Genetic basis for primary ovarian insufficiency

Introduction Approximately 1% of women under the age of 40 years and 0.1% under the age of 30 years experience “premature menopause” [1]. “Premature menopause” or “premature ovarian failure” (POF) has generally been defined as 4–6 months of amenorrhea in women under the age of 40 years associated with serum gonadotropin concentrations in the postmenopausal range and hypoestrogenism (hypergonadotropic hypogonadism). Depending on the age of onset, the disorder can manifest as failure to enter pubertal development and the associated primary amenorrhea (PA), or secondary amenorrhea (SA) after the onset of menarche and the associated pubertal development [2, 3]. Substantial published evidence has demonstrated that POF may have a long and variable clinical course with the possibility of spontaneous remission and even pregnancy many years after the diagnosis. Therefore, the term primary ovarian insufficiency (POI) is now generally accepted as a less stigmatizing term to young women. It is, as well, a more scientifically accurate definition, to describe more clearly a continuum of intermittent and unpredictable ovarian function [4, 5]. The continuum is divided into two categories of clinical states: (1) POI that is overt, meaning that menstrual cycles have become irregular, and (2) POI that is occult (oPOI), meaning that the menstrual cycles are still regular but other evidence supports a conclusion that ovarian function is impaired [5]. POI generates two orders of consequences, hypoestrogenism and infertility at an early age. Hypoestrogenism can nowadays be acceptably treated by hormone replacement therapy, generally given until the age of physiological menopause. In contrast, fertility cannot be recovered when follicle-stimulating hormone (FSH) is in the menopausal range and the diagnosis of overt POI is made. Also, fertility may well be compromised in the phase of the disease when the clinical manifestations are absent (oPOI). The relevance of this disorder is growing dramatically in recent years because women tend to postpone their conception due to economic reasons or working opportunities.