Effects of gonadotropins, insulin and insulin-like growth factor I on ovarian oxytocin and progesterone production

doi:10.1016/0303-7207(91)90125-C

Molecular and Cellular Endocrinology

Volume 78, Issue 3, July 1991, Pages 211-220

https://doi.org/10.1016/0303-7207(91)90125-C Get rights and content

Abstract

Oxytocin is produced in the granulosa-derived cells of the ruminant corpus luteum where its gene is dramatically up-regulated within days of ovulation. Regulation of these processes is poorly understood but oxytocin release can be increased by insulin, insulin-like growth factor I (IGF-I), and gonadotropins. Here we have assessed interactions between these regulatory systems. Follicle-stimulating hormone (FSH), luteinizing hormone (LH) and human chorionic gonadotropin (hCG) caused dose-dependent release of oxytocin from bovine granulosa cells cultured in medium containing 100 ng/ml insulin. The gonadotropins also increased oxytocin mRNA levels and their effects were mimicked by forskolin. The effects of these stimuli on oxytocin and progesterone release were synergistically increased by insulin or IGF-I. Binding studies revealed separate binding sites with characteristics of insulin and IGF-I receptors. Insulin potentiated the effects of hCG and forskolin on oxytocin mRNA levels and release of oxytocin and progesterone in cells from follicles containing > 50 ng/ml estradiol. In cells from follicles containing < 5 ng/ml estradiol these stimuli had little effect on oxytocin release although progesterone release was synergistically increased by insulin and forskolin. The data suggest that gonadotropins regulate oxytocin synthesis and release and that these effects are amplified by insulin or IGF-I acting via their own receptors. Changes associated with maturation of the target cells in vitro appear prerequisite for oxytocin production in response to increased cAMP levels in the presence of insulin or IGF-I.

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The mammalian female reproductive cycle is an intricately regulated process. In normal physiology, insulin-like peptides and gonadotropic hormones such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) initiate signaling cascades that are critical for follicular growth, ovulation, luteinization, steroidogenesis, fertilization, and successful implantation. The pituitary gonadotropins, FSH and LH, play primary roles in directing steroid-hormone biosynthesis and cognate gene expression. In addition, insulin, insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), members of the transforming growth factor-beta (TGF-β) family (e.g., inhibin, activin, follistatin), bone morphogenetic protein (BMG), and growth differentiation factor (GDF) contribute to cytodifferen-tiative control. This chapter highlights the physiological importance of insulin and IGF-1 in steroidogenic gene regulation where relevant transgenic (murine) models are illustrated.
Effects of intraovarian infusion of insulin-like growth factor-I on ovarian follicular function in cattle
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The objective of this study was to determine if increased secretion of intraovarian insulin-like growth factor-I (IGF-I), experimentally induced via minipumps, affects follicular function in cattle. Fourteen cycling Holstein cows were divided equally into two groups: Control, osmotic minipumps (containing vehicle) surgically inserted into each ovary, or IGF-I treated, osmotic minipumps as in Controls but pumping 2.0 μg of recombinant human IGF-I per hr for 7 days. All cows were synchronized with prostaglandin F_2α (2 injections, 11 days apart) and one day after ovulation, the pumps or cannulas from each pump were surgically inserted and secured into the center of the ovarian stroma, and all antral follicles > 4 mm were aspirated. Ovaries were assessed with rectal ultrasound on Days 2, 3, 4, 5, and 6 post-surgery, and removed by left flank ovariectomy on Day 7. Follicular fluid from small follicles (1 to 5 mm, pooled within cow) and individual follicles > 5 mm were collected at ovariectomy for hormone determinations. Intraovarian IGF-I infusion increased concentrations of IGF-I in follicular fluid of small but not large follicles on Day 7 of treatment. Total ovarian weight (26.4 ± 2.6 g), and size of the second largest (9.1 ± 0.2 mm) follicle did not differ (P > 0.10) between control and IGF-I-treated cows. Size of the largest follicle was increased (P < 0.10) in IGF-I-treated versus control cows. Ultrasonography revealed that number of small (2 to 5 mm; 15.5 ± 0.6), medium (6 to 10 mm; 7.6 ± 0.4), and large (>10 mm; 1.4 ± 0.1) follicles did not differ (P > 0.10) between Control and IGF-I-treated cows during Days 2 to 6 of treatment. IGF-I treatment increased (P < 0.05) estradiol concentrations in follicular fluid of small follicles, but had no effect (P < 0.10) on estradiol concentrations in follicular fluid of large follicles, or on progesterone, androstenedione, or IGF binding protein concentrations in small or large follicles. We conclude that a 7-day infusion of IGF-I directly into the stroma of the ovary altered follicular growth and follicular fluid estradiol concentrations.
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Besides gonadotropins various other peptide factors have been implicated in the ovarian follicular growth and steroidogenesis. In this study, the effect of insulin like growth factor-1 on caprine granulosa cell steroidogenesis was investigated in vitro using serum free culture medium. Caprine granulosa cells were obtained from antral follicles classified into three classes: small, <3 mm; medium, 3–6 mm and large, >6 mm in diameter. IGF-1 (10–500 ng/ml) stimulated the secretion of estradiol and progesterone by granulosa cells from all three categories of follicles. However, the effect was more profound on cells from large follicles. IGF-1 (10–500 ng/ml) acted in synergy with FSH (100 ng/ml) to stimulate steroidogenesis by granulosa cells from all three categories of follicles, again the effect was more pronounced in cells from larger follicles. In summary, IGF-1 at physiological concentrations significantly influenced the steroidogenic activity of caprine granulosa cells cultured under serum free conditions. The results also suggest that estrogen and progesterone biosynthesis is differentially regulated by IGF-1 depending upon the size of the follicles from which the cells were obtained.
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The effects of exogenous equine somatotropin (eST) administration on ovarian activity and plasma hormone levels were evaluated on horse and pony mares. The objectives of this study were to determine the effects of eST on follicular development and circulating concentrations of leutinizing hormone (LH), estradiol, progesterone, and insulin-like growth factor I (IGF-I) in cyclic horse and pony mares. Sixteen mares received daily injections (im) of eST at a concentration of 25 μg/kg body weight on either Days 6 through 12 (Treatment A) or 13 through 19 (Treatment B) postovulation. In addition, contemporary mares were similarly given the carrier vehicle and served as controls (Treatments C and D). Blood samples were collected at 24-hr intervals and ultrasonographic evaluations were performed on the ovaries of each mare at 48-hr intervals beginning on the first day of treatment and ending either on the day of ovulation or 5 d postovulation. Circulating levels of insulin-like growth factor-I (IGF-I) were increased in treated mares by Day 3 post-treatment (P < 0.05). Also, mares in Treatment B exhibited a decrease in plasma estradiol concentrations (P < 0.05) when compared with control mares on Days 1 through 5 postovulation of the post-treated estrous cycle. In addition, circulating leutinizing hormone levels were different for mares in Treatment A compared with controls on Days −8 through −1 pre-ovulation (P < 0.05). All follicles present on the ovaries of each mare were measured and placed into one of five categories based on their diameter. Neither the mean number of follicles per size category ⩾8 mm in diameter nor the mean follicular diameter within each size category differed among treatment and control mares. However, eST treatment significantly increased the number of follicles ⩽7 mm on the ovaries of mares treated early in the estrous cycle when compared with control mares on Days 3 and 7 post-treatment and at the onset of standing estrus.
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Effects of gonadotropins, insulin and insulin-like growth factor I on ovarian oxytocin and progesterone production

Abstract

Biochem. Biophys. Res. Commun.

Mol. Cell. Endocrinol.

FEBS Lett.

Anal. Biochem.

FEBS Lett.

Trends Genet.

Endocr. Rev.

Endocrinology

Endocrinology

J. Reprod. Fertil.

Endocrinology

Nature

J. Reprod. Fertil.

J. Receptor Res.

Cell Tissue Res.

Endocrinology

Biol. Reprod.

EMBO J.

Reprod. Fertil. Dev.