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Home , Lordosis behavior, Neuroendocrinology, Reproductive system

BIOLOGY OF 20, 111-127 (1979)

The Neuroendocrinology of Reproduction: An Overview1

ROGER A. GORSKI

Department of and Research Institute, UCLA School of Medicine, Los Angeles, California 90024 Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 INTRODUCTION isms, it may be useful to divide the reproductive Each of the preceding speakers in this process into several distinct phases (Table symposium has already reviewed one important 1). A very early step in the reproductive process facet of the neuroendocrinology of reproduc­ is the differentiation of the two individuals tion. Therefore, it is clearly unnecessary to which will eventually be capable of reproducing present a thorough review of this entire field when mature. Although the concept of the and my approach will be to attempt to present of the reproductive one overall perspective of the role of the brain system is well-known for the internal reproduc­ in the reproductive process while attempting to tive organs and the external genitalia (Wilson, emphasize that which has not already been dis­ 1978), this same concept applies to brain cussed. At best, this discussion will complement function as well. With respect to the peripheral the other presentations, which together do , remember that for a form a rather complete overview of the neuro­ period during development, the male and of reproduction. To begin with, are morphologically indistinguishable. it will be helpful to consider the role of the After subsequent differntiation of the gonadal brain in the reproductive process in very anlage into testis or , the secretory activity general terms. of the male appears to be critical for masculine differentiation of both internal A possible fundamental division of the level reproductive organs and of the external genitalia. of involvement of the brain in reproduction is This concept is apparently also directly applic­ presented in Fig. 1. Control mechanisms able to brain function (Fig. 2). It is well-estab­ which can be independent of another individual lished that the brain of the male and female rat constitute the intrinsic regulatory processes differ functionally; however, these differences involving brain, pituitary and gonad. Those in brain function are not determined directly mechanisms which involve two individuals, the by the neuronal genome, rather, these extrinsic regulatory processes, can be further differences in brain function are established by subdivided into those interactions which the environment during the early involve general afferent stimuli or primary perinatal period, apparently by the modification sensory input such as olfaction. Since sexual of an inherently female brain (Beach, 1975; reproduction by definition involves two indivi­ Flerko, 1975; Gorski, 1971; Gorski et al., duals, the existence of this extrinsic regulatory 1977, Quadagno et al., 1977; Reinisch, 1976). system should not be surprising. However, Note that if development occurs in the absence relatively little attention has been paid to this of gonadal (e.g., the intact or neo- aspect of reproduction, yet there can be impor­ natally spayed female and the neonatally tant endocrine responses to behavioral and castrated male) regardless of the genetic sex of sensory input, as will be described below. the animal, the brain is functionally female in the adult. In contrast, if differentiation occurs Sexual Differentiation of the Brain in the presence of endogenous or exogenous With respect to intrinsic regulatory mechan- gonadal , such a hormone-exposed animal exhibits masculine brain function when adult.

There are a number of brain functions which Original research from the author's laboratory supported by USPHS Grant HD-01182 and by the Ford have been suggested to undergo this process of Foundation. sexual differentiation, although not all in

111 112 GORSKI

GENETIC FEMALE

INTACT MALE

NEONATALLY SPAYED FEMALE INTACT OR SPAYED FEMALE, OR NEONATALLY CASTRATED MALE CASTRATED MALE EXPOSED TO EXOGENOUS STEROIDS Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021

FIG. 1. Highly schematic representation of two levels of involvement of the brain in the regulation of FUNCTIONALLY FUNCTIONALLY reproduction: 1) intrinsic regulatory processes which FEMALE MALE include the reciprocal interactions between brain, pituitary (P) and gonad and 2) extrinsic regulatory FIG. 2. Schematic representation of the influence processes which involve an interaction between two of the perinatal hormone environment on the sexual individuals either at the level of special sensory input differentiation of the rat brain. Regardless of genetic (2a, e.g., olfaction, vision) or general afferent stimuli sex, at (or shortly before) the brain of the rat (2b, e.g., genital stimulation). Abbreviations: A, appears to be potentially female and exposure to adrenal; O, ovary; T, testis; U, . gonadal steroids is required for the development of a functionally masculine brain.

the rat, which is the upon which the present comments will be focused. Note that 1975), gender role (Ehrhardt, 1978) and also this concept appears to apply to the regula­ territorial marking (Lumia et al., 1977). tion of pituitary secretion (Flerko, 1975; Two functional parameters of the reproduc­ Gorski, 1971; Neill, 1974), male and female sex tive neuroendocrine system can be used to behavior (Beach, 1975; Gorski, 1974; Reinisch, illustrate clearly this concept of the sexual 1976), aggressive behavior (Barr et al., 1976; differentiation of the brain. In the adult animal, vom Saal et al., 1976), social and play behavior the female rat has the potential to release (Goy and Resko, 1972; Quadagno et al., 1977), gonadotropins cyclically in the surge mode urination posturing in the dog (Beach, 1974), which is essential for (Brown-Grant, the influence of gonadal hormones on food 1974; Harlan and Gorski, 1977; Mennin and intake and body weight regulation (Nance and Gorski, 1975; Taleisnik et al., 1971) and the Gorski, 1975; Tarttelin et al., 1975), some female also exhibits frequently aspects of learning behavior (Dawson et al., (Gorski, 1974). In contrast, in the adult male, 1975; Denti and Negroni, 1975; Scouten et al., even in the presence of exogenous ovarian hormones, there is no surge of (LH) nor is the genetic male able to exhibit lordosis behavior except occasionally TABLE 1. The neural regulation of reproduction. (Brown-Grant, 1974; Gorski, 1974; Gorski and Wagner, 1965; Harris, 1964; Harris and Levine, Intrinsic regulation Extrinsic regulation 1965; Taleisnik et al., 1971). If exogenous steroids are administered to rats during the Differentiation of brain Special sensory input perinatal period, what are the consequences to Puberty Olfactory cues these animals when they mature? In the case Photoperiod of the male there are no apparent effects of Ovulation Visual displays Sexual behavior Vocalization such perinatal treatment provided the dose of Correlation: ovulation General sensory factors hormone is not excessive; the male will still with sexual behavior Genital stimulation exhibit the typical lack of cyclic gonadotropin Suckling stimulus release and only rarely exhibit lordosis behavior.. Parturition In contrast, if the female is exposed to gonadal NEUROENDOCRINE)LOGY OF REPRODUCTION 113 steroids early in life, there is a marked change; Sutherland and Gorski, 1972). Moreoever, she no longer will exhibit lordosis behavior nor antiestrogenic compounds or aromatase inhibi­ will she show the cyclic release of LH and in tors have been shown to inhibit masculinization fact such an animal is anovulatory and sterile due to injection (Booth, 1977; (Barraclough and Gorski, 1961, 1962; Gorski, Doughty and McDonald, 1974; McEwen et al., 1971, 1974; Harlan and Gorski, 1977; Harris 1977a; Vreeburg et al, 1977). It has also been and Levine, 1965). Although these results could demonstrated that within brain , as represent a pharmacological artifact to exogen­ elsewhere in the body, steroids are metabolized,

ous hormone exposure, the effects of neonatal and testosterone in the brain can be aromatized Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 gonadectomy clearly indicate the importance of to (Naftolin et al., 1975; Selmanoff et the hormone environment for normal develop­ al., 1977). Finally, the nonaromatizable andro­ ment of brain function. If the perinatal female gen dihydrotestosterone fails to masculinize the is gonadectomized, when she is adult she still brain (Korenbrot et al., 1975; Sodersten, 1978; has the capacity (of course following ovarian Whalen and Rezek, 1974). Thus, as already transplantation) to ovulate (Gorski and Wagner, discussed with respect to behavior (Crews, 1965) and also to display high rates of lordosis 1979), we have the seemingly unusual situation responses (Gerall et al, 1973). The neonatally where estradiol appears to be the vehicle for gonadectomized female appears to be essentially masculinization of the brain. Since removal of comparable to the normal female; thus, the the ovary is without apparent consequence to may play little role in the process of sexual differentiation, it was logical to assume sexual differentiation. In contrast, if the testes that the ovaries were relatively quiescent during are removed, we see a marked alteration in the this perinatal period of differentiation. How­ male. When adult, this genetic male is able to ever, when radioimmunoassay for release gonadotropin cyclically (Gorski and became available, it became apparent that Wagner, 1965; Harris, 1964; Pfeiffer, 1936) and during the lifetime of the female rat, the period also exhibits essentially female levels of lordosis when levels in the blood are probably behavior (Feder and Whalen, 1964; Gerall et al., the highest is actually this perinatal period 1967; Grady et al., 1965). (Ojeda et al., 1975; Weisz and Gunsalus, 1973). Although the source and nature of this immune- Since gonadal hormones are also important assayable estrogen is still controversial, it would for reproduction in the adult, these data appear that plasma levels of true estradiol are support the view, first proposed by Phoenix very high in the perinatal female rat. If estrogen et al. (1959), that there are really two funda­ is the hormone which masculinizes the brain mental ways that hormones act on the and if plasma titers of estradiol are very high in central : activational and organi­ the neonatal female, how is masculinization of zational. In general terms, the activational the normal female prevented? effects of steroids refer to the activation or inhibition of already existing neural circuits. In probable explanation of this apparent These are transient effects, as typified by contradiction, it has been shown that in the ovulation or sex behavior. In marked contrast perinatal rat there exists a specific fetal estrogen stand the organizational actions of steroids,: binding protein which has a much greater the effects of steroids which actually determine, affinity for estrogen than for testosterone apparently permanently, the neural systems (Nunez et al, 1971; Plapinger et al., 1973; which will function in the adult animal. Raynaud et al., 1971). Therefore, it has been Although this concept of organizational vs proposed that the high levels of estradiol in the activational effects of steroids will be considered plasma of the perinatal rat are in fact function­ further, there are two important aspects of this ally sequestered by this fetal binding protein, process of sexual differentiation which should whereas in the case of the male, testosterone is be considered first: What is the identity of the relatively free to enter the , where it can hormone which sexually differentiates the brain be aromatized to estradiol and perhaps, work­ and what components of the brain differentiate? ing through estrogen receptor mechanisms, Although the early work in this field utilized bring about masculine sexual differentiation of testosterone and gave rise to concepts such as the brain. androgenization and masculinization, estradiol In spite of the suggestion that the ovaries is apparently more potent in "masculinizing" may play little role in sexual differentiation, the brain than is testosterone (Gorski, 1966; there is a potential consequence of these high 114 GORSKI levels of estrogen in the plasma of the perinatal female rat. Mounting behavior, which might be considered a male sexual characteristic, is less sexually dimorphic in the rat than might be expected (Whalen and Edwards, 1967). How­ ever, if the preoptic area of the of the 2-day-old rat is exposed directly either to testosterone or estradiol, when these animals reach maturity and are tested for male sex Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 behavior under either continuous testosterone or estrogen therapy, there is a significant facilitation of mounting behavior (Christensen and Gorski, 1978). This observation clearly demonstrates that mounting behavior can be subject to the organizational action of steroids. FIG. 3. Highly schematic representation within the Although a speculative hypothesis, it may be right half of the rat brain of the structures which have sugested that the levels of mounting behavior been suggested to modulate gonadotropin secretion exhibited by the "normal" female are a reflec­ (open compartments), reproductive behavior (solid tion of the exposure of her brain to minimal compartment) or both these components of reproduc­ (and perhaps varying from individual to indivi­ tion (shaded compartments). Also indicated are various factors which in turn modulate brain activity. dual) levels of free estradiol not bound by the Abbreviations: Amyg, amygdala;ARC, ; fetal binding protein. CPU, caudate-putamen; DAH, dorsal anterior hypo­ thalamus; HPC, hippocampus; ME, ; However, when one indicates that the brain MRF, mesencephalic ; OB, olfactory undergoes sexual differentiation under the bulb; P, pineal; PD, pars distalis; PN, pars nervosa; influence of gonadal steroids, this statement is POA, preoptic area; S, septum; SC, suprachiasmatic a frank overgeneralization. Within the reproduc­ nucleus. tive system, the compartmentalization of function is very common. Ovarian physiologists are cognizant of whether they are dealing with evaluate these for sexual differences since it is luteal, granulosa or thecal tissue and, in the case likely that sex differences will reside within the of the testes, one may be specifically interested precise neural substrate for the control of an in interstitial cells, seminiferous tubules or adult function. Another approach, however, perhaps Sertoli cells. When it comes to brain is to identify the site of hormone action in the function, compartmentalization perhaps reaches perinatal animal through the use of the direct its highest degree of development. Not only do implantation technique. Since this approach distinct anatomical units comprise the brain, is complicated by the likelihood that pharmaco­ but these units are complexly interconnected logical levels of steroid will be produced at the anatomically. In Fig. 1, the brain is represented site of the implant and/or that diffusion will as a simple box; Fig 3 presents a more realistic, occur, it might be more appropriate to consider nonetheless schematic, view. When a diagram as this question in terms of the possible sites of complicated as this oversimplified picture is hormone uptake in the perinate. However, this viewed, can one accept the statement that the approach assumes that steroid receptor mechan­ brain per se undergoes sexual differentiation? It isms are involved in sexual differentiation, an seems fully as important to reproductive assumption which may or may not be true (see as differentiating the role of the below). Finally, it would be very helpful if one follicle and , to answer this could identify a clear signature of sexual question: Where in the brain does this process differentiation upon which appropriate studies of sexual differentiation occur? This is obviously could be focused. a very difficult question, which cannot be answered completely. However, as part of this overview, it may be useful to list general A Morphological Signature strategies which have been applied to determine of Sexual Differentiation of the Brain the neural site(s) of sexual differentiation. We presently believe that we have discovered One approach is to identify specific neuro­ such a clear signature. Although several labora­ endocrine control sites in the adult and then tories have suggested that there are morphologi- NEUROENDOCRINOLOGY OF REPRODUCTION 115 cal sex differences within the brain, these, phism is not dependent upon the activational almost without exception, have been rather actions of steroids, these data are still consis­ subtle differences, ranging from differences in tent with the possibility that there is simply a nucleolar size to differences in neuronal pro­ genetic morphological difference between male cesses. For example, Raisman and Field (1973) and female. Is this actually have shown that one can sex the brain of the independent of hormones in general or might rat at the level of the electron microscope by there be an action of hormones during the quantifying the specific relationship between perinatal period? To answer this question,

terminals and dendritic shafts or spines additional animals were subjected to the now Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 within the preoptic area. Similarly, Greenough classical perinatal manipulations: castration of et al. (1977) have studied the hamster and the male and administration to the detected a sex difference in the dendritic female. As shown in Fig. 5A, in male rats branch patterning of preoptic Golgi-stained subjected to sham castration on Day 2 and . However, in the study of Nottebohm given oil on Day 4, essentially the same and Arnold (1976), a rather gross sex difference sex difference within the volume of the sexual­ in the brain of the has been discovered. In ly dimorphic nucleus is seen. The volume of the response to the stimulation of this paper, sexually dimorphic nucleus of the sham- Christensen discovered an unexpectedly clear castrated male is significantly larger (P<0.01) and obvious morphological sex difference in the chan that in each of the other groups, including brain of the rat (Gorski et al., 1977, 1978), its genetic counterpart, the neonatally castrated which we suggest may represent that signature male. Nuclear volume in the androgenized of early hormone action which could help female injected with 1 mg testosterone proprio- elucidate the fundamental mechanisms of nate (TP) and the neonatally castrated male are sexual differentiation. both significantly larger (P<0.05 and 0.01, It is possible to sex the rat brain from a respectively) than that of the control female. histological section through what we now call Thus, the perinatal hormone environment does the sexually dimorphic nucleus (SDN) of the not appear to reverse completely this sexual preoptic area, even without magnification (Fig. dimorphism. Although this may be a problem 4). There are several important questions of hormone dose, it also may be due to the fact related to this anatomical sexual dimorphism; that some differentiation occurs prenatally one of course would be whether it is dependent and/or perhaps to the fact that there may on the activational action of gonadal steroids. indeed be genetically determined anatomical The data illustrated in Fig. 5B suggest that it is sexual differences in the brain. In any case, it is not. In terms of the overall volume of the clear that the volume of the sexually dimorphic sexually dimorphic nucleus, there is about an nucleus undergoes hormone dependent changes. 8-fold difference, the male having the larger We do not know the function of this nucleus, if nucleus. In this experiment, adult male and in fact it has a specific function. On the basis of female rats were gonadectomized and sacrificed these data, it would not appear likely that these after specific hormonal treatment, in order neurons regulate either lordosis behavior or to evaluate the volume of the sexually dimor­ gonadotropin release. There is not consistent phic nucleus (Gorski et al., 1978). When the correlation between these nuclear volumes and animals were treated with estrogen and proges­ the ability of the animals to display lordosis terone in a regimen which facilitates lordosis behavior or to exhibit the cyclic surge of behavior in the female, we saw no significant gonadotropin. For example, the neonatally alteration in nuclear volume. Similarly, when castrated male will exhibit lordosis behavior the animals were treated for 2 weeks with and will ovulate if given an ovarian graft, yet its testosterone propionate, which induces male nuclear volume is intermediate between that of sex behavior in the male, we again did not the normal male, which exhibits neither cyclic eliminate, in fact did not alter, the sexual gonadotropin release nor lordosis behavior and dimorphism. Although the data are not shown that of the highly androgenized female, which here, additional animals were rendered hypothy­ also does not display lordosis behavior nor roid with propylthiouracil and again this ovulation. dramatic change in endocrine status did not alter the sexual dimorphism. Recently we have performed a quantitative Although it is clear that the sexual dimor­ analysis of the cells within this nucleus and have concluded that the concentration of 116 GORSKI neurons is comparable in male and female, but brain, which certainly involves its neuroendo- since the volume of the male is so much larger, crine function, appears also to alter the con- the genetic male has many more neurons nectivity of neurons and even neuronal number, within the sexually dimorphic nucleus (Harlan Given these dramatic and permanent effects et al., 1978). Thus, sexual differentiation of the of perinatal hormone exposure, let us return to

B Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 ,"£&*' V ••'• . • « v • : XjmEUi

FIG 4. Thionin stained histological sections (60 Mm) through the sexually dimorphic nucleus (arrows) of the medial preoptic area at the point of its maximum development in two gonadectomized male (A, C) and female (B, D) adult rats. Sections A and B provide general orientation and sections C and D provide greater histological detail. Abbreviations: AC, anterior commissure; OC, optic chiasm; others as in Fig. 3. Reprinted from Gorski, 1978. NEUROENDOCRINOLOGY OF REPRODUCTION 117

PROJECTION NEURON Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021

GENETIC FEMALES GENETIC MALES FIG. 6. Highly schematic representation of projec­ FIG. 5. Influence of the perinatal (A) and adult (B) tion and local circuit neurons. Magnified insert modi­ hormonal environment on the volume of the sexually fied from Schmitt et al., 1976. dimorphic nucleus (SDN) of the medial preoptic area. Perinatal treatment consisted of gonadextomy (gonadx) in males and the injection of oil or testosterone propionate (TP) in females. Manipulation of the hormone environment in adult gonadx animals included posed that the projection neuron represents one oil treatment, the injection of TP for 2 weeks or the specialized system, which may in fact not be injection of estradiol benzoate (EB) for 3 days followed that typical of the anatomical basis of brain by progesterone (P). The latter two treatments would function. The central section of Fig. 6 is meant be expected to restore male and female sexual behavior, to dramatize the existence of neurons which respectively. Modified from Groski et al., 1978. may have rather short rather than the longer projection axons or in fact may not have axons at all. These neurons are presumably the concept of the activational and organiza­ spikeless, that is they do not conduct action tional actions of gonadal steroids. At the potentials and therefore are silent electrophysi- mechanistic level, how similar or how different ologically. Moreover, there appears to be the are these two actions? In the context of this potential for intricate interactions within the overview, this question should be reviewed dendritic fields of various interconnected because of its conceptual significance. Although neurons, giving rise to the concept of local there is a paucity of data to support the follow­ neuronal circuits (Schmitt et al., 1976; van der ing comments, hopefully these statements will Loos, 1976). The view that dendritic branches stimulate further thought, discussion and represent a one way system is probably incorrect. perhaps experimentation. As the insert (Fig. 6) suggests, dendrites may possess presynaptic terminals. Materials can be transported from the soma to the dendritic The Nature of Neuronal Interaction system and then released. In addition, materials It is not surprising that any concept of can also be transported retrogradely from hormone action in the brain borrows heavily terminals to the soma and beyond (Cowan from our understanding of the well-studied and Cuenod, 1975). Moreover, adjacent den­ action of steroids on peripheral tissues such as dritic branches may be able to communicate the uterus or . However, before we without synapses, as indicated in Fig. 6 by the attempt to apply these principles to the brain, presence of an electrotonic or gap junction. let us take a step back and consider the general Finally, complex and presumably functional nature of neuronal interaction. When one units such as reciprocal synapses or serial speaks of the brain, it is likely that the general synapses apparently exist. If one considers the thought that comes to mind is exemplified by fact that certain of these synapses may be the "projection neuron" shown in Fig. 6. The inhibitory and others excitatory, one must projection neuron is essentially polarized agree that the concept of local circuit interaction with input segregated at one end, the dendritic represents a very rich opportunity for the end, and its output segregated at the other end potential influence of the hormonal environ­ of the neuron, at the axonal terminals. Such a ment. It is likely, therefore, that changes in the neuron would generate action potentials chemical environment in such local circuits and therefore can be studied electrophysiologic- dramatically alter the functional capacity ally, Recently, however, it has been pro- or activity of the neurons in such contact. 118 GORSKI

Perhaps the most significant aspects of this mitter synthesis, release or reuptake. In addition, concept of the existence of local circuit neurons this product of hormone action at the level of would be the bidirectional transfer of informa­ the genome might alter membrane potential or tion and the possibility of the long term diffuse it might be transported to the dendritic termin­ modulation of neural function through local als where the steroid-induced product might act chemical modulators or even those modulators as a local modulator of the dendritic field or which come from a distance. In any case, this even as a at a dendritic concept should be incorporated into schemes of synapse. Finally, the product of hormone

hormone action. action may be an enzyme or cofactor which Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 might stimulate a series of steps resulting in a Activational vs Organizational new neurosecretory product or in the renewal Actions of Gonadal Hormones of receptor proteins or it may play a degradative role such as the destruction of luteinizing Figure 7 illustrates one scheme to explain hormone releasing hormone (LHRH) discussed how gonadal steroids might exert their activa­ by Barraclough et al. (1979). The net effect of tional effects on steroid hormone responsive any or all of these events would be the transitory neurons in the adult central nervous system. facilitation or inhibition of neuronal function. The classical concept of hormone action, as understood in the periphery, is adopted here: Possible mechanisms of the organizational the steroid enters the cytoplasm and binds to a actions of steroids on the developing hormonal specific receptor; this steroid-receptor complex sensitive neuron are illustrated diagrammatically then is translocated into the nucleus where in Fig. 8. The steroid hormone may act as a eventually new messenger RNA is formed, local modulator of dendritic function, in this leading to some product. In addition, however, case of a more immature neuron. The steroid it is possible that the steroids act directly on may directly alter neuronal surface characteris­ the membrane of the neuronal soma (see tics, which could be critical in determining final McEwen et al., 1978) or, as is more likely, connectivity, if cell to cell recognition or even steroid hormones in the brain may act as local "attraction" plays an important role in how the modulators of dendritic communication. What brain is compartmentalized (Sidman, 1974; is the function of the product that is theoreti­ Diamond et al., 1976). In addition, steroid cally produced by hormone action on nerve hormones might directly or perhaps more likely cells? Since nerve cells are postmitotic, chemical through classical steroid receptor mechanisms energy does not have to be geared towards (see McEwen et al., 1977b), act within the dividing the cell. However, the product of nucleus and again bring about the synthesis of steroid action might well be transported to the some product which could itself alter neuronal axon terminals and in fact function as a neuro­ transmitter or local modulator of neurotrans­

RETROGRADE TRANSPORT , N \\ (LOCAL MODULATOR OF DENORIT L ) W AND/OR PRESYNAPTIC TERMINALS) LOCAL MODULATIOI ALTER MEMBRANE POTENTIAL ENZYME, NEUROTRANSMITTER ( LOCAL MODULATOR TRANSPORTS) TO AXON OR DENDRITES

ENZYME OR COFACTOR INDUCTIVE, RENEWAL TRANSPORTED TO TERMINALS OR DESTRUCTIVE ROLE NEUROTRANSMITTER AND/OR LOCAL MODULATOR OF NEURO- TRANSMlTTOR SYNTHESIS, RELEASE, OR REUPTAKE

ALTERED CELL NUMBEuR AND/O R CONNECTIVITY TRANSITORY FACILITATION OuR INHIBITIO N OF NEURONAL F ALTERED " NEUROTRANSMITTOR " PRODUCTION / RELEASE ALTERED NEURAL SENSITIVITY FIG. 7. Highly schematic representation of possible mechanisms of the activational effects of gonadal FIG. 8. Highly schematic representation of possible steroids (S) on the adult brain. S-R, steroid-receptor mechanisms of the organizational effects of gonadal complex. steroids (S) on the developing brain. NEUROENDOCRINOLOGY OF REPRODUCTION 119

surface characteristics or function as an enzyme, androgen cycle normally after puberty, but at a V neurotransmitter or local modulator which acts very early age, apparently in response to the in the soma or is transported to the axonal feedback action of gonadal steroids, become and/or dendritic terminals. To bring about a anovulatory (Arai, 1971; Gorski, 1968; Harlan I permanent change in the brain, the action of and Gorski, 1978; Kikuyama and Kawashima, the steroid or steroid-receptor complex within 1966). Further study of these 3 preparations, the nucleus may permanently alter genomic the perinatal rat, the septal lesioned animal and activity. In addition, however, there is another the lightly androgenized animal showing the

way to conceptualize the organizational action delayed anovulation syndrome, may permit us Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 of steroids: in spite of their permanent effect, to determine eventually whether or not the they might only transiently modulate genomic organizational and activational actions of or perhaps just general cellular activity. The steroids on the brain are fundamentally different key to this proposal is that during the process and whether or not there is something unique of development of the central nervous system, about the developing animal rather than the it is clear that sequential steps are critical. mechanism of action of the hormone which J A developing neuron, if it is to make its appro­ permits this permanent alteration in brain priate connections, must reach an appropriate structure and neuroendocrine function. site in an appropriate stage of development in T synchrony with its normal target. It is, there­ fore, possible that the action of steroids in the Correlation of Ovulation with Receptivity developing nervous system of the perinate There is one additional topic with respect to is quite transitory, but since it occurs at a I the intrinsic neuroendocrine regulation of critical time results in a permanent alteration, reproduction (Table 1) which I would like either in cell number, cell connectivity, in to include in this overview: the correlation permanently altered neurotransmitter produc­ between ovulation and sexual behavior. Not tion and/or release or in altered neural sensitivity only is this a significant question with respect to steroids, to and/or to to successful reproduction, it also permits the other chemical factors. introduction of a speculative concept about the It is important to emphasize that although role of releasing hormone producing neurons, the action of steroids on the developing nervous a concept which may have more general signifi­ system may produce a unique alteration in cance. genomic activity which does not occur at any Lordosis behavior in the rat, although clearly other time or may produce a unique product not the only component of female sexual which is not produced at any other time, it is behavior, is a convenient measure of sexual perhaps equally likely that the fundamental receptivity (Gorski, 1974). It is clearly estab­ mechanism of action of steroids on the develop­ lished that lordosis behavior is hormone- ing nervous system, the so-called organizational dependent, in fact, it is dependent upon two action of steroids, is actually comparable to ovarian hormones. Although one can induce in that which occurs in the adult but in the the gonadectomized normal female high levels developing central nervous system, the neuron of lordosis responding with estrogen alone itself is in a unique situation. Therefore, as a (Davidson et al., 1968), a much more brief consequence not of the action of the steroid exposure to estrogen when followed by exposure but of the environmental situation in which the to progesterone is as or more effective in neuron exists, a permanent change is produced. facilitating lordosis behavior as is a much longer Recently we have suggested that this so-called treatment with estrogen alone (Gorski, 1974). organizational action of steroids may not be Moreover, during the normal restricted to the perinatal animal. At least of the rat, the rising titers of estrogen which under two conditions in the adult, steroid trigger the LH surge are then followed by a hormones appear to alter brain function per­ moderate surge in progesterone activity (see manently: 1) Following a lesion of the lateral Barraclough et al., 1979). Thus, in the normal septum, estrogen treatment for about one week rat it would appear that lordosis behavior is the appears to "induce" in male animals the ability consequence of the sequential exposure of the to exhibit high levels of lordosis behavior brain to estrogen followed by progesterone. (Nance et al., 1975, 1977) and 2) female rats What about the mechanisms which correlate which are exposed to a low dose of exogenous ovulation and reproductive behavior? Obviously, 120 GORSKI for successful reproduction from an evolutionary physectomized animals (Pfaff, 1973) or directly point of view, it might be very effective to into the brain ( and Foreman, 1976) and correlate closely these two processes, perhaps as markedly facilitate lordosis behavior. in the case of the reflex ovulators. Nevertheless, This evidence can be put together in terms in the spontaneously ovulating animal, what is of a classification of releasing hormone produc­ it that correlates ovulation with reproductive ing neurons (Fig. 9), which may provide insight behavior? Obviously one prime candidate with respect to the correlation between ovula­ would be hormone levels. The sequential tion and sexual behavior and in neuroendocrin-

exposure of the brain to estrogen and progester­ ology more generally. The term neuroendocrine Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 one clearly facilitates lordosis behavior. Since transducer, which was first proposed by Wurt- the progesterone itself appears to be a conse­ (1971), is excellent since it implies that quence of the surge of LH which ultimately will these particular neurons are able to transduce lead to rupture of the ovarian follicles, the very neural information into a hormonal message, hormone that brings about ovulation may also obviously by the secretion of releasing hormones indirectly facilitate lordosis behavior. But is this into the pituitary portal system. This might, in the only mechanism for correlating reproductive fact, be considered the "typical" neuroendocrine behavior and ovulation? neuron. In addition, it is possible that certain neurons which are equivalent to classical neurons are also releasing hormone producing A Classification of Releasing Hormone Neurons neurons. This group could include the releasing I would like to suggest that there may also hormone neurons found in the brain far removed be a neural element active in this correlation from the hypothalamus and median eminence. and in so doing, make a much more general Also since dopamine, a classical neurotransmit­ statement about the apparent role of releasing ter, may be a release inhibiting hormone producing neurons and in fact to offer hormone (see Gibbs and Neill, 1978), dopamin­ a classification of these neurons. Silverman has ergic neurons would have to be included in this already reviewed the fact that releasing hor­ class. The category of neurons I want to stress mones project to many areas of the brain other can be called neuroendocrine integrator neurons. than to the median eminence (Silverman et al., At one end of its branched axon, this neuron 1979). Moreover, neurons which, based on may secrete into the portal vessels a releasing electrophysiological evidence, project to the hormone, perhaps LHRH, to promote the LH median eminence and are therefore candidates surge necessary for ovulation. At the same time, for producers of releasing hormones, have through its branched axon, it communicates branched axons and also terminate in other speculatively either directly with other releasing areas of the brain (Renaud, 1976; Wilbur et al., hormone producing neurons, even itself or 1976). Thus, it is likely that certain releasing perhaps more importantly with "ordinary" hormone producing neurons terminate both in neurons. Thus, the releasing hormone itself, a the median eminence and elsewhere in the brain. Is it possible that "classical" releasing hormones directly modify neuronal function? It has been shown that releasing hormones, when applied directly to neurons by microion- tophoresis, can modify neuronal activity with some specificity (Kawakami and Sakuma, 1974; Moss, 1976; Wilber et al., 1976). Moreoever, releasing hormones can have behavioral effects. In a gonadectomized female animal primed with estrogen, progesterone administration is followed by a gradual evolution of full lordosis responsiveness within a matter of 4—6 h (Gorski, 1974). A similar development of lordosis CLASSICAL NEUROENDOCRINE NEUROENDOCRINE responding has been observed in an estrogen- NEURON INTEGRATOR TRANSDUCER primed gonadectomized animal in which LHRH FIG. 9. Schematic representation of three possible was injected systemically (Moss et al., 1975). In classes of releasing hormone producing neurons. fact, it is possible to inject LHRH in hypo- Modified from Gorski, 1977. NEUROENDOCRINOLOGY OF REPRODUCTION 121 fragment of the releasing hormone or another characterizes the reproductive process in the chemical substance also produced by this lizard, Anolis carolinensis. neuron, may act as a neurotransmitter or local Although the importance of environmental modulator of dendritic activity and ultimately stimuli for successful reproduction in the ring modulate the activity of neurons which partici­ dove is a classic example of the extrinsic pate in lordosis responding. Thus, these particu­ regulation of reproduction, recent data add a lar neurons, if they do in fact exist, would new dimension to the interaction between be in an excellent position to help bring about mammalian . It is now amply demon­

the correlation between ovulation and repro­ strated that many mammalian species produce Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 ductive behavior. It is clear that the view ultrasonic vocalizations which the human that releasing hormones act solely on the cannot hear but which appear to play a role in may be too simplistic. Releasing the physiology of the animals (see Floody and hormones and other brain or pituitary Pfaff, 1977; Floody et al, 1977). Recently it may play an important role in regulating the has been shown that ultrasonic vocalizations activity of the central nervous system, either as apparently emitted by the male rat can signifi­ putative neurotransmitters and/or modulators cantly facilitate female sexual behavior (Mcin­ of local circuits. tosh et al., 1978). In this experiment, two groups of estrogen-progesterone primed ovariec- tomized females were caged with long term Extrinsic Regulation of Reproduction gonadectomized males. Into one of these identical cages were beamed the sounds or lack Thus far, this overview of the neuroendocrine of them from an empty cage and in the other, control of reproduction has been limited to the ultrasonic vocalizations recorded from a intrinsic regulatory factors. However, as indi­ distant arena were broadcast. Since the cated in Table 1, there is another system to males in the test cages were gonadectomized, consider: the extrinsic regulation of reproduc­ they did not attempt to mount, but nevertheless tion. Moreover, this sytem can be subdivided the females who had been exposed to the into those factors which involve special sensory ultrasonic vocalizations exhibited significantly factors or more general input such as the tactile more solicitory behavior, as measured both by a stimuli of or of suckling. With respect to special sensory input, the importance of olfactory cues in reproductive physiology has been well documented (see Beauchamp et al., 1976). With respect to visual input, it is necessary to consider the importance of photo- period. Although photoperiod is clearly not a stimulus transmitted from one individual to another, it is an extrinsic factor which plays an •* important role in the reproductive process, as has been emphasized within this symposium (Turek and Campbell, 1979). Moreover, the photoperiod may infleunce the physiological significance of extrinsic sensory input (see Fig. 10). In addition to photoperiod, visual stimuli per se can play a critical role in reproduction, particularly in certain species. In the ring ^± dove visual stimuli represent an integral com­ 1245 800 2000 2200 PB ONLY TIME OF ONSET OF OVERNIGHT ponent of the reproductive system. Successful EXPOSURE TO MALES reproduction requires a complex, integrated FIG. 10. Influence of the time of onset of overnight and sequential reciprocal interaction between exposure to male rats on the incidence of ovulation in environmental stimulis, such as the presence of rats in which spontaneous ovulation was blocked by a nest, the behavior of one sex and the endocrine the administration of pentobarbital (PB) on the activity of the individual dove (see Silver, afternoon of proestrus. 'Significantly (P<0.01) 1978). As illustrated by Crews (1979), a different than group given no mating experience. All groups consisted of 10 animals. Unpublished data of comparable inter-individual sequence of events Vitale. 122 GORSKI greater frequency of darting behavior (a com­ assumed that it is unlikely that the differences ponent of female sexual behavior in the rat) in ovulation are related to differences in vocal­ and by a markedly lower latency to show ization. Although an influence of photoperiod darting behavior. There was also a greater is evident from Fig. 10, further study is required display of lordosis behavior to the sniffing to determine whether this effect is mediated activities of the males by the females exposed through changes in tactile sensitivity or hypo­ to the ultrasonic vocalizations. In our own physeal-gonadal responsiveness. laboratory, we have shown that prior sexual The final concept for consideration is a experience within a behavioral test can alter the dramatic example of extrinsic regulation. Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 behavior of the female rat; an animal which is per se is not adequate for successful showing very low levels of receptivity will reproduction, since the female rat must receive increase her rate of lordosis respondiong as she a minimal number of intromissions before she continues to mate (Clemens et al., 1970). On becomes pregnant (Adler, 1969; Terkel and the other hand, in an animal that is highly Sawyer, 1979). To establish this statement, receptive, the receptivity scores will fall upon these investigators took advantage of the fact continued mating (Hardy and DeBold, 1971). that the male rat will have about 8—12 penile Although these observations have been inter­ intromissions before he ejaculates. Therefore, preted in terms of genital or tactile stimulation, they either permitted an experimental female it may be that animal vocalization plays an to mate with a fresh male or allowed males to important role in this phenomenon. The mate with teaser females until they had had potential significance of this form of communi­ approximately 5 intromissions. When these cation clearly requires further study. primed males were then exposed to experimen­ A dramatic example of the extrinsic regula­ tal females, they would ejaculate after a much tion of reproduction is copulation-induced fewer number of intromissions. In this way the ovulation. Although this is a well-known females, although each received one ejaculation, phenomenon in the rabbit and , it does could be divided into those which received high occur in the spontaneously ovulating rat as or low numbers of intromissions. The females well. In the intact female, mating facilitates which received an ejaculation but few intromis­ LH release (Moss et al., 1977) and if spontane­ sions did not get pregnant. ous ovulation is blocked or if sexual receptivity Moreover, 4 days after such a controlled is induced before the time of the normal mating experience, only the group of females ovulatory surge of gonadotropin, copulation which received the high number of intromissions can induce ovulation in this species (Aron et al., was found to be secreting high levels of proges­ 1966; Everett, 1967; Zarrow and Clark, 1968). terone (Fig. 11 A), which presumably correlates The data shown in Fig. 10 indicate that if one with their pregnancy (Adler et al., 1970). blocks spontaneous ovulation by injecting Finally, the recent data of Terkel and Sawyer proestrous rats with pentobarbital, that blockade (1979) demonstrate that a higher percentage of can be completely overcome by housing the the animals that have received a high number of animals with males. Although others have intromissions show the nocturnal pattern of demonstrated this phenomenon much earlier, prolactin surges, which presumably accounts these data are illustrated because they suggest for the secretion of progesterone (Smith et al., that the photoperiod may play a role in this 1975). phenomenon. We have altered the time of onset The final figure illustrates a rather surprising of overnight exposure of these pentobarbital- observation: the female rat in some way can blocked females to males and find that there is apparently keep count of the number of a significant temporal effect. If mating exposure intromissions which she receives over a rather is delayed until 2200 h, then very few of the long period of time (Edmonds et al., 1972). In animals ovulate in response to the copulatory this experiment, the number of intromissions stimuli, even though, at least based on an which the females received was controlled at 2, analysis of behavior during the first half hour, 5, or 10, but importantly, by removing and there is no difference in copulatory performance. replacing the males at appropriate times, It must be pointed out that in these experiments the interval between individual intromissions we have not monitored vocalization. Since the was also varied. When females were allowed to animals were housed in the communal vivarium mate ad libitum or allowed to have an intromis­ and were exposed to males overnight, we sion once every minute, 10 intromissions were NEUROENDOCRINOLOGY OF REPRODUCTION 123

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< 4 ) 10 3-5 15-18 INTROMISSIONS INTROMISSIONS 4-5 NTER-INTROMISSION INTERVAL FIG. 11. Effect of intromission frequency on A, the concentration of plasma progesterone 4 days after FIG. 12. Effect of both the number of intromis­ the controlled mating experience (data from Adler et sions and the inter-intromission interval on the inci­ al., 1970); and B, the incidence of nocturnal prolactin dence of progestational females. Data from Edmonds surges again 4 days after the controlled mating experi­ et al., 1972. ence (data from Terkel and Sawyer, 1979). For emphasis, data from animals receiving the high number of intromissions are illustrated by the solid columns. processes within one individual and others to be perhaps more important in what can be necessary before these females became "proges­ called extrinsic regulation. We have just indicated tational" (Fig. 12). In this study, animals were that genital stimulation, at least as defined by termed progestational if they did not exhibit intromission, in some way can be monitored lordosis behavior for 16 days and if they had quantitatively by the brain of the female, predominantly leukocytic smears. When the resulting in an alteration in her own intrinsic interval between intromissions was fixed at 4—5 regulation of pituitary-ovarian function. More­ min or 10—15 min, again, essentially all of the over, it is clear that various sensory stimuli, animals which received 10 intromissions became whether they be , visual displays or progestational. In fact, when the interval perhaps ultrasonic vocalizations, may also between intromissions was 30 min, still the superimpose their information on the intrinsic animals which received 10 intromissions and mechanisms for the regulation of reproduction. not those which received 5 intromissions We have emphasized that an illustration of the became progestational. By some as yet unex­ brain as a simple box is much too simplistic. plained mechanism, therefore, the neuroendo­ The brain is highly compartmentalized; the crine system of the female rat is able to recog­ specific action of hormones is probably highly nize when she has received more than 5 intro­ localized within specific areas of the brain missions, to retain that information over a which form the regulatory substrate for a period of hours and subsequently, to use that particular function. At the level of the indivi­ information to alter the pattern of prolactin dual neuron, however, the local environment release for a number of days. In earlier studies, within the dendritic fields may be of paramount Everett (1967) demonstrated that the "mem­ importance for normal neuroendocrine regula­ ory" of the copulatory experience can be tion, perhaps even more important than hor­ retained for days before being expressed. This mone-induced alterations in the electrical ability of the female rat to summate some activity of "projection" neurons. Steroid component of the intromission stimulus and hormones may directly or indirectly modulate retain that information is particularly intriguing. activity within local neuronal circuits. Finally, returning to the very beginning of this discussion, the concept of the sexual differentiation of the SUMMARY brain now has a morphological correlate that is easily recognized and may represent a signature This discussion began with a consideration of hormone action. Although the neuroendo­ of simplistic models of the male and female and crine control of reproduction is complex, the suggested that with respect to the neural opportunity to explain these intricate interac­ regulation of reproduction, one can consider tions I find challenging and exciting. The certain factors important in intrinsic regulatory 124 GORSKI reproductive process, of which neuroendocrine Clemens, L. G., Shryne, J. and Gorski, R. A. (1970). mechanisms form only one component, is Androgen and development of progesterone responsiveness in male and female rats. Physiol. indeed complex. However, this should not be Behav. 5, 673-678. discouraging. Additional knowledge at any level Cowan, W. M. and Cue'nod, M. (1975). The use of will be beneficial for the understanding of the axonal transport for the study of neural connec­ process of reproduction and its control, and tions: a retrospective survey. In: The Use of Axonal Transport for Studies of Neuronal thus, for the benefit of mankind. Connectivity. (W. M. Cowan and M. Cuenod, eds.). Elsevier, Amsterdam, pp. 1—24. Downloaded from https://academic.oup.com/biolreprod/article/20/1/111/4559056 by guest on 27 September 2021 REFERENCES Crews, D. (1979). Neuroendocrinology of lizard reproduction. Biol. 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