A Role for IgE in Post-Orgasmic Illness Syndrome: Successful Omalizumab Treatment in Absence of Positive Skin Test to Self Semen

Introduction

Post-orgasmic illness syndrome (POIS) is a rare disease with an unknown epidemiology [1,2]. The condition was first described by Waldinger and Schweitzer in 2002 [3]. Since then, several reports have been published. In 2011, Waldinger et al described 5 diagnostic criteria: symptoms (flu-like symptoms, fatigue, generalized weakness, fever or perspiration, mood disturbances, problems with memory or concentration, incoherent speech, runny nose or nasal congestion, and itchy eyes); onset (seconds, minutes, or hours after ejaculation); duration (2–7 days); consistency (more than 90% of ejaculations); and spontaneous resolution. Criterion 1 (symptoms) was further stratified into 7 clusters of symptoms [4].

In addition to the physical symptoms, POIS places a severe mental and psychological burden on afflicted patients. Patients with POIS may try to avoid intercourse due to fear of symptoms and may be hesitant in seeking romantic relationships [2].

Several different mechanisms of action and treatments were used and reported in the literature, yet the pathophysiology and most efficient treatment remain unknown. Furthermore, this condition often varies; therefore, treatment may need to be tailored individually.

The main theories for the pathophysiology include 5 possible etiologies: immunological-allergic, autonomic dysregulation, hormonal imbalance, opioid withdrawal, and aberrant cytokine activity.

The immunological-allergic theory suggests a hypersensitivity reaction to the seminal fluid. Both type I and type IV reactions may be involved. This theory is supported by reports of positive skin prick testing to self-semen fluid in some patients. Nevertheless, not all studies were able to show positive skin prick testing, and 1 study showed positive intradermal testing in healthy individuals. Hyposensitization to self-semen was reported in a few cases, with a 60–90% success rate [1,2,4,6,7].

The autonomic dysregulation theory suggests that the sympathetic nervous system is dysregulated in POIS. This is supported by the partial success of alpha-blocker treatment (reported success rates: 57–100% of cases) [8,9].

The hormonal imbalance etiology theory suggests hormonal imbalance as the foundation of POIS. Based on this theory, some authors reported beneficial responses with testosterone or βHCG in hypogonadal men [10–12].

The opioid withdrawal theory proposes that a disorder with opioid receptors underlies POIS because there is a consumption of large amounts of endogenous opioids during orgasm [7].

The aberrant cytokine activity theory suggests cytokines as the basis of POIS [13].

These multiple theories have resulted in multiple treatment attempts in this patient population. In addition to the abovementioned treatments, other treatments that have been used and published are antihistamines (success rates up to 90%), selective serotonin reuptake inhibitors (SSRIs), non-steroidal anti-inflammatory drugs (NSAIDs, success rates 80%), and 1 case report of omalizumab use [5].

Despite the effects on patients’ quality of life, research for this syndrome is still scarce.

Here, we describe the case of a patient with POIS successfully treated with omalizumab.

Case Report

A 22-year-old man with a history of allergic rhinitis arrived at our clinic for an evaluation. During the 8 years prior to his arrival, several hours after ejaculation he experienced flu-like symptoms with general weakness and malaise, together with allergic-like symptoms of watery rhinorrhea, sneezing, and itchy eyes, and significant cognitive impairment. Mild symptoms began 2–3 hours after ejaculation, with worsening of the symptoms after 8–10 hours. The episodes lasted 2–3 days, with spontaneous resolution. The symptoms included watery rhinorrhea, sneezing, conjunctivitis and itchy eyes, abdominal pain with soft stool, dysuria, fatigue, muscle pain, lethargy, brain fog, inability to get out of bed, difficulty expressing himself, and a feeling that his brain is “not functioning”. During these days he was unable to go to work. The symptoms started with the first ejaculation that he experienced and continued every time, thus fulfilling all 5 criteria of POIS diagnosis (symptoms, onset, duration, consistency, and spontaneous resolution). These symptoms did not change over the years. Due to these symptoms, he avoided sexual activity and had difficulties with relationships. He was diagnosed by a neurologist prior to arriving at our clinic and had tried treatments with SSRIs, bupropion (anti-depressant), Permixon (Serenoa repens, prescribed due to dysuria), and zinc for his symptoms of POIS, without improvement. He also received Lisdexamfetamine dimesylate for attention deficit hyperactivity disorder.

He arrived for an evaluation after reading online about hyposensitization to sperm.

Upon arrival, we performed skin prick and intradermal (up to 1: 40) tests with the patient’s semen to check for sensitization. Because these tests came out negative, there was no evidence of sensitization, and we concluded that he was unsuitable for hyposensitization. Additional laboratory tests were performed – tryptase levels before and 3 hours after ejaculation were normal (5.18 and 5.55 µg/L), and total serum IgE was elevated with several measurements of 90–336 IU/ml over several years. Tryptase was taken to exclude other mast cell activation diagnoses. Treatment with NSAIDS (naproxen) was initiated, followed by treatment with oral corticosteroids. In addition, he received antihistamines in several dosages. High-dose antihistamines (fexofenadine 180 mg twice daily for 2 days), together with anti-inflammatory drugs, NSAIDs (naproxen 500 mg once daily for 2 days) or steroids (prednisone 30 mg 2 hours prior to ejaculation and 20 mg the day after), were the most beneficial combination prior to omalizumab. This combination alleviated the allergic-like symptoms and general weakness but did not assist with the cognitive symptoms. We decided to try treatment with omalizumab since the symptoms were not fully controlled with the above-mentioned treatments, he had symptoms that could be mediated by mast cells/basophils (sneezing, rhinorrhea, conjunctivitis, itchy eyes), there was no evidence for other etiologies (eg, hormonal imbalance), and treatment with omalizumab was reported once previously [5]. The patient’s medical insurance approved 150 mg of omalizumab once monthly. In Israel, there was no need for ethics committee approval for the use of omalizumab in this patient, since this medication is approved for several other indications and was used in the past for this indication (as mentioned above). Our patient received 300 mg on the first treatment due to an error made by the pharmacist at the counter. He reported that his symptoms were completely resolved. On his second treatment he received 150 mg of omalizumab. He reported that his symptoms resumed. Based on this report, his insurance approved treatment with 300 mg of omalizumab, and he received this treatment and was symptom-free. After 7 months, he tried to stop the treatment, with recurrence of the symptoms. He therefore resumed treatment once more and he is now symptom free and not taking any other additional medications for POIS. He was also able to engage in a relationship.

The patient has consented to this publication.

Discussion

The pathogenesis of POIS is unknown. Over the years, several mechanisms have been proposed.

Our patient presented with mixed symptoms. Some, but not all his symptoms suggested an immunological-allergic-like etiology (eg, rhinorrhea, itchy eyes), and some of his symptoms were non-specific (eg, brain fog). Due to these symptoms, we decided to perform skin tests to determine whether the patient was sensitized to his own semen. In addition, we tested tryptase levels to confirm there was no underlying mast cell disorder. Despite having negative skin tests, the immunological-allergic like etiology seemed the most reasonable considering his symptoms. The patient did not present with symptoms that could suggest other etiologies, such as hormonal imbalance, or sympathetic nervous system dysregulation.

An international survey-based study revealed that sexual medicine experts most commonly prescribe psychotherapy/sexual therapy, antihistamine drugs, and SSRIs for POIS. The study found that 48.3% of the participants reported less than 10% of their patients had symptom improvement, 32.7% reported improvement in 10–30% of patients, and 18% reported improvement in more than 30% of the patients [14]. These results emphasize the need for new treatment options for this condition.

Omalizumab is an anti-IgE monoclonal antibody that is FDA-approved for the treatment of moderate to severe persistent asthma with a positive skin test or in vitro reactivity to a perennial aeroallergen, and for the treatment of chronic idiopathic urticaria (CIU). While the mechanism of action of omalizumab may be clearer in an allergic IgE-mediated process, CIU is not considered an allergen-driven process. The mechanism of action of omalizumab in CIU is not fully understood. Several mechanisms of action in CIU have been proposed and are summarized elsewhere [15]. They include downregulation of IgE receptors on mast cells and basophils (due to lower levels of circulating IgE), reducing activity of IgE autoantibodies against unknown autoantigens, and reducing activity of intrinsically ‘abnormal’ IgE [15]. These mechanisms can be relevant to other non-allergic conditions, and potentially to POIS.

Our patient had negative skin tests to self-semen. Therefore, we had no proof of type I hypersensitivity reaction and did not initiate hyposensitization. High-dose antihistamines alleviated the allergic-like symptoms, and anti-inflammatory medications (NSAIDs or steroids) assisted with malaise and general weakness. The cognitive symptoms, on the other hand, were not responsive to antihistamines, anti-inflammatory medications, SSRI, or Lisdexamfetamine, and continued to impair his quality of life.

Due to the previous success of omalizumab treatment, and because the patient had elevated total IgE levels and allergy-like symptoms, we recommended treatment with omalizumab. We submitted a request to the patient’s medical insurance company, which was approved, and the patient started the treatment.

Within a few weeks of starting treatment, the patient’s symptoms resolved, and he discontinued the use of antihistamines and anti-inflammatory drugs for POIS. He reported significant improvement in his quality of life, and was able to engage in a sexual relationship, which had been impossible for him before. Lastly, he also stopped taking SSRIs. After 7 months, he attempted to stop the treatment, and the symptoms recurred. Therefore, he resumed treatment and the symptoms resolved.

Since this is the second report of treatment with omalizumab, the exact length of treatment is not clear. Omalizumab is a known medication with no known long-term adverse effects (when used in other medical conditions). It is also not known if the effect will continue over time, but since the patient had used many treatments prior to omalizumab, and since this treatment is now the only treatment that he needs, we recommended that he continues omalizumab for life. During follow-up, we will investigate the duration of the effect.

Interestingly, omalizumab was found to be beneficial only at 300 mg, not 150 mg, indicating the importance of dosage, and that higher dosages may be required to treat POIS effectively.

This experience suggests that despite negative skin tests, type I hypersensitivity and mast cells/basophils may play a role in POIS. Specific anti-semen IgE is not available in Israel, but as mentioned above, it is possible that, similarly to CIU, the mechanism of action of omalizumab may include many additional pathways that affect mast cells, basophils, IgE receptors, IgE to unknown autoantigens, and intrinsically ‘abnormal’ antibodies.

Our experience indicates that omalizumab may be useful in treating refractory POIS and should also be considered in patients with allergy-like symptoms. We cannot determine whether the elevated levels of IgE contributed to the treatment’s success, but we recommend considering testing for IgE levels and including the results in the treatment decision process. It is also unclear which specific IgE played a role in this patient. Nevertheless, the symptoms and the response to omalizumab suggests that mast cells/basophils and perhaps IgE can be involved in the etiology.

Further studies are needed to elucidate the role, mechanism, exact indication, and dosage requirements of omalizumab in POIS.

Conclusions

Omalizumab may be considered for the treatment of POIS in patients with allergy-like symptoms and symptoms that cannot be controlled with other medications, even in the absence of a positive skin test to semen. Lower doses may be ineffective.