Growth Hormone for Survival: It's not always controversial

"Hypopituitary adults have a reduced life expectancy, with a 2-fold higher risk of death for cardiovascular disease compared with that in the control population, and [growth hormone deficiency] has been considered the underlying factor influencing this increased mortality."

Lately growth hormone has been given a bad rap because of the controversy of its abuse by healthy, adult athletes and body-builders. That's actually very sad when there is a sizable body of chronically afflicted, growth hormone deficient adults. Hypopitiutarism and panhypopituitarism due to pituitary adenomas, surgery as treatment, and/or infarction leaves most Cushing's Disease survivors with growth hormone deficiency (GHD).

According to recent research, quoted here at Stanford and reiterated by Dr. Theodore Friedman, "GH appears to be one of the first hormones to be lost in patients with pituitary tumors and nearly all patients with two or more other pituitary deficiencies also lack GH."

In a recent issue of Pituitary, a study titled "Effects of 5 years of growth hormone (GH) replacement therapy of cardiac parameters and physical performance in adults with GH deficiency" caught my eye. Although not really news to me, it was nice to see some more validation. The research is outlined exceptionally well, with concise but thorough discussion and analysis.

The bottom line: There may be a slight increase in blood pressure and left ventricular mass with treatment, but this is greatly offset by "positive effects on exercise capacity and maximum oxygen uptake".

Another study states:

...there is no doubt that adult patients with hypopituitarism and GH deficiency have an increased CV risk (odds ratio of 2 for men and 3.5 to 4 for women). "

Improvement of systolic and diastolic pressures, lipid profiles, and plaque formation are also documented. A significant decrease in IMT and CRP were favorable outcomes of GH replacement therapy.

GHD has also been linked to apathy, fatigue, lack of motivation and more. Thus, it becomes not only an issue of mortality, but also an issue of quality of life.

I hope the medical community will educate themselves about GHD. The authors of the Pituitary
study elaborated well:

GHD is associated with hypercoagulability, abdominal obesity, insulin resistance, unfavorable lipid profile, atherosclerosis, increased blood pressure (BP), decreased exercise performance and with reduced pulmonary capacity, left ventricular (LV) mass and LV systolic performance...

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Cenci, M., Soares, D., Spina, L., Lima Oliveira Brasil, R., Lobo, P., Mansur, V., Gold, J., Michmacher, E., Vaisman, M., & Conceição, F. (2009). Effects of 5 years of growth hormone (GH) replacement therapy on cardiac parameters and physical performance in adults with GH deficiency Pituitary DOI: 10.1007/s11102-009-0182-2

Radiosurgery and increased mortality: Is there a connection?

This study takes a brief look at radiosurgery and its possible link to increased mortality. It does not distinguish between single-fractionated radiotherapy such as gamma knife and fractionated stereotactic radiotherapy (FSR).

The authors explore four (4) major areas:

• Cerebrovascular disease following pituitary radiotherapy
• Cerebrovascular mortality following pituitary radiotherapy for non-functioning adenomas
• Impact of pituitary radiotherapy on mortality in acromegaly
• Hypopituitarism and excess mortality following pituitary radiotherapy

I am mainly interested in the first and the last in the list above. These impact those with Cushing's who are considering or have undergone radiotherapy.

Cerebrovascular disease is already a risk with Cushing's patients. In Mortality in Patients Treated for Cushing’s Disease Is Increased, Compared with Patients Treated for Nonfunctioning Pituitary Macroadenoma (Dekkers, et al), the authors conclude:

[M]ortality is increased in patients with Cushing’s disease, compared with both NFMA and acromegaly. This implicates that transient exposure to cortisol excess is a major contributor of the increased mortality, even after cure of Cushing’s disease. This observation may also be of relevance for patients treated with exogenous glucocorticoids for nonendocrine diseases.

Cited in the same study, "Causes of death were cardiovascular disease in 23.4%, cerebrovascular disease in 12.8%, malignancy in 19.1%, and infectious diseases in 17% of all patients. " Thus, there is already a link to mortality due to cerebrovascular disease and Cushing's.

The Ayuk/Stewart analysis cited a "study of 331 patients with pituitary adenomas treated with surgery and radiotherapy [where] increasing doses of radiotherapy were associated with increasing risk of cerebral infarction." They go on to admit there is a lot of debate about what caused the cerebrovascular events, with radiation thought to be a cause due to "changes to the cerebral vasculature".

The Dekkers study counters that: "By regression analysis, in a model adjusted for age and gender, radiotherapy and hypopituitarism were not associated with increased mortality risk."

Ayuk and Stewart, when analyzing the data from multiple sources, disagree. Hypopituitarism is common after treatement for pituitary adenomas. They cite several studies which show "over 50% of patients treated with pituitary radiotherapy will develop deficiencies in one or more anterior pituitary hormones over the following decade." They then analyzed numerous studies which "examined mortality in patients with hypopituitarism and which found increased mortality compared with age-matched controls, predominantly due to cerebrovascular and cardiovascular disease."

In two of the studies analyzed, radiotherapy did not seem to attribute to increased mortality. But in another, larger study of over 1000 patients, "treatment with radiotherapy was associated with a significantly increased mortality rate" when comparing patients who had hypopituitarism from radiotherapy with patients who had hypopituitarism from other treatments or due to tumor.

Age may play a part, also:

The authors also reported higher mortality in patients who had been diagnosed at a younger age, with a standardized mortality ratio of 4.87 in the group younger than 20 years, decreasing to 1.0 in those older than 60 years. This is of particular relevance as over half of the radiotherapy-treated patients were younger than 50 years at the time of treatment.

Overall, the data is unclear about the link between radiotherapy and mortality. The authors were also unclear about whether the hypopituitarism was treated with hormone replacements and what significance this may have. I suspect this was partially due to the information available to them from the studies they analyzed.

John Ayuk, Paul M. Stewart (2008). Mortality following pituitary radiotherapy Pituitary, 12 (1), 35-39 DOI: 10.1007/s11102-007-0083-1

Hypopituitarism and Gamma Knife Radiotherapy

Does radiotherapy cause hypotituitarism when treating pituitary adenoma(s)?

Sometimes tumors cause damage to the pituitary gland which results in hypopituitarism and panhypopitituarism. Surgery to remove the tumor(s) can also cause damage to the pituitary which leads to hypopitutiarism. Sometimes, depending on tumor placement and the amount of pituitary removed, the pituitary regains total function. Nothing is cut-and-dry with this due to the numerous factors surrounding tumors and their removal.

This article takes a look at the effect of radiotherapy on the pituitary. Is hypopituitarism a "given" with radiotherapy or can it be avoided? According to the authors, this depends on the total dose, the fraction size of each irradiation, and the time between each fraction.

Since Gamma Knife is a single-fraction radiosurgery, all radiation is delivered in one dose.

Radiation-induced hypopituitarism occurs in a significant number of patients treated for pituitary adenomas with either stereotactic radiosurgery (SRS), which involves a single dose of stereotactic radiotherapy, as well as following fractionated stereotactic radiotherapy (FSRT).

The authors point out the risk is difficult to establish due to the multiple factors involved, which include:

• surgery
• variations in dosages of radiation
• technique used (SFR vs. FSRT)
• accuracy of placement and imaging
• pre-existing hypopituitarism
• lack of consisten protocol for diagnosing hypopituitarism

They also point out hypopituitarism is "more likely to occur following stereotactic irradiation for
secretory adenomas, as higher doses are generally required to achieve hormonal control." This includes gamma knife.

Since hypopitituarism can include multiple hormones, which are the most apt to be affected? Growth hormone (GH) has the greatest vulnerability. "With higher radiation doses (30–50 Gy), however,the frequency of GH insufficiency substantially increases and can be as high as 50–100%."

Patients irradiated for pituitary tumors have an increased risk for gonadotrophin deficiency with the data presenting "severity from subtle subclinical) abnormalities in secretion detected only by
GnRH testing to severe impairment associated with diminished circulating sex hormone levels."

Normal ACTH deficiency "dramatically increases (27–35%) after intensive irradiation [6, 9, 12] and more so (31–60%) in patients with pituitary adenomas [20, 25, 26]." TSH deficiency follows almost identically with patients irradiated for pituitary tumors.

Women tend to develop hyperprolactemia after SRS/GK which tends to normalize over time. The article was not very clear on this and just briefly touched on it. There didn't seem to be much data on it, either.

More on GK later this week.

Ken H. Darzy, Stephen M. Shalet (2008). Hypopituitarism following radiotherapy Pituitary, 12 (1), 40-50 DOI: 10.1007/s11102-008-0088-4

'The girl who couldn't wake up'-- 5 years of misdiagnosis

"For five years, beginning in 1999 at age 16, Jenkins complained of fatigue, nausea, dizziness, memory loss and severe headaches. She frequently fainted. All she wanted to do was sleep."

A must-read article, 'The girl who couldn't wake up', details the events after Jennifer Julian Jenkins was in a wreck which caused the pituitary to be separated from its stalk (infundibulum). She was misdiagnosed and mistreated for 5 long years.

In addition to the flu, Jenkins was diagnosed with anemia, gastroenteritis and a viral infection. A psychiatrist said there was nothing medically wrong with Jenkins, she was depressed and lazy...

..."At one point, my parents talked about putting me in a mental institution because no matter how hard they tried, nobody could find anything wrong. And the thought of being institutionalized really didn't bother me. All I could think about was, 'At least there, I could sleep without anyone disturbing me.' "

Once a doctor took the time to do two simple tests for cortisol and thyroid, the problem became clear: hypopituitarism. When asked why it took so long for doctors to test and treat her appropriately, Jennifer says, "I hope some of the doctors I saw read this. I hope they slow down, listen to their patients a little more and take the time to figure out what is wrong instead of just chalking everything up to age or depression."

To read more, click here. A sound bite is included.

Jennifer's story will air on Discovery Health's Mystery Diagnosis December 15. Check your local listings for the time.



UPDATE:  The story isn't at the link anymore, but here it is from the Clarion Ledger in full:

Charlie Julian raced up the stairs of the family's Brandon home and into his sister's bedroom, where he found her asleep and unresponsive.

He yelled for her to wake up and gently, but firmly, slapped her face.

"That's when I would just burst out laughing," says Jennifer Julian Jenkins, 25, recalling a day last May when she and her brother reenacted a real-life scene for The Discovery Channel's Mystery Diagnosis series, which will air Dec. 15. "We must've tried it a dozen times and every time he would slap me, I couldn't keep from laughing.

"They finally said, 'Let's just skip the slapping part.' "

It wasn't a laughing matter four years earlier. After being rushed to the hospital, Jenkins' body temperature was a frigid 94.3, her blood pressure a dangerously low 76/61.

Numerous tests were conducted. The best guess doctors could offer: Jenkins was suffering from a severe case of the flu.

For five years, beginning in 1999 at age 16, Jenkins complained of fatigue, nausea, dizziness, memory loss and severe headaches. She frequently fainted. All she wanted to do was sleep.

And she went back in time. Instead of going out with her friends from Brandon High School, Jenkins was content to stay home and play with Barbie dolls.

In addition to the flu, Jenkins was diagnosed with anemia, gastroenteritis and a viral infection. A psychiatrist said there was nothing medically wrong with Jenkins, she was depressed and lazy.

"And I began to believe them," Jenkins says. "To me, I had become this awful, worthless person.

"At one point, my parents talked about putting me in a mental institution because no matter how hard they tried, nobody could find anything wrong. And the thought of being institutionalized really didn't bother me. All I could think about was, 'At least there, I could sleep without anyone disturbing me.' "

Finally in March 2004, after visiting more than 20 specialists and nearly losing her life, two Jackson physicians - Albert Steele and Robert Evans - correctly pinpointed Jenkins' problem. Jenkins was suffering from hypopituitarism. In plain terms, her pituitary gland - located at the base of the brain - had stopped supplying her body with sufficient amounts of hormones.

"For five years, we watched our daughter become someone we barely recognized," says her mother, Marilyn Julian. "And I was treated by most doctors as some micro-managing mother who needed to get out of the way and quit bringing her to see them."

*

On June 7, 1999, Jenkins and her mother were driving home from Columbia after visiting Jenkins' grandmother, who was battling cancer.

Jenkins was driving her mother's new Honda Accord and traveling the speed limit, 65 miles per hour, along U.S. 49 when a car pulled from the shoulder of the median into Jenkins' path.

Upon impact, both cars began to spin. The driver's side of the Honda was struck twice by the other car. Jenkins was knocked unconscious. Her mother suffered two broken ribs. The other driver, a teenage boy in his aunt's car, was not injured.

Jenkins opened her eyes shortly after the ambulance arrived. "I remember hearing my mother screaming for me to wake up, and I had a lot of pain in my neck," she says.

They were treated and released from Simpson General Hospital in Mendenhall. Jenkins and her mother were sore for several weeks but appeared to recover with no complications.

Four months later, Jenkins had her first fainting spell. Jenkins' pediatrician ordered tests of her brain and heart. "When the results came back, the doctor didn't seem too concerned," she says.

Her frustrating medical journey had begun.

A month later, the day before Thanksgiving, Jenkins appeared to be having a stroke. Her speech was slurred. Her mouth drooped on one side. She was admitted to the University of Mississippi Medical Center in Jackson and diagnosed with complex migraines.

"I'd have at least one migraine every month," Jenkins says. "They would put me out for a day or two."

"If Jennifer got a cold, it turned into a major ordeal," Marilyn says. "If she got a stomach bug, she would have to be hospitalized for it. I work at Brandon High School (as choral director and a health teacher). I'm around teenagers all the time. Stomach bugs usually don't put them in the hospital."

Jenkins says her senior year "is a blur ... I see the pictures of my graduation, but I really don't remember it."

Her grades slipped. When she took the ACT again, hoping to improve on the 21 she made as a sophomore, she scored an 18.

She flunked out of Belhaven College her freshman year "because I couldn't stay awake long enough to go to class.

"And my parents didn't know what to think. So we had a big pow-wow. You know, 'You've got to do better. You're sleeping your life away.' But in their defense, they had tried everything and I couldn't even keep a job."

She was so fatigued, Jenkins went into one of the dressing rooms at a department store where she worked and went to sleep. When co-workers came banging on the door, she tried to disguise her voice, hoping they would go away and let her rest.

"Jennifer told me recently that she would tell us anything we wanted to hear back then so we would leave her alone and let her sleep," Marilyn says. "I think about it now, what it must have been like for her."

*

It was Feb. 16, 2004, when Charlie found his sister near death in her bedroom.

"I had an Algebra test that day (at Hinds Community College) and my mom kept calling me, making sure I was awake," Jenkins recalls. "After the third time, I just quit answering."

Marilyn sent Charlie over to check on her.

"I think we all wonder what would have happened if Charlie hadn't been home studying for the Bar exam," Jenkins says.

On a whim, Jenkins' dad - Charles Julian - made an appointment for her to see his internal medicine specialist, Albert Steele.

"Dr. Steele listened to what had been going on, and then he started taking my vitals," she says. "When he took my blood pressure, it basically didn't register. He said, 'I don't see how you're even standing right now.' "

Tests revealed her cortisol level was critically low. Steele referred Jenkins to Robert Evans, an endocrinologist, who discovered Jenkins' thyroid level was low.

"He said, 'I think I know what it is - hypopituitarism - and I'm going to put you on some medicine (Cortef, a steroid, and Levoxyl, which increases one's thyroid level),' " Jenkins recalls. "He told me if that's what it was, I would feel better within 24 to 48 hours."

The next day, Jenkins came running down the stairs, into her parents bedroom and jumped onto the bed.

"That was one of the biggest miracles of our lives," Marilyn says. "She said, 'I realize I'm not a lazy bum, that I've actually been sick this whole time!' My husband and I just sat there in shock."

*

Jenkins is now married to a lawyer, Jacob, and works as a cardiac nurse at St. Dominic Hospital in Jackson.

And she recently tossed the doctors another curve: Jenkins found out three weeks ago she is pregnant.

"I was totally flabbergasted when I heard that," Evans says. "I just didn't think there was any way, because of the (hormonal) problems she had been through, that Jennifer could conceive a child."

So why did Jenkins and her family have to go through 20-something doctors and thousands of dollars before finding two physicians who diagnosed the problem almost immediately?

"Her symptoms were pretty dramatic, but Jennifer was a teenage girl who looked otherwise healthy," says Evans, who has been practicing for 24 years. "It's pretty easy for a doctor to say, 'She's 17. Weak. Dizzy. Give her a little time until she grows up, and it'll go away.'

"And hypopituitarism is not something you see a lot in adolescents. It's usually found in older adults. I give Dr. Steele a lot of credit for testing her cortisol level. And I'm just happy I was able to discover the thyroid problem and prescribe the correct medicine."

Credit also goes to one more physician: Lewis Blevins, a pituitary specialist at Vanderbilt Medical Center in Nashville.

"Dr. Blevins was the first one to connect the car wreck with the pituitary problem, even though my husband and I always suspected it," Marilyn says.

"The pituitary gland is like a cherry on a stalk," Jenkins says. "Dr. Blevins believes the impact during the accident tore the stalk and prevented the pituitary gland from doing its job."

Jenkins takes a daily dose of Dexamethosone and Levoxyl to stimulate her adrenal glands and increase her thyroid levels.

Two tablets every 24 hours and life is great again.

"I hope some of the doctors I saw read this," Jennifer says. "I hope they slow down, listen to their patients a little more and take the time to figure out what is wrong instead of just chalking everything up to age or depression."