Migraine is a major neurological disorder affecting one in nine adults worldwide with a significant impact on health care and socioeconomic systems. Migraine is more prevalent in women than in men, with 17% of all women meeting the diagnostic criteria for migraine. In women, the frequency of migraine attacks shows variations over the menstrual cycle and pregnancy, and the use of combined hormonal contraception (CHC) or hormone replacement therapy (HRT) can unveil or modify migraine disease. In the general population, 18–25% of female migraineurs display a menstrual association of their headache. Here we present an overview on the evidence supporting the role of reproductive hormones, in particular estrogens, in the pathophysiology of migraine. We also analyze the efficacy and safety of prescribing exogenous estrogens as a potential treatment for menstrual-related migraine. Finally, we point to controversial issues and future research areas in the field of reproductive hormones and migraine.

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) encompass a variety of symptoms that occur during the luteal phase of the menstrual cycle and impair daily life activities and relationships. Depending on the type and severity of physical, emotional or behavioral symptoms, women of reproductive age followed for at least two prospective menstrual cycles may receive one of the two diagnoses. PMDD is the most severe form of PMS, predominantly characterized by emotional and behavioral symptoms not due to another psychiatric disorder. PMS and PMDD are common neuro-hormonal gynecological disorders with a multifaceted etiology. Gonadal steroid hormones and their metabolites influence a plethora of biological systems involved in the occurrence of specific symptoms, but there is no doubt that PMS/PMDD are centrally based disorders. A more sensitive neuroendocrine threshold to cyclical variations of estrogens and progesterone under physiological and hormonal therapies is present. Moreover, altered brain sensitivity to allopregnanolone, a metabolite of progesterone produced after ovulation potentiating GABA activity, along with an impairment of opioid and serotoninergic systems, may justify the occurrence of emotional and behavioral symptoms. Even neuro-inflammation expressed via the GABAergic system is under investigation as an etiological factor of PMS/PMDD. Pharmacological management aims to stabilize hormonal fluctuations and to restore the neuroendocrine balance. The rationale of suppressing ovulation supports prescription of combined hormonal contraception (CHC). Its effect on mood is highly variable and depends on biochemical characteristics of exogenous steroids and on type and severity of symptoms. Hormonal regimens reducing the estrogen-free interval or suppressing menstruation seem better choices. Psychoactive agents, such as serotonin reuptake inhibitors (SSRIs), are effective in reducing the symptoms of PMS/PMDD and may be prescribed continuously or only during the luteal phase. Novel therapeutic approaches include inhibition of progesterone receptors in the brain, i.e., with ulipristal acetate, reduced conversion of progesterone with dutasteride, and modulation of the action of allopregnanolone on the brain GABAergic system with sepranolone.

The shift in paradigm from the belief that endometriosis exclusively affects women of reproductive age has brought attention to its manifestation in postmenopausal patients. Despite this emerging awareness, there remains a dearth of information in the literature regarding postmenopausal endometriosis, with uncertainties surrounding its prevalence, clinical significance, optimal management strategies, and prognosis. Clinical manifestations of endometriosis in menopausal patients lack specificity, with pain onset possible at any stage of life. The primary approach for symptomatic postmenopausal endometriosis continues to be surgical excision, serving both diagnostic and therapeutic purposes while mitigating the risk of coexisting malignancies. Managing the disease in postmenopausal women presents challenges due to possible contraindications for menopausal hormone therapy and the elevated risk of recurrence and malignant transformation. However, conclusive data regarding the appropriateness of menopausal hormone therapy in women with endometriosis or a history of the disease are lacking. Current recommendations lean towards prioritizing combined menopausal hormone therapy formulations or tibolone over estrogen-only therapies due to their potentially higher malignancy risk. The possible increased risk of osteoporosis and cardiovascular disease in postmenopausal women with endometriosis is likely linked to a history of surgical menopause at an earlier age, but more research is warranted. This narrative review summarizes the available literature and provides insights into the intricate connection between endometriosis and menopause, shedding light on pathogenesis, symptoms, oncologic risk, diagnosis, and treatment.

Since its discovery, much attention has been drawn to irisin’s potential role in metabolic and reproductive diseases. This narrative review summarizes and updates the possible role played by this fascinating molecule in different physiological (puberty and menopause) and pathological (polycystic ovary syndrome (PCOS), functional hypothalamic amenorrhea (FHA), endometriosis, and gestational diabetes) conditions that can affect women throughout their entire lives. Irisin appears to be an important factor for the hypothalamic–pituitary–gonadal axis activation, and appears to play a role in the timing of puberty onset. Serum irisin levels have been proposed as a biomarker for predicting the future development of gestational diabetes (GDM). Its role in PCOS is still controversial, although an “irisin resistance” mechanism has been hypothesized. In addition to its impact on metabolism, irisin also appears to influence bone health. Irisin levels are inversely correlated with the prevalence of fractures in postmenopausal women. Similar mechanisms have also been postulated in young women with FHA. In clinical settings, further controlled, prospective and randomized clinical trials are needed to investigate the casual relationship between irisin levels and the conditions described and, in turn, to establish the role of irisin as a prognostic/diagnostic biomarker or a therapeutic target.

Childhood obesity has profound effects on puberty in boys and girls, altering its timing, progression, and associated hormonal changes. Also, later male fertility could be impaired by childhood and pubertal obesity in light of the impact of inflammatory markers on semen quality. The aim of this narrative review is to explore the intricate relationship between childhood obesity and its impact on pubertal development and fertility, with a specific focus on boys. Such a relationship between obesity and pubertal timing in males is highly influenced by metabolic, hormonal, genetic, epigenetic, and environmental factors. While many studies suggest that obesity accelerates pubertal onset in boys, some studies do not confirm these findings, especially in cases of severe obesity. In fact, delayed puberty has also been reported in certain instances. Obesity influences fertility through different central and peripheral processes, including an altered endocrine milieu, inflammatory environment, and epigenetic modifications that alter semen quality and vitality, leading to subfertility or infertility. The early identification and management of potential issues associated with obesity are crucial for ensuring optimal reproductive health in adulthood. Further research is essential to clarify these associations and to develop targeted interventions aimed at preventing the negative health outcomes associated with obesity-related disruptions in puberty and fertility.

Asthma is a frequent medical condition in adolescence. The worsening of the most common symptoms perimenstrually is defined as perimenstrual asthma (PMA). The cause of PMA remains unclear, but a role for hormonal milieu is plausible. Data on PMA in adolescents are limited, and its management is not fully established. We aimed to discuss the PMA phenomenon in young females from pathophysiology to preventive strategies, focusing on the relationship with the hormonal pattern. The fluctuation of estrogens at ovulation and before menstruation and the progesterone secretion during the luteal phase and its subsequent withdrawal seem to be the culprits, because the deterioration of asthma is cyclical during the luteal phase and/or during the first days of the menstrual cycle. Conventional asthma therapies are not always effective for PMA. Preventive strategies may include innovative hormonal contraception. Even a possible beneficial effect of other hormonal treatments, including estrogens, progestogens, and androgens, as well as leukotriene receptor antagonists and explorative approach using microbial-directed therapy, is considered. The underlying mechanisms, through which sex-hormone fluctuations influence asthma symptoms, represent a challenge in the clinical management of such a distressing condition. Further studies focused on young females are mandatory to promote adolescent health.