Deconstructing a Syndrome: Genomic Insights into PCOS Causal Mechanisms and Classification

Polycystic ovary syndrome (PCOS) is among the most common disorders of reproductive-age women, affecting up to 15% worldwide, depending on the diagnostic criteria. PCOS is characterized by a constellation of interrelated reproductive abnormalities including disordered gonadotropin secretion, increased androgen production, chronic anovulation, and polycystic ovarian morphology. It is frequently associated with insulin resistance and obesity. These reproductive and metabolic derangements cause major morbidities across the lifespan, including anovulatory infertility and type 2 diabetes (T2D). Despite decades of investigative effort, the etiology of PCOS remains unknown. Familial clustering of PCOS cases has indicated a genetic contribution to PCOS. There are rare Mendelian forms of PCOS associated with extreme phenotypes, but PCOS typically follows a non-Mendelian pattern of inheritance consistent with a complex genetic architecture, analogous to T2D and obesity, that reflects the interaction of susceptibility genes and environmental factors. Genomic studies of PCOS have provided important insights into disease pathways and have indicated that current diagnostic criteria do not capture underlying differences in biology associated with different forms of PCOS. We provide a state-of-the-science review of genetic analyses of PCOS, including an overview of genomic methodologies aimed at a general audience of non-geneticists and clinicians. Applications in PCOS will be discussed, including strengths and limitations of each study. The contributions of environmental factors, including developmental origins, will be reviewed. Insights into the pathogenesis and genetic architecture of PCOS will be summarized. Future directions for PCOS genetic studies will be outlined.

Stem cells and organs-on-chips: new promising technologies for human infertility treatment

Having biological children remains an unattainable dream for most couples with reproductive failure or gonadal dysgenesis. The combination of stem cells with gene editing technology and organ-on-a-chip models provides unique opportunity for infertile patients with impaired gametogenesis caused by congenital disorders in sex development or cancer survivors. But, how will these technologies overcome human infertility? This review discusses the regenerative mechanisms, applications and advantages of different types of stem cells for restoring gametogenesis in infertile patients, as well as major challenges that must be overcome prior to clinical application. The importance and limitations of in vitro generation of gametes from patient-specific human induced pluripotent stem cells (hiPSCs) will be discussed in the context of human reproduction. The potential role of organ-on-a-chip models that can direct differentiation of hiPSCs-derived primordial germ cell-like cells to gametes and other reproductive organoids is also explored. These rapidly evolving technologies provide future prospects for improving fertility to individuals and couples who experience reproductive failure.

New and consolidated therapeutic options for pubertal induction in hypogonadism: in-depth review of the literature

Delayed puberty (DP) defines a retardation of onset/progression of sexual maturation beyond the expected age due to either a lack/delay of the hypothalamo-pituitary-gonadal (HPG) axis activation or a gonadal failure. DP usually gives rise to concern and uncertainty in patients and their families, potentially affecting their immediate psychosocial well-being and also creating longer-term psychosexual sequelae. The most frequent form of DP in younger teenagers is self-limiting and may not need any intervention. Conversely, DP due to hypogonadism requires prompt and specific treatment that we summarize in this review. Hormone therapy primarily targets genital maturation, development of secondary sexual characteristics and the achievement of target height in line with genetic potential, but other key standards of care include body composition and bone mass. Finally, pubertal induction should promote psychosexual development and mitigate both short- and long-term impairments comprising low self-esteem, social withdrawal, depression and psychosexual difficulties. Different therapeutic options for pubertal induction have been described for both males and females but we lack the necessary larger randomized trials to define the best approaches for both sexes. We provide an in-depth and updated literature review regarding therapeutic options for inducing puberty in males and females, particularly focusing on recent therapeutic refinements that better encompass the heterogeneity of this population, and underlining key differences in therapeutic timing and goals. We also highlight persistent shortcomings in clinical practice, wherein strategies directed at “the child with delayed puberty of uncertain aetiology” risk being misapplied to older adolescents likely to have permanent hypogonadism.

Molecular derangements and the diagnosis of ACTH-Dependent Cushing’s syndrome

Endogenous Cushing’s syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders ) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focusses on CS caused by excessive ACTH production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes, and mechanisms by which dysregulation occurs in corticotrope (termed “Cushing’s disease”) and non-corticotrope (so-called “ectopic”) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

From molecule to behavior: hypocretin/orexin revisited from a sex-dependent perspective

The hypocretin/orexin (Hcrt/Orx) system in the perifornical lateral hypothalamus has been recognized as a critical node in a complex network of neuronal systems controlling both physiology and behavior in vertebrates. Our understanding of the Hcrt/Orx system and its array of functions and actions have grown exponentially in merely two decades. This review will examine the latest progress in discerning the roles played by the Hcrt/Orx system in the regulation of homeostatic functions and in the execution of instinctive and learned behaviors. Furthermore, the gaps that currently exist in our knowledge of sex-related differences in this field of study are discussed.

The Role of Iodine for Thyroid Function in Lactating Women and Infants

Iodine is a micronutrient needed for the production of thyroid hormones, which regulate metabolism, growth, and development. Iodine deficiency or excess may alter the thyroid hormone synthesis. The potential effects on infant development depend on the degree, timing, and duration of exposure. The iodine requirement is particularly high during infancy because of elevated thyroid hormone turnover. Breastfed infants rely on iodine provided by human milk, but the iodine concentration in breast milk is determined by the maternal iodine intake. Diets in many countries cannot provide sufficient iodine, and deficiency is prevented by iodine fortification of salt. However, the coverage of iodized salt varies between countries. Epidemiological data suggest large differences in the iodine intake in lactating women, infants, and toddlers worldwide, ranging from deficient to excessive intake. In this review, we provide an overview of the current knowledge and recent advances in the understanding of iodine nutrition and its association with thyroid function in lactating women, infants, and toddlers. We discuss risk factors for iodine malnutrition and the impact of targeted intervention strategies on these vulnerable population groups. We highlight the importance of appropriate definitions of optimal iodine nutrition and the need for more data assessing the risk of mild iodine deficiency for thyroid disorders during the first 2 years in life.

Membrane-initiated estrogen, androgen and progesterone receptor signaling in health and disease

Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized (SRs) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.