Premature Loss Of Ovarian Function Research Articles

Effect of Donor Age on Endocrine Function of and Immune Response to Ovarian Grafts.

Premature loss of ovarian function (POI) is associated with numerous negative side effects, including vasomotor symptoms, sleep and mood disturbances, disrupted urinary function, and increased risks for osteoporosis and heart disease. Hormone replacement therapy (HRT), the standard of care for POI, delivers only a subset of ovarian hormones and fails to mimic the monthly cyclicity and daily pulsatility characteristic of healthy ovarian tissue in reproductive-aged individuals whose ovarian tissue contains thousands of ovarian follicles. Ovarian tissue allografts have the potential to serve as an alternative, cell-based HRT, capable of producing the full panel of ovarian hormones at physiologically relevant doses and intervals. However, the risks associated with systemic immune suppression (IS) required to prevent allograft rejection outweigh the potential benefits of comprehensive and dynamic hormone therapy. This work investigates whether the age of ovarian tissue donor animals affects the function of, and immune response to, subcutaneous ovarian grafts. We performed syngeneic and semi-allogeneic ovarian transplants using tissue from mice aged 6-8 (D7) or 20-22 (D21) days and evaluated ovarian endocrine function and immune response in a mouse model of POI. Our results revealed that tissue derived from D7 donors, containing an ample and homogeneous primordial follicle reserve, was more effective in fully restoring hypothalamic-pituitary-ovarian feedback. In contrast, tissue derived from D21 donors elicited anti-donor antibodies with higher avidity compared to tissue from younger donors, suggesting that greater immunogenicity may be a trade-off of using mature donors. This work contributes to our understanding of the criteria donor tissue must meet to effectively function as a cell-based HRT and explores the importance of donor age as a factor in ovarian allograft rejection.

Pharmacological Protection of Ovaries During Program Drug Chemotherapy in Classical Hodgkin Lymphoma and Non-Hodgkin Lymphoma Patients

Aim. To assess the efficacy of ovarian protection and options for fertility preservation with the use of gonadotropin-releasing hormone agonists (a-GnRH) in patients with classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphomas (NHLs) during program drug chemotherapy.
 Materials & Methods. The study enrolled 247 female patients (187 with cHL and 60 with NHLs) undergoing program drug chemotherapy from 2019 to 2023. The patients were aged 13–42 years (median 24 years). Prior to chemotherapy and after it was completed, the serum anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), and estradiol levels were measured. Besides, antral follicle count was estimated by pelvic ultrasound. To provide ovarian protection during chemotherapy, a-GnRH was administered to 67 (27 %) out of 247 patients. Ovarian reserve was assessed based on ultrasound and AMH, FSH, and estradiol levels in 2–3 months after completing the program of drug chemotherapy or after spontaneous menstrual recovery.
 Results. Menstrual cycle recovered in 194 (78.5 %) out of 247 patients, regardless of lymphoid malignancy variant. Among them, there were 79.7 % (n = 149) of cHL patients and 75 % (n = 45) of NHL patients. Accordingly, ovarian function was lost in 20.3 % (n = 38) of cHL patients and 25 % (n = 15) of NHL patients. Predictors of ovarian function recovery appeared to be age ≤ 28 years and AMH level > 2.45 ng/mL. Pharmacological protection of ovaries did not impact the probability of menstrual cycle recovery. Regardless of immunomorphological variant of lymphoid malignancy, a regular menstrual cycle was completely restored in 48 (71.6 %) out of 67 a-GnRH recipients and in 146 (81.1 %) out of 180 patients without a-GnRH treatment.
 Conclusion. Most of cHL and NHL patients of early reproductive age (≤ 30 years) have a fair chance of menstrual cycle recovery after completing the program drug chemotherapy similar to BEACOPP, EACODD(PP)-14, R-CHOP, R-Da-EPOCH and other regimens. Ovarian reserve cannot be preserved by means of a-GnRH administration during chemotherapy. High baseline FSH and low baseline AMH levels indirectly indicate evidence of impaired ovarian reserve. Patients belonging to this category are those who, if intensive combined cytostatic therapy regimens are planned, should undergo prior oocyte/embryo retrieval with subsequent cryopreservation due to the risk of premature loss of ovarian function.

P-605 Biomechanical characteristics of the ovarian cortex in POI patients and functional outcomes after drug-free IVA

Abstract Study question Is there a relationship between the biomechanical characteristics of ovarian cortex of POI patients and the resumption ovarian function after Drug-Free IVA? Summary answer Physical properties of ovarian cortex in POI are different. A significant ovarian stiffness increase was observed when resumption of ovarian function occurred after Drug-Free IVA. What is known already There is increasing evidence that the ovarian extracellular matrix (ECM) plays a critical role in follicle development. Primordial follicles are localized at the collagen-rich ovarian cortex, which offers a rigid physical environment that supports follicular architecture and increases survival. Therefore, premature loss of ovarian function would be associated with a physically less rigid ovarian cortex. Study design, size, duration Prospective observational cohort study at a tertiary-care university hospital including POI patients according ESHRE criteria who underwent Drug-Free IVA by laparoscopy between January 2018 and December 2019 and were follow-up for a year after intervention. Participants/materials, setting, methods Nineteen patients were included. Resumption of ovarian function was defined as resumption of menstrual cycles (at least three consecutive episodes of menstrual bleeding) and/or the presence of follicles > 10 mm on ultrasound. A sample of ovarian cortex taken during the intervention was analyzed by atomic force microscopy (AFM) in order to quantitatively measure mechanical properties at the nanometer scale (Young’s elastic modulus, E). Main results and the role of chance Median data at intervention were: age = 35 years (28–39); length of amenorrhea = 2 years (1–10); FSH level = 104.4 mIU/ml (38.9–176); and AMH = 0.02 ng/ml (0.01–0.1). Resumption of ovarian function was observed in 10 patients (52.6 %), achieving 2 pregnancies (one spontaneous and one after an IVF cycle). Median stiffness (E) measured by AFM was 2583 Pa (999–11296). There were no differences in clinical and hormonal parameters as a function of resumption of ovarian activity. Remarkably, ovarian cortex stiffness was significantly increased in patients with ovarian activity after Dug-Free VIA: 5519 (2260–11296] vs 1501 [999–3474], p value <0.001. Limitations, reasons for caution The main limitations of the study are the unavailability of ovarian tissue samples from a control group of patients without POI and the inability to perform histological studies on the same samples in which the biomechanical study was carried out. Wider implications of the findings These findings show the high variability of ovarian cortex stiffness in POI and that the increase of this stiffness entails a more favorable status after Drug-Free IVA. This may be related to an ovary with more residual follicles, which would explain a greater chances of ovarian follicular reactivations after treatment. Trial registration number not applicable

Exposure to environmentally relevant concentrations of ambient fine particulate matter (PM2.5) depletes the ovarian follicle reserve and causes sex-dependent cardiovascular changes in apolipoprotein E null mice

BackgroundFine particulate matter (PM2.5) exposure accelerates atherosclerosis and contains known ovotoxic chemicals. However, effects of exposure to PM2.5 on the finite ovarian follicle pool have hardly been investigated, nor have interactions between ovarian and cardiovascular effects. We hypothesized that subchronic inhalation exposure to human-relevant concentrations of PM2.5 results in destruction of ovarian follicles via apoptosis induction, as well as accelerated recruitment of primordial follicles into the growing pool. Further, we hypothesized that destruction of ovarian follicles enhances the adverse cardiovascular effects of PM2.5 in females.ResultsHyperlipidemic apolipoprotein E (Apoe) null ovary-intact or ovariectomized female mice and testis-intact male mice were exposed to concentrated ambient PM2.5 or filtered air for 12 weeks, 5 days/week for 4 h/day using a versatile aerosol concentration enrichment system. Primordial, primary, and secondary ovarian follicle numbers were decreased by 45%, 40%, and 17%, respectively, in PM2.5-exposed ovary-intact mice compared to controls (P < 0.05). The percentage of primary follicles with granulosa cells positive for the mitosis marker Ki67 was increased in the ovaries from PM2.5-exposed females versus controls (P < 0.05), consistent with increased recruitment of primordial follicles into the growing pool. Exposure to PM2.5 increased the percentages of primary and secondary follicles with DNA damage, assessed by γH2AX immunostaining (P < 0.05). Exposure to PM2.5 increased the percentages of apoptotic antral follicles, determined by TUNEL and activated caspase 3 immunostaining (P < 0.05). Removal of the ovaries and PM2.5-exposure exacerbated the atherosclerotic effects of hyperlipidemia in females (P < 0.05). While there were statistically significant changes in blood pressure and heart rate variability in PM2.5-compared to Air-exposed gonad-intact males and females and ovariectomized females, the changes were not consistent between exposure years and assessment methods.ConclusionsThese results demonstrate that subchronic PM2.5 exposure depletes the ovarian reserve by increasing recruitment of primordial follicles into the growing pool and increasing apoptosis of growing follicles. Further, PM2.5 exposure and removal of the ovaries each increase atherosclerosis progression in Apoe-/- females. Premature loss of ovarian function is associated with increased risk of osteoporosis, cardiovascular disease and Alzheimer’s disease in women. Our results thus support possible links between PM2.5 exposure and other adverse health outcomes in women.

Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset.

Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovarian dysgenesis and primary amenorrhea to post-pubertal secondary amenorrhea, with elevated serum gonadotropins and hypoestrogenism. The ovarian defect still remains idiopathic in some cases; however, a strong genetic component has been demonstrated by the next-generation sequencing (NGS) approach of familiar and sporadic POI cases. As recent evidence suggested an oligogenic architecture for POI, we developed a target NGS panel with 295 genes including known candidates and novel genetic determinants potentially involved in POI pathogenesis. Sixty-four patients with early onset POI (range: 10–25 years) of our cohort have been screened with 90% of target coverage at 50×. Here, we report 48 analyzed patients with at least one genetic variant (75%) in the selected candidate genes. In particular, we found the following: 11/64 patients (17%) with two variants, 9/64 (14%) with three variants, 9/64 (14%) with four variants, 3/64 (5%) with five variants, and 2/64 (3%) with six variants. The most severe phenotypes were associated with either the major number of variations or a worse prediction in pathogenicity of variants. Bioinformatic gene ontology analysis identified the following major pathways likely affected by gene variants: 1) cell cycle, meiosis, and DNA repair; 2) extracellular matrix remodeling; 3) reproduction; 4) cell metabolism; 5) cell proliferation; 6) calcium homeostasis; 7) NOTCH signaling; 8) signal transduction; 9) WNT signaling; 10) cell death; and 11) ubiquitin modifications. Consistently, the identified pathways have been described in other studies dissecting the mechanisms of folliculogenesis in animal models of altered fertility. In conclusion, our results contribute to define POI as an oligogenic disease and suggest novel candidates to be investigated in patients with POI.

The different doses of radiation therapy-induced damage to the ovarian environment in rats

Purpose The sequelae of premature loss of ovarian function can undoubtedly have undesirable effects for a woman although radiotherapy is one of the most relevant treatment modalities for various types of malignancies. The aim of this study was to determine the effect of different doses of radiation on ovarian folliculogenesis, inflammation, and apoptotic markers. Materials and methods For this purpose, 40 healthy Wistar albino female rats divided into four groups: 1) Control group; 2) those that were exposed to total body 1 Gy of gamma rays; 3) those that were exposed to the total body 5 Gy of gamma rays, and 4) those that were exposed to total body 10 Gy of gamma rays. External irradiation to the total body was given with gamma irradiation delivered by the Co60 teletherapy machine. The day after radiation application the rats were sacrificed and the ovaries were removed in all groups. Histopathologic examination, follicle counting, and classification were performed in the ovarian tissues. The expression of AMH, TNF-α, IL1-β, Bax, and Bcl-2 was detected. The stained sections were examined for caspase 3 positive apoptotic cell numbers. Results The recorded results revealed that increased radiation dose induced obvious ovarian injuries that were indicated by histopathological, and immunohistochemical alterations, including elevation of ovarian injury markers. A significantly lower number of total and primordial follicles was detected with increasing radiation dose compared with the control group. According to our immunohistochemical results, 10 Gy of gamma rays group had the lowest AMH expression levels, while had the highest TNF-α, IL1-β expression level compared to the control group. When the groups were evaluated in terms of apoptosis, it was seen that the number of caspase 3 positive cells and Bax immunoreactivity intensity increased with radiation dose. In contrast, Bcl-2 immunoreactivity intensity decreased with increasing radiation dose compared with the control group. Conclusions We demonstrate here that dose rate plays an important role when estimating the relation between exposure to an increased dose of ionizing radiation and the risk of ovarian disease. According to these results, certain factors have to be optimized before introducing them into clinics.

Being born preterm or with low weight implies a risk of infertility and premature loss of ovarian function; a national register study

Background: Being born with non-optimal birth characteristics has several long-term consequences on health in general but also for the individual’s reproductive pattern. In premature ovarian insufficiency (POI) the follicles are depleted or dysfunctional. This results in menopause before the age of 40, and for most of the affected women, it causes infertility. The objective of this study was to evaluate the potential effects of being born with non-optimal birth characteristics on the risk of developing POI.Methods: This population-based cohort register study included all women born in Sweden between 1973 and 1993 who were followed until the end of 2012 (age at the end of follow-up ranged between 39 and 59). Women diagnosed with POI were compared with women without this diagnosis with respect to being born small for gestational age, preterm, or with low birth weight. Data on birth characteristics and diagnosis of POI were collected from national registers.Results: A total of 1,033,878 women were included. Being born small for gestational age was associated with a slightly increased odds ratio of POI with 10%. Preterm birth and low birth weight were associated with somewhat increased ORs of POI after exclusion of those born small for gestational age. Similarly, being born preterm or with a low birth weight was also found to be associated with POI to the same extent.Conclusions: Being born with non-optimal birth characteristics may increase the risk of premature ovarian insufficiency.

Bilateral oophorectomy, accelerated aging: Late breaking news on a controversial issue

In this presentation, I will discuss the controversial question: Is bilateral oophorectomy a cause or a consequence of accelerated aging? In 2016, Levine and colleagues reported that the premature loss of ovarian function may lead to an increase in DNA methylation, a biological marker of accelerated aging (Levine et al., 2016). In the same year, Rocca and colleagues reported an association between bilateral oophorectomy performed before menopause and the rate of accumulation of multimorbidity using 18 defined chronic conditions (Rocca et al., 2016). However, it remains difficult in a non-experimental setting to definitively test whether accelerated aging leads to symptoms that prompt bilateral oophorectomy, or whether bilateral oophorectomy prompts accelerated aging (cause-effect uncertainty and confounding by indication). In a 2017 publication, we addressed the cause-effect uncertainty with new analyses restricted to women who did not have any of 18 chronic conditions at baseline (Rocca et al., 2017). The Rochester Epidemiology Project records-linkage system was used to identify 420 premenopausal women who underwent bilateral oophorectomy for a non-cancerous condition before age 46 years from 1988 to 2007 in Olmsted County, MN, and 592 age matched referent women (±1 year) who had not undergone bilateral oophorectomy. After adjustments for several possible confounding variables present at baseline, women who underwent oophorectomy experienced an accelerated rate of accumulation of the 18 chronic conditions considered together (HR = 1.24; 95% CI = 1.12–1.37; p < .001). The single-year incidence rate of new conditions was most different in the first 6 years after oophorectomy, but the difference attenuated thereafter. Findings did not vary by surgical indication for the oophorectomy (benign condition vs. no ovarian condition). Current biomarker data and clinical evidence suggests that bilateral oophorectomy is causally linked to accelerated aging.

Fertilité et insuffisance ovarienne : de nouveaux traitements en perspective ?

The premature loss of ovarian function may have physical and psychological consequences. A better understanding of its mechanism is therefore needed. Because they are affecting the oocyte quality, the decline of the ovarian reserve and high maternal age are implicated in many defects leading to chromosomal defects, modifications of gene expression or alterations of the mitochondrial pattern of the oocyte. However, cellular therapies such as ovarian follicle activation or isolation of ovarian stem cells are promising treatments of ovarian failure.

Molecular Mechanisms and Consequences of Premature Ovarian Aging.

Premature ovarian aging is an important disorder associated with infertility, osteoporosis and cardiovascular disease. Mechanisms that underlie premature ovarian aging are heterogeneous, and involve genetic, environmental and iatrogenic factors. Current practice in the evaluation of a woman with premature ovarian aging involves differentiating gonad dysfunction from pituitary and central nervous system dysfunction, and testing for X chromosome abnormalities as well as FMR1 pre-mutation status. Despite this testing, the diagnosis is unclear in majority of cases and algorithms regarding follow up, family planning, oocyte or embryo cryopreservation is lacking. The medical intervention to preserve fertility, and when to do it in families at risk, is limited by the low predictive value of current markers of ovarian reserve. Vast majority of premature ovarian aging cases are due to dysfunction in the ovarian function. Man made and spontaneous mutations in mice have given us great insights into the genetic components that are critical for ovarian development, and folliculogenesis. Both ubiquitous and ovary specific pathways, are critical for oogenesis and egg maturation. Oocyte differentiation into a totipotent cell requires initial germ cell cyst breakdown to form primordial follicles, recruitment of primordial follicles for development into primary follicles and remarkable growth of the ovarian follicle, which culminates in ovulation. During oogenesis, oocyte undergoes dynamic alterations in gene expressions that are regulated by a set of well-coordinated transcription factors active in the germ line and soma. Early embryogenesis begins during oogenesis, as many maternal effect genes (genes that are inherited from the egg, and affect post-fertilization events) commence transcription during early stages of folliculogenesis. A number of germ cell specific as well as somatic expressed transcriptional regulators are critical in ovarian formation, folliculogenesis and expression of maternal effect genes. These transcriptional regulators include: Foxo3a, Foxl2, Figla, Lhx8, Nobox, Pou5f1, Sohlh1 and Sohlh2. A subset of these transcriptional regulators is mutated in women with ovarian insufficiency and infertility. Studies on transcriptional regulators preferentially expressed in the ovary are important to develop a better understanding of the mechanisms of activation and survival of ovarian follicles, as well as an understanding of ovary specific pathways that can be modulated in the future to regulate fertility and protect against external insults such as chemotherapy. Spontaneous mutations in humans and many Mendelian disorders have also given us an insight into the role of multiple genes in ovarian aging, and aging in general. Genome-wide association studies have identified several loci that modulate the age of menopause, and indicate that ovarian aging is a window to accelerated aging in general. Whole genome sequencing approaches by ours and other laboratories are being applied to identify genetic markers that cause premature ovarian aging. It is hoped that a combination of genetic markers and extensive blood profiling will provide reliable biomarkers that can predict reproductive life span and allow timely cryopreservation of ovarian tissues and oocytes to women at risk for premature loss of ovarian function. Moreover, it is hoped that such biomarkers will help stratify women who are at increased risk for adverse outcomes.

Testosterone concentrations, using different assays, in different types of ovarian insufficiency: a systematic review and meta-analysis

Increasing age and post-menopausal status are associated with decreasing androgen concentrations in females. Women with premature loss of ovarian function, such as primary ovarian insufficiency (POI) or iatrogenic menopause may be at increased risk for diminished testosterone levels at a relatively young age. Differentiation between a hypoandrogenic or normoandrogenic state in women with premature loss of ovarian function is problematic due to trueness and precision problems using various testosterone assays. The current meta-analysis was conducted to evaluate current literature reporting serum total testosterone concentrations under these conditions, including stratification for various testosterone assays. A systematic review and meta-analysis of controlled observational studies were performed. The electronic databases of Pubmed, Embase and the Cochrane Library were systematically searched until October 2011 for comparative studies on total testosterone concentrations in women with spontaneous POI or iatrogenic menopause compared with controls. The literature search, data extraction and critical appraisal, using the Newcastle-Ottawa Scale, were performed by two independent investigators. The effect measure was the weighted mean difference (WMD) with 95% confidence interval (95% CI) in a random effects model. A total of 206 articles for spontaneous POI and 1358 for iatrogenic menopause were reviewed, of which 9 and 17 papers, respectively, were selected for final analysis. Both groups demonstrated significantly lower total testosterone concentrations compared with controls [WMD (95% CI) -0.38 (-0.55 to -0.22) nmol/l, and -0.29 (-0.39 to -0.18) nmol/l, respectively], but with substantial between-study heterogeneity. Subgroup analysis for assay type was statistically significant for spontaneous POI only. Sensitivity analyses of high-quality studies did not change the results, and resulted in a substantial decrease in heterogeneity in spontaneous POI studies. The current meta-analysis demonstrates that total testosterone concentrations are decreased in women with spontaneous POI or iatrogenic menopause. The potential implications of hypoandrogenism in these women remain to be elucidated.

Levonorgestrel‐IUD should be offered before hysterectomy for abnormal uterine bleeding without uterine structural abnormalities: there are no more excuses!

This editorial provides data from a randomized controlled trial of the levonorgestrel-releasing intrauterine system (LNG-IUS) versus hysterectomy in the treatment of 228 women with menorrhagia. The data shows that the LNG-IUS is more beneficial than hysterectomy on lower back pain.

Prophylactic oophorectomy in premenopausal women and long-term health.

To review the data on long-term outcomes in women who underwent prophylactic bilateral oophorectomy, a common surgical procedure that has more than doubled in frequency since the 1960s. Literature review of the published data on the consequences of prophylactic bilateral oophorectomy. Special emphasis was given to the Mayo Clinic Cohort Study of Oophorectomy and Aging. Main outcome measures Overall mortality, cardiovascular disease, cognitive impairment and dementia, parkinsonism, osteoporosis, psychological wellbeing and sexual function. There is a growing body of evidence suggesting that the premature loss of ovarian function caused by bilateral oophorectomy performed before natural menopause is associated with several negative outcomes. In particular, studies have revealed an increased risk of premature death, cardiovascular disease, cognitive impairment or dementia, parkinsonism, osteoporosis and bone fractures, decline in psychological wellbeing and decline in sexual function. The effects involve different organs (e.g. heart, bone, or brain), and different functions within organs (e.g. cognitive, motor, or emotional brain functions). Estrogen treatment may prevent some but not all of these negative outcomes. The potential adverse effects of prophylactic bilateral oophorectomy on heart health, neurological health, bone health and quality of life should be carefully weighed against its potential benefits for cancer risk reduction in women at average risk of ovarian cancer.

Citation classics in Fertility and Sterility, 1975–2004

Citation classics in Fertility and Sterility, 1975–2004

Delayed motherhood through oocyte and ovarian tissue cryopreservation – a perspective from Singapore

Recent advances in oocyte and ovarian tissue cryopreservation technology have brought hope not only to women facing premature loss of ovarian function, but also to healthy women seeking delayed motherhood. This is a major issue of contention in healthcare ethics. Proponents of this new technology argue that this enables women to pursue educational and career goals in their youth, so that they have greater financial security for children in later life. Nevertheless, this argument may be flawed by the reality that even if the cryopreservation of oocytes and ovarian tissue were optimized in the future, this would in no way be a guaranteed route for women to have biological children later in life. Moreover, because only a limited amount of autologous reproductive material can be cryopreserved and stored for a single healthy woman, there is a risk of material depletion before reproductive success is attained. Another prime consideration is the increased morbidity and mortality associated with clinical assisted reproduction in older women. Hence, it is imperative that delayed motherhood through the cryopreservation of oocytes and ovarian tissues be viewed with extreme caution, and mandatory counselling should be given to all patients if such a medical procedure ultimately finds approval for widespread application.

Bilateral oophorectomy and premature menopause

The ovary is a complex metabolic organ. The follicles produce both androgens and estrogens, whereas the stromal tissue synthesizes androgens only. When menopause occurs, both androgen and estrogen levels decrease. The postmenopausal ovary remains a source of endogenous androgens that are converted to estrogen. The consequences of premature removal of the ovaries are not well known. The risks and benefits of menopausal hormone therapy (HT) in women with premature menopause have not been studied. Women who have had surgical menopause experience more severe symptoms and will need to stop estrogen therapy at some point in their lives. Intense symptoms such as hot flashes, night sweats, and insomnia will redevelop, so women should be given informed consent about the need for long-term use of HT and the greater difficulty in discontinuing therapy.

Molecular Imaging of Human Thrombus with Computed Tomography

the potential for premature loss of ovarian function. A leading theory for these ovarian changes is that dechelation of gadolinium following Omniscan injection leads to heavy metal toxicity with subsequent microvascularity effects. Further studies evaluating subchronic toxicity are warranted, examining in greater depth the toxicity observed with Omniscan and evaluating other chelates with similar instability (Optimark).[2]

Selected enquiries into the causation of premature ovarian failure

In most species, reproductive senescence can be explained in the same general terms as physiological senescence. In fact, in some species rapid physiological senescence occurs on the completion of reproduction. The programme in women is unusual in that ovarian function comes to a relatively abrupt halt at 45–50 years of age, when the impact of somatic senescence on most other functions is minimal. Early reproductive senescence has been reported in other species (chimpanzees, macaques and toothed whales) but it is more attenuated and less abrupt. The proximate cause of physiological menopause seems to be oocyte depletion, but less obvious neuroendocrine changes precede or result from the gradual loss of oocytes. This is not surprising as many age-specific processes are controlled by hormones. Hormones provide a way for an animal to co-ordinate the ageing of different tissues. The failure to comprehend completely the reasons for the biological uniqueness of women makes the study of the more extreme examples of premature ovarian failure an important exercise. The premature loss of ovarian function in certain eukaryotic women highlights the role of those special maintenance and repair systems that must be functional in the selection process for healthy germ cells. The purpose of this article is to indicate selected areas of clinical and basic investigation that may provide clues to the mechanisms of untimely ageing of the human ovary. Studies of those human extremes with premature loss, or extended ovarian function, may provide critical insights into the unique discordance between somatic and reproductive senescence that is characteristic of normal women.

The effect of hysterectomy on the age at ovarian failure: identification of a subgroup of women with premature loss of ovarian function and literature review

The age at ovarian failure was determined in 90 women who had previously undergone abdominal hysterectomy with bilateral ovarian conservation and in 226 women who had undergone a spontaneous menopause. The mean age of ovarian failure in the hysterectomized group was 45.4 +/- 4.0 years (standard deviation), and this was significantly lower than the mean age of 49.5 +/- 4.04 years in the nonhysterectomized control group (P less than 0.001). There was a significant correlation between the age at hysterectomy and the age of ovarian failure in the women who were 44 years or less at the time of ovarian failure (r = 0.62, P less than 0.001), implying a causal relationship. The indication for hysterectomy did not influence the time of ovarian failure. Two explanations are proposed as to how conventional surgery for hysterectomy may adversely affect ovarian function.