The Effect of Oral Contraceptive Hormones on Anterior Cruciate Ligament Strength.

BACKGROUND: Women are 2 to 9 times more likely to experience an anterior cruciate ligament (ACL) injury than men. Various hormones including relaxin, progesterone, and estrogen influence ACL strength. Oral contraceptives (OCs) alter these hormone levels; however, studies have yet to comprehensively compare different OCs' effects on the ACL. HYPOTHESIS: OCs with increased progestin-to-estrogen ratios will (1) increase ACL collagen expression, (2) decrease ACL matrix metalloproteinase expression, and (3) increase ACL strength. STUDY DESIGN: Controlled laboratory study. METHODS: Untreated female rats were compared with rats treated with 1 of 5 clinically used OCs: norethindrone (NE) only, NE plus ethinylestradiol (EE), etynodiol diacetate (ED) plus EE, norgestimate (NG) plus EE, and drospirenone (DS) plus EE. Doses were scaled from human doses to account for differences in bioavailability and body weight, and OCs were administered daily via oral gavage for 4 rat estrous cycles (20 days). A total of 36 rats were then sacrificed (6 rats/group). ACLs underwent biomechanical testing to assess ACL strength, stiffness, and maximum load before failure. ACL specimens were also isolated for quantitative real-time polymerase chain reaction analysis to assess collagen, matrix metalloproteinase, and relaxin receptor-1 expression. RESULTS: While the primary structural property of interest (ACL maximum load before failure) was not significantly improved by OC treatment, the main material property of interest (ACL strength) in rats treated with NE only, DS + EE, ED + EE, and NE + EE was significantly increased compared with untreated controls (P = .001, P = .004, P = .004, and P = .04, respectively). The order from strongest to weakest ACLs, which was also the same order as the highest to lowest progestin-to-estrogen ratios, was groups treated with NE only, DS + EE, ED + EE, NE + EE, and lastly NG + EE. Higher ratio formulations also increased the expression of type I collagen (P = .02) and decreased the expression of matrix metalloproteinase-1 (P = .04). CONCLUSION: OC formulations with higher progestin-to-estrogen ratios may be more protective for the ACL than formulations with lower ratios. CLINICAL RELEVANCE: OC formulations with high progestin-to-estrogen ratios may benefit female athletes by reducing their ACL injury risk by decreasing the effects of relaxin on the ACL.

Efficacy and safety of ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms, with an emphasis on contraceptive efficacy. A phase IV trial.

A phase IV trial evaluated the efficacy and safety of a monophasic oral contraceptive formulation, ethynodiol diacetate, 1 mg, plus ethinyl estradiol, 35 micrograms (EDA 1 mg with EE 35 micrograms) (Demulen 1/35). Nine hundred eighty-three community-based obstetrician-gynecologists treated a total of 7,759 patients with EDA 1 mg with EE 35 micrograms for one to eight months. Clinical evaluation forms on 6,382 patients were amenable to analysis for safety (including breakthrough bleeding, ovarian cyst formation and complexion changes); 5,412 patients were evaluable for efficacy (prevention of pregnancy), with a total of 21,440 cycles recorded. The study results were interpreted in terms of the impact on clinical management of oral contraceptive users and the methods, strengths and weaknesses of phase IV trials, particularly as they relate to confirmation of the results reported here.

PIP: From August 1988-June 1989, 983 physicians participated in a phase IV trial by following 7759 women using the monophasic oral contraceptive (OC), Demulen 1/35 (1 mg ethynodiol diacetate and 35 ug ethinyl estradiol) to evaluate its efficacy and safety. The total number of cycles for the study stood at 21,440. In addition, the total woman-years stood at 1787. Only 6382 patients could be evaluated for safety. 4.4% of the patients had adverse reactions to the OC, but only 1.7% of all patients stopped taking it. The leading side effects included nausea (67 cases), headache (45), amenorrhea (42), emotional changes (30), breast pain (19), dysmenorrhea (12), and 11 cases of weight gain, abdominal/pelvic pain, and bloating. Of the 280 reported adverse reactions, only 87 (31%) were considered severe. The leading serious adverse reactions were depression (10) and hypertension (6). Only 5412 patients could be used to determine efficacy. The physicians initially reported 121 (2.2%) pregnancies during the study. The researchers learned that 33 of the 84 returned 2nd questionnaires (response rate, 70%) reported that the women conceived after enrollment but before taking the OC. 36 conceived while taking it, but 8 did not take it daily. Noncompliance may have contributed to pregnancy for the remaining 28 cases. Therefore the 36 confirmed pregnancies made for a failure rate of .7%. 85.7% of the pregnancies happened in the 1st 3 months of taking the OC. Either patient noncompliance or true medication failure accounted for treatment failure. Therefore it is important for physicians to instruct patients on how to take OCs correctly.

Clinical experience with ethynodiol diacetate 0.5 mg daily as an oral contraceptive.

Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicentre open study carried out in General Practice and Family Planning clinics. Five pregnancies were reported, three of which were a result of patient failure. The net pregnancy rate at one year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between four and five days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small decrease in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.

PIP: Femulen, a progestogen only oral contraceptive (ethynodiol diacetate 0.5mg), was evaluated for its contraceptive efficacy and safety in 425 women aged between 16 and 47 years. This was a multicenter open study carried out in General Practice and Family Planning clinics. 5 pregnancies were reported, 3 of which were a result of patient failure. The net pregnancy rate at 1 year for method failure was 0.5%. No ectopic pregnancy was reported. The median length of the menstrual period was between 4 and 5 days and the average length of the non-bleeding interval remained between 24 and 25 days throughout the study. Blood pressure on the whole remained within normal limits. However, there was a small increase in both systolic and diastolic blood pressure which did not reach significant levels. Body weight was unaltered and no abnormality was found in cervical smears. Femulen was shown to be an effective and acceptable contraceptive in women of varying ages.

Dose- and time-dependent effects of a dimeric ethynodiol-testosterone depot-preparation in female rat.

The time- and dose-dependent effects of a dimeric ethynodiol-testosterone ester upon intact and hemi-castrated female rats were compared to those of equivalent doses of norethisterone enanthate plus testosterone enanthate. In intact rats, serum LH was markedly suppressed for at least 8 weeks after a single i.m. injection of 10 or 20 mg of the dimer which exceeded the depot-effect of the combination of the enanthates. A biphasic time-and dose-dependent effect of the dimeric ester upon ovarian and uterine weight was observed. During first 2 weeks following the injection there was a pronounced enlargement of corpora lutea and a marked enhancement of progesterone secretion, probably due to a direct stimulation by the androgens. At the same time, the uteri were markedly enlarged. During the following weeks, the ovaries became progressively smaller and showed degenerative changes, the steroid levels decreased and the uteri became atrophic. When hemi-castrated rats were injected once with 1 and 5 mg of the dimer, LH became suppressed, and the compensatory hypertrophy of the ovary was inhibited. At higher doses, the weight of the ovary and uterus was increased, and the luteal function was stimulated. The results indicate that, even though the gonadotropins are suppressed, there is possibly a direct stimulatory effect of high doses of the intact dimeric molecule upon the uterus, while the stimulation of the corpus luteum function is due to an interference of the transiently elevated testosterone level with ovarian steroid biosynthesis.

[Planning of the treatment of atypical hyperplasia of the endometrium in patients with uterine myoma]. / Planirovanie lecheniia atipicheskoi giperplazii éndometriia u bol'nykh miomoí matki.

The results of a two-stage hormonal treatment of 62 cases of atypical hyperplasia of the endometrium were analysed. Within the first 6 months, patients received 24.0-28.0 g of hydroxyprogesterone capronate each. Six courses of steroid contraceptives such as non-ovlon and bisecurin were given during the second stage when regression of endometrial precancer had already been registered. The results proved hormonal therapy to be highly effective in managing atypical hyperplasia of the endometrium. Complete response was observed in 67.7% of patients. Coexistent uterine myoma affected the efficacy of treatment adversely: only 4 out of 14 patients with atypical hyperplasia of the endometrium with concomitant myoma were good responders. Hormonal treatment was ineffective mainly in cases of myoma of sizes exceeding 8 weeks of gestation and in pre- and postmenopausal patients. This makes the case for surgery.

Serum and placenta levels of ethynylestradiol in presence of ethynodiol diacetate after oral administration.

The ethynylestradiol concentration--in the presence of ethynodiol diacetate--in serum after oral administration was measured by a rapid radioimmunoassay method developed by the authors. It was found that the peak level was reached 1 h after administration, and even after 12 h a significant amount of free ethynylestradiol was present in the serum. The transfer of ethynylestradiol into the placenta was also studied in subjects who were 10-12 weeks pregnant. Placenta/serum quotients were calculated for the ethynylestradiol, and were found to increase in parallel with the dose of the drug administered, proving that an ethynylestradiol enrichment of the placenta occurred as early as 10-12 weeks of pregnancy.

PIP: The ethinyl estradiol concentration--in the presence of ethynodiol diacetate--in serum following oral administration was measured by a rapid radioimmunoassay method developed by the authors. It was found that the peak level was reached 1 hour after administration, and even after 12 hours, a significant amount of free ethinyl estradiol was present in the serum. The transfer of ethinyl estradiol into the placenta was also studied in subjects who were 10-12 weeks pregnant. Placenta serum quotients were calculated for the ethinyl estradiol, and were found to increase in parallel with the dose of the drug administered, proving that an ethinyl estradiol enrichment of the placenta occurred as early as 10-12 weeks of pregnancy.

[Blood serum iron concentration in women using contraceptive agent Angravid-Polfa]. / Zachowanie sie poziomu zelaza w surowicy krwi kobiet stosujacych preparat Angravid-Polfa w celach antykoncepcyjnych.

PIP: The blood-serum iron concentrations were examined in women using Anagravid (Polfa) as an oral contraceptive (OC). The examined subjects used the preparation for 6 months and their results were compared with those women not using a progestogen contraceptive. The results underwent statistical analysis. It was demonstrated that in the group of patients using Anagravid, the blood-serum iron concentrations were significantly higher when compared with those women who did not receive OCs. The mechanism of this phenomenon remains unclear. (author's modified)^ieng

Effect of ethynodiol diacetate with ethinyl estradiol on the mammary glands of rhesus monkeys: a preliminary report.

The oral contraceptive combination of ethynodiol diacetate with ethinyl estradiol (Demulen) was given cyclically to 48 female rhesus monkeys for 5 years. Doses employed were 1, 10, and 50 times the human dose. Treatment did not induce palpable breast nodules, and there were no deaths from mammary gland cancer.

[Efficacy of progestagens in cancer of the corpus uteri]. / Efficacité des progestagènes dans le cancer du corps utérin

PIP: The writer recommends the use of an ethynodiol implant instead of irradiation to reduce the size of uterine carcinoma before surgery.^ieng

Ethynodiol diacetate as a contraceptive.

PIP: 437 multiparous women were given ethynodiol diacetate in continuous microdoses of .35 mg/day, .50 mg/day, .25 mg/twice a day, or .125 mg/twi ce a day. 7 pregnancies occurred during treatment, 5 due to medication failure; 2 were in the .5 mg/day group and 3 were in the .125 mg/twice a day group. Women taking .5 mg/day and .25 mg/twice a day had most menstrual irregularities (10% of the cycles). Side effects noted were: headache, nervousness, nausea and vomiting, and abdominal pain. Most of the patients lost weight; lactation did not appear to be affected by the medication. Uterine tone changed during treatment; there was a decrease in frequency, an increase in intensity and an increase in the tone of the contractions. It is concluded that the contraceptive efficacy was directly related to dosage as were menstrual and uterin disturbances, except for side effects. Ovulation was not inhibited although contraception was produced.^ieng

[Contraceptive effect and tolerance of monthly oral doses of quinestrol (author's transl)].

PIP: 86 fertile women aged 18 to 37 were given 3.5 mg of Quinestrol monthly for a total of 457 cycles and were studied for the effectiveness and tolerance of this contraceptive. In order to induce periodic hemorrhage, 6 mg of the synthetic progestogen ethynodiol diacetate was added to the Quinestrol. Patients were advised to use an additional contraceptive during the first cycle. Only 1 pregnancy took place throughout the study and this occurred in the first month in a patient who had neglected to use another contraceptive during this time. Side effects, which included nausea and vomiting, were reported most often during the 1st month of treatment and became less troublesome as therapy continued. Exceptions were hypermenorrhea and spotting, which occurred more frequently during later treatment cycles. Ovulation was found to occur in 28% to 39% of the cycles, suggesting that the antifertility property of Quinestrol is not due solely to its inhibitory effect on ovulation.^ieng