Abstract
Background
The development and approval of antibodies targeting calcitonin gene-related peptide or its receptor mark a revolutionary era for preventive migraine treatment. Real-world evidence sheds light on rare, stigmatized or overlooked side effects of these drugs. One of these potential side effects is sexual dysfunction.
Case reports
We present two cases of one 42-year-old and one 45-year-old female patient with chronic migraine who both reported sexual dysfunction as a possible side effect of treatment with galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide.
Discussion
As calcitonin gene-related peptide is involved in vaginal lubrication as well as genital sensation and swelling, inhibiting the calcitonin gene-related peptide pathway may lead to sexual dysfunction as a potential side effect.
Conclusion
Sexual dysfunction in female migraine patients might be a rare and overlooked side effect of monoclonal antibodies targeting the calcitonin gene-related peptide pathway. Considering the discomfort and stigma surrounding both migraine and sexual dysfunction, we advocate for an open attitude and awareness among clinicians toward such side effects.
Keywords
Introduction
The development and approval of antibodies specifically targeting the neuropeptide calcitonin gene-related peptide (CGRP) (i.e. galcanezumab, fremanezumab, and eptinezumab) or its receptor (i.e. erenumab) mark a revolutionary era in the preventive treatment of patients with migraine (1). Their safety and tolerability have been proven in randomized placebo-controlled clinical trials (2). Yet, the clinical application of these drugs in real-world settings (i.e. phase IV studies) is characterized by the heterogeneity of migraine patients, often suffering from complex comorbid diseases, while potential long-term side effects remain undetected in traditional clinical trials (1,3). In addition, real-world evidence sheds light on rare, stigmatized or overlooked side effects. One of these potential side effects is sexual dysfunction, which was spontaneously reported by two middle-aged female chronic migraine patients at a headache outpatient clinic, without prior clinical screening for such side effects. Both cases are presented in this article.
Clinical cases
Case report 1
The first case is a 42-year-old Caucasian female migraine patient (BMI 29.1 kg/m2) who suffered from chronic migraine without aura and, once per 1–2 months, with aura. She had a regular menstrual cycle and used a progesterone-only contraceptive for the last 4–5 years.
She was prescribed galcanezumab 120 mg monthly for two years, which was very efficacious, leading to a substantial reduction of her attacks: from two migraine attacks, i.e. four migraine days per week, to seven headache attacks per month. These headache attacks, often unilateral, felt much milder and less painful than without galcanezumab, often lasting only 1–2 days at a time. Yet, approximately 1–2 weeks after initiation, she experienced a remarkable and complete loss of her libido. Sexual arousal also completely disappeared, as she experienced no genital heat, tingling sensation, vulvar swelling, or vaginal lubrication. As a result, achieving an orgasm became almost impossible for her. On the rare occasions when she did, she rated the sensation as only 1–2 out of 10. Remarkably, she felt less feminine and became less concerned about her physical appearance since the use of galcanezumab.
As the patient was certain these libido loss complaints could exclusively be attributed to her use of galcanezumab, she did not visit a psychologist or a sexologist. She reported that she had never faced such a loss of libido before, nor did she experience reduced genital warmth or moisture. While she used to experience pain during intercourse due to her migraine and overactive pelvic floor muscles in the past, her desire remained unaffected. Although she experienced no other side effects due to galcanezumab, she decided to switch to erenumab 140 mg 4-weekly because of her complaints of libido loss. Erenumab appeared to be less efficacious for her migraine, as she still reported (physical activity-induced) daily headaches, and she experienced no obvious improvements in her libido either. Considering the high burden and unbearable pain caused by her migraine attacks, which led to a substantially reduced quality of life, the patient chose to continue the antibody treatments.
The patient did not have any relevant comorbidities, besides a history of medication-overuse headache. Also, she regularly experienced general sadness and fatigue, mainly related to her suffering due to the migraine or as a side effect of previous medications, but was never diagnosed with depression or other psychiatric disease. She reported no other life events or changes in her relationship or drug use that could have caused her symptoms. Further, she had a healthy lifestyle and reported no weight changes.
Case report 2
The second case is a 45-year-old Caucasian female migraine patient (BMI 24.1 kg/m2) who suffered from chronic migraine without aura. She had a regular menstrual cycle and used no hormonal therapies.
She was prescribed galcanezumab 120 mg monthly as well, which led to a successful reduction in her migraine frequency from 10 migraine days to 3–4 migraine days per month. This was, however, accompanied by libido loss – the only side effect that she experienced 2 months after initiating galcanezumab. Remarkably, except for a lower sexual drive, she reported that she had gained 4 kgs in the span of 9 months without any lifestyle modifications. The patient had never experienced such complaints before. After using galcanezumab for almost 11 months, she decided to stop its usage, because she did not consider the improvement in migraine symptoms to be worth the side effects, i.e. the weight gain and loss of libido. After stopping galcanezumab, she noticed an improvement in her libido 2 months later.
Besides some shoulder complaints, for which she used painkillers (paracetamol or ibuprofen) occasionally, she had a blanco medical history. At approximately 20 years of age, she used cyproterone- and ethinylestradiol-containing medicines, which precipitated depressive symptoms. These symptoms, however, promptly subsided following the cessation of the medication, and such depressive manifestations have not recurred since. She was never diagnosed with any gynaecological or hormonal disorders and had a stable relationship with her partner. Importantly, no significant alterations in her personal circumstances had been identified that might have impacted her libido, with the exception of the commencement of galcanezumab.
Discussion
With the introduction of two case reports on women with chronic migraine who spontaneously reported complaints of sexual dysfunction after the initiation of galcanezumab, we aim to raise more awareness of the potential occurrence of this side effect. Sexual dysfunction is characterized by disruption in the stages of the sexual response cycle, but, despite its high incidence (ranging from 25.8% to 91.0%) and negative influence on quality of life, exact underlying mechanisms remain speculative (4,5). This is related to the multidimensionality and complexity of the psychobiology underlying sexual disorders. Given the absence of any complaints related to dyspareunia, vaginismus, anorgasmia or a phobic aversion to sexual contact in both patients, we categorize the presented cases under the classification of “Sexual Arousal Disorder,” in alignment with the international consensus criteria for female sexual dysfunction established in 2000 (4). In addition, both middle-aged migraine patients showed no (peri)menopausal symptoms, although potentially masked by the use of hormones in the first patient. As there is no unanimous agreement on a clear association between menopause status and sexual functioning, especially considering different outcome measures and definitions of perimenopause used throughout the literature, it seems less likely that their libido loss could be viewed as a perimenopausal complaint (6).
Hypothetically, we assume that rather peripheral consequences of CGRP blockade (i.e. lubrication and genital swelling) than central effects (i.e. subjective arousal responses) have played a role in both patients. Indeed, considering the molecule mass of the antibodies, it is unlikely that CGRP could cross the blood-brain barrier in substantial amounts to exert central effects (7). In addition, while its exact role in sexual arousal has not been elucidated completely yet, immunohistochemical findings of the human glans clitoris show the presence of CGRP, predominantly in sensory C-fibers and in colocalization with substance P. CGRP appears to be involved in the physiology of the clitoris by exerting sensory and vasodilating effects – which resembles its effects in the human penis (8,9). In addition, CGRP functions as a neurotransmitter within the human vagina by regulating both blood flow and capillary permeability, due to the juxtaposition of nerve fibres containing CGRP and other vasodilatory substances (such as neuropeptide Y) with the capillary loops in the papillae (10). As a result, blocking the effects of CGRP due to the use of CGRP(-receptor) antibodies could lead to decreased genital response, including less vaginal lubrication (Figure 1). However, despite its established role in migraine, evidence supporting the involvement of CGRP in maintaining several regulatory processes, such as blood ingurgitation in the clitoris or vaginal lubrication, remains sparse. The presence of CGRP-positive nerve fibers in the vagina and clitoris might suggest their involvement in neurogenic inflammatory responses. Consequently, caution is advised in suggesting a direct causal relationship between biological mechanisms and consequences of CGRP inhibition and female sexual dysfunction.
Hypothesized mechanisms that might play a role in the occurrence of sexual dysfunction – more specifically, decreased sexual arousal – in female migraine patients using CGRP(-receptor) targeted antibodies. The left section of the figure demonstrates the possible locations of CGRP-containing nerve fibers and the peripheral effects of CGRP in the female genitals, specifically the human clitoral glans and vagina. More specifically, in both premenopausal and postmenopausal women, the papillae, subepithelial plexus and deep arteries of the vaginal wall have been shown to contain the highest density of CGRP-containing nerve fibers (10).
Further, although the second patient did not report physical changes, but rather only libido loss, it is crucial to realize that the agreement between self-reported and genital arousal measures in women is weak and lower compared to men (11). In addition, women who were diagnosed with sexual arousal disorder do not necessarily seem to be less genitally responsive to visual sexual stimuli than age-matched women without sexual problems – which challenges differences between sexual feelings, affect and genital response as well as the diagnostic criteria (12).
In this sense, these case reports could be regarded as the female counterpart of our previously published case report on a 54-year-old male migraine patient using galcanezumab who reported complaints of erectile dysfunction and whose potency recovered after therapy discontinuation (13). Besides changes in sexual arousal, the first patient reported feeling less feminine as a result, illustrating the psychological or gender-related effects of sexual dysfunction in this female migraine patient.
Admittedly, our cases are not supported by objective methods to assess longitudinal changes in female sexual function, such as Doppler ultrasonography, vaginal photoplethysmography or laboratory tests to assess hormonal profiles. Further, in an ideal setting, the first patient would have also stopped the use of antibodies to evaluate a potential causal relation with an improvement in her libido. However, the severity of the migraine attacks experienced by both patients compelled them to (initially) persist with their antibody treatments. Therefore, these cases do not (yet) fulfill two critical criteria for defining sexual dysfunction a genuine drug-related adverse reaction, i.e. dechallenge (or withdrawal of the antibody) associated with disappearance and rechallenge (or re-administration of the antibody) associated with reappearance of the adverse event. Nevertheless, these cases present clinically realistic scenarios that might be faced by neurologists. Considering the discomfort and stigma surrounding both migraine and sexual dysfunction, and the burden associated with both conditions, we advocate for an open attitude and awareness among clinicians towards such side effects, as these could hamper medication adherence and quality of life. Neurologists need to be cognizant of the potential occurrence of sexual dysfunction in users of CGRP(-receptor) targeted antibodies and its elevated prevalence in specific populations, such as migraine patients with comorbidities such as depressive disorders (14) or (post)menopausal women and those with urogynaecological conditions (15). Indeed, depending on their wishes, treatment options should be reevaluated in such migraine patients and/or they should be referred to sexologists, psychologists and/or gynaecologists.
Conclusion
Sexual dysfunction in female migraine patients might be a rare and overlooked side effect of CGRP(-receptor) targeted antibodies. While further research is needed to confirm its prevalence and underlying biological processes, clinicians and prescribers of these drugs should be aware of its possible occurrence in women with migraine. Considering the stigma surrounding this topic, direct questioning within the clinical setting may be necessary to bring to attention and illuminate this possible side effect.
Clinical implications
Postmarketing surveillance of users of CGRP(-receptor) targeted antibodies is essential to shed light on the efficacy, safety and tolerability of these therapies in the general migraine population. Such data may elucidate infrequent side effects that substantially influence the patient's quality of life, such as sexual dysfunction. Further translational studies are essential to decipher exact psychological and biological processes, including the consequences of inhibition of CGRP activity, potentially leading to decreased sensory and vasodilating effects, which might contribute to a clinical presentation of sexual dysfunction in both male and female migraine patients.
Footnotes
Authors’ note
Informed consent was obtained from both patients for the publication of these case reports.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LA-H and DMB declare no conflict of interest with respect to the research, authorship, and/or publication of this article. EGMC received consultation fees from Allergan, Amgen/Novartis, Eli Lilly and Teva. AMVDB received research grants and/or consultation fees from Allergan, Amgen/Novartis, Eli Lilly, Satsuma, Teva, and Tonix.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Research Council ZonMw/NWO, Vici Grant (09150181910040).