Ovarian reserve in women with primary antiphospholipid syndrome
LYS Yamakami1, PC Serafini1, DB de Araujo2,3, E Bonfa´2, EP Leon2, EC Baracat1 and CA Silva2,4
1Department of Gynecology; 2Division of Rheumatology; 3Department of Rheumatology, Hospital do Servidor Pu´blico Estadual de Sa˜o Paulo,
Sa˜o Paulo, Brazil; and 4Pediatric Rheumatology Unit, Faculdade de Medicina da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
Objective: The objective of this paper is to evaluate ovarian reserve in primary antiphospho-lipid syndrome (PAPS) women and the association between ovarian reserve tests and clinicaland laboratorial parameters, and anti-corpus luteum antibody (anti-CoL). Methods: Wescreened 85 female patients between 18 to 40 years old with APS. Of these, 67 patients wereexcluded because of association with other autoimmune diseases (n ¼ 42), contraindication orunwillingness to stop hormonal contraceptive (n ¼ 21), current pregnancy or breastfeeding(n ¼ 3) and previous ovarian surgery (n ¼ 1). Therefore, a cross-sectional study was conductedin 18 PAPS patients and 24 healthy women. They were evaluated at early follicular phase withmeasurement of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, andanti-Mu¨llerian hormone (AMH) and sonographic antral follicle count (AFC). Serum meas-urement of anti-CoL was determined by immunoblot analysis. All analyses were performedafter at least six months from the last intake of hormonal contraceptive and resumption ofmenstruation. Results: The mean age was comparable in PAPS and controls (33.0 5.0 vs.
30.4 7.0 years; p ¼ 0.19). Regarding ovarian reserve tests, the frequencies of low AFC (10)(56% vs. 22%, p ¼ 0.04) and very low AFC (5) (37% vs. 9%, p ¼ 0.04) were significantlyhigher in PAPS patients than controls. Trends of higher frequencies of reduced (<1.0 ng/ml),low
patients (p ¼ 0.08, p ¼ 0.07 and p ¼ 0.07, respectively). FSH, LH and estradiol were similarin patients and controls. There was no association between low ovarian reserve and specifictypes of antiphospholipid antibodies. Anti-CoL was solely observed in PAPS patients (11%vs. 0%; p ¼ 0.177) and was not related to ovarian reserve tests. Conclusion: Women sufferingfrom PAPS possessed reduced ovarian reserve, with prevalence greater than 50%.
(2014) 23, 862–867.
Key words: Antiphospholipid syndrome; autoimmune diseases; anti-Mu¨llerian hormone;antral follicle count; ovarian reserve test
they might have additional burdens on their repro-ductive health.1,2
Antiphospholipid syndrome (APS) is an auto-
Likewise, it is known that aging, smoking and
ovarian surgery decrease the quantity and quality
either as an isolated condition known as primary
of primordial follicles in the ovaries and, ultim-
APS (PAPS) or in association with other auto-
ately, the ovarian reserve (OR).3,4 Conditions
immune diseases, particularly systemic lupus ery-
such as autoimmune oophoritis,5,6 ovarian ische-
thematosus (SLE).1 Females aﬄicted by PAPS
mia7,8 and corpus luteum hemorrhage9 may lead
have an increased risk of complications during
to diminished OR. Females suﬀering from PAPS
pregnancy, and studies have also implied that
are susceptible to the above-mentioned complica-tions, yet the medical literature lacks informationon how this relevant autoimmune disease aﬀectsthe OR of these women.
Correspondence to: Clovis Artur Silva, Faculdade de Medicina da
Accordingly, we assessed the OR proﬁle of
USP, Reumatologia, Av Dr Arnaldo, 455, 3 andar, sala 3105, Sa˜o
women suﬀering from PAPS by performing hormo-
Paulo – SP – 01246-903, Brazil.
nal evaluations and state-of-the-art pelvic ultra-
Email: [email protected]
and CAS should be considered similar in author order.
sound scanning, and we compared these results
Received 2 November 2013; accepted 6 March 2014
with the OR proﬁle of healthy women.
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Ovarian reserve in PAPSLYS Yamakami et al.
Materials and methods
Demographic data, PAPS manifestations, andtreatment
Patients and controls
Each patient's medical records were carefully
Eighty-ﬁve patients aged 18 to 40 years old with
reviewed concerning clinical, immunological and
treatment ﬁndings. PAPS manifestations were
Outpatient Clinic of the Rheumatology Division
deﬁned as vascular thrombosis (one or more clin-
ical episodes of arterial, venous, or small-vessel
Medicina da Universidade de Sa˜o Paulo and
thrombosis in any tissue or organ) or pregnancy
were invited to participate in this study. These
morbidity (fetal death; premature birth before the
patients were screened for PAPS during the
34th week of gestation because of eclampsia,
period from April 2010 to March 2013. All
severe pre-eclampsia, or placental insuﬃciency;
patients had a previous history of thrombosis,
or three or more consecutive spontaneous abor-
and none were newly diagnosed. None had throm-
tions).1 All patients were on long-term warfarin
bosis at entry and all were on long-term use of
treatment. Brazilian socio-economic stratiﬁcation
warfarin. The median time of warfarin use was
was carried out according to the Associac¸a˜o
5.05 years (0.7–12.9). Participants were excluded
from the study if they were pregnant, breastfeed-
Mercados criteria.10 Body mass index (BMI) was
ing, unwilling to participate in the study, had med-
deﬁned as the weight in kilograms/height in
ical contraindications, possessed an increased risk
of corpus luteum bleeding after stopping use ofprogestogen-only contraceptives,9 underwent pre-
vious ovarian surgery, required systemic chemo-
Complete history and physical examination includ-
therapy, underwent pelvic radiotherapy, were
ing history of the age at menarche and detailed
currently using a long-acting gonadotropin release
obstetric data were recorded.
hormone agonist (GnRH-a), presented with anadditional autoimmune disease, or had an end-
stage renal disease. None of them were underestrogen contraceptive during the study or any-
Blood samples were drawn by venipuncture in the
time during their treatment.
early follicular phase (menstrual cycle day 2
Of the 85 women, 67 were excluded because of
through 4). All sera were processed in a centrifuge
an associated autoimmune condition (n ¼ 42),
and stored at 70C until analysis. Follicle-stimu-
contraindications or unwillingness to stop use of
hormonal contraceptives (n ¼ 21), currently being
12.5 IU/l), luteinizing hormone (LH) (reference
pregnant or breastfeeding (n ¼ 3), or because of
level: 2.4–12.6 IU/l) and estradiol (E2) (reference
previous ovarian surgery (n ¼ 1). Therefore, the
level: 166 pg/ml) were measured by radioimmuno-
assay using a commercial kit (CobasÕ, Roche,
women with PAPS. The control group included
Mannheim, Germany). Intra- and inter-assay coef-
ﬁcients of variation were recommended by the
recruited from the primary care clinic nearby our
manufacturer and were limited to 5.7 and 3.6%,
tertiary hospital. The control volunteers were sub-
respectively. FSH concentrations were considered
ject to the same inclusion and exclusion criteria.
elevated when the levels were equal to or greater
All PAPS participants voluntarily agreed to dis-
than 10 IU/l.4,11,12
continue the use of hormonal contraceptives
Anti-Mu¨llerian hormone (AMH) was measured
during a period of at least six months and had
by enzyme-linked immunosorbent assay (ELISA)
at least two consecutive menstruations to reveal
in duplicated samples (AMH Gen II ELISA,
the onset of normal endocrinological hypothala-
Beckman Coulter Inc, Brea, CA, USA). Intra-
mic-pituitary-ovarian axis activity. None of our
and interassay coeﬃcients of variation were limited
PAPS patients and controls had hypergonado-
to 5.4% and 5.6%, respectively. AMH levels were
trophic amenorrhea, which would suggest primary
classiﬁed by cutoﬀ values: lower than 1.0 ng/ml
ovarian insuﬃciency (high levels of FSH >40 IU/l
(reduced), lower than 0.5 ng/ml (low) and lower
and sustained amenorrhea).9 The local ethics com-
than 0.2 ng/ml (negligible).13,14
mittee of our university hospital approved this
Transvaginal ultrasound was carried out to
study, and informed consent was obtained from
determine the antral follicle count (AFC) and
the mean ovarian volume on the same day that
Ovarian reserve in PAPS
LYS Yamakami et al.
the blood was drawn. Transvaginal ultrasound
was not performed in women not engaged in
Results are shown as the mean standard devi-
ation (SD) or median (range) for continuous vari-
were performed by an experienced, trained, repro-
ables and as percentages for categorical variables.
ductive specialist (LYSY) using a 6.5 MHz endo-
For continuous variables, data were compared by
vaginal transducer (HD3, Philips Ultrasound,
the t test and Mann-Whitney test to evaluate dif-
Bothell, WA, USA) who was blinded to the vol-
ferences between the PAPS group and control
unteers' diagnoses and blood test results. Ovaries
group. For categorical variables, diﬀerences were
were scanned in axial and longitudinal planes, and
assessed by Fisher's exact test. The level of signiﬁ-
at least two measurements of length (L), width
cance was set at 5% (p < 0.05).
(W) and thickness (T) were obtained and used tocalculate mean ovarian volume using the formulafor an ellipsoid (L W T 0.523). The AFCwas calculated by measuring follicles with sizes
from 2 to 10 mm in both ovaries.4,15 AFC meas-urements were classiﬁed clinically as: normal when
Histories of arterial thrombosis, venous thrombosis
there were 10 follicles, low when there were 10
and pregnancy morbidity were detected in 17%,
but >5 follicles, and very low when there were 5
83%, and 33% of the PAPS patients, respectively.
LA, aCL antibodies, and anti-b2-GPI antibodieswere detected in 67%, 83% and 11% of the PAPS
Detection of anti-corpus luteum (anti-CoL) and
patients, respectively. All PAPS patients were nega-
tive for anti-dsDNA, anti-Sm, anti-RNP, anti-Ro/SS-A and anti-La/SS-B autoantibodies.
The presence of autoantibodies directed toward a
The demographic features, gynecologic history,
67 kDa protein in the corpus luteum was deter-
OR test results, and anti-CoL statuses of the PAPS
mined in the patient and control samples using
patients and controls are depicted in Table 1. The
mean age was similar between the PAPS group and
Brieﬂy, crude tissue and cell extracts obtained
controls (33.0 5.0 vs. 30.4 7.0 years; p ¼ 0.189).
from bovine corpus luteum (100 mg/well) were sub-
The BMI, smoking status and the remaining demo-
mitted to polyacrylamide gel electrophoresis under
graphic features were similar in both groups
denaturing and reducing conditions (with sodium
(p > 0.05). The history of deliveries was superior
dodecyl sulfate and b2-mercaptoethanol). Proteins
in PAPS patients when compared to controls (1
were then electrophoretically transferred to a nitro-
(0–6) vs. 0 (0–2), p ¼ 0.02), and there were fewer
cellulose membrane. The membrane strips were fur-
pregnancies per woman in the PAPS group than
ther incubated with blocking buﬀer (5% skimmed
in the controls (17% vs. 54%, p ¼ 0.02).
milk in phosphate-buﬀered saline (PBS)) and
The frequencies of low and very low AFC were
immunoprobed by incubation with serum samples
greater in PAPS patients than in controls (low
diluted 1:10. Reactivity was tagged with an anti-
AFC: 56% vs. 22%, p ¼ 0.042; very low AFC:
human immunoglobulin (Ig)G alkaline phosphat-
37% vs. 9%, p ¼ 0.045). Reduced, low and negli-
ase conjugate and visualized using appropriate
gible AMH levels were observed in PAPS patients
more often than in controls (p
Lupus anticoagulant (LA) was detected accord-
¼ 0.08, p ¼ 0.07 and
ing to the guidelines of the International Society on
¼ 0.07, respectively). Serum FSH, LH and estra-
Thrombosis and Hemostasis.17 Presence of anticar-
diol levels were similar in PAPS patients and con-
diolipin (aCL) antibodies and anti-b2-glycoprotein
trols (p > 0.05). The occurrence of anti-CoL
I (anti-b2-GPI) IgG and IgM were analyzed by
antibodies was observed in two PAPS patients
ELISA.18 The presence of additional autoantibo-
(11%) and no controls (0%) (p ¼ 0.177), and one
dies, including anti-double-stranded DNA (anti-
of these PAPS patients had reduced OR (Table 1).
Crithidia luciliaea substrate), anti-ribonucleopro-tein (anti-RNP), anti-Sm proteins (hemagglutin-
ation assay with rabbit thymus extract), anti-Ro/SS-A and anti-La/SS-B (counterimmunoelectro-
To our knowledge, this is the ﬁrst study to indicate
phoresis using human spleen extract as antigen)
that more than half of women suﬀering from PAPS
have diminished OR. The main strength of this
Ovarian reserve in PAPSLYS Yamakami et al.
Demographic features, gynecologic history, ovarian
Follicle atresia, apoptosis, the location of primor-
reserve tests, and anti-corpus luteum antibody (anti-CoL) in
dial follicles near the granulosa cell layer, and ovar-
primary antiphospholipid syndrome (PAPS) patients and
ian blood supply could make primordial follicle
cohorts more susceptible to microvascular ischemia
events. Furthermore, diminished serum AMHlevels might be brought about by insults to the
ovarian microvasculature. A parallel dysfunction
Current age, years
could be drawn in male PAPS and SLE-related
antiphospholipid patients, in whom morphofunc-
tional penile alterations were observed.24,25
Diminished OR was most likely not related to
Socioeconomic class C or D
Furthermore, unlike patients with other auto-
Age at menarche, years
immune diseases, our patients did not use immuno-
Time between menarche and
current age, years
suppressive agents, such as cyclophosphamide26–29
or glucocorticosteroids,30 that could result in
OR evaluation in patients with chronic auto-
immune diseases may be inﬂuenced by age, throm-
contraceptives, genetics and environmental factors
such as smoking.26,27,29,31 Previous use of medrox-
yprogesterone acetate, an option of contraception
for women with positive aCL and/or LA,32 was not
a relevant factor for this analysis since the drug was
discontinued for at least six months and menstrual
cycle had to be resumed. Additionally, patients and
Mean ovarian volume, mm3a
controls had comparable ages and very low tobacco
smoking habits, which negates these factors as a
Values expressed in mean standard deviation, median (range) or n
causes of low OR. Additionally, none of our
(%). PAPS: primary antiphospholipid syndrome; BMI: body mass
patients had clinical evidence of ovarian throm-
index; FSH: follicle-stimulating hormone; LH: luteinizing hormone;
bosis, which is in accordance with the ﬁndings
AMH: anti-Mu¨llerian hormone; AFC: antral follicle count. an ¼ 16PAPS patients and 23 controls.
described for PAPS patients.33
Regarding OR evaluation, basal serum FSH,
although widely available, has been demonstrated
research was the evaluation of most reliable OR
to have low accuracy in diagnosis of diminished
markers, including AFC and serum AMH, which
OR, especially at early stages, the most important
were obtained at the early follicular phase to avoid
phase to be identiﬁed.27 Today, AMH and AFC are
intramenstrual cycle variations in AMH levels.19,20
the best non-dynamic tests to predict ovarian per-
We used strict criteria to deﬁne PAPS. Moreover,
formance in human reproductive treatment.26,28
all patients discontinued use of hormonal contra-
AMH is produced by granulosa cells of early-
ceptives for at least six months and had resumed
stage follicles and has the advantage of being
two or more consecutive menstrual cycles, suggest-
FSH independent, which makes its level relatively
ing that ovarian function was reestablished. These
stable during all menstrual cycles, and it can be
precautions were taken to obtain consistent OR
used in early evaluation.26 AMH assessment was
evaluations because it is known that AMH concen-
ﬁrst performed in SLE patients31 and it is con-
trations decrease during hormonal contraceptive
sidered a reliable ovarian marker.
use.21–23 However, the main limitation of this
It is unlikely that autoimmunity inﬂuenced the
study is the low sample size, which, in part, is
low OR observed herein, which contrasts with our
accounted for by the strict deﬁnition of PAPS and
female SLE patients who showed an association
the low incidence of this illness.
between anti-CoL antibodies and ovarian dysfunc-
Low OR, as indicated by a signiﬁcant reduction
tion.16 Antibodies directed to pre-ovulatory follicle
in AFC, implies that primordial follicle cohort
cells and not to corpus luteum-speciﬁc antigens
growth may suﬀer insults within an antiphospholi-
may have an impact on OR in PAPS patient. This
pid milieu that manifest as a reduced follicle cohort.
ﬁeld of study deserves further research.
Ovarian reserve in PAPS
LYS Yamakami et al.
The presence of a relatively high parity among
6 La Marca A, Brozzetti A, Sighinolfi G, Marzotti S, Volpe A,
Falorni A. Primary ovarian insufficiency: Autoimmune causes.
PAPS patients is conceivably due to the fear of
Curr Opin Obstet Gynecol 2010; 22: 277–282.
childlessness in these women and to their high preg-
7 Atabekog˘lu C, Tas¸kin S, Kahraman K, et al. The effect of total
nancy morbidities.1 The elevated number of child-
abdominal hysterectomy on serum anti-Mu¨llerian hormone levels:A pilot study. Climacteric 2012; 15: 393–397.
less women in the control group may reﬂect an
8 Hehenkamp WJ, Volkers NA, Broekmans FJ, et al. Loss of ovar-
unanticipated selection of women interested in
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learning about their OR. The focus of our work
parison with hysterectomy. Hum Reprod 2007; 22: 1996–2005.
9 Yamakami LY, de Araujo DB, Silva CA, Baracat EC, de Carvalho
was to assess OR markers in a cross-section
JF. Severe hemorrhagic corpus luteum complicating anticoagula-
study. A future study evaluating OR markers for
tion in antiphospholipid syndrome. Lupus 2011; 20: 523–526.
prediction of pregnancy outcomes will be required.
10 Almeida PM. Crite´rio de classe econoˆmica da Associac¸a˜o
Brasileira de Anunciantes (ABA) e Associac¸a˜o Brasileira dos
In conclusion, the present report identiﬁes a high
Institutos de Pesquisa de Mercado (ABIPEME). In: Almeida
prevalence of diminished OR in PAPS patients.
Further studies are necessary to uncover the mech-
ABIPEME. ABA/ABIPEME: Sa˜o Paulo, 1991, pp.1–29.
11 Kahapola Arachchige KM, Wardrop R, Lim EM, Stuckey B,
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Hadlow N. Waiting for an elevated FSH—too late a marker ofreduced ovarian reserve? Aust N Z J Obstet Gynaecol 2012; 52:460–464.
12 Esposito MA, Coutifaris C, Barnhart KT. A moderately elevated
day 3 FSH concentration has limited predictive value, especially inyounger women. Hum Reprod 2002; 17: 118–123.
This work was supported by grants from Fundac¸a˜o
13 Gleicher N, Weghofer A, Barad DH. Anti-Mu¨llerian hormone
(AMH) defines, independent of age, low versus good live-birth
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Tecnolo´gico (CNPQ 301411/2009-3 to EB and
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15 Hendriks DJ, Kwee J, Mol BW, te Velde ER, Broekmans FJ.
‘‘Sau´de da Crianc¸a e do Adolescente'' da USP
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Praxis für Psychotherapie und Supervision Claus Roeske Aufmerksamkeits- und Konzentrationsstörungen Terminologie Es gibt eine Reihe von Störungen und Erkrankungen, die als Symptome Defizite bei der Aufmerksamkeit, der Konzentration oder der Impulskontrolle haben. Nur wenn es sich dabei um die primäre Problematik handelt spricht man von ADS oder ADHS. Dies sind die gängige Abkürzung und bedeutet „Aufmerksamkeitsdefizit Störung". Das H steht für „Hyperaktivität". Die Störungen der Aufmerksamkeit und Impulskontrol e kann mit und ohne Hyperaktivität vorkommen. Eine weitere gebräuchliche Abkürzung ist HKS, dies bedeutet „hyperkinetisches Syndrom". Manchmal findet man auch den Begriff Zappelphillipsyndrom. Früher verwendet man auch den Begriff „MCD" (minimale cerebrale Dysfunktion). Dies war ein unspezifischer Sammelbegriff, der für al e möglichen Funktionsstörungen verwandt wurde, bei denen man vermutete, dass eine hirnorganische Ursache existieren könnte. Klassifikation Im ICD-10 Klassifikationssystem gehört AD(H)S zu den „Verhaltens- und emotionalen Störungen mit Beginn der Kindheit und Jugend". Im Kapitel F 90 werden die „hyperkinetischen Störungen" zusammengefasst. Hyperkinese bedeutet „übermäßige Aktivität, Unruhe in den Bewegungen mit Muskelzuckungen und unwil kürlichen Bewegungen des Körpers und der Gliedmaßen". (www.duden.de ) „ Diese Gruppe von Störungen ist charakterisiert durch einen frühen Beginn, meist in den ersten fünf Lebensjahren, einen Mangel an Ausdauer bei Beschäftigungen, die kognitiven Einsatz verlangen, und eine Tendenz, von einer Tätigkeit zu einer anderen zu wechseln, ohne etwas zu Ende zu bringen; hinzu kommt eine desorganisierte, mangelhaft regulierte und überschießende Aktivität. Verschiedene andere Auffäl igkeiten können zusätzlich vorliegen. Hyperkinetische Kinder sind oft achtlos und impulsiv, neigen zu Unfällen und werden oft bestraft, weil sie eher aus Unachtsamkeit als vorsätzlich Regeln verletzen. Ihre Beziehung zu Erwachsenen ist oft von einer Distanzstörung und einem Mangel an normaler Vorsicht und Zurückhaltung geprägt. Bei anderen Kindern sind sie unbeliebt und können isoliert sein. Beeinträchtigung kognitiver Funktionen ist häufig, spezifische Verzögerungen der motorischen und sprachlichen Entwicklung kommen überproportional oft vor. Sekundäre Komplikationen sind dissoziales Verhalten und niedriges Selbstwertgefühl." (ICD – 10 ) Weiter wird differenziert zwischen F 90.0 „Einfache Aktivitäts- und Aufmerksamkeitsstörung" F 90.1 „Hyperkinetische Störung des Sozialverhaltens" und zwei weiteren „Restkategorien" bei diagnostischer Unsicherheit (F90.8 und F90.9) F 90.1 wird kodiert, wenn zu den Symptomen einer ADHS auch Störungen des Sozialverhaltens gezeigt werden. Wenn eine Konzentrations- und Aufmerksamkeitsstörung ohne die Symptomatik der Hyperaktivität vorliegt spricht man von ADS. Die passende Kategorie im ICD-10 wäre: F98.8 Sonstige näher bezeichnete Verhaltens- und emotionale Störungen mit Beginn in der Kindheit und Jugend darunter auch Aufmerksamkeitsstörung ohne Hyperaktivität Die Klassifikation des ADS ist derzeit unzureichend. ADS befindest sich in einer Restekategorie mit Symptomatiken wie Daumenlutschen, Exzessiver Masturbation , Nägelkauen, Nasebohren. Wie wird AD(H)S diagnostiziert? Es gibt derzeit keinen Test oder ein anderes medizinische Untersuchungsmethoden, die ADHS sicher beweisen könnte. Die „Diagnose" ist lediglich das Ergebnis eines narrativen Prozesses der Betroffenen und deren Bezugspersonen, einer Verhaltensbeobachtung oder eine messbare Normvariante bei standardisierten Konzentrations- oder Aufmerksamkeitstest.
TÉRMINOS Y CONDICIONES DE COMPRA DE VALEO VALEO PURCHASING TERMS AND CONDITIONS Índice / Table of Contents Oferta; Aceptación, Términos Exclusivos / Offer; Acceptance; Exclusive Terms……………………………………. Cantidad y Vigencia / Quantity and Duration ………………………………………………………………………….