Development of central precocious puberty following cannabinoid use for paediatric epilepsy: causal or coincidence?

Abstract

Research suggests a role for cannabidiol oil in managing certain forms of paediatric onset epilepsy. However, studies on the impact of cannabis on the hypothalamo-pituitary-gonadal (HPG) axis have conflicting results. Delta-9-tetrahydrocannabinol (Δ9-THC) acutely inhibits gonadotropin-releasing hormone in the hypothalamus, reducing testosterone levels by 65% in rhesus monkeys. Additionally, there have been reports of pubertal arrest and delayed puberty in male cannabis users. In contrast, other studies have reported higher testosterone levels following long-term cannabis use.

A 2-year-old boy presented with testicular enlargement, increased penile length and growth of coarse pubic hair developing over 6 months. His mother procured cannabidiol oil online, which he started taking 7 months earlier for severe epilepsy refractory to medical management. Subsequent investigations confirmed central precocious puberty. While it is unclear whether the precocious puberty is a direct consequence of HPG axis activation by Δ9-THC, this case demonstrates a temporal association between cannabis use and development of precocious puberty.

Background

In recent years, cannabis and cannabis-related products have been increasingly considered for the treatment of paediatric onset epilepsy.¹ However, studies determining the impact of these products on the hypothalamo-pituitary-gonadal (HPG) axis have shown conflicting results.² While animal models have shown cannabis to downregulate androgens,³ recent human studies have demonstrated raised serum testosterone levels in long-term cannabis users.^4–6

Central precocious puberty is the onset of puberty below the age of 9 years in boys, attributed to premature activation of the HPG axis.⁷ No previous cases of precocious puberty associated with cannabinoid use have been reported, with no existing evidence investigating the effects of cannabinoids on infants.

In this case report we describe an infant who developed central precocious puberty temporally associated with the use of cannabis oil purchased online. As this is a fairly novel therapeutic, prescribers should develop an awareness for the potential impacts of cannabis use on the HPG axis.

Case presentation

A 2-year-old boy presented with features of precocious puberty, including genital virilisation over the past 6 months. He was known to have severe uncontrolled epilepsy associated with a de novo SCN2A c.743T>C p.(Leu248Pro) mutation. He had global developmental delay presenting with central hypotonia, visual impairment, poor socialisation and poor motor control.

In line with the latest guidance on the interpretation of sequence variants by the American College of Medical Genetics and Genomics,⁸ this SCN2A variant is classified as 'likely pathogenic'. This classification is based on the following moderate-to-strong evidence: the variant is absent from the Genome Aggregation Database, is located in a conserved region considered to be a hot spot, and has previously been described in a patient with epilepsy.⁹ Furthermore, this mutation affects a gene with a low tolerance for missense variation and various in silico tools predict that it may be deleterious.

The patient reportedly had over 20 seizures daily since birth, with the frequency worsening over time. Phenytoin, pyridoxal phosphate, carbamazepine, topiramate, lamotrigine, clobazam and a ketogenic diet had been trialled in the past with limited success. The patient’s mother administered cannabidiol oil purchased on the internet without a prescription, which reportedly reduced his seizure frequency to five daily. He continued using this oil, advertised to have <0.4% delta-9-tetrahydrocannabinol (Δ9-THC) concentration, for 7 months prior to presenting.

The patient’s mother reported growth of coarse pubic hair, change in body odour, facial and truncal acne (figure 1) and an enlarging penis over the past 6 months. On clinical examination, his testicular volume was 5 mL bilaterally and his stretched penile length was 9 cm. Pubertal staging was Tanner stage IV, axillary hair stage II and pubic hair stage III.

Figure 1.

Photograph showing facial acne.

Investigations

The patient’s serum testosterone levels were raised at 19 nmol/L (normal <0.9). 17-Hydroxyprogesterone levels and thyroid function tests were normal. The urinary steroid profile showed a ratio of androgen:cortisol metabolites which were high for his age with an otherwise normal profile. His bone age was equal to his chronological age, which is an atypical finding in central precocious puberty. A gonadotropin-releasing hormone (GnRH) stimulation test demonstrated a peak luteinising hormone (LH) response of 31 U/L (normal <4.0) and follicle stimulating hormone (FSH) level of 6 U/L (normal <2.0). Urine toxicology assay demonstrated the presence of Δ9-THC and cannabidiol (CBD). MRI showed thinning of the corpus callosum and a slight hypoplasia of the cerebellum, but no hypothalamic hamartomas, gross structural sellar or parasellar abnormalities were visualised.

Differential diagnosis

The normal urinary steroid profile excluded specific biosynthetic adrenal disorders resulting in increased production of androgens. In addition to raised testosterone, the positive GnRH stimulation test was consistent with the final diagnosis of central precocious puberty. Cross-sectional imaging of the head excluded a paraneoplastic cause for the central precocious puberty, increasing credibility of the temporal link with cannabis oil use. Furthermore, while there have been reported cases of early precocious puberty in children with genetic abnormalities, it is not a recognised trait of this particular SCN2A mutation.¹⁰

Treatment

The patient was started on triptorelin, a gonadorelin analogue which downregulates GnRH receptors to reduce the effects of LH/FSH, ultimately reducing androgen production.

Discussion

Our patient developed central precocious puberty temporally associated with the use of cannabis oil purchased online. Cannabinoids including Δ9-THC are known to act on cannabinoid type 1 (CB1) receptors expressed densely in the basal ganglia and cerebellum,¹¹ as well as on peripheral cannabinoid type 2 (CB2) receptors.¹² Endocannabinoids act on CB1 receptors to modulate neurotransmitters¹³; exogenous cannabinoids similarly decrease neuronal excitability and inhibit glutamatergic transmission, providing neuroprotection.¹⁴ These neuroprotective mechanisms are also seen in long-term adaptive cellular changes activated by CB1 receptors in response to stress activity on the brain, such as by seizures.¹⁵

Endogenously, CB1 ligands including 2-arachidonoylglycerol and anandamide modulate seizure termination in the minutes following a seizure.¹⁶ Exogenously, Δ9-THC and other cannabimimetics also demonstrably abolish spontaneous temporal lobe seizures in mice by activating CB1.¹⁶ Additionally, CBD acts as a sodium channel blocker, which are particularly effective in the management of SCN2A-associated early infantile epilepsy.^{17 18}

A 2004 review concluded that cannabinoids were more effective than phenobarbital and phenytoin in rats with temporal lobe epilepsy,¹⁹ and a 2018 systematic review found CBD to be more effective than placebo at halving seizure frequency and improving quality of life.²⁰ These findings suggest a role for cannabinoids in the treatment of epilepsy refractory to current anti-epileptic drugs. However, there is generally poor evidence for the use of cannabinoids in treating epilepsy in humans.

Animal and human studies have shown conflicting results on the effects of cannabis on the HPG axis.² In rhesus monkeys and mice, Δ9-THC is known to acutely inhibit GnRH pulse generation in the hypothalamus, reducing levels of testosterone and LH by up to 65%.^{21 22} Cortisol levels are also demonstrably raised with acute cannabis use.²³

However, studies in humans across several decades have been unable to consistently replicate findings. Older studies conclude that cannabinoids decrease or have no effect on androgens, whereas studies from the 21st century associate cannabis with raised serum testosterone. Table 1 summarises the findings of various studies on the impact of cannabis use on reproductive hormones.

Table 1.

Summary of studies showing the impact of cannabis on male reproductive hormones

Study	Summary	Conclusion
Mendelson et al 197425	Testosterone levels of 12 male cannabis smokers compared with 15 male tobacco smokers over a 21-day use period	↔	No association between cannabis and testosterone
Kolodny et al 197426	Testosterone levels of 20 male heavy cannabis users compared with age-matched male never-users	↓	Lower testosterone dose-related to cannabis use
Cushman 197527	Reproductive hormone* levels of 25 male cannabis users compared with 13 male never-users	↔	No association between cannabis and reproductive levels
Coggins et al 197628	Reproductive hormone* levels of 84 male cannabis users compared with 156 male never-users	↔	No association between cannabis and reproductive hormones
Mendelson et al 197829	Testosterone and LH levels of 13 males compared before and after 21-day period of cannabis use	↔	No association between cannabis and testosterone; all values within normal range
Copeland et al 198030	Case report of pubertal arrest in a 16-year-old boy with a history of heavy cannabis use	↓	Cannabis use lowers testosterone and may arrest puberty
Barnett et al 198331	Analysis of existing data of cannabis smoking and IV Δ9-THC infusion in healthy males	↓	Lower testosterone dose-related to cannabis use; takes 24 hours to return to normal
Block et al 199132	Reproductive hormone* levels of 75 male and female cannabis users compared with 74 male and female non-users	↔	No association between cannabis and reproductive hormones
Jabeen et al 20156	Pubertal indicators† of 217 male long-term cannabis-using adolescents compared with 220 male non-users	↑	Cannabis use raises testosterone, LH, cortisol and lowers height by age of 20
Gundersen et al 20155	Testosterone levels of 547 male cannabis users compared with 668 male non-users	↑	Higher testosterone associated with cannabis use
Thistle et al 20174	Testosterone levels of 1577 males correlated with previous cannabis use	↑	Higher testosterone temporally correlated to more recent cannabis use

*Reproductive hormones including testosterone, LH, FSH, prolactin and cortisol.

†Pubertal indicators including testosterone, LH, growth hormone, cortisol levels; and weight, height and body mass index.

FSH, follicle stimulating hormone; LH, luteinising hormone.

This research demonstrates a paradigm shift over decades as larger populations can now be studied with the increasing popularity of cannabis use. More research on the effects of cannabis use on human hormonal markers and clinical outcomes is necessary, and is expected as cannabis continues to become legalised in more countries.²⁴

It is unclear whether the precocious puberty seen in our patient is a direct result of activation of the HPG axis by Δ9-THC. Until a more robust evidence base is established, clinicians should be cautious of hormonal consequences of cannabis-related products, particularly as children with brain abnormalities may be more susceptible to these effects.

Take home messages.

• The level of evidence on the impact of cannabis on the HPG axis is poor

• Recent studies show that cannabis use is associated with increased serum testosterone, raising the question of a possible dose-related effect as higher strength preparations are more readily available

• Clinicians should be aware of hormonal consequences of cannabis-related products

• Children with brain abnormalities may be more susceptible to the adverse consequences of novel and untrialled treatments