Sex steroids and androgen biomarkers in the healthy man study: within-person variability and impact of fasting.

OBJECTIVE: Serum testosterone measurements in clinical practice mostly utilize "direct" (non-extraction) immunoassays which have method-specific bias due to steroid cross-reactivity and nonspecific matrix artifacts. Although more accurate, sensitive, and specific liquid chromatography-mass spectrometry (LCMS) dominates in clinical research, the within-person variability of serum testosterone in healthy men using LCMS measurement is not reported. DESIGN: Longitudinal multi-sampling observational study of men in excellent health over 3 months. METHODS: Elite healthy men (n = 325) over 40 years of age in excellent, asymptomatic health provided 9 blood samples over 3 months with serum testosterone, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) measured by validated LCMS with conventional biochemical and anthropometric variables. RESULTS: Quantitative estimates of within-person variability within day and between day, week, month, and quarter were stable other than an increase due to fasting. The androgen biomarkers most sensitive to age and testosterone among widely used biochemical and anthropometric variables in middle-aged and older men were identified. CONCLUSIONS: This study provides estimates of variability in serum testosterone and the best androgen biomarkers that may prove useful for future studies of androgen action in male ageing.

[When to Stop Contraception - Reasons and Consequences of Delaying Parenthood]. / Verhüten bis es (fast) zu spät ist ­ Gründe und Konsequenzen eines Aufschubs der Elternschaft.

When to Stop Contraception - Reasons and Consequences of Delaying Parenthood Abstract. Women are delaying motherhood for many reasons. However, knowledge on age-related decline of fertility is limited. Many patients and even physicians are not aware that female fertility starts to diminish significantly after the age of thirty-two years, and success rates of in vitro treatment are overestimated in the general population. Apart from maternal age there is no predictor for future fecundity. Physicians should actively discuss reasons for delaying motherhood and options for improving fecundity. During the reproductive life span, women need reliable counselling on contraception and fertility.

[Contraception and Sexual Health]. / Kontrazeption und Sexualität.

Contraception and Sexual Health Abstract. Reliable contraceptive methods allow a free development of sexuality without fear of unwanted pregnancies. They have contributed significantly to a more self-determined sexuality of both women and men at reproductive age. Hormonal contraceptives, which are available in different compositions and application forms, are highly effective, but are nevertheless used less and less for fear of physical and psychological side effects. Current study data regarding sexual health is heterogenous but reflects the clinical experience that hormonal contraceptives usually have no significant effect. However, some women report improved sexual experience, while others suffer from sexual dysfunction. Hormonal contraceptives act primarily on the hypothalamic-pituitary-ovarian axis to prevent folliculogenesis and ovulation. However, they have an effect on all tissues with sex steroid receptors, including peripheral tissues such as genitals, skin. But they also have an effect on neurobiological mechanisms (mainly in the hypothalamic region) essential for human sexual response. They can impact self and partnership perception, libido, and arousal. The observed influences can be explained via various mechanisms such as: lack of fear of unwanted pregnancies and accordingly more liberated sexuality, decrease in gynecological complaints, such as endometriosis-associated dyspareunia or dysmenorrhea, possible improvement of the individual body image (subjective perception of the physical self) and correspondingly improved self-confidence (e.g., by decreasing acne and hirsutism). Individualized contraceptive counselling, taking into account somatic and emotional aspects, is essential and can contribute to the promotion of sexual health and well-being. This review article summarizes the influence of hormonal contraceptive methods on sexual health and well-being and gives recommendations how to deal with contraception-induced sexual dysfunction.

Fertility preservation in male cancer patients: A mixed methods assessment of experiences and needs.

INTRODUCTION: As fertility may be impaired due to gonadotoxic cancer treatment, fertility preservation should be offered to young cancer patients. Despite affirmative guidelines, sperm cryopreservation rates are still unsatisfying. OBJECTIVE: To examine how male cancer patients experience the current practice of counseling regarding fertility preservation and the needs they have for additional online support tools. METHODS: A cross-sectional mixed methods study of men above 18 years old with a cancer diagnosis within the last 10 years. The quantitative part was a retrospective questionnaire-based online survey; the qualitative part used focus-group methodology. The mean age of participants (n=72) was 32.94 years (SD 8.38) and the predominant cancer types were testicular cancer (55.6%), lymphomas (16.7%), and leukemias (13.9%). RESULTS: Participants rated the significance of the counseling as high (M=4.2, SD=1.05) and experienced professionals as supportive (M=4.37, SD=0.66). A majority of participants (70.8%) stated that they would use an additional support tool designed for male cancer patients. The tool should contain not only information about fertility preservation, but also about sexuality, virility, consequences for partners, and experience reports from other patients. CONCLUSIONS: Cancer patients undergoing gonadotoxic therapies should be counseled about fertility preservation. Professional, individualized information and a well-organized fertility preservation process improve the subjective experience of cancer patients. An online support tool that provides information about fertility preservation and general reproductive health was considered as a helpful, low-threshold offer that would be appreciated.

Hormonal Contraception and Female Sexuality: Position Statements from the European Society of Sexual Medicine (ESSM).

INTRODUCTION: Hormonal contraception is available worldwide in many different forms. Fear of side effects and health concerns are among the main reasons for not using contraceptives or discontinuing their use. Although the safety and efficacy of contraceptives have been extensively examined, little is known about their impact on female sexual function, and the evidence on the topic is controversial. AIM: To review the available evidence about the effects of hormonal contraceptives on female sexuality in order to provide a position statement and clinical practice recommendations on behalf of the European Society of Sexual Medicine. METHODS: A comprehensive review of the literature was performed. MAIN OUTCOME MEASURE: Several aspects of female sexuality have been investigated, including desire, orgasmic function, lubrication and vulvovaginal symptoms, pelvic floor and urological symptoms, partner preference, and relationship and sexual satisfaction. For each topic, data were analyzed according to the different types of hormonal contraceptives (combined estrogen-progestin methods, progestin-only methods, and oral or non-oral options). RESULTS: Recommendations according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence criteria and specific statements on this topic, summarizing the European Society of Sexual Medicine position, were developed. CLINICAL IMPLICATIONS: There is not enough evidence to draw a clear algorithm for the management of hormonal contraception-induced sexual dysfunction, and further studies are warranted before conclusions can be drawn. A careful baseline psychological, sexual, and relational assessment is necessary for the health care provider to evaluate eventual effects of hormonal contraceptives at follow-up. STRENGTHS & LIMITATIONS: All studies have been evaluated by a panel of experts who have provided recommendations for clinical practice. CONCLUSION: The effects of hormonal contraceptives on sexual function have not been well studied and remain controversial. Available evidence indicates that a minority of women experience a change in sexual functioning with regard to general sexual response, desire, lubrication, orgasm, and relationship satisfaction. The pathophysiological mechanisms leading to reported sexual difficulties such as reduced desire and vulvovaginal atrophy remain unclear. Insufficient evidence is available on the correlation between hormonal contraceptives and pelvic floor function and urological symptoms. Both S, Lew-Starowicz M, Luria M, et al. Hormonal Contraception and Female Sexuality: Position Statements from the European Society of Sexual Medicine (ESSM). J Sex Med 2019;16:1681-1695.

Chronic low-grade inflammation in polycystic ovary syndrome: is there a (patho)-physiological role for interleukin-1?

The polycystic ovary syndrome (PCOS) is a frequent endocrine disorder in women of reproductive age. Its main characteristics are the ovarian overproduction of androgens and ovulatory dysfunction which lead to severe symptoms such as hirsutism, acne, insulin resistance, and infertility. Despite the frequency and disease burden of PCOS, its underlying causes remain unknown, and no causal therapeutic options are available. In recent years, several studies have shown that women with PCOS present with chronic low-grade inflammation indicating an overactivity of the pro-inflammatory cytokine interleukin-1 (IL-1). We show here how IL-1 might affect the ovarian physiology and pathophysiology in animals and humans by reviewing experimental studies on ovarian IL-1 system gene expression and on the effects of exogenous IL-1 on ovarian functions. Although IL-1 ligands and receptors are expressed within the ovarian cells, IL-1 seems to negatively affect the delicate balance between the sex hormones and dominant follicle development, as well as fertility. Whether blockade of the IL-1 signaling leads to an improvement of PCOS-related hormonal abnormalities and symptoms remains to be elucidated in future interventional studies.

Male sexual function can be maintained without aromatization: randomized placebo-controlled trial of dihydrotestosterone (DHT) in healthy, older men for 24 months.

INTRODUCTION: Male sexual function is highly androgen dependent but whether aromatization of testosterone (T) to estradiol is required remains contentious. AIM: This study aims to investigate the effects of selective estrogen deficiency induced by a nonaromatizable androgen, dihydrotestosterone (DHT), on sexual function of healthy middle-aged and older men. METHODS: Randomized clinical trial of daily transdermal DHT (70 mg) or placebo gel treatment in 114 healthy middle-aged and older (>50 years, mean 60.5 years) men without known prostate disease maintaining selective estrogen deficiency for 24 months. OUTCOME MEASURES AND ANALYSIS: The end points were responses to a psychosexual and mood questionnaire completed before, at 3 months, then at 6 monthly intervals during and 3 months after study. Data were analyzed by mixed model analysis of variance for repeated measures using age and body mass index (BMI) as covariates and including interactions of treatment with age and time-on-study. RESULTS: DHT treatment increased serum DHT with complete suppression of serum T, luteinizing hormone, follicle stimulating hormone, and estradiol throughout the 24-month study resulting in reduced spinal bone density. There were no spontaneous complaints, or discontinuations for, adverse effects on sexual function during the study. DHT administration had no effects on any of 33 measures of sexual function and mood, apart from a mild, but significant decrease in overall sexual desire, which was reversible after cessation of treatment. Increasing age and less often increasing BMI were associated with significant decreases in most aspects of sexual function. CONCLUSIONS: We conclude that aromatization plays only a minimal role in maintenance of sexual function in healthy eugonadal middle-aged or older men, but age and obesity are significantly associated with decreases in most aspects of self-reported sexual function and satisfaction. The dependence of male sexual function on aromatization may be conditional on age and obesity and can be overcome by a nonaromatizable androgen.

Does prior hysteroscopy affect pregnancy outcome in primigravid infertile women?

OBJECTIVE: An increasing proportion of infertile women are subjected to hysteroscopy. The effect of hysteroscopy on the pregnancy rate in assisted reproduction has been demonstrated to be favorable, but cervical dilation in the course of hysteroscopy may have an adverse effect on pregnancy outcome. We sought to investigate the effect of hysteroscopy on the risk of early miscarriage, preterm delivery, low birthweight, and other complications of pregnancy. STUDY DESIGN: This was a longitudinal retrospective cohort study at a university hospital. Data of 654 first-time singleton pregnancies between January 1997 and March 2011 in women with primary infertility were retrieved from a prospective data collection. Four cohorts were constructed based on exposure to hysteroscopy and pregnancy outcome (early miscarriage vs live birth). The primary endpoint was the duration of pregnancy at 37 weeks. Pregnancy outcomes of 167 infertile patients exposed to cervical dilation and hysteroscopy were compared with those of 327 infertile women unexposed to hysteroscopy. RESULTS: The incidence of miscarriage, preterm birth, placenta previa, and premature rupture of membranes after maternal exposure to hysteroscopy was similar to that in women not exposed. CONCLUSION: Prior hysteroscopy in infertile women does not affect subsequent pregnancy outcome.

Performance of direct estradiol immunoassays with human male serum samples.

BACKGROUND: Steroid immunoassays originally required solvent extraction, chromatography, and structurally authentic tracers to avoid interference from steroid cross-reactivity and matrix effects. The demand for steroid assays has driven assay simplification, bypassing this triplet of validity criteria to allow use of unextracted serum, which has introduced bias and nonspecificity at low steroid concentrations. We aimed to evaluate the performance of commercial direct estradiol (E2) immunoassays relative to the reference method of LC-MS and compared serum E2 measurements from each assay with biomarkers of estrogen action. METHODS: We measured serum E2 in duplicate using 5 commercial direct immunoassays and LC-MS in a nested cohort of 101 healthy, asymptomatic men >40 years old from the Healthy Man Study. For each immunoassay, we evaluated the detectability and distribution of serum E2 measurements, CV, and bias (relative to LC-MS) by Passing-Bablok regression and deviance plots. RESULTS: Three assays detected E2 in all samples, whereas E2 was detected in only 53% and 72% of samples by 2 other assays. All 5 assays had positive biases, ranging from 6% to 74%, throughout their ranges. CVs were lower with 4 immunoassays than with LC-MS. LC-MS, but none of the direct immunoassays, correlated with serum testosterone and sex steroid-binding globulin. CONCLUSIONS: The positive bias of direct E2 immunoassays throughout their working range reflects the nonspecific effects of steroid cross-reactivity and/or matrix interference arising from the violation of the triplet validity criteria for steroid immunoassay.

Bilateral breast masses with a rare etiology.

Breast masses have a variety of benign and malignant etiologies. We present the case of a 28-year-old woman with bilateral large painful breast masses that developed rapidly in the three weeks before first presentation. Further investigation revealed bilateral ovarian masses. Biopsies of both ovarian masses were taken, and the pathology reported Burkitt's lymphoma. Additional staging with a PET scan was suggestive of bone marrow involvement, but bone marrow biopsy was negative. Examination of the cerebrospinal fluid did not identify malignant cells. The patient underwent CODOX-M/IVAC chemotherapy, and a complete response was demonstrated after one cycle of treatment. Six months after finishing chemotherapy the patient remained in complete remission. To our knowledge this is the first case reporting simultaneous involvement of breast, ovaries, and bones in Burkitt's lymphoma. Gynecologists and oncologists should be aware of this pattern. Polychemotherapy treatment must be initiated rapidly with curative intent.

Isolation of spermatozoa with low levels of fragmented DNA with the use of flow cytometry and sorting.

OBJECTIVE: To develop a method to select spermatozoa with low DNA fragmentation rates for assisted reproduction technologies (ART). DESIGN: Multistep prospective cohort study. SETTING: University hospital. PATIENT(S): Semen samples of 34 infertile men were prepared in parallel with swim-up and fluorescence-activated cell sorting (FACS), and 11 semen samples were used for testing the staining strategy. INTERVENTION(S): Flow cytometric sorting of YO-PRO-stained spermatozoa. MAIN OUTCOME MEASURE(S): Assessment of recovery of spermatozoa and purity after sorting, quantification of sperm DNA fragmentation and viability after sorting and after swim up preparation. RESULT(S): Staining with YO-PRO could be performed successfully in regular culture medium, both dead and apoptotic spermatozoa were labeled without the dye entering the viable spermatozoa. Compared with the conventional swim-up method, the sorted viable population showed a significantly reduced number of spermatozoa with fragmented DNA. CONCLUSION(S): A novel method has been developed, which not only might improve the outcome of ART, but can also help to clarify the ongoing controversy of the role of DNA fragmentation in male infertility.

First successful pregnancy in Switzerland after prospective sex determination of the embryo through the separation of X-chromosome bearing spermatozoa.

QUESTION UNDER STUDY: The feasibility and the potential advantages of separating X-chromosome bearing spermatozoa for the prevention of a severe X-chromosome linked disorder with the use of intracytoplasmic sperm injection are presented. METHOD: A carrier of muscular dystrophy type Becker was treated with intracytoplasmic sperm injection, using spermatozoa previously stained with the Hoechst dye 33342 and sorted with flow cytometry. RESULTS: After transfer of one single blastocyst, an intrauterine pregnancy arose. In the ninth week of gestation, the female sex of the embryo was confirmed with proof of absence of the SRY gene of the Y-chromosome. After normal pregnancy, the patient delivered a healthy daughter. CONCLUSIONS: The staining of spermatozoa with specific markers and sorting with flow cytometry provides a means of preventing significant disease in the offspring and may help in reducing the number of surplus embryos needed for preimplantation genetic diagnosis.

Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study.

OBJECTIVE: To determine serum concentrations, intra-individual variability and impact of age-related co-morbidities on serum testosterone (T), dihydrotestosterone (DHT), estradiol (E(2)) and estrone (E(1)) in older men. DESIGN: Observational, repeated measures study. PARTICIPANTS: Men (n = 325) with 40 years and older self-reporting very good or excellent health. MEASUREMENTS: Standardized history, physical examination and collection of nine blood samples at fixed time intervals were measured over 3 months (three at 20 min intervals on days 1 (fasting) and 2 (non-fasting), one at days 7, 30 and 90). Serum T, DHT, E(2) and E(1) (n = 2900, > 99% of scheduled samples) measured by liquid chromatography-tandem mass spectrometry (LC-MS) were analysed by linear mixed model analysis with fasting, age and obesity as covariables. RESULTS: Mean serum T did not vary with age (P = 0·76) but obesity (-0·35 nM per body mass index (BMI) unit, P < 0·0001) and ex-smoker status (-1·6 nM, P < 0·001) had significant effects. Serum DHT was increased with age (+0·011 nM per year, P = 0·001) but decreased with obesity (-0·05 nM per BMI unit, P < 0·0001). Serum E(2) did not vary with age (P = 0·31) or obesity (P = 0·12). Overnight fasting increased (by 9-16%, all P < 0·001) and reduced variability in morning serum T, DHT, E(2) and E(1). Non-fasting serum T and DHT were stable over time (day, week, month or 3 months; P > 0·28). CONCLUSIONS: Serum T, DHT and E(2) displayed no decrease associated with age among men over 40 years of age who self-report very good or excellent health although obesity and ex-smoking status were associated with decreased serum androgens (T and DHT) but not E(2). These findings support the interpretation that the age-related decline in blood T accompanying non-specific symptoms in older men may be due to accumulating age-related co-morbidities rather than a symptomatic androgen deficiency state.

Accuracy of calculated free testosterone formulae in men.

BACKGROUND: As reference laboratory methods for measuring free testosterone (FT) by equilibrium dialysis (ED) are laborious, costly and nonautomatable, FT levels are often calculated (cFT) rather than measured. However, the predictive accuracy of such estimates in routine use relative to laboratory measurements is not well defined. We provide a large-scale evaluation of the predictive accuracy for different FT formulae compared with laboratory ED measurement and an analysis of clinical factors that may influence accuracy. METHODS: The accuracy of five different cFT formulae (two equilibrium binding, three empirical) based on immunoassays of total testosterone (TT) and SHBG was evaluated by comparing those estimates with FT measurement by ED in 2159 serum samples from men at a single research laboratory over several years. RESULTS: cFT formulae show systematic discrepancies from the two equilibrium-binding formulae. One empirical formula overestimated FT relative to ED measurements, whereas two newer empirical cFT formulae were more concordant. These discrepancies persisted after correction for serum albumin and were not influenced by obesity, ethnicity or gonadal status. CONCLUSIONS: Commonly used cFT formulae significantly overestimate FT relative to laboratory measurement by ED in male serum samples. The accuracy of the formulae is not influenced by correction for serum albumin, obesity, ethnicity or gonadal status. Such inaccuracy relative to the reference method renders some cFT estimates unreliable for evaluating androgen deficiency as recommended by clinical best practice guidelines.

Factors influencing time course of pain after depot oil intramuscular injection of testosterone undecanoate.

Pain following depot intramuscular (IM) injection of oil vehicle-based drugs has been little studied. This study aimed to determine prospectively the prevalence, determinants, severity and functional consequences of pain during the week after IM injection of 1 000 mg testosterone undecanoate (TU) in a 4-mL castor oil vehicle. Androgen-deficient men receiving regular T replacement therapy at an academic andrology clinic were recruited to report pain scores using a coloured visual linear analogue scale at seven times over the first day and daily for a week after a deep IM gluteal injection. The time course and covariables influencing pain scores were analysed by mixed model analysis of variance (ANOVA). Following 168 injections in 125 men, pain was reported by 80% of men, peaking immediately after injection, reaching only moderate severity, lasting 1-2 days and returning to baseline by day 4. The pain required little analgesic use and produced minimal interference in daily activities. The time course of pain scores was reproducible in the 43 men who underwent two consecutive injections. Pain was more severe in men who had an earlier painful injection, but less severe in older and more obese men. There were negligible differences in post-injection pain experience between experienced nurses administering injections. Deep IM gluteal injection of depot TU in 4-mL castor oil is well tolerated and post-injection pain is influenced by earlier painful injection experience, as well as age and obesity.

Paternal age and reproduction.

BACKGROUND: Due to various sociological factors, couples in developed countries are increasingly delaying childbearing. Besides ethical, economical and sociological issues, this trend presents us with several complex problems in reproduction. Although it is well-known that maternal age has a negative effect on fertility and increases the risk of adverse outcome during pregnancy and in offspring, the paternal influence on these outcomes is less well researched and not well-known. METHODS: We performed a systematic search of PubMed, and retrieved original articles and review articles to update our previous survey in this journal. RESULTS: This review highlights the link between male age and genetic abnormalities in the germ line and summarizes the knowledge about the effects of paternal age on reproductive function and outcome. Increasing paternal age can be associated with decreasing androgen levels, decreased sexual activity, alterations of testicular morphology and a deterioration of semen quality (volume, motility, morphology). Increased paternal age has an influence on DNA integrity of sperm, increases telomere length in spermatozoa and is suggested to have epigenetic effects. These changes may, at least in part, be responsible for the association of paternal age over 40 years with reduced fertility, an increase in pregnancy-associated complications and adverse outcome in the offspring. CONCLUSION: Although higher maternal age can be an indication for intensive prenatal diagnosis, including invasive diagnostics, consideration of the available evidence suggests that paternal age itself, however, provides no rationale for invasive procedures.

Randomized cross-over clinical trial of injectable vs. implantable depot testosterone for maintenance of testosterone replacement therapy in androgen deficient men.

BACKGROUND: Life-long testosterone replacement therapy (TRT) for younger men with organic androgen deficiency is best provided by depot testosterone (T) products. This study compared directly the two long-acting depot T products, subdermal T implants (TI) and injectable T undecanoate (TU) for maintenance of TRT. DESIGN, SETTING AND PARTICIPANTS: Men with organic androgen deficiency (n = 38) undergoing regular TRT at an academic Andrology centre were recruited for a two period, randomized sequence, cross-over clinical trial without intervening wash-out period of TRT maintenance. OUTCOMES: For both depot T products, their pharmacokinetics and pharmacodynamics were evaluated using a range of androgen sensitive clinical, laboratory and quality of life measures as well as preference for ongoing treatment after experience of both products. RESULTS: The two depot T products had distinct pharmacokinetics and were not bioequivalent. However, there were no consistent clinical differences in a comprehensive range of pharmacodynamic measures reflecting androgen effects on biochemistry and haematology, muscle mass and strength, and quality of life, mood and sexual function. The majority (91%) of participants chose TU over TI at study completion. CONCLUSION: Despite significant pharmacokinetic differences, the two depot T products are clinically interchangeable allowing for choice dependent on patient and physician delivery preference in practice but most patients preferred the injectable over the implantable form.

[Comorbidity in infertile couples]. / Begleitende Morbidität bei Sterilität.

Pregnancy is the result of a series of highly complex processes, which can be deranged by multiple disturbances on many different levels. Physicians are increasingly dealing with couples suffering from infertility. This rise in case numbers is mainly due to the fact that couples are more and more delaying childbearing until a later phase of their reproductive life, when their social and professional careers are established. The increasing mean age at the first birth has a negative impact on fertility by deteriorating quality and reducing the quantity of oocytes. With increasing age systemic diseases are becoming more coincidental, which in turn tend to exert negative effects on fecundity and fertility both in males and females. This review highlights some associations between infertility and various common systemic diseases. Both general practitioners and gynecologists should counsel young women about the finity of the reproductive phase of their life. Young couples are to be informed, that a "healthy lifestyle" without smoking, sexual transmitted diseases and without metabolic diseases as diabetes and obesity can have a positive effect not only on their general health but also on their fertility and the outcome of future pregnancies.

Combined PTEN and p27kip1 protein expression patterns are associated with obesity and prognosis in endometrial carcinomas.

PURPOSE: Phosphatase and tensin homologue deleted from chromosome 10 (PTEN) and p27(kip1) proteins are key players of the Akt pathway, which is nutritionally regulated by insulin receptor signaling and influenced by estrogens. In this study, the prognostic relevance of the PTEN/p27(kip1) protein expression in endometrial carcinoma in relationship to the body mass index (BMI) was determined. EXPERIMENTAL DESIGN: BMI and prognosis of 452 surgically treated patients with endometrial carcinoma were correlated with histologic subtype, International Federation of Gynecology and Obstetrics (FIGO) stage, and differentiation grade. The expression of PTEN and p27(kip1) was examined in 257 tumors by immunohistochemistry using a tissue microarray approach. RESULTS: Lack of PTEN was observed in 136 of 257 (53%) tumors and absence of p27(kip1) expression was observed in 106 of 225 (47%) tumors. Absence of both proteins was significantly associated with well-differentiated tumors [PTEN (P < 0.02) and p27(kip1) (P < 0.009)]. Differentiation grade, tumor stage, and histologic type were independent of an increased BMI. Importantly, tumors of obese women expressed significantly less PTEN (P < 0.008) and less p27(kip1) (P < 0.01) than tumors from nonobese patients. Combined absence of both PTEN and p27(kip1) expression characterized a group of 75 (32%) tumors with favorable clinical outcome, particularly in the FIGO stages I and II (P = 0.003) of obese patients. Cox regression analysis revealed that PTEN/p27(kip1) phenotype, FIGO stage, and histologic grade were independent predictors of prognosis in endometrioid endometrial carcinoma. CONCLUSIONS: Inactivation of PTEN/p27(kip1) proteins is a specific feature in the progression of endometrial carcinoma in obese patients. The phenotype of the combined loss of PTEN/p27(kip1) protein expression in obese patients is associated with a significantly better prognosis in endometrioid endometrial carcinoma.