Testosterone & young females: What is known about lifelong effects?

by Kerry Smith, MD

Kerry Smith [a pseudonym], MD, is a board-certified internist in the US who has been practicing since 2004. She is the mother of several children, including a 12-year-old daughter who suddenly developed the notion that she is transgender after being exposed to the idea in her 6th grade classroom. It was this development that led Dr. Smith to research the protocol for medical transition of children. She believes that most physicians are blissfully unaware, as she recently was, of the current standards which aggressively promote unstudied and off-label irreversible medical interventions in children too young to drink, smoke, vote, drive, consent to sex, or even watch an R-rated movie.

Dr. Smith is available to interact in the comments section of her article.

---

What are the risks of giving testosterone to a female for a lifetime?

As the mother of a girl trying on a trans identity, and as a practicing physician, I need an answer to this question.

I’m not the only one. Every day more of us join this club, as the rate of girls questioning their “gender identity” continues to skyrocket, outstripping boys at a previously unimaginable pace. Surely, those who advocate for the medical interventions known as “transitioning” must have a risk-benefit analysis available for parents and patients, before committing young people to a lifetime of pharmaceutical (and potentially surgical) treatment for a poorly defined psychiatric condition?

As a physician who has sworn to do no harm, that’s what I would have assumed.

As it turns out, the WPATH-inspired standard of care, adopted by the US Endocrine Society, has pushed boldly ahead where no medical society has gone before, promoting radical, irreversible body modifications for adolescents using powerful, off-label hormone regimens in the absence of any longterm data about safety.

They are perfectly open about this choice, stating in the standards:

These recommendations place a high value on avoiding the increasing likelihood of an unsatisfactory physical change when secondary sexual characteristics have become manifest and irreversible, as well as a high value on offering the adolescent the experience of the desired gender. These recommendations place a lower value on avoiding potential harm from early hormone therapy.

I suppose it is considered “transphobic” of parents to persist in the nit-picky demand for actual data about what that “potential harm” might consist of, but so be it. Teenagers have always resisted parental concerns about their risky activities. Last time I checked, that didn’t keep us from trying to stop them from using dangerous drugs. Why should testosterone (a schedule III drug in the same category as Suboxone and ketamine) get a free pass?

Sex hormones have a long and checkered history in the US, having been widely celebrated as the fountain of youth before falling from grace after studies belatedly showed multiple adverse health outcomes. This was most striking when the evidence from huge studies WHI, HERS and HERS II demonstrated that, contrary to what earlier observational studies seemed to show, hormone replacement therapy for postmenopausal women actually increased rather than decreased the risk of heart attack, stroke and cancer.

Testosterone had its day in the sun as well, being prescribed not just for the medical condition of hypogonadism, but gleefully promoted as a panacea for the vitality and wellbeing of aging men, for the supposed diagnosis of “low T.” Recently the serious risks of this approach have been described, including increased heart attack and stroke; the FDA eventually placed a warning on testosterone products, and lawsuits are underway; however the shameless promotion to men continues unabated.

As a physician, my first stop for drug information is usually the evidence-based clinical resource UpToDate, which contains full prescribing information for medications available in the US and Canada including dosing, indications, risks, interactions, and other details. I reviewed the entry on testosterone and found that, to my surprise, there is no mention of any suggested dosing regimens for female to male transsexuals.

In the US, once a drug is FDA approved for one use, it is often used “off-label” for other conditions, which is a generally accepted practice. These common, accepted off-label uses will be listed in resources such as UpToDate along with relevant dosing information and warnings. For example, the entry for modafinil, a stimulant, has dosing information listed for the FDA approved indications of narcolepsy, obstructive sleep apnea, and shift-work sleep disorder, as well as for the off-label indications of ADHD, cancer related fatigue, major depressive disorder, and multiple sclerosis related fatigue.

In contrast, the UpToDate entry for testosterone makes no mention of any approved or off-label use for the treatment of transgenderism or gender dysphoria. The only indication for testosterone in females listed is for the adjuvant treatment of postmenopausal women with metastatic breast cancer.

I then checked the FDA prescribing information for Depo-Testosterone (injection) and Androgel (topical), and found a total lack of any reference to use in females for any purpose whatsoever.

Testosterone:  Schedule-III controlled substance. The US FDA doesn’t acknowledge or mention its use, on- or off-label, for FTMs

This absence speaks volumes. While the WPATH Standards of Care would have us believe that “[f]eminizing/masculinizing hormone therapy – the administration of exogenous endocrine agents to induce feminizing or masculinizing changes – is a medically necessary intervention for many transsexual, transgender, and gender nonconforming individuals with gender dysphoria,” the reality is that this treatment is so far out of the mainstream of modern medical standards that it is not yet anywhere reflected in basic prescribing reference materials, even as an off-label use.

Because “transgender medicine” is a new field, there is as yet no meaningful body of data that can definitively answer the question of what risks my daughter might face if she embarks on decades of testosterone injections. Studies promoting this treatment as “safe and effective” are generally limited to a few dozen patients and a year or two of follow up. A review article in the Lancet published in April 2016 touted as providing “an evidence-based overview of the benefits, risks, and effects of testosterone therapy in transgender men” observed that “testosterone decreases HDL cholesterol, increases triglycerides, might increase systolic blood pressure, and might increase the incidence of [type 2] diabetes and metabolic syndrome” but was forced to ultimately conclude that the long term effects are largely unknown due to “a paucity of high-quality data” in this area, a disclaimer found in most articles regarding cross-sex hormone treatment.

The desired effects of testosterone for transgender-identified females are the development of male secondary sex characteristics: hair growth on the face and body, changes in bone structure, increased muscle mass, redistribution/decrease of body fat, deepening of the voice, cessation of menstruation, decreased fertility and clitoral growth are all expected. Of note, even these desired effects may not live up to the hype; clitoral growth can cause pain or numbness and, in some cases, appears to lead to difficulty attaining orgasm; voice changes may not reach the desired pitch, leading some patients to seek out voice deepening surgery; some reports suggest increased muscle mass on a female frame can lead to thoracic outlet syndrome.

Of these effects, the changes to body composition, menstruation and fertility may be reversible (if testosterone is started post-puberty; if administered immediately after puberty blockers, irreversible sterility is the norm). Though testosterone is a known teratogen, there is no shortage of glamorous stories celebrating transmen who manage to conceive and give birth after stopping testosterone. However, changes to voice, bone structure, hair distribution and genitals are usually permanent, even if the hormone is stopped.

Then there are the undesired effects. The most commonly reported one is acne, which is often severe enough to require treatment. Male pattern baldness is also unmasked in those who are genetically predisposed.

More important than cosmetic effects are the changes in markers for cardiovascular disease. Studies tend to show that exogenous testosterone increases LDL (bad cholesterol), lowers HDL (good cholesterol), increases erythrocytes (red blood cells) potentially leading to venous thromboembolism (blood clots) from polycythemia, and increases blood pressure. It has also been shown to increase fluid retention which can contribute to heart failure.

Studies suggest as well that in women (but not men), higher endogenous testosterone levels correlate with insulin resistance and the development of diabetes, and studies suggest that adding testosterone in the form of a drug may increase risk for diabetes.

Even in male patients, studies clearly indicate that testosterone therapy increases the risk of cardiovascular disease including heart attack. One review article notes dryly:

“The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy.” [emphasis added.]

In other words, all studies showed an increase in cardiovascular disease, but this effect was “less prominent” in Big Pharma funded studies. What a surprising coincidence!

Testosterone may cause mood changes. Small studies suggest testosterone treatment in transmen can increase anger, which makes sense, given that abuse of testosterone by bodybuilders is known to sometimes result in “roid rage,” a condition of unchecked anger and aggression. One article reports a case of late onset psychosis associated with testosterone use in a trans-identified female, in whom no other cause could be found.

Testosterone has also been associated with liver damage or tumors, though more often in oral formulations rather than the injectables favored by transgender medicine practitioners. It has been known to impair kidney function. It has been shown to impair mitochondrial function leading to oxidative stress. The list of recommended laboratory tests for monitoring is long.

The effects of testosterone on the ovaries and uterus are not well defined. Early research suggested testosterone administration causes enlarged and cystic ovaries similar to what is seen in polycystic ovary syndrome. While studies in postmenopausal women suggest that testosterone does not stimulate abnormal growth of the endometrium (uterine lining), small studies of young FTM patients suggest that in younger females, testosterone administration does induce proliferative changes in the endometrium, which could theoretically progress to cancer. Cases of ovarian cancer have been noted in females treated with testosterone. These changes to the ovaries and endometrium explain why removal of the uterus and ovaries are often suggested for FTM patients on long term testosterone treatment, though there is no medical consensus on this as there is minimal data.

There is some experience giving testosterone off-label to postmenopausal women for hypoactive sexual desire disorder (HSDD); indeed this treatment is still promoted online and prescribed by some physicians. However, despite promising results for women’s libidos, studies suggest that even low dose testosterone may increase risks for endometrial and breast cancer, and as of yet there is no FDA approval for any form of testosterone for this indication.

So, the state of the art of transgender medicine for a young girl who believes she is a boy is to affirm this belief using hormones and possibly surgery. Current standards promoted by WPATH include puberty suppression using Lupron as young as age 10, followed by cross-sex hormone treatment with testosterone by age 16. It should be noted that in the United States, top gender doctors who see the greatest number of patients often begin cross-sex hormone treatment much earlier (as young as 12 in this recently published study).

We don’t know all the side effects this regimen may produce, but when started before puberty, one effect is certain: permanent sterility.

Aside from that pesky side effect, the expected effects of testosterone treatment include changes in body fat and muscle composition, changes in bone structure, facial/body hair growth and male pattern hair loss, clitoral growth, changes in sexual function, voice deepening, cessation of menstruation, and increased acne.

Likely side effects include adverse changes in cholesterol and blood pressure, leading to increased risk for heart attack and stroke; increased red blood cell mass which increases risks for blood clots; and changes in the ovaries and uterus potentially leading to increased risk of cancer, for which many experts recommend hysterectomy and bilateral salpingo-oophorectomy.

Possible side effects include increased risk of diabetes (another risk factor for heart disease and stroke), possible liver damage, possible kidney damage, risk of mitochondrial damage, and perhaps an increased risk for psychiatric disease.

How significant are these risks? Will they be worth it to a generation of “gender nonconforming” kids as they start their adult lives already committed to a lifetime as chronic medical patients? Will they face premature disability and death?

No one knows. Maybe it will all work out fine. Maybe testosterone really is the fountain of youth, providing strength, energy, vitality and virility to brave young gender outlaws, as they sacrifice their fertility to give birth to their authentic selves with the eager assistance of the medical and pharmaceutical industries.

Maybe.

But medical history is littered with miracle cures gone wrong. Future historians will judge whether the massive increase in girls and young women prescribed testosterone will go down as a triumph of medicine–or an ill-begotten disaster.