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Rhonda Renee Voskuhl is an American physician, research scientist, and professor. She is a member of the Brain Research Institute (BRI) at the David Geffen School of Medicine at UCLA and is the director of its Multiple Sclerosis Program. Voskuhl has published numerous scientific articles in academic journals and has served in the role of principal investigator for several treatment trials investigating potential treatments for multiple sclerosis (MS). [1]
Voskuhl has described her research as "bedside to bench to bedside", meaning observations made in clinical settings are used as a basis for the investigation of the relevant biological mechanisms of action. The information discovered is then applied in a clinical setting, typically through a drug therapy. [2]
Due to well-documented differences in prevalence of MS in males and females, [3] [4] [5] significant research on the autoimmune condition has turned to the neuropreservative effects of sex hormones. Evidence of suppression of MS symptoms in pregnant women in the third trimester [6] ultimately led to a focus on the female sex hormone estriol.
In 2001, Voskuhl published an article outlining discrepancies in EAE between male and female mice; she noted that females were more susceptible to EAE, mirroring the sex-based difference in MS in humans. It was found that the neuroprotective effects of testosterone contributed most to this discrepancy in mice. However, this sex difference is reduced during late pregnancy in females, when estriol levels are significantly higher than other periods of life. Her article established high levels of estriol as a possible explanation for the reduction in EAE symptoms observed during late pregnancy. [7]
In 2002, Voskuhl was part of the investigative team that found that treating non-pregnant women with 8 mg/day estriol helped to relieve symptoms, including lesion number and volume. Upon cessation of treatment, lesion number and volume returned to pre-treatment levels. After reinstituting treatment, lesion number and volume again decreased significantly. Cognitive ability, evaluated by the Paced Auditory Serial Addition Test (PASAT), also improved in those treated with estriol. In the authors' abstract, they indicated that this result warranted further experimentation through a placebo-controlled clinical trial. [8] This experiment was small, with only six women with relapse remitting MS (RRMS) and four women with secondary progressive MS (SPMS) finishing the trial. The authors noted that estriol generally improved symptoms in women with RRMS, but not in those with SPMS. [9]
In a 2011 research article, Voskuhl published data revealing that the estrogen receptor α (ERα) on astrocytes, not neurons, was responsible for the reduction of clinical EAE symptoms in mice. Using a gene knockout system Cre-Lox, the research team was able to remove ERα from neurons and in separate mice, remove ERα from astrocytes. It was found that the mice with ERα knocked out in astrocytes experienced an increase in clinical disease symptoms, macrophage and T-cell inflammation in the central nervous system, and axonal loss. These symptoms were not observed in those mice who had ERα removed from neurons. [10]
In 2016, the results of a Phase II Trial, in which Voskuhl participated, were released, detailing an experiment in which women with RRMS were treated daily with 8 mg estriol or placebo, combined with 20 mg injectable glatiramer acetate - an immunomodulator currently used to treat MS. It was found that women with the estriol treatment had significantly less relapses than the placebo group (0.25 relapses/year and 0.37 relapses/year, respectively), with similar amounts of serious adverse health events. The success of this trial convinced the authors to report that a Phase III Trial was warranted. [11]
In 2008, Voskuhl, together with Dr. Stefan Gold et al., published a study that revealed the effects of treating men with MS with a 10g gel containing 100 mg testosterone. Based upon the shift in cellular and chemical composition, particularly a decrease in IL-2 cell production, an increase in production growth factor TGFβ1, a decrease in CD4+ T cells, and an increase in NK (natural killer) cells, it was found that testosterone may play an important role in immunomodulation and neuroprotection. [12]
In a 2009 review article discussing the effects of sex hormones on MS, Voskuhl and Gold noted that one small trial conducted by a research team headed by Dr. Nancy Sicotte [13] suggested testosterone could be effective in preserving cognitive performance and reducing brain atrophy. [14] However, this trial yielded no significant effect on the formation of brain lesions.
In 2014, Voskuhl participated in an interview discussing estriol as a potential treatment for women with MS. The article discussed how estriol was identified as a potential candidate for drug treatment, including an anecdote about Melissa Glasser, a woman who experienced a reduction in her MS symptoms during each of her four pregnancies. [15]
In 2016, Voskuhl was quoted in an article addressing gender bias in scientific study; she noted that male and female mice had different disease progression in the animal MS model. [16]
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activity: estrone (E1), estradiol (E2), and estriol (E3). Estradiol, an estrane, is the most potent and prevalent. Another estrogen called estetrol (E4) is produced only during pregnancy.
Multiplesclerosis (MS) is a degenerative disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, visual loss, muscle weakness, and trouble with sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks or building up over time. In the relapsing forms of MS, between attacks, symptoms may disappear completely, although some permanent neurological problems often remain, especially as the disease advances.
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of female secondary sexual characteristics such as the breasts, widening of the hips and a female-associated pattern of fat distribution. It is also important in the development and maintenance of female reproductive tissues such as the mammary glands, uterus and vagina during puberty, adulthood and pregnancy. It also has important effects in many other tissues including bone, fat, skin, liver, and the brain.
Interferon beta-1a is a cytokine in the interferon family used to treat multiple sclerosis (MS). It is produced by mammalian cells, while interferon beta-1b is produced in modified E. coli. Some research indicates that interferon injections may result in an 18–38% reduction in the rate of MS relapses.
Estrone (E1), also spelled oestrone, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estriol. Estrone, as well as the other estrogens, are synthesized from cholesterol and secreted mainly from the gonads, though they can also be formed from adrenal androgens in adipose tissue. Relative to estradiol, both estrone and estriol have far weaker activity as estrogens. Estrone can be converted into estradiol, and serves mainly as a precursor or metabolic intermediate of estradiol. It is both a precursor and metabolite of estradiol.
Estriol (E3), also spelled oestriol, is a steroid, a weak estrogen, and a minor female sex hormone. It is one of three major endogenous estrogens, the others being estradiol and estrone. Levels of estriol in women who are not pregnant are almost undetectable. However, during pregnancy, estriol is synthesized in very high quantities by the placenta and is the most produced estrogen in the body by far, although circulating levels of estriol are similar to those of other estrogens due to a relatively high rate of metabolism and excretion. Relative to estradiol, both estriol and estrone have far weaker activity as estrogens.
Interferon beta-1b is a cytokine in the interferon family used to treat the relapsing-remitting and secondary-progressive forms of multiple sclerosis (MS). It is approved for use after the first MS event. Closely related is interferon beta 1a, also indicated for MS, with a very similar drug profile.
Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with rodents and is widely studied as an animal model of the human CNS demyelinating diseases, including multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). EAE is also the prototype for T-cell-mediated autoimmune disease in general.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS). Several therapies for it exist, although there is no known cure.
Estrogen insensitivity syndrome (EIS), or estrogen resistance, is a form of congenital estrogen deficiency or hypoestrogenism which is caused by a defective estrogen receptor (ER) – specifically, the estrogen receptor alpha (ERα) – that results in an inability of estrogen to mediate its biological effects in the body. Congenital estrogen deficiency can alternatively be caused by a defect in aromatase, the enzyme responsible for the biosynthesis of estrogens, a condition which is referred to as aromatase deficiency and is similar in symptomatology to EIS.
Laquinimod is an experimental immunomodulator developed by Active Biotech and Teva. It is being investigated as an oral treatment for multiple sclerosis (MS).
Research in multiple sclerosis may find new pathways to interact with the disease, improve function, curtail attacks, or limit the progression of the underlying disease. Many treatments already in clinical trials involve drugs that are used in other diseases or medications that have not been designed specifically for multiple sclerosis. There are also trials involving the combination of drugs that are already in use for multiple sclerosis. Finally, there are also many basic investigations that try to understand better the disease and in the future may help to find new treatments.
Estetrol (E4), or oestetrol, is one of the four natural estrogenic steroid hormones found in humans, along with estrone (E1), estradiol (E2), and estriol (E3). Estetrol is a major estrogen in the body. In contrast to estrone and estradiol, estetrol is a native estrogen of fetal life. Estetrol is produced exclusively by the fetal liver and is found in detectable levels only during pregnancy, with relatively high levels in the fetus and lower levels in the maternal circulation.
Estriol succinate, sold under the brand name Synapause among others, is an estrogen medication which is used in the treatment of menopausal symptoms. It is taken by mouth, in through the vagina, and by injection.
Neurodegenerative diseases can disrupt the normal human homeostasis and result in abnormal estrogen levels. For example, neurodegenerative diseases can cause different physiological effects in males and females. In particular, estrogen studies have revealed complex interactions with neurodegenerative diseases. Estrogen was initially proposed to be a possible treatment for certain types of neurodegenerative diseases but a plethora of harmful side effects such as increased susceptibility to breast cancer and coronary heart disease overshadowed any beneficial outcomes. On the other hand, Estrogen Replacement Therapy has shown some positive effects with postmenopausal women. Estrogen and estrogen-like molecules form a large family of potentially beneficial alternatives that can have dramatic effects on human homeostasis and disease. Subsequently, large-scale efforts were initiated to screen for useful estrogen family molecules. Furthermore, scientists discovered new ways to synthesize estrogen-like compounds that can avoid many side effects.
Ponesimod, sold under the brand name Ponvory, is a medication for the treatment of multiple sclerosis. It is a sphingosine-1-phosphate receptor modulator.
There are several ways for pharmaceuticals for treating multiple sclerosis (MS) to reach the market.
Erteberel is a synthetic, nonsteroidal estrogen which acts as a selective ERβ agonist and is under development by Eli Lilly for the treatment of schizophrenia. It is specifically under investigation for the treatment of negative symptoms and cognitive impairment associated with the condition. As of 2015, it is in phase II clinical trials for this indication in the United States. Erteberel was also under investigation for the treatment of benign prostatic hyperplasia and reached phase II clinical studies for this use but failed to improve symptoms in men with the condition and development for this indication was discontinued. The drug has also been proposed as a potential novel treatment for glioblastoma.
Autoimmunity refers to a pathologic response of the body's immune system against itself. Autoimmune disease is widely recognized to be significantly more common in women than in men, and often presents differently between the sexes. The reasons for these disparities are not exactly clear, but may in part involve an extra copy of the X chromosome that is present in women compared to the single copy found in men, as well as the higher presence of female sex hormones such as estrogen, which increases immune system response. The risk, incidence, and character of autoimmune disease in women may also be associated with female-specific physiological changes, such as hormonal shifts during menses, pregnancy, and menopause.
Estetrol (E4) is an estrogen medication and naturally occurring steroid hormone which is used in combination with a progestin in combined birth control pills and is under development for various other indications. These investigational uses include menopausal hormone therapy to treat symptoms such as vaginal atrophy, hot flashes, and bone loss and the treatment of breast cancer and prostate cancer. It is taken by mouth.