10. REGULATORY MECHANISM OF OVARIAN FUNCTION

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10. REGULATORY MECHANISM OF OVARIAN FUNCTION Ovarian functin is regulated thrugh the hypthalamic hypphyseal axis and, depending n the type f animal, envirnmental inputs r behaviural activities

FOLLICULAR DEVELOPMENT During the reprductive life f the animals, the vary cntains a large number f fllicles at different stages f develpment.

1 10. REGULATORY MECHANISM OF OVARIAN FUNCTION Ovarian functin is regulated thrugh the hypthalamic hypphyseal axis and, depending n the type f animal, envirnmental inputs r behaviural activities further regulate the functin f the higher centers (Fig. 10-1). FOLLICULAR DEVELOPMENT During the reprductive life f the animals, the vary cntains a large number f fllicles at different stages f develpment. The fllicles lcated in the crtex f the vary are less develped and grw slwer than thse mre centrally lcated. Fllicular develpment is a cntinuus and dynamic prcess, whereby new fllicles are cnstantly grwing hwever, the majrity regress withut ever reaching the vulatry stage (Fig. 10-2). The prprtin f regressing (atretic) fllicles increases with grwth. Atresia is negligible in fllicles with less than tw layers f supprting cells, but very significant in thse with fur r mre layers. Fllicles grw t the preantral stage under a cntrlling mechanism that is nt well understd. With increasing size, fllicles becme mre dependent n gnadtrpins fr grwth. After frmatin f the antrum the grwing fllicle requires stimulatin by FSH fr further grwth. Nrmally the pst-vulatry FSH rise is respnsible fr stimulating the fllwing crp. FSH nt nly cntributes t the frmatin f the antral fllicle, but it is als respnsible fr the frmatin f mre Figure General regulatry mechanism fr varian functin Figure Detailed pathway thrugh which fllicles first prduce estrgen during flliculgenesis and then, clse t vulatin, switches t prgesterne prductin Figure Fllicles are cntinuusly develping and underging atresia, nly a few fully reach vulatry stage FSH receptrs in the granulsa cells, and, the increase in their armatase activity. These granulsa cells will be in charge f estrgen synthesis, using teststerne as a substrate (Fig. 10-3). There are several distinct ppulatins f cells in the fllicle. The mst imprtant are the theca and granulsa V BS 122 Physilgy II 81 Class f 2016

cells. Theca cells are lcated in the periphery f the fllicle and are divided int tw sub ppulatins: the theca externa and the theca interna layer.

Granulsa cells are lcated inside the theca cells, thrugh the basal membrane f the fllicle int the granulsa cells.

The increase in LH and FSH receptrs in theca and granulsa cells respectively, augments the teststerne and estrgen prducing capabilities f the fllicle.

2 cells. Theca cells are lcated in the periphery f the fllicle and are divided int tw sub ppulatins: the theca externa and the theca interna layer. The latter is lcated clser t the basal membrane and plays a fundamental rle in sterid synthesis. Granulsa cells are lcated inside the theca cells, thrugh the basal membrane f the fllicle int the granulsa cells. LH nt nly stimulates teststerne synthesis in theca cells, but it als stimulates frmatin f a large number f LH receptrs in these cells. The increase in LH and FSH receptrs in theca and granulsa cells respectively, augments the teststerne and estrgen prducing capabilities f the fllicle. Estrgens, in cnjunctin with FSH further stimulate the frmatin f LH receptrs in granulsa cells, frm an average f 300 at the beginning f flliculgenesis t a maximum f 120,000 per cell prir t vulatin. Furthermre, circulating estrgens stimulate the gnadtrpes in the pituitary in such a way that their sensitivity t GnRH is increased. At the same time, estrgens stimulate the vulatry centre f the hypthalamus thrugh psitive feedback and, eventually, make it discharge a large amunt f GnRH. This in turn Figure Structure and cmpnents f the Graafian fllicle Figure Bichemical mechanism leading t the cnversin f chlesterl int teststerne, in theca cells and teststerne t estrgens in the granulsa cells Figure Histlgical preparatin f a Graafian fllicle the basal membrane and, in cnjunctin with the theca interna cells, are essential fr sterid prductin (Figs. 10-3, 10-4, 10-5). As the fllicle develps, the type and cncentratins f sterids prduced vary significantly. Teststerne, usually cnverted frm circulatry chlesterl, is prduced by theca cells in the antral fllicle under the influence f LH. Teststerne in these events serves as a precursr fr estrgen which diffuses ut f stimulates the already sensitized pituitary t prduce a large release f LH. This is the prevulatry surge f LH (Figs. 10-3, 10-6). As the fllicles grw, there is prductin f a variety f ther hrmnes with paracrine r autcrine mdulatry rles in fllicular cell differentiatin. Amng these, we can find the Immunreactive Grwth Factr I (IGF-I), Epidermal Grwth Factr (EGF), and Fibrblast Grwth Factr (FGF). All f these influence stridgenesis by granulsa cells. V BS 122 Physilgy II 82 Class f 2016

3 SEASONAL BREEDERS In seasnal breeders the length f the day measured in hurs f light, regulates the secretin f GnRH. The regulatin is indirectly made thrugh mdificatins in the amunt f melatnin prduced by the pineal gland. In shrt-day-breeders, melatnin supprts secretin f GnRH by the tnic centre f the hypthalamus, while in lng-daybreeders it inhibits GnRH. Secretin f melatnin is regulated by the amunt f light that impinges in the retina and it is transprted thrugh the retinal nerves. Light inhibits the prductin f melatnin; therefre, shrt-daybreeders breed in the fall when the days are getting shrter, the reductin in hurs f day light triggers an increase in its prductin. This results in the stimulatin f GnRH prductin with the cnsequent elevatin in gnadtrpin prductin, fllicular activity and eventual vulatin (Fig. 10-7). Figure Sequence f events leading t the failure f vulatin and the start f a perid f anestrus in shrt day breeders when the days are getting lnger First f all, LH stimulates an increase in bld flw t the Graafian fllicle (Fig ). Prevulatry events Figure Sequence f events leading t vulatin in shrt day breeders when the days are getting shrter During the spring, when the days are getting lnger, the increasing hurs f light inhibit the prductin f melatnin t the pint that there is nt enugh supprt fr GnRH and, as a cnsequence, there is nt sufficient prductin f gnadtrpins t supprt fllicular develpment. Ultimately, the fllicles fail t vulate and the animal enters in seasnal anestrus (Fig. 10-8). PREOVULATORY LH SURGE AND OVULATION The effects f the prevulatry surge f LH in the mature fllicle are multiple and simultaneus (Fig. 10-9). Meisis resumes Fllicular rupture PG prductin Multivesicular bdies Relaxin, xytcin Granulsa starts P 4 prductin Figure Main events taking place prir t vulatin At the same time, r immediately after the LH surge, the cumulus Ophrus f the Graafian fllicle is dissciated at the base f the fllicle, and meisis resumes in the vum (Fig ). Meisis is inhibited by a peptide called cyte meisis inhibitr (OMI) which is prduced within the fllicle. OMI appears t be prduced nly while the cumulus is intact. The ther cnsequence f the LH surge is an increase and further shift in sterid prductin by granulsa cells frm estrgens t prgesterne. V BS 122 Physilgy II 83 Class f 2016

These cells develp the ability t synthesize prgesterne frm either pregnenlne, a derivative f chlesterl, r frm circulatry r in situ prduced chlesterl, as luteinizatin starts t take place even befre

Effects f LH surge Increases fllicular bld flw Cumulus separatin Meisis resume Stigma frmatin Increase P 4, decrease E 2 = edema Increase theca cllagenase Granulsa prduces PGs Ovulatin PGE 2

4 These cells develp the ability t synthesize prgesterne frm either pregnenlne, a derivative f chlesterl, r frm circulatry r in situ prduced chlesterl, as luteinizatin starts t take place even befre vulatin. Effects f LH surge Increases fllicular bld flw Cumulus separatin Meisis resume Stigma frmatin Increase P 4, decrease E 2 = edema Increase theca cllagenase Granulsa prduces PGs Ovulatin PGE 2 stimulates Plasmingen activatr PGF 2α stimulates Rupture f lyssmes Ovarian Cntractins Fllicular cntractins As the fllicle is getting ready t vulate, the armatase activity in granulsa cells decreases; therefre, n further cnversin f andrgen t estrgens takes place and; cnsequently, bth, fllicular as well as circulatry levels f estrgen decrease (Fig ). Fllicular edema and the initiatin f stigma frmatin are the immediate cnsequence f these changes. Prgesterne is respnsible fr the stimulatin f the theca cllagenase, an enzyme which stimulates the dissciatin f cells in the area f the stigma. The last recgnized effect f the LH surge is the prductin f prstaglandins by granulsa cells. Tw types f prstaglandins are knwn t have sme rle in the prcess f vulatin. PGE 2, stimulates the plasmingen activatr, an enzyme whichactivates the enzyme plasmin disslves cnnective tissue in the area f the stigma. PGF 2α stimulates the rupture f lyssmes in the apex epithelium facilitating further stigma frmatin; it als stimulates varian cntractins leading t fllicle rupture and; finally stimulates fllicle cntractin fr actual cyte expulsin (Fig ). Figure Specific effects f the LH surge Figure Prcess f fllicule rupture and vulatin LUTEINIZATION Figure Events taking place in the fllicle prir t vulatin, as a cnsequence f the LH surge After the vum has been released and the fllicular fluid expelled, the fllicular cavity is filled with bld t frm the CH (Fig ). V BS 122 Physilgy II 84 Class f 2016

Figure 10-13. Fllwing vulatin the fllicle is filled with bld, granulsa, and theca cells in a structure knwn as the crpus haemrragicum Figure 10-15.

The bld serves as nutrients fr the initial grwth and multiplicatin f the granulsa cells.

The granulsa cells becme luteinized, which means that they start t prduce P 4 instead f Es, under the influence f the lw LH prduced in respnse t GnRH frm the tnic

Ovary with several CL and sme visible develping fllicles Figure 10-14.

reductin in the cncentratin f circulating prgesterne. Under the influence f prgesterne, the uterus des nt carry ut any cntractile activity.

5 Figure Fllwing vulatin the fllicle is filled with bld, granulsa, and theca cells in a structure knwn as the crpus haemrragicum Figure Ovary with several recently vulated fllicles This is a mixture f granulsa cells, theca cells, and bld. The bld serves as nutrients fr the initial grwth and multiplicatin f the granulsa cells. Frm this pint n, the basal membrane f the fllicular cavity is disrupted and the newly frmed rgan becmes highly vascularized. The granulsa cells becme luteinized, which means that they start t prduce P 4 instead f Es, under the influence f the lw LH prduced in respnse t GnRH frm the tnic centre. The CH is then cnverted t a CL. Prlactin frm lacttrpes in the pituitary further supprts CL functins (Figs , 10-15, 10-16). Figure Ovary with several CL and sme visible develping fllicles Figure Frmatin f the crpus luteum CL REGRESSION (LUTEOLYSIS) If fertilizatin des nt take place, several events lead t the eventual destructin f the CL with the cnsequent reductin in the cncentratin f circulating prgesterne. Under the influence f prgesterne, the uterus des nt carry ut any cntractile activity. It seems that in the early stages f the luteal phase, prgesterne als prevents the synthesis f PGF 2α by the uterus. Apparently, this is mediated by blcking the ability f the uterus t develp receptrs fr xytcin but later in the luteal phase this is reversed and, there is a direct relatinship between the number f xytcin receptrs in the endmetrium and its ability t prduce PGF 2α. In the CL, large luteal cells have the ability t synthesize, stre and secrete xytcin. The secretin is dne in a pulsatile V BS 122 Physilgy II 85 Class f 2016

cells. The pulses f xytcin are mirrred with the pulses f PGF 2α, secreted by the endmetrium. Fllwing that, there seems t be a psitive feedback between luteal xytcin and endmetrial PGF 2α.

6 manner. Twards the end f the luteal phase, the frequency and amplitude f the pulses f xytcin is such that the PGF 2α released is sufficient enugh t cause inhibitin f prgesterne synthesis and apptsis f luteal cells. The pulses f xytcin are mirrred with the pulses f PGF 2α, secreted by the endmetrium. Fllwing that, there seems t be a psitive feedback between luteal xytcin and endmetrial PGF 2α. T reach the vary and induce the regressin f the CL, the PGF 2α being drained frm the uterus, has t crss thrugh the endthelial cell f the bld vessels, frm the uterine vein int the varian artery. Using this cunter current mechanism f transfer, PGF 2α retains its bilgical activity, which therwise wuld have been lst at the first passage thrugh the lungs. The regressing CL becmes a crpus albicans (CA) which is n lnger a sterid secreting tissue (Fig ). Befre the uterus attains the capability t prduce PG, it has t be primed by P 4 fr at least fur days in the cw. After this, a new crp f fllicles develps fr vulatin in the next cycle. If fertilizatin takes place, the PGF 2α prduced in the uterus des nt reach the vary, as it is redirected t the INDUCED OVULATORS The queen and the rabbit are plyestrus induced vulatrs. This means that they cycle thrughut the year and that vulatin, and frmatin f the CL des nt take place unless cpulatin ccurs. The length f the cycle and ther pssible events depends n several factrs. The mre relevant factrs are mating, vulatin, cnceptin, pregnancy t cmpletin, and whether r nt lactatin takes place. The typical cycle length, when n mating takes place, is usually 21 days. If breeding takes place but cnceptin fails, the average cycle takes abut 6 weeks (Fig ). The estrus perid varies with the seasn in such a way that in spring, a queen may manifest estrus fr 5 t 14 Figure Pssible sequence f events taking place in a queen based n several determining factrs Figure Mechanism t trigger the regressin f the crpus luteum if the animal des nt get pregnant lumen f the uterus and the CL des nt regress. After this the CL functin is enhanced t prduce mre P 4. This structure becmes the crpus luteum verum r the CL f pregnancy which is respnsible fr the prductin f prgesterne that will serve t maintain pregnancy in its earlier stages r thrughut pregnancy, depending n the species. days per cycle. In ther seasns, a 1 t 6 day estrus perid is mre typical. When citus and vulatin take place, the average cycle is less than 6 days while in nnvulatry cycles, the estrus perid lasts abut 8 days (Fig ). During the nn-breeding cycle, the fllicles develp nrmally frm the cnstantly develping fllicle pl, but in the absence f an vulatry surge f LH, they fail t vulate and regress. A new crp f fllicles starts t develp significantly in rder t establish the next estrus cycle. Since vulatin des nt take place, there is n frmatin f a CL and levels f prgesterne remain undetectable. If breeding takes place, the physical stimulatin f the vagina during cpulatin sends signals thrugh the nervus system t the vulatry centre in the V BS 122 Physilgy II 86 Class f 2016

hypthalamus. In respnse t this input, cells in the hypthalamus release a large discharge f GnRH, which triggers the LH vulatry surge within 90 mins.

7 hypthalamus. In respnse t this input, cells in the hypthalamus release a large discharge f GnRH, which triggers the LH vulatry surge within 90 mins. This results in vulatin between 24 and 50 hurs pst citum. As a result f the vulatry prcess, the fllicles develp int a functinal CL which prduces large amunts f prgesterne (Fig ). Prestrus Prestrus is the perid characterized by early signs, such If cnceptin des nt take place, the animal will nrmally manifest pseudpregnancy fr abut 35 days. After this, cyclical activity resumes. If fertilizatin takes place and pregnancy is maintained, the prductin f prgesterne Figure Endcrine prfiles f a bitch during the cycle Figure Relative hrmnal cncentratins and prfiles f a queen during a cycle in which breeding tk place as ppsed t ne when cpulatin did nt take place will peak at abut 22 days and thereafter decline twards parturitin n the 63 rd day. MONOESTRUS BREEDERS The fx, wlf and the bitch belng t the grup f animals designated as mnestrus breeders. This implies that they have apprximately ne breeding seasn in the year and that in each breeding seasn they manifest estrus and can ptentially vulate multiple va at ne time. As pinted ut earlier, the bitch cycles mre ften than nce a year, averaging three cycles in tw years. The entire estrus cycle is much lnger in mnestrus breeders than in fdprducing animals and sme f the behaviural phases f the estrus cycle verlap with the physilgical prcesses characteristic f a different phase (Fig ). as vulva edema and bld-tinged vaginal secretins, which finish when the bitch accepts the male. During this perid, the female is restless, excitable, and disbedient and manifests frequent munting behaviur. Plydipsia and plyuria are als evident. The vaginal secretins prduce a phermne, methyl-p-hydrxybenzate which attracts males. At this time she des nt accept munting and can be aggressive twards males. On average this phase lasts abut 9 days. Estrus Estrus is described as the perid f male acceptance which als lasts abut 9 days. Hwever, lnger perids f male receptivity are nt uncmmn. The first estrus fllwing puberty is nrmally lnger than the subsequent nes. Ovulatin is highly variable. It may take place between 2 days befre, t 7 days after the initiatin f estrus, the mst cmmn perid being days 1 t 3 after initiatin f estrus. Mst fllicles are vulated in a perid f abut 24 hurs. Endcrinlgically, the vary may be frming the CL and prducing prgesterne while the female still accepts the male. V BS 122 Physilgy II 87 Class f 2016

8 Metestrus If cnceptin des nt take place, metestrus lasts abut 75 days and is defined as the perid between the end f male acceptance and the regressin f the CL. Anestrus Anestrus is a perid f varian inactivity during which there is neither vaginal discharge nr behaviural interest in the male. It lasts apprximately 125 days. V BS 122 Physilgy II 88 Class f 2016

10.REGULATORY MECHANISM OF OVARIAN FUNCTION

10.REGULATORY MECHANISM OF OVARIAN FUNCTION Ovarian functin is regulated thrugh the hypthalamic hypphyseal axis and, depending n the type f animal, envirnmental inputs r behaviural activities further regulate