Hysteroscopic findings in postmenopausal abnormal uterine bleeding: a comparison between HRT users and non-users.

OBJECTIVES: The aim of our study was to investigate hysteroscopic findings in a sample of 410 menopausal women (hormonal replacement therapy, HRT users n = 219 and HRT non-users n = 191) and to evaluate the relationship between the presence of intrauterine disease, the use of HRT and the presence of AUB. METHODS: Two hundred and nineteen women on HRT underwent standard office hysteroscopy by means of the Hamou hysteroscope (in 94 cases for abnormal uterine bleeding (AUB) and in 125 cases for periodic endometrium monitoring). One hundred and ninety-one women who had never received HRT were submitted to office hysteroscopy (154 for AUB and 37 for other reasons). RESULTS: Intrauterine diseases are more frequent in patients who do not use HRT (P = 0.02). Endometrial polyps is a frequent disease present in 30% of the sample (23.7% of HRT users and 30.8% of HRT non-users). Myomas were present in 8.7% of all patients examined (6.8% of HRT users and 11% of HRT non-users). Irregular bleeding in menopause is often associated with endouterine abnormalities: in symptomatic patients the frequency of endouterine diseases was 41% while in asymptomatic patients was 28% (P = 0.003). In patients taking HRT (n = 219) endouterine disease is demonstrated in 37% with AUB and in 26% without AUB (P = 0.07). CONCLUSION: Benign intrauterine diseases (endometrial polyps and submucous myomas) are more frequent in postmenopausal women who do not use HRT. In patients taking HRT irregular bleeding is associated with intrauterine diseases; however, the absence of AUB does not exclude the presence of endometrial polyps or myomas.

[Ultrasonographic and biochemical screening of adnexal masses before operative laparoscopy]. / Screening ultrasonografico e biochimico delle masse annessiali prima di laparoscopia operativa.

BACKGROUND: The object of our study was to evaluate how reliable ultrasonographic and biochemical screening of adnexal masses are in the selection of patients eligible for operative laparoscopy. METHODS: The study was performed at the First Clinic of Obstetrics and Gynecology, University of Rome La Sapienza, Italy. Eighty-seven women of 36.8 +/- 12 years of age, who underwent operative laparoscopy between January 1999 and January 2000 to remove an adnexal lesion, were enrolled. These adnexal lesions had been previously diagnosed on the basis of a pelvic ultrasonographic imaging; this was performed because of follow-up procedure or pelvic pain. The lesions were evaluated preoperatively according to Sassone echographic scoring system. The CA-125 level was determined in 58 patients. RESULTS: Surgery was successful in all 87 cases. In one case the operative laparoscopy had to be turned into laparotomy since the histologic examination revealed an atypical proliferative mucinous cystoadenoma. Sassone total average echographic score was 6.0 +/- 1.7; this is below the discriminant cut-off for malignancy (9). The only case in which Sassone score reached 10 was an atypical cystoadenoma. The CA-125 level was higher than 35 IU/ml (cut-off of this marker) in 13.7% of the patients; these were all affected by endometriosis or had a hemorrhagic corpus luteum. In the patient with atypical cystoadenoma, the CA-125 level was within normal range (29.1 UI/ml). The post-operative period was uneventful in all cases but one, in which the occurrence of pulmonary thromboembolism required a prolonged hospitalization. CONCLUSIONS: The use of Sassone echographic scoring system proved to be very useful and effective in the selection of the patients. Tumor markers are relevant factors only if their evaluation is accompanied by an accurate anamnesis and is supported by the findings of abdominal and transvaginal ultrasonography.

Association between polycystic ovary and fibrocystic breast disease.

OBJECTIVE: The aim of this study was to assess whether or not there was an association between a polycystic ovary (PCO) and fibrocystic breast disease based on ultrasound findings, both pelvic and mammographic. DESIGN: Prospective case-control study. POPULATION: Women aged between 18 and 30 years not using oral contraceptives attending the outpatient ultrasound clinic from January 1996 to December 1998. MAIN OUTCOME: Confirm the association between PCO and fibrocystic breast disease. RESULTS: According to the ultrasound findings, women were allocated to three groups: 351 out of 456 showed normal-appearing ovaries (group A), 93 had polycystic-appearing ovaries/PCO (group B) and 12 had PCO syndrome (group C). In group A, 24 (6.83%) women showed breast pathology. In group B, there was an association between PCO and breast pathology in 53 (56.98%) women, while in group C it was noted in 11 out of 12 (91%). CONCLUSION: This study showed a significant association between PCO and benign pathology. This should encourage the performance of a screening breast sonography on women with PCO.

Estradiol enhances the resistance of LDL to oxidation by stabilizing apoB-100 conformation.

Among different proposed mechanisms to account for the protection exerted by estrogens against cardiovascular diseases, the antioxidant effect has attracted considerable attention. We confirmed that 17-beta-estradiol (E2), when added to human LDL at a 6:1 ratio to apoB-100, markedly delays the phase of massive LDL lipid peroxidation induced by Cu(2+). We also observed an increased oxidative resistance of E2-treated LDL by monitoring the early phase of oxidative degradation on the basis of increased LDL surface polarity by the generalized polarization of the lipophilic fluorescent probe 2-(dimethylamino)-6-lauroylnaphthalene (Laurdan). A scavenging of free radicals by E2 is ruled out since, consistent with its structure, its rate constant for the reduction of peroxy radicals is extremely low, i.e., 0.02% of that of vitamin E. Tryptophan fluorescence lifetime and circular dichroism measurements revealed that (i) apoB-100 undergoes a conformational modification and a progressive loss of secondary structure during lipid peroxidation; (ii) E2 increases apoB-100 secondary structure and modifies its conformation; and (iii) the apoB-100 conformational change induced by E2 makes this protein resistant to modifications brought about by lipid peroxidation. We propose that E2, by affecting apoB-100 secondary structure and conformation, modifies the interaction of this protein with the outer layer of the LDL particle thus increasing its overall oxidative resistance.

[Proposal for an informed consent form for hormonal replacement therapy in ambulatory care]. / Proposta di una scheda di consenso informato alla terapia ormonale sostitutiva nella pratica ambulatoriale.

Hormonal Replacement Therapy (HRT) represents a valid therapeutic approach for menopausal symptoms and for the prevention of cardiovascular disease and osteoporosis. Nevertheless, an informed consent, after a complete information, must be obtained from the patient. This procedure is generally adopted in any medical activity, but the modality of the consent in the HRT administration is not well established (verbal or written?, timing of administration?). The authors propose an informed written consent model to be utilized in menopausal centers; this model synthetically informs about HRT benefits and risks and must be red and signed by the patient. The written consent should be explained through a verbal detailed discussion about it, during which the patient's comprehension must be assured. The informed consent procedure should be renewed every year in long term-users. The influence of the HRT informed consent in menopausal centers must be analyzed in particular as far as women compliance is concerned.

Evaluation of the body composition and fat distribution in long-term users of hormone replacement therapy.

The aim of the study was to evaluate the body composition and fat distribution in long-term users of hormonal replacement therapy (HRT). 18 healthy menopausal women, long-term users of HRT (transdermal estradiol 50 microg continuously administered and 10 mg/day of medroxyprogesterone acetate for 12 days/month) and 18 healthy menopausal women, who had never used HRT were included in the study. Age, menopausal age, parity, weight and height (body mass index, weight/height2), and lifestyle habits were similar. Waist and hip circumference, body composition and waist/hip ratio were measured and the results were analyzed. No significant difference was demonstrated in fat and water percentage, and waist/hip ratio. Nevertheless, the waist circumference of long-term HRT users was significantly lower than that of non-users. In conclusion, abdominal fat in long-term HRT users is lower than that of non-users of similar age, menopausal age and body mass index.

Comparative study on the acceptability of two modern monophasic oral contraceptive preparations: 30 microgram ethinyl estradiol combined with 150 microgram desogestrel or 75 microgram gestodene.

Cycle control and tolerability of two monophasic oral contraceptive pills containing 30 microg ethinyl estradiol (EE) with either 150 microg desogestrel (DSG) or 75 microg gestodene (GSD) were compared in women starting oral contraception. A minimum of 200 healthy women at risk for pregnancy were to be treated for a total of 6 cycles per patient in a prospective, randomized open parallel-group multicenter trial. Two hundred and forty-one subjects were randomized, 115 to DSG/EE and 126 to GSD/EE. Compliance to the study preparation was high (around 95%) in both groups and no pregnancies occurred during the study. Cycle control was excellent; there were no differences between the two groups with regard to incidence of spotting and breakthrough bleeding or duration and intensity of withdrawal bleeding. Side-effects were mild and in general comparable in the two groups. Both at baseline and during treatment, a higher proportion of women taking GSD/EE complained about breast tenderness. This resulted in more early withdrawals because of breast tenderness in the GSD/EE group. It was concluded that monophasic DSG/EE and GSD/EE are equally effective, have similar cycle control and both are generally well tolerated.

[A mammographic evaluation of the morphostructural variations of the breast during hormone-replacement therapy in the postmenopause]. / Valutazione mammografica delle variazioni morfo-strutturali della ghiandola mammaria durante terapia ormonale sostitutiva nella postmenopausa.

INTRODUCTION: Exogenous hormones may cause breast tissue changes, generally increasing its density. We used mammography to detect the to early effects of hormone replacement therapy in postmenopausal women. MATERIAL AND METHODS: We examined 300 postmenopausal women (group A: 70 women in surgical menopause treated with estrogen replacement therapy; group B: 230 women in spontaneous menopause receiving estrogen and progestin replacement therapy). The mammographic patterns, according to Wolfe's classification, were compared with those of group C (case control group of 300 women) and group X after 1 year of therapy. The modification were classified as total and partial changes in mammographic density. The results were analyzed with Pearson's chi 2 test. RESULTS: The evidence of a change in parenchymal pattern was found in 103/300 women (34.3%). Twenty-one women in group A and 82 in group B showed increased mammographic density (the DY breast by Wolfe). Partial changes were observed in 64 cases (21.3%). Comparing groups A and B to groups C and X (before therapy), the changes were statistically significant (p < .001), while comparing groups A and B the difference was not significant (p = 1.000). CONCLUSIONS: The likely widespread use of hormone replacement therapy in the future will require an increase in the number of mammograms and a possible re-evaluation of sensitivity. To improve follow-up timing and to avoid a decrease in sensitivity, radiologists will have to consider both general and specific factors and to pay attention to the patterns of global increase in breast tissue density, the DY pattern of Wolfe's classification.

Microanatomy of the female reproductive organs in postmenopause by scanning electron microscopy.

The detailed three-dimensional ultrastructural features of the reproductive organs of menopausal and postmenopausal women were studied by means of integrated transmission and scanning electron microscopy (SEM) and reported in a new colored microtopographical fashion. These methods revealed significant alterations in the microanatomy of the various reproductive organs specifically related to the decline of plasma estrogen levels. In particular, the ovary progressively showed characteristic wide areas of loss of epithelium with consequent exposure of the underlying connective tissue. Both endometrial and tubal mucosa demonstrated a gradual but often dramatic decrease in the number of ciliated cells which was more evident in the tube. In addition, the non-ciliated (microvillous secretory) cells of the uterus, including both endocervix and tubal mucosa, became flattened and, in some instances, their apical poles developed unusual wrinkles (microridges or microplicae). The ectocervix and vaginal squamous cells presented a reduction in the number of their microridges and changes in the typical structural organization. These microtopographical results showed that the decline of estrogen during the menopause and postmenopause induces important and complex structural changes of the woman's reproductive system, much more detailed than those revealed to date by the use of only conventional optical and transmission electron microscopy (TEM). The three-dimensional findings offer the opportunity to re-evaluate the classic histopathology of the above aging organs using more refined microtopographical and morphophysiopathological parameters.

Effect of oral and transdermal hormone replacement therapy on lipid profile and Lp(a) level in menopausal women with hypercholesterolemia.

OBJECTIVE: The aim of this randomized clinical study was to evaluate the hormonal replacement therapy (HRT) effect on plasma lipoproteins and Lp(a) profile in 42 menopausal women with primary hypercholesterolemia (total cholesterol > 240 mg/dL). SETTING: University clinic. PATIENTS AND METHODS: 42 hypercholesterolemic menopausal women were randomly assigned to the following groups; (1) transdermal estradiol, 50 micrograms + medroxyprogesterone 10 mg/day for days; (2) conjugated equine estrogens, 0.625 mg/day + medroxyprogesterone acetate 10 mg/day for 12 days; (3) no treatment. At baseline and after 3 and 6 months two blood samples were collected with a 24-hour interval in order to reduce intraindividual and laboratory variability. Serum total cholesterol, HDL cholesterol, triglycerides, LDL cholesterol, and Lp(a) were determined. RESULTS: Total cholesterol and LDL cholesterol significantly decreased after 6 months in both treated groups in comparison to untreated women; HDL cholesterol and triglycerides showed only minimal changes. HRT at the dosage utilized in the study did not seem influence the Lp(a) concentrations after 3 and 6 months. CONCLUSIONS: Both transdermal and oral estrogens at medium dosage have a favorable influence on total cholesterol and LDL-cholesterol level of hypercholesterolemic menopausal women, but Lp(a) remains resistant to manipulation.

[The evaluation of the use of DEAE-dextran in glycemic control in diabetic patients in pregnancy]. / Valutazione sull'impiego del DEAE-destrano nel controllo della glicemia in pazienti diabetiche in gravidanza.

Thirty pregnant women with a pre-gestational history of type II diabetes or sugar intolerance and recruited during the second trimester of pregnancy, were administered DEAE-dextran (1 g x 3 times a day) in association with compensatory insulin therapy. Results of the end of trial tests showed amelioration of all of the parameters studied. The sugar curve after 120' from glucose load (100 g at fasting), showed a highly significant decrease at T90. Triglycerides T0 vs T90 gave p = 0.0001, probably due to improved body utilization of the insulin. DEAE-dextran was well tolerated and all of the patients enrolled at the beginning, completed the trial.

Hormone replacement therapy affects various immune cell subsets and natural cytotoxicity.

The effects of hormone replacement therapy (HRT) on lymphocytes and granulocytes have never been determined in detail. Ten healthy menopausal women (age 49-51 years; menopause less than 2 years) were treated for 6 months by administering transdermal estradiol (100 micrograms/day for 21 consecutive days) and oral medroxyprogesterone acetate (10 mg/day from day 10 to day 21). Days 22-28 were therapy-free. All subjects were examined during the first and the last month of treatment: evaluations were carried out on days 0, 8, 21 and 28. CD4+CD45RO+ cells were found to be significantly reduced on day 8. CD56+ cells and CD8+CD11b+ cells were decreased on day 21 and recovered basal level on day 28. Natural killer cell function was transiently increased on day 8 and greatly reduced on day 21. During the first month of therapy, the expression of Leu8 and CD11b antigens on granulocyte membranes was significantly affected by HRT. Taken together, the results indicate that HRT selectively affects various immune cell subsets.

[Effect of GnRH analogues on bone density in the vertebral column and the femur]. / Effetto degli analoghi del GnRH sulla densità ossea della colonna e del femore.

The objective of this study was to evaluate the effect on vertebral and femural bone density of the gonadotropin-releasing hormone (GnRH) analog administration. The changes in mineral bone density after 6 months discontinuation of the GnRH analog treatment were also measured. Forty-three premenopausal women with regular cycles and suffering from uterine myomatosis have been selected for the study. Twenty-eight women (group A) were treated with Goserelin 3.2 mg given as a depot every 28 days for 6 months. Fifteen women were treated with 10 mg of medroxyprogesterone acetate (MPA) from day 16 to day 25 of each month for 6 months. Vertebral and femural bone density was measured (by Hologic QDR-X 1000) just before the start of the study, at 6 months of treatment and at 12 months (after 6 months of discontinuation treatment). Significant loss of vertebral bone density was demonstrated in women treated with GnRH analog. After six months of treatment discontinuation bone mineral density did not recover the pretreatment values. Bone femural density showed a not significant decrease in the GnRH analog group. In our experience, the treatment with GnRH analog in premenopausal women induces a reduction in lumbar bone density that is not reversible after the treatment withdrawal; for this reason it would be safe to add at the GnRH analog a therapy which can prevent the bone loss.

Lumbar and femoral bone density in perimenopausal women with irregular cycles.

OBJECTIVE: The aim of the study was to evaluate the impact of irregular cycles on bone mass in perimenopausal women. SETTING: University clinic. PATIENTS AND METHODS: 118 healthy women aged between 45 and 55 years were divided into three groups according to the previous year's menstrual history (premenopause: regular cycles; perimenopause: irregular cycles; early postmenopause: 1-3 years since the last menstrual cycle). Among the perimenopausal group, only women presenting intervals without menstruation longer than 3 months during the year of the study were selected. Bone mineral density of the lumbar spine and of the proximal femur was measured by dual energy X-ray absorptiometry (DEXA) at the start of the study and after 12 months. RESULTS: The serum estradiol level was significantly lower in postmenopausal women and the FSH serum level showed a significant increase in perimenopausal and postmenopausal women in comparison with premenopausal controls. Bone density at L2-L4, femoral neck, greater trochanter, and total femur did not show significant differences at the beginning of the between-group study. Only the density in Ward's triangle was significantly lower in perimenopausal and postmenopausal women. After twelve months the densities of L2-L4, greater trochanter, Ward's triangle, and total femur showed a significant decrease in postmenopausal women in comparison. The perimenopausal group showed a significant decrease in total femur and Ward's triangle density in comparison with premenopausal. CONCLUSION: The occurrence of marked irregularity of menstrual cycles preceding menopause can influence bone mass, in particular at the femoral site.

The importance of life style after menopause.

There is generally recognized close association between lifestyle and health, even if the exact nature, and importance, of various aspects of the relationship is under investigation, including that between life style and menopause. However, there are abundant and conclusive data showing the positive effect of hormone replacement therapy (HRT) on menopausal symptoms and reduction of long-term menopausal risks. Much is still to be learned, though, about the reciprocal influences of life style, HRT choices, and quality of life. At present the opportunity for HRT is somewhat limited, and physicians are to a degree to blame in this situation by not vigorously counteracting inaccurate popular perceptions of the dangers and benefits of HRT. For purposes of discussion, life style may be taken to be a cluster of interrelated behaviour patterns that depend upon social and economic conditions, education, age, and other factors. The importance of some of these factors in terms of illness and longevity is striking. For instance, a study in England revealed a twofold difference in death rate between unskilled laborers and self-employed professional--and this difference was also applicable to their wives. Income, too, is a determinant of life style. Good health is well correlated with higher income. (Some three-quarters of the elderly poor are women). Smoking is certainly a life style health factor. In recent years, smoking has declined among the upper socioeconomic classes and, indeed, these is now a class gradient in lung cancer deaths. Diet is a factor that is strongly influenced by geography.(ABSTRACT TRUNCATED AT 250 WORDS)

[Echographic monitoring of the endometrium with a transvaginal probe in the menopause. A clinical study of 185 women in the menopause]. / Monitoraggio ecografico dell'endometrio con sonda transvaginale in menopausa. Studio clinico su 185 donne in menopausa.

The aim of our study was to verify the efficacy of transvaginal ultrasound scanning as an indicator of the endometrial status in healthy menopausal women. One hundred eighty five healthy women in natural menopause were examined by vaginal sonography; the endometrial patterns were analyzed and the influence on it of body weight, menopausal age, and hormonal therapy was considered. The presence of irregular and the endometrial histology were related to the ultrasound findings. 38% of the women assumed estrogen plus progestin replacement treatment since one-two years, for menopausal complaints. 17% of all patients reported irregular bleeding during the last month. The majority of women (90%), regardless of the hormone assumption, presented en endometrial thickness less than 10 mm. 10% of untreated and treated women had an endometrial thickness between 10 and 20 mm. Among the subjects with elevated menopausal age is more frequent the imaging of endometrial layer minor than 5 mm in comparison with women in early menopause. 4% of untreated and 10% of treated women without irregular bleeding had an endometrial thickness higher than 10 mm, while 67% of women with irregular bleeding presented an endometrial layer higher than 10 mm. In treated group all women with endometrial thickness greater than 10 mm had amenorrhoea. 86% of patients had endometrial atrophy detected by biopsy; hyperplastic endometrium or endometrial cancer was not demonstrated. In conclusion, vaginal sonography is a simple and reliable method in the study of the endometrial pattern in healthy menopausal women.

[Heterologous mesodermal adenosarcoma of the endocervix. Description of a clinical case]. / Adenosarcoma mesodermico eterologo dell' endocervice. Descrizione di un caso clinico.

We describe a case of an endocervical heterologous mesodermal adenosarcoma, found in a 43 year old woman. Among mesodermal neoplasms, various histological types are distinguished: the carcinosarcoma, the embryonal rhabdomyosarcoma or botryoid sarcoma, and the adenosarcoma; the last is formed by a benign epithelial component and by a malignant stromal component, that may contain heterologous tissues, such as cartilage, skeletal muscle, etc. Adenosarcoma is a tumor of the uterine corpus and seems to be most common among menopausal women. A primitive adenosarcoma of the uterine cervix is very rare; in fact the overall percentage of the uterine cervical sarcoma is 0.2-0.4%. The patient, age 43 years, with regular menstrual bleeding came to an outpatient clinic referring a post coital metrorrhagia. After a control examination, a polyp from the uterine cervix was removed; the histopathologic diagnosis was: fibroangioadenomatous polyp of the isthmus with cartilaginous metaplastic areas. Two months later, the patient was referred to our clinic and another cervical polyp was removed. The histological diagnosis was adenosarcoma with chondrosarcomatous heterologous mesodermal component. Then the patient was operated and the postoperative histological examination confirmed the preoperative diagnosis. A literature review about the uterine adenosarcoma etiopathogenesis is reported, and a suitable diagnostic iter, is discussed.

Hormonal and metabolic effects of transdermal estradiol/progestagen administration in postmenopausal women.

OBJECTIVE: To evaluate the effects on hormonal and metabolic variables and bone density of a transdermal system delivering estrogen and progestagen. DESIGN: Twenty-one patients were included in the study and randomly assigned to the following treatments: group A was treated with transdermal 17 beta-estradiol, 50 micrograms/day (Estraderm TTS 50), from the first to the fourteenth day of the cycle and with a transdermal combination of 17 beta-estradiol (50 micrograms/day) and norethisterone acetate (NETA) 250 micrograms/day during the following 14 days; group B was treated with Estraderm TTS 50 from the first to the twenty-eighth day, adding oral medroxyprogesterone acetate (MPA), 10 mg/day, during the final 14 days. DHEAS, testosterone, SHBG, prolactin, gonadotropins, and estrogens were measured in basal conditions and after 6 months' therapy. In the same schedule, lipid patterns (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides), phosphocalcium variables (osteocalcin, calcitonin, parathormone), and bone mineral density were also studied. RESULTS: Both treatments were efficient in reducing menopausal symptoms. An increase of DHEAS (P < .05) and a decrease of FSH and LH (P < .02, < .01, respectively) were observed in group B. No significant modifications in lipid and lipoprotein metabolism were shown in either group after 6 months. The calcium-regulating hormone osteocalcin (BCG) decreased significantly (P < .05) only in group A; calcitonin, parathormone, and bone density were unchanged after treatment. CONCLUSION: Transdermal administration of estrogen plus progestagen reduces menopausal symptoms, but does not induce changes in metabolic variables and hormonal levels (androgens and prolactin).

Effects of 1-year treatment with ipriflavone on bone in postmenopausal women with low bone mass.

Ipriflavone (IP) (7-isopropoxyisoflavone), a synthetic isoflavone derivative, is active in both inhibiting bone resorption and enhancing osteoblast function. This property suggested its clinical use in the treatment of involutional osteoporosis, and in the prevention of postmenopausal bone mass loss. Forty postmenopausal women with low bone mineral content were enrolled and randomly treated for 12 months with IP 600 mg/day or placebo (PL), according to a double-blind, parallel group design. All patients wee also given an oral calcium supplementation (1 g/day). Bone mineral density (BMD) was measured at the spine (L2-L4) by dual-energy X-ray absorptiometry and at the distal radius by single-photon absorptiometry. Bone metabolism markers (serum calcium, phosphate, osteocalcin, and alkaline phosphatase, and urinary calcium, phosphate, and hydroxyproline) were assessed at the same times. After 12 months, a reduction of BMD was evidenced in the PL-treated group, at both the spine (-2.2%, P < 0.01 vs baseline) and the forearm (-1.2%). In the IP-treated group, an increase of BMD was obtained (+1.2%, P < 0.01 vs placebo, at the spine; +3%, not significant, at the forearm). Bone markers were in the normal range for postmenopausal women; no statistically significant modifications were observed during the treatment period. Three patients were withdrawn from the treatment in the IP-treated group, and two in the PL-treated group for gastrointestinal disturbances. In the other women, the tolerance of the drug was good and the compliance with the oral treatment was excellent.