BACKGROUND: Reproductive disorders and infertility are associated with the risk of obstetric complications and have a negative impact on pregnancy outcome. Affected patients often require assisted reproductive technologies (ART) to conceive, and advanced maternal age is a further confounding factor. The challenge is to dissect causation, correlation and confounders in determining how infertility and reproductive disorders individually or together predispose women to poor pregnancy outcomes. METHODS: The published literature, to June 2015, was searched using PubMed, summarizing all evidences concerning the perinatal outcome of women with infertility and reproductive disorders and the potential mechanisms that may influence poor pregnancy outcome. RESULTS: Reproductive disorders (endometriosis, adenomyosis, polycystic ovary syndrome and uterine fibroids) and unexplained infertility share inflammatory pathways, hormonal aberrations, decidual senescence and vascular abnormalities that may impair pregnancy success through common mechanisms. Either in combination or alone, these disorders results in an increased risk of preterm birth, fetal growth restriction, placental pathologies and hypertensive disorders. Systemic hormonal aberrations, and inflammatory and metabolic factors acting on endometrium, myometrium, cervix and placenta are all associated with an aberrant milieu during implantation and pregnancy, thus contributing to the genesis of obstetric complications. Some of these features have been also described in placentas from ART. CONCLUSIONS: Reproductive disorders are common in women of childbearing age and rarely occur in isolation. Inflammatory, endocrine and metabolic mechanisms associated with these disorders are responsible for an increased incidence of obstetric complications. These patients should be recognized as ‘high risk’ for poor pregnancy outcomes and monitored with specialized follow-up. There is a real need for development of evidence-based recommendations about clinical management and specific obstetric care pathways for the introduction of prompt preventative care measures.

Endometriosis is a benign uterine disorder characterized by menstrual pain and infertility, deeply affecting women’s health. It is a chronic disease and requires a long term management. Hormonal drugs are currently the most used for the medical treatment and are based on the endocrine pathogenetic aspects. Estrogen-dependency and progesterone-resistance are the key events which cause the ectopic implantation of endometrial cells, decreasing apoptosis and increasing oxidative stress, inflammation and neuroangiogenesis. Endometriotic cells express AMH, TGF-related growth factors (inhibin, activin, follistatin) CRH and stress related peptides. Endocrine and inflammatory changes explain pain and infertility, and the systemic comorbidities described in these patients, such as autoimmune (thyroiditis, arthritis, allergies), inflammatory (gastrointestinal/urinary diseases) and mental health disorders.The hormonal treatment of endometriosis aims to block of menstruation through an inhibition of hypothalamus-pituitary-ovary axis or by causing a pseudodecidualization with consequent amenorrhea, impairing the progression of endometriotic implants. GnRH agonists and antagonists are effective on endometriosis by acting on pituitary-ovarian function. Progestins are mostly used for long term treatments (dienogest, NETA, MPA) and act on multiple sites of action. Combined oral contraceptives are also used for reducing endometriosis symptoms by inhibiting ovarian function. Clinical trials are currently going on selective progesterone receptor modulators, selective estrogen receptor modulators and aromatase inhibitors. Nowadays, all these hormonal drugs are considered the first-line treatment for women with endometriosis to improve their symptoms, to postpone surgery or to prevent post-surgical disease recurrence. This review aims to provide a comprehensive state-of-the-art on the current and future hormonal treatments for endometriosis, exploring the endocrine background of the disease.

Adenomyosis is a benign uterine disorder in which endometrial glands and stroma are pathologically demonstrated in the uterine myometrium and it is considered a specific entity in the PALM-COEIN FIGO (polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified – International Federation of Gynecology and Obstetrics) classification of causes of abnormal uterine bleeding (AUB). Although it has always been considered the classic condition of multiparous women over 40 years old who have pain and heavy menstrual bleeding, diagnosed at hysterectomy, the epidemiological scenario has completely changed. Adenomyosis is increasingly identified in young women with pain, AUB, infertility, or no symptoms by using imaging techniques such as transvaginal ultrasound and magnetic resonance. However, there is no agreement on the definition and classification of adenomyotic lesions from both the histopathology and the imaging point of view, and the diagnosis remains difficult and unclear. A uniform and shared reporting system needs to be implemented in order to improve our understanding on imaging features, their relationship with pathogenic theories, and their importance in terms of clinical symptoms and response to treatment. In fact, adenomyosis pathogenesis remains elusive and not a single theory can explain all of the different phenotypes of the disease. Furthermore, adenomyosis often coexists with other gynecological conditions, such as endometriosis and uterine fibroids, increasing the heterogeneity of available data. Treatment requires a lifelong management plan as the disease has a negative impact on quality of life in terms of menstrual symptoms, fertility, and pregnancy outcome and has a high risk of miscarriage and obstetric complications.

Adenomyosis is a common disorder of the uterus, and is associated with an enlarged uterus, heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is characterized by endometrial epithelial cells and stromal fibroblasts abnormally found in the myometrium where they elicit hyperplasia and hypertrophy of surrounding smooth muscle cells. While both the mechanistic processes and the pathogenesis of adenomyosis are uncertain, several theories have been put forward addressing how this disease develops. These include intrinsic or induced (1) microtrauma of the endometrial–myometrial interface; (2) enhanced invasion of endometrium into myometrium; (3) metaplasia of stem cells in myometrium; (4) infiltration of endometrial cells in retrograde menstrual effluent into the uterine wall from the serosal side; (5) induction of adenomyotic lesions by aberrant local steroid and pituitary hormones; and (6) abnormal uterine development in response to genetic and epigenetic modifications. Dysmenorrhea, HMB, and infertility are likely results of inflammation, neurogenesis, angiogenesis, and contractile abnormalities in the endometrial and myometrial components. Elucidating mechanisms underlying the pathogenesis of adenomyosis raise possibilities to develop targeted therapies to ameliorate symptoms beyond the current agents that are largely ineffective. Herein, we address these possible etiologies and data that support underlying mechanisms.

Uterine fibroids (UFs) are the most common female benign pelvic tumors, affecting over 60% of patients aged 30-44 years. UFs are asymptomatic in a large percentage of cases and may be identified incidentally by a transvaginal ultrasound or a magnetic resonance. However, in around 30% of cases UFs affect quality of life (QoL) and women's health, being abnormal uterine bleeding (AUB) and heavy menstrual bleeding (HMB) the most common complaints, along with iron deficiency (ID) and ID anemia (IDA). Medical treatments used for UFs-related AUB include symptomatic agents, such as nonsteroidal anti-inflammatory drugs and tranexamic acid, and hormonal therapies, including combined oral contraceptives, gonadotropin-releasing hormone (GnRH) agonists or antagonists, levonorgestrel intrauterine systems, selective progesterone receptors modulators and aromatase inhibitors. Nevertheless, few drugs are approved specifically for UFs treatment and most of them manage the symptoms. Surgical options include fertility-sparing treatments, such as myomectomy, or non-conservative options, as hysterectomy, especially in perimenopausal women not responding to any treatment. Radiological interventions are also available: uterine artery embolization, high-intensity focused ultrasound or magnetic resonance-guided focused ultrasound, radiofrequency ablation. Furthermore, the management of ID and IDA, as a consequence of acute and chronic bleeding, should be taken into account by using iron replacement therapy both during medical treatment and before and after a surgical procedure. In case of symptomatic UFs, the location, size, multiple UFs or coexistent adenomyosis should guide the choice with a shared decision-making, considering long- and short-term treatment goals expected by the patient, including pregnancy desire or wish to preserve the uterus independently of reproductive goals.