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PIP: In March 1989, ultrasonography revealed a hepatic mass in a 40 year old nulliparous woman who was then referred to the University of Southern California--Los Angeles (UCLA) Liver Unit. She exhibited no symptoms of a liver condition. From 19-28 years old, she took the combined oral contraceptive (OC) Ovulen 21 for irregular menses. After a brief period of taking Ortho Novum 1/80, she took Demulen 1/35-24 between ages 28-34. Her physician diagnoses endometriosis at 34. He stopped OC therapy and prescribed the progestin Norlutate. She had no history of hepatitis, toxin exposure, and previous liver disease. Further no one in her family had had liver disease or neoplasms. Computer tomography identified a 6.5 cm x 3.5 cm mass in the right lobe of the liver which matched a cold defect on a liver scan using technetium Tc 99m sulfur colloid. The mass selectively took up gallium. Arteriography revealed the mass to be a vascular tumor, but it did not exhibit a typical vascular pattern of an adenoma or the neovascularity of hepatocellular carcinoma. Physicians at UCLA used peritoneoscopy to take percutaneous needle biopsies of the right lobe which confirmed a hepatic adenoma. they then removed the right lobe of the liver. The remaining part of the liver was normal. Histologic examinations of the removed section showed features of a well differentiated hepatocellular carcinoma. Further tumor cells had invaded normal hepatic parenchyma. The physicians believed that hepatic adenoma was in the process of transforming into hepatocellular carcinoma in this patient. They thought that long term OC use, and possibly long term progestin use, may have contributed to the formation of the liver neoplasms. They emphasized the need for a pilot study to develop guidelines on surveillance ultrasonography of women taking OCs over a long period.^ieng

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Epidemiologic studies indicate that the risk of complications with oral contraceptive use is related to the steroid content and potency of the various formulations. This paper summarizes human data in which potencies of progestins in oral contraceptives can be compared. Data on delay of menses and endometrial subnuclear vacuolization, an indirect assessment of glycogen deposition, are presented. The relative effects of various progestins on serum lipids and lipoproteins are also summarized. The object of this review is to examine the available scientific evidence which generally supports the conclusion that there is a marked similarity of potency of the dose of various progestins used in many of the formulations currently available in the U.S. The progestins norethindrone, norethindrone acetate and ethynodiol diacetate are roughly equivalent in potency while norgestrel is roughly five to ten times and levonorgestrel ten to 20 times as potent.

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This paper reported the clinical application of Norethisterone-Oxime-Acetate used as a "vacation" pill. The result indicated that pregnancy could be prevented in women who received this drug orally when they themselves or their husband came home on leave. A dose of 2 mg was administered for women on the 1st day when the couples live together, then followed by 1 mg daily successively and an additional pill was given on the morning next to the end of the leave. A high efficacy of 99.75% in terms of cycles proved in 604 women with 825 treated cycles of 604 women. The changes in menstrual cycles, the duration of menstrual bleeding and the amount of flow after treatment were very slight. The incidence of the intermenstrual bleeding and withdrawal bleeding were 2.16%. The author's observation showed that Norethisterone-oxime-Acetate is an active contraceptive pill and possesses the advantages of not only high efficacy, low side effect, but also convenience in use.

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Anovlar induces a mitodepressive effect, producing abnormal prophases and a considerable number of micronuclei, i.e. Anovlar can produce major cytological abnormalities. On the other hand, Lyndiol induces minor abnormalities leaving the process of mitosis to proceed almost normally. Microgynon 30 did not show any effect on any of the mitotic stages. Our conclusion may offer an explanation for the contradictory results found in the literature upon the cytological effect of oral contraceptives, although the major chemical constitution of all contraceptives used is the same, still there are minor differences in their chemical structure. These minor differences in chemical structure may be the deciding cause whether or not a contraceptive is harmful.

PIP: Anovlar induces a mitodepressive effect, producing abnormal prophases and a considerable number of micronuclei, i.e., Anovlar can produce major cytological abnormalities. Conversely, Lyndiol induces minor abnormalities leaving the process of mitosis to proceed almost normally. Microgynon 30 did not show any effect on any of the mitotic stages. The conclusion may offer an explanation for the contradictory results found in the literature of the cytological effect of oral contraceptives, although the major chemical constitution of all contraceptives used is the same, still there are minor differences in their chemical structure. These minor differences may be the deciding factor as to whether or not a contraceptive is harmful.

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PIP: After 20 years of clinical experience, injectable hormonal contraceptives such as norethisterone enanthate (NET) and medroxyprogesterone acetate (MPA) remain one of the most controversial methods currently used for temporary control of fertility in women. Since December 1980 this controversy has been accentuated in Mexico with issuing of regulations by the Secretary of Health and Welfare which initially did not permit promotion of long-acting injectable hormones for contraception purposes, and later, in June 1981, a reconsideration which exclusively authorized use of NET as an injectable contraceptive. Undeniably these official measures and the scientific information, occasionally contradictory, have created confusion about the indications and risks of using these formulations in clinical work. This paper presents an anlysis of the basic pharmacological aspects of long-acting contraceptive progestagens, potential risks for side effects, and some clinical rules for safe use. The authors conclude that injectable contraceptives will continue holding a definite place among hormonal methods of temporary fertility control, particularly with the advent of new administration schemes for NET which have elevated its contraceptive efficacy without appreciably increasing complications. The more rapid metabolism of NET, manifested in the absence of significant effects on body weight, less alteration of the menstrual cycle, and more rapid return of fertility after discontinuation, has considerably increased its popularity, and the possibility exists that with time and an increase in clinical experience, it may replace MPA as the injectable contraceptive of choice. Nevertheless, while investigative studies have not clearly defined the possibilities of potential risk of using these contraceptives, its clinical use must be governed by appropriate selection and careful follow-up of patients.^ieng

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PIP: The contraceptive efficacy of norethindrone acetate (ENTA) implant was evaluated in a study of 79 healthy volunteers aged 19-30 years. The purpose of the study was to 1) relate the menstrual pattern to the average daily release rate of the hormone, 2) assess the concentration of NET in peripheral blood in cases of unintentional pregnancies and ascertain the risk to offspring in such cases, and 3) evaluate the fertility potential and menstrual pattern in the 1-year period after implant removal. In most subjects (59), the implant was removed between the 5th and 8th month. The average release rate was found to be 163.5 mcg/day in subjects with regular menstrual cycles (cycle interval of 25-32 days) compared with 190.9 mcg/day in those with an abnormal menstrual pattern (p0.05). The rate was 143.3 mcg/day in the 19 women who became pregnant during the trial, but this difference is not significant. 15 of the 19 pregnancies occurred between 4 and 8 months, suggesting that the contraceptive efficacy of this implant does not exceed 4-5 months. Mean NET concentration in the sera of the women who became pregnant was 122.5 pg/ml at the time of pregnancy diagnosis. Only 10 subjects complied with the recommendation that their pregnancy be terminated for medical indications. The remaining 9 subjects delivered 6 female and 3 male infants who appeared to clinically normal, despite the fact that 4 had been exposed to the steroid for over 6 weeks. 1 year follow-up was possible in 52 subjects. The menstrual pattern appeared to be regular during this period. 25 of the 44 women in this follow-up group who did not use contraceptive measures became pregnant during the 1st year after implant removal. Additionally, the 9 infants delivered to women during the study period were evaluated for 2-3 years. No adverse changes in growth and development have been observed. This finding suggests that reports associating teratogenicity and progestins in early pregnancy are exagerrated.^ieng

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PIP: This study was conducted to examine the metabolic effect of predetermined, standardized submaximal work loads in relation to the use of an oral contraceptive (OC). A repeated measures design was selected for use in the study. The subjects were 11 female nonathletes, aged 19-20 of relatively constant weight (pretest mean 58.9 kg, posttest mean 59.6 kg) with no apparent water retention at any phase of the menstrual cycle. Subjects were given Norlestrin 21 (1 mg) and were asked to maintain their normal activity and dietary patterns and to refrain from using other medications within 24 hours of any testing period. Each subject was tested on the 4th, 10th and 26th day of her cycle. Workloads were established at 300 and 600 kpm per minute. A Monark bicycle ergometer was used, with cadence established at 50 revolutions/minute. Each subject was required to exercise for a period of 6 minutes or longer until their heart rate reached a steady state. Oxygen consumption determinations were made for 2 consecutive 30 second intervals after steady state had been reached. Open circuit respirometry was used to determine values for VO2. Data analysis was accomplished using a 3x2x2 factorial arrangement of treatments in a randomized complete block design (blocks = women). The findings show that there was a significant increase in the oxygen consumption for standardized work loads of 300 and 600 kpm. The lack of significance among the various interactions leads to the conclusion that the use of Norlestrin 21 was accompanied by a significant increase in the oxygen consumption during the performance of standardized work at these 3 phases of the menstrual cycle. These results support the theory that the use of OCs is accompanied by a shift in the mixture of substrates utilized for submaximal work and that this shift is toward an increased dependence upon triglycerides and a decreased dependence on glycogen. These findings provide a basis upon which to question the value of OCs as a tool to manipulate the menstrual cycle for the purpose of athletic competition.^ieng

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The effect of steroids contained in oral contraceptives, namely ethinylestradiol:17 alpha-ethinyl-1,3,5,(10)-estratriene-3, 17-diol (E) and norethindrone acetate:17 beta-acetoxy-17-ethinyl-4-estren-3-one (N), on cell replication and human chorionic gonadotropin (hCG) secretion by choriocarcinoma cells in monolayer culture and by hydatidiform mole tissue maintained in organ culture were studied. The steroids were added to the culture medium individually or in combination to achieve a range of concentrations (10-10 to 10-4), within and beyond the presumed concentration of these substances in the blood of women taking oral contraceptives. The effect of luteinizing hormone releasing hormone (LHRH) on hCG secretion by choriocarcinoma cells in monolayer culture also was investigated. The rate of hCG production by either choriocarcinoma cells in monolayer culture or by hydatidiform mole tissue maintained in organ culture was not affected by the hormones used in this study; indeed hCG secretion remained reasonably unchanged even with high concentrations of steroids (up to 10-4 M) or LHRH (up to 10-4 mg x ml-1). Cell replication, as measured by increase in amount of cellular protein and DNA, was not stimulated by either of these compounds.

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PIP: This monograph on norethisterone and its acetate (NOR) includes chemical and physical data (synonyms and trade names), structural and molecular formulae and molecular weight of NOR, chemical and physical properties of NOR, and the production, use, occurrence, and analysis of NOR. Production of NOR and its acetate, both of which are not known to occur naturally, occurs via conversion of estrone to its methyl ester which is reduced to estradiol 3-methyl ether with lithium aluminum hydride; NOR acetate is synthesized by acetylating NOR with acetic anhydride in pyridine. NOR has been used for human medicine in a variety of ways: 1) to treat amenorrhea, 2) to treat dysfunctional uterine bleeding, and 3) for treating endometriosis. It has also been used to treat premenstrual tension and dysmenorrhea. Medicinal use of NOR acetate is similar to that for NOR. Analytical procedures for determining NOR as a bulk chemical are presented tabularly. Biological data relevant to the evaluation of carcinogenic risk to humans are presented briefly. With experimental animals, when administered alone NOR and/or its acetate increased the incidence of benign liver tumors in male mice and of pituitary tumors in females; females also suffered granulosa-cell ovarian tumors. NOR in combination with an estrogen increased incidence of pituitary tumors in mice of both sexes. NOR is embryolethal in some species and produces virilization in female fetuses. It is concluded that there is limited evidence for the carcinogenicity of NOR and its acetate in animals. Human studies are not available, but NOR is implicated causally as a progestogenic element in side effects of combined oral contraceptive usage.^ieng

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Ethynyestradiol and mestranol, in doses ranging from 50 to 100 microgram/day, were given to women in 21-day cycles; baboons and beagle dogs received 1 and 4 microgram/kg/day in a similar regimen. After a number of such cycles, megestrol acetate, norethindrone acetate, or dl-norgestrel was given concomitantly. Protein, cholesterol, triglyceride, and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Over the dosage range studied, the effects of the two kinds of estrogen were indistinguishable. Except for human total plasma triglyceride, no dose-related differences were observed. The lowering of serum protein and the increase in cholesterol induced by estrogen were more pronounced in baboons and beagles than in human subjects. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but absent in beagles. In all three species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by the progestins; in the two animal species, triglyceride is normally very low and the estrogen-induced changes were negligible; the phospholipid rose with estrogen but was unaffected by progestins. In sum, the two animal species show many similarities to, as well as important differences from, the human response of plasma lipids to various contraceptive steroids.

PIP: In this comparative study, ethinyl estradiol and mestranol (dose range, 50-100 microg/day) were given to women in a 21-day cycle; baboons and beagle dogs received 1 and 4 microg/kilog/day in a similar regimen. After a number of cycles, mestranol acetate, norethindrone acetate, or d,1-norgestrel was given concomitantly. Protein, cholesterol, triglyceride and phospholipid levels were determined in total plasma and in ultracentrifugally separated lipoprotein fractions. Effects of the 2 kinds of estrogens were indistinguishable over the dosage range studied. Except for human total plasma triglyceride (P .001), no dose-related differences were observed. Lowering of serum protein and increase in cholesterol induced by estrogen were more pronounced in the 2 animal species than in humans. The cholesterol-depressing effect of progestational compounds observed in humans was very pronounced in baboons but was absent in beagles. In all 3 species, estrogen increased the lipoprotein fraction cholesterol, except for human low-density lipoprotein cholesterol, which was decreased. Human plasma triglyceride and phospholipid increased on estrogen administration and were decreased by progestins. In beagles and baboons, triglyceride is normally very low and the estrogen-induced changes were negligible; phospholipid rose with estrogen but was unaffected by progestins.

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A set of empirical results is used to test a model that assigns rankings to oral contraceptives in terms of relative hormonal potencies. The association between the observed incidence of side effects attributed to excess of estrogen and progestin and their incidence as predicted by the model is analyzed. Results of the study show the model to have incorrectly predicted the observed ranking order of symptoms associated with excess estrogen. Further, while the model correctly predicted the oral contraceptive with the highest progestogenic potency (Ovral), the observed ranking order of the other two preparations is shown to be the reverse of that predicted by the model.

PIP: Oral contraceptive (OC) potencies and the side effects attributed to excess estrogen and progestin were analyzed by the use of a model that assigns rankings to OCs in terms of relative hormonal potencies. 480 healthy women were randomly assigned Ovral, Norinyl, or Norlestrin. The results show that Ovral users have significantly (.01 or = p or = .05) higher incidence of symptoms but Norinyl users more frequently reported symptoms of progestin excess than Norlestrin users. The results show the model to have incorrectly predicted the observed ranking order of symptoms associated with excess estrogen while the model correctly predicted the OC with the highest progestogenic potency (Ovral). The observed ranking order of Norinyl and Norlestrin was the reverse of that predicted by the model.

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PIP: 876 women were followed over a 3975-woman-month period after implantation of a single silastic capsule containing 40 mg of norethindrone acetate. Data were analyzed by a life-table method with 3 cut-off dates. Net cumulative pregnancy rate until 7 months was 2.3/100, whereas it rose to 3.9/100 after 8 months of implantation. Net cumulative termination rates rose from .7-10.9 at the end of 7 months and reached 13.6 after 8 months. Removal rates for planned pregnancy, personal, and medical reasons after 8 months were .6, 1.2, and 5.7, respectively. 1.4/100 requested implant removals in preparation for sterilization procedures. Expulsion occurred at a rate of .8/100 at the end of 8 months. The continuation rate was 86.4/100 after 8 months. Menstrual pattern abnormalities showed a reduction with time. This implant seems an acceptable long-term contraception alternative.^ieng

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PIP: Increases in serum triglycerides, cholesterol and pre-beta- and beta-lipoproteins have been considered as significant pathogenic factors regarding the possible thrombotic side effect of treatment with oral contraceptives (OCs) of the combined type containing synthetic estrogen. To investigate the influence of natural estrogen (estradiol-17beta + estriolnorethisterone acetate) vs. synthetic oestrogen (ethinyl estradiol-norethisterone acetate) on serum lipids and lipoproteins in young women compared with independent and individual controls, as controlled doubleblind investigation was performed in 33 women in a total material and 18 women in a selected group. The significant changes were: quantitative increases in serum triglycerides (p , .001) and beta-lipoproteins (p , .01) during treatment with synthetic oestrogen; no such change was observed in subjects on natural oestrogen, which was found to decrease serum cholesterol (p , .05), phospholipids (p , .05), and alpha-lipoprotein (p , .05). Quantitative estimation of serum lipoproteins was found to be more valuable than the relative estimation by electrophoresis. It is concluded that OCs containing natural estrogens induce less significant and, qualitatively, more benign changes in serum lipids and lipoproteins than preparations containing a synthetic estrogen do.^ieng

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The changes in cytohormonal patterns we have studied on 34 patients using various combinations of exogenous estrogenes and progestagens. Comparative analysis of data with the progestagen compounds Non-Ovlon or Gravistat showed a same effect on vaginal smear.

PIP: Effects of the gestagen components of Gravistat and Non-Ovlon on vaginal cytology were observed in 34 women aged 18-34 years. Both preparations contain the same dose of ethinyl estradiol as the estrogen component. Continuous depression of the Karyopyknotic index and the eosinophilia index were associated with both preparations throughout the cycle. No peaks indicative of ovulation were observed. Significant differences in values for the 2 preparations were not observed.

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A rare presentation of acute Intermittent Porphyria is described, in which withdrawal of an oral contraceptive (Gynovlar 21) provoked the first acute attack.

PIP: Estrogens, in common with barbiturates and other drugs provoking acute intermittent prophyria (AIP), increase the activity of delta-ALA synthetase. A case history documenting an AIP attack upon withdrawal of oral contraceptives (OCs) concluded that the patient's high endogenous estrogen secretion on withdrawal revealed an otherwise latent abnormality. A 29-year-old woman who had taken Gynovlar 21 for 8 years with no adverse effects complained of proximal myopathy 3 weeks after cessation of OCs. Though the initial complaint resolved spontaneously upon menstruation, 3 weeks later she complained of acute colicky abdominal pains, anorexia, and muscle aches. Gentamicin therapy was started, and emergency laparotomy was performed 2 days later after the patient developed ileus, sinus tachycardia (100/minute), and hypertension (150/110 mm of Hg). Laparotomy was essentially negative. Postoperatively, the sinus tachycardia and hypertension persisted; Tuinal administration resulted in return of muscle pains and clinical diagnosis of AIP. The patient was treated with Hycal, fluid restriction, and soluble aspirin. After 2 weeks she improved clinically and serum electrolytes were normal. Blood pressure settled to 130/80 and pulse rate to 90/minute. This case appears unique in that symptoms presented upon withdrawal of OCs.

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PIP: 4 healthy women of proven fertility and normal menstrual cycles were implanted with a single silastic implant D, filled with norethindrone acetate (ENTA) in order to study the effect of continuously released low levels of ENTA (150 mcg/day) on serum levels of follicle stimulating hormone, luteinizing hormone, estradiol-17beta, and progesterone and to assess the site of action. Steroids were measured by radioimmunoassay before the implant and 2-4 cycles during the first 8 months of treatment. Values of steroids prior to implant indicate that all subjects were ovulatory before treatment. During the 1st few months of use, values indicate that ovulation continued unsuppressed. Later cycles demonstrated hormonal disturbances with low serum progesterone during the luteal phase in most of the treatment cycles when compared with controls. Results indicate a gradually increasing suppression on the pituitary-gonadal function.^ieng

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PIP: A double-blind crossover study of 480 women taking either Ovral, Norinyl, or Norlestrin was conducted to determine the effects of missing 1 contraceptive tablet in the pill sequence on the incidence of breakthrough bleeding. The women were instructed to take 2 tablets the following day in the case of a missed tablet. The probability of breakthrough bleeding among those women who did not miss a tablet was in the range of .017 to .022, but those who had missed a tablet had a probability .227 to .352. However, the duration of breakthrough bleeding was somewhat less for those who missed a tablet than for those who maintained a regular schedule. The range in probability reflects differences between the compounds used. The results strongly suggest that the risk of breakthrough bleeding is considerably increased when an oral contraceptive pill is omitted from the pill cycle.^ieng

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PIP: A single silastic implant D containing 40 mg norethindrone acetate was inserted subdermally into 6 normal cycling women of reproductive age. Serum norethindrone concentrations were measured by radioimmunoassay involving an antiserum raised against norethindrone 11alph-hemisuccinate-bovine serum albumin. There was an initial high level of circulating steroid up to 2 months when it declined to 80 ng/100 ml serum in 5 subjects. The other subject had an unusually high serum norethindrone level throughout. The serum levels of norethindrone were elevated again when the 1st implant was replaced with the 2nd. A serum concentration of about 80 ng/100 ml of norethindrone is effective in providing contraception. The initial high release of steroid may contribute to menstrual disturbances experienced by some women.^ieng

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PIP: The effects of prolonged daily injections of norethistrone acetate (200 mcg/kg) alone and in combination with ethinyl estradiol (100 mcg/kg) were compared with daily vehicle injection. Locomotor activity was determined continuously for 2 estrus cycles prior to injection, the every 7th day throughout 42 days of treatment. Free and total plasma tryptophan and brain tryptophan and 5-HT (serotonin) were determined on the 43rd day and compared with diestrous values. Locomotor activity declined after both treatments. The norethistrone group had 47% of activity. The combination group was 54% of initial diestrus values. Vehicle controls resumed cyclic changes in locomotor activity within 8 days, while the hormone treatments abolished these cyclic changes. Norethistrone was ineffective in changing brain tryptophan values. The combined treatment caused the reduction of plasma total and free tryptophan, probably due to acceleration of protein synthesis.^ieng

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PIP: Riboflavin excretion in relation to creatinine and the activation coefficient of erythrocyte glutathione reductase (EGR) was studied in 27 women using oral contraceptives for 2-24 months and 12 nonusers. 21 subjects took alpha-norgesterol (.25 mg) and ethinyl estradiol (.05 mg), and 6 women took norethisterone acetate (1 mg) and ethinyl estradiol (.05 mg). Neither EGR activity nor riboflavin excretion of women using oral contraceptives differed significantly from the untreated group. Riboflavin excretion of 24 women using oral contraceptives and all control subjects was acceptable or high ( 80 mcg/gm creatinine) and 25 women using oral contraceptives and 10 control subjects had an activation coefficient of 1.2, which is acceptable. This would suggest that oral contraceptives have no detrimental effect on riboflavin metabolism in women with satisfactory riboflavin nutrition.^ieng

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