Journal of Infertility and Reproductive Biology

Published date: Jun 20 2025

Journal Title: Journal of Infertility and Reproductive Biology

Issue title: Journal of Infertility and Reproductive Biology: Volume 13, Issue 2

Pages: 71 - 81

DOI: 10.18502/jirb.v13i2.18709

Ponneri NaveenDepartment of Biochemistry, Yogi Vemana University, Kadapa-516005, AP

Sri Bhashyam SainathDepartment of Biotechnology, Vikrama Simhapuri University, Nellore-524324, AP

Arifullah MohammedDepartment of Biotechnology, Koneru Lakshmaiah University (KLEF), Vaddeswaram Campus, Guntur, Andhra Pradesh

Ramesh KoduruDepartment of Biochemistry, Yogi Vemana University, Kadapa-516005, AP

Saeed AlshahraniDepartment of Pharmacology and Toxicology, College of Pharmacy, Jazan

Ramachandra Reddy Pamuruprcr-bio@yogivemanauniversity.ac.inDepartment of Biochemistry, Yogi Vemana University, Kadapa-516005, AP

Ghazala MuteebDepartment of Nursing, College of Applied Medical Science, King Faisal University, Al-Ahsa 31982

The current investigation is designed to explore the possible role of fetal exposure to the anti-hypersensitive drug zestoretic, a version of lisinopril (angiotensin-converting enzyme inhibitor) and hydrochlorothiazide (a diuretic drug) on female fertility efficacy in rats at their adulthood.The pregnant rats were oral gavaged withzestoretic 25, 50 and 100 mg/kg body weight on 7, 9, 11 and 13 days of gestation. The F1 female rats were tested with estrus cycle length and reproductive efficacy.Zestoreticfetal exposure induced significant change (P<0.001) in prolonged estrus cycles, reduced body weight, increased implantation loss and resorptions, conception time, mating index, and fertility index in female F1 rats, indicating potential harm to embryonic development and reduced fertility later in life.Though zestoretic reduces high blood pressure, its prenatal exposure harms F1 female reproductive health, causing prolonged estrus cycles, reduced fertility with increased conception time, resorptions and implantation loss. Although rat study results can’t directly apply to humans, caution and strict dosage adherence are advised when using anti-hypersensitive drugs during pregnancy.

Keywords: anti-hypersensitive drugs, estrus cycle, fertility, female rats, reproduction and zestoretic

[1] Berta E, Lengyel I, Halmi S, Zrínyi M, Erdei A, Harangi M, et al. Hypertension in Thyroid Disorders. Front Endocrinol (Lausanne). 2019;10:482.

[2] Mancia G. The antihypertensive effects of the lisinopril-hydrochlorothiazide combination (Zestoretic) in elderly hypertensive patients. The results of a multicenter study. The Italian Zestoretic Study Group. Minerva Cardioangiol. 1994;42(10):483–91.

[3] Olvera Lopez E, Parmar M, Pendela VS, Terrell JM. Lisinopril. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.

[4] White CM. Pharmacologic, pharmacokinetic, and therapeutic differences among ACE inhibitors. Pharmacotherapy. 1998;18(3):588–99.

[5] U.S. Food and Drug Administration (FDA). Zestril (Lisinopril) Use in Pregnancy . Silver Spring (MD): FDA; 2023. https://www.fda.gov/drugsatfda

[6] Monaco CF, Davis JS. Mechanisms of angioregression of the corpus luteum. Front Physiol. 2023;14:1163003.

[7] Yoshimura Y. The Ovarian Renin–Angiotensin System in Reproductive Physiology. Front Neuroendocrinol. 1997;18(3):247–91.

[8] Naveen P, Srivedi V, Reddy PR. Prenatal zestoretic exposure ameliorates developmental landmarks in rat offspring. J Trop Resour Sustain Sci. 2022;10(2):6–11.

[9] Cooper R. Monitoring of the Estrous Cycle in the Laboratory Rodent by Vaginal Lavage. In: Female Reproductive Toxicology. 1993. 11: 45–54.

[10] Crooke A. Experimental endocrinology, a source book of basic techniques. Endeavour. 1965;24(92):114–5.

[11] Cora MC, Kooistra L, Travlos G. Vaginal Cytology of the Laboratory Rat and Mouse. Toxicol Pathol. 2015;43(6):776–93.

[12] Rostami Dovom M, Ramezani Tehrani F, Djalalinia S, Cheraghi L, Behboudi Gandavani S, Azizi F, et al. Menstrual Cycle Irregularity and Metabolic Disorders: A Population-Based Prospective Study. PLoS One. 2016;11(12):e0168402.

[13] Barreto-Chaves MLM, Carrillo-Sepúlveda MA, Carneiro-Ramos MS, Gomes DA, Diniz GP. The crosstalk between thyroid hormones and the Renin–Angiotensin System. Vascul Pharmacol. 2010;52(3–4):166– 70.

[14] Hacıhanefioglu B, Somunkıran A, Mahmutoglu I, Sercelik A, Toptani S, Kervancioglu E, et al. Effect of hypertension therapy with the angiotensin-converting enzyme inhibitor lisinopril on hyperandrogenism in women with polycystic ovary syndrome. Fertil Steril. 2002;77(3):526–8.

[15] Oyedeji K, Olusina D, Alomo TO, Obisesan A, Zachariah R. Effect of Lisinopril (ACE Inhibitor) on Reproductive Function in Female Wistar Rats. J Pharm Sci & Res. 2020;12(7):1185–7.

[16] Rapp K, Wei S, Markovetz M, Roberts M, Yao S, Han L, et al. Inhibition of the Epithelial Sodium Channel (ENaC) Promotes Mucus Hydration in Rhesus Macaque Endocervical Cells. Contraception. 2023;127:110158.

[17] Troffa C, Tonolo G, Melis MG, Manunta P, Soro A, Pala F, et al. Effect of Angiotensin Converting Enzyme Inhibition on the Menstrual Cycle of Hypertensive Women. J Cardiovasc Pharmacol. 1991;18(3):462–7.

[18] Pucci M, Sarween N, Knox E, Lipkin G, Martin U. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits. Expert Rev Clin Pharmacol. 2015;8(2):221–31