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Immune Checkpoint Inhibitor-Related­ Hypogonadism and Infertility: a Neglected Issue in Immuno-Oncology­

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Immune Checkpoint Inhibitor-Related­ Hypogonadism and Infertility: a Neglected Issue in Immuno-Oncology­ Open access Commentary J Immunother Cancer: first published as 10.1136/jitc-2020-002220 on 15 February 2021. Downloaded from Immune checkpoint inhibitor-related hypogonadism and infertility: a neglected issue in immuno-oncology Berna C Özdemir1,2 To cite: Özdemir BC. Immune ABSTRACT reported cases of hypogonadism, 5 were clas- checkpoint inhibitor- related Despite a significant amount of data on incidence and sified as secondary and 1 as primary hypo- hypogonadism and infertility: therapy of immune- related adverse events affecting 4 a neglected issue in immuno- gonadism. A similar analysis of the French virtually all organ systems, the potential impact of immune oncology. Journal for Pharmacovigilance database identified 94 checkpoint inhibitors (ICIs) on gonadal function has not ImmunoTherapy of Cancer cases of ICI-related hypophysitis, of whom been sufficiently studied. The limited evidence available 2021;9:e002220. doi:10.1136/ 8% showed panhypopituitarism.5 Although jitc-2020-002220 suggests that ICI-rela ted primary hypogonadism due to orchitis as well as secondary hypogonadism due to panhypopituitarism can cause secondary hypogonadism, the levels of the pituitary Accepted 31 January 2021 hypophysitis are a potential risk for infertility. A systematic investigation of gonadal function under ICIs is warranted gonadotropins follicle- stimulating hormone given the increasing application of ICIs in the adjuvant (FSH) and luteinizing hormone (LH) were setting, among young adults and children and the possible rarely assessed and supplementation with influence of sex hormone levels on the efficacy and toxicity gonadotropic hormones was mostly lacking.5 of ICIs. In a retrospective single-center review of 154 patients treated with ipilimumab, Since the approval of ipilimumab in 2011, hypophysitis was found in 17 (11%) of the immune checkpoint inhibitors (ICIs) have patients and the anterior portion of the pitu- significantly improved the treatment land- itary gland, responsible for gonadotropin scape of multiple cancer types. According to a secretion, was affected in all cases. The levels recent analysis, approximately 43% of patients of LH, FSH and testosterone were measured with cancer in the USA are eligible for ICIs, of in 11 patients and were low, estradiol was not whom 12% are estimated to respond.1 Nearly measured in the two female patients who all patients undergoing ICIs will experience were postmenopausal. The gonadal function http://jitc.bmj.com/ 6 at least one type of immune- related adverse normalized in two patients. Another center event (irAE), which can occur at any moment also reported an 11% incidence of hypoph- even months or years after therapy discontin- ysitis under ipilimumab. The majority of the uation. Moreover, these irAEs can affect any 15 affected patients presented gonadotropin organ and be severe depending on the therapy deficiency (80%, n=12) that persisted in 16% 7 regimen and underlying health condition of the cases at almost 3 years of follow- up. on September 26, 2021 by guest. Protected copyright. of the patient, with 10%–30% of cases cate- Even in the absence of hypophysitis, low total gorized as grades 3–5.2 Endocrine toxicities testosterone levels were reported in a retro- are among the most common irAEs and, in spective single- center review of patients with contrast to other irAEs, tend to be irreversible melanoma. However, the actual incidence © Author(s) (or their and require life-long hormonal substitution. and extent of ICI-related hypogonadism employer(s)) 2021. Re- use permitted under CC BY-NC. No The most frequent endocrine complications remains unknown because measurements commercial re- use. See rights are thyroid dysfunction (30%), hypophysitis were not repeated nor performed systemati- and permissions. Published by (5.6%–11%), type I diabetes (0.2%–2%), and cally in all analyzed patients.8 BMJ. adrenal insufficiency (0.7%), although rare In addition to this central hypogonadism, 1 Department of Medical cases of hypoparathyroidism have also been ICI- induced inflammation of the gonads can Oncology, Inselspital, Bern 3 University Hospital, University of described. Yet, surprisingly little is known be associated with impaired gonadal func- Bern, Bern, Switzerland about the potential impact of ICIs on gonadal tion, possibly leading to hypogonadism and 2International Cancer Prevention function. A recent analysis of VigiBase, the infertility. Two cases have been reported Institute, Lausanne, Switzerland WHO global database of individual case of patients with metastatic melanoma who Correspondence to safety reports between 2011 and 2019, found developed acute painful swelling of the Dr Berna C Özdemir; a significant, disproportionately increased testicles which turned out to be bilateral 9 10 berna. oezdemir@ insel. ch risk of hypogonadism for ICIs. Of the 13 orchitis and epididymo- orchitis under Özdemir BC. J Immunother Cancer 2021;9:e002220. doi:10.1136/jitc-2020-002220 1 Open access J Immunother Cancer: first published as 10.1136/jitc-2020-002220 on 15 February 2021. Downloaded from ipilimumab- nivolumab and pembrolizumab, respectively. and prevent rejection of the semi- allogenic fetus. In preg- While hormone measurements in the first case showed nant mice, treatment with anti- PD- L1 antibodies dramat- transient primary hypogonadism with low testosterone ically increases the rate of abortion (86%) compared and high LH levels which recovered spontaneously, no with spontaneous abortion (18%), by depleting regula- hormone levels were measured in the second case which tory T cells (Tregs).13 Likewise, in pregnant cynomolgus resolved after treatment with high- dose steroids. An anal- monkeys which received nivolumab from the onset of ysis of 13 metastatic melanoma patients with testicular organogenesis through delivery, increased abortion and autopsy tissue samples showed that six of the seven men premature neonatal death were observed.13 Therefore, (86%) who had received ICIs had impaired spermato- the FDA advises women of childbearing age to use effec- genesis compared with age- matched patients who were tive contraception during treatment with anti- CTLA4 and treatment naïve (n=6).11 No data on potential effects on anti- PD-1 anti- PD- L1 antibodies for at least 3–5 months, female fertility are currently available. respectively, after the last dose.14 This lack of data is astonishing given the vast number Currently, we have only limited knowledge on the of clinical trials performed over the last decade. For effect of checkpoint inhibitors on the outcome of preg- instance, none of the pivotal trials leading to Food nant patients with cancer and their offspring. Three and Drug Administration (FDA approval of ICIs in the cases of ICI therapy in pregnant women with metastatic different indications has provided information regarding melanoma,15–17 as well as two cases18 19 of successful preg- fertility, menopause status, sex hormone levels, or sexual nancy that was conceived during treatment with ICIs health- related quality of life. However, the assessment of with anti- PD1 alone or in combination with anti-CTLA4, gonadal function in reproductive-age men and women were reported. None of the infants showed any develop- undergoing ICIs cannot be deferred any longer. ICIs are mental anomalies, except for congenital hypothyroidism increasingly applied in the curative setting as adjuvant detected in one newborn, possibly representing a fetal therapy where the risk of ICI-related hypogonadism, irAE from maternal anti- PD1 exposure.18 premature menopause or infertility, and their long- term Given that melanoma is the most common malignancy consequences need to be balanced against the reduc- during pregnancy and approximately one- third of all tion of absolute risk of disease recurrence and discussed women diagnosed with melanoma who will be treated with the patient as it might affect the acceptance of such with ICI are of childbearing age,20 investigation of the prophylactic therapies. In addition, the cancer incidence safety of ICIs in an international registry prospectively in young adults is increasing, with currently about 5% of all collecting data on pregnant patients with cancer treated cancers being diagnosed in patients 20–39 years of age. It with ICI could be of great clinical value.20 is therefore likely that in the future more reproductive- age The perturbation of sex hormone levels at the pitu- men and women will be exposed to ICIs and need to be itary or gonadal level is not solely an issue of fertility and informed about the potential for gonadal toxicity.12 Simi- sexual health but might also affect efficacy and toxicity larly, multiple clinical trials are testing ICIs in pediatric of ICIs. It has been reported21 that men derive a greater patients and ICIs are already approved for several indi- benefit from ICIs compared with women, which could be http://jitc.bmj.com/ cations in this population. The current state of evidence attributable to many biological factors including differ- does not provide any meaningful conclusions that can be ences in the host hormonal milieu that affect response used to counsel patients and their families regarding the to ICIs.22 A systematic investigation of the potential risk of hypogonadism and its potential effects on the chil- impact of ICIs on gonadal function could be done by dren’s physical and mental development. retrospectively analyzing sex hormone levels in serum Even in the metastatic setting, patients need to be from patients
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