Role of growth hormone and growth hormone receptor in oocyte maturation

https://doi.org/10.1016/S0303-7207(02)00270-8Get rights and content

Abstract

Near the completion of growth, mammalian oocytes acquire the competence to resume and complete meiosis. In vivo the preovulatory LH surge triggers the resumption of meiosis in the oocyte contained in preovulatory follicles. When immature oocytes and the surrounding cumulus cells are released from their follicular environment, resumption of meiosis is induced spontaneously. Culture of bovine cumulus oocyte complexes (COCs) obtained from antral follicles results in blastocyst formation following in vitro maturation, in vitro fertilisation and in vitro embryo culture. Addition of growth hormone (GH) to the maturation medium accelerates nuclear maturation of cumulus enclosed bovine oocytes, induces cumulus expansion and promotes early embryonic development following in vitro fertilisation. The effect of GH is exerted through the cumulus cells and not mediated by IGF-I. Cumulus cells and the oocyte express mRNA for GH receptor. Using specific inhibitors it has been shown that the effect of GH on oocyte maturation and cumulus expansion is mediated by the cyclic AMP signal transduction pathway. Within COCs both cumulus cells and oocyte show GH immunoreactivity while expression of GH mRNA is only found in the oocyte. These observations point to a paracrine and/or autocrine action of GH in oocyte maturation.

Introduction

Meiosis in mammalian oocytes starts during foetal life and arrests around birth at the end of prophase of the first meiotic division. In the resting pool of primordial follicles the oocytes are small with an average diameter of 20 μm. During folliculogenesis growth commences and in the early antral follicle the oocyte has attained almost its maximal diameter of about 120 m. In rodents, the competence of the oocyte to resume and complete meiotic maturation, is associated with antrum formation. In bovine oocytes meiotic competence is not strictly correlated with antrum formation or maximum size but is associated with almost completely inactivated nucleolar transcriptional activity of the oocyte towards the end of the growth phase at an oocyte diameter of about 110 μm (Fair et al., 1995). In general, meiotic competence is acquired shortly after antrum formation as oocytes are around 80% of final diameter.

Despite the competence to resume meiosis the oocyte maintains its germinal vesicle (GV) stage until the occurrence of the preovulatory LH surge. It has been well documented that the effect of the LH surge is evident only in preovulatory follicles while the remaining pool of follicles is unaffected. The precise mechanism by which LH exerts its action is not fully understood. Fact is, that the hormone acts on the somatic cells of the follicle since the oocyte possesses no LH receptors (Bevers et al., 1997). Resumption of meiosis from the GV stage is manifested by chromosome condensation, disintegration of the nuclear envelope (GV breakdown) and spindle formation. The first meiotic division concludes by segregation of the homologous chromosomes and emission of the first polar body. Immediately thereafter the second metaphase (MII) commences and is arrested again at the second metaphase. This process from resumption of meiosis up to the formation of the MII stage is defined as the nuclear maturation of the oocyte. The meiosis terminates upon fertilisation when sister chromatids are segregated and the second polar body is extruded. Besides the nuclear maturation, the oocyte has also to complete the cytoplasmic maturation i.e. the molecular and structural changes that provide the matured egg the capacity to support fertilisation and early embryonic development. The LH surge also triggers the expansion of the cumulus cells surrounding the oocyte resulting in changes in the junctional communication between the cumulus cells and the mural granulosa cells and communication between the cumulus cells and the oocyte.

When a cumulus oocyte complex (COC) containing a meiotic competent oocyte is released from its follicular environment, the oocyte spontaneously resumes meiosis up to the MII stage as has been first observed by Pincus and Enzmann (1935) using rabbit oocytes. This process is defined as in vitro oocyte maturation. Spontaneous maturation fundamentally involves removal of the inhibitory influence imposed by the follicular environment. Therefore the model does not reproduce accurately the normal mechanism operating in vivo. This should be kept in mind and asks for a restrictive extrapolation of data to what happens in vivo.

A properly matured oocyte is essential for a successful fertilisation and subsequent embryo development. The majority of knowledge on oocyte maturation of mammalian species is based on in vitro maturation of immature oocytes from small and medium sized follicles. Those oocytes are collected for the in vitro production of embryos of domestic species in particular in the bovine, sheep, goat and pig. In order to improve the efficiency of the in vitro embryo production, in the past two decades many studies are conducted on the effect of particular hormones and growth factors on the in vitro maturation of oocytes and the subsequent in vitro embryo development following fertilisation (Bevers et al., 1997). This paper focuses on the effect of growth hormone (GH) on the in vitro maturation of bovine oocytes.

Section snippets

Effect of growth hormone on the in vitro maturation and embryo development

In vitro maturation of bovine oocytes by culture of COCs from small to medium sized follicles for 24 h in tissue culture medium M199 (TCM199) supplemented with 100 ng/ml of bovine GH (NIH-GH-B18) accelerated the process of GV breakdown. In all experiments, culture in MEM without GH served as control. At 4 and 8 h the percentage of oocytes in GV in the GH treated group (54 and 19%) was significantly lower than in the control group (64 and 41%) respectively (Izadyar et al., 1996). Similarly the

GH and GH-receptor expression in oocyte cumulus complexes

In the foregoing part it has been shown that in vitro the nuclear maturation of bovine oocytes in the presence of GH is accelerated as expressed by an advanced occurrence of GVBD and a higher proportion of MII oocytes after 16 h of culture. In contrast, in vitro maturation of denuded oocytes, i.e. COCs from which cumulus cells were removed by vortex before the onset of culture, in the presence of GH resulted in a delayed GV breakdown while at 16 h of culture no difference in the proportion of

Signal transduction pathway

Most of the actions of GH are believed to be mediated by IGF-I that is secreted by various tissues in response to GH. Therefore the question arises whether GH interacts with its receptor and directly accomplishes its effects or whether the stimulation is mediated by IGF-I which also promotes in vitro maturation of bovine oocytes as has been reported (Herrler et al., 1992, Lorenzo et al., 1994). In the rat the stimulatory effect of GH on in vitro oocyte maturation is mediated by IGF-I probably

Concluding remarks

In the last decade it has become clear that GH is an important regulator of ovarian function. In vivo and in vitro studies have shown that GH stimulates preantral and antral follicular development. The hormone has a suppressive effect on apoptosis and affects steroidogenesis of the granulosa cells. Moreover various studies have demonstrated the presence of GHR mRNA and protein in ovarian cells as recently reviewed by Hull and Harvey (2001).

Apart from the rather substantial information from the

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