5-alpha-dihydrotestosterone elevations associated with phentermine use

Abstract

Background:

A case of 5-alpha-dihydrotestosterone (DHT) elevation associated with phentermine initiation is reported, and possible mechanisms are discussed. There are no published reports of this association in the literature.

Methods:

Clinical and laboratory information is described.

Results:

A 72-year-old male with metastatic prostate cancer taking dutasteride to lower his DHT levels initiated phentermine 15 mg daily for weight loss. His DHT level drawn within 1 week prior to starting phentermine was 9.9 pg/ml. When reporting for follow up 2 weeks later, his DHT level had increased to 114 pg/ml. The DHT level was checked again 2 weeks after that visit, and had increased to 174 pg/ml. At that time, phentermine was discontinued, and 1 week later, the DHT level had decreased to 20.1 pg/ml. Over the next 4 months, the patient’s DHT levels were maintained at less than 20 pg/ml. Phentermine 15 mg daily was then reinitiated while his DHT level was 7.5 pg/ml. Two weeks after resuming phentermine, his DHT level had again increased to 196 pg/ml. The patient’s phentermine was then discontinued, and around 1 week later, his DHT level had fallen to 5.1 pg/ml.

Conclusion:

A 72-year-old male with metastatic prostate cancer experienced profound increases in DHT upon initiation of phentermine despite continuation of his baseline dutasteride therapy. The etiology of these increases is still unclear.

Introduction

Dutasteride is metabolized by CYP3A4 and can be administered in combination with bicalutamide to lower 5-alpha-dihydrotestosterone (DHT) levels in patients with prostate cancer.^1,2 Phentermine is indicated for weight loss and is a minor substrate of CYP3A4.^3,4 This case report involves a patient taking dutasteride to lower his DHT levels who initiated phentermine therapy and developed a subsequent and profound increase in DHT levels, which resolved upon phentermine discontinuation on two separate occasions. However, there are no documented drug interactions involving dutasteride and phentermine and no documented effects of phentermine on DHT levels. MEDLINE and Cochrane Library searches without date limits using the terms “phentermine and testosterone” and “phentermine and dutasteride” yielded no pertinent results.

Case presentation

A 72-year-old Caucasian male measuring six feet tall and weighing 90 kg inquired about starting medication to assist with weight loss while being seen in his endocrinology clinic. He was subsequently prescribed phentermine 15 mg daily. His past medical history included prostate cancer with regional metastases, benign prostatic hyperplasia, chronic kidney disease (stage 3), hypertension, mixed hyperlipidemia, impaired fasting glucose, metabolic syndrome, drug-induced gynecomastia, nocturia and insomnia. His other medications included alfuzosin 10 mg daily, anastrozole 1 mg daily, bicalutamide 50 mg daily, desmopressin 0.05 mg nightly, dutasteride 1 mg daily, linaclotide 145 mg daily as needed, melatonin 6 mg nightly, metformin 1000 mg BID, modafinil 100 mg daily, pentoxifylline 400 mg TID, simvastatin 10 mg daily, tadalafil 5 mg daily, telmisartan 80 mg daily, temazepam 15 mg nightly as needed, and zolpidem 5 mg nightly. At that visit, his zolpidem was replaced by trazodone 25 mg nightly. His only drug allergy was to silodosin, with which he experienced shortness of breath. His prostate cancer was diagnosed around 20 years previously, and he was initially treated with radiation therapy. He was then treated with a variety of hormonal therapies, to which he experienced several medication intolerances before being prescribed his current regimen.

His DHT level drawn within 1 week prior to starting phentermine was 9.9 pg/ml, his estradiol was 37 pg/ml, and testosterone 380 ng/dl. All other laboratory values at that time were within normal limits and near his baseline, including serum creatinine 1.14 mg/dl, alkaline phosphatase 73 U/ml, alanine aminotransferase 15 U/ml and aspartate aminotransferase 13 U/ml. When reporting for follow up 2 weeks later, his DHT level had increased to 114 pg/ml. His serum sodium had decreased from 134 to 131 mmol/L, and all other laboratory values remained within normal limits. The DHT level was checked again 2 weeks after that visit, and had increased to 174 pg/ml (estradiol 33 pg/ml, testosterone 340 ng/dl). At that time, phentermine and trazodone were discontinued. His DHT level was drawn 1 week after stopping both medications, and had decreased to 20.1 pg/ml. One week later, estradiol and testosterone levels were checked and found to be 32 pg/ml and 312 ng/dl, respectively. Over the next 4 months, his DHT levels were maintained at less than 20 pg/ml. Phentermine 15 mg daily was then reinitiated while his DHT level was 7.5 pg/ml, estradiol was 27 pg/ml, testosterone was 265 ng/dl, and all other lab values were within normal limits. He was no longer taking trazodone at this time, and had also discontinued telmisartan and anastrozole. New medications compared to the time of previous phentermine initiation included codeine 30 mg q6h PRN, darifenacin 7.5 mg daily, losartan 50 mg BID and tamoxifen 10 mg BID. Two weeks after resuming phentermine, his DHT level had again increased to 196 pg/ml, while estradiol was 30 pg/ml and testosterone was 219 ng/dl. The patient’s phentermine was then discontinued, and around 1 week later his DHT level had fallen to 5.1 pg/ml, while estradiol and testosterone had increased to 33 pg/ml and 319 ng/dl, respectively. None of his other laboratory values changed significantly during this period of time.

Discussion

There are no directly applicable published reports in the literature with which to compare this case. However, the temporal nature of DHT increases with initiation of phentermine and subsequent reductions in DHT levels after phentermine discontinuation are impressive, especially given that these findings were replicated with phentermine reinitiation and subsequent discontinuation. The mechanism for these laboratory changes is not entirely clear. Phentermine is a minor substrate of CYP3A4, but has previously shown to have negligible CYP inhibition.^4,5 It is also not known to be a CYP inducer. While dutasteride is metabolized primarily by CYP3A4 as well, it would be surprising to see such a profound drug interaction in the absence of cytochrome P450 induction by phentermine, which would presumably result in reduced dutasteride levels and increased DHT levels. ¹ Additionally, there are no documented drug interactions between dutasteride and CYP3A4 inducers, perhaps owing to dutasteride’s long terminal half-life, which results in detectable drug levels 4–6 months after therapy discontinuation. Therefore, it seems unlikely that any drug interaction with dutasteride would produce such profound and immediate changes in laboratory values. The Drug Interaction Probability Scale score for the drug interaction between phentermine and dutasteride is 2, indicating a possible drug interaction. While the patient was prescribed other medications that could potentially affect sex hormone concentrations during the times when these DHT fluctuations occurred, including bicalutamide and tadalafil, these medications were stable throughout the time course of events (although medication adherence cannot be confirmed). This patient was also treated with a number of other medications that could have presented potential drug interactions, but essentially all other medications were unchanged during the time course of DHT fluctuations, supporting the theory that phentermine initiation and discontinuation contributed to the changes in DHT serum concentrations.

Another possible explanation for the increase in DHT levels could be directly related to phentermine’s effects on DHT. Phentermine is an amphetamine analogue that suppresses appetite by stimulating norepinephrine and dopamine release in the hypothalamus.^6,7 It has been proposed that amphetamines may increase sexual arousal by producing elevations in testosterone levels as a result of their dopamine-modulating effects. However, studies of other amphetamine substances have not confirmed any associations with testosterone concentration, and there is currently no evidence to support this effect for phentermine.^8,9

Phentermine could also alter DHT concentrations by impacting DHT metabolism. DHT is metabolized to DHT glucuronide, 5α-androstane-3β,17β,-diol (3β-DIOL) and 5α-androstane-3α,17β-diol (3α-DIOL). ¹⁰ The primary pathway of liver metabolism is thought to be through 3α-DIOL via the enzyme 3α-hydroxysteroid dehydrogenase, and it is therefore plausible that phentermine directly affects this degradation pathway. However, we were unable to assess this theory, as degradation products such as 3β-DIOL and 3α-DIOL were not measured.

These proposed mechanisms, shown in Table 1, shed little light on the true etiology of phentermine-associated DHT fluctuations seen in this case report. Regardless, it is recommended that clinicians be cognizant of the possible drug interactions that may exist between phentermine and dutasteride. Phentermine should also be used with caution in combination with other medications metabolized by CYP3A4. Additionally, it should be noted that phentermine may have the propensity to increase DHT levels independent of dutasteride usage. Although fluctuations of estradiol and testosterone levels in accordance with DHT changes were largely unremarkable, we were unable to assess degradation processes of DHT. Further research is needed to determine the true etiology of the DHT elevations seen with phentermine therapy.

Table 1.

Possible mechanisms to explain serum DHT fluctuations.

Phentermine drug interaction with dutasteride (or different medication) via CYP3A4

Phentermine-induced increase in testosterone concentrations

Direct effect of phentermine on DHT degradation pathway

Conclusion

A 72-year-old male with metastatic prostate cancer experienced profound increases in DHT upon initiation of phentermine despite continuation of his baseline dutasteride therapy. The etiology of these increases is still unclear.