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PubMed1997

Ontogeny of FSH receptor messenger ribonucleic acid transcripts in relation to FSH secretion and testicular function in sheep.

The role of alternative splicing of the FSH receptor gene in the generation of FSH receptor proteins and testicular function remains an enigma. To address this issue, this investigation was conducted to determine variations in the expression of alternate FSH receptor mRNA transcripts in relation to changes in FSH release, hormone binding activity and testicular function during pubertal development of ram lambs from two genotypes of sheep (Romanov and a cross between Booroola x DLS) with different sexual precocity. Serum 17 beta-estradiol and testosterone concentrations were used as indices of Sertoli cell and testicular function. The results indicated that increases in Sertoli cell and testicular function normally seen during pubertal development are accompanied by age-dependent reductions in concentration of functional FSH receptors, as determined by binding of iodinated FSH to testicular membrane preparations. During the course of these changes, FSH release was either maintained at a steady level in Romanov lambs or it was gradually reduced in the Booroola x DLS cross, thus indicating that the testis had become more responsive to hormonal signal. This acquisition of heightened sensitivity was also associated with contrasting changes in the level of expression of FSH receptor mRNA transcripts. For both geno-types of sheep, 5 distinct species of mRNA transcripts of approximately 1.1, 1.5, 2.0, 2.5 and 6.5 kb were highly expressed from 11 to 22 weeks of age. Amongst these transcripts, the 1.1 kb molecular species was the most abundant. Specific probing for a previously cloned transcript called 151A1 representing the first 4 exons of the FSH receptor gene revealed a paradoxical increase in the level of expression from 11 weeks up to a maximum at 18-22 weeks of age for both genotypes. Collectively, the results indicated that contrasting changes in the production of specific alternatively spliced mRNA transcripts may mediate changes in FSH receptor expression which apparently accounts for the augmentation in sensitivity and function of the testis during pubertal development. Furthermore, the data provide the first important indication that the novel truncated transcript (151A1), which predictably encodes a soluble protein of either intra- or extracellular fate, could be physiologically relevant.

Animals↗
PubMed1999

Generating FSH antagonists and agonists through immunization against FSH receptor N-terminal decapeptides.

Follicle-stimulating hormone (FSH) via interaction with G-protein coupled specific receptors plays a central role in the control of gametogenesis in mammals of both sexes. In females, FSH is crucial for follicle growth, follicle maturation and ovulation. FSH receptors, together with luteinizing hormone-chorionic gonadotropin and thyrotropin receptors belong to a subfamily of structurally related receptors within the seven transmembrane receptor family. Among several other regions, the N-terminus of these receptors is believed to be responsible for important specific hormone-receptor contact sites. Recombinant filamentous phages displaying at their surface three overlapping N-terminal decapeptides of the FSH receptor, peptides A18-27, B25-34 and C29-38 were constructed. Ewes and female mice were immunized against the three FSH receptor (FSHR) recombinant phages. Immunoglobulins purified from immunized animals were analyzed for their biochemical properties on a Chinese hamster ovary cell line expressing the porcine FSH receptor. AntiA and antiB immunoglobulins (IgGs) behave as antagonists for 125I-FSH binding and for FSH-dependent cAMP production, while antiC IgGs did not compete for hormone binding. By contrast, antibodies against the C29-38 peptide displayed FSH agonist activity and stimulated the FSH receptor, whereas antiA and antiB IgGs did not. Furthermore, when the FSHR phages were used as peptidic vaccines, they induced a reversible inhibition of ovulation rate in ewes, and impaired fertility in female mice.

Amino Acid Sequence↗
PubMed2005

Clinical and hormonal features of selective follicle-stimulating hormone (FSH) deficiency due to FSH beta-subunit gene mutations in both sexes.

OBJECTIVE: To report the clinical, hormonal, and molecular features of a female adolescent with selective FSH deficiency. In addition, a complete review of previous cases is provided, focusing on hormonal aspects. DESIGN: Clinical study. SETTING: University hospital. PATIENT(S): A 16-year-old girl with primary amenorrhea and poor breast development due to isolated FSH deficiency. INTERVENTION(S): Blood drawing before and after GnRH stimulation and pelvic ultrasound examination. MAIN OUTCOME MEASURE(S): Gonadotropin and E(2) measurements and sequencing of the FSH beta-subunit gene. RESULT(S): The patient was referred for primary amenorrhea and partial breast development (Tanner III). Her basal and GnRH-stimulated LH levels were elevated (31 IU/L and 98 IU/L, respectively), whereas her FSH levels were undetectable (<1 IU/L) in both conditions. Estradiol levels were low (<13 pg/mL). Automatic sequencing showed a nucleotide substitution of C for A in exon 3, resulting in a homozygous nonsense mutation in amino acid position 76 (Tyr76X) of the FSH beta-subunit. CONCLUSION(S): The Tyr76X mutation of the FSH beta-subunit was associated with a partial phenotype of FSH deficiency. To date, only four loss-of-function mutations of the FSH beta-subunit have been described in eight patients with undetectable serum FSH and high serum LH levels. Therefore, this unusual hormonal profile strongly suggests a defect in the FSH beta-subunit in both sexes.

Adolescent↗
PubMed1996

Premature luteinization in in vitro fertilization cycles using gonadotropin-releasing hormone agonist (GnRH-a) and recombinant follicle-stimulating hormone (FSH) and GnRH-a and urinary FSH.

OBJECTIVE: To determine if premature luteinization can occur in GnRH agonist (GnRH-a) and FSH (recombinant FSH and human urinary FSH) IVF cycles and whether premature luteinization affects IVF and clinical outcome. DESIGN: Retrospective evaluation of 171 IVF-ET cycles. The cycles were divided into two groups according to the P level on the day of hCG: group I (serum P </= 0.9 ng/mL [conversion factor to SI unit, 3.180]) and group II (serum P >/= 1.1 ng/mL). MAIN OUTCOME MEASURES: Comparison of cycles characteristics and of cumulative exposure of follicular serum E2, FSH, LH, and P as well as of IVF and clinical outcome were made between the study groups. RESULTS: Twenty-three of the 171 cycles (13.4%) demonstrated premature luteinization. The age of the patients, the E2, and LH exposure were similar between the groups. The number of the ampules of gonadotropins (recombinant FSH and urinary FSH) used and the area under FSH and P curve were higher in cycles with premature luteinization. The area under the FSH curve correlated with the area under the P curve. Similar IVF and clinical outcomes were observed in cycles with and without premature luteinization. CONCLUSION: The greater FSH exposure and its correlation with the P exposure suggest that one of the possible factors inducing premature luteinization is the increased FSH-induced LH receptivity in granulosa cells. No adverse effects of premature luteinization on the IVF and clinical outcome were observed.

Adult↗
PubMed1997

Utility of follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and FSH:LH ratio in predicting reproductive age in normal women.

The relative efficacy of follicle stimulating hormone (FSH), luteinizing hormone (LH), FSH:LH ratio and oestradiol is evaluated as a predictor of ovarian reserve (reproductive age) in normal women. Serum levels of FSH, LH, oestradiol and FSH:LH ratios were measured during menstrual cycle days 1-4 in younger (20-25 years; n = 23) and older (40-45 years; n = 32) reproductive age women with regular menstruation and normal reproductive function. On days 1-4, mean levels of FSH, oestradiol and FSH:LH ratios were significantly higher in older compared with younger women. FSH increased in concentration across cycle days in both age groups. A significantly lower LH value in younger versus older women was found only on day 1. Oestradiol showed no change across days in the younger group, but increased significantly from day 1 to day 4 in the older group. FSH values on days 1 or 2 were the best single predictor of age differences. However, the best prediction of age differences was obtained by using the combination of FSH and LH (as opposed to the FSH:LH ratio) on day 1 of the menstrual cycle.

Adult↗
PubMed2006

Transcriptome analysis of FSH and FSH variant stimulation in granulosa cells from IVM patients reveals novel regulated genes.

FSH is crucial for oocyte maturation and fertility and is the main component in infertility treatment in assisted reproduction. The granulosa cells expressing the FSH receptor interact with the oocyte and provide nourishing substrates controlling the oocyte maturation. Thus, transcriptome analysis of granulosa cells stimulated by FSH is of major importance in understanding the communication between oocytes and granulosa cells. In this study, gene expression profiles were assessed in human granulosa cells from normal cycling in vitro maturation (IVM) patients using oligonucleotide gene chips. Granulosa cells were stimulated for 2 h with either FSH or a previously generated glycosylated FSH variant (FSH1208) that exhibited increased in vivo activity because of prolonged half-life. The analysis identified 74 significantly FSH/FSH1208 regulated genes. Amongst these were well known FSH regulated genes as well as genes not previously described to be important in the FSH signalling pathway. These novel FSH regulated genes include transcription factors [cAMP responsive element modulator (CREM)/inducible cAMP early repressors (ICER), GATA 6, ZFN 361, Bcl11a, CITED1 and TCF 8] and other regulatory proteins and enzymes (IGF-BP3, syntaxin and PCK1) possibly important for oocyte/granulosa cell interaction and function. Array data were validated for 13 genes by northern blots or RT-PCR. Furthermore, no significant differences in gene regulation were detected between the two FSH analogs. This work uncovers novel data important for understanding the folliculogenesis. Furthermore, the results suggest that FSH1208 has a gene expression profile like FSH and thus, in the light of known prolonged in vivo activity, might be a candidate for improved infertility treatment.

Adolescent↗
PubMed1988

Follicle-stimulating hormone (FSH) immunoactivity in porcine follicular fluid is not pituitary FSH.

Two inhibitors of FSH binding to receptor have been isolated from porcine follicular fluid and shown to have in vitro biological activity. These inhibitors were distinct separable entities with opposite biological effects (agonist and antagonist) on cultured FSH-responsive Sertoli cells. In light of the fact that the agonist-containing fraction (P4) inhibited [125I]human (h) FSH binding to anti-hFSH antiserum as well as to receptor, characterization of this factor was undertaken to determine its relationship to pituitary FSH. The P4 fraction was further purified by affinity chromatography, which removed a major protein from immunoreactive components. Western blotting of sodium dodecyl sulfate-polyacrylamide gels using polyclonal (anti-hFSH) and monoclonal (anti-hFSH beta) antibodies revealed a major immunoreactive band at 55,000 mol wt (Mr). When electrophoresed under reducing conditions, major immunoreactive proteins at 58,000 and 45,000 Mr were identified. These bands were also observed in extracts from bovine testes and raw porcine follicular fluid after electrophoresis and Western blotting. Whereas the monoclonal antibody used to characterize this inhibitor does not recognize porcine pituitary FSH, the Mr of the immunoreactive proteins are greater than that of pituitary FSH, and the immunoreactive bands do not reduce to subunits, as observed for pituitary FSH under reducing conditions, we conclude that gonadal extracts contain FSH-immunoreactive proteins that are immunologically and biochemically distinguishable from pituitary FSH. While the physiological role of these proteins remains to be determined, their presence in gonadal extracts or fluids vitiates assessment of FSH within the gonad by RIA using antiserum against hFSH.

Animals↗
PubMed1991

Hypersecretion of follicle-stimulating hormone (FSH) after ovariectomy of hypophysectomized, pituitary-grafted rats: implications for local regulatory control of FSH.

Previous observations have shown that a portion of the acute (less than 12 h) FSH hypersecretion after ovariectomy (OVX) is LHRH independent, thereby suggesting that mechanisms governing the acute FSH hypersecretory response to OVX may reside largely within the anterior pituitary gland. Accordingly, the present studies were conducted to determine whether acute OVX-induced FSH hypersecretion can be elicited in an animal model in which the anterior pituitary gland is isolated from diencephalic chemical signals, and if so, whether the hypersecretion could be abated by the FSH-suppressing protein, follistatin. Adult female rats hypophysectomized (H) 1 week earlier received anterior pituitary grafts (H/G) (one to three glands per rat) under the kidney capsule. In order to increase ovarian secretion of negative feedback effectors substances (i.e. estrogen, inhibin), some H/G rats were injected sc with 30 IU PMSG 4-6 days after receiving pituitary transplants, whereas other rats were given the saline vehicle. Two days later (0830 h), a blood sample was obtained via an indwelling atrial catheter inserted the previous day. H/G rats given saline or PMSG then were further subdivided and either castrated or sham castrated. Additional blood samples were obtained from the catheter, and trunk blood was collected from decapitated rats 24 h after OVX for measurement of serum estradiol and PRL levels. For comparison, H rats not receiving renal pituitary transplants were subdivided into similar experimental groups as the H/G rats. Blood samples were also obtained after sham OVX or OVX of pituitary-intact, 4-day cycling rats on diestrous day 1. Ovariectomy of PMSG-treated H rats receiving either one or three pituitary allografts resulted in a significant (P less than 0.01) increase in serum FSH levels by 12 h after OVX followed by a 2- to 3-fold increase in FSH levels by 24 h relative to either the pre-OVX FSH levels measured in this group or the FSH levels measured in PMSG-treated H/G rats 24 h after sham OVX. In contrast, OVX of saline-treated H/G rats failed to elicit FSH hypersecretion. Similarly, FSH hypersecretion was not observed after OVX of saline- or PMSG-treated H rats. Whereas serum LH levels were increased 24 h after OVX of diestrous rats, no such increases were detected 24 h after OVX of any H or H/G rats. In an additional experiment, H rats receiving two pituitary allografts were treated with PMSG and subsequently castrated. Twenty-four hours later, rats were injected iv with either 60 micrograms purified porcine follistatin or saline.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Correlation of follicle-stimulating hormone (FSH)-receptor complex internalization with the sustained phase of FSH-induced calcium uptake by cultured rat Sertoli cells.

We have previously reported that synthetic peptide amides corresponding to regions of the beta-subunit of human FSH [hFSH-beta-(1-15) and hFSH-beta-(51-65)] have the ability to bind calcium and to facilitate its entry into liposomes. In the present study, we have examined the ability of synthetic peptides corresponding to the entire primary structure of hFSH-beta-subunit, to induce calcium influx in cultured rat Sertoli cells. Calcium (as 45Ca2+) uptake in response to 50 microM hFSH-beta-(1-15), hFSH-beta-(21-35), or hFSH-beta-(51-65) peptide amides was 2.5-, 2.4-, and 2.0-fold higher, respectively, than basal uptake. Pretreatment of Sertoli cells for 5 min with phenylarsine oxide (PAO, 80 microM), an inhibitor of receptor-mediated endocytosis, significantly (P < 0.05) reduced 45Ca2+ influx in response to hFSH-beta-(1-15), hFSH-beta-(21-35), and hFSH-beta-(51-65). A delay of 20 min was required, however, before the inhibitory effect of PAO on 45Ca2+ uptake was observed. Specific binding of [125I] hFSH to receptor at 4 C was unaffected by PAO. After 2 h at 37 C, however, approximately 1.6-fold more [125I]hFSH specifically bound at 4 C could be dissociated from the cell surfaces of PAO-pretreated Sertoli cell monolayers, compared to untreated monolayers. This result is consistent with an inhibitory effect of PAO on FSH receptor internalization. Chloroquine (at 100 microM), a lysosomotropic agent known to block FSH degradation, also significantly (P < 0.05) inhibited FSH-induced 45Ca2+ uptake. Extending our earlier studies, these results suggest that the sustained (> 20 min) phase of FSH-induced calcium uptake, also seen in response to synthetic hFSH-beta-(1-15), hFSH-beta-(21-35), and hFSH-beta-(51-65) peptide amides, may occur as a consequence of FSH-receptor complex internalization and FSH degradation. Vesicular uptake of extracellular calcium, which accompanies internalization of FSH-receptor complexes, and release of channel-forming peptides by lysosomal hydrolysis of FSH suggests a novel mechanism whereby FSH increases intracellular calcium levels in Sertoli cells.

Animals↗
PubMed1995

Replacement with recombinant human inhibin immediately after orchidectomy in the hypophysiotropically clamped male rhesus monkey (Macaca mulatta) maintains follicle-stimulating hormone (FSH) secretion and FSH beta messenger ribonucleic acid levels at precastration values.

This study directly tested the inhibin hypothesis by examining the ability of replacement with recombinant human (rh-) inhibin, either alone or in combination with testosterone (T), to maintain FSH secretion and FSH beta messenger RNA (mRNA) at intact levels after orchidectomy in the hypophysiotropically clamped juvenile rhesus monkey. Thirteen male monkeys (11-21 months of age) received an intermittent i.v. infusion of GnRH (0.1 microgram/min for 3 min every 3 h). After 4-6 weeks of GnRH stimulation, 10 animals were orchidectomized, and 3 monkeys were sham castrated. Hormone replacement was initiated at castration and maintained for 4 days. Three monkeys received a combination of inhibin and T replacement, 4 monkeys received replacement with inhibin alone, and 3 monkeys received T replacement alone. A continuous i.v. infusion of rh-inhibin (832 ng/h.kg) was used to replace the testicular protein, whereas SILASTIC capsules were implanted sc for T replacement. The FSH response to castration and hormone replacement was determined by measuring circulating concentrations of this gonadotropin before a GnRH pulse and for 3 h thereafter on the day before surgery and on days 2 and 4 postcastration. Circulating immunoactive inhibin was measured by a RIA that recognizes the free alpha-subunit of inhibin as well as inhibin dimers. At the end of the study, anterior pituitaries were collected for analysis of steady state levels of FSH beta, LH beta, and alpha-subunit mRNAs. Steroid replacement alone, which produced circulating T concentrations in the upper physiological range, failed to prevent the postcastration increases in circulating FSH concentrations and pituitary FSH beta mRNA levels. In contrast, when circulating immunoactive inhibin in T-replaced monkeys was maintained at precastration levels (approximately 2 ng/ml) by infusion of rh-inhibin, FSH secretion and synthesis were held at control values. When T was omitted from combined replacement, the FSH-suppressing action of the recombinant hormone was not compromised. These results demonstrate that rh-inhibin is biologically active in the monkey, and the action of inhibin to suppress FSH synthesis and secretion does not require a concomitant action of T. Moreover, because the hypophysiotropic drive to the pituitary-testicular axis was clamped, the FSH-suppressing action of rh-inhibin must be at the pituitary.

Analysis of Variance↗
PubMed1994

Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transition--an analysis of FSH, oestradiol and inhibin.

This review examines the role of follicle-stimulating hormone (FSH) measurement in assessing the significance of symptoms and possible continuing fertility during the menopausal transition. Follicle-stimulating hormone measurement is advocated frequently as a useful diagnostic tool in perimenopausal patients. Several investigators have shown that the serum FSH level increases in the early--mid-follicular and early postovulatory phases in women over the age of 40 years who continue to experience regular menstrual cycles. The serum oestradiol level may fall (although this is controversial) and the immunoreactive inhibin level falls, being inversely correlated with the rising FSH level. When alterations in menstrual cyclicity or flow commence, signalling the onset of the menopausal transition, FSH levels may change abruptly, rising into the normal postmenopausal range and falling again into the range normally seen in young fertile women. Oestradiol and inhibin generally fluctuate in parallel with each other but inversely to FSH, although at times oestradiol in particular may be increased markedly. Postmenopausal FSH levels may be followed by endocrine evidence compatible with normal ovulation. After the menopause, FSH levels rise 10-15-fold, with low oestradiol and undetectable inhibin levels. It is concluded that FSH measurement is of little value, if any in the assessment of women during the menopausal transition because it cannot be interpreted reliably and because, apparently, ovulatory (and, presumably, potentially fertile) cycles may occur subsequent to the observation of postmenopausal FSH levels. Both oestradiol and inhibin are important negative feedback regulators of circulating FSH.

Adult↗
PubMed1996

Effects of gonadotropin-releasing hormone on bioactivity of follicle-stimulating hormone (FSH) and microstructure of FSH, luteinizing hormone and sex hormone-binding globulin in a testosterone-based contraceptive trial: evaluation of responders and non-responders.

Only a proportion of normal men participating in testosterone-based contraceptive trials develop azoospermia (responders). This study analyzed whether serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) are qualitatively different between responders and non-responders. Determination of in vitro bioactive FSH after stimulation with gonadotropin-releasing hormone (GnRH) and analysis of molecular heterogeneity of serum FSH, LH and SHBG was carried out by chromatofocusing and concanavalin-A affinity chromatography in eight men who had participated in a previous contraceptive study with testosterone buciclate. Blood was withdrawn at 15-min intervals on two basal occasions and 30, 45 and 60 min after i.v. administration of GnRH (100 micrograms). Pools of sera were separated by chromatofocusing in the pH range 3-6 and by lectin chromatography on concanavalin A. Immunoreactive FSH, LH and SHBG were assayed in the eluates. Bioactive FSH was analyzed by the rat Sertoli cell bioassay. Serum bioactive FSH increased after GnRH stimulation, without significant differences between responders and non-responders. The chromatofocusing profiles of serum FSH showed a significant shift towards the less acidic region after GnRH. The isoform distribution was similar in responders and non-responders. No significant differences were found in the relative proportion of FSH, LH and SHBG retained by concanavalin A. It is concluded that the extent of suppression of sperm production by androgen administration cannot be foreseen either on the basis of the response of bioactive FSH to GnRH administration or from the glycosylation pattern of serum FSH, LH and SHBG.

Adult↗
PubMed1986

Different mechanisms controlling FSH and LH release in Japanese quail (Coturnix coturnix japonica): evidence for an inherently spontaneous release and production of FSH.

Plasma concentration of FSH and LH and their content in the adenohypophyses of Japanese quail were estimated by homologous radioimmunoassays based on chicken hormones. The results consistently showed that the plasma concentration of FSH was slightly higher than that of LH, although the FSH content in the adenohypophysis was much lower than that of LH in immature, mature and acutely photostimulated quail. These results prompted experiments in vitro to determine whether the difference was intrinsic. Adenohypophyses were collected and each cut mid-sagittally into two halves; one half was incubated for 20 h with or without chicken hypothalamic extract, and the medium was changed every 1 or 2 h to estimate the FSH and LH released. The other half served to estimate the initial content of FSH and LH in the adenohypophysis. The amount of FSH released was three times more than the original content even when adenohypophyses were incubated without hypothalamic extract, and the residual FSH content in the pituitary after 20 h of incubation was equal to the initial FSH content. In contrast, under the same incubation conditions, little LH was released and the residual LH content was decreased. When hypothalamic extract was added to the medium, LH release was enhanced sixfold compared with the control, whereas the increase in FSH was less than twofold. Spontaneous FSH release was markedly decreased in a Ca2+-deficient incubation medium, suggesting that the release was not due to leakage but to an active secretion mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1988

Increases in the basal secretion rate of follicle-stimulating hormone (FSH) accompany age-associated changes in serum FSH levels on estrus.

This laboratory has recently reported that by 5-6 months of age, alterations in the secretion and production of follicle-stimulating hormone (FSH) occur in virgin female rats which precedes the age-related disruption of estrous cycles and attenuation of preovulatory gonadotropin surges. Specifically, circulating immunoreactive FSH levels are higher on estrus in rats 5 months and older compared to levels measured in 2- to 3-month-old rats. Therefore, the present study was conducted to explore a possible mechanism for this age-related increase in FSH levels. At 1400 hr on proestrus, estrus and diestrus-1, groups (n = 6-12 rats/group) of 3- and 7-month-old, cyclic rats were decapitated, trunk blood was collected, and anterior pituitary glands were bisected and placed in incubation flasks containing 1 ml media (medium 199). Following a 30-min preincubation period, hemipituitary fragments were incubated for an additional 2 hr. Media and serum FSH levels were quantified by RIA. Levels of FSH were twofold higher in the serum of 7-month-old rats than 3-month-old rats on estrus. Similarly, the basal secretion rate (BSR) of FSH (expressed as ng FSH/ml/2 hr) was significantly (P less than 0.05) higher from incubated hemipituitary fragments of 7-month-old estrous rats than from fragments obtained from younger estrous rats (7 month: 1637 ng/ml/2 hr vs 3 months: 1253 ng/ml/2 hr). Neither the serum FSH levels nor the BSR of FSH differed between age groups on proestrus or diestrus-1. These results show that age-associated increases in circulating FSH levels on estrus may be attributed to an enhanced basal secretion of FSH from the pituitary gland.

Age Factors↗
PubMed1992

A synthetic peptide corresponding to amino acids 9-30 of the extracellular domain of the follitropin (FSH) receptor specifically binds FSH.

As deduced on the basis of cloning experiments, the putative extracellular domain of pituitary glycoprotein hormone (lutropin (LH), thyrotropin (TSH), and FSH) receptors (rec) is sufficiently large to suggest involvement in hormone binding. Comparison of the amino acid sequences of the extracellular domains of the glycoprotein hormone receptors indicates that the FSH receptor has a peptide sequence in the external domain close to the amino terminus (residues 9-30) which has no sequence homology to receptors for LH or TSH. To examine whether this region is involved in FSH-receptor interaction, we studied the hormone-binding properties of a corresponding synthetic peptide in several systems. (1) Binding of 125I-hFSH to receptor-containing bovine testis membranes was inhibited by preincubation with FSH rec-(9-30) peptide amide in a concentration-dependent manner. (2) 125I-labeled rec-(9-30) peptide amide bound to ovine, bovine, or human FSH preparations, and the binding was inhibited by solubilized bovine FSH receptor. 125I-labeled rec-(9-30) peptide amide, however, did not bind to LH or TSH. (3) 125I-hFSH bound to unlabeled rec-(9-30) peptide amide, and the binding was inhibited by excess unlabeled FSH, but not by LH or TSH. (4) Scatchard analysis indicated that the FSH rec-(9-30) peptide amide contained a single class of FSH binding sites with a Ka = 1.1 x 10(6) M-1. (5) The binding of 125I-labeled rec-(9-30) peptide amide to hFSH, bFSH or oFSH was effectively inhibited by rabbit polyclonal antibodies raised against rec-(9-30) peptide amide but not by preimmune rabbit serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Development of a bioassay for FSH using a recombinant human FSH receptor and a cAMP responsive luciferase reporter gene.

FSH exerts its actions primarily by increasing cAMP levels via a G protein-linked transmembrane receptor. We report the development of a bioassay for FSH using a cell line that stably expresses the human FSH receptor and a cAMP responsive human glycoprotein hormone alpha subunit luciferase reporter construct. Receptor activation by FSH was measured by changes in luciferase activity. The cell line was shown to express 1.6 x 10(4) receptors per cell which bound FSH with high affinity (Kd 2.76 x 10[-9] M). Human pituitary FSH caused a dose-dependent increase in cAMP (ED50, 190 mIU/ml) and luciferase (ED50, 31.5 mIU/ml) activity. The sensitivity of the bioassay was less than 0.6 mIU/well. Postmenopausal serum, rat, ovine and bovine FSH elicited a dose-dependent increase in luciferase activity. There was no significant stimulation by highly purified human LH or recombinant human TSH. This cell line should be useful in the determination of bioactive FSH and characterization of serum FSH inhibitors.

Animals↗
PubMed2002

Effects of follicle-stimulating hormone (FSH) and human chorionic gonadotropin in individuals with an inactivating mutation of the FSH receptor.

OBJECTIVE: To study the gonadal steroid responses to FSH and hCG in individuals with the inherited Finnish-type inactivating Ala189Val mutation of the FSH receptor gene. DESIGN: Prospective clinical and descriptive study. SETTING: University hospital. PATIENT(S): Two women and one man homozygous for the Ala189Val mutation of the FSH receptor gene, and ovarian biopsies from four affected and four healthy women, and four normal fetuses. INTERVENTION(S): Individuals were treated with increasing doses of recombinant FSH (300 IU/day start, 900 IU/day final) and/or a single dose of hCG (5000 IU). Ovarian biopsies were used in immunohistochemical analyses for detection of aromatase cytochrome P450 and transcription factor GATA-4. In situ 3'-end labeling analyses were used for detection of apoptosis. MAIN OUTCOME MEASURE(S): Measurements of serum concentrations of follicle-stimulating hormone, leuteinizing hormone, inhibin A and B, estradiol, testosterone (T), androstenedione, and prolactin, immunostaining for ovarian aromatase, GATA-4, and apoptosis. RESULT(S): Administration of FSH had no effect on production of the steroids. Similarly, human chorionic gonadotropin (hCG) treatment, alone or after FSH administration, failed to raise serum steroid concentrations. Ovarian apoptosis was absent, and the expression of transcription factor GATA-4 and aromatase was negligible in the ovarian biopsies from Ala189Val homozygous individuals. CONCLUSION(S): The Ala189Val mutation of the FSH receptor gene results in a complete block of FSH action in vivo. Furthermore, the failure of hCG to increase both ovarian estradiol and testosterone secretion emphasizes the possible contribution of FSH in regulating ovarian androgen synthesis, and supports the concept that both gonadotropins are necessary for appropriate ovarian steroidogenesis in humans.

Adult↗
PubMed2004

Human follicle-stimulating hormone receptor (FSH-R) promoter/enhancer activity is inhibited by transcriptional factors, from the upstream stimulating factors family, via E-box and newly identified initiator element (Inr) in FSH-R non-expressing cells.

To localize the regulatory elements in the human follicle-stimulating hormone receptor (FSH-R) promoter/enhancer and to determine the role of upstream stimulatingfactors (USFs) in these elements, we transiently transfected constructs of FSH-R promoter/enhancer in pGL3 luciferase reporter plasmids into Chinese hamster ovary cells and the activities were determined by measuring luciferase luminescence of the cell lysates. The 5'-flanking regions of the human FSH-R gene from nt -1485 to -1 with respect to the gene translation start site were amplified by polymerase chain reaction (PCR) and subcloned in pGL3. Deletion mutants were created using PCR or restriction enzyme digestion. Mutation in the E-box sequence from nt -124 to -119 (E-box 3), in the construct from -224 to nt -1 or in the Inr element, which encompasses the transcriptional start site at nt -99, resulted in a substantial reduction in the human FSH-R promoter/enhancer activity. Overexpression of upstream stimulating factor-1 (USF1) suppresses the activity of the human FSH-R promoter/enhancer via Inr and E-box elements. Upstream stimulating factor-2 (USF2) decreases FSH-R promoter/enhancer activity by acting on E-box 3. The results indicate that E-box 3 and the Inr element are important elements of the human FSH-R promoter/ enhancer. USF family members inhibit FSH-R gene activity by acting via these elements. USF1 and USF2 suppress human FSH-R promoter/enhancer activity by acting on E-box 3. USF1 also decreases activity by interacting with the Inr element.

Animals↗