In addition to their roles in IGF transport, the six IGF-binding proteins (IGFBPs) regulate cell activity in various ways. By sequestering IGFs away from the type I IGF receptor, they may inhibit mitogenesis, differentiation, survival, and other IGF-stimulated events. IGFBP proteolysis can reverse this inhibition or generate IGFBP fragments with novel bioactivity. Alternatively, IGFBP interaction with cell or matrix components may concentrate IGFs near their receptor, enhancing IGF activity. IGF receptor-independent IGFBP actions are also increasingly recognized. IGFBP-1 interacts with alpha(5)beta(1) integrin, influencing cell adhesion and migration. IGFBP-2, -3, -5, and -6 have heparin-binding domains and can bind glycosaminoglycans. IGFBP-3 and -5 have carboxyl-terminal basic motifs incorporating heparin-binding and additional basic residues that interact with the cell surface and matrix, the nuclear transporter importin-beta, and other proteins. Serine/threonine kinase receptors are proposed for IGFBP-3 and -5, but their signaling functions are poorly understood. Other cell surface IGFBP-interacting proteins are uncharacterized as functional receptors. However, IGFBP-3 binds and modulates the retinoid X receptor-alpha, interacts with TGFbeta signaling through Smad proteins, and influences other signaling pathways. These interactions can modulate cell cycle and apoptosis. Because IGFBPs regulate cell functions by diverse mechanisms, manipulation of IGFBP-regulated pathways is speculated to offer therapeutic opportunities in cancer and other diseases.

/pdf/cellular-actions-of-the-insulin-like-growth-factor-binding-sganno3kh8.pdf

Cellular actions of the insulin-like growth factor binding proteins.

Mammalian ovaries consist of follicles as basic functional units. The total number of ovarian follicles is determined early in life, and the depletion of this pool leads to reproductive senescence. Each follicle develops to either ovulate or, more likely, to undergo degeneration. The dynamics of ovarian follicle development have interested endocrinologists and developmental biologists for many years. With the advent of assisted reproductive techniques in humans, the possibility of regulating follicle development in vivo and in vitro has gained clinical relevance. In this review, we focus upon key branching points during the development of ovarian follicles as well as factors involved in determining the eventual destiny of individual follicles. We discuss inconsistencies in the literature regarding the definitions of follicle recruitment and selection and propose to name the two major steps of follicle development as initial and cyclic recruitment, respectively. Because some of these disparities have arisen due to differences in the animal systems studied, we also compare the development of the ovarian follicles of both humans and rats. We also review the status of knowledge of several puzzling clinical issues that may provide important clues toward unlocking the mechanisms of follicle development.

https://redlara.com/images/arq/LOC1_recrutamento.pdf

Initial and cyclic recruitment of ovarian follicles.

I. Introduction IN THE adult ovary, folliculogenesis starts when follicles leave the pool of resting follicles (RF) to enter the growth phase. From there, the early growing follicle undergoes a developmental process including a dramatic course of cellular proliferation and differentiation. In primates, only one follicle commonly reaches the preovulatory stage every cycle; most follicles fail to complete this maturation scheme, dying in the process termed atresia. In recent years, a picture has emerged depicting the classic endocrine control of ovarian function by LH and FSH, entangled in a maze of regulatory systems hinging on cell-cell interactions between follicular cells, via action of a variety of molecules (1–3). Different types of cell-cell interactions have been described. In paracrine regulations, a molecule synthesized by one cellular type is released into the interstitial milieu to act directly on another cellular type. In autocrine regulations, molecules synthesized by one cellular type are rel...

/pdf/regulation-of-ovarian-follicular-development-in-primates-4srrm0fi7f.pdf

Regulation of ovarian follicular development in primates: facts and hypotheses.

In recent years, exciting progress has been made towards unravelling the complex intraovarian control mechanisms that, in concert with systemic signals, coordinate the recruitment, selection and growth of follicles from the primordial stage through to ovulation and corpus luteum formation. A plethora of growth factors, many belonging to the transforming growth factor-beta (TGF-beta ) superfamily, are expressed by ovarian somatic cells and oocytes in a developmental, stage-related manner and function as intraovarian regulators of folliculogenesis. Two such factors, bone morphogenetic proteins, BMP-4 and BMP-7, are expressed by ovarian stromal cells and/or theca cells and have recently been implicated as positive regulators of the primordial-to-primary follicle transition. In contrast, evidence indicates a negative role for anti-Mullerian hormone (AMH, also known as Mullerian-inhibiting substance) of pre-granulosa/granulosa cell origin in this key event and subsequent progression to the antral stage. Two other TGF-beta superfamily members, growth and differentiation factor-9 (GDF-9) and BMP-15 (also known as GDF-9B) are expressed in an oocyte-specific manner from a very early stage and play key roles in promoting follicle growth beyond the primary stage; mice with null mutations in the gdf-9 gene or ewes with inactivating mutations in gdf-9 or bmp-15 genes are infertile with follicle development arrested at the primary stage. Studies on later stages of follicle development indicate positive roles for granulosa cell-derived activin, BMP-2, -5 and -6, theca cell-derived BMP-2, -4 and -7 and oocyte-derived BMP-6 in promoting granulosa cell proliferation, follicle survival and prevention of premature luteinization and/or atresia. Concomitantly, activin, TGF-beta and several BMPs may exert paracrine actions on theca cells to attenuate LH-dependent androgen production in small to medium-size antral follicles. Dominant follicle selection in monovular species may depend on differential FSH sensitivity amongst a growing cohort of small antral follicles. Changes in intrafollicular activins, GDF-9, AMH and several BMPs may contribute to this selection process by modulating both FSH- and IGF-dependent signalling pathways in granulosa cells. Activin may also play a positive role in oocyte maturation and acquisition of developmental competence. In addition to its endocrine role to suppress FSH secretion, increased output of inhibin by the selected dominant follicle(s) may upregulate LH-induced androgen secretion that is required to sustain a high level of oestradiol secretion during the pre-ovulatory phase. Advances in our understanding of intraovarian regulatory mechanisms should facilitate the development of new approaches for monitoring and manipulating ovarian function and improving fertility in domesticated livestock, endangered species and man.

/pdf/tgf-beta-superfamily-members-and-ovarian-follicle-2f533am5ir.pdf

TGF-beta superfamily members and ovarian follicle development.

The primary function of the corpus luteum is secretion of the hormone progesterone, which is required for maintenance of normal pregnancy in mammals. The corpus luteum develops from residual follic...

https://www.physiology.org/doi/pdf/10.1152/physrev.2000.80.1.1

Mechanisms Controlling the Function and Life Span of the Corpus Luteum

It isnot clearwhether the turnover of ovarianfollicles during the estrouscycle in cattleisContinuous and independent of thephase of the cycle,or whether waves of follicular growth occur at specifictimes of the cycle. To clarifythis controversy, the pattern of growth and regression of ovarian follicles was characterized during a complete estrous cycle in ten heifers by daily ultrasonographic examinations. Follicles � 5 mm were measured and theirrelativelocationswithin the ovary were determined in order tofollow the sequentialdevelopment of each individual follicle. Results indicated the presence of either two (n = 2 heifers), three (n = 7), or four (n = I) waves of follicular growth per cycle.Each wave was characterizedby the development of one large (dominant) follicle and a variable number of smaller (non-dominant) follicles. In the most common pattern observed (threewaves/cycle),thefirst, second, and third waves started on Days 1.9 ± 0.3, 9.4 ± 0.5, and 16.1 ± 0.7 (X ± SEM), respectively. The dominant follicle in the third wave was the ovulatory follicle. The maximal sizeand the growth rateof the dominant folliclein the second wave were significantlylower than inthe other waves, but no significant difference was observed between the first and third waves. For the two heifers that had two follicularwaves/cycle,the waves startedon Days 2 and 11, whereas in the remaining heifer (four waves/cycle), the waves began on Days 2, 8, 14, and 17, respectively. At 0, 1, 2, 3, and 4 days before estrus, the ovulatory follicle was the largest follicle in the ovaries in 100%, 95%, 74%, 35%, and25% offollicular phases monitored, respectively. The relative size of the preovulatory follicle at the completion of luteolysis (progesterone< I ng/ml) was negatively correlated (r = -0.90; p<0.0001) with the interval of time between the end of luteolysis and the luteinizinghormone surge,suggestingthat the length of proestrus isdetermined by the sizeof thepreovulatoryfollicleat the beginning ofproestrus.In conclusion,thisstudy shows thatthe development of ovarian follicles�5 mm in heifers occurs inwaves and thatthe most common pattern isthreewaves per estrouscycle.

/pdf/ovarian-follicular-dynamics-during-the-estrous-cycle-in-3zhq139zsl.pdf

Ovarian follicular dynamics during the estrous cycle in heifers monitored by real-time ultrasonography.

Evidence from several species indicates that the initial stages of follicular growth proceed very slowly. In contrast, the stages after antrum formation are much more rapid. Atresia seems to be most prevalent as follicles approach the size at which they could be recruited for potential ovulation. Although most follicles become atretic around that stage, a few are recruited into a cohort or wave of follicles that continue to grow beyond the stage at which atresia normally occurs. Next, a species-specific number of follicles is selected for dominance. In some species (e.g. rats, primates, pigs), dominant follicles develop only during the follicular phase and are thus destined for ovulation. In another group of species (e.g. cattle, sheep, horses), recruitment, selection, and dominance occur at regular intervals, but only the dominant follicle present during the follicular phase ovulates. There is evidence that the mechanism that allows some follicles to be recruited for potential dominance/ovulation is a small elevation in basal FSH that, by chance, occurs around the time the follicle would normally begin atresia. Some recruited follicles are saved from atresia for only a short time. Only the dominant follicle(s) selected from among the recruited follicles grows to ovulatory or near-ovulatory size. What determines which follicle(s) becomes dominant is not known, but dominance appears to be maintained by negative feedback effects of products of the dominant follicle on circulating FSH. Selection and dominance are accompanied by progressive increases in the ability of thecal cells to produce androgen and granulosa cells to aromatize androgen to estradiol.(ABSTRACT TRUNCATED AT 250 WORDS)

Ovarian follicular growth and development in mammals.

In cattle the development of ovarian follicles greater than or equal to 5 mm occurs in waves, with either two or three waves per estrous cycle. To increase our understanding of the control of follicular dynamics in cattle, the present study was designed to characterize the pattern of follicular development during artificially lengthened estrous cycles. Cycles were lengthened by intravaginal insertion of Silastic devices containing progesterone [Controlled Internal Drug Release devices (CIDRs)]. Control heifers (group 1) received blank devices, whereas treated heifers received one (group 2) or two CIDRs (group 3) from days 14 to 28 after estrus. In groups 2 and 3, the insertion of CIDRs prevented return to estrus at the normal time and increased cycle length as compared to the control group (30.0 +/- 0.0 and 31.0 +/- 0.3 vs. 21.0 +/- 0.7 days, respectively, P less than 0.05). After natural luteolysis and between days 22 and 28 of cycle, progesterone concentrations were maintained at lower levels in group 2 (range = 0.9-2.1 ng/ml) than in group 3 (range = 3.7-4.9 ng/ml, P less than 0.003). Follicular development and regression were monitored daily by ultrasonography. The number of follicular waves per cycle was identical in groups 1 and 2 (2.7 waves per cycle), despite the significantly longer cycles in group 2. In group 2, the presence of one CIDR altered the normal pattern of follicular development by promoting the prolonged growth of the ovulatory follicle, and associated with it, a complete absence of follicular recruitment. When compared to ovulatory follicles in controls (group 1), ovulatory follicles in group 2 were detected on the ovaries for a longer time (1.8-fold), reached a greater maximal size (1.4-fold), and were dominant for a longer time (3-fold). Heifers in group 3 had significantly more follicular waves per cycle than groups 1 and 2 (3.8 vs. 2.7 waves per cycle, respectively, P less than 0.05), due to the production of additional follicular waves during the lengthened cycle in three of six heifers. The other three heifers in group 3 showed patterns of follicular development similar to those of group 2. All heifers in the control group had normal preovulatory rises in estradiol and LH. During the period of treatment (days 14-28), 17 beta-estradiol concentrations were higher in heifers in group 2 (lower progesterone levels) than in heifers in group 3 (higher progesterone levels; P less than 0.0001). No differences were observed in basal LH concentrations between groups 2 and 3.(ABSTRACT TRUNCATED AT 400 WORDS)

Lengthening the Bovine Estrous Cycle with Low Levels of Exogenous Progesterone: A Model for Studying Ovarian Follicular Dominance*

The early stages of follicular development: activation of primordial follicles and growth of preantral follicles

In cattle, the development of ovarian follicles 5 mm or larger occurs in either two or three consecutive follicular waves per estrous cycle. When the luteal phase is artificially lengthened with an intravaginal progesterone-releasing device (CIDR) that maintains subluteal levels (i.e. levels of progesterone that are below normal luteal levels, but higher than basal follicular phase levels), prolonged development of the ovulatory follicle is observed. To study the endocrinological correlates of prolonged follicular dominance and to test the hypothesis that it is mediated by effects of plasma progesterone on LH pulse frequency, heifers (n = 6/group) were treated with blank CIDRs (no progesterone, control group), with one CIDR for 14 days from day 14 of the cycle (1 CIDR group), or with one CIDR for 14 days from day 14 plus a second CIDR during days 24-28 (2 CIDR group). Cycle length was significantly longer in the 1 and 2 CIDR groups than in the controls (30.2 +/- 0.2 and 31.8 +/- 0.5 vs. 21.6 +/- 0.4 days,...

Joanne E. Fortune

Papers

Ovarian follicular dynamics during the estrous cycle in heifers monitored by real-time ultrasonography.

Ovarian follicular growth and development in mammals.

Lengthening the Bovine Estrous Cycle with Low Levels of Exogenous Progesterone: A Model for Studying Ovarian Follicular Dominance*

The early stages of follicular development: activation of primordial follicles and growth of preantral follicles

Ovarian follicular dominance in cattle: relationship between prolonged growth of the ovulatory follicle and endocrine parameters