Is early menopause a different entity from POI?
Dr. Panagiotis G. Anagnostis, MD, PhD, MSc, FRSPH
Specialist in Endocrinology, Diabetes and Metabolism,
Assistant Professor of Internal Medicine,
Division of Endocrinology, 3rd Department of Internal Medicine, “Papageorgiou” General Hospital, Aristotle University of Thessaloniki, Thessaloniki, GreecePremature ovarian insufficiency (POI), which affects 1%–3% of postmenopausal women, is associated with an increased risk of cardiovascular disease, mainly including fatal and non-fatal coronary heart disease (mostly attributed to increased incidence of cardiovascular risk factors, such as diabetes mellitus and arterial hypertension), heart failure and atrial fibrillation. POI is also associated with increased risk of fractures, due to osteoporosis and sarcopenia, as well as, cognitive impairment and depression. Early menopause (EM, defined as age at menopause <45 years), which covers 10% of the postmenopausal population, shares the same adverse health consequences and, in most cases, to the same degree, with POI. Moreover, women who experience EM are at increased all‐cause mortality (relative risk 1.12, 95% confidence interval 1.03–1.21, according to an older meta-analysis), compared with those of age at menopause > 45 years. Therefore, a unifying term for EM and POI, such as ‘premature menopause’, may be proposed, using the age threshold of <45 years. This could provide a broader coverage of these women, substantiating the need for prompt administration of hormone replacement therapy (HRT) in women with EM, not for the sole purpose of vasomotor symptom relief (simply as ‘menopausal hormone therapy’), but as a true ‘HRT’ to potentially reduce the risks mentioned above, covering all women with age at menopause <45 years. However, the benefits of this approach, which precludes a higher oestrogen dose up to the normal age of menopause, need to be proven in well‐designed randomized controlled trials. Moreover, long‐term adherence to HRT should also be achieved to obtain the maximum benefit. Therefore, there is an imperative need for more research that indicates the best way to offer HRT at different ages of early hypoestrogenism since, even in women with POI, there is high heterogeneity in the way and time during which it is prescribed.
Practical Management Strategies of Vasomotor Symptoms (VMS) and Vulvovaginal Atrophy (VVA) in the Menopausal Transition
Dimitrios G. Goulis,
Professor in Reproductive Endocrinology, Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece
Vasomotor symptoms and vulvovaginal atrophy represent the most prevalent and clinically impactful sequelae of the hypoestrogenic state accompanying the menopausal transition, affecting up to 80% and 50% of postmenopausal women, respectively. Unlike VMS, which frequently attenuate over time, vulvovaginal atrophy (VVA), now more comprehensively termed genitourinary syndrome of menopause (GSM), follows a progressive, chronic course in the absence of targeted intervention, necessitating individualized, evidence-based management strategies.Systemic menopausal hormone therapy (MHT) remains the most efficacious intervention for moderate-to-severe VMS, with estrogen-progestogen combinations indicated in non-hysterectomized women to mitigate endometrial proliferative risk. Transdermal estradiol formulations are favored owing to their superior pharmacokinetic profile, avoidance of first-pass hepatic metabolism, lower thrombogenic potential, and reduced impact on triglyceride levels relative to oral preparations. Micronized progesterone is the progestogen of choice when endometrial protection is required, offering a more favorable cardiovascular and breast safety profile. For women with contraindications to estrogen or those preferring non-hormonal alternatives, selective serotonin-norepinephrine reuptake inhibitors (SNRIs) — particularly venlafaxine — and the recently approved neurokinin B receptor antagonists (e.g., fezolinetant) represent emerging first-line non-hormonal pharmacotherapy with demonstrated efficacy in reducing hot flush frequency and severity.The management of GSM/VVA should be addressed independently, as systemic MHT doses are often insufficient to fully restore urogenital tissue. Low-dose vaginal estrogen, available as creams, tablets, or flexible rings, achieves therapeutic local tissue concentrations with negligible systemic absorption, rendering it appropriate even in women who are otherwise considered poor candidates for systemic therapy, including most breast cancer survivors. Ospemifene, an oral selective estrogen receptor modulator, provides a systemic non-estrogen alternative for dyspareunia. Vaginal dehydroepiandrosterone (prasterone) offers dual androgenic and estrogenic receptor activity within urogenital tissues, addressing both epithelial atrophy and sexual dysfunction. Non-hormonal adjuncts, including long-acting vaginal moisturizers and pH-balanced lubricants, remain integral components of comprehensive GSM management.Shared clinical decision-making, incorporating individual risk stratification (particularly cardiovascular, thromboembolic, and breast cancer risk) remains paramount. Periodic reassessment of symptom burden, therapeutic benefit, and evolving risk profiles should guide treatment duration and modification.
RECURRENT PREGNANCY LOSS IN POLYCYSTIC OVARY SYNDROME: UNDERLYING GENETIC AND METABOLIC CONTRIBUTORS
Prof. Asanidze Elene, Georgia
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine-metabolic disorder associated with an increased risk of adverse pregnancy outcomes, including recurrent pregnancy loss (RPL). The mechanisms underlying this association remain incompletely understood and are likely multifactorial, involving interactions among metabolic, endocrine, vascular, and genetic factors.
Insulin resistance and compensatory hyperinsulinemia may be central contributors to pregnancy loss in women with PCOS. Together with obesity and hyperandrogenism, these abnormalities may impair oocyte quality, endometrial receptivity, implantation, trophoblast function, and early placentation. Women with PCOS and RPL have been reported to demonstrate greater metabolic disturbance than women with PCOS and successful pregnancies, suggesting that the severity of metabolic dysfunction may influence pregnancy prognosis.
Hyperhomocysteinemia may represent an additional metabolic and vascular contributor. Elevated homocysteine concentrations have been described in women with PCOS and have been associated with insulin resistance. Potential mechanisms linking hyperhomocysteinemia with pregnancy loss include endothelial dysfunction, oxidative stress, altered vascular homeostasis, and impaired placental adaptation.
Genetic variants influencing homocysteine metabolism and fibrinolysis may further modify susceptibility to pregnancy loss in PCOS. MTHFR C677T and A1298C polymorphisms, particularly homozygous C677T and compound C677T/A1298C genotypes, have been investigated because of their potential influence on folate-dependent homocysteine metabolism. Similarly, the PAI-1 4G/5G polymorphism, particularly the 4G/4G genotype, has been investigated through its association with increased PAI-1 expression, reduced fibrinolytic activity, and impaired placental microvascular adaptation. Although associations between PAI-1 variants and RPL have been supported by meta-analysis, their specific contribution to PCOS-associated RPL remains uncertain. Heterogeneity among studies and limited clinical utility preclude interpretation of MTHFR and PAI-1 variants as established causal determinants or validated biomarkers.
PCOS-associated RPL should therefore be considered within an integrated metabolic, endocrine, vascular, and genetic framework rather than attributed to a single molecular abnormality. The coexistence of insulin resistance, hyperinsulinemia, obesity, hyperandrogenism, hyperhomocysteinemia, and potential genetic modifiers may define an adverse metabolic–endocrine phenotype associated with increased risk of pregnancy loss in women with PCOS. Recognition of this phenotype may support more individualized assessment of women with PCOS and RPL and provide a framework for interpreting emerging clinical and research data.
Ovarian function ceases way before other organs start to fail; lessons learned from DNA testing?
Joop S.E. Laven , Div Reproductive Endocrinology and Infertility, Dept OBGYN, Erasmus University Medical Centre, Rotterdam, The Netherlands
The ovary is the first organ in the human body to undergo aging, affecting both fertility and overall health. There is overwhelming evidence that most genes associated with the age of menopause are involved in DNA repair mechanisms, including double-strand break repair, mismatch repair, and base excision repair. The remaining associated loci are linked to cellular energy metabolism and immune responses. Recent analyses have revealed coordinated changes in transcriptomes and chromatin accessibility across different ovarian cell types during aging, with granulosa cells exhibiting the greatest number of aging-associated differentially expressed genes. Furthermore, the ovary is among the organs that harbor the highest number of long genes, which are particularly susceptible to gene-length-dependent transcriptional decline. This severely impairs the transcriptional machinery and significantly contributes to aging as an etiological factor. The gradual accumulation of unrepaired DNA damage leads to cell death and cellular senescence. In turn, this results in the exhaustion of cellular renewal capacity and dysfunction of affected organs, ultimately contributing to aging of the entire soma. A similar erosion of genomic integrity occurs within the germ cell line and the ovaries. Subsequently, the systemic “survival” response intentionally suppresses sex steroid hormone production, which may contribute to the onset of menopause. These processes are expected to act synergistically to promote ovarian silencing and establish menopause. Interestingly, women with Polyendocrine Metabolic Ovarian Syndrome (PMOS) enter menopause later on in life compared to those without PMOS. This is due to the fact that they harbor the better DNA repair and maintenance variants. Hence, they are able to repair damage adequately and as such this diminishes the impact of such damage on the ovaries. As a consequence nature grants them a longer reproductive life span. In conclusion somatic aging appears to be a primary driver of the decline in ovarian function in women and in women with PMOS this process is significantly delayed.
Key Words:
DNA Damage and Repair genes, Menopause, PMOS, Reproductive Life Span
Continuous reproductive identity: A new information architecture for reproductive medicine
Prof Jacques Kadoch , Université de Montréal | The Fertility Partners | Clinique ovo, CanadaAssisted reproductive medicine has evolved into one of the most data-intensive and technologically sophisticated areas of medicine. Yet its information systems remain largely organized around isolated encounters, treatment cycles, institutions, and software platforms. A reproductive journey, however, does not follow these boundaries. It may extend over many years and involve patients, gametes, embryos, cryopreservation, genetic testing, pregnancies, and outcomes across multiple clinical and laboratory environments. As a result, essential reproductive information can become fragmented precisely when continuity matters most.
This presentation introduces Continuous Reproductive Identity (CRI) , a conceptual framework proposing that reproductive information should be organized around the continuity of the reproductive journey rather than around individual episodes of care.
At its core is a simple principle: every relevant biological entity and clinical event should retain its own identity while remaining persistently connected to the reproductive journey from which it originates. This allows relationships between patients, gametes, embryos, procedures, laboratory events, pregnancies, and outcomes to remain traceable over time, even when care moves between systems or institutions.
To operationalize this concept, the framework introduces the Reproductive Identity Graph (RIG) , a structured information model capable of representing these relationships while preserving provenance, chronology, governance, and chain of custody. Rather than creating another centralized database, CRI proposes an interoperable and vendor-neutral architecture in which institutions can maintain control of their data while participating in a shared information framework.
Such an architecture could have implications far beyond documentation. Persistent reproductive identity could strengthen patient safety and traceability, improve longitudinal and cumulative outcome assessment, facilitate interoperability and registry science, and provide more reliable foundations for artificial intelligence and federated research.
The central proposition is that reproductive medicine may have reached an information bottleneck: increasingly sophisticated treatments and technologies are being built upon information systems that were not designed to represent the biological and temporal complexity of reproduction.
Moving from episode-based records toward continuous reproductive identity may therefore represent an important next step in the evolution of reproductive medicine, creating an information architecture that reflects reproductive care as it actually occurs not as a collection of isolated cycles, but as a connected reproductive journey.
Estetrol: Role in MHT/HRT?
Prof Johannes Ott, Austria
Estetrol (E4), which is naturally produced in the fetus’ liver, is used as a new estrogen in combined oral contraception. Notably, it is a stimulator of nuclear estrogen receptor alpha (ERα) rather than of the membrane Erα, where it acts in an antagonistic manner. Thus, E4 offers a specific estrogenic profile with low overall estrogenicity, which is thought to contribute to a reduced thrombotic risk compared to other oral estrogens. Its minimal interaction with the hepatic cytochrome P450 enzyme system also leads to a reduced potential for drug-drug interactions. Given this specific profile and the fact that it is already established in combined oral contraception together with drospirenone, it also is of notable interest in menopausal hormone therapy.
Natural progesterone versus artificial progestogens
Prof Johannes Ott, Austria
Endometriosis, a benign, chronic inflammatory condition characterized by the presence and growth of endometrial implants outside the uterine cavity, presents a unique challenge in the postmenopausal period. This is due to the risk for recurrence and the risk for malignancy, especially ovarian cancer, which is often associated with menopausal hormone therapy. Although artificial progestogens offer the benefit of a more suppressive effect on the endometrium as well as on endometriotic lesions and, thus, are thought to lower the above mentioned risks during menopausal hormone therapy, they also introduce higher risks for breast cancer and stroke. The benefits and risks of natural progesterone versus artificial progestogens in the setting of menopausal hormone therapy and endometriosis are discussed in this lecture.
Epigenetics and reprogramming
David Monk, Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, UK
Studies have demonstrated an increased risk for adverse perinatal outcomes, including fetal growth restriction, preeclampsia, and preterm birth following ART. These reports strongly suggest variability in epigenetic regulation, which is further supported by the increased incidence of rare imprinting disorders following assisted conception. It remains to be determined if altered epigenetic profiles are gamete-derived or acquired post-fertilization; either way, they could influence embryo, fetal and placenta growth. However, there is little in the way of follow-up studies to determine the long-term adverse outcomes associated with these modest epigenetic changes. In my presentation I will discuss the current standing of research addressing the epigenetic state of human pre-implantation embryos, including the development of low input and single-cell multiomic techniques to quantify DNA methylation reprograming and embryonic genome activation. Using genomic imprinting as a model system of maintained germline-derived epigenetic state, I will describe how methylation in the placenta is associated with intrauterine growth. Finally, I will explain how research in the fields of imprinting disorders and infertility converge to clarify the function of the subcortical maternal complex and the oocyte cytoplasmic lattice. These structures are encoded by key maternal-effect genes, which lead to a spectrum of phenotypes when mutated, ranging from fertilization failure through to multi-locus imprinting disturbances.
Debate: Routine use of PRP & stem cells in POI? – FOR
Pietro Molinaro, MD
IVIRMA Global Research Alliance, IVIRMA Rome, Rome, Italy
University of Valencia, School of Medicine and Dentistry, Valencia, Spain
Premature ovarian insufficiency (POI) remains a major challenge in reproductive medicine, particularly for women seeking pregnancy with their own oocytes. While oocyte donation is an established reproductive option, regenerative approaches such as intraovarian platelet-rich plasma (PRP) and stem cell-based treatment are being investigated to support residual ovarian activity.
These approaches share the goal of improving the ovarian microenvironment but differ in their biological mechanisms. PRP delivers platelet-derived growth factors and signalling molecules that may influence angiogenesis, tissue repair and follicular function. Stem cell-based strategies act predominantly through paracrine signalling: secreted cytokines, growth factors and extracellular vesicles may modulate inflammatory pathways, oxidative stress, vascularisation, stromal function and granulosa-cell survival. Experimental evidence supports a role for these signals in preserving or supporting existing follicles; generation of new human oocytes has not been clinically demonstrated.
Autologous stem cell ovarian transplantation (ASCOT), using bone marrow-derived cells mobilized and delivered to the ovary, has provided proof-of-concept evidence of ovarian niche modulation. Early clinical studies have reported follicular activity, changes in ovarian reserve markers and pregnancies in selected women with poor ovarian response. Related translational research investigates cell-secreted factors as a possible alternative to direct cell administration. However, these findings cannot be assumed to apply equally to established POI.
For intraovarian PRP, observational studies have described increased antral follicle counts and, in some poor responders, improved oocyte maturation and fertilisation. In women with POI, such biological changes have not consistently translated into better IVF outcomes or live births. Interpretation of both PRP and stem cell studies is limited by small cohorts, heterogeneous treatment protocols, incomplete controls and spontaneous intermittent ovarian activity in POI.
The case for regenerative medicine is therefore a case for rigorous, targeted clinical development rather than claims of an established cure. Future trials must clarify mechanisms, standardise treatment, identify patients with residual follicular potential and assess safety and live birth outcomes. PRP and stem cell-based approaches should not yet be offered as unrestricted routine care, but their distinct biological pathways justify continued investigation within controlled clinical research.
Managing severe premenstrual disorders especially in perimenopause
Nick Panay
Consultant Gynaecologist: Queen Charlotte’s & Chelsea Hospital
Professor of Practice: Imperial College London
Past President: International Menopause SocietyMany women experience mild physical and emotional cycle related symptoms which are not particularly troublesome. However, when severe these symptoms can lead to a breakdown in interpersonal relationships and interference with normal activities. These symptoms can be particularly troublesome in the late reproductive and perimenopause years due to increasing hormonal fluctuations which can trigger symptoms in genetically predisposed, hormonally vulnerable, women.When PMS in severe, it may satisfy the American Psychiatric Association DSM-V criteria for premenstrual dysphoric disorder (PMDD). The International Society for Premenstrual Disorders (ISPMD) has made recommendations for a new classification with core (typical, pure or reference disorders associated with spontaneous ovulatory menstrual cycles) and variant premenstrual disorders (such as symptoms of an underlying psychological or somatic disorder significantly worsening premenstrually, now known as premenstrual exacerbation[PME]). PMS/PMDD continues to be poorly understood and in many cases inadequately managed. It can be the cause of considerable morbidity and mortality.Alternatives to traditional therapy, such as agnus castus show promise in randomized clinical trials but more data are needed. Data on use of natural progesterone alone remain controversial, although many women derive considerable benefit from this preparation. Synthetic progestogens should not be used as they can replicate the symptoms of PMS/PMDD.The more established therapies for which randomized controlled data exist are the combined “fourth” generation combined hormonal contraceptives (CHC) e.g. the 24/4 or flexible regimen 20mcg ethinylestradiol / 3mg drospirenone, transdermal estradiol, selective serotonin re-uptake inhibitors (not ideal in perimenopause) and GnRH analogues with add back HRT. Newer CHCs delivering estradiol and estetrol and the GnRH antagonists are promising but lack data specifically for PMS/PMDD. Hysterectomy with BSO and adequate HRT remains an important option for severely afflicted women whose family is complete and have not responded to other therapies.
Support for patients and health professionals is available from the National Association for Premenstrual Syndromes (NAPS) https://www.pms.org.uk/ and the International Association for Premenstrual Disorders https://iapmd.org. This presentation will use the UK RCOG Green Top Guideline No 48 and the 2026 updated NAPS guidelines on the Management of Premenstrual Syndrome / PMDD as its basis https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/premenstrual-syndrome-management-green-top-guideline-no-48/.
Should hormone therapies be started in pre/perimenopausal women?
Nick Panay
Consultant Gynaecologist: Queen Charlotte’s & Chelsea Hospital
Professor of Practice: Imperial College London
Past President: International Menopause SocietyRecent IMS, ESE and other guidance has highlighted the challenges faced by healthcare professionals (HCPs) in trying to manage the symptoms of the perimenopause using evidence based licensed hormone therapy options whilst providing concomitant contraception where required. There is too much misinformation currently reaching HCPs and the public, particularly from social media, regarding what is safe and effective and what is not. Although currently available contraceptive options provide effective strategies for managing the menopausal transition, unmet needs remain in those with severe or persistent menopause associated symptoms. Among licensed therapies, only the 52 mg LNG-IUD, when combined with estrogen therapy tailored to the woman’s needs, comes close to addressing the full spectrum of contraceptive, gynecological, and menopausal requirements.Cyclic hormone therapies with body identical or body similar hormones may improve genuine menopause associated symptoms such as VMS and GSM but are often associated with adverse effects such as bleeding problems and breast tenderness due to lack of cycle control / suppression, with excess levels of estrogen levels at times. Combined Hormonal Contraceptives (CHC) delivering natural estrogens e.g. estradiol, estetrol are an appealing option for perimenopausal women, especially into their early 50s, because of their more favorable pharmacological profile. However, their use for menopause associated symptoms is supported primarily by expert opinion rather than direct clinical evidence, they often lack licensing over 50 years, and the current medical eligibility criteria do not distinguish them from EE-containing formulations. Persistence of cycle related symptoms often warrants additional cycle suppression; the growth of GnRH antagonists has provided more practical options than were previously available with GnRH agonists, but they remain off label for managing cycle related symptoms such as PMS/PMDD.Absence of licensing for many perimenopausal hormonal therapies remains a prescribing challenge. It is therefore imperative that research and development continues to expand licensed options, and that these options are accessible to as many women globally as possible to avoid unnecessary suffering during the menopause transition. In the meantime, it is my thesis in this debate that with judicious use of hormone and cycle suppression therapies in the pre/perimenopause, distressing symptoms can be optimized whilst adverse effects are kept to a minimum.
Neurokinin targeted therapies – genuine alternatives to MHT?
Nick Panay
Consultant Gynaecologist: Queen Charlotte’s & Chelsea Hospital
Professor of Practice: Imperial College London
Past President: International Menopause SocietyThe wider the armamentarium of evidence based, licensed treatment options, the easier it is to individualise and personalise treatment. Personalisation of treatment leads to empowerment of women to make choices that are right for their own bodies. It therefore behoves us as HCPs to provide as much choice as possible to our patients. Women presenting with distressing menopause-related issues should therefore be offered evidence based, safe, effective non-hormonal as well as hormonal options as part of the treatment toolkit.
Neurokinin Targeted Therapies (NKTs) such as fezolinetant and elinzanetant provide effective, safe, licensed treatment options for vasomotor symptom (VMS) management and potentially additional holistic benefits in women with VMS, such as alleviation of sleep disturbances, and improvement in quality of life. Although there are no head-to-head clinical trials comparing the efficacy and safety of NKTs to hormone therapies for VMS, post hoc network meta-analyses have shown similar efficacy. Previous ‘alternative’ interventions for menopausal problems such as SSRIs/SNRIs, gabapentin, oxybutynin have been unlicensed for VMS in most countries, with limited efficacy and significant adverse effects.
There have been minimal adverse effects reported from the NKT studies such as somnolence and headaches; although liver enzyme elevations have been reported, there have been no liver injury cases in the controlled phase 3 randomised clinical trials (Hy’s Law); there are no detectable hormonal effects on endometrium or breast tissues. NKTs are therefore safe for women with risk factors for estrogen sensitive malignancy such as breast cancer; elinzanetant is licensed in many countries for women with VMS associated with adjuvant endocrine therapies. NKTs may also be a good option for situations where there is reluctance to initiate MHT e.g. smokers, women > 60yrs and/or >10yrs after FMP, and in those with high BMI (>35).
Patients seeking benefits in addition to VMS symptom relief e.g. genitourinary syndrome of menopause, musculoskeletal symptoms and bone benefits should still be guided towards systemic and topical MHT. However, whilst systemic MHT is highly effective, it is not without potential problems such as breakthrough bleeding, progestogen intolerance, VTE with oral preparations, and a possible small increase in breast cancer risk. NKTs should therefore be regarded as genuine alternatives to MHT for management of VMS and sleep disturbances associated with menopause.
