“They Paused Puberty but Is There a Cost?”
“Bone Health: Puberty Blockers Not Fully Reversible.”
UT Southwestern Medical Center
Dr. M. Brett Cooper
Headlines such as these from major national news outlets have begun to cast doubt on one of the medications used in treating gender-diverse adolescents and young adults. GnRH agonists, such as leuprorelin and triptorelin, were first approved by the Food and Drug Administration in the 1980s and have been used since then for a variety of medical indications. In the decades since, these medications have been successfully used with a generally favorable side effect profile.
GnRH agonists and puberty
In the treatment of precocious puberty, GnRH agonists are often started prior to the age of 7, depending on the age at which the affected patient begins showing signs of central puberty. These include breast development, scrotal enlargement, and so on. GnRH agonists typically are continued until age 10-12, depending on the patient and an informed discussion with the patient’s parents about optimal outcomes.1 Therefore, it is not uncommon to see these medications used for anywhere from 1 to 4 years, depending on the age at which precocious puberty started.
GnRH agonists are used in two populations of transgender individuals. The first group is those youths who have just started their natal, or biological, puberty. The medication is not started until the patient has biochemical or physical exam evidence that puberty has started. The medication is then continued until hormones are started. This is usually 2-3 years on average, depending on the age at which the medication was started. This is essentially comparable with cisgender youths who have taken these medications for precocious puberty. The second population of individuals who use GnRH agonists is transgender women who are also on estrogen therapy. In these women, the GnRH agonist is used for androgen (testosterone) suppression.
Concerns over bone health
One of the main concerns recently expressed about long-term use of GnRH agonists is their effect on bone density. Adolescence is a critical time for bone mineral density (BMD) accrual and this is driven by sex hormones. When GnRH agonists are used to delay puberty in transgender adolescents, this then delays the maturation of the adult skeleton until the GnRH agonist is stopped (and natal puberty resumes) or cross-sex hormones are started. In a recent multicenter study2 looking at baseline BMD of transgender youth at the time of GnRH agonist initiation, 30% of those assigned male at birth and 13% of those assigned female at birth had low bone mineral density for age (defined as a BMD z score of <–2). For those with low BMD, their physical activity scores were significantly lower than those with normal BMD. Thus, these adolescents require close follow-up, just like their cisgender peers.
There are currently no long-term data on the risk of developing fractures or osteoporosis in those individuals who were treated with GnRH agonists and then went on to start cross-sex hormone therapy. Some studies suggest that there is a risk that BMD does not recover after being on cross-sex hormones,3 while another study suggested that transgender men recover their BMD after being on testosterone.4 It is still unclear in that study why transgender women did not recover their BMD or why they were low at baseline. Interestingly, a 2012 study5 from Brazil showed that there was no difference in BMD for cisgender girls who had been off their GnRH agonist therapy for at least 3 years, as compared with their age-matched controls who had never been on GnRH agonist therapy. These conflicting data highlight the importance of long-term follow-up, as well as the need to include age-matched, cisgender control subjects, to better understand if there is truly a difference in transgender individuals or if today’s adolescents, in general, have low BMD.