Preimplantation genetic testing for monogenic conditions (PGT-M) is the process of testing embryos created in vitro to screen for specific monogenic conditions. Embryos unaffected by the condition of interest can then be selectively transferred to the uterus to establish a pregnancy. PGT-M is a reproductive option for individuals with an increased chance of having a child with a monogenic condition. By enabling the selection of unaffected embryos, it reduces the likelihood of transmitting the condition. It also enables the conception of a biologically related child, while minimizing the potential need to consider termination of pregnancy. For these reasons, PGT-M often emerges as the preferred reproductive option for individuals in this indication group. As uptake of PGT-M continues to grow, clinicians are increasingly required to navigate the range of technical, clinical, practical, and ethical considerations involved in its provision. This review offers a practical overview of PGT-M-covering its definition, regulatory frameworks, and technical development, through to laboratory work-up and clinical application. It also explores the limitations, ethical challenges, and experiences of PGT-M users, with the aim of supporting clinicians in the delivery of PGT-M care.
As genomic sequencing becomes more prevalent in reproductive medicine, clinicians must remain knowledgeable about the purpose of each ordered test, the principles of variant classification, and how to interpret and integrate findings into clinical decision-making. This review outlines the American College of Medical Genetics and Genomics (ACMG) standardized guidelines for sequence variant interpretation and highlights anticipated updates in the forthcoming v4.0 framework. When next-generation sequencing is performed for a clinical condition, incidental findings of pathogenic and likely pathogenic variants in medically actionable genes (MAGs) may be identified. Conditions included on the ACMG MAG list are typically highly penetrant, primarily autosomal dominant or X-linked, and have established interventions that can alter disease trajectory. Carrier screening enables the identification of autosomal recessive and X-linked variants in prospective parents that predispose them to genetic disease in their children. The ACMG's tier-based recommendations support universal Tier 3 screening, targeting conditions with a carrier frequency of at least 1 in 200 and moderate/severe phenotypes, while Tier 4 screening is reserved for individuals with consanguinity or significant family history. While technical genomic advances enhance the delivery of precision medicine, they introduce challenges, including higher rates of uncertain findings and the need for more careful clinical interpretation.
Clinical genetics in reproductive medicine has moved from cytogenetic assessment to integrated, genome-wide diagnostics that resolve both sequence-level and structural variation. For patients facing infertility, recurrent pregnancy loss, fetal structural anomalies, or early onset pediatric disease, contemporary care follows a reflexive pathway that links karyotyping, chromosomal microarray (CMA), and exome or genome sequencing (GS) with advanced structural platforms including optical genome mapping (OGM) and long-read sequencing. Karyotyping remains indispensable for aneuploidy and balanced rearrangements. CMA outperforms karyotyping for submicroscopic copy number variants and is guideline-endorsed in prenatal diagnosis. Trio exome or GS increases diagnostic yield and clinical utility in fetuses with anomalies and in children with neurodevelopmental disorders or other congenital anomalies. Professional societies now recommend exome or GS as first-tier test in many pediatric scenarios. Long-read sequencing resolves repeats and complex structural variants. OGM provides a single assay, genome wide structural view with strong multisite clinical concordance, including prenatal validations. We present a pragmatic algorithm that orders structure- and sequence-based tests to shorten time, reduce serial testing, and improve counseling and reproductive planning. Together, these modalities support precise diagnoses, tighter recurrence risk estimates, and alignment of care with patient values.
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by absent or incomplete pubertal development due to impaired production, secretion, or action of gonadotropin-releasing hormone (GnRH). When associated with anosmia or hyposmia, it is termed Kallmann syndrome. CHH exhibits striking clinical and genetic heterogeneity, encompassing either sporadic or familial cases, with inheritance patterns that include X-linked, autosomal dominant, and autosomal recessive transmission. Over the past few decades, major advances uncovered the molecular basis of CHH, shedding light on the intricate neuroendocrine regulation of human reproduction. A growing repertoire of genes has been implicated in CHH molecular pathogenesis, encoding proteins involved in the ontogeny and function of GnRH neurons. Notably, pathogenic variants in genes typically associated with complex syndromes have also been identified in patients with isolated CHH or subtle syndromic manifestations, suggesting a wide spectrum of expressivity and incomplete penetrance. Furthermore, spontaneous hypogonadism reversal, either permanent or temporary, may occur in some patients, suggesting a potential neuroplasticity within the GnRH neuronal network. This review summarizes recent advances in the molecular genetics of CHH, emphasizing the expanding spectrum of causative genes and their inheritance patterns.
Primary ovarian insufficiency (POI) is a heterogeneous condition that worldwide affects up to 3.7% of women under 40 years of age. POI manifestations are diverse, ranging from ovarian dysgenesis and primary amenorrhea to a later onset ovarian dysfunction, secondary amenorrhea, and diminished ovarian reserve. These conditions result in infertility and elevated risk for osteoporosis and cardiovascular disease. Over the past decade, substantial progress has been made in understanding the complexities of ovarian biology and oocyte development, particularly in identifying involved pathways, etiology, underlying mechanisms, and POI-associated genes. In this review, we focus on chromosomal and monogenic causes of POI leading to syndromic and isolated forms in humans. We provide an updated summary on 272 genes reported in at least two unrelated individuals with a clinical diagnosis of POI. This information supports healthcare professionals in making informed decisions regarding genetic testing and genetic counseling. This review underlines the critical role of molecular diagnosis in understanding and managing POI, highlighting both the current progress and the existing limitations in translating genetic findings and knowledge into effective diagnostic practice.
Preimplantation genetic testing for aneuploidy (PGT-A) has become a widely adopted component of in vitro fertilization (IVF) practice. However, PGT-A is not a single, uniform test; its predictive value and clinical utility remain highly dependent on test performance and interpretation, both of which vary substantially between laboratories and platforms. This article aims to define the intended goals of PGT-A, evaluate methods for proper test validation, and explore how validation data impacts clinical counseling and decision-making. Particular attention is given to newer diagnostic categories such as mosaicism and segmental aneuploidy, for which clinical validation is limited and inter-laboratory variability is high. While PGT-A can reduce futile embryo transfers and support elective single embryo transfer, misapplication of unvalidated results may reduce IVF success rates. To ensure responsible use of PGT-A, clinicians must demand transparent, assay-specific validation data and use this information to guide evidence-based counseling for embryo transfer, storage, and disposition.
Endometriosis is a prevalent gynecological condition affecting approximately 10% of women of reproductive age and up to 50% of those with infertility. It is characterized by the presence of endometrial-like tissue outside the uterine cavity. Despite its high prevalence, diagnosis is often delayed by up to 10 years from symptom onset, partly due to the historical lack of accurate, noninvasive diagnostic tools. Although major reproductive societies continue to define videolaparoscopy as the gold standard for diagnosing endometriosis, it does not reliably predict disease extent. Consequently, once a presumptive diagnosis is established, accurate and detailed imaging is invaluable for patient management. Comprehensive endometriosis mapping enhances surgical planning, facilitates appropriate triage to specialized centers for advanced disease, and improves patient counseling regarding potential complications and risks.
Endometriosis is a complex, chronic disorder that has the potential to produce long-term negative impact on the life and function of patients who carry this diagnosis. Endometriosis is thought to impact up to 10 to 15% of women across the globe and up to 90% of patients with pelvic pain. Yet, many questions remain regarding the true pathogenesis of this disease, as well as the best approach to surveillance and treatment. What we do know is that, as there remains no cure for endometriosis, management of this disease is best achieved with a longitudinal approach, with consideration of immediate disease features and other potential sequelae. The ideal treatment approach typically involves more conservative lifestyle changes, including dietary modifications, and incorporation of medication therapy, typically at the very least involving some form of hormone suppression therapy. The role of surgery remains dependent on both the patient's clinical course and the provider. Here, we explore both the known and the unknown in endometriosis management, with key updates on the potential implications of hysterectomy.
Estrogens, including estradiol and estrone, and androgens, including testosterone, are locally produced in adipose tissue throughout a woman's lifespan. Already in fertile-aged women, subcutaneous and visceral adipose tissue produce notable amounts of estrogens despite ongoing ovarian estrogen synthesis. After menopause, adipose tissue becomes the most important producer of estrogens. A decrease in circulating estrogen concentrations coincides with a relative increase in the amount of visceral adipose tissue and an increased risk for metabolic disorders. Furthermore, local adipose tissue biosynthesis of sex steroids may regulate the distribution of adipose tissue between the subcutaneous and visceral depots. Further studies are needed to characterize the relation of local adipose tissue sex steroid milieu to local and circulating markers of adipose tissue and metabolic dysfunction. This can shed more light on the increasing adiposity and metabolic burden associated with menopause. Here, we discuss the roles estrogens and androgens play in adipose tissue distribution and function before and after menopause, and highlight the role of local sex steroid biosynthesis, or intracrinology, in determining local tissue sex steroid environments.
Menopause represents a cardio-metabolic transition, but cardiovascular (CV) health in women is highly influenced by other reproductive milestones and conditions, which delineate a cardio-reproductive lifeline. Reproductive history represents an opportunity to identify women at elevated risk of CV events after menopause, going beyond traditional CV risk factors. This review aims to summarize the impact of reproductive milestones, gynecological conditions, and pregnancy-related factors on cardio-metabolic health at midlife. The main physio-pathological mechanisms likely implicated in linking reproductive events and CV disease risk are described, as well as the impact of specific conditions (early/late menarche and menstrual dysfunction [functional hypothalamic amenorrhea, polycystic ovary syndrome, benign gynecological conditions (endometriosis, adenomyosis, and fibroids), infertility, adverse pregnancy outcomes, and premature/early natural or surgical menopause]). Data indicate that a reproductive checklist in midlife women is warranted for primary prevention and intervention.
Perimenopausal women have specific needs when it comes to contraception. Although fertility rates generally decrease after age 40, pregnancy is still possible and may be associated with a higher risk of obstetric and fetal complications. Moreover, women may experience bothersome symptoms during perimenopause due to anovulatory cycles and fluctuating estrogen levels, such as abnormal uterine bleeding, vasomotor symptoms, migraines, and mood disorders. Additionally, age increases the risk of the most common side effects of well-known contraceptives, particularly those containing estrogen. For this reason, contraception counseling during perimenopause should be tailored to the woman's characteristics. It should include three steps: evaluating the woman's needs and symptoms; evaluating the potential benefits of the chosen method; evaluating risk factors that may contraindicate certain choices. No contraceptive method is contraindicated solely based on age. Among combined hormonal contraceptives, if no contraindication exists, natural estrogens should be preferred after 40 years old. On the other hand, progestin-only methods can also be safely used in the presence of cardiovascular risk factors. This review will address the main reasons why a woman may need an HC method and how to make a tailored and informed choice.
