Risk Of Premature Ovarian Insufficiency Research Articles

Ovarian tissue biopsy for cryopreservation by vaginal natural orifice transluminal endoscopic surgery: a new approach for a minimal invasive ovarian biopsy

Vaginal natural orifice transluminal endoscopic surgery (vNOTES) is an emerging surgical procedure that combines the advantages of the vaginal approach with laparoscopic vision and instrumentation [1]. Shorter hospitalization and lower postoperative pain associated to vNOTES [2] may be explained by the advantages of this innovative surgical approach (such as absence of abdominal incisions, shorter operating time, lower insufflation pressure) [2;3]. Ovarian tissue cryopreservation allows to preserve reproductive and endocrine functions in young women with oncological disease at risk of premature ovarian insufficiency (POI) caused by gonadotoxic treatments [4]. Ovarian tissue biopsy for cryopreservation consists of a large biopsy of one or both ovaries [4] that is usually performed by laparoscopy. Then, the removed ovarian tissue is cryopreserved for the future transplant after cancer remission. Volume of ovarian biopsy ranges from 50% of the ovary for women at moderate risk of POI to 70 % or whole ovary for women at high risk [5]. Inclusion criteria for ovarian tissue cryopreservation are women aged less than 35 who cannot delay start of oncological treatments for follicles cryopreservation, with a moderate or high risk of POI and good chance of 5-year survival [6]. Ovarian tissue cryopreservation cannot be performed if tumor treatments include uterine irradiation or for tumors at risk of ovarian metastases (as in case of ovarian cancer, leukemia, neuroblastoma, Burkitt lymphoma) [7]. Despite widespread adoption of vNOTES in gynecology, ovarian biopsy for cryopreservation has never been performed using this route. Step-by-step explanation of the procedure with descriptive text and narrated video footage. Tertiary level referral academic center. A 27-years-old patient recently diagnosed with low grade follicular non-hodgkin lymphoma was referred to our center for ovarian tissue cryopreservation before chemotherapy. The patient included in this study gave informed consent for publication of the video and posting of the video online including social media, the journal website, scientific literature websites (such as PubMed, ScienceDirect, Scopus, etc.) and other applicable sites. Due to the nature of the study, IRB approval was not required. Access to peritoneal cavity was created by a 3 cm posterior colpotomy. Peritoneum was then opened using cold scissors and temporarily fixed to the posterior vaginal wall. The Gelpoint Mini Advanced Access Platform (Applied Medical, Rancho Santa Margarita, CA, USA), with one 10 mm and two 5 mm trocars, was used as vNOTES port. The inner Alexis ring of the Gelpoint was inserted through the colpotomy into the pouch of Douglas. An hysterometer was placed into the uterine cavity to keep the uterus anteverted during the surgery. A pneumoperitoneum was created to a pressure of 8 mmHg and the operating table was tilted to 20° Trendelenburg position. A 10-mm rigid 30° camera was inserted in the inferior and larger trocar and both the ovaries were visualized. 70 % of the left ovary was removed with cold scissors, in order to minimize trauma on the surgical specimen. After removal of the Gelpoint cap, ovarian biopsy was immediately picked-up by the biologist of our fertility center. The ovary was coagulated with bipolar instrument. Hysterometer was then replaced by a uterine manipulator to perform tubal patency test and blue dye passage through both the salpinges was observed. Finally, the Alexis retractor and the stich on the posterior peritoneum were removed and the vagina was sutured using interrupted stiches. Total operative time was 25 minutes. Ovarian tissue biopsy for cryopreservation by vNOTES. No intraoperative and postoperative complications were reported and the patient was discharged after 24 hours from surgery. VNOTES may be a feasible alternative approach to laparoscopy for ovarian tissue cryopreservation: it allows an easy access to the ovaries and removal of different tissue volumes. Patients undergoing ovarian cryopreservation may benefit of vNOTES approach since a rapid post-operative recovery is crucial to start chemotherapy in a short time. As for other vNOTES surgical procedures, accurate selection of patients seems to be crucial for a successful ovarian tissue cryopreservation [8]. We think that inclusion and exclusion criteria reported for other gynecologic procedures performed through vNOTES may also be valid for ovarian tissue cryopreservation by vNOTES [9]. Women at high risk of pelvic adhesions (such as coexistent endometriosis, previous pelvic surgery or inflammatory pelvic disease), with elevated Body Mass Index or enlarged uterus as well as women with cervical, vaginal or uterine cancer cannot be considered for this approach since all these factors are associated to failure of vNOTES. On the other hand, women with no history of surgery, endometriosis and large myomas may benefit from vNOTES approach and these women represent most of patients who undergo ovarian tissue cryopreservation.

Cryopreservation of ovarian tissue for fertility preservation in breast cancer patients: time to stop?

Fertility preservation is currently offered to young women with breast cancer to increase their chances of motherhood after a potentially gonadotoxic treatment. Ovarian stimulation with oocyte vitrification and cryopreservation of ovarian tissue remain the most commonly used methods of choice. Whichever method is preferred is very much dependent on the practice and experience of the clinics, although for breast cancer in particular one method might be superior to the other. Cryopreservation of ovarian tissue is inevitably associated with the iatrogenic reduction of the ovarian reserve of a patient and should only be offered to women with a high risk of premature ovarian insufficiency following treatment. However, for younger breast cancer survivors, pregnancy and delivery rates are reassuringly high, even after chemotherapy. Despite its widespread use, few women come back to make use of their cryopreserved tissue. It is argued here that cryopreservation of ovarian tissue is not an appropriate option for breast cancer patients and discuss the reasons for this opinion.

Laparoscopic medulla-sparing ovarian tissue biopsy for cryopreservation: step-by-step surgical technique

To describe a laparoscopic technique for ovarian tissue biopsy (OTB) for fertility preservation. In the last years, the demand for fertility preservation has grown because of the increasing survival rates among patients with cancer and the rising awareness of the importance of quality of life after gonadotoxic therapy. Among fertility-sparing approaches, ovarian tissue cryopreservation is a valid strategy to preserve ovarian endocrine and reproductive function in prepubertal and postpubertal women who will undergo gonadotoxic cancer treatments. Currently, there is no universal consensus regarding ovarian tissue retrieval technique for fertility preservation. Step-by-step description of the surgical technique with narrated video footage. Academic tertiary hospital. Patients with a high risk of premature ovarian insufficiency, usually due to gonadotoxic treatments, who undergo OTB for fertility preservation were included in the study. In this video, we present the clinical case of a 28-year-old patient affected by Hodgkin lymphoma who underwent laparoscopy for OTB before chemotherapy. After exposing the chosen ovary, an incision at the tubal pole of the ovary is made with scissors. Through section and dissection, a large cortical biopsy of the ovary is performed without removing and avoiding any damage to the medulla. At the end of the procedure, hemostasis was achieved with selective coagulation using bipolar coagulation. Step by step educational video. The post-operative course was uneventful and the patient was discharge 24 hours after surgery. Standardization of a step-by-step laparoscopic technique can provide an effective method to optimize ovarian tissue removal while minimizing tissue injury. Medulla-sparing ovarian biopsy allows retrieval of only the cortical part of the ovary, maximizing the number of primordial follicles obtained without damaging the vascular supply of the ovary contained within the medulla. Primordial follicles are resistant to cryoinjury owing to their relatively inactive metabolism, and they are usually found at approximately 0.8 mm below the surface of the cortex. This technique could also reduce the back-table processing time of the ovarian tissue before cryopreservation. One disadvantage could be the difficulty of the technique compared to an oophorectomy because it requires a skilled surgeon that can easily find the cleavage plane between the medulla and the cortex, even in patients submitted to previous chemoradiotherapy or during gonadotropin-releasing hormone analogue therapy.

Previous cancers in women diagnosed with premature ovarian insufficiency: A nationwide population-based case-control study.

To investigate the occurrence of previous cancer diagnoses in women suffering from premature ovarian insufficiency (POI) and compare it with the general population, shedding light on the association between cancer, cancer treatments, and POI. We conducted a nationwide case-control study based on registry data from various sources, including the Social Insurance Institution, Finnish Population Information System, and Finnish Cancer Registry spanning from 1953 to 2018. Our participants comprised all women in Finland who, between 1988 and 2017, received hormone replacement therapy reimbursement for ovarian insufficiency before the age of 40 years (n = 5221). Controls, matched in terms of age and municipality of residence, were selected from the Finnish Population Information System (n = 20 822). Our main exposure variable was a history of cancer diagnosis preceding the diagnosis of POI. We analyzed odds ratios (OR) to compare the prevalence of previous cancers in women with POI with that in controls, stratifying results based on cancer type, age at cancer diagnosis, and the time interval between cancer diagnosis and POI. We also assessed changes in OR for previous cancer diagnoses over the follow-up period. Out of the women diagnosed with POI, 21.9% had previously been diagnosed with cancer, resulting in an elevated OR of 36.5 (95% confidence interval [CI] 30.9 to 43.3) compared with 0.8% of the controls. The risk of developing POI was most pronounced during the first 2 years following a cancer diagnosis, with an OR of 103 (95% CI 74.1 to 144). Importantly, this risk remained elevated even when the time interval between cancer and POI exceeded 10 years, with an OR of 5.40 (95% CI 3.54 to 8.23). This study reveals that 21.9% of women with POI have a history of cancer, making the prevalence of cancer among these women 27.5 times higher than age-matched controls in the Finnish population. The risk of developing POI is most substantial in the first 2 years following a cancer diagnosis. These findings underscore the role of cancer treatments as an etiological factor for POI and emphasize the importance of recognizing the risk of POI in cancer survivors for early diagnosis and intervention.

Sexual and Reproductive Health Care after Gonadotoxic Treatment in Females at a Tertiary Pediatric Hospital

Study ObjectivesRecommendations from the Children's Oncology Group Long-Term Follow-Up (COG-LTFU) Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer emphasize the importance of reproductive health care, yet little is known regarding adherence to these recommendations and non-fertility-related sexual and reproductive health (SRH) outcomes. MethodsFollow-up of outcomes on the basis of the COG-LTFU guidelines was assessed in female patients who underwent fertility preservation consultation before gonadotoxic therapy between 2016 and 2022 at a single institution and were at least 6 months from treatment completion. ResultsWe included 140 patients, with a mean time of 2.7 years from treatment completion. Eighty-six patients were 12 years old or older, of whom sexual activity was recorded in 59 (68.7%), and 12 of 31 (38.7%) sexually active patients underwent sexual function assessment. The 57 (66.3%) patients at high risk of premature ovarian insufficiency (POI) at diagnosis were more likely than minimal-risk counterparts (29, 33.7%) to have abnormal uterine bleeding (42.1% vs 17.2%, P = .03), to be diagnosed with POI (29.8% vs 0%, P = .01), and to have sexual activity recorded (77.2% vs 51.7%, P = .03). Of 17 patients with POI, 82.4% were on hormone replacement therapy, and 58.8% had undergone bone mineral density testing. ConclusionThis study adds to the limited literature regarding non-fertility-related SRH outcomes after gonadotoxic therapy and illustrates opportunities to improve adherence to the COG-LTFU guidelines. Increased attention to SRH guidelines may increase detection and treatment of SRH conditions, improving the health and quality of life of female cancer survivors.

Impact of Systemic Therapy on Fertility in Women with Early-Stage Breast Cancer.

Fertility concerns are common among young women diagnosed with breast cancer, as systemic therapy increases the risk of premature ovarian insufficiency and delays family planning. Here, we review the impact of systemic therapies, including chemotherapy, endocrine therapy, HER-2 directed therapy, PARP inhibitors, and immunotherapy, on ovarian reserve. With an improved understanding of disease biology, fewer women are treated with gonadotoxic chemotherapy. There are limited data on the fertility impact of novel targeted treatments and immunotherapy, though preclinical and preliminary studies suggest an impact on fertility is possible. Notably, a recent study investigated the outcomes in women who interrupted adjuvant endocrine therapy to attempt pregnancy. Further research is needed to characterize the fertility impact of novel therapies in breast cancer. Individualized fertility counseling should be offered to all women to discuss the possible impact of therapy on ovarian reserve and options for fertility preservation and timing of pregnancy.

FRI421 Immunomodulatory Therapy Can Improve Fertility In Women With Autoimmune Premature Ovarian Insufficiency - A Proof Of Concept Study

Abstract Disclosure: A.L. Hirschberg: None. S. Björnsdottir: None. I. Gunnarsson: None. F. Sergouniotis: None. E. Vogt: None. M. Øksnes: None. E.S. Husebye: None. S. Bensing: None. O. Kämpe: None. Introduction: Autoimmune disorders are associated with increased risk of premature ovarian insufficiency (POI), leading to early menopause and infertility. The etiology of autoimmune POI remains unknown, but measurable levels of anti-Mullerian hormone indicate that some follicles may be intact. We asked if rituximab, a B cell specific anti-CD20 monoclonal drug could improve the ovarian response to gonadotropin stimulation and restore fertility. Methodology: In this open label pilot study, nine women aged 18-35 years, BMI 19-30 kg/m2 with autoimmune POI (S- FSH > 40 IE/L), of which six had Addison’s disease, were included. The procedure comprised controlled ovarian hyperstimulation according to a standard high dose protocol with daily subcutaneous injections of follitropin alpha, prior to, and 4 months after, two infusions of 1-gram rituximab 2 weeks apart, and a follow-up period of 12 months. If positive response to ovarian stimulation was obtained, GnRH antagonist was given to prevent premature ovulation and choriogonadotropin alpha to induce ovulation. When possible, oocytes were retrieved for cryopreservation and later fertilization. Results: None of the nine patients responded to ovarian stimulation prior to rituximab treatment (mean stimulation days 15.7 ± 1.6 days). After rituximab therapy, five of seven responded with follicular development, and in four women mature eggs were harvested (oocyte yield 3-13 oocytes) for preservation. Four of these five women experienced spontaneous menstrual bleedings and decreased vasomotor symptoms. All responders had autoimmune Addison’s disease, whereas two women with no response had Myasthenia gravis and Hashimoto thyroiditis, respectively. We observed no serious drug reactions or other complications. Conclusions: We have shown for the first time that rituximab can restore menstrual bleedings and enable egg retrieval with the potential to restore fertility in patients with autoimmune POI. This could become an alternative fertility treatment to egg donation, which is the only option today. Presentation: Friday, June 16, 2023

FRI556 Thyroid Autoimmunity Leading To Premature Ovarian Insufficiency (POI) In A Euthyroid Young Woman

Abstract Disclosure: P. rimal: None. M. Moeed: None. C. Musurakis: None. A. Ojha: None. W. Akhtar: None. C.P. Barsano: None. M.F. Siddiqui: None. Introduction: Premature Ovarian Insufficiency is rare in young women and affects only 0.1% before the age of 30. The causes of POI in most cases remain unidentified, with autoimmunity being responsible for 4-30% of the cases. We present the case of a young euthyroid woman who presented for the evaluation of primary amenorrhea and diagnosed with POI associated with thyroid autoimmunity. Clinical Case: A 28-year-old Afghani woman with no known co-morbidities was referred to endocrinology clinic for the work up of primary amenorrhea. She was a goitrous and had normal secondary sexual characteristics and a history of withdrawal bleeding with OCP. There was no known personal or family history of autoimmune disease. Work up revealed hypergonadotropic hypogonadism with high FSH, 55 mIU/ml[Ref range for postmenopausal woman 16.7-113], high LH, 20.28 mIU/ml [Ref range for postmenopausal woman 10.8-58.69] and low estradiol, <2 pg/ml. Anti-Mullerian hormone was low, <0.08ng/ml [RefRange 0.69-13.39] signifying inadequate ovarian reserves and pelvic ultrasound confirmed atrophic ovaries. Etiological work up revealed normal female karyotype, 46XX, and negative FMR gene mutation testing for Fragile X syndrome. Thyroid functions were normal TSH, 3.3 mIU/L (0.27-4.2) and Free T4, 1.29 ng/dl[Ref Range 0.70-2.7]. Autoimmune work up was negative for adrenal 21-OH antibody and anti-ovarian antibodies. However, patient had strongly positive thyroid peroxidase (TPO) antibodies, 613.77 mIU/L[Ref range 0.0-9.0] consistent with thyroid autoimmunity. DXA scan revealed osteopenia. Thus, the diagnosis of POI associated with thyroid autoimmunity was established. HRT with estradiol patch and progesterone was initiated. Calcium, Vitamin D supplements and fertility counseling were provided. Conclusion: Thyroid disease is the most common autoimmune disease associated with POI. Studies have shown higher risk of POI and infertility in patients with Hashimoto’s and Graves’ diseases with co-existing high titers of TPO or anti-thyroglobulin antibodies. Ovaries are subject to autoimmune attack that leads to diminished ovarian reserves. However, until now the association of isolated elevation of TPO antibodies with POI has not been established. A Study by Osuka et al. did not find any significant difference in AMH levels between TPO and non-TPO positive euthyroid women and concluded that unlike hypothyroid women, thyroid autoantibodies were not likely to influence ovarian reserves in euthyroid women. Our case is unique where POI is associated with isolated elevation of TPO antibodies in the absence of clinical thyroid disease. This signifies the possibility that ovarian failure may precede the onset of thyroid disease in patients with thyroid autoimmunity and should be suspected and treated at an early stage, before ovarian reserves are diminished. Presentation: Friday, June 16, 2023

The Role of Lifestyle and Dietary Factors in the Development of Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) is a condition that arises from dysfunction or early depletion of the ovarian follicle pool accompanied by an earlier-than-normal loss of fertility in young women. Oxidative stress has been suggested as an important factor in the decline of fertility in women and POI. In this review, we discuss the mechanisms of oxidative stress implicated in ovarian ageing and dysfunction in relation to POI, in particular mitochondrial dysfunction, apoptosis and inflammation. Genetic defects, autoimmunity and chemotherapy, are some of the reviewed hallmarks of POI that can lead to increased oxidative stress. Additionally, we highlight lifestyle factors, including diet, low energy availability and BMI, that can increase the risk of POI. The final section of this review discusses dietary factors associated with POI, including consumption of oily fish, mitochondria nutrient therapy, melatonin, dairy and vitamins that can be targeted as potential interventions, especially for at-risk women and in combination with personalised nutrition. Understanding the impact of lifestyle and its implications for POI and oxidative stress holds great promise in reducing the burden of this condition.

Premature ovarian insufficiency caused by the treatment of ovarian malignant mixed germ cell tumor: a case report

Background: Premature ovarian insufficiency (POI) will bring women early and long-term adverse consequences, including estrogen deficiency-related symptoms (hot flashes, sweating, decreased libido, insomnia, etc.) and significantly increases the risk of chronic diseases including Alzheimer's disease, cardiovascular disease and osteoporosis, along with increased risk of early death. More importantly, POI has greater harm to women’s fertility. Mostly the causes of POI are unknown. Most important are iatrogenic factors such as radiotherapy, chemotherapy and surgery, which increase the risk of POI.

O-083 Ovarian reserve, Reproductive function and Pregnancy outcomes among Female survivors of childhood Hodgkin lymphoma: results from the DCOG LATER-VEVO Later study

Abstract Study question What is the impact of treatment for Hodgkin lymphoma (HL) on clinical reproductive markers and pregnancy outcomes? Summary answer Impaired markers of ovarian reserve in childhood HL survivors substantiate risk of a reduced fertile life span. Pregnancy outcomes seem reassuring at a young age. What is known already Childhood Hodgkin Lymphoma (HL) is nowadays highly curable with survival rates over 90%. Chemotherapy and radiation are associated with late adverse effects including risk of reduced ovarian function and -reserve. Study design, size, duration This study was embedded within the DCOG LATER-VEVO study, a nationwide, multicenter, retrospective cohort study performed between 2004 and 2014, in which the reproductive ability of 1106 female childhood cancer survivors was studied and compared to 798 controls (siblings and females from the general population). Participants/materials, setting, methods The current analysis included all female childhood HL survivors, treated between 1963 and 2002, and controls who provided written informed consent to participate in the LATER-VEVO study. Data collection consisted of a questionnaire and timed clinical measurements (blood sample and transvaginal ultrasound). Serum anti-Mullerian hormone (AMH), FSH, inhibin B, the antral follicle count (AFC) and self-reported (first) pregnancy rates and -outcomes were evaluated in linear and logistic regression models . Main results and the role of chance 84 HL survivors and 798 controls were included, aged 29.6 (IQR 19.8-36.6) and 32.7 (IQR 19.7-49.6) years old at time of assessment. Median age at HL diagnosis was 13.4 years (IQR 6.4-16.4), with median time since diagnosis of 16.5 (IQR 8.4;36.6) years. Cyclophosphamide equivalent dose (CED-score) exceeded 6000mg/m2 in 56 women and 14 survivors received pelvic irradiation. All clinical markers were significantly deteriorated in survivors (odds-ratio for low AMH (<p10) 10.1 [95%CI 4.9;20.6]; low AFC (<p10) 4.6 [95%CI 2.1;9.9]; elevated FSH (>10IU/l) 15.3 [95%CI 5.7;41.1], low Inhibin B (<20ng/l) 3.6 [ 95%CI 1.7;7.7], all p < 0.001, 45 survivors and 413 controls). Pregnancy and live birth rates were comparable between survivors and controls (±80% live birth, ±20% miscarriage). However survivors were significantly younger of age at first pregnancy (27.0 years vs 29.0 yrs, P = 0.04, 42 survivors and 389 controls). Time to first pregnancy seemed to be increased in survivors (adjusted odds-ratio for time to pregnancy >12 months was 2.5 [95% CI 1.1;5.6] in survivors, p = 0.031). No significant differences in birth weight or gestational age were observed. Gonadotoxicity was specifically present after treatment with procarbazine and higher CED-score. No clear effect of age at diagnosis was observed. Limitations, reasons for caution The studied cohort comprised a relatively young population. Risk of premature ovarian insufficiency could not be assessed and a considerable number of women indicated they considered themselves too young to aim to achieve pregnancy. Heterogeneity in received treatment and sample size issues complicated the extent of the analyses. Wider implications of the findings HL survivors appear to have an impaired ovarian reserve, however chance to achieve pregnancy seems reassuring at a young age. Additional studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic. Trial registration number NTR2922

Chemotherapy alone vs. chemotherapy plus radiotherapy in female adolescent and young adults with Hodgkin's lymphoma: reproductive health outcomes.

To examine the effects of Hodgkin's lymphoma and its treatment on reproductive health in female adolescent and young adults (AYA). We conducted a retrospective, population-based, matched-cohort study of female patients with Hodgkin's lymphoma diagnosed at 15-39years of age from 1995 to 2014 in Ontario, Canada. Three female individuals with no history of cancer (unexposed) were matched by birth year and census subdivision to each patient with cancer (exposed). In a subset of the cohort (2005 onwards), the Hodgkin's lymphoma patients were further classified into two groups for analysis based on treatment exposure: (1) chemotherapy alone or (2) combined chemotherapy and radiation. Reproductive health outcomes were infertility, childbirth, and premature ovarian insufficiency (POI). Relative risks (RR) were calculated using modified Poisson regression adjusted for income quintile, immigration status, and parity. A total of 1443 exposed and 4329 unexposed individuals formed our cohort. Hodgkin's lymphoma patients were at an increased risk of infertility (aRR 1.86; 95% CI 1.57 to 2.20) and POI (aRR 2.81; 95% CI 2.16 to 3.65). While the risk of infertility persisted in both treatment groups (chemotherapy alone, combined chemotherapy plus radiotherapy), the increased risk of POI was only statistically significant in the chemotherapy plus radiotherapy group. No differences in childbirth rates were observed, overall or by treatment exposure compared with unexposed individuals. Female AYA survivors of Hodgkin's lymphoma face an increased risk of infertility, independent of exposure to chemotherapy alone, or chemotherapy plus radiotherapy. The risk of POI is higher in those requiring radiotherapy vs. chemotherapy alone. These results emphasize the importance of pre-treatment fertility counseling and reproductive health surveillance for AYAs diagnosed with Hodgkin's lymphoma.

Association of genetic disorders and congenital malformations with premature ovarian insufficiency: a nationwide register-based study.

Are genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)? A wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI. POI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7-15% of POI cases. This population-based study included 5011 women diagnosed with POI in 1988-2017. The data were collected from various national registries and covers women with POI nationwide. We identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date. Of the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1-1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1-39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2-43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10-14 years old, OR 24.1, 95% CI 15.1-38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had. Some women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers. GD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations. Oulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare. N/A.

Loss of p16 does not protect against premature ovarian insufficiency caused by alkylating agents

BackgroundChemical agents such as alkylating agents (AAs) that are commonly used for the treatment of cancer cause great damage to the ovaries, thereby significantly increasing the risk of premature ovarian insufficiency (POI). However, the exact molecules underlying AA-induced POI remain largely obscure. Upregulation of the p16 gene may contribute to the progression of POI. As yet, no in vivo data from p16-deficient (KO) mice are available to demonstrate a critical role of p16 in POI. In the present study, we employed p16 KO mice to investigate whether loss of p16 could protect against POI caused by AAs.MethodsWT mice and their p16 KO littermates received a single dose of BUL + CTX to establish an AA-induced POI mouse model. One month later, oestrous cycles were monitored. Three months later, some of the mice were sacrificed to collect sera for measurements of hormone levels and ovaries for measurements of follicle counts, the proliferation and apoptosis of granulosa cells, ovarian stromal fibrosis and vessels. The remaining mice were mated with fertile males for the fertility test.ResultsOur results showed that treatment with BUL + CTX significantly disrupted the oestrous cycles, increased the levels of FSH and LH while decreasing the levels of E2 and AMH, decreased the counts of primordial follicles and growing follicles while increasing the counts of atretic follicles, reduced the vascularized area in the ovarian stroma, and decreased fertility. All of these results were comparable between WT and p16 KO mice treated with BUL + CTX. In addition, ovarian fibrosis was not increased significantly in WT and p16 KO mice treated with BUL + CTX. Growing follicles with normal appearance had normally proliferating granulosa cells (without apparent apoptosis).ConclusionWe concluded that genetic ablation of the p16 gene did not attenuate ovarian damage or help preserve the fertility of mice challenged by AAs. This study demonstrated for the first time that p16 is dispensable for AA-induced POI. Our preliminary findings suggest that targeting p16 alone may not preserve the ovarian reserve and fertility of females treated with AAs.

Gonadal Function in Female Adolescent and Young Adult Survivors of Childhood Cancer.

Childhood cancer survivors (CCSs) are at risk for premature ovarian insufficiency (POI). The aim of this study is to evaluate ovarian function and associated health outcomes in female adolescent and young adult survivors of childhood cancer. Sixty-nine female CCSs were enrolled. Medical records of CCSs were retrospectively reviewed. The subjects were categorized into three groups according to follicular stimulating hormone (FSH) levels (cutoff, 12, 40 IU/L). Anti-müllerian hormone (AMH) level less than 1 ng/mL was considered low AMH level. Of 69 subjects, 14 (20.3%) had POI and 14 (20.3%) had FSH levels between 12 and 40 IU/L. Forty-one of 69 (59.4%) had normal FSH levels. Pelvic irradiation and stem cell transplantation (SCT) were more frequently performed in subjects with POI (p=0.001 and p < 0.001). AMH levels were remarkably low when FSH levels were over 12 IU/L (p < 0.001). In multivariate analysis, cyclophosphamide equivalent dose and SCT were significant treatment factors for developing low AMH levels (p=0.005 and p=0.002, respectively). Total, low-density lipoprotein cholesterol and triglyceride were significantly different in three groups according to FSH levels (p=0.047, p=0.030, and p=0.045). Z-score of femur neck bone mineral density was significantly reduced when FSH levels were increased (p=0.011). Gonadal dysfunction is common in CCSs. Gonadal function was associated with a few treatment factors known to increase the risk of POI. Regular monitoring of gonadal function is needed for better health outcomes.

Risk of Premature Ovarian Insufficiency after Human Papilloma Virus Vaccination: A PRISMA Systematic Review and Meta-Analysis of Current Evidence

(1) Background: Premature ovarian insufficiency (POI) has been linked to human papilloma virus (HPV) vaccination in small case-reports. The aim of this meta-analysis was to evaluate the risk of POI after HPV vaccination. (2) Methods: Electronic searches in MEDLINE Scopus, LILACS, ClinicalTrials.gov, EMBASE, PROSPERO, Cochrane CENTRAL and other registries were searched from inception to September 2022. Inclusion criteria were cohort studies of female children or adolescents vaccinated with quadrivalent (4vHPV), bivalent (2vHPV) or 9-valent (9vHPV) vaccine and compared to unvaccinated, other HPV vaccine, or vaccinated with other childhood vaccine girls. Primary outcome was risk of POI after vaccination. (3) Results: Four studies, including 1,253,758 patients, were included. Overall, there was no significant risk for POI between 4vHPV and controls (unvaccinated or other vaccines) (RR 0.47 (95% CI 0.14 to 1.59) I2 = 75%), or unvaccinated only controls (RR 0.75 (95% CI 0.22 to 2.49) I2 = 26%). One study reported a significant reduction of POI risk for 4vHPV relative to the other childhood vaccinations (RR 0.03 (95% CI 0.00 to 0.21)); meanwhile, one study showed no increased risk with 4vHPV relative to 2vHPV and 9vHPV (RR 0.93 (95% CI 0.33 to 2.64)). (4) Conclusions: 4vHPV vaccination does not seem to increase risk of POI relative to unvaccinated people or other childhood vaccines. No difference was seen with 4vHPV vaccine relative to 2vHPV and 9vHPV. Moreover, the risk of POI after HPV vaccination is relatable to worldwide incidence, giving reassurance about safety.

Premature ovarian insufficiency in female adolescent and young adult survivors of non-gynecological cancers: a population-based cohort study

BackgroundThe risk of premature ovarian insufficiency (POI) is increased in adolescent and young adult (AYA) cancer survivors, with the prevalence depending on cancer diagnosis, treatment, and patient factors. Prior studies are limited by sample size and type of cancer included. The objective of this study was to assess the risk of POI in female AYA survivors of non-gynecologic cancers, using a population-based approach.MethodsThis population-based retrospective cohort study comprises 21,666 females, 15–39 years old, diagnosed with a single non-gynecologic cancer in Ontario, Canada from 1995 to 2015.Through health administrative data linkage, participants were followed until their 40th birthday, December 31, 2018, bilateral oophorectomy, loss of health insurance eligibility or death. Each cancer survivor was matched to 5 females who were not diagnosed with cancer (unexposed, n = 108,330). Women with bilateral oophorectomy or a prior menopause diagnosis were excluded. POI was identified through use of the ICD-9 code for menopause (ICD9-627). Modified Poisson regression models were used to calculate the adjusted relative risk (aRR) of POI for AYA cancer survivors compared to unexposed individuals, adjusted for income, parity, age, and immigration status.ResultsThe occurrence of POI was higher in survivors of AYA cancer versus unexposed patients (5.4% vs. 2.2%). Survivors of AYA cancer had an increased risk of POI relative to unexposed patients (aRR 2.49; 95% CI 2.32–2.67). Risk varied by type of cancer: breast (4.32; 3.84–4.86), non-Hodgkin’s lymphoma (3.77; 2.88–4.94), Hodgkin’s lymphoma (2.37; 1.91–2.96), leukemia (14.64; 10.50–20.42), thyroid (1.26; 1.09–1.46) and melanoma (1.04; 0.82–1.32). Risk varied by age at time of cancer diagnosis, with a higher risk among females diagnosed at age 30–39 years (3.07; 2.80–3.35) than aged 15–29 years (1.75; 1.55–1.98).ConclusionsAYA survivors of non-gynecologic cancers are at an increased risk of POI, particularly survivors of lymphomas, leukemia, breast, and thyroid cancer. The risk of POI is increased for those diagnosed with cancer at an older age. These results should inform reproductive counseling of female AYAs diagnosed with cancer.

Association of Coenzyme Q10 with Premature Ovarian Insufficiency

The aim of the study was to analyze the relationship between levels of coenzyme Q10 (CoQ10) and the risk of premature ovarian insufficiency (POI). In this cross-sectional case–control study, 32 women with POI and 58 women with normal menstrual cycles were recruited. The serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), CoQ10 and total cholesterol were measured. The association of CoQ10 with POI was assessed using binary logistic regression analysis. The CoQ10/total cholesterol ratio was significantly lower in the women with POI than in the women with normal menstrual cycles (120.94 ± 25.35 nmol/mmol vs 138.97 ± 39.19 nmol/mmol, P = 0.021). The serum CoQ10/total cholesterol ratio was inversely associated with POI (the unadjusted odds ratio (OR) = 0.984, 95% CI: 0.970–0.998, P = 0.027). The same trend was found after adjusting for confounding factors (such as age, body mass index, annual household income and education) (OR = 0.976, 95% CI: 0.956–0.996, P = 0.020). The serum CoQ10/total cholesterol ratio was inversely associated with POI, indicating that antioxidant deficiency may be a risk associated with the development of POI. CoQ10 may be a protective factor for ovarian tissue.

Модифицированный раздел доабортного консультирования

The problem of pregnancy termination is multifaceted. According to the current legislation, women who come to a healthcare facility for an induced termination of pregnancy undergo pre-abortion counseling. During the consultation, the specialist has several tasks: to compare the arguments for pregnancy termination or preservation; to help competently assess the current life situation; to consider ways to solve problems; to provide information about federal and regional support measures for pregnant women and families with children; to inform about possible negative consequences of an artificial termination of pregnancy. The authors believe that in addition to psychological assistance to women in the situation of choice, it is of great importance to provide detailed information about the negative reproductive consequences of abortion, including the problem of premature ovarian insufficiency. Due to the high prevalence of premature ovarian insufficiency among female population, it seems necessary to supplement the existing pre-abortion counseling procedure with a section devoted to the problem of physiological and pathological loss of ovarian reserve and the impact of pregnancy termination on this process. To inform a woman about her risk of premature ovarian insufficiency and about her presence of this condition in general would allow a woman to consciously avoid additional negative influences (smoking, alcohol, stress), make an informed decision about her reproductive plans and their timing, and possibly resort to oocyte cryopreservation methods in cases where the risks of premature ovarian insufficiency are extremely high. When premature ovarian insufficiency is already diagnosed, the only way to have a baby is to use assisted reproductive technology, but with the use of donor eggs.

A predictive model of the effect of therapeutic radiation on the human ovary.

Radiation to the female pelvis as part of treatment for cancer predisposes young women to develop Premature Ovarian Insufficiency (POI). As the human female is born with their full complement of non-growing follicles which decline in an exponential fashion until the menopause, the age at which POI occurs is dependent on the age of the patient at treatment and the dose received by the ovary. A model that predicts the age at which POI occurs for a known dose at a known age will aid counselling patients on their fertility risk. Patients deemed to be at high risk of POI may be considered to be good candidates for established fertility preservation techniques. An updated and externally validated model of the age-related decline in human ovarian reserve was combined with the best available estimate of the median lethal dose LD50 for the human ovary. Using known age at diagnosis and posited radiotherapy treatment plan to estimate the dose to the least-affected ovary, we use an age-related model of the decline in ovarian reserve to generate a personalized age prediction of premature ovarian insufficiency. Our algorithm is available as an online calculator which graphs model outputs to inform discussions around survivor fertility. We report four example cases across different ages and diagnoses, each with two carefully designed photon and proton treatment plans. The treatment options are compared in terms of remaining fertile lifespan for the survivor. International oncology guidelines now mandate the consideration of later fertility when reviewing treatment options for children diagnosed with cancer. Our calculator (https://sites.cs.st-andrews.ac.uk/radiosensitivity), and the underlying algorithm and models, allow detailed predictions of the impact of various radiotherapy plans on fertility. These patient-specific data enhance pre-treatment discussions around post-treatment fertility and fertility preservation.