Neural participation in ovarian control

TINS- October 1978

87

Neural participation in ovarian control Ida Gerendai and B. Halbsz i

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In this article, Ida Gerendai and B~ia Halas: describe the eh'gant studies from which they have derired the eridence for the existence and pathways of efferent and afferent neural connections between the o rary and hypothalamus, and the role which the: e pathway.~ have to play in gonadal-hypothalamic feedback. The model which th(9" ha~,, use,l concert~s the effects of compensatory ovarian h.rpertrophy following hemiorariectomy. For the neuroendocrinologist, the inroh,ement of possible neural path~tays in areas pre~io~.dv considered to be only under a humoral c~ntrol, ha.~ many far-rea( hing implicat~on,~, and ma.v prorith' explanations for a number of preriously im,xplicable obser~'ations.

The occurrence of compensatory ovarian hypertrophy (COIl) in which the remaining ovary increases in weight following the removal of one ovary has been acknowledged for a long time ~. This phenomenon has been widely accepted to be based on a pure negative feedback control mechanism, wherein the hemiovariectomy-induced decreased sex-steroid level is followed by increased pituitary gonadotrophin (mainly FSH) secretion which causes the increase in nu.'nber of follicles, hyperovulation, and weight increase of the remaining gonad. However, not all of the information available is consistent with this explanation. For example, in a recent report t° evidence has been presented to indicate that a non-steroidal material may be involved in a humoral feedback: after unilateral ovariectomy, follicle-stimulating hormone (FSH) levels increased over the period 4-28 h after operation, whereas progesterone levels dropped within 2 h. Plasma luteinizing hormone (LH) and 17~.oestradiol levels were generally unaffected. Administration of progesterone did not interfere with the increase in FSH levels, whereas, after injection of bovine follicular fluid, FSI-I levels did not rise after the removal of one ovary. The authors concluded, therefore, that increased FSH levels after unilateral ovariectomy are induced by transient decreases in peripheral levels of a non-steroidal 'inhibin-like" ovarian factor of a type present in bovine follicular fluid. In our working hypothesis, we postulate that, apart from the hormonally controlled hypothalamo-pituitary-gonadal axis, a gonadal-hypothalamic neural axis might exist, too, and both systems would be required for the normal development of compensatory ovarian hypertrophy. To test this idea we investigated the role of the ovarian nerves, the significance of

the spinal cord, and the significance of the hypothalamus in the development of ovarian growth follo~ ing hemiovariectomy. The ov~ian nerves As surgical denervatio~i ,~.fthe rat ovary is practically impossible, ~,:-.-brought about local pharmacological degeneration of the ovarian adrenergic nerves ~.ith 6-hydroxydopamine (6-OHDA) by means of a technique developed by us': the ovary is placed in situ into a small capsule containing 6-OHDA mixed with a neutral cream. This treatment prevented the usual weight increase of the remaining ovary ! week after hemigonadectom~,. On the other hand. in rats ~,ith t~o o~aries. local treatment of one of the gonads ~ith 6-OHDA resulted in a ~ignificant ~eight increase of the other ovar.,, ~. These observations indicate thai the ovarian nerves destroyed b~ 6-OHDA are required for the development of the compensatory ovarian hypertrophy. The) suggest further that these nerves contain both afferem (leading towards the CNS) and efferent elements in:olved in the mechanism mentioned. Iv other words. these findings are consistent with the vie~ that there might be a peripheral neural signal by which the remaining ovary is 'informed" of the absence of the other, and that neural elements of the remaining ovary might also participate in the conveyance of the stimulus to the ovarian cells, leading to the hypertrophy of the organ. Such ~n ass,Jmpti~n is derked from the findings obtained in hypophysectomized and u,~ilaterall) ovariectomized rats. We found that there is a less severe ovarian atrophy 2 ~eeks following" hypophysectomy if one of ~he ovaries is removed together ~ith the pituitary, as compared with animals having two ovaries. This suggests that the whole mechanism responsible for the dcvc!..~..,lent of corn-

pensatory o,,arian h.~pertroph2, operates, at iea,t in part. exen in the absence of the pituitau,. But of course s~ithout gonadotrophins neither normal osarian functiou nor compensator.~ osarian hypertrophy can

occur.

The data obtained from local application of 6-OHDA on the o~ar.~ ma,, be interpreted as an indication that the chemical character of the neural elements in,,ol~ed in the mechanism discussed are at least partl) adrenergic in nature. The spinal cord fhe obser~ation.~ obtaincd in animals with hemitran~c~.ta~n of the ~pmal cord lend further support to the a.,,,,umpt~on ~f the exl~tence of a gon,ldal-h.~poIhalamic neural path~a~. ~,t,e found th,lt hemttran~ection of the ~,~'lnal cord at the tenth thoracic ~ertebral (T-10) !e~cl contralatera! 1o ,he ~ide of unilateral o~ariectom,, prc~ented tt,¢ compens,ttor.~ o~arian h~pertroph.',; ho ,c~er. ~he,a the ~pinai cord lesion was on the same s~de as that on which the unilater~d o~ ~riectom~ had been performed° there ~as no interference ~ith the h.~pertroph~ of the remaining ovar). These data suggest that the major part of the postulated neural path~;L~s arising and terminating in the o~aries are located in the side of the spinal cord contralateral to that of the remo,,ed o,.ar,., at least al the level of T-10. The h.vpothalamus B.,. means of hght- and electrom microscopic autoradiograp'ty ~e investigated the rate of tritiated Icucine incorporation into the arcuate nucleus of the two sides after unilateral ovariectomy °. Left- or right-side hemigonadectom~ induced significantly higher relative radioacti~,e concentration in the contralateral arcuate nucleus to the side of o,,ariectomy .,~ El~.~erlNorth-Holland Biom~:d,Tal P~ess 1978

881 th;:n in the ipsilateral side. No difference was detected in the concentration of the ne'vly-synthesized proteins between the lef~- and the right-side of the arcuate nuclei of intact females, in this !atter group the rate of labelled amino acid incorporation into the arcuate neurones of the two sides was between the two exlremes given by the arcuate neurbnes or/either side of the hypothalamus observed in the hemiovariectomized animals. As unilateral effects can develop only on neural pathways, these findings may he interpreted as further indirect evidence for the existence of a neural connection be-ween the hypothalamic arcuate nucleus and the ovat3". Lutehttzing hormone-releasing hormone (LHRH)

Several authors have observed increased pi.tuitary gonadotrophin (primarily FSH) secretion following unilateral ovariecto~7. it may be assumed that this is the consequence of increased synthesis and/or release of h:'pothalamic LHRH content of the mediob~sal hypothalamus tMBH) of the two halves in unilaterally ovariectomized rats. Two weeks following uni~ lateral ovariectomy there is significantl) more LHRH in that half of the MBH ipsilateral Io the removed ovary than it, the contr~i~teral sideL In accordance with the data ~n the literature, bilateral ovariectomy results in reduced L H R H content ~n both h~lv~s of the MBH. The c(,.tralateral difference in the

hypothalamic LHRH content after unilateral ovariectomy strongly suggests that a neural input from the ovary reaches the hypothalamic LHRH structures, it seems reasonable to assume that a neurallymediated stimulus induced by unilateral ovariectomy might increase the activity of the LHRH-synthesizing neurones: in other words, the LHRH-producing neurones can be considered te be the site where the neural input is transformed into a hormonal event. Our-~bservations, however, do not give any indication whether the postulated neural efferents to the ovary arise from the MBH or from other brain structures. Hypothalamie deafferentation Unilateral interruption of all neural connections to and from the MBH prevents the compensatory ovarian hypertrophy following the removal of one ovary when the two operations were carried out on the same side. In contrast, unilateral isolation of the MBH from the rest of the brain is without effect if it is on the opposite

T I N S - October 1978

be a non-steroidal "inhibin-like" ovarian factoras mentioned in the introduction. An interplay between FSH and the suspected afferent pathway at the ovarian level ovaries. The prevention o f compensatory ovarian might be assumed as well. An increasing amount of evidence indihypertrophy by unilateral deafferentation of the MBH yields further experimental cates that, as in the ovary, a similar neural evidence for the participation of an mechanism might be involved in the ovarian-hypothalamic neural component development of compensatory adrenal in the mechanism discussed, in addition, hypertrophys. It is tempting to speculate that since at the hypothalamic level the pathways critical for the occurrence of the com- compensatory organ growth develops not pensatory ovarian hypertrophy may be only in the paired endocrine glands, but assumed to be situated mainly on the came also in the liver, kidney, and salivary gland t, the compensatory growth of each side as the removed ovary. of these organs, at least in part, may be Gt,K t ~ conclusions mediated by a similar neural mechanism. There is considerable evidence suggesting Salivary gland hypertrophy can be prethat, besides the hormonal events, a pure ;c:lted by surgical denervation of the neural component is also involved in the remaining gland'. Kidney compensatory development of compensatory ovarian hypertrophy develops also in hypophysechypertrophy following hemiovariectomy. tomized animals'. However, our attempts This postulated neural mechan;sm in- to block the compensatory kidney growth cludes the ovarian adrenergic elements, by hemitranu'ction of the spinal cord or an ascending and/or descending pathway by unilateral hypothalamic deafferentation through the spinal cord, the MBH, and have been unsuccessful to date. By extending the possible significance probably also other structures of the CNS. i~ appears that the neural structures of the postulated neural mechanism, one participating in this mechanism are at the can suppose that it might have a reguhypothalamic level on the side of the latory role not only i n the development removed ovary, and at the level of T-10 of compensatory ovarian hypertrophy, but of the spinal cord contralateral to it. All also in other functions of the ovary, the findings mentioned in this article can including ovulation. be explained assuming the following course of the pathways in question: the fibres of Reading list I. Bucher, N. L. and Malt, R. A. (1971) In: the postulated ascending pathway partly Regeneration of Liver and KidneT, Little cross below the T-10 level of the sp!nal Brown and Co.. Boston. cord, and partly run uncrossed. The crossed 2. Burden, H. W. (1978) in: g. E. Jo.~es (ed.) fibres terminate on both sides of the The Vertebrate Orary, Plenum Prt~s, New hylSothalamus and other related structures. York (in-press). 3. Dallmann, M. F., Engeland, W. C. and The descending pathway, or at least its McBride, M. H. (1977) Ann. N.Y. ,4cad. major part, probably crosses above the ScL 297, 373-392. T-10 level of the spinal cord. It should he 4. Dicker, S. E., Greenbaum, A. L. and mentioned that it is most likely that all Morris, C. A. (1977) J. Physiol. (London) of the postulated pathways are multi273, 241-253. 5. Gerendai, !. and Hal~sz, B. (1976) Neurosynaptic. The described course of the endocrinology 21,331-337. pathways is just one possibility and there 6. Gerendai, i., Marehetti, B., Maugeri, S. are several other- as well. Further and Scapagnini, U. (1978) Neuroendomorphological and physiological studies ~inology (in press). are needed to clarify the suspected path7. Gcrendai, i., Rotsztejn, W. H., Marchetti, B., Kordon, C. and Scapagnim, U. (1978) ways and to prove their real functional Newoscience Letters (in press). significance. 8. Hall, D. H. and Schneyer, C. A. (1978) It could well he that the postulated Cell Tiss. Res. 187, 147-151. neural reflex mechanism is coupled with 9. Hatai, S. (1913) J. Exp. Zool. 1.%297-314. the hormonal events occurring after the 10. Weischen, R., Dullaart, J. and De Jong, F. H. (1978) Biol. Reprod. 18, 421-427. removal of one ovary. In the light of the data described above, one might assume that the ascending pathway from the ovary to the hypothalamus could be at least one signal which induces, via the Ida Gerendai is A~sistant Professor, and B~la Haldsz Professor end Chairman, of the 2nd hypothalamic gnnadotrophin-releasing Department of Anatomy, Histology and Embryohormone, the release of FSH following logy of Semmeiweis University Medic~l School, hemiovariectomy. Another signal might T6zolt6 u.58, H-1094 Budapest, Hungory.

side to the side without the ovary. Unilateral hypothalamic deafferentation, by itself, does not affect the weight of the