Administration of progesterone BioRelease LA inhibits follicular growth in llamas (Lama glama) regardless of follicle diameter at the start of treatment.

The aims of the study were twofold: first, the comparison of the pharmacokinetics parameters of two doses of Progesterone BioRelease® LA, (BioRelease Technologies, Lexington, KY, USA) one of 300 mg and other of 150 mg and their effects on ovarian dynamics in llamas. Based on the results from the first study, the aim of the second study was to evaluate the effect of the doses of 150 mg of progesterone on follicular activity considering the stage of the largest follicle at the beginning of treatment. The results in Study 1 showed that both doses of the formulation induced plasma progesterone concentrations higher than 1 ng/ml during the first 6 days of treatment in all females, progesterone concentrations steadily decline until Day 5 following by a slowly decrease. The total amount of progesterone released during treatment was higher in Group 300 than in Group 150 (p = 0.045). Mean maximum concentrations were 14.9 ± 2.24 and 14.3 ± 2.16 ng/ml for Group A versus Group B (p = 0.58), and they were registered on Day 1.5 ± 0.22 and 1.7 ± 0.34 days, respectively (p = 0.10). None of the animals of Group A showed progesterone concentration below 1 ng/ml during all studied period. The treatment applied in Study 2 was efficient in inhibiting the ovarian follicular dynamics and to start a superestimulatory treatment. The use of progesterone Biorelease® LA of 150 mg in comparison with the dose of 300 mg could be more effective in the use of synchronization protocols in llamas for AI or prior to the application of an ovarian superstimulatory treatment.

Preparation of TPP-crosslinked chitosan microparticles by spray drying for the controlled delivery of progesterone intended for estrus synchronization in cattle.

PURPOSE: Planned reproduction in cattle involves regulation of estrous cycle and the use of artificial insemination. Cycle control includes the administration of exogenous progesterone during 5-8 days in a controlled manner allowing females to synchronize their ovulation. Several progesterone delivery systems are commercially available but they have several drawbacks. The aim of the present contribution was to evaluate chitosan microparticles entrapping progesterone as an alternative system. METHODS: Microparticles were prepared by spray drying. The effect of formulation parameters and experimental conditions on particle features and delivery was studied. A mathematical model to predict progesterone plasma concentration in animals was developed and validated with experimental data. RESULTS: Microparticle size was not affected by formulation parameters but sphericity enhances as Tween 80 content increases and it impairs as TPP content rises. Z potential decreases as phosphate content rises. Particles remain stable in acidic solution but the addition of surfactant is required to stabilize dispersions in neutral medium. Encapsulation efficiencies was 69-75%. In vitro delivery studies showed burst and diffusion-controlled phases, being progesterone released faster at low pH. In addition, delivery extend in cows was affected mainly by particle size and hormone initial content, while the amount injected altered plasma concentration. Theoretical predictions with excellent accuracy were obtained. CONCLUSION: The mathematical model developed can help to find proper particle features to reach specific delivery rates in the animals. This not only save time, money and effort but also minimized experimentation with animals which is desired from an ethical point of view.

A simple pharmacokinetic model linking plasma progesterone concentrations with the hormone released from bovine intravaginal inserts.

On the basis of pharmacokinetic modeling, this study provides some insights into predicting in vivo plasma progesterone concentrations when using bovine intravaginal inserts for systemic progesterone delivery. More significantly, this contribution is the first attempt to build a simple pharmacokinetic model that links plasma progesterone concentrations with the hormone released from bovine intravaginal inserts. After evaluating three rival pharmacokinetic models and considering some phenomena involved in the intravaginal administration of progesterone, a primary pharmacokinetic model having a good data fitting capability with only two adjustable parameters is proposed to the above mentioned task. Kinetic parameters are given for lactating Holstein dairy cows with two levels of daily milk yields; and non-pregnant, non-lactating Holstein-Friesian cattle. Model predictions indicate the occurrence of a preferential distribution of the intravaginally administered progesterone dose through a first uterine pass effect.

Pharmacokinetics of progesterone in lactating dairy cows: gaining some insights into the metabolism from kinetic modeling.

Progesterone pharmacokinetics were analyzed for plasma hormone concentrations ranging from linear to saturated metabolism in lactating Holstein cows with differing daily milk yields. The adequacy of 2-coupled first-order (bi-exponential equation), hyperbolic (Michaelis-Menten equation), and sigmoidal (Hill equation) kinetic models to describe the experimental progesterone pharmacokinetic profiles was examined on a statistical basis. After nonlinear regression and statistical analysis of the data-fitting capability, a simple one-compartment model based on Hill equation proved to be most adequate. This model indicates an enzyme-catalyzed metabolism of progesterone involving cooperative substrate-binding sites, resulting from allosteric effects that yield a sigmoidal saturation rate curve. Kinetic parameters were estimated for 2 groups of lactating Holstein cows with different daily milk yields. We found, for the first time, a remarkable quantitative agreement of the Hill coefficient value with that reported in pharmacokinetic studies involving cytochrome P450, family 3, subfamily A (CYP3A)-mediated reactions in other mammals, humans included. It seems that positive cooperativity makes enzymes much more sensitive to plasma progesterone concentration, and their activities can undergo significant changes in a narrow range of concentration as characteristic of sigmoidal behavior. Therefore, the values of classical pharmacokinetic parameters, such as the elimination constant, half-life, and clearance rate, were found to be highly dependent on the plasma progesterone concentration.

Polyisoprene matrix for progesterone release: in vitro and in vivo studies.

Latex, a polyisoprene (PI) hydrophobic elastomer, was evaluated in vitro and in vivo as a matrix for intravaginal steroid hormone delivery. Matrices containing hormone were prepared by swelling latex in chloroform that contained soluble progesterone (P4). In vitro studies demonstrate that P4 release from PI follows a zero order model during at least 100 h and depends on initial load up to 10 mg cm(-2). The release of P4 from a PI matrix was found to be two times faster than from a polydimethylsiloxane (PDMS) matrix. FT-IR and X-ray powder diffraction analysis of P4 polymorphs show that when nucleated in PDMS, the hormone crystallizes only in alpha-form while in latex, crystallizes as a mixture of alpha- and beta-form. In vivo studies show that devices with a PI matrix containing 0.5 g of P4 are effective to reach plasma levels above 1 ng ml(-1) that are needed to synchronize estrous in cattle. Altogether, the results show that PI, a vulcanized polymer with a carbon-carbon backbone, can be used as a new matrix for the intravaginal administration of progesterone with improved release profile than silicone and that the matrix can influence the crystalline state of the hormone.

Extended use of a progesterone-releasing vaginal ring in nursing women: a phase II clinical trial.

AIM: This study evaluates the performance of extended use of a progesterone (P)-releasing vaginal ring (PVR) in nursing women. METHOD: An open-label, noncomparative study on the safety and contraceptive efficacy of PVR replaced every 4 months of use (instead of 3 months) in 192 PVR acceptors. PVR use was initiated at day 59+/-2 (mean+/-SD) postpartum and continued until weaning or completing the use of three PVRs. RESULTS: Plasma P levels attained with the ring decreased from 17+/-1 to 14+/-1 nmol/L (mean+/-SE) from the third to the fourth month of use. These levels are still over the critical level of 10 nmol/L required for contraceptive protection. One pregnancy occurred in the third month of use of the second ring in 1998 woman-months of exposure. Extended use of the ring did not appear to affect breast-feeding performance or the rate of infant growth, and lactational amenorrhea was prolonged. No differences in the characteristics of bleeding between the third and fourth month of ring use were observed. CONCLUSION: The results indicate that use of the PVR for 4 months represents a safe and effective contraceptive for nursing women.

Pharmacokinetics of natural progesterone vaginal suppository.

Natural and synthetic progesterone have been used to treat luteal insufficiency, premenstrual syndrome, and in infertile patients. The transvaginal route has advantages, such as lack of local pain, avoidance of first-pass hepatic metabolism, rapid absorption, high bioavailability and local endometrial effect. The aim of this study was to evaluate the pharmacokinetic of natural progesterone administered as vaginal suppositories of 25, 50 or 100 mg. Thirty-five healthy ovulating patients, 31.54 +/- 1.29 (mean +/- SEM) years old, in the follicular phase of the menstrual cycle (between days 7 and 10) participated in the study. They were separated in three groups and received vaginal suppositories containing either 25, 50 or 100 mg of natural progesterone. Progesterone serum concentration reached maximal levels within 2 or 3 h after the administration and was similar for the three groups (7.27 +/- 2.8 ng/ml; 8.84 +/- 3.14 ng/ml; 9.82 +/- 9.8 ng/ml, respectively). This study demonstrated that vaginally administered progesterone could reach levels that are similar to those obtained in ovulatory and luteal phases. The progesterone regimen for adequate endometrial protection and in vitro fertilization (IVF) programs still remains to be studied.

Mechanism of action of the potent sodium-retaining steroid 11, 19-oxidoprogesterone.

We have demonstrated previously that a planar conformation of the molecular frame is required for steroids to acquire optimal sodium-retaining activity and binding properties to the mineralocorticoid receptor (MR). One of the most active sodium-retaining compounds tested in those studies was 11, 19-oxidoprogesterone. Despite its biological potency, the relative affinity of 11,19-oxidoprogesterone for the MR is 5-fold lower than that of 21-deoxycorticosterone and 10-fold lower than aldosterone. Such a discrepancy may be assigned to uncommon biopharmacological properties of this synthetic steroid or an unusual molecular mechanism of action. In this work, we studied the biopharmacological and mechanistic features of 11,19-oxidoprogesterone. We show that both the pharmacokinetic properties of 11,19-oxidoprogesterone and its ability to transform and translocate the MR into the nucleus are undistinguishable from aldosterone. However, the capability of the serine/threonine phosphatase inhibitor tautomycin to impair nuclear translocation of the aldosterone-MR complex is not observed for the 11,19-oxidoprogesterone-MR complex. In addition, the binding properties of both steroids are differentially affected by modification of crucial lysyl residues of the MR. Kinetic studies performed on the aldosterone-MR complex in the presence of low concentrations of oxidopregnane suggest that 11,19-oxidoprogesterone may bind to the MR in a different binding site from the aldosterone binding pocket. Consistent with this postulate, a biologically inactive dose of 0.6 ng of oxidopregnane is able to potentiate the mineralocorticoid effect of a suboptimal dose of aldosterone.

Preregistration study on the safety and contraceptive efficacy of a progesterone-releasing vaginal ring in Chilean nursing women.

The contraceptive efficacy and safety of a progesterone-releasing vaginal ring (PVR) manufactured in Chile were compared to that of the Copper T 380A IUD (T-Cu) in nursing women enrolled at three Chilean clinics. A total of 285 volunteers chose to use the PVR and 262 the T-Cu. Plasma progesterone levels attained with the ring decreased from 25 to 14 nmol/L from month 1 to month 3 of use. Ring replacement was scheduled every 3 months. Volunteers continued in the study until weaning or completing the continuous use of four PVRs. No pregnancies occurred in 2320 and 2183 woman-months of exposure with the PVR and the T-Cu, respectively. Lower continuation rates in the first 6 months because of problems with use and a longer lactational amenorrhea were observed in the PVR than in the T-Cu group. Breast-feeding performance and infant growth were similar in both groups. These results confirm the high efficacy and safety of the PVR for nursing women and have led to the registration of the PVR by Chilean health authorities.

PIP: This study compares the contraceptive efficacy and safety of a progesterone-releasing vaginal ring (PVR) manufactured in Chile and a Copper T 380A IUD (T-Cu) in nursing women enrolled at three Chilean clinics. A total of 285 volunteers used the PVR and 262 used T-Cu. Plasma progesterone levels attained with the ring decreased from 25 to 14 nmol/l from month 1 to month 3 of use. Ring replacement was scheduled every 3 months. Volunteers continued in the study until weaning or completing the continuous use of 4 PVRs. There were no pregnancies in 2320 and 2183 woman-months of exposure with the PVR and the T-Cu, respectively. Lower continuation rates in the first 6 months because of problems with use and a longer lactational amenorrhea were seen in the PVR group. Breast-feeding performance and infant growth were similar in both groups. These results prove the high efficacy and safety of the PVR for nursing women. This has led to the registration of the PVR by Chilean health authorities.

Modificaciones de los patrones mamográficos con diversos esquemas de hormonoterapia de reemplazo en mujeres postmenopáusicas / Modification of breast radiographic patterns with several hormonal therapy schemes in postmenopausal women

La mamografía constituye el método de mayor sensibilidad en el diagnóstico precoz de cáncer de mama y en especial en las mujeres mayores, con mamas tipo "Radiolúcidas". Es de indicación absoluta en mujeres candidatas a recibir HTR y para su seguimiento. La relación entre la HTR y el riesgo de desarrollar un cáncer de mama es un tema controversial aún no resuelto. Sin embargo estudios recientes señalan que la HTR puede inducir un aumento de la densidad mamográfica (DxMx). El aumento de la DxMx ha sido identificado como uno de los factores asociados a fallas en el Screening de cáncer de mama. El objetivo de nuestro estudio, realizado en 2 centros mamográficos privados, fue evaluar las modificaciones de la DxMx en 210 pacientes que recibían distintos esquemas de HTR durante 1 año de observación. Se dividieron en 7 grupos terapéuticos de 30 pacientes cada uno y se compararon contra un grupo control de similares características. Para cuantificar las modificaciones de la DxMx se usaron los patrones de Wolfe. Considerando los 7 grupos de tratamiento en forma global se obtuvo un aumento de la DxMx en un 32,3 por ciento. El grupo Tibolona y Estriol presentó el menor porcentaje de cambios en la DxMx y fue similar al grupo control sin HTR. El mayor porcentaje de aumento en la DxMx se observó en los grupos que recibieron valerianato de estradiol (E2) en forma exclusiva o en esquema secuencial con MPA (66,7 por ciento) y 56,7 por ciento respectivamente). El grupo que recibió estrógenos conjugados en forma exclusiva mostró un aumento de la DxMx de un 43 por ciento y el grupo con estrógenos conjugados más MPA secuencial la DxMx aumentó en un 26,7 por ciento. El grupo que recibió esquema continuo combinado con valerianato de estradiol más MPA (2,5 mg) evidenció un aumento de la DxMx de un 30 por ciento. Estos resultados señalan la necesidad de agregar al informe Mx los cambios observados en la DxMx como consecuencia de la HTR ya que permite al clínico adecuar los esquemas terapéuticos a la respuesta individualizada de cada mujer

Sodium-retaining activity of some natural and synthetic 21-deoxysteroids.

The effect of progesterone and six other C21-deoxysteroids on renal sodium retention by male adrenalectomized rats was compared with the effect exerted by the natural corticoids aldosterone, 11-deoxycorticosterone, and corticosterone. Steroids were active in the following order: aldosterone > 11,19-oxidoprogesterone > 5 alpha H-3,20-pregnanedione > or = 5 beta H-3,20-pregnanedione > progesterone = 11-ketoprogesterone > 6,19-oxidoprogesterone = 11-keto-6,19-oxidoprogesterone > or = corticosterone. All C21-deoxysteroids, except 11,19-oxidoprogesterone, exhibited parabolic log dose-response functions, indicating an effect that opposes renal sodium retention at high doses. 11,19-Oxidoprogesterone and the natural corticoids exhibited normal, exponential, log dose-response curves. Diverse geometric parameters related to molecular planarity were calculated and their correlation with biopharmacological properties was attempted. The best linear regression was obtained for correlation of the concavity of log dose-response parabolas (second-order coefficients) of C21-deoxysteroids with the C3 = O/ring D angle of these molecules. A good linear regression could also be obtained for correlation of the affinity of C21-deoxysteroids, except 11,19-oxidoprogesterone, for purified type I mineralocorticoid receptors with those angles. The latter correlation deteriorated upon incorporation of the affinity data for the three natural corticoids, due to similar affinities of these hormones for type I mineralocorticoid receptors, but could be restored when the binding data for the unpurified, corticosterone-binding globulin-containing stage of the receptors were considered. In vivo binding data followed the same trend as that for unpurified receptors.

[Synthetic progestogens versus oral progesterone]. / Progestágenos sintéticos vs progesterona oral.

The antecedents of progesterone natural hormone and related structural groups, chemically and biologically, were described. The synthesis and semi-synthesis of these compounds, is reviewed, and molecular changes, which gave more potency for clinical use, is reviewed. The pharmacology of these groups is manifested, particularly, by the identification of a receptor, its physico-quemical characteristics and relative affinity for tissues as endometrium and myometrium. Furthermore, the progestational quality, the antiestrogenic one, antiandrogenic one and its applications, were evaluated. Finally, several biologic indicators which support the use of oral progesterone and that suggest the re-evaluation of tissular dynamics in reproductive tract, were reviewed.

The place of progesterone in human contraception.

Progesterone, the natural hormone produced by the corpus luteum and other steroid-secreting glands, is endowed with antiestrogenic action and has a fundamental role in the initiation and maintenance of pregnancy and in the regulation of gonadotropin secretion. Although it was discovered half a century ago, it has found little clinical use as a therapeutic agent due to its low potency and extensive degradation following oral administration in comparison with a variety of highly potent synthetic analogs that became available in the last three decades. When delivered systemically, a large proportion of the dose bypasses degradation in the gut and liver, and progesterone can achieve effective levels in target tissues for clinical use. Sustained administration via compressed pellets implanted subdermally or silicone rubber rings placed in the vagina produced circulating levels of progesterone within the lower third of those found in the luteal phase of the human menstrual cycle. Those levels were shown to delay the recovery of fertility in nursing women without adverse effects to the mother or the infant. Progesterone transferred to the babies via the breast milk did not change their rate of pregnandiol-3-alpha glucuronide excretion. It is concluded that sustained administration of the natural hormone progesterone may be an effective and safe contraceptive method for nursing women.