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.

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.

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.

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.

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.

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.

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.

A comparison of nine scales to detect depression in Parkinson disease: which scale to use?

OBJECTIVE: The Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study compared the psychometric properties of 9 depression scales to provide guidance on scale selection in Parkinson disease (PD). METHODS: Patients with PD (n = 229) from community-based neurology practices completed 6 self-report scales (Beck Depression Inventory [BDI]-II, Center for Epidemiologic Studies Depression Rating Scale-Revised [CESD-R], 30-item Geriatric Depression Scale [GDS-30], Inventory of Depressive Symptoms-Patient [IDS-SR], Patient Health Questionnaire-9 [PHQ-9], and Unified Parkinson's Disease Rating Scale [UPDRS]-Part I) and were administered 3 clinician-rated scales (17-item Hamilton Depression Rating Scale [HAM-D-17], Inventory of Depressive Symptoms-Clinician [IDS-C], and Montgomery-Åsberg Depression Rating Scale [MADRS] and a psychiatric interview. DSM-IV-TR diagnoses were established by an expert panel blinded to the self-reported rating scale data. Receiver operating characteristic curves were used to estimate the area under the curve (AUC) of each scale. RESULTS: All scales performed better than chance (AUC 0.75-0.85). Sensitivity ranged from 0.66 to 0.85 and specificity ranged from 0.60 to 0.88. The UPDRS Depression item had a smaller AUC than the BDI-II, HAM-D-17, IDS-C, and MADRS. The CESD-R also had a smaller AUC than the MADRS. The remaining AUCs were statistically similar. CONCLUSIONS: The GDS-30 may be the most efficient depression screening scale to use in PD because of its brevity, favorable psychometric properties, and lack of copyright protection. However, all scales studied, except for the UPDRS Depression, are valid screening tools when PD-specific cutoff scores are used.

Terms, definitions and measurements to describe the sonographic features of the endometrium and intrauterine lesions: a consensus opinion from the International Endometrial Tumor Analysis (IETA) group.

The IETA (International Endometrial Tumor Analysis group) statement is a consensus statement on terms, definitions and measurements that may be used to describe the sonographic features of the endometrium and uterine cavity on gray-scale sonography, color flow imaging and sonohysterography. The relationship between the ultrasound features described and the presence or absence of pathology is not known. However, the IETA terms and definitions may form the basis for prospective studies to predict the risk of different endometrial pathologies based on their ultrasound appearance.

Pilot trial of 1-octanol in essential tremor.

1-Octanol (an 8-C alcohol currently used as a food-flavoring agent) is known to inhibit tremor in essential tremor (ET) animal models at a much lower dose than ethyl alcohol. The authors conducted a randomized, placebo-controlled pilot trial of a single oral dose of 1 mg/kg of 1-octanol in 12 patients with ET. No significant side effects or signs of intoxication were observed. 1-Octanol significantly decreased tremor amplitude for up to 90 minutes. The results suggest 1-octanol as a well-tolerated and safe potential treatment for ET. Further trials are warranted.

Accelerometry to distinguish psychogenic from essential or parkinsonian tremor.

The authors measured postural wrist tremor with accelerometry in patients with psychogenic (n = 6), essential (n = 11), and parkinsonian (n = 12) tremor. Tremor was measured in one hand, while the other hand either rested or tapped to an auditory stimulus at 3 and 4 or 5 Hz. Psychogenic tremors showed larger tremor frequency changes and higher intraindividual variability while tapping. Accelerometry may differentiate psychogenic from essential and parkinsonian tremor.

Transrectal scanning: an alternative when transvaginal scanning is not feasible.

OBJECTIVE: In scanning the female pelvis the clear images of transvaginal sonography (TVS) result from placing the transducer close to the region of interest. The advantages of TVS over transabdominal sonography (TAS) and transperineal sonography are well documented. Transrectal scanning is proposed mostly for ultrasound guidance in draining a pelvic abscess. Our aim was to investigate the applicability of transrectal scanning (TRS) for cases in which TVS is impossible. METHODS: Forty-two patients with an absolute or a relative contraindication to TVS were scanned transabdominally and transrectally. The TRS was performed using a transvaginal probe, which was lubricated and slowly advanced into the rectum. The technique used was similar to that of TVS. Images were compared for resolution and quality. RESULTS: All scans were completed without significant patient discomfort or complaints. TRS was clearly superior to TAS in 31 cases. In nine cases TAS furnished some clinical information but TRS yielded better images. Only in one such case was TAS similar in quality to TRS. In four obese patients TAS did not reveal sufficient pelvic anatomy to generate a clinical diagnosis, whereas TRS revealed two sets of normal ovaries and two patients with ovarian cysts. In the two cases with vaginal agenesis TRS revealed the diagnosis of Rokitansky-Küster syndrome. In three of the four patients with ruptured membranes the cervix could be measured precisely. CONCLUSION: Transrectal scanning should be used liberally after proper patient selection and counseling. The images obtained are superior to TAS and comparable to those obtained by TVS.