Endocrine treatment of gynecomastia

In essence there are two treatment modalities for gynecomastia. One is aimed at treating the relative or absolute excess of estrogen (endocrine treatment). You’ll mostly see the selective estrogen receptor modulator (SERM) tamoxifen (Nolvadex) being used for this, as it has a nice track record for it in the literature.

An issue with endocrine treatment, however, is that it isn’t always as effective. One reason for this is that the gynecomastia changes over time. The tissue will eventually undergo (irreversible) fibrosis and hyalinization [1]. This will effectively render it unresponsive to endocrine treatment. It’s difficult to say how long it will take before gynecomastia becomes unresponsive to endocrine treatment, but the literature mentions 1 year [2] to 2 years [3]. However, some authors have booked success with endocrine treatment in gynecomastia present for more than 2 years [4].

The other very effective option, is surgery. While effective, it can have some downsides. One of them being economical, since it’s quite expensive and tends to not be covered by most health insurances.

In this article I will focus on the endocrine treatment of gynecomastia. As I have described in my earlier article What causes gynecomastia?, the main culprit lies in estrogen action. As such, I will focus on SERMs and aromatase inhibitors (AIs).

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Selective estrogen receptor modulators (SERMs)

To my knowledge, three different SERMs have been used in clinical studies for treating gynecomastia: tamoxifen (Tamoxifen), clomiphene (Clomid), and the lesser known raloxifene. Most of these studies have been in the treatment of pubertal gynecomastia or gynecomastia due to prostate cancer treatment (anti-androgen therapy). However, it doesn’t really seem to matter in regard to what treatment option to pick. Being a bit simplistic, but treatment-wise: gynecomastia is gynecomastia.

Most data available on tamoxifen, and it performs well

A review notes that 10 – 20 mg tamoxifen/Nolvadex daily for 3 – 9 months has shown an efficacy of up to 90 % for the resolution of gynecomastia [3]. Another review mentions that tamoxifen results in partial regression in approximately 80 % and complete regression in about 60 % of cases with gynecomastia [5]. Interestingly, in a recent cohort study including 81 patients with idiopathic gynecomastia, 90.1 % had a compete resolution of their gynecomastia in response to tamoxifen treatment (10 mg daily) [6]. What’s interesting about this study, is that the mean duration of swelling prior to treatment (loosely how long the gyno was present already), was actually longer in those who had complete resolution (22 months) than in those who didn’t (17 months). However, there did seem to be a trend toward a larger size of the gynecomastia (as measured by ultrasound) in those who didn’t achieve complete resolution. Unfortunately, the cohort size was too small to demonstrate a statistical significant difference in gynecomastia size, despite the difference being more than twofold. Nevertheless, it suggests that size, rather than how long it has been present, is a better indicator of success of endocrine therapy in idiopathic gynecomastia. Finally, the high percentage of success in this study might have been related to the duration of treatment. Most studies only last one or a couple of months. The authors of this study therefor write that they led the duration of treatment depend in accordance with a response rather than using a rigid treatment protocol. The mean duration of treatment in those where gynecomastia was resolved was nearly 7 months, with quite some variation (standard deviation of 4.8 months). I guess you could say that patience is a virtue.

What should be kept in mind, is that the situation is different when you develop gynecomastia during an anabolic steroid cycle. If you read on the internet, it seems almost everyone gets gynecomastia during their androgenic anabolic steroid cycle. But what does the literature actually say? Unfortunately, fairly little. The trials ran by Bhasin et al. with dosages up to 600 mg testosterone enanthate weekly up to 20 weeks didn't even list gynecomastia as a side effect. However, one large trial does mention gynecomastia explicitely [7]. A total of 271 subjects received 200 mg testosterone enanthate weekly for a minimum of 6 months. Only 9 (around 3%) of these subjects developed gynecomastia.

The chance of actual gynecomastia might also be higher due to contaminated gear. A recent paper had qualitatively tested 272 samples of AAS for their contents as part of a prospective study in AAS users [8]. The paper notes that 14 % of the samples contained estrogens/progestogens. (Unfortunately no distinction is made between the two. Estradiol valerate was found in samples containing boldenone [personal communication]). Obviously you're at a higher risk of developing gynecomastia if you're administering estrogen.

Anyways, I'm drifting off. In the case you do develop gynecomastia during your cycle, a higher dosage of tamoxifen/Nolvadex than described above might be needed. Tamoxifen functions as a competitive antagonist. So if there's more estrogen, you'll also need more tamoxifen to compete with it in order to obtain the same effect. Ten mg daily seems an appropriate dosage under physiological conditions. However, if gynecomastia occurs during a cycle with testosterone, estradiol levels will obviously be a lot higher. It seems that estradiol levels barely increase further when testosterone levels are increased beyond 100 nmol/L [249]. Which is roughly the concentration you’ll reach with 500 mg testosterone enanthate weekly. Given that a dosage of 75 to 100 mg weekly is approximately in line with physiological concentrations, you could argue that you need to add 10 mg tamoxifen for every 100 mg of testosterone enanthate weekly (up to a maximum of 500 mg). Since the increase in estradiol with increased doses of testosterone isn’t linear, you could say that 30 to 40 mg tamoxifen daily is plenty with high dosages of testosterone (500 mg or more weekly) to treat gynecomastia during a cycle. However, it is also imagineable that some might require more than that, due to differences in metabolism of tamoxifen.

Clomiphene (Clomid) has very little data for gynecomastia

Awfully little can be found on the efficacy of clomiphene for the treatment of gynecomastia. I'm just gonna cite the abstract of the most recent (1983!) trial on it here [10]. Perhaps the reason why there's so little data on it, is because it's not that effective.

Twelve boys, aged 12 to 19 years, with persistent gynecomastia were treated with the antiestrogen, clomiphene citrate, at a dose of 50 mg/day by mouth for one to three months. The mean breast size decreased by 0% to 36%, with only five boys experiencing a reduction of greater than 20%. Five boys subsequently required reduction mammoplasty. Levels of urinary gonadotropins, serum testosterone, and estradiol increased significantly during therapy. Since the ratio of testosterone to estradiol remained unchanged during treatment, the antiestrogen effects were achieved primarily at the level of breast tissue. Clomiphene citrate (Clomid) in a dose of 50 mg/day resulted in only small decreases in persistent pubertal gynecomastia and was not a satisfactory medical therapy for the condition.

Raloxifene has little data too

Raloxifene is a relatively new SERM, belonging to a different class of SERMs than tamoxifen (Nolvadex) and clomiphene (Clomid): benzotiophenes instead of triphenylethylene/chloroethylene derivative. I’ve only been able to find one clinical trial in which raloxifene was used in the treatment of gynecomastia [11]. Unfortunately, it was not a randomized-controlled trial (RCT), but a retrospective chart review, which leaves it open to all sorts of biases rendering it impossible to draw firm conclusions from.

Aromatase inhibitors

Given the central role of estrogens in the development of gynecomastia, aromatase inhibitors (AIs) seem very appealing. After all, they inhibit the enzyme (aromatase) that converts androgens to estrogens. For example, it converts testosterone to the predominant estrogen estradiol. Unfortunately, only a few trials have examined the use of AIs in the treatment of gynecomastia.

In a double-blind RCT, 1 mg anastrozole (an AI; Arimidex) daily was compared to placebo for the treatment of pubertal gynecomastia [12]. The total treatment period was 6 months. At the end of the treatment period, 38.5 % of the patients receiving anastrozole had a response, whereas 31.4 % of those receiving placebo had a response (defined as a >50% reduction in total breast volume after 6 months). This difference between the groups was not statistically significant. Anastrozole did lead to a large increase in the testosterone to estradiol ratio. However, roughly half the subjects had gynecomastia for atleast two years, which renders them less suspectible to respond to endocrine treatment. This might have partly explained the results, assuming anastrozole actually worked.

Other trials also seem to suggest anastrozole doesn’t work well for this. Another situation in which gynecomastia often occurs is that of prostate cancer treatment. More specifically, treatment with the anti-androgen bicalutamide. In a double-blind RCT, prostate cancer patients received either bicalutamide with a placebo or in combination with tamoxifen (20 mg daily) or anastrozole (1 mg daily) for 48 weeks [13]. Gynecomastia developed in 73 % of patients receiving placebo, 10 % of patients receiving tamoxifen and 51 % of patients receiving anastrozole. As such, anastrozole seems ill-suited in the prevention of developing gynecomastia, whereas tamoxifen appears very effective. It should be noted that an absolute deficiency of androgen action is the hallmark in bicalutamide treatment rather than estrogen excess (as is the case with AAS usage). Nevertheless, tamoxifen demonstrated great efficacy.

In accordance with these findings, Saltzstein et al. found tamoxifen to be very effective in both the prevention and treatment of bicalutamide-induced gynecomastia, whereas anastrozole showed only minimal efficacy [14].

I have been unable to find clinical trials evaluating the efficacy of the two other common AIs, exemestane or letrozole, for the treatment of gynecomastia. Given the similar potency of these two aromatase inhibitors compared to anastrozole in reducing serum estrogen (see my article The efficacy of aromatase inhibitors in men), it seems unlikely they’ll be more beneficial than anastrozole in this regard.

Concluding: tamoxifen (Nolvadex) is the primary drug for treatment of gynecomastia

Concluding, tamoxifen (Nolvadex) is the mainstay of endocrine treatment for gynecomastia. Aromatase inhibitors lack ample evidence and the scarce evidence there is suggests they are only minimally effective. Considering the reasonable % of AAS samples that might also contain estrogen (and thus not requiring any conversion by aromatase), AIs seem even less appealing.


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