Progesterone Hypersensitivity in Assisted Reproductive Technologies: Implications for Safety and Efficacy.

The global rise in the age of childbirth, influenced by changing sociodemographic patterns, has had a notable impact on fertility rates. Simultaneously, assisted reproductive techniques (ARTs) have become increasingly prevalent due to advancements in reproductive medicine. The paper explores the intersection between the surge in ARTs and the rising number of iatrogenic autoimmune progesterone dermatitis (APD). Autoimmune progesterone dermatitis, commonly known as progesterone hypersensitivity, manifests itself as a mucocutaneous hypersensitivity syndrome. It is characterized by a wide range of dermatological symptoms, with urticaria and maculopapular rashes being the most prominent signs. Concurrently, systemic symptoms, such as fever, angioedema, and, in severe instances, anaphylaxis, may ensue. This dermatologic condition poses a significant challenge to women of childbearing age. This intricate syndrome frequently manifests itself in conjunction with menstruation or pregnancy as a reaction to physiological fluctuations in endogenous progesterone. However, given that exposure to exogenous progesterone is an integral component of various modern therapies, secondary APD has also been described. Our findings unveil a heightened likelihood of developing secondary progesterone hypersensitivity in ART patients that is attributed to the administration of exogenous progesterone through intramuscular, intravaginal, and oral routes. The study also explores available therapeutic interventions for facilitating viable pregnancies in individuals grappling with autoimmune progesterone dermatitis within the context of ARTs. This comprehensive analysis contributes valuable insights into the intricate relationship between reproductive technologies, dermatological challenges, and successful pregnancy outcomes.

Exogenous Progestogen Hypersensitivity and its Increasing Association with Assisted Reproductive Techniques (ART)/in vitro Fertilization (IVF).

Progestogen hypersensitivity (PH) also known as autoimmune progesterone dermatitis is a rare clinical entity that may be triggered by endogenous progesterone (menstrual cycles and pregnancy) or exogenous progestin exposure (examples: contraceptive medicines, in vitro fertilization treatments). It is a poorly recognized syndrome due to its heterogeneous clinical presentation. The pathomechanism of PH is believed to be primarily IgE mediated but less commonly other immune responses may be involved. Management is usually focused on symptomatic control with medications. Recently, with the increasing use of exogenous progestins for in vitro fertilization more cases of hypersensitivity to exogenous progestins have been reported. Progesterone is an essential drug in the luteal phase support improving chances of implantation and pregnancy rates, and hence, PH is an important and difficult challenge to manage in these patients. Because patients require IVF and there is no alternative to progesterone, desensitization is suggested as an approach to endure fertility treatments and provides symptom control in refractory cases. Here, we will review the different aspects of PH.

Progesterone Hypersensitivity: The Utility of a Janus Kinase Inhibitor for Recurrent Erythema Multiforme.

BACKGROUND: Progestogen hypersensitivity (PH) is a rare phenomenon reported in women with an immunologic response to rising progesterone levels in the luteal phase. This disease's rarity and clinical spectrum make it challenging to diagnose. CASE: In this case report, we will discuss a 14-year-old female with monthly oral mucositis and palmar lesions consistent with erythema multiforme. Over 2 years, she underwent an extensive multidisciplinary workup and was trialed on many different medical therapies. SUMMARY AND CONCLUSION: The prevalence of PH has grown in the literature over the past decade. Due to progesterone's role in many biochemical pathways, the pathophysiology is complex. Although many modalities are efficacious for treating PH's cyclical eruptions, we propose treatment with a Janus kinase inhibitor when hormonal management alone is insufficient.

Progesterone Hypersensitivity Induced by Exogenous Progesterone Exposure.

Progesterone hypersensitivity (PH) is a rare hypersensitivity reaction to either endogenous or exogenous progesterone. There are around 200 reported cases of progesterone hypersensitivity in the medical literature. We present the case of a 31-year-old female who presented with cyclical urticaria and angioedema after exogenous progesterone exposure. Her symptoms would begin a few days before her menstrual cycle began and resolve after menstruation. She only had partial recovery of her symptoms with antihistamines, steroids, montelukast, and omalizumab. She needed treatment with oral contraceptives and had a resolution of symptoms, but subsequently developed a recurrence again. Given the rarity of this condition, the diagnosis is often delayed. This diagnosis should be considered for women of reproductive age who present with cyclic hypersensitivity or allergic symptoms.

Progestogen Hypersensitivity.

Progestogen hypersensitivity (PH) is a heterogeneous disease characterized by diverse cutaneous manifestations, bronchospasm, and/or anaphylaxis. Possible triggers include ovarian progesterone and exogenous progestogens. The timing of symptoms is critical to diagnose PH: during the luteal phase of the menstrual cycle for the endogenous form and after exposure to progestins for exogenous PH. Diagnostic modalities such as progesterone skin testing have low sensitivity and specificity for PH. When exogenous PH is suspected, the allergist should consider a progestogen challenge. Treatment strategies should be tailored for each patient, including symptom-directed therapies, ovulation suppression, and progesterone desensitization. Future studies should explore the mechanisms of PH, validation of diagnostic criteria, and standardization of treatment strategies.

Chronic Urticaria Suspected to be Caused by a 13.5 mg Levonorgestrel Intrauterine Device (Skyla®).

Chronic urticaria (CU) is a hive-like rash lasting over six weeks. Common associations include low vitamin D, thyroid autoantibodies, and Helicobacter pylori (H. pylori) infection, among others. Progesterone has been documented to trigger CU, by endogenous or exogenous progesterone. The use of intrauterine devices (IUDs) has been a popular source of birth control, with many containing progesterone. Although rarely reported, some patients have been seen to have an urticarial reaction after implantation of an IUD. Here, we present a case of a patient with progesterone-induced chronic urticaria, likely triggered by implantation of a 13.5 mg intrauterine device implant (Skyla®, Bayer, Whippany, NJ, USA). To the best of our knowledge, this is the first case to report the association between Skyla® and chronic urticaria.

A focused report on progestogen hypersensitivity.

INTRODUCTION: Progestogen Hypersensitivity (PH) is caused by increased sensitivity to either exogenous or endogenous progestogens. It is characterized by recurrent cutaneous eruptions including erythema multiforme, eczema, urticaria, and angioedema, which may be associated with systemic symptoms including asthma and anaphylaxis. AREAS COVERED: Symptoms may be persistent or cyclical, coinciding with progestogen levels. With increased use of oral contraceptives and hormonal treatments for fertility, the prevalence of PH is expected to continuously increase. Several proposed immunological mechanisms, diagnostics, and treatment modalities have been proposed. Most treatments focus on suppressing ovulation and progesterone secretion or inducing tolerance through progesterone desensitization. EXPERT OPINION: Although there has been increased recognition both clinically and in the medical literature, there is still a general lack of knowledge of PH and its clinical features in the medical community. An improved understanding of the underlying pathophysiology as well as more available commercial testis, such as ELISA that accurately measures specific IgE to progesterone, are expected to broaden and improve opportunities for disease recognition and symptom control. It is essential for physicians across specialties to recognize how to diagnose PH and either manage this condition or refer these patients to a specialist with experience treating PH.

Effect of omalizumab for autoimmune progesterone dermatitis refractory to bilateral oophorectomy: a case report.

BACKGROUND: Autoimmune progesterone dermatitis (APD) is a rare skin condition caused by sensitivity to high levels of progesterone secreted during the luteal phase of the menstrual cycle. This may be due to various pathophysiological mechanisms including a Type I and Type IV hypersensitivity reaction. Here we present the case of a patient with APD whose episodic flares were controlled by the addition of omalizumab, after a bilateral oophorectomy failed to resolve her symptoms. CASE PRESENTATION: A 34-year-old female presented to our Endocrine clinic with marked Cushingoid features secondary to high-dose oral prednisone prescribed for APD diagnosed 6 years earlier. She first developed a pruritic maculopapular rash on her arms and legs just after the birth of her second child in 2009. The rash was also associated with headaches and diffuse angioedema. Symptoms occurred for 1-2 weeks, in a cyclical fashion, during the luteal phase of each menstrual cycle and subsided within a few days after menses. The severity of symptoms increased as time went on, and flare-ups began to also include dyspnea, nausea, vomiting and abdominal pain. Her symptoms improved with administration of oral prednisone, but she continued to experience breakthrough symptoms. After multiple failed treatment modalities, she elected bilateral oophorectomy in 2018. However, her symptoms of APD persisted and she still required high-dose oral prednisone. Her condition was further complicated by vasomotor menopausal symptoms and progressive iatrogenic Cushing's syndrome. She eventually was started on Omalizumab, which suppressed further recurrences of APD symptoms and allowed her to wean off prednisone. Vasomotor menopausal symptoms responded well to the addition of conjugated estrogens with bazedoxifene. However, her symptoms of diffuse bony pain and arthralgias which started whilst on prednisone have persisted in spite of discontinuing prednisone. CONCLUSIONS: To our knowledge, this is only the third case of APD which was successfully treated with Omalizumab and the first case where a bilateral oophorectomy failed to resolve symptoms of APD in the literature. This case also demonstrates the complications of vasomotor menopausal symptoms secondary to a bilateral oophorectomy, as well as the adverse effects of long-term glucocorticoid therapy.

Autoimmune progesterone dermatitis in the adolescent population.

BACKGROUND/OBJECTIVE: Autoimmune progesterone dermatitis (APD) is a rare autoimmune hypersensitivity reaction that occurs cyclically at the peak of endogenous progesterone production during the menstrual cycle in women. No study characterizing APD in the adolescent population is found; it appears likely to be underdiagnosed and undertreated. METHODS: A retrospective, single-center, review of all adolescent and pediatric patients (<20 years old at onset) with documented diagnosis of APD. RESULTS: Seventeen adolescent APD patients were included (mean age at diagnosis: 14.4 ± 2 years, mean interval of 13.6 ± 11.1 months between symptom onset and diagnosis). Twelve patients presented with urticaria, two with fixed drug eruption. Erythema multiforme, eczema, and recurrent aphthous stomatitis were present in one patient each. Exposure to exogenous progestin was present in two patients prior to disease onset. Progesterone skin test was performed in six patients with positive results in two. Fourteen patients received antihistamines and/or a topical corticosteroid. Combined oral contraceptives (COCs) were given to eleven patients, in seven via continuous daily dosing. Gonadotropin-releasing hormone agonist (GnRHa) was used in five, progesterone desensitization in four, omalizumab in two, and danazol in one patient. CONCLUSIONS: Adolescent APD is associated with a significant delay in diagnosis. The most common manifestation is urticaria. Exogenous exposure to progestins is uncommon in adolescent APD. Continuous COC, GnRHa, and progesterone desensitization have been used to control symptoms. Large, multicenter studies are required to better define, diagnose, and treat this under recognized condition among adolescent patients.

Ulcerative Stomatitis as the Sole Manifestation of Progesterone Hypersensitivity.

Oral mucosal involvement of autoimmune progesterone dermatitis is exceedingly rare. This report presents a woman with very painful ulcerative stomatitis that recurred with every menstrual period, in the absence of other clinical manifestations. Ulcers were eventually controlled with oral tamoxifen treatment for three months. Subsequent follow-up visits showed complete resolution of her oral ulcerative lesions. The non-specific nature of her oral ulcers resulted in multiple medical and dental consultations and a delay in reaching the final diagnosis. Clinicians should be aware of the possibility of progesterone hypersensitivity when painful oral ulcerative lesions appear concurrently with each progesterone surge.

Autoimmune progesterone dermatitis presenting as recurrent, marked angioedema-like lip changes: An unusual presentation of an uncommon problem.

Autoimmune progesterone dermatitis is a rare condition with varying clinical presentations. We present a case of autoimmune progesterone dermatitis presenting as recurrent, marked angioedema-like lip swelling without any other skin changes.

Progestogen Sensitization: a Unique Female Presentation of Anaphylaxis.

PURPOSE OF REVIEW: Progestogen hypersensitivity (PH) is a condition which typically occurs in women in childbearing years with a spectrum of symptoms ranging from urticaria with or without angioedema, dermatitis to systemic anaphylaxis. Herein, a clinical case of PH is presented followed by a discussion on the evaluation, diagnosis, and management of PH. RECENT FINDINGS: Progestogen hypersensitivity (a.k.a. "autoimmune progesterone dermatitis") symptoms are associated with exogenous progestin exposure (e.g., contraceptive medicines, in vitro fertilization therapy) or endogenous progesterone from progesterone surges during the luteal phase of the menstrual cycle and pregnancy. This condition can be difficult to recognize due to its heterogeneous clinical presentation. The mechanism of PH is believed to be primarily IgE-mediated; however, less commonly other immune responses may be involved. There is now a useful progesterone specific IgE immunoassay to assist in diagnosis and well-defined treatment algorithms that can be used to successfully manage PH. The epidemiology of PH is still poorly elucidated but is likely to be encountered by clinicians and especially allergists given the extensive use of oral contraceptives and increased use of supra-physiologic doses of progesterone required to support pregnancy in IVF. Including PH in the differential diagnosis of women presenting with cyclic hypersensitivity will accelerate diagnosis and successful management of this condition.

Case of autoimmune progesterone dermatitis presenting as necrotic migratory erythema successfully controlled by danazol.

Autoimmune progesterone dermatitis (APD) is a rare cutaneous disorder with cyclic skin eruptions during the luteal phase of the menstrual cycle. Patients can present with various clinical manifestations, including urticaria and angioedema, erythema multiforme, eczema, fixed drug eruption and centrifugal erythema annulare. In our case, however, the patient's skin lesions mimic necrotic migratory erythema (NME) which is most commonly associated with glucagonoma and rarely with liver disease, inflammatory bowel disease, malnutrition and other tumors. To our knowledge, this is the first case of NME-like APD and is successfully controlled by danazol. This also sheds lights on the etiologic diversity of NME.

Autoimmune progesterone dermatitis following vaginal progesterone exposure in pregnancy.

In the non-pregnant state, exogenous as well as endogenous fluctuations of progesterone have been demonstrated to cause a rare delayed hypersensitivity reaction known as autoimmune progesterone dermatitis. We describe the case of a 20-year-old woman in her second pregnancy who presented to our delivery unit at 31 weeks and 3 days gestation for a cutaneous breakout with pruritic pustules, blisters, and crusts across her chest back and extremities 23 days after the initiation of vaginal progesterone. After suspension of the vaginal progesterone, the patient's cutaneous lesions resolved. Differential diagnosis and management strategies are discussed. With the increased use of progesterone during pregnancy, complications arising from their use will rise. Clinicians should be aware of their potential adverse effects and consider autoimmune progesterone dermatitis in the differential diagnosis of patients presenting with pruritic lesion in pregnancy.

Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers.

Anaphylaxis is the most serious of all allergic reactions and can be fatal. The diagnosis is frequently delayed, and misdiagnosis often occurs with asthma or urticaria. Biomarkers such as tryptase are not routinely checked, and appropriate treatment with epinephrine is not administered in a majority of cases, increasing the risk of poor outcomes. The objective of this review is to provide a better understanding of the pathophysiology of anaphylaxis with a description of phenotypes, endotypes, and biomarkers available in both the clinical and research settings. Expanding knowledge with regard to the presentation, causes, and triggers for anaphylaxis among health care providers will improve its diagnosis and management, increase patient safety, and decrease morbidity and mortality.

Progestogen Hypersensitivity.

PURPOSE OF REVIEW: Progestogen hypersensitivity (PH) is a rare disorder which usually occurs in women of childbearing age with symptoms ranging from urticaria with or without angioedema, multiple organ involvement consistent with allergic anaphylaxis, to a spectrum of other non-evanescent skin eruptions. In this review, we present a clinical vignette of PH and discuss the clinical presentation and proposed pathomechanisms, diagnosis, and treatment of PH. RECENT FINDINGS: The hypersensitivity symptoms are associated with exogenous progestin exposure (e.g., contraceptive medicines, in vitro fertilization therapy) or endogenous progesterone from progesterone surges during the luteal phase of the menstrual cycle and pregnancy. Recognition of this condition can be challenging to the clinician due to its heterogeneous clinical presentation. It has been recently proposed to use the new term "progestogen hypersensitivity" to replace "autoimmune progesterone dermatitis" due to the lack of evidence supporting an autoimmune mechanism for this disorder. In addition, diagnostic and treatment algorithms are now available that can lead to successful management of this condition. More new developments of Progesterone desensitization protocols are now available which appear to be the safest and most effective long-term treatment option for PH. With the extensive use of oral contraceptives and increased use of supra-physiologic doses of progesterone to support pregnancy in in vitro fertilization, there is likely to be a higher prevalence of PH in the future than currently recognized. Therefore, the allergist-immunologist will be required to collaborate with gynecologists and reproductive endocrinologists to diagnose and treat this condition.

Progestogen Hypersensitivity: An Evidence-Based Approach to Diagnosis and Management in Clinical Practice.

Heterogeneous presentations of disease pose particular diagnostic and management challenges to the clinician. Progestogen hypersensitivity (PH) classically consists of hypersensitivity symptoms to endogenous progesterone during the luteal phase of the menstrual cycle. However, with the rise of assisted fertility and the exponential growth in the use of exogenous progestins for contraception, PH's prevalence and symptom heterogeneity have increased. In this article, we focus on the clinical approach to PH diagnosis with an emphasis on key elements of the history, physical, and testing modalities. We also review the current evidence for successful management and treatment across a broad range of patients.