M. Tébar

Centre d'Études et d'Expertise sur les Risques, l'Environnement, la Mobilité et l'Aménagement

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J. E. Sánchez‐Criado

Cordoba University

Antonio Ruíz

Universidad de Las Palmas de Gran Canaria

C. Bernal Bellido

Hospital Universitario Virgen del Rocío

José E. Sánchez‐Criado

University of Córdoba

D. Gónzalez

University of Córdoba

J. Th. J. Uilenbroek

Erasmus University Rotterdam

Guadalberto Hernández

Universidad de La Laguna

Frank H. de Jong

Diponegoro University

Francisco Gaytán

University of Córdoba

Rafaela Aguilar

University of Córdoba

Cooperative Institutions

Centre d'Études et d'Expertise sur les Risques, l'Environnement, la Mobilité et l'Aménagement

University of Córdoba

Laboratoire Aménagement Économie Transports

Erasmus University Rotterdam

Laboratoire Ville Mobilité Transport

Universitat Autònoma de Barcelona

Cordoba University

Boston Children's Hospital

Pediatrics and Genetics

Center for Northern Studies

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RU486-Treated Rats Show Endocrine and Morphological Responses to Therapies Analogous to Responses of Women with Polycystic Ovary Syndrome Treated with Similar Therapies1

Biology of Reproduction (1996)

Antonio Ruíz Rafaela Aguilar M. Tébar Francisco Gaytán José E. Sánchez‐Criado

Administration of 4 mg of the antiprogestagen RU486 to 4-day-cyclic rats over 8 consecutive days starting on the day of estrus (Day 1) induced and anovulatory cystic ovarian condition with endocrine and morphological features similar to those exhibited in polycystic ovarian disease (PCO). To determine whether the RU486-treated rat responds in an analogous fashion to therapies similar to those that have been used to treat human PCO, RU486-treated rats were injection on Days 5 and 7 with 1) 1 mg of an LHRH antagonist (LHRHa), 2) 5 IU of human FSH (hFSH), 3) 2 mg of the antiandrogen flutamide (FLU), 4) 1 mg of the antiestrogen tamoxifen (TMX), or 5) 1 mg of the dopamine agonist bromocriptine (BRC). Controls were intact cyclic rats decapitated on estrus and rats injected with RU486 and the corresponding vehicles (saline or 70% ethanol) used with LHRHa, hFSH, FLU, TMX, and BRC injections. RU486-treated rats were decapitated on Day 9, and the serum concentrations of LH, FSH, prolactin (PRL), testosterone (T), and estradiol-17 β (E2) were determined. Pituitary and ovary weight, number of follicular cysts, size of the corpora lutea, and rates of follicular growth and atresia were also noted. Finally, the ovulatory response to ovine LH (oLH) in rats treated with RU486 and injected with various doses of hFSH (5, 10, or 20 IU) was evaluated. While administration of LHRHa and of TMX decreased the serum concentrations of LH, T and E2 and the LH/FSH and T/E2, ratios, and injections of BRC and of FLU increased the serum concentration of LH and T, the administration of hFSH (10 IU) to RU486-treated rats increased only the serum levels of E2. All treatments decreased, though in different degrees, both the number of cysts and the rate of follicular atresia, and stimulated follicular growth. The positive effects on follicular growth and atresia were significantly higher in those rats injected with hFSH. Moreover, RU486-treated rats injected with different doses of hFSH ovulated in a dose-dependent manner in response to oLH. Rates deprived of the actions of progesterone through the administration of the antiprogestagen RU486 had 1) endocrine and morphologic alterations comparable to those observed in women with PCO, 2) analogous responses to therapies similar to those that have been used to treat human PCO, and 3) an ovulatory response to combined treatment with FSH and LH. These results establish the fundamental adequacy of using the RU486-treated rat as a PCO model.

10.1095/biolreprod55.6.1284

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Citations (36)

Periovulatory LHRH, LH and FSH secretion in cyclic rats treated with RU486: effects of exogenous LHRH and LHRH antagonist on LH and FSH secretion at early oestrus

Journal of Endocrinology (1994)

J. E. Sánchez‐Criado Guadalberto Hernández C. Bernal Bellido D. Gónzalez M. Tébar

Abstract The antiprogesterone RU486 injected on the morning of pro-oestrus blunts the preovulatory secretion of LH and FSH and abolishes the secondary secretion of FSH during oestrus without affecting ovulation in the rat. To ascertain whether the secretion of LHRH is involved in these effects, we studied the effects of RU486 (4 mg/0·2 ml oil), given s.c. at 0800 h on pro-oestrus, on LHRH secretion into the pituitary stalk blood vessels and on peripheral plasma concentrations of LH and FSH at 1800 h on pro-oestrus and 0200 h on oestrus. Furthermore, we determined the effects of an s.c. injection of 1 mg of an LHRH antagonist (LHRH-A; ORG30276) at 2000 h on pro-oestrus and those of an i.p. injection of 100 ng LHRH (Peninsula 7201) at 0100 h on oestrus on serum concentrations of LH, FSH and oestradiol at 0200 h on oestrus in oil- and RU486-treated rats. RU486 decreased LHRH secretion at 1800 h on prooestrus while this was increased at 0200 h on oestrus. While the reduction of preovulatory LHRH secretion in RU486-treated rats coincided with a reduction in both LH and FSH surges during the evening of pro-oestrus, the increased LHRH secretion during the early hours of oestrus was only accompanied by an increased concentration of LH. An injection of LHRH stimulated, while that of LHRH-A inhibited serum concentrations of LH at 0200 h on oestrus in both oil- and RU486-treated rats. An injection of LHRH-A had no effect on FSH concentration at 0200 h on oestrus in either oil- or RU486-treated rats. On the contrary, exogenous LHRH increased FSH concentration at 0200 h on oestrus only in oil-treated rats. The results indicate that, in the rat, progesterone secretion during the afternoon and evening of pro-oestrus enhances preovulatory LHRH and suppresses LHRH release during early oestrus into the pituitary stalk blood vessels on the afternoon of pro-oestrus and during early oestrus respectively. While the secretion of LH during early oestrus is blunted by progesterone and entirely coupled to LHRH secretion, the secondary secretion of FSH during oestrus is not dependent on endogenous LHRH and at the same time is completely dependent on the actions (direct and/or indirect) of progesterone. Journal of Endocrinology (1994) 141, 7–14

Gonadotropin

10.1677/joe.0.1410007

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Citations (25)

Serum levels of GH, IGF-I, LH and ovarian steroids in cyclic and RU486-treated rats

Journal of Endocrinological Investigation (1997)

Antonio Ruíz M. Tébar A. Pérez-Romero María Ángeles Rol J. E. Sánchez‐Criado

Gonadotropin

10.1007/bf03346918

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Citations (12)

The steroid antagonist RU486 given at pro-oestrus induces hypersecretion of follicle-stimulating hormone from oestrus afternoon to early metoestrus in the rat

European Journal of Endocrinology (1997)

J. E. Sánchez‐Criado M. Tébar Antonio Ruíz Liana Padrón

Administration of the steroid antagonist RU486 to cyclic rats at pro-oestrus blunts the preovulatory surge of LH and suppresses the first and second surges of FSH. In addition, administration of oestradiol to RU486-treated rats reactivates the LH surge the following day. The present study explored the effects of RU486 (4 mg/0.2 ml oil), administered at 0800 h on the day of pro-oestrus, on serum FSH and LH concentrations through oestrus and early metoestrus. RU486 induced a hypersecretion of FSH, which started at 1400 h on the day of oestrus and was maintained until 0800 h on the day of metoestrus. Because the timing and magnitude of this secretion of FSH were similar to those of the periovulatory secretion of FSH during pro-oestrus and early oestrus in intact cyclic rats, we investigated the effects of: 1) LHRH antagonist (LHRHa) injected at either 0900 h or 2000 h on the day of oestrus, 2) oestradiol benzoate injected at 1600 h on the day of pro-oestrus and at 0900 h on the day of oestrus, 3) bovine follicular fluid (bFF) given either at 1100 h or at 2000 h on the day of oestrus, or 4) adrenalectomy (ADX) at 1100 h on the day of oestrus, on serum FSH and LH concentrations at 1800 h on the day of oestrus and at 0200 h on the day of metoestrus in rats injected with RU486 at pro-oestrus. The results showed that 1) both components (late oestrus and early metoestrus) of FSH hypersecretion in RU486-injected rats in pro-oestrus were inhibited by oestradiol benzoate and bFF, 2) the metoestrous component was not affected by LHRHa, whereas the oestrous component was partially reduced, and 3) ADX partially reduced serum FSH concentrations only on the day of metoestrus, possibly because, as the serum concentrations of corticosterone reflected, the antiglucocorticoid activity of 4 mg RU486 lasted only 24 h. The results support the hypothesis that blockade of progesterone actions at pro-oestrus results in the maintenance of the daily neural signal that activates the release of gonadotrophins. Whereas the expression of LH secretion requires high levels of oestradiol, FSH secretion is expressed against a background of low oestradiol levels. The results of this study also indicate that the release of FSH during oestrus and metoestrus in rats injected with RU486 at pro-oestrus is a consequence of the lack of ovarian negative feedback inhibition on the pituitary.

Antiglucocorticoid

10.1530/eje.0.1370281

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Citations (11)

The antiprogestin RU486 dissociates LH and FSH secretion in male rats: evidence for direct action at the pituitary level

Journal of Endocrinology (1999)

J. E. Sánchez‐Criado C. Bernal Bellido M. Tébar Antonio Ruíz D. Gónzalez

Administration of 4 mg of the antisteroid RU486 over 8 consecutive days to adult male rats dissociated in vivo and in vitro gonadotrophin secretion, increasing FSH and decreasing LH secretion. In subsequent experiments we evaluated the involvement of testicular or adrenal secretory products, as well as hypothalamic LHRH, in the effects of 4 consecutive days of RU486 treatment on the secretion of gonadotrophins. The first day of RU486 injection was designated day 1, subsequent days being numbered consecutively. Groups of rats injected with oil (0.2 ml) or RU486 (4 mg) were: (i) injected s.c. from day 1 to day 4 with the antiandrogen flutamide (10 mg/kg); (ii) bilateral orchidectomized (ORCH) on day 1; and (iii) bilateral adrenalectomized (ADX) on day 1. Controls were given flutamide vehicle or were sham operated. To ascertain whether the secretion of LHRH is involved in the effects of RU486 on gonadotrophin secretion, we measured the LHRH secretion into the pituitary stalk blood vessels at 1100 h on day 5 in oil- or RU486-treated rats. Additional oil- and RU486-treated rats were injected i.p. with 100 ng LHRH at 1000 h on day 5, or s.c. with 1 mg LHRH antagonist (LHRH-ANT) at 1000 h on days 2 and 4. Controls were given saline. All animals were decapitated at 1100 h on day 5, trunk blood collected and serum stored frozen until FSH, LH and testosterone assays.%While ADX had no effect on FSH and LH secretion in either oil- or RU486-treated rats, the removal of androgen negative feedback with flutamide treatment or by ORCH substantially increased serum levels of FSH and LH in both oil- and RU486-treated rats, and thus annulled the effects of RU486. No differences in pituitary stalk plasma LHRH concentrations were found between oil- and RU486-treated rats. Injection of LHRH increased serum FSH and LH concentrations in oil-treated rats but only, and to a lesser extent, LH concentrations in RU486-treated rats. Treatment with LHRH-ANT decreased serum concentrations of FSH and LH in both oil- and RU486-treated rats. These results suggest that RU486 inhibited LHRH-stimulated LH secretion at the pituitary level, and that FSH secretion increased in response to a reduction in the negative feedback of androgen.

Flutamide

Gonadotropin

10.1677/joe.0.1600197

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Citations (23)

Acidosis láctica por metformina en la Unidad de Cuidados Intensivos

Revista Española de Anestesiología y Reanimación (2014)

M. Tébar Nero Luís I. Olmos Sanchez Luciano Aguilera

10.1016/j.redar.2013.11.008

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Citations (3)

Follicular and Luteal Progesterone Play Different Roles Synchronizing Pituitary and Ovarian Events in the 4-Day Cyclic Rat1

Biology of Reproduction (1995)

M. Tébar Antonio Ruíz Francisco Gaytán José E. Sánchez‐Criado

Administration of 4 mg of the antiprogestagen RU486 to 4-day cyclic rats during proestrus induced a 1-day shortening of the ovarian cycle, a reduction in ovulatory rate that was reversed by an injection of exogenous human (h)FSH in the evening of proestrus, and the absence of the LH-inhibiting effect of exogenous estradiol resulting in a 24-h advancement of the preovulatory LH surge. These effects were not present when RU486 was injected during estrus. RU486 injected during either proestrus or estrus increased serum levels of LH and estradiol-17β in diestrus and reduced the magnitude of the preovulatory surge of gonadotropins. Only rats treated with RU486 during estrus showed increased follicular size and acceleration of oocyte maturation on proestrous afternoon. These results demonstrate that in 4-day cyclic rats receiving an injection of RU486 during proestrus, the low ovulatory rate is a consequence of a reduced secondary FSH surge-induced follicular recruitment in the afternoon of estrus and that the shortening of the estrous cycle is the result of an advanced desensitization to the negative feedback of estradiol on LH secretion. Furthermore, since the administration of RU486 during proestrus blocks both follicular and luteal progesterone actions whereas injection during estrus blocks only luteal progesterone actions, we suggest that, in 4-day cyclic rats, the actions of progesterone during diestrus retard maturation of follicles via the lowering of serum LH concentrations and that the actions of progesterone in proestrous evening delay the desensitization to the negative estrogen feedback on LH secretion.

10.1095/biolreprod53.5.1183

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Citations (12)

Inappropriate ovarian feedback in basal gonadotropin secretion in 4-day cyclic rat treated with mifepristone: Role of endogenous estradiol

Journal of Endocrinological Investigation (1994)

M. Tébar C. Bernal Bellido Rafaela Aguilar José E. Sánchez‐Criado

Flutamide

Gonadotropin

Antiestrogen

Basal (medicine)

10.1007/bf03347730

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Citations (6)

One day estrous cycle shortening induced by antiprogestagen RU486 administration in proestrus to 4-day cyclic rats.

PubMed (1995)

M. Tébar Antonio Ruíz J. E. Sánchez‐Criado

Administration of 4 mg of the antiprogestagen RU486 to 4-day cyclic rats in proestrus, which blocks proestrous and diestrous progesterone actions, induced a one day shortening of the ovarian cycle and a reduction of the ovulation rate in the following cycle. These effects were not present when RU486 was administered in estrus or metestrus. RU486 injections either in proestrus or estrus increased the serum levels of LH and 17 beta-estradiol during metestrus. However, only rats injected with RU486 in proestrus presented a 24 hour advancement of the preovulatory surge of gonadotropins and a lack of the LH-inhibiting effect of exogenous estradiol. These results suggest that, in 4-day cyclic rats, the secretion of progesterone by the corpora lutea during diestrous phase retards the follicular development by lowering the serum concentrations of LH, whereas progesterone secretion by the preovulatory follicles in proestrus regulates the estrous cycle length by antagonizing the desensitization of the pituitary to the estrogen negative feedback on LH secretion.

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Follicular and luteal progesterone synergize to mantain 5-day cyclicity in rats.

Journal of Physiology and Biochemistry (1996)

J. E. Sánchez‐Criado Antonio Ruíz M. Tébar J.A.M. Mattheij

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Citations (5)