RESUMEN
INTRODUCTION: Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. OBJECTIVE: We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I-II studies involving patients with breast, ovarian, endometrial, and prostate cancer. RESULTS: Among the 88 patients in two phase I-II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient's liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. CONCLUSIONS: These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.
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Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Gonanos/uso terapéutico , Antagonistas de Hormonas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/tratamiento farmacológico , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Preparaciones de Acción Retardada , Femenino , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Gonanos/administración & dosificación , Gonanos/efectos adversos , Antagonistas de Hormonas/administración & dosificación , Antagonistas de Hormonas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: In PTEN-loss models, the phosphatidylinositol 3-kinase (PI3K)/AKT and androgen receptor signaling pathways cross-regulate by reciprocal feedback whereby inhibition of one activates the other, creating a rationale for co-targeting. We studied the irreversible, pan-isoform inhibitor of Class I PI-3K PX-866 singly (part A) and with abiraterone acetate (AA) in patients on AA with rising prostate-specific antigen (PSA) (part B). PATIENTS AND METHODS: The primary endpoint was lack of progression at 12 weeks. Exploratory endpoints included changes in circulating tumor cells (CTC), pharmacodynamic studies on platelets (part A), and archival tumor exploration of PTEN as predictor of response (part B). RESULTS: A total of 43 and 25 patients accrued to parts A and B, respectively. In part A, 14 (33%) patients were progression-free at 12 weeks, with 2 partial objective responses and 1 confirmed PSA response. Favorable CTC conversion (< 5 CTC/7.5 mL) occurred in 6 (24%) of 25 evaluable patients. In part B, 11 of 25 patients had measurable disease. Six (24%) patients were progression-free at 12 weeks. No objective or PSA responses were observed. For all 68 patients, the most common toxicities were diarrhea (53 patients), nausea (36), anorexia (24), fatigue (22), and vomiting (20). Among 17 patients for whom PTEN testing was possible, 3 had PTEN homozygous deletion and 14 had no change. No correlation between PTEN status and response was seen. CONCLUSIONS: PX-866 had modest single agent activity. Adding AA to PX-866 showed no evidence of resistance reversal. Strategies to combine PI3K inhibition with androgen receptor-targeted therapies could consider initiation earlier, combination with other agents, and/or recruiting a selected population.
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Androstenos/administración & dosificación , Gonanos/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Androstenos/efectos adversos , Androstenos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Canadá , Progresión de la Enfermedad , Gonanos/efectos adversos , Gonanos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Células Neoplásicas Circulantes/efectos de los fármacos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Gonanos/uso terapéutico , Receptores de Progesterona/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Preparaciones de Acción Retardada , Femenino , Gonanos/efectos adversos , Gonanos/farmacocinética , Semivida , Humanos , Persona de Mediana Edad , Náusea/etiología , Metástasis de la Neoplasia , Recurrencia Local de NeoplasiaRESUMEN
BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. PATIENTS AND METHODS: Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. RESULTS: A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. CONCLUSION: The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Gonanos/administración & dosificación , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cetuximab/efectos adversos , Neoplasias Colorrectales/mortalidad , Supervivencia sin Enfermedad , Femenino , Gonanos/efectos adversos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), and antitumor activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with cetuximab in patients with incurable colorectal cancer or squamous cell carcinoma of the head and neck. METHODS: PX-866 was administered at escalating doses (6-8 mg daily) combined with cetuximab given at a 400 mg/m(2) loading dose followed by 250 mg/m(2) weekly. A "3 + 3" study design was used. Prior therapy with anti-EGFR therapies, including cetuximab, was allowed. RESULTS: Eleven patients were enrolled. The most frequent treatment-emergent adverse event was diarrhea (90.1%), followed by hypomagnesemia (72.2%), vomiting (72.2%), fatigue (54.5%), nausea (54.5%), rash (45.5%) and peripheral edema (40%). No dose limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent PX-866 MTD. Best responses in 9 evaluable patients were: 4 partial responses (44.4%), 4 stable disease (44.4%), and 1 disease progression (11.1%). The median progression free survival was 106 days (range: 1-271). CONCLUSION: Treatment with PX-866 and cetuximab was tolerated with signs of anti-tumor activity. Further development of this combination is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/sangre , Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Cetuximab , Fosfatidilinositol 3-Quinasa Clase I , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Gonanos/administración & dosificación , Gonanos/efectos adversos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Criterios de Evaluación de Respuesta en Tumores Sólidos , Carcinoma de Células Escamosas de Cabeza y Cuello , Proteínas ras/genéticaRESUMEN
BACKGROUND: This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours. METHODS: PX-866 was administered at escalating doses (4-8 mg daily) with docetaxel 75 mg m⻲ intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers. RESULTS: Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1-569). A non-significant association between longer PFS for PIK3CA-MUT/KRAS-WT vs PIK3CA-WT/KRAS-WT was observed. CONCLUSION: Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gonanos/uso terapéutico , Neoplasias/tratamiento farmacológico , Taxoides/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/sangre , Supervivencia sin Enfermedad , Docetaxel , Femenino , Gonanos/efectos adversos , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de las Quinasa Fosfoinosítidos-3 , Taxoides/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Increased iron stores are associated with greater cardiovascular risk in postmenopausal women. Oral contraceptive pill (OCP) use decreases the volume of menstrual blood loss and increases iron stores, but the link between OCP use, iron stores and cardiovascular risk in premenopausal women has not been characterized. STUDY DESIGN: We conducted a cross-sectional study of 23 healthy OCP users to determine the association between type and duration of OCP exposure, iron stores, and vascular endothelial function [flow-mediated dilation (FMD) in the brachial artery]. RESULTS: Median duration of OCP use was 45 months. FMD in the brachial artery was significantly associated with progestin type used (estranes/gonanes vs. drospirenone) and duration of OCP use (both p<.05) but not iron stores. In multivariate analysis, progestin type was the only independent predictor of FMD. CONCLUSIONS: Use of OCP containing drospirenone was independently associated with greater FMD in the brachial artery and, thus, a potentially more favorable cardiovascular risk profile, when compared with use of OCP containing estranes/gonanes.
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Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/inducido químicamente , Anticonceptivos Orales/administración & dosificación , Anticonceptivos Orales/efectos adversos , Endotelio Vascular/efectos de los fármacos , Hierro/sangre , Adulto , Androstenos/administración & dosificación , Androstenos/efectos adversos , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Arteria Braquial/diagnóstico por imagen , Arteria Braquial/efectos de los fármacos , Enfermedades Cardiovasculares/patología , Estudios Transversales , Estranos/administración & dosificación , Estranos/efectos adversos , Femenino , Ferritinas/sangre , Gonanos/administración & dosificación , Gonanos/efectos adversos , Humanos , Modelos Lineales , Ultrasonografía , Vasodilatación/efectos de los fármacos , Adulto JovenRESUMEN
The antiglucocorticoid action of the antiprogestin RU 38486 has interfered with its successful clinical application in long-term treatment. Several new antiprogestins (Org 31710, Org 31806 and ZK 98299) have recently been developed with the aim to eliminate this side-effect. We have used a human lymphocyte proliferation assay to estimate the antiglucocorticoid potency of RU 38486 and the newer antiprogestins. In this assay 100 nmol/L RU 38486 shifted the dexamethasone inhibition curve by at least one order of magnitude. The other antiprogestins showed no effect at 100 nmol/L. RU 38486 (30 nmol/L) was able to antagonize 1000 nmol/L dexamethasone. The other antiprogestins showed only slight effects even at 1000 nmol/L. We conclude that the new antiprogestins have antiglucocorticoid effects that are one to two orders of magnitude lower than that of RU 38486. This may make them more suitable than RU 38486 for application in long-term antiprogestin treatment.
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Glucocorticoides/antagonistas & inhibidores , Antagonistas de Hormonas/efectos adversos , Antagonistas de Hormonas/farmacología , Mifepristona/efectos adversos , Mifepristona/farmacología , Progestinas/antagonistas & inhibidores , Unión Competitiva , Dexametasona/antagonistas & inhibidores , Resistencia a Medicamentos , Estrenos/efectos adversos , Estrenos/metabolismo , Estrenos/farmacología , Furanos/efectos adversos , Furanos/metabolismo , Furanos/farmacología , Gonanos/efectos adversos , Gonanos/metabolismo , Gonanos/farmacología , Antagonistas de Hormonas/metabolismo , Humanos , Hidrocortisona/sangre , Técnicas In Vitro , Activación de Linfocitos/efectos de los fármacos , Neoplasias Meníngeas/tratamiento farmacológico , Neoplasias Meníngeas/metabolismo , Meningioma/tratamiento farmacológico , Meningioma/metabolismo , Mifepristona/metabolismo , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/metabolismoRESUMEN
OBJECTIVES: The effects of the antiprogestin onapristone (ZK 98.299) on fertility; menstrual cycle length; duration of menses; serum estradiol, progesterone, and cortisol concentrations; and endometrial morphologic features were studied in adult bonnet monkeys. STUDY DESIGN: Five animals were treated subcutaneously with the vehicle and another nine with either 2.5 (n = 4) or 5 mg of onapristone per animal (n = 5). Treatment was initiated on day 5 of the first treatment cycle, and thereafter onapristone was administered every third day for four to seven consecutive cycles. The females were placed with adult males during the periovulatory period, which was assessed by frequent analysis of serum estradiol concentrations. In the final treatment cycle an endometrial biopsy was performed on day 8 after a midcycle estradiol peak in the ovulatory cycle, or around day 20 if the cycle was anovulatory. Blood samples for estradiol, progesterone, and cortisol measurement were collected every third day, except for the periovulatory period when sampling was more frequent. RESULTS: Each of the five animals treated with the vehicle became pregnant: one in the first, three in the second, and one in the third mated cycle, whereas only one of nine treated with onapristone became pregnant. Four animals treated with 2.5 mg of onapristone for 17 cycles and another four treated with a 5 mg dose for 21 cycles did not conceive. In eight animals that did not conceive the first three treatment cycles of six were ovulatory, and in the remaining two animals two cycles of each were ovulatory. During treatment the mean menstrual cycle length was not altered significantly; however, in one it was shortened and in another two it was prolonged. Similarly, the mean duration of menses was not significantly affected, but in some cycles it was reduced. Moreover, there was only slight bleeding in some treatment cycles. Ovulation occurred in 30 of 45 treatment cycles, including the final treatment cycle during which the biopsy was taken, as indicated by serum estradiol and progesterone concentrations. In some of the ovulatory cycles prolonged treatment suppressed luteal activity; however, in the ovulatory cycles the duration of follicular and luteal phases was not significantly affected. In the anovulatory cycles there was a delayed increase in serum estradiol concentrations, suggesting a partial inhibition of folliculogenesis. In treated animals endometrial growth and development was retarded and rendered out of phase. In animals treated with the higher (5 mg) onapristone does the endometrial glands had partially regressed, the secretory activity was blocked, and stromal compaction was evident. The treatment had no significant effect on serum cortisol levels. CONCLUSIONS: This study demonstrates that low-dose onapristone treatment throughout the menstrual cycle prevents pregnancy without disturbing the menstrual cycle and ovulation in the majority of cycles. However, anovulation and luteal insufficiency occurred in some animals during prolonged treatment. The contraceptive effect in the ovulatory cycles seems primarily related to the retardation of endometrial development resulting in the inhibition of endometrial receptivity. It appears likely that a dose or treatment regimen of onapristone that will inhibit endometrial receptivity and prevent implantation without affecting the menstrual cycle even on prolonged treatment could be identified.
PIP: Antiprogestin drugs such as RU 486 (mifepristone), ZK 98.299 (onapristone), and HRP 2000 block progesterone action at the receptor level. They bind to progesterone and glucocorticoid receptors, which leads to an antagonistic instead of an agonistic response. Treatment with these antiprogestins, depending upon the dose, retards endometrial development and impairs gonadotropin release, thereby blocking ovulation. The hypothalamus, pituitary, and endometrium, however, differ in their sensitivity to the antiprogestins, with the endometrium being sensitive to doses which do not seem to affect ovulation. The authors report on their study of the effects of onapristone upon the fertility; menstrual cycle length; duration of menses; serum estradiol, progesterone, and cortisol concentrations; and endometrial morphologic features in adult bonnet monkeys for four-seven consecutive cycles. The study was undertaken to assess the feasibility of using onapristone as a contraceptive agent and to determine its mechanism of action. Onapristone was dissolved in benzyl benzoate and then diluted in castor oil (1:10, vol/vol). 0.5 ml of the vehicle was used to administer each dose subcutaneously. Five monkeys were treated subcutaneously with the vehicle, four monkeys each with 2.5 mg of onapristone, and five each with 5 mg of onapristone. The study found low-dose onapristone treatment throughout the menstrual cycle to prevent pregnancy without disturbing the menstrual cycle and ovulation in the majority of cycles. Anovulation and luteal insufficiency did, however, occur in some animals during prolonged treatment. The contraceptive effect in the ovulatory cycles seems mainly related to the retardation of endometrial development resulting in the inhibition of endometrial receptivity. The authors find it likely that a dose or treatment regimen of onapristone which will inhibit endometrial receptivity and prevent implantation without affecting the menstrual cycle even on prolonged treatment could be identified.
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Anticonceptivos Femeninos , Endometrio/efectos de los fármacos , Gonanos/administración & dosificación , Antagonistas de Hormonas/administración & dosificación , Progestinas/antagonistas & inhibidores , Animales , Cuerpo Lúteo/efectos de los fármacos , Cuerpo Lúteo/fisiología , Endometrio/anatomía & histología , Estradiol/sangre , Femenino , Gonanos/efectos adversos , Gonanos/farmacología , Macaca radiata , Ciclo Menstrual/efectos de los fármacos , Ovulación/efectos de los fármacos , Embarazo , Progesterona/sangreRESUMEN
The effects of the antiprogestin onapristone on the menstrual cycle were assessed in surgically sterilized volunteer women. The steroid was given orally at the dose of 5, 15 or 50 mg/day, from day 5 to day 11 of the cycle. Ovarian ultrasonography and hormonal determinations in plasma and urine were used to monitor the pre-treatment, treated and post-treatment cycles. Onapristone, given at a dose of 5 mg/day, affected follicular growth inconsistently. The dose of 15 or 50 mg/day arrested follicular growth and oestradiol increase and delayed gonadotrophin surge, extending the length of the follicular phase in five of seven women in each group. After discontinuation of treatment the leading follicle resumed its growth and ovulation occurred as judged by the elevation of plasma progesterone, preceded in most but not all cases by an echographic image of follicular collapse. The ensuing luteal phases were not significantly altered in length or plasma progesterone concentration. Cortisol concentrations were unaffected and no serious side-effects were recorded. The antifolliculotrophic effect of onapristone demonstrated here, together with previous reports of similar activity of mifepristone in women, indicate that this may be a general property of compounds that interfere with progesterone receptor function.
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Gonanos/farmacología , Folículo Ovárico/efectos de los fármacos , Adulto , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Estradiol/sangre , Estradiol/orina , Femenino , Hormona Folículo Estimulante/sangre , Fase Folicular/efectos de los fármacos , Gonanos/efectos adversos , Gonanos/sangre , Humanos , Hormona Luteinizante/sangre , Ciclo Menstrual/efectos de los fármacos , Folículo Ovárico/fisiología , Ovario/diagnóstico por imagen , Ovulación/efectos de los fármacos , Progesterona/sangre , Factores de Tiempo , UltrasonografíaRESUMEN
The third generation of combination estrogen/progestogen oral contraceptives (OCs) first became available in the early 1980s. The gonanes (e.g., norgestimate, desogestrel, and gestodene) are alternatives to the long-standing progestogens, norethindrone and norgestrel/levonorgestrel. While the newer compounds are related to levonorgestrel, their biochemical structure differs. All, however, are strongly progestogenic with respect to ovulation inhibition and are very selective in their affinity for endometrial progesterone receptors. At present, experience with the third-generation combined OCs is relatively limited, and extensive comparative data have yet to be accrued. Nevertheless, these ultra-low-dose compounds appear to be as efficacious as the traditional OCs, while their cycle control may be slightly superior. In addition, the incidence of minor side effects, such as nausea, weight gain, and mastalgia, compares favorably with that of the earlier OCs. In combination with estrogen, these new progestogens have revealed a neutral or possibly beneficial effect on lipid/lipoprotein metabolism. Thus, the newer progestogens do not appear to have adverse effects on the cardiovascular system and offer a range of noncontraceptive health benefits.
PIP: A study using data from the United Kingdom (UK), Denmark, and Sweden and an ongoing study in the UK found a significant association between estrogen content of high dose combined oral contraceptives (OCs) and all thromboses except venous thrombosis of lower limb. In fact, the ongoing study and another study both found a distinct association between progestogen dose and arterial disease. These association prompted formulators to decrease OC estrogen and progestogen (norethindrone and levonorgestrel) content. These new formulations entered the market after 1975. The early 1980s witnessed the introduction of yet another generation of genane progestogens which were developed in hoped of reducing the incidence of thrombosis. Clinical trials found their contraceptive effectiveness to be comparable to those of the older demonstrated that their effect on associated incidence of bleeding is similar to the older OCs and falls over time. Moreover, even though the 3rd generation OCs have brought on the same side effects (weight gain, mastalgia, and nausea) as the others, the frequency has been at least, and often less, than the others. So far data have not implicated the 3rd generation OCs in impairing glucose tolerance. In addition, research has demonstrated that 3rd generation formulations cause a small increase in high density lipoprotein and either did not change or reduced low density lipoprotein and total cholesterol levels. Thus the new combined OCs do not promote atherosclerotic changes in lipid metabolism. Even though more research is needed, the data have indicated that physicians should continue to prescribe the 3rd generation OCs.