and the Therapeutic Effect of Lupron
by John Hines
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1. Naturally Occurring
Steroids in the Mammal
While the word steroid often receives negative attention due
to the use of synthetic steroids by professional athletes, it has long been known that the
mammalian body produces a number of its own natural steroids which are essential for
normal functioning of the body. It has been useful to divide the natural steroids produced
by the mammalian body into two groups:
- the androgens (a.k.a. the sex steroids) which are
produced primarily by the gonads (testicles in the male animal, and ovaries in the female
animal). Examples of sex steroids include estrogen, progesterone and testosterone. The
androgens are important for normal sexual development and reproduction.
- the corticosteroids (a.k.a. the adrenal steroids)
which are produced by the cortex (outermost layers) of the adrenal gland. Examples of
adrenal steroids include cortisol and aldosterone. The adrenal steroids are important for
maintaining normal metabolism and body fluid electrolyte balance. The production of
corticosteroids is controlled separately from production of sex steroids.
While this neatly classifies natural steroids by their site of
production and is still very useful for a basic understanding, it has been discovered that
sex steroids can also be produced in small amounts by the adrenal glands. Thus, the
production of sex steroids can continue even in neutered animals lacking gonads.
Ordinarily, this continued production of sex steroids has little consequence, since the
animals are incapable of reproducing.
However, in the case of adrenal disease in the domesticated ferret
(a.k.a. hyperadrenalcorticoidism), the adrenal gland begins to produce much
higher amounts of sex steroids than it would normally. This elevated level of sex steroids
will lead to the very serious health problems associated with adrenal disease. It is not
known for certain what causes the adrenal gland to become overactive there may be
more than one possible cause. It is known that under normal conditions the adrenal gland
is controlled by the pituitary gland, as part of an overall endocrine system called the
2. The HPA Axis
The adrenal glands, located above the kidneys, are under the chemical
control of the pituitary gland, which is located below the base of the brain; in turn, the
pituitary gland is under the direct control of an area of the brain known as the
hypothalamus. Together, the hypothalamus, pituitary and adrenal glands form one of the
major endocrine systems of the body, commonly called the H-P-A axis (see fig. 1).
Figure 1: The HypothalamusPituitaryAdrenal, or HPA Axis
|In the context of sex steroid production (by either the gonads or by
the adrenal glands), the hypothalamus first releases a chemical called GnRH
(gonadotropin release hormone) which goes directly to the pituitary, GnRH is released by
the hypothalamus in short, discrete pulses not in a steady stream. In response to
GnRH, the pituitary is itself stimulated to releases its own hormones, which are called luteinizing
hormone (LH) and follicle-stimulating hormone (FSH). The LH and FSH enter
the bloodstream and will travel to the gonads to stimulate production and maturation of
sperm or ovum for reproductive purposes (fig. 2). They will also increase the level of sex
steroids produced by the gonads.
Figure 2: Normal Androgen Production via Pathways of HPA Axis
|Since the adrenal glands are also capable of limited production of sex
steroids, they too will respond similarly to the LH and FSH, and increase their androgen
3. Overproduction of Sex
in Adrenal Disease
The problem of adrenal disease in ferrets arises when a small portion of
the adrenal gland called the zona reticularis begins to overproduce and release
sex steroids into the body. The most direct method of correcting this problem has been
removal of the affected adrenal gland(s): no more adrenal gland means no more zona
reticularis, therefore no more sex steroids (assuming the ferret has also been neutered).
The downside of this approach, aside from the general risks involved
with any invasive procedure, is that removal of the adrenal gland can also deprive the
body of the various other hormones that are also produced by the adrenal gland. These
include the other adrenal steroids (cortisol, aldosterone) and adrenalin (which is
produced in the adrenal medulla, or interior). If BOTH adrenal glands need to be removed,
the ability of the ferret to make these necessary hormones will be severely diminished.
Often hormone replacement therapy is necessary to ensure recovery of the ferret.
As described earlier, the adrenal glands are under the control of the
pituitary gland. Hormones (FSH and LH) released from the pituitary gland into the
bloodstream travel to the adrenal gland and turn on sex steroid production and
secretion. Thus, an alternative method of reducing the secretion of sex steroid from the
adrenal gland would be to block the pituitary gland from producing FSH and LH (fig. 3).
Figure 3: Adrenal Gland Overreacts to Pituitary Hormones
|If these pituitary hormones were absent from the body, sex steroid
production and secretion by the zona reticularis would be substantially reduced if not
eliminated altogether. This approach would make the removal of the adrenal glands
unnecessary and thereby spare the ferrets ability to produce the other adrenal
hormones. It is by this mechanism intervention at the level of the pituitary
that Lupron most likely can correct hyperadrenalcorticoidism.
4. How Lupron
As mentioned earlier, GnRH is released by the hypothalamus in a
pulsatile manner to stimulate the pituitary to release FSH and LH into the bloodstream. It
is necessary for normal pituitary function that the hypothalamus release GnRH in brief,
discontinuous pulses rather than sustained, continuous secretion. The pituitary gland can
and will rapidly lose its responsiveness to GnRH if exposed to the chemical for extended
intervals of time. This phenomenon is called desensitization.
Lupron (leuprolide acetate) is a synthetic version of GnRH. It is more
stable than the natural hormone and therefore is degraded much more slowly within the
body. This is the key to how Lupron works. Once injected into the bloodstream, Lupron acts
at the pituitary gland just as natural GnRH does. However, since Lupron is administered at
a relatively high dosage and isnt degraded easily, the sustained presence of the
drug actually causes the pituitary to desensitize, and thus cease production of LH and FSH
Figure 4: Desensitization of Pituitary by Lupron
|Without circulating FSH and LH, the adrenal gland stops production of
androgens, and thus the blood levels of androgens drop and the ferret recovers from
5. Limitations of Lupron Therapy
While some ferrets with adrenal disease do well on Lupron, the scenario
where a ferret may be unresponsive to Lupron may also exist. This scenario could arise if
the adrenal gland has become diseased in a way such that the zona reticularis will produce
androgens independent of any regulation by FSH and LH. If this should occur, the adrenal
gland would probably continue to hyper-secrete androgens even after Lupron therapy has
reduced levels of FSH and LH. However, since some ferrets do respond well to Lupron, it is
often worth trying if the ferret owner is uncomfortable with the idea of surgery as a
Also, Lupron therapy is a life-long protocol: the ferret will require
regular doses of Lupron to keep the malfunctioning adrenal gland under control. In the
long run, this can be more expensive than surgery, which is presumably a one-time
Norris, David O. (1980). Vertebrate Endocrinolology. Lea & Febiger,
Murad, Ferid. (1990). Hormones and Hormone Antagonists. In
Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor, eds., Goodman and Gilmans The
Pharmacological Basis of Therapeutics, 8th ed. Pergamon Press, New York.
John Hines is a grad student in Pharmacology, at
the University of Pennsylvania. His ferret, Nikita, is receiving herbal treatment
(Devils Club Supreme) for symptoms of an insulinoma, and at least so far isnt
showing any signs of adrenal problems. Nikita receives veterinary care at the Animal and
Bird Health Care Center in Cherry Hill, NJ.
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© 1999 John Hines. All Rights Reserved. Used by Permission.