Estrogen Mediates Metabolic Syndrome-Induced Erectile Dysfunction: A Study in the Rabbit

Linda Vignozzi MD, PhD; Sandra Filippi PhD; Paolo Comeglio PhD; Ilaria Cellai PhD; Annamaria Morelli PhD; Matilde Marchetta PhD; and Mario Maggi MD

ONLINE: September 21, 2014 – The Journal of Sexual Medicine

DOI: 10.1111/jsm.12695


Past research has found that an excess of estrogen can lead to reproductive health problems in both animal and human males. Estrogen receptor α (ERα) can mediate these problems in fetuses and infants.

However, there is limited data on the effects of excess estrogen in adult penile function.

This study examined the role of estrogens in erectile dysfunction associated with metabolic syndrome (MetS) in rabbits.

Methods and Materials

Male New Zealand White rabbits were used in this study. The rabbits were fed a standard rabbit diet for one week. Then, they were randomly assigned to a control group or a treatment group. For the next twelve weeks, the control group continued with the standard diet. The treatment group ate a high-fat diet (HFD).

The treatment group was divided into two subgroups. One subgroup received tamoxifen. The other was given testosterone.

Blood samples were taken at baseline and at the twelve-week point. These samples were analyzed for glucose, total cholesterol, triglycerides, testosterone (T), and 17β-estradiol (E2). Blood pressure was also taken.

At this time, the rabbits were sacrificed. The corpora cavernosa, seminal vesicles, prostate, and visceral fat were harvested.

The researchers also conducted the following evaluations: oral glucose tolerance test, in vitro contractibility studies, rabbit penile smooth muscle cell cultures, and quantitative mRNA expression assay.


Rabbits who ate the HFD had symptoms similar to those of MetS in humans, including hyperglycemia, high triglycerides, high cholesterol, increased blood pressure, and visceral fat accumulation. These rabbits also had a sex steroid imbalance, with decreased testosterone and increased 17β-E2 plasma levels.

Other findings included the following:

• Genes associated with erections were influenced by E2 but not testosterone.

• Increasing concentrations of circulating E2 were negatively associated with acetylcholine (Ach)-induced relaxation. They were positively associated with responsiveness to sodium nitroprusside (SNP).

• A positive relationship between circulating T levels and Ach-induced relaxation was found.

• HFD rabbits that were given testosterone had improved glycemia and glucose tolerance and a significant reduction in visceral fat. In these rabbits, circulating E2 was completely restored to the same level as rabbits fed the regular diet.

• Ach-induced relaxation and SNP responsiveness were normalized by both T and tamoxifen in HFD rabbits.

• 17β-E2 effects were reverted by tamoxifen and restored up to control level.


The authors noted that in this animal model, high E2 rather than low T was associated with an impairment of endothelium-dependent relaxation and ED. In vivo treatment with T and tamoxifen partially restored HFD-induced ED.

They added, that both HFD-induced low T and high E2 levels were associated with Ach hyporesponsiveness in rabbit corpora cavernosa. But after further analysis, only E2 retained a significant and negative association with Ach responsiveness.

“By iterative modeling, we now show that E2, more than T or MetS, were negatively associated with almost all of the nitrergic and RhoA/ROCK signaling genes,” they wrote.

They also found that penile expression of the smooth muscle marker αSMA decreased as a function of E2 levels, but not T levels.

They suggested that both increased E2 and a reduced penile smooth muscle representation “cooperate in impairing erectile function in HFD rabbits.”

It is possible that T dosing normalized HFD-induced hyperestrogenism because T reduced visceral fat and “significantly blunted” ERα expression. Tamoxifen also caused an increase in testosterone levels.

“Considering that tamoxifen increases T and T decreases E2 and ERα, it is difficult to isolate the specific role of each of these two sex steroids on penile erection,” the authors wrote.

Overall, they concluded: “This study demonstrates, for the first time, that HFD-induced ED is more associated with a high E2, rather than a low T, milieu. HFD-induced ED is partially restored by in vivo treatment not only with T but also with the nonsteroidal ER antagonist, tamoxifen.”