Is Low-Dose Prescribing a Possible New Naturopathic Modality?

Men’s Fertility Restored with Lisinopril

By Nora Jane Pope, FCP

This article examines the off-label use of low-dose lisinopril for treating idiopathic male infertility based on a compelling Nigerian study. It explores how lose-dose prescribing could be a naturopathic modality and highlights drug-herb synergies that could enhance therapeutic outcomes.

Introduction to Low-Dose Lisinopril for Male Fertility

A 2012 study published in the Clinical Pharmacology and Therapeutics journal presents a compelling example of restorative fertility.¹ 

The study suggests that a blood pressure drug from the ACE inhibitor class called lisinopril could improve outcomes for men struggling with infertility. 

Scientists at the Department of Pharmacology and Therapeutics, College of Medicine, University of Nigeria, conducted this research as part of a Five-Year Randomized, Controlled Crossover Pilot Study. The study revisits the concept of repurposing drugs for off-label uses, in this case, treating idiopathic male infertility.

Discoveries are accidents that happen to a prepared mind

“This preliminary study was occasioned by our previous, independent observations (albeit fortuitous) that normalization of seminal fluid parameters occurred in two men with long-standing idiopathic azoospermia and that their spouses became pregnant. The common factor between the two men was treatment with low-dose (2.5 mg/day) lisinopril, an angiotensin-converting enzyme inhibitor (ACEI) that had been prescribed for concomitant hypertension,”¹ said A U Mbah, lead author of the 2012 Nigerian study.

What is lisinopril?

Originally developed as an ACE inhibitor medication for hypertension, Lisinopril has since gained some attention for its broader effects on increasing sperm counts.     

Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxy-peptidase that generates the vasoconstricting peptide angiotensin II and inactivates the vasodilating peptide bradykinin. 

ACE inhibitors raise bradykinin by blocking the conversion of bradykinin into inactive peptides. This results in higher levels of bradykinin, which lowers blood pressure. Improved sperm parameters are the result of active bradykinin being present to exert its positive actions on Sertoli cells.²

Lisinopril and Fertility: The Study at the University of Nigeria

The study, led by researchers at the University of Nigeria, focused on a group of normotensive men diagnosed with idiopathic infertility, characterized by oligospermia. 

The study demonstrated that lisinopril treatment improved the sperm quality in these men. By targeting the ACE enzyme, the drug appeared to enhance the sperm cells’ ability for successful conception, boosting their chances of successful pregnancy. 

The research, though relatively small in scale, showed that lisinopril improved not only the number of sperm but their quality, translating into higher pregnancy rates.

The Mbah Nigeria study came about in a classic “necessity is the mother of invention” situation. In vitro fertilization (IVF) is not readily available in Nigeria due to its costs. Nigeria is considered a low-and medium-income country (LMIC). For men who typically face fewer options in poorer outcomes, low-dose Lisinopril offers a potential economical solution.

Study criteria were intentionally rigorously exclusive to rule out as many variables as possible.

• Oligo-astheno-teratospermia (sperm of low concentration, reduced motility, and increased abnormal morphology) was a requirement. 
• Sperm parameters included: between 10-20 million sperm count; 13% morphology; and over 40% motility.
• Age was limited to 24-34. 
• The work-up to determine idiopathic infertility confirmed none of the following: thyroid issue, prostatitis, anatomical hindrances like varicoceles. 
• The couples had to report over 24 months of infertility.

The design included a cross-over component at 96 weeks. 

• Week one through 96: In the first half, group A (n = 17) was on active medication (2.5 mg Lisinopril), and in the second half, Group B  (n = 16) was on inactive placebo.
• Week 96 through 192: group A was switched to an inactive placebo and group B was switched to active medication (2.5 mg lisinopril). 

Semen analyses were performed at six, 12, 24, 48 and 96 weeks.

33 men entered the study yet 28 completed it. The pregnancy rate was 48.5% for men who entered the study and 57% for those who completed the study. The full-term delivery rate was 46% for those who completed the study.

All three pregnancies occurred in the first 96 weeks (between 21 and 88 weeks) of the study only in the Group A treatment group on active medication, not the placebo group.

From Week 96 to 192, an additional eight pregnancies occurred in the same treatment group A, which were switched to the inactive placebo, in keeping with the cross-over design of the study, indicating that lisinopril continued to exert its therapeutic effects. An additional five pregnancies occurred in the Group B. 

Besides pregnancy rates, the semen analyses showed improved motility from weeks 12-48 (P < 0.001); increased sperm counts from weeks 24-102 (P < 0.0001); and improved morphology from weeks 12-112 (P < 0.04). 

While these early results are encouraging, the researchers involved in the study are cautiously optimistic. 

The study’s small sample size means that further large-scale trials are needed to confirm its efficacy and safety. More research to determine whether lisinopril can be safely and effectively used in broader populations of men facing fertility challenges is a welcome development. 

How Low-Dose Pharmacology Aligns with Naturopathic Medicine

The University of Nigeria study fits into a larger trend of repurposing existing drugs for off-label uses.  As scientific advancements shed light on how drugs like lisinopril affect human reproduction, the future of fertility treatment looks increasingly innovative. 

Many naturopathic jurisdictions across North America are seeking an increased scope of practice in the pharmacological sphere. Low-dose medications are philosophically consistent with naturopathic philosophy and welcome to the scope of practice. 

To Review our Guiding Principles:

#1 – Do No Harm: Minimal Effective Dosing

This is the foundation of the Hippocratic Oath

Prescribing the minimum and effective dose in a targeted fashion and with a restorative strategy reduces the possibility of undesirable side effects. In the Nigeria study, low-dose lisinopril, given at 2.5 mg/day for restorative fertility, was fraction of the typical 20-25 mg/d for hypertension. Hypotension is not a side effect.

#2 – Harness The Healing Power of Nature: Potential for Drug-Herb Synergies

Naturopathic doctors (NDs) should consider potential interactions when combining lisinopril with botanical medicine. Lisinopril is water-soluble and, as such, is not metabolized by cytochrome p450 enzymes, meaning isozyme interactions are likely non-existent. Its half-life is 10-12 hours, allowing for the safe inclusion of botanical supplements taken five to six hours later. 

This approach can foster a positive drug-herb interaction: a gentle, additive effect where both the drug and herb are synergistic, working through a similar mechanism of action. No p450 enzymes are blocked or antagonized, ensuring the drug’s efficacy remains intact. Astragalus, Licorice, and Baical Skullcap act as gentle ACE inhibitors.3,4,5 An additive effect can be safely achieved when these herbs are taken five to six hours after the 2.5mg of lisinopril.

#3 – Doctor as Teacher: Teach fertility-focused Intercourse with Cycle Charting

To address a gap in the study, I would have recommended teaching cycle charting to the couples in the study.  By tracking the woman’s fertile days, the couples could have timed intercourse to align with her most fertile period, potentially enhancing the chances of conception. This could have had an additional positive impact on the overall outcomes.⁶

#4 – Identify and Treat the Cause and Remove Obstacles to Cure

The causes of male infertility are multifactorial. There are many low-dose, off-label uses of different medications and their mode of action to point to the following potential root causes seen in male infertility: 

• Lisinopril – low bradykinin 
• Low Dose Naltrexone – disturbed endorphins⁷.
• Indomethacin – elevated prostaglandins⁸. 

Antioxidants – elevated lipid peroxidation⁹.

 #5 – Treat The Whole Person

Prescribing involves context, full history, and full workup. Perhaps bradykinin could be included in the differential for male infertility. As Dr. Mbah says in the 2012 study: “A possible explanation for this observed action of lisinopril may be found in our current knowledge about the relationship between gonadal ACE and gonadal kininase II. All the products of the kinin–bradykinin–kallikrein system have been found in human male genital secretions. The kinins have been shown to increase spermatogenesis, sperm motility, and sperm metabolism, even in minute concentrations……. It is possible that lisinopril, through the inhibition of kininase II, produces the observed effects on sperm quantity and quality by causing an accumulation of the products of the kinin–bradykinin–kallikrein system within the testicular milieu..”

 #6 – Teach Prevention

Nigerian men are experiencing declining sperm counts, a trend observed in other industrialized countries. As a major producer of petroleum products in the region, environmental exposures may contribute to this issue.

Could Low-Dose Lisinopril Revolutionize Male Fertility Treatment in Naturopathic Medicine?

What began as two case reports evolved into a hypothesis, ultimately culminating in this compelling study. Could low-dose lisinopril revolutionize male fertility treatment within naturopathic medicine? Could we consider low-dose restorative pharmacology a new naturopathic modality? Furthermore, is there potential for a beneficial drug-herb interaction to enhance its efficacy?

During my naturopathic medical practice from 2002 to 2019, I leveraged any successful treatment as a learning tool. When a drug successfully treats a patient, it creates an opportunity to reverse-engineer the medication and identify its botanical analog. This allowed me to prescribe botanicals in conjunction with prescription medication without any negative interactions. 

When administered in the lowest effective dose and with a restorative strategy, medications align seamlessly with naturopathic medicine’s philosophical framework.

---

---

References:

1.  Mbah AU et al, Clin Pharmacol Ther. 2012 Apr;91(4):582-9. Low-dose lisinopril in normotensive men with idiopathic oligospermia and infertility: a 5-year randomized, controlled, crossover pilot study
doi: 10.1038/clpt.2011.265. Epub 2012 Feb 29.

2.  N Atanassova ¹, L Kancheva, B Somlev, Immunopharmacology. Bradykinin stimulates prepubertal rat germ cell proliferation in vitro, 1998 Nov;40 (3):173-8.
doi: 10.1016/s0162-3109(98)00037-x.

3.  Wu JS, Li JM, Lo HY, Hsiang CY, Ho TY, J Ethnopharmacol. Anti-hypertensive and angiotensin-converting enzyme inhibitory effects of Radix Astragali and its bioactive peptide AM-1. 2020 May 23;254:112724. doi: 10.1016/j.jep.2020.112724. Epub 2020 Feb 28. PMID: 32119952 

4.  Haoran Li ¹, Yicheng Zhang ¹, Gaole Dai ¹, Ciren Zhaxi ¹, Yi Wang ¹, Shufang Wang ^2, Food Chem. Identification and quantification of compounds with Angiotensin-converting enzyme inhibitory activity in licorice by UPLC-MS, 2023 Dec 15:429:136962.doi: 10.1016/j.foodchem.2023.136962. Epub 2023 Jul 20.

5.  Pharm Biol. Inhibitory activities of baicalin against renin and angiotensin-converting enzyme, 2012 Apr;50(4):401-6. doi: 10.3109/13880209.2011.608076. Epub 2011 Dec 2. PMID: 22136493

6. Day 21 No More Day 21 No More (ndnr.com) by Nora Jane Pope. Accessed November 18, 2024

7.  Xiaofan Xiong ^1,2,†, Lingyu Zhang ^1,2,†, Meiyang Fan ^1,2, Lin Han ^1,2, Qiuhua Wu ^1,2, Siyuan Liu ^1,2, Jiyu Miao ^1,2, Liying Liu ², Xiaofei Wang ², Bo Guo ^1,2, Dongdong Tong ^1,2, Lei Ni ¹, Juan Yang ^1,2,*, Chen Huang ^1,2,*, Cells. 2019 Oct 16;8(10):1265. doi: 10.3390/cells8101265 β-Endorphin Induction by Psychological Stress Promotes Leydig Cell Apoptosis through p38 MAPK Pathway in Male Rats

8. Aris Kaltsas ¹, Athanasios Zachariou ², Fotios Dimitriadis ³, Michael Chrisofos ¹, Nikolaos Sofikitis ^2,*, Diseases. 2024 Sep 11;12(9):209. doi: 10.3390/diseases12090209 Empirical Treatments for Male Infertility: A Focus on Lifestyle Modifications and Medicines
9. M Fraczek ¹, D Szkutnik, D Sanocka, M Kurpisz, Ginekol Pol. 2001 Feb;72(2):73-9. [Peroxidation components of sperm lipid membranes in male infertility] [Article in Polish]