Biodurability of retrieved silicone gel breast implants

This study analyzed the shells of single-lumen silicone gel breast implants within the general context of device durability in vivo. The investigation included the major types of gel-filled implants that were manufactured in the United States in a 30-year period. The implants analyzed were Cronin seamed (two explants and one control), Silastic 0 and Silastic I (18 explants and seven controls), and Silastic II (22 explants and 43 controls). The biodurability of the explants was investigated with measurements of the mechanical and chemical properties of the various types of silicone gel control and explanted shells, with implantation times ranging from 3 months to 32 years. The shell properties measured for the controls and explants included the stress-strain relationships, tensile strength, elongation, tear resistance, moduli, cross-link density, and amount of extractable material in the shell. In addition, the mechanical properties of shells that had been extracted with hexane were analyzed for both explants and control implants. The silicone gel explants investigated in this study included some of the oldest explants of the various major types that have been tested to date. For assessment of long-term implantation effects, the data obtained in this study were combined with all known data from other institutions on the various major types of gel implants. The study also addressed the failure mechanisms associated with silicone gel breast implants. The results of the study demonstrated that silicone gel implants have remained intact for 32 years in vivo and that degradation of the shell mechanical and chemical properties is not a primary mechanism for silicone gel breast implant failure.     

Variability in the properties of silicone gel breast implants.

Several generations of silicone gel breast implants have been produced by implant manufacturers. The primary material usually viewed as the base material in the manufacture of implants is polydimethylsiloxane. Polymeric reactions are notorious for their variability and nonuniformity. The elastomer used in different types of implants can have vastly different properties. Furthermore, the material properties associated with a particular type of implant can vary considerably from one lot to the next. Considering the various designs, styles, and manufacturing techniques associated with silicone gel implants, knowledge of the original properties of the implants before implantation is important in determining the effects of aging in vivo. This study was conducted to investigate differences in key mechanical and chemical properties of silicone gel breast implant materials. The two types of implants chosen for analysis were Silastic I and Silastic II control implants. Material property data were determined for both types of controls and significant differences were found in their values. Lot-to-lot variability was also investigated and found to be significant.     

Women's psychosocial outcomes of breast augmentation with silicone gel-filled implants: a 2-year prospective study

This study examined the experiences of 360 women receiving bilateral breast augmentation with Dow Corning's Silastic MSI (textured) or Silastic II (smooth) gel-filled mammary implants. Before surgery, the women completed a quantitative assessment of their surgical expectations and concerns. At 6, 12, and 24 months postoperatively, they rated their satisfaction with surgery and its specific psychosocial outcomes, their concerns, and benefits-to-risks appraisals of the augmentation. The women reported very high levels of satisfaction with the procedure and its psychosocial outcomes, which did not change over time. Throughout the 2-year period, over 90 percent of the women were satisfied with surgery and their resultant body-image changes. Their concerns about risks, reported by 19 percent before surgery, declined after surgery and remained subsequently stable. Most participants (75 to 85 percent) reported that the benefits of surgery exceeded its risks. Postoperative events such as significant capsular contracture that compromised aesthetic results diminished aspects of satisfaction, whereas less obvious events did not. Systematic analysis of attrition (i.e., missing assessments) did not indicate any biases because of complications or psychosocial outcomes. Evaluation of a possible impact of the publicity surrounding the Food and Drug Administration's voluntary moratorium on the use of silicone gel-filled breast implants, which occurred during the study, revealed a limited effect, if any, on women's psychosocial outcomes. Findings are discussed in relation to the study's methodological strengths and limitations and with respect to the broader context of patient care.     

Effect of povidone iodine on silicone gel breast implants in vitro: implications for clinical practice

Irrigation of breast implants and breast implant pockets with various solutions, including povidone iodine, has been a common practice among plastic surgeons for many years. Recent reports of potential weakening of silicone tubing have led the Food and Drug Administration to pronounce any contact of povidone iodine with breast implants a contraindication. An in vitro experimental study was undertaken to assess the effect of povidone iodine on the physical properties of silicone breast implant shells. Identical specimens were obtained from the shells of silicone breast implants according to published standards. The specimens were randomly assigned to eight groups of five and incubated in various solutions of decreasing concentration of povidone iodine (10% to 0.01%), and a control group (0.9% saline) was used. The containers were stored in a warming cabinet at 37 degrees C for 4 weeks. Testing of the specimens for tensile strength following 4 weeks of incubation showed no significant difference among any of the groups, including the control group. In addition, no correlation was shown between the concentration of the solution used and the tensile strength of the specimens.     

Scanning electron microscopy characterization of surgical instrument damage to breast implants.

In this article, mechanisms of breast-implant failure caused by surgical instruments commonly used to perform implantation, breast biopsies, needle localization procedures, cyst aspirations, and explantation are described. Failure was artificially induced in breast-implant shells using various types of surgical instruments, including scalpels, suture needles, hypodermic needles, hemostats, and Adson forceps. Field-emission scanning electron microscopy (SEM) was used to document the morphology of the failure sites produced by these instruments. Micrographs were used to categorize failure according to a specific type of surgical instrument. SEM micrographs were also obtained on explants that failed in situ, and the morphology of the corresponding failure sites was examined. The study was designed to document a range of failure mechanisms associated with gel-filled, saline-filled, double-lumen (saline-gel), and soybean oil-filled implants. The results of the study also demonstrate that SEM can often be used to determine the cause of breast-implant failure.     

The silicone gel-filled breast implant controversy: an update

Learning Objectives: After studying this article, the participant should: 1. Be familiar with the medical uses of silicone. 2. Have a working knowledge of the most important epidemiologic studies regarding silicone gel-filled breast implants. 3. Be aware of the issues about which patients desiring breast augmentation or reconstruction with implants must be counseled.     

An analysis of telephone interview data collected in 1992 from 820 women who reported problems with their breast implants to the food and drug administration

How health care providers deal with concerns and feelings of women who have problems with their breast implants affects the women's satisfaction with their breast implants, yet in 1992 little was known about the concerns and feelings of these women. A qualitative analysis of in-depth telephone interviews conducted in 1992 with 820 women from all regions of the United States who reported problems with their breast implants to the Food and Drug Administration and responded to an invitation to be interviewed provided data. Respondents were primarily 40 to 69 years of age at the time of interview, Caucasian, married, and educated beyond high school. The sample was almost equally divided in reason for breast implants, with 65 percent being dissatisfied with their breast implants. Nearly all of the women had heard of problems with silicone gel-filled implants. Their main sources of information were television, newspapers, and magazines rather than their physicians or the breast implant manufacturers. Some women tried to avoid hearing the reports, and many tried to put the reported problems out of their minds. However, a majority (88.7 percent) wanted more information. The women expressed feelings of anger, regret, and worry, and repeatedly said they needed more information. Women who contacted the Food and Drug Administration about breast implant problems needed accurate and honest information from health care professionals. They wanted their physicians to explore their symptoms, fears, and concerns.     

Prevalence of silicone breast implant rupture among Danish women

The durability of silicone gel-filled breast implants is of concern, but there are few epidemiological studies on this issue. To date, most of the relevant findings are derived from studies of explantation, which suffer from bias by including women with symptoms or concerns about their implants. As part of a long-term magnetic resonance imaging study of the incidence of rupture, this study involved 271 women with 533 cosmetic breast implants who were randomly selected from among women who underwent cosmetic breast implantation from 1973 through 1997 at one public and three private plastic-surgery clinics in Denmark. The prevalence of rupture was determined from the first magnetic resonance screening. The images were evaluated by four independent readers, using a standardized, validated form. The outcomes under study were rupture, possible rupture, and intact implant. Ruptures were categorized as intracapsular or extracapsular. Overall, 26 percent of implants in 36 percent of the women examined were found to be ruptured, and an additional 6 percent were possibly ruptured. Of the ruptured implants, 22 percent were extracapsular. In multiple regression analyses, age of implant was significantly associated with rupture among second- and third-generation implants, with a 12-fold increased prevalence odds ratio for rupture of implants that were between 16 and 20 years of age, compared with implants between 3 and 5 years of age. Surgitek implants (Medical Engineering Corporation, Racine, Wis.) had a significantly increased prevalence odds ratio of 2.6 for rupture, compared with the reference implants. No significant association was found with the position (subglandular or submuscular) or the type of implant (single- or double-lumen). Extracapsular ruptures were significantly associated with a history of closed capsulotomy (p = 0.001). In the future, the authors plan to examine the women in their cohort with a second magnetic resonance imaging scan to establish the incidence of rupture, a parameter unknown to date in the literature, and to further characterize those factors associated with the actual risk of rupture.     

Textured-surface saline-filled silicone breast implants for augmentation mammaplasty

The earliest silicone breast implants were smooth-surface, silicone rubber devices filled with either silicone gel or saline. Because of persistent problems with capsular contracture, polyurethane-covered silicone implants were developed as an alternative. Particularly in the short run, these alternatives proved highly successful at reducing the incidence of capsular contracture. By 1990, polyurethane-covered implants were rapidly becoming the preferred implant choice of many plastic surgeons, but for legal, regulatory, financial, and safety reasons they were withdrawn from the market by Bristol-Myers in 1991. Meanwhile, during the late 1980s, surface texturing and improved materials became available on other silicone breast implants and expanders. Most studies suggest that textured-surface silicone gel-filled implants, saline-filled implants, and tissue expanders have less frequent capsular contracture than their smooth-surface counterparts.     

Local intracerebral implants of estrogen masculinize some aspects of the zebra finch song system

The song system of zebra finches is sexually dimorphic: the volumes of the song control nuclei and the neurons within these nuclei are larger in males. The song system of hatching female zebra finches is masculinized by systemic treatment with estrogen. We investigated the locus of this estrogen action by using microimplants of estradiol benzoate (EB). We implanted female zebra finch nestlings 10–13 days old with Silastic pellets containing approximately 2 μg EB at one of several sites: near the higher vocal center (HVC), in the brain distant from HVC, or in the periphery either under the skin of the breast or in the peritoneal cavity. Controls were either unimplanted or implanted near HVC with Silastic pellets without hormone. The brains were fixed by perfusion at 60 days, and the volumes of the song control regions as well as the sizes of individual neurons were measured. Neurons in HVC were lerger (more masculine) in the HVC-implanted group than in other groups, which did not differ among themselves. The size of neurons in the robust nucleus of the archistriatum (RA) and the lateral magnocellular nucleus ofthe neostriatum (lMAN) were inversely correlated with the distance of the EB pellet to HVC; neurons in RA and lMAN were larger when the EB pellets were closer to HVC. This result suggests that implants near HVC were at or near a site of estrogen action. To our knowledge, this is the first demonstration that localized brain implants of estrogen cause morphological masculinization in any species. 1994 John Wiley & Sons, Inc.     

Early treatment of young female rats with progesterone delays the aging-associated reproductive decline: a counteraction by estradiol

We have recently reported that successive treatments of young virgin rats with progesterone (P) implants produce elevated circulating P and consistently low estradiol (E2) concentrations, and subsequently delay the aging-associated reproductive decline. Inasmuch as E2 has been implicated in causing the loss of regular estrous cyclicity in aging rats, the present study examined if the concomitant presence of moderately increased circulating E2 levels could counteract the effects of P implants on reproductive aging. Starting at 3 1/2 mo and continuing to 8 mo of age, regularly cyclic, virgin rats received either s.c. Silastic implants of P (P-implanted), blank Silastic implants (virgin controls), or P + E2 implants (P + E2-implanted) for 3 wk, followed by implant removal for 1 wk. Each of these implant treatments was repeated in the same female rats 5 times. Blood samples were obtained on different days of the estrous cycle from the control group and on Day 11 of successive treatments with P or P + E2 implants for measurements of serum P and E2 values. At 8 1/2 and 10 mo of age, estrous cyclicity of these same virgin rats was again monitored, and 10-mo-old regularly cyclic females from each treatment group were mated with young fertile males to complete term pregnancies. While virgin controls showed cyclic increases in E2 and P secretion during the estrous cycle, P-implanted virgins exhibited consistently low serum E2 and moderately increased P levels during 5 successive treatments. The latter indicates a potent inhibition of ovarian E2 secretion by P implants.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcification properties of saline-filled breast implants

Three patients requested explantation of their saline-filled breast implants. Bilateral calcification had occurred in all six implants. Four of the implants were manufactured by McGhan Corporation (Santa Barbara, Calif.), and two, by the Simaplast Company (Toulon, France). All implants had been inserted in the subglandular plane and had been in place for 7 to 23 years. At the time of explantation, patients were 32, 34, and 44 years old. Calcification on the surface of the implants and capsules was analyzed. Implant surface calcification was clinically evident on all six implants, appearing as ivory-colored, tenaciously adherent deposits, only on the anterior surface of the implant. Capsular calcification, which was observed only microscopically, was characterized by poorly organized, irregularly shaped, calcified agglomerates; this calcification also occurred only on the anterior surface of the capsule, adjacent to the area of calcification on the implant. Ultrastructural analysis of scrapings from the implant surface showed large, electron-dense aggregates of crystals, with individual crystals measuring approximately 40 x 10 x 10 nm. In contrast, capsular calcification was characterized by two patterns of deposition, spherulitic aggregates of needle-shaped crystals and areas of metaplastic bone. The individual crystals were approximately 40 x 10 x 10 nm. Energy-dispersive x-ray spectroscopy of specimens from the areas of calcification on the implant and capsule surfaces demonstrated calcium and phosphorus. Electron diffraction of crystals from the implant and capsule surfaces demonstrated the D-spacings characteristic of calcium apatite. There were many differences between the calcification properties of these six saline implants and those of silicone gel implants. For example, mineralization has not been observed on the surface of gel implants, but in these saline implants it occurred primarily on the implant surface. Also, capsular calcification has been observed clinically in gel implants across the surface of the capsule (except at the site of attachment of a Dacron patch), but in this study it was observed only microscopically and was located on the anterior surface of the capsule, adjacent to the area of calcification on the implant. In addition, crystals 100 times larger than those observed on the six saline implant capsules have been observed on the surface of gel implant capsules. A model is presented to explain the mechanism of calcification associated with breast implants and to explain the observed differences between saline-filled and gel-filled implants.     

Recurrence of subglandular breast implant capsular contracture: anterior versus total capsulectomy

The objective of this study was to determine whether the type of capsulectomy, anterior or total, affects the recurrence of capsular contracture around subglandular silicone-gel breast implants. A retrospective analysis was performed of patients who underwent either anterior or total capsulectomy for Baker grade 3 or 4 subglandular capsular contracture in our unit. All patients were invited to a review clinic where their capsular status was assessed. There were 100 anterior- disc capsulectomies in 60 patients between 1988 and 1997 and 99 total capsulectomies in 60 patients between 1990 and 1998. The follow-up in the former group was a median of 7 years and mean 6.9 years, compared with median 2.5 and mean 3.1 years in the latter group. Eighty-six percent of the implants removed from both groups at capsulectomy were smooth-walled gel-filled implants. Sixty-nine breasts in the anterior group received textured gel implants at capsulectomy; the remaining 31 received polyurethane-coated Meme implants. In the total capsulectomy group, all but two breasts (one patient) received textured gel implants. After review, the capsular status was known in 80 percent of the anterior and 92 percent of the total capsulectomy group. The review clinic found eight new contractures in five patients to have developed in the anterior compared with none in the total group. Recurrent contractures affected 50 percent of patients (46 percent of breasts) in the anterior and 11 percent of patients (10 percent of breasts) in the total capsulectomy group. Kaplan-Meier survival analysis was applied to the data. By including only patients who received textured gel implants at capsulectomy, the Logrank found a statistical difference between the two treatment groups (0.01 < p < 0.5). We believe that this study provides some evidence that total capsulectomy for subglandular silicone breast implant capsular contracture results in a lower capsular recurrence than anterior- disc capsulectomy. The pattern and risk of recurrence after total capsulectomy and exchange for a modern textured prosthesis appear to approach those following primary augmentation.     

Capsule injection for the prevention of contracture

From 1990 through 1999, 164 patients with prior augmentation mammaplasty underwent implant removal by the author, and 128 of the patients had the implants replaced. Of that group, 86 were noted on preoperative examination to have capsule contracture of grade III or IV. Patients with preoperative capsule contracture were offered the option of a postoperative injection of triamcinolone intended to prevent recurrent contracture. Patients who elected to have replacement with gel-filled implants were excluded. A total of 48 patients underwent injection of triamcinolone 4 to 6 weeks after surgery. Of the remaining 38 patients, 12 were not offered injection because they selected gel-filled implants and 26 declined injection. Follow-up ranged from 8 months to 10 years (mean, 46 months), and no patient was followed up for less than 8 months. Of the 48 patients who received injections, two developed recurrent contracture, one at 3 years and one at 4.5 years. Of the 26 patients who declined injection, eight had recurrent contracture (three bilateral) within 12 months. These data suggest that in this high-risk group of patients, a postoperative injection of triamcinolone can reduce the risk of recurrent contracture.     

Saline-filled breast implant safety and efficacy: a multicenter retrospective review

Our center undertook an industry-funded, outcomes-based, multicenter, retrospective review to evaluate the safety and efficacy of saline-filled breast implants. Our review was part of a pre-market approval review process mandated by the U.S. Food and Drug Administration. The design of our review was modeled on a Plastic Surgery Educational Foundation outcomes study previously conducted by our center. For this study, several significant changes were made to our previous protocol, including improved patient tracking, stronger biostatistical support, and a mandatory 10-year minimum patient follow-up period. Physician-reported and patient-reported data on 450 patients with 882 saline-filled breast implants placed between January 1, 1980, and June 30, 1986, were obtained. Mean patient follow-up period was 13.0 years. Most implants (93.9 percent) were placed for breast augmentation. Seventy-four percent were placed in a submammary position; 25.6 percent, subpectorally; and 0.2 percent, subcutaneously. The overall complication rate was 20.2 percent. Reoperation for capsular contracture or implant deflation was necessary in 104 of 450 patients (23.1 percent). Deflation occurred in 73 implants (8.3 percent) and was underreported according to the physicians' record review alone. This deflation rate is higher than the 5.5 percent previously reported by our center. However, 26 of these 73 deflations (35.6 percent) occurred in a single cohort of patients at one center using Surgitek saline implants. If this cohort is excluded, the deflation rate drops to 5.8 percent, a figure more consistent with data published in the literature and found in our previous study. Of the 73 deflations, spontaneous deflation was reported for 50 (74.6 percent), and the remainder were iatrogenic. Actuarial survival of the non-Surgitek implants was 98.4 percent to 99.8 percent at 5 years and 96.9 percent to 98.9 percent at 10 years (95 percent confidence interval). Risk factors for implant deflation included the use of Surgitek saline-filled implants (odds ratio = 17.5, p < 0.01), use of Heyer-Schulte and Mentor model 1800 implants (odds ratio = 3.0, p < 0.01), and implant size greater than 450 cc (odds ratio = 1.01, p < 0.02). Risk factors for capsular contracture included submammary implant position (odds ratio = 2.05, p = 0.03) and implant size greater than 450 cc (odds ratio = 1.01, p < 0.01). Overall, satisfaction was high: 93 percent of patients were "satisfied" or "very satisfied" with their implants. As in our earlier study, risk factors for patient dissatisfaction were reconstruction after mastectomy (odds ratio = 7.6, p = 0.011), significant breast firmness (odds ratio = 6.2, p < 0.001), and patient desire for smaller implants (odds ratio = 3.0, p = 0.020). In conclusion, our review provides additional outcomes-based evidence that saline-filled breast implants remain a safe, effective alternative to silicone gel-filled models.     

Hormonal regulation of maternal behavior in rats: stimulation following treatment with ectopic pituitary grafts plus progesterone

Changes in hormone secretions during pregnancy help to stimulate the onset of maternal behavior at parturition. To date, studies have demonstrated that estradiol (E2) appears to be a necessary component in the hormonal induction of maternal behavior in rats and other mammals. In the present study, we have reevaluated the contribution of E2, progesterone (P), and hormone-secreting pituitary grafts in the rapid induction of maternal behavior by measuring the behavioral effects of exposure to various combinations of P and prolactin-secreting ectopic pituitary grafts in the absence of estrogen. Adult hypophysectomized and nonhypophysectomized nulliparous rats were ovariectomized 2-3 days (Treatment Day 1) after their arrival in our laboratory. In Experiment #1, experimental, hypophysectomized rats were implanted s.c. with 6 P-filled Silastic capsules and given 2 anterior pituitary (AP) glands that were grafted beneath the kidney capsule on Treatment Day 1. Controls were given blank implants and were sham-grafted. P-filled and blank Silastic capsules were removed on Day 11, and behavioral testing was conducted once-a-day beginning on Day 12 for eleven days. Animals treated with P-plus-pituitary grafts displayed full maternal behavior significantly faster than did controls (median latencies of 3.0 and 7.5 days, respectively). In Experiment #2, nonhypophysectomized rats were assigned to one of three treatments. On Treatment Day 1, one group of rats received 6 P-filled Silastic implants and had 2 AP glands grafted under their renal capsules. A second group of animals received 6 P capsules and was sham-grafted, while controls were given blank implants and were sham-grafted.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of breast implants on the radiographic detection of microcalcification and soft-tissue masses

Current implants for breast augmentation containing silicone gel, saline, or both can totally obscure mammographic detection of microcalcifications and soft-tissue masses. To investigate the possibility of developing a more radiolucent implant, radiographs were obtained of silicone shells that contained silicone gel, saline, silicone gel and saline, polyurethane-covered silicone gel, gelatin, sunflower oil, and peanut oil. All radiographs were obtained using a Siemens Mammomat by placing the implant over an American College of Radiology mammography phantom. Results were measured by the ability to visualize or resolve the artifacts in the mammography phantom. The silicone shell alone minimally altered artifact resolution. Silicone shells filled with silicone gel, silicone gel and saline, saline alone, polyurethane-covered silicone gel, and gelatin were equal in radiodensity and completely obscured all phantom artifacts. Silicone shells filled with peanut oil and sunflower oil had equal radiodensity and allowed visualization of large microcalcifications and some soft-tissue masses. Current implants used for augmentation mammaplasty can totally obscure mammographic detection of microcalcifications and soft-tissue masses. A more radiolucent breast implant is possible, and further research is needed to define the best filler material and test its biocompatibility.     

Silicone gel-filled breast implant integrity: a retrospective review of 478 consecutively explanted implants

Concern has been expressed over the long-term integrity of silicone gel breast implants. There are no large series representing experience with these implants outside of the United States. A retrospective case note review of explanted silicone breast implants was performed; 478 implants have been explanted during the past 11 years and relate to the use of these devices since 1971. Loss of implant integrity was not simply related to its age in vivo. Failure was more likely with implants of the late 1970s and early 1980s (second generation) and with subpectoral placement. Implant failure was independent of capsular contracture as the indication for removal (p = 0.09). There is no evidence that the currently used textured silicone gel breast implants are subject to the same loss of integrity as previous examples of these devices. The life span of these implants, the first of which are approaching 10 years in vivo, is at present unknown. Information concerning the integrity of silicone gel breast implants is essential in the current climate for counseling of both new and old implant recipients.     

The deposition of talc in patients with silicone gel-filled breast implants.

This study was initiated to understand why talc was found in the entrance wounds and pericapsular scars of patients with silicone breast implants. Twenty-five surgical gloves made between 1977 and 1992 by a major glove manufacturer were evaluated with infrared spectroscopy. Seven gloves manufactured before early 1983 contained talc. Later manufactured gloves contained calcium carbonate instead of talc. Talc-containing gloves were submitted to independent laboratories for scanning electron microscopic examination and x-ray microanalysis to obtain finer detail. Remnants of the mold-release agent talc were found in the matrix of the patient-contact side of the glove. Wetting studies showed that silicone oil (gel bleed) immediately wet the surface of rubber glove. After donning, silicone oil was massaged between the thumb and index finger of each washed, talc-containing glove for 1 minute and then daubed from the glove to a microscopic slide. The slide was viewed with polarized light microscopy for the presence of talc crystals. Transfer of talc occurred using silicone oil, but not saline, in each talc-containing glove. Three factors were likely involved in the greater talc deposition that occurred with patients undergoing silicone gel-filled breast implantation than in patients undergoing other surgical procedures. (1) The wetting of the gloves with silicone gel bleed from implants loosened the talc in the glove matrix. (2) Hand-intensive surgical use freed the talc from the gloves. (3) Loose talc adhered to the silicone elastomer of the breast implants and was deposited with implant placement.     

Aging and chronic estradiol exposure impair estradiol-induced cornification but not proliferation of vaginal epithelium in C57BL/6J mice

Long-term exposure of adult female rodents to estrogen has many deleterious effects on reproductive neuro-endocrine structure and function, but its effects on peripheral target tissues are not well known. This study was designed to determine whether chronic exposure of young mice to estradiol (E2) alters the response of the vagina to E2, and if so, whether aging potentiates this alteration. Eight-week-old mice were ovariectomized (ovx) and given subcutaneous Silastic or polyethylene (PE) implants containing E2. Silastic implants produced supra-physiologic E2 levels, while E2 levels in PE-implanted mice were within the physiologic range. Initially all E2-exposed mice showed vaginal cornification (CORN). However, CORN soon began to decline and was virtually absent 3-5 mo after implantation, despite evidence of continued, albeit reduced, release of E2 from the implants. Mice were reimplanted with new E2 implants to determine whether the loss of CORN resulted from an altered response to E2 or from a decreased release of E2 from the implants. Vaginas of mice previously exposed to either Silastic (high E2) or PE (low E2) implants failed to cornify in response to new E2 implants, whereas vaginas of mice that had been initially exposed to implants without E2 cornified in response to identical E2 implants. When old (23 mo) acutely ovx mice were given E2-containing Silastic implants, the peak level and duration of CORN were only one-third and one-fifth, respectively, of that seen in young mice. Non-cornifying epithelia from both young and old chronically E2-exposed mice were as hyperplastic and active mitotically as cornifying epithelia, indicating that the loss of CORN was not a result of decreased epithelial proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)