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Query: UMLS:C0021359 (infertility)
 26,075 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A variety of mutations and polymorphisms of genes regulating female and male reproductive functions have been discovered during the last few years. These include several inactivating and activating mutations in LH receptor genes. The first mutation of FSH receptor (FSHR) gene was discovered in six Finnish families. This inactivating Ala189Val transition in the extracellular receptor domain causes primary amenorrhea, arrest of follicular development and infertility in homozygous women. In contrast to females, this mutation did not cause absolute infertility in males but only suppressed spermatogenesis. Another inactivating mutation of the FSHR gene has been found at position 191 (Asn191Ile) in a healthy fertile woman. The studies on inactivating FSHR mutations demonstrate that normal ovarian function is critically dependent on FSH while, in contrast to earlier views, male fertility is less strictly dependent on normal FSH action.
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PMID:Inactivating FSH receptor mutations and gonadal dysfunction. 992 9

In a search for pathophysiological causes of idiopathic male infertility we investigated the occurrence of mutations of the FSH receptor in 48 men with this disorder. The entire FSH receptor gene was analyzed by single stranded conformation polymorphism analysis (SSCP). A heterozygous point mutation without functional consequences, exchanging Val to Ala in codon 341, was found in one patient. SSCP analysis led to the identification of 2 polymorphisms in exon 10 associated in 2 discrete FSH receptor allelic variants, i.e. Thr307-Asn680 and Ala307-Ser680. The frequency and distribution of the two allelic variants was further analyzed in 86 proven fathers and 75 infertile men by SSCP (codon 307) and restriction fragment length polymorphism (codon 680). The 2 receptor isoforms showed similar Mendelian distribution in proven fathers and in infertile men. Serum FSH, inhibin B, and combined testicular volume did not differ between subjects with different receptor isoforms. Binding studies in transiently transfected COS-7 cells showed similar binding affinity for the two receptor variants. Moreover, the Ala307-Ser680 and the Thr307-Asn680 FSH receptors responded in vitro to FSH with comparable cAMP production. These data suggest that different isoforms of the FSH receptor with similar functional properties exist in normal and infertile men. We conclude that mutations of the FSH receptor or the FSH receptor genotype do not play a pathogenic role in male idiopathic infertility. The possibility that different FSH isoforms might interact differently with the 2 receptor variants remains to be investigated.
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PMID:Mutational analysis of the follicle-stimulating hormone (FSH) receptor in normal and infertile men: identification and characterization of two discrete FSH receptor isoforms. 1002 48

The production of male gametes depends on the concerted action of the two gonadotropins FSH and LH on the testis. The action of LH is mediated through the production of testosterone by the Leydig cells. Since male germ cells possess neither FSH nor androgen receptors, the action of FSH and testosterone occurs through the Sertoli cells. Although the precise function of these two hormones remains elusive, the existing evidence suggest that both FSH and testosterone are able to stimulate all phases of spermatogenesis. In the male FSH is required for the determination of Sertoli cell number, and for induction and maintenance of normal sperm production. The crucial role of FSH in male gonadal function has been clearly illustrated by the discovery of a patient with an activating mutation of the FSH receptor. This patient had been hypophysectomized because of a pituitary tumor and, under testosterone substitution was unexpectedly fertile in spite of undetectable serum gonadotropin levels and had fathered three children. In this patient we could demonstrate a heterozygous activating mutation of the FSH receptor which resulted in cAMP production independent of FSH stimulation. This finding represents the first description of an activating mutation of the FSH receptor and demonstrates that FSH alone maintains spermatogenesis in man. On the other hand, the effects of the lack of FSH action are unclear. Among five men with a homozygous inactivating mutation of the FSH receptor only one was infertile and spermatogenesis was variably affected in the others. However, serum inhibin B values in these men were not completely suppressed and serum FSH levels were only moderately elevated, indicating the possibility that FSH receptor function was not completely abolished by the mutation. Elimination of FSH action is a prerequisite to suppress completely spermatogenesis for contraceptive purposes, while administration of both LH and FSH is necessary to induce sperm production in patients with hypogonadotropic hypogonadism. Experimental immunization of male monkeys against FSH markedly reduced germ cell proliferation and even induced infertility. At the cellular level, FSH stimulates the cAMP-dependent activation of protein kinase A in Sertoli cells, but the molecular mechanism of FSH action is poorly understood. In the primate, the gonadotropin withdrawal achieved by administration of a GnRH antagonist leads to a premeiotic arrest of germ cell proliferation, probably due to inhibition of the mitotic division of A-pale spermatogonia. Therefore, FSH might be the prime inducer of spermatogonial proliferation, while the successive maturation process could proceed independently of FSH. In summary, clinical and experimental evidence support the concept of an irreplaceble role of FSH in the primate. Only the combination of FSH and testosterone, however, supports a qualitatively and quantitatively fully normal spermatogenesis.
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PMID:Role of FSH in male gonadal function. 1045 80

In contrast to the general contention, infertility can be an inherited condition. Some of the genetic causes of male and female infertility have turned out to be due to inactivating mutations in the gonadotropin and gonadotropin receptor genes. The topic of the present text is to review current knowledge on mutations affecting the function of follicle-stimulating hormone (FSH). This gonadotropin, by binding to its specific G protein-coupled cell membrane receptor (FSHR), is important for normal gonadal function. Mutations affecting gonadotropin genes are extremely rare, but recent genetic studies have revealed that the pathogenesis of subfertility or infertility can be due to mutations in the FSH receptor (FSHR) gene. While mutations affecting FSHR are sporadic, polymorphism of the FSHR gene seems to be a common phenomenon. To date, six inactivating and only one activating mutation have been detected in the FSHR gene. In contrast to LHR gene, the majority of these mutations affect the extracellular domain of the receptor. Together with animal models using the transgenic and knock-out approaches, systematic analysis of alterations in the FSHR gene increases our knowledge on the structure and function of the FSHR and demonstrates that the integrity of each FSHR segment is required for proper expression of the fully active protein and for normal gonadal function. Mutations in the FSHR gene have different consequences in the reproductive function depending on the sex of the patient: while normal ovarian function is critically dependent on FSH, male fertility is possible with minimal or absent FSH action.
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PMID:Follicle-stimulating hormone ligand and receptor mutations, and gonadal dysfunction. 1071 62

Although mutations in human gonadotrophin and gonadotrophin receptor genes are rare, they have greatly elucidated the physiology and pathophysiology of gonadotrophin action. These 'nature's transgenics' have been corroborated by mouse transgenic and knock-out models. An inactivating mutation of the human LHbeta chain and knock-out of the mouse common alpha-chain show that pituitary LH is not needed to stimulate fetal testicular steroidogenesis and male sexual differentiation. In mice, early testicular steroidogenesis is apparently gonadotrophin-independent and, in humans, it is regulated by placental hCG. Pituitary LH becomes necessary only after birth. Inactivating LH receptor mutations block prenatal hCG action, thus inhibiting male-type sexual differentiation. In females, this process is autonomous, and LH becomes important only at puberty; inactivation of LH receptor causes anovulatory infertility. Activating LH receptor mutations cause male-limited gonadotrophin-independent precocious puberty in males, but no apparent phenotype in females. Animal models for LH or LH receptor inactivation are not yet available. Inactivating FSH ligand and receptor mutations cause infertility because of a lack of follicular maturation in women. Findings in men are controversial, since FSHbeta inactivation is related to azoospermia, whereas the cognate receptor inactivation only suppresses spermatogenesis without causing absolute infertility. The FSHbeta and FSH receptor knock-out mice display phenocopies of the human FSH receptor mutation. Information about activating FSH receptor mutations is still insufficient. Hence, the above human mutations have brought important new information about the role of gonadotrophins in reproductive functions. The genetically modified animal models provide useful tools to explore the pathogenesis and new treatment modalities of infertility, and to develop new contraceptive strategies.
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PMID:The Parkes lecture. Mutations of gonadotrophin and gonadotrophin receptor genes: what do they teach us about reproductive physiology? 1086 28

Because the ovarian response to FSH stimulation in assisted reproduction is variable, ranging from hyporesponse to hyperresponse, with the possible complication of ovarian hyperstimulation, it would be of great benefit to predict the response of the patients to FSH. To date, no clear-cut predictors of ovarian responsiveness to FSH have been identified. In this study, we investigated the role of two distinct FSH receptor (FSHR) variants, Thr307/Asn680 and Ala307/Ser680, in the response to FSH in women undergoing controlled ovarian stimulation. The FSHR polymorphism at position 680 was analyzed by restriction-fragment-length polymorphism in 161 ovulatory women below the age of 40 yr. With reference to the couple, infertility has been diagnosed as being attributable to male causes (76%), tubal factor (11%), or both (13%). The distribution was 29% for the Asn/Asn, 45% for the Asn/Ser, and 26% for the Ser/Ser FSHR variant. Peak estradiol levels, number of preovulatory follicles, and number of retrieved oocytes were similar in the 3 groups. However, basal FSH levels were significantly different among the 3 groups (6.4 +/- 0.4 IU/L, 7.9 +/- 0.3 IU/L, and 8.3 +/- 0.6 IU/L for the Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively, P < 0.01). The number of FSH ampoules required for successful stimulation was significantly different among the 3 groups (31.8 +/- 2.4, 40.7 +/- 2.3, and 46.8 +/- 5.0 for the Asn/Asn, Asn/Ser, and Ser/Ser groups, respectively, P < 0.05). According to multiple linear regression analysis, the number of ampoules needed could be predicted from a linear combination of both the type of polymorphism and basal FSH levels (P < 0.001). These clinical findings demonstrate that the ovarian response to FSH stimulation depends on the FSHR genotype.
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PMID:Ovarian response to follicle-stimulating hormone (FSH) stimulation depends on the FSH receptor genotype. 1099 35

LH/hCG receptors were disrupted by gene targeting in embryonic stem cells. The disruption resulted in infertility in both sexes. The gonads contained no receptor mRNA or receptor protein. Serum LH levels were greatly elevated, and FSH levels were moderately elevated in both sexes; estradiol and progesterone levels decreased but were not totally suppressed in females; testosterone levels were dramatically decreased and estradiol levels moderately elevated in males. The external and internal genitalia were grossly underdeveloped in both sexes. Abnormalities included ambiguous vaginal opening, abdominal testes, micropenis, dramatically decreased weights of the gonads and reproductive tract, arrested follicular growth beyond antral stage, disarray of seminiferous tubules, diminished number and hypotrophy of Leydig cells, and spermatogenic arrest beyond the round spermatid stage. LH/hCG receptor gene disruption had no effect on FSH receptor mRNA levels in ovaries and testes, progesterone receptor (PR) levels in ovaries and androgen receptor (AR) levels in testes. However, it caused a dramatic decrease in StAR and estrogen receptor-alpha (ERalpha) mRNA levels and an increase in ERbeta mRNA levels in both ovaries and testes. Estradiol and progesterone replacement therapy in females and testosterone replacement in males, to determine whether phenotype and biochemical changes were a consequence of decreased gonadal steroid levels or due to a loss of LH signaling, revealed complete restoration of some and partial restoration of others. Nevertheless, the animals remained infertile. It is anticipated that the LH receptor knockout animals will increase our current understanding of gonadal and nongonadal actions of LH and hCG.
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PMID:Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene. 1114 49

Follicle-stimulating hormone (FSH), a dimeric glycoprotein synthesized in the anterior pituitary gland, is important for the production of sex steroids and gametes. FSH-beta (FSH beta) and FSH receptor (FSHR) knockout mice display impaired ovarian follicular development and infertility in females and small testes, oligospermia, and fertility in males. Humans with FSH beta gene mutations tend to have a more severe phenotype than those with FSHR gene mutations, although infertility and varying degrees of impaired sex steroid production occur in both types of mutations. Data from human and mouse mutations in the FSH beta and FSHR genes suggest that FSH is necessary for normal pubertal development and fertility in males and females.
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PMID:Mutations in the follicle-stimulating hormone-beta (FSH beta) and FSH receptor genes in mice and humans. 1129 19

The development of knockout mouse models for the FSH-beta subunit, the FSH receptor, and LH-receptor performed in different laboratories has confirmed and extended our knowledge concerning the critical role of these hormone-signaling systems in spermatogenesis. In this article, we summarize the phenotypic changes observed in male FSH receptor knockout (FORKO) mice. Young FORKO males have underdeveloped testis with 50% reduction in Sertoli cells, suggesting that FSH-R signaling is required very early for gonadal development, maturity, and function. These mice experience delayed puberty with postponement in the formation of round spermatids. Adult males show reduction in serum testosterone levels despite normal circulating LH concentration, indicating disturbances in Sertoli-Leydig cell communication. As a consequence of reduced sperm production and sperm quality, adult FORKO males have reduced fertility. Aberrant sperm from FORKO males have retention of cytoplasmic droplets and inadequate DNA compaction, hallmarks of infertility in many species including man. Interestingly, these changes are also experimentally inducible in FSH- and/or FSH-R-immunized male bonnet monkeys, creating a state of infertility. Reports of human mutations in FSH-beta and the FSH receptor also indicate that spermatogenesis is dependent on this system. Further investigations in FORKO males should be helpful in uncovering the downstream genes involved in sustaining Sertoli cell function and maintenance of the quantitative and qualitative aspects of spermatogenesis. This might pave the way for treatment of male infertility and contraception.
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PMID:The role of follicle-stimulating hormone in spermatogenesis: lessons from knockout animal models. 1175 Jul 36

Follicle-stimulating hormone(FSH) plays important roles in gametogenesis and steroidogenesis in human gonads. Both activating and inactivating mutations have been detected only a few number in the gene for the FSH receptor. Inactivating mutations in the gene for the FSH receptor are involved in some female patients of hypergonadotropic hypogonadism with infertility. Only one activating mutation of FSH receptor was reported to have fertile functions in a hypophysectomized man. This article describes the reported genetic alterations of FSH receptor in humans and reviews how help us to understanding the molecular biology in the pathogenesis of gonadal dysfunction.
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PMID:[Mutations in the follicle-stimulating hormone receptor genes in patients with gonadal dysfunction]. 1185 13


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