Excess of severe autoimmune diseases in women with premature ovarian insufficiency: a population-based study.

STUDY QUESTION: Is there an association between premature ovarian insufficiency (POI) and severe autoimmune diseases before and after POI diagnosis? SUMMARY ANSWER: Women with POI had at least one hospital-treated autoimmune disorder preceding POI diagnosis 2.6 times more often compared with matched female controls, and a 2- to 3-fold risk for these diseases for several years after POI diagnosis. WHAT IS KNOWN ALREADY: It has been suggested that autoimmunity is an important factor in the pathogenesis of POI. Estimations of the prevalence of POI cases with autoimmune origin have ranged from 4% to 50%. STUDY DESIGN, SIZE, DURATION: This population-based registry study included 3972 women diagnosed with spontaneous POI between 1988 and 2017 and 15 708 female population controls and used both case-control and cohort analysis. Autoimmune disease diagnoses were evaluated from childhood until the end of the year 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with POI were identified from the reimbursement registry of the Finnish Social Insurance Institution by their right to hormone replacement therapy (HRT). Four female population controls matched by age and municipality of residence were searched for each POI case to form a reference cohort. Women with a history of cancer or bilateral oophorectomy were excluded. Severe autoimmune disorder diagnoses for the years 1970-2017 were identified from the Hospital Discharge Registry. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using binary logistic regression for cases of having any, or one or more, specific autoimmune diseases preceding the index date (the date when reimbursement for HRT was granted for the POI) among women with POI as compared to controls. Standardized incidence ratios (SIR) with 95% CIs for getting diagnosed with an autoimmune disease after the index date in 3-year follow-up periods among women with POI (who did not have these diseases prior to the index date) were also calculated. The expected numbers of autoimmune disease cases were based on the incidence of first-onset severe autoimmune disease among the controls. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of having at least one severe autoimmune disease in women with POI was 5.6% (n = 233), with an OR of 2.6 (95% CI 2.2, 3.1) when compared to population controls. Women with POI had an increased prevalence of several specific autoimmune diseases prior to the index date compared to controls: polyglandular autoimmune diseases (OR 25.8, 95% CI 9.0, 74.1), Addison's disease (OR 22.9, 95% CI 7.9, 66.1), vasculitis (OR 10.2, 95% 4.3, 24.5), systemic lupus erythematosus (OR 6.3 95% CI 4.2, 20.3), rheumatoid arthritis (OR 2.3, 95% CI 1.7, 3.2), sarcoidosis (OR 2.3, 95% CI 1.2, 4.5), inflammatory bowel diseases (OR 2.2, 95% CI 1.5, 3.3), and hyperthyroidism (OR 1.9, 95% CI 1.2, 3.1); whereas the prevalence of diabetes type 1 and ankylosing spondylitis did not differ between the women with POI and the reference cohort. The SIRs for being diagnosed for the first time with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI 2.3, 3.4), during the first three years after POI diagnosis, decreasing gradually to 1.3 (1.1, 1.6) after 12 years. LIMITATIONS, REASONS FOR CAUTION: This study only included autoimmune disorders diagnosed in specialized health care; hence, the overall prevalence of autoimmune disorders in women with POI may be higher. WIDER IMPLICATIONS OF THE FINDINGS: Severe autoimmune diseases have a strong association with POI, suggesting that immunological mechanisms play a pivotal role in POI. Future studies should focus on specific autoimmune mechanisms behind POI, from both preventive and curative perspectives. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by Oulu University Hospital. S.M.S. received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. H.S. received grants from the Finnish Menopause Society, the Oulu Medical Research Foundation, the Finnish Research Foundation of Gynecology and Obstetrics, UniOGS graduate school, The Finnish Medical Society Duodecim, Orion Research Foundation, and the University of Oulu Scholarship Fund. M.-M.O. received a grant from the Sakari Alhopuro Foundation and the Finnish Diabetes Research Foundation. None of the funders had any involvement in the study design or its execution or reporting. The authors do not have any competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

First live birth before surgical verification of endometriosis-a nationwide register study of 18 324 women.

STUDY QUESTION: Do women with endometriosis have lower first live birth rate before surgical diagnosis than women without verified endometriosis? SUMMARY ANSWER: Compared to reference women, the incidence of first live birth was lower in women prior to surgical verification of endometriosis irrespective of the type of endometriosis. WHAT IS KNOWN ALREADY: Endometriosis is associated with pain and reduced fertility. The mechanism of infertility is partly explained by anatomical, endocrinological, and immunological changes. Over the past decades, the treatment of both endometriosis and infertility has evolved. Knowledge of fertility far before surgical diagnosis of endometriosis in large cohorts and of different types of endometriosis has been lacking. The diagnostic delay of endometriosis is long, 6-7 years. STUDY DESIGN, SIZE, DURATION: Retrospective population-based cohort study focused on the time period before the surgical verification of endometriosis. All women with surgical verification of endometriosis in 1998-2012 were identified from the Finnish Hospital Discharge Register and the reference cohort from the Central Population Register. Data on deliveries, gynecological care, and sociodemographic factors before the surgical diagnosis were gathered from Finnish national registers maintained by the Finnish Institute for Health and Welfare, the Digital and Population Data Services Agency, and Statistics Finland. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women aged 15-49 years at the time of surgical verification of endometriosis (ICD-10: N80.1-N80.9) in Finland during 1998-2012 were identified (n = 21 620). Of them, we excluded women born in 1980-1999 due to the proximity of the surgical diagnosis (n = 3286) and women left without reference (n = 10) for the final endometriosis cohort of 18 324 women. From the final cohort, we selected sub-cohorts of women with isolated diagnosis of ovarian (n = 6384), peritoneal (n = 5789), and deep (n = 1267) endometriosis. Reference women were matched by age and residence and lacked registered clinical or surgical diagnosis of endometriosis (n = 35 793). The follow-up started at the age of 15 years and ended at the first birth, sterilization, bilateral oophorectomy, hysterectomy, or until the surgical diagnosis of endometriosis or corresponding index day-whichever came first. Incidence rate (IR) and the incidence rate ratio (IRR) of first live birth before the surgical verification of endometriosis with corresponding CIs were calculated. In addition, we reported the fertility rate of parous women (the number of all children divided by the number of parous women in the cohort) until the surgical verification of endometriosis. The trends in first births were analysed according to the women's birth cohort, type of endometriosis, and age. MAIN RESULTS AND THE ROLE OF CHANCE: Surgical diagnosis of endometriosis was set at the median age of 35.0 years (IQR 30.0-41.4). Altogether 7363 women (40.2%) with endometriosis and 23 718 (66.3%) women without endometriosis delivered a live born infant before the index day (surgery). The IRs of the first live birth per 100 person-years were 2.64 (95% CI 2.58-2.70) in the endometriosis cohort and 5.21 (95% CI 5.15-5.28) in the reference cohort. Between the endometriosis sub-cohorts, the IRs were similar. The IRR of the first live birth was 0.51 (95% CI 0.49-0.52) between the endometriosis and reference cohorts. Fertility rate per parous woman before the surgical diagnosis was 1.93 (SD 1.00) and 2.16 (SD 1.15) in the endometriosis and reference cohorts (P < 0.01). The median age at the first live birth was 25.5 (IQR 22.3-28.9) and 25.5 (IQR 22.3-28.6) years (P = 0.01), respectively. Between the endometriosis sub-cohorts, women in the ovarian sub-cohort were the oldest at the time of surgical diagnosis with the median age of 37.2 years (IQR 31.4-43.3), (P < 0.001). Altogether 44.1% (2814) of the women with ovarian, 39.4% (2282) with peritoneal, and 40.8% (517) with deep endometriosis delivered a live born infant before the diagnosis. IRRs between the endometriosis sub-cohorts did not differ. Fertility rate per parous woman was lowest, 1.88 (SD 0.95), in the ovarian sub-cohort compared to 1.98 (SD 1.07) in the peritoneal and 2.04 (SD 0.96) in deep endometriosis (P < 0.001). Women with ovarian endometriosis were oldest at first live birth compared to women in other sub-cohorts with a median age of 25.8 years (IQR 22.6-29.1) (P < 0.001). Cumulative distributions of first live birth were presented according to age at first live birth and birth cohorts of the participants. LIMITATIONS, REASONS FOR CAUTION: The increasing age at first live birth, increasing practice of clinical diagnostics, conservative treatment of endometriosis, a possible effect of coexisting adenomyosis, and use of artificial reproductive treatments should be considered when assessing the results. In addition, the study is limited due to possible confounding effects of socioeconomic factors, such as level of education. It should be noted that, in this study, we assessed parity only during the years preceding the surgical verification of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: The need for early diagnosis and relevant treatment of endometriosis appears clear given the impairment of fertility prior to its surgical verification. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Hospital District of Helsinki and Uusimaa and by Finska Läkaresällskapet. The authors report no conflicts of interest. All authors have completed the ICMJE Disclosure form. TRIAL REGISTRATION NUMBER: N/A.

Does climacteric status impact regulation of the autonomic nervous system at the age of 46 years?

OBJECTIVE: To investigate whether an earlier-onset climacteric phase is associated with autonomic imbalance at the age of 46 years. METHODS: This cross-sectional birth cohort study included 2661 women aged 46 years. Participants were divided into climacteric (n = 359) and preclimacteric (n = 2302) groups based on menstrual history and follicle stimulating hormone values. The mean heart rate (HR), low-frequency (LF) power, high-frequency (HF) power and LF/HF ratio were analyzed from heart rate variability recordings. The variables were compared between the groups using multivariable linear regression models, including body mass index, smoking and physical activity. The effects of hormone therapy and hot flashes on autonomic function were evaluated in sub-analyses. RESULTS: Climacteric women had a lower mean HR in seated (71.9 ± 10.5 vs. 72.6 ± 10.4 bpm, p = 0.015) and standing (81.2 ± 12.8 vs. 83.6 ± 12.1 bpm, p = 0.002) positions compared to preclimacteric women, and the differences remained significant after the adjustments. In the sub-analyses, more frequent hot flashes were associated with a lower LF power and LF/HF ratio in the sitting position. CONCLUSIONS: The present study suggested an association between greater parasympathetic activation in women with more advanced climacteric status at the age of 46 years.

Trends in the incidence, rate and treatment of miscarriage-nationwide register-study in Finland, 1998-2016.

STUDY QUESTION: What changes have occurred in the incidence of miscarriage, its treatment options, and the profile of the women having miscarriages in Finland between 1998 and 2016? SUMMARY ANSWER: The annual incidence of registry-identified miscarriage has declined significantly between 1998 and 2016, and non-surgical management has become the dominant treatment. WHAT IS KNOWN ALREADY: Miscarriage occurs in 8-15% of clinically recognized pregnancies and in ~30% of all pregnancies. Increasing maternal age is associated with an increasing risk of miscarriage. The treatment of miscarriage has evolved significantly in recent years: previously, surgical evacuation of the uterus was the standard of care, but nowadays medical and expectant management are increasingly used. STUDY DESIGN, SIZE, DURATION: We conducted a nationwide retrospective cohort study of 128 381 women that had experienced a miscarriage that was managed in public healthcare between 1998 and 2016 in Finland. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used the National Hospital Discharge Registry for the data. Women aged 15-49 years that had experienced their first miscarriage during the follow-up period and had miscarriage-related diagnoses during their admission to public hospital were included in the study. Miscarriages were defined by the 10th Revision of the International Statistical Classification of Diseases and related Medical Problems (ICD-10) diagnostic codes O02*, O03* and O08*. Women with ectopic, molar and continuing pregnancies and induced abortions were excluded. Treatment was divided into surgical and non-surgical treatment using the surgical procedure codes. MAIN RESULTS AND THE ROLE OF CHANCE: The annual incidence of registry-identified miscarriage has declined from 6.8/1000 15-49-year-old women in 1998 to 5.0/1000 in 2016 (P < 0.001). Also, the incidence rate of registry-identified miscarriage (i.e. the proportion of miscarriages of registry-identified pregnancies [i.e. deliveries, induced abortions, and miscarriages]) has declined from 112/1000 15-49-year-old pregnant women in 1998 to 83/1000 in 2016 (P < 0.001). The largest decrease in this proportion occurred among women over 40 years of age, among whom 26.5% of registry-identified pregnancies in 1998 ended in miscarriage compared to that of 16.4% in 2016. The proportion of missed abortion has increased (30.3 to 38.8%, P < 0.001) whereas that of blighted ovum has decreased (25.4 to 12.8%, P < 0.001). The proportion of registry-identified miscarriages seen among nulliparous women has increased from 43.7 to 49.6% (P < 0.001). Mean age at the time of miscarriage remained at 31 years throughout the study. Altogether, 29% of all miscarriages were treated surgically and 71% underwent medical or expectant management. The proportion of surgical management has decreased from 38.0 to 1.6% for spontaneous abortion, from 60.7 to 9.4% for blighted ovum and 70.9 to 11.2% for missed abortion between 1998 and 2016. LIMITATIONS, REASONS FOR CAUTION: This study includes only women with registry-identified pregnancies, i.e. women who were treated in public hospitals. However, the number of women treated elsewhere is presumed to be small. Neither can this study estimate the number of women having spontaneous miscarriage with no hospital contact. WIDER IMPLICATIONS OF THE FINDINGS: Both the annual incidence and incidence rate of miscarriage of all registry-identified pregnancies has decreased, and non-surgical management has become the standard of care. These findings are of value when planning allocation of healthcare resources and at individual level considering fertility and miscarriage questions. We speculate that improving ultrasound diagnostics explains the increasing proportion of missed abortion relative to other types of miscarriage. More investigation is needed to examine potential risk factors, complications and morbidity associated with miscarriages. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the research funds of the Helsinki and Uusimaa hospital system, by a personal grant from Viipurin Tuberkuloosisäätiö to R.L. and by a personal grant from The Finnish Cultural Foundation to N.H. The authors have no conflicts of interest to declare.

Intrauterine adhesions following an induced termination of pregnancy: a nationwide cohort study.

OBJECTIVE: Intrauterine adhesions (IUAs) are a problematic complication after termination of pregnancy, but their incidence is unknown. Our objective was to assess the incidence of IUAs following induced termination of pregnancy and the risk factors for IUAs. DESIGN: Retrospective cohort study. SETTING: A nationwide registry study. SAMPLE: All women undergoing induced termination of pregnancy (n = 80 015) in Finland between 2000 and 2008. METHODS: The data were retrieved from the Finnish Abortion Registry and the Hospital Discharge Registry. The diagnosis of IUAs or complications was based on the diagnostic codes (International Statistical Classification of Diseases and Related Health Problems 10th Revision, ICD-10) and operative codes according to the Nordic Medico-Statistical Committee (NOMESCO) Classification of Surgical Procedures (NCSP). IUAs were defined as ICD-10 code N85.6 or operative code LCG02. A subanalysis of IUA cases and five matched controls was performed. MAIN OUTCOME MEASURES: The incidence of and risk factors for IUAs. RESULTS: A total of 12 (1.5 per 10 000) IUA diagnoses were identified from 79 960 eligible induced terminations of pregnancy. The rate of IUAs was 1.5 and 2.0 cases per 10 000 terminations of pregnancy following medically and surgically induced termination of pregnancy, respectively (P = 0.19). In a subgroup analysis of IUA cases and five matched controls, surgical treatment of the remaining products of conception following termination of pregnancy significantly increased the risk of IUAs (odds ratio, OR 5.50; 95% confidence interval, 95% CI 1.46-20.79; P = 0.012). CONCLUSION: IUAs that require further treatment are rare after an induced termination of pregnancy. Surgical evacuation following medical or surgical termination of pregnancy was a risk factor for the diagnosis of IUAs. These results suggest that trauma to a recently pregnant uterus is an important risk factor for IUAs. TWEETABLE ABSTRACT: IUA is rare after induced termination of pregnancy (iTOP), but surgical evacuation is a risk factor for IUAs.

Medical versus surgical termination of pregnancy in primigravid women--is the next delivery differently at risk? A population-based register study.

OBJECTIVE: To compare the effect of medical versus surgical termination of pregnancy (TOP), performed in primigravid women, on subsequent delivery. DESIGN: Population-based register study. SETTING: Finland 2000-2009. POPULATION: All primigravid women (n = 8294) who underwent TOP during first trimester of pregnancy by medical (n = 3441) or surgical (n = 4853) method, and whose subsequent pregnancy resulted in singleton delivery. METHODS: The women were identified in the Finnish Register of Induced Abortions, and the data were linked to the Medical Birth and the Hospital Discharge Registries. MAIN OUTCOME MEASURES: Risk of preterm birth, low birthweight, small-for-gestational-age (SGA) infant and placental complications (placenta praevia, placental abruption, retained placenta, placenta accreta). RESULTS: No statistically significant differences in the incidences of preterm birth (4.0% in the medical group versus 4.9% in the surgical group), low birthweight (3.4% versus 4.0%), SGA infants (2.6% versus 2.9%) or placental complications (2.6% versus 2.8%) emerged between the two groups. After adjusting for various background factors, medical TOP was not associated with significantly altered risks of preterm birth (odds ratio [OR] 0.87, 95% confidence interval [95% CI] 0.68-1.13), low birthweight (OR 0.90, 95% CI 0.68-1.19), SGA infant (OR 0.87, 95% CI 0.64-1.20) or placental complications (OR 0.98, 95% CI 0.72-1.34) versus surgical TOP. In a sub-analysis excluding women who underwent surgical evacuation following the index TOP, medical TOP was associated with a reduced risk of preterm birth (P < 0.01), but the difference became insignificant after adjusting for gestational age at the time of TOP, inter-pregnancy interval, maternal age, cohabitation status, socio-economic status, residence and smoking during pregnancy. CONCLUSIONS: A history of one medical versus surgical TOP, performed in primigravid women, is associated with similar obstetric risks in the subsequent delivery.

Birth outcomes after induced abortion: a nationwide register-based study of first births in Finland.

STUDY QUESTION: Is the perinatal health of first-born children affected by the mother's previous induced abortion(s) (IAs)? SUMMARY ANSWER: Prior IAs, particularly repeat IAs, are correlated with an increased risk of some health problems at first birth; even in a country with good health care quality. WHAT IS KNOWN ALREADY: A positive association between IA and risk of preterm birth or a dose-response effect has been found in some previous studies. Limited information and conflicting results on other infant outcomes are available. STUDY DESIGN, SIZE AND DURATION: Nationwide register-based study including 300 858 first-time mothers during 1996-2008 in Finland. PARTICIPANTS/MATERIALS, SETTING AND METHODS: All the first-time mothers with a singleton birth (obtained from the Medical Birth Register) in the period 1996-2008 (n = 300 858) were linked to the Abortion Register for the period 1983-2008. MAIN RESULTS AND THE ROLE OF CHANCE: Of the first-time mothers, 10.3% (n = 31 083) had one, 1.5% had two and 0.3% had three or more IAs. Most IAs were surgical (88%) performed before 12 weeks (91%) and carried out for social reasons (97%). After adjustment, perinatal deaths and very preterm birth (<28 gestational week) suggested worse outcomes after IA. Increased odds for very preterm birth were seen in all the subgroups and exhibited a dose-response relationship: 1.19 [95% confidence interval (CI) 0.98-1.44] after one IA, 1.69 (1.14-2.51) after two and 2.78 (1.48-5.24) after three IAs. Increased odds for preterm birth (<37 weeks) and low birthweight (<2500 g and <1500 g) were seen only among mothers with three or more IAs: 1.35 (1.07-1.71), 1.43 (1.12-1.84) and 2.25 (1.43-3.52), respectively. LIMITATIONS, REASONS FOR CAUTION: Observational studies like ours, however large and well-controlled, will not prove causality. WIDER IMPLICATIONS OF THE FINDINGS: In terms of public health and practical implications, health education should contain information of the potential health hazards of repeat IAs, including very preterm birth and low birthweight in subsequent pregnancies. Health care professionals should be informed about the potential risks of repeat IAs on infant outcomes in subsequent pregnancy. STUDY FUNDING/COMPETING INTEREST(S): National Institute for Health and Welfare and the Academy of Finland. No competing interests.

Effect of mifepristone on the corpus luteum in early pregnancy.

OBJECTIVE: The antiprogestin mifepristone is widely used for medical termination of pregnancy (TOP). Previous studies have suggested that the mechanism of mifepristone is based on its action in the endometrium and myometrium. The aim of this study was to evaluate the possible effects of mifepristone on corpus luteum activity. METHODS: This was a prospective, longitudinal controlled study to which 20 patients undergoing medical TOP (study group) and 20 patients with normal ongoing pregnancy (control group) were recruited. Medical TOP was induced with 200 mg of mifepristone followed by 0.8 mg of misoprostol 2 days later. Three-dimensional ultrasound examinations and hormone assays (progesterone, human chorionic gonadotropin, and 17-hydroxyprogesterone) were performed in both groups on the day of, and 2 days after, administration of mifepristone. Total volume (vascularized + non-vascularized) of the dominant (containing corpus luteum) and non-dominant ovary and serum hormone levels were measured. RESULTS: After administration of mifepristone, a decrease in serum progesterone levels was observed with a simultaneous decrease in the non-vascularized volume of the dominant ovary in the study group. No such changes were observed in the control group. CONCLUSIONS: The observations indicate that, in addition to trophoblastic tissue, the corpus luteum is also the target of mifepristone.

Estimation of the Young's modulus of articular cartilage using an arthroscopic indentation instrument and ultrasonic measurement of tissue thickness.

We evaluated whether the use of cartilage thickness measurement would improve the ability of the arthroscopic indentation technique to estimate the intrinsic stiffness of articular cartilage. First, cartilage thickness and ultrasound reflection from the surface of bovine humeral head were registered in situ using a high-frequency ultrasound probe. Subsequently, cartilage was indented in situ at the sites of the ultrasound measurements using arthroscopic instruments with plane-ended and spherical-ended indenters. Finally, full-thickness cartilage disks (n=30) were extracted from the indented sites (thickness=799-1654microm) and the equilibrium Young's modulus was determined with a material testing device in unconfined compression geometry. We applied analytical and numerical indentation models for the theoretical correction of experimental indentation measurements. An aspect-ratio (the ratio of indenter radius to cartilage thickness) correction improved the correlation of the indenter force with the equilibrium Young's modulus from r(2)=0.488 to r(2)=0.642-0.648 (n=30) for the plane-ended indenter (diameter=1.000mm, height=0.300mm) and from r(2)=0.654 to r(2)=0.684-0.692 (n=30) for the spherical-ended indenter (diameter=0.500mm, height=0.100mm), depending on the indentation model used for the correction. The linear correlation between the ultrasound reflection and the Young's modulus was r(2)=0.400 (n=30). These results suggest that with large indenters, knowledge of the cartilage thickness improves the reliability of the indentation measurements, especially in pathological situations where cartilage thickness may be significantly lower than normal. Ultrasound measurements also provide diagnostically important information about cartilage thickness as well as knowledge of the integrity of the superficial zone of cartilage.

Optimization of the arthroscopic indentation instrument for the measurement of thin cartilage stiffness.

Structural alterations associated with early, mostly reversible, degeneration of articular cartilage induce tissue softening, generally preceding fibrillation and, thus, visible changes of the cartilage surface. We have already developed an indentation instrument for measuring arthroscopic stiffness of cartilage with typical thickness >2 mm. The aim of this study was to extend the applicability of the instrument for the measurement of thin (<2 mm) cartilage stiffness. Variations in cartilage thickness, which will not be known during arthroscopy, can nonetheless affect the indentation measurement, and therefore optimization of the indenter dimensions is necessary. First, we used theoretical and finite element models to compare plane-ended and spherical-ended indenters and, then, altered the dimensions to determine the optimal indenter for thin cartilage measurements. Finally, we experimentally validated the optimized indenter using bovine humeral head cartilage. Reference unconfined compression measurements were carried out with a material testing device. The spherical-ended indenter was more insensitive to the alterations in cartilage thickness (20% versus 39% in the thickness range 1.5-5 mm) than the plane-ended indenter. For thin cartilage, the optimal dimensions for the spherical-ended indenter were 0.5 mm for diameter and 0.1 mm for height. The experimental stiffness measurements with this indenter correlated well with the reference measurements (r = 0.811, n = 31, p < 0.0001) in the cartilage thickness range 0.7-1.8 mm. We conclude that the optimized indenter is reliable and well suited for the measurement of thin cartilage stiffness.