Estrogen receptors regulate pulmonary alveolus formation and estrogen is required for alveolar architectural stability, and induces alveolar regeneration in mice.

World-wide, 600 million people suffer from the chronic obstructive pulmonary diseases (COPD), chronic obstructive bronchitis and emphysema, with some three million dying from the diseases each year. COPD is caused by chronic respiratory inflammation, proteolytic breakdown of airway tissue and consequent loss of elastic recoil in the lungs.

This serious healthcare problem is paralleled by global sales of around US$2.8 billion which will increase in value significantly over the next decade. This will be driven by the aging population and the approval of marketed asthma products for the treatment of COPD. For example, Advair and Symbicort (both inhaled corticosteroid/long-acting beta2-agonist combinations) were initially approved as asthma therapeutics but were used off-label for the treatment of COPD. However both of these have now been approved for the treatment of COPD which will see prescribing rates rise above off-label levels. This together with new product launches, including Boehringer Ingelheim's Spiriva will see the market value rise to at least $5.5 billion by 2011. Spiriva (tiotropium bromide), the first specific drug for COPD, is co-marketed by Pfizer. Approximately 50% of the 30 million COPD patients in the seven major markets are undiagnosed however the increased awareness accompanying Pfizer's entry into the COPD arena is expected to help overcome low diagnosis rates and is seen by analysts as pathway to unlocking the true COPD patient potential. This offers a further reason for the expected expansion in the COPD market (for a full analysis of the COPD market click here).

Following several successful drug launches to the respiratory market in the past five years, companies are seeking the next blockbuster drug in a high potential market. Multiple potential treatment pathways, an enormous patient population, and a relatively high level of unmet need in COPD have promoted a deep respiratory pipeline. However, among over 70 products in Phase I development or later, only a handful are in Phase III or registration phases of development (for an evaluation of emerging treatments of COPD click here). PDE-4 inhibitors are anticipated to be the next novel drug class to reach the respiratory market, with the launch of Altana's Daxas (roflumilast) expected over the next two years, but the superiority of Spiriva will likely lead to these 'second-to-market' drugs battling for market share with xanthines and other add-on therapies.

With a number of novel therapies showing disappointing results, there remains a particular need to develop drugs that control the underlying inflammatory and destructive processes that cause COPD as no currently available drug therapy reduces the relentless progression of COPD. In contrast to the enormous advances made in asthma management little significant progress has been made in COPD therapeutics. In particular while headway is being made in the development of anti-inflammatory agents that would be expected to slow disease progression few strategies have been identified that may reverse airway damage. The target that has received the greatest attention in this respect is the retinoic acid receptor. Retinoic acid increases the number of alveoli in developing rats and, remarkably, reverses the histological and physiological changes induced by elastase treatment of adult rats (this is one model that has been used in the study of COPD). Despite these promising data other studies employing alternative models have been less encouraging and the search for airway remodeling agents for use in COPD continues.

One particularly interesting report appears in August's edition of the American Journal of Cellular & Molecular Physiology. In this report Massaro & Massaro from Georgetown University School of Medicine report that the estrogen receptor may represent a molecular target for future COPD therapeutics. It has been previously shown that ovariectomy in sexually immature rats diminishes the formation of alveoli a phenomenon prevented by estrogen. This suggests that estrogen may play a role in alveolar development. The Georgetown group demonstrate that estrogen receptor alpha and estrogen receptor beta, the only recognized mammalian estrogen receptors, are both required for the formation of a full complement of alveoli in female mice. In addition to playing a role in alveolar formation estrogen receptor beta also contributes to lung elastic tissue recoil. Mirroring these observations, ovariectomy in adult mice produces a rapid loss of alveoli and of alveolar surface area. This phenomenon is reversed by estrogen replacement.

This important study reveals that estrogen receptors regulate alveolar size and number as well as airway elasticity in a non-redundant manner and that estrogen is required for maintenance of already formed alveoli. Furthermore estrogen can induce alveolar regeneration following ovariectomy in adult mice.

It is generally accepted that lung function diminishes with age and that smoking accelerates this decline providing the underlying cause of COPD. It has however been observed that some individuals are much more susceptible to the development of COPD than others. Of interest a second paper published this year reports that women may be more predisposed to develop COPD than men. Women also develop emphysema or other types of COPD at an earlier age than men and experience a greater degree of lung damage than men do from smoking the same number of cigarettes. The reasons for this gender difference are not clear but may be due to women having smaller airway. In addition, the findings of the present study suggest the involvement of hormonal status in the susceptibility to COPD. Perhaps more importantly the study suggests that therapeutic agents that activate the estrogen receptor may limit the development of COPD or even reverse damage.

Considerable attention is currently being paid to identifying novel routes of administration for a wide variety of therapeutics. One class of drug for which different routes of administration have been evaluated is the hormone replacement therapies. For example, a number of transdermal hormonal replacement therapies have been developed. Like transdermal administration, interest in inhaled therapeutics is also growing and of particular relevence to the data coming out of Georgetown University EstroLast was under development by Alkermes as an estrogen-based hormonal replacement therapy. The active compound of this technology was delivered using Alkermes' airway drug delivery sytem. The results of the present study suggest that this approach to hormone replacement therapy may gain significant interest as awareness of accelerated COPD as a possible effect of menopause becomes clearer.
 

Entry date Tuesday, August 31, 2004

Adapted from Massaro & Massaro, J Physiol Lung Cell Mol Physiol. 2004 Aug 6 [Epub ahead of print]