PT-141 in men: a central, not vascular, mechanism

Another way into sexual function

PDE5 inhibitors act in erectile tissue: they amplify a response that has already started. Bremelanotide (PT-141) works further upstream. It is a synthetic α-MSH analog that acts as an agonist at the MC3R and MC4R melanocortin receptors, which are expressed mainly in the central nervous system¹. That is why the urology literature groups it with centrally acting agents, alongside the dopamine, serotonin and testosterone systems¹⁴. This article focuses on men and on mechanism; the shared origin with melanotan II and the approval in women are covered in Melanotan II and PT-141: chemical cousins, opposite stories.

What the laboratory shows about mechanism

The role of MC4R in erection was described with genetic and pharmacological tools. Merck researchers showed in 2002 that a selective MC4R agonist increased erectile activity induced by cavernous nerve stimulation in normal mice but not in mice lacking the receptor; that copulatory behavior was reduced in mice without MC4R; and that the receptor was expressed in human and rat penis, in rat spinal cord, hypothalamus and pelvic ganglion and in nerve fibers of the glans, but not in rat primary corpus cavernosum smooth muscle cells².

With PT-141 itself, systemic administration in rats activated hypothalamic neurons (increased c-Fos), in the same region that connects to the corpus cavernosum in pseudorabies virus tracing studies; in rats and nonhuman primates it produced erections¹. Bremelanotide activates several melanocortin receptor subtypes, with MC4R the most relevant at therapeutic doses; in the brain, MC4R is expressed mainly in the medial preoptic area (mPOA) of the hypothalamus³. The current hypothesis, based on animal studies, is that it activates presynaptic MC4Rs in that region and increases the release of dopamine, an excitatory neurotransmitter of sexual desire³.

The background: melanotan II in men

Clinical interest began with melanotan II, the compound PT-141 derives from. In a double-blind crossover trial in 10 men with psychogenic erectile dysfunction, 8 of 10 developed clinically apparent erections; mean duration of tip rigidity above 80% was 38.0 minutes versus 3.0 with placebo (p = 0.0045)⁴. In 10 men with organic risk factors, the compound initiated patient-reported erections after 12 of 19 injections versus 1 of 21 with placebo, and reported sexual desire was higher; nausea was frequent and 4 of 19 injections were associated with severe nausea⁵.

The PT-141 trials in men

Intranasal route (Diamond, 2004). In healthy men and in patients with mild-to-moderate erectile dysfunction who responded to sildenafil, the RigiScan-measured erectile response was statistically significant versus placebo at doses above 7 mg, with the first erection at about 30 minutes. Half-life was 1.85 to 2.09 h. Flushing and nausea were the most common adverse events; no maximum tolerated dose was identified⁶.

Subcutaneous route (Rosen, 2004). In healthy men without visual stimulation, doses of 0.3 to 10 mg produced a significant erectile response above 1.0 mg. In patients with an inadequate response to 100 mg sildenafil, both 4 and 6 mg produced a significant response versus placebo in a crossover design⁷. This is the most interesting finding for clinicians: a different mechanism that worked where the vascular pathway fell short.

Combination with sildenafil (Diamond, 2005). In 19 men who responded to a PDE5 inhibitor, 7.5 mg intranasal PT-141 plus 25 mg sildenafil produced a greater erectile response than sildenafil alone, with no new or more frequent adverse events than with either drug alone⁸.

Sildenafil non-responders (Safarinejad and Hosseini, 2008). In 342 men, 10 mg intranasal was associated with positive clinical results in 33.5% versus 8.5% with placebo (p = 0.03), with more adverse events in the active group⁹. This trial should be read with caution: in 2023 the journal published an expression of concern about the article⁹, and another bremelanotide trial by the same author, in women, was retracted¹⁰.

Why development moved to women

The intranasal route had two problems. According to the program's investigators, absorption was highly variable, so some study subjects received more exposure than needed and others less; and the formulation "could elevate BP in both men and women"¹¹. The program moved to the more predictable subcutaneous route and to hypoactive sexual desire disorder in premenopausal women¹¹. The two RECONNECT phase 3 trials enrolled 1,267 women and showed increases in desire (+0.35) and reductions in distress (−0.33) versus placebo, both P < 0.001¹². The FDA approved Vyleesi in 2019 for that indication¹³.

Where the evidence ends

• No approval in men. The Vyleesi label states that it "is not indicated for the treatment of HSDD in postmenopausal women or in men" and that it is not indicated to enhance sexual performance¹³.
• Blood pressure. With 1.75 mg subcutaneous, systolic pressure rose by up to 6 mmHg and diastolic by up to 3 mmHg, peaking at 2–4 hours, with a heart rate reduction of up to 5 bpm; values generally returned to baseline within 12 hours. It is contraindicated in uncontrolled hypertension or known cardiovascular disease¹³. In an ambulatory monitoring study in 397 women, systolic increases were about 2.4 to 3.2 mmHg versus placebo and transient¹¹.
• Nausea. It was the most common adverse reaction in the phase 3 trials: 40% versus 1% with placebo; 13% needed an antiemetic and 8% left the study¹³.
• Focal hyperpigmentation. Reported in 1% with up to 8 doses per month (face, gums, breasts); with daily dosing for 8 days it reached 38%, was more frequent in darker skin, and resolution was not always confirmed¹³.
• Small, older data in men. The male trials are phase 1–2, from 2004–2008, mostly sponsor-run, with laboratory endpoints such as RigiScan⁶⁷⁸; the largest is under an expression of concern⁹.