RESUMO
OBJECTIVE: To study women with a poor response to ovarian hormone stimulation, known as low responders. Genetic defects in the FSH receptor gene (FSHR) were analyzed as well as antimüllerian hormone (AMH) for ovarian reserve. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENT(S): Two hundred fifty-nine patients total: 74 low responders; 88 patients receiving assisted reproduction therapy (ART) with a normal ovarian response; and 97 women with a normal fertility status. INTERVENTION(S): DNA from patients was analyzed using real-time polymerase chain reaction. Serum concentrations of AMH were assessed using ELISA. MAIN OUTCOME MEASURE(S): The FSHR variants Asn680Ser (rs6166), Ala189Val (rs121909658), Ile160Thr (rs121909659), Thr449Ile (rs28928870) and the serum AMH concentrations were assessed. RESULT(S): With the exception of the frequent Asn680Ser polymorphism, no homozygotic SNPs of FSHR were found. In the group of ART patients, Thr160/Ile160 variants were more frequent in comparison with women with normal fertility. The Ser680/Ser680 was more frequent in ART patients than in women with normal reproductive function. The rate of live births was markedly reduced, particularly in the low responder group. No difference was noted in the distribution of the Ala189Val and Thr449Ile variant. Low serum AMH values were observed in 75% of the low responder group. CONCLUSION(S): FSHR gene variations such as Asn680Ser, Ala189Val, Thr449Ile, and Ile160Thr did not seem to be a decisive factor of poor response to fertility treatment, whereas the low ovarian reserve determined by AMH is considered more crucial.
Assuntos
Hormônio Antimülleriano/sangue , Fármacos para a Fertilidade Feminina/uso terapêutico , Variação Genética , Gonadotropinas/uso terapêutico , Infertilidade Feminina/terapia , Indução da Ovulação/métodos , Ovulação/efeitos dos fármacos , Receptores do FSH/genética , Adulto , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Ensaio de Imunoadsorção Enzimática , Feminino , Fertilização in vitro , Frequência do Gene , Alemanha , Humanos , Infertilidade Feminina/sangue , Infertilidade Feminina/genética , Infertilidade Feminina/fisiopatologia , Nascido Vivo , Ovulação/genética , Projetos Piloto , Gravidez , Taxa de Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Injeções de Esperma Intracitoplásmicas , Falha de TratamentoRESUMO
Severe ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening complication during assisted reproduction technology (ART). The aetiology of this condition is still not fully understood. Several gene variations in the FSH receptor (FSHR) gene have been identified for the very rare cases of spontaneous OHSS. There are only few published data on gene variations in sterility and iatrogenic OHSS and no data regarding aromatase (cytochrome P450 19A1; CYP19A1). Ninety-one ART patients with OHSS, eighty-eight ART patients without OHSS and ninety-seven women with assumed normal fecundity were analysed for the FSHR single nucleotide polymorphism (SNP) gene variations Asn680Ser (rs6166), Ala189Val, Ile160Thr, Thr449Ile (rs28928870) and the CYP19A1 rs10046 locus using real-time PCR. In addition, exon 10 of FSHR of two patients with spontaneous hyperreactio luteinalis (HL) was sequenced. Significantly lower frequencies of homozygous Ser680/Ser680 (P=0.035) and heterozygous Thr160/Ile160 (P=0.039) were found in patients with normal fecundity than those undergoing ART. The Ile160Thr SNP with a frequency of 6.7 and 6.1% in ART patients with and without OHSS respectively does not represent a rare mutation as previously published. There were no differences in the frequencies of all other gene variations. Of two patients with HL, both had homozygous point mutations for Ser680/Ser680 and one was heterozygous for Ile160Thr and CYP19A1 rs10046. The FSHR gene variations Asn680Ser as well as Ile160Thr may be contributing factors in unexplained sterility. The other FSHR coding gene variations and CYP19A1 rs10046 investigated are most likely not involved in the aetiology of iatrogenic OHSS or sterility.