Testosterone Cypionate Withdrawal and Discontinuation Syndrome: What to Expect When You Stop

What the label actually says

The Drug Abuse and Dependence section describes withdrawal symptoms after supratherapeutic testosterone use: 'Individuals taking supratherapeutic doses of testosterone may experience withdrawal symptoms lasting for weeks or months which include depressed mood, major depression, fatigue, craving, restlessness, irritability, anorexia, insomnia, decreased libido and hypogonadotropic hypogonadism' [1].

The same section lists the behaviors the label associates with anabolic steroid addiction: taking greater doses than prescribed, continuing use despite medical and social problems caused by it, spending significant time obtaining the drug when supplies are interrupted, giving drug use higher priority than other obligations, and having difficulty stopping despite wanting to [1].

The Depo-Testosterone label identifies testosterone as a Schedule III controlled substance [1].

How exogenous testosterone suppresses your own

While exogenous androgens are being given, the body's own testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH), and at large doses sperm production may also be suppressed through feedback inhibition of follicle stimulating hormone (FSH) [1].

Testosterone cypionate is an oil-soluble ester. Injected into muscle it is absorbed slowly from the oil depot, which is why the label can space injections two to four weeks apart, and its half-life after intramuscular injection is about 8 days [1]. The label does not give a timeline for how quickly that pituitary signaling recovers after the last injection [1].

Whose withdrawal the reports describe

The label notes that abuse usually involves doses higher than recommended, often combined with other anabolic androgenic steroids [1]. Two studies fill in the dose picture. In a randomized trial, 31 healthy men received 100, 250 or 500 mg of testosterone cypionate per week for 14 weekly injections; pharmacokinetic modeling suggested that suppression of endogenous testosterone secretion, LH synthesis and spermatogenesis was more severe and lasted longer in the 250 mg and 500 mg groups [2]. A separate review reports that about 30% of anabolic steroid users appear to develop a dependence syndrome, and that both humans and animals show a well documented withdrawal syndrome [3].

The randomized trial used abuse-level doses in healthy volunteers, and the review covers anabolic steroid users. How often someone on the labeled replacement range of 50 to 400 mg every two to four weeks [1] notices anything after a final injection is not something the label or these studies put a number on.

Timeline after the last injection

Three facts set the frame: the labeled dosing interval is two to four weeks [1], the half-life after intramuscular injection is about 8 days [1], and the label describes withdrawal after supratherapeutic doses as lasting weeks to months [1]. The label gives that range, tied to supratherapeutic doses, rather than a day-by-day schedule.

Mood and psychiatric symptoms

The label lists depression and anxiety among adverse reactions seen during treatment [1], and depressed mood and major depression among the withdrawal symptoms after supratherapeutic doses [1]. The abuse section lists serious psychiatric manifestations including major depression, mania, paranoia, psychosis, delusions, hallucinations, hostility and aggression, and notes these reactions are reported voluntarily from a population of uncertain size, so their frequency cannot be reliably estimated [1].

Fertility and sperm recovery

The Depo-Testosterone label states that at large doses of exogenous androgens sperm production may be suppressed through FSH feedback, possibly lowering sperm count, and that oligospermia may occur at high dosages [1].

Recovery data come mostly from men whose sperm production was suppressed by hormones rather than from men with hypogonadism. An integrated analysis of 30 studies, 1,549 healthy men with normal hormone function using androgen or androgen-progestin contraception, found a median of 3.4 months for sperm concentration to return to 20 million per mL; 67% recovered by 6 months, 90% by 12 months, 96% by 16 months and 100% by 24 months, with faster recovery after shorter-acting testosterone and shorter treatment [4].

Among 66 men treated for infertility after testosterone use, who stopped testosterone and received high-dose hCG plus a selective estrogen receptor modulator, 46 (70%) reached a total motile count above 5 million within 12 months; 64.8% of men who had been azoospermic did, compared with 91.7% of men who had been cryptozoospermic, and older age and longer testosterone use predicted slower recovery [5]. The Endocrine Society guideline recommends against starting testosterone therapy in men who plan to have children in the near term [6].

What has been studied for recovery

In a case series of 49 men with azoospermia or severe oligospermia (under 1 million sperm per mL) while taking exogenous testosterone, 47 men (95.9%) had sperm production return or improve while receiving hCG 3,000 units subcutaneously every other day plus clomiphene, tamoxifen, anastrozole or recombinant FSH, at an average of 4.6 months, with a mean first density of 22.6 million per mL [7]. The study did not compare their recovery with untreated men.

A review of anabolic steroid-induced hypogonadism found that symptomatic hypogonadism can follow anabolic steroid use and may depend on dose, duration and type of steroid, and that management options are judicious testosterone replacement, hCG and selective estrogen receptor modulators; no quality studies met the criteria for a meta-analysis [8].