Norgestrel may be a potential therapy for retinal degenerations

Abstract

Retinal degenerations cover a broad spectrum of diseases, retinitis pigmentosa being the most common inherited retinal degeneration. It remains an untreatable disorder, partly owing to its genetic complexity and variability. Gene therapies, stem cell transplantation and administration of slow release growth factors are some of the treatments currently under development for the treatment of this disease. More recently, steroid hormones, now known to have functions within the CNS aside from their traditional targets, have been suggested as potential therapeutic agents. Progestogenic hormones are thought to modulate pro-survival pathways in the retina and since these hormones are produced naturally in the body their value as potential therapeutic agents is clear. Current data detailing the pro-survival effects of progestogens in the brain and particularly in the eye will be discussed.

Keywords::

• growth factor
• norgestrel
• photoreceptor
• progesterone
• retinitis pigmentosa
• survival

1. Introduction

Degeneration of photoreceptors, the light sensing cells of the vertebrate retina has severe consequences for patient vision. Retinitis pigmentosa (RP), one of a number of disorders affecting photoreceptors has a broad genetic base with mutations identified in over 60 different genes at the time of writing and inheritance can be autosomal dominant (ad), autosomal recessive (ar) or X-linked (https://sph.uth.tmc.edu/retnet/sum-dis.htm#B-diseases). In terms of intervention, gene replacement therapies are being widely researched for arRP, in addition to a two-pronged gene suppression in conjunction with gene replacement approach for sufferers of adRP with mutations specifically in the rhodopsin gene [1]. However, while these methodologies have yielded success in animal models and are expected to undergo clinical evaluation in humans shortly, individual RNAi-based suppressors must be generated to target each affected gene, which complicates matters specifically for adRP.

Treatments are also currently under development that have the potential to be broadly applied to all forms of RP irrespective of the underlying mutation. These include successful transplantation of sheets of retinal cells with the retinal pigment epithelial layer intact from human fetuses into six RP patients in a non-randomized clinical trial [2]. Fifty percent of the patients included in this trial demonstrated improved visual acuity. However, the ethical implications of such research and the availability of source material continue to restrain progress in this controversial area. Similar ethical issues surround the use of human stem cells as a treatment in humans, however, they have been used successfully in animal models [3]. Slow release of neurotrophic factors is also being investigated, specifically encapsulated human cells genetically modified to secrete ciliary neurotrophic factor (CNTF). Detailed in their progress report of 2009, Neurotech noted that in Phase II trials, photoreceptor preservation was observed in early and late-stage RP patients treated with this cell encapsulation technology. This is the arena where steroid hormones like norgestrel, with their potentially broad treatment spectrum, and using a slow release system which is not based on encapsulated human cells, but some other secretion system, could fit as prospective therapeutics for RP.

2. Mechanism

Norgestrel is a synthetic progestogen with effects similar to progesterone, is Food and Drug Administration (FDA) approved and is found at concentrations of 0.075 – 0.35 mg (daily dosage) in versions of the progesterone-only mini pill. Progestogens are highly insoluble in water and when given orally, have a wide person-to-person variability in absorption. However, synthetic progestins, such as norgestrel, are widely used in reproductive medicine as they are rapidly absorbed, have a longer half-life than progesterone and maintain stable levels in the blood. Although the reproductive system is the primary target for progestogens, these hormones belong to a family of neurosteroids for which neuroprotective functions have been described [4]. Long-lasting effects of progestogens are mediated by nuclear progesterone receptors (A and B), which function as ligand-activated transcription factors, while rapid signaling events independent of transcriptional or genomic regulation are thought to be initiated by binding to non-classical membrane receptors [5]. The body of research published on the effects of norgestrel outside the area of contraception is currently very limited, therefore, studies using naturally occurring progesterone will be discussed at length.

3. Progestogens as modulators of neuronal survival

Baulieu et al. coined the term neurosteroid as a result of their discovery that steroids could be synthesized in the central nervous system (CNS) and affect neurotransmission by interaction with receptors [6]. The first evidence that hormones might influence the extent of CNS injury was provided by studies using a model of traumatic brain injury (TBI) which showed that female rats recover better than males. Pre-treatment with progesterone results in significantly smaller brain lesions after TBI and similarly positive outcomes have been noted in models of stroke, multiple sclerosis and spinal cord injury [7]. Following three decades of preclinical research, two independent human trials were carried out at two different sites to test the use of progesterone in TBI. The ProTECT (Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment) study was done in a single location in the USA with a primary goal of establishing drug safety. A second trial carried out in China included 159 patients with severe TBI and demonstrated a reduction in mortality at 6 months from 32 to 18% in placebo-treated versus progesterone-treated subjects. Two major Phase III clinical trials are now underway (ProTECT III and SyNAPSe) to provide more robust data on the effectiveness of progesterone treatment in TBI.

In terms of retinal disease, evidence confirms that neurosteroidogenesis occurs in the retina, particularly de novo production of pregnenolone, the precursor for synthesis of progesterone and all other steroids [8]. In addition, nuclear receptors A and B are both expressed in the retina alongside certain cell surface receptors [9], but there is little information as to which specific retinal cells express these receptors, except for the membrane-associated progesterone receptor component 1 is known to be expressed by retinal Müller cells, photoreceptors and the retinal pigment epithelium [10]. Therefore, the retina appears to be a bona fide target of progestogens and indeed steroids in general. However, the outcomes of various studies investigating the protective effects of progesterone in retinal degeneration models are inconsistent in their findings. Progesterone administered by intraperitoneal injection (i.p.) (4 mg/kg) protected the inner nuclear and nerve fiber layers in a model of retinal ischemia in rats [11] but neither i.p. administration (60 mg/kg) nor daily dosage (2.5 mg/day) with progesterone protected rat photoreceptors from cell death in models of light damage [12,13]. However, our recent study involving i.p. administration of norgestrel (100 mg/kg) showed significant protection of mouse photoreceptor cells in both a light-induced and an inherited retinal degeneration model [14]. Clearly, a higher concentration of norgestrel is used which could contribute to the positive results described. In addition, synthetic progestogens are more rapidly absorbed than progesterone and maintain stable levels in the blood, therefore, it's possible that if higher concentrations of norgestrel were available for longer, more drug could potentially cross the blood–retina barrier reaching the target tissue.

The downstream effects of norgestrel in the retina seem to be achieved by increasing the production of pro-survival factors. Progesterone has been strongly linked with the production of basic fibroblastic growth factor (bFGF) in non-neuronal tissues such as the ovaries and uterus [15]. Furthermore, a norgestrel-only intrauterine release system significantly increases plasma and endometrial bFGF level [16]. In our recent publication, we observed norgestrel-mediated induction of bFGF, a neurotrophic factor repeatedly associated with protection from light-induced photoreceptor degeneration, in the retina. This result is not unprecedented in neuronal tissue, induction of BDNF expression has been observed in the CNS in response to progesterone [17]. Therefore, induction of neurotrophic factors could account for some of the potent pro-survival properties of norgestrel, complementing the growth factor-based therapies that are currently under development for the treatment of retinal disease.

4. Expert opinion

RP is a rare disease, however, the 1 in 4000 people worldwide that it affects remain without treatment or cure. While gene-based approaches are highly useful and recent advances are very positive, development of a therapy such as norgestrel that could potentially treat all RP sufferers or indeed individuals with photoreceptor cell loss irrespective of the underlying cause is highly desirable. This scenario could include the condition age-related macular degeneration, the most common cause of vision loss in aging populations of the developed world, since photoreceptor cell loss is a central feature of this disease. Recent results in mouse models of retinal degeneration show that apoptosis and cell loss is delayed and endogenous survival pathways are activated in response to norgestrel. The survival capacity of the retina appears to be boosted in animal models at least temporarily which could, with respect to the slow rate of degeneration in the human condition, translate into a significant delay to cell and vision loss. These results correlate with the many studies showing that progesterone reduces cerebral edema and improves cognition and learning in brain injury models.

However, all progestogens may not be alike in their capacity to enhance survival in the retina. Mixed results with naturally occurring progesterone, in addition to concerns raised about neurological health following chronic use of medroxyprogesterone acetate in contraceptives or hormone therapy [18] highlight the need for more thorough examination of the effects of these hormones on the CNS and retina. Therefore, while the current data describing the pro-survival effects of progestogens in the brain are very compelling, studies in the retina though encouraging are at a far less advanced stage. In terms of the future of norgestrel as a potential therapeutic agent, if issues surrounding ocular drug delivery could be addressed, then long-term studies in animal models would become more feasible and clinical trials might follow providing vital patient data.

Declaration of interest

This work was supported by Science Foundation Ireland and the Health Research Board of Ireland. The authors state no conflict of interest and have received no payment in preparation of this manuscript.