Hormonal Medications for Genitourinary Syndrome of Menopause.

Genitourinary syndrome of menopause is a common, under-reported, and undertreated chronic progressive condition requiring long-term treatment. Hypoestrogenism in the urogenital tissues is associated with bothersome dyspareunia, vulvovaginal symptoms, overactive bladder, and frequent urinary tract infections. Vaginal hormone therapies, including vaginal estrogen and intravaginal dehydroepiandrostenedione, are safe and effective and improve symptoms and clinical findings. Systemic hormone therapy treats vulvovaginal atrophy less effectively than vaginal hormone therapies with increased stress and urge urinary incontinence. Oral ospemifene effectively treats vaginal dryness and dyspareunia. Clinicians need to ask about symptoms of genitourinary syndrome of menopause, confirm the diagnosis, and suggest appropriate treatment options.

Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause: OASIS 1 and 2 Randomized Clinical Trials.

Importance: Safe and effective nonhormonal treatments for menopausal vasomotor symptoms (VMS) are needed. Objective: To evaluate the efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of moderate to severe menopausal vasomotor symptoms. Design, Setting, and Participants: Two randomized double-blind phase 3 trials (OASIS 1 and 2) included postmenopausal participants aged 40 to 65 years experiencing moderate to severe vasomotor symptoms (OASIS 1: 77 sites in the US, Europe, and Israel from August 27, 2021, to November 27, 2023, and OASIS 2: 77 sites in the US, Canada, and Europe from October 29, 2021, to October 10, 2023). Intervention: Once daily oral elinzanetant, 120 mg, for 26 weeks or matching placebo for 12 weeks followed by elinzanetant, 120 mg, for 14 weeks. Main Outcomes and Measures: Primary end points included mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12, measured by the electronic hot flash daily diary. Secondary end points included Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality of Life questionnaire total score from baseline to week 12. Results: Eligible participants (mean [SD] age, OASIS 1: 54.6 [4.9] years; OASIS 2: 54.6 [4.8] years) were randomized to elinzanetant (OASIS 1: n = 199; OASIS 2: n = 200) or placebo (OASIS 1: n = 197; OASIS 2: n = 200). A total of 309 (78.0%) and 324 (81.0%) completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean (SD) VMS per 24 hours were 13.4 (6.6) vs 14.3 (13.9) (OASIS 1) and 14.7 (11.1) v 16.2 (11.2) (OASIS 2). Baseline VMS severity was 2.6 (0.2) vs 2.5 (0.2) (OASIS 1) and 2.5 (0.2) vs 2.5 (0.2) (OASIS 2). Elinzanetant significantly reduced VMS frequency at week 4 (OASIS 1: -3.3 [95% CI, -4.5 to -2.1], P < .001; OASIS 2: -3.0 [95% CI, -4.4 to -1.7], P < .001) and at week 12 (OASIS 1: -3.2 [95% CI, -4.8 to -1.6], P < .001; OASIS 2: -3.2 [95% CI, -4.6 to -1.9], P < .001). Elinzanetant also improved VMS severity at week 4 (OASIS 1: -0.3 [95% CI, -0.4 to -0.2], P < .001; OASIS 2: -0.2 [95 CI, -0.3 to -0.1], P < .001) and week 12 (OASIS 1: -0.4 [95% CI, -0.5 to -0.3], P < .001; OASIS 2: -0.3 [95% CI, -0.4 to -0.1], P < .001). Elinzanetant improved sleep disturbances and menopause-related quality of life at week 12, and the safety profile was favorable. Conclusions and Relevance: Elinzanetant was well tolerated and efficacious for moderate to severe menopausal VMS. Trial Registration: ClinicalTrials.gov Identifier: OASIS 1: NCT05042362, OASIS 2: NCT05099159.

Selective Estrogen Receptor Modulators in Gynecology Practice.

Selective estrogen receptor (ER) modulators have variable tissue specific estrogen agonist and antagonist activities. Tamoxifen is approved for treatment and prevention of breast cancer; acts as an endometrial estrogen agonist. Raloxifene is approved for prevention and treatment of osteoporosis and prevention of breast cancer. The selective ER modulators bazedoxifene paired with conjugated estrogens relieves vasomotor symptoms and prevents bone loss with neutral effects on breast and amenorrhea similar to placebo. Ospemifene is approved to treat dyspareunia. Lasofoxifene is in development for resistant ER positive breast cancer. Estetrol (E4), synthesized by human fetal liver, has dual weak-estrogenic/antiestrogenic features, now approved as a contraceptive.

Management of Menopause and the Role For Hormone Therapy.

Hormone therapy remains the most effective treatment for menopausal symptoms but decisions are complex, requiring an assessment of benefits and risks and determination of best treatment type, dose, and duration. Benefits exceed risks for most women with bothersome menopausal symptoms or high risk for fracture if initiated under age 60 years or within 10 years since menopause. Long-term mortality and safety data from the Women's Health Initiative is reassuring, with no increase in deaths from cardiovascular disease or cancer compared with placebo after 18 years of follow-up and a trend towards less mortality in those who initiate hormone therapy ages 50 to 59 years.

Hormone Therapy: Key Points From NAMS 2017 Position Statement.

The goal of the 2017 North American Menopause Society Hormone Therapy (HT) Position Statement is to remove fear about HT and encourage individualized shared decision making, using best available evidence. Systemic HT is safe and effective for symptomatic menopausal women aged younger than 60 years and within 10 years of menopause. Special populations of early menopause, high risk for fracture, risk of breast or uterine cancer, and extended duration are discussed. With longer duration of use, periodic evaluation and reassessment of health risks are needed. Lowered doses, transdermal therapies or newer options may enhance the benefit:risk ratio for HT.

Tissue-selective Estrogen Complex for Menopausal Hormone Therapy.

The first approved tissue-selective estrogen complex is a pairing of conjugated estrogen combined with the selective estrogen-receptor modulator, bazedoxifene. Advantages include relief of menopausal symptoms without the increased chance of bleeding or breast tenderness unlike with traditional estrogen-progestin therapy, which is associated with both bleeding and breast tenderness. Tissue-selective estrogen complex effects on relief of vasomotor symptoms, prevention of bone loss, improvement in vaginal symptoms, lack of significant cardiovascular effects beyond the expected 2-fold increase in venous thrombosis, neutral effect on breast, and protective effects on the endometrium are discussed.

Management of Menopausal Symptoms for Women Who Are at High Risk of Thrombosis.

For women at elevated risk of thrombosis, clinicians are challenged to relieve menopausal symptoms without increasing the risk of thrombosis. Oral menopausal hormone therapy increases the risk of venous thromboembolism by 2-fold to 3-fold. Observational studies suggest less thrombotic risk with transdermal therapies and with progesterone over synthetic progestogens (progestins), but the data are limited. Beneficial nonpharmacologic therapies include cognitive behavioral therapy and clinical hypnosis, whereas beneficial nonhormonal pharmacologic therapies include selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. For treatment of the genitourinary syndrome of menopause, vaginal lubricants and moisturizers, low-dose vaginal estrogen, and intravaginal dehydroepiandrosterone are options.

Design of OASIS 1 and 2: phase 3 clinical trials assessing the efficacy and safety of elinzanetant for the treatment of vasomotor symptoms associated with menopause.

OBJECTIVE: Elinzanetant is a selective neurokinin-1,3 receptor antagonist in development for the treatment of vasomotor symptoms (VMS) associated with menopause. The pivotal, double-blind, randomized, placebo-controlled phase 3 studies Overall Assessment of efficacy and Safety of elinzanetant In patients with vasomotor Symptoms (OASIS) 1 and 2 will assess the efficacy and safety of elinzanetant in women with VMS. METHODS: The OASIS 1 and 2 pivotal studies are designed in accordance with regulatory guidance. Postmenopausal women with moderate/severe VMS are randomized to receive 120 mg elinzanetant or placebo once daily for 12 weeks, followed by a 14-week active treatment extension. Primary endpoints are the mean change in frequency and severity of moderate/severe VMS from baseline to weeks 4 and 12. Key secondary endpoints will assess the onset of action and effects on sleep disturbance and menopause-related quality of life. Primary and key secondary endpoints will be analyzed using a mixed model with repeated measures. Feedback from postmenopausal women with VMS was used during protocol development. RESULTS: Women confirmed the relevance of endpoints that assess the impact of VMS, sleep disturbance, and mood changes, and the need for new nonhormone treatments. Educational materials around study design, conduct and expected assessments and procedures were developed based on questions and concerns raised by women. CONCLUSIONS: The OASIS 1 and 2 pivotal phase 3 studies will enable assessment of the efficacy and safety of elinzanetant as a treatment for VMS, together with its effect on sleep disturbances, depressive symptoms, and menopause-related quality of life. Feedback from postmenopausal women with VMS was used to maximize patient centricity in the trials.

Long-term efficacy and safety of questionnaire-based initiation of urgency urinary incontinence treatment.

OBJECTIVE: The objective of the study was to determine the longer-term efficacy and safety of initiating treatment for urgency-predominant urinary incontinence (UUI) in women diagnosed using a simple questionnaire rather than an extensive evaluation. STUDY DESIGN: Women completing a 12 week randomized controlled trial of fesoterodine therapy for UUI diagnosed by questionnaire were invited to participate in a 9 month, open-label continuation study. UUI and voiding episodes were collected using voiding diaries. Participant satisfaction was measured by questionnaire. Safety was assessed by the measurement of postvoid residual volume and adverse event monitoring; if necessary, women underwent a specialist evaluation. The longitudinal changes in UUI and voiding episodes were evaluated using linear mixed models adjusting for baseline. RESULTS: Of the 567 women completing the randomized trial, 498 (87.8%) took at least 1 dose of medication during this open-label study. Compared with the baseline visit in the randomized trial, fesoterodine was associated with a reduction in total incontinence episodes per day and urgency incontinence episodes per day at the end of the open-label study (adjusted mean [SE], 4.6 [0.12] to 1.2 [0.13] and 3.9 [0.11] to 0.9 [0.11], respectively, P < .0001 for both). Most women were satisfied with treatment (89%, 92%, and 93% at 3, 6, and 9 months, respectively). Twenty-six women experienced 28 serious adverse events, 1 of which was considered possibly treatment related. Twenty-two women had a specialist evaluation: 5 women's incontinence was misclassified by the 3 Incontinence Questions; none experienced harm because of misclassification. CONCLUSION: Using a simple validated questionnaire to diagnose and initiate treatment for UUI in community-dwelling women is safe and effective, allowing timely treatment by primary care practitioners.

Osteoporosis treatment and prevention for postmenopausal women: current and future therapeutic options.

Osteoporosis, a "silent disease," is often unrecognized until fracture. Lifestyle modification with nutritional counseling is recommended during menopausal transition. Bone density testing is recommended for women aged 65 years and older, younger postmenopausal women with risk factors, or to follow therapy. Bisphosphonates treat osteoporosis (prevent bone resorption). Raloxifene and hormone therapy prevent bone loss and fracture, with extraskeletal benefits. Denosumab treats osteoporosis, although bone effects reverse rapidly. Teriparatide (anabolic therapy) is considered for women at high risk of fracture. Bazedoxifene with conjugated estrogens, novel delivery of teriparatide, new parathyroid hormone proteins, anti-sclerostin antibodies, cathepsin K inhibitors, and stem cell therapies are in testing.

Concerns About Compounded Bioidentical Menopausal Hormone Therapy.

ABSTRACT: Following the release of the Women's Health Initiative data, women began to use compounded bioidentical hormone therapy (cBHT) in the misguided belief of greater safety and efficacy than traditional hormone therapy. New guidelines recommend government-approved hormone therapy for symptomatic healthy menopausal women younger than 60 years or within 10 years of menopause at the time of initiation. For women requesting bioidentical hormones, those similar to the hormones present before menopause, there are many government-approved hormone therapies with extensive pharmacokinetic, safety, and efficacy data provided with package inserts delineating efficacy, safety, and potential risks. For women requesting non-Food and Drug Administration-approved (cBHT), these cBHTs lack data on pharmacokinetics, safety, and efficacy and are not provided a label detailing risk. Their use should be restricted to women with allergies or dosing or formulations not available in government-approved therapies. Pellet therapy providing women with supraphysiologic hormone dosing raises even more safety concerns.

Multidisciplinary Management of Menopause: Symposium Proceedings.

This proceeding summarizes a symposium on multidisciplinary management of menopause held on July 30, 2021 as part of the Health of Women 2021 conference. The workshop featured presentations by national experts who provided insights into multidisciplinary approaches to the management of menopause, vasomotor symptoms and genitourinary syndrome of menopause, bone health (including osteoporosis, muscular strength, and mobility), as well as sexual and psychological health during menopause. In this study, we highlight the major points of each presentation and the resultant discussion.

Approach to the Patient With New-Onset Secondary Amenorrhea: Is This Primary Ovarian Insufficiency?

Menstrual cyclicity is a marker of health for reproductively mature women. Absent menses, or amenorrhea, is often the initial sign of pregnancy-an indication that the system is functioning appropriately and capable of generating the intended evolutionary outcome. Perturbations of menstrual regularity in the absence of pregnancy provide a marker for physiological or pathological disruption of this well-orchestrated process. New-onset amenorrhea with duration of 3 to 6 months should be promptly evaluated. Secondary amenorrhea can reflect structural or functional disturbances occurring from higher centers in the hypothalamus to the pituitary, the ovary, and finally, the uterus. Amenorrhea can also be a manifestation of systemic disorders resulting in compensatory inhibition of reproduction. Identifying the point of the breakdown is essential to restoring reproductive homeostasis to maintain future fertility and reestablish reproductive hormonal integrity. Among the most challenging disorders contributing to secondary amenorrhea is primary ovarian insufficiency (POI). This diagnosis stems from a number of possible etiologies, including autoimmune, genetic, metabolic, toxic, iatrogenic, and idiopathic, each with associated conditions and attendant medical concerns. The dual assaults of unanticipated compromised fertility concurrently with depletion of the normal reproductive hormonal milieu yield multiple management challenges. Fertility restoration is an area of active research, while optimal management of estrogen deficiency symptoms and the anticipated preventive benefits of hormone replacement for bone, cardiovascular, and neurocognitive health remain understudied. The state of the evidence for an optimal, individualized, clinical management approach to women with POI is discussed along with priorities for additional research in this population.

Risks of Testosterone for Postmenopausal Women.

Transdermal testosterone therapy, dosed within premenopausal physiologic testosterone ranges, used alone or with menopausal hormone therapy for postmenopausal hypoactive sexual desire disorder, has shown short-term efficacy, with few androgenic side effects. After natural or surgical menopause, meaningful improvements include an additional satisfying sexual episode per month; improvement in desire, arousal, orgasm, pleasure, and responsiveness; and a reduction in distress. Long-term data on cardiovascular, cancer, and cognitive safety are lacking. No approved testosterone preparation is available for women. Compounded testosterone creams or reduced dosing of male-approved therapies represent off-label use. Injections or pellets cause supraphysiological testosterone levels and are not recommended.

Menstrual cycle-related exacerbation of disease.

Exacerbation of common medical and mental health disorders at specific phases of the menstrual cycle is a prevalent phenomenon. Although the precise cause is unclear, studies implicate complex interactions between the immune and neuroendocrine systems. The menstrual cycle also is a trigger for the onset of depressive disorders, including premenstrual dysphoric disorder, a disorder specific to the luteal phase of the menstrual cycle, and depression associated with the transition to menopause. This article discusses common mental health problems exacerbated by the menstrual cycle, with a particular focus on premenstrual dysphoric disorder and perimenopausal depression. Throughout the reproductive lifespan, routine screening and assessment for the presence of common psychiatric disorders are critical for accurate diagnosis and provision of effective treatment. Management options include referral or consultation with a primary care provider or psychiatrist; treatment options for premenstrual dysphoric disorder and perimenopausal depression include pharmacotherapy with antidepressant agents and/or psychotherapy. Hormones may be helpful.

Cervical cancer and human papillomavirus in indigenous Guyanese women.

OBJECTIVE: The purpose of this study was to determine the prevalence of cervical disease, human papillomavirus infection, and human papillomavirus (HPV) genotypes in indigenous villages of Guyana. STUDY DESIGN: This is a retrospective analysis of a clinical cervical cancer screening and treatment program: 2250 women underwent cytologic screening; 1423 women were concomitantly screened for HPV. HPV genotyping was performed in 45 women with high-grade dysplasia and in 9 women with cervical carcinoma. RESULTS: We found invasive cervical carcinoma in 0.80% of the women, cervical intraepithelial neoplasia II and III in 5.07% of the women, and a high-risk HPV infection rate in 19.3% of the women, all of which peaked between the ages of 20-30 years. Sixteen genotypes were detected in women with high-grade dysplasia or cancer: HPV 31, 25.0%; HPV 16, 22.7%; HPV 18, 13.6%. The rate of HPV 16 and 18 in cervical cancer was 55.50%. CONCLUSION: Indigenous Guyanese women have a high rate of cervical cancer and high-grade dysplasia, with an apparent predominance of HPV 16 and 18 in invasive cancer and overrepresentation of HPV 31 in high-grade dysplasia.