Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.
Eyes front and ears open. Class is now in session.
The disease that we will be learning about today is:
Acromegaly
What is Acromegaly?
- Acromegaly is a condition caused by too much growth hormone (GH) in the blood
- GH is released into the bloodstream by the pituitary gland, where it travels through the body causing a number of effects
- Acromegaly is characterized by progressive disfigurement of the face and extremities
- Too much GH in children is called gigantism and is very rare
- Acromegaly is the same disorder as gigantism but occurs after the growth plate cartilage fuses in adulthood
- A rare disorder with 80,000 patients worldwide
- Prevalence is between 50 to 70 cases per million people
- Approximately 1000 new cases are diagnosed in the US each year
- Most commonly occurs in middle-aged people (average age 40)
- Males and females affected equally
How Do You Get It?
- Acromegaly is caused by a non-cancerous tumor in the pituitary gland in approximately 95% of cases (pituitary adenoma)
- Most cases of acromegaly occur because a tumor of the pituitary adenoma produces excess GH
- Secretion of GH by a pituitary tumor leads to excess IGF-1, causing abnormal tissue growth
- Some pituitary adenomas grow slowly and take years to be noticed and others are more aggressive
- Pituitary adenomas are often caused by a genetic mutation that is not present at birth but acquired during life
- The cause of the defect is unknown
- The tumors are not genetically inherited
- The remaining cases of acromegaly are caused by other types of tumors that secrete growth hormone or GHRH
- The tumors can be in the pituitary or elsewhere in the body, such as the pancreas, lungs, or adrenal glands
- Acromegaly caused by excess GH and excess GHRH have the same symptoms
- GH is one in a series of hormones that controls tissue growth
- The hypothalamus produces growth hormone-releasing hormone (GHRH)
- GHRH stimulates the pituitary to produce Growth Hormone and release it into the bloodstream
- The hypothalamus also produces somatostatin, another hormone that stops secretion of GH
- GH in the bloodstream stimulates the liver to produce a protein called insulin-like growth factor 1 (IGF-1)
- IGF-1 promotes growth of bone and other tissues
- Excess growth hormone and IGF-1 in the blood cause most of the physical problems in acromegaly
- Too much IGF-1 causes bone growth that leads to changes in physical appearance and function
- Excess IGF-1 causes enlargement of organs such as the heart, which can result in heart failure and rhythm disorders
- Excess GH can lead to diabetes, high levels of triglycerides, and heart disease
What Are The Symptoms?
- Excess Growth Hormone present in acromegaly causes a wide variety of symptoms in the body:
- Abnormal enlargement of the hands and feet
- Increased prominence of jaw and/or forehead
- New overbite, underbite, or spreading out of teeth
- Swelling of tongue
- Deepening of the voice in males
- Increased number of skin tags
- Oily skin and excessive sweating
- Carpal tunnel syndrome
- Sleep apnea
- Arthritis
- Headache
- High blood pressure
- Diabetes mellitus (adult-onset or Type 2)
- Heart disease, including heart failure due to heart enlargement
- Increased risk of thyroid cancer
- Increased risk of colon polyps
- Other symptoms are caused by the enlargement of the pituitary tumor:
- A loss of the outer peripheral vision
- Headaches
How Is It Treated?
- Goals of treatment:
- Control GH hyper-secretion
- Reduce IGF-1 to age and gender-matched normal
- Eradicate or control tumor mass
- Preserve normal pituitary function
- Reverse or ameliorate the symptoms of acromegaly
- Restore life expectancy to that of the general population
- Patients frequently require surgery combined with medication to control acromegaly
- Surgery
- First-line treatment
- Complete removal of tumor is not always possible
- When surgery doesn’t completely remove the tumor or surgery is not advisable, further therapy is needed to reach normal GH and IGF-1 levels
- Surgery is most successful in patients with blood GH levels below 45 ng/ml before the operation and with pituitary tumors no larger than 10 mm in diameter
- The most effective option to achieve rapid and complete cure
- Long term cure depends on the size of the tumor
- Microadenomas (<10mm) have an 80-85% chance of cure
- Macroadenomas (>10mm) have an 50-60% chance of cure
- If the cure doesn’t occur, with surgery, the reduction in tumor mass can result in considerable recovery and also improve the response of subsequent medication
- Long term cure depends on the size of the tumor
- The most common surgical technique used is endoscopic transsphenoidal, which involves accessing the tumor through the nose
- Very large tumors that extend into the brain cavity may require opening the skull (craniotomy) to access the tumor
- Some tumors which have grown beyond the area of the sella (the bony cavity in the skull base where the pituitary gland is located) cannot be completely removed
- Medical Therapy
- Used if surgery and/or radiation don’t lower GH levels
- Not a cure
- Usually needs to be taken for life
- Medications can be used to treat acromegaly either after surgery, before surgery to reduce tumor size, and during the interval between administration of radiation and normalization of the serum IGF-1 level
- Most frequently, medications are prescribed if surgery doesn’t entirely alleviate the symptoms of acromegaly
- There are 3 types of medications used to treat acromegaly:
- Somatostatin Analogs (SSAs)
- Usually the first medication tried for those who still have symptoms after surgery
- Synthetic version of the body’s natural hormone somatostatin
- When somatostatin is released it stops the production of growth hormone
- Potential to reduce tumor size
- Effective in lowering GH and IGF-I levels in 50 to 70 percent of patients
- SSA’s interfere with the excessive secretion of GH by the pituitary gland and can produce rapid declines in GH levels
- Three SSAs have been approved in the US
- When SSA’s are required as a method of treatment, it has been shown that about 60% of patients are SSA “responders”
- Responders show a decrease GH/IGF-1 in 3-6 months
- Patients are considered resistant to SSA when acromegaly is not biochemically controlled after 6 months of treatment despite maximum recommended doses
- Sandostatin LAR
- Octreotide acetate for injectable suspension
- Novartis Pharmaceuticals
- Indicated for long-term maintenance therapy in acromegalic patients who have had an inadequate response to surgery and/or radiotherapy or for whom surgery and/or radiotherapy is not an option
- FDA approved 1998
- Control of both GH and IGF-1 levels
- 20-40mg by injection from healthcare professional every 4 weeks
- Requires mixing by healthcare professionals before use
- Somatuline Depot
- Lanreotide injection
- Ipsen Pharma
- Indicated for the long-term treatment of patients with acromegaly who had an inadequate response to or cannot be treated with surgery and/or radiotherapy
- FDA approved 2007
- Proven GH and IGF-1 reduction
- 60-120mg every 4 weeks by injection
- Available in premixed syringes
- Some patients are able to dose every 6-8 weeks if dosing every 4 weeks has controlled IGF-1 levels and symptoms
- Signifor
- Approved by the FDA and EMA in 2014
- Growth Hormone Receptor Antagonists (GHRAs)
- Block GH from making IGF-1
- GHRAs lower the IGF-1 levels in people with acromegaly
- Can reduce symptoms of acromegaly
- No effect on tumor size
- Usually tried after SSA’s
- SOMAVERT (pegvisomant) is the sole growth hormone antagonist available for treatment of acromegaly in the US
- When patients are SSA resistant or unable to tolerate treatment with SSA’s, treatment with Somavert (pegvisomant) is considered
- FDA approval March 2003
- The only medicine designed to specifically block the effects of excess growth hormone in acromegaly
- Somavert can normalize IGF-1 levels in 75-90% of cases but has no effect on GH.
- Somavert does not arrest tumor growth
- Somavert is a recombinant DNA protein containing 191 amino acid residues to which several polyethylene glycol (PEG) polymers are covalently bonded
- It is synthesized by a specific strain of Escherichia coli bacteria that has been genetically modified by the addition of a plasmid that carries a gene for GH receptor antagonist
- Somavert selectively binds to growth hormone (GH) receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction
- This inhibition of signal results in the decrease of insulin-like growth factor (IGF-I) and IGF binding proteins
- Dopamine Agonists
- Works by preventing the release of GH from the pituitary tumor
- Will normalize GH and IGF-1 levels in only up to 8% of patients – effective in only a small minority of patients
- Large doses associated with significant side effects
- Bromocriptine, a dopamine agonist, is available in the US as Parlodel produced by Validus Pharmaceuticals
- Parlodel is taken orally
- Inhibits the secretion of prolactin in humans
- Can lower levels of GH and IGF-I in some people
- Some people may develop compulsive behaviors, such as gambling, while taking this medication
- In 2012, Validus Pharmaceuticals acquired US rights to Parlodel from Novartis as the patent protection had expired
- Cabergoline (Dostinex)
- Some success has been had with combination treatments as well
- Somatostatin Analogs (SSAs)
- Radiation
- Conventional radiation therapy controls GH/IGF-1 hypersecretion in 50% to 60% of cases within 10 to 15 years, but with a number of side effects
- Can be used if surgery doesn’t completely remove the tumor
- Irradiation is a slow process and can take years to reduce GH levels to normal
- Once GH levels are normalized, the effects of radiation are permanent
- Used less frequently than in the past due to the availability of effective medication
- Still used to reduce the need for lifelong medication and in hopes of a permanent cure
- Takes from between several years to over a decade for radiotherapy to work
- The radiation technique typically used is stereotactic radiosurgery, one version of which is ‘gamma knife’ radiosurgery
- Remission rates with radiation therapy range from 17-50% during two to five years of follow-up
- Hypopituitarism (failure of the pituitary gland) is reported in more than half of the patients who have received radiation after 5-10 years
- Hypopituitarism has been linked to increased mortality
- Secondary tumors can develop many years later in areas that were in the path of the radiation beam
- Prognosis
- Prior to recent years with the routine implementation of more effective treatment, the mean mortality estimate for acromegaly was 2 to 3 fold the expected level in the general population
- Left untreated, acromegaly can lead to worsening diabetes mellitus and hypertension. The disease also increases a patient’s risk for cardiovascular disease and colon polyps that may lead to cancer
- Prognosis has improved due to modern surgical and pharmacologic treatment strategies. A recent meta-analysis showed that the overall mortality ratio for patients remains elevated.
- Patients’ survival, and their quality of life, has been improved by more aggressive treatment of acromegaly comorbidities such as hypertension, diabetes, and sleep apnea as well as stricter guidelines for monitoring GH and IGF-1
- It is well known that surgical cure may normalize mortality but similar data are not available for patients receiving medical treatment
Where Can I Learn More???
- Check out our cornerstone on this disease here.
