A brief history of research on 5-alpha reductase inhibitors

For broader historical perspective, see the timeline and sources on the early history of finasteride.

This complex body of research can be thought of in phases:

Origins: 1974–1979

The development of 5-alpha reductase inhibitors (5-ARIs) was prompted by a 1974 study by Julianne Imperato-McGinley and colleagues on individuals with atypical sexual development in a remote village in the Dominican Republic. When these individuals matured into adulthood, they had small prostates and no recession of the hairline. These traits were attributed to a deficiency in the enzyme 5-alpha reductase (5-AR). Imperato-McGinley went on to publish dozens of papers on 5-alpha reductase deficiency and related topics. (See also: Further reading on guevedoces and the early history of finasteride.)

Drug development and Proscar approval, 1981–1992

In the 1980s, Merck, SmithKline Beckham and other companies developed compounds inhibiting 5-AR, filed patents and tested the compounds in animal studies.

In 1992, the Finasteride Study Group published an article on finasteride as a treatment for benign prostatic hyperplasia (BPH) in The New England Journal of Medicine. Also in 1992, FDA approved Merck’s application for Proscar (finasteride, 5 mg/day) for the treatment of BPH.

Propecia development and approval, 1992–1997

In the mid-1990s, trials were run on finasteride for androgenetic alopecia culminating in FDA approval of Propecia (finasteride 1 mg) in late 1997.

Whereas Proscar was used by urologists to treat men 50 and older, Propecia would be used by dermatologists to treat hair loss in much younger men, 18 and older.

Quiet period, 1998–2009

Following approval of Propecia, there was a slow trickle of papers, averaging about 10 per year. During this period, finasteride was studied as a treatment to prevent prostate cancer. GSK developed another 5-ARI, Avodart (dutasteride) which was approved for the treatment of BPH in 2001.

Concerns about persistent adverse effects and post-finasteride syndrome, 2010–present

In December 2010, the first paper on persistent adverse effects of 5-ARIs, by Traish et al., was published online. Two more papers followed in 2011, by Irwig & Kolukula and Goldstein. In September 2011, the first known research meeting on post-finasteride syndrome occurred in Trieste, Italy (program).

From this point, research on adverse effects of 5-ARIs accelerated:

As of August 2022

Whereas earlier papers came from the fields of urology and dermatology, research during this period brought new perspectives including genetics, neuroendocrinology and pharmacovigilance:

  • Androgen receptor polymorphisms. From 2014–2016, Sabina Cauci and colleagues explored whether post-finasteride symptoms might correlate with CAG and GGN polymorphisms on androgen receptor. The results were inconclusive.
  • Neuroendocrinology & pharmacology. Roberto Melcangi, Silvia Giatti and colleagues at the University of Milan launched a research program that has produced over a dozen papers. They have explored post-finasteride syndrome and post-SSRI sexual dysfunction in humans and animal models.
  • Pharmacovigilance. Since 2018 there has been a burst of papers analyzing pharmacovigilance signals of 5-ARIs. Broadly, these papers attribute adverse event reports to coincidental factors such as nocebo effect and stimulated reporting, while discounting the role of the drugs themselves. (Critical commentary may be found in Responding to a literature of doubt and Context matters.)
  • Penile abnormalities. Animal studies and a few recent human studies have demonstrated associations of 5-ARI use with penile abnormalities.
  • Epigenetic changes. A 2021 paper by Howell et al. reported altered gene expression in post-finasteride syndrome patients. PFS Network has announced a study of epigenetic changes associated with post-finasteride syndrome, to be carried out by the Institute for Human Genetics at University Medical Center Schleswig-Holstein (Germany).

More research and background

Papers are grouped by symptom / clinical presentation here. Several systematic reviews and meta-analyses have been published in recent years.

See also: a more general historical timeline and the most-published researchers on adverse effects of 5-ARIs.