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Minireview: Genetic Models for the Study of Gonadotropin Actions

Department of Pathology (K.H.B., M.M.M.), Department of Molecular and Human Genetics (K.H.B., M.M.M.), and Department of Molecular and Cellular Biology (M.M.M.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., Professor and Stuart A. Wallace Chair, Department of Pathology, One Baylor Plaza, Baylor College of Medicine, Houston, Texas 77030. E-mail: . mmatzuk{at}bcm.tmc.edu

	Abstract

Top Abstract Introduction Mouse Models and Human... Mouse Models of Aberrant... Peptide Hormone Feedback to... Transcriptional Control of the... Other Pituitary Hormones, IGF-1,... Conclusions References

 
Fertility in both sexes relies on complex physiological and molecular processes with many levels of regulation, and our ability to alter the mammalian genome using transgenic technology has greatly enhanced our understanding of these processes. There are numerous commonalities in human and mouse physiology, and the list of mouse models recapitulating recognized and idiopathic human reproductive defects is growing at an ever-increasing rate. In this review, we focus on genetic models of gonadotropin actions, summarizing features of transgenic mice that phenocopy defects in gonadotropin production and gonadotropin receptor responses seen in patients. In addition, we provide examples of mouse models with genetic alterations influencing pituitary FSH and LH production and their effects. These include: 1) transgenic mice with aberrations in steroid hormone, inhibin, and activin feedback pathways; 2) knockouts that demonstrate specific in vivo functions of pituitary transcription factors; and 3) models with alterations in other pituitary hormones, IGF-1, and leptin signaling pathways, which affect both the central and peripheral endocrine axis. What we have to learn from these and other models will continue to revise our conceptions of physiology, identify new targets for contraception, and improve our tools for understanding, diagnosing, and treating cases of human endocrinopathies and pathologies of the reproductive tissues.

	Introduction

Top Abstract Introduction Mouse Models and Human... Mouse Models of Aberrant... Peptide Hormone Feedback to... Transcriptional Control of the... Other Pituitary Hormones, IGF-1,... Conclusions References

 

"Whenever man comes up with a better mousetrap, nature immediately comes up with a better mouse."

	Mouse Models and Human Gonadotropin Signaling Pathologies

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THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) axis is fundamental to the endocrine control of gametogenesis in mammals, and because of its long-recognized physiological importance, many human mutations disrupting the normal function of the axis have already been characterized, and several relevant mouse models have been engineered. The pituitary gonadotropins, FSH and LH, are central to this endocrine communication. FSH and LH are heterodimeric glycoproteins each comprised of a common -subunit and a unique ß-subunit; functional dimers are synthesized and secreted into the circulation in response to hypothalamic GnRH. The human common -, FSHß-, and LHß-subunits are glycosylated 92-, 111-, and 121-amino acid peptides, respectively (1). FSH and LH elicit intracellular signaling pathways by binding to their respective G protein-coupled transmembrane receptors, FSH receptor (FSHR) and LH receptor (LHR), in somatic gonadal cells to regulate follicular development, ovulation, and steroidogenesis in females, and spermatogenesis, testicular growth, and steroidogenesis in males (2, 3). The human FSHR and LHR proteins are 695- and 701-amino acid glycoproteins, respectively. Loss-of-function and gain-of-function human mutations in components of the HPG axis have been described previously (4, 5, 6), and examples are given in Table 1 and illustrated in Fig. 1.

View larger version (19K): [in this window] [in a new window]   Figure 1. The HPG endocrine axis is illustrated with several key components of the signaling relay. Within the central portion of the axis, the actions of hypothalamic GnRH mediate the production of the anterior pituitary heterodimeric gonadotropins, FSH and LH. These bind to FSHR and LHR in the periphery to regulate gametogenesis and steroidogenesis. At each level of the axis, mutations in human genes are known to cause defects in the development or function of the reproductive system; examples are listed on the right.

In contrast to humans, in which no GnRH mutation has been identified, a naturally occurring 33.5-kb deletion truncating the Gnrh gene in mice (11) results in a model of hereditary hypogonadism (hpg), which phenocopies the HHG of patients with defects in GnRH production or responsiveness. Hypogonadism is also a feature of a knockout mouse model harboring a null allele at the glycoprotein hormone common -subunit locus; besides reproductive defects, the knockout mouse is hypothyroid and displays proportional dwarfism owing to loss of TSH function (12). These and other relevant mouse models with reproductive phenotypes are shown in Table 2. No mutations altering the amino acid sequence of the common -subunit have been described in humans. It has been hypothesized that a deleterious mutation in the human -subunit gene (GLYCA) would result in embryonic lethality because in humans (and not in mice) the -subunit is also shared with human chorionic gonadotropin (hCG) (4). Embryo-derived hCG maintains ovarian luteal cells, and is thereby required for pregnancy during the first trimester. Substantiating this, the most highly expressed hCGß-subunit-encoding genes are highly conserved, with no individuals homozygous for a deletion of the CGß cluster (13).

Loss of FSH signaling causes infertility in women (19), and this condition can be modeled by disrupting either the FSHß (Fshb) or Fshr loci in mice. Women who are homozygous or compound heterozygous for inactivating ligand (frameshift/truncation and missense) or receptor (missense) mutations exhibit normal preantral follicle development, but no antral-stage follicles capable of ovulation form. These women typically present clinically as cases of primary amenorrhea and sexual infantilism. Both Fshb and Fshr knockouts in mice phenocopy the human mutations in this regard, displaying female infertility, uterine hypoplasia, and folliculogenesis blocks before antrum formation (20, 21, 22). Although estradiol is present in the serum of these mice, the mRNAs encoding P450 side chain cleavage and P450 aromatase estrogenic enzymes are markedly down-regulated in the ovaries of Fshb knockout mice (23). Both Fshb and Fshr knockout females also exhibit high levels of circulating LH (20, 21, 22). In both models, this is a progressive effect, with less LH seen in younger mice than in older mice. It is believed that LH and LH-induced androgen synthesis in the Fshr model contribute to the development of ovarian sex-cord stromal tumors, which are seen in 92% of these mice by 12 months of age. In these tumors, there is loss of granulosa cell proliferation control programs, accompanied by an up-regulation of Sertoli cell markers, Müllerian-inhibiting substance, and GATA-4 transcription factor (24). In men, FSHß and FSHR mutations have been associated with variable degrees of impairment of spermatogenesis and sometimes with delayed puberty (4). However, men with FSHR null mutations can father children (25). Fshb and Fshr knockout male mouse models are fertile but have lowered sperm counts and decreased testicular size. Therefore, it seems that FSH activity, while necessary for optimal sexual development and spermatogenesis, is dispensable for male, but not female, fertility in both humans and mice.

A transgenic mouse model overexpressing high levels of human FSH has also been developed (26). The transgenic males demonstrate stimulated Leydig cell function, elevated serum testosterone, and infertility; females exhibit infertility with hemorrhagic and cystic ovaries. These mice may prove valuable in modeling gonadal and more global physiological effects of FSH hyperstimulation. Consistent with the high conservation of FSHß genes in mice and humans, synthesis of human FSHß under its own promoter in the gonadotropes of mice lacking the endogenous FSHß-subunit restores normal fertility in male and female mice (27). Moreover, partial rescue of the knockout phenotype was observed in mice ectopically expressing human FSH (human - and FSHß-subunits) under the direction of the mouse metallothionein-I promoter (27). Together, these studies demonstrate functional conservation between mouse and human FSHß promoter elements, as well as between the two FSHß peptides in terms of their abilities to assume glycosylation patterns, dimerize with the mouse -subunit, route to secretory granules independent of LH, and bind and activate the mouse FSHR.

Loss of isolated LH signaling function can arise from defects in the unique LHß-subunit or LHR. One loss-of- function missense mutation in the hormone subunit was identified in an infertile man presenting with low testosterone levels, Leydig cell hypoplasia, and elevated immunoreactive but functionally ineffective LH (28). Several LHR mutations have been discovered to cause defects in receptor activity of variable severity. Phenotypes range from micropenis and hypospadias in the case of hypomorphic alleles to male pseudohermaphroditism and female infertility associated with a barrier to preovulatory follicle development, ovulation, and luteinization (4). These conditions are partially modeled by targeted deletion of the Lhr locus in mice; homozygotes demonstrate normal prenatal sexual development but are infertile (29). Male Lhr knockouts have defects in testicular growth and descent, Leydig cell hypoplasia, and a block in spermatogenesis at the round spermatid stage. Female knockouts have underdeveloped ovaries and uteri, and their ovaries do not contain preovulatory stage follicles or corpora lutea; thus, the Lhr knockout in female mice very closely models the pathology of women with LH resistance. It is notable that hpg (GnRH mutant) male mice closely phenocopy the Lhr mutant male mice, whereas the hpg female phenotype mimics that of Fshb and Fshr knockouts at early timepoints (<6 wk of age) but reflects a combined FSH/LH signaling defect at later points. This observation is consistent with studies showing that androgen administration to hpg male mice can restore spermatogenesis (30). Interestingly, the androgens produced by Leydig cells in response to LH may not be as crucial to spermatogenesis as estrogens that are then synthesized from androgen substrates. Provision of exogenous estradiol to hpg males increases testis weight and rescues qualitatively normal spermatogenesis in the absence of measurable androgens (31).

Gain-of-function mutations of LHR have been described in families with autosomal dominant male precocious puberty (32). Although no mouse models phenocopy this disorder, transgenics have been engineered to overexpress the bovine LHß-subunit with a C-terminal extension of the hCGß- subunit (bLHß-CTP); there is a prolonged serum half-life of the chimeric LH hormone (33). These in vivo studies corroborate findings of Boime and colleagues (34, 35), who demonstrate that the presence of the hCGß C terminus of several of the glycoprotein hormone ß-subunits (e.g. hCGß, FSHß) extends the circulating half-life. Interestingly, female bLHß-CTP transgenics have a 10-fold increase in circulating immunoreactive LH and exhibit impaired ovulation, a prolonged luteal phase, ovarian cysts, and granulosa/theca cell tumors on some genetic backgrounds (36). In addition, in immature transgenic females, enhanced LH and steroid hormones cause precocious follicular development and vaginal opening (37). Studies of these transgenic mice may shed light on the roles of LH in polycystic ovarian syndrome and the development of postmenopausal ovarian stromal tumors, as well as identify genetic modifiers of these phenotypes (36).

	Mouse Models of Aberrant Steroid Hormone Feedback to the Pituitary

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Gonadotropins promote peripheral steroid production by inducing the expression of gonadal steroidogenic enzymes; steroid hormones then produced feedback to negatively regulate pituitary FSH and LH production (1, 38, 39). This paradigm is supported by studies of mouse models with alterations in steroid hormone receptors or steroid biosynthesis that develop secondary anomalies in gonadotropin production. For example, knockout mice lacking an estrogen receptor, ER, which is normally expressed in the hypothalamus, pituitary and gonads, exhibit female infertility associated with anovulation and the development of hemorrhagic, polycystic ovaries by 20–22 d of age (40, 41). The disruption to estrogen feedback signaling results in overexpression of gonadotropin subunit mRNAs in the pituitary (42) and chronically elevated serum LH (43). High levels of circulating LH are key to the ovarian pathogenesis in the ER knockout mice, and treatment with a GnRH antagonist precludes ovarian cyst formation (44). In contrast, female mice lacking ERß, which has a relatively restricted pattern of expression, are fertile, and preliminary studies indicate that there is no change in serum LH (45). ERß signaling plays some role, however, in the regulation of the hypothalamic-pituitary-gonadal endocrine axis, at least in the absence of ER activity. Double knockout females lacking ER and ERß have higher serum LH levels that do ER single knockouts, and exhibit a different ovarian phenotype in which granulosa cells take on a Sertoli cell-like morphology and express Sertoli cell markers, Müllerian-inhibiting substance, sulfated glycoprotein-2, and Sox9 (46).

Male ER knockout mice are infertile because of a disruption of fluid reabsorption from the lumen of the epididymis, which is important for concentration and maturation of spermatozoa; increased pressure from the accumulation of fluid leads to testicular atrophy and degeneration of the seminiferous epithelium in mature males (47). This phenotype does not have an obvious relationship to the only clinical case of an ER mutation, that of a man with estrogen resistance caused by a homozygous nonsense mutation in ER (48). The 28-yr-old patient presented with incomplete epiphyseal closure and continued linear growth into adulthood. Biochemical analyses provided evidence of increased bone turnover, and bone mineral density was low. Serum estradiol, FSH, and LH levels were elevated; serum testosterone was normal. Interestingly, the patient also had impaired glucose tolerance and hyperinsulinemia, and ER knockout male mice have increases in total body fat and in serum cholesterol and leptin levels after sexual maturity (49). These findings underscore the importance of estrogens in the bone and lipid metabolism, and have important implications for the use of hormonal contraceptions and estrogen replacement therapies in women, and appreciating the effects of exposure to environmental estrogens.

Estrogen production is abrogated in the P450 aromatase knockout mouse model, the female reproductive phenotype of which closely resembles that of ER knockout mice. Female P450 aromatase knockouts have high serum levels of LH and FSH, are infertile owing to a block in follicular development and ovulation defects, and develop hemorrhagic ovarian cysts by 21–23 wk of age (50, 51). Male P450 aromatase knockouts develop progressive infertility characterized by an arrest in early spermiogenesis, germ cell apoptosis, high circulating LH, and Leydig cell hyperplasia (52). Heritable aromatase deficiency has been described in patients with mutations at the aromatase locus (CYP19) (53). In the absence of fetal aromatase (and therefore placental estrogens), there is an elevation of testosterone and androstenedione in both maternal and fetal circulations. This causes pseudohermaphroditism in homozygote females, and virilization of the mother during her pregnancy. In the absence of ovarian aromatase activity, young girls exhibit hypergonadotropic hypogonadism and develop follicular cysts; with the onset of puberty, the ovaries become enlarged and further polycystic and there is progressive virilization. In males, the aromatase deficiency is associated with macro-orchidism, high circulating FSH, LH, and testosterone, as well as hyperinsulinemia and abnormal plasma lipids. In both women and men, aromatase deficiency is associated with delayed epiphyseal fusion and osteopenia (53).

An aromatase-overexpressing mouse model has been developed to study the effects of enhanced conversion of androgens to estrogens on male reproduction. These mice carry a transgene expressing human aromatase under the constitutive human ubiquitin C promoter, which is active in multiple mouse tissues by embryonic d 15. These mice have cryptochidism with Leydig cell hyperplasia and disrupted spermatogenesis, as well as underdevelopment and defects of accessory sex organs. Serum hormone assays reveal elevated estrogen, reduced testosterone, and reduced FSH, with no change in average LH levels but a reduction in LH level variation (54). The cryptorchidism is likely due to a disruption of steroid effects during prenatal development. The etiology of the Leydig cell hyperplasia is less clear, though both cryptorchidism and exposure to estrogens have been associated with testicular tumorigenesis in mice, and cryptorchidism is a risk factor in humans (55). Leydig cell tumorigenesis is reported in a second aromatase-overexpressing transgenic model in which the aromatase coding sequence is expressed under the mouse mammary tumor virus (MMTV) promoter. The expression leads to Leydig cell tumors that express high levels of ER, and up-regulation of a G1S phase cell cycle promoter, cyclin D1, known to be modulated by estrogen exposure (56). The MMTV promoter in this mouse model also drives aromatase expression in the mammary glands and this results in preneoplastic lesions (57). Interestingly, vitamin D has also been recently shown to be important for estrogen biosynthesis in both the ovary and testis. Studies of knockout mice lacking the vitamin D receptor reveal attenuation of gonadal P450 aromatase activity, histological abnormalities of the uterus, ovary, and testis consistent with estrogen deficiency, and elevated levels of LH and FSH (58). Together, the phenotypes of these models indicate important in vivo roles for the sex steroid hormones as mediators of the HPG endocrine axis and also as cell cycle controllers and differentiation factors in hormonally responsive peripheral tissues in both males and females.

	Peptide Hormone Feedback to the Pituitary

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In addition to steroid hormones, peptide endocrine factors released from the gonads affect pituitary FSH and LH production. Inhibins (:ßA and :ßB heterodimers) and activins (ßA:ßA and ßB:ßB homodimers, and ßA:ßB heterodimers) are members of the TGFß superfamily named for their respective abilities to suppress and enhance FSH production. These peptides are synthesized in granulosa cells of the ovary and Sertoli cells of the testis and are also found in other tissues where they have been implicated in diverse biological processes (59). Male and female knockout mice lacking the -subunit (Inha^-/-), and therefore depleted of the biological effects of both inhibins, have high circulating activins and FSH, and develop steroidogenic sex-cord stromal tumors of the granulosa cell and Sertoli cell lineage. These tumors are associated with a cachexia-like wasting syndrome, which typically causes death between 8 and 18 wk of age (60, 61). In addition, superovulation experiments in younger knockout females indicate that there are defects in late stages of follicle development, and transplant experiments demonstrate important paracrine roles of ovarian inhibins in maintaining the granulosa cell phenotype and averting the formation of Sertoli tubule-like structures (62). FSH and LH are critical to the processes of tumorigenesis in these mice, as double mutant mice homozygous for the hypogonadal (hpg) mutation at the Gnrh locus and the Inha knockout allele do not develop tumors (63), and Fshb and Inha double knockouts develop tumors with later onset and a less aggressive course, a finding that is particularly pronounced in double knockout males (26). In contrast to the Inha^-/- model, mice that overexpress the rat inhibin coding sequence under the control of the metallothionein promoter have reduced FSH levels in both sexes and elevated LH levels in females. In addition, females exhibit subfertility owing to a decrease in the number of ovulated oocytes, a defect that can be corrected with the provision of exogenous gonadotropins (64).

Recent clinical evidence indicates that inhibins may regulate human gonadotropin production, and ultimately affect the duration of a woman’s reproductive potential. A point mutation in the human INHa gene, resulting in a nonconservative amino acid change (Ala²⁵⁷Thr), has been associated with premature ovarian failure (65). The mutation was found in three patients who presented with secondary amenorrhea, low serum estrogens, and elevated gonadotropins, at ages 16, 20, and 24 yr of age. The authors of the study suggest that a decrease in the bioactivity of the mutant inhibin led to persistently enhanced gonadotropins, and premature depletion of ovarian follicular reserves. Low levels of circulating inhibins and high levels of FSH have been associated with premature ovarian failure before, though this study is the first to implicate inhibins in the condition’s etiology. We anticipate that future studies of inhibin mutations, and clinical assessments of inhibin and FSH levels preceding ovarian failure, will be informative.

When inhibin knockout mice are castrated, they develop steroidogenic tumors of the adrenal cortex, indicating that inhibin signaling is key to proliferation control in the adrenal glands, as well as the gonads (61). Gonadal tumors and the development of adrenal cortical tumors upon castration are also features of a transgenic model expressing the SV40 T antigen (Tag) under the control of the mouse inhibin promoter (66, 67). Despite similarities in their phenotypes, the endocrine environments in which gonadal tumors develop in these two mouse models are quite distinct, with a progressive decrease in serum LH and FSH in the Tag overexpresser being noted as ovarian tumorigenesis proceeds (68). Nevertheless, there is a critical function of the gonadotropin hormones in this model, as is demonstrated by the findings that: 1) the hpg mutation prevents the Tag mice from developing both gonadal and adrenal tumors (69); 2) adrenal tumor cells express LHR and respond to LH by up-regulating steroid production in vitro (70); and 3) suppression of serum LH by exogenous testosterone administration precludes tumor development (69). Similarly, elevated serum LH in the bLHß-CTP transgenic model promotes LHR expression and induces steroidogenesis in the adrenal cortex (71). Such LH action may also be involved in tumorigenesis in the inhibin knockout models, where there is a striking induction of LHR and P450 aromatase mRNAs in adrenal tumors (our unpublished data). Together, these mouse models provide evidence for important regulatory roles of inhibins and LH on nongonadal steroidogenesis and tumorigenesis.

Homozygote mice with a null mutation engineered at the activin/inhibin ßA locus (Inhba^-/-) die neonatally due to craniofacial defects that prevent suckling, and until more recently this had precluded further studies pertaining to the role of activin subunit in reproduction. The null phenotype, however, can be rescued by replacing the activin/inhibin ßA coding sequence with that of the activin/inhibin ßB gene, conferring the activin/inhibin ßA expression pattern on this related sequence (63% amino acid identity). Knock-in mice demonstrate enlarged external genitalia, hypogonadism, and diminished female fertility, indicating unique and previously unrecognized functions of the activin/inhibin ßA protein product in reproduction (72). Serum FSH levels in these mice are slightly increased, though whether this reflects loss of pituitary inhibin :ßA signaling, enhanced activin ßB:ßB signaling, or is simply secondary to gonadal defects remains to be investigated. Knockout mice lacking a functional ßB locus (Inhbb^-/-) have developmental defects in eyelid closure, prolonged gestation, and a failure of mothers to nurse their litters (62, 73). The latter is also a primary characteristic of oxytocin knockout mice (74), and therefore, together these phenotypes substantiate that activin ßB is an important in the induction of this hypothalamic/posterior pituitary hormone (75).

Signaling pathways that mediate activin and inhibin effects are complex, and no receptor or downstream signaling protein mutations have been described that phenocopy the mutant models lacking functional ligands. In the case of activin signaling, however, transgenic mouse models with altered expression of activin-interacting proteins have elucidated specific aspects of activin function in FSH regulation. Activin receptor type II (ActRII) has been shown to relay activin-mediated induction of FSH, as knockout mice lacking ActRII have suppressed FSH levels in the pituitary and serum; LH levels are not affected. Mutant ActRII mice also exhibit gonadal pathologies at least in part due to the lack of FSH, including a delay in fertility and reduced testicular growth in males, and infertility, underdeveloped uteri, follicular atresia and reduced numbers of corpora lutea in females (76). Bioactivities of activin dimers are modulated by their association with a binding protein, follistatin; the interaction is believed to antagonize activin functions in the pituitary (62, 77). Follistatin knockout mice have numerous embryonic defects and die in the perinatal period (78), but the role of follistatin in controlling FSH levels can be appreciated from studies of transgenics overexpressing follistatin under the control of the metallothionein promoter. Lines of mice with widespread expression of the transgene exhibit suppression of serum FSH, and defects in gonadal growth and gametogenesis that can be partially ascribed to FSH deficiency (79).

	Transcriptional Control of the Gonadotropin Genes

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Knockout mouse models have led to the functional characterization in vivo of several pituitary transcription factors important in mediating gonadotropin expression or providing for the survival of neuroendocrine cell populations in the hypothalamus and pituitary. One of these factors is steroidogenic factor-1 (SF-1), originally identified because of its role in directing the expression of cytochrome P450 steroid hydroxylases in the ovary, testis and adrenal gland. Knockout mice lacking SF-1 have profound defects in endocrine development that affect multiple levels of the HPG axis. Newborn SF-1 knockout mice have gonadal and adrenal agenesis, female sex traits, absence of the ventromedial hypothalamic nucleus, and impaired gonadotrope expression of GnRHR, FSH, and LH (80, 81, 82). Heterozygote mice are phenotypically normal. To circumvent the complexity of the SF-1 null phenotype and establish its role specifically in pituitary hormone production, tissue-specific SF-1 knockout mice have been engineered (83). In these mice, a portion of the endogenous SF-1 locus is marked for excision by Cre-recombinase enzyme by the introduction of tandem loxP sites, and a Cre-recombinase-encoding transgene is expressed under the -glycoprotein hormone subunit promoter specifically in cells of the anterior pituitary. In both males and females, the pituitary SF-1 loss-of-function caused sexual infantilism and hypogonadism, and gonadotrope cells failed to express appreciable levels of GnRHR, FSH, or LH (83). Essentially, all gonadotropic effects of the anterior pituitary are lost in these mice, the hypogonadism being as pronounced as when gonadotrope cells are ablated by targeted toxin expression (84), but there is no defect in gonadal or adrenal development during embryogenesis. In several respects, the SF-1 null mouse phenocopies the effects of a heterozygous mutation in the human FTZF1 gene encoding SF-1. The mutation has been described in a single patient (85) and is a loss-of-function 2-bp missense change affecting the DNA binding domain of the SF-1 protein and eliminating its recognition of the SF-1 canonical nucleotide sequence. The XY female patient presented with adrenal failure in the first 2 wk of life and had streak gonads with poorly differentiated tubule structures. Despite similarities to the knockout model, there was elevation of gonadotropin hormones in this patient in response to administration of GnRH. It is possible that FSH and LH production during this test relied upon the function of SF-1 transcribed from the normal allele.

The reason for the SF-1 haploinsufficiency seen in humans and not mice remains unclear, though dosage sensitivity is also a hallmark of two other human conditions involving related transcriptional regulators and their roles in gonadal development and sex determination. WT-1 (Wilms tumor-1) and DAX-1 (dosage-sensitive sex-reversal-adrenal hypoplasia, congenital critical region on the X chromosome 1, gene 1) proteins interact directly with SF-1 to promote and repress, respectively, its transactivation of target genes, including Müllerian-inhibiting substance (86). Heterozygote XY children with a dominant negative mutation of WT-1 have Denys-Drash syndrome, characterized by male pseudohermaphroditism, urogenital aberrations, and nephroblastoma (87). In contrast, XY sex reversal can result from duplication of the DAX-1 locus in the dosage-sensitive sex reversal region of the X chromosome (88). Aspects of the Denys-Drash syndrome phenotype are recapitulated in heterozygous mice with a truncation in WT-1 (89), whereas DAX-1 overexpressing transgenics create a dosage-sensitive sex reversal-like condition in mice with a hypomorpic Sry (sex determining region of chromosome Y) allele (90). These and other mouse models with sex determination phenotypes are reviewed by Whitworth and Behringer (91).

At birth and throughout adult life, a homeobox-containing transcription factor, OTX1 (orthodenticle homolog 1), is expressed in the pituitary and is involved in the transactivation of several glycoprotein hormone subunit genes. In addition to neurological abnormalities, Otx^-/- mice exhibit a prepubescent period of dwarfism and hypogonadism owing to decreases in GH, FSH, and LH; the condition corrects itself by 4 months of age and knockout mice then have restored growth and gonadal function (92, 93). The defect in these mice does not include alterations in the hypothalamic expression of GnRH or the pituitary expression of GnRHR. During the hypogonadotropic, hypogonadal period, knockout males had a block in spermatogenesis and females had ovaries devoid of antral follicles and corpora lutea. These histological findings were not seen in older fertile knockouts, in which there was recovery of all stages of sperm and follicle development (93). The Otx knockout phenotype is particularly intriguing because of the window in which it is apparent, this being the first example of a mouse model for investigating causes and effects of delayed growth and puberty, and the regulation of temporal-restricted molecular mechanisms in the onset of sexual maturity.

Mutant mouse models have defined in vivo functions of the early growth response (Egr) family of zinc finger transcriptional activators in regulating pituitary hormone production, hindbrain development, peripheral nerve myelination, muscle spindle morphogenesis, and spermatogenesis (94, 95, 96, 97, 98, 99). Two of these transcription factors are critical in the establishment of the HPG endocrine axis, EGR1 (also known as nerve growth factor 1A) and EGR4. Though the Egr1 gene is expressed widely during development, the phenotypes of Egr1 mutant mice are relatively restricted. The first Egr1 mutant mouse model was engineered by inserting a neomycin selection cassette into the DNA-binding region of the EGR1 coding sequence (Egr1^neo), and the primary defect is female sterility due to LH insufficiency (94). Homozygote mutant females show loss of estrous cyclicity, uterine hypoplasia, and no luteinized cells in their ovaries, though corpora lutea are evident upon pregnant mare’s serum gonadotropin and hCG treatment. FSH is produced in these mice and is up-regulated upon ovariectomy, but LHß-subunit mRNA expression is critically compromised. By contrast, Egr1^neo homozygote mutant male mice have no defects in fertility or spermatogenesis (94), though knockout males lacking EGR4 are infertile because of germ cell maturation defects (99). To examine functional redundancies between EGR1 and ERG4, Egr1^neo, Egr4^-/- double mutant mice were bred. Interestingly, double mutant males, unlike Egr1^neo or Egr4^-/- single mutants, demonstrated low levels of serum LH, low serum testosterone, and atrophy of androgen-responsive organs (100). Because steroidogenesis was restored by the addition of an LH receptor agonist, the defect in these mice appears to be in pituitary production of this gonadotropin (100). Therefore, though EGR1 is critical for LH production in the maintenance of female fertility, in Egr1^neo mutant males EGR4 compensates by establishing adequate LH to support androgen production. A second Egr1 mutant mouse line has been generated by targeted insertion of the lacZ (ß-galactosidase) gene into the Egr1 locus (Egr1^lacZ), and these mice have several notable phenotypic differences compared with Egr1^neo mice (95). In these mice, somatotrope development and production of GH in both sexes is impaired, male fertility is critically compromised (but can be rescued by LH administration), and female infertility cannot be rescued by LH administration and is associated with a down-regulation of LHR. These findings suggest singular and previously unexpected roles for EGR1 and its target genes in nongonadotrope pituitary cells, LH production in males, and LHR production in females. Whether the Egr^neo allele is a hypomorphic allele or whether the Egr^lacZ allele creates aberrations apart from abrogating EGR1 expression remains to be explored.

	Other Pituitary Hormones, IGF-1, and Leptin Affect Multiple Levels of the Endocrine Axis

Top Abstract Introduction Mouse Models and Human... Mouse Models of Aberrant... Peptide Hormone Feedback to... Transcriptional Control of the... Other Pituitary Hormones, IGF-1,... Conclusions References

 
The physiological complexities of the HPG axis can be further appreciated by studies of mouse models with disruptions of endocrine and paracrine factors known to affect central and peripheral components of the axis. Nongonadotrope anterior pituitary cell lineages and their product hormones may play important roles in establishing bidirectional gonadotrope-gonad communications. Ames and Snell dwarf mice [with mutations in Prop1 (paired like homeodomain factor 1; prophet of Pit1) and Pit1 (pituitary specific transcription factor 1) genes, respectively, encoding pituitary transcription factors] have TSH, prolactin (PRL), and GH deficiencies due to defects in thyrotrope, lactotrope, and somatotrope transcriptional regulation. In addition, both mouse models also display HHG, despite the absence of a direct role for the disrupted transcription factors in gonadotrope ontogeny or gene regulation (101, 102, 103). Interestingly, HHG and failure to respond to exogenous GnRH is a feature of patients with homozygous or compound heterozygous PROP1 mutations (with considerable variability depending upon the exact nature of the mutation), but not in patients with even complete loss-of-function mutations of the human PIT1 gene, POU1F1 (POU domain, class 1, transcription factor 1) (104).

To gain an understanding of the direct and indirect effects of nongonadotropin pituitary hormones on ovarian function represents an important challenge today for endocrinologists and researchers. Thyroid hormone has been implicated in the function of the lactotrope and somatotrope cell lineages in the anterior pituitary, which produce PRL and GH, respectively (105). Clinically, both hypothyroidism and hyperthyroidism in women have been associated with menstrual abnormalities, infertility, and complications in pregnancy (106, 107, 108). Moreover, analyses of a genetic mouse model of hypothyroidism (hyt) caused by TSH deficiency have demonstrated that thyroid hormone is important for peripheral gonadotropin hormone response and female fertility in mature animals (109). Postpartum hyperprolactinemia suppresses the HPG axis by inhibiting GnRH production (110), and defects in PRL regulation have been associated with reproductive abnormalities in patients, though the roles of PRL signaling outside of mammary tissue are still not well understood. Female knockout mouse models lacking PRL or PRL receptor are infertile due to defects in luteinization, and PRL receptor knockouts also exhibit irregularities in estrous cyclicity, as well as a failure to support oviductal embryogenesis (111, 112).

GH is crucial for growth and the onset of sexual maturity, both by its direct effects binding the GH receptor (GHR) and by the effects of downstream IGF-1. Knockout mice lacking the GHR have growth and reproductive defects. Females exhibit subfertility, and a delay in the onset of sexual maturity that can be corrected by administration of IGF-1 (113). GHR knockout males have low levels of circulating FSH and IGF-1, low plasma testosterone, and an attenuation in their steroidogenic response to exogenous LH owing to down-regulation of LHR in the testes (114). In contrast, transgenic males that overexpress a human GH transgene under the metallothionein promoter have enhanced transcription of FSH and LH mRNAs, increased serum levels of LH, and an increase in LH release in response to GnRH (103). Female transgenics in which bovine GH expressed by the phosphoenol pyruvate carboxykinase promoter, though unable to maintain pregnancies due to PRL deficiencies, have an increase in the numbers of preovulatory follicles and corpora lutea, and a decreased granulosa cell apoptosis in developing follicles (115, 116). This latter phenotype may in part reflect enhanced IGF-1 function in developing follicles (117). There is no readily evident clinical correlate for these phenotypes, and reports of reproductive defects in patients with alterations in GH regulation most commonly describe cases of hypogonadism in patients with acromegaly. GH overexpression in such patients has been associated with amenorrhea in women and testosterone deficiency in men, even in the absence of hyperprolactinemia (118).

Many biological effects of GH have been attributed to its induction of IGF-1 in peripheral tissues, and studies of Igf1 knockouts have revealed important functions of this growth factor in prenatal and postnatal growth, as well as within the gonads. Igf1 knockout males and females are infertile. In males, there is a marked reduction of plasma testosterone, and an inhibition of LH-mediated testosterone production in testicular organ culture experiments (119). In females, there are hypoplastic uteri and no ovulatory response to exogenous gonadotropins (119). Further examination of the Igf1 null ovaries revealed a block in follicular development reminiscent of that of the FSH knockout mouse and a lack of FSHR expression; this finding and the coexpression of Igf1 and Fshr mRNAs in healthy, growing follicles has led to the proposal that IGF-1 up-regulates FSHR and is needed for FSH induction of steroidogenesis (120). Consistent with a role for IGF-1 in steroidogenesis, both girls and boys with Laron syndrome (primary GH resistance) treated with IGF-1 develop elevated serum androgen levels and secondary effects of androgens (121, 122). Therefore, it seems that GH may influence gonadal functioning both by promoting central FSH and LH production, and by enabling gonadotropin response in the gonads, directly and through up-regulation of IGF-1. It should be noted that other physiological parameters influence IGF-1 levels and activities; metabolic defects in -glutamyl transpeptidase mice lead to decreases in IGF-1 levels and similar reproductive phenotypes (123).

Just as GH has pleiotropic effects on the HPG axis, leptin, a protein released from adipocytes, acts upon endocrine circuits at multiple locations. Leptin-deficient ob/ob mice are obese, infertile, and have characteristics of HHG with enhanced functioning of negative feedback pathways on gonadotropin production reminiscent of immature animals (124, 125). Similarly, leptin receptor-deficient db/db mice are obese and hypogonadal (126). In vitro studies have indicated that leptin normally functions at both the level of the hypothalamus (enhancing GnRH production), and at the level of the anterior pituitary (enhancing FSH and LH production) to promote the establishment of adult circulating gonadotropin levels (127). Interestingly, leptin may function dichotomously in HPG axis functioning, up-regulating GnRH, FSH, and LH production centrally, but down-regulating steroidogenesis in peripheral tissues (128, 129, 130, 131). To understand the effects of leptin and body fat content on the reproductive endocrine axis in humans represents a field of research with important implications for health care practices. Lean persons have decreased circulating leptin levels compared with obese persons (132). It may be speculated that low leptin levels contribute to the suppressed GnRH, low gonadotropins, abnormal glycosylation of gonadotropins, and delay of menarche or amenorrhea observed in young women athletes and anorexics (133, 134). Obese patients have elevated serum leptin levels but may exhibit leptin resistance so that some biological effects of leptin are attenuated. Roles that leptin signaling and other metabolic regulation pathways play in the development of the altered sex steroid profile and amenorrhea seen in obese women remain to be elucidated. Human mutations resulting in obesity have been described affecting both leptin (135, 136) and the leptin receptor (137). In the case of the leptin receptor mutation, two sisters homozygous for a nonsense mutation presented with early-onset obesity, attenuated levels of growth hormone and IGF-1, hypothalamic hypothyroidism, and did not undergo pubertal development. Their endocrine profile showed low levels of estrogens and gonadotropins that persisted without response to GnRH administration. This clinical case underscores the importance of metabolic pathways in the control of the reproductive axis and other endocrine communications, and the continued utility of the ob/ob and db/db mouse models to study leptin pathologies in humans.

	Conclusions

Top Abstract Introduction Mouse Models and Human... Mouse Models of Aberrant... Peptide Hormone Feedback to... Transcriptional Control of the... Other Pituitary Hormones, IGF-1,... Conclusions References

 
Cases of human disease and transgenic mouse models offer powerful means for appreciating the molecular components of endocrine pathways, including the direct, indirect and compensatory results in vivo of their aberrant functioning. Loss-of-function mutations produce hypomorphic and null alleles in mice that recreate deficiency and resistance syndromes in humans. Transgenic overexpressers and targeted subtle mutations may mimic activating mutations or the effects of hypersecretion syndromes in patients. In some instances, mutant mice closely phenocopy human disorders, stand as important proofs-of-principle, and provide us with models for testing our understanding of etiologies and potential medicinal interventions. In some, unexpected phenotypes call our attentions to unrecognized endocrine relationships, and the pathophysiological bases for previously inexplicable clinical observations. These genetic models will continue to reveal to us aspects of the human endocrine system.

	Acknowledgments

 

	Footnotes

 
Abbreviations: ActRII, Activin receptor type II; CG, chorionic gonadotropin; DAX-1, dosage-sensitive sex-reversal-adrenal hypoplasia, congenital critical region on the X chromosome 1, gene 1; Egr, early growth response; ER, estrogen receptor; FSHR, FSH receptor; GHR, GH receptor; GnRHR, GnRH receptor; hCG, human CG; HHG, hypogonadotropic hypogonadism; HPG, hypothalamic-pituitary-gonadal; Inha, inhibin ; lacZ, ß-galactosidase; LHR, LH receptor; MMTV, mouse mammary tumor virus; OTX1, orthodenticle homolog 1; Pit1, pituitary-specific transcription factor 1; POU1F1, POU domain, class 1, transcription factor 1; PRL, prolactin; Prop1, paired like homeodomain factor 1, prophet of Pit1; SF-1, steroidogenic factor-1; Sry, sex determining region of chromosome Y; WT-1, Wilms tumor 1.

Received January 16, 2002.

Accepted for publication March 14, 2002.

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