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Role of inhibin in the regulation of FSH secretion and folliculogenesis in cows
REPE&ON SCIENCE
ELSEWIER
Animal Reproduction Science 42 (1%)
563-570
Role of inhibin in the regulation of FSH secretion a&folliculogenesis in cows K. Taya a**, H. Kaneko b, T. Takedomi ‘, H. Kishi a, G. Watanabe a a Laboratory of Veterinary Physiology, Tokyo Vniversity of Agriculture &d Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183, Japan b Depariment of Animal Production, Kyushu National Agricultural Experiment Station, Nishigoshi, Kumamoto 861-11, Japan ’ Central Research Institute for Feed and Livestock, ZEN-NON, Tsukuba, Ibaraki 300-33, Japan
Abstract
‘lhis review focuses on the role of inhibin and oestradiol in the hormonal regulation of ovarian foiliculogenesis during the oestrous cycle in cows and other domestic animals, using data from the cow, sheep, pig, horse, rat aud hamster. The evidente reviewed confirms-the role of iirhibin as a chemical signal of the number of growing follicles in the ovary to the pituitary gland to reduce the secretion of follicle stimulating hormone (FSH) to a leve1 ,which maint@rs the species-specific number of ovulations. It is argued that ovarian inhibin may be the most important hormone for determining the species-specifk number of ovulations in both single and multiple ovulatory species. On the other hand, evidente presented in the review also confírms the importante of ovarian oestradiol acting as a chemical signal to indicate the maturity of_growing folliles to the hypothalamo-pituitary system. This induces the preovulatory luteinising hormone (LH) smge to cause ovulation. Keywords: Inhibin; Oestradiol; FSH; LH; Domestic animal; Folliculogenesis
1. Introduction Follicle stimulating hormone (FSH) is essential for the developmenr and ‘maintenance of ovarian follicles in mammals. The secretion of FSH by the pitnitary gland is controlled by stimulatory effects of gonadotropin-releasing hormone from the hppothalamus and inhibitory effects of ovarian hormones, such as steroid hormones and inhibin. It is now beyond questíon that inhibin is a major regulator of the secretion of FSH by the
* Corresponding author. Tel.: 0423-67-5767; fax: 423-60-8830; e-mail: [email protected]. 0378-4320/%/$15.00 0 1996 Elsevier Science B.V. Al1 rights reserved. Pfl SO378-4320(96)015321
564
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400 -
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100 -
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5-4-3-2-10 1 2 3 4 5 6 7 0 1,2 3 4 5 0 1 2 3 4 5 Time from the initiation of each follicular wave (days)
’Follicula~ phase
Luteal phase
‘Follicblar phare
Fig. 1. (a) Development and regressionof dominant follicles and mean numberof normal follicles (over 4 mm in diameter). (b) Change in plasma conceatration of ocstradiol and progesterone.(c) lnhibin and FSH during the complete oestrous cycle in the cow. In (a), an astetisk representsdetection of ovulation. Data from seven cows are clustered around the initiation of each follicular wave (day 1 is day of the emergence of follicular wave). From Kaneko et al. (1995a).
anterior pituitary gland in various mammals (De Jong, 1988; Taya, 1993) with two other peptides, activin and follistatin, having local regulatory effects in the anterior pituitary gland (Mather et al., 1992). In the present review, we summarise evidente on the role of inhibin and oestradiol in the control of FSH secretion and folliculogenesis in the cow and other domestic animals.
2. Inhibin as a circulating hormone, acting to suppress the secretion of FSH 2.1. Cycling animals on inverse relationship between circulating inhibin and FSH has been demonstmted during the oestrous cycle of various mammals, such as cattle (Kaneko et al., 1995a), sheep (Findlay et al., 1990), goats (Mukai et al., 1989), horses (Roser et al., 1994), Pigs
K. Taya et al./Animal
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(Hasegawa et al., 19881, monkeys (Fraser et al., 1989; Nozaki et al., 19911, humans (McLachlan et al., 1987), rats (Hasegawa et al., 1989; Watanabe et al., 19901, hamsters (Kishi et al., 1995) and elephants (Brown et al., 1991). Fig. 1 shows changes in the concentration of immunoreactive (ir-) inhibin, oestradiol, progesterone and FSH in plasma during the normal oestrous cycle of Japanese brown cows (Kaneko et al., 1995a). The pattems of growth and regression of follicles in the ovary were also characterized by daily ultrasonographic examination. In this breed of cow, three waves of follicular development were observed during the early-luteal, mid-luteal and follicular phases. A dominant follicle was identified in each wave. During the growth of the dominant follicle, other follicles ceased their growth, while the emergence of the subsequent follicular wave occurred after the dominant follicle either ceased to grow or ovulated. Since there was a differente in the timing of the emergence of each follicular wave in individual animals, data on al1 hormones were clustered around the initiation of each follicular wave (day 1 being the day of emergence of the wave, indicated by an increase in the number of follicles), to clarify relationships between follicular development and hormonal profiles (Fig. l(b) and (c)). The diameter of the dominant follicle and the number of presumed normal follicles are also presented (Fig. I(a)). The concentration of plasma FSH was high prior to the emergence of each follicular wave and began to decrease with the appearance of the wave. It remained low during the growing phase of a dominant follicle. The number of normal follicles in each wave decreased in the period of low plasma FSH, while the dominant follicle continued to grow. Plasma concentrations of ir-inhibin increased concomitant with the emergence of each wave. In the first and third waves, concentrations of ir-inhibin and oestradiol reached a high leve1 in the growing phase of the dominant follicles and decreased when the dominant follicle ceased its growth, or ovulated. In contrast, plasma FSH leve1 showed a significant increase in the regression phase or around ovulation of the dominant follicle. During the second wave, there was no significant increase in plasma concentration of oestradiol, while ir-inhibin levels increased. There was a clear inverse relationship between plasma concentration of FSH and ir-inhibin throughout the oestrous cycle. 2.2. Superovulated animals A quantitative relationship between an increase in inhibin secretion and suppression of FSH secretion in vivo was also demonstrated in superovulating cows (Kaneko et al., 1992). Quine chorionic gonadotropin (eCG) increased the number of follicles of various sizes by 4 days after administration. In addition, the second growth of large follicles occurred within 2 days after superovulation. Both bioactivity and immunoreactivity of inhibin increased during the two waves of growth of large follicles, suggesting that bovine follicles secrete a large amount of bioactive and immunoreactive inhibin in the circulation in response to eCG. Plasma concentration of oestradiol also increased concomitantly with the increase in inhibin. A marked suppression of FSH concentration during eCG treatment occurred inversely with the increase in plasma leve1 of inhibin and oestradiol. These findings indicate that, in superovulating cattle treated with eCG, an increase in the number of follicles is involved in suppression of endogenous FSH secretion by means of enhanced secretion of inhibin and/or oestradiol.
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Oestradiol is thought to be a potent ovarian factor that inhibits FSH secretion in cows as wel1 as sheep (Martin et al., 1988; Mann et al., 1990). A negative correlation between plasma concentration of oestradiol and FSH is noted during the follicular phase (Kaneko et al., 1991; Kaneko et al., 1995a). Injection of oestradiol at a supraphysiological dosage has been found to decrease concentration of plasma FSH in ovariectomised heifers (Kesner and Convey, 19821, and replacement with a combination of oestradiol and progesterone found in the luteal phase was shown to reduce FSH concentrations in ovariectomised heifers to leve1 within these observed during the oestrous cycle (Price and Webb, 1988). On the ether hand, it is also known that steroid-free bovine follicular fluid (Ireland et al., 1983; Quirk and Fortune, 1986; Beard et al., 1989) or highly purified bovine inhibin (Beard et al., 1990) have the ability to suppress FSH secretion in ovariectomised and cyclic heifers. These studies suggest the possibility that inhibin and oestradiol are involved in the regulation of FSH secretion in the intact and superovulating cow.
3. Immunoneutralisation of endogenous inhibin and oestradiol To clarify the physiological role of inhibin and oestradiol in the regulation of FSH secretion during the oestrous cycle of cows, animals were passively immunized against the two hormones. Treatment with inhibin antiserum (inhibin-AS) resulted in a marked increase in the plasma concentration of FSH and oestradiol but not luteinising hormone (LH) or progesterone, compared with tbat after treatment with control serum (Kaneko et al., 1993). Treatment with inhibin-AS markedly increased the number of small, medium and large follicles. These results provide strong evidente that inhibin is an important factor in the inhibitory regulation of FSH secretion during the mid-luteal phase of cows when oestradiol secretion is low, and also demonstrate that an increase in endogenous FSH secretion after immunoneutralization of circulating inhibin stimulates the rapid growth of a large number of follicles. The relative importante of inhibin and oestradiol in the regulation of FSH secretion was then tested during the follicular phase of the bovine oestrous cycle when oestradiol secretion is at its highest, by immunoneutralization of circulating inhibin and oestradiol (Kaneko et al., 1995b). Cows were divided into four groups and given injections of prostaglandin F,, (PG) i.m. twice at 8 h intervals on Day 10 of the oestrous cycle (Day 0 is day of oestrus) to induce luteal regression. At 48 h after the first PG injection, each group of four cows received an injection of one of the following: 100. ml castrated goat serum (control serum), 100 ml inhibin-AS, 100 ml antiserum against oestradiol (oestradiol-AS), or a combination of 100 ml inhibin-AS and 100 ml oestradiol-AS. The LH surge occurred within 2 days after injection of the control serum or inhibin-AS, whereas it was not detected in either of the groups passively immunized against oestradiol, indicating that passive immunization against oestradiol blocks a positive feedback effect of oestradiol on LH secretion. There was no clear differente in basal concentration of LH among the four groups. Injection of the inhibin-AS resulted in a marked increase in the concentration of FSH compared with the value in the control group, while there was no significant change in concentration of plasma FSH after
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injection of the oestradiol-AS. Combined administration of the inhibin-AS and oestradiol-AS also produced a marked increase in plasma concentration of FSH. The FSH response to the combined immunization was longer in duration than the response to immunization with inhibin alone. Treatment with the inhibin-AS, either alone or in combination with the oestradiol-AS, induced the growth of a large number of small, medium, and large follicles compared with numbers in the controls. NO increase in the number of follicles was noted in the oestradiol-immunised animals. These results provide strong evidente that inhibin is an important factor in the inhibitory regulation of FSH secretion during the follicular phase as wel1 as the luteal phase of cows, suggesting also that oestradiol has a synergistic effect with inhibin on FSH secretion.
4. A functional model of inhibin and oestradiol actions Granulosa cells of ovarian follicles in mammals produce two hormones, inhibin and oestradiol, to regulate the oestrous cycle. The physiological roles of these two ovarian hormones have been confirmed as follows: inhibin is (1) a main inhibitor of FSH secretion, (2) a chemical signal of the number of growing follicles in the ovary, and mus (3) a key hormone in determining species-specifïc ovulation rates. On the other hand, oestradiol acts as (1) a signal of follicular maturation in the ovary, and (2) a signal determining the timing of the preovulatory LH surge.
5. Tbe use of inhibin vaccination in domestic animal production Active immunization against inhibin-enriched fractions of follicular fluid, synthetic peptide fragments of the o-subunit of inhibin and recombinant-DNA-derived o-subunit results in an increase in ovulation rate in sheep and cattle (O’Shea et al., 1994). Active immunization of gilts against recombinant-DNA-derived inhibin a-subunit (Brown et al., 1990) and of mares against a synthetic fragment of the inhibin a-subunit (McCue et al., 1992; Mckinnon et al., 1992) also results in an increase in ovulation rate. In these studies, it is postulated that immunoneutralization of endogenous inhibin wil1 lead to an increase in circulating FSH concentration by attenuation of its negative feedback action on the anterior pituitary and an increase in the number of follicles ovulating. Recent findings by Glencross et al. (1994) that active immunization of heifers against a synthetic fragment of inhibin leads to a sustained rise in plasma FSH concentration that is associated with an increase in the number of large follicles developing during the preovulatory and postovulatory waves of follicular development, and with an increase in ovulation rates, support the hypothesis. In addition, in Holstein heifers, neutralization of inhibin by antiserum during the luteal phase of the bovine oestrous cycle induces a rise in plasma FSH concentration and following luteolysis, there are multiple ovulations (Takedomi et al., 1995). Recently, ultrasound-guided follicular aspiration has been developed for the collection of oocytes from living animals and in vitro production of bovine embryos (Pieterse
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et al., 1988). Previous studies have shown that oocytes can be successfully collected from cycling cattle on a weekly basis (Gibbons et al., 1994). The effects of active immunization of cattle against inhibin on ovarian follicular development and ultrasound-guided transvaginal follicular aspiration were determined using Japanese black cows (Konishi et al., unpublished observation, 19%). The results demonstrated that active immunization against inhibin can enhance ovarian follicular development and the number of oocytes collected by transvaginal follicular aspiration. Inhibin immunisation had no effect on the grade of aspirated oocytes for IVF, indicating that this may be the most effective method to improve the efficiency of in vitro production of bovine embryos. In tbe near future, inhibin vaccination may be used to overcome variability in superovulation in cattle and sheep for embryo transfer. Less variable and repeated induction of superovulation may be achieved with inhibin vaccination in cattle and sheep.
Acknowledgements This article is respectfully dedicated to Professor Emeritus Shuji Sasamoto, Laboratory of Veterinary Physiology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183, Japan, in honour of his retirement. This work was supported in part by a gram-in-aid (Bio Media Program, BMP96-V-2-2) from the Ministry of Agriculture, Forestry and Fisheries of Japan and The Ito Foundation.
References Beard, A.J.. Savva, D., Glencross, R.G., McLeod, B.J. and Knight, P.G., 1989. Treatment of ovariectomized heifers witb bovine follicular fluid specifically suppresses pituitary levels of FSH-E mRNA. J. Mol. Endocrinol., 3: 85-91. Beard, J.A., Castillo, R.J., McLeod, B.J., Glencross, R.G. and Knight, P.G., 1990. Comparison of the effects of crude and highly purified bovine inhibin (Mr 32000) on plasma concentrations of FSH and LH in chronically ovariectomized ptepubertal heifers. J. Endocrinol., 125: 21-30. Brown, R.W., Hungerford, J.W., Greenwood, P.E., Bloor, R.J., Evans, D.F., Tsonis, C.G. and Forage, R.G., 1990. Immunization against recombinant bovine inhibin a-subunit causes increased ovulation rates in gilt% J. Reprod. Fertil., 90: 199-205. Brown, J.L., Citino. S.B., Bush, M., Lehnhardt, J. and Phillips, L.G., 1991. Cyclic pattems of luteinizing hormone, follicle-stimulating hormone, inhibin, and progesterone secretion in me Asian elephant (Elephas maximus). J. Zoo. Wildlife Med., 22: 49-57. De Jong, F.H., 1988. Inhibin. Physiol. Rev., 68: 555-607. Fmdlay, J.K., Clarke, Ll. and Robertson, D.M., 1990. Inhibin concentrations in ovariau and jugular venous plasma and the relationship of inhibin with FSH and LH during the ovine estrous cycle. Endocrinology, 126: 528-535. Fraser, H.M., Robertson, D.M. and de Kretser, D.M., 1989. Immunoteactive inhibm concentrations in serum throughout the menstrual cycle of the macaque:suppression of inhibin during me luteal phase after treatment with an LHRH antagonist. J. Endocrinol., 121: R9-12. Gibbons, J.R., Beal, W.E., Krisher, R.L., Faber, E.G., Pearson, R.E. and Gwazdauskas, F.C., 1994. Effects of once- versus twice-weekly transvaginal follicular aspiration on bovine oocyte recovery and embryo development. ‘llteriogenology, 42: 405-419.
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Glencross, R.G., Bleach, E.C.L., Wood, S.C. and Knight, P.C., 1994. Active immunization of heifem against inhibin: effects on plasma concentrations of gonadotrophins, steroids and ovarian follicular dynamics during prostaglandm-synchronized cycles. J. Reprod. Fertil., 100: 599-605. Hasegawa, Y., Miyamoto, K., Iwamura, S. and Igarashi, M., 1988. Changes in serum concentrations of inhibin in cyclic pigs. J. Endocrinol., 118:211-219. Hasegawa, Y., Miyamoto, K. and Igarashi, M., 1989. Changes in serum concentrations of immunoreactive inhibin during the oestrous cycle of the rat. J. Endocrinol., 121: 91- 100. Iteland, J.J., Curato, A.D. and Wilson, J., 1983. Effect of charcoal-treated bovine follicular fluid on sectetion of LH and FSH in ovariectomized heifers. J. Anim. Sci., 57: 1512-1516. Kaneko, H., Terada, T.. Taya, K., Watanabe, G., Sasamoto, S., Hasegawa, Y. and Igarashi, M., 1991. Ovarian follicular dynamics and concentrations of oestradiol-l7B, progesterone, luteinizing honnone and follicle stimulating hormone during the periovulatory phase of the oestrous cycle in the cow. Rep&. Fertil. Dev., 3: 529-535. Kaneko, H., Watanabe, G., Taya, K. and Sasamoto. S., 1992. Changes in peripheral levels of bioactive and immunoreactive inhibin, estradiol- 17B, progesterone, luteinizing hormone, and follicle-stimulating hormone associated with follicular development in cows induced to superovulate with equine chorionic gonadotropins. Bio]. Rep&., 47: 76-82. Kaneko, H., Nakanishi, Y., Taya, K., Kishi, H., Watanabe, G., Sasamoto, S. and Hasegawa, Y., 1993. Evidente that inhibin is an important factor in the regulation of FSH secretion during the mid-luteal phase in cows. J. Endocrinol., 136: 35-41. Kaneko, H., Kishi, H., Watanabe, G., Taya, K., Sasamoto, S. and Hasegawa, Y., 1995a. Changes in plasma concentrations of immunoreactive inhibin, estradiol and FSH associated with follicular waves during the estrous cycle of the cow. J. Rep&. Dev., 41: 311-320. Kaneko, H., Nakanishi, Y. Akagi, S., Arai, K., Taya, K., Watanabe, G., Sasamoto, S. and Hasegawa, Y., 1995b. Immunoneutrahzation of inhibin and estradiol during die follicular phase of the estrous cycle in cows. Biol. Reprod., 53: 931-939. Kesner, J.S. and Convey, E.M., 1982. Interaction of estradiol and luteinizing hormone releasing hormone on follicle stimulating hormone release in cattle. J. Anim. Sci., 54: 817-821. Kishi, H., Taya, K., Watanabe, G. and Sasamoto, S., 1995. Follicular dynamics and secmtion of inhibin and oestradiol-17B during the oestrous cycle of the hamster. J. Endocrinol., 146: 169-176. Mann, G.E., Campbell, B.K., McNeilly, A.S. and Baird, D.T., 1990. Effects of passively immunizing ewes against inhibin and oestradiol during the follicular phase of the oestrous cycle. J. Endocrinol., 125: 417-424. Martin, G.B., Price, C.A., Thiery, J-C. and Webb, R., 1988. Interactions between inhibin, oestradiol and progesterone in the control of gonadotrophin secretion in the ewe. J. Rep&. Fertil., 82: 319-328. Mather, J.P., Woodruff, T.K. and Krummen, L.Y., 1992. Paracrine regulation of reproductive function by inhibin and activin. Proc. Sec. Exp. Bio]. Med., 201: 1-15. McCue, P., Carney, N., Hughes, 1.. Rivier, J.. Vale, W. and Lasley, B., 1992. Gvulation and embryo recovery rates following immunization of mares against an inhibin alpha-subunit fragment. Theriogenology, 38: 823-831. Mckinnon, A.O., Brown, R.W., Pashen, R.L., Greenwood, P.E. and Vasey, J.R., 1992. Increased ovulation rates in mares after immunisation agauist recombinant bovine inhibin cu-subunit. Equine Vet. J., 24: 144-146. McLachlan, R.I., Robertson, D.M., Healy, D.L., Burger, H.G. and de Kretser, D.M., 1987. Circulating immunoreactive inhibin levels during die normal human menstrual cycle. Endocrinology, 65: 954-961. Mukai, S., Mori, Y., Nagashima, H., Hasegawa, Y. and Hoshino, K., 1989. Changes in plasma gonadotrophins, ovarian steroids and inhibin concentrations in gihs following progesterone treatment with implantable osmotic pumps. Anim. Reprod. Sci., 20: 287-297. Nozaki, M., Watanabc, G., Taya, K., Katakai, Y. and Sasamoto, S.. 1991. Circulating inhibin levels during normal menstrual cycle in the Japanese monkey. Jpn. J. Anim. Rep&., 37: 97-103. O’Shea, T., Hillard, M.A., Anderson, S.T., Bindon, B.M., Fmdlay, J.K., Tsonis, C.G. and Wilkins, J.F.. 1994. Inhibin immunization for increasing ovulation rate and superovulation. Theriogenology, 41: 3- 17. Pietcrse, M.C., Kappen, K.A., Kruip, Th.A.M. and Taverne, M.A.M., 1988. Aspiration of bovine occytes during transvaginal ultrasound scanning of the ovaries. Theriogenology, 30: 7.5-762.
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Price, C.A. and Webb, R., 1988. Steroid control of gonadotropin secretion and ovarian function in heifers. Endccrinology, 122: 2222-223 1. Quirk, S.M. and Fortune, J.E., 1986. Plasma concentrations of gonadotrophins, preovulatory follicular development and luteal function asscciated with bovine follicular fluid-induced delay of cestrus in heifers. J. Reprod. Fertil., 76: 609-621. Roser, J.F., McCue, P.M. and Hoye, E., 1994. Inhibin activity in the mare and stallion. Dom. Anim. Endocrinol., 11: 87-100. Takedomi, T., Kaneko, H., Aoyagi, Y., Nakanishi, Y. and Taya, K., 1995. Effects of passive immunization against bovine inhibin on ovulation rate and circulating FSH leve1 in Holstein heifers. Theriogenology, 43: 333. Taya, K., 1993. Roles of inhibin in regulation of FSH secretion and folliculogenesis in mammals. Curr. Trends Exp. Endocrinol., 1: 97-116. Watanabe, CL Taya, K. and Sasamoto, S., 1990. Dynamics of ovarian inhibin secretion during the oestrous cycle of the rat. J. Endocrinol., 126: 151-157.
ELSEWIER
Animal Reproduction Science 42 (1%)
563-570
Role of inhibin in the regulation of FSH secretion a&folliculogenesis in cows K. Taya a**, H. Kaneko b, T. Takedomi ‘, H. Kishi a, G. Watanabe a a Laboratory of Veterinary Physiology, Tokyo Vniversity of Agriculture &d Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183, Japan b Depariment of Animal Production, Kyushu National Agricultural Experiment Station, Nishigoshi, Kumamoto 861-11, Japan ’ Central Research Institute for Feed and Livestock, ZEN-NON, Tsukuba, Ibaraki 300-33, Japan
Abstract
‘lhis review focuses on the role of inhibin and oestradiol in the hormonal regulation of ovarian foiliculogenesis during the oestrous cycle in cows and other domestic animals, using data from the cow, sheep, pig, horse, rat aud hamster. The evidente reviewed confirms-the role of iirhibin as a chemical signal of the number of growing follicles in the ovary to the pituitary gland to reduce the secretion of follicle stimulating hormone (FSH) to a leve1 ,which maint@rs the species-specific number of ovulations. It is argued that ovarian inhibin may be the most important hormone for determining the species-specifk number of ovulations in both single and multiple ovulatory species. On the other hand, evidente presented in the review also confírms the importante of ovarian oestradiol acting as a chemical signal to indicate the maturity of_growing folliles to the hypothalamo-pituitary system. This induces the preovulatory luteinising hormone (LH) smge to cause ovulation. Keywords: Inhibin; Oestradiol; FSH; LH; Domestic animal; Folliculogenesis
1. Introduction Follicle stimulating hormone (FSH) is essential for the developmenr and ‘maintenance of ovarian follicles in mammals. The secretion of FSH by the pitnitary gland is controlled by stimulatory effects of gonadotropin-releasing hormone from the hppothalamus and inhibitory effects of ovarian hormones, such as steroid hormones and inhibin. It is now beyond questíon that inhibin is a major regulator of the secretion of FSH by the
* Corresponding author. Tel.: 0423-67-5767; fax: 423-60-8830; e-mail: [email protected]. 0378-4320/%/$15.00 0 1996 Elsevier Science B.V. Al1 rights reserved. Pfl SO378-4320(96)015321
564
K. Taya et al. /Animal
5
Reproduction Science 42 (1996) 563-570
400 -
g
300 -
E .E !L
200 -
100 -
- 1oE a _ 5, 5 v)
--wou
5-4-3-2-10 1 2 3 4 5 6 7 0 1,2 3 4 5 0 1 2 3 4 5 Time from the initiation of each follicular wave (days)
’Follicula~ phase
Luteal phase
‘Follicblar phare
Fig. 1. (a) Development and regressionof dominant follicles and mean numberof normal follicles (over 4 mm in diameter). (b) Change in plasma conceatration of ocstradiol and progesterone.(c) lnhibin and FSH during the complete oestrous cycle in the cow. In (a), an astetisk representsdetection of ovulation. Data from seven cows are clustered around the initiation of each follicular wave (day 1 is day of the emergence of follicular wave). From Kaneko et al. (1995a).
anterior pituitary gland in various mammals (De Jong, 1988; Taya, 1993) with two other peptides, activin and follistatin, having local regulatory effects in the anterior pituitary gland (Mather et al., 1992). In the present review, we summarise evidente on the role of inhibin and oestradiol in the control of FSH secretion and folliculogenesis in the cow and other domestic animals.
2. Inhibin as a circulating hormone, acting to suppress the secretion of FSH 2.1. Cycling animals on inverse relationship between circulating inhibin and FSH has been demonstmted during the oestrous cycle of various mammals, such as cattle (Kaneko et al., 1995a), sheep (Findlay et al., 1990), goats (Mukai et al., 1989), horses (Roser et al., 1994), Pigs
K. Taya et al./Animal
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(Hasegawa et al., 19881, monkeys (Fraser et al., 1989; Nozaki et al., 19911, humans (McLachlan et al., 1987), rats (Hasegawa et al., 1989; Watanabe et al., 19901, hamsters (Kishi et al., 1995) and elephants (Brown et al., 1991). Fig. 1 shows changes in the concentration of immunoreactive (ir-) inhibin, oestradiol, progesterone and FSH in plasma during the normal oestrous cycle of Japanese brown cows (Kaneko et al., 1995a). The pattems of growth and regression of follicles in the ovary were also characterized by daily ultrasonographic examination. In this breed of cow, three waves of follicular development were observed during the early-luteal, mid-luteal and follicular phases. A dominant follicle was identified in each wave. During the growth of the dominant follicle, other follicles ceased their growth, while the emergence of the subsequent follicular wave occurred after the dominant follicle either ceased to grow or ovulated. Since there was a differente in the timing of the emergence of each follicular wave in individual animals, data on al1 hormones were clustered around the initiation of each follicular wave (day 1 being the day of emergence of the wave, indicated by an increase in the number of follicles), to clarify relationships between follicular development and hormonal profiles (Fig. l(b) and (c)). The diameter of the dominant follicle and the number of presumed normal follicles are also presented (Fig. I(a)). The concentration of plasma FSH was high prior to the emergence of each follicular wave and began to decrease with the appearance of the wave. It remained low during the growing phase of a dominant follicle. The number of normal follicles in each wave decreased in the period of low plasma FSH, while the dominant follicle continued to grow. Plasma concentrations of ir-inhibin increased concomitant with the emergence of each wave. In the first and third waves, concentrations of ir-inhibin and oestradiol reached a high leve1 in the growing phase of the dominant follicles and decreased when the dominant follicle ceased its growth, or ovulated. In contrast, plasma FSH leve1 showed a significant increase in the regression phase or around ovulation of the dominant follicle. During the second wave, there was no significant increase in plasma concentration of oestradiol, while ir-inhibin levels increased. There was a clear inverse relationship between plasma concentration of FSH and ir-inhibin throughout the oestrous cycle. 2.2. Superovulated animals A quantitative relationship between an increase in inhibin secretion and suppression of FSH secretion in vivo was also demonstrated in superovulating cows (Kaneko et al., 1992). Quine chorionic gonadotropin (eCG) increased the number of follicles of various sizes by 4 days after administration. In addition, the second growth of large follicles occurred within 2 days after superovulation. Both bioactivity and immunoreactivity of inhibin increased during the two waves of growth of large follicles, suggesting that bovine follicles secrete a large amount of bioactive and immunoreactive inhibin in the circulation in response to eCG. Plasma concentration of oestradiol also increased concomitantly with the increase in inhibin. A marked suppression of FSH concentration during eCG treatment occurred inversely with the increase in plasma leve1 of inhibin and oestradiol. These findings indicate that, in superovulating cattle treated with eCG, an increase in the number of follicles is involved in suppression of endogenous FSH secretion by means of enhanced secretion of inhibin and/or oestradiol.
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Oestradiol is thought to be a potent ovarian factor that inhibits FSH secretion in cows as wel1 as sheep (Martin et al., 1988; Mann et al., 1990). A negative correlation between plasma concentration of oestradiol and FSH is noted during the follicular phase (Kaneko et al., 1991; Kaneko et al., 1995a). Injection of oestradiol at a supraphysiological dosage has been found to decrease concentration of plasma FSH in ovariectomised heifers (Kesner and Convey, 19821, and replacement with a combination of oestradiol and progesterone found in the luteal phase was shown to reduce FSH concentrations in ovariectomised heifers to leve1 within these observed during the oestrous cycle (Price and Webb, 1988). On the ether hand, it is also known that steroid-free bovine follicular fluid (Ireland et al., 1983; Quirk and Fortune, 1986; Beard et al., 1989) or highly purified bovine inhibin (Beard et al., 1990) have the ability to suppress FSH secretion in ovariectomised and cyclic heifers. These studies suggest the possibility that inhibin and oestradiol are involved in the regulation of FSH secretion in the intact and superovulating cow.
3. Immunoneutralisation of endogenous inhibin and oestradiol To clarify the physiological role of inhibin and oestradiol in the regulation of FSH secretion during the oestrous cycle of cows, animals were passively immunized against the two hormones. Treatment with inhibin antiserum (inhibin-AS) resulted in a marked increase in the plasma concentration of FSH and oestradiol but not luteinising hormone (LH) or progesterone, compared with tbat after treatment with control serum (Kaneko et al., 1993). Treatment with inhibin-AS markedly increased the number of small, medium and large follicles. These results provide strong evidente that inhibin is an important factor in the inhibitory regulation of FSH secretion during the mid-luteal phase of cows when oestradiol secretion is low, and also demonstrate that an increase in endogenous FSH secretion after immunoneutralization of circulating inhibin stimulates the rapid growth of a large number of follicles. The relative importante of inhibin and oestradiol in the regulation of FSH secretion was then tested during the follicular phase of the bovine oestrous cycle when oestradiol secretion is at its highest, by immunoneutralization of circulating inhibin and oestradiol (Kaneko et al., 1995b). Cows were divided into four groups and given injections of prostaglandin F,, (PG) i.m. twice at 8 h intervals on Day 10 of the oestrous cycle (Day 0 is day of oestrus) to induce luteal regression. At 48 h after the first PG injection, each group of four cows received an injection of one of the following: 100. ml castrated goat serum (control serum), 100 ml inhibin-AS, 100 ml antiserum against oestradiol (oestradiol-AS), or a combination of 100 ml inhibin-AS and 100 ml oestradiol-AS. The LH surge occurred within 2 days after injection of the control serum or inhibin-AS, whereas it was not detected in either of the groups passively immunized against oestradiol, indicating that passive immunization against oestradiol blocks a positive feedback effect of oestradiol on LH secretion. There was no clear differente in basal concentration of LH among the four groups. Injection of the inhibin-AS resulted in a marked increase in the concentration of FSH compared with the value in the control group, while there was no significant change in concentration of plasma FSH after
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injection of the oestradiol-AS. Combined administration of the inhibin-AS and oestradiol-AS also produced a marked increase in plasma concentration of FSH. The FSH response to the combined immunization was longer in duration than the response to immunization with inhibin alone. Treatment with the inhibin-AS, either alone or in combination with the oestradiol-AS, induced the growth of a large number of small, medium, and large follicles compared with numbers in the controls. NO increase in the number of follicles was noted in the oestradiol-immunised animals. These results provide strong evidente that inhibin is an important factor in the inhibitory regulation of FSH secretion during the follicular phase as wel1 as the luteal phase of cows, suggesting also that oestradiol has a synergistic effect with inhibin on FSH secretion.
4. A functional model of inhibin and oestradiol actions Granulosa cells of ovarian follicles in mammals produce two hormones, inhibin and oestradiol, to regulate the oestrous cycle. The physiological roles of these two ovarian hormones have been confirmed as follows: inhibin is (1) a main inhibitor of FSH secretion, (2) a chemical signal of the number of growing follicles in the ovary, and mus (3) a key hormone in determining species-specifïc ovulation rates. On the other hand, oestradiol acts as (1) a signal of follicular maturation in the ovary, and (2) a signal determining the timing of the preovulatory LH surge.
5. Tbe use of inhibin vaccination in domestic animal production Active immunization against inhibin-enriched fractions of follicular fluid, synthetic peptide fragments of the o-subunit of inhibin and recombinant-DNA-derived o-subunit results in an increase in ovulation rate in sheep and cattle (O’Shea et al., 1994). Active immunization of gilts against recombinant-DNA-derived inhibin a-subunit (Brown et al., 1990) and of mares against a synthetic fragment of the inhibin a-subunit (McCue et al., 1992; Mckinnon et al., 1992) also results in an increase in ovulation rate. In these studies, it is postulated that immunoneutralization of endogenous inhibin wil1 lead to an increase in circulating FSH concentration by attenuation of its negative feedback action on the anterior pituitary and an increase in the number of follicles ovulating. Recent findings by Glencross et al. (1994) that active immunization of heifers against a synthetic fragment of inhibin leads to a sustained rise in plasma FSH concentration that is associated with an increase in the number of large follicles developing during the preovulatory and postovulatory waves of follicular development, and with an increase in ovulation rates, support the hypothesis. In addition, in Holstein heifers, neutralization of inhibin by antiserum during the luteal phase of the bovine oestrous cycle induces a rise in plasma FSH concentration and following luteolysis, there are multiple ovulations (Takedomi et al., 1995). Recently, ultrasound-guided follicular aspiration has been developed for the collection of oocytes from living animals and in vitro production of bovine embryos (Pieterse
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et al., 1988). Previous studies have shown that oocytes can be successfully collected from cycling cattle on a weekly basis (Gibbons et al., 1994). The effects of active immunization of cattle against inhibin on ovarian follicular development and ultrasound-guided transvaginal follicular aspiration were determined using Japanese black cows (Konishi et al., unpublished observation, 19%). The results demonstrated that active immunization against inhibin can enhance ovarian follicular development and the number of oocytes collected by transvaginal follicular aspiration. Inhibin immunisation had no effect on the grade of aspirated oocytes for IVF, indicating that this may be the most effective method to improve the efficiency of in vitro production of bovine embryos. In tbe near future, inhibin vaccination may be used to overcome variability in superovulation in cattle and sheep for embryo transfer. Less variable and repeated induction of superovulation may be achieved with inhibin vaccination in cattle and sheep.
Acknowledgements This article is respectfully dedicated to Professor Emeritus Shuji Sasamoto, Laboratory of Veterinary Physiology, Tokyo University of Agriculture and Technology, Fuchu, Tokyo 183, Japan, in honour of his retirement. This work was supported in part by a gram-in-aid (Bio Media Program, BMP96-V-2-2) from the Ministry of Agriculture, Forestry and Fisheries of Japan and The Ito Foundation.
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