Satoko Osuka

One-year follow-up of serum antimüllerian hormone levels in patients with cystectomy : are different sequential changes due to different mechanisms causing damage to the ovarian reserve?

OBJECTIVE To investigate whether the serum antimüllerian hormone (AMH) levels recover within 1 year after cystectomy for endometriomas, and to analyze the pattern of sequential changes in the serum AMH levels. DESIGN Prospective study. SETTING University hospital. PATIENT(S) Thirty-nine patients undergoing cystectomy for unilateral endometrioma (n = 22) and bilateral endometriomas (n = 17). INTERVENTION(S) Serum samples collected 2 weeks before, and 1 month and 1 year after surgery were assayed for AMH levels. MAIN OUTCOME MEASURE(S) Assessment of the ovarian reserve damage based on alterations in the serum AMH levels and the association with parameters of endometriosis and surgery for endometriomas. RESULT(S) The median AMH levels were 3.56, 1.90, and 2.10 ng/mL before, 1 month after, and 1 year after surgery, respectively. Twenty patients showed higher AMH levels 1 year after surgery than 1 month after surgery (increase group); 19 patients showed lower AMH levels (decrease group). We found a statistically significant difference in the number of follicles removed by surgery between the two groups. CONCLUSION(S) The decrease in the serum AMH levels caused by cystectomy can recover. Our results suggest that removal of ovarian cortex might be involved in the decrease of the ovarian reserve just after surgery, and that a continuous decrease of the ovarian reserve after cystectomy might be attributed to other mechanisms.

Kisspeptin in the hypothalamus of two rat models of polycystic ovary syndrome.

Hyperandrogenism, disturbance of the hypothalamus-pituitary-ovary axis followed by elevated serum luteinizing hormone (LH) levels, and insulin resistance are involved in the complicated pathophysiology of polycystic ovary syndrome (PCOS). Kisspeptin is coexpressed with neurokinin B (NKB) in the arcuate nucleus (ARC), the center of the gonadotropin-releasing hormone pulse generator that is responsible for pulsatile LH secretion. We compared 2 androgenized rat models of PCOS to evaluate the estrous cycle, hormonal profiles, and expression of kisspeptin and NKB in the ARC. Rats in our postnatal dihydrotestosterone (DHT)-treatment model exhibited weight gain and persistent diestrus with normal LH levels. In contrast, irregular cycles, with elevated LH serum levels and normal body weight, were found in the prenatally DHT-treated rats. We also found increased signals of kisspeptin and NKB in the ARC of the prenatally DHT-treated rats, and not in the postnatally DHT-treated rats. Our results suggest that prenatal exposure to androgens may result in higher kisspeptin and NKB levels in the ARC, which could be associated with 1 phenotype of PCOS that is characterized by normal body weight and higher LH secretion, whereas in postnatally DHT-treated rats, characteristics such as weight gain and normal LH levels are seen in the obese PCOS phenotype.

Increase of kisspeptin-positive cells in the hypothalamus of a rat model of polycystic ovary syndrome

Kisspeptin, a hypothalamic neuropeptide, is expressed in the arcuate nucleus (ARC) that is considered as the center of the gonadotropin-releasing hormone (GnRH)-pulse generator. We hypothesized that kisspeptin expressed in the ARC is implicated in the disturbance of the hypothalamus−pituitary−ovary axis observed in polycystic ovary syndrome (PCOS). To test this hypothesis, we evaluated the hormonal profiles, luteinizing hormone (LH) pulse, and ARC kisspeptin immunoreactivity in a PCOS rat model using the anti-progestin RU486. We found an alteration of the LH pulse, including a trend towards an increased mean LH concentration and area under the curve, and a significant upregulation of the mean LH pulse amplitude. Additionally, a higher number of kisspeptin-positive cells was observed in the ARC of RU486-treated rats than in the ARC of intact rats. These results suggest the possible involvement of hypothalamic kisspeptin in the hypothalamus−pituitary−ovary axis and therefore, in PCOS pathophysiology.

Usefulness of the Ultrasensitive Anti-Müllerian Hormone Assay for Predicting True Ovarian Reserve

Serum concentration of anti-Müllerian hormone (AMH) is a useful marker for ovarian reserve. Measurement of AMH in clinical practice has gained widespread use to predict parameters such as the ovarian response, menopause, and recovery after chemotherapy. However, undetectable AMH levels assayed by conventional enzyme-linked immunosorbent assay (ELISA) kits fail to predict depletion of follicles because of low sensitivity of the kits. We investigated whether a recently developed ultrasensitive ELISA kit, picoAMH, would be more effective at detecting very low AMH levels in association with menstrual status. We analyzed 68 women with undetectable serum AMH levels using an ELISA kit, AMH Gen II. The AMH concentration of the same samples was detected in 36 samples using picoAMH; 32 samples were within the standard range, and 4 samples were out of the standard range but still detectable. Thirty-two women whose AMH levels were undetectable using the picoAMH all showed amenorrhea. We also found a significant correlation between the classes of serum AMH levels (undetectable, detectable under the limit of quantification, and measurable within the assay range) and menstrual status. Five of the 6 amenorrheic women with detectable AMH eventually achieved follicle growth. The present study demonstrated that very low AMH levels detectable using picoAMH correspond well to current and future ovulation status. This suggests that serum AMH levels can be useful for the assessment of ovarian reserve and follow-up of women with a declined ovarian reserve.

Anti-Müllerian hormone as a marker of ovarian reserve: What have we learned, and what should we know?

Ovarian reserve reflects the quality and quantity of available oocytes. This reserve has become indispensable for the better understanding of reproductive potential. Measurement of the serum anti-Müllerian hormone (AMH) level allows quantitative evaluation of ovarian reserve. It has been applied to a wide range of clinical conditions, and it is well established that the measurement of serum AMH levels is more useful than qualitative evaluation based on the menstrual cycle. AMH levels are monitored during infertility treatments; in patients undergoing medically assisted reproductive technology; and in the diagnosis of ovarian failure, polycystic ovarian syndrome, and granulosa cell tumor. It is also useful in the evaluation of iatrogenic ovarian damage. Population-based studies have indicated a potential role for serum AMH in the planning of reproductive health management. While AMH is currently the best measure of ovarian reserve, its predictive value for future live births remains controversial. Furthermore, there is a serious practical issue in the interpretation of test results, as currently available assay kits use different assay ranges and coefficients of variation due to the absence of an international reference standard. The pros and cons of the serum AMH level as a definitive measure of ovarian reserve merits further review in order to guide future research.

Anti-Müllerian hormone as a possible predictor of fecundability in subfertile women over 38 years: a retrospective cohort study

Abstract Anti-Müllerian hormone (AMH) is a relatively novel method for examining the ovarian reserve that reflects female reproductive function. In the era in which the number of women delaying attempts to conceive has increased, a good predictor for long-term fecundability has been explored. We performed the retrospective cohort study to investigate whether initial serum AMH levels are useful for predicting long-term fertility during infertility treatments. We recruited 149 women in the retrospective cohort, and 52 women were gravid during the follow-up period. According to the multiple logistic analyses, only age was found to have a significant correlation with pregnancy success in all women. In women ≥38 years, significantly higher serum AMH levels were detected in the pregnant group (median = 2.83 ng/mL, range = 1.11–6.29 ng/mL) than the non-pregnant group (median = 1.22 ng/mL, range = 0–9.46 ng/mL; p = 0.015). None of the women with serum AMH levels <0.7 ng/mL were pregnant during treatment. AMH may be used to identify poor pregnancy prospects in women who are above 38 years.

Anti-Müllerian hormone levels after laparoscopic cystectomy for endometriomas as a possible predictor for pregnancy in infertility treatments

Abstract We assessed the associations between preoperative and postoperative serum anti-Müllerian hormone (AMH) levels and parameters of endometriosis and endometriomas surgery with the success of infertility treatments after cystectomy. Seventeen out of 54 patients got pregnant during the infertility treatments. In these patients, the median interval from surgery to conception was 16.3 months. The serum AMH levels 1-year postoperatively were significantly higher in the pregnant group compared to the non-pregnant group (3.44 ± 1.78 versus 2.17 ± 2.24 ng/ml, p = 0.049). The median interval from surgery to recurrence was 34.4 months, and no significant differences were found in the serum AMH levels at any time point between the recurrence and non-recurrence groups. Serum AMH levels 1 year after laparoscopic cystectomy for endometriomas may predict the success of postoperative infertility treatments, but not a recurrence of endometriomas.

Follicle dynamics: visualization and analysis of follicle growth and maturation using murine ovarian tissue culture

PurposeTo visualize and analyze follicle development in ovarian tissue culture using physiological concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in order to establish an ovarian tissue culture system that enables efficient in vitro growth of follicles.MethodsOvarian tissues from 4-week-old female ICR mice were sliced and cultured. Images of ovarian tissues in culture were obtained at 24-h or 30-min intervals by using a microscope. The area of each follicle observed in the ovarian tissue slices was tracked and analyzed in association with oocyte maturation.ResultsWe were able to track the development of each follicle using this culture system. Follicle growth was associated with oocyte maturation. Meiotically matured oocytes (MII) were obtained from 33% of all follicles investigated. Approximately, a quarter of follicles (24%) did not grow and resulted in atresia.ConclusionFollicle dynamics were successfully visualized and analyzed in murine ovarian tissue culture. We were able to obtain mature oocytes from the fully grown follicles in vitro. This culture system would be helpful for efficient in vitro culturing of ovarian tissues.

Serum pentraxin 3 as a possible marker for mature cystic teratomas

Abstract Pentraxin 3 (PTX3) is an inflammatory mediator that is released by a wide range of tissues and cells. Elevated PTX3 levels may represent a useful diagnostic and/or prognostic marker for a number of diseases. The purpose of this study was to investigate serum PTX3 levels in benign gynecological conditions including mature cystic teratomas (MCTs), endometriomas, and uterine leiomyomas. Serum PTX3 levels of the MCT group were found to be significantly higher compared to those of the other groups, including healthy controls (p = 0.001), although carbohydrate antigen 19-9 (CA19-9) did not exhibit a significant difference. Serum PTX3 levels of the MCT, but not the endometrioma group, were also found to have significantly decreased post-operatively (mean ± standard deviation, 4.98 ± 2.10 to 3.61 ± 1.53 ng/mL). Immunohistochemical analyses demonstrated positive staining for PTX3 protein in the sebaceous glands, epidermal tissues, and hair roots of MCT specimens. PTX3 is expressed by MCTs and is associated with increased serum concentrations compared to healthy controls and patients with either endometriomas or uterine leiomyomas. We conclude that serum PTX3 levels could be used as a potential diagnostic marker for MCTs, especially helpful in differentiating them from endometriomas with elevated expression of CA19-9.

Upregulation of Fibroblast Growth Factors Caused by Heart and Neural Crest Derivatives Expressed 2 Suppression in Endometriotic Cells: A Possible Therapeutic Target in Endometriosis

Several features exist that distinguish endometriotic cells from eutopic endometrial cells. Progesterone resistance is one of the main distinguishing features, although how progesterone resistance affects the phenotype of endometriotic cells is not fully elucidated. Heart and neural crest derivatives expressed 2 (HAND2) is a transcriptional factor that plays an important role in maintaining endometrial function in a progesterone-dependent manner. Therefore, we explored whether progesterone-dependent HAND2 is implicated in the progression of endometriosis. HAND2 was less expressed by endometriotic tissues compared to endometrial tissues. Suppression of HAND2 expression induced fibroblast growth factor 1 (FGF1), FGF2, and FGF9 in endometriotic stromal cells and consequently enhanced migration and invasion capacity. AZD4547, a FGF receptor inhibitor, diminished the migration and invasion of endometriotic cells in vitro. In the murine model of endometriosis, AZD4547 showed suppressive effects on the development of endometriotic lesions at a relatively low concentration. In conclusion, we demonstrated that FGF1, FGF2, and FGF9 are downstream effectors of HAND2 in endometriotic cells. Since HAND2-dependent FGFs play roles in enhancing invasive capacity of endometriotic cells, our results suggest that FGF receptor inhibitors, such as AZD4547, can be promising therapeutic targets for endometriosis.