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Ovarian cortex from 5 girls below the age of 5 years with galactosemia had morphological normal primordial follicles, though no growing follicles were observed (A–E). A fraction of the follicles in (C) appeared to have lost the oocyte nucleus and be in a process of atresia. An age-matched control ovary (0.6 years old) had morphologically normal follicles (F)
Source publication
PurposeThe 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 co...
Citations
... GALT gene variants exhibit significant ethnic and regional differences; c. [3,5,24,25]. There are no reports of a predominant type of GALT gene variant in the Chinese population. ...
Background
Galactosemia is an autosomal recessive disorder resulting from an enzyme defect in the galactose metabolic pathway. The most severe manifestation of classic galactosemia is caused by galactose-1-phosphate uridylyltransferase (GALT) deficiency, and this condition can be fatal during infancy if left untreated. It also may result in long-term complications in affected individuals.
Case presentation
This report describes a patient whose initial clinical symptoms were jaundice and liver dysfunction. The patient’s liver and coagulation functions did not improve after multiple admissions and treatment with antibiotics, hepatoprotective and choleretic agents and blood transfusion. Genetic analysis revealed the presence of two variants in the GALT gene in the compound heterozygous state: c.377 + 2dup and c.368G > C (p.Arg123Pro). Currently, the variant locus (c.377 + 2dup) in the GALT gene has not been reported in the Human Gene Mutation Database (HGMD), while c.368G > C (p.Arg123Pro) has not been reported in the Genome Aggregation Database (GnomAD) nor the HGMD in East Asian population. We postulated that the two variants may contribute to the development of classical galactosemia.
Conclusions
Applications of whole-exome sequencing to detect the two variants can improve the detection and early diagnosis of classical galactosemia and, more specifically, may identify individuals who are compound heterozygous with variants in the GALT gene. Variants in the GALT gene have a potential therapeutic significance for classical galactosemia.
... Это согласуется с результатами, полученными L.S. Mamsen и соавт. В данном исследовании шести девочкам с галактоземией в возрасте до 12 лет была проведена криоконсервация ткани яичника: нормальная плотность и морфология фолликулов яичников наблюдались у пяти девочек (все в возрасте 5 лет и младше), при этом у девочки с КГ, которой было 11,7 года, фолликулов в яичниках обнаружено не было [15]. Следует отметить, что такие параметры, как низкий уровень АМГ, повышенный уровень ФСГ и уменьшение числа антральных фолликулов (AFC), не исключают возможности наличия рассеянных мелких фолликулов, находящихся в состоянии покоя [14]. ...
... Метод криоконсервации ткани яичников предполагает хирургическое извлечение ткани яичника, при этом кора яичника изолируется, рассекается на фрагменты и затем криоконсервируется [15]. Существуют сомнения относительно эффективности этого метода у пациенток с КГ: есть опасения, что повреждение яичников, возможно, уже произошло, при этом сам процесс удаления ткани яичников еще больше уменьшит овариальный резерв [11]. ...
... Тем не менее, имеются ограниченные данные о безопасности и эффективности этого метода: известно об одном живорожденном после криоконсервации ткани яичников, а также несколько сообщений об успешной индукции полового созревания с помощью пересаженных в раннем подростковом возрасте тканей, что подтверждает эффективность применения данного метода в препубертатном периоде [6]. Учитывая прогрессирующую потерю фолликулов, данный метод может быть рекомендован пациенткам с КГ в первое десятилетие жизни [15], а проведение этой процедуры у молодых девушек препубертатного возраста, по некоторым данным, является процедурой выбора. Однако возникновение самопроизвольной беременности у некоторых пациенток с КГ, несмотря на ПНЯ, делает необходимым принятие взвешенного решения о применении методов сохранения фертильности [6]. ...
Background . Galactosemia is a congenital disorder of carbohydrate metabolism caused by a defect in any of the enzymes of galactose metabolism. One of the long-term complications is premature ovarian insufficiency (POI), which is more common in patients with the c.563A>G (Q188R) mutation in the homozygous state in the galactose-1-phosphate uridylyltransferase (GALT) gene. At the same time, fertility factors may be higher in patients with POI caused by classical galactosemia (CG) compared with other causes of POI, which makes it difficult to resolve the issue of the need to use fertility preservation methods for this group of patients in the prepubescent period. Case report. This article describes two clinical observations of patients with CG who were diagnosed with hypergonadotropic hypogonadism. Patient A. was initiated hormone replacement therapy (HRT) at the age of 11, and according to the results of osteodensitometry, there is currently no decrease in bone mineral density. In patient C. at the age of 14, before the start of HRT, ovaries without pronounced follicular apparatus, osteopenia and osteoporosis were detected. The issue of the necessity and timing of the use of fertility preservation methods is being considered. Conclusion . Patients with CG are recommended to monitor hormonal profile indicators for timely administration of HRT. Cryopreservation of ovarian tissue should be considered as one of the options for maintaining fertility in patients with CG, taking into account that some of them still have the possibility of spontaneous pregnancy, despite the POI.
... This method produced good results when compared to 13 density counts from a single laboratory, with 87% correlation between observations and predictions, and was externally validated by showing 90% correlation when using 15 densities from the published literature (McLaughlin et al. 2015). The approach continues to be used when assessing ovarian reserve in the younger than 25 age group, with further model validation from studies comparing controls to subjects with Turner syndrome (Mamsen et al. 2019), galactosemia (Mamsen et al. 2018), and exposure to chemotherapy (El Issaoui et al. 2016;McLaughlin et al. 2017). OV can therefore be used to predict NGF populations in healthy females for ages ranging from childhood to postmenopausal ages, and can hence be used to compare estimated reproductive age to known chronological age in a variety of settings. ...
The human ovarian reserve is defined by the number of non-growing follicles (NGFs) in the ovary, with the age-related decline in NGF population determining age at menopause for healthy women. In this chapter, the concept of ovarian reserve is explored in detail, with a sequence of models described that in principle allow any individual to be compared to the general population. As there is no current technology that can count the NGFs in a living ovary, we move our focus to biomarkers for the ovarian reserve. Using serum analysis and ultrasound it is possible to measure anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and ovarian volume (OV) and to count numbers of antral follicles (AFC). These are compared, with ovarian volume being the closest to a true biomarker for a wide range of ages and with AMH and AFC being the most popular for post-pubertal and pre-menopausal ages. The study of genetic and subcellular biomarkers for the ovarian reserve has produced less concrete results. Recent advances are described and compared in terms of limitations and potential. The chapter concludes with an overview of the future study indicated by our current knowledge and by current controversy in the field.KeywordsOvarian reserveMathematical modelReproductive ageBiomarkerFertilityMenopause
... Olesen et al. Reproductive Biology and Endocrinology (2023) 21:28 Background Cryopreservation and autotransplantation of human ovarian cortex tissue has gained ground worldwide as the only fertility preserving option for prepubertal girls and patients in need of immediate cancer treatment [1][2][3][4]. Since the first live birth in 2004 [5], the number of live births has now exceeded 200 and live births rates in women transplanted with ovarian tissue range from 20-30% [6][7][8][9][10][11]. Following ovarian tissue transplantation (OTT) an endocrine recovery of 72-95% has been reported [6]. ...
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.
... In evolution, however, patients show ovarian failure with primary or secondary amenorrhea, and hypogonadism is documented in 80% to 90% of women with classic galactosemia. Other manifestations are delayed development and learning difficulties that worsen with age as well as a decrease in bone mineral density, and most patients having speech disorders, impaired motor function, and balance disorders [56][57][58]. ...
Galactosemia is an inborn metabolic disorder caused by a deficient activity in one of the enzymes involved in the metabolism of galactose. The first description of galactosemia in newborns dates from 1908, ever since complex research has been performed on cell and animal models to gain more insights into the molecular and clinical bases of this challenging disease. In galactosemia, the newborn appears to be born in proper health, having a window of opportunity before developing major morbidities that may even be fatal following ingestion of milk that contains galactose. Galactosemia cannot be cured, but its negative consequences on health can be avoided by establishing precocious diagnosis and treatment. All the foods that contain galactose should be eliminated from the diet when there is a suspicion of galactosemia. The neonatal screening for galactosemia can urge early diagnosis and intervention, preventing complications. All galactosemia types may be detected during the screening of newborns for this disorder. The major target is, however, galactose-1-phosphate uridyltransferase (GALT) deficiency galactosemia, which is diagnosed by applying a combination of total galactose and GALT enzyme analysis as well as, in certain programs, mutation screening. Most critically, infants who exhibit symptoms suggestive of galactosemia should undergo in-depth testing for this condition even when the newborn screening shows normal results. The decision to enroll global screening for galactosemia among the specific population still faces many challenges. In this context, the present narrative review provides an updated overview of the incidence, clinical manifestations, diagnosis, therapy, and prognosis of galactosemia, questioning under the dome of these aspects related to the disease the value of its neonatal monitoring.
... For galactosemia patients, genetic counseling regarding the risk of infertility; and a pediatric endocrinologist follow-up are recommended. In prepubertal patients, OTC [81] may be considered. If no ovarian activity is detected or COH fails, oocyte or embryo donation at the time the patient would like to build her family is optional [82]. ...
The ovarian reserve is finite and begins declining from its peak at mid-gestation until only residual follicles remain as women approach menopause. Reduced ovarian reserve, or its extreme form, premature ovarian insufficiency, stems from multiple factors, including developmental, genetic, environmental exposures, autoimmune disease, or medical/surgical treatment. In many cases, the cause remains unknown and resulting infertility is not ultimately addressed by assisted reproductive technologies. Deciphering the mechanisms that underlie disorders of ovarian reserve could improve the outcomes for patients struggling with infertility, but these disorders are diverse and can be categorized in multiple ways. In this review, we will explore the topic from a perspective that emphasizes the prevention or mitigation of ovarian damage. The most desirable mode of fertoprotection is primary prevention (intervening before ablative influence occurs), as identifying toxic influences and deciphering the mechanisms by which they exert their effect can reduce or eliminate exposure and damage. Secondary prevention in the form of screening is not recommended broadly. Nevertheless, in some instances where a known genetic background exists in discrete families, screening is advised. As part of prenatal care, screening panels include some genetic diseases that can lead to infertility or subfertility. In these patients, early diagnosis could enable fertility preservation or changes in family-building plans. Finally, Tertiary Prevention (managing disease post-diagnosis) is critical. Reduced ovarian reserve has a major influence on physiology beyond fertility, including delayed/absent puberty or premature menopause. In these instances, proper diagnosis and medical therapy can reduce adverse effects. Here, we elaborate on these modes of prevention as well as proposed mechanisms that underlie ovarian reserve disorders.
... According to a recent study, these girls maintain healthy follicles in early age, thus being candidates for cryopreservation. However, the fertility rates of a preserved tissue of such origin needs to be evaluated, making this method experimental for this group of patients [65]. The relative frequency of malignancies as indication for cryopreservation ranged from 67 to 95% [11,63]. ...
Cancer during childhood and adolescence remains a major public health issue, affecting a significant portion of this age group. Although newer anti-cancer treatments have improved survival rates, this comes at a cost in terms of gonadotoxic effects. As a result, the preservation of fertility is important. Ovarian tissue cryopreservation, one of the newest methods, has some advantages, especially for prepubertal patients: no need for ovarian stimulation, thus, no further risk for estrogen-sensitive cancer types, and preservation of more and better-quality primordial follicles of the ovarian cortex. The most frequent indications include treatment with alkylating agents, ovarian-focused radiotherapy, leukemias, lymphomas, brain and neurological tumors, as well as Turner syndrome and benign hemoglobinopathies. An expected survival exceeding 5 years, the absence of systematic disease and an overall risk of premature ovarian insufficiency over 50% are among the criteria that need to be fulfilled in order for a patient to undertake this method. Orthotopic transplantation is more frequently used, since it can allow both live birth and the recovery of endocrine function. Reimplantation of malignant cells is always a major risk and should always be taken into consideration. Histological analysis, as well as immunohistochemical and molecular methods, are needed in order to improve the search for malignant cells before transplantation. Ovarian tissue cryopreservation appears to be a method with specific benefits, indications and risks which can be an important tool in terms of preserving fertility in younger women.
... Three fertility preservation procedures are available: ovarian tissue, mature oocyte, and/or embryo cryopreservation [82]. Even though cryopreservation reduces the ovarian reserve, this technique is now associated with an increasing success rate and low complication rate [83]. Intrafamilial oocyte donation is another approach to address subfertility in CG. ...
Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented.
... Ovarian tissue was processed into squares in 15 sites from 11 countries (20,65,. In total, 17 different sites (29.3%) from 12 countries process ovarian tissue into dimensions that were categorized into fragments (Table 1) (21,62,77,. Fragments with the dimensions of 2 x 2 mm (length, width) were the most common in 5 sites. ...
... This site processed a 9-year-old Ewing's sarcoma participant's ovarian tissue into 5 x 4 mm 2 (64). Six galactosemia participants at this site had one ovary removed for fertility preservation at the ages of 1.7, 0.9, 4.5, 0.3, 2.9, and 11.7 and ovarian tissue was cut into the dimensions: 5 x 5, 4 x 3, 3 x 3, 3 x 2, 2 x 2, and 2 x 2 mm 2 , respectively (77). Additionally at this site, 25 leukemia participants had 5 x 1 mm 2 strips cryopreserved (71). ...
Ovarian tissue cryopreservation (OTC) is the only pre-treatment option currently available to preserve fertility for prepubescent girls and patients who cannot undergo ovarian stimulation. Currently, there is no standardized method of processing ovarian tissue for cryopreservation, despite evidence that fragmentation of ovaries may trigger primordial follicle activation. Because fragmentation may influence ovarian transplant function, the purpose of this systematic review was ( 1 ) to identify the processing sizes and dimensions of ovarian tissue within sites around the world, and ( 2 ) to examine the reported outcomes of ovarian tissue transplantation including, reported duration of hormone restoration, pregnancy, and live birth. A total of 2,252 abstracts were screened against the inclusion criteria. In this systematic review, 103 studies were included for analysis of tissue processing size and 21 studies were included for analysis of ovarian transplantation outcomes. Only studies where ovarian tissue was cryopreserved (via slow freezing or vitrification) and transplanted orthotopically were included in the review. The size of cryopreserved ovarian tissue was categorized based on dimensions into strips, squares, and fragments. Of the 103 studies, 58 fertility preservation sites were identified that processed ovarian tissue into strips (62%), squares (25.8%), or fragments (31%). Ovarian tissue transplantation was performed in 92 participants that had ovarian tissue cryopreserved into strips (n = 51), squares (n = 37), and fragments (n = 4). All participants had ovarian tissue cryopreserved by slow freezing. The pregnancy rate was 81.3%, 45.5%, 66.7% in the strips, squares, fragment groups, respectively. The live birth rate was 56.3%, 18.2%, 66.7% in the strips, squares, fragment groups, respectively. The mean time from ovarian tissue transplantation to ovarian hormone restoration was 3.88 months, 3.56 months, and 3 months in the strips, squares, and fragments groups, respectively. There was no significant difference between the time of ovarian function’ restoration and the size of ovarian tissue. Transplantation of ovarian tissue, regardless of its processing dimensions, restores ovarian hormone activity in the participants that were reported in the literature. More detailed information about the tissue processing size and outcomes post-transplant are required to identify a preferred or more successful processing method.
Systematic Review Registration
[ https://www.crd.york.ac.uk ], identifier [CRD42020189120].
... Primary ovarian insufficiency (POI) with ovarian follicular depletion leading to subfertility is reported in at least 80% of female patients despite a galactose-restricted diet, representing a heavy burden for female patients [6,[117][118][119][120][121]. The etiology of ovarian failure and timing of ovarian damage (pre-or postnatal) have not yet been resolved, although studies suggest that follicular depletion has an early initiation [117,120,[122][123][124]. Ovarian imaging results show an early onset of ovarian failure (n = 14) [125]. ...
... Ovarian imaging results show an early onset of ovarian failure (n = 14) [125]. Moreover, Mamsen et al. have shown normal follicle morphology and follicle densities in galactosemic girls under 5 years (n = 5) [122]. This is supported by the finding of low anti-Mullerian hormone (AMH) levels and low antral follicle counts relative to age-matched controls, suggesting that follicular dysfunction occurs early in life [126,127]. ...
... The early occurrence of damage supports cryopreservation of ovarian tissue at a very young age as a treatment option [122,125]. Cryopreservation of ovarian tissue has been applied for several years to preserve fertility in patients with (mostly) malignant pathologies that undergo treatments with a detrimental effect on fertility. In recent years, the optimization of cryopreservation strategies and thawing/warming protocols has been achieved, expanding the opportunities for females with various pathologies [130,131]. ...
Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches.
