Clinically Used Hormone Formulations Differentially Impact Memory, Anxiety-Like, and Depressive-Like Behaviors in a Rat Model of Transitional Menopause

A variety of U.S. Food and Drug Administration-approved hormone therapy options are currently used to successfully alleviate unwanted symptoms associated with the changing endogenous hormonal milieu that occurs in midlife with menopause. Depending on the primary indication for treatment, different hormone therapy formulations are utilized, including estrogen-only, progestogen-only, or combined estrogen plus progestogen options. There is little known about how these formulations, or their unique pharmacodynamics, impact neurobiological processes. Seemingly disparate pre-clinical and clinical findings regarding the cognitive effects of hormone therapies, such as the negative effects associated with conjugated equine estrogens and medroxyprogesterone acetate vs. naturally circulating 17β-estradiol (E2) and progesterone, signal a critical need to further investigate the neuro-cognitive impact of hormone therapy formulations. Here, utilizing a rat model of transitional menopause, we administered either E2, progesterone, levonorgestrel, or combinations of E2 with progesterone or with levonorgestrel daily to follicle-depleted, middle-aged rats. A battery of assessments, including spatial memory, anxiety-like behaviors, and depressive-like behaviors, as well as endocrine status and ovarian follicle complement, were evaluated. Results indicate divergent outcomes for memory, anxiety, and depression, as well as unique physiological profiles, that were dependent upon the hormone regimen administered. Overall, the combination hormone treatments had the most consistently favorable profile for the domains evaluated in rats that had undergone experimentally induced transitional menopause and remained ovary-intact. The collective results underscore the importance of investigating variations in hormone therapy formulation as well as the menopause background upon which these formulations are delivered.

Metabolomic Effects of Hormone Therapy and Associations With Coronary Heart Disease Among Postmenopausal Women

Background: In the WHI-HT trials (Women’s Health Initiative Hormone Therapy), treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), whereas oral conjugated equine estrogens (CEE) did not. Methods: Four hundred eighty-one metabolites were measured at baseline and at 1-year in 503 and 431 participants in the WHI CEE and CEE+MPA trials, respectively. The effects of randomized HT on the metabolite profiles at 1-year was evaluated in linear models adjusting for baseline metabolite levels, age, body mass index, race, incident CHD, prevalent hypertension, and diabetes. Metabolites with discordant effects by HT type were evaluated for association with incident CHD in 944 participants (472 CHD cases) in the WHI-OS (Women’s Health Initiative Observational Study), with replication in an independent cohort of 980 men and women at high risk for cardiovascular disease. Results: HT effects on the metabolome were profound; 62% of metabolites significantly changed with randomized CEE and 52% with CEE+MPA (false discovery rate–adjusted P value<0.05) in multivariable models. Concerted increases in abundance were seen within various metabolite classes including triacylglycerols, phosphatidylethanolamines, and phosphatidylcholines; decreases in abundance was observed for acylcarnitines, lysophosphatidylcholines, quaternary amines, and cholesteryl/cholesteryl esters. Twelve metabolites had discordant effects by HT type and were associated with incident CHD in the WHI-OS; a metabolite score estimated in a Least Absolute Shrinkage and Selection Operator regression was associated with CHD risk with an odds ratio of 1.47 per SD increase (95% CI, 1.27–1.70, P <10 -6 ). All twelve metabolites were altered in the CHD protective direction by CEE treatment. One metabolite (lysine) was significantly altered in the direction of increased CHD risk by CEE+MPA; the remaining 11 metabolites were not significantly changed by CEE+MPA. The CHD associations of a subset of 4 metabolites including C58:11 triacylglycerol, C54:9 triacylglycerol, C36:1 phosphatidylcholine and sucrose replicated in an independent dataset of 980 participants in the PREDIMED trial (Prevención con Dieta Mediterránea). Conclusions: Randomized treatment with oral HT resulted in large metabolome shifts that generally favored CEE alone over CEE+MPA in term of CHD risk. Discordant metabolite effects between HT regimens may partially mediate the differences in CHD risk between the 2 WHI-HT trials.

Randomized Trial Evaluation of Benefits and Risks of Menopausal Hormone Therapy Among Women Aged 50-59

The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women’s Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy post-menopausal women aged 50-79 at 40 U.S. clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens, and 16,608 participants with uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over an 18-year (median) follow-up period (1993-2016) risk for a global index, defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality, is reduced with conjugated equine estrogens with hazard ratio (95% confidence interval) of 0.82 (0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (0.95, 1.19) were non-significant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.

A Dermatologist’s Approach to Genitourinary Syndrome of Menopause

Background: Genitourinary syndrome of menopause (GSM) is a debilitating condition caused by hypoestrogenism that presents with vaginal dryness and dyspareunia as well as other genital, sexual, and urinary symptoms. Previously known as atrophic vaginitis, the term GSM is now used. Objective: To help familiarise dermatologists with diagnosing and managing GSM. Methods: In total, 218 articles were identified and reviewed by 2 independent authors using PubMed. Articles included were from December 2005 to December 2015. Sixty-seven articles met our inclusion criteria. Results: GSM is a clinical diagnosis, requiring the presence of symptoms that should be bothersome and not accounted for by another condition. A pH test may help with diagnosis as vaginal pH will be increased from acidic to neutral. The Papanicolaou test is not recommended because of poor clinical correlation. First-line treatment is low-dose local vaginal estrogen therapy, which has proven efficacy and safety. Serum estrogen levels are not significantly affected with the exception of creams containing high-dose conjugated equine estrogens. Other options have yet to be approved for use in Canada but show promise. Conclusion: GSM is a debilitating and common condition that suffers from barriers to diagnosis and treatment. Current treatments are well tolerated, rewarding, and effective with rapid onset.

Hormone Replacement Therapy for Surgical Menopause: Is there an Ideal Drug? A Comparative Study of Conjugated Equine Estrogens and Tibolone

ABSTRACT Objective To compare the effects of continuous combined conjugated equine estrogens (CEE) with those of tibolone on symptom control, lipid profile, and tolerability in women with surgical menopause. Materials and methods This was a randomized controlled trial study conducted in the Department of Obstetrics and Gynaecology of Global Rainbow Hospital Pvt. Ltd., Agra (2014–2016) comprising 150 women. Generally, healthy postmenopausal women having undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy irrespective of age and indication of surgery and no absolute contraindications to hormone replacement therapy (HRT) or tibolone were enrolled. Fifty subjects did not receive any HRT, 50 were treated with CEE 0.625 mg, and 50 were given tibolone 2.5 mg for 13 treatment cycles, each of 28 days. Results were statistically analyzed regarding drug efficacy in amelioration of menopausal symptoms and side effects at follow-up periods of 1, 6, and 12 months. Results A total of 150 subjects were enrolled and received at least one dose of the study medication, of which 134 (89.4%) subjects completed the study (n = 40 in CEE and n = 44 in tibolone). The incidence of postmenopausal symptoms decreased significantly over time in the treatment groups, compared with baseline, including significant decreases in the incidence of urogenital and sexual health symptoms, with p-values 0.001 and 0.004 in cases that received CEE and tibolone respectively. Significant differences in symptom control (other than hot flashes) were observed between treatment groups in a few different cycles for different symptoms, but no consistent or clinically significant trends were observed. Significant decreases in total cholesterol (5.6%) and low-density lipoprotein cholesterol (7.5%) were observed at cycle 13, compared with baseline, in the CEE group, and significant decreases in high-density lipoprotein cholesterol (8.5%) and triglycerides (13.7%) were observed at cycle 13, compared with baseline, in the tibolone group. Significant weight gain was observed at cycle 13 in the tibolone group (3.05 kg), compared with the CEE group (0.96 kg). The incidences of adverse events were similar in both treatment groups. Conclusion Women treated with CEE and tibolone showed significant improvement of climacteric symptoms, including urogenital and sexual health symptoms. Treatment with either preparation significantly improved subjective wellbeing, vasomotor symptoms, and vaginal dryness. The CEE and tibolone each induced a different mix of beneficial changes in the lipid profile. It is seen that tibolone seems to be effective on estrogen withdrawal symptoms and with its acceptable androgenic side effects can be an appropriate selection for HRT in postmenopausal women with decreased sexual desire. How to cite this article Gupta N. Hormone Replacement Therapy for Surgical Menopause: Is there an Ideal Drug? A Comparative Study of Conjugated Equine Estrogens and Tibolone. J South Asian Feder Menopause Soc 2017;5(1):11-15.