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Eugene D. Albrecht - One of the best experts on this subject based on the ideXlab platform.

  • Luteal Function in Baboons with Administration of the Antiestrogen Ethamoxytriphetol (MER-25) Throughout the Luteal Phase of the Menstrual Cycle’
    2016
    Co-Authors: Eugene D. Albrecht, Arthur L. Haskins, Gary D. Hodgen, Gerald J. Pepe
    Abstract:

    Administration of the antiestrogen Ethamoxytriphetol (MER-25) during late baboon gestation has been reported to result in a marked decline in progesterone (P) production rate. Since both the placenta and corpus luteum appear to secrete P during late baboon gestation, this decline in P may reflect a loss in luteal and/or placental function. Therefore, the present study determined the effect of administration of the antiestrogen MER-25 upon serum steroid concentrations during the luteal phase of the baboon menstrual cycle, a tijne when the source of P is almost exclusively the corpus luteum, Six baboons were bled throughout a control menstrual cycle and during daily administration (15 mg/kg BW, p.o.) of MER-25 throughout the luteal phase of the following cycle. Mean ( ± SEM) length of the luteal phase of the menstrual cycle was the same in baboons with no treatment (18 ± 0 days) and after MER-25 administration (18 ± 0 days). Mean ( ± SEM) serum concentra-tions of P were similar in the luteal phase with no treatment (5.2 ± 0.7 ng/ml) and during MER-25 ad-ministration (5.0 ± 0.6 ng/ml). Serum P attained similar peak values of concentration in the luteal phase before and after antiestrogen administration and was detectable in the serum for a similar duration of the lutes] phase of both cycles. Mean ( ± SEM) serum concentrations of 17-hydroxyprogesterone (17-01(P)

  • Influence of fetectomy on serum pregnancy-associated plasma protein-A concentrations in the baboon.
    Biology of reproduction, 1994
    Co-Authors: Gerald J. Pepe, Brendan J. Waddell, Michael J. Sinosich, Eugene D. Albrecht
    Abstract:

    In baboons as in humans, the placenta is a source of various peptides, including pregnancy-associated plasma protein-A (PAPP-A). However, our present understanding of the regulation of PAPP-A production is incomplete. We have demonstrated that after fetectomy, the baboon placenta retains steroidogenic capacity and is maintained in utero until delivered spontaneously close to term. We have suggested, therefore, that fetectomy provides a valuable in vivo approach to elucidating the role(s) of the fetus, and of the hormones (e.g., estrogen and progesterone) dependent upon the presence of the fetus, in the regulation of placental steroidogenesis during primate pregnancy. Therefore in the present study we utilized the fetectomy model to evaluate the respective roles of the fetus, estrogen, and progesterone on placental PAPP-A. Estradiol, progesterone, and PAPP-A concentrations were determined by RIA in maternal blood collected under ketamine anesthesia on Days 78-100 (n = 5), Days 102-144 (n = 4), and Days 146-164 (n = 3) of gestation (term = Day 184) in control baboons (Papio anubis) and on Days 110-164 in baboons fetectomized on Day 100 (n = 9). Studies were also conducted in five animals in which placental estrogen was increased by maternal treatment on Days 70-100 with androstenedione and in three animals treated on Days 140-164 with the antiestrogen, Ethamoxytriphetol (MER-25; 25 mg/day/kg BW). PAPP-A levels were analyzed by ANOVA and Duncan's multiple range test and were compared with placental wet weight (g) previously determined on Day 100 (78 5) and on Day 165 (171 ± 6) in untreated baboons; on Day 100 in androstenedione-treated baboons (79 ± 3); and on Day 165 in antiestrogen-treated (188 ± 8) and fetectomized (99 ± 24) baboons. Mean (± SE) serum estradiol concentrations (ng/ml) were greater on Day 164 (2.5 ± 1.0) than on Day 100 (1.0 ± 0.3), increased on Day 100 by administration of androstenedione (4.8 ± 1.6), and decreased on Day 165 by fetectomy (0.12 ± 0.01). Serum progesterone exhibited no significant rise or fall during the second half of gestation and averaged 10.3 ± 1.4 ng/ml. Concentrations of progesterone late in gestation were reduced (p < 0.05) by treatment with MER-25 (3.1 ± 0.5) and by fetectomy (1.5 ± 0.2). PAPP-A (mIU/L) increased (p < 0.05) throughout the second half of gestation from a mean (± SE) of 32.2 ± 6.2 on Day 78 to 94.5 ± 11.6 on Days 160-164. Prior to fetectomy, PAPP-A on Days 96-100 (56.1 ± 5.0) was similar to the corresponding values in controls. However, after fetectomy, serum PAPP-A did not continue to increase with advancing gestation: the mean concentration in the 4-day interval prior to delivery (69.9 ± 7.9 mIU/ L) was lower (p < 0.05) than that in the intact controls (94.5 ± 11.6 mIU/L) but was not different from that measured before fetectomy on Day 100. When expressed relative to placental weight, however, PAPP-A levels in fetectomized baboons at term were comparable to those in untreated controls. PAPP-A was not altered by treatment with androstenedione or MER-25 and was not detectable ( 12.2 mIU/L) after delivery of the placenta Collectively, these findings indicate that production of PAPP-A during baboon pregnancy is determined in large part by the mass of functioning trophoblast and/or by factors that regulate growth of the trophoblast and is not regulated by estrogen or progesterone. In addition, we suggest that the present demonstration of continued secretion of PAPP-A, and the previously documented capacity for aromatization of androgens to estrogen after fetectomy, confirm the viability of the placenta as well as the value of this in vivo animal model for the study of fetoplacental function during primate pregnancy.

  • Regulation of placental low-density lipoprotein uptake in baboons by estrogen: dose-dependent effects of the anti-estrogen Ethamoxytriphetol (MER-25).
    Biology of reproduction, 1991
    Co-Authors: Michael C. Henson, Gerald J. Pepe, Eugene D. Albrecht
    Abstract:

    In the present study, increasing amounts of the anti.estrogen !-(p-2-diethylaininoethoxyphenyl)-!-phenyl.2-p-methoxyphenolethanol (MER-25) were administered to pregnant baboons (Papio anubis) to block the action of endogenous estrogen and to determine effect on placental low-density lipoprotein (LDL) uptake. Pregnant baboons were untreated (n = 8) or received MER25 orally at a dosage of 25 (n = 10), 50 (n = 8), or 75 (n = 4) mg/kg BW daily on Days 140-170 of gestation (term = 184 days). Placentas were removed on Day 170 of gestation and villous tissue was dispersed with 01% collagenase. Placental cells (106) were incubated in Medium 199 for 12 h at 37#{176}C with increasing amounts of 1251-LDL, with or without a 100.fold excess of unlabeled baboon LDL Mean (±SEM) placenta! uptake (ng/�g cell protein) of ‘251-LDL was 55% (6.4 ± 1.0), 75% (3.6 ± 0.7), and 81% (2.7 ± 0.2) lower (p < 0.001) in baboons that received MER-25 in doses of 25, 50, and 75 mg/kg BW, respectively, than in untreated baboons (14.2 ± 1.3 ng/�Lg cell protein). Maximal effect occurred with 50 mg MER-25, because LDL uptake was not further decreased with greater levels of MER-25. Dissociation constants for placental LDL uptake, as determined by Scatchard analysis, were unaltered by anti-estrogen treatment. The amount of ‘25l-LDL degradation by placental cells of untreated and MER-25.treated baboons was proportional to LDL uptake. Peripheral serum progesterone (P4) concentrations on Days 140-170 were 45% (6.! ± 0.2 ng/ml), 55% (5.0 ± 0.3 ng/ml), and 58% (4.6 ± 0.3 ng/ml) lower (p < 0.001) in baboons receiving MER-25 at 25, 50, and 75 mg/kg BW, respectively, than in untreated (11.0 ± 0.6 ng/ml) baboons. These results indicate that anti.estrogen treatment decreased the amount of placental LDL uptake/degradation and placental P4 production in a dose-responsive manner, but did not alter receptor affinity for the lipoprotein. Because LDL uptake was decreased to 19% of normal with the estrogen receptor antagonist MER-25, we suggest that the placental LDL receptor is regulated primarily by estrogen during baboon pregnancy.

  • Activation of the Baboon Fetal Pituitary-Adrenocortical Axis at Midgestation by Estrogen: Adrenal Δ5-3β-Hydroxysteroid Dehydrogenase and 17α-Hydroxylase-17,20-Lyase Activity*
    Endocrinology, 1991
    Co-Authors: Gerald J. Pepe, Eugene D. Albrecht
    Abstract:

    We have recently demonstrated that treatment of pregnant baboons with androstenedione (delta 4 A) at midgestation to increase estrogen production induced a pattern of placental cortisol (F) metabolism which was similar to that at term and resulted in de novo F production by the fetus, presumably by activation of the fetal hypothalamic-pituitary-adrenocortical axis. The present study was designed to examine the subcellular events in the fetal adrenal that were apparently stimulated by estrogen-induced alterations in transplacental corticosteroid metabolism. Therefore, we determined the effects of estrogen treatment at midgestation and removal of estrogen action near term on the specific activity of the rate-limiting enzymes delta 5-3 beta-hydroxysteroid dehydrogenase (3 beta HSD) and 17-hydroxylase-17,20-lyase (17 alpha-OHase). Fetal adrenals were obtained on day 100 (n = 11) or day 165 (n = 11) of gestation (term = day 184) from untreated animals, on day 100 from animals receiving delta 4 A daily between days 70-100 (n = 9) to increase placental estrogen production, and on day 165 from baboons treated daily between days 130-164 with antiestrogen Ethamoxytriphetol (MER-25; n = 7). The activity of 17 alpha-OHase was determined by incubating adrenal microsomes (105,000 x g) with [3H] progesterone, NAD+, and NADH in phosphate buffer. The radiolabeled products 17-hydroxyprogesterone, delta 4 A, and testosterone were purified, and enzyme activity expressed as picograms of product per min/mg tissue. The activity of 3 beta HSD was determined by incubating adrenal microsomes with [3H]pregnenolone and NAD+ in phosphate buffer. The radiolabeled progesterone product was purified, and enzyme activity was expressed as nanograms per min/mg tissue. Treatment with delta 4 A increased estrogen concentration at midgestation 3-fold to levels comparable to those measured near term. Although fetal adrenal weight was greater at term than at midgestation (p less than 0.05), weight was not increased by delta 4 A treatment. The specific activity (mean +/- SE) of fetal adrenal 17 alpha-OHase at midgestation (181 +/- 29) was increased (P less than 0.05) 3-fold by treatment with delta 4 A to levels (591 +/- 105) comparable to those in adrenal microsomes prepared from untreated animals near term (816 +/- 130). Enzyme activity in adrenals of MER-25-treated baboons was 40%, but not significantly lower than that in term controls.(ABSTRACT TRUNCATED AT 400 WORDS)

C.w. Weems - One of the best experts on this subject based on the ideXlab platform.

Gerald J. Pepe - One of the best experts on this subject based on the ideXlab platform.

  • Luteal Function in Baboons with Administration of the Antiestrogen Ethamoxytriphetol (MER-25) Throughout the Luteal Phase of the Menstrual Cycle’
    2016
    Co-Authors: Eugene D. Albrecht, Arthur L. Haskins, Gary D. Hodgen, Gerald J. Pepe
    Abstract:

    Administration of the antiestrogen Ethamoxytriphetol (MER-25) during late baboon gestation has been reported to result in a marked decline in progesterone (P) production rate. Since both the placenta and corpus luteum appear to secrete P during late baboon gestation, this decline in P may reflect a loss in luteal and/or placental function. Therefore, the present study determined the effect of administration of the antiestrogen MER-25 upon serum steroid concentrations during the luteal phase of the baboon menstrual cycle, a tijne when the source of P is almost exclusively the corpus luteum, Six baboons were bled throughout a control menstrual cycle and during daily administration (15 mg/kg BW, p.o.) of MER-25 throughout the luteal phase of the following cycle. Mean ( ± SEM) length of the luteal phase of the menstrual cycle was the same in baboons with no treatment (18 ± 0 days) and after MER-25 administration (18 ± 0 days). Mean ( ± SEM) serum concentra-tions of P were similar in the luteal phase with no treatment (5.2 ± 0.7 ng/ml) and during MER-25 ad-ministration (5.0 ± 0.6 ng/ml). Serum P attained similar peak values of concentration in the luteal phase before and after antiestrogen administration and was detectable in the serum for a similar duration of the lutes] phase of both cycles. Mean ( ± SEM) serum concentrations of 17-hydroxyprogesterone (17-01(P)

  • Influence of fetectomy on serum pregnancy-associated plasma protein-A concentrations in the baboon.
    Biology of reproduction, 1994
    Co-Authors: Gerald J. Pepe, Brendan J. Waddell, Michael J. Sinosich, Eugene D. Albrecht
    Abstract:

    In baboons as in humans, the placenta is a source of various peptides, including pregnancy-associated plasma protein-A (PAPP-A). However, our present understanding of the regulation of PAPP-A production is incomplete. We have demonstrated that after fetectomy, the baboon placenta retains steroidogenic capacity and is maintained in utero until delivered spontaneously close to term. We have suggested, therefore, that fetectomy provides a valuable in vivo approach to elucidating the role(s) of the fetus, and of the hormones (e.g., estrogen and progesterone) dependent upon the presence of the fetus, in the regulation of placental steroidogenesis during primate pregnancy. Therefore in the present study we utilized the fetectomy model to evaluate the respective roles of the fetus, estrogen, and progesterone on placental PAPP-A. Estradiol, progesterone, and PAPP-A concentrations were determined by RIA in maternal blood collected under ketamine anesthesia on Days 78-100 (n = 5), Days 102-144 (n = 4), and Days 146-164 (n = 3) of gestation (term = Day 184) in control baboons (Papio anubis) and on Days 110-164 in baboons fetectomized on Day 100 (n = 9). Studies were also conducted in five animals in which placental estrogen was increased by maternal treatment on Days 70-100 with androstenedione and in three animals treated on Days 140-164 with the antiestrogen, Ethamoxytriphetol (MER-25; 25 mg/day/kg BW). PAPP-A levels were analyzed by ANOVA and Duncan's multiple range test and were compared with placental wet weight (g) previously determined on Day 100 (78 5) and on Day 165 (171 ± 6) in untreated baboons; on Day 100 in androstenedione-treated baboons (79 ± 3); and on Day 165 in antiestrogen-treated (188 ± 8) and fetectomized (99 ± 24) baboons. Mean (± SE) serum estradiol concentrations (ng/ml) were greater on Day 164 (2.5 ± 1.0) than on Day 100 (1.0 ± 0.3), increased on Day 100 by administration of androstenedione (4.8 ± 1.6), and decreased on Day 165 by fetectomy (0.12 ± 0.01). Serum progesterone exhibited no significant rise or fall during the second half of gestation and averaged 10.3 ± 1.4 ng/ml. Concentrations of progesterone late in gestation were reduced (p < 0.05) by treatment with MER-25 (3.1 ± 0.5) and by fetectomy (1.5 ± 0.2). PAPP-A (mIU/L) increased (p < 0.05) throughout the second half of gestation from a mean (± SE) of 32.2 ± 6.2 on Day 78 to 94.5 ± 11.6 on Days 160-164. Prior to fetectomy, PAPP-A on Days 96-100 (56.1 ± 5.0) was similar to the corresponding values in controls. However, after fetectomy, serum PAPP-A did not continue to increase with advancing gestation: the mean concentration in the 4-day interval prior to delivery (69.9 ± 7.9 mIU/ L) was lower (p < 0.05) than that in the intact controls (94.5 ± 11.6 mIU/L) but was not different from that measured before fetectomy on Day 100. When expressed relative to placental weight, however, PAPP-A levels in fetectomized baboons at term were comparable to those in untreated controls. PAPP-A was not altered by treatment with androstenedione or MER-25 and was not detectable ( 12.2 mIU/L) after delivery of the placenta Collectively, these findings indicate that production of PAPP-A during baboon pregnancy is determined in large part by the mass of functioning trophoblast and/or by factors that regulate growth of the trophoblast and is not regulated by estrogen or progesterone. In addition, we suggest that the present demonstration of continued secretion of PAPP-A, and the previously documented capacity for aromatization of androgens to estrogen after fetectomy, confirm the viability of the placenta as well as the value of this in vivo animal model for the study of fetoplacental function during primate pregnancy.

  • Regulation of placental low-density lipoprotein uptake in baboons by estrogen: dose-dependent effects of the anti-estrogen Ethamoxytriphetol (MER-25).
    Biology of reproduction, 1991
    Co-Authors: Michael C. Henson, Gerald J. Pepe, Eugene D. Albrecht
    Abstract:

    In the present study, increasing amounts of the anti.estrogen !-(p-2-diethylaininoethoxyphenyl)-!-phenyl.2-p-methoxyphenolethanol (MER-25) were administered to pregnant baboons (Papio anubis) to block the action of endogenous estrogen and to determine effect on placental low-density lipoprotein (LDL) uptake. Pregnant baboons were untreated (n = 8) or received MER25 orally at a dosage of 25 (n = 10), 50 (n = 8), or 75 (n = 4) mg/kg BW daily on Days 140-170 of gestation (term = 184 days). Placentas were removed on Day 170 of gestation and villous tissue was dispersed with 01% collagenase. Placental cells (106) were incubated in Medium 199 for 12 h at 37#{176}C with increasing amounts of 1251-LDL, with or without a 100.fold excess of unlabeled baboon LDL Mean (±SEM) placenta! uptake (ng/�g cell protein) of ‘251-LDL was 55% (6.4 ± 1.0), 75% (3.6 ± 0.7), and 81% (2.7 ± 0.2) lower (p < 0.001) in baboons that received MER-25 in doses of 25, 50, and 75 mg/kg BW, respectively, than in untreated baboons (14.2 ± 1.3 ng/�Lg cell protein). Maximal effect occurred with 50 mg MER-25, because LDL uptake was not further decreased with greater levels of MER-25. Dissociation constants for placental LDL uptake, as determined by Scatchard analysis, were unaltered by anti-estrogen treatment. The amount of ‘25l-LDL degradation by placental cells of untreated and MER-25.treated baboons was proportional to LDL uptake. Peripheral serum progesterone (P4) concentrations on Days 140-170 were 45% (6.! ± 0.2 ng/ml), 55% (5.0 ± 0.3 ng/ml), and 58% (4.6 ± 0.3 ng/ml) lower (p < 0.001) in baboons receiving MER-25 at 25, 50, and 75 mg/kg BW, respectively, than in untreated (11.0 ± 0.6 ng/ml) baboons. These results indicate that anti.estrogen treatment decreased the amount of placental LDL uptake/degradation and placental P4 production in a dose-responsive manner, but did not alter receptor affinity for the lipoprotein. Because LDL uptake was decreased to 19% of normal with the estrogen receptor antagonist MER-25, we suggest that the placental LDL receptor is regulated primarily by estrogen during baboon pregnancy.

  • Activation of the Baboon Fetal Pituitary-Adrenocortical Axis at Midgestation by Estrogen: Adrenal Δ5-3β-Hydroxysteroid Dehydrogenase and 17α-Hydroxylase-17,20-Lyase Activity*
    Endocrinology, 1991
    Co-Authors: Gerald J. Pepe, Eugene D. Albrecht
    Abstract:

    We have recently demonstrated that treatment of pregnant baboons with androstenedione (delta 4 A) at midgestation to increase estrogen production induced a pattern of placental cortisol (F) metabolism which was similar to that at term and resulted in de novo F production by the fetus, presumably by activation of the fetal hypothalamic-pituitary-adrenocortical axis. The present study was designed to examine the subcellular events in the fetal adrenal that were apparently stimulated by estrogen-induced alterations in transplacental corticosteroid metabolism. Therefore, we determined the effects of estrogen treatment at midgestation and removal of estrogen action near term on the specific activity of the rate-limiting enzymes delta 5-3 beta-hydroxysteroid dehydrogenase (3 beta HSD) and 17-hydroxylase-17,20-lyase (17 alpha-OHase). Fetal adrenals were obtained on day 100 (n = 11) or day 165 (n = 11) of gestation (term = day 184) from untreated animals, on day 100 from animals receiving delta 4 A daily between days 70-100 (n = 9) to increase placental estrogen production, and on day 165 from baboons treated daily between days 130-164 with antiestrogen Ethamoxytriphetol (MER-25; n = 7). The activity of 17 alpha-OHase was determined by incubating adrenal microsomes (105,000 x g) with [3H] progesterone, NAD+, and NADH in phosphate buffer. The radiolabeled products 17-hydroxyprogesterone, delta 4 A, and testosterone were purified, and enzyme activity expressed as picograms of product per min/mg tissue. The activity of 3 beta HSD was determined by incubating adrenal microsomes with [3H]pregnenolone and NAD+ in phosphate buffer. The radiolabeled progesterone product was purified, and enzyme activity was expressed as nanograms per min/mg tissue. Treatment with delta 4 A increased estrogen concentration at midgestation 3-fold to levels comparable to those measured near term. Although fetal adrenal weight was greater at term than at midgestation (p less than 0.05), weight was not increased by delta 4 A treatment. The specific activity (mean +/- SE) of fetal adrenal 17 alpha-OHase at midgestation (181 +/- 29) was increased (P less than 0.05) 3-fold by treatment with delta 4 A to levels (591 +/- 105) comparable to those in adrenal microsomes prepared from untreated animals near term (816 +/- 130). Enzyme activity in adrenals of MER-25-treated baboons was 40%, but not significantly lower than that in term controls.(ABSTRACT TRUNCATED AT 400 WORDS)

Yoshie S. Weems - One of the best experts on this subject based on the ideXlab platform.

Michael C. Henson - One of the best experts on this subject based on the ideXlab platform.

  • Regulation of placental low-density lipoprotein uptake in baboons by estrogen: dose-dependent effects of the anti-estrogen Ethamoxytriphetol (MER-25).
    Biology of reproduction, 1991
    Co-Authors: Michael C. Henson, Gerald J. Pepe, Eugene D. Albrecht
    Abstract:

    In the present study, increasing amounts of the anti.estrogen !-(p-2-diethylaininoethoxyphenyl)-!-phenyl.2-p-methoxyphenolethanol (MER-25) were administered to pregnant baboons (Papio anubis) to block the action of endogenous estrogen and to determine effect on placental low-density lipoprotein (LDL) uptake. Pregnant baboons were untreated (n = 8) or received MER25 orally at a dosage of 25 (n = 10), 50 (n = 8), or 75 (n = 4) mg/kg BW daily on Days 140-170 of gestation (term = 184 days). Placentas were removed on Day 170 of gestation and villous tissue was dispersed with 01% collagenase. Placental cells (106) were incubated in Medium 199 for 12 h at 37#{176}C with increasing amounts of 1251-LDL, with or without a 100.fold excess of unlabeled baboon LDL Mean (±SEM) placenta! uptake (ng/�g cell protein) of ‘251-LDL was 55% (6.4 ± 1.0), 75% (3.6 ± 0.7), and 81% (2.7 ± 0.2) lower (p < 0.001) in baboons that received MER-25 in doses of 25, 50, and 75 mg/kg BW, respectively, than in untreated baboons (14.2 ± 1.3 ng/�Lg cell protein). Maximal effect occurred with 50 mg MER-25, because LDL uptake was not further decreased with greater levels of MER-25. Dissociation constants for placental LDL uptake, as determined by Scatchard analysis, were unaltered by anti-estrogen treatment. The amount of ‘25l-LDL degradation by placental cells of untreated and MER-25.treated baboons was proportional to LDL uptake. Peripheral serum progesterone (P4) concentrations on Days 140-170 were 45% (6.! ± 0.2 ng/ml), 55% (5.0 ± 0.3 ng/ml), and 58% (4.6 ± 0.3 ng/ml) lower (p < 0.001) in baboons receiving MER-25 at 25, 50, and 75 mg/kg BW, respectively, than in untreated (11.0 ± 0.6 ng/ml) baboons. These results indicate that anti.estrogen treatment decreased the amount of placental LDL uptake/degradation and placental P4 production in a dose-responsive manner, but did not alter receptor affinity for the lipoprotein. Because LDL uptake was decreased to 19% of normal with the estrogen receptor antagonist MER-25, we suggest that the placental LDL receptor is regulated primarily by estrogen during baboon pregnancy.