An Effect On The Nervous System

1. The Medical Officer evaluating Lupron stated that “It is difficult to understand why symptoms seem to decrease within two – four weeks of starting the drug, prior to even well-established hypogonadism and amenorrhea.” (20)
2. Lupron caused pain relief within two – four weeks of starting the drug and before low estrogen levels occurred?
   What caused the pain relief?
3. “Opiate-mediated processes are involved in the initiation and control over seizures to the brain.” (12)
4. “Both B-endorphin and Leu- and Met-enkephalin produced EEG seizures at lower doses than were needed to produce analgesia.” (19)
5. Opioid peptides caused seizures that are brief, have a short latency, are limited to limbic sites, and are NOT associated with behavioral convulsions.” (18)

I. Neuropharmacological Actions of an LH-RH GnRH) Agonist Analog In Mice and Rats.

LH-RH (GnRH) Agonist Analogs Effect Endogenous Opiates and Are Dopamine Antagonists:

1. The LH-RH agonist analog “were studied in several pharmacological tests in mice, and the peptide was found to exert sedative-anxiolytic, neuroleptic or dopamine antagonist and analgesic activities.” “In further experiments, the central inhibitory actions of” the LH-RH agonist analog “were demonstrated to be partially reversible by the opiate antagonist naloxone,* indicating the possible role of endogenous opioids in the peptide effects.”(14)
2. The results indicate that the agonist analog of LH-RH “has an inhibitory effect on the central nervous system, and the mechanism of its action may involve dopaminergic transmission and/or endogenous opiates.”(13)
3. In experiments with naloxone and one single dose of an LH-RH agonist analog “we found that the effects of the hormone were naloxone-reversible in the tail-flick test, in the open-field test (with the exception of grooming), and in the picrotoxin test, but not in the catalepsy and cage-climbing test.” (13)
4. Some of the actions, such as apomorphine-induced cage climbing behaviour or cataleptic reactions, were mediated via the dopaminergic system, while others, such as locomotion, nociception (tail-flick) picrotoxin-induced seizure etc. were mediated via endogenous opiates. ()
5. “The analgesic activity of the analog in the tail-flick test (which is considered to be a specific pain-test for opiates), was totally blocked by a low, specific dose of naloxone, indicating that endogenous opioids play an important role in the mechanism of action of this peptide.” (12)
6. “The peptide also induces significant analgesia in the tail-flick test, suggesting an important interaction between LH-RH and endogenous opioid peptides.” (15)
7. In the hot-plate test, an LH-RH agonist analog “significantly increased the pain-threshold latency of mice.” “In the tail-flick test, the situation was quite similar.” (14)
8. The LH-RH agonist displayed a sedative-like action. (16)
9. “The peptide induced analgesia was totally naloxone reversible. The results indicated that the agonist analog of LH-RH exert potent actions on the central nervous system, and the mechanism of effects many involve dopaminergic transmission and/or endogenous opiates.” (15)
10. “The opiate antagonist was fully able to antagonize the analgesic effect of the peptide [LH-RH agonist analog] in the tail-flick test.” (12)
11. “The LH-RH analogue caused a dose-dependent analgetic response in the hot-plate and tailflick methods. However, naloxone blocked the antinociceptive action of the LH-RH analogue only in the tail-flick method.” (16)
12. There were increases in latencies of pain perception in the hot-plate test and tail-flick test after subcutaneous administration of an LH-RH agonist analog. (12)
    In a human clinical trial, in which pancreatic cancer patients received chronic treatment with an LH-RH agonist analog, a decrease in abdominal pain was reported by the patients after just 3 weeks. (12)

Catalepsy-Like Immobility and LH-RH (GnRH) Agonist Analogs:

• “A catalepsy-like immobility was elicited” by an LH-RH agonist analog. (12)
• “The behavior resembled the cataleptic state induced by classical neuroleptic drugs.” (12)

II. GnRH (LH-RH) is a Neuropeptide

1. A neuropeptide is an endogenous peptide that influences neural activity or functioning. (17)
2. A neuropeptide is any of the molecules composed of short chains of amino acids found in brain tissue, often localized in axon terminals at synapses; they are classified as putative neurotransmitters, although some [LH, FSH, GH] are also hormones. (18)

III. Neurological Symptoms Reported With IVF

As of 1994, paresthesia was the 3rd most common side effect reported to the FDA for women.(8) Paresthesia is an abnormal spontaneous sensation, such as of burning, pricking, tickling, or tingling. (9)

In 1990 Dr. Ashkenazi and colleagues reported the following neurological symptoms after exposure to a GnRH analog for IVF-ET.(1)

Patient 1:

8 days after only 1 monthly injection of a GnRH analog “the patient started to complain of various neurological symptoms, such as severe headaches of the migraine cephalic type, numbness and tingling of the face, paresthesia and weakness of hands, arms, and legs, and sensory ataxia. These signs were first felt along one side of the body, and several days later on the other side.”(1) In the next IVF cycle, she was treated with a different GnRH-analog, this time in the form of a nasal spray. “Ten [10] days later, identical neurological signs appeared, severe headaches, numbness of the face, and paresthesias of the right hand and leg.”(1)

Patient 2:

Twelve (12) days after only 1 monthly injection “the patient started to complain of severe unilateral (left) migraine headaches, as well as of paresthesias, weakness, and numbness of the left arm and hand.”(1)

“During the next IVF cycle 3 months later, she was again” given the same GnRH-analog and “10 days later her symptoms, mainly unilateral headaches, and left arm/hand numbness and paresthesia, recurred.”(1)

Patient 3:

Ten (10) days after only 1 monthly injection for an IVF cycle, “the woman started to complain of paresthesia and numbness of her left hand.”(1) In the following IVF cycle, she was treated with the same GnRH-analog and “10 days later the patient complained of severe migraine, numbness of the left side of the face, as well as paresthesia and numbness of her left hand.”(1)

Dr. Ashkenazi et al stated that “the mechanisms of action responsible for this complication is not clear.”(1) However, “a direct effect of potent GnRH-analog on the central nervous system resulting in neurological effects independent of the hypothalamus-pituitary-gonadal axis is posssible.”(1)

Dr. Ashkenazi points out that “it is quite possible that mild cases with minor symptoms have escaped notice; thus, the occurence of this type of complication may be far more common than we realize.”(1)

Patient 4:

In 1991, Dr Penzias and colleagues reported a case of “transient facial and neck paresthesia” with a GnRH-analog in a 26-year-old woman being treated for endometriosis.(7) On the 23rd day of the medication the patient noted left breast pain, and the “onset of lower facial and neck tingling and numbness on the side contralateral [opposite] to drug administration.”(7)

It should be noted that these four cases were the only cases reported in the medical literature that discuss paresthesia. In addition, the following statistics have been reported:

14 % developed paresthesia of the hand when given Lupron Depot (3.75 mg) for fibroids. (10)
7 % developed paresthesia when given Lupron Depot (3.75 mg) for endometriosis. (11)
5 % developed paresthesia of the hand when given Lupron Depot (1.88 mg) for fibroids.(10)

IV. GnRH-analogs Affect the Autonomic Nervous System

In 1995, Dr. John Mathias stated that “gonadotropin-releasing hormone (GnRH) analogs are not like any other medication currently available for treatment of disease. As we continue to learn more about these analogs’ mechanisms of action, it is increasingly apparent that they do not just affect the gonadal hormones, but are powerful modulators of autonomic neural function.”(5)

“GnRH analogs [Lupron] may exert direct effects upon the Autonomic Nervous System.”(6)

In 1989, Dr. John Mathias patented Lupron’s effect on the autonomic nervous system for motility disorders (irritable bowel syndrome).(6) In the patent application, Mathias states that “evidence suggest that these diseases derive from abnormalities of the autonomic nervous system” and that Lupron may “exert direct effects upon the autonomic nervous system.”(6) In addition, Mathias conducted the clinical trials for TAP/Abbott in an attempt to gain FDA approval of Lupron for the very use in which he owns the patent. Although Mathias published the results from his Phase II clinical trials, Lupron has NOT gained FDA approval for irritable bowel syndrome.(21) (It is interesting to note that, according to Mathias, women who naturally had less estrogen (ie. natural menopause) required MORE Lupron.)

REFERENCES

1. Ashkenazi J, Goldman JA, Dicker D, Feldberg D, Goldman GA. Adverse neurological symptoms after gonadotropin-releasing hormone analog therapy for in vitro fertilization cycles. Fertility & Sterility. 53: 4: 1990; p. 738-740.
2. Speroff L, Glass RH, Kase NG. Clinical Gynecologic Endocrinology and Infertility, 2nd edition. Baltimore, Williams & Wilkins, 1982.
3. Klijn JGM, Foekens JA. Extrapituitary action of GnRH analogues. Gynecol Endocrinol 1(Suppl): 16: 1988.
4. Mathias JR, Clench MH. Placebo Controlled Study Randomizing Leuprolide Acetate. Digestive Diseases and Sciences. June 1995; 40: 6: p. 1405-1407.
5. “Treatment of motility disorders with a GnRH analog” by John R. Mathias. US Patent # 5166192 (Filed: Aug. 14, 1991).
6. Penzias AS, Gutmann JN, Seifer DB, DeCherney AH. Facial and neck paresthesia associated with nafarelin administration. Fertility & Sterility. 1991; 56: 2: p. 357-358.
7. Adverse Reactions Reported to US Food and Drug Administration as Part of the Spontaneous Reporting System/Division of Epidemiology, through December, 1994.
8. Stedman’s Medical Dictionary. Williams and Wilkins Company. Baltimore, 1979.
9. Watanabe Y, Nakamura G, Matsuguchi H, Nozaki M, Sano M, Nakano H. Efficacy of a low-dose leuprolide acetate depot in the treatent of uterine leiomyomata in Japanese women. Fertility & Sterility. 1992; 58: 1: p.66-71.
10. Facts and Comparisons, 1994.
11. Kadar T, Telegdy G, Schally AV. Partial Reversal Of Behavioral Action Of The Agonist D-Trp-6-LH-RH By Naloxone In Mice. Life Sciences. 1990; 46: 7: p.463-470.
12. Kadar T, Telegdy G, Schally AV. Neuropharmacological Actions of the Superactive Agonist Analog D-Trp-6-LH-RH After Peripheral Injection into Mice. Neuropeptides. 1990; 17: p.81-86.
13. Kadar T, Telegdy G, Schally AV. An LH-RH Antagonist Inhibits the Behavioral Effects of the Agonist D-Trp-6-LH-RH in Mice. Pharmacology Biochemistry and Behavior. 1992; 41: 4: p.665-668.
14. Kadar T, Telegdy G, Schally AV. Behavioral Effects of Centrally Administered LH-RH Agonist in Rats. Physiology & Behavior. 1992; 51: 3: p.601-605.
15. Kadar T, Telegdy G, Balazs M. Involvement of Neurotransmitter and Neuropeptides in Behavioral Action of Some Neurohormones. Pol. J. Pharmacol. Pharm. 1990; 42: p.537-547.
16. Pickworth WB, Gerard-Ciminera J, Lathers CM. Stress, Arrhythmias, and Seizures. In Epilepsy and Sudden Death, C.M. Lathers, P.S. Schraeder (Eds.). Marcel Dekker, Inc., New York, p.437.
17. Frenk H. Pro- and Anticonvulsant Actions of Morphine and the Endogenous Opioids: Involvement and Interactions of Multiple Opiate and Non-Opiate Systems. Brain Research Reviews. 1983; 6: p.197-210.
18. US Food and Drug Administration. NDA #20011.
19. Mathias JR, Clench MH, Reeves-Darby VG, Fox LM, Hsu PH, Roberts PH, Smith LL, Stiglich NJ. Effect of Leuprolide Acetate in Patients with Moderate to Severe Functional Bowel Disease. Digestive Diseases and Sciences. 39: 6: 1994; p. 1155-1162.