Differential diagnosis of abnormal uterine bleeding.

The causes of abnormal uterine bleeding include a wide spectrum of diseases of the reproductive system and nongynecologic causes as well. The differential diagnosis of abnormal excessive uterine bleeding includes organic causes that may be subdivided into reproductive tract disease, iatrogenic causes, and systemic disease. Reproductive tract disease that may result in abnormal uterine bleeding comprises the complications of pregnancy (threatened, incomplete, or missed abortion, ectopic pregnancy, trophoblastic disease, placental polyp, and subinvolution of the placental site), malignant tumors (endometrial, cervical, vaginal, vulvar, and oviduct malignancies and granulosa theca cell ovarian tumors), infection (endometritis, salpingitis), and other benign pelvic disorders (traumatic lesions of the vagina, severe vaginal infections, foreign bodies, cervical polyps, cervical erosion, cervicitis, submucous uterine leiomyomas, adenomyosis, endometriosis, and endometrial polyps). Iatrogenic causes of abnormal uterine bleeding include sex steroids, hypothalamic depressants, digitalis, phenytoin, anticoagulants, and intrauterine contraceptive devices. Systemic diseases that may cause abnormal uterine bleeding include hypothyroidism, cirrhosis, and coagulation disorders. Abnormal uterine bleeding that occurs in a woman of reproductive age should be considered the result of complication of pregnancy until proved otherwise. Abnormal uterine bleeding occurring in a woman of perimenopausal or postmenopausal age should be considered the result of a malignancy until proved otherwise. Menorrhagia occurring in an adolescent should be attributed to a coagulopathy until proved otherwise. When an organic cause of abnormal uterine bleeding cannot be found, then by exclusion the diagnosis of dysfunctional uterine bleeding is assumed. Coagulation disorders, particularly von Willebrand disease, are more common than many physicians realize. Women with a history of high-risk factors, all adolescents with menorrhagia, women with anovulatory dysfunctional uterine bleeding who fail medical or surgical therapy, and women with ovulatory dysfunctional uterine bleeding without an anatomic uterine lesion should be screened for a coagulopathy.

Management of abnormal uterine bleeding.

Patients treated for dysfunctional uterine bleeding are separated into two groups: those with acute bleeding episodes and those with chronic repetitive bleeding problems. An acute bleeding episode is best controlled with the use of high-dose estrogen. A curettage is indicated for patients with acute bleeding resulting in hypovolemia, and a curettage or hysteroscopically directed biopsies is indicated for women with risk factors for endometrial cancer who have persistent bleeding problems. The management of anovulatory dysfunctional uterine bleeding is determined by the needs of the patient. In the adolescent medroxyprogesterone acetate is administered orally once a day for 10 days each month for > or = 3 months, and the patient is monitored closely thereafter. Oral contraceptives are used for women of reproductive age with anovulatory bleeding episodes who also require contraception. Clomiphene citrate is used for women of reproductive age with anovulatory bleeding who want to conceive. Oral medroxyprogesterone acetate is administered 10 days each month for 6 months for the treatment of anovulatory dysfunctional uterine bleeding alone in this age group. For the perimenopausal patient dysfunctional uterine bleeding may be treated by the administration of cyclic progestin or cyclic conjugated equine estrogens for 25 days with the concomitant administration of medroxyprogesterone acetate for days 18 to 25. The perimenopausal patient with dysfunctional uterine bleeding who is a nonsmoker and does not have evidence of vascular disease may also be treated with low-dose combination oral contraceptives. The long-term treatment for women with ovulatory dysfunctional uterine bleeding is the most difficult type of dysfunctional uterine bleeding to manage. The long-term therapy is directed at the reduction in menstrual blood loss. For these patients prolonged progestin use, oral contraceptives, nonsteroidal antiinflammatory drugs, antifibrinolytic agents, danazol, and as a last resort gonadotropin-releasing hormone agonists are part of the therapeutic armamentarium. A combination of two or more of these agents is often required to successfully control the abnormal bleeding. For patients who no longer desire future fertility and have associated pelvic pathologic disorders or for those who fail all medical regimens, surgical therapy may be considered. Either hysterectomy or endometrial ablation has been used. Patients with von Willebrand's disease and excessive menstrual blood loss may be misdiagnosed as having dysfunctional uterine bleeding. van Willebrand's disease is the most common bleeding disorder and is present in approximately 1% of the population. It is much more common than previously recognized. There are improved diagnostic tests to identify this disorder and, most important, there is a high-concentration desmopressin acetate nasal spray available as treatment that does not involve the risk of transmission of hepatitis and human immunodeficiency virus.

The menopausal syndrome.

The average life span of women living in the United States is approximately 80 years of age, with one-third of those years spent after menopause. Of the approximately 35-40 million postmenopausal American women, only 10% are currently using estrogen replacement therapy. Atrophy of the genitourinary system may be prevented or reversed with estrogen therapy. In addition, 75% of all postmenopausal women have vasomotor symptoms severe enough to lead them to seek medical consultation. For 65%, these symptoms persist for at least 1 year, and for 20%, the hot flushes are present for more than 5 years. Estrogen replacement therapy is the treatment of choice for the management of vasomotor symptoms, with or without additional behavior symptoms, and should be considered safe for most postmenopausal women. It protects the bones and, most important, the cardiovascular system.

Biologic effects of equilin sulfate in postmenopausal women.

In order to determine the relative potency of equilin sulfate (EqS), a major constituent of conjugated equine estrogens, 15 women received oral doses of EqS (0.15, 0.31, and 0.625 mg) for 25 days. Doses of 0.31 and 0.625 mg significantly stimulated hepatic globulins. This stimulatory effect ranged from being 1.5 to 8 times greater than the effects of comparable doses of estrone sulfate and conjugated equine estrogens. A significant stimulation in high-density lipoprotein-cholesterol occurred with as little as 0.15 mg of EqS. Elevations in the high-density lipoprotein/low-density lipoprotein-cholesterol ratio occurred with EqS, which resulted in an approximately 4-fold greater response than that achieved with comparable doses of conjugated equine estrogens. The fasting urinary calcium/creatinine ratio was only significantly lowered with 0.625 mg of EqS and was less potent than conjugated equine estrogens in this regard. It is concluded that EqS is a potent estrogen that contributes significantly to the hepatic stimulatory effects of conjugated equine estrogens. These data also provide support for the suggestion that there may be a dissociation in potency between estrogenic effects on liver and bone.

Termination of early gestation with the anti-progestin steroid RU 486: medium versus low dose.

RU 486 is a synthetic steroid which has antiprogesterone and antiglucocorticoid activity. In order to determine the optimal dosage of this drug to terminate early pregnancy, we treated 106 healthy women with normal pregnancies by real time ultrasound examination whose gestational duration was less than 49 days from onset of last menses with either a medium or low dose treatment regimen. A total of 66 patients received the medium dose regimen (100 mg/day X 7 days). Another 10 patients received ergonovine (0.2 mg/day X 6 doses) on Day 4 of the same RU 486 treatment regimen. In the first group, 48 (73%) aborted successfully and, of the second group, 6 (60%) aborted. Eighty percent of the subjects in this group of 76 patients reported side effects of nausea and vomiting, heavy bleeding, severe menstrual cramps or headache. All these side effects were successfully treated with analgesic and antiemetic medication. The remaining 30 subjects were treated with a low dose regimen (50 mg/day X 7 days). Of these 30, 15 (50%) aborted; this incidence was significantly less (p less than 0.05). Following the medium dose treatment regimen, the AM cortisol levels were significantly elevated on treatment Days 4 and 8, as compared to baseline (p less than 0.001), although the mean levels were still within the normal range. With the low dose, there was a non-significant rise in AM cortisol values. Thus the rise in cortisol was significantly greater in the former group than the latter (p less than 0.05). With the medium dose regimen, the women who aborted had significantly lower (p less than 0.05) pretreatment mean B-HCG and progesterone levels than the group that failed to abort. Mean serum levels of RU 486 were not significantly different between the group who aborted and those who did not. RU 486 is a promising agent for termination of early pregnancy.

Pregnancy termination with a high and medium dosage regimen of RU 486.

Sixty healthy pregnant women who wished to terminate their pregnancy and who were no more than 49 days pregnant were treated with one of three different dose regimens of a synthetic progesterone receptor blocker, RU 486. Serum cortisol was measured to determine the antiglucocorticoid effects of this compound. The high dose but shorter treatment regimen (400 mg/day RU 486 X 4 days or 200 mg/day X 4 days) was associated with a high (greater than 80%) rate of side effects, especially nausea, vomiting, weakness and heavy bleeding and a low rate of success (10%). A group of 50 subjects received the medium dose but longer treatment regimen (100 mg/day X 7 days). This group had less side effects (40-60%) and a 72.3% success rate of complete abortion. The AM cortisol values were significantly elevated in all treatment groups but higher in those receiving the high dose. These values returned to normal one week following cessation of treatment. Medium dose but longer duration (100 mg/day X 7 days) of RU 486 treatment is associated with a higher success rate and less side effects than higher dose therapy administered over a shorter period. There were no predictive indices to determine which subjects would respond successfully. The reason for the failure of the drug in 30% of the subjects on the medium dose is not known at this time.

Ovulation inhibition with nafarelin acetate nasal administration for six months.

A group of 24 women with normal menstrual cycles were treated with nafarelin acetate administered in doses of either 125 micrograms or 250 micrograms daily intranasally for 6 months. Each subject was studied for one ovulatory control cycle, six treatment cycles, and post-treatment until the return of ovulation was documented. Once a week progesterone, estradiol, follicle stimulating hormone, and luteinizing hormone were measured in the serum. Acute hormone responses to nafarelin acetate were determined on day 1, day 98 and day 186 of treatment. Two subjects failed to complete the treatment phase. One subject using the 250 micrograms daily dose of nafarelin acetate discontinued treatment on the sixth day because of heavy uterine bleeding. One subject using the 125 micrograms daily dose of the study drug terminated treatment on day 126 because of a 21-pound weight gain. There were significantly less presumed ovulatory cycles at the higher dose (2 out of 60 cycles) than at the lower dose (10 out of 54 cycles) (p less than 0.01). On the average menstrual cycles were reestablished 28.5 +/- 8.3 (S.D.) days after discontinuing the 125 micrograms daily dose and 33.7 +/- 17.9 (S.D.) days after terminating the 250 micrograms daily dose. With the higher dose of nafarelin acetate there were significantly fewer bleeding episodes, less number of days of bleeding, and longer cycles. During the treatment phase the area under the LH curve was significantly less and the acute response of LH in the last week of treatment was significantly less with the higher dose of drug. With both doses of nafarelin acetate the acute responses of LH, FSH and estradiol were significantly greater on day 1 than on either day 98 or day 186. Side effects observed during this study included galactorrhea (2 subjects) and vasomotor symptoms (7 subjects).

A clinical trial of the Delta-T intrauterine device: immediate postpartum insertion.

The Copper T-220C intrauterine device was modified for use in early postpartum insertions. Biodegradable extensions consisting of No. 2 chromic suture were added to the horizontal arms of the device to enhance retention. This new device, Delta-T IUD, was inserted in 100 patients within 55 hours of the delivery of the placenta. No uterine perforations or cervical lacerations occurred in this study. There was one accidental pregnancy 4 months following the IUD insertion. Seven IUDs were removed for bleeding and pain. There was one case of postpartum endometritis. Seventeen IUD expulsions occurred. Expulsions were more frequent at the beginning of the study and when the IUD was inserted more than 30 minutes after delivery of the placenta. The immediate postpartum insertion of IUDs with the event rates observed in this study is acceptable in situations where alternatives for other family planning modalities or interval insertion of intrauterine devices are not feasible.

PIP: The Copper T-220C IUD was modified for early use in postpartum insertion. Biodegradable extensions consisting of No. 2 chronic sutures were added to the horizontal arms of the device to enhance retention. This new device, Delta-T, was inserted in 100 patients within 55 hours of delivery of the placenta. No uterine perforations or cervical lacerations occurred during this study. There was 1 accidental pregnancy 4 months following IUD insertion. 7 IUDs were removed for bleeding and pain. There was 1 case of postpartum endometritis. 17 IUD expulsions occurred. Expulsions were more frequent at the beginning of the study and when the IUD was inserted more than 30 minutes after delivery of the placenta. The immediate postpartum IUD insertion with the event rates observed in this study is acceptable in situations where alternatives for other family planning modalities or interval insertion of IUDs are not feasible.

Methods to determine success of attempts to terminate early gestation pregnancies with prostaglandin vaginal suppositories.

One-hundred subjects received vaginal suppositories containing prostaglandin analogues in order to terminate their pregnancies of 49 days gestation or less. This non-surgical method was successful in 61 subjects, failed in 35 subjects and four subjects were lost to follow-up. Success of prostaglandin therapy cannot be predicted using pretreatment clinical parameters, pretreatment serum beta-hCG levels, or the passage of tissue from the vagina based upon history obtained from the subject. The passage of tissue histologically identified as of fetal origin is a definitive way to determine the success of pregnancy termination but the passage of tissue obtained by history is not. Of the 61 subjects in whom the prostaglandin suppositories were a success, 56 (92%) had a beta-hCG level day 7 +/- 2 following treatment which was 15% or less than the pretreatment value and 5 had beta-hCG levels which were more than 15% of the pretreatment value. All subjects with beta-hCG levels 5 to 9 days after the abortion that were less than 15% of the pretreatment concentrations had a successful termination. Of 35 subjects in whom the prostaglandin suppositories were unsuccessful, 26 had a beta-hCC level 7 +/- 2 days following treatment which was greater than the pretreatment level and 9 had beta-hCG levels less than the pretreatment value. The results of this study indicate that when prostaglandin vaginal suppositories are used to terminate early gestations, if there is no decline in beta-hCG levels 7 +/- 2 days following treatment, the pregnancy should be terminated by another method.

Comparison of pharmacodynamic properties of various estrogen formulations.

A group of 23 healthy postmenopausal women received one or more 2-week courses of daily administration of the following estrogen preparations: piperazine estrone sulfate (Ogen), 0.3, 0.625, 1.25, 2.5, and 5.0 mg; micronized estradiol (Estrace), 1, 2, and 10 mg; conjugated estrogens (Premarin), 0.3, 0.625, 1.25, and 2.5 mg; ethinyl estradiol (Estinyl), 10 and 20 micrograms; and diethylstilbestrol, 0.1 and 0.5 mg. Each dosage of each formulation was ingested by three women. In those women who received more than one dosage, each course was separated by a drug-free interval of at least 4 weeks. Pretreatment and posttreatment levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), corticosteroid-binding globulin-binding capacity, sex hormone-binding globulin-binding capacity, angiotensinogen, estrone, and estradiol were determined. The relative potency of these five estrogen formulations was determined by parallel line analysis for each of these responses, except LH. On a weight basis, piperazine estrone sulfate and micronized estradiol were equipotent for all responses. Conjugated estrogens suppressed FSH in a fashion equipotent to that of the other nonsynthetic estrogens; however, for all three hepatic parameters, the response was exaggerated twofold to threefold. The synthetic estrogens, diethylstilbestrol and ethinyl estradiol, were relatively more potent on a weight basis for every response and produced the most marked response (fourfold to eighteenfold in excess of their FSH suppression) for the hepatic parameters.

Termination of early gestation with 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2.

Vaginal suppositories containing 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2 were administered to 40 subjects in an attempt to induce an early abortion. All subjects were 49 days or less from their last menstrual period. Ten subjects (Group A) received the 75-mg suppository followed in 6 hours by a 30-mg suppository, ten subjects (Group B) received the 30-mg suppository followed in 2 hours by the 75-mg suppository and twenty subjects (Group C) received a 30-mg suppository followed in 3 hours by a second 30-mg suppository and in three more hours, at the discretion of the principal investigator, they could receive a third 30-mg suppository. Twenty-seven subjects (68%) had a successful termination of their pregnancy using the multiple vaginal prostaglandin suppository regimens. Seven subjects from Group A, 6 subjects from Group B, and 14 subjects from Group C successfully aborted. One subject in Group B and one subject in Group C were lost to follow-up and the remaining 11 subjects (28%) failed to abort. Twenty-six subjects reported side effects which included nausea, emesis, diarrhea, and uterine cramping requiring analgesia. Thirty-four subjects experienced hyperpyrexia of 99.6 degrees or greater and 12 subjects had their body temperature reach 101 degrees or higher. The use of vaginal suppositories containing 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2 did not significantly increase the overall abortifacient efficacy of this method from the 60% rate we previously observed with (15S)-15-methyl-prostaglandin F2 alpha methyl ester suppositories.

The menopause.

Hormone-replacement therapy for postmenopausal women has associated benefits and risks. The advantages of the administration of estrogen to postmenopausal women include preventing or reversing the atrophic changes of the genitourinary system, slowing of facial aging, relieving hot flushes and psychological symptoms, preventing atherosclerotic heart disease and retarding the development of osteoporosis. The disadvantages of the administration of estrogen to postmenopausal women include rare but serious clinical sequelae associated with the ingestion of the synthetic estrogen when it is one component of the combination oral contraceptives, increased risk of cancer developing in the estrogen-dependent organs and uterine bleeding. The benefits of long-term cyclic estrogen-gestagen therapy in preventing osteoporosis far outweigh the risks.

The effects of estrogen on adrenal androgens in oophorectomized women.

The serum levels of adrenal androgens (aa) are lower in oophorectomized (OO) than in ovulating (OV) women. This study was carried out in an effort to further investigate these findings and to study the effects of administration of estrogen on the levels of aa in OO women. Ten OO and seven OV women participated in this study in which aa were measured basally and after stimulation with adrenocorticotropic hormone (ACTH), both before and 4 weeks after conjugated estrogens (CE). Seven women received 0.625 mg of CE, and five received 2.5 mg of CE. Compared to OV women, OO women had significantly lower levels of androstenedione (Adione), dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), testosterone (T), delta 5-androstenediol (Adiol), and 17 beta-estradiol (E2) (p less than 0.01). In response to ACTH, OO women had smaller responses to Adione (p less than 0.05), DHEA (p less than 0.005), DHEA-S (p less than 0.01), 17-OH progesterone (17 Prog) (p less than 0.01), and 17-OH pregnenolone (17 Preg) (p less than 0.1). Furthermore, after ACTH, the ratio of 17 Prog/Adione was significantly higher in OO women (p less than 0.01), thus suggesting reduced 17,20-demolase (17,20D?) activity. Similarly, OO women had higher ratios of 127 Preg/17 Prog (p less than 0.1), DHEA/Adione (p less than 0.01), and Adiol/T (p less than 0.01), thereby suggesting reduced 3 beta ol dehydrogenase-isomerase (3 beta ol) activity. In response to CE, there was a dose-related increase in aa and cortisol. After 2.5 mg of CE, aa were significantly higher and similar to those levels in OV women. despite the known increases in sex hormone binding globulin-finding capacity and transcortin after estrogen, unbound T increased slightly, as did urinary free cortisol in women treated with 2.5 mg of CE. After treatment with estrogen, there was a dose-related change in the ACTH-stimulated steroid ratios that indicated and increase in 17,20D and 2 beta ol activities. In women who were gien 2.5 mg of CE, these enzyme activities were similar to those in OV women.

Termination of early gestation with (15S)-15-methyl prostaglandin F2 alpha methyl ester vaginal suppositories.

Vaginal suppositories containing (15S)-15-methyl prostaglandin F2 alpha methyl ester were administered to 40 subjects, in an attempt to induce an early abortion. All subjects were 49 days or less from their last menstrual period. Ten subjects received a 3-mg suppository followed in 3 hours by a 1 mg suppository, ten subjects received the 1-mg suppository followed in 3 hours by a 3-mg suppository, and twenty subjects received the 3-mg suppository followed in 1 hour by the 1-mg suppository. Twenty-four subjects (60%) had a successful termination of their pregnancy using the two vaginal prostaglandin suppository regimen. All subjects who aborted had 10 percent or less of their pretreatment levels of beta-hCG 7 to 22 days after therapy. Sixteen subjects (40%) did not abort. One of the subjects who failed treatment refused the second suppository due to gastrointestinal side effects and uterine cramping following the insertion of the 1-mg suppository. A second subject had an incomplete abortion and developed mild endometritis. Sixteen subjects reported side effects which included nausea, emesis, diarrhea, uterine cramping requiring analgesia, restlessness, shakiness, and dizziness. The addition of the second vaginal suppository containing this particular prostaglandin analogue did not significantly increase the overall abortifacient activity of this method.

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. I-Use effectiveness. An international comparative trial.

PIP: Contraceptive vaginal rings (CVRs), with approximate daily release rates of 250-290 mcg of levonorgestrel and 150-180 mcg of estradiol and manufactured in a shell design, were studied for effectiveness and acceptability in multicentered trials involving 1103 ring users in Brazil, Chile, Dominican Republic, Sweden, U.S., Denmark/Finland, and Nigeria. A comparison group of 533 women used the oral contraceptive Nordette. Both 1st and all segment 1 year gross pregnancy rates among CVR users were less than 3/100, rates similar to Nordette users. Continuation at 1 year was 50/100 users of the ring (all segments) and 38/100 among Nordette users, more of whom were lost to follow-up. Gross 1 year rates of termination for medical reasons ranged from 25-29/100. Ring users were more likely to terminate for vaginal problems and pill users for headache, nausea, and associated reasons. These trials indicate that CVRs of this design are as effective and have continuation rates equal to and possibly superior to Nordette under the same study conditions.^ieng

A multicenter study of levonorgestrel-estradiol contraceptive vaginal rings. II-Subjective and objective measures of effects. An international comparative trial.

Comparative clinical trials of 2 sizes of contraceptive vaginal rings and of an oral contraceptive were undertaken at 8 investigational sites (9 clinics). More than 500 women enrolled on each of the 3 study regimens. Side effects of the rings and of Nordette, the oral contraceptive, were evaluated by noting spontaneous complaints, by recording medications taken and by physical examination. Inquiries about changes in the frequency of specific conditions were made at the end of the subjects participation in the first year of the study. The incidence of spontaneous complaints was similar among users of the 2 different-sized rings and of the pill.