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6 PCOS
101
literature could be explained by the different study designs, selection of controls, criteria used for the denition of PCOS, the lack of hormonal assessments, the variety in ultrasound equipment and settings, and, nally, the arbitrary selection of vessels in 2D ultrasound [93, 116].
2D ultrasound assessment of blood ow could be subjective through color Doppler maps that are no longer used or objective by measuring ow velocity and resistance with pulsed-wave Doppler (PWD). PWD is used to depict the ow velocity waveform from the vessel of interest. Angle correc­tion is applied whenever necessary to t the incident beam. The waveforms are then analyzed manually (at least three optimal waveforms in a row) or auto­matically to calculate peak systolic velocity (PSV), end-diastolic velocity (EDV), resistance index (RI), pulsatility index (PI), and, lately, capacitance index (CI), which is the area under the curve for the dia­stolic part of the waveform, and S/D ratio that is the ratio of the PSV divided by the EDV [93, 116]. A strong correlation was reported between stromal PI and LH/FSH [118].
Three-dimensional ultrasound assessment of blood ow is easy to perform. When the power Doppler signal is optimal, the 3D volume box is opened, and a 3D sweep scan is performed. Then the VOCAL program quanties the information using the histogram facility, and the blood ow indices are calculated automatically (see Fig.6.5). Vascularization index (VI) represents the ratio of color voxels within the total dataset relative to both color and gray information, pro­viding, thus, an indication of the number and/or size of the vessels lying in the area of interest and, therefore, the degree of vascularity. VI is expressed as a percentage of the ovarian volume. Flow index (FI) is the mean power Doppler intensity, and as the intensity of the signal is dependent on the number of erythrocytes within a given volume at any time, this index is consid­ered reective of the average intensity of ow inside the ovary. Vascularization ow index (VFI) represents the ratio of the weighted color voxels to total voxels. VFI is calculated by mul­tiplying VI and FI and gives a unied value for both vascularity and volume ow reecting the tissue perfusion [119].
These indices are all signicantly affected by volume ow, attenuation, vessel number, and erythrocyte density, but in different ways. The VI and VFI seem to have a more predictable rela­tionship, whereas the FI often demonstrates a more complex cubic relationship that is not always logical. Further work is required before a better understanding of 3D power Doppler ultra­sound imaging is achieved [120]. However, the ndings are controversial even with 3D power Doppler.
Some studies showed increased vascularity and blood ow in the ovaries of women with PCOS [107, 121123] explained possibly by the higher vascular endothelial growth factor (VEGF), while others did not report any signi­cant difference [85, 93, 94, 106, 107]. Higher ovarian VFI was correlated with lower BMI, hyperandrogenism, greater LH/FSH values, ovar­ian volumes, and follicle numbers [93, 94, 123]. The 3D ultrasound approach is preferable because it provides the possibility to examine the blood ow and vascularization in the whole ovary, avoiding the arbitrary selection of a single vessel, or even to dene a region and calculate separately the ow within and around this region [87, 124].
The basal stromal ow measurement is con­sidered to have no predictive value in PCOS with regard to pregnancy, since the ow indices between conception and non-conception cycles in women with PCOS undergoing IVF are similar [116, 149]. Nevertheless, the stromal blood per­fusion has been proven the most relevant predic­tor of ovarian response to controlled ovarian stimulation compared to ovarian or stromal vol­ume [92, 149]. Jarvela etal. compared the vascu­larization per follicle between women with PCOS and controls, after pituitary suppression during IVF.Women with PCOS had lower ovarian vas­cularization per follicle and demanded lower doses of FSH to achieve a similar level of vascu­larization after stimulation with FSH and hCG administration [106]. Moreover, there was a sig­nicant positive correlation between the number of retrieved oocytes and vascularized ovarian vol­ume after stimulation. Still, the calculation of ovarian vascularization per follicle was ambigu­ous, and there was no report to clinical outcome.
102
A. M. Monzo et al.
Role ofUltrasound inMonitoring theEects ofLaparoscopic Ovarian Drilling
Laparoscopic ovarian drilling (LOD) is an effec­tive, although interventional, therapy of anovula­tory infertility in women with PCOS. LOD is considered by the ESHRE/ASRM PCOS consen­sus workshop the second-line intervention in the clomiphene citrate-resistant PCOS patients [125]. Usually, ovarian cortex is drilled in three to six points per ovary with a bipolar electrosur­gical probe, unipolar needle electrode, or laser [126129].
The success of LOD could be estimated with ultrasound given that the ovarian volume reduces 3weeks after intervention [147] and also the stro­mal blood ow in the early follicular phase of the rst postoperative cycle or 3months after drilling [121, 122, 148]. The 3D Doppler assessment showed signicantly higher ovarian stromal VI, FI, and VFI coexisting with higher AMH levels in PCOS compared to controls before drilling and decreased ovarian blood ow, AFC, and AMH concentrations after drilling [121, 122, 130]. The same results were observed after a 6-month fol­low- up of PCOS patients undergoing ovarian drilling by transvaginal hydrolaparoscopy [128]. There was no difference in stromal blood perfu­sion between responders (spontaneous ovulation after LOD) and nonresponders with PCOS [122] and any clinical outcome report. However, decreased AMH levels and AFC after LOD may indicate a possible diminished ovarian reserve, and this surgical treatment must be carefully indi­cated [160].
Uterine Size andPerfusion
Literature references upon uterine ultrasound characteristics in PCOS are scarce. The uterine volume has been found either smaller [131, 132] or bigger [19, 133] in women with PCOS and lower in 40% of adolescent with the syndrome [134] and also in correlation with LH [133]. In few studies, a new criterion was suggested, the ratio of ovarian to uterine volume with an upper
limit of 1.0 which was doubted and abandoned [132, 135]. Endometrial thickness was diverse in women and adolescents with PCOS [134, 136,
137] without correlation with the time interval
since the last period [134]. Nevertheless, in a more recent study, there was no difference in endometrial thickness and volume between women with PCOS and controls [138].
The uterine and endometrial blood ow was found lower in women with PCOS [110, 111,
123, 134, 139143] with the exemption of one
study [138]. The lower uterine and endometrial blood perfusion is reected in higher values of Doppler indices as PI and RI in PCOS and is cor­related with obesity and hyperandrogenemia (higher levels of androstenedione, DHEAS, and LH/FSH) [110, 111, 142, 143]. Furthermore, uterine perfusion increases with exogenous estro­gen and progesterone as well as antiandrogen administration [139, 144], while there is a signi­cant negative correlation between estrogens and uterine PI [145]. This impaired uterine perfusion was associated with metabolic disorders and risk factors for cardiovascular events [140, 141]. The only study to investigate the endometrial blood ow with 3D Doppler did not reveal any signi­cant difference between PCOS and controls in 2D pulsed-wave (uterine arteries) and 3D power Doppler (endometrial and subendometrial blood ow) indices, apart from signicantly disturbed endometrial perfusion in women with PCOS and clinical signs of hyperandrogenemia diagnosed only by 3D Doppler [138]. On the other hand, 6months of metformin treatment in obese PCOS women showed a signicant increase in the endo­metrial thickness, endometrial volume, and endo­metrial and subendometrial vascularity indices (VI, FI, VFI). No change in the RI and PI of the uterine artery in both periovulatory and midluteal phases was seen. Measures were also performed using 3D Doppler sonography. These results sug­gest that metabolic, endocrine, vascular, and anti­inammatory effects of metformin improve markers of endometrial receptivity [146].
PCOS is also associated with recurrent miscar­riages [150]. Likewise, hyperandrogenemia has been reported as a serious etiology of recurrent pregnancy loss, regardless of PCOS, possibly due
6 PCOS
103
to lower endometrial and subendometrial blood perfusion secondary to elevated uterine arterial resistance [151158]. Altogether, higher uterine resistance and lower ovarian stromal resistance, as reported in women with PCOS due to hyperan­drogenemia and unopposed estrogens, are indica­tive of failure of conception in IVF and recurrent miscarriage. Recent evidence conclude that PCOS according to the Rotterdam Criteria increase the risk of miscarriage in lean women undergoing pre-implantation genetic diagnosis, and transfer of a single euploid blastocyst transfer [159]. Thus, further research and maybe threshold value estab­lishment, especially, in 3D power Doppler could contribute to a prognosis algorithm of failed implantation and miscarriage in women with PCOS undergoing assisted reproduction.

Future Points

PCOS is a persistent challenge to the clinician, as the phenotype of the syndrome can vary widely from puberty to postmenopause, and diagnostic criteria must be assessed taking into account the broad and heterogeneous spectrum, even in the same patient throughout her life. Ultrasound examination has an outstanding position in the diagnosis and management of women with PCOS.However, there is still place for improve­ment and many matters that should be addressed. The research regarding the ultrasound evaluation and the diagnostic and prognostic markers of PCOS is insufcient. The methodology and mainly the diagnostic criteria applied in existing studies are not unanimous and widely accepted. The heterogenous phenotypic spectrum of the syndrome renders necessary the clustered investi­gation both of clinical and ultrasound indices as well as the correlation of hormonal ndings with the clinical practice. Finally, the application of 3D ultrasound seems promising, at least in research level, as it provides better spatial aware­ness, more objective volumetric and vasculariza­tion assessment, reduced scanning time, and better intra- and interobserver variability, despite the higher cost and training requirements. Nevertheless, 3D ultrasound does not seem to add much in clinical practice for the present.

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Part IV
Ultrasound of the Uterus