Infertility Clinical Trial
Official title:
A New Algorithm to Predict Ovarian Age Combining Clinical, Biochemical and 3D-ultrasonographic Parameters: OvAge
To collect data of clinical, biochemical and 3D-ultrasonographic parameters of a population of fertile women aged 18-55 in order to design a new algorithm able to predict ovarian age and to evaluate the reliability of a multimodal diagnostic evaluation of ovarian age in term of both reproductive prognosis and distance to menopause following the guidelines of the Standards for Reporting of Diagnostic Accuracy initiative (STARD)
The normal process of reproductive aging varies considerably among women. This implies that
some women remain highly fertile until the fifth decade of their life, whereas others face
the loss of natural fertility already in their mid-thirties. Female reproductive aging seems
to be largely based on age related changes in ovarian function. Decreasing numbers of
follicles, coinciding with diminished oocyte quality, dictate the gradual changes in
menstrual cycle regularity and monthly fecundity which inevitable evolution will be
menopause. The mechanisms behind the observed gradual decline of the follicle pool and the
reduced oocyte quality are far from being fully understood, although recent knowledge
regarding the endocrine, paracrine, genetic, and metabolic factors involved has led to a
better understanding of this immensely complex puzzle.
Within the context of normal female reproductive aging, as already outlined, large
individual variation exists in the age at which the various reproductive events occur. This
variation has major implications for the preventive management of age-related decreased
fertility and general health risks associated with extremely early menopause in conditions
such as POF. Moreover, distance from menopause is an important parameter which can lead
clinician's choice in the appropriate timing for surgical treatment of benign gynecological
pathologies.
Although chronological age is the most important predictor of physiological ovarian response
to endogenous and exogenous Follicle-stimulating Hormone (FSH), both environmental and
genetic factors contribute to biological ovarian ageing, so that chronological and
biological age are not always equivalent. Among genetic factors able to determine age at
which menopause will occur, the most important are the size of the initial oocyte stock, the
proportion that undergoes atresia and the rate of initiation of follicles growth. It has
been suggested, moreover, that certain single nucleotide polymorphisms (such as regarding
FSH receptors genotype) also affect sensitivity to gonadotrophins and ovarian ageing
[Alviggi 45]. Environmental factors such as diet, cigarette smoking, regimens of
chemotherapy or radiotherapy, endometriosis or ovarian surgery may shorten the functional
lifespan of a woman's ovaries too.
Even if the continuous follicles loss will only be recognized in the late stages by cycle
irregularity, endocrine and ultrasound markers have emerged over the last decade that may
express more accurately the follicle number decline over a long time period. Among endocrine
parameters, the most studied and used in clinical practice are FSH, Estradiol (E2) and
Anti-Mullerian Hormone (AMH).
Basal FSH, extensively studied over the past few decades, provides the most indirect marker
of ovarian reserve. FSH levels increase with advancing age, by reducing the negative
feedback on FSH release from the pituitary [broekm vecchio 10]. High FSH levels therefore
represent small cohort size. To exclude the possibility that confounding factors, such as E2
levels greater than 50 pg/ml, suppress FSH secretion, this parameters have to be always
evaluated together on menstrual cycle days 1-4.
In women with varying degrees of hypergonadotropism (ranging from imminent ovarian failure
to full-blown POF), however, the better parameter to assess the extent of ovarian follicle
depletion seems to be represented by AMH (Broekm 109). It is a dimeric glycoprotein with
autocrine and paracrine actions in follicle development, exclusively produced by granulose
cells of preantral (primary and secondary) and small antral follicles (2-7 mm in diameters).
The number of small antral follicles is directly related to the total size of the primordial
follicle pool (Broekm 68). With the decrease in the number of antral follicles with age, AMH
serum levels also become diminished (Br 66, 95, 104) and will invariably become undetectable
near menopause (Br 65). Recent studies have indeed suggested that AMH serum levels represent
ovarian quantitative reserve (Br 105-107) and may provide an index of age at menopause.
Regarding ultrasound markers, several studies, recently, demonstrated that Antral Follicle
Count (AFC), defined as the total number of antral follicles, sized 2-10 mm, present in both
ovaries, represents a better marker than either chronological age or basal FSH for assessing
the ovarian biological age [alviggi 89] and it has also been correlated with the occurrence
of the menopausal transition (broekm 66), indicating that this parameter relates strongly
with the quantitative aspects of ovarian reserve.
As for AFC, ovarian volume, measured by vaginal ultrasound, has been associated to the
ovarian functional asset and also transvaginal ultrasound with the use of power Doppler is
often used to evaluate the blood flow through the ovary in natural cycles. Several studies,
moreover, have shown that ovarian flow index at the baseline ultrasound scan are correlated
with subsequent follicular response and may be a new indicator for predicting ovarian
responsiveness in IVF treatment (Sattar 2005) The added value of ovarian volume and stromal
blood flow, however, either individually or together, to AFC and endocrine markers, in the
predictability of ovarian age has not been assessed in a multivariate module.
The challenge of any ovarian reserve tests, anyhow, lies in the possibility of identifying
women with a reduced reproductive life span at such an early stage in their lives that
adequate action can be taken. Basal endocrine levels and sonographic parameters, however,
are usually considered to have low specificity and sensitivity when used both to predict low
ovarian reserve in infertile women (Younis 2010) and to prognosticate distance from
menopause. Although these simple tests have been extensively investigated in the past they
have seldom been looked into in combination. On the contrary, improvement of tests for the
identification of women with a reduced ovarian life span will probably come from combining
endocrine and imaging evaluations.
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