(045) Sex-Steroid–Sensitivity Syndrome: A Distinct Variant of Pentad Super Syndrome in Women With Gynecologic and Sexual Health Complaints

Abstract Introduction Pentad Super Syndrome (PSS) describes the clustering of hypermobility, dysautonomia, gastrointestinal (GI) dysfunction, autoimmune features, and mast-cell activation symptoms. Although recognized in connective-tissue and allergy contexts, its relationship to sex-steroid status has not been investigated. Clinical observation suggested that estradiol fluctuation or decline may precipitate or exacerbate these multisystem features in women, and that estradiol supplementation can attenuate them. We hypothesize that a drop in circulating estradiol may trigger or unmask a Sex-Steroid–Sensitivity Syndrome (SSSS) characterized by the PSS phenotype but responsive to estrogen repletion. Objective To characterize a potential estradiol-linked variant of Pentad Super Syndrome in women presenting with gynecologic and sexual health complaints, and to evaluate whether physiologic estradiol supplementation alleviates multisystem symptoms associated with estradiol decline. Methods A retrospective chart review was performed of women evaluated between 2023 and 2025 at a sexual-medicine and women’s-health clinic. Inclusion required documentation of all five PSS components. Hypermobility was confirmed by Beighton criteria, while dysautonomia, GI dysfunction, autoimmune disorders, and mast-cell–related symptoms were abstracted from clinical records. All patients received systemic transdermal estradiol (0.05–0.1 mg daily). Changes in quality of life and symptom domains were reviewed over twelve weeks. Results Fifteen women aged 19–64 were included, representing reproductive, perimenopausal, and menopausal stages. All demonstrated Beighton-confirmed hypermobility and exhibited dysautonomia, GI dysfunction, autoimmune features, and mast-cell–related symptoms consistent with PSS. Within twelve weeks of initiating estradiol therapy, 87% of patients reported meaningful improvement in dysautonomic and GI symptoms, such as reduced POTS flares, temperature instability, bloating, and constipation. Vestibulodynia and autoimmune symptoms remained largely unchanged. No patient achieved complete remission of the full multisystem cluster. Of note, 93% of patients also described baseline ADHD-like symptoms and noted subjective improvement in attention and executive function after estradiol supplementation. Conclusions Our findings support a mechanistic link between estradiol deficiency and expression of a multisystem phenotype resembling Pentad Super Syndrome. We propose the term Sex-Steroid–Sensitivity Syndrome (SSSS) for this variant, in which declining estradiol may alter connective-tissue stability, mast-cell activation thresholds, and autonomic regulation, producing overlapping somatic and neurocognitive symptoms. Partial improvement with physiologic estradiol replacement suggests that hormonal modulation is both pathogenic and therapeutic. Recognition of SSSS as an estrogen-linked disorder may broaden understanding of systemic symptoms associated with reproductive aging and guide targeted management and future research. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Organicare.