Presidential reflections: how we got here, where we might go.

Pieter van Keep was a founder and the third president of the International Menopause Society (IMS). He died, sadly, in 1991. Since then, every retiring president of the IMS has delivered the Pieter van Keep Memorial Lecture. This is an edited version of that lecture delivered at the 18th World Congress of the IMS in Lisbon, Portugal in 2022. In the article, President Steven R. Goldstein describes the path he followed that led him to the presidency of the IMS, including his original entry into transvaginal ultrasound, then gynecologic ultrasound and, ultimately, menopausal ultrasound. His was the first description of the benign nature of simple ovarian cysts, the ability of transvaginal ultrasound to exclude significant tissue in patients with postmenopausal bleeding and the significance of endometrial fluid collections in postmenopausal patients, just to name a few. However, it was his description of the unusual ultrasound appearance in the uterus of women receiving tamoxifen therapy that allowed his entry into the world of menopause. This, ultimately, led to leadership positions, and ultimately the presidency of the American Institute of Ultrasound in Medicine, the North American Menopause Society and, finally, the IMS, all chronicled in this article. In addition, the article describes in detail the activities of the IMS during the COVID pandemic.

Selective estrogen receptor modulators and bone health.

Selective estrogen receptor modulators (SERMs) are synthetic molecules that bind to the estrogen receptor and can have agonistic activity in some tissues while being estrogen antagonistic in others. While not all SERMs are clinically available in all parts of the world, this article will review preclinical and clinical effects of various SERMs on bone. These include tamoxifen, used as adjuvant therapy in breast cancer patients as well as for breast cancer prevention; raloxifene, approved for osteoporosis prevention and treatment as well as breast cancer prevention; bazedoxifene, approved for prevention of osteoporosis and also in combination with conjugated equine estrogen for treatment of vasomotor symptoms and prevention of bone loss in postmenopausal patients; and ospemifene, approved for treatment of dyspareunia due to vulvovaginal atrophy/genitourinary syndrome of menopause. Thus, these SERMs are a diverse group of estrogen agonist/antagonists that seem to have class effects in the bone and breast, although the amount of clinical trial data is quite variable. However, there does not seem to be the same unidirectional class activity in tissues like the uterus or vagina. Health-care providers should be cognizant of all available information in helping patients make the best possible shared decision-making choices.

Skin, hair and beyond: the impact of menopause.

The skin is an endocrine organ and a major target of hormones such as estrogens, androgens and cortisol. Besides vasomotor symptoms (VMS), skin and hair symptoms often receive less attention than other menopausal symptoms despite having a significant negative effect on quality of life. Skin and mucosal menopausal symptoms include dryness and pruritus, thinning and atrophy, wrinkles and sagging, poor wound healing and reduced vascularity, whereas skin premalignant and malignant lesions and skin aging signs are almost exclusively caused by environmental factors, especially solar radiation. Hair menopausal symptoms include reduced hair growth and density on the scalp (diffuse effluvium due to follicular rarefication and/or androgenetic alopecia of female pattern), altered hair quality and structure, and increased unwanted hair growth on facial areas. Hormone replacement therapy (HRT) is not indicated for skin and hair symptoms alone due to the risk-benefit balance, but wider potential benefits of HRT (beyond estrogen's effect on VMS, bone, breast, heart and blood vessels) to include skin, hair and mucosal benefits should be discussed with women so that they will be able to make the best possible informed decisions on how to prevent or manage their menopausal symptoms.

Ability to successfully image endometrium on transvaginal ultrasound in asymptomatic postmenopausal women.

OBJECTIVES: Numerous studies indicate that endometrial thickness of ≤ 4 mm on transvaginal ultrasound (TVS) is a reliable test to exclude endometrial cancer in women with postmenopausal bleeding (PMB), such that biopsy is not needed. However, not all postmenopausal women have anatomy that allows reliable measurement of endometrial thickness. This study was undertaken to evaluate the frequency of, and the reasons for, an inability to adequately visualize the endometrium on TVS. METHODS: A total of 472 consecutive asymptomatic postmenopausal women underwent TVS as part of their routine gynecological care. Their charts and TVS images were reviewed, and, if possible, endometrial thickness was recorded. If the endometrium was not adequately visualized, the reason for inadequacy was recorded, as judged by the examiner. Other demographic characteristics recorded included the number of years since menopause, body mass index (BMI) and current use of hormone replacement therapy. RESULTS: Of the 472 women, 292 (61.9%) had an endometrium that was well visualized, in whom endometrial thickness could be measured reliably (mean, 3.0 (range, 1.0-28.0) mm). In the other 180 postmenopausal women (38.1%), a distinct endometrium was not adequately visualized. The reasons for non-visualization were fibroids (n = 95, 20.1% of the overall cohort), adenomyosis (n = 35, 7.4% of the overall cohort) and an axial uterus (n = 50, 10.6% of the overall cohort). Mean interval from menopause was 14.0 (range, 1-50) years and 14.1 (range, 1-40) years in the visualized and non-visualized cohorts, respectively (P = 0.83). Mean BMI was 23.9 (range, 16.3-41.5) kg/m2 in the visualized cohort and 25.4 (range, 18.0-39.9) kg/m2 in the non-visualized cohort (P = 0.015). CONCLUSIONS: TVS has become an accepted first step in the evaluation of PMB. However, in our cohort, 38.1% of women had anatomical reasons for non-visualization of the endometrium and lack of a reliable endometrial thickness measurement, including fibroids, adenomyosis or an axial uterus. There was no significant difference between groups in the interval from menopause or current use of hormone replacement therapy, but the mean BMI of the non-visualized group was significantly higher than in the visualized group. Clinicians should be cognizant of these potential limitations of TVS in the initial evaluation of women with PMB. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Update on bone health: the International Menopause Society White Paper 2021.

Osteoporosis and associated fractures present a major challenge in improving global health outcomes. Key clinical aspects are the definition of osteoporosis and associated fractures, fracture risk prediction, stratification of risk of fracture, intervention thresholds and the most appropriate intervention based on integration of aforementioned. Correct understanding and application of these concepts are essential to stem the increasing tide of fragility fractures associated with an aging population. The role of muscle strength and function, sarcopenia, and the newly emerging concept of osteosarcopenia in maintaining bone health are discussed in detail.

Uterine bleeding with hormone therapies in menopausal women: a systematic review.

Uterine bleeding is a common reason why women discontinue menopausal hormone therapy (HT). This systematic review compared bleeding profiles reported in studies for continuous-combined HT approved in North America and Europe for moderate to severe vasomotor symptoms in postmenopausal women with a uterus. Non-head-to-head studies showed that uterine bleeding varies by formulation and administration route, with oral having a better bleeding profile than transdermal formulations. Cumulative amenorrhea over a year ranged from 18 to 61% with oral HT and from 9 to 27% with transdermal HT, as reported for continuous-combined HT containing 17ß-estradiol (E2)/progesterone (P4) (56%), E2/norethisterone acetate (NETA) (49%), E2/drospirenone (45%), conjugated equine estrogens/medroxyprogesterone acetate (18-54%), ethinyl estradiol/NETA (31-61%), E2/levonorgestrel patch (16%), and E2/NETA patch (9-27%). Amenorrhea rates and the mean number of bleeding/spotting days improved over time. The oral E2/P4 combination was amongst those with lower bleeding rates and may be an appropriate alternative for millions of women seeking bioidentical HT and/or those who have bleeding concerns with other HT.

Treatment of moderate to severe dyspareunia with intravaginal prasterone therapy: a review.

The loss of sex steroids (e.g. estradiol, dehydroepiandrosterone [DHEA], progesterone) that causes menopause commonly affects a woman's general health and produces bothersome physical changes that may interfere with normal sexual and genitourinary functioning. Although both over-the-counter and prescription treatments are available, there remains a large unmet need, as less than 10% of women are treated. Adrenal DHEA and its sulfate are the most abundant steroids in humans. Here we review the development of intravaginal prasterone, the synthetic equivalent to endogenous DHEA. Prasterone is approved by the US Food and Drug Administration for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. Prasterone has been shown to decrease the pain associated with dyspareunia, and to improve vaginal pH, as well as superficial and parabasal cell counts, while maintaining serum hormone levels within the range of those seen in normal postmenopausal women. Unlike other menopausal prescription therapies, intravaginal prasterone does not carry a boxed warning, thus allowing the clinician and patient to engage in meaningful and reassuring discussion around a new approach that treats this common, debilitating condition.

Abnormal uterine bleeding in perimenopause.

Abnormal uterine bleeding is one of the commonest presenting complaints encountered in a gynecologist's office or primary-care setting. The wider availability of diagnostic tools has allowed prompt diagnosis and treatment of an increasing number of menstrual disorders in an office setting. This White Paper reviews the advantages and disadvantages of transvaginal ultrasound, blind endometrial sampling and diagnostic hysteroscopy. Once a proper diagnosis has been established, appropriate therapy may be embarked upon. Fortunately, only a minority of such patients will have premalignant or malignant disease. When bleeding is sufficient to cause severe anemia or even hypovolemia, prompt intervention is called for. In most of the cases, however, the abnormal uterine bleeding will be disquieting to the patient and significantly affect her 'quality of life'. Sometimes, reassurance and expectant management will be sufficient in such patients. Overall, however, in cases of benign disease, some intervention will be required. The use of oral contraceptive pills especially those with a short hormone-free interval, the insertion of the levonorgestrel intrauterine system, the incorporation of newer medical therapies including antifibrinolytic drugs and selective progesterone receptor modulators and minimally invasive treatments have made outpatient therapy increasingly effective. For others, operative hysteroscopy and endometrial ablation are proven therapeutic tools to provide both long- and short-term relief of abnormal uterine bleeding, thus avoiding, or deferring, hysterectomy.

Terms, definitions and measurements to describe sonographic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group.

The MUSA (Morphological Uterus Sonographic Assessment) statement is a consensus statement on terms, definitions and measurements that may be used to describe and report the sonographic features of the myometrium using gray-scale sonography, color/power Doppler and three-dimensional ultrasound imaging. The terms and definitions described may form the basis for prospective studies to predict the risk of different myometrial pathologies, based on their ultrasound appearance, and thus should be relevant for the clinician in daily practice and for clinical research. The sonographic features and use of terminology for describing the two most common myometrial lesions (fibroids and adenomyosis) and uterine smooth muscle tumors are presented.

Ambras Syndrome: First Reported Case in Bangladesh and its Oral Rehabilitation.

People with rare hypertrichosis syndromes became crowd-drawing money-making phenomena in many 19th century sideshow acts. These individuals have been referred to as dog-men, hair-men, and werewolves. In 1993, Baumister et al. described congenital hypertrichosis lanuginose or Ambras syndrome: a distinct form of congenital hypertrichosis characterized by excessive hair growth over the body and face associated with facial and occasional dental anomalies. Much is not known about this syndrome since fewer than 50 cases have been documented worldwide. In this case report, a nine year old girl presented with excessive hair growth throughout her body that was denser along her midline. Furthermore, her face displayed the typical dysmorphic features characteristic of Ambras syndrome: a round tip nose, thickened nasal cartilage, antiverted nares, prominent philtrum with deep groove, and a trapezoid mouth. Oral examination revealed normal oral mucosa with completely missing and unerupted decidious and permanent teeth. Panoramic radiographs confirmed unerupted deciduous teeth. Previous case reports have mentioned the presence of occasional dental anomalies such as retarded first and second dentition and absence of some teeth. However, this is the first reported case of Ambras syndrome presenting with complete anodontia. Prior cytogenetic studies performed on persons with Ambras syndrome have implicated a balanced pericentric inversion of chromosome 8. However, it is likely that dental anomalies are likely a result of a different genetic rearrangement. Further studies are needed to explore the cause of this rare phenotype of Ambras syndrome with complete unerupted dentition.

Pharmacological management of fluid overload.

BACKGROUND: Standard treatment practice for the hypotensive patient with poor tissue perfusion is rapid volume resuscitation; in some scenarios, such as septic shock, this is performed with targeted goal-directed endpoints within 6 h of presentation. As a result, patients often develop significant positive fluid accumulation, which has been associated with poor outcomes above certain thresholds. METHODS: The aim of the current paper is to provide guidance for active pharmacological fluid management in the patient with, or at risk for, clinically significant positive fluid balance from either resuscitation for hypovolaemic shock or acute decompensated heart failure. RESULTS: We develop rationale for pharmacological fluid management targets (prevention of worsening fluid accumulation, achievement of slow vs rapid net negative fluid balance) in the context of phases of critical illness provided in the earlier Acute Dialysis Quality Initiative 12 papers.

Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy.

OBJECTIVE: Assessment of 12-month safety of ospemifene 60 mg/day for treatment of postmenopausal women with vulvar and vaginal atrophy (VVA). METHODS: In this 52-week, randomized, double-blind, placebo-controlled, parallel-group study, women 40-80 years with VVA and an intact uterus were randomized 6 : 1 to ospemifene 60 mg/day or placebo. The primary objective was 12-month safety, particularly endometrial; 12-week efficacy was assessed. Safety assessments included endometrial histology and thickness, and breast and gynecological examinations. Efficacy evaluations included changes from baseline to week 12 in percentage of superficial and parabasal cells and vaginal pH. RESULTS: Of 426 randomized subjects, 81.9% (n = 349) completed the study with adverse events the most common reason for discontinuation (ospemifene 9.5%; placebo 3.9%). Most (88%) treatment-emergent adverse events with ospemifene were considered mild or moderate. Three cases (1.0%) of active proliferation were observed in the ospemifene group. For one, active proliferation was seen at end of study week 52, and diagnosed as simple hyperplasia without atypia on follow-up biopsy 3 months after the last dose. This subsequently resolved with progestogen treatment and dilatation and curettage. In six subjects (five ospemifene (1.4%), one placebo (1.6%)) endometrial polyps were found (histopathology); however, only one (ospemifene) was confirmed as a true polyp during additional expert review. Endometrial histology showed no evidence of carcinoma. Statistically significant improvements were seen for all primary and secondary efficacy measures and were sustained through week 52 with ospemifene vs. placebo. CONCLUSIONS: The findings of this 52-week study confirm the tolerance and efficacy of oral ospemifene previously reported in short- and long-term studies.

Approach to hyperuniformity of steady states of facilitated exclusion processes.

We consider the fluctuations in the number of particles in a box of sizeLdinZd,d⩾1, in the (infinite volume) translation invariant stationary states of the facilitated exclusion process, also called the conserved lattice gas model. When started in a Bernoulli (product) measure at densityρ, these systems approach, ast→∞, a 'frozen' state forρ⩽ρc, withρc=1/2ford = 1 andρc<1/2ford⩾2. Atρ=ρcthe limiting state is, as observed by Hexner and Levine, hyperuniform, that is, the variance of the number of particles in the box grows slower thanLd. We give a general description of how the variances at different scales ofLbehave asρ↗ρc. On the largest scale,L≫L2, the fluctuations are normal (in fact the same as in the original product measure), while in a regionL1≪L≪L2, with bothL1andL2going to infinity asρ↗ρc, the variance grows faster than normal. For1≪L≪L1the variance is the same as in the hyperuniform system. (All results discussed are rigorous ford = 1 and based on simulations ford⩾2.).

The Utility of Urinary NGAL as an Alternative for Serum Creatinine to Detect Acute Kidney Injury in Infants Exposed to Nephrotoxic Medications in the Neonatal Intensive Care Unit.

INTRODUCTION: Nephrotoxic medication (NTM) exposure is commonly associated with acute kidney injury (AKI) in the neonatal intensive care unit (NICU). Baby Nephrotoxic Injury Negated by Just-in-Time Action (NINJA) is a quality improvement program that assesses for AKI in those exposed to NTM with daily serum creatinine (SCr) levels. However, blood draws for SCr are invasive and have clinical disadvantages. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is a promising indicator of AKI. We tested the hypothesis that uNGAL could reliably screen for NTM-AKI in the Baby NINJA program. METHODS: This two-center prospective study screened 174 NICU subjects, of whom 148 met screening criteria from January 29, 2019, to September 18, 2020. Daily SCr and urine samples were obtained for up to 7 days of NTM exposure plus 2 days after exposure ended or end of AKI. AKI was defined by a SCr rise of 50% from baseline. The highest uNGAL obtained was evaluated to determine its relationship to the diagnosis of AKI. Logistic regression models were used to determine optimal uNGAL cutoffs. RESULTS: The negative predictive value of a uNGAL value ≥250 ng/mL was 96.8% (95% CI = 93.3-100%). Urine NGAL ≥400 ng/mL demonstrated the highest ROC-AUC value of 0.72 with a positive likelihood risk for AKI of 2.76 (1.39-4.13). DISCUSSION/CONCLUSION: We propose that uNGAL could be used to screen for NTM-AKI and thus replace many blood draws needed in those exposed to NTM. The ideal uNGAL threshold requires further investigation in infants.

Evaluation of new geological reference materials for uranium-series measurements: Chinese Geological Standard Glasses (CGSG) and macusanite obsidian.

Recent advances in high-resolution, rapid, in situ microanalytical techniques present numerous opportunities for the analytical community, provided accurately characterized reference materials are available. Here, we present multicollector thermal ionization mass spectrometry (MC-TIMS) and multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS) uranium and thorium concentration and isotopic data obtained by isotope dilution for a suite of newly available Chinese Geological Standard Glasses (CGSG) designed for microanalysis. These glasses exhibit a range of compositions including basalt, syenite, andesite, and a soil. Uranium concentrations for these glasses range from ∼2 to 14 µg g(-1), Th/U weight ratios range from ∼4 to 6, (234)U/(238)U activity ratios range from 0.93 to 1.02, and (230)Th/(238)U activity ratios range from 0.98 to 1.12. Uranium and thorium concentration and isotopic data are also presented for a rhyolitic obsidian from Macusani, SE Peru (macusanite). This glass can also be used as a rhyolitic reference material, has a very low Th/U weight ratio (around 0.077), and is approximately in (238)U-(234)U-(230)Th secular equilibrium. The U-Th concentration data agree with but are significantly more precise than those previously measured. U-Th concentration and isotopic data agree within estimated errors for the two measurement techniques, providing validation of the two methods. The large (238)U-(234)U-(230)Th disequilibria for some of the glasses, along with the wide range in their chemical compositions and Th/U ratios should provide useful reference points for the U-series analytical community.

Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice.

The resilience and strength of bone is due to the orderly mineralization of a specialized extracellular matrix (ECM) composed of type I collagen (90%) and a host of non-collagenous proteins that are, in general, also found in other tissues. Biglycan (encoded by the gene Bgn) is an ECM proteoglycan that is enriched in bone and other non-skeletal connective tissues. In vitro studies indicate that Bgn may function in connective tissue metabolism by binding to collagen fibrils and TGF-beta (refs 5,6), and may promote neuronal survival. To study the role of Bgn in vivo, we generated Bgn-deficient mice. Although apparently normal at birth, these mice display a phenotype characterized by a reduced growth rate and decreased bone mass due to the absence of Bgn. To our knowledge, this is the first report in which deficiency of a non-collagenous ECM protein leads to a skeletal phenotype that is marked by low bone mass that becomes more obvious with age. These mice may serve as an animal model to study the role of ECM proteins in osteoporosis.