The full paper is available:
Carmalt JL, Scansen BA
Development of two surgical approaches to the pituitary gland in the Horse
Vet Q. 2018 Dec;38(1):21-27. doi: 10.1080/01652176.2017.1415488 (PubMed)
Surgery for Equine Cushing’s Disease: A Possibility? KER Jan 2018
A major problem with this research is that the cause of PPID is not hyperplasia, hypertrophy or adenoma formation in the pituitary gland, it is loss of dopaminergic neurons in the hypothalamus. Surgery on the pituitary gland will not reduce the primary cause of PPID.
Bear in mind that a lot of older research into PPID is based on untreated horses with advanced PPID - these horses may have had "grossly enlarged pituitary glands", but it is now being suggested that with earlier and better diagnosis of PPID, plus regular treatment with pergolide , either a constant low dose for several years (Schott H), or an initially higher dose that perhaps is reduced once symptoms are brought under control (Durham A), PPID may not progress to the advanced stage with hyperplasia and hypertrophy leading to adenoma formation.
The paper suggests that daily treatment with oral pergolide is costly and "labor and management intensive". Costly, yes, particularly when horses require higher doses of pergolide, and while the only licensed treatment for horses is Prascend. However, the exclusive licence for Prascend expires in 2020 in the UK, and if other manufacturers enter the market, prices may come down. "Labor and management intensive" - giving a daily pill to a horse, compared to serious, expensive and potentially life-threatening surgery? Whilst it can be difficult to persuade some horses to take their daily medicine, how many owners would choose the latter - even if surgery was effective? The authors suggest that giving daily pergolide to horses that are "extensively or pasture managed" and "infrequently handled" may not be possible... frankly, such horses are probably fairly unlikely to have PPID diagnosed or to be treated for it if PPID were diagnosed. Horses kept in these conditions are probably more likely to be young horses, and young horses don't get PPID. The authors suggest that there is emotional stress for owners deailing with horses with a chronic ongoing disease. But surgery to remove pituitary adenomas will not cure PPID (see below), and treatment with pergolide in many cases is extremely effective, allowing horses with PPID to live normal lives. Are the authors identifying real problems?
Cushing's disease in dogs and humans is caused by a tumour in the pituitary gland. PPID in horses is caused by degeneration of dopamine-producing neurons in the hypothalamus (found in the lower part of the brain, above the pituitary gland), which, if not controlled through use of dopamine agonists like pergolide, can eventually lead to the formation of adenomas (benign tumours) in the pituitary gland. Prior to the formation of adenomas, an increase in the number and size of pars intermedia cells occurs because of the lack of stimulus to stop producing hormones - due to the reduced quantity of dopamine reaching the pituitary gland, the body is telling the pars intermedia to produce more hormones, and to do this, it has to increase its factory size...and eventually these increased cells form benign tumours called adenomas.
Removing these adenomas in cases of PPID will not stop the progression of PPID - it is the lack of dopamine that causes and drives the progression of PPID. There might be a short-term reduction in hormone output because the factory size has been reduced, but cells can often increase in number very quickly, so is it likely that cell numbers would quickly increase back to meet the hormone production the lack of dopamine is stimulating? Even if the surgery did help for a period of time, a horse would still need a treatment to replace the missing dopamine - so there is no way surgery could replace medical treatment. Well, not unless they could implant a slow-release dopamine replacement - that might be interesting.
The research was basically trying to find a surgical route to reach the pituitary gland in horses, which is perfectly reasonable.
The first attempts on cadavers were a myeloscopic approach which was abandoned due to too much bleeding, and a trans-sphenopalatine sinus approach that was abandoned due to inadequate access to the sinus, plus the proximity of the optic chiasm to the pituitary gland would make this technique unfeasible. The pituitary gland was accessible with a ventral trans-basispheniodal osteotomy approach in cadaver heads, but when this was carried out on a live horse under anesthetic, a slip of the drill caused uncontrollable hemorrhage and the horse was euthanased. An approach through the deep facial vein allowed access to the ventral cavernous sinus and the pituitary gland in cadaver heads. This approach was then carried out on two live horses: access for a long flexible needle to the pituitary gland was achieved on one healthy horse, but on the other horse that had PPID, a needle injecting dye missed the pituitary gland and emptied into the cavernous sinus blood instead. Both horses were euthanased while under the anesthetic, so recovery and adverse effects from this procedure are not known. This procedure was technically demanding, with accurate positioning being critical, and possible additional complications including damage to blood vessels and nerves in the guttural pouch, with intractable dysphagia which can lead to pneumonia and death, and introduction of infection. The authors note that this method would be likely to cause "collateral damage to the pars nervosa or pars distalis".
The authors state that it is not known how much surgical removal or cell destruction would be necessary to return a horse to being clinically normal, and that the goal would not be to remove all pars intermedia hormone output. However, no mention is made of the fact that the pituitary abnormality is the result, not the cause, of PPID. The authors state that "anything other that complete resolution of clinical signs will be unsuitable in the horse because there is already an oral daily medication for PPID" - but without daily medication to replace the dopamine not being produced by the hypothalamus, surely the cause of PPID will continue, and a horse could risk life threatening surgery for no great long-term improvement in clinical signs and continue to suffer from PPID.
The research is valuable for describing successful and unsuccessful approaches to the equine pituitary gland, but the article suggesting that this research "offers owners hope for viable alternatives to daily pergolide" is misleading.
Carmalt JL, Scansen BA
Development of two surgical approaches to the pituitary gland in the Horse
Vet Q. 2018 Dec;38(1):21-27. doi: 10.1080/01652176.2017.1415488 (PubMed)
Surgery for Equine Cushing’s Disease: A Possibility? KER Jan 2018
A major problem with this research is that the cause of PPID is not hyperplasia, hypertrophy or adenoma formation in the pituitary gland, it is loss of dopaminergic neurons in the hypothalamus. Surgery on the pituitary gland will not reduce the primary cause of PPID.
Bear in mind that a lot of older research into PPID is based on untreated horses with advanced PPID - these horses may have had "grossly enlarged pituitary glands", but it is now being suggested that with earlier and better diagnosis of PPID, plus regular treatment with pergolide , either a constant low dose for several years (Schott H), or an initially higher dose that perhaps is reduced once symptoms are brought under control (Durham A), PPID may not progress to the advanced stage with hyperplasia and hypertrophy leading to adenoma formation.
The paper suggests that daily treatment with oral pergolide is costly and "labor and management intensive". Costly, yes, particularly when horses require higher doses of pergolide, and while the only licensed treatment for horses is Prascend. However, the exclusive licence for Prascend expires in 2020 in the UK, and if other manufacturers enter the market, prices may come down. "Labor and management intensive" - giving a daily pill to a horse, compared to serious, expensive and potentially life-threatening surgery? Whilst it can be difficult to persuade some horses to take their daily medicine, how many owners would choose the latter - even if surgery was effective? The authors suggest that giving daily pergolide to horses that are "extensively or pasture managed" and "infrequently handled" may not be possible... frankly, such horses are probably fairly unlikely to have PPID diagnosed or to be treated for it if PPID were diagnosed. Horses kept in these conditions are probably more likely to be young horses, and young horses don't get PPID. The authors suggest that there is emotional stress for owners deailing with horses with a chronic ongoing disease. But surgery to remove pituitary adenomas will not cure PPID (see below), and treatment with pergolide in many cases is extremely effective, allowing horses with PPID to live normal lives. Are the authors identifying real problems?
Cushing's disease in dogs and humans is caused by a tumour in the pituitary gland. PPID in horses is caused by degeneration of dopamine-producing neurons in the hypothalamus (found in the lower part of the brain, above the pituitary gland), which, if not controlled through use of dopamine agonists like pergolide, can eventually lead to the formation of adenomas (benign tumours) in the pituitary gland. Prior to the formation of adenomas, an increase in the number and size of pars intermedia cells occurs because of the lack of stimulus to stop producing hormones - due to the reduced quantity of dopamine reaching the pituitary gland, the body is telling the pars intermedia to produce more hormones, and to do this, it has to increase its factory size...and eventually these increased cells form benign tumours called adenomas.
Removing these adenomas in cases of PPID will not stop the progression of PPID - it is the lack of dopamine that causes and drives the progression of PPID. There might be a short-term reduction in hormone output because the factory size has been reduced, but cells can often increase in number very quickly, so is it likely that cell numbers would quickly increase back to meet the hormone production the lack of dopamine is stimulating? Even if the surgery did help for a period of time, a horse would still need a treatment to replace the missing dopamine - so there is no way surgery could replace medical treatment. Well, not unless they could implant a slow-release dopamine replacement - that might be interesting.
The research was basically trying to find a surgical route to reach the pituitary gland in horses, which is perfectly reasonable.
The first attempts on cadavers were a myeloscopic approach which was abandoned due to too much bleeding, and a trans-sphenopalatine sinus approach that was abandoned due to inadequate access to the sinus, plus the proximity of the optic chiasm to the pituitary gland would make this technique unfeasible. The pituitary gland was accessible with a ventral trans-basispheniodal osteotomy approach in cadaver heads, but when this was carried out on a live horse under anesthetic, a slip of the drill caused uncontrollable hemorrhage and the horse was euthanased. An approach through the deep facial vein allowed access to the ventral cavernous sinus and the pituitary gland in cadaver heads. This approach was then carried out on two live horses: access for a long flexible needle to the pituitary gland was achieved on one healthy horse, but on the other horse that had PPID, a needle injecting dye missed the pituitary gland and emptied into the cavernous sinus blood instead. Both horses were euthanased while under the anesthetic, so recovery and adverse effects from this procedure are not known. This procedure was technically demanding, with accurate positioning being critical, and possible additional complications including damage to blood vessels and nerves in the guttural pouch, with intractable dysphagia which can lead to pneumonia and death, and introduction of infection. The authors note that this method would be likely to cause "collateral damage to the pars nervosa or pars distalis".
The authors state that it is not known how much surgical removal or cell destruction would be necessary to return a horse to being clinically normal, and that the goal would not be to remove all pars intermedia hormone output. However, no mention is made of the fact that the pituitary abnormality is the result, not the cause, of PPID. The authors state that "anything other that complete resolution of clinical signs will be unsuitable in the horse because there is already an oral daily medication for PPID" - but without daily medication to replace the dopamine not being produced by the hypothalamus, surely the cause of PPID will continue, and a horse could risk life threatening surgery for no great long-term improvement in clinical signs and continue to suffer from PPID.
The research is valuable for describing successful and unsuccessful approaches to the equine pituitary gland, but the article suggesting that this research "offers owners hope for viable alternatives to daily pergolide" is misleading.
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