Ovarian function and the immune system

Medical

OVARIAN

Hypotheses

FUNCTlON

A. Bukovsky Child, 147

5:

415-436,

AND THE

1979

IMMUNE SYSTEM

and J. Presl. Research lnsti 10 Prague 4, Podoli, Nabr. K.

tute for the Care of Mother Marxe 157, Czechoslovakia.

and

ABSTRACT A hypothesis is presented on the interaction between the immune system and ovary in the regulation of the reproductive system and in the origin of some of its disorders. It has been suggested that the beginning, duration and age dependent failure of ovarian ovulatory function depends among other things on the adequate relationship between the immune system and appropriate ovarian target structures. The cyclicity of ovarian function is considered to be primarily dependent on the induction of a specific cyclic immune response to the ovary. Similarly, the selection of a species-specific number of ovulating follicles during sexual maturity is thought to be ensured by immune mechanisms. This hypothesis, on the role of the immune system in regulation of ovulatory ovarian function respects the physiological effect of gonadotropins and steroids on the ovarian structures. The interact ion between the ovary and the hypothalamus-pituitary system appears to be modulabetween the ovary and the immune system. ted by the relationship Key words

Med ical

:

immune female

subject

Cycle-immune systemsexual ontogeny.

heading:

ovarian

immunity - immunity, menstruation - ovary sex menstruation.

function

cellu lar - ovu lation

- ovulation

-

lymphatic system - reproduct ion

-

INTRODUCTION Recently, which are endocrine physiology

many experimental data on ovarian function have been pub1 i shed difficult to interpret in terms of the commonly accepted neuroconcept. Similarly, the explanation of some well known facts in and the pathology of reproduction is difficult, too.

We shall attempt to summarize these observations thesis of the ovarian function dependence on the could help to explain these experimental results which have been overlooked in the literature. 415

and to form a working hvpoimmune system (IS), which and clinical experiences

Incompleteness regulation

of

the

present

neuro-endocrine

concept

of

ovarian

function

The contemporary concept of ovarian function regulation is based on the hypothalamus-hypophysis-ovary system assuming mutual connections between the neurotransmi tters, hypothalamic releasing hormones, gonadotropins and ovarian steroids, and regulation by a system of feedbacks (the long - external, short - internal, and ultra short ones). The limbic system and the cerebral cortex are considered to be the superior integrating centers (for review see 1). Most probably, the direct influence of the central nervous system on ovarian function is exhibited through the autonomic nervous system, too. There are regulatory roles for other endocrine glands, particularly the the thyroid and the pineal. adrenals, The neuro-endocrine concept, however, fails to explain all the physiological facts in woman, i.e. the prenatal and perinatal refractoriness of morphologically differentiated ovaries to gonadotropins, the beginning of ovarian function at puberty and its definitive failure in the menopause, the speciesconstant number of ovulating follicles and the duration of the ovarian cycle. The concept fails to explain both the peak of ovarian estrogen secretion which increases and decreases before the peak secretion of the gonadotropins and the age-dependent frequency of ovarian ovulatory cycles, first increasing, later decreasing. The temporally limited function of the corpus luteum in the ovulatory cycle and its “regression” after the first trimester of pregnancy can hardly be clarified using present concepts. The exact reason for the interruption of the menstrual cycle during pregnancy (and its sporadic continuation at the beginning of the first trimester), as well as the new start of the ovulatory ovarian cycle post partum have not been explained as yet. The present concept does not succeed in explaining a number of experimental data in rats and mice for example ovarian “dysgenesis” after neonatal thyand delay of the critical period of so-called neuronal mectomy (2,3,4,5) competence of the hypothalamus by cortisol treatment (6). In contrast to the idea of an irreversible alteration of the sexual differentiation of the hypothalamus by effective steroids (early steroid syndrome) transplantation of intact ovaries at 120 days of age into neonatally androgenized female ovariectomized at the age of 40 days, induces an ovulatory cycle (7,8). rats, as well as the prevention of steroid-induced sterility These experiments, in neonatal rats by thymocyte suspensions (g), superovulation after cyclophosphamide (10) and x-ray treatment (11) or ovarian cycle alteration after antithymocyte serum treatment in adult rats (12) suggests that in the development and regulation of ovarian function both the hypothalamus-pituitary and immune system (IS) participate. According to our hypothesis, “leukocyte” infiltration of follicles during atresia in guinea pig ovaries (13) and in infant human ovarian follicles in advanced developmental stages (14) corroborates the participation of the IS in the regulation of the ovarian function. The role of the IS is confirmed also by the possibility of autoimmune failure of ovarian function in adult women (15-19).

416

Ovarian There is ontogeny

differentiation

and

ontogeny

of

the

remarkable coincidence between of IS in humans and rats (Table

system

the differentiation 1).

Table

Relationship ovarian

immune

of

the

ovary

and

1

between the immune system maturation differentiation in the woman and rat. (reference numbers are in brackets)

and

____Ll_r_s_t___a_e_e_~_?_!3_2_%L._o_L.___ Species

Duration of Pregnancy (days)

Small

Antibody Production

Cavitated Foll icles

Lymphocytes

Oogon i a

56

(20)

56

(21)

112

(20)

133-154

(1)

16

(20)

14,5

(22)

28

(20)

29-31

(1)

A very early contact of the immature IS with antigen results in induction of immunotolerance in the sense of self-recognition (autotolerance). Autotolerance against a specific antigen is an actively induced process of loss of Mature immunocompetent cells then do not react the selective immune response. with the antigen. The so-called “forbidden clones” of immune cells which are able to destroy the antigens of their own tissues are eliminated or partly inhibited by the thymus where the autotolerance is probably established and ma i nta i ned. An alternative possibility is tolerance induction in immature lymphoid cells. The autotolerance appears to be a dynamic process, which is repeatedly renewed in newly originating immunocompetent cells (for review see 23). OVARIAN Physiological

FUNCTION

induction

of

AND THE the

IMMUNE SYSTEM - WORKING HYPOTHESES

immune

response

to

the

ovary:

hypothesis

I

We assume that a mature ovary includes both the primarily tolerated (autotolerated) structures and those without any tolerance because they were not present during the embryonal and/or fetal adaptive period. The latter ones are considered IS control”. Their natural decrease is suppleto be “under mented by the primary tolerated structures which are supposed to be supplemented from the spare indifferent structures. The complex effect of gonadotropins and steroids transforms a primordial Ovary-specific antigens follicle or an adult ovary into a tertiary one. the theta interna and in atretic tertiary were found in the zona pellucida, follicles where the presence of the zona pellucida material is presumed (24,251

417

All the specific ovarian antigens are presumably absent in the ovary during the time the autotolerance is being established under physiological conditions. We suppose that the specific immune response (“intolerance”) to the ovarian structures carrying primarily non-tolerant antigens is induced during a time sufficiently remote from the adaptive stage (hypothesis I). The interval is considered a “refractory stage” of IS ontogeny. In this stage the IS no longer responds with autotolerance against any newly formed antigens and it is unable to give a specific response to any new antigens of transplantation and/or an organ-specific type. The “intolerance” is mainly determined by the antigenicity of the structures being in direct contact with lymphatic drainage (theta interna). The relation between the ovary and the IS is supposed to be realised at the regional lymphatic nodule level. All the cavitated follicles in the rat ovary were found to undergo atresia with round-cell infiltration of the granulosa during the course of the fourth week after birth (from the 21st day of life) (26). The cytotoxicity of immune lymphocytes seems to be directed against the granulosa, with altered antigenic structure coincident with cavitation of the follicle and differentiation of the theta and primary interstitial tissue. After the appearance of this type of atresia in ontogeny all the cavitated follicles degenerate in this way. Evidently, the atresia is of a continual character in this period. Cyclic

immune

response

to

ovary:

hypothesis

II

A change of a primarily continual immune response to nontolerated ovarian antigens into a cyclic one in the further period of ontogeny is presumed; therefore, the destructive interference is only of limited duration. After the destruction of primarily non-tolerated ovarian structures by the interference of the IS there then follows a depression of the immune response. The latent period between the two cytotoxic effects is species-specific and The depression of immune corresponds to the length of the ovulatory cycle. response enables the follicles to reach a sufficient degree of maturity, which The time-limited effect of the is essential for the function of the organ. IS on repeatedly regenerating tertiary follicles is supposed to be a cyclic immune intolerance” (hypothesis I I). process - a “cyclic During the fifth week after birth rat ovaries include both cavitating follicles attacked by round-cell infiltration and intact preovulatory tertiary there is no ovulation (absence of corpora lutea) (26) follicles. However, at the time of potential maturity of the stimulatory estrogen feedback (27). In rats in contradistinction to primates, however, there are neither evident oscillations of circulating estrogen levels before estrarche nor anovulatory estrous cycles after estrarche. This hypothesis of species-specific cyclic immune responses to the non-tolerated transplantation-type antigens seems to be supported by experimental observations in which rats reject a tumorous or heterologous graft in 8-y days Subsequent grafts are rejected within 3-4 days after first implantation. time agrees with the duration of estrous cycle in (28) . The rejection rat. According to our idea (29) the IS generally requires a period lasting just for one ovulatory cycle to verify the persistence of the intolerated 418

transplantation antigen and to induce a delayed immune response in the In the presence of such an antigen, the period necessary for organ i sm. the occurrence of a cytotoxic response by immune lymphocytes (killer cells) lasts again for the duration of one ovulatory cycle. Hence we assume that the period from the first contact with a transplantation and/or organspecific antigen up to the start of the first cytotoxic response generally corresponds with two ovulatory cycles (Figure 1).

I

ICL (12

OCL)

4

OCL

ICL-species specific immune Figure 1: Hypothetical immune cycle (IC). RT-reserve tissue (autotolerated) ; OCL-ovarian cycle length; cycle length; Ll-lymphoid ceils initiating the TT-target tissue for the immune response; specific IC; L2-lymphoid cells controlling the duration of the specific TT presence and then inducing the “killer cells” (L3) affecting the TT; l-specific membrane antigens the specific TT; L3-“ki 1 ler ccl 1s” destroying 2-L2 differentiate in contact with of the non-tolerated TT affect the Ll; 4-simultaneously, a part of the the TT cells after the middle of the ICL; the released membrane antigen induces target cell population is destroyed, 3-“ki 1 ler ccl 1s” (Lj) a new IC (Ll) but postponed by a half of its length; .5-the first IC terminates differentiate again after the middle of the ICL; with the origin of “killer cells” (L3) destroying the TT, the previously induced IC continues (L2) and, concomitantly, a new IC is induced (L;).

We suppose that, just after the recognition of the lasting presence of one non-tolerated transplantation antigen (within the time of one ovulatory a part of the cell population bearing cycle after the first antigen effect), by lymphoid cells responsible for verifying the this ant ige:. is destroyed presence of target tissues (The identification of target cells induces, proMembrane antigens bably via immune RNA, the development of ki 1 ler cells). released from target cells in this way then induce a further parallel

419

immune cycle

but

which

is

shifted

by one

ovulatory

cycle

length.

The cytotoxic destruction affects only the non-tolerated structures of tertiary follicles. The cellular immune response is preceded by the humoral response of specific antibodies retarding follicle growth. The response terminates shortly before the cellular cytotoxic effect. The interval between the end of the specific humoral response and beginning of the cytotoxic effect as well as between the end of the cytotoxic effect and the beginning of the humoral response corresponds to the period of progressive growth of target tissue (Figure 1). Primarily tolerated structures of noncavitated follicles serve as a source of the ever repeating regeneration of tissue-bearing foreign antigens. This mechanism is considered to be one of the factors determining the cyclic growth and destruction of the ovarian foll icles. The proper impulse for the growth is given by the pituitary gonadotropins’ effect. Establishment

of

quantitatively

limited

immune tolerance:

hypothesis

III

A species-specific and constant number of follicles survives the hypothetic destructive effect of the IS during each ovulatory cycle. Therefore, an Against the background of additional presumption has to be constructed: the above-mentioned cyclic immune response (“cyclic immune intolerance”) a quantitatively limited (incomplete) immune tolerance - “superposed tolerance” - develops (hypothesis I I I). Hence a constant number of target cells is protected from the cytotoxic effect of the killer cells. The constant amount of target tissue (follicles) may further differentiate, up There is an indirect to ovulating, while the rest undergo immune destruction. the ovary left after hemicastration in laboratory proof for this hypothesis: rodents produces the same number of ovulating follicles as did both ovaries before hemispaying (30,31,32). the species-constant number of cavitated The IS is supposed to “permit” follicles to reach the ovulatory stage not earlier than sexual maturity The cyclic destruction of all other follicles left has been completed. results in a decrease in the circulating estradiol concentration followed In our opinion, the by release of pituitary LH which induces ovulation. preovulatory effect of the IS on the ovary determines both the length of the ovulatory cycle (Figure 2) (see hypothesis II) and the number of ovulations in the particular cycle. PHYSIOLOGY Immune system

and

OF OVARIAN ovarian

FUNCTION

function

IN RELATION

TO THE

IMMUNE SYSTEM

development

The three above-mentioned hypotheses explain a remarkable latent period between reaching the potential maturity of stimulating estrogen feedback in the rat (27) and woman (34). and the beginning of its function

420

ICL (--2OCL 1

I

t

OCL

I

LH

LH

1 yl,

LH

t

+L+ _,

r-7

\

I

I

\

I

9

'9

\

I

r-

I I

I

E2

t2-

M

M

Figure 2. Relationship between the immune and ovarian cycle in woman. lg-geni tal tract immunoglobul ins (quoted according symbols see Figure 1. estradiol; LH-preovulatory plasma LH peak; Schumacher (33) ; E2-plasma menstruation.

For to M-

In the late juvenile stage of the rat a round-cell infiltration at first affects all the follicles which have reached a certain phase of development (cavitation) and, thus, blocks ovulation. The immune response has a continual character and the production of ovarian estrogens is low. The absence of a cyclic immune response (see hypothesis II) prevents juvenile ovaries from achieving a cyclic reduction of estrogen production, i.e. the impulse This idea provides an explanation for the for a preovulatory LH release. strange inhibitory mechanism suppressing the cyclic function of an adult female ovary transferred to a juvenile female rat with a potentionally mature stimulating estrogen feedback while a juvenile ovary transferred to a mature rat demonstrates cyclic function (for review see 35). The period of temporary predominance of anovulatory cycles in woman after menarche can be considered a period already established “cyclic intolerance” without any firmly established rate of “super(see hypothesis I I), however, (see hypothesis III) the gradual setting up of which is posed tolerance” assumed in this period (Figure 3).

421

ONTOGENY

OF

ME

IMMUNE

SYSTEM

ONTOGENY

OF

THE

REPRODUCTIVE

FUNCTION

Figure 3. Ontogeny of the immune system and ovarian function in woman. Immune svstem-horizontal axis: I-adaDtive ohase of the IS develooment: II-refractory phase of the IS development; Illa-phase of continual immune response; Illb-phase of weakening continual immune response; lllc-phase of cyclic immune response, I lId-phase of cyclic immune response with “superposed tolerance”; Illb+-phase of growing continual immune response; Illa+-phase of continual immune response finally affecting also the primarily tolerated (autotolerated) ovarian structures, i.e. autoimmunity; (II+)-failure of the immune response (danger of neoplasia (neo). Thick line-humoral immunity to the controlled ovarian structures; -Vertical axis: length of arrows-degree of suppression of the controlled ovarian structures. Ovarian function-horizontal axis: A-embryonal period; B-fetal period; C-childhood, D-Puberty; E-adolescence; F-reproductive age; G-premenopause; H-postmenopause; l-senescence;. -Vertical axis: l-primordial and primary stage of follicular development: foll icles; 4follicles; 2-secondary foll icles; j-tertiary (cav tated) cystically degenerated follicles; 5-neoplasia; o o 000000 - ovulations.

’

Immune system

and

the

ovarian

cycle

The atresia of tertiary follicles inducing the rap i d fall of plasma estradiol concentration followed by release of pituitary LH is caused by the IS (see hypothesis I I). However, all maturing foil icles are not destroyed by the establ i shed “superposed tolerance” (see hypothesis Ill) and their speciesspecific constant number reaches the preovulatory stage. The decrease in circulating estradiol concentration releases LH. The peak LH induces ovulation of an exactly determined number of preovulatory follicles left in the ovary after the effect of IS. In conformity with the neuro-endocrine of LH is considered to be the cause of atresia of all concept this peak other estrogen-producing follicles.

422

Studies on the kinetics of follicular growth (36) have revealed their conA growing follicle becomes either an ovulatory tinuous differentiation. Under physiological conditions the number foil icle or it undergoes atresia. of cavitated follicles in the ovary exceeds the number of ovulations (37). Superovulation after administration of an exogenous gonadotropin is supposed So its to be caused by the temporarily premature ovulatory effect of LH. effect interferes with a higher number of the ovarian follicles even before A paradoxically increased number their physiological reduction by the IS. of ovulations and litters was obtained by X-ray treatment of female rats in The same effect was reached after cyclothe cycle before mating (11). phosphamide treatment which suggest that the explanation is a reduction of the follicular atresia rate (10). The suppression of follicular atresia by pregnant mare serum (38) could be Atresia is rare in preantral foil icles assumed also as being due to the IS. Two types of atresia are to be distinbut frequent in cavitated ones (14). 1. Atresia with multifocal degeneration of the granulosa, connected guished: with disintegration of granulosa cells in the presence of round-cell infiltrat ion. 2. Atresia of follicles as a uniform degeneration of the granulosa layer in terms of nuclear pyknosis. The former is assumed to be caused by a cytotoxic effect of the IS (see hypothesis I), the latter is considered, in agreement with others, to be influenced by LH (39) and/or by a suppression of the follicular sensitivity to FSH due to progesterone (40). The first type of atresia (26) is characteristic of the degeneration of the granulosa layer beginning with maturation of the immunocompetence of the IS against the tumor specific transplantation antigens in mice (41), i.e. after the third week of life. In connection with the suppression of the atresia by PMSG in this period (38) we recall the known high sensitivity of the IS to chorionic gonadotropin (42). Corpora lutea are also not present in the adaptive stage of the ontogeny of We have not found any paper dealing with the antigenic specifity the IS. of the corpora lutea. It is of interest that the definitive morphologic degeneration (39) of the corpora lutea appears just in the period coinciding with the expected effect of the IS on the ovary at the preovulatory period i .e. in the period of presumed follicular selection. The prostaglandins which probably take part in functional luteolysis (43) are also produced by macrowhose function is closely related to the IS. phages (44)) The secretory endometrium as well can be considered a primarily non-tolerated tissue. An organ-specific antigen was found in the endometrial stroma and Without any further speculation we would like to the uterine glands (24). draw attention to a marked preand menstrual lympho-leucocytic infiltration of the uterine mucosa and to an increased concentration of prostaglandins (45,46,47). Changes

in

the

ovarian

function

with

age

In the course of ageing in the rat the number of ovulating follicles consThis is in striking coincidence with the agetantly decreases (32,48). dependent alterations of IS response (49,50,51), more pronounced in females the decreasing immunocompetence due to ageing is (52,53) . We assume that connected with a decrease in “superposed tolerance” (see hypothesis I I I).

423

in

Thus, the number of follicles surviving the preovulatory effect of the IS is diminished. The age-depen-ent alterations of the IS are also responsible for the gradually delayed rejection of a graft (52). In the same period an irregularity of the ovarian cycle can be observed (48). In humans a stimulating effect of phytohemagglutinin on lymphocyte transformation becomes reduced with aging (54). The incidence of autoantibodies in women after the age of 40 (but not in men) increases progressively (53). Ovary

and

immune system

during

pregnancy

There is no ovulation during pregnancy and lactation although follicles growing in the ovary (55,56). Moreover, the human ovary is under the of an excess of chorionic gonadotropin which causes superovulation in pregnant animals (57).

are influence non-

The implantation of the blastocyst probably alters the previously determined relationship between the ovary and the IS (see hypotheses I, I I, I I I). The blastocyst is recognized as a new antigen in the lymphatic drainage of the reproductive organs. Its influence on the IS seems to be the same as that of Under normal conditions the time of ovarian antigens on the ovulatory cycle. The immune cycle implantation is exactly determined by previous ovulation. (see hypothesis II) is expected to be extremely vulnerable in that period. a new antigen may induce a new specific immune cycle in the lymTherefore, phatic drainage of the uterus and ovaries and could depress the existing embryo produces demonstrable amounts of the cycle. Moreover , the developing chorionic gonadotropin beginning from the stage of blastocyst (58,59) that If we presume the beginning of a spedepresses the IS (for review see 42). cific immune response in women following a latency of two ovulatory cycle lengths from the antigen effect (Figure l), the end of the third month of appears the menstrual age of pregnancy (i.e. the 8th - 9th week from nidation) In the same period there is to be a critical period for the fetal future. a rapid decrease in chorionic gonadotropin excretion, the corpus luteum regresses and most abortions of an afetal conceptus, “tolerated” up to this time, are accumulated. A rapidly increasing level of plasma progesterone may also affect the relationship between the ovary and the IS in pregnancy. We interpret a lowered responsiveness of follicles to FSH as due to interfere by progesterone (40). We suppose the reduced sensitivity of the follicular granulosa to the FSH leads to the reduction of follicular growth and, thus, the atresia of the nonstimulated follicle. The altered sensitivity to FSH can be connected with the inability of granulosa cells to change their antigenic properties. The impulse for the further induction of cyclic immune responses to the follicles disappears because of interruption of a supply of follicular granulosa antigen (see hypothesis II) but the continual immune response (probably of a humoral nature) to the follicles continues. In the vaginal smear of puerperal women the postpartal parabasal cells can indeed be found (60) recalling the inhibition of ovarian function in juveniles or in old age. It has been demonstrated that the IS undergoes an acute involution during most outstanding during the third month after the last menstruation pregnancy, (for review see 42). The acute involution of the IS continues in the course of lactation irrespective of an eventual gonadectomy in experimental animals. The interruption of lactation causes the restitution of IS function (42). 424

One or two of expected programmed two estrous

pseudomenstruations are not uncommon during This is in agreement with our bleedings. cyclic function of the IS in the reproductive or menstrual cycles (Figure 1).

pregnancy suggestion organs

at the times (29) of a for the next

the former character of the menstrual cycle can be Following pregnancy, appearance or disappearance of anovulachanged, i.e. its length, regularity, We assume that a the length and intensity of bleeding, etc. tory cycles, relationship is gradually developing anew between the IS and the target This relationship disappeared structures of the reproductive system. either due to the involution of the IS mentioned above, and/or due to the By the end of absence of inducing follicular antigens during pregnancy. pregnancy and lactation the continuous (see hypothesis I) and later cyclic (see hypothesis I I) intolerance of the IS to the target structures of the The next step is the restoration of the reproductive tract is restored. “superposed tolerance” (see hypothesis I I I). Immune

system

and

the

age-dependent

failure

of

ovarian

function

a gradual increase in anovulatory cycles during the premenopausal In women, period results in the complete disappearance of cyclic activity of the ovar The commonly accepted hypothesis at present explains this fact by a gradual loss of ovarian sensitivity to the gonadotropins. The production of estrogens decreases and their lowered blood level causes an increase in gonadoSimultaneously, the “stock” of the oocytes is depleted. tropin secretion. The follicular system thus undergoes a gradual reduction (for review see Ovarian function in rats expires in similar manner. 61).

es

It is noteworthy that a mature rat ovary grafted to an ovariectomized senile rat does not ovulate (62,63). In contrast, an ovary of an old rat grafted to an ovariectomized but still ovulating rat starts its function again (63). These experiments contradict the accepted theory of the physiological failure of ovarian function. They could imply an extraovarian mechanism. Transient renewal of ovarian function in old rats can be obtained by various drugs that influence the CNS (L-dopa) (48,64,65) and/or the IS (progesterone, We assume a participation of extraovaACTH, ether stress) (42,66,67,68). rian mechanisms in the physiological age-dependent failure of ovarian function as well as in the transient, drug-induced reversal of this condition. It could be dependent on serious functional changes of IS connected with increasing age (5O,69). There is, however, also an important functional dependence of the IS function upon the CNS (70). We suggest the physiological age-dependent failure of ovarian function to be a certain return to the period before the beginning of regular ovulatory activity. The age-dependent impairment of the IS function could be reflected mainly in a decreasing response to that ovarian antigen which is in close contact with lymphatic drainage, i.e. the antigen of the theta interna of cavitating follicles (see hypothesis I). In a woman, we consider the age of about 40 years as the period of increased tolerance to antigens fully conThis period is characterized by a higher incidence trolled up to that time. of neopiasia and by impairment of ovarian function. Later on, the relations between IS and the ovary develop gradually in a reverse manner to that before the beginning of the reproductive period (Figure 3). A possible

425

relationship between the IS and the physiological menopause has already been anticipated by others (Tl), although based on autoimmunity only. We are not far from the idea that the autoimmune condition reflects the final relation between the ovary and the IS in very old age. In general, we suggest that the alteration of mutual connections between the ovary and the IS during the physiological impairment of ovarian function in aging is, at the beginning, characterized by an undesirable weakening of the immune response to the primarily intolerated (“controlled”) ovarian antigens. The originally cyclic immune response to these antigens (see hypothesis II) later regresses into a continual one. In the event of extension of the continual immune response to the primarily tolerated (autotolerated) noncavitated follicles an autoimmune condition results (Figure 3). SOME DISORDERS OF OVARIAN FUNCTION IN EXPERIMENTAL AND IMMUNE SYSTEM - ROLE OF THE THYMUS

ANIMALS

In those neonatally thymectomized animals (mouse, hamster and rat) that appeared to develop endocrine disorders the thymectomy itself induces a marked alteration of the immuno-competence (72). In animals, in which the neonatal thymectomy is not followed by an immune alteration (i.e. rabbit, guinea pig and sheep) an evident endocrine impairment cannot be detected like to stress the existence of similar species-dependent (72,73). We should differences in sensitivity to the “early” steroid treatment with the resulting syndrome of anovulatory sterility (74,75,76,77,78,79,80). An assumption was proposed of a mutual dependence of the thymus and the endocrine system in the mammalia ontogeny (73,81). The functional changes of the endocrine system are considered to be primary causes for age-dependent changes this idea and and alterations of the IS function (73). We do not agree with assume, that the age-dependent changes in the endocrine function in contrast, are caused by the age-dependent changes of the IS, whose function in the ontogeny is programmed during the period when the interrelations with the endocrine The mutual relationship of both systems in early system are being formed. ontogeny can be demonstrated by evidence of both the IS failures of a “wasting syndrome” type after neonatal administration of steroids in sensitive species (for review see 73) and the emergence of an immediate (72) or delayed (3) ovarian function failure following neonatal and/or early postnatal thymectomy. Special attention is drawn to the ovarian dysfunction in mice with a congeThese homozygous nu/nu BALB/c nital defect of the thymus (72,82,83,84). mice demonstrate a delayed beginning of puberty (82,83) similarly to rats following long-lasting postnatal estrogen treatment (85). Our histological findings in the ovaries of 13 nu/nu mice at three and half to six months degenerated corpora lutea in two animals, tertiary of age were as fol lows: follicles under various degrees of atresia in 12 animals, sporadic intact cavitating follicles reaching only the early stages of cavitation in three Except for the oldest mouse without any follicles and oocytes, only mice. intact noncavitated follicles were found in all remaining 12 animals (86). The same uniform pattern of general atresia of tertiary follicles as well as and ovulatory follicles was found in adult rats after the total lack of preThe similar character of the prolonged postnatal treatment with estrogen. ovarian morphology was found in controls only during the fourth week of life (26).

426

Since there is no maturation of the preand ovulatory follicles In mice with a congenital thymic defect or after a neonatal thymectomy owing to the enhanced it seems that the perinatal presence of the thymus in sensitive atresia, species (i .e. in those in which the adaptive period of IS development is considered to be present in early postnatal period) corresponds at least partly to the extent of fol 1 icular atresia in maturity. The thymectomy in mice performed on the seventh day of life or later, does not result in an impairment of the ovarian function (3). Therefore, we suggest that the regional lymphoid system is autonomous during that period as it has already been outfitted by the thymus for the further differentiation of deeper interrelations between the ovary and the IS (see hypothesis II, Ill). IMMUNE SYSTEM AND SOME DISORDERS

OF OVARIAN

FUNCTION

IN WOMAN -

According to our hypotheses (see hypothesis I, II, Ill) the disorders of the ovarian function in woman can be understood not only as the genuine disorders of the hypothalamus - pituitary or the ovaries but likewise as impairments of the ovarian function due to an altered relationship between “controlled” ovarian antigens and the IS. Two fundamental types of ovarian antigen - IS interrelations damage may be proposed: 1.

Anovulatory disorders culminating in a polycystic ovary consider them a consequence of a decreased response of resulting in an increased tolerance of the “controlled” the so-called “plus” disorders.

2.

More infrequent anovulatory disorders culminating in an auto-immune impairment of the ovary. They can be considered a consequence of an increased response of the IS to the ovary, resulting in a decreased tolerance of the “control led” ovarian antigens - the so-called “minus” disorders.

Immune The 1.

system

following

and

the

“plus”

can

be

termed

or

anovulation

Superovulation (Table 2).

disorders “plus”

of

ovarian

syndrome. We the IS to the ovary ovarian antigens -

function

disorders: due

to

an

increased

“,superposed

tolerance”

TABLE 2 OVULATORY DISORDERS DUE TO ALTERED “SUPERPOSED TOLERANCE” (SEE HYPOTHESIS

stage of Alteration of “Superposed Tolerance” complete increased norma 1 decreased absent

immune Destruction Preovulatory Follicles

absent decreased norma I increased complete

of

III)

IN RAT

Preovulatory LH Release

Ovulatory Conditions

absent present present present present

anovulation+ superovulation normal ovulation subovulation anovulation++

No. of follicles

Ovulating (approx.)

----

+anovulation due to defect of preovulatory ++anovulation due to absence of preovulatory +++“pl us ” disorder of ovarian function *+++“minus” disorder of ovarian function

427

peak of LH secretion follicles

none-++

many+++ normal few+‘++ none++++

2.

Extremely extended interval with resulting oligomenorrhoea

of

the cyclic immune response or amenorrhoea (Table 3).

DISORDERS

DUE TO ALTERATION

OF THE CYCLIC

RESPONSE TO THE OVARY (SEE HYPOTHESIS

ovary

I I)

IMMUNE

IN WOMAN

Menstrual Cycle

Cyclic Immune Response Absence of Immune Destruction of Cavitated Foil icles

Amenor rhoea Dysfunctional Bleeding+

Interval response

Oligomenorrhoea+

of Immune pro1 onged

or

Eumenor rhoea

Norma 1 Interval Response

the

3

TABLE

OVARIAN

to

Polymenorrhoea++

of Immune Shortened

Amenorrhoea (Endometrial

Continual Destruction of Cavitated Fol 1 icles

Atrophy)++

f”plus disorder of ovarian function ++“minus” disorder of ovarian function

3.

Lowered responsiveness of the IS or a lack of it to some “controlled” The result may be an anovulatory menstrual dysfunction ovarian antigens. up to amenorrhoea and a polycystic ovary syndrome (Table 4).

Immune system

and

The

“minus”

so-cal

led

so-ca

1 led

“minus”

ovarian

or totally absent cycle (Table 2).

disorders

disorders

of

ovarian

in women are

“superposed

tolerance”

function

characterized

By lowered anovulatory

2.

By shortening the interval of the cyclic immune response or only by a continual immune response to the primarily intolerated ovarian structures resulting in more pronounced menstrual dysfunction (Table 3).

3.

By the autoimmune alteration of the between the IS and the physiologically (Table 4).

428

in

follows

1.

ovary caused primarily

resulting

as an

by impaired interrelation tolerated structures

TABLE 4

SURVEY OF OVULATORY DISORDERS DUE TO ALTERED BASIC RELATIONS

BETWEEN THE IMMUNE SYSTEM (IS)

OVARY (SEE HYPOTHESIS

IN WOMEN

Clinical condition

Immune response to the primarily tolerated ovarian antigens

lmnune response to “control led ovarian antigens

1)

AND THE

Menstrual cyc It?

Ovulatory conditions

Absent

Absent

Prenatal+ period

Anovulation

Amenorrhoea or dysfunctional bleeding+++

Weak

Absent

Polycystic ovary

Anovulation

Amenorrhoea or dysfunctional bleedi ngtt+

Weakened

Absent

Microcystic ovary

Anovulation

01 igomenorrhoea or dysfunctional bleeding+++

Strong

Absent

Norma

Ovulation

Eumenorrhoea

Strong

Weak

Ovarian failure

Anovulat

St rang++

Strong

Ovarian failure

Anovulation

+This kind pathological

of

%ontrolled that should +++“plus” ++++“minus”

immune response conditions.

can

occur

structures do not differentiate be primarily tolerated were

disorder disorder

of of

ovarian ovarian

I

also

in

the

because destroyed.

ion

postnatal

the

Amenorrhoea+‘++

period

“reserve”

under

structures

function function

In line with our hypotheses it might be possible to take in to consideration the therapy of some thoroughly analyzed cases of ovarian dysfunction with non-specific or specific immunotherapy and/or adequate hormonal treatment well.

as

CONCLUSIONS In as

summary, follows:

1.

Autotolerance is induced by those ovarian structures that are present during the adaptive period of IS development, i.e. non-cavitated foll icles and other ovarian structures without specific antigens in maturity. The adaptive period terminates at the latest simultaneously with the beginning of follicular cavitation in ontogeny. It is probably limited already by the capability of the IS to produce the immunoglobulins.

our

hypotheses

on the

ovary

429

-

IS

interrelation

can

be presented

2.

After a refractory period of the IS development, specific immune response (“intolerance”) is induced towards the structures of cavitated fol1 icles during the period of immunocompetence to the antigens of the transplantation type. The specific immune response is supposed to be determined by the antigenicity of theta interna. The cytotoxic effect proper is directed against granulosa cells of cavitated follicles. The IS controls both the specific ovarian follicular antigens and partly even the persistence of corpora lutea. The immune control of other organ-specific antigens in the reproductive system is presupposed as well.

3.

In the further course of the ontogeny the original continual ponse to the ovary is converted into the cyclic “intolerance”. dition has been established in women even before adolescence, or mena rche .

4.

The selection of the species-specific tolerance” ensured by the “superposed background of the cyclic “intolerance”. established in the earliest period of

5.

Sexual maturity is conditioned by both the morpho-functional the hypothalamus-pituitary system and the adequate relationship the IS and the ovary.

6.

Interrelations between the ovary and the IS are not permanent. They are repeatedly reestablished in dependence on the “supply” of ovarian antigens In principle, they are conditioned by the stage of to the regional IS. ovarian differentiation, which is determined by the level of plasmatic and by the functional condition of gonadotropins and ovarian steroids, the regional IS being controlled by central lymphoid structures (thymus) and factors influencing the IS nonspecifically (steroids, LH, hCG). An important role belongs to the central nervous system (CNS) influencing the CNS is affected the gonadotropin secretion and the IS function; by the external environment and afferent signals transmitted by the vegeEven the direct feedback between the hypothalamustative nervous system. pituitary and IS cannot be ruled out.

immune resThis conat the time

number of ovulating follicles which was established against This protective mechanism sexual maturity.

is the is

maturity of between

7. The cyclicity

is considered to be primarily dependent of ovarian function on induction of specific cyclic immune response (“intolerance”) to the Moreover, the ovarian function is also dependent ovarian target structures. Production of estrogen is determinated by the on gonadotropin action. A preovulatory influence of IS on estrogen producing FSH above all. The rise ovarian structures results in a decrease in plasmatic estradiol. and fall of the estrogen induces the hypothalamic LH-Rh release and thereby Thus, the hypothalamusthe cyclic secretion of pituitary LH is achieved. pituitary female cycle appears as primarily dependent on the cyclic response of the IS to the intolerated ovarian structures, and, secondarily, to the complex IS - ovary - FSH - interrelation.

8. The physiological

failure of the ovarian function with ageing is caused It results above all by age-dependent impairment of the IS function. in a disarrangement of the IS-ovary interrelations in a sequence quite inverse to that which had been established in the period prior to sexual maturity.

430

9.

10.

The growing and ontogeny above all.

complexity is thought

of morphorfunctional IS structure in phylogeny to be dependent on female reproductive demands

The above mentioned work), J hypotheses the ovulatory ovarian function respect dotropins and steroids on the ovarian the ovary and the hypothalamus-pituitary by the relationship between the ovary

on the

role

of

IS

in

regulation

of

the physiology effects of the gonastructures. The interaction between system appears to be modulated and immune mechanisms (Figure 4).

1

S

J

Relationship among the hypothalamus-pituitary Figure 4. ductive organs and the immune system: S - “supersystem” between reproductive function, Sl - system of feedbacks pituitary system and the ovary, S2 - system of feedbacks system and the reproductive organs.

EXPERIMENTAL The ideasdiscussed and immunological should be possible

require sphere.

to

experimental They could

system, the reproregulating the the hypothalamusbetween the immune

PROOF

confirmation in the be tested by available

study: 431

endocrinological technqiues.

It

1.

The role of the adaptive period during the immune system development for the future ovarian function, i.e. the effect of those ovarian antigens during the adaptive period which are supposed to be non-tolerated in maturity.

2.

The presence of lymphoid undergoing atresia during estradiol.

3.

The cyclicity nodes to the

4.

The effect of progesterone ccl lular FSH receptors.

cells the

of the cellular local treatment

within the preovulatory

cavitated period

immune response with transplantation on the

follicular

of

ovarian peaking

within the antigen. growth

and

follicles plasma

regional

on the

lymphatic

ovarian

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