Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotropin-releasing hormone analogues and on subsequent implantation and pregnancy rates.

OBJECTIVE: To assess the effect of pretreatment with an oral contraceptive (OC) on ovarian cyst formation during pituitary suppression with buserelin acetate. DESIGN: Prospective randomized trial. SETTING: Academic medical center. PATIENT(S): Eighty-three patients who were undergoing IVF-ET treatment. INTERVENTION(S): Patients in the study group were pretreated with an OC for 14 days starting on the first day of menstruation. The administration of SC buserelin acetate was initiated on the last day of OC administration. Patients in the control group began to receive buserelin acetate on day 2 of menstruation. Hormonal assays and ultrasound scans were performed on the first day of menstruation, and 7, 11, and 14 days after the commencement of buserelin acetate administration. Thereafter, these tests were performed weekly until pituitary suppression was achieved. MAIN OUTCOME MEASURE(S): Incidence of cyst formation. RESULT(S): A cyst developed in 27 patients in the control group (52.9%) and no patients in the study group (odds ratio [OR]=115; 95% confidence interval [CI]=10-617). Patients in the study group achieved pituitary suppression faster (median difference [MD]=7 days; 95% CI=4-14) and required fewer ampules of gonadotropin (MD=10; 95% CI=6-14). They recruited more follicles (MD=3; 95% CI=0-5) and had higher pregnancy rates (37.2% versus 33.3%). CONCLUSION(S): Pretreatment with an OC abolishes ovarian cyst formation, shortens the time required to achieve pituitary suppression, and decreases gonadotropin requirements without having a negative effect on pregnancy rates.

PIP: Administration of a gonadotropin-releasing hormone analog (GnRH-a) before ovarian stimulation with gonadotropins in women undergoing in vitro fertilization (IVF) treatment produces higher pregnancy and live birth rates, but also results in formation of ovarian cysts that must be treated before stimulation can commence. The effect of pretreatment with an oral contraceptive (OC) on ovarian cyst formation during pituitary suppression with the GnRH-a buserelin acetate was investigated in a prospective randomized trial of women undergoing IVF at Royal Victoria Hospital (Montreal, Quebec, Canada). 51 women were pretreated with an OC for 14 days, starting on the first day of menstruation, and began buserelin acetate (500 mcg/day) on the last day of OC administration. The 51 women in the control group were treated with the standard protocol of 500 mcg/day of buserelin acetate starting on the second day of menstruation. A cyst developed in 27 controls (52.9%) but in no women pretreated with OCs (odds ratio, 115; 95% confidence interval, 10.7-617.5). 49 pretreated women (96.1%) compared with 22 controls (43.1%) achieved pituitary suppression after 7 days of GnRH-a administration. Pretreated women also required a median of 10 fewer ampules of gonadotropin than controls, recruited a median of 3 more follicles than their non-pretreated counterparts, and had higher pregnancy rates (37.2% and 33.3%, respectively). OCs are assumed to prevent the formation of ovarian cysts during GnRH-a administration through a dual effect of pituitary suppression and ovarian protection. OC pretreatment enables a significant simplification of the long standard protocol of GnRH-a administration.

[Current monophasic hormonal contraception]. / Suvremennata monofazna khormonalna kontratseptsiia.

Data are presented from an investigation of the use of monophasic contraceptive pills chosen by different age groups. Analyses are made of the data obtained from the Bulgarian Association for Family Planning (BAFP) card index for the last two years. Information is given on the number of observed cycles, type of applied contraceptive pill, aims of their application (contraception, treatment of acne, menstrual disturbances etc.), age of patients, as well as any possible adverse effects--change in blood pressure, bodyweight changes, intermenstrual bleeding, hairiness, breast problems, paraclinical changes, etc. The observed cycles show a very small percentage of adverse effects with hormonal contraception, mainly during the first 2 or 3 cycles, with predominance of intermenstrual bleeding. No bodyweight changes or increased hairiness were observed.

PIP: The data for this analysis were obtained from the records of the Bulgarian Association for Family Planning (BAFP); the data covered a period of 3 years and were for 593 women with a total menstrual cycle of 3132. The most frequently used monophasic oral contraceptives were Cilest (containing norgestimate and ethinyl estradiol), used by 233 women, Marvelon (containing desogestrel and ethinyl estradiol), used by 154 women, Microgynon FE, used by 117 women, and Nordette (containing levonorgestrel and ethinyl estradiol), used by 89 women. The preparations were used mainly for contraception, but some women used them for menstrual regulation (27 women used Nordette for this purpose and so did 25 women use Marvelon for such a purpose), and a small percentage of the women used them for used dysmenorrhea. 103 (43.2%) women who used Cilest were in the 14-19 age group, while 106 (45.4%) of them were in the 20-25 age group. In the 14-19 age group 20 (17.2%) used Microgynon, 18 (20.2%) used Nordette, and 60 (38.8%) relied on Marvelon. In the 20-25 age group the respective figures were 79 (67.2%) for Microgynon, 40 (44.9%) for Nordette, and 67 (42.5%) for Marvelon. Some of the unfavorable metabolic effects of oral contraceptives included the increase of LDL and the reduction of HDL levels and androgenic effects. The most frequent side effect was intermenstrual bleeding, of which there were 19 cases for Cilest, 7 for Microgynon, 5 for Nordette, and 11 for Marvelon. Menstruation was prolonged in 4 women using Cilest and in 5 using Marvelon. 5 women using Cilest, 2 using Microgynon, and 2 using Nordette had headache. Other adverse effects included episodes of galactorrhea, discomfort, mastopathy, and bloating in the stomach. These effects did not pose a risk to general or reproductive health and did not justify discontinuation of use for these preparations.

A pilot study of the effect of methotrexate or combined oral contraceptive on bleeding patterns after induction of abortion with mifepristone and a prostaglandin pessary.

Although a combination of mifepristone and a prostaglandin is a safe, acceptable alternative to vacuum aspiration for inducing abortion in early pregnancy, the longer period of vaginal bleeding after medical abortion is a disadvantage. The present study investigated whether administration of the combined oral contraceptive pill (COC) or the injection of methotrexate at the time of abortion would shorten the period of vaginal bleeding after medical abortion. After having a medical abortion induced with mifepristone (200 mg) and 0.5 mg gemeprost pessary, 80 women were randomized to four groups of 20 women each; Group A, COC; Group B, control; Group C, 50 mg/m2 methotrexate; and Group D, placebo injection. There was no significant difference in the duration of bleeding between Groups A and B (median 14 and 17 days) or between Groups C and D (18 and 15 days), or in the amount of bleeding (4 days of heavy bleeding in each group). The first period occurred sooner in Group A who took the COC (median/range: 25/15-54 control group versus 32/16-46 days, p < 0.04). The administration of methotrexate was associated with a temporary elevation in liver enzyme concentration in one woman. It is concluded that women who wish to use COC can start immediately after medical abortion. Addition of methotrexate after abortion has no significant beneficial effect on patterns of bleeding and cannot be recommended.

PIP: The capability of administration of a combined oral contraceptive (OC) or injection of methotrexate at the time of medical abortion to shorten the duration of vaginal bleeding was assessed in a randomized trial conducted in Edinburgh, Scotland, in 1996-97. 80 women seeking pregnancy termination at less than 63 days' gestation were given 200 mg oral mifepristone, followed 48 hours later by 0.5 mg cervagem by vaginal pessary. After the products of conception had passed, women received one of the following four regimens: Group A--an OC (30 mcg ethinyl estradiol and 150 mcg levonorgestrel) to be started immediately after termination; Group B--the same OC, to be started on the first day of the next menstrual period; Group C--50 mg/sq. mm of methotrexate; or Group D--placebo (saline) injection. There was no significant difference between Groups A and B in the median duration of bleeding (14 and 17 days, respectively) or between Groups C and D (18 and 15 days, respectively). Women in all four groups experienced 4 days of heavy bleeding. The first menstrual period occurred after a median of 25 days in Group A compared with 32 days in the other groups. These results indicate that methotrexate administration after medical abortion has no significant beneficial effect on bleeding patterns. Although OCs also failed to control bleeding, their initiation immediately after medical abortion can be considered to ensure rapid restoration of menstruation and provide women with reassurance that they are not pregnant again.

The use of two estrogen preparations (a combined contraceptive pill versus conjugated estrogen cream) intravaginally to treat urogenital symptoms in postmenopausal Thai women: a comparative study.

OBJECTIVE: To determine whether the combined contraceptive pill used intravaginally was as effective as the standard conjugated estrogen cream for the treatment of urogenital symptoms in postmenopausal Thai women. SUBJECTS AND METHODS: In a randomized clinical trial, 40 postmenopausal women with urogenital symptoms were randomly allocated to two treatment groups for 8 weeks. The first group (n = 20) received a combined contraceptive pill by the vaginal route, one tablet per week at bedtime for 8 weeks. Each tablet contained 250 microg levonorgestrel plus 30 microg ethinyl estradiol. The second group (n = 20) was given 1 gm of an intravaginal conjugated estrogen cream at bedtime, three times in the first week, twice in the second week, and then once a week for the next 6 weeks (1 gram of conjugated estrogen cream contained 0.625 mg conjugated equine estrogens). Subjects were questioned about their urogenital symptoms, and vaginal cytologic smears, vaginal bacterial cultures, and urine cultures were performed before treatment and after 2, 4, and 8 weeks of therapy. RESULTS: The vaginal pH and the proportion of the fecal type bacteria decreased in both groups, with no statistically significant difference between the groups. The karyopyknotic index and the maturation index were improved during treatment in both groups. An increase in the proportion of lactobacilli were recorded in both groups after therapy, with no significant difference between the two groups. No significant changes were observed in urinary bacteria. The therapy (combined contraceptive pill and estrogen cream) had a marked effect on urogenital symptoms (vaginal dryness, dyspareunia, urinary frequency, and urinary urgency), with impressive improvement comparably in both groups. CONCLUSIONS: A combined contraceptive tablet administered vaginally once a week can alleviate urogenital symptoms in Thai postmenopausal women as effectively as the vaginal estrogen cream. However, the pills are much less expensive and are easily obtained in developing countries.

PIP: A randomized clinical trial conducted in Bangkok, Thailand, investigated whether intravaginal use of a combined oral contraceptive (OC) is as effective for the treatment of urogenital symptoms in postmenopausal women as the standard regimen of conjugated estrogen cream. 40 postmenopausal women (mean age, 54 years) with urogenital symptoms related to estrogen deficiency were allocated to one of two treatment groups for 8 weeks. The first 20 women received one OC (250 mcg of levonorgestrel and 30 mcg of ethinyl estradiol) per week; the remaining 20 women were given estrogen cream (0.625 mg conjugated equine estrogens) at bedtime 3 times in the 1st week, twice in the 2nd week, and weekly for the last 6 weeks. Vaginal pH and the proportion of fecal-type bacteria decreased, the karyopyknotic and maturation indices improved, and the proportion of vaginal colonization with lactobacilli increased in both groups, with no significant differences between treatments. Also recorded in both groups were impressive improvements in vaginal dryness, dyspareunia, urinary frequency, and urinary urgency. No significant changes were observed in urinary bacteria. Combined OCs are less expensive than vaginal estrogen cream and more readily available in developing countries. Since they are as effective as the cream at alleviating urogenital symptoms in postmenopausal women, their use for this purpose merits consideration.

The condom: an effective penile dressing.

PIP: An effective penile dressing should support the wound, prevent contamination, and minimize edema and hematoma formation. Traditional penile dressings are cumbersome to apply and hard to secure. This report describes use of a condom to provide support after operations on the adult penis. After surgery, the penis is loosely wrapped with sterile gauze and a condom is rolled down over the dressing to the base of the penis. The tip of the condom is cut off and the ring of latex at its base is divided to prevent constriction. Patients can urinate through the excised tip. In 12 patients who received this regimen, the dressing remained in place for the desired duration and condom removal was painless. The most common indication for use of this dressing has been Nesbit's procedure.^ieng

Randomised comparative trial of the levonorgestrel intrauterine system and norethisterone for treatment of idiopathic menorrhagia.

OBJECTIVE: To compare the efficacy and acceptability of the levonorgestrel intrauterine system and norethisterone for the treatment of idiopathic menorrhagia. DESIGN: A randomised comparative parallel group study. SETTING: Gynaecology outpatient clinic in a teaching hospital. PARTICIPANTS: Forty-four women with heavy regular periods and a measured menstrual blood loss exceeding 80 ml. METHODS: Twenty-two women had a levonorgestrel intrauterine system inserted within the first seven days of menses, and 22 women received norethisterone (5 mg three times daily) from day 5 to day 26 of the cycle for three cycles. MAIN OUTCOME MEASURES: The main outcome measure was the change in objectively assessed menstrual blood loss after three months of treatment. RESULTS: When menstrual blood loss at three months was expressed as a percentage of the control, the levonorgestrel intrauterine system reduced menstrual blood loss by 94% (median reduction 103 ml; range 70 to 733 ml), and oral norethisterone by 87% (median reduction 95 ml; range 56 to 212 ml). After three cycles of treatment 76% of the women in the levonorgestrel intrauterine system group wished to continue with the treatment, compared with only 22% of the norethisterone group. CONCLUSIONS: Both the levonorgestrel intrauterine system and oral norethisterone in this regimen provided an effective treatment for menorrhagia in terms of reducing menstrual blood loss to within normal limits. The levonorgestrel intrauterine system was associated with higher rates of satisfaction and continuation with treatment, and thus offers an effective alternative to currently available medical and surgical treatments for menorrhagia.

PIP: The efficacy and acceptability of two new approaches to the treatment of idiopathic menorrhagia--the levonorgestrel intrauterine system and norethisterone--were compared in 45 women recruited from a gynecology outpatient clinic at a UK teaching hospital. All study participants had heavy regular periods and a measured menstrual blood loss exceeding 80 ml. 22 women were randomly assigned to have a levonorgestrel intrauterine system inserted within the first 7 days of menses and 22 women received 5 mg of norethisterone 3 times daily from day 5 to day 26 of their cycle for 3 cycles. Compared to baseline, the levonorgestrel intrauterine system reduced menstrual blood loss by 94% (median reduction, 103 ml) and oral norethisterone reduced it by 87% (median reduction, 95 ml). Recorded in both treatment groups were significant decreases in breast tenderness, mood swings, intermenstrual bleeding, and interferences in daily life caused by menstruation. After 3 treatment cycles, 64% of women in the levonorgestrel group indicated they liked the treatment "well" or "very well" and 77% elected to continue the regimen. In the norethisterone group, these rates were only 44% and 22%, respectively. Although both regimens reduced menstrual blood loss to within normal limits, the levonorgestrel intrauterine system was associated with higher satisfaction and thus offers an effective alternative to currently available medical and surgical treatments for menorrhagia.

Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris.

BACKGROUND: An excess of androgen is believed to contribute to development of acne in some patients. Because oral contraceptives (OCs) may reduce the active androgen level, hormonal therapy with OCs has been used successfully to treat patients with acne, although this treatment has previously not been studied in placebo-controlled trials. OBJECTIVE: Our purpose was to evaluate the efficacy of a triphasic, combination OC (ORTHO TRI-CYCLEN [Ortho-McNeil Pharmaceutical, Raritan, N.J.], norgestimate/ethinyl estradiol) compared with placebo in the treatment of moderate acne vulgaris. METHODS: Two hundred fifty-seven healthy female subjects, 15 to 49 years of age with moderate acne vulgaris, were enrolled in a multicenter, randomized, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects received either 3 consecutive weeks of the OC (i.e., tablets containing a fixed dose of ethinyl estradiol [0.035 mg] and increasing doses of norgestimate [0.180 mg, 0.215 mg, 0.250 mg]) followed by 7 days of inactive drug or placebo (color-matched tablets). Efficacy was assessed by facial acne lesion counts, an investigator's global assessment, a subject's self-assessment, and an analysis of within-cycle variation (cycle 6) in lesion counts. RESULTS: Of the 160 subjects in whom efficacy could be evaluated, the OC group showed a statistically significantly greater improvement than the placebo group for all primary efficacy measures. The mean decrease in inflammatory lesion count from baseline to cycle 6 was 11.8 (62.0%) versus 7.6 (38.6%) (p = 0.0001), and the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) (p = 0.0001) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of the active treatment group versus 65.4% of the placebo group were rated as improved at the end of the study (p < 0.001). Six of the seven secondary efficacy measures (total comedones, open comedones, closed comedones, papules, pustules, and the subject's self-assessment of study treatment) were also significantly more favorable in the OC group compared with the placebo group. CONCLUSION: An OC containing 0.035 mg of ethinyl estradiol combined with the triphasic regimen of norgestimate is a safe and effective treatment of moderate acne vulgaris in women with no known contraindication to OC therapy.

PIP: To evaluate the efficacy of a triphasic combined oral contraceptive (OC) in the treatment of moderate acne vulgaris, 231 healthy US volunteers 15-49 years of age with this dermatologic condition were enrolled in a phase III, multicenter, double-blind, placebo-controlled clinical trial. Each month for 6 months, subjects (n = 110) received either 3 consecutive weeks of Ortho Tri-Cyclen (containing a fixed dose of 0.035 mg of ethinyl estradiol and 0.180, 0.215, and 0.250 mg of norgestimate) followed by 7 days of inactive drug or placebo. The OC group showed significantly greater improvement than controls on all efficacy measures. The mean decrease in inflammatory lesion count from baseline to the sixth cycle was 11.8 (62.0%) among cases and 7.6 (38.6%) in controls, while the mean decrease in total lesion count was 29.1 (53.1%) versus 14.1 (26.8%) in the OC and placebo groups, respectively. In the investigator's global assessment, 93.7% of women in the treatment group and 65.4% of controls were rated as improved at the end of the study. Similarly, more cases than controls considered their acne "improved" at the study's end and expressed a preference for this therapy over other forms of acne treatment. These findings indicate that treatment of moderate acne vulgaris with a low-dose triphasic OC is safe and effective in women with no contraindications to OC use.

Treatment of adenomyosis-associated menorrhagia with a levonorgestrel-releasing intrauterine device.

OBJECTIVE: To evaluate the efficacy and tolerability of treatment with a levonorgestrel-releasing intrauterine device (IUD) in women affected by adenomyosis-associated menorrhagia. SETTING: Tertiary care center. DESIGN: Prospective, open, noncomparative study. PATIENT(S): Twenty-five women aged 38 to 45 years with recurrent menorrhagia associated with adenomyosis diagnosed at transvaginal ultrasonography participated in this study. INTERVENTION(S): An IUD releasing levonorgestel 20 mcg/day was inserted in each patient within 7 days of the start of menstrual flow. All of the patients were requested to compile a pictorial blood loss assessment chart each month. They underwent clinical and transvaginal ultrasound examinations 3, 6, and 12 months after IUD insertion. MAIN OUTCOME MEASURE(S): Menstrual pattern; serum hemoglobin, ferritin, and iron level changes. RESULT(S): One patient experienced IUD expulsion 2 months after device insertion and another requested removal of the IUD 4 months after insertion because of persistent irregular blood loss. Six months after IUD insertion, amenorrhea was observed in 2 patients and oligomenorrhea in another, spotting occurred occasionally in 7, and 13 had scanty but regular flow. One year of follow-up has been completed by the remaining 23 women: 2 with amenorrhea, 3 with oligomenorrhea, 2 with spotting, and 16 with regular flows. Significant increases in hemoglobin, hematocrit, and serum ferritin have been observed, but the lipid metabolism and clotting variables have remained unchanged. CONCLUSION(S): Our findings indicate that marked and safe relief from adenomyosis-associated menorrhagia can be obtained with the use of a levonorgestrel-releasing IUD.

PIP: The efficacy and tolerability of treatment of adenomyosis-related menorrhagia with a levonorgestrel-releasing IUD were investigated in a prospective study of 25 women recruited from a tertiary care center in Italy. All women reported recurrent menorrhagia of at least 6 months' duration and underwent abdominal and transvaginal ultrasonography, hysteroscopy, and endometrial biopsy before study entry. An IUD releasing 20 mcg/day of levonorgestrel was inserted within 7 days of the onset of menses and follow-up examinations were conducted 3, 6, and 12 months after insertion. 1 woman experienced IUD expulsion 2 months after insertion and another requested removal at 4 months because of persistent irregular blood loss. 6 months after IUD insertion, amenorrhea was observed in 2 women, oligomenorrhea in 1 woman, and occasional spotting in 7 women; the remaining 13 women had scanty but regular periods. At 12 months, 2 women reported amenorrhea, 3 had oligomenorrhea, 2 had spotting, and 16 had regular periods. All menstrual anomalies were well tolerated. IUD-related side effects included headache (24%), breast tenderness (16%), seborrhea or acne (24%), and weight gain (28%). Significant increases in hemoglobin, hematocrit, and serum ferritin were recorded; there were no changes in lipid metabolism or clotting variables. These findings suggest that insertion of a levonorgestrel-releasing IUD represents a viable alternative to hysterectomy in the treatment of adenomyosis. It is speculated that the IUD produces deciduation and subsequent marked hypotrophy of eutopic endometrium.

The levonorgestrel-releasing intrauterine device: a wider role than contraception.

The Levonorgestrel-releasing intrauterine device (LNG IUD) provides excellent contraception; it may reduce the rate of pelvic inflammatory disease (PID) and ectopic pregnancy compared to other 'modern' copper releasing IUDs; it can safely be used in the puerperium for breast-feeding mothers, and it significantly reduces menstrual blood loss and pain. While it was developed primarily as a contraceptive, its potential role in managing heavy and painful menstruation and the symptoms of the climacteric may eventually be just as important. Amongst developed countries New Zealand and Australia have some of the highest hysterectomy rates. By the age of 50 years 1 in 4 women in New Zealand and 1 in 5 women in Australia will have had a hysterectomy (A,B). In New Zealand 90% of these are performed for heavy menstrual bleeding and fibroids (A). The LNG IUD has been shown to be effective treatment for both these conditions and its introduction to New Zealand and Australia would offer women an additional choice beyond surgery.

Bone mineral changes in young women with hypothalamic amenorrhea treated with oral contraceptives, medroxyprogesterone, or placebo over 12 months.

OBJECTIVES: The objectives of this study were to assess (1) whether treatment with oral contraceptives, in comparison with medroxyprogesterone and placebo, improved bone mineral in women with hypothalamic amenorrhea and (2) whether treatment with medroxyprogesterone, in comparison with placebo, improved bone mineral in women with hypothalamic oligomenorrhea. STUDY DESIGN: The study was a randomized, controlled clinical trial. Twenty-four white women, aged 14 to 28 years, with hypothalamic amenorrhea or oligomenorrhea were prospectively enrolled for a 12-month intervention period. Amenorrheic subjects were randomized to receive oral contraceptives, medroxyprogesterone, or placebo. Oligomenorrheic subjects were randomized to receive medroxyprogesterone or placebo. Bone mineral was measured by dual-energy x-ray absorptiometry at baseline and at 6 and 12 months. RESULTS: In amenorrheic subjects spine and total body bone mineral measurements at 12 months were greater in the oral contraceptive group than in the medroxyprogesterone and placebo groups when baseline bone mineral measurements, body weight, and age were controlled for (p < or = 0.05). There were no differences in hip bone mineral calcium and bone mineral density measurements at 12 months among the three groups. In oligomenorrheic subjects there was no detectable improvement in bone mineral associated with medroxyprogesterone use. CONCLUSIONS: This study supports the hypothesis that oral contraceptive use in women with hypothalamic amenorrhea will improve lumbar spine and total body bone mineral.

PIP: The objectives of this study were to assess 1) whether treatment with oral contraceptives (OCs), in comparison with medroxyprogesterone and placebo, improved bone mineral content and density in women with hypothalamic amenorrhea and 2) whether treatment with medroxyprogesterone, in comparison with placebo, improved bone mineral content and density in women with hypothalamic oligomenorrhea. The study was a randomized, controlled clinical trial. 24 White women, aged 14-28 years, with hypothalamic amenorrhea or oligomenorrhea were prospectively enrolled for a 12-month intervention period. Amenorrheic subjects were randomized to receive OCs, medroxyprogesterone, or placebo. Oligomenorrheic subjects were randomized to receive medroxyprogesterone or placebo. Bone mineral content and density were measured by dual-energy x-ray absorptiometry at baseline and at 6 and 12 months. In amenorrheic subjects spine and total body bone mineral measurements at 12 months were greater in the OC group than in the medroxyprogesterone and placebo groups when baseline bone mineral measurements, body weight, and age were controlled for (p or= 0.05). There were no differences in hip bone mineral calcium and bone mineral density measurements at 12 months among the three groups. In oligomenorrheic subjects there was no detectable improvement in bone mineral content and density associated with medroxyprogesterone use. This study supports the hypothesis that OC use in women with hypothalamic amenorrhea will improve lumbar spine and total body bone mineral content and density.

The levonorgestrel intrauterine system in the management of menorrhagia.

OBJECTIVE: To assess the effect of a levonorgestrel releasing intrauterine system in the management of menorrhagia. DESIGN: A prospective study. SETTING: A district general hospital in South Wales. METHODS: Fifty women with a failed trial of medical therapy and awaiting hysterectomy or transcervical resection of the endometrium (TCRE) were treated with a levonorgestrel intrauterine system. The menstrual loss was estimated using a modified pictorial chart together with a full blood count and ferritin measurement preinsertion and at three and six to nine months postinsertion. RESULTS: The menstrual loss was reduced to acceptable levels in 37 women at three months and a further four by six to nine months. In all, 41 patients were taken off the waiting list for surgery, four of whom became amenorrhoeic. There was no significant change in full blood count nor ferritin measurement despite unscheduled bleeding for six to eight weeks postinsertion. Fifty-six percent of patients noticed considerable improvement or cure of their premenstrual syndrome symptoms; 80% noted a reduction in dysmenorrhoea. CONCLUSION: The levonorgestrel releasing intrauterine system is an effective nonsurgical treatment for the management of menorrhagia and dysmenorrhoea that has additional benefit as a contraceptive and in relieving premenstrual syndrome.

PIP: A prospective study involving 50 women recruited from a district general hospital in South Wales indicated that the levonorgestrel-releasing intrauterine system (LNG-IUS) represents an effective nonsurgical treatment for menorrhagia and dysmenorrhea. Treatment for menorrhagia with a combination of prostaglandin synthetase inhibitors and antifibrinolytic drugs had failed in these women, and they were on a waiting list for hysterectomy or transcervical resection of the endometrium. Menstrual loss was estimated using a modified pictorial chart and the full blood count and ferritin were measured preinsertion and at 3 and 6-9 months postinsertion. The device was spontaneously expelled in 6 women and almost all subjects experienced some unscheduled bleeding during the first 6-8 weeks postinsertion. Of the 42 women who attended the 3-month visit, 37 were satisfied with the results of the LNG-IUS device and wished to continue; only 5 had no significant reduction in their menstrual scores. Also observed was a reduction in clots and "flooding" and marked improvements in associated dysmenorrhea. 4 women became amenorrheic and 28 were cured of their premenstrual syndrome symptoms. There was no significant change in the full blood count or ferritin. At the 6-9 month visit, 4 of the 5 women who previously reported no change in menstrual scores now reported their menstrual loss was acceptable.

Gonadotropin-releasing hormone analog plus an oral contraceptive containing desogestrel in women with severe hirsutism: effects on hair, bone, and hormone profile after 1-year use.

To evaluate the usefulness of D-Trp-6-luteinizing hormone-releasing hormone (LHRH) (triptorelin), a gonadotropin-releasing hormone (GnRH) analog (GnRHa), plus an oral contraceptive (OC) in the treatment of severe hirsutism, a total of 48 women between 19 and 35 years of age suffering from polycystic ovary syndrome (PCOS) with severe hirsutism were studied. Hyperandrogenism of adrenal origin was excluded in all subjects. Twenty-three patients received 3.75 mg D-Trp-6-LHRH intramuscularly monthly for 1 year plus an OC containing 30 micrograms ethinyl-estradiol and 150 micrograms desogestrel. A second group of 25 subjects received an OC containing 35 micrograms ethinyl-estradiol and 2 mg cyproterone acetate (CPA). Immediately before and after months 6 and 12 of therapy, bone mineral density (BMD) and Ferriman-Gallwey scores were evaluated and follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHEAS), 17-OH-progesterone (17-OHP), and sex hormone-binding globulin (SHBG) were determined. After 1 year of follow-up study, the combination of a GnRHa plus OC resulted in a decrease of hirsutism similar to that observed in the CPA group (41.9% v 40.5%) and in a suppression of gonadotropins and ovarian steroids in all treated women, without significant changes in bone density. The GnRHa-OC combination can potentially be used in the treatment of hirsutism and hyperandrogenism.

Combination oral contraceptives.

PIP: Although an individual assessment of the risks and benefits is always essential, combined, low-dose oral contraceptives (OCs) are an effective method of fertility control, even for women with chronic medical problems. In addition to contraception, therapeutic uses of combined OCs include acne, anovulatory uterine bleeding, control of bleeding with blood dyscrasias, dysmenorrhea, endometriosis, hirsutism, hypothalamic amenorrhea, ovarian hormone replacement, polycystic ovarian syndrome, premenstrual syndrome, and recurrent functional ovarian cysts. This article presents guidelines for clinicians on the selection of combined OC users, counseling, contraindications, and management of adverse effects. It further outlines general considerations for the prescription of combined OCs to women with hypertension, diabetes mellitus, migraine headaches, and epilepsy.^ieng

Dual suppression with oral contraceptives and gonadotrophin releasing-hormone agonists improves in-vitro fertilization outcome in high responder patients.

Certain patients have a tendency for high response to gonadotrophin therapy which is often not ameliorated with prior gonadotrophin-releasing hormone agonist (GnRHa) suppression. As a result, these patients are frequently cancelled and often experience ovarian hyperstimulation syndrome (OHSS) episodes during in-vitro fertilization (IVF)-embryo transfer cycles. Patients with polycystic ovarian syndrome (PCOS) have been noted to be particularly sensitive to exogenous gonadotrophin therapy. We have developed a protocol which is effective in improving IVF outcome in high responder patients, including those with PCOS. Oral contraceptive pills (OCP) are taken for 25 days followed by s.c. leuprolide acetate, 1 mg/day, which is overlapped with the final 5 days of oral contraceptive administration. Low-dose gonadotrophin stimulation is then initiated on the third day of withdrawal bleeding in the form of either human menopausal gonadotrophins or purified urinary follicle-stimulating hormone at a dosage of 150 IU/day. Over a 5 year period, we reviewed our experience utilizing this dual method of suppression in 99 cycles obtained in 73 high responder patients. There were only 13 cancellations prior to embryo transfer (13.1%). The clinical and ongoing pregnancy rates per initiated cycle were 46.5 and 40.4% respectively. Only eight patients experienced mild-moderate OHSS following treatment. For those patients who had undergone previous IVF-embryo transfer cycles at our centre, significant improvements were noted in oocyte fertilization rates, embryo implantation rates and clinical/ongoing pregnancy rates with this protocol. Hormonal analyses revealed that the chief mechanism may be through an improved luteinizing hormone/follicle-stimulating hormone ratio following dual suppression. An additional feature of this dual method of suppression is significantly lower serum androgen concentrations, particularly dehydroepiandrosterone sulphate.

PIP: Presented is a protocol that is effective in improving in vitro fertilization (IVF) outcome in women with a tendency for a high response to gonadotrophin therapy. High responders to exogenous gonadotrophin therapy show recruitment of large numbers of follicles, rapid estradiol responses, and a significant cycle cancellation rate due to the potential risk of hyperstimulation during IVF-embryo transfer attempts. Women with polycystic ovarian syndrome are especially sensitive to exogenous gonadotrophin therapy. The protocol entails 25 days of oral contraceptive (OC) use, followed by 1 mg/day of subcutaneous leuprolide acetate overlapped with the final 5 days of OC therapy. On the third day of withdrawal bleeding, gonadotrophin stimulation is initiated through either human menopausal gonadotrophins or purified urinary follicle-stimulating hormone (150 IU/day). This approach permits normalization of the luteinizing hormone/follicle-stimulating hormone ratio and reduces ovarian androgen concentrations, while circumventing the initial gonadotrophin flare response. This protocol was tested in a retrospective review (1990-94) of 99 cycles from 73 high-responder women treated at a US infertility center. There were only 13 cancellations (13.1%) prior to embryo transfer. The clinical and ongoing pregnancy rates per initiated cycle were 46.5% and 40.4%, respectively. Only 8 women experienced ovarian hyperstimulation syndrome after treatment. Among women who had undergone previous IVF embryo transfer cycles at the center, the present regimen was associated with significant improvements in oocyte fertilization rates, embryo implantation rates, and pregnancy rates.

Effect of Depo-Provera or Microgynon on the painful crises of sickle cell anemia patients.

Forty-three homozygous (SS) female sickle cell anemic patients with a history of at least one painful crisis per month and desiring a reversible contraceptive were administered DMPA/3 months or Microgynon monthly. A third group of 16 surgically sterilized patients served as control. Patients were followed for 1 year to assess possible effects of the contraceptives on the patients' painful crises. No changes were observed in any of the groups in the hematological parameters. At the end of the study, 70% of the patients receiving DMPA were pain-free and only 16% of those still reporting painful crises rated them as intense. Patients receiving Microgynon also had an amelioration of the painful crises, although at a lower rate; after 12 months, 45.5% still experienced some crises. Although less marked than in the other groups, 50.5% of the control patients also reported an improvement of their painful crisis, which may be a result of closer medical care.

PIP: The effects of a combined oral contraceptive (Microgynon 30, containing ethinyl estradiol and levonorgestrel) and a progestogen-only injectable contraceptive (Depo-Provera) on the intensity and frequency of painful crises were investigated in 43 homozygous sickle cell anemia patients at the World Health Organization Collaborative Center for Research in Human Reproduction in Panama. Only women with a history of at least one painful crisis per month were enrolled. The patients were randomly assigned to receive Depo-Provera (n = 13) or Microgynon (n = 14) for 12 months; the remaining 16 patients--surgically sterilized controls-- received no treatment. No changes were recorded throughout the study period in any of the three groups in hematological parameters. In addition, there were no pregnancies or treatment-related side effects. In the Depo-Provera group, the percentage of patients with painful crises diminished steadily from 50% at 3 months to 30% at 12 months. Moreover, 84% of painful episodes experienced by Depo-Provera acceptors were characterized as moderate or mild. Among women in the Microgynon group, the rate of painful crises dropped from 72.7% at 3 months to 45.5% at 12 months. Controls also reported a 50.5% decline in painful crises, presumably as a result of increased individual attention from medical staff. These findings suggest that Depo-Provera can be safely and effectively used for contraceptive purposes in sickle cell anemic patients, with a concomitant beneficial effect on painful crises.

Short-term gonadotropin suppression with oral contraceptives benefits poor responders prior to controlled ovarian hyperstimulation.

PIP: A comparative study of four treatment regimens for women with a history of poor response to controlled ovarian hyperstimulation (COH) during attempts at in vitro fertilization (IVF) and embryo transfer suggested the feasibility of pretreatment with oral contraceptives (OCs). The 60 women enrolled in the study exhibited one or more of the following in an initial stimulated IVF cycle: three or fewer dominant follicles recruited, serum estradiol levels of 300 pg/ml or below, and/or a spontaneous luteinizing hormone (LH) surge prior to oocyte retrieval. Study subjects were assigned to one of four protocols: Group I--OCs for 3 weeks followed by COH; Group II--luteal phase leuprolide acetate with subsequent COH; Group III--short-flare Lupron with subsequent COH; and Group IV--COH alone. COH consisted of 150 IU/day of pure follicle-stimulating hormone (pFSH) and 150 IU/day of human menopausal gonadotropin (hMG). The mean age of women in each group ranged from 36.0 to 38.8 years. There were no significant differences among groups in terms of number of days of stimulation, total ampoules of hMG and pFSH required, peak serum estradiol and progesterone, number of oocytes retrieved and fertilized, and embryos transferred. However, the pregnancy rate was significantly higher (p 0.05) in Group I (9/30, 30%) than in Group II (2/32, 6%), Group III (0/11, 0%), and Group IV (0/10, 0%). The good outcome associated with OC pretreatment may reflect production or alterations of local ovarian growth factors and/or changes in endometrial expression. Administration of exogenous estrogen may be particularly beneficial for perimenopausal women in their forties with ovarian follicular depletion.^ieng

Oral contraceptive therapy for polycystic ovary disease after chronic gonadotropin-releasing agonist administration. Predictors of continued ovarian suppression.

OBJECTIVE: To study the beneficial effects of oral contraceptive (OC) therapy following gonadotropin-releasing hormone agonist (GnRH-a) administration in women with polycystic ovary disease (PCOD). STUDY DESIGN: Twenty-three hyperandrogenic women (aged 15-39) were randomized into two groups; GnRH-a (depot every 28 days) for six months or combination therapy (GnRH-a plus OC "addback") for six months. Following six months of treatment with either therapy, all patients received OC therapy for at least six months. The hormonal state was evaluated at three-month intervals. RESULTS: Hormone levels of luteinizing hormone (LH), testosterone (T) and free T remained suppressed within the normal range in 11 of 17 patients (65%) during the six months of OC only therapy, while the other six patients showed "escape" from suppression, with the LH, T and free T concentrations rising to pre-GnRH-a treatment levels. Use of OC addback therapy did not potentiate the long-acting therapeutic effect of GnRH-a pretreatment; three of six patients in the escape group were pretreated with combination therapy and three with GnRH-a only. CONCLUSION: In the majority of women with PCOD, OC therapy following GnRH-a administration was effective in maintaining ovarian androgen suppression. Failure to maintain ovarian suppression in this patient population was associated with higher elevations of baseline free T concentrations.

PIP: Clinical investigators randomly allocated 24 hirsute women aged 15-39 years with polycystic ovary disease (PCOD) to either the treatment program offering an injection of leuprolide acetate (a highly potent gonadotropin-releasing hormone agonist [GnRH-a]) for depot suspension (3.75 mg) at 28-day intervals for six months or the treatment program offering both the same injection and a combined oral contraceptive (OC) as add-back for six months. At three months, one woman moved out of state and withdrew from the study. After six months of either GnRH-a treatment regimen, all remaining 23 women received only OCs for six more months. Six women did not successfully complete the OC therapy and were excluded from the statistical analyses. The investigators aimed to examine the benefits of OC use in the management of women with PCOD after six months of pretreatment with the GnRH-a. During the OC-only treatment period, 11 (65%) of 17 patients still had suppressed levels of luteinizing hormone (LH), testosterone (T), and free T within the normal range. These levels increased to pre-GnRH-a treatment levels in the remaining six women, indicating escape from ovarian suppression. Three of six women in the escape group received combination therapy for pretreatment, while the other three received only GnRH-a. The women in the escape group had a higher baseline free T concentration than the suppressed group (5.1 vs. 3.3 ng/dl; p = 0.02). The findings revealed that OC therapy following GnRH-a administration effectively maintained ovarian androgen suppression in most women with PCOD. They also indicated that failure to maintain this suppression had a significant association with higher baseline free T concentrations.

Depot medroxyprogesterone acetate versus an oral contraceptive combined with very-low-dose danazol for long-term treatment of pelvic pain associated with endometriosis.

OBJECTIVE: Our purpose was to evaluate the efficacy and safety of depot medroxyprogesterone acetate versus an oral contraceptive combined with very-low-dose danazol in the long-term treatment of pelvic pain in women with endometriosis. STUDY DESIGN: Eighty patients with endometriosis and moderate or severe pelvic pain were randomized to treatment for 1 year with intramuscular depot medroxyprogesterone acetate 150 mg every 3 months or a cyclic monophasic oral contraceptive (ethinyl estradiol 0.02 mg, desogestrel 0.15 mg) combined with oral danazol 50 mg a day for 21 days of each 28-day cycle. The women were asked to grade the degree of their satisfaction at the end of therapy. Variations in severity of symptoms during treatment were determined by a 10 cm visual analog and a 0- to 3-point verbal rating scale. RESULTS: Twenty nine of 40 subjects (72.5%) in the depot medroxyprogesterone acetate group were satisfied after 1 year of therapy compared with 23 of 40 (57.5%) in the oral contraceptive plus danazol group (chi 2(1) = 1.37, p = 0.24, odds ratio 1.95, 95% confidence interval 0.76 to 4.97). A significant decrease was observed in all symptom scores in both study groups. At 1-year assessment dysmenorrhea was significantly greater in women allocated to oral contraceptive plus danazol. CONCLUSION: Depot medroxyprogesterone acetate seems to be an effective, safe, and convenient low-cost treatment for pelvic pain associated with endometriosis. However, women should be carefully counseled regarding menstrual changes and the potential prolonged delay in the return of ovulation.

PIP: The tolerability and effectiveness of depot medroxyprogesterone acetate (DMPA), compared with an oral contraceptive (OC) combined with low-dose danazol, in the long-term treatment of pelvic pain in women with endometriosis were evaluated in a randomized clinical trial. 40 women were allocated to each treatment regimen. At the 1-year assessment, a significant decrease was observed in all symptom scores of the visual analog and the verbal rating scale in both study groups. Only pain at menstruation was significantly greater in women in the OC group (because of the absence of regular flow in subjects in the DMPA group). In the DMPA group, 1 woman (2.5%) was very satisfied with her treatment, 28 (70%) were satisfied, 2 (5%) were uncertain, and 1 (2.5%) was very dissatisfied. Corresponding figures for the OC-danazol group were 6 (15%), 17 (42.5%), 4 (10%), 12 (30%), and 1 (2.5%). Overall, 72.5% of women in the DMPA group compared with 57.5% of those in the OC group were pleased after 1 year of treatment. It was concluded that, in selected women with highly symptomatic endometriosis, DMPA offers good analgesic results with tolerable side effects.

Effects on acne of two oral contraceptives containing desogestrel and cyproterone acetate.

OBJECTIVE: To compare the effects of a low-dose oral contraceptive containing desogestrel (Marvelon) and an anti-androgenic preparation containing cyproterone acetate (Diane) in Oriental women suffering from acne. METHODS: In an open-label, bi-center, randomized study, 32 women using Marvelon and 34 using Diane were followed for 6 treatment cycles. The measured variables were objective and subjective severity of acne, and related biochemical variables such as sex hormone-binding globulin and free and total testosterone. RESULTS: In Center A, with both preparations a decrease in mean objective acne score was observed, reaching statistical significance with Diane (P < .05). In addition, there was a significant between group difference at cycle 6 (P < .05). In Center B, a consistent and significant decrease in mean acne score was observed with Marvelon after three and six treatment cycles (P < .05 and P < .01) and with Diane after six treatment cycles (P < .001). There were no significant between-group differences. The decrease in percentage of severe/moderate acne was statistically significant with Marvelon in Center B (P = 0.002) and with Diane in Centers A (P = 0.014) and B (P = 0.004). Both preparations increased plasma levels of sex hormone binding globulin and seemed to decrease those of total and free testosterone, but no statistically significant relationships between acne severity and biochemical variables could be detected. CONCLUSION: Both Marvelon and Diane are effective in the treatment of acne in Oriental women who also need reliable contraception, without marked differences between the preparations.

PIP: In Thailand, at the Prince of Sonkhla University in Sonkhla (Center A) and Rajvithi Hospital in Bangkok (Center B), researchers compared data on 32 women using a low-dose combined oral contraceptive (OC) containing 150 mcg desogestrel plus 30 mcg ethinyl estradiol (Marvelon) with data on 34 women using an OC containing 2000 mcg cyproterone acetate plus 50 mcg ethinyl estradiol (Diane) to examine their efficacy in acne treatment. All the women presented with acne and were between 16 and 30 years old. The study consisted of a baseline cycle and 6 successive treatment cycles. The mean objective acne score decreased with both OCs in Center A. This decrease was significant with Diane after 3 and 6 treatment cycles (p 0.05). At cycle 6, the mean objective score for Diane was much lower than that for Marvelon (p 0.05). At Center B, the mean objective score consistently and significantly decreased with Marvelon after 3 and 6 treatment cycles (p 0.05 and p 0.01, respectively) and with Diane after 6 treatment cycles (p 0.001). No significant between-group differences existed for Center B. The percentage of women with moderate/severe acne decreased significantly with Marvelon at Center B (p = 0.002) and with Diane in Centers A (p = 0.014) and B (p = 0.004). Both Diane and Marvelon significantly increased plasma levels of sex hormone binding globulin at 3 and 6 treatment cycles (p 0.01). They tended to reduce plasma levels of total and free testosterone. This decrease only reached significance with Marvelon, however (p 0.05). There were no significant associations between acne severity and biochemical variables. These findings suggest that both OCs cause significant improvement in acne in most Asian women who also may need a reliable contraceptive. There were no significant differences between the two OCs.

Oral contraceptive pills, gonadotropin-releasing hormone agonists, or use in combination for treatment of hirsutism: a clinical research center study.

The effectiveness of oral contraceptive pills (OCPs), GnRH agonist (GnRH-a), and a combination of OCPs and GnRH-a in the treatment of hirsute women was compared and the impact of these treatments on hormonal and Ca metabolism was investigated. Thirty-three women were prospectively enrolled and randomized into three treatment groups (11 in each group). The serum levels of LH, estradiol, testosterone, free testosterone, androstenedione, and 17-hydroxyprogesterone declined in all 3 treatment groups, whereas the inclusion of GnRH-a treatment tended to promote a more rapid decrease in these hormone levels. Total cholesterol, low density lipoprotein, and high density lipoprotein levels remained unchanged. The assessment of hirsutism by the Ferriman-Gallwey score revealed a similar 25% reduction in score by all three treatment groups by 6 months. In addition, no difference was detected between groups with respect to hair diameters and the vellus index. Clinical assessment of hirsutism at 3 months by the patients revealed that the GnRH-a and the OCPs-plus-GnRH-a groups had better responses than the group on OCPs alone, but by 6 months all three groups were similar. The symptoms of hot flashes and vaginal dryness were greatest in subjects treated with GnRH-a alone. Serum Ca, phosphorus, alkaline phosphatase, osteocalcin, and 2-h fasting and 24-h urinary Ca excretion levels all increased significantly in subjects treated with the GnRH-a alone, whereas a decrement or no changes occurred for these measurement in the other two groups. The estimated Ca balance was unchanged in the OCPs and the OCPs-plus-GnRH-a groups but declined by 90 mg/day from baseline in the GnRH-a-treated women (p < or = 0.001). Bone density significantly decreased in the lumber spine in women treated with GnRH-a alone, with a less marked decline in the femoral neck. In contrast, women receiving OCPs plus GnRH had increased bone density in the lumbar spine. It is concluded that: 1) clinical measures of hirsutism are not different after 6 months of treatment with OCPs alone, GnRH-a alone, or a combination of the two; 2) the decline in gonadotropins and steroid hormones and improvement in clinical response were more rapid and pronounced when GnRH-a treatment was added to OCP administration; and 3) the negative impact of GnRH-a alone on Ca balance and bone loss limits its usefulness as a single agent for long-term therapy of hirsutism.

PIP: The effectiveness of oral contraceptive pills (OCPs), GnRH agonist (GnRH-a), and a combination of OCPs and GnRH-a in the treatment of hirsute women (modified Ferriman-Gallwey score 10), 20-39 years old, was compared and the impact of these treatments on hormonal and Ca metabolism was investigated. 33 women were prospectively enrolled and randomized into 3 treatment groups (11 in each group): 1) OCPs [35 mcg ethinyl estradiol plus 1 mg norethindrone administered cyclically]; 2) GnRH-a, 3.75 mg im, every 4 weeks for 24 weeks; or 3) a combination of both OCPs and GnRH-a at the above doses taken concurrently. All medications were administered for 6 months. The serum levels of LH, estradiol, testosterone, free testosterone, androstenedione, and 17-hydroxyprogesterone declined in all 3 treatment groups. The assessment of hirsutism by the Ferriman-Gallwey score revealed a similar 25% reduction in score by all 3 treatment groups by 6 months. The symptoms of hot flashes and vaginal dryness were greatest in subjects treated with GnRH-a alone. Serum Ca, phosphorus, alkaline phosphatase, osteocalcin, and 2-h fasting and 24-h urinary Ca excretion levels all increased significantly in subjects treated with the GnRH-a alone. In the OCP groups there was significant decline in serum Ca from baseline to 24 weeks (p or = 0.01). There was significant urinary loss of Ca in the GnRH-a group with respect to 24-hour excretion (p or = 0.001). The estimated Ca balance was unchanged in the OCPs and the OCPs-plus-GnRH-a groups, however, it declined by 90 mg/day from baseline in the GnRH-a-treated women from 111 +or- 43 to 21 +or- 58 mg/day (p or = 0.001). Bone density significantly decreased (by 2.7%) in the lumber spine in women treated with GnRH-a alone (p or = 0.02), with a less marked decline in the femoral neck. The negative impact of GnRH-a alone on Ca balance and bone loss limits its usefulness as a single agent for long-term therapy of hirsutism.