Four low-cost alternatives to puberty blockers for transgender adolescents

Disclaimer: I am not a doctor, and this is not medical advice. Do not take any medication without appropriate medical supervision.

Puberty suppression for transgender youth, developed in the 1990s, is one of the most important advances in the history of transition treatment. With the use of fully reversible GnRH analogue medications to halt natural puberty in appropriately diagnosed adolescents, and the later addition of cross-sex hormones, these youth are largely spared the development of gender-inappropriate sex characteristics: facial and body hair growth, voice deepening, and masculine facial structure and body shape in trans girls; and breast growth and hip widening in trans boys. As a result, many will not have to undergo costly and invasive procedures in adulthood to reverse the unwanted effects of original puberty, such as facial feminization surgery and chest reconstruction.

Treatment with puberty blockers is known to lead to measurably better outcomes for trans youth compared to transitioning in adulthood. Following use of puberty blockers and later treatment with cross-sex hormones and surgery, this population no longer experiences gender dysphoria, with overall psychological functioning comparable to their cisgender peers, and good quality of life (de Vries et al., 2014). Conversely, withholding puberty blockers from gender-dysphoric adolescents can result in worsening of dysphoria, depression, self-harm, and suicidality (Radix & Silva, 2014).

Because of the clear benefits of puberty blockers for trans youth, this treatment protocol is supported by the American Academy of Pediatrics, American Psychological Association, American Psychiatric Association, American Academy of Child and Adolescent Psychiatry, American College of Obstetricians and Gynecologists, and many more professional medical organizations. Blockers for trans kids are now offered by dozens of major hospitals and gender clinics across the United States.

However, many trans youth and their families still struggle to access these medically necessary treatments, often due to the expense of GnRH analogues and uneven insurance coverage of these medications for kids with gender dysphoria. But biology does not wait – these youth are in a critical developmental period, and foregoing puberty blockers can have lifelong consequences (Giordano, 2008). In light of these challenges, trans kids deserve more accessible and affordable options for blocking puberty. A number of recent studies have provided clinical evidence that inexpensive generic medications can be used in place of GnRH analogues for effective puberty suppression in trans youth, offering a potential alternative to more costly treatment.

GnRH analogues: Advantages and disadvantages

Gonadotropin-releasing hormone analogues, or GnRH analogues, are long-acting medications which can temporarily and reversibly “press pause” on natural puberty. By acting on the pituitary gland, these puberty blockers prevent the release of chemical signals which stimulate the production of estrogen and testosterone, halting the changes of puberty caused by these sex hormones (Byne et al., 2012). In trans youth, puberty blockers are typically given at Tanner developmental stages 2 and 3, usually around ages 11 to 12. This allows more time for kids to consider whether they want to continue transitioning via cross-sex hormones and surgery, without the stress of ongoing unwanted pubertal development. Those who choose not to transition can stop taking blockers, and their original puberty will resume and progress normally.

While gender specialists consider GnRH analogues to be the preferred treatment for blocking puberty in trans adolescents, these drugs can be very expensive. Puberty blockers are typically administered in the form of a 1-month or 3-month depot injection, or a 1-year implant inserted under the skin. A Lupron (leuprolide) 3-month shot can cost $4,000-6,000, and a 1-year histrelin implant costs $20,000 as Supprelin LA or $3,500 as Vantas (Stevens, Gomez-Lobo, & Pine-Twaddell, 2015). Health insurance carriers may refuse to cover the cost of blockers: a 2015 study of two youth gender clinics found that only 72% of patients received blockers paid for by insurance, with many having to file appeals (Stevens et al., 2015). In 2015, pediatric endocrinologist Norman Spack at Boston Children’s Hospital stated that fewer than 20% of his trans patients since 2007 had their treatment with blockers covered by insurance. Ongoing uncertainties regarding US healthcare law, insurance markets, and transgender exclusions may further jeopardize trans adolescents’ access to affordable puberty blockers.

Even in the UK where blockers are provided through the NHS, trans youth may have to wait 17 weeks for a first appointment, with some facing delays of 9 months:

Green said Mermaids had recently had calls from parents who had been told their child would have to wait nine months for an appointment at Tavistock.

“I spoke to one family who will have to wait until November [for their daughter’s first appointment at the clinic],” said Green. “The mother was absolutely desperate because her daughter is 14, her daughter’s voice has started to break, facial changes and hair are around the corner, her Adam’s apple will become more pronounced. These are changes that will affect her for the rest of her life.”

Because treatment with puberty blockers requires parental consent, trans kids with unsupportive family may be denied access to this medication even when it is clearly necessary. While the structural barriers to appropriate care for trans youth must continue to be addressed, those systemic changes may not occur quickly enough for kids who are experiencing the wrong puberty today. All of these obstacles point to a more immediate need for other puberty suppression options for this vulnerable population.

1. Medroxyprogesterone acetate

Numerous medical publications have noted that progestins such as medroxyprogesterone acetate (MPA), given orally or as a long-acting depot injection (Depo-Provera), can be used as a less expensive alternative to GnRH analogues for puberty suppression. The Endocrine Society’s 2009 clinical guidelines state (Hembree et al., 2009):

GnRH analogs are expensive and not always reimbursed by insurance companies. Although there is no clinical experience in this population, financial considerations may require treatment with progestins as a less effective alternative. They suppress gonadotropin secretion and exert a mild peripheral antiandrogen effect in boys. Depo-medroxyprogesterone will suppress ovulation and progesterone production for long periods of time, although residual estrogen levels vary. In high doses, progestins are relatively effective in suppression of menstrual cycling in girls and women and androgen levels in boys and men.

The guidelines add: “Their efficacy, however, is far less than that of the GnRH analogs.” Version 7 of the WPATH Standards of Care also makes note of MPA as an option (Coleman et al., 2011):

For puberty suppression, adolescents with male genitalia should be treated with GnRH analogues, which stop luteinizing hormone secretion and therefore testosterone secretion. Alternatively, they may be treated with progestins (such as medroxyprogesterone) or with other medications that block testosterone secretion and/or neutralize testosterone action. Adolescents with female genitalia should be treated with GnRH analogues, which stop the production of estrogens and progesterone. Alternatively, they may be treated with progestins (such as medroxyprogesterone). Continuous oral contraceptives (or depot medroxyprogesterone) may be used to suppress menses.

MPA was also used for the treatment of precocious puberty in cis children before GnRH analogues were developed (Lynch, Khandheria, & Meyer, 2015):

In the 1960s and early 1970s MPA in a depot form was commonly utilized to treat central precocious puberty by inhibiting the secretion of gonadotropins and/or interfering with gonadal steroid synthesis (see Table 1). It was shown to suppress breast development, promote amenorrhea, and halt sexual hair development in young children treated in the 1970s. … MPA causes cessation of menstrual bleeding and regression of female puberty with no effect on bone age advancement, but its effectiveness in suppressing puberty and sometimes even reversing it was documented in those cases. There is also questionable improvement in male height. A previous study found that adrenal function and pituitary reserve during treatment with depot MPA remained normal.

Rosenthal (2014) provides recommended dosages of oral or depot MPA for puberty suppression in trans youth: “Medroxyprogesterone acetate orally (up to 40 mg/d) or im (150 mg every 3 mo)”. A study of 7 AMAB and 7 AFAB trans adolescents treated with MPA at the University of Texas found that both oral and depot MPA were effective “for stopping menstrual periods in adolescent females and delaying puberty in adolescent males” (Lynch et al., 2015):

Medroxyprogesterone was used in this study as an alternative treatment option because of its proven efficacy for the treatment of precocious puberty and its low cost. To avoid the need to give an injection, the oral form was sometimes used. It is administered as a daily oral dose or depot injection once every 2 to 3 months. Because of its use as a contraceptive a 150-mg depot injection at 3-month intervals was known to sometimes stop menstrual periods.

The authors note that the oral dose of MPA had to be increased over time for trans girls:

Seven male-to-female individuals between stages 2 and 4 puberty were treated initially with the oral form of MPA (10 mg–30 mg PO bid). The dose of medication increases as the child gets older and the testosterone rises. Testosterone blood levels were checked every 3 to 6 months and whenever the patient had a concern. Adjustments of the MPA were made to keep the testosterone in the prepubertal range—that is, below 50 ng/dl. The MPA dose increased until age 15–16 when estradiol therapy was added and the dose of MPA was slowly reduced.

Additionally, more frequent administration of depot MPA was required for trans boys:

Six were treated with depot MPA with a starting dose of 150 mg IM every 3 months. Their age at presentation beginning medication ranged from 13 to 18 years old and all were Tanner stage 5 (and menstruating regularly). Although the depot form of MPA was started every 90 days, subsequently everyone required dosing to be at least every 60 days to completely stop the menstrual bleeding.

Two participants, one AMAB and one AFAB, chose to discontinue MPA and resume living as their assigned gender, with their original puberty continuing normally. Treatment with MPA, a generic medication, is significantly less expensive than using GnRH analogues:

The cost is approximately $30 a month for the oral regimen and $30.86 for the 150 mg depot MPA injection.

The authors concluded: “MPA is effective, safe, and affordable. Response to treatment and compliance are favorable.” They further added that “none of the patients discontinued therapy because of unwanted side-effects.”

2. Spironolactone

The WPATH Standards of Care state that spironolactone, a generic oral anti-androgen commonly used by adult trans women in the US, can be used in place of GnRH analogues to suppress puberty in trans girls (Coleman et al., 2011):

Alternative treatment options include progestins (most commonly medroxyprogesterone) or other medications (such as spironolactone) that decrease the effects of androgens secreted by the testicles of adolescents who are not receiving GnRH analogues.

A 2017 review of puberty suppression treatments for trans youth also noted spironolactone as an option for these girls (Mahfouda et al., 2017):

To induce natural breast development and lessen masculinisation in male-to-female patients, antiandrogenic progestins such as cyproterone acetate and spironolactone are important for lessening the effects of testosterone. Spironolactone, which works via androgen receptor blockade to subdue androgen-dependent hair growth, has been offered to male-to-female patients who choose not to take GnRH agonists.

Shumer, Nokoff, & Spack (2016) describe the clinical use of spironolactone to prevent the unwanted effects of original puberty in adolescent trans girls:

Finally, spironolactone is an oral medication most commonly used as a weak diuretic, which also acts as a weak androgen receptor antagonist. This medication can be used by MTF individuals to reduce the effects of testicular androgen production. We most commonly use spironolactone when the patient is troubled by the development of facial and body hair. Although spironolactone will not cause regression of the terminal hair follicles, patients on spironolactone therapy may require less frequent shaving or electrolysis treatments.

Rosenthal (2014) offers dosing information for trans girls using spironolactone for puberty suppression:

Spironolactone (25 to 50 mg/d with gradual increase to 100 –300 mg/d orally, divided into twice daily dosing)

In a study of 84 gender-dysphoric youth who presented for treatment from 1998 to 2011, 25 adolescent trans girls opted for spironolactone instead of GnRH analogues (Khatchadourian, Amed, & Metzger, 2014). However, all of the girls using spironolactone were already at Tanner stage 4 or 5 of male puberty, and began taking it at a relatively late age (median 17.5 years, range 15–22 years).

While literature contains little information on the cost of treatment with spironolactone, GoodRx lists the price of 30 doses of 100mg generic spironolactone as ranging from $10–73 at various pharmacies (as of 21 July 2017).

3. Cyproterone acetate

Cyproterone acetate (CPA) is a generic oral progestin with anti-androgenic properties, unapproved in the US but widely used by adult trans women in Europe. Mahfouda et al. (2017) and Shumer et al. (2016) mention CPA as an option for puberty suppression in trans girls, and Rosenthal (2014) provides dosage guidance:

Cyproterone acetate (gradual increase up to 100 mg/d orally; not available in United States)

Tack et al. (2017) followed 27 AMAB trans youth who were given CPA for puberty suppression for an average of 12 months, and described the advantages and disadvantages of this treatment compared to GnRH analogues:

CA effectively suppresses gonadotropin-independent precocious puberty and was used to suppress central precocious puberty before the advent of GnRHas. Treatment with CA (Androcur, Bayer AG, Leverkusen, Germany) is more than five times cheaper than treatment with GnRHas, which in Belgium are not reimbursed for the treatment of transgender persons, and can be administered orally. The potent antiandrogenic effects result from its ability to competitively inhibit androgen binding on the androgen receptor, translocation of the androgen receptor to the nucleus, and inhibition of androgen-mediated transcriptional activation. CA decreases growth of body hair and to a lesser extent facial hair and decreases sexual desire, which is often a cause of distress in natal boys with GD. Because of these potent effects and the high costs of GnRHas, CA is used in our center in adolescents who already have established secondary sexual characteristics (Tanner stage ≥ 4) to alleviate distress before the addition of estrogens.

Participants took 50mg CPA daily, resulting in reduced testosterone levels and mild feminizing effects, and a cessation in further unwanted secondary sex characteristics:

CA was effective in decreasing total and free testosterone levels, although the upper female-typical threshold was not reached. … Although gonadotropins were not suppressed with CA, subjectively, adolescents experienced clear beneficial effects resulting from decreased testosterone activity. … As with GnRHa, established secondary sexual characteristics did not regress. However, while using CA, subtle changes toward the desired sex took place, such as limited breast development and a shift in some biochemical parameters.

While all of these girls were already at Tanner stage 4 of male puberty, many reported “decreased facial shaving frequency” and “decreased spontaneous erections”. One participant chose to discontinue CPA and resume their original puberty. Although CPA is unavailable in the US, overseas vendors list prices ranging from $0.98 (IHP, 2017) to $1.43 (ADC, 2017) per 50mg tablet.

4. Lynestrenol or norethindrone

Lynestrenol is an oral synthetic progestin with androgenic effects, and a prodrug of norethindrone – it is almost immediately processed by the body into its active form, norethindrone. Limited literature is available on the use of lynestrenol as a puberty blocker, and it appears to be used more frequently in trans boys than in trans girls. Tack et al. (2016) reported the use of lynestrenol in 45 adolescent trans boys for an average of 12.6 months. These patients had already reached at least Tanner stage 4 of female puberty, but were not yet old enough to begin cross-sex hormones, and lynestrenol was a less expensive alternative to GnRH analogues for them:

However, in many countries, expensive GnRHa are not reimbursed to treat GD, and in these cases, androgenic progestins are a valuable alternative to induce amenorrhea, especially in adolescents who already have advanced development of secondary sex characteristics at the start of treatment or in adults. Lynestrenol (L) (Orgametril®) 5 mg is approximately 13 times cheaper than GnRHa (€85 versus €1100 per year in Belgium), and as it is taken orally, it does not require intramuscular injections. Both medications are not reimbursed to treat adolescents with GD in Belgium and are at the expense of patients. For these reasons, L is mostly used in our center to suppress menstruation in FtM adolescents with an established diagnosis of persisting GD at Tanner stage B4 or further who are not eligible yet for cross-sex hormones (CSH) therapy in view of their young age.

The authors found a substantial reduction in both testosterone and estradiol levels during treatment with lynestrenol:

The expected hormonal changes of L were obvious after 6 months of monotherapy: T had decreased by almost 30% whereas E2 had decreased by almost 60%.

However, they add that lynestrenol “is probably less effective than GnRHa in inducing total amenorrhea and in suppressing gonadotropins and hence development of secondary sex characteristics”, and conclude that it is “specifically indicated in adolescents with advanced pubertal development and in situations where GnRHa are not reimbursed”.

Shumer et al. (2016) mention norethindrone, an oral progestin (Micronor or Aygestin) that can “reduce the pulsatile release of LH and also directly inhibit sex hormone production at the level of the gonad”. They describe the use of norethindrone “to suppress androgen production” in a 15-year-old trans girl at Tanner stage 4 of male puberty who was denied insurance coverage for GnRH analogues (she was also given “spironolactone to inhibit androgen action, and 17ß-estradiol to promote breast development and feminization”).

Norethindrone at a dose of 5mg daily was also used for suppression of menses in a 16-year-old trans boy prior to treatment with cross-sex hormones:

A 16-year-old biologic female presented to a gender clinic after receiving a diagnosis of gender dysphoria by a mental health professional. The teen was especially dysphoric with monthly menses, but the family was uneasy about committing to irreversible therapy with testosterone. Treatment with norethindrone 5 mg oral daily was initiated, and the monthly menses were suppressed, with resulting improvement in well-being. At age 18, the patient had made a complete social transition and elected to start testosterone, prescribed at 50 mg subcutaneous weekly, at which point norethindrone was discontinued without subsequent return of menses on testosterone monotherapy.

Summary

GnRH analogues remain the most effective known approach to puberty suppression in appropriately diagnosed gender-dysphoric adolescents; this is the most thoroughly studied and widely recommended treatment. However, financial and logistical constraints may prevent trans youth from obtaining puberty blockers in a timely manner, with delays potentially resulting in a lifelong impact on their health. Affordable generic medications for pubertal suppression, while generally seen as being less effective than GnRH analogues, can be an important option for trans girls and boys who might otherwise face the full brunt of the wrong puberty. The published literature on these alternatives remains somewhat limited, and further studies would be immensely valuable to youth in need of effective and accessible puberty blocking methods. ■

References

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