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Final maturation of follicles has, in connection with ovarian stimulation and infertility treatment, traditionally been achieved by the administration of a human chorionic gonadotropin (hCG) bolus trigger of 5,000 to 10,000 IU. This trigger serves two purposes: induce oocyte maturation; and serve as luteal phase support owing to its long half-life. It now appears that the hCG bolus trigger is unable to support both these two purposes optimally. In particular, after an hCG trigger, the early luteal phase is hormonally abnormal and different from conditions observed in the natural menstrual cycle: the timing of the initiation of hCG and progesterone rise is much faster after an hCG trigger than in a natural menstrual cycle; the maximal concentrations of hCG and progesterone considerably exceed those naturally observed; and the timing of the peak progesterone concentration after an hCG trigger is advanced several days compared with the natural cycle. Furthermore, the hCG trigger without any follicle-stimulating hormone activity may induce oocyte maturation less efficiently than the combined luteinizing hormone and follicle-stimulating hormone surge normally seen. Collectively, the endometrium is likely to be advanced after an hCG trigger, and the implantation potential is probably not optimal. The precise effect on pregnancy rates after the different progressions of hCG and progesterone concentrations during the early luteal phase has not yet been determined, but more individualized methods using more physiological approaches are likely to improve reproductive outcomes.

Final maturation of follicles has, in connection with ovarian stimulation and infertility treatment, traditionally been achieved by the administration of a human chorionic gonadotropin (hCG) bolus trigger of 5,000 to 10,000 IU. This trigger serves two purposes: induce oocyte maturation; and serve as luteal phase support owing to its long half-life. It now appears that the hCG bolus trigger is unable to support both these two purposes optimally. In particular, after an hCG trigger, the early luteal phase is hormonally abnormal and different from conditions observed in the natural menstrual cycle: the timing of the initiation of hCG and progesterone rise is much faster after an hCG trigger than in a natural menstrual cycle; the maximal concentrations of hCG and progesterone considerably exceed those naturally observed; and the timing of the peak progesterone concentration after an hCG trigger is advanced several days compared with the natural cycle. Furthermore, the hCG trigger without any follicle-stimulating hormone activity may induce oocyte maturation less efficiently than the combined luteinizing hormone and follicle-stimulating hormone surge normally seen. Collectively, the endometrium is likely to be advanced after an hCG trigger, and the implantation potential is probably not optimal. The precise effect on pregnancy rates after the different progressions of hCG and progesterone concentrations during the early luteal phase has not yet been determined, but more individualized methods using more physiological approaches are likely to improve reproductive outcomes.

OBJECTIVE: To characterize ovarian follicles of girls and young women with Turner syndrome (TS) who underwent ovarian tissue cryopreservation (OTC).DESIGN: Retrospective case-control study.SETTING: University hospital.PATIENT(S): Fifteen girls and young women with TS aged 5-22 years at OTC were included, together with 42 control girls and young women aged 1-25 years who underwent OTC because of cancer.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): Follicle density (follicles/mm3), morphology, and health were assessed in ovarian cortex biopsies from TS patients and compared with controls. Hormone concentrations were measured in serum and follicle fluids. Immature cumulus oocyte complexes were obtained and matured in vitro.RESULT(S): Follicles were found in 60% of the biopsies (9 of 15) from TS ovaries. In 78% of the ovaries (7 of 9) with follicles, the follicle density was within the 95% confidence interval of the control group. There was a high rate of abnormal follicle morphology. Six follicle-specific proteins were expressed similarly in TS and control ovaries. However, apoptosis and zona pellucida protein expression were found to be abnormal in TS. Turner syndrome follicle fluid from small antral follicles had lower concentrations of estrogen and testosterone and higher concentrations of antimüllerian hormone than controls. Thirty-one cumulus oocyte complexes were collected from one patient and cultured for 48 hours in vitro, resulting in five metaphase II oocytes (maturation rate 16%, degeneration rate 19%).CONCLUSION(S): The benefits of OTC may be limited to a highly selected group of TS mosaic patients in whom a sizeable pool of normal follicles is present at OTC.

OBJECTIVE: To characterize ovarian follicles of girls and young women with Turner syndrome (TS) who underwent ovarian tissue cryopreservation (OTC).DESIGN: Retrospective case-control study.SETTING: University hospital.PATIENT(S): Fifteen girls and young women with TS aged 5-22 years at OTC were included, together with 42 control girls and young women aged 1-25 years who underwent OTC because of cancer.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): Follicle density (follicles/mm3), morphology, and health were assessed in ovarian cortex biopsies from TS patients and compared with controls. Hormone concentrations were measured in serum and follicle fluids. Immature cumulus oocyte complexes were obtained and matured in vitro.RESULT(S): Follicles were found in 60% of the biopsies (9 of 15) from TS ovaries. In 78% of the ovaries (7 of 9) with follicles, the follicle density was within the 95% confidence interval of the control group. There was a high rate of abnormal follicle morphology. Six follicle-specific proteins were expressed similarly in TS and control ovaries. However, apoptosis and zona pellucida protein expression were found to be abnormal in TS. Turner syndrome follicle fluid from small antral follicles had lower concentrations of estrogen and testosterone and higher concentrations of antimüllerian hormone than controls. Thirty-one cumulus oocyte complexes were collected from one patient and cultured for 48 hours in vitro, resulting in five metaphase II oocytes (maturation rate 16%, degeneration rate 19%).CONCLUSION(S): The benefits of OTC may be limited to a highly selected group of TS mosaic patients in whom a sizeable pool of normal follicles is present at OTC.

PURPOSE: The aim was to describe the first experience with fertility preservation by cryopreservation of ovarian tissue (OTC) in pre-pubertal girls with galactosemia and further to characterize ovarian follicular morphology and expression of proteins important for ovarian function.METHODS: Retrospectively, follicle density was estimated in ovarian cortical tissues from 6 pre-pubertal girls below the age of 12 years diagnosed with galactosemia and from 31 girls below the age of 18 years who had one ovary removed for fertility preservation for other reasons prior to gonadotoxic treatment. Additionally, expression of 4 glycoproteins important for follicle development were analyzed with immunohistochemistry in two galactosemic ovaries (aged 0.9 and 1.7 years) and compared to normal age-matched controls. The proteins included were: anti-Müllerian hormone (AMH) pro-mature and C-terminal, growth differentiation factor-9 (GDF-9), bone morphogenetic protein 15 (BMP-15), and pregnancy-associated plasma protein A (PAPP-A).RESULTS: Girls with galactosemia below the age of 5 years presented with morphological normal follicles and follicle densities within the 95% confidence interval (CI) of controls. No follicles were detected in the ovary from an 11.7-year-old girl with galactosemia. Expression of AMH, GDF-9, BMP-15, and PAPP-A appeared similar in follicles from girls with galactosemia and controls.CONCLUSIONS: These findings suggest that young girls with galactosemia maintain follicles in early childhood and fertility cryopreservation may be considered an option in this patient group. The pathophysiology of galactosemia leading to an accelerated follicle loss is unknown and it is currently unknown to what extent transplanted ovarian tissue can sustain fertility in adult life.

Background Perfluoroalkyl substances (PFASs) are bio-accumulative pollutants, and prenatal exposure to PFASs is believed to impact human foetal development and may have long-term adverse health effects later in life. Additionally, maternal cigarette smoking may be associated with PFAS levels. Foetal exposure has previously been estimated from umbilical cord plasma, but the actual concentration in foetal organs has never been measured. Objectives The concentrations of 5 PFASs and cotinine – the primary metabolite of nicotine – were measured in human foetuses, placentas, and maternal plasma to evaluate to what extent these compounds were transferred from mother to foetus and to determine if the PFAS concentrations were associated with maternal cigarette smoking. Methods Thirty-nine Danish women who underwent legal termination of pregnancy before gestational week 12 were included; 24 maternal blood samples were obtained together with 34 placental samples and 108 foetal organs. PFASs and cotinine were assayed by liquid chromatography/triple quadrupole mass spectrometry. Results In foetal organs, the average concentrations of perfluorooctanesulphonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDa), and perfluorodecanoic acid (PFDA) were 0.6 ng/g, 0.2 ng/g, 0.1 ng/g, 0.1 ng/g, and 0.1 ng/g, respectively. A significant positive correlation was found between the exposure duration, defined as foetal age, and foetal to maternal ratio for all five PFASs and cotinine. Smokers presented 99 ng/g cotinine in plasma, 108 ng/g in placenta, and 61 ng/g in foetal organs. No correlation between the maternal cotinine concentrations and PFAS concentrations was found. Conclusions PFASs were transferred from mother to foetus, however, with different efficiencies. The concentrations of PFOS, PFOA, PFNA, PFUnDA, and PFDA in foetal organs were much lower than the maternal concentrations. Furthermore, a significant correlation bet

STUDY QUESTION Do women with BRCA1 or BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration?SUMMARY ANSWER Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH.WHAT IS KNOWN ALREADY The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan.STUDY DESIGN, SIZE, DURATION This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform.PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25–45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking.MAIN RESULTS AND THE ROLE OF CHANCE Mean AMH concentration was negatively associated with age (P < 0.001). Mutation carriers were younger at blood draw than non-carriers (P ≤ 0.031). BRCA1 mutation carriers had, on average, 25% (95% CI: 5%–41%, P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11–3

For the last two decades, exogenous progesterone administration has been used as luteal phase support (LPS) in connection with controlled ovarian stimulation combined with use of the human chorionic gonadotropin (hCG) trigger for the final maturation of follicles. The introduction of the GnRHa trigger to induce ovulation showed that exogenous progesterone administration without hCG supplementation was insufficient to obtain satisfactory pregnancy rates. This has prompted development of alternative strategies for LPS. Augmenting the local endogenous production of progesterone by the multiple corpora lutea has been one focus with emphasis on one hand to avoid development of ovarian hyper-stimulation syndrome and, on the other hand, to provide adequate levels of progesterone to sustain implantation. The present study evaluates the use of micro-dose hCG for LPS support and examines the potential advances and disadvantages. Based on the pharmacokinetic characteristics of hCG, the mathematical modelling of the concentration profiles of hCG during the luteal phase has been evaluated in connection with several different approaches for hCG administration as LPS. It is suggested that the currently employed LPS provided in connection with the GnRHa trigger (i.e. 1.500 IU) is too strong, and that daily micro-dose hCG administration is likely to provide an optimised LPS with the current available drugs. Initial clinical results with the micro-dose hCG approach are presented.

OBJECTIVE: To study the impact of first-line antineoplastic treatment on ovarian reserve in young girls returning for ovarian tissue cryopreservation (OTC) in connection with a relapse.DESIGN: Retrospective case-control study.SETTING: University hospitals.PATIENT(S): Sixty-three girls under the age of 18 years who underwent OTC before (group 1: 31 patients) and after (group 2: 32 patients) their initial cancer treatment.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): Follicular densities (follicles/mm(3)) measured from an ovarian cortical biopsy before OTC. The ovarian volume (mL) of entire ovaries excised for OTC was also monitored.RESULT(S): There was no statistically significant difference in the mean age or follicular density between groups 1 and 2 (334 ± 476/mm(3) vs. 327 ± 756/mm(3)). In contrast, the ovarian volume and total number of ovarian cortex chips cryopreserved were statistically significantly lower in patients who received gonadotoxic treatment before OTC (mean ± standard deviation [SD]: ovarian volume, 5.3 ± 3.1 mL vs. 2.9 ± 2.1 mL, respectively; number of cortex chips: 21.3 ± 8.1 vs. 15.2 ± 7.1, respectively). The reduction in the estimated ovarian reserve ranged from 10% to 20% in children to around 30% in adolescent girls (>10 years).CONCLUSION(S): Girls under the age of 10 tolerate a gonadotoxic insult better than adolescents, who may experience up to a 30% reduction in the ovarian reserve via first-line gonadotoxic treatment, which at present is considered to have little effect on the follicle pool. This information will improve counseling of young female cancer patients in deciding whether to undergo fertility preservation treatment.

The measurement of ovarian volume has been shown to be a useful indirect indicator of the ovarian reserve in women of reproductive age, in the diagnosis and management of a number of disorders of puberty and adult reproductive function, and is under investigation as a screening tool for ovarian cancer. To date there is no normative model of ovarian volume throughout life. By searching the published literature for ovarian volume in healthy females, and using our own data from multiple sources (combined n = 59,994) we have generated and robustly validated the first model of ovarian volume from conception to 82 years of age. This model shows that 69% of the variation in ovarian volume is due to age alone. We have shown that in the average case ovarian volume rises from 0.7 mL (95% CI 0.4 -- 1.1 mL) at 2 years of age to a peak of 7.7 mL (95% CI 6.5 -- 9.2 mL) at 20 years of age with a subsequent decline to about 2.8mL (95% CI 2.7 -- 2.9 mL) at the menopause and smaller volumes thereafter. Our model allows us to generate normal values and ranges for ovarian volume throughout life. This is the first validated normative model of ovarian volume from conception to old age; it will be of use in the diagnosis and management of a number of diverse gynaecological and reproductive conditions in females from birth to menopause and beyond., Comment: 14 pages, 7 figures

Qualitative modelling is a technique integrating the fields of theoretical computer science, artificial intelligence and the physical and biological sciences. The aim is to be able to model the behaviour of systems without estimating parameter values and fixing the exact quantitative dynamics. Traditional applications are the study of the dynamics of physical and biological systems at a higher level of abstraction than that obtained by estimation of numerical parameter values for a fixed quantitative model. Qualitative modelling has been studied and implemented to varying degrees of sophistication in Petri nets, process calculi and constraint programming. In this paper we reflect on the strengths and weaknesses of existing frameworks, we demonstrate how recent advances in constraint programming can be leveraged to produce high quality qualitative models, and we describe the advances in theory and technology that would be needed to make constraint programming the best option for scientific investigation in the broadest sense., Comment: 15 pages plus references

Human ovarian reserve is defined by the population of nongrowing follicles (NGFs) in the ovary. Direct estimation of ovarian reserve involves the identification of NGFs in prepared ovarian tissue. Previous studies involving human tissue have used hematoxylin and eosin (HE) stain, with NGF populations estimated by human examination either of tissue under a microscope, or of images taken of this tissue. In this study we replaced HE with proliferating cell nuclear antigen (PCNA), and automated the identification and enumeration of NGFs that appear in the resulting microscopic images. We compared the automated estimates to those obtained by human experts, with the "gold standard" taken to be the average of the conservative and liberal estimates by three human experts. The automated estimates were within 10% of the "gold standard", for images at both 100x and 200x magnifications. Automated analysis took longer than human analysis for several hundred images, not allowing for breaks from analysis needed by humans. Our results both replicate and improve on those of previous studies involving rodent ovaries, and demonstrate the viability of large-scale studies of human ovarian reserve using a combination of immunohistochemistry and computational image analysis techniques.