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Neural participation in ovarian control
TINS- October 1978
87
Neural participation in ovarian control Ida Gerendai and B. Halhsz i
ii
ii
In this article, Ida Ger~ndai and &;la Haldsz describe dw elegant studieLfronl which the)' have derived the evidence for the existence and pathli;ays of efferent and afferent neural connections between the ovary and hypothalamus, and the role which these pathways have to play in gonadal-h)Tothalamic feedback. The nrodel which they hal'e used concerns the effects of compensatory ovarian h)pertrophy following hemiovariectonly. For the neuroendocrinologist, the invoh,ement of possible neural part, ways hi areas prevmusl.i, considered to be only lmder a humeral control, has many far-re~,ching implications, and may provide explanations Jbr a number of previously inexplicable observations. The occurrence of compensatory ovarian hypertrophy (COH) in which the remaining ovary increases in weight following the removal of one ovary has been acknowledged for a long time 9. 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 number 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/° 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 operauon, whereas progesterone levels dropped within 2 h. Plasma luteiniziog hormone (LH) and 17/3-oestradiol levels were generally unaffected. Administration of progesterone did not interfere with the increase in FSH levels, whereas, after injection of bovine follicular fluid, FSH levels did not rise after t|~e 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 ~he role of the ovarian nerves, the significance of
the spinal cord, and the significance of the hypothalamus in the development of ovarian growth following hemiovariectomy. The ovarian nerves
pensatory ovarian hypertroph) operates, at least in part, even in the absence of the pituitary. But of course v, ithout gonadotrophins neither ,aormal ovarian functiou nor compensatory ovarian hypertrophy can occur. The data obtair'_d from local application of 6-OHDA on the o, ary may be interpreted as an indication that the chemical character of the neural elements involved in the mechanism discussed are at least partly adrenergic in nature.
As surgical denervation of the rat ovary is practically impossible, we brought about local pharmacological degeneration of the ovarian adrenergic nerves with 6-hydroxydopamine (6-OHDA) by means of a technique developed by us2: the ovary is placed in situ into a small capsule containing 6-OHDA mixed with .a neutral cream. This treatment prevented the The spinal cord The observations obtained in animals usual weight increase of the remaining ovar) ! week after hemigonadectomy. On with hemitransection o r the spinal cord the other hand, in rats with two ovaries, lend further support to the assumption local treatment of one of the gonads with of the existence of a gonadal-h)pothalamic neural path~a). We found that 6-OHDA resul,ed in a significant weig~ hemitransection of the spinal cord at increase of the other ovary G. These observations indicate th., the the tenth thoracic vertebral {T-10) level ovarian nerves destroyed by 6-OHDA are contralateral to the side of unilateral required for the development of the ovariectomy prevented the compensator) compensatory ovarian hypertrophy. They ovarian hypertrophy; however, when the suggest further that these nerves contain spinal cord lesion was on the same side as both afferent (leading towards the CNS) that on which the unilateral ovariectomy and efferent elements involved in the had been performed, there ~as no intermechanism mentioned. In other words, ference with the h) pertroph) of the these findings are coexistent v:ith the view remaining ovary. These data suggest that the major part that there might be a peripheral neural signal by which the remaining ovary is of ,?,e postulated neural path~vays arising 'informed' of lhe absence of the other, an4 terminating in the ovaries are located and that neurat elements of the remaining in the side of the spinal cord contralateral ovary might also participate in the to that of the removed ovary, at least at conveyance of the stimulus to the ovarian the level of T-10. cells, leading to the hypertrophy of the organ. Such an assumption is derived The hypothalamus Ecy means of light- and electronft'om the findings obtained in hypophysectomized a , d unilaterally ovariecto- microscopic autoradiog~aphy we investimized rats. We lound that there is a less gated the rate of tritiated leucine incorsevere ovarian atrophy 2 weeks following poration into the arcuate nucleus of the hypophysectomy if one of the ova:ies is two sides after unilateral ovariectomy ~. removed together with the pituitary, as Left- or right-side hemigonadectomy incompared with animals having two ovaries. duced significantly higher relative radioThis suggests tha', the whole mechanism active concentration in the contralateral responsible for the development of corn- arcuate nucleus to the side of ovariectomy ElsevicctNorth-t4"~ll~,~d Biomedical
Pr¢~ 1978
T I N S - October 1978
88 thzn in the ipsilateral side. No difference was detected in the concentration of the newly-synthesized proteins between the left- and the right-side of the arcuate nuclei of intact females. In this latter group the rate of labelled amino acid incorporation into the arcuate neurones of the two sides was between the two extremes given by the arcuate neurones on either side of the hypolhalamus observed in the hemiovariectom~zed animals. As unilateral effects can develop only on neural pathways, these findings may be interpreted as further indirect evidence for the existence of a neural connection between the hypothalamic arcuate nucleus and th.~ ovary. Luteinizing hormone-releasing hormone (LHRH) Several authors have observed increased pituitary gonadotrophin (primarily FSH) secretion following unilateral ovariectomy. It may be assumed 'that this is the consequence of increased synthesis and/or release of hypothalamie LHRH content of the mediobasal hypothalamus (MBH) of the two l~alves in unilaterally ovariectomized rats. Two weeks following unilateral ovariectomy there is significantly more LHRH in that half of the MBH ipsilateral to the removed ovary than in the contralateral sideL In accordance with the dala in the literature, bilateral ovariectomy results in reduced L H R H content in both halves of the MBH. The contralateral difference in the hypothalamic LHRH content after unilateral .ovariectomy strongly suggests that a neura.l input from the ovary reaches the hypothalamic LHRH structures. It seems reasonable to assume that a neurallymediated stimulus induced by unilateral o variectomy might increase the activity of the LHRH-synthesizing neurones: in other ~vords, the LHRH-producing neurones can be considered to be the site where the neural input is transformed into a hormonal event. Our observations, however, do not give any indication whether the postulated neural efferents to the ovary arise from the MBH or from other brain structures. Hypotl~alamie deafferentafion Unilateral interruption of all neural connections to and from the MBH prevents the cc,mpensatory ovarian hypertrophy following the removal of one ovary when the two operations were carried out on the same side. In contrast, unilateral isolation o f the MBH from the rest of the brain is witr~tout effect if it is on the opposite
side to the side without 'tl~e ovary. Unilateral hypothalamic deafferentation, by itself, does not affect the weight o f the ovaries. The preve~.tion of compensatory ovarian hypertrophy by unilateral deafferentation of the MBH yields further experimental evidence for the participation of an ovarian-hypoth~iamic neural component in the mechanism discussed. In addition, at the hypothalamic level the pathways critical for the occurrence of the compensatory ovarian hypertrophy may be assumed to be situated mainly on the same side as the removed ovary. General conclusions There is considerable evidence suggesting that, besides the hormonal events, a pure neural component is also involved in the development o f compensatory ovarian hypertrophy following bemiovariectomy. This postulated neural mechanism includes the ovarian adrenergic elements, an ascending and/or descending pathway through the spinal cord, the MBH, and probably also other structures of the CNS. -It appears that the neural structures participating in this mechanism are at the hypothalamic level on the side of the removed ovary, and at the level of T-10 of the spinal cord contralateral to it. All the findings mentioned in this article can be explained assuming the following course of the pathways in question: the fibres of the postulated ascending pathway partly cross below the T-10 level of the spinal cord, and partlyrun uncrossed. Thecrossed fibres terminate on both sides of the hypothalamus and other related structures. The descending pathway, or at least its major part, probably crosses above the T-10 level of the spinal cord. It should be mentioned that it is most likely that all of the postulated pathways are multisynoptic. The described course of the pathways is just one possibility and there are several others, as well. Further morphological and physiological studies are needed to clarify the suspected pathways and to prove their real functional significance. It could well be that the postulated neural reflex mechanism is coupled with the hormonal events occurring after the removal of one ovary. In the light o f 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 hypothalamic gonadotrophin-releasing hormone, the release of FSH following hemiovariectomy. Another signal might
be a non-steroidal 'inhibin,like' ovaria6 factoras tnentioned in the introduction. An interplay between FSH and the suspected afferent pathway at the ovarian level might be assumed as well. An increasing amount of evidence indicates that, as in the ovary, a similar neural mechanism .might be involved in the development of compensatory adrenal h~/pertrophy a. It is tempting to speculate that since 'compensatory organ growth develops not only in the paired endocrine glands, but also in the liver, kidney, and salivary gland 1, the compensator) growth of each of these organs, at least in part, may be mediated by a similar neural mechanism. Salivary gland hypertrophy can be prevented by surgical denervation of the remaining gland s. Kidney compensatory hypertrophy develops also in hypophysectomized animals 4. However, our attempts to block the compensatory kidney growth by hemitransection of the spinal cord or by unilateral hypothalamic deafferentation have been unsuccessful to date. By extending the possible significance of tile postulated neural mechanism, one can suppose that it might have a regulatory role not only in the development of compensatory ovarian hypertrophy, but also in other functions of the ovary, includieg ovulation. Reading list I. Buc~.er, N. L. and Malt, R. A. 0971) In: Regeneration of Liver and Kidney, Little Brown and Co., Boston. 2. Burden, H. W. (1978) In-: R. E. Jones led.) Ti,e Vertebrate Ovary, Plenum Press, New York (in press). 3. Dal)mann, M. F., Engeland, W. C. and McBride, M. H. (1977) Ann. N.Y. Acad. SoL 297, 373-392. 4. Dicker, S. E., Greenbaum, A. L. and Morris, C. A. (1977) J. PhyaioL (London) 273, 241-253. 5. Gerendai, I. an~- Halftsz, B. (1976) Nearoendocrino~1ogy 21,331-337. 6. Gerendai, I., Marchetti, B., Maugeri, S. and Scapagnini, U. (1978) Neuroendocrinology (in pre~s). 7. Gerendai, I,, Rotsztejn, W. H., Marchetti, B., Kordon, C. and Scapagninl, U. (1978) Neuro~cience Letters (in press).
8. Hall, D. H. and $chneyer, C. A. (1978) Cell Tiss. Res. 187, 147-151. 9. Hatai. S. (1913) J. Exit. Zooi. 15, 297-314. 10. Welschen, R., Dullaart, J. and De Jong, F. H. (1978) "liol. Repr¢.d. 18, 421-427.
Ida Gerendo.i is Assistant Professor, and Bdla Hal~z ~'~fessor and Chairman, of the 2nd Department of Anatomy, Histologyand Embryology of Semmelweis University Medical School. Fiizoltd u.58, H.1094 Budapest, Hungary.
87
Neural participation in ovarian control Ida Gerendai and B. Halhsz i
ii
ii
In this article, Ida Ger~ndai and &;la Haldsz describe dw elegant studieLfronl which the)' have derived the evidence for the existence and pathli;ays of efferent and afferent neural connections between the ovary and hypothalamus, and the role which these pathways have to play in gonadal-h)Tothalamic feedback. The nrodel which they hal'e used concerns the effects of compensatory ovarian h)pertrophy following hemiovariectonly. For the neuroendocrinologist, the invoh,ement of possible neural part, ways hi areas prevmusl.i, considered to be only lmder a humeral control, has many far-re~,ching implications, and may provide explanations Jbr a number of previously inexplicable observations. The occurrence of compensatory ovarian hypertrophy (COH) in which the remaining ovary increases in weight following the removal of one ovary has been acknowledged for a long time 9. 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 number 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/° 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 operauon, whereas progesterone levels dropped within 2 h. Plasma luteiniziog hormone (LH) and 17/3-oestradiol levels were generally unaffected. Administration of progesterone did not interfere with the increase in FSH levels, whereas, after injection of bovine follicular fluid, FSH levels did not rise after t|~e 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 ~he role of the ovarian nerves, the significance of
the spinal cord, and the significance of the hypothalamus in the development of ovarian growth following hemiovariectomy. The ovarian nerves
pensatory ovarian hypertroph) operates, at least in part, even in the absence of the pituitary. But of course v, ithout gonadotrophins neither ,aormal ovarian functiou nor compensatory ovarian hypertrophy can occur. The data obtair'_d from local application of 6-OHDA on the o, ary may be interpreted as an indication that the chemical character of the neural elements involved in the mechanism discussed are at least partly adrenergic in nature.
As surgical denervation of the rat ovary is practically impossible, we brought about local pharmacological degeneration of the ovarian adrenergic nerves with 6-hydroxydopamine (6-OHDA) by means of a technique developed by us2: the ovary is placed in situ into a small capsule containing 6-OHDA mixed with .a neutral cream. This treatment prevented the The spinal cord The observations obtained in animals usual weight increase of the remaining ovar) ! week after hemigonadectomy. On with hemitransection o r the spinal cord the other hand, in rats with two ovaries, lend further support to the assumption local treatment of one of the gonads with of the existence of a gonadal-h)pothalamic neural path~a). We found that 6-OHDA resul,ed in a significant weig~ hemitransection of the spinal cord at increase of the other ovary G. These observations indicate th., the the tenth thoracic vertebral {T-10) level ovarian nerves destroyed by 6-OHDA are contralateral to the side of unilateral required for the development of the ovariectomy prevented the compensator) compensatory ovarian hypertrophy. They ovarian hypertrophy; however, when the suggest further that these nerves contain spinal cord lesion was on the same side as both afferent (leading towards the CNS) that on which the unilateral ovariectomy and efferent elements involved in the had been performed, there ~as no intermechanism mentioned. In other words, ference with the h) pertroph) of the these findings are coexistent v:ith the view remaining ovary. These data suggest that the major part that there might be a peripheral neural signal by which the remaining ovary is of ,?,e postulated neural path~vays arising 'informed' of lhe absence of the other, an4 terminating in the ovaries are located and that neurat elements of the remaining in the side of the spinal cord contralateral ovary might also participate in the to that of the removed ovary, at least at conveyance of the stimulus to the ovarian the level of T-10. cells, leading to the hypertrophy of the organ. Such an assumption is derived The hypothalamus Ecy means of light- and electronft'om the findings obtained in hypophysectomized a , d unilaterally ovariecto- microscopic autoradiog~aphy we investimized rats. We lound that there is a less gated the rate of tritiated leucine incorsevere ovarian atrophy 2 weeks following poration into the arcuate nucleus of the hypophysectomy if one of the ova:ies is two sides after unilateral ovariectomy ~. removed together with the pituitary, as Left- or right-side hemigonadectomy incompared with animals having two ovaries. duced significantly higher relative radioThis suggests tha', the whole mechanism active concentration in the contralateral responsible for the development of corn- arcuate nucleus to the side of ovariectomy ElsevicctNorth-t4"~ll~,~d Biomedical
Pr¢~ 1978
T I N S - October 1978
88 thzn in the ipsilateral side. No difference was detected in the concentration of the newly-synthesized proteins between the left- and the right-side of the arcuate nuclei of intact females. In this latter group the rate of labelled amino acid incorporation into the arcuate neurones of the two sides was between the two extremes given by the arcuate neurones on either side of the hypolhalamus observed in the hemiovariectom~zed animals. As unilateral effects can develop only on neural pathways, these findings may be interpreted as further indirect evidence for the existence of a neural connection between the hypothalamic arcuate nucleus and th.~ ovary. Luteinizing hormone-releasing hormone (LHRH) Several authors have observed increased pituitary gonadotrophin (primarily FSH) secretion following unilateral ovariectomy. It may be assumed 'that this is the consequence of increased synthesis and/or release of hypothalamie LHRH content of the mediobasal hypothalamus (MBH) of the two l~alves in unilaterally ovariectomized rats. Two weeks following unilateral ovariectomy there is significantly more LHRH in that half of the MBH ipsilateral to the removed ovary than in the contralateral sideL In accordance with the dala in the literature, bilateral ovariectomy results in reduced L H R H content in both halves of the MBH. The contralateral difference in the hypothalamic LHRH content after unilateral .ovariectomy strongly suggests that a neura.l input from the ovary reaches the hypothalamic LHRH structures. It seems reasonable to assume that a neurallymediated stimulus induced by unilateral o variectomy might increase the activity of the LHRH-synthesizing neurones: in other ~vords, the LHRH-producing neurones can be considered to be the site where the neural input is transformed into a hormonal event. Our observations, however, do not give any indication whether the postulated neural efferents to the ovary arise from the MBH or from other brain structures. Hypotl~alamie deafferentafion Unilateral interruption of all neural connections to and from the MBH prevents the cc,mpensatory ovarian hypertrophy following the removal of one ovary when the two operations were carried out on the same side. In contrast, unilateral isolation o f the MBH from the rest of the brain is witr~tout effect if it is on the opposite
side to the side without 'tl~e ovary. Unilateral hypothalamic deafferentation, by itself, does not affect the weight o f the ovaries. The preve~.tion of compensatory ovarian hypertrophy by unilateral deafferentation of the MBH yields further experimental evidence for the participation of an ovarian-hypoth~iamic neural component in the mechanism discussed. In addition, at the hypothalamic level the pathways critical for the occurrence of the compensatory ovarian hypertrophy may be assumed to be situated mainly on the same side as the removed ovary. General conclusions There is considerable evidence suggesting that, besides the hormonal events, a pure neural component is also involved in the development o f compensatory ovarian hypertrophy following bemiovariectomy. This postulated neural mechanism includes the ovarian adrenergic elements, an ascending and/or descending pathway through the spinal cord, the MBH, and probably also other structures of the CNS. -It appears that the neural structures participating in this mechanism are at the hypothalamic level on the side of the removed ovary, and at the level of T-10 of the spinal cord contralateral to it. All the findings mentioned in this article can be explained assuming the following course of the pathways in question: the fibres of the postulated ascending pathway partly cross below the T-10 level of the spinal cord, and partlyrun uncrossed. Thecrossed fibres terminate on both sides of the hypothalamus and other related structures. The descending pathway, or at least its major part, probably crosses above the T-10 level of the spinal cord. It should be mentioned that it is most likely that all of the postulated pathways are multisynoptic. The described course of the pathways is just one possibility and there are several others, as well. Further morphological and physiological studies are needed to clarify the suspected pathways and to prove their real functional significance. It could well be that the postulated neural reflex mechanism is coupled with the hormonal events occurring after the removal of one ovary. In the light o f 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 hypothalamic gonadotrophin-releasing hormone, the release of FSH following hemiovariectomy. Another signal might
be a non-steroidal 'inhibin,like' ovaria6 factoras tnentioned in the introduction. An interplay between FSH and the suspected afferent pathway at the ovarian level might be assumed as well. An increasing amount of evidence indicates that, as in the ovary, a similar neural mechanism .might be involved in the development of compensatory adrenal h~/pertrophy a. It is tempting to speculate that since 'compensatory organ growth develops not only in the paired endocrine glands, but also in the liver, kidney, and salivary gland 1, the compensator) growth of each of these organs, at least in part, may be mediated by a similar neural mechanism. Salivary gland hypertrophy can be prevented by surgical denervation of the remaining gland s. Kidney compensatory hypertrophy develops also in hypophysectomized animals 4. However, our attempts to block the compensatory kidney growth by hemitransection of the spinal cord or by unilateral hypothalamic deafferentation have been unsuccessful to date. By extending the possible significance of tile postulated neural mechanism, one can suppose that it might have a regulatory role not only in the development of compensatory ovarian hypertrophy, but also in other functions of the ovary, includieg ovulation. Reading list I. Buc~.er, N. L. and Malt, R. A. 0971) In: Regeneration of Liver and Kidney, Little Brown and Co., Boston. 2. Burden, H. W. (1978) In-: R. E. Jones led.) Ti,e Vertebrate Ovary, Plenum Press, New York (in press). 3. Dal)mann, M. F., Engeland, W. C. and McBride, M. H. (1977) Ann. N.Y. Acad. SoL 297, 373-392. 4. Dicker, S. E., Greenbaum, A. L. and Morris, C. A. (1977) J. PhyaioL (London) 273, 241-253. 5. Gerendai, I. an~- Halftsz, B. (1976) Nearoendocrino~1ogy 21,331-337. 6. Gerendai, I., Marchetti, B., Maugeri, S. and Scapagnini, U. (1978) Neuroendocrinology (in pre~s). 7. Gerendai, I,, Rotsztejn, W. H., Marchetti, B., Kordon, C. and Scapagninl, U. (1978) Neuro~cience Letters (in press).
8. Hall, D. H. and $chneyer, C. A. (1978) Cell Tiss. Res. 187, 147-151. 9. Hatai. S. (1913) J. Exit. Zooi. 15, 297-314. 10. Welschen, R., Dullaart, J. and De Jong, F. H. (1978) "liol. Repr¢.d. 18, 421-427.
Ida Gerendo.i is Assistant Professor, and Bdla Hal~z ~'~fessor and Chairman, of the 2nd Department of Anatomy, Histologyand Embryology of Semmelweis University Medical School. Fiizoltd u.58, H.1094 Budapest, Hungary.