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Allergic reactions to seminal plasma

Allergic reactions to seminal plasma
Literature review current through: Jan 2024.
This topic last updated: Sep 21, 2022.

INTRODUCTION — The term "human seminal plasma" (HSP) refers to the components of human semen other than spermatozoa. Allergic reactions to proteins in HSP usually present as either systemic reactions or localized vaginal reactions during or following vaginal sexual intercourse, which are prevented by condom use. The clinical manifestations, epidemiology, pathophysiology, diagnosis, and management of hypersensitivity reactions to HSP will be discussed in this topic. The term "seminal plasma hypersensitivity" (SPH) will be used throughout.

CLINICAL MANIFESTATIONS

Signs and symptoms — Seminal plasma hypersensitivity (SPH) reactions present either as systemic allergic reactions/anaphylaxis or as localized vaginal reactions. Characteristics of systemic and localized SPH are summarized in the table (table 1). The largest review of published cases included 74 women. Seventy percent (52 patients) experienced systemic symptoms. Forty percent of those with systemic reactions also had local reactions, whereas approximately one-third of patients had only local reactions [1]. All types of reactions are prevented by the use of condoms, which is a critical component of the clinical history. (See 'Gynecologic evaluation' below.)

Systemic reactions — Initial symptoms of immediate-type systemic SPH commonly include localized vulvar and vaginal pruritus and/or edema, followed by diffuse pruritus, nasal obstruction, itchy eyes, urticaria, and/or angioedema, often involving the face, lips, tongue, and throat. Gastrointestinal symptoms and respiratory symptoms of dyspnea, wheezing, and stridor have also been reported during systemic reactions. Life-threatening anaphylaxis with profound hypotension and cardiovascular collapse requiring emergency treatment was reported in 16 patients in the series of 74 women mentioned previously, indicating that severe reactions are not characteristic [1]. Anaphylactic deaths attributable to SPH have not been confirmed [1]. Symptoms typically occur during or within minutes after coitus, although symptom onset was more than one hour in 13 percent of cases [1].

Timing of immediate reactions — Immediate SPH reactions typically begin within minutes after ejaculation. In the large series already described, 87 percent of allergic reactions began within the first 30 minutes following ejaculation [1]. This time course is consistent with an immediate-type allergic reaction (ie, beginning within one hour of exposure to the allergen). Symptoms usually resolved within 24 hours, although some symptoms (ie, vaginal pain, recurrent urticaria, and malaise) can persist for several days. One patient has been described in whom human seminal plasma (HSP)-induced anaphylaxis was followed a few days later by worsening of pre-existing eczema [2].

Rare types of delayed reactions — In addition to immediate-type systemic reactions, there are case reports of a patient presenting with a fixed cutaneous eruption [3] and a serum sickness-like reaction [4]. These reactions were delayed by several hours to days.

Local reactions — Local vaginal reactions to seminal plasma are manifested primarily as severe burning and pain but may be associated with vulvar or vaginal itching and edema [1]. Because the most common symptoms are pain and burning, this reaction is often not recognized as allergic in nature. Symptoms and signs may begin immediately following ejaculation or may be delayed in onset by minutes to hours. Vulvar and vaginal discomfort can last several days [5].

Reactions to skin contact with HSP — An immediate-onset systemic reaction, including pruritic rash accompanied by periorbital angioedema, was reported in one case after cutaneous exposure to HSP without any history of vaginal intercourse [6]. Localized urticaria or eczema has been reported following contact of the skin with HSP [7]. Symptoms from oral contact have not been reported.

Emotional impact — The development of SPH places significant strain on relationships [5]. In addition, couples present with anxiety about their ability to conceive, although this is usually not a problem if the disorder is managed effectively. (See 'Conception and pregnancy' below.)

EPIDEMIOLOGY — Seminal plasma hypersensitivity (SPH) is seen exclusively in female patients. Over 60 percent of females presenting with human seminal plasma (HSP) allergy are between the ages of 20 and 30, although new-onset symptoms have been reported after age 50 in both pre- and post-menopausal females [1]. A significant proportion of patients experience symptoms with their first episode of intercourse [1,8]. (See 'Allergens' below.)

Prevalence — The general prevalence of SPH is unknown, although it has been described worldwide [9-13]. There are only approximately 80 cases of SPH that are well-documented in the medical literature. However, due to the socially sensitive nature of this problem and the broad differential diagnosis of localized reactions, it is likely under-reported or mistaken for nonallergic vulvovaginitis [5]. A questionnaire survey was conducted to estimate prevalence among 1000 females in North America who voluntarily reported postcoital symptoms [5]. In this survey, 266 females reported 130 events (84 systemic and 46 localized). Reactions were classified as "probable" HSP hypersensitivity reactions if symptoms were consistently prevented by use of condoms. Skin testing and serum-specific immunoglobulin (Ig)E were not performed to confirm SPH. However, based on this analysis, it was estimated that approximately 40,000 females suffer from localized and/or systemic SPH in the United States [5].

Natural history — Anecdotal cases of HSP-allergic reactions specific to a certain male partner have been reported in females tolerating intercourse with previous partners [9]. However, once SPH has developed, it is usually persistent and continues to occur with the female's current partner as well as with future male partners [1,8]. There are no known reports of "natural tolerance" developing with repetitive intercourse.

POSSIBLE RISK FACTORS — A history of other allergic disorders was present in over 80 percent of females with seminal plasma hypersensitivity (SPH) in the large review previously described [1]. Anecdotal reports suggest that adult atopic dermatitis and asthma are common clinical features of females presenting with severe human seminal plasma (HSP)-induced anaphylaxis [2,10,14]. However, HSP anaphylaxis has also been reported in nonatopic women [15,16].

Based upon case reports, SPH has been associated with reproductive events or surgical procedures, such as long intercourse-free periods (eg, pregnancy), menopause, insertion of an intrauterine device, and hysterectomy, although the clinical relevance of these procedures is unclear because many females develop HSP allergy with their first intercourse [1]. A possible association with previous prostatectomy or reversal of vasectomy in the male partner has been noted, although SPH is not related to spermatozoan sensitization. However, survey studies have not been able to substantiate the association of these surgical procedures or other risk factors with causing SPH [17].

PATHOGENESIS

Systemic reactions — Most systemic seminal plasma hypersensitivity (SPH) reactions are caused by a type I immunoglobulin (Ig)E-mediated hypersensitivity reaction [1]. Evidence for this includes positive immediate-type skin testing with whole seminal plasma and in vitro basophil histamine release [18].

There is anecdotal evidence that other immunologic mechanisms can account for some uncommon types of systemic reactions, such as serum sickness-like reactions. There is at least one case report of a delayed-onset systemic reaction consisting of periorbital edema, skin rash, arthralgias, and diarrhea beginning approximately eight hours after ejaculation and lasting four to five days [4]. A Gell and Coombs type III immunologic mechanism was implicated in this reaction.

Local reactions — In contrast with systemic reactions, localized reactions to human seminal plasma (HSP) do not appear to involve IgE nor have other causative immune mechanisms been clearly established [18-22].

Allergens — Multiple allergenic proteins with molecular weights ranging from 12 to 75 kDa have been identified in HSP related to systemic SPH [1,8,23]. Of note, sperm proteins have not been implicated as allergens, and artificial insemination using sperm intensively washed free of HSP is well-tolerated in females with severe SPH. (See 'Conception and pregnancy' below.)

The observation that approximately 41 percent of all SPH reactions occur following the first episode of sexual intercourse suggests that susceptible females can become sensitized without such exposure, perhaps through prior skin contact or sensitization to cross-reacting allergens [1,8]. The prevalence of HSP-specific IgE in females without HSP allergy has not been studied.

Prostate-specific antigen (PSA) may be the causative allergen in many patients, although semenogelin and lactoferrin have also been identified as possible allergens. In a case report, serum-specific IgE binding to a 33 kDa protein with a molecular weight identical to PSA was demonstrated in a patient with HSP anaphylaxis [24]. There are some data to suggest that sensitization may result from exposure to cross-sensitizing dog proteins, although this is only a theory and has not been confirmed. In one study, 24 percent of patients with serum-specific IgE to dog dander exhibited IgE binding to PSA, suggesting existence of cross-reactivity between the major HSP allergen, PSA, and dog epithelial allergen, Can f 5, which was later identified as dog PSA [25,26]. Dog PSA exhibits over 80 percent homology with human PSA. Based on these data, it is possible that females with preexisting dog allergy may be at greater risk for SPH. However, in our experience, not all females with SPH are dog owners, and although dog allergens are abundant in most indoor environments, patients are not always sensitized to dog allergen. Thus, the role of dog exposure as a possible source of sensitization remains unclear. Although commercially available component testing can identify IgE directed against Can f 5, we do not recommend this as part of the routine evaluation of SPH.

DIAGNOSTIC EVALUATION

Diagnosis based on clinical history — The gold standard for the diagnosis of seminal plasma hypersensitivity (SPH) is a history of localized and/or systemic allergic symptoms following exposure to ejaculate, which are prevented by the use of condoms and not explained by any other disorder.

Note that condoms must be donned before initiating intercourse. Symptoms may not be prevented if condoms are donned later, just before ejaculation, as exposure can occur to some degree before full ejaculation.

The following questions are helpful in determining if a patient's history is consistent with local, systemic, or a mixed type of SPH:

Local – Do you experience the sensation of vaginal burning and pain during unprotected intercourse or immediately after ejaculation? If yes, is it prevented by use of a condom that is donned before initiating intercourse?

Systemic – Have you experienced hives, swelling (angioedema), chest tightness, shortness of breath, wheezing, diarrhea, dizziness, or loss of consciousness during intercourse or immediately after ejaculation? If yes, is it prevented by use of a condom that is donned before initiating intercourse?

Consider other allergens — Other possible allergens that could cause postcoital symptoms include natural rubber latex as well as food or medications ingested by the male partner within two to three hours before intercourse and passed to the female partner through the ejaculate [27,28].

The female partner should be questioned about latex condom exposure (note that some condoms are latex-free) and reactions to other latex-containing items (table 2). Natural rubber latex-sensitized females may experience reactions only with condom use.

If the female has known allergies to foods or medications, the history should be explored to determine if a food or drug could have been ingested by the male partner within two to three hours prior to intercourse. (See 'Differential diagnosis' below.)

Gynecologic evaluation — If not already done, the patient should have a thorough evaluation by a gynecologist to exclude other causes of vaginal discomfort. (See 'Differential diagnosis' below.)

Referral — Patients suspected of having SPH should be referred to an allergist with knowledge of the evaluation and management of the disorder, if possible.

Skin testing with whole seminal plasma

Indications — Females with any form (systemic, local, or mixed) of SPH are candidates for skin testing. Positive results are seen most consistently in females with immediate, systemic reactions (figure 1). However, skin testing with human seminal plasma (HSP) is not a standardized procedure, and the negative and positive predictive values are unknown. Thus, a positive skin test supports the diagnosis of an immunoglobulin (Ig)E-mediated allergy to HSP, but a negative result does not exclude it. The gold standard for diagnosis is a consistent history of SPH and resolution of symptoms with use of a condom. (See 'Diagnosis based on clinical history' above.)

Protocol — Skin testing with whole seminal fluid after removal of spermatozoa is performed using skin prick testing (also called epicutaneous testing) only. Intracutaneous/intradermal testing is not recommended to whole seminal fluid due to irritant responses [29]. Positive (eg, histamine) and negative (saline diluent) controls should be included, as with skin testing to any allergen.

Only the whole seminal fluid is used for skin prick testing as spermatozoa are not the cause of SPH [30]. To obtain a sample of whole seminal fluid, the male partner submits a pooled fresh semen sample collected at home over three to five consecutive days in a single sterile collection cup that is kept refrigerated until submitted to the treatment center for processing the day of testing and treatment. The number of collection days varies depending on the semen volume collected, as 8 to 10 mL is typically sufficient for completing testing and treatment. Prior to centrifugation to remove spermatozoa, the pooled ejaculate is allowed to liquefy by sitting undisturbed for 30 minutes at room temperature. It is spun down in a centrifuge (1000 g) for approximately 30 minutes to separate the spermatozoa from the whole seminal fluid (the upper layer). Since spermatozoa are not involved in causing SPH, their removal helps to concentrate the relevant whole seminal fluid proteins used for intravaginal graded desensitization.

The male partner serves as a control and undergoes identical skin tests to exclude the possibility of false-positive irritant skin reactions in the female patient. Although infection risk is minimal with the prick technique, using the male partner as the control subject for skin testing minimizes the risk of transferring an infectious agent to someone not already exposed. Technical issues related to skin testing are reviewed separately. (See "Overview of skin testing for IgE-mediated allergic disease", section on 'Controls'.)

Interpretation of results — A skin prick test with undiluted whole HSP eliciting a wheal of 3 mm greater than or equal to the negative saline control with surrounding erythema (ie, flare response) is positive, supporting the diagnosis of SPH. The male partner should have a negative result; however, often the male has a positive skin prick test result, the clinical relevance of which is unclear. For localized SPH, the skin prick test is often equivocal or negative in the female, which does not exclude the diagnosis, as this variant of SPH is believed to be non-IgE mediated.

If the clinical history is suggestive of SPH and skin prick testing with whole HSP is negative, it may be a false-negative result due to low concentrations of HSP allergens. In the latter case, sensitization can be further evaluated with skin prick testing using individual HSP fractions (see 'Referral for advanced evaluation' below). As with whole HSP, intradermal testing is not recommended. Alternatively, the diagnosis can be based on clinical history alone.

In vitro testing (not recommended) — Specific IgE assays for seminal plasma are commercially available, but these tests are not clinically validated. It is the authors' experience that these tests are rarely positive, even in patients with HSP anaphylaxis, and a negative test result does not exclude SPH. Therefore, skin prick testing with whole or fractionated HSP is preferred over in vitro testing, provided the patient is not dermatographic.

Referral for advanced evaluation — When a false-negative result is suspected, HSP allergens can be separated based upon molecular weight by column fractionation, which is performed at specialized treatment centers and is relatively costly and labor intensive [31]. Couples confirmed to have localized and/or systemic SPH are candidates for HSP desensitization (see 'Desensitization' below). It is recommended to first attempt intravaginal graded desensitization with dilutions of whole seminal plasma obtained from the male partner. If this approach is not successful, then subcutaneous immunotherapy (SCIT) to fractionated HSP proteins can be performed, although in the experience of the authors, this is seldom required [30].

Fractionation requires that the male partner collect multiple ejaculate samples, for a total of about 10 mL. The pooled sample is centrifuged at 1000 g for approximately 30 minutes to separate the spermatozoa from the HSP. The HSP is then run through a column, which isolates those fractions of HSP by molecular weight proteins [15,32,33]. Five or more HSP fractions are typically collected, filter-sterilized by syringe through a 0.22 micron filter, dialyzed to exclude all materials below molecular weights of 6000 to 8000, and cultured to ensure no contamination with microorganisms [34]. Prick and intracutaneous skin testing are performed with each fraction to determine which ones are allergenic. If indicated, HSP SCIT may then be performed with one or more of the allergenic fractions.

DIFFERENTIAL DIAGNOSIS — There are several conditions that should be considered in the differential diagnosis of seminal plasma hypersensitivity (SPH):

Vulvodynia – Vulvodynia (also known as vulvar vestibulitis syndrome) is a condition of chronic pain localized to the vulva or vestibule and triggered by vulvar penetration or physical activity. The clinical manifestations of vulvodynia and local human seminal plasma (HSP) hypersensitivity overlap. SPH has been confirmed in a subset of patients diagnosed with vulvodynia. Serum-specific immunoglobulin (Ig)E bound to seminal plasma was detected in 50 percent of vulvodynia patients reporting pain exclusively during or after coitus and prevented by condoms [20,35]. It is possible that some patients have both SPH and other causes of vulvodynia. (See "Vulvar pain of unknown cause (vulvodynia): Clinical manifestations and diagnosis", section on 'Associated symptoms'.)

Chronic candidiasis and possible Candida hypersensitivity – Other gynecologic conditions that can be confused with localized SPH include chronic vulvovaginal candidiasis causing dyspareunia [1,36]. This condition is not prevented by use of condoms. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis" and "Vulvar pain of unknown cause (vulvodynia): Clinical manifestations and diagnosis", section on 'Allergy'.)

Allergic or irritant reactions to other substances – Local allergic or irritant-contact reactions may be attributed to lubricants, spermicides, vaginal contraceptives, or local anesthetics used in latex condoms, nonlatex condoms, and other barrier devices. Couples may have tried various barrier devices and found some are tolerated while others are not. If necessary, patch testing can be performed to identify a device that does not cause contact reactions. (See "Patch testing".)

Exercise-induced asthma – Exercise-induced bronchoconstriction (EIB) or postcoital asthma triggered by sexual intercourse can be confused with HSP-induced anaphylaxis. However, use of a condom does not prevent EIB. Patients suspected of having EIB can be instructed to use an inhaled bronchodilator 10 minutes before intercourse, which should partially or completely prevent symptoms. (See "Exercise-induced bronchoconstriction", section on 'Clinical manifestations'.)

Latex allergy – Natural rubber latex allergy can cause localized or systemic allergic reactions when latex condoms are used. If symptoms occur when latex condoms are used, a leak in the condom product must be excluded. If this cannot be excluded, nonlatex condoms should be tried. The latex-allergic patient should be advised to use polyurethane nonlatex condoms that can effectively prevent human immunodeficiency virus (HIV) transmission. When latex allergy is suspected, evaluation should be conducted using approved latex skin test reagents (not available in the United States) and/or serum-specific IgE to latex. Concurrent sensitization to both latex and HSP has been reported [37]. The evaluation and diagnosis of latex allergy is reviewed separately. (See "Latex allergy: Epidemiology, clinical manifestations, and diagnosis".)

Anaphylaxis to drugs or foods ingested by the partner – Females with preexisting anaphylactic sensitivity to specific drug (penicillin, vinblastine) or food allergens (walnuts) have been reported to experience local or systemic allergic reactions triggered by coital exposure to those drugs or foods ingested by the male partner shortly prior to intercourse [1,27,38]. In such cases, reactions only occur when the male partner ingests the allergenic food or drug or receives the drug in a period of hours to one day before intercourse. With some medications (eg, chemotherapy), the medication may be present in the male partner's body for several days, which must be considered when evaluating the temporal pattern of reactions. In either scenario, allergic reactions with intercourse do not occur consistently. Sensitization to suspected allergens should be confirmed in female patients with appropriate tests. Unprotected sexual intercourse can be resumed safely if the causative allergen is avoided by the male partner for several days prior to sexual intercourse.

Physical urticaria induced by vibration, pressure, or vigorous activity – Case reports have described patients with diffuse urticaria and angioedema after vigorous sexual intercourse, but these patients also developed urticaria after other activities [39].

MANAGEMENT — Management options include condom use, prophylactic medications taken prior to intercourse, and desensitization. Intravaginal-graded desensitization to dilutions of whole seminal fluid is preferred because it is simpler to provide, safe, effective, and less costly. Subcutaneous desensitization using purified fractionated seminal plasma proteins would be recommended only in cases not optimally controlled after intravaginal-graded desensitization when there are no other options. Coitus interruptus is another possible strategy, although most couples find this impractical [40].

Our approach — Females with seminal plasma hypersensitivity (SPH) who have experienced systemic reactions (ie, anaphylaxis) should be provided with an epinephrine autoinjector and trained in appropriate use. If they do not wish to conceive in the near future and accept condom use, we counsel on the importance of putting the condom on early in intercourse to avoid any contact with human seminal plasma (HSP). In females with either systemic or local reactions who wish to conceive naturally or who do not accept condom use, we suggest desensitization. We prefer an intravaginal desensitization protocol rather than a subcutaneous protocol because the intravaginal approach is simpler, less costly, and usually successful.

Epinephrine for anaphylaxis — An epinephrine autoinjector should be prescribed for patients with SPH who have experienced previous systemic allergic reactions to HSP. They should be counseled on how and when to self-inject epinephrine. Detailed information for providers and patients is found separately. (See "Prescribing epinephrine for anaphylaxis self-treatment" and "Patient education: How to use an epinephrine autoinjector (The Basics)" and "Patient education: Using an epinephrine autoinjector (Beyond the Basics)".)

Condoms — Prevention of exposure to HSP allergens and subsequent local and systemic allergic reactions is most easily accomplished by regular use of condoms, which should be put on before initiating intercourse to avoid contact between the vaginal tissues and pre-ejaculate (as well as ejaculate). Patients are warned that unprotected intercourse without condoms can lead to more severe localized or systemic reactions. Other than using condoms, desensitization to HSP is the only known effective treatment for preventing allergic reactions during intercourse. However, this approach does not address the risks of HSP reactions occurring as a result of a leaking or defective condom. In addition, condom use does not meet the needs of couples who wish to conceive naturally.

Prophylactic antihistamines and cromolyn — In a case report, premedication with antihistamines was effective in preventing mild postcoital systemic urticarial reactions [14]. However, in the experience of the authors, antihistamine pretreatment has not been demonstrated to be effective in preventing HSP anaphylaxis. Intravaginal cromoglycate has been used prior to intercourse to prevent localized vaginal reactions with very inconsistent results and is not recommended [1].

Conception and pregnancy — HSP hypersensitivity (local or systemic) is not associated with reduced fertility, although data on long-term outcomes are limited. However, it makes the process of conceiving unpleasant (local reactions) or overtly dangerous (systemic reactions). Two approaches to conception are possible in females with HSP allergy:

Intravaginal or subcutaneous desensitization procedures can allow couples to conceive naturally. Uncomplicated pregnancies and births have been consistently achieved in this manner [41,42].

Artificial insemination with spermatozoa extensively washed free of HSP, although this approach does not allow for natural conception.

Desensitization — Desensitization (or, more accurately, induction of tolerance) to HSP can be performed via intravaginal or subcutaneous routes. It is appropriate for patients who find condom use unacceptable or for those wishing to conceive naturally. It is useful for both systemic and local reactions. These procedures should only be performed in a clinical facility that is fully equipped and adequately staffed for treating anaphylaxis.

Following successful desensitization, the patient can tolerate unprotected sexual intercourse with the patient's male partner. However, it is recommended that the couple have unprotected intercourse two to three times weekly to maintain tolerance. Tolerance has been previously demonstrated for females with systemic SPH ex vivo by a shift from Th2 to Th1 cytokines and an increase in T regulatory cells pre- and post-HSP desensitization, which was not demonstrated for localized SPH [18]. The mechanism by which desensitization prevents localized/non-immunoglobulin (Ig)E-mediated SPH is unknown.

Outcomes — The authors have desensitized approximately 50 patients with localized and/or systemic SPH using the protocols described here and have found this approach to be successful in preventing reactions during intercourse in over 90 percent of patients.

For systemic reactions – In the authors' experience, nearly all females with systemic reactions to HSP can be successfully treated and can conceive normally. In addition to the authors' experience, there are several case reports of intravaginal desensitization [40,41,43,44].

For local reactions – The outcomes of females with localized reactions to HSP are more variable. Many females undergoing desensitization will continue to have mild burning after contact with semen, which gradually dissipates over time with continued contact. A retrospective series included 12 patients treated in the authors' clinic with subcutaneous immunotherapy (SCIT) for localized HSP reactions [45]. Patients were contacted by phone and asked a series of questions about how successful the treatment was and about subsequent efforts to conceive. Seven of 12 reported that treatment completely resolved their symptoms. Within this group, two subsequently had normal-term pregnancies, and one was pregnant at the time of the study. Two patients conceived but then miscarried. One patient did not try to conceive, and another was unable to. Another five patients reported that treatment was only partly successful or unsuccessful. Within this group, three had normal-term pregnancies. Overall, one-half of the 12 women with localized HSP reactions had successful-term pregnancies. This study had two findings of particular interest. First, three of the patients who had successful-term pregnancies experienced only partial or no relief of symptoms from the treatment, so successful treatment is not essential for pregnancy. Second, patients who experience difficulty conceiving following treatment may have an unrelated fertility problem and should be referred for further evaluation.

Intravaginal protocol — Intravaginal desensitization has advantages over subcutaneous injection therapy in that it does not require a laboratory or incur the significant costs associated with collection, preparation, and analysis of HSP fractions. Intravaginal desensitization is performed with whole seminal fluid [30]. The male partner collects two to three semen samples for a total of 3 to 5 mL of volume. These can be pooled and stored in the refrigerator. On the day of the procedure, the semen is spun in a centrifuge (1000 g) for 20 minutes, and the liquid portion is drawn off the top and used for the protocol. The pellet is discarded. A series of 10-fold dilutions is prepared as follows:

The supernatant is labeled 1:1 (undiluted).

Draw up 0.2 mL of the 1:1 solution and inject it into a vial containing 1.8 mL of normal saline and mix gently. Label this solution 1:10.

Draw up 0.2 mL of the 1:10 solution and inject into a vial containing 1.8 mL of saline and mix gently. Label this solution 1:100.

Continue this process four more times until the solution is diluted 1:1,000,000. For patients with a history of severe anaphylaxis (eg, involving respiratory or hemodynamic compromise), an even greater dilution may be appropriate.

The patient is positioned in the lithotomy position with a pillow under the buttocks to create an upward angle of the pelvis such that the solutions do not drain out, and the patient remains in this position for the entire procedure. A chaperone should be present throughout. Note the state of the patient's skin, lungs, and external vaginal tissues at baseline.

Using a 3 cc syringe, draw up 2 mL of the most dilute solution (1:1,000,000 dilution), remove the needle from the syringe, and deposit the sample in the vaginal vault [30,42]. Record the time of each administration and any symptoms that develop. Increasing 10-fold concentrations are then given every 15 minutes, until a dose of the undiluted whole seminal fluid is deposited. Any symptoms that develop during the protocol are typically mild. If symptoms do develop, we generally decrease to the last tolerated dose and then advance again. After the final dose is given, the patient remains recumbent for 30 minutes.

The couple is then instructed to have unprotected intercourse the next morning and to call the clinic if there are any symptoms. Unprotected intercourse needs to occur two to three times weekly to maintain the desensitized state. (See 'Maintenance of desensitization' below.)

If intravaginal desensitization is not successful and the couple wishes to conceive naturally, referral for subcutaneous desensitization with fractionated HSP should be considered [46]. Another option is omalizumab therapy. (See 'Other therapies' below.)

Subcutaneous immunotherapy — Successful SCIT was first reported in a patient with seminal plasma anaphylaxis using HSP fractions isolated from pooled samples of the male partner's ejaculate in 1984 [32]. The HSP fraction was selected based on its ability to elicit a positive intracutaneous test and induce histamine release from the patient's basophils. Note that intracutaneous (intradermal) testing, which is generally more sensitive than prick testing, can be used in this context because the fractions have been filter-sterilized and cultured, so they are less nonspecifically irritating, and there is no concern about microbial contamination.

A rapid two-day SCIT protocol with HSP fractions has been used successfully in treating patients with IgE-mediated localized and systemic HSP reactions [15,34]. The authors' clinic has successfully desensitized approximately 30 patients using this approach. Once the highest dose is reached, no further injections are needed, and desensitization is maintained with regular intercourse.

Maintenance of desensitization — After desensitization by either the intravaginal or subcutaneous route, patients maintain the desensitized state by having unprotected intercourse with their partner at least two to three times weekly [32]. Less frequent intercourse may not be adequate to maintain tolerance. In the authors' experience, couples are generally successful with this approach. Non-barrier methods should be used for birth control when the couple does not want to conceive. Interruption of regular sexual intercourse can result in loss of tolerance and recurrence of postcoital allergic reactions. Therefore, if one partner must travel for a period of time, samples of semen can be collected in advance, refrigerated for short time periods or frozen for longer time periods and de-thawed when ready to use. Samples can then be self-inserted by the female intravaginally with a needleless syringe every three days to maintain tolerance.

Other therapies — Another alternative approach for conception is artificial insemination with washed spermatozoa [8,47]. Most HSP-allergic patients tolerate such procedures well, although allergic reactions have been reported [48,49]. (See 'Conception and pregnancy' above.)

Omalizumab — There has been one case of a patient with confirmed systemic SPH treated successfully with omalizumab, a recombinant DNA-derived humanized immunoglobulin G1 monoclonal antibody that binds specifically to free human IgE and to membrane-bound IgE on B lymphocytes [50]. Use of omalizumab is considered safe in pregnancy based on experience with patients with asthma and chronic urticaria, although we know of no reports of patients with SPH who conceived while receiving omalizumab.

SUMMARY AND RECOMMENDATIONS

Signs and symptoms – Reactions to human seminal plasma (HSP) may present with either localized vaginal reactions, which are typically non-immunoglobulin (Ig)E mediated, systemic allergic reactions (including anaphylaxis), which are IgE-mediated, or both (table 1). The signs and symptoms begin within minutes to hours after ejaculation. (See 'Clinical manifestations' above.)

Epidemiology – Seminal plasma hypersensitivity (SPH) is more common than realized based on survey estimates. It may be under-reported because of the socially sensitive nature of the problem or misdiagnosed as vulvovaginitis. The disorder occurs exclusively in females, most typically between the ages of 20 and 30 years but can occur in older females pre- and post-menopause. Once established, it usually occurs with other male partners and is persistent in the absence of desensitization therapy. (See 'Epidemiology' above.)

Diagnosis – Diagnosis of systemic SPH should be suspected based upon the clinical history of suggestive signs and symptoms that are prevented by condom use when the condom is donned before initiating intercourse. Skin testing results, when positive, support the diagnosis, but skin testing with HSP is not standardized, and the positive and negative predictive values are unknown. Sensitization to HSP is demonstrated by skin prick testing with whole seminal plasma or allergen-containing fractions of HSP. Skin prick testing is usually positive in females with systemic reactions and often equivocal or negative in females with localized reactions. Male partners can also undergo skin testing and serve as controls. (See 'Diagnostic evaluation' above.)

Differential diagnosis – The differential diagnosis includes the various disorders that present as vulvodynia and dyspareunia, reactions to other allergens (eg, latex) or substances applied to the vaginal area (including foods or medications ingested by the male partner), exertion-related disorders (eg, exercise-induced bronchoconstriction), and chronic candida vulvovaginitis and Candida vulvovaginal hypersensitivity. (See 'Differential diagnosis' above.)

Epinephrine for systemic reactions – Any female who has experienced anaphylaxis due to HSP allergy should have an epinephrine autoinjector prescribed and should be counseled to have it readily available during intercourse, as well as how and when to use it to self-inject epinephrine. (See 'Epinephrine for anaphylaxis' above.)

Females who do not wish to conceive – For females with localized or systemic reactions who do not wish to conceive, HSP exposure can be avoided through careful use of condoms, provided this is acceptable to the couple. This approach to management is simple, although there is some risk to the patient if a condom leaks or breaks. (See 'Condoms' above.)

Indications for desensitization – For females with localized or systemic reactions who find condom use unacceptable or wish to conceive naturally, we suggest HSP desensitization (Grade 2C). Desensitization can be accomplished using either intravaginal or subcutaneous protocols. For most patients, we suggest intravaginal desensitization rather than subcutaneous, because it is simpler, less costly, and usually successful. (See 'Desensitization' above.)

Other therapies Omalizumab has been reported to control the symptoms of systemic SPH, and artificial insemination with sperm washed free of HSP is another approach to conception that has been well-tolerated by females with HSP hypersensitivity. (See 'Other therapies' above.)

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  31. The author's program, which is based at the University of Cincinnati College of Medicine, in Cincinnati, Ohio, can be accessed at the URL provided. The author is not aware of other centers in the United States that perform HSP fractionation and subcutaneous immunotherapy. www.Seminalplasmaallergy.org (Accessed on October 18, 2021).
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  43. Lee J, Kim S, Kim M, et al. Anaphylaxis to husband's seminal plasma and treatment by local desensitization. Clin Mol Allergy 2008; 6:13.
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  45. Tan J, Bernstein JA. Fertility and human seminal plasma (HSP) hypersensitivity. Ann Allergy Asthma Immunol 2013; 111:145.
  46. The author's program for HSP fractionation and desensitization can be accessed through the website listed. The program is based at the University of Cincinnati College of Medicine, Cincinnati, Ohio. The author is not aware of other centers in the United States that have published experience in fractionating HSP. Seminalplasmaallergy.org (Accessed on April 01, 2012).
  47. Iwahashi K, Miyazaki T, Kuji N, Yoshimura Y. Successful pregnancy in a woman with a human seminal plasma allergy. A case report. J Reprod Med 1999; 44:391.
  48. Sohn SW, Lee HS, Yoon YS, Park HS. Successful intravaginal desensitization in a woman with seminal plasma anaphylaxis after artificial insemination failure. J Investig Allergol Clin Immunol 2014; 24:276.
  49. Frapsauce C, Berthaut I, de Larouziere V, et al. Successful pregnancy by insemination of spermatozoa in a woman with a human seminal plasma allergy: should in vitro fertilization be considered first? Fertil Steril 2010; 94:753.e1.
  50. Burguete-Cabanas MT, Fajardo-Ramirez OR, Yesaki R, et al. Omalizumab for hypersensitive reaction to seminal plasma: A case report. Allergol Int 2018; 67:278.
Topic 13529 Version 15.0

References

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