Mark D. Hornstein, M.D. Department of Obstetrics and Gynecology Brigham and Women’s Hospital Boston, Massachusetts

A. Albert Yuzpe, M.D. Department of Obstetrics and Gynecology University of Western Ontario Medical School London, Ontario, Canada

Kenneth A. Burr-y, M.D. Department of Obstetrics and Gynecology Oregon Health Sciences University Portland, Oregon

Le Roy Heinrichs, M.D. Department of Obstetrics and Gynecology Stanford University Medical Center Stanford, California

Veasy L. Buttram, Jr., M.D. Department of Obstetrics and Gynecology Baylor University Medical Center Houston, Texas

Eric S. Orwoll, M.D. Department of Medicine Oregon Health Sciences University Portland, Oregon January 21, 1997

REFERENCES

Hornstein MD, Yuzpe AA, Burry KA, Heinrichs LR, Buttram VC Jr, 01~011 ES. Prospective randomized double-blind trial of 3 versus 6 months of nafarelin therapy for endometriosis associated pelvic pain. Fertil Steril 1995;63:955-62. Luciano AA, Tursoy RN, Carleo J. Evaluation of oral me- droxyprogesterone acetate in the treatment of endometriosis. Obstet Gynecol 1988;72:323-7. Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertil Steril 1993;60:75-9.

Editorial Comment “Child of a Looser God”

The letters from Drs. Odom and Kauppila concern- ing the relative efficacy and cost of three different agents for the treatment ofpain due to endometriosis are thoughtful contributions. The use of each of these drugs for the treatment of pelvic endometriosis has been approved by the Federal Food and Drug Admin- istration (FDA). Drs. Odom and Kauppila point out that medroxyprogesterone acetate (MPA, Provera, [The Upjohn Company, Kalamazoo, MichiganU orally or by injection is equally effective, compared

Vol. 67, No. 5, May 1997

to other agents in the relief of pain from pelvic endo- metriosis and is considerably cheaper. The price dif- ferential is probably related to the fact that the patent and exclusivity rights for Depo-Provera (DMPA) have expired. The Upjohn Company makes no attempt to market Provera for this indication. This is one of the quirks of medical economics. The cost of a drug is largely determined by the current status of the patent rights of the manufacturer or sponsor. To this date 0996) no other company has attempted to manufac- ture and market DMPA other than Upjohn.

Medroxyprogesterone acetate is no longer a trendy drug. It has been around for a long time and has been used in mega-doses for the adjunctive treatment of metastatic endometrial and renal cancer without significant side effects. With this drug, clinical data is plentiful and scientific judgment can be relatively precise. After years of post-marketing surveillance at all dose levels in both children and adults throughout the world, it appears to have almost no significant systemic toxicity except for two infrequently promul- gated complications of long term use: (1) Develop- ment of Gushing’s Syndrome and (2) Development of Osteoporosis.

In general, both of these side effects occur when MPA is given in high doses over prolonged periods of time. The first is related to the interaction of Prov- era with the glucocorticoid receptor and signalling system (1). This was especially noted in patients re- ceiving maximal doses of DMPA (500-3,000 mgl week) for the treatment of endometrial cancer. The second complication is related to the significant amount of hypoestrogenism that may occur in some patients receiving high doses of DMPA over pro- longed periods of time. In such patients, the serum levels of estradiol may fall to 2OpglmL with accom- panying reductions in serum FSH and LH levels. This hypoestrogenic state may lead to a diminution in uterine size, weight, and bone mineral density. This loss of bone is particularly conspicuous in the trabecular bone of the lumbar vertebrae (2). Perhaps a redeeming feature of this complication is that bone density may be restored in most women when they stop using MPA (3). An extreme, but vivid, example of bone loss due to DMPA and the development of multiple fractures was described by S. Mark in 1994 (4). These side effects, though they occur only in un- usual circumstances, help to remind us that the basic mechanism of action of the drug is to suppress pitu- itary gonadotropins. The time lapse in recognizing these side effects also serves to emphasize that the post-marketing surveillance of a drug can be just as important as the original clinical studies that brought about its initial FDA approval. In fact the FDA at the time of the approval of DMPA for contra-

Letters-to-the-editor 977

ception in 1992 recommended continued surveillance (Phase IV studies) for changes in bone mineral den- sity in patients using this form of contraception (5). An admonition in this regard is part of the in-pack- age labelling for DMPA. This warning and the recent studies by Cundy (2)point out the need to periodically monitor serum estradiol levels in patients receiving long-term continuous Provera.

Drs. Odom, Kauppila, and Hornstein have pointed out a comparison of these three drugs in the relief of pain in pelvic endometriosis and their relative cost. Perhaps we might hear more from the readership concerning their personal experience with DMPA and their perception of risk factors in the use of differing agents for the relief ofpain due to pelvic endometrio- sis. This is a discussion that especially lends itself to coffee table consumption and cyberspace. Please send your contributions to the E-mail address of the editor (Internet: obgyn.pmcdonouQmail.mcg.edu). However, you must understand in advance that this might be considered a bovine attempt to start a mu- tual interchange within the journal that is not subject to control or peer review. It is the type of format that would warm the heart of our new editor-‘“The Child of a Looser God”-and tease or haunt the alter ego of our Editor’s ‘%ditor”-Roger Kempers.

Paul G. McDonough, M.D., Editor, Letters

REFERENCES

1. Siminoski K, Goss P, Drucker DJ. The Cushing syndrome induced by medroxyprogesterone acetate. Ann Int Med 1989; 111:758-601.

2. Cundy T, Farquhar CM, Cornish J, Reid IR. Short-term ef- fects of high dose oral medroxyprogesterone acetate on bone density in pre-menopausal women. J Clin Endocrinol Metabol 1996;81:1014-7.

3. Cundy T, Cornish J, Evans MC, Roberts H, Reid IR. Recovery of bone density in women who stop using medroxyprogester- one acetate. Br Med J 1994;308:247-8.

4. Mark S. Case report premenopausal bone loss and depo-me- droxyprogesterone acetate in menstruation. Int J Gynecol Obstet 1994;47:269-72.

5. Kaunitz AM. Long-acting injectable contraception with depot medroxyprogesterone acetate. Am J Obstet Gynecol 1994; 170:1543-g.

ing chamber, such as the Neubauer hemocytometer, was available. In the early eighties, for the first time, a shallow chamber O.Ol-mm deep was developed by Makler (2) and appeared in the market (Sefi Medical Instruments, Haifa, Israel). This was followed later on by other shallow chambers, most of them dispos- able. The authors compared the accuracy of the dis- posable with the reusable chambers, using latex beads as a reference standard.

The reliability of sperm counts performed by the hemocytometer has already been criticized (3). Inac- curacies were attributed to technicians’ errors and properties of the semen specimens. However, the ac- curacy of the chamber from the engineering stand- point was never doubted. It was ascribed to the insig- nificant depth variations among chambers (a tolerance of less than 4%) that contribute negligible errors in counts (4). This explains why most studies that evaluated various chambers compared them with the hemocytometer, and the World Health Or- ganization (WHO) recommendation to use it as a reference for assessing the accuracy of other cham- bers (5). The main drawback of the hemocytometer is the need to dilute semen and to wait for sperm precipitation before counting. The shallow chambers were designed for rapid sperm analysis from undi- luted semen. However, their shallowness induced variations between counts due to more than 10% tolerance of chambers depth compared with the low tolerance of the hemocytometer. It is therefore clear that if beads of identical concentration are counted by several chambers, the closer the results from a tested chamber to those obtained with the hemocy- tometer, the more accurate that chamber should be considered.

In their article, the authors showed that counts of beads with the hemocytometer and Makler chamber were almost identical. This finding clearly points to the high accuracy of the Makler chamber, thereby supporting similar reports by others (4). Concomi- tantly, they revealed more than 40% difference in counts between the hemocytometer and the dispos- able cells.

In general, counts of small particles, like beads,

Standardization of Counting Chambers are directly proportional to the depth of the chamber

for Sperm Analysis in which they are loaded. Hence, depth of chambers can be determined by counting beads, applied from

To the Editor: the same stock, and comparing results among cham- bers when one of them serves as a reference. If the

The accuracy of counting chambers for sperm disposable cells were considered such a reference, analysis is still under debate. In this regard, some the hemocytometers must have been more than 140 conclusions drawn by the authors in the October micrometers deep! The existence of such hemocy- 1996 issue (1) of Fertility and Sterility@ seem to be tometers is very unlikely. confusing. A conclusion like this is hard to accept even by

Until the late seventies, only a 0. l-mm deep count- referring to the report on the variations among

978 Letters-to-the-editor Fertility and Sterility@