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PubMed1999

Roles of extracellular matrix in follicular development.

The cellular biology and changes in the extracellular matrix of ovarian follicles during their development are reviewed. During growth of the bovine ovarian follicle the follicular basal lamina doubles 19 times in surface area. It changes in composition, having collagen IV alpha 1-26 and laminin alpha 1, beta 2 and gamma 1 at the primordial stage, and collagen IV alpha 1 and alpha 2, reduced amounts of alpha 3-alpha 5, and a higher content of laminin alpha 1, beta 2 and gamma 1 at the antral stage. In atretic antral follicles laminin alpha 2 was also detected. The follicular epithelium also changes from one layer to many layers during follicular growth. It is clear that not all granulosal cells have equal potential to divide, and we have evidence that the granulosal cells arise from a population of stem cells. This finding has important ramifications and supports the concept that different follicular growth factors can act on different subsets of granulosal cells. In antral follicles, the replication of cells occurs in the middle layers of the membrana granulosa, with older granulosal cells towards the antrum and towards the basal lamina. The basal cells in the membrana granulosa have also been observed to vary in shape between follicies. In smaller antral follicles, they were either columnar or rounded, and in follicles > 5 mm the cells were all rounded. The reasons for these changes in matrix and cell shapes are discussed in relation to follicular development.

Animals↗
PubMed1987

Recruitment of multiple follicular development for in vitro fertilization in the presence of a viable intrauterine pregnancy.

Stimulation of multiple follicular development was induced concurrent with a viable early intrauterine pregnancy; the infant was subsequently delivered at term. Despite the pregnancy, the ovaries responded successfully to gonadotropin stimulation. In addition, three recovered oocytes were successfully fertilized, and two subsequently cleaved. Thus pregnancy does not create a state of ovarian refractoriness or a hormonal milieu totally deleterious to the initial stages of embryo development.

Adult↗
PubMed2000

Dynamic changes in the intrafollicular inhibin/activin/follistatin axis during human follicular development: relationship to circulating hormone concentrations.

Previous studies of normal human ovaries suggest that inhibins, activins, and follistatin (FS) are produced in a stage-specific pattern indicative of intraovarian, autocrine/paracrine roles in regulating follicle development. However, these studies relied largely on surgical specimens and thus include little information about the menstrual cycle stage or dominant follicle status at the time follicles or ovaries were obtained. The purpose of this study was to 1) determine the pattern of intrafollicular hormone biosynthesis across antral follicle development in normal women, 2) compare hormone concentrations in dominant and nondominant follicles from the same ovary, and 3) examine the relationship between dominant follicle hormone content and circulating hormone levels. Intrafollicular estradiol, progesterone, and inhibin A concentrations increased significantly with follicle size or maturity, whereas significant inverse relationships were observed for androstenedione and the androstenedione/estradiol (A:E) ratio. In contrast, neither inhibin B, activin A, nor free FS varied consistently with size or maturity. Estradiol, progesterone, and inhibin A levels and A:E ratio were significantly lower in nondominant follicles compared to the dominant follicle aspirated from the same ovary. Although intrafollicular and serum concentrations of each hormone followed the same general pattern as follicles develop, the human follicular fluid/serum gradients changed during the follicular phase and were different for estradiol and inhibin A, suggesting the presence of stage-specific differences in pharmacodynamics. These results are consistent with the hypothesis that the orderly transition from an activin-dominant to an inhibin A/FS-dominant microenvironment is critical for dominant follicle development.

Activins↗
PubMed1992

Administration of human luteinizing hormone (hLH) to macaques after follicular development: further titration of LH surge requirements for ovulatory changes in primate follicles.

After stimulation of multiple follicular development, endogenous LH surges elicited by GnRH or GnRH agonist were of insufficient duration (4-14 h) to evoke oocyte maturation and luteinization in this species. In this study, periovulatory LH surge requirements were further titrated using hLH as the ovulatory stimulus. Beginning at menses, rhesus monkeys were treated with human gonadotropins for 9 days to stimulate follicular growth. To induce ovulatory maturation on day 10, animals received: 1) hCG (1000 IU, im; n = 8); 2) highly-purified, urinary hLH (2542 IU, im; n = 4); or 3) hLH (2542 IU, im) followed by three injections of hLH (200 IU, im) at 8-h intervals (0800, 1600, 2400 h) daily during the luteal phase until menses (n = 3). Oocytes and luteinizing granulosa cells were obtained via follicle aspiration 27 h after the initial hLH or hCG injection. Estradiol and progesterone levels were measured in daily serum samples by RIA. Bioactive LH levels were determined at selected intervals within 36 h of the hLH ovulatory stimulus. Nuclear maturity of oocytes was evaluated as an indicator for reinitiation of meiosis. Luteinizing granulosa cells were processed for indirect immunocytochemistry using a monoclonal antibody to human progesterone receptor. In vitro progesterone production by luteinizing granulosa cells over 24 h was also assessed in the absence and presence of hCG. In all groups, serum estradiol rose to similar peak levels on day 10. After hLH, bioactive LH levels peaked (1262 +/- 79 ng/mL; mean +/- SEM) by 2-6 h, declined thereafter but remained above surge levels (100 ng/mL) for 18-24 h. Within 24 h of hLH injection, serum progesterone increased to 13 +/- 3 nmol/L, but returned to baseline in 1-6 days. In contrast, higher levels of progesterone were observed after hCG (114 +/- 51 nmol/L) and during luteal phase treatment with hLH (137 +/- 25 nmol/L) and the luteal phase was longer (11.5 +/- 0.4 and 14.3 +/- 0.7 days, respectively). Of the total cohort of oocytes aspirated, the proportion of oocytes resuming meiotic maturation (metaphase I plus metaphase II) was similar after hCG (76%) and hLH (74%). However, the proportion of oocytes maturing to metaphase II tended to be less (P = 0.08) after hLH (13%) than hCG (22%). Fertilization rates were similar between the two groups. Progesterone receptor was detected in nuclei of luteinizing granulosa cells from all animals receiving hCG, but only in some given hLH.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Reduced ovarian follicular development as a consequence of low body condition in ewes.

The effect of body condition on ovarian follicular development was investigated in Scottish Blackface ewes in high and low body condition. Follicles were dissected from ovaries on days 11 and 12 of the luteal phase and 24 h after prostaglandin-induced luteal regression. Ewes in low body condition had a lower ovulation rate (low: 0.9; high: 1.8 P less than 0.05) and lower mean plasma levels of FSH during both the luteal (low: 54; high: 72 micrograms/l) and follicular (low: 34; high: 43 micrograms/l) phases of the cycle. Low body condition was associated with a reduced number of large (greater than or equal to 4 mm) follicles in both the luteal and follicular phases, and in low condition a lower proportion of these follicles was oestrogenic and potentially ovulatory as assessed by follicular fluid levels of oestradiol. However, within the different oestrogenic classifications of these large follicles there were no significant differences in the steroidogenic capacity as assessed by the concentrations of either oestradiol or testosterone in follicular fluid, basal and hCG-stimulated testosterone production, thecal 125I hCG binding or basal and testosterone-stimulated oestradiol production by granulosa cells in relation to body condition. These results suggest that body condition influences ovulation rate by altering the concentration of FSH in blood, which in turn affects the number of potentially ovulatory follicles growing beyond 4 mm.

Animals↗
PubMed1982

Ovarian follicular development leading to first ovulation and accompanying gonadotrophin levels as studied in the unilaterally ovariectomized rat.

Ovarian follicular development was studied in the rat during a 15-day period preceding first ovulation. Ovaries were obtained by unilateral ovariectomy performed at various ages and the rats were allowed to live until the day after first ovulation. The timing of this ovulation was compared with that in unoperated, paired control rats of the same age. For estimation of gonadotrophin levels, blood was taken from the paired control rats at the time when experimental rats were unilaterally ovariectomized. There was no evidence that unilateral ovariectomy had any influence on the timing of first ovulation. Therefore the ovaries obtained could be dated in relation to first ovulation, and follicular growth during the final prepubertal period could thus be studied in a genuine developmental sequence. Results revealed that follicular growth leading to first ovulation starts at +/- 8 days before this ovulation; follicular processes taking place are comparable to those found during the adult 5-day cycle but proceed more slowly. Gonadotrophin concentrations accompanying the follicular dynamics and measured at 11.00 h, showed a clear tendency for FSH concentrations to decrease with increasing age, i.e. approaching first ovulation. Concentrations of LH did not show a definite pattern and were generally low, although in some individual rats relatively high LH values ( greater than 100 micrograms/l) were found in the period of 5-3 days before first ovulation.

Animals↗
PubMed1990

Role of midcycle FSH surge in follicular development.

The present study was undertaken to examine the importance of the proestrous surge of FSH for follicular development during the following cycles in the rat. The midcycle FSH surges were blocked in several consecutive cycles (1-5) by injecting proestrous rats with pentobarbital. The rats were sacrificed on the day of proestrus following the appropriate number of blocked FSH surges and their ovaries were removed for either direct measurements or for histological workout. The number and diameter of follicles were determined in the excised ovaries. Two or three cycles of barbiturate treatment reduced the number and diameter of the follicles. No large follicles (greater than 0.4 mm) were observed in the ovaries of rats in which four or five gonadotropin surges were blocked. A repeat experiment with concomitant supplementary hCG administration yielded the same results. Addition of exogenous FSH canceled the effect of pentobarbital. The cohort observed on ovaries after four cycles of treatment with pentobarbital and FSH resembled that observed in control rats. Histological measurements supported the results obtained with fresh ovaries. It is therefore suggested that in the third cycle preceding the ovulatory one, the midcycle FSH surge determines which follicles will be able to adequately develop in the following three cycles. In the cycle preceding the ovulatory one, the midcycle FSH peak 'rescues' a group of follicles and prepares them for a proper response to the FSH elevation taking place at the beginning of the subsequent ovulatory cycle. This process allows the selection of the dominant follicles which will respond by ovulation to the ensuing LH peak.

Animals↗
PubMed2000

Effect of administering a crude equine gonadotrophin preparation to mares on follicular development, oocyte recovery rate and oocyte maturation in vivo.

In mares, the shortage of oocytes and the variability in nuclear maturation at a certain time of the oestrous cycle hinders the optimization of methods for in vitro maturation and in vitro fertilization. Increasing the number of small-to-medium-sized follicles available for aspiration in vivo may increase the overall oocyte yield. The aims of the present study were to investigate whether administration of crude equine gonadotrophins affects follicular development, oocyte recovery rate, in vivo oocyte maturation and follicular concentrations of meiosis-activating sterols. During oestrus, all follicles >/= 4 mm were aspirated from 19 pony mares (first aspiration: A1). Over the next 8 days, the mares were treated daily with either 25 mg crude equine gonadotrophins (n = 10) or physiological saline (n = 9). Between day 1 and day 8, follicular growth was monitored by ultrasonography. On day 8, all follicles >/= 4 mm were evacuated (second aspiration: A2) and nuclear maturation of the recovered oocytes was assessed after orcein staining. Follicular growth between A1 and A2, as well as the number and size of follicles at A2 were similar for control mares and mares treated with crude equine gonadotrophins. The oocyte recovery rates at A1 and A2 were similar. At A2, the oocyte recovery rate and oocyte maturation in vivo were not affected by treatment with crude equine gonadotrophins. The number of expanded cumulus oophorus complexes recovered from follicles </= 29 mm was significantly higher at A1 than at A2. The number of oocytes at the germinal vesicle stage was significantly higher at A2 (41.5%) than at A1 (17.8%). Meiosis-activating sterols (FF-MAS and T-MAS) were identified in follicular fluid recovered at A2. Follicular concentrations of FF-MAS and T-MAS were unaffected by treatment with crude equine gonadotrophins. The present study demonstrates that follicular aspiration during oestrus allowed a new follicular population to develop and resulted in a higher degree of synchronization of oocyte development with respect to cumulus expansion and nuclear maturation. The availability of a more homogeneous population of oocytes might facilitate a better optimization of in vitro maturation and in vitro fertilization techniques in mares. Administration of crude equine gonadotrophins during early dioestrus did not affect the growth of small follicles, the oocyte yield after aspiration or oocyte maturation in vivo.

Animals↗
PubMed1997

[Regulation of ovarian follicular development by epidermal growth factor in IVF superovulation cycles].

OBJECTIVE: To study the role of epidermal growth factors (EGFs) in the regulation of ovarian follicular development in in vitro fertilization (IVF) superovulation cycles. METHODS: In situ hybridyzation and immunochemistry were used to locate EGF, transforming growth factor alpha (TGF alpha) and their receptor (EGFR) in 10 normal ovarian specimens and in 5 granulosa cell samples obtained from IVF egg retrieval procedure. Radioimmunoassay was used for 6 sex hormones and radioreceptor assay for EGFs (mainly including EGF and TGF alpha) determinations in the serum and follicular fluid. RESULTS: (1) EGF was not detected in the ovary, while EGFR and TGF alpha were found to be present in human granulosa cells. (2) Serum EGFs levels increased with the development of follicles, and EGFs levels in the follicular fluid were higher than those of the matched plasma. No correlation was found between EGFs and sex hormones. CONCLUSIONS: TGF alpha but not EGF might be synthesized locally, acting on the granulosa cells in an autocrine fashion through EGFR in granulosa cells. Serum EGFs levels (including EGF and TGF alpha) might be stimulated by exogenous gonadotropins.

Adult↗
PubMed1986

Comparison of two brands of clomiphene citrate for stimulation of follicular development in a program for in vitro fertilization.

Although clomiphene citrate (CC) is used frequently to stimulate multiple follicular development in in vitro fertilization programs, comparison of the two commercially available types has been limited. Therefore, a comparison was made of Serophene (Serono Laboratories, Inc., Randolph, MA) and Clomid (Merrell Dow Pharmaceuticals, Inc., Cincinnati, OH), using the same dosage regimen of CC (150 mg/day for days 3 to 7 of the cycle). Weights and ages of the two groups were not different. Serum estradiol (E2) levels were significantly elevated in Clomid cycles, but the number of developing follicles was not different between the two brands. The percentages of patients in each group who underwent laparoscopy, oocyte recovery, oocyte fertilization, and embryo transfer were also equivalent. Among patients undergoing laparoscopy, no differences in oocyte recovery, oocyte fertilization, and embryo development were noted. Thus, despite greater elevation of serum E2 levels with Clomid, no difference in stimulation regimen outcome was observed.

Adult↗
PubMed1993

Comparative follicular development in Meishan and Large White gilts during prepubertal periods and its relation to hormonal stimulation.

Changes in follicular development in the left ovary and ovarian response to hormonal injections (hCG or eCG and hCG) in the right ovary were studied in Meishan gilts (n = 36) at 3, 2, and 1 standard deviations (SD) before the mean age of puberty (51, 64, and 77 days of age) and in Large White gilts (n = 24) at 3 and 1 SD (140 and 166 days of age). Left ovaries were removed at the time of hormonal treatments and the remaining ovaries were removed 18 h after hCG was injected alone (hCG) or 72 h after eCG was injected (eCG-hCG). Both nonatretic and atretic (> 4 pyknotic bodies) antral follicles > 0.6 mm in diameter were identified in the left ovaries by histological techniques. LH-sensitive follicles were identified in the right ovaries by counting follicles with dispersed cumulus cells around the oocytes. All large White gilts showed the presence of antral follicles at both 3 and 1 SD before puberty while 6, 7, and 12 Meishan gilts had antral follicles > 0.6 mm at 3, 2, and 1 SD before puberty, respectively. In Large White gilts, the mean number of nonatretic antral follicles > 0.6 mm remained constant at 3 and 1 SD before puberty, while in Meishan gilts, the mean number increased as gilts got older. Mean percentage of class 1 nonatretic follicles (0.6-1.12 mm) of the total number of nonatretic follicles increased significantly with age in Meishan gilts (p < 0.02), while those of class 3 (2.01-3.56 mm) decreased significantly (p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1986

Subtle abnormalities in follicular development and hormonal profile in women with unexplained infertility.

A prospective study of six unselected couples diagnosed as having unexplained infertility was done. In three of six patients, subtle abnormalities in follicular development were detected. In the first case poor follicular growth was observed. There was a premature small rise of luteinizing hormone (LH) with subsequent low levels of estradiol (E2) in the late follicular phase and unusual wide LH peak. This was followed by low progesterone levels in the luteal phase. In the second case follicular growth was abrupted by premature LH surge. This surge was triggered by early rise of E2 level while the follicle was still small in size. In the third case luteinized unruptured follicle syndrome was diagnosed, on ultrasound examination. All of the abnormalities were repetitive.

Adult↗
PubMed1991

Stage of ovarian follicular development associated with the initiation of steroidogenic competence in avian granulosa cells.

Previously described models for avian ovarian steroidogenesis, using mature, 25-40-mm preovulatory follicles as the source of tissues, were based on the assumption that interaction of the granulosa layer, as the predominant source of progesterone, with adjacent theca cells is required for maximal production of C21, C19, and C18 steroids. In the present study, we evaluated the steroidogenic capacity of ovarian cells isolated from less mature, 6-8-mm and 9-12-mm follicles in the chicken ovary (representative of a stage of development 2-3 wk prior to ovulation) to determine at which stage of follicular development granulosa and/or theca cells become steroidogenically competent. Granulosa cells collected from 6-8-mm follicles were found to be virtually incompetent to produce steroids, containing extremely low basal levels of progesterone (12 pg/5 x 10(5) cells) and failing to respond with increased steroid output following a 3-h exposure to ovine LH (oLH; 0.1 and 100 ng/0.5 ml), ovine FSH (oFSH; 100, 500, and 1,000 ng/0.5 ml), 8-bromo-cyclic adenosine monophosphate (8-bromo-cAMP; 0.33 and 3.33 mM) or 25-hydroxycholesterol (250 and 2,500 ng/0.5 ml). However, addition of pregnenolone (20 and 200 ng/0.5 ml) to granulosa incubations resulted in significantly increased progesterone levels. Granulosa cells of 6-8-mm follicles also failed to increase cAMP formation in the presence of oLH (10, 100, and 1,000 ng/0.5 ml) and 3-isobutyl-1-methylxanthine (IBMX; 10 microM), but responded to stimulation with 1,000 ng oFSH (4.4-fold increase over basal) or 10 microM forskolin (32-fold increase over basal) in the presence of IBMX. In contrast, granulosa cells isolated from 9-12-mm follicles and incubated for 3 h in vitro were found to contain basal progesterone levels 200-fold higher than those found in granulosa cells of 6-8-mm follicles. Furthermore, granulosa cells of 9-12-mm follicles markedly increased progesterone production following incubation in the presence of oFSH (100-1,000 ng/0.5 ml), 8-bromo-cAMP (0.33 and 3.33 mM), or 25-hydroxycholesterol (250 and 2,500 ng/0.5 ml). However, these granulosa cells remained unresponsive to oLH (0.1, 10, and 100 ng/0.5 ml), failing to increase cAMP accumulation (in the presence of IBMX) and progesterone output. Theca cells of small yellow follicles were found to produce measurable basal levels of progesterone, androstenedione, and estradiol, and levels of each steroid were significantly increased following a 3-h challenge with oLH, 8-bromo-cAMP, 25-hydroxycholesterol, and pregnenolone.(ABSTRACT TRUNCATED AT 400 WORDS)

Androstenedione↗
PubMed1975

Delayed allatectomy and feeding in Phormia regina (Meig): effects on follicular development.

A delay in feeding a protein meal to the female blow-fly following allatectomy results in inhibition of follicular development in the previtellogenic stage. On the other hand, a protein meal given immediately after the operation permits 55% of the flies that do not deposit yolk in their oocytes fail to do so because of the absence of a corpus allatum hormone necessary for the synthesis of vitellogenin.

Animals↗
PubMed2003

Expression of nitric oxide synthase-3 in porcine oocytes obtained at different follicular development.

The present study was designed to determine the localization of nitric oxide synthase-3 (NOS-3) in porcine follicles during follicular development. A 130-kDa NOS-3 protein was found with greater frequency much in the oocytes than in the cumulus cells, as revealed by Western blotting analysis. The content of NOS-3 in the oocyte was higher in large follicles (> 7-mm diameter) than in small follicles (< 2-mm). The data by Western blotting showed the same pattern as the observations obtained from the immunohistochemical studies, in which the periphery of the oocyte stained strong positive. The inner surface cell layer of granulosa cells and cumulus cells were positive staining, especially in large antral follicles. In the primordial follicles, NOS-3 was restricted to the cytoplasm of oocytes, and no stained product was observed in the nucleus of oocytes or granulosa cells. A significant synthesis of NO by oocytes was observed in the presence of ionomycin, but not in the absence of ionomycin, indicating that oocyte NOS-3 functions in response to transient elevations in the intracellular calcium level. We concluded that NOS-3 is expressed in the oocyte from the primordial follicular stage to antral follicular stage, and that it is functional at least in the antral follicles.

Animals↗
PubMed1989

Abdominal ultrasonography versus transvaginal scanning: accuracy in follicular development evaluation and prediction for oocyte retrieval in stimulated cycles.

Abdominal and vaginal sonographic monitoring were compared in 45 patients undergoing follicular development for the purposes of artificial insemination (N = 22) and in vitro fertilization (IVF; N = 23). Transvaginal sonography recorded a significantly (p less than 0.05) higher number of follicles from cycle day 10 on, compared to the abdominal (sector and linear) approach. Starting on day 8, the size of the dominant follicle was also significantly (p less than 0.05) higher when transvaginal endosonography was used. The number of follicles greater than 15 mm on the day of human chorionic gonadotropin (hCG) administration was correlated with the number of oocytes retrieved in patients undergoing IVF. There was a significant linear correlation when transvaginal (r = 0.86, p less than 0.001) and sector (r = 0.57, p less than 0.05) scans were used.

Female↗
PubMed2025

Celastrol modulates IRS1 expression to alleviate ovarian aging and to enhance follicular development.

Ovarian aging significantly contributes to the decline of the female reproductive system, adversely affecting fertility and endocrine homeostasis. To address the challenges posed by reproductive aging, natural products have shown promising preventive and therapeutic effects. Here, we investigated the beneficial effects of natural compound celastrol on ovarian development and aging, together with its underlying mechanisms. We found that celastrol administration at a concentration of 3&#xa0;mg/kg promoted follicle development in young mice and enhanced porcine oocyte maturation, while regulating granulosa cell proliferation and apoptosis. In 12-month-old mice (equivalent to middle-aged adults), celastrol exhibited similar beneficial effects. Transcriptomic analysis revealed that differentially expressed genes post-celastrol treatment were associated with steroid biosynthesis, estrogen signaling pathways, type 2 diabetes, insulin secretion, meiosis, and apoptosis. Additionally, insulin receptor substrate 1 (IRS1), an adapter protein in insulin signaling, was shown to advance puberty in young mice and to facilitate oocyte maturation. Overexpression of IRS1 in oocytes promoted follicular development and oocyte maturation, resulting in enhanced steroid hormone levels, whereas IRS1 knockdown inhibited these processes. Our findings indicate that celastrol may regulate ovarian development and aging by modulating IRS1 expression and its related pathways, suggesting celastrol as a novel small-molecule compound targeting IRS1, and offering new perspectives for potential therapeutic strategies against reproductive aging and infertility.

Animals↗
PubMed2001

Angiogenesis during follicular development in the primate and its inhibition by treatment with truncated Flt-1-Fc (vascular endothelial growth factor Trap(A40)).

The aims of this study were to 1) quantify changes in angiogenesis during follicular growth in a primate model; 2) investigate the molecular regulation using in situ hybridization of vascular endothelial growth factor (VEGF), its receptor, Flt-1, the angiopoietins (Ang-1 and Ang-2), and their receptor, Tie-2; 3) elucidate the role of VEGF in follicular angiogenesis by blocking its action by treatment with a soluble truncated form of the Flt-1 receptor, (VEGF Trap(A40)). Changes in angiogenesis were quantified using bromodeoxyuridine to obtain a proliferation index, and CD31 immunocytochemistry to visualize endothelial cell area. Percentage of proliferating endothelial cells was calculated by double labeling for bromodeoxyuridine and CD31. Vascularization was first observed in follicles containing four granulosa cell layers. A significant increase in proliferation in the thecal layer was observed from the early to late secondary stage, and dual staining showed that 25% of proliferating cells were of endothelial cell origin. VEGF messenger RNA (mRNA) was expressed in granulosa cells with an increase of grain density from late secondary to tertiary follicles. Ang-1 was weakly expressed in the theca of tertiary follicles. Ang-2 mRNA was not detected in any follicles. The mRNA for the Flt-1 and Tie-2 receptors was localized in endothelial cells of the theca. Unexpectedly, Tie-2 mRNA was also found in granulosa cells of early follicular stages and its translation was confirmed by immunocytochemistry. VEGF trap treatment for 3 days resulted in an 87% decrease of proliferation in the theca of secondary and tertiary follicles, a reduction in endothelial cell area and a marked decline in Flt-1 mRNA expression. Granulosa cell proliferation also decreased. These results show that onset and establishment of the follicle vasculature takes place early during follicular development. The ability of VEGF trap treatment to severely restrict follicular angiogenesis establishes that VEGF is the major regulator of this process in the primate ovary.

Angiotensin II↗