ABSTRACT
Premature ovarian failure occurs in almost 1% of women under age 40. Molecular alterations of the FSH receptor (FSHR) have recently been described. A first homozygous mutation of the FSHR was identified in Finland. More recently, we described two new mutations of the FSHR in a woman presenting a partial FSH-resistance syndrome (patient 1). We now report new molecular alterations of the FSHR in another woman (patient 2) who presented at the age of 19 with primary amenorrhea contrasting with normal pubertal development. She had high plasma FSH, and numerous ovarian follicles up to 3 mm in size were evidenced by ultrasonography. Histological and immunohistochemical examination of ovarian biopsies revealed the presence of a normal follicular development up to the antral stage and disruption at further stages. DNA sequencing showed two heterozygous mutations: Asp224Val in the extracellular domain and Leu601Val in the third extracellular loop of FSHR. Cells transfected with expression vectors encoding the wild type or the mutated Leu601Val receptors bound hormone with similar affinity, whereas binding was barely detectable with the Asp224Val mutant. Confocal microscopy showed the latter to have an impaired targeting to the cell membrane. This was confirmed by its accumulation as a mannose-rich precursor. Adenylate cyclase stimulation by FSH of the Leu601Val mutant receptor showed a 12+/-3% residual activity, whereas in patient 1 a 24+/-4% residual activity was detected for the Arg573Cys mutant receptor. These results are in keeping with the fact that estradiol and inhibin B levels were higher in patient 1 and that stimulation with recombinant FSH did not increase follicular size, estradiol, or inhibin B levels in patient 2 in contrast to what was observed for patient 1. Thus, differences in the residual activity of mutated FSHR led to differences in the clinical, biological, and histological phenotypes of the patient.
Subject(s)
Amenorrhea/genetics , Mutation , Ovary/physiopathology , Receptors, FSH/genetics , Adenylyl Cyclases/drug effects , Adenylyl Cyclases/metabolism , Adult , Amenorrhea/drug therapy , Animals , COS Cells/drug effects , COS Cells/metabolism , Female , Follicle Stimulating Hormone/pharmacology , Follicle Stimulating Hormone/therapeutic use , Gene Silencing , Humans , Immunohistochemistry , Male , Ovary/diagnostic imaging , Ovary/pathology , Phenotype , Primary Ovarian Insufficiency/drug therapy , Primary Ovarian Insufficiency/genetics , Protein Processing, Post-Translational , Receptors, FSH/drug effects , Receptors, FSH/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sequence Analysis , UltrasonographyABSTRACT
PIP: Hormonal contraception was made legal in France in 1967, and it was used by 28% of French women between 20-44 in 1978. There has been in the past few years a drop in the number of OC (oral contraception) users, largely due to the many and well publicized side effects, the best known of which are metabolic effects, cardio- and cerebrovascular effects, coagulation effects, and hepatic effects. There is no doubt that the incidence of mortality is increased, in certain subjects, by OC use, especially in patients over 35. Certain predisposed subjects, such as those with familial antecedents of thrombotic accidents, or hypertensive subjects, should not use OC. There are, however, several types of OC, i.e. combined, or estroprogestational, and progestin only contraception, in high or in low doses. Each type of contraception is indicated for a particualr group of women only, and contraindicated to others. Only an expert physician can decide which type is better suited to a particular client. Research is being conducted in several countries to study better and safer types of contraception.^ieng