Nonsteroidal signals originating in the gonads.

PHYSIOLOGICAL REVIEWS Vol. 72, No. 3, July 1992 Printed in U.S.A.

Nonsteroidal JACQUELINE Departments

Signals Originating

F. ACKLAND,

NEENA

B. SCHWARTZ,

KELLY

of Neurobiology

and Physiology and of Biochemistry, Northwestern University, Evanston,

in the Gonads E. MAYO,

AND

Molecular Illinois

Biology,

ROBIN

and Cell Biology,

I. Introduction ........................................................................................... A. Testis ............................................................................................... B. Ovary .............................................................................................. C. Criteria for factor identification and verification ................................................. II. Gonadal Peptides ...................................................................................... A. Inhibin family of hormones ....................................................................... B. Relaxin ............................................................................................. C. Oocyte meiosis inhibitor ........................................................................... D. Follicle regulatory protein ........................................................................ E. Plasminogen activator ............................................................................. F. Extracellular matrix proteins ..................................................................... G. Growth factors .................................................................................... H. Androgen-binding protein ......................................................................... I. Peptide hormones originally identified in other glands ........................................... J. Other testicular proteins .......................................................................... K. Other ovarian proteins ............................................................................ L. Other peptides ..................................................................................... III. Summary ..............................................................................................

Over the past 60 years a picture has emerged of how the mammalian gonad develops during ontogenesis, the sequential steps of gametogenesis, the enzymatic cascade of steroidogenesis, the action of gonadotropins on each of the cell types, and the gonadal feedback signal regulation of gonadotropin secretion. This generally accepted picture is summarized for the testis and the ovary in this section as a background for the presentation of the material on gonadal peptides. The germ cells form in the yolk sac and migrate to the mesoderm of the genital ridge. During this migration they increase in numbers by mitosis. The genetic composition of the sex chromosomes controls whether the cortex of the ridge develops into an ovary or the medulla of the ridge develops into a testis (359,536). The basic cellular heterogeneity of the gonads lies in this dual germ cell-somatic cell origin. In turn, two somatic cell types develop, epithelial derivatives and mesenchyma1 tissue. A. Testis issues

The testis forms earlier life. At birth only the initial

2. Adult morphological than the ovary in prenatal stages of spermatogenesis

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are seen. Puberty, with its rising titers of gonadotropic hormones, permits meiosis and spermiogenesis to take place. The Sertoli cells (SCs) are closely associated with the germ cells within the seminiferous tubule; another somatic cell type, the peritubular myoid cells, surrounds the tubule. Thus the germ cells are isolated within a barrier, consisting of peritubular cells, a basal lamina, and the tight junctions formed by SCs. These junctions separate the intratubular compartment into two compartments, the basal compartment in contact with the basal lamina and the adluminal compartment that contains the germ cells that have advanced to meiosis and that remain in this tightly sealed off compartment during spermiogenesis and spermiation (246,247,251,252). The tight junctions between contiguous SCs form in the rat at about day ZO postnatally. Outside the tubules lie the capillaries and another somatic-derived cell, the interstitial or Leydig cell. During prenatal life SCs secrete a protein, Mullerian duct-inhibiting substance (MIS), which is responsible for loss of the Mullerian ducts and derivatives in the male fetus (see sect. IIA3). Early in fetal life, the Leydig cells secrete testosterone, which is responsible for inducing male genitalia and some neuronal alterations.

I. INTRODUCTION

1. Ontogenetic

E. DODSON

characteristics

The tight junctions formed by the SCs provide a virtual “testis-blood” barrier, resulting in the fluid in

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the adluminal space (rete testis fluid) having quite a different composition from plasma (800). The interstitial space between capillary endothelium and the tight junctions of the seminiferous tubule contains all substrates and nutrients available to Leydig cells, peritubular myoid cells, and SCs and through them to the germ cells. The volume and testosterone level in the interstitial space can be controlled by gonadotropins, as well as local factors, with testosterone constituting an important local signal from Leydig cells to peritubular cells and SCs and an SC signal, perhaps gonadotropinreleasing hormone (GnRH) (660; see sect. II I3), acting back on the Leydig cell. 3. Remodeling

of testicular

tissue

During the spermatogenic cycle (stages VII and VIII), a remodeling occurs in adjacent SCs such that new tight junctions form basally moving groups of preleptotene spermatocytes into an intermediary compartment between the upper tight junctions and the newly formed basal tight junctions (252). This type of tissue remodeling, as well as the interactions seen between cell types in vitro, make it likely that proteases, as well as constituents of the extracellular matrix (ECM), are secreted. 4. Stages of gametogenesis Fourteen stages of cell associations in seminiferous tubule have been described (129). These are cell associations circling the tubule, with the wave of development appearing to move in a spiral inward. The stem cell population undergoes mitosis, with some spermatogonia moving on to proceed to meiosis, but first undergoing six mitoses. After the last mitosis, type B spermatogonia form preleptotene primary spermatocytes, intitiating meiosis by duplicating their DNA. Cells then pair their chromosomes in pachytene. At midpachytene (VI-VIII) transcription increases. At stage XIV both meiotic reduction divisions are found. The haploid spermatids then undergo spermiogenesis, leading to formation of spermatozoa. It has been recently recognized that the germ cell associations are accompanied by changes in SC morphology and biosynthetic capacity (555). Changes have been documented in lipids, acid phosphatase and other enzymes, follicle-stimulating hormone (FSH) binding, adenosine 3’,5’-cyclic monophosphate (CAMP) production, phosphodiesterase activity, androgen content, androgen-binding globulin secretion rate, and plasminogen activator (PA) secretion (555). These observations strongly suggest well-localized two-way communication between SCs and germ cells. 5. Gonadotropin

eflects

The lack of spermatogenesis in the absence of the anterior pituitary gland focused attention early on the

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necessary role of the gonadotropic hormones, FSH and luteinizing hormone (LH). Receptors for FSH are only found on SCs (707), and receptors for LH are only found on Leydig cells (102). The germ cells do not have gonadotropin receptors, indicating that the effects of the gonadotropin hormones on spermatogenesis must be indirect through somatic cells. Follicle-stimulating hormone can induce estradiol secretion from SCs when provided with androgen precursor from Leydig cells (181). The highest levels of aromatase activity in these cells is at about day 30 in rats, and after this time FSH fails to exert large changes in estradiol secretion or in CAMP, the second messenger for FSH in SCs (708). During the early postnatal period when FSH secretion is elevated (524) and SC responsivity is highest, the initial cycles of spermatogenesis are in progress in rats, eventually leading to production of mature spermatozoa when testosterone secretion is enhanced toward the time of puberty. In rats, after this time, hypophysectomy and LH replacement or just testosterone replacement can induce spermatogenesis, albeit in reduced numbers (140, 710). In other species, however, including humans, FSH replacement is required for resumption of spermatogenesis in addition to testosterone or LH. In at least one photoperiodic species, the Djungarian hamster, onset of stimulatory photoperiods elicits an FSH secretion unaccompanied by LH, which, within 1 wk, induces a visible advancement in spermatogenesis (651). Luteinizing hormone receptors are found in the membranes of Leydig cells; this hormone is a complete signal for testosterone production from cholesterol or acetate (102). Luteinizing hormone acts through an adenylate cyclase mechanism and controls a number of steroidogenic enzymes, including the cytochrome P-450 enzyme (557). In addition to causing testosterone secretion, LH can alter the rate of formation of interstitial fluid; this has been suggested to occur indirectly by means of LH causing testosterone secretion, which induces SCs to secrete a local factor (GnRH?) acting on the capillary endothelium (660). The mechanism of FSH or testosterone stimulation of spermatogenesis is not well understood. The SC is closely connected to the clone of premeiotic germ cells that it surrounds (626), and in vitro survival of germ cells is facilitated by coculturing them with SCs (746). It has been assumed that the close physical connection facilitates the exchange of nutrients and regulatory signals from the SCs. Two SC protein products, androgenbinding protein (ABP) and transferrin, can be bound by germ cells (170). On the other hand, some evidence exists that the germ cells may in turn regulate the SCs (399). As for possible mechanisms, it has been assumed that testosterone acts on SCs and through them on the associated germ cells. Evidence suggests that midpachytene primary spermatocytes and steps 7 and 19 spermatids, present in stages VII and VIII of the seminiferous epithelium, are particularly vulnerable to loss after removal of LH and FSH. At this stage the SCs produce maximum ABP and have the highest local testosterone at this stage (see Ref. 555).


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6. Cell-cell interactions

Several kinds of experimental evidence have focused attention on local cell-cell interactions in the testis. The ability of testosterone to support some spermatogenesis in the adult hypophysectomized rat indicated the potential importance of Leydig cell-germ cell interaction. Coculture of SCs with peritubular cells permits more normal morphology, longer survival in serum-free medium, and formation of a basal laminalike structure in both types of cells; this results from secretion of components of the ECM and secretion of a protein by the peritubular cells, called P-Mod-S (251, 252). Culture of SCs on a porous substrate permits polarization of the cells and two-compartment secretion (346). Additionally, superfusion rather than static medium (345) has permitted directional secretion of such proteins as transferrin and ABP; addition of peritubular cells changes the ratio of the proteins secreted and the relative direction of their secretion (347). The importance of serum inclusion on SC function has been noted (347), but little work has been done to test possible contributions of growth factors to this function. The observation that peritubular cells, which are mesenchyma1 in origin, possess testosterone receptors and influence the epithelial SCs is probably another example of the importance of mesenchymal-epithelial interactions (139). Sertoli cell-Leydig cell interactions have been suggested beyond the “testosterone on SC” hypothesis. The mitogenic factor of SCs influences cell proliferation in the testis (55), and a GnRH-like protein from SCs may have local effects on Leydig cells (660). Even more convincing than these observations that local intercellular communication must be going on, however, is the demonstration that the germ cell associations in tubules are associated with SC and Leydig cell morphology and function. The clear necessity for overall gonadotropin regulation, which on its own can only yield uniform control within the testis, obscured this necessity for local regulation until recent years. B. Ovary I. Ontogenetic issues

After the initial induction of ovarian tissue when germ cells bearing the XX sex chromosome arrive, the meiosis starts in germ cells. As the first stage of meiosis begins, granulosa cells (GCs) appear to arise from the surround and organize around the primary oocytes to form follicles (85). The number of follicles and oocytes present in the mammalian ovary at this early fetal or postnatal stage (depending on species) is the maximum number that will ever be there. Each oocyte remains in the diplotene stage of prophase I of meiosis indefinitely until that follicle matures and is stimulated by an ovulatory surge of LH (243). The oocyte does grow in size during development, however, and follicles may gain

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another layer of GCs between the enclosed oocyte and the basement membrane that encloses the follicle. Most of the follicles that are formed at the onset of ovarian development will undergo atresia and disappear. Thus the supply of oocytes for reproduction in female mammals is severely limited, unlike the continuing spermatogonial mitosis seen in the male. Complete maturation of given follicles, with increasing differentiation of GCs and development of appropriate gonadotropin receptors and of a follicular antrum, does not occur until puberty. 2. Follicles Follicles in the mature ovary consist of varying numbers of layers of GCs and an oocyte surrounded by the zona pellucida, which is closely attached to the GC layer that is next to it. The GCs are limited by a wellformed basement membrane; surrounding the basement membrane is a layer of cells known as theta cells. In the nonmature follicle, no capillaries cross the basement membrane. As a given follicle matures the GCs are first connected by adherence junctions (21), but gap junctions appear at the time of onset of gonadotropin action on the follicle and the time of appearance of the antrum. Cell-cell communication of ions, small organic molecules, and CAMP through these junctions is postulated. The GCs immediately surrounding the zona pellucida are connected to the oocyte by microvilli and gap junctions. Thus in the maturing follicle there is a clear pathway for signals among the cells contained within the basement membrane. 3. Role of gonadotropin and localization of receptors to luteinixing hormone and follicle-stimulating hormone

It is not clear when receptors to gonadotropins develop in the ovary; in the macaque, receptors to FSH develop prenatally earlier in the testis than in the ovary (342). Primordial follicles throughout life may not have FSH receptors until GC mitosis increases. However, even very small preantral follicles may show FSH receptors, and under the influence of local estrogen, GCs divide and the total number of FSH receptors within a given follicle increases. At this same stage of development the GCs do not have LH receptors; the only LH receptors are in the thecal cells outside the basement membrane. As follicles mature under the continuing influence of local estradiol and FSH, the GCs acquire LH receptors, a process that is part of the process of differentiating into luteinized tissue (105,601). It is apparent that in mammals, at least, two gonadotropins are required throughout reproductive life to permit complete maturation of follicles (649). Low levels of LH can cause thecal cells to secrete testosterone and androstenedione, but these cells do not contain aromatase in most species (326). The “two steroid, two cell” hypothesis of estradiol formation discussed in the testis is generally accepted in the mamma-


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lian ovary as well (326,601). The mechanism of action of FSH is via CAMP, working at several sites: it induces aromatase activity and increases progesterone and ZOa-hydroxyprogesterone biosynthesis by increasing mitochondrial cytochrome P-450 levels and cholesterol side-chain cleavage activity and by inducing 3@hydroxysteroid dehydrogenase and 20a-hydroxysteroid dehydrogenase (602). The mechanism of action of LH on GCs, once they have acquired appropriate receptors, is principally to induce increased progesterone secretion stimulatin g cholesterol es terase, inducing cholesterol side-chain cl.eavage enzyme and 3@-hydroxys teroid dehydrogenase. Luteinizing hormone can also maintain aromatase enzymes, causing continued estradiol secretion. Gonadotropic hormones and other factors change not only steroidogenic enzymes and gonadotropin receptors as part of the cell differentiation process, but they also change cell morphology. Follicle-stimulating hormone causes flattened GCs to assume a more spherical shape. Mitochondrial size and polymorphism increase; microvilli (which bear LH receptors) increase, as do gap junctions. The ECM on which GCs are cultured can direct GC morphology and formation of gap junctions, as well as aspects of steroidogenesis. In turn, GCs secrete various components of the ECM (see sect. IIF), suggesting that ovarian somatic cells, as is the case for testicular cells, strongly interact with ECM (21). As a follicle matures and differentiates the GCs acquire LH receptors. When the preovulatory LH and FSH surges occur, estradiol secretion drops and progesterone secretion increases. The preovulatory surges cause germinal vesicle breakdown (GVBD) and resumption of meiosis, with the oocyte shedding the first polar body. This action, particularly of LH, is not directly on the oocyte, which lacks LH receptors, but is an action on surrounding GCs. The tight connections between the cumulus cells and the oocyte break after the preovulatory surges. Various theories (see sect. IIC) have been advanced regarding the mechanism of maintenance of incomplete meiosis throughout life until a given follicle matures that is then terminated after the gonadotropin surges. The preovulatory surges also cause a loosening of GC connections, breakdown of the follicular wall, and increased accumulation of follicular fluid. There are undoubtedly proteases involved in this process; PA and other enzymatic processes (211) have been suggested as the causative agent(s). Proteolysis permits the oocyte, surrounded only by the cumulus cells of the corona radiata, to leave the follicle and enter the oviduct where fertilization can take place. If fertilization occurs, meiosis is completed, leaving a haploid egg, and a second polar body is ejected.

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LH and FSH by triggering a release of GnRH (423). In many species estradiol alone cannot suppress FSH by negative feedback as well as it suppresses LH; it was this observation in female rats that caused us to search for a female inhibin or folliculostatin (456, 650). 5. A tresia

Follicles, once they begin to grow, are susceptible to atresia; steroidogenesis is altered to favor androgen production and morphological breakdown occurs, with GC beading, oocyte destruction, and eventual dissolution of the structure (219). The process of atresia can start in very small follicles or in mature follicles that fail to ovulate in response to LH surge. It is not known what initiates atresia and why contiguous follicles in the ovary can have such different fates; whatever the selection process is, it clearly has local factors operating (478). 6. Ovulation and formation

of a corpus luteum

Various proximal factors have been said to be involved with the transduction of the preovulatory LH signal: PA, collagenase, and prostaglandin. What remains in the ovary is a corpus luteum (CL), which is formed by invasion of capillaries into the basement membrane, the mingling of thecal cells and GCs (18), and the altered expression of steroidogenic enzymes such that progesterone secretion is favored (602). Control of luteotrophic and luteolytic processes shows tremendous species differences in mammals (62433) and may involve LH, FSH, prolactin, and such local factors as estradiol and prostaglandins. Follicular fluid is the accumulated fluid that bathes the GCs and cumulus cells. It closely resembles serum except for the highest molecular mass proteins (191, 478). It also contains steroids in very high concentrations, which vary with the stage of the ovarian cycle. Follicular fluid has proven to be an excellent source of many of the peptide factors believed to be secreted by GCs. Follicular fluid is much closer to serum than is the composition of the rete testis fluid inside the tight junctions formed by the SC adhesions (654). The oocyte within the cumulus cell mass is connected to the follicular fluid, and some components, such as CAMP, can move across from the fluids (199). However, for both sets of germ cells it is clear that the environment surrounding the germ plasma is controlled tightly by the somatic cells, SCs, and GCs. 7. Cell-cell interactions

4. Feedback of ovarian hormones on gonadotropin secretion

Estradiol, in addition to its ability to suppress LH, can also trigger the release of the preovulatory surges of

There are numerous cell-cell interactions in the ovary. The homologies between the SCs and the GCs are striking (246); both show receptors to FSH and possess the aromatase enzyme complex, both are closely at-


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tached to the germ cells, and both synthesize components of the ECM (see sect. IIF). Both SCs and GCs are removed from direct contact with a capillary bed and both benefit cytoarchitecturally from contact with components of the ECM. Local circulatory competence is controlled in both the testis and the ovary with stage of spermatogenesis or CL formation eliciting local changes. Thecal cells and GCs cooperate not only in synthesizing estradiol, but also both cells form a CL. The clearest example in the ovary of local regulation is the selection of follicles to be recruited into the growing pool, to become atretic, or to become dominant. Each species recruits and ovulates a characteristic number of follicles at each cycle, and removal of an ovary on one side is compensated for by an increased ovulation rate in the remaining ovary. Just as remarkable as compensatory ovulation is the acquisition of dominance by just one follicle on one side in many species. What are the signals that choose some follicles rather than others and that then assure maturation of one or more follicles? These questions have led to the postulation of several factors acting within the ovary or between ovaries.

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Skinner (681a) has classified local factors as having three different functions: regulatory (i.e., acting as a signal), environmental (i.e., modifying the matrix surrounding the cell), and nutritional (i.e., providing necessary substrates or ions). Strictly speaking, only the regulatory function is a paracrine signal, but we discuss all peptides claimed to be made in the gonads, whatever their function, as signal, matrix, or nutritional. Furthermore, we discuss factors that have been claimed to be hormones or otherwise appear in the circulation, such as inhibin, relaxin, ABP, and follicular regulating protein (FRP). II. GONADALPEPTIDES

A summary ble 1.

of the gonadal peptides is given in Ta-

A. Inhibin Family of Hormones I. Inhibin

C. Criteria

for Factor

Identification

and Verification

Crucially important in identification and validation of peptide factors is a valid, reliable, and sensitive bioassay for unidentified peptides. The search for inhibin in the gonads is a prime example of the prolonged delay that can occur between postulating the existence of a factor on physiological grounds and proving its existence. The delay was in large part due to the failure to develop a reliable bioassay; finally an in vivo assay was developed [the acutely ovariectomized female (456)] as well as a more sensitive in vitro bioassay [the dispersed pituitary cell assay (282)]. Findlay et al. (236) has elucidated three criteria that must be met to define a factor as a paracrine or autocrine regulator. One must show 1) that it is produced locally, 2) that the local production is controlled under physiological conditions, and 3) that the substance exerts biological effects at physiological concentrations on neighboring cells or on the same cells that produce them. Conventional chemical isolation steps can then be established to yield enhancement of specific activity and purification. Once some of the protein has been isolated, then the amino acid sequence can be obtained by sequencing techniques or isolation of cDNA. Detection of mRNA expression in the gonad confirms that the factor is produced there. To answer the question of whether the factor production is regulated, one can measure the content of factor by bioassay or radioimmunoassay (RIA) or the content of message and see if changing input to the gonad, like gonadotropins, changes content. The third criterion of Findlay et al. for confirmation of a “local” factor is that it must act on the cell that produces it (autocrine) or on neighboring cells (paracrine). Essentially this criterion postulates the demonstration of receptors for the peptide within the gonad itself.

Inhibin is perhaps the prototype of those gonadal factors discovered out of physiological necessity. The biological basis for gonadal regulation of pituitary function was formulated in 1923 by Mottram and Cramer (508), who observed hypertrophy of rat pituitary cells following radiation-induced testicular damage. In 1923, McCullagh (472) demonstrated that the appearance of these hypertrophied cells could be inhibited by the injection of a water-soluble extract from bovine testis and termed the active substance inhibin. The inhibin-like activity of ovarian origin has also been referred to as folliculostatin (650); because recent results suggest identity of these activities, the term inhibin is used here (81). I) STRUCTURE. Although the FSH-suppressing activity of gonadal origin had been shown to be nonsteroidal and proteinaceous (160, 650), characterization of this material proved difficult (for reviews see Refs. 106, 158). Quite recently, several groups reported the purification and characterization of inhibin from follicular fluid (435, 494, 611, 617). The emerging results indicate that inhibin, from this source, is a heterodimeric glycoprotein that exists in multiple biologically active forms. Porcine inhibin is a 32,000-Da protein composed of two disulfide-bound subunits of 18,000 (cu) and 14,000 Da (6). Two related, yet distinct, forms of the smaller P-subunit termed ,& and & have been described (435), and both complex with the a-subunit to form biologically active inhibin (termed inhibin A and inhibin B). Similar results have been obtained for bovine inhibin, but in this case the ,&-subunit seems to exist in two forms (14,000 and 44,000 Da), the larger of which is an amino-terminally extended form of the smaller (256, 618). The complete amino acid sequences of inhibins for porcine, bovine, human, and rat sources have been de-


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1. Nonsteroidal gonadal factors

TABLE

Protein

Sex

Evidence For Synthesis

Compartment

Receptor

Regulatory

Factors

References

F

Granulosa, theta, CL

Prot, RNA, Imm, Bio

ND

FSH, EGF, IGF-I, GnRH, VIP, TGF

M

Sertoli, Leydig

ND

Activin

F

Granulosa

Prot, RNA, Imm, Bio Prot, RNA

Ovary

FSH, EGF, endorphin FSH

MIS

M F

Spermatocytes Granulosa, cum ulus ooph orus

Prot, RNA Prot, RNA

ND ND

ND LH, FSH

400, 436, 488, 648, 718,778 207,418 61, 100, 356, 523,

M

Fetal testis, Sertoli

Prot, RNA

ND

Developmental

793 100, 179, 357, 359,

Follistatin

F

Follicles

Prot, RNA

ND

LH, FSH

Seminal plasma inhibins Relaxin

M

Seminal fluid, Leydig, prostate CL, theta

RNA, Imm, Bio

ND

ND

Prot, RNA, Imm, Bio Prot, RNA, Imm, Bio Imm Bio Prot, Imm

Uterus, cervix

ND

Pubic symphysis

?PRL, LH, OT, PGs

ND ND ND

ND ND FSH, GnRH

24 200,751 172,173,316,540

ND ND ND ND Luteal, granulosa Leydig, Sertoli, spermatocytes Granulosa, theta, luteal

ND ND FSH, GnRH ND LH, FSH, GH, EGF, TGF, PDGF, E LH, FSH, GH, FGF, EGF Gonadotropins

349,437 395 683, 690 686, 693 5, 163a,

ND FSH ND ND

Inhibin

F

Placenta, uterus OMI FRP PA ECM proteins IGF-I

M F F F M F M F M

Interstitial, Sertoli, prostate Follicular fluid Follicular fluid, granulosa, luteal Granulosa Sertoli Granulosa, follicular fluid Peritubular, Sertoli Granulosa

Bio, Imm Bio, Imm Prot, Imm Prot, Imm Prot, RNA

66, 435, 471, 487, 494, 611,617, 821,832 43, 67,158,487

745 618, 676, 767, 823, 834 260, 410, 425, 590, 672 76, 77,580,668

155, 292, 321,498,538

Sertoli, peritubular, spermatogenic, Leydig Granulosa, theta

Prot

Sertoli, Leydig Theta, interstitial Peritubular, Sertoli, Leydig CL

Imm, Bio, RNA RNA RNA, Imm Bio, RNA

EGF-R ND ND

TGF-fi

M F M F M F

Theta, interstitial,

Imm, Bio, RNA

ND

M F

Sertoli

PDGF

Bio, RNA Bio

Leydig ND

Fibronectin, TGF-0 FSH ND

F M

Ovary Semen, seminal vesicle, testis, spermatocytes, spermatids Sertoli, prostate

Imm, RNA

ND Sertoli

ND LH, T

Prot, RNA, Imm, Bio Imm, Prot, RNA

ND

FSH, T

250,286,288,517

ND

ND

RNA

Sertoli

LH, FSH, CRF, androgens

116, 374, 393, 428, 443,484 117, 118, 216, 270, 458,573,759, 841 374,375 262,370,373-375, 838,839 183 183,458,477 33, 127,328,460

EGF-like

TGF-tu bFGF

NGF

F

ABP

M

POMC

F

granulosa

M

CL, interstitial, granulosa Leydig

Enkephalin

F M

Ovary Testis

RNA, Imm RNA, Imm

ND ND

ND FSH

Dynorphin

F M F

RNA Prot, RNA

ND ND ND

ND ND

M

Ovary Leydig Ovary, follicular fluid, ?granu losa Interstiti al, Sertoli

Imm, Bio

Yes-rat

ND

F

CL, granulosa

Imm, Bio, RNA

Neurophysin

LH,

GnRH-like

Oxytocin

luteal,

Imm, Bio, RNA

73, 88, 115, 163, 432,605, 724 104, 194, 277, 322, 353,361, 625, 797

197, 317, 763 3,13,392,442,682 692, 733

276a, 387,525 FSH,

ND

766 180,376,514,688 56, 691,736 69, 295, 384, 467, 496,498,499 401,402 38, 300, 315, 539, 568

27, 62, 95, 126, 304,328,662 FSH,

PGF,

192, 239, 258, 318, 341,575, 639, 807,810


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TABLE

SIGNALS

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l----Continued Protein

Sex

Evidence For Synthesis

Compartment

Vasopressin

M F M

Testis, Leydig Ovary, follicular Sertoli, Leydig

Renin

F M F M F M M

CL, ovary, follicular ND Leydig, germ cells

M M F F F M F

Peritubular Sertoli, epi thelial Follicular fluid Granulosa CL Testis, seminal plasma Nerve fibers

Prot, Bio Bio Bio Bio Bio

VIP

M F

c-mos

Angiotensin

II

ANF CRF P-Mod-S Clusterin LI and LS GnSIF LH-RBI FSH-RBI NPY, CGRP, substance P, PHM, somatostatin

Receptor

Regulatory

Factors

fluid

Imm, RNA Imm, RNA

ND ND Vl-Leydig

ND ND ND

Follicular

fluid, theta, luteal

Imm, Bio

ND

LH, FSH

Leydig Follicular

fluid

RNA Imm, RNA

ND Ovary, granulosa Leydig Granulosa, CL Leydig Leydig

LH, FSH ND ND ND ND ND

None

ND ND ND ND ND ND ND

ND ND ND ND ND ND ND

Nerve fibers

RNA

ND

ND

F

Oocytes

Prot, RNA, Imm

ND

Developmental

M

Germ cells

Prot, RNA, Imm

ND

ND

fluid

Imm ND RNA

References

453,570 257,637, ‘790,807 362, 363, 453, 492, 526 86, 177, 229, 378, 652 167,522,554 138,147,333,585 548 377,549,798 241,559 35, 148, 209, 737, 773,837 684,685,687 248 105,107 642 596,598, 696 89, 157, 281, 354, 473,480, 505, 550, 558 14, 157, 265, 281, 407,492 519, 584, 627, 628, 806 519,583,584

ABP, androgen-binding protein; ANF, atria1 natriuretic factor; bFGF, basic fibroblast growth factor; Bio, bioactivity; CGRP, calcitonin gene-related peptide; CL, corpus luteum; CRF, corticotropin-releasing factor; E, estrogen; ECM, extracellular membrane; EGF, epidermal growth factor; EGF-R, EGF receptor; F, female; FGF, fibroblast growth factor; FRP, follicle regulatory protein; FSH-RBI, FSH-receptor binding inhibitor; GH, growth hormone; GnRH, gonadotropin-releasing hormone; GnSIF, gonadotropin surge-inhibiting factor; IGF-I, insulinlike growth factor I; Imm, immunoreactivity; LH-RBI, luteinizing hormone-receptor binding inhibitor; LI, luteinization inhibitor; LS, luteinization stimulator; M, male; MIS, Mullerian-inhibiting substance; ND, not determined; NGF, nerve growth factor; NPY, neuropeptide Y; OMI, oocyte meiosis inhibitor; OT, oxytocin; PA, plasminogen activator; PDGF, platelet-derived growth factor; PG, prostaglandin; PHM, peptide histidine methionine; POMC, proopiomelanocortin; PRL, prolactin; Prot, protein; T, testosterone; TGF, transforming growth factor; VIP, vasoactive intestinal peptide.

duced by molecular cloning of the corresponding cDNAs (207,240,462,471,821). This structural analysis has revealed that each of the three inhibin subunits is encoded by a separate gene and that each mature subunit resides at the carboxy-terminal end of a much larger precursor protein. Structural and sequence similarities among the inhibin subunit precursors suggest that they arose via sequential gene duplication events. In addition, the ,&subunits of inhibin share a substantial sequence identity with an emerging family of proteins with growthregulating properties, the prototype of which is transforming growth factor-p (TGF-P) (463). This family also includes activin and MIS, which are discussed in sections II, A2 and AS. II) LOCALIZATION. Substances exhibiting FSH-suppressing activity (i.e., bioactivity) have been demonstrated in ovarian extracts, follicular fluid, and GC-conditioned medium (160,205,314,650). Histochemical techniques have demonstrated that GCs of the ovary are the primary producers of inhibin. Immunohistochemical experiments have shown localization of the inhibin cu-subunit to both GCs and luteal cells in the ovary (136, 487). In situ hybridization has been used in the ovary to

localize inhibin cy-and ,&mRNAs to the mural GCs (818). The presence of inhibin mRNAs in luteal cells remains controversial in rats (151,488,818) and sheep (623,760), but it appears to be present in primates (152, 647). Extragonadal sources of inhibin have also been recently identified, including placenta (471, 487), adrenals (135, 489), and pituitary (489). Numerous investigators have demonstrated inhibin bioactivity both in vitro and in vivo by showing suppression of pituitary FSH in animals treated with a steroidfree testicular preparation, including testis fluid, testicular lymph, seminal plasma, and SC-conditioned medium (113,190, 368,448, 521, 655, 709). In males, the SC appears to be the major producer of inhibin (for review see Ref. 43). Inhibin can be detected immunohistochemitally in SCs (136,489). There are a few reports suggesting that the a-subunit and possibly inhibin itself are produced by Leydig cells (604,616,657), and ,&-immunostaining has been detected in the nuclei of spermatocytes (657). III) REGULATION. Inhibin is involved in a classic negative feedback loop with FSH, and FSH has been shown to be a major regulator of inhibin. Treatment of imma-


738

ACKLAND,SCHWARTZ,MAYO,AND

ture animals with pregnant mare’s serum gonadotropins (PMSG) led to an increase in inhibin activity (417) and mRNA levels (150,490). Investigators have also observed FSH-induced inhibin bioactivity from cultured GCs (23,305). Following the development of an antibody for inhibin, a stimulatory effect of FSH on immunoassayable inhibin levels was observed in vivo (610) and in cultured GCs (66, 720, 843). Follicle-stimulating hormone-induced accumulation of inhibin a-subunit mRNA has been observed both in intact animals and in cultured GCs (151,400,471,821). Because inhibin is apparently not stored in the ovary to any great extent, regulation of synthesis may occur at the transcriptional level (64) in keeping with the observed affect of FSH on a-mRNA production. These FSH effects are apparently mediated by CAMP, since CAMP analogues or agents that stimulate adenylate cyclase are also effective in stimulating inhibin secretion (9, 720). Other factors have been shown to influence inhibin secretion. In vivo, injection of estrogen into hypophysectomized immature female rats led to increased plasma inhibin (612). Whether this is a direct effect on inhibin production is unclear. In cultured GCs, one group reported an effect of gonadal steroids only on FSH-induced inhibin secretion (720), whereas others have found estrogen alone can elevate basal inhibin mRNA levels (765). In addition to FSH, a variety of other polypeptide hormones appear to affect either basal or FSH-induced inhibin production; these include the stimulatory effects of insulin-like growth factor I (IGF-I), insulin, vasoactive intestinal peptide (VIP), activin, and TGF-P and the inhibitory effects of epidermal growth factor (EGF) and GnRH in GCs (66,400,612,720, 820,843-845).

Regulation in males has recently been reviewed (43). Inhibin protein and mRNA levels are positively regulated by FSH in vivo and in vitro, but regulation of the CY-and &-chains is independent. In males, hypophysectomy leads to a decrease in the level of a subunit expression, and levels can be restored with exogenous FSH. However, the ,&-subunit does not change or is only slightly elevated with these treatments (228, 391, 616). As in the female, these effects of FSH are probably mediated via CAMP (67, 776). In addition to FSH, inhibin production can be stimulated by adenosine and EGF, whereas P-endorphin is inhibitory (131,506,507). Interestingly, although IGF-I stimulates and EGF inhibits production in GCs, IGF-I has no influence on the level of inhibin in SCs (739) and EGF-stimulated inhibin production (507). IV) ACTIONS. Following the characterization of the pituitary gonadotropins, FSH and LH, testicular inhibin was postulated to exert a specific negative regulatory effect on pituitary FSH (381). The major impetus for seeking an inhibin of ovarian origin came from experiments indicating the inadequacy of estrogen as feedback regulator of FSH following unilateral or bilateral ovariectomy (83, 90, 813). A substantial amount of evidence supports a role for inhibin in the regulation of

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FSH secretion. This has recently been reviewed (158) and is only briefly reviewed here. An important role for inhibin in regulating pituitary FSH secretion in vivo seems likely. Comparison of inhibin bioactivity with peripheral FSH levels during the rodent estrous cycle indicated an inverse correlation between the two, consistent with a feedback role for inhibin in the control of FSH release (22, 162, 253, 282). This observation has been extended and confirmed by the direct measurement of inhibin levels during the estrous cycle, using an RIA for the a-subunit (1, 301). These investigators have shown an inverse relationship between the secondary FSH surge and inhibin levels during the period from proestrous evening to estrous morning. A similar temporal pattern of inhibin expression was observed for inhibin mRNAs using in situ hybridization techniques (488,818). Closer examination of mRNA levels around the time of ovulation in rats (610, 819) has led to the following hypothesis. The secondary FSH surge recruits new follicles and stimulates inhibin production in these follicles. The increasing levels of inhibin suppress FSH. Hypothalamic GnRH stimulates the ovulatory surge of gonadotropins that, paradoxically, shuts down inhibin secretion. The rapid decline in inhibin then allows the secondary FSH surge to occur. A similar series of events can be induced in immature female rats with proper hormonal manipulation (153,490).

Further support for a role of inhibin in regulation of FSH secretion comes from experiments in which animals are infused with antibodies to inhibin (613) or are immunized with inhibin to produce their own antibodies (235, 495, 822). In all cases, serum FSH levels are elevated and there is an increase in the number of ova produced. The mechanism by which inhibin decreases FSH production is not completely known, but several effects of inhibin on the pituitary have been described. Besides decreasing FSH secretion, inhibin can decrease receptor number, making the gonadotrophs less responsive to GnRH (801). Potential paracrine roles for inhibin in the ovary have not been fully examined, but a few reports suggest that inhibin may act locally. Hsueh et al. (327) demonstrated that inhibin could enhance LH-stimulated androgen biosynthesis in thecal cells but that inhibin did not have an effect on steroidogenesis in GCs (334). Inhibin partially blocked activin-stimulated growth in Chinese hamster ovary cells (CHO) cells (274), and a synthetic fragment of the inhibin a-chain bound to ovarian GnRH receptors and interfered with FSH-stimulated processes (311). In males, inhibin clearly plays a role in regulating FSH in the immature animal (for review see Ref. 158). Recent experiments further support this role, since injection of antibodies to inhibin into immature male rats (137,608) or monkeys (483) led to decreased FSH levels. This effect was not seen in adults, however. In experiments looking at levels of FSH and inhibin in bilateral and unilateral castrate and cryptorchid rats, inhibin


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and FSH levels did not show a simple inverse relationship, and the investigators suggest that other factors may contribute to FSH regulation in addition to inhibin (609). The role of inhibin in adult males is less clear except in seasonal breeders where it appears to regulate FSH during testicular growth (for review see Ref. 158). In other species, in certain experimental paradigms, FSH will stimulate and increase inhibin levels (237,391,476). However, at least in rats, infusion of inhibin antibodies into adults does not affect FSH levels (137, 608). A role for inhibin as a paracrine modulator of testicular function has begun to be explored. Reported effects of exogenously administered inhibin preparation to the testes include impairment of spermatogenesis and altered steroid production (327, 600). Interesting in this regard is the observation that inhibin appears to be highest in immature animals and to regress following the initiation of spermatogenesis and formation of the bloodtestes barrier (775). This pattern has also been seen with both cy- and ,&inhibin mRNA in rat testes (489). Bhasin et al. (63) found inhibin mRNA content within seminiferous tubules varied with the stage of the cycle. Also, in rats, the major direction of secretion switches from the base of SCs in immature males to the luminal side in adults. Further work should clarify a paracrine role for inhibin in the male. 2. Activin

During the purification of inhibin from porcine follicular fluid, several groups identified fractions possessing FSH-stimulating activity. Characterization of this material resulted in the identification of Z&000-Da proteins that are disulfide-linked dimers of the inhibin ,&subunits and are themselves members of the TGF-P family. A &J,-homodimer (778) and a PA-&-heterodimer (436) have been identified, and the names activin A and activin AB have been suggested for these molecules to denote their opposing biological activity compared with inhibin. The term FSH-releasing protein has also been applied to the ,&-homodimer and euthyroid differentiation factor (EDF) is identical to activin A (214). I) LOCALIZATION. Antibodies to activin are not widely available so evidence for the localization of activin in the gonads has mainly been deduced from the presence of ,&chain mRNA. In rats, both ,&subunit mRNAs are expressed in the ovary, whereas the ,&subunit mRNA seems to be preferentially expressed in the testis (207,489). The ,&mRNAs have been shown by in situ hybridization to be exclusively localized to GCs of both the adult ovary (488, 818) and the immature rat ovary (490). The ,&-mRNA is found mainly in immature male rat testis, and Esch et al. (207) suggests that the PAmRNA might not be exnressed in adult testis, leading to

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an absence of activin A. The ,&-mRNA is localized primarily in SCs; however, ,& immunostaining has been detected in the nuclei of spermatocytes (657), and activin secretion has been seen in the TM3 cell line derived from a Leydig cell tumor (418). II) REGULATION. The availability of cDNA probes to the ,&subunits has allowed localization of the activin mRNAs, but this information is difficult to interpret in that the ultimate biological fate of the product of these mRNAs is uncertain, since they might form either an inhibin or activin molecule. Immunological probes specific for the activins are not yet widely available but will clearly be important for further understanding of the expression and regulation of these hormones. Some data showing exclusive production of ,&subunit mRNA suggest there are certain times when activin may be produced. Meunier et al. (489) have shown that, in rats, fl-mRNA levels are much higher than cu-mRNA levels in some tissues, suggesting activin may be preferentially formed in these tissues, which include bone marrow and placenta. Also, expression of the ,&-message in rats was seen in large tertiary follicles just before ovulation (488). In contrast to rats, Schwa11 et al. (647) found small antral follicles in monkey ovaries produced ,& exclusively, whereas in dominant follicles, only cyand PA were expressed. The regulation of activin is poorly understood and will clearly be the object of future research. III) RECEPTORS AND BINDING PROTEINS. Binding sites for activin/EDF have been demonstrated in GCs, suggesting a local site of action and possibly a paracrine function (400,718). In addition, follistatin has been suggested to be an activin-binding protein (530). IV) ACTIONS. The activins are stimulators of pituitary FSH secretion in vitro and also appear to have a strong stimulatory effect on FSH synthesis (99, 778), and infusion of activin into immature rats (648) and monkeys (475) led to increased gonadotropin secretion. The physiological importance of gonadal activin on gonadotropin secretion remains to be established, however. Because activin is related to TGF-P, the possibility arose that, like TGF-P, the activins may serve to regulate cell proliferation or differentiation. Furthermore, the demonstration that activin and EDF were identical (214) and that activin, purified from follicular fluid, acted as a potent stimulatory of erythropoeisis (842) lends support to this hypothesis. This suggests that activin might also exert paracrine or autocrine effects on cellular differentiation within the gonads, and recent evidence indicates this is indeed the case. Activin has been shown to suppress testosterone production from Leydig and thecal cells (327). In bovine ovary, activin decreases progesterone production (680). Estrogen production is stimulated by activin in rat GCs, but the effects on progesterone production are unclear (334,823). Activin can also inhibit oxytocin secretion from bovine ovary (680), stimulate inhibin secretion from rat GCs (400), and inhibit growth of CHO-1 cells (274).


ACKLAND,SCHWARTZ,MAYO,

740 3. Mullerian-inhibiting

substance

Mullerian-inhibiting substance fits into both categories of substances discussed in this review. It was originally isolated as the factor from male testis that induced regression of the Mullerian duct (358, 359); however, the serendipitous finding of MIS in the adult ovary suggested it also has another function. The existence of MIS as a testicular hormone has long been recognized, but the recent characterization of the molecule and its subsequent identification as a member of the TGF-0 family has led to new insights into its role in gonadal development. Mullerian-inhibiting substance produced in the undifferentiated testes mediates regression of the Mullerian duct, which would otherwise develop into female reproductive structures (179,359). Mullerian-inhibiting substance is a glycoprotein hormone composed of two disulfide-linked subunits, each of -70,000 Da (358). Both cDNA and genomic clones encoding MIS were recently identified, and sequence analysis of these clones showed that the carboxy-terminal domain of the 575-amino acid MIS molecule has marked homology to both TGF-P and the ,&subunits of inhibin and activin (100,569). Although the cysteine residues involved in interchain disulfide binding are conserved and MIS is active as a dimer, the MIS carboxy-terminal domain does not appear to be cleaved from the precursor, as is the case for both TGF-0 and the ,&subunits of inhibin and activin. However, 520% of MIS protein is cleaved during isolation from tissues, and MIS can yield a TGF-P-like fragment when digested with plasmin (563). Mullerian-inhibiting substance has similar growth inhibitory properties to those observed for TGF-P. It has been found to antagonize EGF-stimulated proliferation of A431 cells, and the mechanism of this antagonism is apparently by blocking autophosphorylation of the EGF receptor (134). Results at both the protein level (179) and mRNA level (100) indicate that MIS production in the male is high during fetal life, drops following birth, but remains at low levels in the adult, consistent with its role in early sexual differentiation. This is quite similar to the temporal pattern of expression of testicular inhibins (particularly the P-subunits) described in section IIA. Production of MIS in the testes has been localized to the SC (745), and its production is not regulated by either FSH or testosterone (793, 799). The 5’ flanking region of the gene contains an SPl site and a functional (in vitro) estrogen receptor-binding site (284) so regulation may be mediated through other hormones. The role of continued MIS production by the adult testes remains to be determined. Immunoassays for human MIS have recently been developed and should yield new information on its presence and function (for review see Ref. 493). In addition to its testicular expression, both MIS activity and MIS mRNA have been found in the ovary (100, 356). Mullerian-inhibiting substance has been immunohistochemically localized to GCs of antral follicles, particularly to cells of the corona radiata (61). In the ovarv, MIS has been implicated as an oocyte maturation

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inhibitor. Takahashi et al. (723) showed that MIS could inhibit GVBD in rat oocytes in vitro but not in mouse oocytes. Epidermal growth factor, which induces oocyte maturation, could antagonize MIS (769). However, the ability of MIS to inhibit GVBD has been disputed (753). The expression of MIS in the ovary is consistent with this role. Mullerian-inhibiting substance has been localized to antral GCs and the cumulus oophorus in growing oocytes and in GCs nearest the oocyte in preantral follicles (61, 770). It was first apparent on day 4 of life and increased after this. During the estrous cycle, MIS decreases just before meiosis resumes on proestrus, and this pattern was seen in PMSG-primed immature rats after human chorionic gonadotropin (hCG) injection (768). Overexpression of MIS in transgenic mice, as expected, leads to inhibition of the Mullerian duct. However, at birth, females had few oocytes, and these were lost over the next 2 wk (51). All that remained of the ovaries were some structures resembling seminiferous tubules. This same effect had been seen in freemartins or in female calves injected with MIS (794). The physiological role of MIS in the adult female remains to be determined, but functions in ovarian development or in meiotic inhibition are possible. 4. “lnhibin-like”

hormones

I) FOLLISTATIN. During the isolation of inhibin and activin, a side fraction was found that also inhibited FSH secretion from pituitary cell cultures. It was structurally distinct from inhibin, was not related to the TGF-0 family, and was named follistatin (618,767,834). Genes encoding porcine (208,678), human (677), and rat (676) follistatin have been cloned. The deduced amino acid sequences were highly homologous, and the gene structure was conserved among the three species. Human and porcine cDNA clones were alternatively spliced to yield two forms of follistatin of either 317 or 344 amino acids, whereas rat clones only encode for a 344-amino acid protein. The carboxy-terminal region of the large form contains acidic amino acids, and it is hypothesized that these may facilitate transport in plasma. The smaller forms without the acidic tail may act in a paracrine fashion. In immature female rats, follistatin gene expression was upregulated by PMSG. Follistatin mRNA was highest over secondary and tertiary follicles, was reduced in preovulatory follicles, and was very low over primordial follicles (676). Although follistatin was isolated by its ability to inhibit FSH secretion, its physiological role remains to be established. One report suggested that follistatin may be an activin-binding protein (530). Follistatin also increased FSH-stimulated progesterone secretion from GCs in vitro but suppressed estrogen and inhibin secretion (823), suggesting that it may have paracrine effects. II)SEMINALPLASMAINHIBINS. Previoustothecharacterization of inhibin from follicular fluid, the structures of several small peptides possessing FSH-sup-


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pressing activity were reported. These share no structural homology to the TGF-P family of proteins. The first of these was a 31-amino acid peptide isolated from human seminal plasma (590,653). Subsequently, Li et al. (425) described additional seminal plasma peptides of 52 and 92 amino acids that represented carboxy-terminal extensions of the 31-amino acid inhibin-like peptide and termed these cu-inhibin-52 and cw-inhibin-92. a-Inhibin92 was reported to be much more potent than the smaller forms at inhibiting FSH secretion from pituitary cultures and was found to be localized in the human pituitary and hypothalamus in addition to seminal fluids (590). The same group reported that a-inhibin-31 was localized to Leydig cells of the testes (410). Human seminal plasma inhibin may also be a sperm-coating antigen (41, 351, 780). Another seminal plasma peptide with inhibin activity termed P-inhibin was subsequently isolated and shown to be a 94-amino acid peptide with a sequence distinct from that of cu-inhibin-92 (672). With the use of immunohistochemistry, ,0-inhibin was found in epithelial cells of the prostate of several species, including humans (260). Levels of ,0-inhibin rise around puberty, and elevated levels have also been found in patients with prostatic tumors (673). The physiological role of these seminal vesicle peptides in FSH regulation remains unclear. The extent to which these peptides exhibit FSH-suppressing activities appears to vary markedly with the exact bioassay used, and several groups have reported that both the seminal plasma cy- and ,@-inhibins do not inhibit FSH using the dispersed pituitary cell culture assay (158,388, 440). Neither of the seminal plasma inhibin-like peptides bears any structural similarity to inhibins isolated from follicular fluid. B. Reluxin

The polypeptide hormone relaxin was first discovered in 1926 by Hisaw (313), who found that serum from pregnant rabbits or guinea pigs caused a relaxation of the pubic symphysis in female guinea pigs at estrus. A preparation of the relaxative substance from sow CL was named relaxin in 1932 (231). During the period 1950-1960, bioassays for relaxin were developed based on its actions on the guinea pig pubic symphysis, the mouse pubic symphysis, and the inhibition of uterine motility (for review see Ref. 711). The availability of these bioassays eventually led to the purification and sequencing of relaxin from rats and pigs (344,664, 670), and the advent of molecular biology techniques led to the isolation and sequencing of cDNA for rat preprorelaxin (332). Several reviews have been published giving detailed accounts of the structure and function of relaxin (24, 76, 77, 580, 668). 1. Structure

The primary structure of relaxin consists of two polvpeptide chains, A and B; the length of these chains

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varies between species, the A chain having 22-24 amino acids and the B chain 26-35 amino acids. The chains are covalently linked by two interchain disulfide bonds. The location of these disulfide bonds is homologous to those of insulin. Like insulin, relaxin is derived from a higher molecular mass precursor peptide, with the excision of a joining peptide (C-peptide) that links the A and B chains being necessary for the mature form of both hormones. Relaxin is now accepted to be a member of the growing family of IGFs (71). However, there is only -25% amino acid sequence homology between insulin and relaxin in rats and in pigs. There are also considerable sequence differences (up to 50%) between relaxin from different species in contrast to the considerable homology that exists between insulin sequences from different species. Multiple forms of porcine relaxin have been reported, which appear to be due to small differences in the length of the B chain; these differences can be partly accounted for by different extraction techniques used to isolate the hormones and may be minimized if tissue is extracted in acid conditions designed to prevent proteolysis. The considerable sequence differences that exist between relaxin from different species have resulted in different biological and immunological activities for these relaxins in the various RIAs and bioassays that have been described. It is therefore preferable that relaxin immunological and biological activities are determined using species homologous systems wherever possible. 2. Localization

Most sources of production have been determined by the physicochemical characterization of tissue extracts or by immunohistochemistry. More recently in situ hybridization has been used to detect relaxin in rat ovaries. I) PREGNANCY. The CL of pregnancy is undoubtedly the major source of relaxin in pigs and rats, although CL from nonpregnant pigs and rats has also been shown to contain relaxin (263, 332, 671). In humans the CL of pregnancy is capable of producing relaxin (466,812), but this has not been as intensively studied as other species. In cows and guinea pigs, however, the CL produces little or no relaxin (233, 553). Placental relaxin has been detected in the human, although the amounts present are much lower than in human CL of pregnancy (234, 826). However, in pregnant mares (713), rabbits (195), cats (714), and sheep (808) the placenta appears to be a major source of relaxin. Small amounts of relaxin are present in rat placenta (579), but little or no relaxin is present in cow placenta (233). The factors controlling the synthesis and production of relaxin in the placenta are not known. II) ESTROUS CYCLE. In pigs, relaxin immunostaining of CL (17) and immunoreactivity and bioactivity of ovarian extracts (671) have been detected and shown to change during the estrous cycle, although levels were verv much lower than those detected in pregnant ani-


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ACKLAND, SCHWARTZ,MAYO,

mals. Messenger RNA for relaxin has been detected in the nonpregnant sow ovary (77). In rats, relaxin levels measured by RIA are low throughout the cycle compared with pregnancy levels but do vary with cycle stage (671). Messenger RNA for relaxin has been detected in the CL of nonpregnant rats (332), and cycling rats have relaxin receptors in myometrial tissue (485). Relaxin is detectable in porcine follicular fluid, even in the absence of CL (79), and follicle wall preparations can produce relaxin in vitro, levels of which increase when the cells undergo spontaneous luteinization. Although GCs can produce small amounts of relaxin in vitro, the main source of relaxin in preovulatory follicles appears to be the thecal cells (39, 215). The uterus has been considered to be a source of relaxin, but demonstration is difficult as it is also a target tissue for the hormone, and direct measurement of relaxin in uterine tissue may be due to receptor occupancy, rather than tissue synthesis. To date the guinea pig is the only species where relaxin synthesis in the uterus (the endometrial gland) has been unequivocably demonstrated (553). Uterine content in guinea pigs increases with gestation, as ovarian content declines (520). Relaxin receptors are located in the myometrium of the guinea pig uterus; thus it is possible that in guinea pigs relaxin acts as a true local hormone, being produced by the endometrium, with the myometrium as its target tissue. III) MALES. In males, relaxin has been detected by immunolocalization techniques in the interstitial cells and, to a lesser extent, in the SCs of pig testes (189,825). However, this localization of relaxin may be due to the testes being a target tissue for relaxin rather than a site of production. High levels of immunoreactive relaxin have been detected in human seminal plasma, and the source has been shown to be the prostate gland (213,444). 3. Regulation I) PREGNANCY. In pigs, relaxin in the CL increases steadily from about day 20 of gestation until reaching maximum levels around day 110 and then decreases rapidly within the 16 h before delivery. Serum relaxin levels are low until day 100, rise gradually until 3 days before delivery, then rise rapidly to peak during the 24 h before delivery and then decline rapidly (665). These levels are consistent with the observation that relaxin accumulates in the granules of the luteal cells during pregnancy (367,403,404) and is then released during the rapid degranulation that occurs during the 2 days before birth. This prepartum release of relaxin is very precisely timed and also occurs in aging CL in hysterectomized pigs. Several factors have been proposed as promoting the luteal regression that appears to be associated with the simultaneous surge of relaxin. These include central nervous system- and pituitary-derived factors such as prolactin (728), LH (225), oxytocin (17), and also prosta-

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glandins (669, 728). In pigs, factors from the fetuses, placenta, or uterus do not seem to be involved in controlling relaxin production (24). Using a reverse hemolytic plaque assay, Taylor and Clark (730-732) have shown that relaxin release from luteal cells isolated from pregnant sows was stimulated by prostaglandin E, (PGE,) and inhibited by hCG, whereas oxytocin had no effect. Using this system to determine possible second messenger systems involved in inhibin release, they found that protein kinase C activation stimulated release, whereas dibutyryl CAMP and guanosine 3’,5’-cyclic monophosphate (cGMP) inhibited relaxin release. In rats the principal source of relaxin is also the CL of pregnancy. Ovarian content is detectable in extracted tissue from day 8 of gestation, reaching a maximum 2-3 days before delivery, and then declining rapidly by 2 days postpartum (667). Serum levels are detectable by RIA from day IO of gestation, rise steadily to peak immediately before partuition, and decline rapidly (667). The production and release of relaxin in pregnant rats are clearly controlled by the fetuses and placenta. Levels increase with increasing numbers of fetuses, and the placenta appears to promote relaxin synthesis, as well as progesterone synthesis, through mediating the actions of estrogen during the second half of pregnancy (273). The antepartum surge in serum relaxin is most likely accounted for by an accelerated release of relaxin from storage granules. There is evidence that this surge is associated with functional luteolysis and is linked to the photoperiod (579). Both LH and PGE,, may be involved in this antepartum release (275, 668). It is also clearly associated with an antepartum decline in progesterone levels to lO,OOO Da. Porcine LH-RBI was active in the testes. II) BINDING

FOLLICLE-STIMULATING INHIBITORS.

HORMONE

RECEPTOR-

The FSH-RBI activity in serum and gonadal extracts from a number of species is associated with nondialyzable (high molecular mass) and dialyzable (low molecular mass) components. Recently, Sluss et al. (697) isolated two FSH-RBIs from porcine follicular fluid, a low-molecular-mass form that inhibits target cell steroidogenesis and a high-molecularmass form that stimulates steroidogenesis. The lowmolecular-mass form was subsequently purified (696). It was shown to be a complex glycoprotein, and its amino acid composition was determined. Studies on the mechanism of action of the low-molecular-mass FSH-RBI from human serum have shown that it does not appear to prevent FSH binding by interacting with FSH itself. Rather it acts by preventing FSH binding to the receptor and dissociating FSH, which is already bound (598). These actions do not appear to be species specific, since human, rat, pig, and cow serum all had the same effects. Concentrations of FSHRBIs have been correlated with biochemical parameters of follicular development (694). Although FSH-RBIs could function as physiological modulators of target cell responsiveness to FSH, much remains to be determined about the structures, distribution, and modes of action of these gonadotropinbinding inhibitors. L. Other Peptides 1. Peptides associated with nerves

Several peptides have been isolated from ovary and are now thought to be associated with nerves. These include VIP, neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P, and somatostatin. Vasoactive intestinal peptide is a 28-amino acid peptide that is amidated at the carboxy terminus and was originally isolated from gut tissue (630). It has multiple actions, including pancreatic secretion, vasodilation, and smooth muscle relaxation (see Ref. 629). It is also present in brain and peripheral nerves and may function as a neurotransmitter. Peptide histidine methionine (PHM) is a closely related peptide synthesized from a common precursor (338) and is encoded on the same gene (72). The VIP fibers are associated with blood vessels and smooth muscle in the ovary and genitourinary tract of pigs, cats, rats, and mice (407). The VIPergic fibers are supplied to the ovary via the superior ovarian nerve


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(157), and cell bodies are located in the dorsal root ganglion and are hence thought to be visceral afferents or sensory nerves. Because VIP had been associated with neuronal structures, the presence of mRNA for VIP and PHM in the ovary was surprising (281). These investigators suggest that mRNA may be present in neuronal processes and that synthesis of VIP in the ovary may be locally regulated. Both VIP and PHM have been shown to have a variety of effects on the ovary. Fredricks et al. (242) found that infusions of VIP into rabbits increased progesterone secretion but had no effect on production of estrogen, testosterone, or on fertility. Vasoactive intestinal peptide was found to increase progesterone and estrogen in a dose-dependent manner from rat GCs in vitro (154); however, it did not stimulate an increase in the LH receptor. Peptide histidine methionine was also active but to a lesser extent than VIP. Vasoactive intestinal peptide was shown to increase synthesis of cytochrome P-450s~~ in rat ovarian cells in vitro, and this is proposed as the mechanism by which it stimulates steroidogenesis (748). In the hen, VIP (but not PHM) can stimulate steroidogenesis but inhibits PA synthesis (352). Kasson et al. (364) isolated two populations of GCs from hypophysectomized immature DES-treated rats based on their responsiveness to VIP and FSH. Vasoactive intestinal peptide stimulated steroidogenesis in one group more effectively, whereas FSH was more effective in the second group. A role for VIP has been suggested in puberty in female rats. Vasoactive intestinal peptide-immunoreactive fibers are present in the pubertal rat ovary in interstitial tissue and around blood vessels (14), and VIP or CAMP, but not FSH or other peptides, can stimulate aromatase activity in ovaries from neonates (265). On the first proestrus, VIP causes a marked increase in the release of estrogen and on the following diestrus leads to increased progesterone production. This group suggests that VIP may be important in the developing ovary to initiate steroidogenesis and may be involved in puberty. Neuropeptide Y is a 36-amino acid peptide originally isolated from porcine brain (727) and is widely distributed throughout the peripheral nervous system (576). Neuropeptide Y enters the rat ovary via the plexus nerve and is colocalized with norepinephrine-containing fibers (473,480), and cell bodies for NPY-containing neurons are found in the preaortic ganglion. These fibers are thought to be efferent or sympathetic neurons. The NPY nerves were localized by immunohistochemistry to interstitial tissue, follicles, and blood vessels in the ovary (354,550). Neuropeptide Y inhibits contraction of smooth muscle in the vas deferens (449). A role in regulation of blood flow has been suggested because of its anatomic localization near blood vessels and its well-known vasoconstrictive effects (734). Substance P is a member of the tachykinin family and was originally isolated from rat brain and intestine (for review see Ref. 419). Papka et al. (550) and Dees et al. (157) found substance P-immunoreactive nerves

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reaching the ovary by the nervous plexus. Substance Pcontaining neurons are thought to be visceral afferent, and their cell bodies are found in the dorsal root ganglion. Calcitonin gene-related peptide is a 37-amino acid peptide generated from calcitonin precursor mRNA by alternative splicing (624). Calcitonin gene-related peptide-immunoreactive fibers are found associated with blood vessels in immature rat ovary (89) and enter via the plexus nerve. A few of these fibers colabel with substance P but not tyrosine hydroxylase or NPY. However, CGRP does not have an effect on steroidogenesis in GCs in vitro, and it is speculated that CGRP may have a role in vasodilation. Somatostatin is a 40-amino acid peptide with one disulfide bridge (for review see Ref. 777). Somatostatin has been found in the testis, and levels are reduced with hypophysectomy (558). Levels were found to be low in prepubertal rats but increased with age. Immunoreactive somatostatin was also found in porcine ovaries at higher levels than in plasma (505). With the use of retrograde tracing, somatostatin-immunoreactive fibers were found in the celiac ganglion (480). 2. c-mos

The oncogene viral mos (v-mos) was originally isolated as the transforming factor of Moloney murine sarcoma virus (552, 781). Because many viral oncogenes have homologous counterparts in normal tissue (termed cellular or c-oncogenes), Propst and Vande Woude (584) screened mouse tissues and found expression only in testis, ovaries, and embryos. The testis transcript was 1.7 kb, the ovarian transcript was 1.4 kb, and the embryonic transcript had 2.3- and 1.3-kb fragments. The size heterogeneity was shown to be due to different initiation start sites, since the 3’ ends of all the transcripts were identical (583). The c-mos transcript was low in testis for the first 3 wk of life and reached adult levels by day 30, whereas the ovary transcript was higher at preweaning than in adult. In situ hybridization analysis revealed that c-mos mRNA was localized in oocytes in the ovary and over germ cells in the haploid stage in the testis (519). Goldman et al. (272) showed that c-mos mRNA was absent in male mice with a germ cell defect and also present in round spermatids (haploid stage) and in oocytes. The c-mos mRNA was shown to decline in oocytes during maturation and was low at the twocell stage. In vitro maturation of oocytes showed decreased levels of c-mos after 7-17 h incubation, corresponding to metaphase I progressing to metaphase II (518). Taken together these data seem to indicate that c-mos has a function in maturation of sperm and oocytes. Sagata et al. (627) provided further evidence that c-mos is involved in the process of oocyte maturation in Xenopus. They showed that oocytes induced to mature with progesterone synthesize a 39,000-Da phosphoprotein, designated pp39”““, which can be immunoprecipi-


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tated with antibodies to the c-3nos protein product. In addition, oocytes injected with antisense oligonucleotides to c-mos (which would block transcription of the endogenous gene) did not go through GVBD. This suggested that pp39”“” was required for maturation-promoting factor activity, GVBD, and oocyte maturation. O’Keefe et al. (537) confirmed this in mice, showing that microinjection of antisense oligonucleotides would allow the first meiotic division to occur but not the second. When c-‘YYLOS was decreased, chromosome decondensation and nuclear reformation occurred and two-cell cleavage began. Recently c-‘YYLOS has been proposed to be the cytostatic factor that had been demonstrated by Meyerhof and Masui (491). When c-3nos mRNA was injected into Xenopus embryos at the two-cell stage, cleavage was arrested at metaphase (628). Injection of unfertilized egg cytoplasm, which presumably contains pp39”““, arrests cleavage. However, if the cytoplasm is immunoprecipitated first with antibodies to pp39”““, cleavage occurs. They showed that pp39”“” was synthesized and hyperphosphorylated during maturation and could be specifically degraded by calpain, a Ca2+-dependent protease present in oocytes (806). It is hypothesized that the presence of pp39”“” prevents meiosis in the oocyte. A drop in pp39”“” would allow the oocyte to undergo the first meiotic division. Levels would then increase to arrest the oocyte at this stage until fertilization. The Ca2’ influx at fertilization would activate calpain, which in turn would degrade pp39”“” and allow for mitosis to occur in the embryo. The evidence to date is consistent with a role for C-~/OS as the cytostatic factor. III.

SUMMARY

The discovery of the various peptide factors in the gonads followed different paths. A number of factors were specifically searched for because of physiological experiments that predicted that an activity from the gonads was necessary to explain phenomena. Such was the case for gonadal steroids and for such peptide factors as inhibin, MIS, OMI, FRP, seminal plasma inhibin, relaxin, PA factor and other proteases, and ABP. In the process other factors such as activin and follistatin were serendipitously discovered. A second group of factors was discovered because in vitro experiments of various combinations of gonadal cell types failed to replicate in vivo findings, suggesting missing signals. Such substances are the panoply of growth factors aiding in differentiation and growth promotion and inhibition: LS and LI, P-Mod-S, clusterin, and various components of the ECM. Finally, and most recently, another set of peptides has been identified because immunological or molecular probes have been used to search gonadal tissue for factors originally discovered elsewhere; these include POMC, GnRH-like peptide, oxytocin, AVP, angiotensin, ANF, CRF, neural peptides, and c-‘ynoos. Our understanding of the relationship of most of these peptides to the local signals necessary for gonadal

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function is still very elementary. Clearly some like relaxin and inhibin function as important hormones, and ABP, for example, probably functions importantly in transporting testosterone down the tubule. Most local paracrine or autocrine peptide signals appear to act in relationship to gonadotropin levels probably in local differentiation in the process of gamete maturation, but this is only conjecture at this point. No experimental verification that any of these factors is involved in follicle selection for recruitment or for atresia is yet available. For many of the factors local receptors have not yet been identified. The richness of the variety of peptides in the gonads suggests that microanalysis of cellcell signaling would be rewarding, but at the time of this writing such investigations are not yet possible. REFERENCES 1. ACKLAND, J. F., J. B. D’AGOSTINO, S. J. RINGSTROM, J. P. HOSTETLER, B. G. MANN, AND N. B. SCHWARTZ. Circulating radioimmunoassayable inhibin during periods of transient follicle-stimulating hormone rise: secondary surge and unilateral ovariectomy. Biol. Reprod. 43: 347-352, 1990. 2. ADAMS, M. L., AND T. J. CICERO. The ontogeny of immunoreactive ,&endorphin and ,&lipotropin in the rat ovary. Biochem. Biophys. Res. Commun. 159: 1171-1176,1989. 3. ADASHI, E. Y., AND C. E. RESNICK. Antagonistic interactions of transforming growth factors in the regulation of granulosa cell differentiation. Endocrinology 119: 1879-1881, 1986. 4. ADASHI, E. Y., C. E. RESNICK, C. S. CROFT, J. V. MAY, AND D. GOSPODAROWICZ. Basic fibroblast growth factor as a regulator of ovarian granulosa cell differentiation: a novel non-mitogenie role. Mol. Cell. Endocrinol. 55: 7-14, 1988. 5. ADASHI, E. Y., C. E. RESNICK, A. J. D’ERCOLE, M. E. SVOBODA, AND J. J. VAN WYK. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endow. Rev. 6: 400-421,1985. 6. ADASHI, E. Y., C. E. RESNICK, E. R. HERNANDEZ, A. HURWITZ, AND R. G ROSENFELD. FSH inhibits the constitutive release of insulin-like growth factor binding proteins by cultured rat ovarian granulosa cells. Endocrinology 126: 1305-1307,199O. 7. ADASHI, E. Y., C. E. RESNICK, E. R. HERNANDEZ, J. V. MAY, A. F. PURCHIO, AND D. R. TWARDZIK. Ovarian transforming growth factor-p (TGF-P): cellular site(s), and mechanism(s) of action. Mol. Cell. Endocrinol. 61: 247-256, 1989. 8. ADASHI, E. Y., C. E. RESNICK, E. R. HERNANDEZ, M. E. SVOBODA, AND J. J VAN WYK. Characterization and regulation of a specific cell membrane receptor for somatomedin-C/insulin-like growth factor I in cultured rat granulosa cells. Endocrinology 122: 194-201, 1988. 9. ADASHI, E. Y., C. E. RESNICK, AND R. G. ROSENFELD. Insulin-like growth factor-I (IGF-I) and IGF-II hormonal action in cultured rat granulosa cells: mediation via type I but not type II IGF receptors. Endocrinology 126: 216-222,199O. 10. ADASHI, E. Y., C. E. RESNICK, M. E. SVOBODA, AND J. J. VAN WYK. Somatomedin C enhances induction of LH receptors by FSH in cultured rat granulosa cell. Endocrinology 116: 2369-2375, 1985. 11. ADASHI, E. Y., C. E. RESNICK, M. E. SVOBODA, AND J. J. VAN WYK. Somatomedin-C synergizes with FSH in the acquisition of progestin biosynthetic capacity by cultured rat granulosa cell. Endocrinology

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man ovaries: similarity to the GnRH-like ovarian protein of the rat. J Clin. EndocrinoZ. Metub. 64: 1288-1293, 1987. ATTARDI, B., H. S. KEEPING, S. J. WINTERS, F. KOTSUJI, AND P. TROEN. Effect of inhibin from primate sertoli cells and GnRH on gonadotropin subunit mRNA in rat pituitary cell cultures. Mol. Endocrinob 3: 1236-1242,1989. AUDHYA, T., C. S. HOLLANDER, D. H. SCHLESINGER, AND B. HUTCHINSON. Structural characterization and localization of corticotropin-releasing factor in testis. Biochim. Biophys. Actu 995: lo-16,1989. AVALLET, O., M. VIGIER, M. H. PERRARD-SAPORI, AND J. M. SAEZ. Transforming growth factor 0 inhibits leydig cell functions. Biochem. Biophys. Res. Commun. 146: 575-581,1987. AX, R. L., AND R. J. RYAN. The porcine ovarian follicle. IV. Mucopolysaccharides at different stages of development. Biol. Reprod. 20: 1123-1132,1979. AYER-LELIEVRE, C., L. OLSON, T. EBENDAL, F. HALLBOOK, AND H. PERSSON. Nerve growth factor mRNA and protein in the testis and epididymis of mouse and rat. Proc. NutZ. Acud. Sci. USA 85: 2628-2632,1988. BAGNELL, C. A., L. B. FRANDO, B. R. DOWNEY, B. K. TSANG, AND L. AINSWORTH. Localization of relaxin in the pig follicle during preovulatory development. Biol. Reprod. 37: 235-240,1987. BAIRD, A., N. EMOTO, S. SHIMASAKI, A. M. GONZALEZ, B. FAUSER, AND A. J. W. HSUEH. Fibroblast growth factors as local mediators of gonadal function. In: Growth Factors and the Ovary, edited by A. N. Hirshfield. New York: Plenum, 1989, p. 151-160. BANDIVDEKAR, A. H., K. GOPALKRISHNAN, AND A. R. SHETH. Antibodies to human seminal plasma inhibin cause sperm agglutination and impairment of cervical mucus penetration and sperm-egg attachment. Adv. Contrucept. 3: l-2,1987. BARANAO, J. L. S., AND J. M. HAMMOND. Comparative effects of insulin and insulin-like growth factors on DNA synthesis and differentiation of porcine granulosa cell. Biochem. Biophys. Res. Commun. 124: 484-490, 1984. BARDIN, C. W., P. L. BORRIS, C. SHAHA, Z. M. GENG, V. ROSSI, J. VAUGHAN, W. W. VALE, J. VOGLMAYR, AND C.-L. C. CHEN. Inhibin structure and function in the testis. Ann. NYAcud. Sci. 564: lo-23,1989. BARDIN, C. W., C. Y. CHENG, M. A. MUSTO, AND G. L. GUNSALUS. The Sertoli cell. In: The Physiology of Reproduction, edited by E. Knobil and J. Neil. New York: Raven, 1988, p. 933974. BARDIN, C. W., C. SHAHA, J. MATHER, Y. SALOMON, A. N. MARGIORIS, A. S. LIOTTA, I. GERENDAI, C.-L. CHEN, AND D. T. KRIEGER. Identification and possible function of proopiomelanocortin-derived peptides in the testis. Ann. NY Acud. Sci. 438: 346-364,1984. BAUKAL, A. J., T. BALLA, L. HUNYADY, W. HAUSDORFF, G. GUILLEMETTE, AND K. J. CATT. Angiotensin II and guanine nucleotides stimulate formation of inositol 1,4,5-triphosphate and its metabolites in permeabilized adrenal glomerulose cell. J. Biol. Chem. 263: 6087-6092, 1988. BAXTER, R. C., J. L. MARTIN, AND D. J. GADELSMAN. Identification of human semen insulin-like growth factor I/somatomedin C immunoreactivity and binding protein. Actu Endocrinol. 106: 420-427,1984. BECK, K., I. HUNTER, AND J. ENGEL. Structure and function of laminin: anatomy of a multidomain protein. FASEB J. 4: 148160,199O. BEERS, W. H., AND S. STRICKLAND. A cell culture assay for follicle stimulating hormone. J. Biol. Chem. 253: 3877-3881, 1978. BEERS, W. H., S. STRICKLAND, AND E. REICH. Ovarian plasminogen activator: relationship to ovulation and hormonal regulation. CeLZ6: 387-394, 1975. BEHRINGER, R. R., R. L. CATE, G. J. FROELICK, R. K. PALMITER, AND R. L. BRINSTER. Abnormal sexual development in transgenic mice chronically expressing mullerian inhibiting substance. Nature Lond. 345: 167-170,199O. BELLIN, M. E., AND R. L. AX. Chondroitin sulfate: an indicator of atresia in bovine follicles. Endocrinology 114: 428-434, 1984. BELLIN, M. E., R. L. AX, N. LAUFER, B. C. TARLATZIS, A. H.


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CHERNEY, D. FELDBERG, AND F. P. HASELTINE. Glycosaminoglycans in follicular fluid from women undergoing in vitro fertilization and their relationships to cumulus expansion, fertilization and development. Fertil. Steril. 45: 244-248, 1986. 54. BELLIN, M. E., B. C. WENTWORTH, AND R. L. AX. Comparisons of the ability of follicular fluid glycosaminoglycans and chemically desulfated heparin to compete for heparin-binding sites on granulosa cells. Biol. Reprod. 37: 293-300, 1987. 55. BELLVE, A. R., AND L. A. FERG. Cell proliferation in mammalian testis: biology of the seminiferous growth factor (SGF). Recent Prog. Hwm. Res. 40: 531-567,1984. M. A. CHAU56. BENAHMED, M., C. COCHET, M. KERAMIDAS, VIN, AND A. M. MORERA. Evidence for a FSH dependent secretion of a receptor reactive transforming growth factor P-like material by immature sertoli cells in primary culture. Biochem. Biophys. Res. Commun. 154: 1222-1231,1988. 57 BENAHMED, M., A. M. MORERA, M. C. CHAUVIN, AND E. DE PERETTI. Somatomedin C/insulin-like growth factor I as a possible intratesticular regulator of leydig cell activity. MO!. Cell. Endocrinol. 50: 69-77,1987. 58. BENDELL, J. J., AND J. DORRINGTON. Rat theta/interstitial cells secrete a transforming growth factor-p-like factor that promotes growth and differentiation in rat granulosa cell. Endocrinology 123: 941-948,1988. 59. BERG, T., J. SULNER, C. Y. LAI, AND R. L. SOFFER. Immunohistochemical localization of two angiotensin I-converting isoenzymes in the reproductive tract of the male rabbit. J Histochem. Cytochem. 34: 753-760,1986. 60. BERNIER, M., P. CHATELAIN, J. P. MATHER, AND J. M. SAIZ. Regulation of gonadotropin receptors, gonadotropin responsiveness, and cell multiplication by somatomedin-c and insulin in cultured pig leydig cells. J. Cell. Physiol. 129: 257-263, 1986. 61. BEZARD, J., B. VIGEIR, D. TRAN, P. MANLEON, AND N. JOSSO. Immunocytochemical study of antimullerian hormone in sheep ovarian follicles during fetal and postnatal development. J. Reprod. Fertil. 80: 509-516, 1987. 62. BHASIN, S., D. HEBER, M. PETERSON, AND R. SWERDLOFF. Partial isolation and characterization of testicular GnRH-like factors. Endocrinology 112: 1144-1146, 1983. 63. BHASIN, S., L. A. KRUMMEN, R. S. SWERDLOFF, B. S. MORELOS, W. H. KIM, G. DIZEREGA, N. LING, F. ESCH, S. SHIMASAKI, AND J. TOPPARI. Stage dependent expression of inhibin CY and PB subunits during the cycle of the rat seminiferous epithelium. Endocrinology 124: 987-991,1989. 64. BICSAK, T. A., S. B. CAJANDER, W. VALE, AND A. J. W. HSUEH. Inhibin: studies of stored and secreted forms by biosynthetic labeling and immunodetection in cultured rat granulosa cells. Endocrinology 122: 741-748, 1988. 65. BICSAK, T. A., M. SHINONAKA, M. MALKOWSKI, AND N. LING. Insulin-like growth factor-binding protein (IGF-BP) inhibition of granulosa cell function: effect on cyclic adenosine 3’,5’monophosphate deoxyribonucleic acid synthesis and comparison with the effect of an IGF-I antibody. Endocrinology 126: 184-189, 1990. 66. BICSAK, T. A., E. M. TUCKER, S. CAPPEL, J. VAUGHAN, J. RIVIER, W. VALE, AND A. J. W. HSUEH. Hormonal regulation of granulosa cell inhibin biosynthesis. Endocrinology 119: 27112719,1986. 67. BICSAK, T. A., W. VALE, J. VAUGHAN, E. M. TUCKER, S. CAPPEL, AND A. J. W. HSUEH. Hormonal regulation of inhibin production by cultured sertoli cells. Mol. Cell Endocrinol. 49: 211217,1987. 68. BISWAS, S. B., R. W. HAMMOND, ANDL. D. ANDERSON. Fibroblast growth factors from bovine pituitary and human placenta and their functions in the maturation of porcine granulosa cells in vitro. Endocrinology 123: 559-566, 1988. 69. BLAIR, E. I., J. E. ESTES, J. KESKIUJA, I. C. KIM, AND D. W. SCHOMBERG. Human platelet derived growth factor preparations contain a separate activity which potentiates FSH mediated induction of LH receptor in cultured rat granulosa cells: evidence for TGFP. Endocrinology 123: 2003-2008,1988. 70. BLASCHUK, O., K. BURDZY, AND I. B. FRITZ. Purification and characterization of a cell-aggregating factor (Clusterin). the ma-

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jor glycoprotein in ram rete testis fluid. J. Biol. Chem. 258: 77147720,1983. BLUNDELL, T. L., AND R. E. HUMBEL. Hormone families: pancreatic hormones and homologous growth factors. Nature Lond. 287: 781-787,198O. BODNER, M., M. FRIDKIN, AND I. GOZES. Coding sequences for vasoactive intestinal peptide and PHM-27 peptide are located on two adjacent exons in the human genome. Proc. Natl. Acad. Sci. USA 82: 3548-3551, 1985. BORLAND, K., M. MITA, C. L. OPPENHEIMER, L. A. BLINDERMAN, J. MASSAGUE, P. F. HALL, AND M. P. CZECH. The actions of insulin-like growth factors I and II on cultured sertoli cells. Endocrinology 114: 240-246, 1984. BORLAND, K., K. E. MUFFLY, AND P. F. HALL. Production of components of extracellular matrix by cultured rat Sertoli cells. Biol. Reprod. 35: 997-1008, 1986. BROWN, J. L., AND J. J. REEVES. Absence of specific LHRH receptors in ovine, bovine, and porcine ovaries. Biol. Reprod. 29: 1179-1182,1983. BRYANT-GREENWOOD, G. D. Relaxin as a new hormone. En-

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Evaluation of the Contribution of Signals Originating from Large Blood Vessels to Signals of Functionally Specific Brain Areas.

Intracellular signaling in the gonads.

Role of the gonads in hypertension-prone rats.

Adenocarcinoma originating in the thyroglossal duct.

Plasticity and regeneration of gonads in the annelid Pristina leidyi.

Cardiac pheochromocytoma originating in the interatrial septum.

bies.201200081).

Reciprocal interaction between bone and gonads.

Nonsteroidal anti-inflammatory drugs and the heart.

Laparoscopic removal of 46XY gonads located within the inguinal canals.

Nonsteroidal anti-inflammatory agents.

Nonsteroidal anti-inflammatory drugs--the clinical dilemmas.

Atrial tachycardia originating from the aortomitral junction.

Early development of gonads in Muscovy duck embryos.

Treatment of childhood cancer: effects on gonads.

Nonsteroidal Anti-Inflammatory Drugs and the Kidney.

Treatment of childhood cancer: effects on the gonads.

Molecular regulation of hypothalamus-pituitary-gonads axis in males.

Ligandin in steroidogenically active cells of rat gonads.

Nonsteroidal anti-inflammatory drug-induced acute ulcers in the colon.

Effects of nonsteroidal antiestrogens in the in vitro rat uterus.

Identification of side population cells in chicken embryonic gonads.

Germ cell nuclear factor regulates gametogenesis in developing gonads.

Gonads in Histiostoma mites (Acariformes: Astigmata): structure and development.