Istvan J. Merchenthaler, MD, PhD, DSc

Dudas, B and Merchenthaler, I.: Topography and associations of leu-enkephalin and luteinizing hormone-releasing hormone neurons in the human diencephalon. J. Clin. Endo. Metab.88:1842-1848, 2003.

Bernstein, L.R., Mackenzie, A.C.L., Kraemer, D.C., Morley, J.E., Farr, S., Chaffin, C.L., Merchenthaler, I. Shortened estrous cycle length, increased FSH levels, FSH variance, and oocyte spindle aberrations and early declining fertility in aging senescence-accelerated mouse prone-8 (SAMP8) mice: concomitant characteristics of human mid-life female reproductive aging. Endocrinology, 155:2287-3000, 2014.

Prokai, L., Nguyen, V.,  Szarka, Sz., Ughy, B., Sabnis, G., Bimonte-Nelson, H.A.,  McLaughlin, K.J., Talboom, J.S., Conrad, C.D., Brodie, A., Gould, T.D., Koulen,P., Merchenthaler, I., Prokai-Tatrai, K. Metabolism-based targeting of 17β-estradiol into the brain. Science Translational Medicine, 7, 29,ra113, 2015.

Merchenthaler, I., Lane, M., Sabnis, G., Brodie, A., Prokai-Tatrai, K.,  Prokai, L. Novel treatment of menopausal hot flushes with an estradiol bioprecursor in two animal models of thermoregulatory dysfunction. Nature, Scientific Reports, 6:30721, 2016.

During the first fifteen years of my research career, my work was focused on neuropeptides, especially peptides that regulate anterior pituitary function (i.e., hypophysiotropic hormones). Utilizing stereotaxic surgeries, retrograde labeling and immunocytochemistry, I provided the first descriptions of several of these peptide hormones. My PhD and DSc degrees were based on studies dealing with luteinizing hormone–releasing hormone (LHRH), corticotropin-releasing hormone (CRH), growth hormone-releasing hormone (GH-RH), thyroid-releasing hormone (TRH), and endogenous opioid peptides.

Later, when I was at the National Institute of Environmental Health Sciences/NIH in Research Triangle Park, NC, I become interested in the co-localization of neuropeptides and the regulation of co-localization by sex hormones. These studies have led to the discovery of sex-specific and estrogen-dependent co-localization of LHRH with galanin in the preoptic area of the hypothalamus and the prolactin-dependent co-localization of enkephalins and dopamine in the tuberoinfundibular dopaminergic (TIDA) neurons. The work in this field has resulted in many publications in prestigious journals, including a few in the Proceedings of the National Academy of Sciences, USA. Although later my interest turned toward sex steroid hormones and their receptors (see below), I still have a lasting affection for neuropeptides.

In 1994, I joined Wyeth Research, a pharmaceutical company, as the Director of the Functional Morphology Division of the Women’s Health Research Institute. My primary activity was to support the discovery of novel tissue-selective estrogen therapeutics. My specific goal in this complex drug discovery process was to identify an estrogen receptor ligand that alleviates hot flushes in an animal model without stimulating the uterus and the breast. Bazedoxifene, which was discovered by our group, is such an estrogen receptor (ER) ligand; now is available to menopausal women. While at Wyeth, a novel estrogen receptor (ER-beta [REβ]) was discovered and we were among the first, and many times the first, providing the description of its distribution and the regulation of its synthesis in rodents. As we knew from animal models that estrogens provide neuroprotection in several neurodegenerative diseases and cerebrovascular stroke, my interest turned toward cerebrovascular stroke and its prevention/treatment with estrogen. Utilizing rodent models of stroke, in collaboration with Dr. Phylis Wise’s group at University of Kentucky, we showed that ER-alpha, the classical ER plays a critical role in neuroprotection.

 In 2004, I came to the University of Maryland, Baltimore (UMB) and started to teach Human Anatomy, Histology and Embryology, and continued my research. For years, I collaborated with Drs. David H. Coy and Jerome L. Maderdrut of the Peptide Research Laboratory at Tulane University, to evaluate novel, proteolysis-resistant, and receptor subtype-specific pituitary adenylate cyclase-activating polypeptide (PACAP) analogs. PACAP has remarkable anti-inflammatory and immunosuppressive activities. In addition, it has remarkable cytoprotective activities: it stimulates neurogenesis, induces the expression of DNA-repair enzymes, reduces edema, etc. Unlike other peptides, PACAP crosses the blood-brain barrier via a saturable uptake mechanism. We evaluated PACAP analogs in mouse models of experimental stroke and traumatic brain injury, and diabetic neuropathy models.

Since 2006 I have been collaborating with Dr. Laszlo Prokai at North Texas Health Science Center, Fort Worth, TX who, while studying estrogen metabolism, has discovered an intracellular redox cycle by which estradiol, following scavenging free radicals, is converted to a steroid (DHED is its abbreviated name) which then is converted back to estrogen via a reductase using NADPH. This conversion takes place only in the brain. Therefore, DHED can be considered as a pro-estrogen and can be used as a pro-drug delivery approach for the brain. DHED is soluble water (i.e., druggable), does not bind to any receptors, and penetrates the blood-brain barrier with high efficacy. Once in the brain, it is converted to estradiol. My current effort focuses on testing DHED in a primate model of hot flush utilizing the non-invasive infrared imaging to measure changes in skin temperature. The results clearly show that DHED prevents ovariectomy-induced hot flushes in rhesus macaques. As many actions of testosterone in men are mediated via estradiol following the aromatization of testosterone to 17β-estradiol, DHED can be given to men to alleviate age-associated hypo androgenic symptoms (hot flushes, depression, cognitive impairment, insomnia, and reduced libido) or similar symptoms in castrated men suffering from prostate cancer or aged individuals. 

From 2014 I have been collaborating with Dr. Lori Bernstein, Adjunct professor of UMB to develop therapies for advanced aged women. As our hypothesis is that the elevated FSH levels are the primary reason for infertility, our efforts have been to use drugs that reduce FSH to levels, characteristic for young women.

I strongly believe that complex diseases with specific chronological patterns of pathologic events such as Alzheimer’s disease, stroke, traumatic brain and spinal cord injuries, etc. cannot be cured or prevented by a single therapeutic that focuses on a single target/pathway. Therefore, during the last two-three decades I have been interested in exploring the therapeutic uses of pleiotropic treatment with PACAP and estrogens (DHED).

Pending:

R21 No ID yet (Merchenthaler, PI)  07/01/2026-06/30/2028                                                     0.6 cal

07/01/2024-06/30/2026                           

NIA/NIH                                                                                                                                                  $275,000

Assessment of pro-cognitive properties and effect on gene expression of a prolonged exposure to letrozole in aged mice.

Overview:  This proposal will evaluate the effect of letrozole on cognition and gene expression in the hippocampus in aged female mice     

Role PI

R01AG099894 (Merchenthaler-Mamczarz, MPI) 04/01/2026-03/31/2031          2.4 cal. months

NCI/NIH                                                                                                                                      $499,997

Role of the endocannabinoid system in the development of cognitive impairment induced by subacute exposure to non-blocking acetylcholinesterase doses of chlorpyrifos

Overview: The objective of the studies proposed here is to investigate the role of the endocannabinoid system, the role of CB1 receptors specifically, in the development of CPF-induced cognitive impairment and brain neuropathology. The application will evaluate short- and long-term effects of CPF exposure on the endocannabinoid system and functional and neurochemical changes related to this exposure of guinea pigs.

Role: PI

Active:

R01AG070072 (Merchenthaler I, Prokai L, Puche A, MPI)        09/01/2020-08/31/2025    4.2 cal. months

NIH/NIA                                                                                                                                       $3,009.022

Brain-selective estrogen therapy for menopausal hot flushes in an advanced translational animal model.

Overview: To evaluate the brain-selective estrogen as a side effect-free therapy for menopausal hot flushes in rhesus monkeys

Role: PI

R01CA246929 (Lacreuse A, Prokai L, Merchenthaler I, MPI)    07/01/2020-06/30/2025   0.60 cal. months

NIH/NCI                                                                                                                                      $3,509.413

Impact of brain estrogens on cognition and brain aging in a non-human primate.

Overview: This proposal uses a primate model to understand how aromatase inhibitors affect the brain and behavior and to test whether a drug that delivers estrogens exclusively to the brain can safely alleviate these deficits.

Role: MPI

Completed:

R21MH129809-02 (Brown PI)                             10/01/22-09/31/24                              0.6 cal. months

NIH/NIMH                                                                                                                                    $221,705

Estrogen modulation of the lateral habenula and its ability to inhibit midbrain dopamine neurons.

Overview: This proposal tests the hypothesis that circulating estrogen mediates the observed sex
difference in lateral habenula (LHb)-induced inhibition of midbrain dopaminergic neuronal firing in rats

Role: Co-I

University of Maryland Claude D. Pepper Older Americans Independence Center   0.0 cal. month

UM-OAIC,  Mamczarz (PI)                                                                                                                       

Overview: A combination therapy with a brain-selective estrogen and physical exercise to halt or slow the progression of cognitive decline.

Role: Co-I    

VA 1 I01 BX006018-01 Gould, T.   (PI)

Estradiol treatment of stress-related psychiatric disorders in Veterans

01/01/2023-12/31/2025
Overview: The primary objective is to evaluate the protective effects of Brain-selective estrogen (DHED) on depression, anxiety and sleep in a male muse model.

Role: Collaborator

R01ES027822 Merchenthaler, Gullapalli (MPI)

Targeting M1/M3 Muscarinic Receptors to Treat Gestational Pesticide Poisoning

01/01/2018-12/31/2022                                                                                                             1.2 cal. months
NIEHS/NIH
The primary objective of this study is to test the hypothesis that, in part by sparing M2 muscarinic receptors (mAChRs) and potentially by blocking nicotinic receptors in addition to M1/M3 mAChRs, trihexyphenidyl (THP) will be more potent and efficacious than atropine to treat gestational OP insecticide poisoning.

Role: PI

NIH/NIA 1 R01CA21550 Prokai-Merchenthaler (MPI)
04/01-2018-03/31/2021                                                                                                           2.4 cal. months

Brain-selective therapy to alleviate hot flushes of prostate cancer patients.  

Overview: To show that the pro-estrogen DHED in the brain is converted into estrogen and then prevents hot flushes on orchidectomized rats. We also wish to show that this conversion does not take place in the periphery, i.e., DHED will not stimulate the growth of prostate cancer cells implanted into nude mice.

Role: PI (MPI)

NIH/NINDS  5 R21 NS099778-02 Merchenthaler/Yarowsky (MPI)
02/01/2017-01/31/2019                                                                                                           1.2 cal. months

Effect of PACAP on the progression of Parkinson’s disease in chronic mouse model

Overview: This project will explore the protective effects of metabolically stable and receptor subtype-specific analogs of PACAP on the progression of PD when administered at the onset of the disease

NIH/NIA R21AG050900-02 Merchenthaler/Urbanszki (MPI)
04/15/2016-3/31/2018                                                                                                               1.2 cal. months

Establishment of a primate model for menopausal hot flushes.

Overview: This project will establish a non-human primate model to measure hot flushes with the non-invasive infrared technology

Role: PI (MPI)

NIH/SBIR  Ngyuen  (PI)
01/08/2016-07/31/2017                                                                                                              1.0 cal. month

A novel remedy of hot flushes for breast cancer patients undergoing aromatase inhibitor therapy.

Overview: This project will evaluate DHED (pro-estrogen) in a male rat model of hot flush

Role: PI of subcontract

NIH/NICHD   5 K12                HD43489-5         Tracy   (PI)
01/09/2012-08/31/2017                                                                                                           1.2 cal. months Maryland’s Organized Research Effort in Women’s Health (MORE-WH). This project will provide interdisciplinary mentored training in women’s health research to junior faculty scholars in an effort to foster the expansion of women’s health research across a variety of disciplines.

Role: Research Director

MIH/NIA R21HD078077-01 Wallen/Prokai/Merchenthaler (MPI)
08/05-2013-08/04/2015                                                                                                              1.2 cal. month

Effects of brain-selective estradiol on gene expression and female sex behavior.

Overview: The purpose of this application is to collect preliminary data on the role of a CNS-selective estrogen on the female sex behavior of rhesus monkeys.

Role: PI (MPI)

NIH/NIA 5R21AG033864-02 Merchenthaler (PI)
04/01/2012 - 03/31/2014                                                                                                     1.2 cal. month

Hot flushes and SNPs of the norepinephrine and serotonin transporter genes. The main goal is to study the effects of these SNPs on the efficacy of SSRIs in alleviating hot flushes.

Role: PI

NIH/NIA 3R01AG031535-01A2S1 Merchenthaler (PI)
09/30/2009 - 02/28/2012                                                                                                        2.4 cal month

Novel treatment of menopausal hot flushes with para-quinol of estrogen. To study if para-quinol of estrogen prevents depression/anxiety and sleep disturbances in animal models.

Role: PI

• Teaching (lectures and laboratory) Human Gross Anatomy and Histology to medical students
• Teaching (lectures and laboratory) Human Gross Anatomy and Embryology to dental students
• Co-Course Master: Biology of Aging, Gerontology Program
• Occasional lectures on GPILS-623, 645, 641 programs
• Lecturing on the menopause to Nursing School students
• PhD Thesis Committees
• Master Thesis mentor
• BIRCWH Research Director and mentor

• Immunocytochemistry
• In situ hybridization histochemistry
• Animal models of hot flush, stroke, type 1 and type 2 diabetes

Employment/Experience

• 1974-1986: Assistant Professor, Department of Anatomy, Medical School, Pécs, Hungary.
• 1981-1983: Visiting Scientist, Department of Cell Biology and Anatomy, University of North Carolina, Chapel Hill, NC
• 1984: Visiting Scientist, US-Japan Biomedical Research Laboratories, Tulane University, New Orleans, LA
• 1986-1988: Associate Professor Anatomy/Histology/Embryology, University Medical School, Pécs, Hungary
• 1988-1994: Section Head, Visiting Scientist, NIEHS/NIH, Research Triangle Park, NC
• 1994-2003: Director, Women’s Health Research Institute, Wyeth Research, Collegeville, PA
• 2003-2004: Distinguished Research Scientist, Women’s Health and Bone Institute, Wyeth Research, Collegeville, PA
• 2004-present: Professor, Department of Epidemiology, University of Maryland, Baltimore, MD
• 2004-present: Professor, Department of Anatomy and Neurobiology, University of Maryland, Baltimore, MD

Editorial Positions:

• 1994-1998:  Board Member, Endocrinology
• 2008-2012:  Board Member, Endocrinology
• 2005- present: Frontiers, Editorial board member
• 2025- present: I. J. Mol. Neurosci,  Guest editor

Reviewer:

• Ad hoc reviewer for more than 20 scientific journals
• Ad hoc reviewer for NIH/NIMH Study Sections, National Science Foundation, Alzheimer’s Association, the Hungarian Academy of Sciences, and NHMRC (Australia)