Isabelle Streuli

Clinical uses of anti-Müllerian hormone assays: pitfalls and promises

OBJECTIVEnTo investigate whether the controversy about fluctuations of anti-Müllerian hormone (AMH) levels during the menstrual cycle results from differences between the immunoassays currently available: the Beckman Coulter Immunotech kit (Fullerton, CA) and the Diagnostic Systems Laboratories kit (Webster, TX).nnnDESIGNnProspective trial.nnnSETTINGnFertility clinics of two tertiary university hospitals.nnnPATIENT(S)nOne hundred sixty-eight blood samples from three different populations. Serial samples at set intervals from the LH surge were taken in a fourth population of 10 volunteers.nnnINTERVENTION(S)nWe remeasured AMH levels by using the Diagnostic Systems Laboratories kit in 168 blood samples in which AMH initially had been measured by using the Beckman Coulter assay. We also conducted serial AMH measurements (n = 7) during the menstrual cycle of 10 women.nnnMAIN OUTCOME MEASURE(S)nLinear regression of AMH levels determined by using 2 different assays and analysis of variance of serial measurements in the menstrual cycle.nnnRESULT(S)nWe found a linear relationship between the 2 methods, with a correlation coefficient of 0.88. When repeated individual AMH measures were longitudinally analyzed in relation to the LH surge, a slight but significant decrease was observed after ovulation.nnnCONCLUSION(S)nDifferences in AMH fluctuations during the menstrual cycle reported in recent publications do not result from the use of different AMH assays. The changes in AMH levels after ovulation are slight, yet statistically significant. However, the fluctuations observed are smaller than intercycle variability and therefore are not clinically relevant as far as AMH measurements for clinical purposes are concerned. In daily practice, AMH therefore can be measured anytime during the menstrual cycle.

In women with endometriosis anti-Müllerian hormone levels are decreased only in those with previous endometrioma surgery

STUDY QUESTIONnAre anti-Müllerian hormone (AMH) levels lower in women with endometriosis, notably those with endometriomas (OMAs) and deep infiltrating lesions, compared with controls without endometriosis?nnnSUMMARY ANSWERnEndometriosis and OMAs per se do not result in lower AMH levels. AMH levels are decreased in women with previous OMA surgery independently of the presence of current OMAs.nnnWHAT IS KNOWN ALREADYnThe impact of endometriosis and OMAs per se on the ovarian reserve is controversial. Most previous studies have been conducted in infertile women. The strength of our study lies in the following points: (i) the selection of women undergoing surgery and not only according to the presence of infertility, (ii) the classification of women with endometriosis and controls based on strict surgical and histological criteria.nnnSTUDY DESIGN, SIZE, DURATIONnCross-sectional study using data prospectively collected in all non-pregnant <42-year-old patients, who were surgically explored for a benign gynaecological condition at a university tertiary referral centre between 2004 and 2008. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. AMH levels were measured in serum samples drawn in the month preceding surgery, without regard to menstrual phase or hormonal therapy.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnOperations were done on 1262 women between 2004 and 2008, of which 1133 signed the informed consent. Of the 566 women with a visual diagnosis of endometriosis, 411 had histologically proven endometriosis. Frozen serum samples for the AMH measurement were available in 313 of them. Out of the 554 women without visual endometriosis and without past endometriosis surgery, 413 had a frozen serum sample for the AMH measurement. Univariate analysis examined AMH levels according to baseline patient characteristics, the presence and type of endometriosis (superficial lesion, OMA, deep infiltrating lesion) and previous OMA surgery. Analysis of variance-covariance then examined the effects of co-variables on AMH levels. Finally, logistic regressions were conducted to examine the odds ratio (OR) of having AMH levels <1 ng/ml according to the same co-variables.nnnMAIN RESULTS AND THE ROLE OF CHANCEnThe difference in AMH levels between women with endometriosis and controls did not reach significance (3.6 ± 3.1 versus 4.1 ± 3.4 ng/ml, P = 0.06). Analysis of variance-covariance demonstrated that AMH levels significantly decreased with age (P < 0.001) and in women with prior OMA surgery irrespective of whether OMAs were present or not at the time of study (P < 0.05). Logistic regression revealed that two major factors were related to AMH levels <1 ng/ml: (i) age (compared with <29 years; 30-34 years OR = 3.1, 95% CI: 1.5-6.4, P = 0.01; 35-39 years OR = 7.0, 95% CI: 3.5-14.1, P = 0.001; ≥40 years OR = 20.8, 95% CI: 9.1-47.4, P = 0.001) and (ii) prior OMA surgery (OR = 3.0, 95% CI: 1.4-6.41, P = 0.01).nnnLIMITATIONS, REASONS FOR CAUTIONnThe selection of our study population was based on a surgical diagnosis. Women with an asymptomatic form of endometriosis are therefore not included in our study. We cannot exclude that infertile women with OMAs associated with a diminished ovarian reserve, as assessed during their infertility work-up, were less likely to be referred for surgery and might therefore be underrepresented.nnnWIDER IMPLICATIONS OF THE FINDINGSnOur findings suggest that OMAs per se do not diminish the ovarian reserve reflected by AMH levels but that alterations seen in women with endometriosis are a deleterious consequence of OMA surgery. These findings should be taken into account in the decision to operate OMAs in women with a desire for future pregnancy.nnnSTUDY FUNDING/COMPETING INTERESTSnnnnSTUDY FUNDINGnnone. Potential competing interests: none.

Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis

BACKGROUNDnThe objective of this study was to evaluate the significance of severe preoperative pain for patients presenting with ovarian endometrioma (OMA).nnnMETHODSnThree hundred consecutive patients with histologically proven OMA were enrolled at a single university tertiary referral centre between January 2004 and May 2010. Complete surgical excision of all recognizable endometriotic lesions was performed for each patient. Pain intensity was assessed with a 10-cm visual analogue scale (VAS). Pain was considered as severe when VAS was ≥ 7. Prospective preoperative assessment of type and severity of pain symptoms (VAS) was compared with the peroperative findings (surgical removal and histological analysis) of endometriomas and associated deeply infiltrating endometriosis. Correlations were sought with univariate analysis and a multiple regression logistic model.nnnRESULTSnAfter multiple logistic regression analysis, uterosacral ligaments involvement was related with a high severity of chronic pelvic pain [odds ratios (OR) = 2.1; 95% confidence interval (CI): 1.1-4.3] and deep dyspareunia (OR = 2.0; 95% CI: 1.1-3.5); vaginal involvement was related with a higher intensity of lower urinary symptoms (OR = 13.4; 95% CI: 3.2-55.8); intestinal involvement was related with an increased severity of dysmenorrhoea (OR = 5.2; 95% CI: 2.7-10.3) and gastro-intestinal symptoms (OR = 7.1; 95% CI: 3.3-15.3).nnnCONCLUSIONSnIn case of OMA, severe pelvic pain is significantly associated with deeply infiltrating lesions. In this situation, the practitioner should perform an appropriate preoperative imaging work-up in order to evaluate the existence of associated deep nodules and inform the patient in order to plan the surgical intervention strategy.

An update on the pharmacological management of endometriosis

Introduction: Endometriosis is a common disease that causes pain symptoms and/or infertility in women in their reproductive years. The disease is characterised by the presence of endometrium-like tissue – glands and stroma – outside the uterine cavity. Different treatment options exist for endometriosis including medical and surgical treatments or a combination of the two approaches. The most commonly used medications are non-steroidal anti-inflammatory drugs, GnRH agonists, androgen derivatives such as danazol, combined oral contraceptive pills, progestogens and more recently the levonorgestrel intrauterine system. Areas covered: The authors review current medical treatments used for symptomatic endometriosis and also discuss new treatment approaches. The authors conducted a literature search for randomised controlled trials related to medical treatments of endometriosis in humans, searched the Cochrane library for reviews and also searched for registered trials that have not yet been published on ClinicalTrials.gov. Expert opinion: The medical treatment of endometriosis is effective at treating pain and preventing recurrence of disease after surgery. Remarkably, the oral contraceptive pill taken continuously is as effective as GnRH-a, while causing far less side-effects. Conversely, no treatment currently exists for enhancing fecundity in women whose infertility is associated with endometriosis. As all existing therapies of endometriosis are contraceptive, great efforts should be targeted at researching novel products that reduce the disease expression without shuttering ovulation.

Use of oral contraceptives in women with endometriosis before assisted reproduction treatment improves outcomes

In women with endometriosis, including those with endometriomas, 6 to 8 weeks of continuous use of oral contraception (OC) before assisted reproduction treatment (ART) maintains ART outcomes comparable with the outcomes of age-matched controls without endometriosis. In contrast, ART outcomes are markedly compromised in endometriosis patients who are not pretreated with OC. Ovarian responsiveness to stimulation was not altered by 6 to 8 weeks use of pre-ART OC, including in poor responders with endometriomas.

Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency.

OBJECTIVEnTo compare the prevalence of intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency (oPOI) and in controls.nnnDESIGNnObservational study.nnnSETTINGnDivision of Infertility and Service of Genetic Medicine, Geneva University Hospitals.nnnPATIENT(S)nThe study group consisted of 27 infertile women with oPOI referred by infertility specialists for FMR1 testing in 2005-6 because of unexplained poor response to controlled ovarian hyperstimulation or altered hormonal profiles. The control group consisted of 32 women undergoing genetic testing for conditions unrelated to mental retardation or ovarian function. The DNA samples were anonymized.nnnINTERVENTION(S)nIn the study group, data were collected concerning reproductive/family history, hormonal markers, possible fertility treatment outcomes, and results of karyotype and FMR1 testing. In the control group, FMR1 gene testing was done. The only clinical data available in controls were sex and indication for genetic testing.nnnMAIN OUTCOME MEASURE(S)nDistribution of FMR1 alleles.nnnRESULT(S)nSix (22%) of 27 women with oPOI had FMR1 alleles of >40 repeats (intermediate to premutation range), compared with one (3%) of 32 controls.nnnCONCLUSION(S)nThese results suggest that women with oPOI might be at risk of carrying alleles in the intermediate and premutation range.

Deep infiltrating endometriosis is associated with markedly lower body mass index: a 476 case–control study

BACKGROUNDnAn inverse association between BMI and endometriosis has been reported but remains controversial. We decided to evaluate the association between BMI and the different types of endometriosis, classified as superficial endometriosis (SUP), deep infiltrating endometriosis (DIE) and ovarian endometrioma (OMA).nnnMETHODSnFrom a prospective database of patients who underwent gynecological surgery between February 2005 and October 2008, we compared 238 patients with a histological diagnosis of endometriosis to 238 age- and smoking-status-matched controls using a prospective preoperative questionnaire and surgical data. Numerical variables means were compared for matched pairs, and non-parametric variables using Wilcoxon test. The Odds ratios for all types of endometriosis adjusted for confounding variables were computed according to predefined BMI groups [1(<18.5), 2 (≥18.5 and <22), 3(≥22 and <25), 4(≥25)], taking Group 3 as the reference population.nnnRESULTSnBMI was significantly lower for all 238 patients (21.70 ± 3.7 versus 23.29 ± 4.1, P < 0.001), for 101 OMA patients (21.88 ± 3.8 versus 22.99 ± 4, P < 0.038), and for 97 DIE patients (21.35 ± 3.4 versus 23.35 ± 3.8, P < 0.001) compared with their own controls, but not for the 40 SUP patients. Patients in Group 1 had adjusted odds ratios as high as 3.3 [95% confidence interval (CI): 1.6-6.8] for DIE and 2.7 (95% CI: 1.1-6.8) for OMA; in Group 2, the adjusted oddd ratios were 2.6 (95% CI: 1.3-5.5) for DIE and 2.9 (95% CI: 1.5-5.4) for OMA.nnnCONCLUSIONSnEndometriotic patients have lower BMI than age- and smoking-status-matched controls, independent of confounding variables. Patients with the lowest BMI (<18.5) are at a high risk of DIE.

Serum and peritoneal interleukin-33 levels are elevated in deeply infiltrating endometriosis

BACKGROUNDnInterleukin 33 (IL-33) is a cytokine involved in fibrotic disorders. We have analyzed IL-33 levels in the sera and peritoneal fluids of women with various forms of endometriosis and investigated the correlation with disease activity.nnnMETHODSnWe conducted a prospective laboratory study in a tertiary-care university hospital between January 2005 and December 2010. Five hundred and ten women with histologically proven endometriosis and 132 endometriosis-free controls were enrolled in this study. Complete surgical exploration of the abdominopelvic cavity was performed in each patient. Blood samples and peritoneal fluids were obtained before and during surgical procedures, respectively. IL-33 was measured by an enzyme-linked immunosorbent assay in sera and peritoneal fluids, and the concentrations correlated with the extent and the severity of endometriotic lesions.nnnRESULTSnIL-33 was detectable in 23.1% of serum samples from all 642 women studied and 75.0% of peritoneal fluid samples studied (44 women with endometriosis and 36 controls). Serum IL-33 was higher in deeply infiltrating endometriosis (DIE) (median, 104.9 pg/ml; range, 8.0-104.9) than in endometriosis-free women (median, 61.3 pg/ml; range, 7.5-526.0; P = 0.022) or in women affected by superficial endometriosis (median, 36.8 pg/ml; range, 7.5-179.0; P < 0.001). Peritoneal IL-33 was higher in DIE than in endometriosis-free women (median, 642.0 pg/ml; range, 25.9-3350.6 versus median, 194.2 pg/ml; range, 12.7-1818.2, respectively; P = 0.003). We found positive correlations between serum IL-33 concentration and intensity of dysmenorrhea (r = 0.174; P = 0.028) and gastrointestinal symptoms (r = 0.199; P = 0.027), total number of DIE lesions (r = 0.224; P = 0.016) and the worst DIE lesion (r = 0.299; P < 0.001).nnnCONCLUSIONSnIn spite of the number of samples with undetectable levels, serum IL-33 is abnormally elevated in women with endometriosis and principally in DIE. Elevated serum IL-33 is correlated with the intensity of preoperative painful symptoms, and with the extent and severity of the DIE. IL-33 may be considered as a novel cytokine involved in the pathogenesis of DIE.

Cancer and fecundity issues mandate a multidisciplinary approach

OBJECTIVEnTo review the existing options for preserving fecundity in young cancer patients, outlining the differences that exist in each individual cancer situation and how these affect our choice of fecundity-preserving measures.nnnDESIGNnReview the pathophysiology data on ovarian function that serve for outlining the advantages and/or drawbacks of certain fecundity-preserving measures such as ovarian freezing and emergency IVF. Provide support arguments for outlining the need for setting locally rooted cancer and fecundity task forces that throw the bases for a multidisciplinary approach in this field.nnnSETTINGnReview of literature data.nnnPATIENT(S)nWomen of reproductive age affected with different types of cancer.nnnMAIN OUTCOME MEASURE(S)nOutcome of selected emergency fertility preserving measures such as ovarian tissue freezing followed by grafting or emergency IVF.nnnRESULT(S)nWhen performed in the 30s-the typical age for breast cancer, the most frequently encountered cancer in women of reproductive age, ovarian freezing hampers ovarian recovery and the chances for spontaneous pregnancy.nnnCONCLUSION(S)nBased on a review of the different situations encountered, we recommend that fecundity-preserving measures offered to young cancer patients, including ovarian freezing and emergency IVF, emanate from multidisciplinary approaches.

AMH concentration is not related to effective time to pregnancy in women who conceive naturally

This study determined whether anti-Müllerian hormone (AMH) concentration influences the time necessary to conceive a live-born child--effective time to pregnancy (eTTP)--in a population of women who conceived naturally. This is an observational study of 87 women with a planned spontaneous pregnancy resulting in a live birth. eTTP was assessed retrospectively by a questionnaire and AMH was measured in a frozen serum sample from first trimester of pregnancy. eTTP was correlated with age (r=-0.24, P=0.02), but not with AMH (r=-0.10) or body mass index (r=0.05). With logistic regressions, the only variable that affected the probability of pregnancy within 3 or 6 months was age, irrespective of whether an AMH concentration limit of 1.0 ng/ml or 2.0 ng/ml was chosen. In conclusion, this study suggests that there is no relationship between AMH concentration and eTTP and therefore speaks against determining AMH in women who are not infertile for the purpose of predicting their chances of pregnancy. The findings are concordant with previous reports describing AMH as a quantitative but not a qualitative marker of ovarian reserve and therefore does not reflect a womans ability to become pregnant. Anti-Müllerian hormone (AMH) is secreted by small growing ovarian follicles and reflects a womans ovarian reserve - the number of primordial follicles at a given time. AMH concentrations has been extensively studied in infertile women but there are only scarce data on AMH in non-infertile women. Our objective was to determine whether AMH concentrations influence the time necessary to conceive a live-born child - also called effective time to pregnancy (eTTP) - in a population of women who conceived naturally. We conducted an observational study between 2007 and 2009 in which we assessed eTTP retrospectively in 87 women who had delivered a live-born child and measured AMH in a frozen blood sample collected during the first trimester of pregnancy. The results of our study show, as expected, a decrease of AMH concentrations as age increases but no relationship between AMH and eTTP. In conclusion, our study results suggest AMH concentrations do not influence the time necessary to conceive a live-born child spontaneously and therefore speak against determining AMH in women who are not infertile for the purpose of predicting their chances of pregnancy. Our findings are concordant with previous reports describing AMH as a quantitative but not a qualitative marker of ovarian function that does therefore not reflect a womans ability to become pregnant.