Fertile Eunuch Syndrome with the Mutations (Trp8Arg and Ile15Thr) in the .BETA. Subunit of Luteinizing Hormone

Shiraishi, Koji; Naito, Katsusuke

doi:10.1507/endocrj.50.733

Cited by 16 publications

(6 citation statements)

References 19 publications

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“…For example, there might be an LH receptor variant that is widespread in the Japanese population and is associated with a lower affinity to the V-LH but not to the WT-LH. Furthermore, since such a factor(s) should also be present in males as well as in females, this would be consistent with the development of testicular dysfunction in a Japanese male patient homozygous for the V-LH [9].…”

Section: Discussionsupporting

confidence: 68%

Association of Common LH Variant with Hyperfunctional Promoter in a Japanese Infertile Woman

Liu

Ogata²,

Maruyama

et al. 2005

Endocr J

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Abstract. A common LH variant (V-LH) with Trp8Arg and Ile15Thr is often associated with ovarian dysfunction primarily in the Japanese population, and the LHB gene encoding V-LH is linked with a hyperfunctional promoter that could partly compensate for the somewhat weak biological effect of the V-LH in the Finnish and other several populations. We analyzed the promoter region in a Japanese infertile woman homozygous for the V-LH, to examine whether the hyperfunctional promoter is present or absent in the Japanese V-LH carriers with ovarian dysfunction. Direct sequencing was performed for a 661 bp promoter region from -8 to -668 bp of LHB, revealing homozygosity for eight nucleotide substitutions (-238A>G, -276G>A, -489C>A, -490T>A, -504T>A, -506T>C, -525T>G, and -552C>T) that are identical to those found in the hyperfunctional promoter. The results suggest that ovarian dysfunction frequently observed in the Japanese V-LH carriers would be due to some population-specific genetic and/or environmental factor(s) rather than to the lack of the hyperfunctional promoter and the resultant low biological effect of the V-LH. In addition, the tight linkage between the two missense substitutions in the coding region and the eight nucleotide substitutions in the promoter region of LHB appears to be common to various ethnic groups. A genetic variant of LH (V-LH) with two completely linked Trp8Arg and Ile15Thr substitutions in the LH b-subunit gene (LHB) has been identified in various populations [1,2]. This common V-LH is immunologically undetectable when a monoclonal antibody recognizing an epitope present in the intact LH a/b dimer is utilized. Trp8Arg is primarily responsible for the altered immunoreactivity, whereas Ile15Thr introduces an extra glycosylation site into the LH b chain. The V-LH has a stronger in vitro bioactivity and a shorter circulatory half-life than the wildtype LH (WT-LH), and the overall hormonal function appears to be somewhat weaker in the V-LH than in the WT-LH [1,2]. The functional difference between the V-LH and the WT-LH may predispose the V-LH carriers to ovarian disorders. Notably, association of the V-LH homozygosity with irregular menses and infertility, and that of the V-LH heterozygosity with infertility and premature ovarian failure (POF), have frequently been observed in the Japanese population [3][4][5][6], whereas such findings are absent in the Finnish population and have not clearly been demonstrated in other Caucasian populations [1,2]. In this regard, although LHB encoding V-LH is accompanied by additional eight nucleotide changes in the promoter region that enhance the promoter activity by ~40% and compensate for the bio-

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Section: Discussionsupporting

confidence: 68%

Association of Common LH Variant with Hyperfunctional Promoter in a Japanese Infertile Woman

Liu

Ogata²,

Maruyama

et al. 2005

Endocr J

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“…A mild form of isolated LH deficiency is the underlying pathophysiology of the “fertile eunuch” syndrome, characterized by the absence of signs of hypoandrogenism until puberty, when eunuchoid proportions become apparent in males with normal testis volume and sperm production. Mutations in GNRHR (66) and LHB (67) genes have been described.…”

Section: Pathophysiology Of Fetal-onset Male Hypogonadismmentioning

confidence: 99%

Spreading the Clinical Window for Diagnosing Fetal-Onset Hypogonadism in Boys

et al. 2014

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In early fetal development, the testis secretes -independent of pituitary gonadotropinsandrogens and anti-Müllerian hormone (AMH) that are essential for male sex differentiation. In the second half of fetal life, the hypothalamic-pituitary axis gains control of testicular hormone secretion. Follicle-stimulating hormone (FSH) controls Sertoli cell proliferation, responsible for testis volume increase and AMH and inhibin B secretion, whereas luteinizing hormone (LH) regulates Leydig cell androgen and INSL3 secretion, involved in the growth and trophism of male external genitalia and in testis descent. This differential regulation of testicular function between early and late fetal periods underlies the distinct clinical presentations of fetal-onset hypogonadism in the newborn male: primary hypogonadism results in ambiguous or female genitalia when early fetal-onset, whereas it becomes clinically undistinguishable from central hypogonadism when established later in fetal life. The assessment of the hypothalamic-pituitary-gonadal axis in male has classically relied on the measurement of gonadotropin and testosterone levels in serum. These hormone levels normally decline 3-6 months after birth, thus constraining the clinical evaluation window for diagnosing male hypogonadism. The advent of new markers of gonadal function has spread this clinical window beyond the first 6 months of life. In this review, we discuss the advantages and limitations of old and new markers used for the functional assessment of the hypothalamic-pituitary-testicular axis in boys suspected of fetal-onset hypogonadism. Keywords: hypopituitarism, cryptorchidism, micropenis, disorder of sex development, testosteroneThe concept of male hypogonadism is usually associated with the adult patient, and rarely thought of as a condition in the prepubertal boy. Furthermore, male hypogonadism is most frequently equated to hypoandrogenism. Androgens are the dean of testicular hormones, and the normal testis produces very little or no testosterone during most of infancy and childhood. It is therefore easy to understand why the term hypogonadism is almost absent from the pediatrician's terminology. However, many hypogonadal states in the male bear their origin in fetal life. With the advent of direct markers of Sertoli cell function, hypogonadism can be identified in boys beyond the early postnatal critical window of pituitary-gonadal activation (1) -called "mini-puberty" by some authors -and before pubertal age. In this review, we address the diagnostic approaches of fetal-onset male hypogonadism based on the physiology and pathophysiology of the hypothalamic-pituitary-testicular axis ontogeny. ONTOGENY OF THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS FETAL LIFE: THE FIRST VERSUS THE SECOND AND THIRD TRIMESTERSThe gonadotropin-releasing hormone (GnRH) neurons derive from cells present in the nasal placode in the sixth fetal week (2), which migrate together with olfactory axons and blood vessels through the cribriform plate and arrive in the developing forebrain...

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“…In this case, a mutation in the LHB subunit produced a variant LH with lower receptor-binding activity. When treated with hCG, the patient virilized normally with correction in his semen parameters; however, upon cessation of hCG, his hypogonadism returned (Shiraishi and Naito 2003).…”

Section: Isolated Luteinizing Hormone or Folliclestimulating Hormone mentioning

confidence: 95%

Endocrinopathies in Male Infertility

2010

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Fertile Eunuch Syndrome with the Mutations (Trp8Arg and Ile15Thr) in the .BETA. Subunit of Luteinizing Hormone

Cited by 16 publications

References 19 publications

Association of Common LH Variant with Hyperfunctional Promoter in a Japanese Infertile Woman

Association of Common LH Variant with Hyperfunctional Promoter in a Japanese Infertile Woman

Spreading the Clinical Window for Diagnosing Fetal-Onset Hypogonadism in Boys

Endocrinopathies in Male Infertility

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