The role of estrogen metabolites in human ovarian function.

Estrogens produced by the ovary play diverse roles in controlling physiological changes in the function of the female reproductive system. Although estradiol acts through classical nuclear receptors, its metabolites (EMs) act by alternative pathways. It has been postulated that EMs act through paracrine-autocrine pathways to regulate key processes involved in normal follicular growth, corpus luteum (CL) development, function, and regression. The present review describes recent advances in understanding the role of EMs in human ovarian physiology during the menstrual cycle, including their role in anovulatory disorders and their action in other target tissues.

A plain language summary of the long-term relugolix combination therapy study for uterine fibroids.

What is this summary about? This is a summary of a research study (known as a clinical trial) called the LIBERTY extension study. The LIBERTY extension study is a long-term study looking at how well a medicine called relugolix combination therapy worked in reducing blood loss during menstrual periods in women with uterine fibroids with heavy menstrual periods. Women were included in the extension study if they finished the 24-week LIBERTY 1 or LIBERTY 2 studies. Heavy menstrual periods were considered to be menstrual blood loss of about one-third of a cup of blood (80 ml) per cycle for two cycles or about two-thirds of a cup of blood (160 ml) during one cycle. The LIBERTY extension study also looked at whether relugolix combination therapy was safe to take for up to 1 year. What were the results? Out of 770 total women with uterine fibroids with heavy menstrual bleeding who took part in the LIBERTY 1 and LIBERTY 2 studies, 476 took part in the LIBERTY extension study. From the start of the LIBERTY 1 and LIBERTY 2 studies through the end of the LIBERTY extension: 163 women took relugolix combination therapy for 52 weeks 149 women took relugolix alone for 12 weeks followed by relugolix combination therapy for 40 weeks 164 women took placebo for 24 weeks followed by relugolix combination therapy for 28 weeks The LIBERTY extension study showed that most women in all three treatment groups responded to relugolix combination therapy by having less bleeding during their menstrual periods, having improved anemia symptoms, and having stable bone mineral loss. Side effects were similar across treatment groups, and the most common side effects were headaches and hot flushes. What do the results mean? Women with uterine fibroids with heavy menstrual bleeding taking relugolix combination therapy may have fewer uterine fibroid bleeding symptoms for up to 1 year of treatment. Clinical Trial Registration: NCT03049735 (ClinicalTrials.gov) (LIBERTY 1) Clinical Trial Registration: NCT03103087 (ClinicalTrials.gov) (LIBERTY 2) Clinical Trial Registration: NCT03412890 (ClinicalTrials.gov) (LIBERTY extension study).

A plain language summary of the safety of relugolix combination therapy and improvement in symptoms in women with uterine fibroids from the LIBERTY 1 and LIBERTY 2 studies.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of research studies (known as clinical trials) called LIBERTY 1 and LIBERTY 2. The LIBERTY 1 and LIBERTY 2 studies looked at how well a medication called relugolix combination therapy worked to reduce heavy bleeding at the time of menstruation compared with placebo. The studies also looked at what side effects were reported in women with uterine fibroids and heavy menstrual bleeding. WHAT WERE THE RESULTS?: Researchers looked at 388 adult women in the LIBERTY 1 study and 382 adult women in the LIBERTY 2 study. All women had heavy menstrual bleeding with uterine fibroids before the start of the LIBERTY 1 and LIBERTY 2 studies. The women were given one of three treatments during the studies: relugolix combination therapy or placebo for 24 weeks, or delayed relugolix combination therapy (relugolix alone for the first 12 weeks, then relugolix combination therapy for the last 12 weeks of the studies). More women taking relugolix combination therapy in the LIBERTY 1 study (73%) and LIBERTY 2 study (71%) had menstrual blood loss of less than one-third of a cup (80 mL) and had reduction of at least 50% less blood loss during their last menstrual period after 24 weeks of taking the medicine compared with placebo (LIBERTY 1: 19% and LIBERTY 2: 15%). The women taking relugolix combination therapy also had less pain than those taking placebo. Side effects were similar across treatment groups. Headaches and hot flushes were the most common side effects. WHAT DO THE RESULTS MEAN?: More women with uterine fibroids taking relugolix combination therapy for 24 weeks were likely to have fewer uterine fibroid symptoms than women receiving placebo. Clinical Trial Registration: NCT03049735 (LIBERTY 1); NCT03103087 (LIBERTY 2).

Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas.

OBJECTIVE: In the LIBERTY 1 and LIBERTY 2 placebo-controlled trials, once-daily relugolix combination therapy reduced menstrual blood loss volume and pain in women with heavy menstrual bleeding associated with uterine leiomyomas and was well tolerated, with preservation of bone mineral density (BMD) through 24 weeks. Here we report the long-term efficacy and safety of relugolix combination therapy treatment for up to 52 weeks. METHODS: Women with uterine leiomyoma-associated heavy menstrual bleeding who completed any treatment arm in either the LIBERTY 1 or LIBERTY 2 trial were eligible to enroll in a 28-week long-term extension study. All participants received once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) in the extension study. The primary efficacy endpoint was the proportion of women who achieved or maintained a menstrual blood loss volume of less than 80 mL and a 50% or greater reduction in menstrual blood loss volume from LIBERTY study baseline to the last 35 days of treatment (defined as responders ). Analyses were conducted for all three randomized treatment groups from pivotal studies. RESULTS: Overall, 477 women enrolled, 476 were treated, and 363 (76.1%) completed 52 weeks. Among patients treated with relugolix combination therapy through 52 weeks (n=163), sustained improvement in heavy menstrual bleeding was observed in 87.7% (responders). The least squares mean menstrual blood loss volume reduction was 89.9%, with 70.6% of patients achieving amenorrhea. At week 52, 59.0% of patients with anemia at baseline had improvements in hemoglobin concentration of greater than 2 g/dL. Distress due to uterine leiomyoma-associated symptoms measured by the BPD (Bleeding and Pelvic Discomfort) scale score was reduced by 51.3 points. Sustained reductions in uterine and uterine leiomyoma volume were observed. Bone mineral density was preserved through week 52. CONCLUSION: Improvements in heavy menstrual bleeding and anemia and reduction of uterine leiomyoma-associated symptom burden were sustained through up to 52 weeks of treatment with relugolix combination therapy in women with uterine leiomyomas. No new safety concerns were identified, and BMD was maintained. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT03049735; NCT03103087; NCT03412890. FUNDING SOURCE: Myovant Sciences GmbH.

Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

Significance of pro-angiogenic estrogen metabolites in normal follicular development and follicular growth arrest in polycystic ovary syndrome.

STUDY QUESTION: Do alterations in pro- and anti-angiogenic estrogen metabolites in follicular fluid (FF) contribute to the follicular growth arrest and anovulation associated with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: FF of PCOS women with anovulation have reduced levels of pro-angiogenic estrogen metabolites (EMs) and vascular endothelial growth factor (VEGF) compared to that of fertile women with regular menstrual cycles, but exogenous gonadotropins increase the pro-angiogenic EMs and VEGF levels in PCOS women. WHAT IS KNOWN ALREADY: PCOS is characterized by the arrest of follicular development that leads to chronic anovulation. Follicular arrest is generally associated with elevated plasma levels of luteinizing hormone (LH), androgens and anti-Mullerian hormone (AMH). There is also reduced angiogenesis in the follicles of PCOS women compared to those of normal cycling women. It is known that angiogenesis is a critical factor during follicular development. We and other investigators have explored the role of EMs in ovarian angiogenesis, particularly in human corpus luteum function, showing that 4-hydroxyestrone (4-OHE1) and 16-ketoestradiol (16-kE2) have pro-angiogenic effects while 2-methoxyestradiol (2-ME2) and 2-methoxyestrone (2-ME1) have anti-angiogenic effects. Additionally, 2-hydroxyestradiol (2-OHE2), which is produced in the ovary, has proliferative and pro-angiogenic properties. We hypothesized that EMs could be involved in angiogenesis necessary for ovarian follicular development in fertile women, and that dysregulation of these factors may contribute to follicular arrest in PCOS. The relationship between EMs, VEGF and AMH in the pathophysiology of follicular arrest in PCOS has not been previously studied at a follicular level in anovulatory women without ovulation induction. STUDY DESIGN, SIZE, DURATION: This is a comparative experimental study of serum and FF collected from different sized follicles (antral ˂10 mm and dominant ˃16 mm) of women with and without ovarian stimulation. The study included women with regular menstrual cycles who were proven to be fertile (n = 20) and PCOS women with follicular arrest who were candidates for ovarian drilling (n = 17), as well as other patients requiring ovarian stimulation, i.e. control women undergoing IVF for male factor infertility (n = 12) and PCOS women undergoing IVF (n = 17). In vitro studies were carried out on granulosa-lutein cells (GCs) obtained from subsets of women undergoing IVF for male factor infertility (n = 6) and PCOS women undergoing IVF (n = 6). GCs were maintained in culture for up to 6 days. PARTICIPANTS/MATERIALS, SETTING, METHODS: Intrafollicular estradiol, estrone and EMs concentrations were determined by high performance liquid chromatography-mass spectrometry. Testosterone in serum was measured by RIA, and LH, FSH and sex hormone-binding globulin in serum were measured with IRMA kits. AMH was determined in serum and FF by enzyme linked immunosorbant assay (ELISA). VEGF levels were measured in FF and conditioned medium by ELISA. Conditioned medium were obtained from cultured GCs. The angiogenic potential was assessed by in vitro angiogenic assays. MAIN RESULTS AND THE ROLE OF CHANCE: Pro-angiogenic EMs (4-OHE1, 16-kE2 and 2-OHE2) and VEGF were lower in FF of antral follicles of PCOS women with follicular arrest compared those of fertile women with ovulatory cycles (P < 0.05). In contrast, higher concentrations of AMH were found in FF of antral follicles from PCOS women with follicular arrest compared to those of fertile women with ovulatory cycles (P < 0.05). Exogenous gonadotropins used in IVF increased pro-angiogenic EMs and VEGF production in PCOS women, reaching similar profiles compared to control women receiving gonadotropins in their IVF treatment for male factor infertility. The pro-angiogenic EM 2-OHE2 increased the angiogenic potential and VEGF levels of GCs from PCOS women compared to the basal condition (P < 0.05). These findings suggest that there is a role for pro-angiogenic EMs in the control of follicular VEGF production. LIMITATIONS, REASONS FOR CAUTION: The limitations include the possibility that in vitro analysis of GCs might not reflect the in vivo mechanisms involved in the pro-angiogenic action of 2-OHE2 since GCs obtained at the time of oocyte retrieval belong to a very early stage of the luteal phase and might not be representative of GCs during follicular growth. Therefore, our findings do not conclusively rule out the possibility that other in vivo mechanisms also account for defective angiogenesis observed in PCOS. WIDER IMPLICATIONS OF THE FINDINGS: The present study highlights the significance of EMs, angiogenic factors and AMH and their interaction in the pathophysiology of follicular development in PCOS. This study provides new insights into the role of pro-angiogenic factors in follicular arrest in PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by CONICYT/FONDECYT 1140693 and NIH grant R01HD083323. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

New Diagnostic Criteria of Polycystic Ovarian Morphology for Adolescents: Impact on Prevalence and Hormonal Profile.

BACKGROUND: The ultrasonographic criteria used to identify polycystic ovarian morphology (PCOM) during adolescence have changed over time. Recently, a Worldwide Pediatric Consensus (PedC) defined PCOM using stricter criteria than the previous recommendations of the Rotterdam Consensus (RC) and Androgen Excess-Polycystic Ovarian Syndrome Society (AES/PCOS) criteria. The aim of this study was to determine the prevalence of PCOM in healthy adolescents according to the 3 reported diagnostic criteria and compare the hormonal profile in females with and without PCOM based on the PedC criteria. METHODS: Nonobese adolescents (n = 102) with regular menstrual cycles were studied. Transabdominal ultrasound and hormonal profiles were assessed during the follicular phase. PCOM was defined on the basis of the 3 published criteria. RESULTS: On the basis of the PedC, RC, and AES/PCOS criteria, PCOM was diagnosed in 13, 34, and 24% of adolescents, respectively. Adolescents with and without PCOM according to the PedC criteria had similar androgen levels. Serum anti-Müllerian hormone (AMH) levels were elevated in adolescents with PCOM, irrespective of the criteria used. CONCLUSIONS: Use of the new PedC diagnostic criteria for PCOM results in a lower prevalence of this ultrasonographic pattern in adolescents, but this condition is not associated with hyperandrogenism. Elevated AMH is associated with PCOM in adolescents regardless of the criteria used to determine the ultrasonographic pattern.

Pregestational type 2 diabetes and gestational diabetes exhibit different sexual steroid profiles during pregnancy.

Higher androgen levels are observed in non-pregnant women with diabetes. Whether this hormonal profile is found during pregnancy is unknown. The aim of this study was to determine the sexual steroids levels in pregnant women with pregestational type 2 (T2D) and gestational diabetes (GD) compared to healthy control (C) pregnant women during the second half of pregnancy. A prospective study of 69 pregnant women with T2D (n = 21), GD (n = 24) and control (C, n = 24) was followed up during the second half of gestation. Clinical assessments and blood samples were collected at 26.7 (25-27.8); 34 (32-34.9) and 37.5 (37-40) weeks of gestation. Androgens, sex hormone-binding globulin (SHBG), estrogens, estradiol/testosterone (E/T) ratio, insulin, glucose, HOMA-IR, were measured. Testosterone, insulin and homeostatic model assessment of insulin resistance (HOMA-IR) levels were higher in T2D compared with C at each sampling point during pregnancy, even after adjusting for BMI and age. Estrogens levels and estradiol/testosterone ratio were lower in T2D and GD compared with C. Hyperandrogenemia, and higher insulin resistance is observed in T2D, but not in GD during pregnancy. Decreased estrogen and E/T ratio found in T2D and GD suggests a diminished aromatase activity during gestation. T2D and GD are associated with specific changes in sexual steroids and insulin resistance levels during pregnancy.

Hirsutism and oligomenorrhea are appropriate screening criteria for polycystic ovary syndrome in adolescents.

We evaluated the association of hirsutism and oligomenorrhea (persistent menstrual cycles > 45 days) as screening criteria for the detection of biochemical hyperandrogenism (BH) and polycystic ovaries (PCOM) during adolescence and determined which androgens, granulosa cell hormone, ultrasonographic parameters have the best association with polycystic ovary syndrome (PCOS). Hirsute girls with oligomenorrhea (N = 26 Hirs/Oligo group) and non-hirsute girls with regular cycles (N = 63, C group) were studied. Prevalence of BH and PCOM, diagnostic performance of androgens and ultrasound parameters for PCOS diagnosis were analyzed. BH and PCOM prevalence were higher in the Hirs/Oligo girls than in the C girls (76.9% versus 25.5%; 92.3% versus 33.3%, respectively; p < 0.0001). A complete PCOS phenotype (Hirs/Oligo with BH and PCOM) was observed in 73.1% of the Hirs/Oligo group. The presence of both BH and PCOM was observed in 7.9% of the C group. The parameters with the best diagnostic performance were free androgen index ≥6.1, testosterone ≥2.4 nmol/L, follicle number ≥12 and ovarian volume ≥10 ml anti-Müllerian hormone (AMH) exhibited a low diagnostic accuracy. Hirsutism and persistent menstrual cycle over 45 days are highly associated with BH and PCOM suggesting that the presences of both criteria are necessary for the diagnosis of PCOS during adolescence.

Transient expression of progesterone receptor and cathepsin-l in human granulosa cells during the periovulatory period.

OBJECTIVE: To study in vivo the progesterone receptor (PR) expression levels in human granulosa cells (GCs) during the periovulatory period and the affect of the protein kinase A (PKA) pathway on PR expression and cathepsin-L expression-activation. DESIGN: Experimental study. SETTING: University research unit. PATIENT(S): Twenty-five women of reproductive age. INTERVENTION(S): Follicular fluid and GCs obtained from spontaneous cycles before and during the normal luteinizing hormone surge, and samples obtained 36 hours after human chorionic gonadotropin (hCG) administration in patients undergoing in vitro fertilization. MAIN OUTCOME MEASURE(S): To determine PR, cathepsin-L messenger RNA (mRNA) analysis via real-time polymerase chain reaction, and protein of PR, cathepsin-L, and PKA in human GCs. RESULT(S): The Western blot analysis revealed that bands of PR (isoform A) were the most abundant and that mRNA (PR-A and PR-B) have a temporal pattern of expression throughout the periovulatory period. The protein levels of PR and cathepsin-L were up-regulated by hCG. The abundance of PR was diminished in the presence of PKA inhibitor, and cathepsin-L with PR receptor antagonist. CONCLUSION(S): The transient expression of PR in human GCs of the preovulatory follicle suggests that PR and its ligand play a role in the activation of cathepsin-L, which is presumably involved in the degradation of the follicular extracellular matrix during human ovulation.

Ovarian function in adolescents with McCune-Albright syndrome.

OBJECTIVE: To evaluate ovarian function, especially ovulation rate, in adolescents with McCune-Albright syndrome (MAS) and a history of peripheral precocious puberty. DESIGN: Prospective cross-sectional study. SETTING: Academic center. PATIENT(S): A total of eight adolescents with MAS were compared with 15 healthy adolescents matched by age, Tanner stage and body mass index. INTERVENTION(S): We determined basal gonadotropins, sex steroids, sex hormone binding globulin, anti-Müllerian hormone, glucose and insulin. A leuprolide acetate test was performed to measure luteinizing hormone (LH) and follicle stimulating hormone (FSH) (at 0 and 3 h), and 17B-estradiol, testosterone and 17-OH-progesterone (at 0 and 24 h). Salivary progesterone levels were used to assess ovulation during the 13th, 18th, 23rd and 28th days of each menstrual cycle for three to five consecutive cycles, and one pelvic ultrasound was performed during the follicular phase. MAIN OUTCOME MEASURE(S): Ovulation rate in adolescents with MAS. RESULT(S): The proportion of ovulatory cycles was 52.6% in controls compared with 35.7% in patients with MAS. CONCLUSION(S): The adolescent girls with MAS appear to have a lower ovulatory rate compared with controls.

Elevated anti-Müllerian hormone (AMH) and inhibin B levels in prepubertal girls with type 1 diabetes mellitus.

OBJECTIVE: Elevated anti-Müllerian hormone (AMH) and adrenal androgen levels have been observed during childhood in girls at risk of developing polycystic ovarian syndrome (PCOS). The aim of this study was to evaluate ovarian function and adrenal steroid levels in prepubertal girls with type 1 diabetes mellitus (T1D). DESIGN: Cross-sectional study. PATIENTS/MEASUREMENTS: We evaluated hormonal and ultrasonographic characteristics in girls with T1D (N = 73) and compared them to characteristics found in a control group of healthy girls (N = 86). Data are reported as geometric means (95% CI). RESULTS: Prepubertal girls with T1D had higher levels of AMH (29·1 pmol/l (23·2-36·3) vs 20·9 pmol/l (16·6-26·1), P = 0·038), inhibin B (arithmetic mean: 16·7 pg/ml (11·6-21·7) vs 11·7 pg/ml (10·0-13·5), P = 0·044) and dehydroepiandrosterone sulphate (DHEAS) (0·3 nmol/l (0·2-0·6) vs 0·2 nmol/l (0·1-0·3)) than controls (P = 0·045). During puberty, decreasing AMH levels were observed in girls with T1D only (P < 0·0001). Girls with T1D in Tanner stages 4-5 had lower AMH levels than their paired healthy controls (10·1 pmol/l (7·4-13·9) vs 15·7 pmol/l (11·6-21·3), respectively, P = 0·047). CONCLUSIONS: Our observations indicate that prepubertal girls with T1D may exhibit similar endocrine findings to those of other girls at risk of developing PCOS. The elevated levels of AMH and inhibin B suggest that higher numbers of follicles are present in the ovary during childhood in these patients and that insulin treatment may act as a local growth factor. In addition, AMH levels differed in prepubertal and pubertal girls, suggesting that the effect of T1D on ovarian folliculogenesis changes once gonadotrophin levels rise during puberty.

Polycystic ovarian morphology in postmenarchal adolescents.

OBJECTIVE: To evaluate the association of polycystic ovary morphology (PCOM) with ovarian function in adolescents and to determine its time course during two years of follow-up. DESIGN: Prospective study. SETTING: Academic center. PATIENT(S): Twenty healthy adolescents were followed from 2-4 years after menarche. INTERVENTION(S): We performed annual ultrasonographic and hormonal studies. Ovulation was assessed during 6 consecutive months by measuring salivary progesterone levels. MAIN OUTCOME MEASURE(S): Persistence of PCOM during the years following menarche; ovulation in girls with PCOM. RESULT(S): PCOM was observed in 40%, 35%, and 33.3% of the ultrasonographic studies performed at 2, 3, and 4 years after menarche, respectively. The concordance between ultrasonographic diagnosis at 2 and 4 years postmenarche (50%) was nonsignificant (kappa = 0.08). PCOM was not associated with abnormalities in ovulatory rate, menstrual cycle duration, lipid levels, or homeostatic model assessment of insulin resistance. However, lower FSH (4.8 ± 1.3 vs. 6.1 ± 1.9 mUI/ml) were observed in girls with PCOM compared with those without PCOM. Similar T and stimulated 17-hydroxyprogesterone on the leuprolide test were observed in girls with and without PCOM. CONCLUSION(S): PCOM is an inconstant finding in healthy adolescents and does not appear to be associated with decreased ovulatory rate or metabolic abnormalities in healthy adolescents. This finding suggests that PCOM may correspond to a physiologic condition during early adolescence.

Assessment of diagnostic competence of plasmatic androgens on polycystic ovary syndrome based on receiver operator characteristic curves.

OBJECTIVE: This study was designed to assess the diagnostic potency of different androgens in hyperandrogenaemia criterion on polycystic ovary syndrome (PCOS) based on receiver operator characteristic (ROC) curves analysis. METHODS: We evaluated 55 PCOS patients and 27 healthy fertile women (control). Androgen evaluation included bio-available testosterone (BAT) by ammonium sulphate precipitation, Free Testosterone Index (FTI), androstenedione (A), total testosterone and dehydroepiandrosterone sulphate (DHEA-S). RESULTS: The androgen tests with the best diagnostic capacities were FTI and BAT. Although T and A had similar diagnostic potencies, A detected 5% of PCOS patients that could not be recognised by FTI, BAT (%), or T. The association of FTI, BAT (%) and A identified 96.36% of the hyperandrogenaemic patients. DHEA-S showed a wide dispersion of values and therefore poor discriminatory competence. DISCUSSION: This study suggests that routine androgen evaluation in PCOS should include FTI, BAT and A to avoid misdiagnosis. ROC curve analysis of these tests on patients with the complete spectrum of PCOS phenotypes is needed to confirm these results.

Hormonal profile in women with polycystic ovarian syndrome with or without type 1 diabetes mellitus.

CONTEXT: Anti-Müllerian hormone (AMH) levels are increased in polycystic ovarian syndrome (PCOS), but it is not known whether other forms of hyperandrogenism, such as PCOS observed in women with type 1 diabetes mellitus (DM1), are also associated with elevated AMH levels. OBJECTIVE: Our objective was to compare AMH and steroid levels in women with PCOS with and without DM1. DESIGN: We compared the clinical, hormonal, and ultrasonographic characteristics of 17 women with PCOS and DM1 (DM1+PCOS), 20 women with PCOS without DM1 (PCOS), and 35 normal women (control) in a cross-sectional study. RESULTS: The Ferriman-Gallwey score, serum testosterone, free androgen index, 17OH-progesterone, and ovarian volume were elevated in both groups of PCOS women compared with controls. Serum androstenedione, LH/FSH ratio, and follicle number, however, were higher and SHBG was lower in PCOS compared with DM1+PCOS and controls. AMH levels were higher in PCOS (76.0 +/- 36.3 pmol/liter) than in DM1+PCOS (18.8 +/- 7.4 pmol/liter) and controls (13.9 +/- 8.3 pmol/liter). AMH levels correlated with follicle number in the three groups. Serum AMH/follicle number ratio was higher in PCOS than in DM1+PCOS and controls. CONCLUSIONS: Women with DM1+PCOS have normal levels of AMH, inhibin B, estradiol, SHBG, and LH/FSH, suggesting that the pathophysiology of hyperandrogenism in PCOS patients with DM1 appears to be different from that in PCOS without DM1. However, hirsutism score and androgen levels were similar in both groups of women with PCOS. We postulate that insulin treatment acts as a co-gonadotropin increasing follicle recruitment, hence not increasing AMH levels.

Factores pronósticos en éxito de inseminación intrauterina / Prognosis elements in success of intrauterine insemination

La inseminación intrauterina es una técnica ampliamente utilizada por la Medicina reproductiva en el tratamiento de causas específicas de infertilidad, como también como coadyuvante. En el éxito de este método influyen diversos factores que se analizan en esta revisión y cuyos resultados se comentan.

Deterioro cognitivo leve y enfermedad de Alzheimer inicial en adultos mayores / Mild cognitive impairment and the onset of Alzheimerïs disease in older adults

El diagnóstico precoz de una demencia es importante para su manejo clínico y para un eventual tratamiento farmacológico. Se presenta el resultado del seguimiento clínico de 36 adultos mayores que consultaron por fallas de la memoria y tenían un Minimental test de Folstein inicial de 25 a 30 puntos; se planteó el diagnóstico de Deterioro Cognitivo Leve, sin demencia. Fueron controlados durante un período de 6 a 70 meses (promedio 31). Quince de ellos evolucionaron hacia una probable enfermedad de Alzheimer, 11 mejoraron clínicamente con tratamiento farmacológico y apoyo y fueron catalogados como trastornos emocionales. En los otros 10 pacientes el cuadro clínico se mantuvo estable y se reafirmó el diagnóstico de Deterioro Cognitivo Leve. Se discute la dificultad de establecer límites entre el envejecimiento normal, el Deterioro Cognitivo Leve y la enfermedad de Alzheimer inicial; la posible anosognosia de los últimos podría ser un elemento diagnóstico. Se recomienda el uso de una evaluación neuropsicológica objetiva y de un seguimiento prolongado antes de formular un diagnóstico clínico definitivo. En el futuro los progresos de la evaluación neuropsicológica, radiológicas y de laboratorio permitirían un diagnóstico más precoz de estas entidades