Fertility preservation after chemotherapy for Hodgkin lymphoma

Kaaij, Marleen A. E. van der; Echten-Arends, Jannie van; Simons, Arnold; Kluin-Nelemans, Hanneke C.

doi:10.1002/hon.939

Cited by 85 publications

(56 citation statements)

References 115 publications

(75 reference statements)

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“…Both platinums (such as CBP) and anthracyclins (DOX) interfere with DNA replication and as such are particularly toxic to dividing granulosa cells of secondary and antral follicles, albeit with distinct toxicity profiles (55), and thus represent ideal targets for an MIS oncofertility intervention. CPA is an alkylating agent, a class that is particularly damaging to germ cells, and is the most problematic gonadotoxic chemotherapeutic in the clinic, particularly because it is often used in young girls with hematological cancers (57). We found that MIS had a particularly dramatic protective effect in the case of DNA-damaging agents (Fig.…”

Section: Discussionmentioning

confidence: 75%

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Kano

Sosulski

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

166

171

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The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman's reproductive lifespan, resulting in menopause. Müllerian inhibiting substance (MIS) (or anti-Müllerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy.M üllerian inhibiting substance (MIS), also known as antiMüllerian hormone (AMH), has long been appreciated for its role in sex differentiation and reproduction, and sensitive ELISAs measuring blood levels are used in fertility clinics around the world as a measure of ovarian reserve (1-6). MIS plays important roles in the development of the gonad and the differentiation of the urogenital ridge. In the male fetus, MIS produced by the developing testes causes regression of the Müllerian duct (7). In the female fetus, MIS may play a role in early follicle assembly in the gonad by primordial germ cells (not to be confused with primordial follicles), since mice overexpressing MIS are devoid of germ cells shortly after birth (8), and, similarly, ex vivo incubation of fetal ovaries with MIS results in the inhibition of follicle assembly (9). These data highlight a role of MIS during fetal development that is distinct from its regulatory role of folliculogenesis postnatally.In the adult, MIS is produced predominantly by the cumulus (less so by the mural) granulosa cells of secondary and early antral...

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Section: Discussionmentioning

confidence: 75%

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Kano

Sosulski

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

166

171

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“…40 The guidelines recommend fertility preservation (semen cryopreservation in male patients, ovarian tissue or oocyte cryopreservation in female patients) before the initiation of chemotherapy with alkylating agents or pelvic RT. 41,42 Oophoropexy should be considered to preserve ovarian function in premenopausal women if pelvic RT is contemplated.…”

Section: Treatment Guidelines Diagnosis and Workupmentioning

confidence: 99%

“…96,97 Other combinations (eg, ABVD) are only rarely associated with infertility. 42,98 Because women who have received chemotherapy with alkylating agents and who maintain short-term fertility may experience premature menopause, 40 this should be taken into consideration with respect to family planning.…”

Section: Myelosuppressionmentioning

confidence: 99%

Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Hoppe¹,

Advani²,

Ai³

et al. 2017

J Natl Compr Canc Netw

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OverviewHodgkin lymphoma (HL) is an uncommon malignancy involving lymph nodes and the lymphatic system. Most patients are diagnosed between 15 and 30 years of age, followed by another peak in adults aged ≥55 years. In 2017, an estimated 8,260 people will be diagnosed with HL in the United States and 1,070 will die of the disease. AbstractThis portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects. Please NoteThe NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

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“…At higher cumulative doses, alkylator containing regimens may cause prolonged azoospermia in 90-100 % of men. 55 A few studies have evaluated male fertility following cyclophosphamide-containing regimens given to children and young adults with sarcomas and other cancers [56][57][58] and suggest that the incidence of sterility will be low if the cyclophosphamide dose is less than 7.5 g/m 2 . Data concerning ovarian function following CT for female children and young adults with HL suggest that the ovaries of children and adolescents are less sensitive to the effects of alkylating agents than the ovaries of older women; females over 30 years have a much higher risk of acute ovarian failure.…”

Section: Gonadal Toxicitymentioning

confidence: 99%

“…However, with long-term follow-up, the cumulative risk of menopause before the age of 40 becomes the same irrespective of treatment age, and the incidence of early menopause in young female survivors may be as high as 37 %. 55,59,60 Options for fertility preservation in women receiving cytotoxic therapies are available in some jurisdictions (see, for example, recommendations from the network FertiPROTEKT [available at: www.fertiprotect.eu]).…”

Section: Gonadal Toxicitymentioning

confidence: 99%

Hodgkin’s Lymphoma in Adolescents and Young Adults

Rodríguez¹,

Punnett²

2012

Oncology &Amp; Hematology Review (US)

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Adolescents and young adults (AYAs) are defined as those individuals between the ages of 15 and 39 years.1 AYAs with cancer are considered a vulnerable group, in large part due to psychosocial challenges in this population, including lack of insurance, low rates of clinical trial enrollment, issues pertaining to independence, and concerns about body image and fertility. Hodgkin's lymphoma (HL) is the most common cancer observed among AYAs. 6 There is a slight overall male predominance in this age group, with a male:female ratio of 1.2. [6][7][8][9] Prior history of infection with Epstein-Barr virus (EBV) has been associated with an increased risk of HL. 10 Among AYAs, however, molecular studies show that EBV is related to HL in only a minority of cases and that it is unlikely to play a major etiologic role. 11,12The most common histological subtype of HL among the adolescent and young adult (AYA) population is nodular sclerosing classical HL, occurring in 50-80 % of patients. [7][8][9]13,14 Over the past decades, the prognosis of HL has dramatically improved, 15 but the optimal treatment of AYA patients remains undefined and patients continue to be treated on many different regimens with either pediatric or adult protocols. We will examine available literature regarding outcomes for the AYA population and discuss the therapy-related long-term sequelae. Studies Examining Adolescent and Young Adult OutcomesStudies focusing specifically on AYAs diagnosed with HL are scarce. Reviewing the literature, we found eight studies, and their main characteristics are summarized in The results of these studies should be interpreted with caution, however, as historical practices no longer considered appropriate, such as staging laparotomy and splenectomy, were employed, as well as older chemotherapy and radiotherapy protocols. AbstractAdolescents and young adults (AYAs) are defined as those individuals between the ages of 15 and 39 years. Hodgkin's lymphoma (HL) is the most common cancer observed in AYAs. Over the last two decades, significant improvements in both survival from HL and the reduction of therapy-related late effects have resulted from the work of collaborative study groups in pediatric and adult domains. The adolescent and young adult (AYA) population falls between these domains. AYA patients are in a critical developmental transition, with significant psychosocial challenges that may impact on the outcome of the primary treatment as well as on the medical care and surveillance of long-term sequelae in survivors. This article will examine available literature regarding outcomes for HL in the AYA population, identifying issues unique to this group, therapeutic options, and specific concerns in follow-up. KeywordsHodgkin's lymphoma, therapy, late effects, adolescents and young adults, second malignancies Disclosure:The authors have no conflicts of interest to declare.

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Fertility preservation after chemotherapy for Hodgkin lymphoma

Cited by 85 publications

References 115 publications

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Hodgkin Lymphoma Version 1.2017, NCCN Clinical Practice Guidelines in Oncology

Hodgkin’s Lymphoma in Adolescents and Young Adults

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