Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers.

To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan-Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III-IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I-II (74, 82, and 86%; P<0.0001) and stage III-IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.

Inhibin and CD99 (MIC2) expression in uterine stromal neoplasms with sex-cord-like elements.

Uterine mesenchymal neoplasms with sex-cord-like elements are designated as endometrial stromal tumor with sex-cord-like elements (ESTSCLE) or uterine tumor resembling ovarian sex-cord tumor (UTROSCT), depending on the extent of sex-cord-like differentiation. Occasionally, sex-cord elements similar to those in ESTSCLE and UTROSCT occur in uterine adenosarcomas. To determine whether the sex-cord-like elements in these tumors show immunohistological evidence of sex-cord differentiation, we studied a series of uterine neoplasms for expression of inhibin, a peptide hormone expressed by normal ovarian granulosa cells and ovarian sex-cord neoplasms, and CD99, a protein also expressed by granulosa cells, Sertoli cells, and some ovarian sex-cord tumors. Thirty uterine mesenchymal neoplasms (five epithelioid or plexiform smooth muscle tumors, three endometrial stromal tumors, two mixed endometrial stromal and smooth muscle tumors, 10 ESTSCLE, five UTROSCT, and five miscellaneous stromal processes) and five epithelial neoplasms were evaluated for expression of CD99 (clone 12E7) and inhibin (clone R1) in formalin-fixed, paraffin-embedded tissue. Three of 10 (30%) ESTSCLE and five of five (100%) UTROSCT were inhibin and CD99 immunoreactive. Inhibin staining was confined to the areas with sex-cord-like differentiation, and staining was generally much stronger and more extensive in areas featuring prominent foam cells. There were no differences in the degree or intensity of staining for inhibin in premenopausal and postmenopausal women. CD99 expression tended to correlate with inhibin and was typically confined to similar cell types in the individual neoplasms. Weak CD99 immunoreactivity was seen in one additional epithelioid smooth muscle tumor, whereas all other mesenchymal and epithelial neoplasms studied for inhibin and CD99 were negative. These results provide further immunohistological support for true sex-cord differentiation within uterine mesenchymal proliferations and suggest that the degree of sex-cord differentiation may correlate with the expression of these markers.

Diffusely infiltrative endometrial adenocarcinoma: an adenoma malignum pattern of myoinvasion.

The prognostic significance of a diffusely infiltrative intramyometrial growth pattern was evaluated in 110 cases of low-stage (stages I and II) endometrial adenocarcinoma. Fifty cases were associated with diffuse infiltration (DI group), and 50 cases had more conventional granulation tissue type intramyometrial infiltration (GTT group). Ten cases with carcinomatous involvement of deeply situated adenomyosis (ADMY group) were also studied. The diffusely infiltrative "adenoma malignum" growth pattern featured typically round, regular individual glands, clearly within myometrium but with minimal or absent stromal or inflammatory cell response. Myoinvasion of the conventional sort was characterized by irregular, sharply angulated abnormal glands within myometrium without interposed normal glands or endometrial stroma. The abnormal glands were surrounded, at least focally, by edematous stroma with granulation tissue type reaction and/or an inflammatory cell infiltrate. Mean follow-up was 77.8 months (range 3-219 months) for the patients with diffusely infiltrative myoinvasion and deep adenomyosis and 86.9 months (range 1-206 months) for the patients with conventional myoinvasion. Recurrence-free survival for patients with stage I disease and conventional myoinvasion (94%) was similar to that of patients with diffuse adenoma malignum infiltration (98%; p = 0.13). Survival rates for both groups were also similar. Two (4%) of the 50 patients with diffusely infiltrative adenoma malignum pattern of myoinvasion died of endometrial carcinoma 36 and 72 months after hysterectomy, and 2 (4%) of the 50 patients with conventional myoinvasion died 34 and 67 months after hysterectomy (p = 0.41). Survival in these patients correlated with depth of myometrial invasion and stage. There were no recurrences in the patients with deep adenomyosis. These results suggest that although endometrial carcinomas with diffuse myometrial infiltration are fully capable of aggressive clinical behavior, they do not appear to behave any more aggressively than those with conventional myometrial invasion. Prognostic indicators of clinically aggressive disease are similar to those that have been previously identified for endometrial carcinomas with the more conventional pattern of myometrial infiltration. They include cervical involvement, deep myometrial invasion, higher histologic grade, and lymph-vascular space invasion. Endometrial carcinomas with extensive involvement of adenomyosis and adjacent foci of minimal myometrial infiltration appear to have very low malignant potential, but the number of cases with this finding and adequate clinical follow-up is limited. This finding needs to be confirmed in a much larger series of cases.

Value of skin biopsies in assessing prognosis and progression of acute graft-versus-host disease.

Skin biopsies are commonly performed after allogeneic bone marrow transplantation (BMT) to help establish the origin of a new skin rash in a transplant recipient. Histologic criteria and a grading system for acute graft-versus-host reaction of the skin are well established. Histologic diagnosis, however, can be difficult and is based on interpretation of subtle changes that show significant overlap with features seen in other entities that can be responsible for a skin rash in the posttransplantation period such as drug reactions, viral exanthems, and the effects of chemotherapy. We retrospectively reviewed 179 skin biopsies from 137 patients who had undergone allogeneic BMT. We compared 98 skin biopsies from 71 patients with acute graft-versus-host disease (GvHD) with 81 biopsies from 66 patients who underwent biopsy to exclude GvHD but did not go on to develop the disease on clinical grounds. Two observers reviewed each slide without knowledge of the clinical situation and graded 16 histologic parameters. No single parameter (e.g., dyskeratotic keratinocytes, basal vacuolization, satellitosis, necrotic cells in appendages) achieved statistical significance on univariate analysis. A search for factors to separate GvHD biopsies from non-GvHD biopsies using logistic regression failed to reveal a single best predictor or a combination of predictors. We conclude that skin biopsies after allogeneic BMT are of limited use in predicting the progression of a skin rash to clinical grade II or higher GvHD.

Lymphangioleiomyomatosis of the uterus simulating high-stage endometrial stromal sarcoma.

Symptomatic uterine lymphangioleiomyomatosis (LAM) simulating high-stage uterine sarcoma in a patient with tuberous sclerosis complex is reported. A 49-year-old female presented with abdominal pain and anemia. Preoperative workup revealed a uterine mass and a large amount of peritoneal free fluid and possible metastatic implant along the lateral edge of the liver. The patient also had a large right pleural effusion. A fungating anterior uterine fundal mass with apparent perforation and intraabdominal hemorrhage was found on laparotomy. A portion of the mass was excised and initially interpreted as an endometrial stromal sarcoma. Microscopic examination revealed multiple vascular epithelioid smooth muscle proliferations in the uterus and serosal surface of the fallopian tube and periaortic lymph node lymphangioleiomyomas. The uterine, fallopian tube, and nodal lesions were positive for smooth muscle actin, desmin, and HMB-45, findings characteristic of LAM. Additional examination of the patient revealed stigmata of tuberous sclerosis complex. Although uterine LAM is uncommon, it may be associated with pelvic and/or abdominal symptoms and may simulate a primary uterine mesenchymal neoplasm.

Adenoid cystic carcinoma of the submandibular gland with symptomatic ovarian metastases.

We report the clinical and pathologic features of an adenoid cystic carcinoma of the submandibular gland that metastasized to the ovaries 10 years after initial presentation. A 30-year-old woman underwent excision of a right submandibular adenoid cystic carcinoma followed by regional external beam radiation therapy. Three years later, she underwent extended hepatic resection and localized radiotherapy to the hepatic region for metastatic disease. The patient was without evidence of disease for 7 years when she developed pelvic pain and a pelvic mass was found. A solid and cystic 10-cm left ovarian mass and a single metastatic tumor nodule involving the right ovary were excised via the laparoscope. Histologically, the tumor was identical to the patient's initial salivary gland neoplasm. The neoplastic cells were CAM 5.2 positive, S100 positive, muscle-specific actin positive, and smooth muscle actin positive. Ultrastructurally, characteristic pseudocysts (pseudolumina) with abundant basal lamina and true glandular lumina lined by short microvilli were present. Other than a single anecdotal account of a parotid gland adenoid cystic carcinoma, this case represents the first documented report of an adenoid cystic carcinoma of salivary gland origin that was associated with symptomatic ovarian metastases. This case demonstrates that the ovary is a potential site for metastatic disease many years following the diagnosis and treatment for a primary neoplasm however uncommon or remote the site of origin. Since metastatic adenoid cystic carcinoma can rarely present as an ovarian mass, a clinical history of this neoplasm should be heavily weighed in the differential diagnosis of any unusual ovarian tumor with a predominant cribriform, trabecular, or tubular pattern.

Atypical polypoid adenomyofibroma (APA) versus well-differentiated endometrial carcinoma with prominent stromal matrix: an immunohistochemical study.

It can be extremely difficult in some cases to distinguish atypical polypoid adenomyomas (APAs) from invasive adenocarcinoma in an endometrial curettage or biopsy specimen. In order to determine if immunophenotypic features can be exploited to differentiate between these two entities in problematic cases, a series of APAs and myoinvasive well-differentiated endometrial carcinomas (WDCAs) were studied with a panel of standard immunohistochemical markers. All 23 APAs had stromal smooth muscle actin (SMA) reactivity, 12 of 23 had variable degrees of stromal desmin reactivity, and nine of 22 had CD34-positive stromal cells. All epithelial components of the APAs were cytokeratin (AE1 and CAM5.2) positive, whereas 22 of 23 were positive for estrogen receptor (ER) and progesterone receptor (PR). Among the 10 myoinvasive WDCAs, all contained at least some SMA-positive stromal cells, seven of 10 desmin-positive stromal cells, and four of eight CD34-positive stromal cells. All carcinomas studied demonstrated CAM5.2 and PR-positive epithelia; nine of 10 were ER positive. We conclude that the immunophenotype of APAs does not differ significantly from well-differentiated endometrial adenocarcinoma and that immunophenotyping is of little value in distinguishing APA from carcinoma. Because the stroma in APAs histologically and immunophenotypically more closely resembles a hybrid myofibromatous stroma, we prefer to refer to these lesions with the modified designation "atypical polypoid adenomyofibroma," although "APA" may be retained for clinical use.

Transitional cell neoplasms of the ovary and urinary bladder: a comparative immunohistochemical analysis.

Walthard cell nests, the Brenner tumor (benign, proliferating, low malignant potential, and malignant), and primary ovarian transitional cell carcinoma are considered to be primary female genital tract proliferations of transitional-type (urothelial) epithelium on conventional light microscopic grounds. In order to further investigate the similarities (or dissimilarities) of proliferations of female genital tract transitional epithelium and urothelium, we compared transitional cell proliferations (TCPs) of the female genital tract (n = 25) and urinary bladder (n = 15) using antibodies to carcinoembryonic antigen (CEA; clone 0062), carbohydrate determinant 19-9 (CA19-9; clone 1116-NS-19-9), cytokeratin 7 (CK-7; clone OV-TL 12/30), and cytokeratin 20 (CK-20; clone Ks 20.8), four monoclonal antibodies that have been shown to stain transitional cell urothelial proliferations. Both groups of tumors exhibited significant staining for CEA, CA19-9, and CK-7, and the difference in numbers of cases staining was not significant. CA19-9 was present in 15 of 25 female genital tract TCPs as compared with 12 of 15 bladder TCPs; CEA was present in 17 of 25 female genital tract TCPs and nine of 15 comparable bladder TCPs. CK-7 was present in all cases studied with the exception of one Walthard cell nest and a malignant Brenner tumor that was not immunoreactive with the other antibodies tested. In contrast, 13 of 15 bladder TCPs were CK-20 positive, whereas only one of 25 female genital tract TCPs was positive (< 5% of cells). Walthard cell nests and benign Brenner tumors were more likely to be CA19-9 positive than were Brenner tumors of low malignant potential, malignant Brenner tumors, and primary transitional cell carcinoma of the ovary. We conclude that despite their apparent morphologic and immunologic similarity to TCPs of the urinary bladder (particularly at the histologically low-grade end of the transitional cells spectrum), Walthard cell nests and ovarian Brenner tumors constitute an immunophenotypically distinct form of TCP.

Atypical polypoid adenomyofibromas (atypical polypoid adenomyomas) of the uterus. A clinicopathologic study of 55 cases.

We present the clinicopathological and immunohistochemical features of 55 atypical polypoid adenomyofibromas, a definitional expansion of an entity previously reported as "atypical polypoid adenomyoma" (APA) of the uterus. Patients ranged in age from 25 to 73 (mean, 39.9) years. All but two of the patients were premenopausal, and 14 were undergoing evaluation for infertility. Histologically, the lesions featured a biphasic proliferation of architecturally complex and cytologically atypical endometrial glands within a myofibromatous stroma. The histologic pattern ranged from widely separated and loosely clustered irregular but branched glands embedded in broad zones of cellular myofibromatous stroma to those possessing crowded, markedly complex, branching glands separated by sparse intersecting fascicles of fibromuscular tissue. The stroma in all cases was actin or desmin positive or both. Morular/squamous metaplasia was present in all but two cases and florid in most. All cases exhibited architecturally complex glands, and in 25 cases the architectural complexity was indistinguishable from that of well-differentiated endometrial adenocarcinoma, as we have defined it; that is, they had a high architectural index. Twenty-nine patients were initially treated with polypectomy or curettage followed by hormonal therapy; persistent or recurrent APA developed in 45% of the patients in this group (33% with low architectural index vs. 60% with high architectural index). Five patients had successful pregnancies despite persistent disease. Superficial myoinvasion was identified in the hysterectomy specimen in two of 12 APAs with a high architectural index but not in 21 APAs with a low architectural index. All patients are alive and well 1 to 112 months after diagnosis (mean, 25.2 months). On the basis of this study, we propose that APAs with markedly complex glands (high architectural index) be designated "atypical polypoid adenomyofibromas of low malignant potential" (APA-LMP) to emphasize the potential risk for myometrial invasion. A treatment program featuring local excision accompanied by close follow-up is warranted for APA despite the presence of recurrent or persistent disease. Patients with APA-LMP may also, in selected cases, be managed with less than hysterectomy, although (as with the usual well-differentiated carcinoma) there is a small but definite risk associated with this approach.

Proposed criteria for the diagnosis of well-differentiated endometrial carcinoma. A diagnostic test for myoinvasion.

Existing criteria for separating clinically benign but architecturally complex or cytologically atypical endometrial proliferations (hyperplasia or metaplasia) from well-differentiated endometrial carcinoma are underspecified and poorly reproducible, in part due to the absence of a uniformly agreed on methodologically independent outcome against which to judge the efficacy of competing sets of criteria. Because myoinvasion is the first unambiguous indicator of clinically aggressive behavior for proliferations in this spectrum, we have employed the presence or absence of myoinvasion as a tool to develop clinically meaningful diagnostic criteria for the separation of complex atypical hyperplasia/metaplasia from well-differentiated carcinoma (CAHM/WDCA). We obtained the paired endometrial samplings and hysterectomy specimens of 520 patients; these were split into a training set of 306 cases and a test set of 214. The presence or absence of myoinvasion was assessed from an examination of the hysterectomy specimen. For the purposes of this study, myoinvasion was defined as the presence of irregular intramyometrial glands surrounded by a granulation tissue-like response. To determine the morphologic features that were most predictive of myoinvasion, a series of endometrial architectural, cytological, and stromal features was initially evaluated on the training set (149 myoinvasive and 157 nonmyoinvasive). Using a variety of exploratory data techniques including the classification algorithm CART, we developed a diagnostic rule for predicting myoinvasion that employed one architectural feature (glandular complexity captured by a pictorial architectural index) and two cytological features (nuclear pleomorphism and prominence of nucleoli). Extensive squamous differentiation, fibroblastic stroma, necrosis, stromal foam cells, and other cytologic features did not provide additional predictive value when cross-validated. The true misclassification rate of the CART-generated prediction rule was further assessed by applying the rule to the test set drawn largely from community hospitals. The sensitivity and specificity of this rule for detecting myoinvasion was 99.5 and 57%. The likelihood ratio was 2:1, (i.e., using prior odds of myoinvasion in the CAHM/WDCA spectrum of 1:10, the posterior odds on myoinvasion using the CART-generated rule would be 1:5). Comparison of the CART-generated myoinvasion prediction rule with the Kurman and Norris endometrial stromal invasion criteria for well differentiated endometrial carcinoma (25), using receiver operator characteristic curve (ROC) techniques, demonstrated a significant improvement in the ability to separate myoinvasive from non-myoinvasive endometrial proliferations with the CART-generated rule; the average area under the curve for the CART-generated rule was 0.78 (SE = 0.02) versus 0.67 (SE = 0.03) for the endometrial stromal invasion criteria.(ABSTRACT TRUNCATED AT 400 WORDS)

CD34 expression by gastrointestinal tract stromal tumors.

Gastrointestinal stromal tumors (GISTs) are neoplasms arising in the wall of the gastrointestinal tract that frequently show evidence of smooth muscle differentiation, either by their appearance alone or by immunohistology. A significant number of these neoplasms fail to react with any markers of muscle differentiation, however. A subset of these neoplasms have epithelioid features, and the presence of these features can give rise to confusion with other neoplasms, such as carcinomas and melanomas. Here we show that the CD34 monoclonal antibody My10 reacts with 19 of 23 (83%) of these lesions, including both those with and without epithelioid features. Five of 10 epithelioid and one of 13 spindled neoplasms lacked detectable muscle-specific actin (MSA), smooth muscle actin (SMA), and desmin; all six were CD34 reactive. Immunoblotting experiments show that the antigen on these stromal neoplasms has a molecular weight identical to that found on hematopoietic cells. The frequency and intensity of the reactivity of GISTs with anti-CD34 antibodies are distinctly higher than those reported for smooth muscle neoplasms of soft tissue and myometrium. This reactivity can be a useful adjunct in the diagnosis of difficult cases, especially in those exhibiting epithelioid morphology.

A comparative immunohistochemical study of uterine smooth muscle neoplasms with emphasis on the epithelioid variant.

We evaluated the immunophenotypes of 22 spindled and 36 epithelioid uterine smooth muscle neoplasms (SMNs) and 16 extrauterine nongastrointestinal spindled smooth-muscle neoplasms for various markers. The epithelioid neoplasms were subdivided into two histological groups designated true and intermediate, the former showing typical epithelioid features and the latter showing epithelioid features that could be explained by cross-sectioning of blunt spindled cells. Desmin, muscle-specific actin, and smooth muscle actin were equally sensitive in detecting muscle differentiation in all these neoplasms. The true epithelioid variants were more frequently keratin positive but less frequently positive for vimentin, CD34 or the muscle markers, compared with their spindled counterparts. The intermediate epithelioid variants more closely resembled the spindled neoplasms in their immunostaining for muscle markers, vimentin, and CD34 but like the true epithelioid variants were relatively frequently positive for keratin. CD34 was positive in 36% of the spindled and 6% of the true epithelioid uterine SMNs, in most cases faintly. Antikeratin AE1 was positive more frequently than CAM5.2, with 18% of the spindled and 35% of the true epithelioid neoplasms being AE1 positive. The immunophenotype of uterine SMNs, including the epithelioid variant, permits their distinction from carcinomas based on their frequent reactivity for muscle markers in spite of their high rate of keratin positivity. They show sufficient overlap in immunoreactivity with endometrial stromal sarcomas to preclude definitive differentiation from them on immunohistochemical features alone.

Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases.

A recent trend in the classification of uterine smooth muscle neoplasms (USMNs) into clinically benign and clinically malignant groups has been to move from exclusive reliance upon mitotic index (MI) to an approach that incorporates additional histopathologic characteristics. In furtherance of this goal, we assessed a variety of histopathologic features of 213 problematic smooth muscle neoplasms for which we had > or = 2 years of clinical follow-up data or for which there was an unfavorable outcome. One hundred and thirteen of these patients have had a minimum follow-up of 5 years, and 48 have been followed for > or = 10 years. Cases eliminated from the study group included USMNs with a significant myxoid or epithelioid component and cases of intravenous leiomyomatosis. USMNs, whether cellular or not, with no cytologic atypia and with a mitotic index (MI = number of mitotic figures [mf]/10 high-power fields [hpf]) of < 5 mf/10 hpf (usual leiomyomas) were also excluded unless they had unusual features or were associated with an adverse clinical outcome. Fifty-six patients were initially treated by myomectomy or another form of local tumor removal; the remainder had a hysterectomy. From a wide variety of light microscopic features assessed, the important predictors that emerged, using a variety of data exploratory techniques, were MI, the degree of cytologic atypia, and the presence or absence of coagulative tumor cell necrosis (CTCN). Stratification of the USMNs with respect to these three features resulted in a five-group classification of USMNs with the following major characteristics. Group 1: Of the 89 USMNs with an MI in the range 5 < or = MI < 20 without CTCN and with no more than mild atypia, 88 were clinically benign. One patient with a tumor in this group died of metastatic disease 96 months after her uterine cervical primary neoplasm was removed. Combining our data with that in the literature, the failure rate in this group is approximately 1/200 (0.5%). This low failure rate warrants the use of the label "leiomyoma with increased mitotic index" for USMNs with these histologic features. Two patients whose USMNs were characterized by mild atypia, no necrosis, and MI < 5 developed identical-appearing pulmonary metastases and were judged in retrospect to have the syndrome "benign metastasizing leiomyoma." Group 2: USMNs with no CTCN and diffuse moderate to severe atypia fell into two groups based on the MI. For those patients whose neoplasms had an MI > or = 10 mf/10 hpf, four of 10 failed.(ABSTRACT TRUNCATED AT 400 WORDS)

Cyclic hormone replacement therapy using quarterly progestin.

OBJECTIVES: To determine whether cyclic progestin, when part of postmenopausal hormone replacement therapy, can be used quarterly instead of monthly without increasing the risk of endometrial hyperplasia. In addition, we determined whether this hormone replacement therapy regimen produces an acceptable menstrual pattern. METHODS: The subjects were 214 postmenopausal women, mean (+/- standard deviation) age 56.2 +/- 5.4 years, who had regularly used hormone replacement therapy (consisting of Premarin 0.625 mg/day with monthly cyclic medroxyprogesterone, 5 or 10 mg) for a mean of 5.4 +/- 4.5 years (minimum 1 year). The study intervention consisted of changing the subjects' treatment from the usual monthly progestin to four 3-month (ie, quarterly) cycles of medroxyprogesterone, 10 mg/day for 14 days. Endometrial histology was evaluated by doing endometrial biopsies at study outset and after 1 year. Scheduled and unscheduled vaginal bleeding was reported in daily diaries. RESULTS: Endometrial hyperplasia was found in 1.5% of 199 women completing follow-up, a rate similar to the 0.9% prevalence found at baseline. Compared with monthly medroxyprogesterone, quarterly medroxyprogesterone resulted in longer menses (7.7 +/- 2.9 versus 5.4 +/- 2.0 days) and more reports of heavy menses (31.1 versus 8.0%) and unscheduled bleeding (15.5 versus 6.8%). Despite these problems, women preferred the quarterly regimen by nearly four to one. CONCLUSIONS: In a 1-year trial, quarterly medroxyprogesterone appeared as safe as monthly medroxyprogesterone and was preferred by most women. This schedule may be useful for women seeking relief from monthly use of progestin and monthly menses.