AMH and other markers of ovarian function in patients with Turner syndrome - a single center experience of transition from pediatric to gynecological follow up.

Turner syndrome (TS) is a chromosomal disorder that affects about 1 in 2500 female births and is characterized by the partial or complete absence of the second X chromosome. Depending on karyotype, TS is associated with primary ovarian insufficiency (POI). Approximately 50% of girls with a mosaic 45, X/46, XX karyotype may enter puberty spontaneously, but only 5-10% of women with TS achieve pregnancy without egg donation. In this review, we will evaluate the clinical use of markers of ovarian function in TS patients. Based on longitudinal studies of serum concentrations of reproductive hormones as well as ovarian morphology in healthy females and patients with TS, we will evaluate how they can be applied in a clinical setting. This is important when counseling patients and their families about future ovarian function essential for pubertal development and fertility. Furthermore, we will report on 20 years of experience of transition from pediatric to gynecological and adult endocrinological care in our center at Rigshospitalet, Copenhagen, Denmark.

Effects of needle puncturing on re-vascularization and follicle survival in xenotransplanted human ovarian tissue.

BACKGROUND: Ovarian tissue transplantation can restore fertility in young cancer survivors, however the detrimental loss of follicles following transplantation of cryopreserved ovarian tissue is hampering the efficiency of the procedure. This study investigates whether needle puncturing prior to transplantation can enhance revascularization and improve follicle survival in xenotransplanted human ovarian cortex. METHODS: Cryopreserved human ovarian cortex pieces (N = 36) from 20 women aged 24-36 years were included. During the thawing process, each piece of tissue was cut in halves; one half serving as the untreated control and the other half was punctured approximately 150-200 times with a 29-gauge needle. The cortex pieces were transplanted subcutaneously to immunodeficient mice for 3, 6 and 10 days (N = 8 patients) and for 4 weeks (N = 12 patients). After 3, 6 and 10 days, revascularization of the ovarian xenografts were assessed using immunohistochemical detection of CD31 and gene expression of angiogenic factors (Vegfα, Angptl4, Ang1, and Ang2), and apoptotic factors (BCL2 and BAX) were performed by qPCR. Follicle density and morphology were evaluated in ovarian xenografts after 4 weeks. RESULTS: A significant increase in the CD31 positive area in human ovarian xenografts was evident from day 3 to 10, but no significant differences were observed between the needle and control group. The gene expression of Vegfα was consistently higher in the needle group compared to control at all three time points, but not statistically significant. The expression of Ang1 and Ang2 increased significantly from day 3 to day 10 in the control group (p < 0.001, p = 0.0023), however, in the needle group this increase was not observed from day 6 to 10 (Ang2 p = 0.027). The BAX/BCL2 ratio was similar in the needle and control groups. After 4-weeks xenografting, follicle density (follicles/mm3, mean ± SEM) was higher in the needle group (5.18 ± 2.24) compared to control (2.36 ± 0.67) (p = 0.208), and a significant lower percentage of necrotic follicles was found in the needle group (19%) compared to control (36%) (p = 0.045). CONCLUSIONS: Needle puncturing of human ovarian cortex prior to transplantation had no effect on revascularization of ovarian grafts after 3, 6 and 10 days xenotransplantation. However, needle puncturing did affect angiogenic genes and improved follicle morphology.

AMH concentrations in infancy and mid-childhood predict ovarian activity in adolescence: A long-term longitudinal study of healthy girls.

Background: Anti-Müllerian hormone (AMH) is produced by granulosa cells in small growing ovarian follicles. In adult women, serum concentrations of AMH reflect the ovarian reserve of resting primordial follicles, and low AMH is associated with risk of early menopause. In contrast, patients with polycystic ovary syndrome (PCOS) have elevated AMH. The primary aim of this study was to evaluate the individual tracking of serum AMH concentrations, as well as whether AMH in early childhood reflects ovarian activity in adolescence. Methods: In this large longitudinal study of healthy girls were examined from infancy to adolescence (1997-2019) including physical examination, assessment of serum concentrations of reproductive hormones (in infancy, median age 0.3 yrs; mid-childhood, 7.2 yrs; puberty, 11.3 yrs; and adolescence, 15.9 yrs), transabdominal ultrasound (TAUS, puberty and adolescence) and magnetic resonance imaging (MRI, puberty) of the ovaries. Findings: Each girl maintained her relative AMH concentration (expressed as standard deviation (SD) scores) over time; mean variation of individual age adjusted AMH concentrations was 0.56 ± 0.31 SD.Serum concentrations of AMH in adolescence correlated with AMH in infancy and childhood; infancy: r = 0.347; mid-childhood: r = 0.637; puberty: r = 0.675, all p < 0.001.AMH correlated negatively with FSH concentrations in all age groups (infancy: r = -0.645, p < 0.001; mid-childhood: r = -0.222, p < 0.001; puberty: r = -0.354, p < 0.001; adolescence: n = 275, r = -0.175, p = 0.004).Serum AMH concentrations in mid-childhood correlated with the number of follicles in puberty (TAUS and MRI) as well as in adolescence (TAUS); e.g. total number of follicles: TAUS puberty (r = 0.607), MRI puberty (r = 0.379), TAUS adolescence (r = 0.414), all p < 0.001.AMH concentration in infancy as well as in mid-childhood predicted low AMH (<10 pmol/L) in adolescence; AMH infancy <7.5 pmol/L as predictor of low AMH in adolescence: sensitivity 0.71, specificity 0.70, AUC 0.759; AMH mid-childhood < 8.4 pmol/L as predictor of low AMH in adolescence: sensitivity 0.88, specificity 0.87, AUC 0.949.Girls with high serum AMH concentration in mid-childhood (AMH >30.0 pmol/L vs. other girls) had higher adolescent LH (median 4.53 vs. 3.29 U/L p = 0.041), LH/FSH ratio (1.00 vs 0.67, p = 0.019), testosterone (1.05 vs 0.81 nmol/L, p = 0.005), total number of follicles (23 vs. 19, p = 0.004), and higher prevalence of irregular cycles (10/15 = 67% vs. 28/113 = 25%, p = 0.002). Interpretation: The present findings suggest remarkably stable ovarian activity from small growing follicles in healthy girls, supporting AMH in early life as a useful clinical tool to predict future ovarian activity. Funding: The work was supported by The Center on Endocrine Disruptors (CeHoS) under The Danish Environmental Protection Agency and The Ministry of Environment and Food (grant number: MST-621-00 065), the EU (QLK4-CT1999-01422; QLK4-2001-00269), the Novo Nordisk Foundation and The Danish Ministry of Science Technology and Innovation (2107-05-0006). A.S.B. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 464240267. KM receives honoraria from Novo Nordisk A/S for teaching at the Danish annual postgraduate course of pituitary diseases.

[Reproductive surgery for female infertility].

Although assisted reproductive technology has reduced the need for surgery for women with infertility, there is evidence to support, that targeted reproductive surgery can improve fertility and pregnancy outcomes. In the last decades, increased access to minimal invasive surgery has brought a new era to reproductive surgery. An integration of reproductive surgery in the fertility treatment is therefore recommended. The patient should be offered detailed information regarding the pros and cons before the surgical treatment, as the evidence in the field is sparse, which is discussed in this review.

Changes in abdominal subcutaneous adipose tissue phenotype following menopause is associated with increased visceral fat mass.

Menopause is associated with a redistribution of adipose tissue towards central adiposity, known to cause insulin resistance. In this cross-sectional study of 33 women between 45 and 60 years, we assessed adipose tissue inflammation and morphology in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) across menopause and related this to menopausal differences in adipose tissue distribution and insulin resistance. We collected paired SAT and VAT biopsies from all women and combined this with anthropometric measurements and estimated whole-body insulin sensitivity. We found that menopause was associated with changes in adipose tissue phenotype related to metabolic dysfunction. In SAT, postmenopausal women showed adipocyte hypertrophy, increased inflammation, hypoxia and fibrosis. The postmenopausal changes in SAT was associated with increased visceral fat accumulation. In VAT, menopause was associated with adipocyte hypertrophy, immune cell infiltration and fibrosis. The postmenopausal changes in VAT phenotype was associated with decreased insulin sensitivity. Based on these findings we suggest, that menopause is associated with changes in adipose tissue phenotype related to metabolic dysfunction in both SAT and VAT. Whereas increased SAT inflammation in the context of menopause is associated with VAT accumulation, VAT morphology is related to insulin resistance.

Use of cryopreserved ovarian tissue in the Danish fertility preservation cohort.

OBJECTIVE: To evaluate the use of cryopreserved ovarian tissue in the Danish fertility preservation cohort. DESIGN: Retrospective cohort study. SETTING: University hospitals and fertility clinics. PATIENT(S): Ovarian tissue cryopreservation (OTC) was performed for 1,186 Danish girls and women from 1999-2020, of whom 117 subsequently underwent ovarian tissue transplantation (OTT). Subgroup 1 included 759 patients with a follow-up period of >5 years. Out of these, OTT rates were further analyzed for those patients who were alive and aged >24 years in July 2020 (subgroup 2; n = 554). INTERVENTION(S): OTC and OTT. MAIN OUTCOME MEASURE(S): OTT, death, donation of tissue. RESULT(S): In subgroup 1, 14% of the patients had undergone OTT, 18% had died, 9% had donated their tissue for research, and 59% still had their tissue stored. In subgroup 2, 19% had undergone OTT and for most diagnoses the OTT rates ranged from 15% to 22% with benign hematologic diseases having the highest OTT rate (35%). On the basis of the entire cohort, stratified age analysis indicated that women aged ≥30 years at OTC were more likely to return for OTT than women aged 18-29 years at OTC; mean storage times were 3.7 and 3.6 years, respectively. Only 4% of the girls aged <18 years at OTC had undergone OTT. CONCLUSION(S): The OTT rates depended on the diagnosis, age at OTC, and follow-up time. Specific criteria are needed for reporting and comparing OTT rates. Six out of 10 patients still had their cryopreserved tissue stored and longer follow-up is needed, especially for younger girls.

Preserved postprandial suppression of bone turnover markers, despite increased fasting levels, in postmenopausal women.

CONTEXT: Menopause leads to an increased bone turnover associated with a high risk of fractures. Bone turnover is inhibited by meal intake, to some extent mediated by gut hormones, and interventions based on these endocrine changes may have potential in future prevention of osteoporosis. OBJECTIVE: To investigate whether postmenopausal women exhibit postprandial suppression of bone turnover markers to the same extent as premenopausal women, despite higher fasting levels. Furthermore, to assess whether menopausal differences in bone turnover markers are related to postmenopausal changes in plasma gut hormone levels. METHODS: A cross-sectional study of 21 premenopausal, 9 perimenopausal, and 24 postmenopausal women between 45 and 60 years of age. Serum/plasma levels of bone turnover markers and gut hormones were investigated during a 120 min oral glucose tolerance test. Bone turnover markers included N-terminal propeptide of type-I procollagen (PINP, bone formation marker) and carboxyterminal collagen I crosslinks (CTX-I, bone resorption marker). Gut hormone secretion was evaluated from responses of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and glucose-dependent insulinotropic polypeptide (GIP). RESULTS: Fasting levels of s-CTX-I were increased in peri- and postmenopausal women compared to premenopausal women (p = 0.001). Despite higher fasting levels, the relative postprandial s-CTX-I suppression was comparable across menopausal status (p = 0.14). Fasting levels of s-PINP were also increased in postmenopausal women compared to premenopausal women (p < 0.001) with comparable and modest s-PINP suppression over menopause (p = 0.13). Postprandial plasma GLP-1 (p = 0.006) and GLP-2 (p = 0.01) were significantly increased in postmenopausal women compared to premenopausal women while GIP responses were slightly increased in the perimenopausal group (p = 0.02) but comparable between pre- and postmenopausal women. None of the postprandial gut hormone increases predicted postprandial bone turnover suppression in these women. CONCLUSIONS: Glucose-induced suppression of bone turnover markers is preserved in postmenopausal women, despite significantly higher fasting values, indicating that CTX-I lowering treatments based on these postprandial mechanisms might be a feasible strategy to prevent postmenopausal osteoporosis.

Menstrual Pattern, Reproductive Hormones, and Transabdominal 3D Ultrasound in 317 Adolescent Girls.

CONTEXT: The knowledge of normal variation of reproductive hormones, internal genitalia imaging, and the prevalence of gynecological disorders in adolescent girls is limited. OBJECTIVE: The study aimed to describe reproductive parameters in postmenarchal girls from the general population including the frequency of oligomenorrhea, polycystic ovary syndrome, and use of hormonal contraception. DESIGN: The Copenhagen Mother-Child Cohort is a population-based longitudinal birth cohort of 1210 girls born between 1997 and 2002. SETTING: University hospital. PARTICIPANTS: A total of 317 girls were included, with a median age of 16.1 years and time since menarche of 2.9 years. MAIN OUTCOME MEASURE(S): Tanner stage, height, weight, age at menarche, menstrual cycle length and regularity, ovarian/uterine volume, and number of follicles were recorded. Serum concentrations of FSH, LH, anti-Müllerian hormone (AMH), inhibin B, estradiol, testosterone, SHBG, androstenedione, dehydroepiandrosterone sulfate, 17-OH-progesterone, and IGF-1 were measured. RESULTS: Twenty girls (6.3%) had oligomenorrhea and differed significantly in serum androgens and AMH, age at and time since menarche from girls with regular cycles. Twenty-seven girls were classified with PCOS (8.5%) and had significantly higher 17-OH-progesterone, estradiol, AMH, LH, and age at menarche than the reference group. Girls on oral contraception had significantly higher serum SHBG concentrations and lower serum concentrations of all hormones except AMH and IGF-1. Ovarian follicles 2 to 29.9 mm correlated positively with serum AMH (P < 0.0001). CONCLUSIONS: Most 16-year-old girls had regular menstrual cycles, normal reproductive hormones, and uterine and ovarian ultrasound. Serum AMH reflected ovarian follicle count and may be a useful biomarker of ovarian reserve.

Increased systemic inflammation and altered distribution of T-cell subsets in postmenopausal women.

AIM: To investigate markers of systemic inflammation in pre- and postmenopausal women and identify possible predictors of systemic inflammation with menopause. METHODS: Cross-sectional study of 69 healthy women between 45- and 60 years. Blood samples were collected to assess leukocyte subsets and plasma cytokines. MRI and DXA scans were performed to assess body composition. Through uni- and multivariate analyses, follicle-stimulating hormone (FSH), visceral fat mass and age were evaluated as predictors of systemic inflammation in relation to menopause. RESULTS: Postmenopausal women tended to have higher leukocyte counts (5.4 x109 vs. 4.9 x109 cells/l, p = 0.05) reflected in increased total lymphocytes (1.8 x109 vs. 1.6 x109 cells/l, p = 0.01) and monocytes (0.5 x109 vs. 0.4 x109 cells/l, p = 0.02), compared to premenopausal women. Increased visceral fat mass was a strong predictor of high leukocyte subsets. Postmenopausal women had higher plasma TNF-α (2.24 vs. 1.91 pg/ml, p = 0.01) and IL-6 (0.45 vs. 0.33 pg/ml, p = 0.004) compared to premenopausal women and high FSH was a significant predictor of increased plasma TNF-α, IL-1ß and IL-6. Menopause was further associated with increased T-cells (1,336 vs. 1,128 cells/µl, p = 0.04) reflected in significantly higher counts of exhausted-, senescent-, and memory CD4+ T-cell subsets. CONCLUSIONS: Menopause is associated with increased systemic inflammation as well as exhausted- and senescent T-cells. We suggest, that both increased visceral fat mass and declining sex hormone levels might contribute to postmenopausal systemic inflammation and calls for further large-scale studies to confirm these findings.

[Fertility counselling of younger women after cancer treatment].

Girls and younger women of fertile age are at risk of infertility and premature ovarian insufficiency, if they have received chemotherapy or radiotherapy. While many are offered fertility preservation before treatment, many are left with a need for follow-up after treatment, which is pointed out in this review. At the fertility clinic at Rigshospitalet, Denmark, a follow-up clinic has been introduced for previous cancer patients with focus on reproductive health, including assessment of ovarian function, planning of future pregnancies and initiation of hormone replacement therapy if needed.

Ovarian cortical follicle density in infertile women with low anti-Müllerian hormone.

PURPOSE: To evaluate the association between anti-Müllerian hormone (AMH) and follicle density in infertile women with diminished ovarian reserve (DOR) versus women with normal ovarian reserve? METHODS: Case-control study comparing follicle densities in ovarian cortex from 20 infertile women with DOR (AMH ≤ 5 pmol/L) and 100 controls with presumed normal ovarian reserve. RESULTS: For all women > 25 years, the follicle densities correlated positively with AMH levels. For each single picomole per liter increase in AMH the follicle density increased by 6% (95% CI 3.3-8.5%) when adjusted for age. This was similar for women with DOR and controls. The follicle density was 1.8 follicles/mm3 cortical tissue in women with DOR versus 7.0 in age-paired controls (p = 0.04). The women with DOR had a median AMH of 1.8 pmol/L versus 14.4 pmol/L in the age-paired control group (p < 0.001). The ratio of AMH/follicle density was 1:1 (1.8/1.8) in women with DOR and 2:1 (14.4/7.0) in the age-paired controls. Analyses for gonadotropin receptor polymorphisms could not explain the characteristics of women with DOR. The proportion of secondary follicles was higher in women with DOR compared with controls (4.6% versus 1.4%, p = 0.0003). Pooling all patients, the follicle density decreased significantly by 7.7% for every year added (p < 0.0001). The women with DOR had lower follicle densities than the controls, but the slopes were equal in the two cohorts. CONCLUSIONS: Follicle density and AMH concentrations correlate also when AMH is low. However, AMH is only a reliable marker for the true ovarian reserve when age is included in the estimation and women with DOR may have more follicles than their AMH levels imply.

Biopsying, fragmentation and autotransplantation of fresh ovarian cortical tissue in infertile women with diminished ovarian reserve.

STUDY QUESTION: Can ovarian biopsying per se and/or autotransplantation of fragmented ovarian cortical tissue activate dormant follicles and increase the number of recruitable follicles for IVF/ICSI in women with diminished ovarian reserve (DOR)? SUMMARY ANSWER: Ovarian biopsying followed by immediate autotransplantation of fragmented cortical tissue failed to increase the number of recruitable follicles for IVF/ICSI 10 weeks after the procedure either at the graft site or in the biopsied ovary, but 12 of the 20 women subsequently had a clinical pregnancy during the 1-year follow-up. WHAT IS KNOWN ALREADY: Infertile women with DOR constitute a group of patients with poor reproductive outcome mainly due to the low number of mature oocytes available for IVF/ICSI. Recent studies have shown that in vitro activation of residual dormant follicles by both chemical treatment and tissue fragmentation has resulted in return of menstrual cycles and pregnancies in a fraction of amenorrhoeic women with premature ovarian insufficiency. STUDY DESIGN, SIZE, DURATION: This is a prospective clinical cohort study including 20 women with DOR treated at the fertility clinic, Rigshospitalet, Denmark, during April 2016-December 2017. Non-pregnant patients were on average followed for 280 days (range 118-408), while women who conceived were followed until delivery. Study follow-up of non-pregnant patients ended in September 2018. PARTICIPANTS, MATERIALS, SETTING, METHODS: The study included infertile women aged 30-39 years with preserved menstrual cycles, indication for IVF/ICSI and repeated serum measurements of anti-Müllerian hormone (AMH) ≤ 5 pmol/L. Patients were randomized to have four biopsies taken from either the left or the right ovary by laparoscopy followed by fragmentation of the cortical tissue to an approximate size of 1 mm3 and autotransplanted to a peritoneal pocket. The other ovary served as a control. Patients were followed weekly for 10 weeks with recording of hormone profile, antral follicle count (AFC), ovarian volume and assessment for ectopic follicle growth. After 10 weeks, an IVF/ICSI-cycle with maximal ovarian stimulation was initiated. MAIN RESULTS AND THE ROLE OF CHANCE: No difference in the number of mature follicles after ovarian stimulation 10 weeks after the procedure in the biopsied versus the control ovaries was observed (1.0 vs. 0.7 follicles, P = 0.35). In only three patients, growth of four follicles was detected at the graft site 24-268 days after the procedure. From one of these follicles, a metaphase II (MII) oocyte was retrieved and fertilized, but embryonic development failed. Overall AMH levels did not change significantly after the procedure (P = 0.2). The AFC increased by 0.14 (95% CI: 0.06;0.21) per week (P < 0.005), and the biopsied ovary had on average 0.6 (95% CI: 0.3;-0.88) follicles fewer than the control ovary (P = 0.01). Serum levels of androstenedione and testosterone increased significantly by 0.63 nmol/L (95% CI: 0.21;1.04) and 0.11 nmol/L (95% CI: 0.01;0.21) 1 week after the procedure, respectively, and testosterone increased consecutively over the 10 weeks by 0.0095 nmol/L (95% CI: 0.0002;0.0188) per week (P = 0.045). In 7 of the 20 patients, there was a serum AMH elevation 5 to 8 weeks after the procedure. In this group, mean AMH increased from 2.08 pmol/L (range 1.74-2.34) to 3.94 pmol/L (range 3.66-4.29) from Weeks 1-4 to Weeks 5-8. A clinical pregnancy was obtained in 12 of the 20 (60%) patients with and without medically assisted reproduction (MAR) treatments. We report a cumulated live birth rate per started IVF/ICSI cycle of 18.4%. LIMITATIONS, REASON FOR CAUTION: Limitations of the study were the number of patients included and the lack of a non-operated control group. Moreover, 9 of the 20 women had no male partner at inclusion and were treated with donor sperm, but each of these women had an average of 6.8 (range 4-9) unsuccessful MAR treatments with donor sperm prior to inclusion. WIDER IMPLICATIONS OF THE FINDINGS: Although 12 out of 20 patients became pregnant during the follow-up period, the current study does not indicate that biopsying, fragmenting and autotransplanting of ovarian cortical tissue increase the number of recruitable follicles for IVF/ICSI after 10 weeks. However, a proportion of the patients may have a follicular response in Weeks 5-8 after the procedure. It could therefore be relevant to perform a future study on the possible effects of biopsying per se that includes stimulation for IVF/ICSI earlier than week 10. STUDY FUNDING/COMPETING INTEREST(S): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. The funders had no role in the study design, data collection and interpretation, or decision to submit the work for publication. None of the authors have a conflict of interest. TRIAL REGISTRATION NUMBER: NCT02792569.

Autotransplantation of fragmented ovarian cortical tissue: a laparoscopic demonstration.

OBJECTIVE: To describe and demonstrate a simple and secure procedure for laparoscopic autotransplantation of fragmented ovarian cortical tissue in women with diminished ovarian reserve as part of in vitro activation (IVA) of ovarian follicles. DESIGN: Step-by-step video explanation of the surgical procedure with still pictures and surgical video clips to demonstrate the detailed technique. SETTING: Fertility clinic and obstetrics and gynecology department at a university hospital. PATIENT(S): Women with idiopathic diminished ovarian reserve and indication for in vitro fertilization (IVF), aged 25 to 39 years with an antral follicle count bilaterally of ≤5, antimüllerian hormone level of ≤5 pmol/L, and two ovaries. INTERVENTION(S): The laparoscopic autotransplantation consists of six steps: [1] obtaining ovarian cortical biopsy samples, [2] preparing the peritoneal pocket, [3] fragmenting the ovarian cortical tissue into pieces of approximately 1 mm3, [4] installing the tissue fragments into a catheter, [5] transplanting the tissue fragments into the peritoneal pocket, and [6] closing the peritoneal pocket with a surgical clip. After the procedure, the patients are evaluated with blood samples and ultrasound scans followed by controlled ovarian stimulation. Ethics committee approval was obtained. MAIN OUTCOME MEASURE(S): Feasibility of a six-step laparoscopic autotransplantation procedure using fragmented ovarian cortical tissue. RESULT(S): A simple, fast laparoscopic procedure for taking biopsy samples and autotransplanting cortical tissue fragments in an all-in-one procedure ensures the rapid handling and correct placement of the small tissue fragments. The procedure is performed in an outpatient setting with an operation time of 1 hour. We have performed this procedure on 20 patients with no complications. CONCLUSION(S): In vitro activation is a new, developing option for women in fertility treatment who have diminished ovarian reserve. Fragmentation of murine ovarian tissue has shown to suppress the Hippo pathway, thereby initiating proliferation and growth. This surgical procedure resembles that used when transplanting pieces of frozen-thawed ovarian tissue for fertility restoration, but the fragmented ovarian tissue is only 1 mm3, which makes it difficult to transplant. Until now no surgical procedures for transplanting small IVA fragments of cortical tissue has been published. With this video we report in detail a simple way of autotransplanting small fragments of IVA cortical tissue using what is already accessible in the operating theater. Among the many advantages of this procedure are its short duration (1 hour) and outpatient setting, which enable fast recovery and minimal postoperative pain. The procedure also allows fast handling and minimal manipulation of the tissue (limited to the fragmentation). The effect of autotransplantation of fragmented tissue in women with diminished ovarian reserve is currently being studied in ongoing trials. If the technique is combined with chemical IVA, a better outcome may be seen.

Ectopic Lipid Deposition Is Associated With Insulin Resistance in Postmenopausal Women.

Context: Menopause is associated with an increased incidence of insulin resistance and diabetes. Objective: The aim of this study was to explore the lipid deposition in liver and skeletal muscle and investigate the association with insulin sensitivity in postmenopausal and premenopausal women. Design and Setting: Single-center cross-sectional study of 55 healthy women between 45 and 60 years of age. We measured lipid deposition in the liver with magnetic resonance spectroscopy, intramuscular and intra-abdominal lipid deposition with MRI, body composition with a dual-energy X-ray absorptiometry scan, and insulin sensitivity with the composite Matsuda Index. Outcome Measures: We studied the association between fat distribution, ectopic lipid deposition, and insulin sensitivity in pre- and postmenopausal women. Results: Postmenopausal women had an increased lipid deposition in the liver [0.68% (0.44 to 0.99) vs 0.49% (0.38 to 0.64), P = 0.01] and skeletal muscle [3% (2 to 4) vs 2% (1 to 3), P = 0.001] and had a 28% lower Matsuda insulin sensitivity index during an oral glucose tolerance test (6.31 ± 3.48 vs 8.78 ± 4.67, P = 0.05) compared with premenopausal women. Total fat mass and leg fat mass were stronger predictors of ectopic lipid deposition, and visceral fat mass was a stronger predictor of both ectopic lipid deposition and insulin resistance in postmenopausal women compared with premenopausal women. Conclusions: For a given subcutaneous and visceral fat depot size, postmenopausal women show increased ectopic lipid deposition and insulin resistance compared with premenopausal women. It is suggested that lipid deposition in liver and skeletal muscle may represent important mechanistic links between the changes in fat depots and the increased incidence of insulin resistance seen after menopause.

Mortality and Risk of Cancer After Prophylactic Bilateral Oophorectomy in Women With a Family History of Cancer.

BACKGROUND: Current international guidelines recommend systemic hormone therapy (HT) to oophorectomized women until the age of natural menopause. Despite an inherited predisposition to estrogen-dependent malignancies, the guidelines also apply to women oophorectomized because of a family history of cancer. The objective of this study was to investigate the impact of HT on mortality and risk of cancer in women oophorectomized because of a family history of cancer. METHODS: A nationwide, population-based cohort was used to study women oophorectomized because of a family history of cancer (n = 2002). Comparison cohorts included women from the background population individually matched on age (n = 18 018). Oophorectomized women were subdivided into three groups: oophorectomized at 1) age 45 years or younger not using HT, 2) age 45 years or younger using HT, 3) older than age 45 years, and their respective population comparison cohorts. RESULTS: Women oophorectomized at age 45 years or younger using HT had increased overall mortality (mortality rate ratio [MRR] = 3.45, 95% confidence interval [CI] = 1.53 to 7.79), mortality because of cancer (MRR = 5.67, 95% CI = 1.86 to 17.34), and risk of overall cancer (incidence rate ratio [IRR] = 3.68, 95% CI = 1.93 - 6.98), primarily reflected in an increased risk of breast cancer (IRR = 4.88, 95% CI = 2.19 - 10.68). Women oophorectomized at age 45 years or younger not using HT and women oophorectomized at older than age 45 years did not have increased mortality, mortality because of cancer, or risk of overall cancer, but they had increased risk of breast cancer (IRR = 2.64, 95% CI = 1.14 to 6.13, and IRR = 1.72, 95% CI = 1.14 to 2.59, respectively). CONCLUSIONS: Use of HT in women oophorectomized at age 45 years or younger with a family history of cancer is associated with increased mortality and risk of overall cancer and breast cancer. Our study warrants further investigation to establish the impact of HT on mortality and cancer risk in oophorectomized women with a family history of cancer.

Androgens and Psychosocial Factors Related to Sexual Dysfunctions in Premenopausal Women∗: ∗2016 ISSM Female Sexual Dysfunction Prize.

INTRODUCTION: The female sexual response is complex and influenced by several biological, psychological, and social factors. Testosterone is believed to modulate a woman's sexual response and desire, because low levels are considered a risk factor for impaired sexual function, but previous studies have been inconclusive. AIM: To investigate how androgen levels and psychosocial factors are associated with female sexual dysfunction (FSD), including hypoactive sexual desire disorder (HSDD). METHODS: The cross-sectional study included 428 premenopausal women 19 to 58 years old who completed a questionnaire on psychosocial factors and had blood sampled at days 6 to 10 in their menstrual cycle. Logistic regression models were built to test the association among hormone levels, psychosocial factors, and sexual end points. MAIN OUTCOME MEASURES: Five different sexual end points were measured using the Female Sexual Function Index and the Female Sexual Distress Scale: impaired sexual function, sexual distress, FSD, low sexual desire, and HSDD. Serum levels of total and free testosterone, androstenedione, dehydroepiandrosterone sulfate, and androsterone glucuronide were analyzed using mass spectrometry. RESULTS: After adjusting for psychosocial factors, women with low sexual desire had significantly lower mean levels of free testosterone and androstenedione compared with women without low sexual desire. None of the androgens were associated with FSD in general or with HSDD in particular. Relationship duration longer than 2 years and mild depressive symptoms increased the risk of having all the sexual end points, including FSD in general and HSDD in particular in multivariate analyses. CONCLUSION: In this large cross-sectional study, low sexual desire was significantly associated with levels of free testosterone and androstenedione, but FSD in general and HSDD in particular were not associated with androgen levels. Length of relationship and depression were associated with FSD including HSDD. Wåhlin-Jacobsen S, Kristensen E, Tønnes Pedersen A, et al. Androgens and Psychosocial Factors Related to Sexual Dysfunctions in Premenopausal Women. J Sex Med 2017;14:366-379.

Mono-ovulation in women with polycystic ovary syndrome: a clinical review on ovulation induction.

Polycystic ovary syndrome (PCOS) affects 5-10% of women of reproductive age and is the most common cause of anovulatory infertility. The treatment approaches to ovulation induction vary in efficacy, treatment duration and patient friendliness. The aim was to determine the most efficient, evidence-based method to achieve mono-ovulation in women diagnosed with PCOS. Publications in English providing information on treatment, efficacy and complication rates were included until September 2015. Systematic reviews, meta-analyses and randomized controlled trials were favoured over cohort and retrospective studies. Clomiphene citrate is recommended as primary treatment for PCOS-related infertility. It induces ovulation in three out of four patients, the risk of multiple pregnancies is modest and the treatment is simple and inexpensive. Gonadotrophins are highly efficient in a low-dose step-up regimen. Ovulation rates are improved by lifestyle interventions in overweight women. Metformin may improve the menstrual cycle within 1-3 months, but does not improve the live birth rate. Letrozole is effective for ovulation induction, but is an off-label drug in many countries. Ovulation induction in women with PCOS should be individualized with regard to weight, treatment efficacy and patient preferences with the aim of achieving mono-ovulation and subsequently the birth of a singleton baby.

Is there a correlation between androgens and sexual desire in women?

INTRODUCTION: For women, the correlation between circulating androgens and sexual desire is inconclusive. Substitution with androgens at physiological levels improves sexual function in women who experience decreased sexual desire and androgen deficiency from surgical menopause, pituitary disease, and age-related decline in androgen production in the ovaries. Measuring bioactive testosterone is difficult and new methods have been proposed, including measuring the primary androgen metabolite androsterone glucuronide (ADT-G). AIM: The aim of this study was to investigate a possible correlation between serum levels of androgens and sexual desire in women and whether the level of ADT-G is better correlated than the level of circulating androgens with sexual desire. METHODS: This was a cross-sectional study including 560 healthy women aged 19-65 years divided into three age groups. Correlations were considered to be statistically significant at P<0.05. MAIN OUTCOME MEASURE: Sexual desire was determined as the total score of the sexual desire domain of the Female Sexual Function Index. Total testosterone (TT), calculated free testosterone (FT), androstenedione, dehydroepiandrosterone sulfate (DHEAS), and ADT-G were analyzed using mass spectrometry. RESULTS: Sexual desire correlated overall with FT and androstenedione in the total cohort of women. In a subgroup of women aged 25-44 years with no use of systemic hormonal contraception, sexual desire correlated with TT, FT, androstenedione, and DHEAS. In women aged 45-65 years, androstenedione correlated with sexual desire. No correlations between ADT-G and sexual desire were identified. CONCLUSIONS: In the present study, FT and androstenedione were statistically significantly correlated with sexual desire in the total cohort of women. ADT-G did not correlate more strongly than circulating androgens with sexual desire and is therefore not superior to measuring circulating androgens by mass spectrometry.

Current attitudes on self-use and prescription of hormone therapy among New York City gynaecologists.

OBJECTIVE: The results of the Women's Health Initiative studies dramatically altered hormone therapy use around the world. In countries outside the United States, self-use in physicians remained unaltered while prescription use declined, implying that physicians may not concur with the findings. We wished to explore prevailing attitudes among American physicians by examining New York City obstetrician-gynaecologists' self-use and prescription use of hormone therapy. STUDY DESIGN: All board-certified obstetrician-gynaecologists in New York City were invited to complete and return a detailed, previously validated questionnaire concerning hormone therapy use. RESULTS: Two hundred and nine questionnaires were returned, for a response rate of 12% (209/1797). Gynaecologists agreed with the findings from the Women's Health Initiative studies regarding indications and contraindications to hormone therapy use. Even so, three-quarters of female gynaecologists and female partners of male gynaecologists (74%; 67/91) use or have previously used hormone therapy. However, only 27.3% (21/77) of male gynaecologists and 12.3% (14/114) of female gynaecologists recommend hormone therapy to all menopausal women regardless of contraindications. Gynaecologists remain divided in their attitude toward hormone therapy; 30% of gynaecologists felt that hormone therapy use generally prolonged women's lives, 36% felt it was not useful in prolonging women's lives, and 33% were unsure. CONCLUSION: Since the publication of the Women's Health Initiative findings, New York City gynaecologists prescribe hormone therapy to fewer patients. However, they continue to self-use hormone therapy at much higher rates, even as they seem to concur with Women's Health Initiative recommendations, contributing to the ongoing controversy surrounding the validity of the Women's Health Initiative findings.

Type of hormone therapy and risk of misclassification at mammography screening.

OBJECTIVE: Current users of hormone therapy (HT) are known to have a lower accuracy of mammography screening than do never users. We studied whether the risk of misclassification depends on type of hormone, administration, regimen, and dose of the therapy. METHODS: We linked data from mammography screening registers with drug prescription registers from Fyn, Denmark to identify current and never HT users among screening participants. We compared false-positive risks and interval cancer proportions between current users of different HT preparations, taking women's age, breast density, screen number, and age of comparison mammogram into account. RESULTS: Estrogen therapy users had a significantly higher false-positive risk when the administration was by injection instead of oral (relative risk [RR], 2.37; 95% CI, 1.37-4.09). Women using sequential estrogen plus progestogen therapy had a significantly higher false-positive risk (RR, 1.94; 95% CI, 1.16-3.26) and a nonsignificantly higher interval cancer proportion (RR, 4.29; 95% CI, 0.69-26.53) when the administration of both hormones was transdermal instead of oral. Using tibolone instead of comparable hormones gave a nonsignificantly lower false-positive risk and a nonsignificantly higher interval cancer proportion. CONCLUSIONS: Our data showed increased risks of misclassification at mammography screening among women using estrogen injections or transdermal, sequential estrogen plus progestogen. Tibolone seems to offer no advantage regarding accuracy of screening mammography.