Ovarian follicular development in cattle

Transcription

1 Ovarian follicular development in cattle John P Kastelic Professor of Theriogenology Head, Department of Production Animal Health University of Calgary Calgary, Alberta, Canada

2 Overview Prenatal development Postnatal development (including puberty) Follicular waves Selection of dominant follicle 2- vs 3-wave cycles

3 Prenatal follicular growth Day of gestation! 40 primordial germ cell migration 60 intense mitotic division 80 cell cords fragment, meiosis begins (oocyte arrested in Prophase I) 150 mitosis ceases

4 Oogenesis

5 Stages of ovarian follicular development (Fair, 2003)

6 Postnatal follicular development Waves present at 2 wk of age Each wave is preceded by rise in FSH Interval between waves increases with time Diameter of largest follicle increases to puberty

7 Dominant follicles in prepubertal calves 14 Follicle diameter (mm) weeks 42 weeks 36 weeks 34 weeks 24 weeks 14 weeks 8 weeks 2 weeks Days after wave emergence

8 Maximum follicle diameter and number of follicles >3 mm (2-60 wk) Rawlings et al, 2003

9 FSH and LH in postnatal development Early rise (6-24 wk) in LH (due to increased pulse amplitude) and FSH Subsequent decline d before first ovulation, increased LH pulse frequency, but FSH ~ constant Ovulation without estrus, short cycle Next cycle is normal length, fertility increases to 3 rd ovulation

10 Gonadotropin concentrations and LH pulsatility Rawlings et al

11 Control of gonadotropins Not well understood Initial suppression may be estrogen-dependent opiodergic mechanism d before first ovulation, decreasing sensitivity of LH to suppression Increasing estradiol causes LH surge

12 Two stages of antral follicle development Slow phase: >30 d from antrum formation to small follicle (3-5 mm) Fast phase: 5-10 d, includes wave emergence, growth, selection, dominance (ovulation or regression of dominant follicle)

13 Follicle development takes ~ 90 d, perhaps during negative energy balance (NEB) 20 Bovine Ovulatory Follicle diameter (mm) Primordial Primary Secondary Tertiary Days Redrawn from Fair 2003

14 Follicular waves Follicles develop in waves (7-11 follicles, 4 mm in diameter present at wave emergence) Emergence of wave preceded by increase in FSH

15 2-wave interovulatory intervals (n=11) FSH concentration (ng/ml) A OV A Dominant follicle Wave 1 Wave 2 FSH C B OV 3-wave interovulatory intervals (n=5) Dominant follicle FSH Wave 1 Wave 2 Wave 3 B C D Diameter (mm) of dominant follicle FSH and waves FSH elicits wave FSH decline associated with selection Effect is systemic OV Number of days from ovulation OV

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17 FSH Essential for stimulation of follicle growth Wave emergence (4-5 mm), same time as peak FSH Suppression of FSH suppresses follicle growth Exogenous FSH stimulates follicle growth and can delay follicle selection

18 Exogenous bfsh (Mihm et al., 1997)

19 Effects of dominance Antral follicles in slow growth phase unable to enter fast growth phase Administration of FSH does not consistently hasten emergence of next wave Loss of dominance (e.g. follicle removal)! increased FSH and emergence of new wave

20 Declining FSH Declining FSH due to effects of many follicles Only dominant follicle continues to grow Subordinate follicles have decreased E 2 and increased lower molecular weight IGF binding proteins (IGFBP) Only dominant follicle can continue to grow

21 Estradiol and inhibin FSH stimulates E 2 and inhibin-a (higher in DF) E 2 and inhibin act alone and together to suppress FSH Estradiol increases expression of genes for aromatase, 3-beta-HSD, receptors for FSH and LH in granulosa cells E 2 upregulates itself by increasing androgen synthesis

22 IGF system IGF-1, IGF-2, receptors, IGFBP and IGFBP proteases Proteases degrade IGFBP, liberate IGF Dominant follicle has lower IGFBP and higher IGF-1 Pregnancy-associated-plasma-protein-A (PAPP-A; IGFBP protease), induced by FSH, is higher in dominant follicle

23 IGF-1 and E 2 Increased IGF-1 and FSH increase E 2 synthesis, suppressing plasma FSH and preventing subordinate follicles from acquiring PAPP-A IGF-1 and E 2 stimulate each other and increase follicle responsiveness to gonadotropins

24 Effects of LH LH apparently contributes to E 2 and IGF-1 Essential for stimulation of androgen production by thecal cells LH controls post-selection estrogen production and lifespan of dominant follicle Atresia occurs if <1 LH pulse/2 h Persistent follicles result from increased LH pulse frequency (e.g. due to low P4)

25 Model for selection Ginther et al.

26 Overview of selection Selection is a process of suppression Any follicle in a wave is a potential DF Competitive and progressive Gradient of suppression (several days) What dictates hierarchy? Chance size difference? Resources (e.g. number of granulosa cells or gonadotropin receptors) Proximity to blood vessels? Utilization of FSH and LH, E 2, inhibin, IGF, IGFBP

27 Co-dominance >1 dominant follicle consider defect in selection Double ovulations usually due to co-dominance (occasionally different waves) Incidence of double ovulations 20 vs 7% in dairy cows with high vs low milk production High rate of steroid catabolism decreases E 2, delays suppression of FSH

28 Final growth and ovulation Dominant follicles grow after selection In absence of LH surge, dominant follicle regresses and new wave emerges If there is an LH surge, final maturation, and ovulation LH surge causes meiosis to resume; arrests at metaphase of meiosis II

29 Two versus three waves Lactating Holsteins more likely to have 2 waves Beef and dairy heifers have either 2 or 3 waves Dairy and beef cows with 3 waves had higher pregnancy rates; shorter interval for development of ovulatory follicle and/or delayed regression of CL (longer interval for maternal recognition of pregnancy)

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31 Wave pattern 2-Wave 3-Wave Day of emergence of Wave Wave Wave ! Ovulation to CL regression (d) 16 19! Interovulatory interval (d) 20 23! Day 0 = ovulation Ginther et al., 1989

32 No. follicles per wave variable between animals (Burns et al, 2005, Biol Reprod) repeatable within individuals (Burns et al, 2005, Biol Reprod) indicative of ovarian reserve (Ireland et al, 2008, Biol Reprod) Proportion of cows (%) 7% 5% 4% 2% Frequency distribution of number of follicles 3 mm on a random day of cycle in dairy cows (n = 416) 0% Number of follicles

33 Hypothesis Maternal nutritional restriction during the first 110 d of pregnancy decreases number of ovarian follicles during postnatal life

34 Materials and methods 60 crossbred beef heifers (fed above or below maintenance for first 110 d of gestation) Control 1.2M (n=25) Restricted 0.6M (n=35)

35 Results (birth)! Female calves: 10 Restricted, 13 Control! Not different at birth: Gestation length Placenta weight, number of cotyledons Any measure Body of weight calf size Weight (C 40 ± 1kg, R 39 ± 2kg) 280! Weight (kg) Control (n 13) Restricted (n 10) Age (wk)

36 Maternal undernutrition reduced no. follicles ( 3 mm) 30 * * * Mean no. follcles Control Restricted Age (wk)

37 No. follicles in waves Animal with high numbers of follicles have: Lower FSH and LH concentrations Similar E2 concentrations Higher P4 concentrations! Animals with low numbers of follicles may have poorer fertility than animals with high numbers.

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39 Conclusion Maternal nutritional restriction had no influence on birth weight, growth rate or follicle wave dynamics, but caused long-term negative effects on numbers of ovarian follicles and perhaps fertility

40 Peak milk yield and maximum NEB during conception and fetal ovarian development Conception Fetal ovarian development (Risco & Melendez, 2002)

41 Proposed hypothesis: Fetal under-nutrition & reduced fertility Maternal nutrition/nutrient partitioning Follicle numbers Luteal P4? Effects on fetal development Adult fertility Pituitary function? Lifetime development

42 Evidence for association between antral follicle count (AFC) and fertility Cows with a high AFC had higher pregnancy rates, shorter calving to conception intervals and fewer services during the breeding season compared to cows with a low AFC (Mossa et al. 2012). Higher pregnancy rates in beef heifers with a high versus lower AFC (Cushman et al. 2009). Humans with low numbers of follicles have lower fertility (Baerwald et al. 2003).

43 Effect of follicle numbers on fertility in dairy cattle Mossa et al. 2012

44 Estrus synchronization with PGF Response depends on: 1. Stage of development of the CL 2. Stage of development of the DF Growing - early static phase - ovulate in 3 to 4 d Late static - regressing phase - ovulate in 5 to 7 d 44

45 50 Estrus after PGF (d) 40 Animals (%) Days after PGF Seguin, 1987

46 2-waves 3-waves

47 Increasing pregnancy rate in GnRH-based protocols Detect estrus for those showing estrus early Presynch - 2 doses PGF - Progestin presynchronization - G6G or Double Ovsynch Incorporate a progestin device (especially in heifers and anestrous cows) 47

48 PRESYNCH-OVSYNCH 14/11 d Sun Mon Tues Wed Thurs Fri Sat PGF PGF GnRH PGF GnRH FTAI

49 Pregnancy rate (%) Florida Kansas Ovsynch Presynch + Ovsynch Moreira et al., 2002; El-Zarkouny et al., 2004

50 DOUBLE OVSYNCH Sun Mon Tues Wed Thurs Fri Sat GnRH PGF GnRH GnRH PGF GnRH FTAI

51 Double Ovsynch vs Presynch/Ovsynch DO PRE/OVS n = 337 Souza et al., 2008

52 Cows without a CL at first GnRH Double Ovsynch Total 6.3% (23/366) 1 Lactation 2 Lactation 3.0 % (5/168) 8.8% (18/204)! Presynch 24.7% (92/373) 16.8 % (29/173) 31.5 % (63/200)! P - value! <0.01! <0.01! <