SUMMARY: In 1997, Merck brought to FDA a simplified story about finasteride’s effects: that the drug reduces levels of one androgen and slightly increases another. In fact, the drug disrupts chemical signaling much more broadly, in the brain, reproductive system and elsewhere. Since the drug’s approval, men who used finasteride have had impairments linked to the same signaling pathways disrupted by finasteride. In summary, Merck only told part of the story about finasteride’s mechanism, keeping risks out of view.
In November 1997, Merck applied to the U.S. Food and Drug Administration for approval of finasteride as a treatment for male pattern baldness. The drug maker explained that the drug reduces levels of dihydrotestosterone (DHT) and produces a modest increase in its precursor, testosterone. Merck described finasteride as a “specific inhibitor” of an enzyme, but omitted other effects of this inhibition.1
Similarly, a 1995 paper stated that “finasteride produces a selective androgen deprivation by lowering DHT but not T with very few drug-related side effects…”2 (emphasis added).
Yet Merck’s earlier studies had already revealed that finasteride’s impact was broader—and even without research, it is evident from general biochemistry. Merck knew this, but deflected attention away from the drug’s broader effects. This simpler story would be less likely to raise questions about drug risks from FDA and physicians.
Background on steroid synthesis
We will briefly review the pathways that produce steroids, and their role in behavior. Steroids are characterized by having four rings.A Testosterone and estrogen are usually called hormones, but chemically they are steroid molecules. They are just two within a complex cascade shown in Figure 2. This occurs in multiple organs including the brain, liver, reproductive system, kidney and skin, with variations in each location.
Downstream in the cascade (bottom-right of Figure 2), certain steroids bind to androgen receptors, involved in male sexual function. Others play a supporting role in signaling that underlies memory, stress, anxiety, sleep, thought and emotions (by modulating NMDA, GABA-A and dopamine receptors3). These pathways help us navigate opportunities and risks within a changing social and physical environment.4
The effects of finasteride on steroid pathways
Finasteride inhibits the enzyme 5-alpha reductase (5-AR). This reduces levels of steroids produced by the enzyme. Traish (2011) points out that 5-AR converts six steroids into derivatives:5
- Testosterone → 5ɑ-dihydrotestosterone
- 4-androstenedione → 5ɑ-dihydroandrostanedione
- Progesterone → 5ɑ-dihydroprogesterone
- Deoxycorticosterone → 5ɑ-dihydrodeoxycorticosterone
- Corticosterone → 5ɑ-dihydrocorticosterone
- Aldosterone → 5ɑ-dihydroaldosterone
Three of these conversions are shown in Figure 3.
Limiting one step may also have effects farther downstream and upstream. Merck’s research confirmed this, and later studies extended these findings. Figure 4 shows the broader impact of finasteride on steroid levels.
When Merck submitted its Propecia application to FDA, the company knew the effects on steroid metabolism were widespread. A Merck researcher and collaborators described the drug’s effects this way in 1990 (emphasis added):
Finasteride-treated subjects and male pseudohermaphrodites with inherited 5ɑ-reductase deficiency, therefore, have global defects that affect both hepatic and peripheral 5ɑ-reductase activities.7
In a 1999 publication by Merck researchers, Figure 1 showed two different reactions involving 5-AR, but the pharmacodynamics only focused on the effect on DHT.8 And as mentioned earlier, when making its case to FDA in 1997, Merck only focused on effects on two steroids, testosterone and DHT. The drug label also mentions only these effects, but not other effects of inhibiting the 5-AR enzyme.9
Inhibiting the 5-AR enzyme has direct impact on six different steroids, as well as other steroids upstream and downstream. Merck limited its explanation to just one of these reactions which is linked to the drug’s efficacy (because DHT is believed to contribute to male pattern hair loss).1,9
The drug maker frequently used the word “selective” since finasteride inhibits just one of two variants of 5-AR. At the same time, the drug broadly disturbs the delicate machinery of steroid synthesis, but this received no mention in official documents. Merck drew attention to one aspect of the story—the one that supported drug efficacy—while omitting information that would raise concerns about risks.
If the drug’s full biochemical impact had been disclosed earlier, or discerned by FDA reviewers, it could have raised red flags about risks. In the decades since the drug was approved, a pattern has emerged in men who experienced harms. The organs and functions most commonly and severely affected—sexuality, mental status, cognition and memory—depend on steroid signaling. The writing was on the wall as early as 1990, but Merck excluded information that could jeopardize its aspiration to reap billions of dollars in profits.
A. In popular knowledge, the term steroid brings to mind bodybuilding; however, here it refers to a chemical structure with four rings. The steroids testosterone and estrogen are commonly called hormones. Others are called neurosteroids because of their role in brain signaling.
⚠️ = conflict of interest due to Merck involvement.
1. U.S. Food and Drug Administration; Division of Dermatologic and Dental Drug Products. Review and Evaluation of Pharmacology and Toxicology Data (NDA 20-788 000-BP). Submitted November 5, 1997.
2. ⚠️ Gormley GJ. Finasteride: a clinical review. Biomed Pharmacother. 1995;49(7-8):319-324. doi:10.1016/0753-3322(96)82658-8 [Author is a Merck researcher]
3. Giatti S, Diviccaro S, Serafini MM, et al. Sex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role. Front Neuroendocrinol. 2020. doi:10.1016/j.yfrne.2019.100804 • PubMed
4. Schiffer L, Barnard L, Baranowski ES, et al. Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review. J Steroid Biochem Mol Biol. 2019. doi:10.1016/j.jsbmb.2019.105439 • PMC full text
5. Traish AM. 5α-reductases in human physiology: an unfolding story. Endocr Pract. 2012. doi:10.4158/EP12108.RA • PubMed
6. Reddy DS. Role of hormones and neurosteroids in epileptogenesis. Front Cell Neurosci. 2013. doi:10.3389/fncel.2013.00115 • PMC full text
7. ⚠️ Imperato-McGinley J, Shackleton C, Orlic S, Stoner E. C19 and C21 5 beta/5 alpha metabolite ratios in subjects treated with the 5 alpha-reductase inhibitor finasteride: comparison of male pseudohermaphrodites with inherited 5 alpha-reductase deficiency. J Clin Endocrinol Metab. 1990. doi:10.1210/jcem-70-3-777 • PubMed [Includes a Merck researcher (ES) as co-author]
8. ⚠️ Kaufman KD, Dawber RP. Finasteride, a type 2 5ɑ-reductase inhibitor, in the treatment of men with androgenetic alopecia. Expert Opin Investig Drugs. 1999. doi:10.1517/135437184.108.40.2063 • PubMed [By Merck researchers; lead author was Director of Propecia clinical development]
9. Merck & Co., Inc. Prescribing Information: PROPECIA (finasteride) Tablets, 1 mg. December 8, 2001.
10. ⚠️ Gormley GJ, Stoner E, Rittmaster RS, et al. Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab. 1990. doi:10.1210/jcem-70-4-1136 • PubMed [Funded by Merck and co-authored by Merck researchers]
11. Dušková M, Hill M, Stárka L. The influence of low dose finasteride, a type II 5α-reductase inhibitor, on circulating neuroactive steroids. Horm Mol Biol Clin Investig. 2010. doi:10.1515/HMBCI.2010.010 • PubMed
12. Stanczyk FZ, Azen CG, Pike MC. Effect of finasteride on serum levels of androstenedione, testosterone and their 5α-reduced metabolites in men at risk for prostate cancer. J Steroid Biochem Mol Biol. 2013. doi:10.1016/j.jsbmb.2013.02.015 • PubMed
Marchetti PM, Barth JH. Clinical biochemistry of dihydrotestosterone. Ann Clin Biochem. 2013. doi:10.1258/acb.2012.012159 • PubMed
Studies of finasteride’s effect on steroid levels
|Study and method||Relevant findings|
|Imperato-McGinley et al (1990)7|
Included a Merck researcher as co-author and used Merck trial data.
The subgroup of interest were 29 men aged 45–75, taking finasteride doses of 0.2–80 mg per day. Steroid ratios were measured by assay of urinary metabolites at 0, 3 and 6 months.
|– Elevated ratio of etiocholanolone(5β)/androsterone(5ɑ)|
– Elevated 5β/5ɑ ratios of 11β-hydroxyandrostenedione, cortisol, and corticosterone
(Finasteride lowers levels of 5ɑ-reduced steriods which are in the denominator of each ratio.)
|Gormley et al (1990)10|
Three authors were Merck researchers, and the study was supported by grants from Merck.
30 male volunteers ages 40–77 took low doses of finasteride (0.04, 0.12, 0.2, and 1.0 mg) for 14 days. Steroid levels were measured by serum assay.
|On day 14, androstanediol glucuronide and androsterone glucuronide levels were decreased in each group receiving finasteride.|
Suppression was similar to that of dihydrotestosterone.
|Dušková et al (2009)11|
20 men with average age of 69.2 with benign prostate hyperplasia. Took finasteride 5 mg for 4 months. Steroid levels were measured by serum assay.
|Androsterone, epiandrosterone, dehydroepiandrosterone, 16α-hydroxydehydroepiandrosterone, 7α-hydroxydehydroepiandrosterone and allopregnanolone levels were all significantly lower.|
Allopregnanolone was down a median of over 300%. Epietiocholanolone was up by over 600%.
|Stanczyk el al (2013)12|
~26 men aged 57–79 years with elevated PSA levels were administered finasteride (5 mg). Blood was taken at baseline, 1, 3, 6 and 12 months. Steroid levels were measured by serum assay.
|At 1 month|
– 3α-androstanediol glucuronide ↓ 75.7%
– Androsterone glucuronide ↓ 43.0%
At 3 months
– Androsterone glucuronide ↓ 22.2%
– Testosterone ↑ 34.5%
– Androstenedione ↑ 18.3%
Review article — see text for citations.
|5ɑ-reductase is involved in these conversions:|
– Testosterone to dihydrotestosterone
– 4-Androstenedione to 5ɑ-dihydroandrostenedione
– Progesterone to 5ɑ-dihydroprogesterone
– Deoxycorticosterone (DOC) to 5ɑDH-DOC
– Corticosterone to to 5ɑ-dihydrocorticosterone
– Aldosterone to 5ɑ-dihydroaldosterone