Testosterone Enanthate Withdrawal and Discontinuation Syndrome: Side Effects Explained

What the label says about stopping testosterone enanthate

The prescribing information for testosterone enanthate injection covers withdrawal in a short passage inside its Drug Abuse and Dependence section. It states that individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months, and names them: depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism [1]. The same section states that drug dependence in individuals using approved doses of testosterone for approved indications has not been documented [1].

Elsewhere the label states that testosterone is a Schedule III controlled substance, and it tells prescribers to consider testosterone and anabolic steroid abuse in patients who present with serious cardiovascular or psychiatric adverse events [1].

How enanthate suppresses your own testosterone

Testosterone enanthate is an ester of testosterone in oil, injected deep into the gluteal muscle. The label says total doses above 400 mg per month are generally not required because of the prolonged action of the preparation, and that injections more often than every two weeks are rarely indicated [1].

While testosterone enanthate is being used, it suppresses the body's own testosterone production through feedback inhibition of pituitary luteinizing hormone, and at large doses it also suppresses follicle-stimulating hormone, which suppresses sperm production [1].

Symptoms the label lists

The withdrawal list mixes psychological and physical symptoms: depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism [1]. Elsewhere the same label lists anxiety, depression, increased or decreased libido and headache among reported adverse reactions [1], and among abuse-related reactions it lists testicular atrophy, subfertility and infertility [1].

How long withdrawal lasts

The timeline data come from men who used anabolic-androgenic steroids, usually at high doses and often in combination. In a cross-sectional study of 24 former long-term steroid users compared with 36 weightlifters who had never used them, five of the 19 untreated former users had serum testosterone below 200 ng/dL despite having stopped for 3 to 26 months [2]. Those men also had smaller testicular volumes and lower scores on the sexual desire subscale of the International Index of Erectile Function than the comparison group [2].

That study measured men at a single point in time, and its authors concluded that steroid-withdrawal hypogonadism appears to be common and frequently prolonged in long-term misusers [2]. It does not give a timeline for men stopping prescribed intramuscular enanthate at replacement doses.

Depression and mood during withdrawal

This has been measured in steroid users. In the same study of 24 former long-term users, seven (29%) had experienced a major depressive episode during steroid withdrawal, and four of those seven had not had a major depressive episode at any other time [2]. Two men (8%) had not regained normal libidinal or erectile function despite adequate replacement testosterone [2].

The enanthate label lists depression and anxiety among adverse reactions to the drug itself [1], and it lists serious psychiatric manifestations, major depression among them, among reactions reported with anabolic-androgenic steroid abuse [1].

Libido, erections and testicular size

Decreased libido appears in the label's withdrawal list [1]. In the 24-user study, untreated former users scored lower on the sexual desire subscale than non-users, an estimated difference of 2.4 points on a 10-point scale [2]. Their testicular volume was also smaller, by an estimated 2.3 mL [2]. The enanthate label lists testicular atrophy among abuse-related reactions [1].

Sperm and fertility after stopping

Testosterone suppresses sperm production through FSH feedback, and the enanthate label says that oligospermia may occur at high dosages [1].

For how quickly sperm returns, the data come from a different setting: hormonal male contraception. An integrated analysis of 30 studies in 1,549 healthy men with normal testosterone found a median of 3.4 months for sperm concentration to recover to 20 million per mL, with faster recovery after shorter treatment and shorter-acting testosterone preparations [3]. Those were healthy volunteers on experimental contraceptive regimens, not men with hypogonadism stopping prescribed enanthate.

Two case series describe sperm outcomes in men who had been using testosterone and had fertility problems, both during treatment given to restore fertility. In a retrospective series of 49 men with azoospermia or severe oligospermia while on exogenous testosterone, sperm production returned or counts improved in 47 of 49 men (95.9%) receiving human chorionic gonadotropin 3,000 units subcutaneously every other day plus clomiphene, tamoxifen, anastrozole or recombinant FSH, averaging 4.6 months, with a mean first sperm density of 22.6 million/mL and no significant difference by type of testosterone used [4]. The study did not compare that treatment with recovery without it. In a second series of 66 men given high-dose hCG plus a selective estrogen receptor modulator after stopping testosterone, 46 (70%) reached a total motile count above 5 million within 12 months; older age and longer testosterone use predicted slower recovery [5].

hCG and clomiphene: what the studies show

A 2014 review of anabolic steroid-induced hypogonadism found no quality studies that met meta-analysis criteria, and described management options as judicious testosterone replacement, hCG, and selective estrogen receptor modulators [6].

For clomiphene, a prospective study of 36 men with hypogonadism (total testosterone under 300 ng/dL) given 25 mg daily found mean testosterone rose from 247.6 to 610.0 ng/dL by the first follow-up at 4 to 6 weeks, and the testosterone-to-estradiol ratio improved from 8.7 to 14.2; no side effects were reported [7]. That was a prospective cohort without a comparison group [7].

Tapering

The enanthate label gives dosing intervals and no tapering schedule [1]. Its indication is replacement in men whose own testosterone production is deficient, from primary hypogonadism (testicular failure) or hypogonadotropic hypogonadism (pituitary or hypothalamic causes) [1]. Where the cause of that deficiency persists, stopping replacement leaves it untreated.