Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality

doi:10.1016/0378-5122(94)00898-H

Maturitas

Volume 21, Issue 3, April 1995, Pages 227-236

https://doi.org/10.1016/0378-5122(94)00898-H Get rights and content

Abstract

To investigate the role of androgens in increasing bone density and improving low libido in postmenopausal women, we have studied the long-term effects of estradiol and testosterone implants on bone mineral density and sexuality in a prospective, 2 year, single-blind randomised trial. Thirty-four postmenopausal volunteers were randomised to treatment with either estradiol implants 50 mg alone (E) or estradiol 50 mg plus testosterone 50 mg (E&T), administered 3-monthly for 2 years. Cyclical oral progestins were taken by those women with an intact uterus. Thirty-two women completed the study. BMD (DEXA) of total body, lumbar vertebrae (L1–L4) and hip area increased significantly in both treatment groups. BMD increased more rapidly in the testosterone treated group at all sites. A substantially greater increase in BMD occurred in the E&T group for total body (P < 0.008), vertebral L1–L4 (P < 0.001) and trochanteric (P < 0.005) measurements. All sexual parameters (Sabbatsberg sexual self-rating scale) improved significantly in both groups. Addition of testosterone resulted in a significantly greater improvement compared to E for sexual activity (P < 0.03), satisfaction (P < 0.03), pleasure (P<0.01), orgasm (P < 0.035) and relevancy (P < 0.05). Total cholesterol and LDL-cholesterol fell in both groups as did total body fat. Total body fat-free mass (DEXA, anthropometry, impedance) increased in the E&T group only. We concluded that in postmenopausal women, treatment with combined estradiol and testosterone implants was more effective in increasing bone mineral density in the hip and lumbar spine than estradiol implants alone. Significantly greater improvement in sexuality was observed with combined therapy, verifying the therapeutic value of testosterone implants for diminished libido in postmenopausal women. The favourable estrogenic effects on lipids were preserved in women treated with T, in association with beneficial changes in body composition.

References (29)

RB Mazess et al.
Monitoring skeletal response to estrogen
Am J Obstet Gynecol.
(1989)
S Campbell et al.
Estrogen therapy and the menopausal syndrome
Clin Obstet Gynecol
(1977)
B Maoz et al.
The effects of estrogen therapy on the sex life in postmenopausal women
Maturitas
(1980)
JWW Studd et al.
The Climacteric
Clin Obstet Gynecol
(1977)
HG Burger et al.
The management of persistent symptoms with estradiol-testosterone implants: clinical, lipid and hormonal results
Maturitas
(1984)
RB Mazess et al.
Dual energy X-ray absorptiometry for total body and regional bone mineral soft tissue component
Am J Clin Nutr
(1990)
AG Need et al.
Effects of nandrolone decanoate and antiresorptive therapy on vertebral density in osteoporotic postmenopausal women
Arch Intern Med
(1989)
M Savvas et al.
Skeletal effects of oral estrogen compared with subcutaneous estrogen and testosterone in postmenopausal women
Br Med J
(1988)
T Garnett et al.
The effects of plasma estradiol levels on increases in vertebral and femoral bone density following therapy with estradiol and estradiol and testosterone implants
Obstet Gynecol
(1992)
WH Utian
The true clinical features of postmenopausal oophorectomy and their response to estrogen therapy
S Afr Med J
(1972)

PA Van Keep et al.

Sexual relations in the ageing female

JWW Studd et al.

Estradiol and testosterone implants in the treatment of psychosexual problems in the postmenopausal woman

Br J Obstet Gynecol

(1977)

HG Burger et al.

Effect of combined implants of estradiol and testosterone on libido in postmenopausal women

Br Med J

(1987)

MGT Dow et al.

Hormonal treatment of sexual unresponsiveness in postmenopausal women

Br J Obstet Gynecol.

(1983)

Cited by (473)

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women
2021, Journal of Sexual Medicine
The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD).
To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD.
The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method.
A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up.
Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data.
This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring.
This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging.
Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.
Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2021;18:849–867.
Use of Testosterone in Postmenopausal Women
2021, Endocrinology and Metabolism Clinics of North America
Methodological Challenges in Studying Testosterone Therapies for Hypoactive Sexual Desire Disorder in Women
2020, Journal of Sexual Medicine
Testosterone has been studied for its benefits on sexual health for decades. The research regarding testosterone in women has produced evidence that this is a potential treatment for women suffering from female sexual dysfunction. There are several limitations of the testosterone trials that can affect their interpretation and challenges posed by some regulatory agencies that have prevented approval of any testosterone treatment for women in several countries.
To summarize the challenges of testosterone trials in terms of study populations, patient-reported outcomes, validated instruments in research, confounders, and regulatory barriers.
A thorough review of published data on testosterone for the treatment of women's sexual health problems was undertaken. A detailed evaluation of the limitations of these trials was conducted and incorporated with the published evidence on the regulatory processes involved in moving testosterone from clinical research to drug approval.
Main outcome measures are assessment of clinical trial populations, survey tools, confounders, and regulatory barriers.
There is some heterogeneity of study populations included in testosterone trials in women. Similarly, there have been differences in instruments used to assess patient-reported outcomes and often minimal control for potential confounders. The regulatory agency had posed a challenge to approve any testosterone treatment for women based on unproven concerns and a lack of regulatory guidance for drug developers.
There is strong evidence that shows testosterone is effective for treating sexual health concerns in the women included in clinical trials.
Strengths include thorough review of published literature and trial design for sexual health concerns. Limitations include being restricted to English Language publications and not having access to unpublished clinical trial data.
Testosterone trials in women have been limited by homogeneity in the study populations and outcomes measured. Drug development has been hampered by inconsistent regulatory barriers.
Rowen TS, Davis SR, Parish S, et al. Methodological Challenges in Studying Testosterone Therapies for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2020;17:585–594.
Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data
2019, The Lancet Diabetes and Endocrinology
The benefits and risks of testosterone treatment for women with diminished sexual wellbeing remain controversial. We did a systematic review and meta-analysis to assess potential benefits and risks of testosterone for women.
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for blinded, randomised controlled trials of testosterone treatment of at least 12 weeks' duration completed between Jan 1, 1990, and Dec 10, 2018. We also searched drug registration applications to the European Medicine Agency and the US Food and Drug Administration to identify any unpublished data. Primary outcomes were the effects of testosterone on sexual function, cardiometabolic variables, cognitive measures, and musculoskeletal health. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42018104073.
Our search strategy retrieved 46 reports of 36 randomised controlled trials comprising 8480 participants. Our meta-analysis showed that, compared with placebo or a comparator (eg, oestrogen, with or without progestogen), testosterone significantly increased sexual function, including satisfactory sexual event frequency (mean difference 0·85, 95% CI 0·52 to 1·18), sexual desire (standardised mean difference 0·36, 95% CI 0·22 to 0·50), pleasure (mean difference 6·86, 95% CI 5·19 to 8·52), arousal (standardised mean difference 0·28, 95% CI 0·21 to 0·35), orgasm (standardised mean difference 0·25, 95% CI 0·18 to 0·32), responsiveness (standardised mean difference 0·28, 95% CI 0·21 to 0·35), and self-image (mean difference 5·64, 95% CI 4·03 to 7·26), and reduced sexual concerns (mean difference 8·99, 95% CI 6·90 to 11·08) and distress (standardised mean difference −0·27, 95% CI −0·36 to −0·17) in postmenopausal women. A significant rise in the amount of LDL-cholesterol, and reductions in the amounts of total cholesterol, HDL-cholesterol, and triglycerides, were seen with testosterone administered orally, but not when administered non-orally (eg, by transdermal patch or cream). An overall increase in weight was recorded with testosterone treatment. No effects of testosterone were reported for body composition, musculoskeletal variables, or cognitive measures, although the number of women who contributed data for these outcomes was small. Testosterone was associated with a significantly greater likelihood of reporting acne and hair growth, but no serious adverse events were recorded.
Testosterone is effective for postmenopausal women with low sexual desire causing distress, with administration via non-oral routes (eg, transdermal application) preferred because of a neutral lipid profile. The effects of testosterone on individual wellbeing and musculoskeletal and cognitive health, as well as long-term safety, warrant further investigation.
Australian National Health and Medical Research Council.
Onset of the Menopause Transition: The Earliest Signs and Symptoms
2018, Obstetrics and Gynecology Clinics of North America
New Possibilities for Hormonal Vaginal Treatment in Menopausal Women
2023, Journal of Clinical Medicine

View all citing articles on Scopus

^☆: Presented at the 7th International Congress on the Menopause; Stockholm, Sweden, June 20–24, 1993 - Abstract Nos. 49 & 432.

View full text

Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality☆

Abstract

Am J Obstet Gynecol.

Clin Obstet Gynecol

Maturitas

Clin Obstet Gynecol

Maturitas

Am J Clin Nutr

Effects of nandrolone decanoate and antiresorptive therapy on vertebral density in osteoporotic postmenopausal women

Arch Intern Med

Skeletal effects of oral estrogen compared with subcutaneous estrogen and testosterone in postmenopausal women

Br Med J

The effects of plasma estradiol levels on increases in vertebral and femoral bone density following therapy with estradiol and estradiol and testosterone implants

Obstet Gynecol

The true clinical features of postmenopausal oophorectomy and their response to estrogen therapy

S Afr Med J

Sexual relations in the ageing female

Estradiol and testosterone implants in the treatment of psychosexual problems in the postmenopausal woman

Br J Obstet Gynecol

Effect of combined implants of estradiol and testosterone on libido in postmenopausal women

Br Med J

Hormonal treatment of sexual unresponsiveness in postmenopausal women

Br J Obstet Gynecol.