Division of spermatogonial stem cells 1 produces daughter cells that either maintain their stem cell identity or undergo differentiation to form mature sperm. The Sertoli cell, the only somatic cell within seminiferous tubules, provides the stem cell niche through physical support and expression of surface proteins and soluble factors 2,3 . Here we show that the Ets related molecule 4 (ERM) is expressed exclusively within Sertoli cells in the testis and is required for spermatogonial stem cell self-renewal. Mice with targeted disruption of ERM have a loss of maintenance of spermatogonial stem cell self-renewal without a block in normal spermatogenic differentiation and thus have progressive germ-cell depletion and a Sertoli-cell-only syndrome. Microarray analysis of primary Sertoli cells from ERM-deficient mice showed alterations in secreted factors known to regulate the haematopoietic stem cell niche. These results identify a new function for the Ets family transcription factors in spermatogenesis and provide an example of transcriptional control of a vertebrate stem cell niche.

Mutant mice with a combined deficiency of growth hormone (GH), prolactin, and thyrotropin, and knockout mice with GH resistance, live longer than their normal siblings. The extension of life span in these animals is very large (up to 65%), reproducible, and not limited to any particular genetic background or husbandry conditions. In addition to demonstrating that genes control aging in mammals, these findings suggest that GH actions, growth, and body size may have important roles in the determination of life span. We describe the key phenotypic characteristics of long-living mutant and knockout mice, with an emphasis on those characteristics that may be related to delayed aging in these animals. We also address the broader topic of the relationship between GH, growth, maturation, body size, and aging, and we attempt to reconcile the well-publicized antiaging action of GH with the evidence that suppression of GH release or action can prolong life.

Although the primary control of gonadotropin secretion is by the hypothalamic GnRH and the gonadal function is controlled by the pituitary gonadotropins and prolactin, the emerging evidence suggests a vital role of the somatotropic axis, growth hormone (GH), and insulin-like growth factor-I (IGF-I) in the control of the pituitary and gonadal functions. It has been shown that GH deficiency, GH resistance, and experimental alterations in IGF-I secretion modify folliculogenesis, ovarian maturation, ovulation, and pregnancy, and in the male, GH/IGF-I plays an important role in spermatogenesis and the Leydig cell function. The primary focus of this review is to examine the role of GH/ IGF-I on the onset of puberty, fertility, pituitary, and gonadal endocrine functions. A number of studies have revealed that fertility is affected in GH-deficient dwarf and in IGF-I gene-ablated mice, possibly due to subnormal function of either the pituitary gland or the gonads. In the female GH receptor gene knockout (GHR-KO) mice, there was impairment in follicular development, ovulation rate, sexual maturation, production of and responsiveness to pheromonal signals, and the corpus luteum function. In IGF-I-deficient male GHR-KO mice, puberty is delayed, spermatogenesis is affected, and neuroendocrine-gonadal function is attenuated. Similarly, in some of the human Laron syndrome patients, puberty is delayed due to GH resistance. These data suggest that, in addition to GnRH and gonadotropins, GH/IGF-I influences the pituitary and gonadal functions in animals and humans.

The role of GH in the control of pituitary and testicular function is poorly understood. GH receptor gene knockout (GHR-KO) mice were recently produced. As these mice are good experimental animals to assess the influence of the effects of GH and insulin-like growth factor-I (IGF-I), the present studies were undertaken. Young adult male GHR-KO mice and their normal siblings were tested for fertility and subsequently injected (i.p.) with saline or GnRH (1 ng/g BW) in saline. Fifteen minutes later, blood was obtained via heart puncture. Plasma IGF-I, PRL, LH, and testosterone concentrations were measured by RIAs. In addition, the testicular testosterone response to LH treatment was evaluated in vitro. The results indicate that the absence of GH receptors (GHRs) was associated with an increase (P < 0.005) in plasma PRL levels, and circulating IGF-I was not detectable. Although the basal plasma LH levels were similar in GHR-KO mice relative to those in their normal siblings, the circulating LH response to GnRH treatment was significantly (P < 0.001) attenuated. Plasma testosterone levels were unaffected by disruption of the GHR gene. However, basal (P < 0.01) and LH-stimulated (P < 0.001) testosterone release from the isolated testes of GHR-KO mice were decreased. The rate of fertility in GHR-KO male mice was also reduced. These results indicate that the lack of GHRs (with GH resistance and lack of IGF-I secretion) induces hyperprolactinemia and alters the effect of GnRH on LH secretion as well as testicular function. Thus, GH and IGF-I influence pituitary and gonadal functions in male mice.

We examined multiple aspects of reproductive function in growth hormone receptor gene knockout (GHR-KO) and normal mice to clarify the role of growth hormone in female reproduction. In adult animals, estrous cycle duration was comparable in all mice housed individually but was significantly longer in group-housed GHR-KO females. Histological evaluation of ovaries of adult females at estrus showed that the numbers of preovulatory follicles and corpora lutea were significantly reduced in GHR-KO mice, as was the plasma estradiol level. The number of atretic preovulatory follicles was reduced in GHR gene-ablated animals. Although reverse transcription polymerase chain reaction analysis revealed reduced ovarian insulin-like growth factor I (IGF-I) mRNA expression in GHR-KO females, the expression of several steroidogenic enzyme mRNAs did not differ between groups. The numbers of active corpora lutea and uterine implantation sites were reduced in GHR-KO females at Day 7 of gestation. When young females were mated to normal males, latency to first mating and age of the female at first mating were significantly delayed in GHR-KO females, but maternal age at first conception was similar between groups. Significantly fewer virgin GHR-KO females exhibited pseudopregnancies when initially placed with vasectomized normal males than did normal female counterparts. Growth hormone resistance and IGF-I insufficiency negatively impacted 1) follicular development/ovulation rate, 2) sexual maturation, 3) production of and responsiveness to pheromonal signals, and 4) the ability of virgin females to respond to coitus by activation of luteal function. Although GHR-KO female mice are fertile, they exhibit quantitative deficits in various parameters of reproductive function.

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Availability of recombinant growth hormone (GH) and development of long-acting formulations of this material will undoubtedly lead to widespread use of GH in animal industry and in medicine. GH can act, directly or indirectly, on multiple targets, but its influence on the reproductive system and on the hormonal control of reproduction is poorly understood. Overexpression of GH genes in transgenic animals provides a unique opportunity to study the effects of long-term GH excess. Transgenic mice overexpressing bovine, ovine, or rat GH (hormones with actions closely resembling, if not identical to, those of endogenous [mouse] GH), exhibit enhancement of growth, increased adult body size, and reduced life-span as well as a number of endocrine and reproductive abnormalities. Ectopic overexpression of bovine GH (bGH) driven by metallothionein or phosphoenolpyruvate carboxykinase promoters is associated with altered activity of hypothalamic neurons which produce somatostatin, loss of adenohypophyseal GH releasing hormone (GHRH) receptors, and suppression of endogenous (mouse) GH release. Elevation of plasma levels of GH (primarily bGH) and insulin-like growth factor (IGF-I) in these transgenic mice leads to increases in the number of hepatic GH and prolactin (PRL) receptors, in the serum levels of GH-binding protein (GHBP), in the percent of GHBP complexed with GH, and in the circulating insulin levels. In addition, plasma adrenocorticotropic hormone (ACTH) and corticosterone levels are elevated. Plasma levels of luteinizing hormone (LH), as well as its synthesis and release, are not consistently affected, but follicle-stimulating hormone (FSH) levels are suppressed, apparently due to pre- and post-translational effects. Pituitary lactotrophs exhibit characteristics of chronic enhancement of secretory activity, and plasma PRL levels are elevated. Prolactin responses to mating or to pharmacological blockade of dopamine synthesis are abnormal. Reproductive life span and efficiency are reduced in both sexes, with the severity and frequency of reproductive deficits being related to plasma bGH levels. Most transgenic females expressing high levels of bGH are sterile due to luteal failure. Overexpression of human GH which, in the mouse, interacts with both GH and PRL receptors leads to additional endocrine and reproductive abnormalities including stimulation of LH beta mRNA levels and LH secretion, loss of responsiveness to testosterone feedback, overstimulation of mammary glands, enhanced mammary tumorigenesis, and hypertrophy of accessory reproductive glands in males.

To evaluate the influence of growth hormone (GH) on hypothalamic-pituitary-testicular function, GH-deficient adult male Ames dwarf mice were treated (s.c.) twice daily for 8 days with either vehicle or bovine GH (25 micrograms/injection/mouse). Normal male siblings treated with vehicle served as controls. Two in vivo experiments were conducted. In experiment 1, on Day 8, mice were treated (i.p.) with either saline or LHRH (1 ng/g b.w.) in saline. Fifteen minutes later, blood was obtained via heart puncture to assess plasma insulin-like growth factor-I (IGF-I), LH, and testosterone (T) levels by RIAs. In experiment 2, on Day 7, mice were bilaterally castrated and received injections of either oil or T propionate (1 microgram/g b.w.) in oil. Eighteen to twenty hours later, blood was obtained as in experiment 1, and plasma IGF-I and LH levels were determined. In addition to these in vivo experiments, testicular androstenedione and T responses to hCG stimulation in vitro were evaluated. Administration of GH to dwarf mice increased (p < 0.001) plasma IGF-I levels, whereas IGF-I was not detectable in control dwarf mice. Plasma IGF-I concentrations were higher in normal mice than in treated dwarf mice. Basal LH levels were lower (p < 0.025) in dwarf mice than those in normal mice. In dwarf mice, GH treatment increased (p < 0.001) plasma LH levels. The effect of LHRH on LH secretion was increased (p < 0.001) in dwarf mice pretreated with GH, but this LH response was lower than in normal siblings that received vehicle only.(ABSTRACT TRUNCATED AT 250 WORDS)