Background Hypersensitivity to one's own sex hormones is not a new concept but it is an underappreciated one. Such a phenomenon may explain a large proportion of symptoms related to the menstrual cycle (such as premenstrual syndrome, PMS), cyclic pain syndromes or unexplained infertility. In this study we propose a novel diagnostic tool of hormonal skin testing which reveals sex hormones sensitivity with high clinical correlation, and a subsequent successful desensitization technique. Methods A group of 35 women with confirmed diagnosis of PMS were enrolled in the study in which they underwent a hormonal skin diagnostic skin testing procedure by intradermal injections of Progesterone (P), Estradiol (E2), Estrone (E1) and Estriol (E3). Skin reaction was monitored, and according to the reaction the patients were treated by serial desensitization by similar serial injections or placebo solvent. Response to treatment was monitored by assessing the change in the severity of PMS related symptoms. Results We show a positive correlation between PMS severity and skin sensitivity to sex hormones. Subsequent desensitization procedure led to a significant improvement in the severity of PMS related symptoms. Conclusions The testing and desensitization procedure is safe, sensitive and bares a high therapeutic potential in approach to resistant hormonal cycle related syndromes. ClinicalTrials.gov Identifier NCT00873262 : Evaluation of Safety/Efficacy of Diagnostic Skin Test Panel and Desensitization Hormone Kit for Treatment of Premenstrual Syndrome (PMS) 2009.