Isolated FSH Deficiency Research Articles

Abstract #1312066: Transient Isolated Follicle-Stimulating Hormone (FSH) Deficiency Along With Azoospermia in a Patient Treated for Non-Hodgkin Lymphoma

Male subfertility can be due to diverse reasons, including anatomic, genetic, hormonal, iatrogenic causes, etc. Isolated FSH deficiency is a rare cause of male subfertility, reported only in a few cases till date. We report a case of a transient isolated FSH deficiency in a patient with azoospermia and subfertility with history of treated high-grade diffuse large B-cell lymphoma.

Isolated FSH deficiency. A rare cause of male infertility

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Conditional Deletion of FOXL2 and SMAD4 in Gonadotropes of Adult Mice Causes Isolated FSH Deficiency.

The glycoprotein FSH, a product of pituitary gonadotrope cells, regulates ovarian follicle development in females and spermatogenesis in males. FSH is a heterodimer of the common α gonadotropin subunit and the hormone-specific FSHβ subunit (a product of the Fshb gene). Using a conditional knockout approach (Cre-lox), we previously demonstrated that Fshb expression in mice depends on the transcription factors forkhead box L2 (FOXL2) and SMAD4. Deletion of Foxl2 or Smad4 alone led to FSH deficiency, female subfertility, and oligozoospermia in males. Simultaneous deletion of the two genes yielded a greater suppression of FSH and female sterility. The Cre-driver used previously was first active during embryonic development. Therefore, it is unclear whether FOXL2 and SMAD4 play important roles in the development or adult function of gonadotropes, or both. To address this question, we developed a tamoxifen-inducible Cre-driver line, which enabled Foxl2 and Smad4 gene deletions in gonadotropes of adult mice. After tamoxifen treatment, females with previously demonstrated fertility exhibited profound reductions in FSH levels, arrested ovarian follicle development, and sterility. FSH levels were comparably reduced in males 1 or 2 months after treatment; however, spermatogenesis was unaffected. These data indicate that (1) FOXL2 and SMAD4 are necessary to maintain FSH synthesis in gonadotrope cells of adult mice, (2) FSH is essential for female reproduction but appears to be unnecessary for the maintenance of spermatogenesis in adult male mice, and (3) the inducible Cre-driver line developed here provides a powerful tool to interrogate gene function in gonadotrope cells of adult mice.

Isolated FSH Deficiency

Isolated FSH deficiency was first described in a young woman with primary amenorrhea. A homozygous deletion of two base pairs affecting the FSHβ gene was later reported to account for isolated FSH deficiency in an Italian woman. A few other cases of isolated FSH deficiency were described with compound heterozygous or homozygous mutations in the coding region of the FSHβ gene. Previously we report clinical, biochemical, and molecular analyses of a young male patient affected with isolated FSH deficiency and azoospermia with no evidence of mutations in the coding sequence of the FSHβ gene. The number of patients with isolated FSH deficiency reported to date in the literature is limited. FSH is thought to be essential for both steroid production necessary for puberty and gametogenesis in human males and females. Although FSHß gene mutations are considered to be relatively rare, their identification increases our understanding of normal reproductive physiology.

Isolated FSH deficiency revealing a granulosa cell tumor

We report a case of a 41-year-old woman with a recent secondary amenorrhea and infertility. The initial assessment ruled out premature ovarian failure, polycystic ovary syndrome and led to suspect a hypothalamo-pituitary cause. However, the unusual hormone pattern with a very low level of FSH, normal levels of LH and estradiol, associated with a positive progesterone test suggested the presence of a FSH inhibiting factor: the unexpectedly high levels of inhibin B and AMH were suggestive of a granulosa cell tumor as showed by the radiologic findings. This prompted a surgical exploration, which confirmed the putative diagnosis. This case report illustrates the inhibin B and AMH values and the modern-day pelvic imaging data encountered in menstrual irregularities caused by a granulosa cell tumor.

A new FSHβ mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: functional characterization and ovarian response to human recombinant FSH

Mutations of the FSHbeta gene, causing in women isolated FSH deficiency and hypogonadism, are very rare and only a few have been described. To describe the phenotype and response to recombinant human (rh) FSH of a female patient with a novel homozygous loss-of-function mutation of FSHbeta, and to characterize in vitro the molecular mechanisms responsible for the FSH inactivation. A 29-year-old woman with primary amenorrhea and impaired pubertal development associated with isolated FSH deficiency. Sequencing of the FSHbeta gene revealed a homozygous 1 bp (G) deletion at codon 79 (c.289delG) of exon 3 which produced a frameshift at codon 79 (A79fs108X) and a premature stop codon at codon 109. The wild-type and mutant FSHbeta cDNAs inserted into expression vector were cotransfected into Chinese hamster ovary cells with the alpha-subunit. Wild-type FSH was readily detectable in culture medium, whereas no mutant FSH was detectable by either immunoassay or in vitro bioassay. Mutant FSHbeta protein could not be detected in western blot. In response to a 15-day treatment with rhFSH, sonography revealed multifollicular development in the ovaries. Circulating levels of estradiol and inhibin B were dramatically increased, whereas anti-Mullerian hormone decreased. Serum LH first decreased and then increased, inducing multiovulation associated with supraphysiologic progesterone and inhibin A levels. A novel FSHbeta mutation was detected in a hypogonadal woman. rhFSH was effective in ovulation induction in the patient but with signs of ovarian hyperstimulation. The high pretreatment LH levels could contribute to this excessive ovarian response to rhFSH.

Effects of follicle-stimulating hormone and human chorionic gonadotropin on gonadal steroidogenesis in two siblings with a follicle-stimulating hormone β subunit mutation

To quantify gonadal steroid responses to different gonadotropin regimens. Transversal clinical study. Academic medical center. A 41-year-old woman and her 37-year-old brother with isolated FSH deficiency due to a homozygous Tyr76X FSH beta subunit gene (FSHB) mutation. Initially, serial LH samples were drawn overnight. After 2-day dexamethasone suppression, steroids were measured at baseline and after hCG, recombinant FSH, or hCG + recombinant FSH administration. Pulse number, peak amplitude, and mean overnight LH levels, as well as basal and stimulated FSH, LH, T, E(2), DHEAS, 17alpha-hydroxyprogesterone (17-OHP), and androstenedione (A). The mean +/-SD overnight LH was 49.2 +/- 5.7 mIU/mL and 9.1 +/- 2.9 mIU/mL; there were 8 pulses/8 hours and 9 pulses/9 hours, with mean amplitudes of 53.4 +/- 6.5 mIU/mL and 11.7 +/- 1.9 mIU/mL, for the woman and man, respectively. There was no steroid response to recombinant FSH, hCG, or hCG + recombinant FSH in the woman. In the man, T increased after hCG, recombinant FSH, and hCG + recombinant FSH, whereas E(2), A, and 17-OHP increased only after hCG + recombinant FSH. This report constitutes the first detailed endocrine study of a man with isolated FSH deficiency due to an FSHB mutation and suggests that FSH may have a positive regulatory effect on healthy LH-stimulated Leydig cells, probably mediated by its primary action on Sertoli cells, in a paracrine mechanism.

FSHβ Gene Mutations in a Female with Partial Breast Development and a Male Sibling with Normal Puberty and Azoospermia

FSH is a dimeric pituitary glycoprotein hormone that regulates gonadal function. Human mutations in the FSH beta gene have been shown to produce complete deficiency states in which pubertal development and reproductive capacity are inhibited. To date, no patients with partial or complete pubertal development due to FSH beta mutations have been documented in humans. We describe and characterize affected siblings, a male and a female, with evidence of pubertal development due to homozygosity for a Tyr76X nonsense mutation in the FSH beta gene. In vitro analysis of this mutant demonstrates unmeasurable FSH by immunoassay and by two different bioassays, using either cAMP (homologous FSH bioassay) or estradiol (rat granulosa cell assay) as the endpoints. In additional in vitro analyses, mutants previously found in patients with a phenotype of complete FSH deficiency (Cys51Gly and Val61X) and the Tyr76X were compared in the same immuno- and bioassays. All mutations failed to produce measurable FSH by all assays. Unexpectedly, these siblings with isolated FSH deficiency due to a nonsense FSH beta mutation had some evidence of puberty, suggesting that other factors might preserve gonadal steroidogenesis in the absence of FSH or that current bioassays cannot discriminate among very low FSH levels.

Pseudo-isolated FSH deficiency caused by inhibin beta-secreting ovarian tumors: report of three cases.

Objective: True isolated FSH deficiency is a rare cause of pubertal failure caused by a mutation in the FSH gene. We report three cases with serum values of FSH consistent with isolated FSH deficiency, but clinical presentations inconsistent with that diagnosis. In each case extremely low values of FSH were due to endocrinologically active ovarian tumors.

Compound heterozygote FSH? gene mutation in a woman with delayed puberty and isolated FSH deficiency

Compound heterozygote FSH? gene mutation in a woman with delayed puberty and isolated FSH deficiency

Follicle-stimulating hormone is required for quantitatively normal inhibin secretion in men.

Inhibin is a glycoprotein hormone produced by the testis and ovary which is postulated to be an important regulator of pituitary FSH secretion. Animal data indicate that inhibin is produced by the Sertoli cells of the testis under the influence of FSH. To determine the role of FSH withdrawal and replacement in the control of inhibin secretion in man, we measured serum inhibin concentrations in men in whom isolated FSH deficiency had been produced by chronic hCG administration; this was followed by FSH replacement. After a 3-month control period, four normal men received hCG for 7 months, resulting in suppression of serum FSH to undetectable levels and urinary FSH excretion to prepubertal levels. Their mean serum inhibin levels fell to 70% of control values during hCG administration [362 +/- 60 (+/- SE) vs. 518 +/- 56 U/L; P less than 0.01]. While continuing hCG, testosterone enanthate was administered for a further 6 months. Serum FSH and inhibin levels remained suppressed to a similar degree. Testosterone administration then was ceased, and hCG continued for a further 2-4 months. Then, while continuing hCG administration, FSH was replaced as either highly purified human FSH (n = 2) or human menopausal gonadotropin (n = 2) for a period of 4-10 months. Serum FSH levels increased to the mid- and upper normal male ranges, respectively. FSH replacement restored serum inhibin levels to 522 +/- 56 U/L (P = NS vs. control). In summary, prolonged selective FSH deficiency induced by chronic hCG administration suppressed inhibin secretion. Replacement of FSH activity restored inhibin secretion to control values. We conclude that 1) FSH is not absolutely required for inhibin secretion in men; and 2) the maintenance of quantitatively normal inhibin secretion requires the combined action of both gonadotropins.

Releasing Factor Tests in Men with Oligozoospermia

FSH levels were assayed in 300 men attending with infertile marriages. From this number, releasing factor tests were carried out in 24 men with oligozoospermia and an initial FSH below our normal mean. In all of these cases there was a response to releasing factor. Isolated FSH deficiency is likely to be rare in adult men presenting with infertility and no previous endocrinological history.

Isolated FSH Deficiency in a Male

This report describes the case of a 26-year-old man investigated because of infertility. The patient appeared healthy with normal sexual activity, physical appearance and karyotype. Repeated semen analyses showed a marked oligozoospermia. A testicular biopsy specimen revealed arrested spermatogenesis and normal Leydig cells. Hormone analyses were normal except for a markedly reduced serum FSH level. Only a few such cases have been previously reported.

Development of anti-human FSH antibody in a patient with isolated FSH deficiency.

Antibodies to human FSH were documented in the serum of a patient previously shown to have isolated FSH deficiency. These antibodies developed subsequent to the administration of a second course of Human Menopausal Gonadotrophins (Pergonal 500). Using the ammonium sulfate precipitation method, antibodies were detected in the first week after cessation of Pergonal 500 therapy. Characterization of the antibody showed that (a) it was associated with the IgG fraction of the patient's serum; (b) addition of excess Pergonal 500 lead to rapid dissociation of 125I-FSH binding to serum; (c) pituitary FSH (LER-1366) and 2nd IRP-hMG, but not Hartree human LH, displaced 125I-FSH tracer bound to serum and (d) there was no binding of tracer insulin, hGH and LH by serum. Antibody has remained detectable over a 5-month period of observation.