Bucking big growth hormone health $s

[Guest guest]

Hi All,

The pdf-available below may be worth seeing for the references on how growth

hormone

may affect aging positively. There seems to be a fair bit of legal language

included, though.

The growth hormone industry makes " $1.5 to $2 billion " annually from growth

hormone?

This October 26, 2005 report is unlikely to be in Medline yet, but it seems to

have

no abstract anyway.

That Drs. Perls and Olshansky are being sued by the American Academy of

Anti-Aging

Medicine and others (see below Disclosure) may not surprise.

This Week in JAMA

JAMA. 2005;294:1993.

Growth Hormone for " Antiaging "

Clinical and legal issues in the marketing, distribution, and administration of

growth hormone for antiaging purposes.

Provision or Distribution of Growth Hormone for " Antiaging " : Clinical and Legal

Issues

T. Perls; Neal R. Reisman; S. Jay Olshansky

JAMA. 2005;294:2086-2090.

The distribution and marketing of human growth hormone (HGH or GH) via Web sites

and

antiaging clinics has grown into a multimillion-dollar antiaging industry.1-4

Despite congressional hearings warning of deceptive marketing claims and the

potential health and economic dangers associated with the antiaging industry,5-6

and

statements issued by the National Institute on Aging7-9 and the Federal Trade

Commission,10 the distribution and use of GH for antiaging is now common. For

example, entering the terms " HGH " and " anti-aging " into the Google search engine

generated 3,410,000 hits as of September 26, 2005, many representing Web sites

and

clinics marketing and selling GH.

Worldwide annual sales of GH are estimated to be $1.5 to $2 billion.4, 11

Vance12

has suggested that 30% of GH prescriptions in the United States are for

indications

not approved by the Food and Drug Administration (FDA), which would include

antiaging and athletic enhancement. In 2000, Langreth13 quoted an antiaging

industry

source as stating that 30 000 people were receiving injectible GH for antiaging

at

the time. United States officials reportedly estimated that 25 000 to 30 000

older

individuals were treated with GH for antiaging in 2004.11 In 2002, one antiaging

clinic reported that one third of its 4000 patients were spending $400 to $500

per

month for GH injections.11

While precise figures on total GH distribution and use cannot be obtained, to

estimate annual GH distribution in the United States, we contacted IMS Health

(Fairfield, Conn), an independent pharmaceutical industry research company. IMS

Health projects total national sales and prescription totals from a computerized

panel of 22,000 retail pharmacies, including chain pharmacies, independents,

mass

merchandisers, and food store–based pharmacies, representing approximately 45%

of

the total prescription sales for the US retail market. IMS Health also collects

information from approximately 50 mail service outlets representing 70% of the

US

mail service market ( Palumbo, written communication, IMS Health, April

2005).

Information from IMS Health indicates that a total of 212,921 new and refill GH

prescriptions were filled by retail and mail service pharmacies in 2004 (

Palumbo, written communication, IMS Health, April 2005). These prescriptions

generated total sales of approximately $622 million ($427 million via mail

services

and $9.5 million via clinics), constituting 89% of sales for the class of drugs

" anabolic hormones " (this class, for market surveillance purposes, includes GH)

( Palumbo, unpublished data, IMS Health, 2005). Of these GH prescriptions,

74%

were for individuals aged 20 years and older and 43.7% were for individuals aged

40

to 59 years. These sales and prescription figures include legal prescribing for

adult GH deficiency (GHD, defined below) and AIDS wasting syndrome, but do not

include distribution of GH from antiaging Web sites. In 2002, physicians within

the

antiaging industry estimated that 100,000 individuals obtained the drug without

a

prescription.11

Prescribing and administering GH has become a routine intervention14 in an

industry

that is variably called " antiaging, " " regenerative, " " longevity, " or

" age-management " medicine, although not all physicians using these designations

administer GH to their patients. A nonsystematic viewing of numerous Web sites

revealed that the cost of pills and sprays allegedly containing GH is

substantial,

with both costing the consumer as much as $200 to $300 for what marketers

indicate

as a month’s supply (T.T.P., unpublished data, 2005). By contrast, the

injectible

form of GH typically costs from $500 to $1000 per month.13

Clinical Effects of GH

Growth hormone has been documented to improve some measures of body composition,

including increased muscle mass, reduced total body fat, improved skin

elasticity,

and reduced rate of bone demineralization,15 but without positive effects on

strength, functional capacity, or metabolism.15-19 Furthermore, the positive

effects

may be short-lived: in a study of 148 patients with adult GHD (defined below),

the

modest beneficial effects on body composition (eg, 5% increase in lean body

mass)

disappeared for most individuals after 24 months of treatment, and 38% of study

participants dropped out because of lack of subjective improvement.20 In

addition,

the healthy lifestyle that patients who receive injectible GH are often

encouraged

to adopt, rather than the GH itself, may contribute to changes in body

composition.

Growth hormone is associated with substantial adverse effects. In a clinical

trial

of healthy women (n = 57) and men (n = 74) aged 65 to 88 years, GH administered

subcutaneously at an initial dose of 30 µg/kg, 3 times per week, then reduced to

20

µg/kg, was associated with carpal tunnel syndrome in 38% of women vs 7% of those

taking placebo, and in 24% of men vs 0% taking placebo; edema in 39% of women

(0%

for placebo) and 30% of men (12% for placebo); and arthralgias in 46% of women

(7%

for placebo) and 41% of men (0% for placebo). Eighteen men treated with GH

developed

glucose intolerance or diabetes compared with 7 men in the nontreatment group.17

In a placebo-controlled clinical trial of GH (0.1 mg/kg/d of GH) for AIDS

wasting

syndrome in 510 patients, the most common reasons for dose reduction and/or drug

discontinuation were arthralgia, myalgia, edema, carpal tunnel syndrome, and

elevated glucose and triglyceride levels, with 36% of individuals reporting

arthralgias (vs 11% of those taking placebo), 30% reporting myalgias (12% for

placebo), and 26% reporting peripheral edema (3% for placebo).21 Because of

these

high rates of adverse effects,22 nonsustained improvements in quality of

life23-24

and anabolic effects,24-25 and the drug’s high cost, even the treatment of AIDS

wasting syndrome with GH has little support.23, 26-27 The doses used in these

studies are similar to those suggested by antiaging Web sites selling GH.

Another concern is the possibility of an increased cancer risk with long-term GH

treatment28 and the potentiating effects of insulin-like growth factors (IGFs)

on

cancer.29 Mukhina et al30 reported that autocrine production of GH by mammary

carcinoma cells facilitates cellular growth and suggested that such growth may

be

sufficient to cause breast carcinoma to become invasive and metastatic.

To our knowledge, no studies have assessed long-term efficacy or safety of GH

administration as an antiaging intervention in humans. Proponents of GH claim

that

aging is caused by an age-related decline in GH levels and therefore GH

supplementation can stop or reverse aging,3, 14 but scientific findings counter

or

fail to support this hypothesis. Transgenic mice that produce supraphysiological

levels of GH for their age have markedly reduced life spans and experience

premature

onset of age-related cognitive changes.31 Rats with adult-onset GHD and

decreased

IGF-1 levels have a 30% decrease in tumor incidence and a 16% decrease in

disease

burden.32 Growth hormone–resistant and GH-deficient mutant mice experience

substantially increased life spans.33

Legal Distribution of GH in the United States

As is the case for anabolic steroids, the legal provision and distribution of GH

is

narrowly defined. In 1988 and again in 1990, Congress amended the Food, Drug,

and

Cosmetic Act (FDCA) to enact more stringent controls with higher penalties for

offenses involving the distribution of anabolic steroids and HGH [codified at 21

USC

333(e)(1)].34 In 1993, the provisions outlawing the distribution of specifically

growth hormone were recodified as 21 USC 333(f) (pursuant to PL No. 103-80,

3(e),

107 Stat 775). Section 303(f)(1) of the FDCA permits distribution of HGH in

connection with (1) " treatment of a disease " or (2) " other recognized medical

condition " that has been authorized by the Secretary of Health and Human

Services.34-35 Provision of GH is legal for children with short stature (defined

as

a height >2 SDs below the mean for the child’s age and sex) who have GHD, poor

growth due to renal failure, syndrome, or Prader-Willi syndrome, and for

children small for gestational age (children who at birth were 2 SDs below the

mean

for weight or length or both who maintain a small body size beyond the age of 2

years)36 and for idiopathic short stature37 (defined as height >2.25 SDs below

the

mean for age and sex, or the shortest 1.2% of children).38-39

In adults, the FDA has stated that distribution of GH is legal for only 2

conditions

(S. Silverman, Director, Division New Drugs and Labeling Compliance, FDA,

written

communication, 2005 [may be viewed at http://www.bumc.bu.edu/centenarian]):

wasting

syndrome of AIDS (this does not include lipodystrophy26) and GHD, the latter of

which must meet 2 diagnostic criteria40: biochemical diagnosis of adult GHD by

means

of a subnormal response to the standard growth hormone stimulation test (peak

GH,

<5.0 ng/L); and patients who have adult GHD either alone or with multiple

hormone

deficiencies (hypopituitarism) as a result of pituitary disease, hypothalamic

disease, surgery, radiation therapy, or trauma or patients who were GH deficient

during childhood.

The stimulation test for GHD is performed with GH-releasing hormone (or factor),

arginine, glucagon, or insulin-induced hypoglycemia. Only 1 case per 10 000

adults

per year meet these criteria for the diagnosis of GHD; 3 cases per 10 000 also

include adults who received GH treatment as children.41 The prevalence of adult

GHD

in the United States is estimated to be 50 000, and the incidence is

approximately

6000 per year, but a substantial portion of adults with GHD are not currently

being

treated with GH.41 Measurement of IGF-1 levels (a proxy for GH levels) in older

adults, when demonstrated to be lower than that of young adults, does not

constitute

a scientific39, 42 or legally40 accepted diagnosis of GHD.

Marketing and Distribution of GH for Antiaging

In the United States, GH is commonly marketed, distributed, and prescribed for

antiaging under the pretext of " off-label use. " 14 However, off-label

distribution or

marketing of GH to treat aging or aging-related conditions is illegal. Unlike

most

FDA-approved medications, GH can only be distributed for indications

specifically

authorized by the Secretary of Health and Human Services35—aging and its related

disorders are not among such indications.43-44 Furthermore, the FDA has clearly

indicated that GH is not a dietary supplement.43 Growth hormone was approved as

a

drug by the FDA in 194043 prior to enactment of the 1994 Dietary Supplements

Health

and Education Act and, because it is a drug, it cannot be classified as a

dietary

supplement.43 In addition, dietary supplements must be intended for ingestion.45

The

FDCA defines the term " dietary supplement " in 21 USC 321 (ff)(2)(A)(i) to mean a

product that is " intended for ingestion. " Consequently, a product that is not

intended for ingestion cannot meet the definition of a dietary supplement.44

Growth

hormone is bioavailable only in injectible form, and therefore this is another

reason why it cannot be classified as a dietary supplement.39

The FDA’s position on the illegality of distributing GH as an antiaging

treatment is

conveyed in warning letters to Web sites marketing GH43-44 (other warning

letters

can be viewed at: http://www.fda.gov/foi/warning.htm and entering the term

" growth

hormone " ). The penalties chapter of the FDCA states under section 303 [333]35:

(1) Except as provided in paragraph (2), whoever knowingly distributes, or

possesses with intent to distribute, human growth hormone for any use in humans

other than the treatment of a disease or other recognized medical condition,

where

such use has been authorized by the Secretary of Health and Human Services under

section 505 and pursuant to the order of a physician, is guilty of an offense

punishable by not more than 5 years in prison, such fines as are authorized by

title

18, or both.

(2) Whoever commits any offense set forth in paragraph (1) and such offense

involves an individual under 18 years of age is punishable by not more than 10

years

imprisonment, such fines as are authorized by title 18, or both.

(3) Any conviction for a violation of paragraphs (1) and (2) of this

subsection

shall be considered a felony violation of the Controlled Substances Act for the

purposes of forfeiture under section 413 of such Act.

(4) As used in this subsection the term " human growth hormone " ' means

somatrem,

somatropin, or an analogue of either of them.

(5) The Drug Enforcement Administration is authorized to investigate offenses

punishable by this subsection.

The penalties for distribution or provision of GH for antiaging purposes are

substantial. Per the FDA’s letter to Dr Perls: " Section 303 provides for up to

five

years in prison, or ten years if the offense involves a minor. It also permits

courts to impose fines of up to $250 000 for an individual or $500 000 for an

organization, or alternatively, twice the gross gain or loss from the offense

(see

18 USC 3571), as well as forfeiture of property used in or derived from

violations

of the HGH law. " (S. Silverman, Director, Division New Drugs and Labeling

Compliance, FDA, written communication, 2005 [may be viewed at

http://www.bumc.bu.edu/centenarian]).

Those who distribute GH via the Internet violate another law. Per the FDCA, GH

must

be prescribed by a physician who, " based upon an individualized determination of

a

proper course of treatment, authorizes the drug’s distribution to a patient

under

his supervision " 34 (see also 21 USC 353[1]).46 Review of numerous Web

sites

that sell GH reveals either no steps taken to provide such supervision, or in

the

case of those who claim to provide supervision, the law may still be violated if

the

supervising physician never meets the patient (examples available on request).

Distributing drugs such as anabolic steroids or GH in this manner is termed

" misbranding, " a practice that in other contexts has resulted in the prosecution

and

conviction of laypersons, pharmacists, and physicians as a felony.34

Common marketing practices regarding GH and related products may also be

illegal. In

a recent case brought before the US District Court by the Federal Trade

Commission

(FTC) regarding a defendant selling products claimed to contain GH,47 the FTC

stated

several claims that illustrate findings that can lead to fines and disciplinary

action:

1. " The dissemination of false advertisement for the purpose of inducing the

purchase of a drug or device pursuant to 15 USC 52(a) is an unfair or deceptive

practice within the meaning of 15 USC 45(a). "

2. " The defendant deceptively promotes and sells HGH products with claims

that

are wholly false and cannot be substantiated. "

3. " The defendant's claims are false and cannot be substantiated with

competent

scientific evidence. "

Searching the Internet, numerous law-related Web sites, and specifically the FDA

and

US Department of Justice Web sites, reveals examples of lawsuits pertaining to

distribution of GH for " antiaging. " Misleading claims led one company to

voluntarily

destroy $515 000 worth of its HGH product.48 Another company pleaded guilty to

the

felony charge of illegally distributing GH without physicians’ orders, paid a

$500

000 criminal fine, and forfeited $1.25 million in profits made in sales of

approximately 100 000 bottles of its GH oral spray.49 Two Oregon physicians were

prosecuted by the Oregon attorney general, with the assistance of the FDA and

the US

Department of Justice, for misrepresenting GH to consumers " as a harmless

panacea

for the effects of aging " while prescribing, promoting, and selling GH at their

clinic and via the Internet.50-51 Two Florida businesses, named in an FTC

complaint

along with 2 individuals involved in the businesses, including one who is a

physician, " agreed to a federal court order requiring them to pay up to $20

million

in consumer redress—the largest monetary judgment ever obtained in an FTC health

fraud case—to settle charges that they deceptively claimed that their pills and

sprays would increase consumers’ human growth hormone (HGH) levels and provide

anti-aging benefits. " 52 The FTC indicated that the total sales of their

products,

including the dietary supplement " ultimate HGH " and the sublingual sprays

" Master

HGH " and " Super HGH " exceeded $70 million. Importation and distribution of

counterfeit GH has also been prosecuted.53-55

Responsibilities Regarding GH

Physicians and other health care professionals should be aware that current law

explicitly prohibits the distribution of GH except for clearly and narrowly

defined

indications. Distribution for other uses, or off-label use, such as for

antiaging,

age-related conditions, and enhancing athletic performance, are illegal.2, 35,

43,

45 Although GH is not a schedule III drug, section 303 [333] f(5) of the FDCA

clearly provides the Drug Enforcement Administration with the responsibility of

enforcing the laws governing human GH.35

Given the clinical concerns and the legal issues involved, we believe that

physicians or other persons who currently market, distribute, or administer GH

to

their patients for any reason other than the well-defined approved (ie, legal)

uses

of the drug, should not do so. Pharmaceutical companies that manufacture GH

should

play a more effective role in making physicians and the public aware of the

circumstances in which the marketing and distribution of GH are legal and

illegal.

Federal and state agencies should be allocated resources to better deal with the

illegal distribution of GH. Finally, the FDA and professional and lay

organizations

are in excellent positions to conduct awareness campaigns to educate physicians

and

the public about the legal and medical ramifications of GH use for antiaging.

Disclosure: Drs Perls and Olshansky report that they are defendants in a lawsuit

brought against them by the American Academy of Anti-Aging Medicine and others.

Al Pater, PhD; email: old542000@...

__________________________________

- PC Magazine Editors' Choice 2005

http://mail.