Targeted disruption of luteinizing hormone β-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility

Abstract

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) act on gonadal cells to promote steroidogenesis and gametogenesis. Clarifying the in vivo roles of LH and FSH permits a feasible approach to contraception involving selective blockade of gonadotropin action. One way to address these physiologically important problems is to generate mice with an isolated LH deficiency and compare them with existing FSH loss-of-function mice. To model human reproductive disorders involving loss of LH function and to define LH-responsive genes, we produced knockout mice lacking the hormone-specific LH␤-subunit. LH␤-null mice are viable but demonstrate postnatal defects in gonadal growth and function resulting in infertility. Mutant males have decreased testes size, prominent Leydig cell hypoplasia, defects in expression of genes encoding steroid biosynthesis pathway enzymes, and reduced testosterone levels. Furthermore, spermatogenesis is blocked at the round spermatid stage, causing a total absence of the elongated spermatids. Mutant female mice are hypogonadal and demonstrate decreased levels of serum estradiol and progesterone. Ovarian histology demonstrates normal thecal layer, defects in folliculogenesis including many degenerating antral follicles, and absence of corpora lutea. The defects in both sexes are not secondary to aberrant FSH regulation, because FSH levels were unaffected in null mice. Finally, both male and female null mice can be pharmacologically rescued by exogenous human chorionic gonadotropin, indicating that LH-responsiveness of the target cells is not irreversibly lost. Thus, LH␤ null mice represent a model to study the consequences of an isolated deficiency of LH ligand in reproduction, while retaining normal LH-responsiveness in target cells.is a member of the glycoprotein hormone family that includes follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (1, 2). These hormones are heterodimers consisting of a common ␣-subunit noncovalently linked to a hormone-specific ␤-subunit. LH binds to G-protein coupled receptors on Leydig cells in the testis and granulosa and theca cells in the ovary (1, 2). During pubertal and postpubertal gonad development, LH promotes steroidogenesis required for normal reproductive function (1, 2). Less clear are its functions during embryonic gonad development, although evidence suggests that early gonad development is independent of gonadotropin stimulation (3, 4).Intercellular communication within the testis is essential for normal spermatogenesis (5, 6). In response to FSH, the Sertoli cells secrete various factors that affect Leydig cell function (7,8). Similarly, testosterone produced from Leydig cells is required for spermatogenesis (7,8). In females, ovarian folliculogenesis and ovulation are critically dependent on synchronized activities of both FSH and LH (9, 10). Previously, we and others have used genetic models, including FSH␤, FSH-receptor, and LHreceptor knockout mice, to study the physiological roles of gonadotropins in gonad developmen...

Extragonadal LH/hCG action—Not yet time to rewrite textbooks

“…LHβ KO phenotype has been recently reported (Ma et al, 2004). As expected, the phenotype closely resembles that of LHR KO mice, with infertility of both sexes, hypoplastic sex organ development and reduced androgen and estrogen levels.…”

Role of androgen and gonadotrophins in the development and function of the Sertoli cells and Leydig cells: Data from mutant and genetically modified mice

“…Functional LHR in humal fetal Leydig cells is thus compulsory for their androgen synthesis, whereas in the mouse, as discussed above, paracrine or other endocrine factors must be able to maintain sufficient androgen synthesis by the fetal Leydig cells to induce masculinisation. The same species difference in fetal Leydig cell function is not, however, found in the case of LH inactivation (LofranoPorto et al, 2007;Valdes-Socin et al, 2004;Weiss et al, 1992;Ma et al, 2004)). In the human, placental hCG (an agonist of LH) can take over the function of missing LH while in the mouse, as we have shown, a number of different factors are able to compensate for missing LH.…”

“…In the mouse and rat it is not, however, clear how fetal Leydig cell function is regulated. Postnatal Leydig cells are critically dependent on LH and fetal Leydig cells respond to LH in vitro but Leydig cell function is normal in the fetus in the absence of LH or its receptor (O'Shaughnessy et al, 1998;Zhang et al, 2001b;Ma et al, 2004).…”

“…There is evidence that the adult Leydig cell population will start to differentiate in the absence of LH Zhang et al, 2004;Teerds et al, 2007) but Leydig cell numbers are reduced to about 10% of normal (Baker and O'Shaughnessy, 2001) and androgen production is barely detectable (O'Shaughnessy et al, 1998;Zhang et al, 2001a;Ma et al, 2004). Androgen also appears to be essential for adult Leydig cell function, at least in the mouse (Murphy et al, 1994;O'Shaughnessy et al, 2002;Eacker et al, 2008) and there is evidence, going back a number of years, that FSH may also play a role in Leydig cell function.…”

Segment- And Cell-Specific Expression of Dtype Cyclins in the Postnatal Mouse Epididymis

“…Furthermore, genetic studies using mutant mouse models have identified defects in morphogenesis (Bomgardner et al, 2003;Kitagaki et al, 2011;Podlasek et al, 1999), development (Robaire, 2005;Tomaszewski et al, 2007;Yoshio et al, 2010), and function (Grover et al, 2005;Krishnamurthy et al, 2001;Krishnamurthy et al, 2000;Ma et al, 2004;Mendive et al, 2006) of the epididymis as a result of deletions engineered in various gene loci.…”