FSHR Mutations

Inactivating Mutations

Several inactivating mutations have been detected in the FSH-R gene, most of them in women with hypergonadotropic hypogonadism (9) (see Fig. 3). The complete form of FSH-R mutation in women causes the total arrest of follicular development (57), a process which is dependent on FSH action. The incomplete forms cause a partial phe-notype that is responsive to high-dose gonadotropin treatment (74,75). In addition to the Finnish-type FSHR inactivation (C ^ T transition, causing Ala189Val mutation), which has been found in multiple families (57), all other FSH-R mutations detected have been sporadic (9,74-77).

Five men with totally inactivating mutation of FSH-R have been described from Finland (53). These men were identified because they were homozygous brothers of women with hypergonadotropic hypogonadism caused by FSH-R mutation. The men were normally masculinized, with normal puberty and virilization. Their testes were mildly or severely reduced in size, and all had pathological semen samples, although, conspicuously, none was azoospermic (Table 2). Moreover, two of the men each had fathered two children. As expected, the men had high FSH levels, low inhibin-B, normal or slightly elevated LH, but normal testosterone concentrations (53). Both testic-ular sizes and the endocrine parameters of the five men displayed considerable variability. Besides the large age range of the subjects (29-55 yr), this may reflect the individual variability in the importance of FSH in maintaining testicular function. More detailed conclusions are limited by the small sample size. These findings were rather surprising because of the concept of a fundamental role for FSH in spermato-genesis, particularly the pubertal initiation of this process. Findings in these men demonstrated that FSH action per se is not necessary for qualitatively complete spermatogenesis. However, FSH is needed for qualitatively and quantitatively normal spermatogenesis but not necessarily for fertility. Subsequent experiments in mice in which FSH-R or FSHfi gene expression was disrupted produced similar results (54-56); the animals were fertile, but their testes were reduced in size and their sper-matogenesis was qualitatively and quantitatively suppressed. The mild phenotype of the men with FSH-R mutation indicated that they cannot be readily distinguished phenotypically from other men with idiopathic oligozoospermia. In fact, when this was studied in a region with high allelic frequency (1%, northern Finland) for the

Table 2

Semen Analyses and Some Hormone Levels on Men Homozygous for the Inactivatin Ala189Val FSHR Mutation

Table 2

Semen Analyses and Some Hormone Levels on Men Homozygous for the Inactivatin Ala189Val FSHR Mutation


Age (Yr)


Testis size ml (right/left)

Sperm analysis




Inhibin B

sperm count/mL vol. mL

(at age)





Two children

16.5/ 16.5

5 x 106









Two children

13.5 / 15.8

< 0.1 x 106










4.0 / 4.0

< 0.1 x 106










8.6 / 6.0

42 x 106










8.0 / 8.0

< 1.0 x 106







Reference range

> 20 x 106




inactivating FSH-R mutation, the frequency of the mutation was the same in a cohort of men with idiopathic oligozoospermia and in normal controls (53). There was no apparent disturbance in pubertal development in these individuals. The sperm quality in the five men was highest in the youngest individual suggesting that the spermato-genic capacity in the absence of FSH action may be compromised—these men may be fertile only as young adults.

The discrepancy between the azoospermia of the three men with FSHfi mutation (see above) and the oligoasthenozoospermia, but not azoospermia, in the men with FSH-R mutation is puzzling. One explanation is that azoospermia is the real pheno-type of total elimination of FSH action, and the receptor mutation described is only partial, with partial inactivation of FSH action that does not totally impede spermato-genesis. All evidence collected thus for about the inactivating Ala189Val FSH-R mutation shows, however, that it is near-totally inactivating because of the sequestration of the mutant receptor inside the cell (78). A minute fraction of the mutated receptor may reach the cell surface but is unable to mediate the signal properly even at high FSH levels. Cells transfected with the mutated FSH-R gene are devoid of the basal constitutive adenylyl cyclase activity that can be displayed in cells transfected with WT FSH-R (53). Likewise, women with this mutation are totally resistant to FSH treatment (79). A second explanation is that oligozoospermia is the true pheno-type of FSH deficiency, and the two subjects with inactivating FSH3 mutation have a second disturbance in the regulation of spermatogenesis predisposing to azoospermia. This is quite likely because spermatogenesis is a process that is regulated by a complex network of endocrine, paracrine, and autocrine mechanisms. Two key players in this process with paramount importance are testosterone and FSH. The importance of FSH may be relative; if all other factors function properly, FSH is not vital, and, therefore, men with FSH-R mutation have complete spermatogenesis. If, on the other hand, there is a failure in some other mechanism, then the function of FSH becomes critical. The Israeli patient (35) with FSH3 mutation had an additional failure in testosterone production that might explain the critical role of loss of FSH function. The Swedish patient was treated for extended periods of time with FSH, but there was no spermato-genic response (52). It is possible in his case that key paracrine mechanisms had failed and FSH replacement could not compensate for those deficiencies. Furthermore, these two patients were studied because of azoospermia, whereas the FSH-R mutation patients were detected because they were the brothers of women homozygous for this mutation. Hence, the outcome of genotype/phenotype correlations partly depends on which end of the cascade the search is initiated.

In conclusion, the majority of information available implies that FSH action per se is not mandatory for the pubertal initiation of spermatogenesis or for male fertility. However, FSH improves spermatogenesis both qualitatively and quantitatively. The phenotype of men with defective FSH-R function varies from severe to mild impairment of spermatogenesis, in the face of apparently normal Leydig cell androgen production. The azoospermia of men with FSHfi mutation may result from additional contributing factors and not solely to FSH deficiency. However, it is apparent that additional cases of genetically proven FSH deficiency are needed before the existing discrepancy between the phenotypes of the ligand and receptor deficiency can be reconciled. At the moment, it may be useful to state that treatment of men with FSH, who have idiopathic oligozoospermia and normal to elevated FSH concentrations, has no scientific basis and that prospects for developing a male contraceptive method based on inhibition of FSH secretion or action are not promising.

Activating Mutation

There is one somewhat controversial report of a man with an activating mutation of the FSH-R gene (80). The patient previously underwent hypophysectomy and radiotherapy because of a pituitary tumor, and, despite panhypopituitarism and unmeasurable serum gonadotropin levels, he displayed persistent spermatogenesis during testosterone treatment. Detailed studies of this patient were undertaken because androgen treatment is usually not sufficient to maintain spermatogenesis in the absence of gonadotropins. A heterozygous Asp567Gly mutation was found in the third intracellular domain of exon 10 of his FSH-R gene (see Fig. 3), and it was shown in vitro to have marginal constitutive activity. Because the WT FSH-R has a considerable constitutive activity without ligand in such cell line transfection studies (53), the marginal elevation of cAMP production in the presence of the FSH-R mutation must be interpreted with caution. Moreover, the patient's serum testosterone level was 5 nmol/L 3-4 mo after discontinuing testosterone replacement, a value fivefold to eightfold higher than in bilaterally orchidectomized men. Thus, his phe-notype may not represent solely the effect of FSH alone on spermatogenesis or androgen synthesis in the absence of LH stimulation. In my view, a fair conclusion at this point is that undisputed information about the phenotype of an activating FSH-R mutation in man is not yet available. Such mutations are possible, however, as has been shown with site-directed mutagenesis (81), but whether they cause a phenotype in vivo has not yet been resolved. A search for FSH-R mutations in candidate diseases, such as premature ovarian failure, ovarian tumors, megalotestes, precocious puberty, and twin pregnancies, has yielded negative results (82-86). It also remains possible that activating FSH-R mutation has no abnormal phenotype, or that it differs totally from our educated guesses. An animal model would be seminal in resolving this intriguing question.

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