities to one of three treatment groups. They aimed to evaluate the effectiveness of a combined oral contraceptive (OC) with 250 mcg levonorgestrel and 50 mcg ethinyl estradiol (EE) and of 50 mcg EE alone in treating bleeding irregularities. Bleeding irregularities were defined as prolonged bleeding (i.e., 8 or more continuous days of bleeding or spotting) or irregular bleeding (i.e., current bleeding episode initiated after a bleeding-free interval of less than 15 days). Age, parity, duration of Norplant use, and length of bleeding episode before treatment were similar in all three groups (i.e., OC, EE, and placebo). The OC group was significantly more likely to experience ceased bleeding within three days than the two other groups (91% vs. 67% for EE group [p 0.01 from OC group] and 15% for placebo group [p 0.0005 from both treatments]). Bleeding lasting for at least one week occurred less often in the OC group than the two other groups (2% vs. 14% for EE group and 50% for placebo group [p 0.0005 for both treatments]). Duration of bleeding was significantly lower in the OC group than the other two groups (2.6 days vs. 5.4 days for EE group and 12.3 days for placebo group; p 0.0001). Even though women in both hormonal treatment groups were more likely to experience gastralgia or nausea than the placebo group (33-40% vs. 4%; p 0.005), the side effects rarely interrupted treatment. These findings suggested that the OC is a very good effective treatment for bleeding irregularities and is a practical treatment since it is available at all Profamilia clinic sites.
Asunto(s)
Anticonceptivos Femeninos/efectos adversos , Anticonceptivos Orales Combinados/uso terapéutico , Congéneres del Estradiol/uso terapéutico , Etinilestradiol/uso terapéutico , Levonorgestrel/efectos adversos , Hemorragia Uterina/tratamiento farmacológico , Adulto , Análisis de Varianza , Distribución de Chi-Cuadrado , Implantes de Medicamentos , Femenino , Humanos , Levonorgestrel/uso terapéutico , Estudios Prospectivos , Hemorragia Uterina/inducido químicamenteRESUMEN
Levonorgestrel serum levels and sex hormone binding globulin (SHBG) were measured in 82 women during different years of use of Norplant implants. The ratio between levonorgestrel and SHBG was calculated as an indicator of the free biologically active fraction of levonorgestrel (free levonorgestrel index, FLI). These parameters were then correlated with the presence of luteal activity, as determined by progesterone levels above 9.6 nmol/L, in a sampling run of 10 samples taken twice a week for five consecutive weeks. Levonorgestrel serum levels remained constant around 1.0 nmol/L during the five-year period. SHBG levels were below normal for the first 18 months of use, returning to normal levels during the last three years of use. The FLI in the first two years was significantly higher than that observed in the later years. The frequency of cycles with luteal activity was 12% during the first 2 years, increasing to 44% in the latter years, when FLI levels were lower. Our results suggest that the changes in SHBG and consequently in the free biologically active fraction of levonorgestrel may largely account for the differences in degree of ovarian suppression observed between the first two years of use of Norplant implants and the latter three, even in the absence of a significant variation in total levonorgestrel concentrations.
Asunto(s)
Levonorgestrel/sangre , Levonorgestrel/farmacología , Fase Luteínica/efectos de los fármacos , Globulina de Unión a Hormona Sexual/análisis , Implantes de Medicamentos , Femenino , Humanos , Estudios Longitudinales , Ovario/efectos de los fármacos , Progesterona/sangre , RadioinmunoensayoRESUMEN
OBJECTIVE: To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. DESIGN: Observational, prospective, case-controlled comparative study. SETTING: The Family Planning Clinic of PROFAMILIA, in Santo Domingo, Dominican Republic. PATIENTS, PARTICIPANTS: Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate. INTERVENTIONS: Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for one menstrual cycle. RESULTS: Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from normal controls. CONCLUSIONS: Anovulation is clearly one of the main mechanisms of action of Norplant, but even in presumptive ovulatory cycles, the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.
PIP: The study sought to examine the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. This observational, prospective, case-controlled, comparative study occurred at the Family Planning Clinic of PROFAMILIA in Santo Domingo, Dominican Republic. 31 subjects agreed to receive Norplant contraceptive implants between 13-77 months prior to this study and there were 12 nonhormonal contraceptors who also volunteered to participate. Follicle stimulating hormone, luteinizing hormone, estradiol (E2), and progesterone (P) were serially assayed for 1 menstrual cycle, and almost 1/2 of the cycles of norplant acceptors were anovulatory: the remainder (55%) had some form of dysfunction such as diminished gonadotropin surge, luteal phase insufficiency (low P levels and shortened luteal phase), and E2 profiles different from controls. Anovulation is clearly 1 of the main mechanisms of Norplant action, but even in presumptive ovulatory cycles, the dysfunctions described could have contributed to the high contraceptive effectiveness of Norplant.
Asunto(s)
Anticonceptivos Orales Combinados/farmacología , Norgestrel/farmacología , Ovulación/efectos de los fármacos , Adulto , Anovulación/inducido químicamente , Estudios de Casos y Controles , Anticonceptivos Orales Combinados/administración & dosificación , Implantes de Medicamentos , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Levonorgestrel , Hormona Luteinizante/sangre , Norgestrel/administración & dosificación , Progesterona/sangre , Estudios ProspectivosRESUMEN
Ovarian endocrine function was assessed in 88 women using NORPLANT subdermal implants during different periods of use and in a control group of 15 women using non-hormonal contraception. Blood samples for estradiol (E2) and progesterone (P) assays were obtained twice a week for five consecutive weeks. Three distinct E2 patterns were observed: one was characterized by fluctuating levels within a normal range (20 to 400 pg/ml), a second pattern corresponded to continuous low E2 levels (below 75 pg/ml in the 10 samples) and the third was characterized by high broad estradiol peaks reaching over 400 pg/ml. The proportion of sampling runs characterized by normal fluctuating levels increased from 38% in the first two years of use to 80% during the fifth year of use. Low E2 profile was only observed during the first two years of use (27%) and in only 1 case at the beginning of the third year of use (5%). The percentage of cycles with high broad estradiol peaks remained between 20-40% without a clear tendency to change in either direction with duration of use. Thirty-three percent of the observed sampling runs had luteal activity (P above 3 ng/ml). The proportion of runs with luteal activity increased from 14% during the first two years of use to 40% during the third and fourth, and 60% during the fifth year of use. All control subjects had luteal activity. The mean highest progesterone level was lower in the NORPLANT runs (8.7 +/- 3.9 ng/ml) as compared to the controls (11.3 +/- 3.8 ng/ml). NORPLANT sampling runs with luteal activity had normal fluctuating E2 levels with only one exception. However, not all cycles with normal E2 levels showed luteal activity. On the other hand, all runs with low E2 levels or high broad E2 peaks were without luteal activity. In summary, women using continuous low-dose levonorgestrel contraception through NORPLANT subdermal implants, have a variable degree of ovarian activity as compared with the more complete depression of ovarian function observed among pill or injectables' users. Ovarian activity becomes closer to normal during the third through fifth year of use.
PIP: Ovarian endocrine function was assessed in 88 women using NORPLANT subdermal implants during different periods of use and in a control group of 15 women using non-hormonal contraception. Blood samples for estradiol (E) and progesterone (P) assays were obtained twice a week for 5 consecutive weeks. 3 distinct E patterns were observed; one was characterized by fluctuating levels within a normal range (20 to 400 pg/ml), a 2nd pattern corresponded to continuous low E levels (below 75 pg/ml in the 10 samples) and the 3rd was characterized by high broad estradiol peaks reaching over 400 pg/ml. The proportion of sampling runs characterized by normal fluctuating levels increased from 38% in the first 2 years of use to 80% during the 5th year of use. Low E profile was only observed during the first 2 years of use (27%) and in only 1 case at the beginning of the 3rd year of use (5%). The % of cycles with high broad estradiol peaks remained between 20-40% without a clear tendency to change in either direction with duration of use. 33% of the observed sampling runs had luteal activity (p 3 ng/ml). The proportion of runs with luteal activity increased from 14% during the first 2 years of use to 40% during the 3rd and 4th, and 60% during the 5th year of use. All control subjects had luteal activity. The mean highest progesterone level was lower in the NORPLANT runs (8.7 + or - 3.9 ng/ml) as compared to the controls (11.3 + or - 3.8 ng/ml). NORPLANT sampling runs with luteal activity had normal fluctuating E levels with only 1 exception. However, not all cycles with normal E levels showed luteal activity. On the other hand, all runs with low E levels or high broad E peaks were without luteal activity. In summary, women using continuous low-dose levonorgestrel contraception through NORPLANT subdermal implants, have a variable degree of ovarian activity as compared with the more complete depression of ovarian function observed among pill or injectables' users. Ovarian activity becomes closer to normal during the 3rd through 5th year of use. (Author's).