What reproductive follow-up for adolescent and young women after cancer? A review.

Fertility capacity has been shown to be one of the main concerns of young cancer survivors. Gonadotoxic treatments may lead to both premature ovarian failure and/or infertility. This review aimed to define which, and when, reproductive indicators should be followed-up to help doctors to counsel patients regarding their fertility and ovarian function, and to determine if a second stage of fertility preservation after the end of cancer treatment is clinically relevant. Longitudinal assessment of anti-Müllerian hormone (AMH) concentrations during cancer treatment indicates the degree of follicular depletion, and allows discrimination between low and high gonadotoxic treatments. Sustained low AMH concentrations after treatment, especially in the case of alkylating protocols, may reduce the duration of the conception window significantly, and expose the patient to the risk of premature ovarian failure. It remains unknown whether this may impact further fertility capacity because of the lack of systematic follow-up of adolescent and young adult (AYA) women after chemo-radiotherapy. It appears that dedicated reproductive follow-up of AYA women under cancer treatment is needed to refine fertility preservation strategies, and to determine if low AMH concentrations after treatment impact the chance of pregnancy in this specific survivor population.

Longitudinal study of AMH variations in 122 Adolescents and Young Adults (AYA) and non-AYA lymphoma patients to evaluate the chemo-induced ovarian toxicity to further personalise fertility preservation counselling.

STUDY QUESTION: What is the influence of age and chemotherapy regimen on the longitudinal blood anti-Müllerian hormone (AMH) variations in a large series of adolescents and young adult (AYA) (15-24 years old) and non-AYA (25-35 years old) lymphoma patients? SUMMARY ANSWER: In case of alkylating regimen treatment, there was a deep and sustained follicular depletion in AYA as well as non-AYA patients; however in both groups, the ovarian toxicity was extremely low in cases of non-alkylating treatments. WHAT IS KNOWN ALREADY: AMH is now well-recognised to be a real-time indicator of ovarian follicular depletion and recovery in women treated by chemotherapy. Its longitudinal variations may discriminate between highly and minimally toxic protocols regarding ovarian function. It has been shown, in different cancer types, that age, type of chemotherapy regimen and pre-treatment AMH levels are the main predictors of ovarian recovery. Large studies on longitudinal AMH variations under chemotherapy in lymphoma patients are few but can provide the opportunity to assess the degree of follicle loss at a young age. STUDY DESIGN, SIZE, DURATION: This prospective cohort study was conducted in the Fertility Observatory of the Lille University Hospital. Data were collected between 2007 and 2016. Non-Hodgkin or Hodgkin lymphoma patients (n = 122) between 15 and 35 years old were prospectively recruited before commencing chemotherapy. Patients were treated either by a non-alkylating protocol (ABVD group; n = 67) or by an alkylating regimen (alkylating group; n = 55). PARTICIPANTS/MATERIALS, SETTING, METHODS: Serial AMH measurements were performed at baseline (AMH0), 15 days after the start of chemotherapy (AMH1), 15 days before the last chemotherapy cycle (AMH2), and at time 3, 6, 9, 12, 18 and 24 months from the end of chemotherapy. The whole study population was divided into two groups according to age: AYA (15-24; n = 65) and non-AYA (25-35; n = 57). All patients received a once monthly GnRH agonist injection during the whole treatment period. A linear mixed model was used to account for the repeated measures of single patients. MAIN RESULTS AND THE ROLE OF CHANCE: At baseline, non-AYA patients had higher BMI and lower AMH levels than AYA patients. All AYA and non-AYA patients having received ABVD protocols had regular cycles at 12 months of follow-up. In case of alkylating regimens, amenorrhoea was more frequent in non-AYA patients than in AYA patients at 12 months (37% vs 4%, P = 0.011) and at 24 months (24% vs 4%, P = 0.045). We distinguished a similar depletion phase from AMH0 to AMH2 between ABVD and alkylating groups but significantly different recovery phases from AMH2 to AMH + 24 months. AMH recovery was fast and complete in case of ABVD protocols whatever the age: AMH reached pre-treatment values as soon as the 6th month of follow-up in the AYA group (mean (95% CI) in log AMH M0 vs M6: 3.07 (2.86 to 3.27) vs 3.05 (2.78 to 3.31), P = 1.00) and in the non-AYA group (mean (95% CI) in log AMH M0 vs M6: 2.73 (2.40 to 3.05) vs 2.47 (2.21 to 2.74), P = 1.00). In contrast, no patients from the alkylating group returned to pre-treatment AMH values whatever the age of patients (AYA or non-AYA). Moreover, none of the AMH values post-chemotherapy in the non-AYA group were significantly different from AMH2. Conversely in the AYA group, AMH levels from 6 months (mean (95% CI) in log AMH: 1.79 (1.47 to 2.11), P < 0.001) to 24 months (mean (95% CI) in log AMH: 2.16 (1.80 to 2.52), P ≤ 0.001) were significantly higher than AMH2 (mean (95% CI) in log AMH: 1.13 (0.89 to 1.38)). Considering the whole study population (AYA and non-AYA), pre-treatment AMH levels influenced the pattern of the AMH variation both in alkylating and ABVD protocols (interaction P-value = 0.005 and 0.043, respectively). Likewise, age was significantly associated with the pattern of the recovery phase but only in the alkylating group (interaction P-value =0.001). BMI had no influence on the AMH recovery phase whatever the protocol (interaction P-value = 0.98 in alkylating group, 0.72 in ABVD group). LIMITATIONS, REASONS FOR CAUTION: There was a large disparity in subtypes of protocols in the alkylating group. The average duration of chemotherapy for patients treated with alkylating protocols was longer than that for patients treated with ABVD. WIDER IMPLICATIONS OF THE FINDINGS: These results make it possible to develop strategies for fertility preservation according to age and type of protocol in a large series of young lymphoma patients. In addition, it was confirmed that young age does not protect against ovarian damage caused by alkylating agents. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Agence Régionale de Santé Hauts de France and Agence Onco Hauts-de-France who provided finances for AMH dosages (n° DOS/SDES/AR/FIR/2019/282). There are no competing interests. TRIAL REGISTRATION NUMBER: DC-2008-642 and CNIL DEC2015-112.

Pregnancy after chemoradiotherapy in childhood: Complications and recommendations - about one case.

The question of pregnancy prognosis after radio chemotherapy is unaddressed. We report here the case of three successive spontaneous pregnancies 17 years after the management of a thigh rhabdomyosarcoma treated by radiochemotherapy. In 2018 the patient aged 22 presented with a spontaneous miscarriage. In 2019, she obtained a new spontaneous pregnancy. At 21 W G, she presented with threatened late miscarriage and gave birth to a live girl who would die. Three months after delivery, she had spontaneous pregnancy. At 18 W G, emergency cervical cerclage was performed. At 35 W G the ultrasound found severe intrauterine growth retardation. Cesarean section was performed allowing the birth of a girl in good health status. Childbirth was complicated by 1L8 postpartum hemorrhage secondary to uterine atony, controlled after surgical revision. To conclude, pregnancy in a patient with a history of pelvic irradiation in childhood must be considered high-risk pregnancy and its management must be multidisciplinary.

Management of endometriosis: CNGOF/HAS clinical practice guidelines - Short version.

First-line diagnostic investigations for endometriosis are physical examination and pelvic ultrasound. The second-line investigations are: targeted pelvic examination performed by an expert clinician, transvaginal ultrasound performed by an expert physician sonographer (radiologist or gynaecologist), and pelvic MRI. Management of endometriosis is recommended when the disease has a functional impact. Recommended first-line hormonal therapies for the management of endometriosis-related pain are combined hormonal contraceptives (CHCs) or the 52mg levonorgestrel-releasing intrauterine system (IUS). There is no evidence base on which to recommend systematic preoperative hormonal therapy solely to prevent surgical complications or facilitate surgery. After surgery for endometriosis, a CHC or 52mg levonorgestrel-releasing IUS is recommended as first-line treatment when pregnancy is not desired. In the event of failure of the initial treatment, recurrence, or multiorgan involvement, a multidisciplinary team meeting is recommended, involving physicians, surgeons and other professionals. A laparoscopic approach is recommended for surgical treatment of endometriosis. HRT can be offered to postmenopausal women who have undergone surgical treatment for endometriosis. Antigonadotrophic hormonal therapy is not recommended for patients with endometriosis and infertility to increase the chances of spontaneous pregnancy, including postoperatively. Fertility preservation options must be discussed with patients undergoing surgery for ovarian endometriomas.

[First line management without IVF of infertility related to endometriosis: Result of medical therapy? Results of ovarian superovulation? Results of intrauterine insemination? CNGOF-HAS Endometriosis Guidelines]. / Prise en charge de l'infertilité en première intention hors FIV : performances du traitement médical ? Performances de la stimulation ovarienne ? Performances des inséminations ? RPC Endométriose CNGOF-HAS.

INTRODUCTION: Using the structured methodology of French guidelines (HAS-CNGOF), the aim of this chapter was to formulate good practice points (GPP), in relation to optimal non-ART management of endometriosis related to infertility, based on the best available evidence in the literature. MATERIALS AND METHODS: This guideline was produced by a group of experts in the field including a thorough systematic search of the literature (from January 1980 to March 2017). Were included only women with endometriosis related to infertility. For each recommendation, a grade (A-D, where A is the highest quality) was assigned based on the strength of the supporting evidence. RESULTS: Management of endometriosis related to infertility should be multidisciplinary and take account into the pain, the global evaluation of infertile couple and the different phenotypes of endometriotic lesions (good practice point). Hormonal treatment for suppression of ovarian function should not prescribe to improve fertility (grade A). After laproscopy for endometriosis related to infertility, the Endometriosis Fertility Index should be used to counsel patients regarding duration of conventional treatments before undergoing ART (grade C). After laparoscopy surgery for infertile women with AFS/ASRM stage I/II endometriosis or superficial peritoneal endometriosis, controlled ovarian stimulation with or without intrauterine insemination could be used to enhance non-ART pregnancy rate (grade C). Gonadotrophins should be the first line therapy for the stimulation (grade B). The number of cycles before referring ART should not exceed up to 6 cycles (good practice point). No recommendation can be performed for non-ART management of deep infiltrating endometriosis or endometrioma, as suitable evidence is lacking. DISCUSSION AND CONCLUSION: Non-ART management is a possible option for the management of endometriosis related to infertility. Endometriosis Fertilty Index could be a useful tool for subsequent postoperative fertility management. Controlled ovarian stimulation can be proposed.

[Management of endometriosis: CNGOF-HAS practice guidelines (short version)]. / Prise en charge de l'endométriose : recommandations pour la pratique clinique CNGOF-HAS (texte court).

First-line investigations to diagnose endometriosis are clinical examination and pelvic ultrasound. Second-line investigations include pelvic examination performed by a referent clinician, transvaginal ultrasound performed by a referent echographist, and pelvic MRI. It is recommended to treat endometriosis when it is symptomatic. First-line hormonal treatments recommended for the management of painful endometriosis are combined with hormonal contraceptives or levonorgestrel 52mg IUD. There is no evidence to recommend systematic preoperative hormonal therapy for the unique purpose of preventing the risk of surgical complications or facilitating surgery. After endometriosis surgery, combined hormonal contraceptives or levonorgestrel SIU 52mg are recommended as first-line therapy in the absence of desire of pregnancy. In case of initial treatment failure, recurrence, or multiple organ involvement by endometriosis, medico-surgical and multidisciplinary discussion is recommended. The laparoscopic approach is recommended for the surgical treatment of endometriosis. HRT may be offered in postmenopausal women operated for endometriosis. In case of infertility related to endometriosis, it is not recommended to prescribe anti-gonadotropic hormone therapy to increase the rate of spontaneous pregnancy, including postoperatively. The possibilities of fertility preservation should be discussed with the patient in case of surgery for ovarian endometrioma.

[Deeply infiltrating endometriosis and infertility: CNGOF-HAS Endometriosis Guidelines]. / Endométriose profonde et infertilité, RPC Endométriose CNGOF-HAS.

Deeply infiltrating endometriosis is a severe form of the disease, defined by endometriotic tissue peritoneal infiltration. The disease may involve the rectovaginal septum, uterosacral ligaments, digestive tract or bladder. Deeply infiltrating endometriosis is responsible for disabling pain and infertility. The purpose of these recommendations is to answer the following question: in case of deeply infiltrating endometriosis associated infertility, what is the best therapeutic strategy? First-line surgery and then in vitro fertilization (IVF) in case of persistent infertility or first-line IVF, without surgery? After exhaustive literature analysis, we suggest the following recommendations: studies focusing on spontaneous fertility of infertile patients with deeply infiltrating endometriosis found spontaneous pregnancy rates about 10%. Treatment should be considered in infertile women with deeply infiltrating endometriosis when they wish to conceive. First-line IVF is a good option in case of no operated deeply infiltrating endometriosis associated infertility. Pregnancy rates (spontaneous and following assisted reproductive techniques) after surgery (deep lesions without colorectal involvement) varie from 40 to 85%. After colorectal endometriosis resection, pregnancy rates vary from 47 to 59%. The studies comparing the pregnancy rates after IVF, whether or not preceded by surgery, are contradictory and do not allow, to date, to conclude on the interest of any surgical management of deep lesions before IVF. In case of alteration of ovarian reserve parameters (age, AMH, antral follicle count), there is no argument to recommend first-line surgery or IVF. The study of the literature does not identify any prognostic factors, allowing to chose between surgical management or IVF. The use of IVF in the indication "deep infiltrating endometriosis" allows satisfactory pregnancy rates without significant risk, regarding disease progression or oocyte retrieval procedure morbidity.

[Endometriosis and fertility preservation: CNGOF-HAS Endometriosis Guidelines]. / Endométriose et préservation de la fertilité, RPC Endométriose, CNGOF-HAS.

Fertility preservation (FP) techniques are progressing rapidly these past few years thanks to the oocyte vitrification. Indication of FP techniques is now extended to non-oncological situation that may induce risk of premature ovarian failure. Ovarian endometriosis can lead to premature ovarian failure and further infertility due to the high risk of ovarian cysts recurrence and surgery. To date, there is no cohort study regarding FP and endometriosis as well as no recommendation. Our purpose is to review the arguments in favor of FP in this specific area and to elaborate strategies according to each clinical form.

[Management of assisted reproductive technology (ART) in case of endometriosis related infertility: CNGOF-HAS Endometriosis Guidelines]. / Stratégies de prise en charge de l'infertilité en assistance médicale à la procréation dans un contexte d'endométriose, RPC Endométriose, CNGOF-HAS.

The management of endometriosis related infertility requires a global approach. In this context, the prescription of an anti-gonadotropic hormonal treatment does not increase the rate of non-ART (assisted reproductive technologies) pregnancies and it is not recommended. In case of endometriosis related infertility, the results of IVF management in terms of pregnancy and birth rates are not negatively affected by the existence of endometriosis. Controlled ovarian stimulation during IVF does not increase the risk of endometriosis associated symptoms worsening, nor accelerate the intrinsic progression of endometriosis and does not increase the rate of recurrence. However, in the context of IVF management for women with endometriosis, pre-treatment with GnRH agonist or with oestrogen/progestin contraception improve IVF outcomes. There is currently no evidence of a positive or negative effect of endometriosis surgery on IVF outcomes. Information on the possibilities of preserving fertility should be considered, especially before surgery.

[Systematic proposal of fertility preservation by mature oocyte cryopreservation for recurrent benign ovarian tumors]. / Proposition systématique de préservation de la fertilité par congélation d'ovocytes en cas de tumeur ovarienne bénigne.

OBJECTIVES: To investigate prospectively the pattern of the follicular growth and to characterize the COH outcome in terms of oocyte number and maturity in patients with voluminous recurrent benign ovarian tumors with a high surgical risk of significant reduction of the ovarian follicular content. METHODS: The inclusion criteria were: age between 18 and 36, presence of at least one benign ovarian tumor (≥ 5cm) with high risk of recurrence. The fertility preservation cycle was performed at least 3 months after the cyst surgery. The controlled ovarian stimulation was performed after the ovarian reserve was assessed (AMH measurement and sonographic antral follicle count). Triggering was performed by hCG when at least 3 follicles reached 18mm of diameter. Metaphase II oocytes were cryopreserved by the vitrification technique. RESULTS: Twenty-four women with dermoid, endometrioma or seromucinous cysts were included from January 2015 to July 2016. All of them had previous ovarian surgery. Mean AMH levels were 15.3pmol/L. The mean number of total oocytes retrieved was 7±5. The mean number of metaphase II oocytes was 4.4±4. The incidence of low ovarian response was 38%. Among the patients, 86% had less than 8 metaphase II oocytes vitrified. Seven patients asked for a second cycle in order to have more oocytes. CONCLUSION: We demonstrated the feasibility of the systematic proposal of fertility preservation by oocyte cryopreservation in this group of young patients with recurrent ovarian benign tumors. Taking into account history of previous surgery and high incidence of low ovarian reserve, the ovarian response under stimulation was frequently poor with, as consequence, low retrieved oocyte number per cycle. An oocyte accumulation strategy is then proposed to enhance further pregnancy chances.

[Assisted reproductive techniques in single women: Which proposals for which demands?]. / Assistance médicale à la procréation chez la femme célibataire : quelles propositions pour quelles demandes ?

The French bio-ethic law concerning ART is more restricted than in other countries. Techniques can only be applied in heterosexual couples presenting a documented infertility. Nevertheless, concerns about fertility planning are numerous in young women, leading to a growing demand of reproductive medicine consultations. Two situations can be distinguished: firstly, single patients wishing sperm donation and, secondly, single patients who wish to preserve their fertility for future parenting project. This latter situation can be discussed in the French legislative context while the other will require soliciting the neighboring European teams.

[Practical clinical aspects of oocyte vitrification for fertility preservation]. / Aspects cliniques pratiques de la vitrification ovocytaire en oncofertilité

Oocyte vitrification is a preservation fertility strategy, which can be performed in women after puberty to preserve gametes before beginning a gonadotoxic anticancer treatment. Based on available literature and our personal data, we aim to provide an overview about the feasibility, the clinical and logistic difficulties of oocyte vitrification in the field of oncofertility: limit age for oocyte cryopreservation, time required and protocols for ovarian controlled stimulation, ovarian response to stimulation, for what hopes of pregnancy?

[Steroid 21-hydroxylase deficiencies and female infertility: pathophysiology and management]. / Déficits en 21-hydroxylase et infertilité féminine: de la physiopathologie à la prise en charge thérapeutique.

Steroid 21-hydroxylase deficiency is the most common adrenal genetic disease and is also named congenital adrenal hyperplasia. Depending on the severity of CYP21A2 gene mutations, there are severe or "classical" forms and moderate or "nonclassical" forms of 21-hydroxylase deficiency. The enzyme deficiency causes a disruption of adrenal steroidogenesis, which induces hyperandrogenism and elevated plasma levels of progesterone and 17-hydroxyprogesterone, the two substrates of 21-hydroxylase. These endocrine abnormalities will disrupt gonadal axis, endometrial growth and maturation and finally secretion of cervical mucus. All these phenomena contribute to a female hypofertility. Infertility is more severe in classical forms. When to become pregnant, treatment with hydrocortisone or dexamethasone can limit the production of adrenal androgens and progesterone and improves spontaneous pregnancy rates while minimizing the risk of miscarriage, which is usually relatively high in this disease. When planning pregnancy in patients with a 21-hydroxylase deficiency, genotyping the partner is required to screen for heterozygozity (1/50) and to assess the risk of transmission of a classical form in the progeny.

[Polycystic ovary syndrome: what are the obstetrical risks?]. / Syndrome des ovaires polymicrokystiques: une pathologie à risque obstétrical?

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and the leading cause of female infertility. This condition is frequently associated with significant metabolic disorders, including obesity and hyperinsulinemia. Therefore, it seems essential to focus on the pregnancy of these patients and possible obstetric complications. Many studies suggest an increase in the risk of obstetric pathology: early miscarriage, gestational hypertension, preeclampsia, gestational diabetes mellitus diagnosed during early pregnancy, prematurity, low birthweight or macrosomia, neonatal complications and cesarean sections. However, it is difficult to conclude clearly about it, because of the heterogeneity of definition of PCOS in different studies. In addition, many confounding factors inherent in PCOS including obesity are not always taken into account and generate a problem of interpretation. However it seems possible to conclude that PCOS does not increase the risk of placental abruption, HELLP syndrome, liver disease, postpartum hemorrhage, late miscarriage and stillbirth.

[Use of conventional assisted reproductive technologies and history of cancer: what are the results?]. / Recours aux techniques conventionnelles d'assistance médicale à la procréation en cas d'antécédent cancer: quels résultats?

Therapeutic advances in oncology have improved the prognosis for long-term survival of children and young adults. As well as other couples or because of adverse side effects of cancer treatments on reproductive function, some cancer survivors will therefore be brought to use assisted reproductive technologies (intrauterine inseminations, in vitro fertilization, intracytoplasmic sperm injection, oocyte or sperm donation…). The purpose of this review is to summarize available scientific datas regarding success rate of assisted reproductive technologies in cancer survivors.

[Fertility preservation strategies in young women in case of breast cancer or hematologic malignancy]. / Stratégies de préservation de la fertilité chez la femme jeune atteinte de cancer du sein ou d'hémopathie maligne.

The incidence of cancer in young patients as well as survival rates is steadily increasing. The question of fertility capacity is therefore of great importance regarding the quality of life after cancer. According to the ASCO recommendations, every patient should be advised about the chemotherapy-induced ovarian damage and fertility preservation possibilities. Several options can be discussed: embryo and/or oocytes freezing and ovarian tissue cryopreservation. Fertility preservation techniques are progressing rapidly but it still remains difficult to establish precise flow-charts according to age, marital status, type, dose and timing of chemotherapy.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on adrenal insufficiency and osteoporosis]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: insuffisance corticotrope et ostéoporose.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on secondary adrenal insufficiency and osteoporosis post-transplant.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on dyslipidemia and thyroid disorders]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: dyslipidémie et thyropathie.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview on dyslipidemia and thyroid disorders post-transplant.

[Management of endocrine dysfunctions after allogeneic hematopoietic stem cell transplantation: a report of the SFGM-TC on gonadal failure and fertility]. / Suivi et prise en charge des troubles endocriniens en post-greffe de cellules souches hématopoïétiques: insuffisance gonadique et fertilité

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of short and long-term endocrine dysfunction following allogeneic stem cell transplantation. The key aim of this workshop was to give an overview gonadal failure, fertility preservation and post-transplant.