Primary Amenorrhea and Premature Ovarian Insufficiency.

This review focuses on primary amenorrhea and primary/premature ovarian insufficiency due to hypergonadotropic hypogonadism. Following a thoughtful, thorough evaluation, a diagnosis can usually be discerned. Pubertal induction and ongoing estrogen replacement therapy are often necessary. Shared decision-making involving the patient, family, and health-care team can empower the young person and family to successfully thrive with these chronic conditions.

Optimising health after early menopause.

The typical age at menopause is 50-51 years in high-income countries. However, early menopause is common, with around 8% of women in high-income countries and 12% of women globally experiencing menopause between the ages of 40 years and 44 years. Menopause before age 40 years (premature ovarian insufficiency) affects an additional 2-4% of women. Both early menopause and premature ovarian insufficiency can herald an increased risk of chronic disease, including osteoporosis and cardiovascular disease. People who enter menopause at younger ages might also experience distress and feel less supported than those who reach menopause at the average age. Clinical practice guidelines are available for the diagnosis and management of premature ovarian insufficiency, but there is a gap in clinical guidance for early menopause. We argue that instead of distinct age thresholds being applied, early menopause should be seen on a spectrum between premature ovarian insufficiency and menopause at the average age. This Series paper presents evidence for the short-term and long-term consequences of early menopause. We offer a practical framework for clinicians to guide diagnosis and management of early menopause, which considers the nature and severity of symptoms, age and medical history, and the individual's wishes and priorities to optimise their quality of life and short-term and long-term health. We conclude with recommendations for future research to address key gaps in the current evidence.

Practice guideline on ovarian tissue cryopreservation and transplantation in the prevention and treatment of iatrogenic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) refers to the decline of ovarian function before the age of 40. POI causes a reduction in or loss of female fertility, accompanied by different degrees of menopausal symptoms, which increases the risk of chronic diseases related to early menopause and seriously affects patients' quality of life and health. It is conservatively estimated that at least one million prepubertal girls and women of reproductive age in China are at risk of iatrogenic POI caused by radiotherapy and chemotherapy every year. With the development of medical technology and the breakthrough of scientific and technological advances, preventing and treating iatrogenic POI have become possible. International and national guidelines consider cryopreserved ovarian tissue transplantation to be the most promising method of preserving the ovarian function and fertility of prepubertal girls and women of reproductive age who cannot delay radiotherapy and chemotherapy. In order to guide the clinical application of ovarian tissue cryopreservation and transplantation technology in China, the Guideline Working Group finally included 14 scientific questions and 18 recommendations through a questionnaire survey, field investigation, and consultation of a large number of Chinese and English literature databases in order to provide a reference for colleagues in clinical practice.

Ovarian Suppression: Early Menopause, Late Effects.

PURPOSE OF REVIEW: Pre-menopausal women diagnosed with hormone receptor (HR) breast cancer are candidates for prolonged hypoestrogenism to improve cancer outcomes. However, the disease benefit eclipses the toxicities associated with ovarian function suppression (OFS), which are often under-reported. RECENT FINDINGS: Increased risk of mortality from cardiovascular disease, bone disorders, and metabolic disorders is well reported in women with no history of cancer, after surgical oophorectomy or premature ovarian failure. Vasomotor symptoms, urogenital atrophy, weight gain, sexual dysfunction, cognitive decline, and sleep disturbances contribute to the increased non-compliance associated with OFS, especially in younger women. Balancing the toxicities of prolonged OFS with its benefits should be critically analyzed by providers when making recommendations for their patients. Supportive care to manage multi-system toxicities and to counteract the long-term impact on all-cause mortality should be emphasized by every cancer program. Future studies with OFS should incorporate patient outcomes and strategies for symptom management in addition to focusing on improving disease outcomes.

Ovarian Insufficiency: Clinical Spectrum and Management Challenges.

The term "ovarian insufficiency" describes the decline of ovarian function resulting in fertility loss and the marked decrease of ovarian steroid hormone production. From a clinical standpoint, ovarian insufficiency presents in three different settings. The first is natural menopause at midlife occurring at the average age of 51 years. The second arises after surgical oophorectomy owing to disease or elective cancer prophylaxis. Finally, primary or premature ovarian insufficiency is characterized by menopause occurring before age 40, often of undetermined etiology, but at times linked with genetic mutations, autoimmune syndromes, metabolic conditions, iatrogenic etiologies, and toxic exposures. Each clinical situation presents unique concerns and management challenges. The majority of women with intact ovaries who live to age 51 experience natural menopause, with early menopause <45 years. In the United States, surgical menopause with bilateral oophorectomy occurs in ∼600,000 women per year. The timing and specific clinical indication for oophorectomy alters management. Primary ovarian insufficiency occurs in 1% of women, although recent estimates suggest the prevalence may be increasing. Symptoms of ovarian insufficiency include hot flashes or vasomotor symptoms, mood disorders, sleep disruption, and vaginal/urinary symptoms. Health concerns include bone, cardiovascular, and cognitive health. Management of symptoms and preventive strategies varies depending upon the age, clinical situation, and specific health concerns of each individual. Treatment options for symptom relief include cognitive behavior therapy and hypnosis, nonhormonal prescription therapies, and hormone therapy. Tailoring the therapeutic approach over time in response to age, emerging medical issues, and patient desires constitutes individualized care.

Premature ovarian insufficiency: a review on the role of tobacco smoke, its clinical harm, and treatment.

Premature ovarian insufficiency (POI) is a condition in which the quantity of follicles and the quality of oocytes gradually decrease. This results in an estrogen secretion disorder and abnormal follicle development, which can lead to related diseases, early onset of menopause, sexual dysfunction, and an increased risk of cardiovascular issues, osteoporosis, and depression, among others. This disease significantly impacts the physical and mental health and overall quality of life of affected women. Factors such as genetic abnormalities, oophorectomy, radiotherapy for malignancy, idiopathic conditions, and an unhealthy lifestyle, including smoking, can accelerate the depletion of the follicular pool and the onset of menopause. Extensive research has been conducted on the detrimental effects of tobacco smoke on the ovaries. This article aims to review the advancements in understanding the impact of tobacco smoke on POI, both in vivo and in vitro. Furthermore, we explore the potential adverse effects of common toxicants found in tobacco smoke, such as polycyclic aromatic hydrocarbons (PAHs), heavy metals like cadmium, alkaloids like nicotine and its major metabolite cotinine, benzo[a]pyrene, and aromatic amines. In addition to discussing the toxicants, this article also reviews the complications associated with POI and the current state of research and application of treatment methods. These findings will contribute to the development of more precise treatments for POI, offering theoretical support for enhancing the long-term quality of life for women affected by this condition.

Aberrantly High FBXO31 Impairs Oocyte Quality in Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI), which is defined as loss of ovarian function that occurs before the age of 40, causes menstrual disturbances, infertility, and diverse health problems in females. Despite the limited understanding of the molecular basis underlying POI pathology, we had previously demonstrated that the cooperation of miR-106a and FBXO31 plays a pivotal role in diminished ovarian reserve (DOR), with FBXO31 serving as a putative target of miR-106a. In this study, we found that FBXO31 is aberrantly expressed in granulosa cells of POI patients, leading to accumulated reactive oxygen species (ROS) and cell apoptosis via the p53/ROS pathway. Furthermore, our results demonstrated that high levels of FBXO31 in mouse ovaries impair oocyte quality. Our study revealed that FBXO31 may serve as a novel indicator and play a significant role in the etiology of POI.

Premature ovarian insufficiency, early menopause, and induced menopause.

Premature ovarian insufficiency (POI) is a condition in which there is a decline in ovarian function in women who are younger than 40 years resulting in a hypo-oestrogenic state with elevated gonadotrophins and oligomenorrhoea/amenorrhoea. This leads to short term complications of menopausal symptoms and long-term effects on bone and cardiovascular health, cognition as well as the impact of reduced fertility and sexual function associated with this condition. It is managed by sex steroid replacement either with HRT or combined hormonal contraception until the age of natural menopause (51) and this can provide a beneficial role with both symptom control and minimising the long-term adverse effects associated with this condition. Women who undergo a menopause between 40 and 45 years are deemed to have an "early menopause". The limited data available for this group suggest that they also have an increased morbidity if not adequately treated with hormone therapy. As such, women who have an early menopause should be managed in a similar way to those with POI, with the recommendation that they should take HRT at least until the natural age of menopause. This is the same for induced menopause that is caused by medical or surgical treatment that impacts the ovaries. It is important to ensure early diagnosis and access to specialist care to help support and manage these patients to reduce the symptoms and risks of long-term complications. This review looks at the diagnosis, causes, short and long-term complications and management of POI, early and induced menopause.

The influence of environmental factors on premature ovarian insufficiency and ovarian aging.

Premature ovarian insufficiency and ovarian aging are complex conditions that affect women's reproductive health and overall well-being. They are both characterized by hypergonadotropic hypogonadism and infertility, and together affect about 1 in 100 women by the age of 40. This review explores the influence of environmental factors on the development and progression of premature ovarian insufficiency and ovarian aging. When referring to environmental factors, we include a wide range of external agents and conditions, including chemicals, socioeconomic factors and lifestyle choices. Through a review of the literature, we attempt to highlight the link between environmental factors and ovarian health. We examine the impact of endocrine-disrupting chemicals, such as bisphenol A and phthalates, on ovarian function and investigate the mechanisms by which these chemicals can disrupt hormone signaling pathways, leading to alterations in ovarian reserve, oocyte quality, and folliculogenesis. Moreover, we explore lifestyle factors like obesity, stress, smoking and alcohol in relation to their effects on ovarian aging. Epigenetic changes may play a crucial role in the prevalence of premature ovarian insufficiency. Understanding the impact of environmental factors on premature ovarian insufficiency and ovarian aging is very important in public and clinical health contexts. By identifying risk factors, healthcare providers can develop targeted and strategic prevention and intervention plans. Furthermore, this knowledge can promote reproductive health and minimize exposure to harmful environmental agents.

Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort.

BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer. METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available. FINDINGS: 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy. INTERPRETATION: POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer. FUNDING: Canadian Institutes of Health Research, US National Cancer Institute.

Primary Ovarian Insufficiency and Ovarian Aging.

Primary ovarian insufficiency (POI) is a complex condition of aberrant ovarian aging. POI etiologies are varied, and most cases have no identifiable underlying cause. Caring for women with POI requires an approach that understands the importance of ovarian function in a variety of target organs and tissues.

Primary ovarian insufficiency in cancer survivors: Keys to optimal management.

INTRODUCTION: Primary ovarian insufficiency (POI) carries significant morbidity, causing infertility, sexual disfunction, decreased bone density, cardiovascular risk, emotional distress and early mortality. OBJECTIVE: To know the incidence and current management of POI in childhood/adolescent solid tumour survivors. MATERIAL AND METHODS: We conducted a multicentre observational study. It included female patients aged 12-18 years with a diagnosis of solid tumour and meeting clinical or biochemical criteria for POI. The risk was estimated based on the criteria of the Pediatric Initiative Network of the Oncofertility Consortium. RESULTS: We found an incidence of 1.5 (30 cases of POI): The median age at the time of the event was 14 years (standard deviation, 2.09). The solid tumours associated most frequently with POI were Ewing sarcoma and brain and germ cell tumours. Eighty-three percent of patients did not undergo fertility preservation. Sixty-three percent reported not having undergone menarche at the time of ovarian failure. Ninety-seven percent were at high risk of gonadal toxicity, yet 47% were not monitored before the diagnosis. The median time elapsed to the occurrence of the event was 43.5 months after diagnosis and 29.5 months after completing treatment. The Kaplan-Meier curves showed that approximately 30% of POI cases developed within 2 years of diagnosis and that women at Tanner stage 1 developed insufficiency later than women at Tanner stage 5. CONCLUSIONS: There is room for improvement in the follow-up of women at risk of POI in Spain. The tools currently available facilitate risk assessment at the time of treatment planning and allow the implementation of monitoring, education, early diagnosis, fertility preservation, and replacement therapy as needed. All of this would achieve significant improvement in health outcomes.

[Follow-up analysis of sex hormone levels and prognosis in women after hematopoietic stem cell transplantation].

Objective: To investigate the levels of sex hormone and fertility in female patients after hematopoietic stem cell transplantation (HSCT), as well as their correlation with conditioning regimens, and analyse the effect of hormone replacement therapy (HRT) in young women after HSCT. Methods: Retrospective case series study. The clinical data of 147 women who underwent HSCT in the First Affiliated Hospital of Soochow University from January 2010 to January 2021 were retrospectively analyzed. The sex hormone levels were measured and followed-up, and the survival, menstrual fertility and the use of HRT of the patients were also followed-up. The sex hormone levels were measured after transplantation, and the ovarian function was evaluated. Independent sample t test and χ2 test were used for comparison between the two groups. Results: The median age of the 147 patients was 26 (range, 10-45) years. Of them, 135 patients received allogeneic HSCT and 12 patients received autologous HSCT. Furthermore, 129 patients received myeloablative conditioning, and 18 patients received reduced conditioning dose. The median follow-up time was 50 months (range, 18-134 months). Five patients died of disease recurrence during follow-up. Of the 54 patients with subcutaneous injection of zoladex, three recovered menstruation spontaneously after transplantation, and all of them were myeloablative conditioning patients, one patient gave birth to twins through assisted reproductive technology. Ninety-three patients did not use zoladex before conditioning, two patients with aplastic anemia with non-myeloablative transplantation resumed menstruation spontaneously, and conceived naturally. The level of follicle stimulating hormone after transplantation in patients receiving myeloablative conditioning regimen was significantly higher than that in patients receiving reduced-dose conditioning regimen [(95.28±3.94) U/L vs. (71.85±10.72) U/L, P=0.039]. Among 147 patients, 122 patients developed premature ovarian failure, 83 patients received sex hormone replacement therapy after transplantation, and 76 patients recovered menstruation and improved endocrine function. Conclusions: The incidence of premature ovarian failure is high in female patients after HSCT, and patients have a chance at natural conception. Reducing the dose of conditioning regimen and the application of zoladex before transplantation can reduce ovarian of conditioning drugs. HRT after transplantation can partially improve the endocrine function of patients.

Clinical pregnancy in Turner syndrome following re-implantation of cryopreserved ovarian cortex.

Turner syndrome (TS) leads to a characteristic phenotype, including premature ovarian insufficiency and infertility. Ovarian tissue cryopreservation (OTC) is becoming an established fertility preservation strategy for both pre- and post-pubertal females and may offer the chance of having a biological family to selected patients with TS. To date, women with TS have had ovarian tissue cryopreserved but there are few reports of autologous re-implantation and none of pregnancy. We herein report, to our knowledge, the first clinical pregnancy in a patient with TS, conceived naturally following re-implantation of cryopreserved ovarian tissue which had been removed soon after spontaneous puberty. This provides proof of concept for OTC as a means of fertility preservation in TS.

The effects of human amnion membrane-derived mesenchymal stem cells conditioned medium on ionizing radiation-induced premature ovarian failure and endoplasmic reticulum stress-related apoptosis mechanism.

OBJECTIVES: Premature ovarian failure (POF) is defined as the cessation of menstrual periods for at least 4-6 months before the age of 40 years, accompanied by FSH values measuring over 40 IU/L for a month. Radiation therapy, one of the cancer treatment methods, is known to accelerate ovarian aging by reducing and eliminating the number of primordial follicles in the ovarian follicle pool. Ionizing radiation has been reported to cause POF. The objective of this study is to investigate the impact of mesenchymal stem cell conditioned medium (hAMSCs-CM), which is isolated from the amniotic membrane of human placenta, on premature ovarian failure (POF) caused by whole-body irradiation. The study will focus on the ER stress and apoptosis mechanisms in the process. STUDY DISAYN: A POF model was created by exposing rats to 7 Gy of whole-body irradiation. Serum-free hAMSCs-CM were then administered via the tail vein. Follicle count was performed on the ovaries, and immunohistochemistry was used to determine the expressions of GRP78, CHOP, IRE-1, caspase-12, caspase-9, caspase-3. TUNEL was also carried out, and levels of serum FSH, LH, E2, AMH, and oxidative stress marker 8-OHdG were measured. RESULTS AND CONCLUSION: The application of hAMSCs-CM has been found to have a positive impact on follicles affected by radiation. After treatment, the number of primordial, primary, secondary, and graafian follicles, which had previously decreased due to radiation, showed an increase. Furthermore, the number of atretic follicles, which had been increasing due to radiation, showed a decrease. ER is one of the targets affected by ionizing radiation. After ionizing radiation, the expressions of ER stress-related markers and apoptosis markers increased in the ovary. After hAMSCs-CM administration, the expressions of these markers and number of TUNEL-positive cells decreased. Following irradiation, anti-mullerian hormone (AMH) and estradiol (E2) levels decreased, while follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels increased. After administration of hAMSCs-CM, AMH and E2 levels increased, while FSH and LH levels decreased. Amnion membrane-derived mesenchymal stem cell conditioned medium can play a therapeutic role in ionizing radiation-induced premature ovarian failure by reducing endoplasmic reticulum stress and apoptosis.

Hormone replacement in premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is defined as loss of ovarian function in women less-than 40 years. This review summarises the causes and the possible treatment options. POI can be idiopathic, caused by genetic, autoimmune, or metabolic disease, or be induced by cancer therapy or surgery. POI causes infertility, increased morbidity and mortality, and decreased quality of life. Hormonal replacement therapy (HRT) can alleviate symptoms of POI and should be initiated at diagnosis. The benefit of HRT outweighs the minor side effects in most cases and should be continued until age of natural menopause.

COVID-19-related premature ovarian insufficiency: case report and literature review.

OBJECTIVE: The aim of this study is to present the case report of a 36-year-old woman developing premature ovarian insufficiency (POI) after COVID-19 and review the literature referring to the possible impact of SARS-CoV-2 infection on female reproduction. METHODS: A 36-year-old nulligravida with normal menstrual cycles, non-smoker, with a normal body mass index and no pelvic surgery or oncological treatment in her medical history presented to the Infertility Center of the Institute of Mother and Child in Warsaw after a year of unsuccessful attempts to get pregnant. During diagnostic process she was affected by COVID-19 with a mild manifestation and thereafter she presented amenorrhea with intense hot flushes. Further diagnostic confirmed the diagnosis of POI. RESULTS: There is a strong molecular basis for a possible effect of SARS-CoV-2 infection on the female reproductive system; however, the results of available research are conflicting. All of these aspects are discussed in detail. CONCLUSIONS: SARS-CoV-2 infection may cause serious complications that cast a long shadow on a patient's future life and health. Further research is needed to assess the real impact of SARS-CoV-2 infection on female reproductive health, as well as potential preventive and therapeutic strategies for women affected with COVID-19.