Nanostructured transdermal hormone replacement therapy for relieving menopausal symptoms: a confocal Raman spectroscopy study

Marco Antonio Botelho, Dinalva Brito Queiroz, Gisele Barros, Stela Guerreiro, Pierre Fechine, Sonia Umbelino, Arão Lyra, Boniek Borges, Allan Freitas, Danilo Caldas de Queiroz, Ronaldo Ruela, Jackson Guedes Almeida, Lucindo Quintans Jr, Marco Antonio Botelho, Dinalva Brito Queiroz, Gisele Barros, Stela Guerreiro, Pierre Fechine, Sonia Umbelino, Arão Lyra, Boniek Borges, Allan Freitas, Danilo Caldas de Queiroz, Ronaldo Ruela, Jackson Guedes Almeida, Lucindo Quintans Jr

Abstract

Objective: To determine the safety and efficacy of a transdermal nanostructured formulation of progesterone (10%) combined with estriol (0.1%) + estradiol (0.25%) for relieving postmenopausal symptoms.

Methods: A total of 66 postmenopausal Brazilian women with climacteric symptoms of natural menopause received transdermal nanostructured formulations of progesterone and estrogens in the forearm daily for 60 months to mimic the normal ovarian secretory pattern. Confocal Raman spectroscopy of hormones in skin layers was performed. Clinical parameters, serum concentrations of estradiol and follicle-stimulating hormone, blood pressure, BI-RADS classification from bilateral mammography, and symptomatic relief were compared between baseline and 60 months post-treatment. Clinicaltrials.gov: NCT02033512.

Results: An improvement in climacteric symptoms was reported in 92.5% of women evaluated before and after 60 months of treatment. The serum concentrations of estradiol and follicle-stimulating hormone changed significantly (p<0.05) after treatment; the values of serum follicle-stimulating hormone decreased after 60 months from 82.04±4.9 to 57.12±4.1 IU/mL. A bilateral mammography assessment of the breasts revealed normal results in all women. No adverse health-related events were attributed to this hormone replacement therapy protocol.

Conclusion: The nanostructured formulation is safe and effective in re-establishing optimal serum levels of estradiol and follicle-stimulating hormone and relieving the symptoms of menopause. This transdermal hormone replacement therapy may alleviate climacteric symptoms in postmenopausal women.

Conflict of interest statement

No potential conflict of interest was reported.

Figures

Figure 1
Figure 1
Skin layer analysis - concentration of progesterone nanoparticles in the dermis. The skin depth concentration was measured at 1, 3, 6, 21, and 24 hours after transdermal application. (Model 3510 SCA, River Diagnostics, Rotterdam, The Netherlands).
Figure 2
Figure 2
Effect of the transdermal nanoemulsion on estradiol serum levels (ESLs) in 66 women receiving transdermal hormone replacement therapy (THRT) for 60 months. The nanoemulsion was administered topically in postmenopausal women. Mean values are shown, and the SEs are indicated by error bars. *p<0.05 was considered significantly different from baseline values (Student's t-test).
Figure 3
Figure 3
Effect of nanoparticle formulation emulsion on FSH serum concentration in 66 women receiving transdermal hormone replacement therapy (THRT) for 60 months. The nanoemulsion was administered topically to postmenopausal women. Mean values are shown, and the SEs are indicated by error bars. *p<0.05 was considered significantly different from baseline values (Student's t-test).
Figure 4
Figure 4
A. Zeta potential analysis on Progesterone (10%) formulation administered topically in 66 postmenopausal women submitted to THRT during 60 months. Zetasizer Nano ZS90 (Malvern Instruments Ltd., UK, England). B. Zeta potential analysis on Progesterone (10%) formulation administered topically in 66 postmenopausal women submitted to THRT during 60 months. Zetasizer Nano ZS90 (Malvern Instruments Ltd., UK, England). C. Scanning Electron Microscopic Analyses of progesterone particles morphology administered topically in 66 postmenopausal women submitted to THRT during 60 months (TESCAN SEM-Model VEGA/XMU, Brno, Czech Republic). D. Raman Confocal spectroscopy analysis on skin layers. The skin depth concentration of progesterone was measured at 1, 3, 6, 21 and 24 hours in Stratum Cornum (SC); Viable Epidermis (EPI); Dermis (D) after transdermal application. Mean values are shown, SEM is indicated by error bars. *p<0.05 was considered significantly different compared to the first hour values (Model 3510 SCA, River Diagnostics, Rotterdam, The Netherlands).

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