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. Besodeoxifen, which was discovered by our group, is such an estrogen receptor (ER) ligand; it is now available for menopausal women. However, we could not identify a brain- or central nervous system-specific estrogen.

While at Wyeth, a novel estrogen receptor (ER-beta) was discovered and we were among the first, and many times the first, scientists who provided 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 again and continued my research. I have been collaborating with Dr. Laszo Prokai at North Texas Health Science Center, Fort Worth, TX who, while studying estrogen’s 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 that uses 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 water soluble (i.e., drugable), 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 developing a primate model of hot flush utilizing the non-invasive infrared imaging to measure changes in skin temperature. Development of such a model would give a boost for further research on DHED, addressing hot flushes. 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 hypoandrogenic symptoms (hot flushes, depression, cognitive impairment, insomnia, and reduced libido) or similar symptoms in castrated men suffering from prostate cancer. 

My love for neuropeptides and neuroprotection has not ended. 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. I am interested in exploring the therapeutic uses of pleiotropic treatment with estrogens or pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP is a 38-amino-acid peptide and 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. In experimental stoke and traumatic brain and spinal cord injury models, PACAP provides neuroprotection hours after the injury. However, its half-life is short (4-6 minutes) and therefore, the native peptide is not practical to use as a therapeutic. To circumvent this problem, in collaboration with Drs. David H. Coy and Jerome L. Maderdrut of the Peptide Research Laboratory at Tulane University, we are going to evaluate novel, proteolysis-resistant, and receptor subtype-specific PACAP analogs with long half-lives in animal models of traumatic brain and spinal cord injuries and diabetic neuro- and nephropathies.

Another area where PACAP can be utilized is the chemotherapy-associated infertility. PACAP protects against the toxic effects of chemotherapeutic agents in granulosa cells of the ovaries and it is our hope that it will preserve the fertility of women under chemotherapy due to hematopoietic cancers or multiple sclerosis. The PACAP analogs will be tested as soon as our R21 applications, to be submitted in February, are funded. The Peptide Research Laboratory has been highly successful in translating basic peptide research into marketable medicines. It has developed two peptide-based drugs (triptorelin and lanreotide) that have been on the market in the U.S. and the European Union for over a decade.

Ongoing Research Support

(Pending Support) Merchenthaler-Mamczarz, MPI’s
07/01/2024-10/30/2026
$424,875
NIH
Role of the endocannabinoid system in the development of chlorpyrifos-induced cognitive impairment and Alzheimer’s disease related brain neuropathology: a guinea pig model

The primary objective is to evaluate the role of CB1 receptors in mediating the effects of acute, low dose of chlorpyrifos on cognition in guinea pigs.

Role: Co-investigator

R01AG070072 Merchenthaler I, Prokai L, Puche A. (MPI’s)
01/15/2021-12/31/2025
$3,009.02
NIH
Brain-selective estrogen therapy for menopausal hot flushes in an advanced translational animal model.

The primary objective is to evaluate the preventive effect of Brain-selective estrogen (DHED) on menopausal hot flushes in rhesus macaques.

Role: Co-investigator

R01CA246929 Lacreuse A, Prokai L, Merchenthaler I. (MPIs)
01/01/2021- 12/31/2025
$3,509.413
NIH
Impact of Brain Estrogens on Cognition and Brain Aging in a Non-human Primate

The primary objective is to evaluate the protective effect of Brain-selective estrogen (DHED) on cognitive and memory functions in marmosets.

Role: Co-investigator

5R21MH129809-02 Brown, P.L. and Merchenthaler, I.
01/01/2023-12/31/2025
$221,705
NIH
Estrogen modulation of the lateral habenula and its ability to inhibit midbrain dopamine neurons

The primary objective is to evaluate the effect of estrogen on the interplay between the lateral habenula and midbrain and on motivation and reward learning in both female and male rats.

Role: Co-investigator

VA 1 I01 BX006018-01 Gould, T.
01/01/2023-12/31/2025
$1,243.343
Veterans Administration
Estradiol treatment of stress-related psychiatric disorders in Veterans

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

R01CA246929 (Lacreuse A, Prokai L, Merchenthaler I., MPI)
07/01/2020-06/30/2025  0.60 cal. months
NIH/NCI
$457,718 (direct costs, first budget year)

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

R01AG070072 (Merchenthaler I, Prokai L, Puche A., MPI)
09/01/2020-08/31/2025 4.2 cal. Months
NIH/NIA
$450,000 (direct costs, current budget year)

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-MPI

Completed Research Support

R01ES027822 Merchenthaler, Gullapalli (PIs)
01/01/2018-12/31/20221.2 cal months
$542,187 (direct + indirect)
NIEHS/NIH
Targeting M1/M3 Muscarinic Receptors to Treat Gestational Pesticide Poisoning

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: Co-investigator

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

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

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 calendar

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

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 calendar

Establishment of a primate model for menopausal hot flushes. 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 calendar

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

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 calendar

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

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 calendar

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

NIH/NIA 1R01AG031535-01A2 Merchenthaler (PI)
07/01/2008 - 06/30/2012 2.4 calendar

Novel treatment of menopausal hot flushes with para-quinol of estrogen. The main goal is to determine whether para-quinol of estrogen prevents hot flushes 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

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)