Gonadotropin Suppression for 7 Years After a Single Histrelin Implant for Precocious Puberty

Douglas Villalta; Jose B. Quintos


J Endo Soc. 2022;6(2) 

In This Article


Our patient is the first described in the literature to show continuous suppression of gonadotropin hormones more than 3 years after a single subdermal GnRHa implant. Gonadotropins were suppressed for 7 years after a single subdermal histrelin implant. A summary of the timeline of the patient course is found in Table 1. There have been no studies that have observed a single histrelin implant showing continuous suppression for this length of time.

In a phase 3 prospective open-label study, Silverman et al observed biochemical suppression of the hypothalamic-pituitary-gonadal (HPG) axis 1 month after implantation of the subdermal GnRHa implant. Sustained gonadotropin suppression was seen over 72 months with annual replacement of the histrelin implant. Tanner breast stages in females were found to be unchanged after 60 months of treatment with histrelin implants; in addition, 1 boy had similar testicular size and Tanner stage of pubic hair after 60 months of treatment. The bone age advancement throughout the study decreased from 2.85 years to 1.28 years in the participants who received the histrelin implant without having received any other form of GnRHa treatment prior to enrollment into the study.[2] After explantation, there is a return of menarche in girls and testicular enlargement in boys within 1 year in those with CPP.[6] Besides the study from Lewis et al that demonstrated continuous suppression of a single histrelin implant over 2 years, the literature only shows suppression with yearly replacement of the histrelin implant.[5] Our case report argues that the duration of suppression from a single implant is possible beyond 2 years. Our patient's bone age went from 2 years advanced to 3 years delayed after 7 years of treatment. Despite this, the patient still attained a height within 1 SD of his mid-parental height (171.5 cm vs mid-parental height of 175.3 cm; see Figure 1) Linear growth is not yet complete as his growth velocity is 2.7 cm/year and bone age x-ray of the left hand was 14 years. In our patient iatrogenic hypogonadotropic hypogonadism from the retained subdermal GnRHa implant caused prolonged gonadotropin and sex steroid suppression. This allowed for continued bone growth beyond the normal time where closure of the epiphyseal growth plates would be seen. Prolonged growth due to delayed fusion of the growth plate can also be seen in aromatase deficiency and estrogen resistance. The patients do not have a pubertal growth spurt due to the absence of or resistance to sex steroids.[7] The 50 mg histrelin implant provides release of continuous GnRHa for treatment of CPP. Given a dose of 65 mcg/day in a single implant, a yearly device would theoretically last 2 years. Lewis et al found that a single histrelin implant is effective for up to 2 years.[5] However, in our patient, a single subdermal implant provided continuous gonadotropin suppression for 7 years. The mechanism for this suppression is not clear and pharmacokinetics studies need to be further elucidated by larger prospective trials.

Figure 1.

Height for age growth chart at initial presentation, after having the histrelin implant for 7 years, and then 4 months after the implant was removed. Each circle represents a growth measurement. Mid-parental height is marked with a symbol on the right side of the growth chart.

Gynecomastia is the growth of glandular breast tissue in males. It is a result of an imbalance between the availability of testosterone and estrogen. Due to the relatively increased estrogen level secreted by the testes during pubertal development, gynecomastia is a common temporal manifestation seen in adolescent males. Common causes of gynecomastia in males include testicular tumors such as Leydig-cell or Sertoli-cell tumors, adrenal neoplasms, and Klinefelter syndrome.[8] Drugs have also been implicated in cases of gynecomastia which may further impair the balance between estrogen and androgen production. Marijuana has been studied as a potential cause of gynecomastia; however, according to a review article in Andrology, there is insufficient evidence to make a significant association between marijuana use and presence of gynecomastia.[9] The patient in this case report had been taking medical marijuana based on a cannabidiol-dominant strain to manage epilepsy for 6 years prior to his presentation after being lost to follow-up with bilateral gynecomastia. Given that the literature has not been able to show marijuana's association with gynecomastia, it is unlikely the medical marijuana contributed to his presentation. The gynecomastia in our patient could be due to hypogonadism/testosterone deficiency due to continuous gonadotropin hormone suppression with the histrelin implant for more than 7 years. Even though serum LH is suppressed in our patient, the sex steroids (testosterone 8.7 ng/dL and estradiol 9.9 pg/mL) are measurable. One possibility for our patient's gynecomastia could be the peripheral conversion of adrenal androgens to estrogen. In addition, the karyotype analysis performed ruled out Klinefelter syndrome, another common cause of gynecomastia.