THE NATIONAL LUPRON VICTIMS NETWORK - Fibroids



THE NATIONAL LUPRON VICTIMS NETWORK - Fibroids

THE NATIONAL LUPRON VICTIMS NETWORK

Return to: THE NATIONAL LUPRON VICTIMS NETWORK Homepage

LUPRON: FIBROIDS

"There is NO evidence that estrogen directly stimulates myoma growth." (32)

Why are YOU being given Lupron?

In 1990, Andrew J. Friedman, MD, Susan M. Lobel, MD, Mitchell S. Rein, MD, and Robert L. Barbieri, MD, stated

the following: "In addition to the potential therapeutic uses of GnRH agonists in the treatment of uterine

leiomyomas,

these agents may be used as probes [a device used to get information] to help elucidate

[explain] the biology of [fibroids] these common symptom-producing tumors." (2)

In 1990, Mitchell S. Rein, MD, Andrew J. Friedman, MD, Murugan R. Pandian, PhD, and Linda J. Heffner, MD, PhD, stated the following:

"The gonadotropin-releasing hormone agonist (GnRH-a) leuprolide acetate depot was used as a biologic probe to investigate the possible roles of insulin-like growth factors (IGFs) I and II in fibroid growth." (14)

Up to 40% of women, over the age of 35, have fibroids. (1)

Other words for fibroid(s): leiomyoma, myoma, leiomyomata, myomata

I. FDA APPROVAL FOR FIBROIDS IS ONLY FOR PREOPERATIVE (before surgery) ANEMIA DUE TO FIBROIDS:

"Reported series indicate that approximately 10% of patients requiring surgical therapy for leiomyomas have a hematocrit of less than or equal to 35, and approximately 50% of these patients have a hematocrit less than or equal to 30%." (3) In other words, according to the above information:

approximately 90% of patients who require surgery for fibroids will have a hematocrit equal to or greater

than 35.

[A hematocrit of 36 is considered normal for a woman.]

In 1989, the manufacturer tried to gain approval of Lupron for the following indication:

"the temporary, symptomatic relief of leiomyoma uteri (uterine fibroids) for a period up to 6 months, especially in patients where reduction in uterine volume and/or improvement in hematologic parameters is important. Treatment may be prior to surgery or when surgery is not desirable."

In a 5 to 2 vote, a US Food and Drug Administration advisory committee panel voted not to recommend approval of Lupron for the above indication." (4)

The manufacturer withdrew the application.

However, a document dated/stamped March 13, 1995, just one month before the approval of Lupron for fibroids, contained the following concluding remarks about the entire NDA (New Drug Application) for fibroids from a medical officer at the FDA: "I don't believe that the drug should be approved for the following reasons:

1. The data did not demonstrate a clinically significant gain in hemoglobin with Lupron plus iron over iron therapy alone. The actual gain was l.l-1.2g/dl hemoglobin in the Lupron group, which I do not consider to be clinically significant. A difference of 2g/dl between groups would have been impressive.

2. The perceived benefits do not outweigh the risks of exposing pre-menopausal women to bone mineral density loss, significant cholesterol, lipid and liver function changes, as well as other adverse events that were reported more often for Lupron Depot treated patients than for iron only treated patients.

3. In the study that provided blood donation and transfusion data:

It was not shown that there was a clinically significant decrease in number of Lupron treated patients requiring blood transfusion.

Nor was it shown that there was a clinically significant increase in number of Lupron treated patients who were suitable to provide autologous blood for their surgery.

4. There was no additional data provided that linked any of the other Advisory Committee Recommendations to

benefits of GnRH agonist therapy." (4) "RECOMMENDATIONS: NON-APPROVAL FOR THE INDICATIONS SOUGHT [March 13,1995]."(4)

However, on March 20, 1995 the Supervisory Medical Officer wrote the following:

"I have studied the review of this NDA [New Drug Application] by [the above doctor], the Medical Officer, dated

March 13, 1995, and the Consultation by Dr. Bruce Stadel, dated March 16, 1995. Although I share the view of

other gynecologists in this Group that [the above doctor] demonstrates good clinical judgement in establishing a

conservative stance concerning the use of Lupron Depot for the treatment of women with leiomyomata, Dr. Stadel's

analysis makes it clear that the sponsor has achieved the standards for approval established in 1991, before [the

above doctor] began work at the Agency."

"Therefore, I recommend approval of the NDA [New Drug Application], with the following indications:"

"Iron therapy for one month is first line preoperative treatment of patients with anemia caused by uterine

leiomyomata.

Lupron Depot 3.75 mg plus iron is second line treatment for women who fail to improve on iron alone but should

not be provided for more than 3 months." (4)

On March 30, 1995, the following was written to the manufacturer:

"This new drug application provides for the treatment of anemia caused by uterine leiomyomata in women who

fail iron therapy." (4)

In April, 1995, Lupron finally gained approval for the following limited indication:

"Lupron depot 3.75mg and iron therapy are indicated for the preoperative [before surgery] hematologic

improvement of patients with anemia caused by uterine fibroids." (4)

- "The clinician may wish to consider a one-month trial period on iron alone inasmuch as some of the patients

will respond to iron alone." (4)

- "Lupron may be added if the response to iron alone is considered inadequate. Recommended duration of

therapy with Lupron Depot is up to 3 months." (4)

- Retreatment cannot be recommended since safety data beyond 6 months are not available." (4)

H. LUPRON WAS NOT APPROVED FOR THE FOLLOWING:

1. Lupron was NOT approved to prevent blood transfusions or allow for autologous donations (donating your blood for yourself)

a. According to FDA documents:

"In the study that provided blood donation and transfusion data:

- It was not shown that there was a clinically significant decrease in number of Lupron treated patients requiring blood transfusion.

- Nor was it shown that there was a clinically significant increase in number of Lupron treated patients who were suitable to provide autologous blood for their surgery. (4)

b. Friedman et al compared the following:

Group A = Lupron Depot 3.75 mg every 4 weeks for 3 months before myomectomy. Group B = Placebo before myomectomy. (8)

1. Blood donations:

"All patients were encouraged to donate up to 3 units of blood before myomectomy. "(8) Group A [Lupron] donated 2.4 +/- 0.2 units of blood before surgery compared with Group B [Placebo] donated 2.2 +/- 0.3 units of blood before surgery.

2. Blood transfusions:

According to Friedman, "4 patients [Group A/[Lupron]: 2 patients; Group B/[Placebo]: 2 patients] required blood transfusions intraoperatively or in the immediate postoperative period." (8)

2. Lupron was NOT approved to prevent blood loss intraoperatively (during surgery) or the immediate postoperative (after surgery) period.

a. Klitz et al concluded that "neither dose of LA [Lupron Depot 3.75 or 7.5 mg] aided in the reduction of

blood loss at myomectomy and therefore should not be used routinely." (5)

b. According to Coddington, et al "objective measures, such as operative time and blood loss, were not

modified by leuprolide acetate [Lupron Depot] pretreatment." (6)

c. Fedele et al reported that intra-operative blood loss during myomectomy was not significantly less in the

group exposed to a GnRH-a.

There was a mean blood loss of 235ml with the GnRH-a treated group and 275ml with the control group.

This is a difference of approximately 40ml which was determined not to be statistically significant. 40 ml is

equivalent to approximately 3 tablespoons. (7)

3. Lupron was NOT approved to make surgery easier or as an advantage to surgery

a. "Some have cast doubt on the wisdom of pre-operative LHRH analogue treatment in view of the fact that the

fibroid 'capsule' is less evident and excision may be more difficult." (10)

b. "The ease of myomectomy after GnRH agonist treatment has been a source of intense debate." "Some have

claimed that preoperative GnRH agonist treatment may decrease the surgeon's ability to find the proper

surgical plane surrounding the myoma." (9)

c. There is "degeneration of some leiomyomas necessitating piecemeal enucleation at myomectomy." (2)

d. "The obliteration of the myoma-myometrial interface may explain the difficult enucleation of the myomatous

nodules often encountered by surgeons in [GnRH-a] treated patients." (15)

e. "In performing hysterectomy, apart from the reduced size of the uterus, there is perhaps no great advantage

in the use of pretreatment with LHRH analogues." (11)

f. "Our results did not demonstrate that any advantage was gained by pre-operative administration" of a

GnRHa (not Lupron ). (7)

4 Lupron was NOT approved to prevent hysterectomies

According to FDA documents:

"Mean shrinkage with Lupron on average in all 4 studies ranges from 42.2% to 24%. This reduction is consistent

with the literature. This reduction in volume, however, did not result in fewer abdominal hysterectomies; or in

fewer hysterectomies and more myomectomies in patients who desired maintaining their reproductive capacity."

(4)

5. Lupron was NOT approved to avoid surgery

(SEE FIBROID REGROWTH below)

6. Lupron was NOT approved as a "bridge" to natural menopause

Matta et al stated, "we have reservations about advocating the use of LHRH agonists in perimenopausal symptomatic women with the aim of controlling their symptoms until natural occurrence of the menopause." (12) It seems unwise to impose bone loss as a side-effect of therapy in women who will develop further osteoporosis after the natural menopause. (12)

7. Lupron was NOT approved to cure fibroids

a. Lupron is NOT a cure for fibroids.

b. “There is currently no adequate long-term medical [drug] therapy for myomas and surgery; either hysterectomy or myomectomy remains the treatment of choice." (5)

c. "Currently surgery is the treatment of choice in women with leiomyomata who require therapy/()

8 Lupron was NOT approved to allow for a vaginal (hysteroscopic) myomectomy

(SEE SUBMUCOUS FIBROIDS below [coming soon])

9. Lupron was NOT approved to allow for a vaginal hysterectomy

10. Lupron was NOT approved to shrink fibroids

11. Lupron was NOT approved to alter the incision location

12. Lupron was NOT approved to increase fertility

13 Lupron was NOT approved to use after surgery 14. Lupron was NOT approved to postpone surgery

III. DESTRUCTION OF CAPSULE AROUND FIBROID FROM LUPRON:

1. "Some have cast doubt on the wisdom of pre-operative LHRH analogue treatment in view of the fact that the fibroid 'capsule' is less evident and excision may be more difficult." (10)

2. "The ease of myomectomy after GnRH agonist treatment has been a source of intense debate." "Some have claimed that preoperative GnRH agonist treatment may decrease the surgeon's ability to find the proper surgical plane surrounding the myoma." (9)

3. There is "degeneration of some leiomyomas necessitating piecemeal enucleation at myomectomy." (2)

4. 91 % of the patients showed obliteration of the cleavage plane after recieving Lupron Depot (3.75 mg) for 3 months. "The obliteration of the myoma-myometrial interface may explain the difficult enucleation of the myomatous nodules often encountered by surgeons in [GnRH-a] treated patients." (15)

IV. RATE OF SHRINKAGE OF FIBROIDS/UTERUS WITH LUPRON IS DIFFERENT THAN IN MENOPAUSE:

1. According to Shaw 64% of the reduction in uterine volume during 4 months on a GnRH-a will occur during the 1st month even though estradiol (E2) levels are increased above normal for at least half of that first month (10-14 days). (11)

2. Shaw also stated that "it is apparent that a marked reduction in uterine size occurs maximally during the 1st month of treatment with an LHRH analogue. This is perhaps more remarkable since the first 10-14 days of exposure to the agent is the agonist phase with an increased oestradiol [estradiol] output." (11)

a. "Even at the end of the 4th week of administration when down-regulation of the pituitary has been achieved, the suppression of circulating oestradiol 17-beta is still not maximal, and this may not occur until the 2nd or 3rd month of administration." (11)

b. "By the 3rd or 4th month of adminstration, the maximum reduction in size has been achieved with no further significant reduction occurring, even with continued treatment." (11)

c.

|MONTH |MONTHLY AVERAGE % REDUCTION | During 10-14 days of the 1st month, |

| | |

| |IN UTERINE VOLUME estradiol levels are increased above normal |

| | |

| |26.5% |

|1st |, , |

| | |

|2nd |10.2 % |

|3rd |3.8% |

| |* |

|4th |0. 9% |

|~~" | |

3. Malta stated "the rate of reduction in volume associated with LHRH agonist therapy is much greater than that observed in the immediate postmenopausal period." (12)

4. Coddington, using another GnRH-a, stated that "the rate of size reduction that occurred after the initiating of therapy is somewhat faster than we would have anticipated based on our clinical experience and our observation of the rate of shrinkage of leiomyomata after spontaneous, natural menopause." (16)

5. "The "rate of reduction was greater during the 1st month of [GnRH-a] treatment." (17)

V. POSSIBLE CAUSES OF SHRINKAGE OF FIBROIDS AND/OR UTERUS:

A. DECREASES IN GROWTH HORMONE (GH) & INSULIN-LIKE GROWTH FACTOR-1 (IGF-1):

1. Friedman, Rein, Pandian and Barbieri studied women who received Lupron Depot 3.75mg for 12 weeks for fibroids. They stated that "leuprolide acetate treated patients also demonstrated significant decreases in serum growth hormone (GH) and insulin-like growth factor-1 (IGF-1) concentrations." (13)

2. Friedman. Rein, Pandian and Barbieri also stated that "in this placebo-controlled double blind study,

significant decreases in mean fasting GH [Growth Hormone] and IGF-1 concentration were noted after 12 weeks of leuprolide acetate depot therapy in women with leiomyomata." (13)

3. Rein, Friedman, Pandian and Heffner stated that "growth hormone is considered the primary regulator of IGF-1 secretion." (14)

4. Friedman, Rein, Pandian and Barbieri concluded that "it is possible that the decrease in GH [Growth Hormone] concentrations seen in leuprolide-treated patients may be partly responsible for the decrease noted in mean uterine volume." (13)

B. DECREASED BLOOD FLOW TO BRAIN, FIBROIDS & UTERUS WHILE ON LUPRON:

1. In 1994 Berman stated that Lupron "shuts down blood flow to the frontal lobes of the brain." (18)(19)

2. According to Reinsch et al Lupron Depot (3.75 mg) is "effective in decreasing blood flow to the uterus." After 3 months of Lupron (3.75 mg) uterine artery blood flow decreased by 21%. (21)

3. In 1988 Matta, using another GnRH analog stated that "it is possible that the reduction in [fibroid] volume could be in part related to induced changes in uterine blood flow." (22)

a. The Resistance Index nearly doubled in 4 months on a GnRH agonist. As the Resistance Index went

up, the blood flow went down. The Resistance Index (RI) reflects vascular resistance. (22)

b. Matta also stated that the "diastolic flow signals could not be detected by the end of treatment in the

uterine vessels of 3 patients [43%] and the fibroid arterial supply in 2 patients [29%], when the values

for R[esistance] I[ndex] were considered equal to 1 in each of these measurements." (22)

c. Matta concludes that at the end of treatment with GnRHa for 4 months, "were associated with

significant increases in the mean Resistance Index values for the uterine and fibroid vasculature, thus

indicating reduction in blood flow." (22)

4. Shaw stated that "it is possible that the reduction in uterine volume is partly related to induced changes in uterine blood flow." ()

VI. INCREASED FIBROID RECURRENCE BECAUSE OF MISSED FIBROIDS DURING SURGERY DUE TO GnRH-a USAGE:

1. Fedele et al stated that "the ultrasound examination performed 6 months after surgery demonstrated a greater frequency of recurrence in the short term in the women treated with [a GnRH-a]." (7)

There was an "increase in the frequency of recurrence [of fibroids] from 10% in the control group to 70% in the [GnRH-a] treated one." (7)

The greater frequency of rapid myoma recurrence in the patients treated preoperatively with [a GnRH analogue] is in all probability attributable to the decrease in volume and consistency of the myomas induced by the analogue, making the smaller tumors no longer identifiable during operation." (7)

2. "A potential disadvantage of preoperative agonist treatment is that small uterine fibroids may be missed intraoperatively, resulting in increased recurrence rates." (20)

VII. SUBMUCOUS FIBROIDS & HEMORRHAGE WITH LUPRON:

1. Friedman reported 3 cases of "dramatic and severe vaginal bleeding" in women with submucous fibroids treated with Lupron. "In all cases, acute anemia developed, necessitating blood transfusions [3-4 units of packed red blood cells] and emergency myomectomies." "In all cases, hyaline degeneration of resected submucous tumors was noted, with focal necrosis and hemorrhage." (23)

2. Nakamura et al reported that 8% of patients who had all types of fibroids experienced "sudden severe vaginal bleeding 6 to 7 months after discontinuation of [GnRH-a] therapy and underwent hysterectomy for submucous leiomyomata." "The final pathological diagnosis demonstrated submucous leiomyoma associated with focal necrosis, liquefaction, and hyaline degeneration." "It is important to note that LH-RH-a treatment for submucosal leiomyomata appears less effective, despite a greater degree of E suppression. Treatment of patients with submucousal leiomyomata using a LH-RH-a should therefore be carefully evaluated before its clinical recommendation." (26)

3. Thorp and Katz reported a case of a woman with a submucous fibroid that suddenly began hemorrhaging after 8 weeks of Lupron exposure. This patient received 4 units of packed red blood cells. Thorp and Katz concluded that "if hysteroscopy, ultrasound or magnetic resonance imaging [MRI] reveals submucous myomas, the clinician should be aware that profuse vaginal bleeding can ensue with leuprolide acetate" [Lupron]. (27)

VIII. CHANGES THAT OCCUR IN FIBROIDS AFTER EXPOSURE TO LUPRON:

1. Jeffers et al stated that "degenerative and iatrogenic changes are likely to be encountered more often in myomectomy and hysterectomy specimens with increased use of GnRH analogues." (31)

2. Banagiano et al stated that "histological evaluation of fibroid masses obtained from women who underwent

hysterectomy after LHRH analogue treatment shows in all instances, varying degrees of degeneration. Hyalinisation is a common picture and it is noteworthy that intense hyalinisation is almost invariably observed around blood vessels." (10)

3. Deligdisch et al found that 17% of patients exposed to Lupron Depot (3.75 mg) for 3 months showed "lymphocytic infiltrates consisting of aggregates of mature lymphoid cells." None were found in the placebo group. "In some patients treated with LA [Lupron] for extended periods of time (> 6 months), not included in our study, we have observed bizarre atypical giant multinucleated cells." (15)

- Nodular "hyaline degeneration consisting of nodular confluent acellular areas was described and distinguished from the interstital hyaline degeneration that is commonly seen in uterine leiomyomata. Nodular hyaline degeneration was seen in 63% of Lupron exposed patients and "1 untreated case in which it turned out, retrospectively, that the patient had received medroxyprogesterone acetate in the past."(15)

- Obliteration of the cleavage plane was found in 91% of the Lupron patients "The obliteration of the myoma-myometrial interface may explain the difficult enucleation of the myomatous nodules often encountered by surgeons in treated patients. "(15)

4. Crow et al gave 11 patients a GnRH-a (9 a monthly depot for 3 months and 2 a 3-month depot). 18% "showed extreme crowding of nuclei, which produced a densely cellular appearance." "Such an appearance was not seen in any control cases, nor had it been observed in normal diagnostic practice." (29)

- 27% of the 11 patients had lymphocytes of which:

One case had "nuclear crowding which could not be measured objectively because there were significant numbers of inflammatory cells (mainly lymphocytes) contributing to the numbers of nuclei within the lesion. This was not a feature found in any of the control cases, but a specific search revealed that 2 other treated samples showed a few such cells." (29)

- One of the two patients [50%] treated with the 3-month depot also showed lymphoid cell infiltration. (29)

- Another case "showed a very marked infiltrate with lymphocytes and plasma cells with formation of

lymphoid follicles. The infiltrating cells in this case were identified as B lymphocytes (expressing CD 20

antigen) and plasma cells." (29)

- "Those cases showing the most marked histological effects also showed ultrastructural changes with loss of

the myofibrillar structures and evidence of degenerative changes of cytoplasmic organelles, and in 1 case

even breakdown of the cytoplasmic membrane. In addition some cases showed a chronic inflammatory cell

infiltrate of lymphoctes and plasma cells." "Nonspecific cell damage would be expected to elecit a neutrophil

rather than a lymphocytic response." (29)

- "It is important for histopathologists to be aware of the range of appearances in leiomyomas treated with

GnRH analogues, especially the markedly hypercellular picture, which could be diagnostically confused with

endometrial stromal lesions." (29)

5. Rutgers stated that with Lupron Depot for 3 months "the mean external arterial diameter in the myomas of the GnRH-a-treated patients was 24% smaller than those in the placebo subjects." "75% of the GnRH-a-treated subjects stained showed fibrosis of both intima and media." "Placebo-treated subjects showed no intimal thickening or only a rare vessel with intimal fibrosis." (28)

6. Cohen et al evaluated the microscopic changes in fibroids following the use of a GnRH agonist. The "results showed increased cellulariry and hyalinization in leiomyomata [fibroids] following GnRH agonist treatment." (24)

7. Rein et al stated that "the total protein concentration of myomas from patients treated with the GnRH agonist [Lupron] was 30% higher than that of myomas from placebo-treated controls, and the DNA concentration was 75% higher." "Comparison of the molar composition of the amino acids showed that hydroxylysine, hydroxyproline, proline, glycine, and alanine were increased relative to the other amino acids." (30)

8. Rein et al stated that "the shrinkage in fibroid and uterine volumes that is associated with chronic administration of a GnRH-a [Lupron] could be the result of cell death. "(14)

IX. ESTROGEN & PROGESTERONE RECEPTORS AFTER EXPOSURE TO GnRH-a:

1. Rein et al stated that "fibroid specimens from patients treated with LA [Lupron] demonstrated statistically greater ER [estrogen receptor] and PR [progesterone receptor] content when compared with luteal phase specimens from placebo-treated controls." (25)

2. Cohen et al stated that "another complex phenomenon is related to the changes in estrogen and progesterone receptors following GnRH treatment. These receptors are increased in [GnRH-a] treated leiomyomata." (24)

X. FIBROID REGROWTH AFTER LUPRON:

1. Nakamura stated that "after cessation of [GnRH-a] therapy, however, the mean uterine volume increased to 106 % of the pretreatment volume." (26)

2. Shaw stated that "within 3 months of discontinuing [GnRH-a] treatment, the mean total uterine volume had returned to 102 +/-10.5% of original pretreatment volume." (11)

REFERENCES:

(1) Cirkel U, Ochs H, Schneider HPG. Experience with Leuprorelin Acetate Depot in the Treatment of Fibroids: A German Multicentre Study. Clinical Therapeutics. 14(Suppl A): 1992; p. 37-47.

(2) Friedman AJ, Label SM, Rein MS, Barbierei RL. Efficacy and safety considerations in women with uterine leiomyomas treated with gonadotropin-releasing hormone agonists: The estrogen threshold hypothesis. Am JObstet Gynecol. 163: 1990; p. 1114-1119.

(3) Stovall TG. Gonadotropin-Releasing Hormone Agonists: Utilization Before Hysterectomy. Clinical Obstsetrics and Gynecology. 36: 3: 1993; p. 642-649.

(4) US Food and Drug Administration, NDA # 19-943; Lupron Depot for the treatment of anemia associated with uterine fibroids.

(5) Klitz RJ, Rutgers ], Phillips J, Murugesapillai ML, Kletzky OA. Absence of a dose-response effect of leuprolide acetate on leiomyomata uteri size. Fertility & Sterility. 61: 6: 1994; p. 1021-1026.

(6) Coddington CC, Brzyski R, Hansen KA, Corley DR, McMyre-Seftman K, Jones HW. Short Term Treatment with Leuprolide Acetate is a Successful Adjunct to Surgical Therapy of Leiomyomas of the Uterus. Surgery, Gynecology & Obstetrics. 175: 1992; p. 57-63.

(7) Fedele L , Vercellini P, Bianchi S, Brioschi, D, Dorta M. Treatment with GnRH agonists before myomectomy and the risk of short-term myoma recurrence. British Journal of Obstetrics and Gynaecology. 97: 1990; p. 393-396.

(8) Friedman AJ, Rein MS, Harrison- Atlas D, Garfield JM, Doubilet PM. A randomized, placebo-controlled, double-blind study evaluating leuprolide acetate depot treatment before myomectomy. Fertility and Sterility. 52: 1989; p. 728-733.

(9) Friedman AJ. Use of Gonadotropin-Releasing Hormone Agonists Before Myomectomy. Clinical Obstsetrics and Gynecology. 36: 3: 1993; p. 650-659.

(10) Benagiano G. Uterine Fibroids: Literature Review and Summary of Posters. Hormone Research. 32 (suppl 1 ): 1989; p. 120-124.

(11) Shaw R. Mechanism of LHRH Analogue Action in Uterine Fibroids. Hormone Research. 32 (suppl 1): 1989; p. 150-153.

(12) Malta WHM, Shaw RW, Nye M. Long-term follow-up of patients with uterine fibroids after treatment with the LHRH agonist buserelin. British Journal of Obstetrics and Gynaecology. 96: 1989; p. 200-206.

(13) Friedman AJ, Rein MS, Pandian MR, Barbieri RL. Fasting serum growth hormone and insulin-like growth factor-I and -II concentrations in women with leiomyomata uteri treated with leuprolide acetate or placebo. Fertility & Streility. 53: 2: 1990; p. 250-253.

(14) Rein MS, Friedman AJ, Pandian MR, Heflher LJ.The Secretion of Insulin-Like Growth Factors I and II by Explant Cultures of Fibroids and Myometrium

From Women Treated With a Gonadotropin-Releasing Hormone Agonist. Obstetrics and Gynecology. 76; 3: Part 1; 1990; p. 388-394.

(15) Deligdisdi L, Hirschmann S, Altcheck A. Pathologic changes in gonadotropin releasing hormone agonist analogue treated uterine leiomyomata. Fertility & Sterility. 67: 5; 1997; p. 837-841.

( 1 6) Coddington CC, Collins RL, Shawker TH, Anderson R, Loriaux DL, Winkel CA. I^ong-acting gonadotropin hormone-releasing hormone analog used to treat uteri. Fertility & Sterility. 45: 5: 1986; p. 624-629.

(17) Perl V, Marquez J, Schally AV, Comaru-Schally AM, Leal G, Zacharias S, Gomez-Lira C. Treatment of leiomyoma uteri with D-Trp6-luteinizing hormone-releasing hormone. Fertility & Sterility. 48: 3: 1987; p. 383-389.

(18) Hale, E. Research Links Sex Hormones to Human Brain and Learning. Gannett News Service. Nov. 1 994.

(19) Society for Neuroscience .Annual Meeting Abstracts. 1994. p. 1271.

(20) Kessel B, Liu J, Mortola J, Berga S, Yen SSC. Treatment of uterine fibroids with agonist analogs of gonadotropin-releasing hormone. Fertility & Sterility. 49:3: 1988; p. 538-541.

(21) Reinsch RC, Murphy AA, Morales AJ, Yen SSC. The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: A prospective, randomized study. Am J Obstet Gynecol. 170: 6: 1994. p. 1623-1628.

(22) Matta WHM, Stabile I, Shaw RW, Campbell S. Doppler assessment of uterine blood flow changes in patients with fibroids receiving the gonadotropin-releasing hormone agonist Buserelin. Fertility & Sterility. 49: 6: 1988; p. 1083-1085.

(23) Friedman AJ. Vaginal hemorrhage associated with degenerating submucous leiomyomata during leuprolide acetate treatment. Fertility & Sterility. 52: 1: 1989; p. 152-154.

(24) Cohen D, Mazur MT, Jozefczyk MA, Badawy, SZA. Hyalinization and Cellular Changes in Uterine Leiomyomata After Gonadotropin Releasing Hormone Agonist Therapy. The Journal of Reproductive Medicine. 39: 5: 1994; p. 377-380.

(25) Rein MS, Friedman AJ, Stuart JM, MacLaughlin DT. Fibroid and myometrial steroid receptors in women treated with gonadotropin-releasing hormone agonist leuprolide acetate. Fertility & Sterility. 53: 6: 1990; p. 1018-1023.

(26) Nakamura Y, Yoshimura Y, Yamada H, Ubukata Y, Ando M, Suzuki M. Treatment of uterine leiomyomata with a luteinizing hormone-releasing hormone agonist: the possibility of nonsurgical management in selected perimenopausal women. Fertility & Sterility. 55: 5: 1991; p. 900-905.

(27) Thorp JM, Katz VL. Submucous Myomas Treated with Gonadotropin Releasing Hormone Agonist and Resulting in Vaginal Hemorrhage. Journal of Reproductive Medicine. 36: 8: 1991; p. 625-626.

(28) Rutgers JL, Spong CY, Sinow R, Heiner J. Keuprolide Acetate Treatment and Myoma Arterial Size. Obstetrics & Gynecology. 86: 3: 1995; p. 386-388.

(29) Crow J, Gardner RL, McSweeney G, Shaw RW. Morphological Changes in Uterine Leiomyomas Treated by GnRH Agonist Goserelin. International Journal of Gynecological Pathology. 14: 1995; p. 235-242.

(30) Rein MS, Barbieri RL, Welch W, Gleason RE, Caulfield JP, Friedman AJ. The Concentrations of Collagen-Associated Amino Acids Are Higher in GnRH Agonist-Treated Uterine Myomas. Obstetrics & Gynecology. 82: 6: 1993; p. 901-905.

(31) Jeffers M, Cowan C, Lunan CB. Degenerative changes in myometrium simulating diffuse leiomyomatosis after treatment with gonadotrophin releasing hormone analogue. Journal of Clinical Pathology. 48: 1995; p. 278-280.

(32) Rein MS, Barbieri RI, Friedman AJ. Progesterone: A critical role in the pathogenesis of uterine myoma. Am J Obstet Gynecol 172: 1: 1995; p. 14-18.

This Is A Work In Progress

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download