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Problems in evaluating chronic toxicity of contraceptive steroids in dogs.
The long-term effects of oral contraceptive steroids including a combination of norethindrone and ethynylestradiol, a sequential regimen of dimethisterone and ethynylestradiol, and daily administration of megestrol acetate were studied in female beagle dogs at dose levels of 1, 10, or 25 times the projected human dose levels. The major findings included cystic endometrial hyperplasia and pyometra requiring hysterectomies and alopecia for the norethindrone-ethynylestradiol and dimethisterone-ethynylestradiol treated dogs. These groups did not have accentuated mammary development or treatment-related hyperplastic or neoplastic changes. For dogs given dimethisterone-ethynylestradiol, numerous acne-like lesions occurred in the skin of the mammary areas. Dogs given the higher dose levels of megestrol acetate had marked mammary stimulation, hyperplastic and neoplastic changes in the mammary glands, and clinical and pathologic changes typical of diabetes mellitus. Mammary changes of nodular hyperplasia, benign mixed tumor, and adenocarcinoma appeared as distinct entities although constant and intense mammary stimulation may be a common denominator. Such mammary changes have not been found in long-term studies in monkeys or rats with megestrol acetate, and the relevance of the canine mammary changes to projecting potential tumorigenesis in women is questioned.
Severe atypical endometrial changes and sequential contraceptive use.
Of eight young women, seven had a diagnosis of well-differentiated endometrial adenocarcinoma and one had atypical endometrial hyperplasia. The average age was 40.1 years, with 6.04 years of dimethisterone-ethinyl estradiol (Oracon) sequential contraceptive use. The patients were not typical of those in whom endometrial carcinoma develops. Although these cases do not prove that long-term administration of dimethisterone-ethinyl estradiol causes endometrial adenocarcinoma or atypia, they indicate that it may do so.
Lower esophageal sphincter pressure in women using sequential oral contraceptives.
Lower esophageal sphincter pressure, basal gastric pH, and fasting plasma gastrin were measured sequentially in female volunteers who were using oral contraceptives. No difference in basal gastric pH or fasting plasma gastrin was observed during any of the three selected periods studied. Lower esophageal sphincter pressure was the same during menses (20.8 +/- 1.7) when the volunteers took no medication during the phase of the cycle when the volunteers were ingesting ethinylestradiol (18.3 +/- 1.7). Lower esophageal sphincter pressure decreased significantly (P less than 0.01) to 9.4 +/- 1.2 during the phase of the cycle when the volunteer took the progestation agent, dimethisterone, as well as ethinylestradiol. It is therefore proposed that the progessive rise in plasma progesterone alone or in combination with estrogens that occurs during the course of pregnancy might be responsible for the increased incidence of symptomatic heartburn in pregnant women.
Comparative studies of the ethynyl estrogens used in oral contraceptives. II. Antiovulatory potency.
The occurrence or inhibition or ovulation was inferred from the plasma progestin level measured in the last week of 430 control cycles and of 4,638 cycles from fertile women receiving various antiovulatory steroids, singly and in combination. The substances tested included: mestranol and ethynylestradiol (EE) of homogeneous bioavailability, used alone in a range from 50 to 100 mug per day; these same dose levels combined with various progestins; and finally various proprietary combination and sequential low-dose regimens undergoing clincial trials. Statistical analysis showed ethynylestradiol and mestranol alone to be equipotent over the tested range, although at 50 mug per day superiority of mestranol over EE was suggested. Two preparations of EE at 50 mug per day, one of them a sequential with dimethisterone, showed different potency. At 50 mug per day no estrogen, alone or with a sequential progestin, reached a satisfactory level of effectiveness. However, very small amount in the range of 20 to 40 mug per day were highly effective when combined with quantities of various 19-nor progestins which by themselves are well below the antiovulatory level. This indicated that a synergism exists between these two classes of compounds insofar as their antiovulatory effect is concerned, thus explaining the high contraceptive effectiveness observed with very-low-dose combination regimens.
Multi-omics dynamic profiling reveals predictive biomarkers for first-line immunochemotherapy in extensive-stage small-cell lung cancer.
BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with a poor prognosis. Although first-line immunochemotherapy improves clinical outcomes, robust prognostic biomarkers for this treatment modality remain unavailable. The aim of this study was to identify non-invasive, easily accessible, and dynamically monitored biomarkers of ES-SCLC by machine learning integrating serum metabolomics, lipidomics, and proteomics at multiple time points. METHODS: A total of 816 serum samples were collected from ES-SCLC patients receiving first-line immunotherapy combined with chemotherapy or first-line chemotherapy for metabolomics, lipidomics, and proteomics analysis. The immunochemotherapy cohort was randomly divided into training and validation subsets at a 6:4 ratio. Biomarkers were identified using machine learning algorithms, and their prognostic significance was evaluated through receiver operating characteristic (ROC) analysis, Kaplan–Meier survival analysis, and multivariate Cox regression. Potential metabolic pathways and mechanisms were further explored via integrated multi-omic analysis. RESULTS: The immunochemotherapy exhibited a prolonged median progression-free survival (PFS) and higher objective response rate (ORR) compared to the chemotherapy group. A total of 5 serum metabolites (uric acid, L-aspartate-semialdehyde, dimethisterone, xanthine, L-cysteine), 6 lipids (Cer d18:1/26:0, Cer d18:2/25:0, SM d18:1/20:1, SM d17:1/25:1, DG O-18:1_16:0, PS 18:0_24:0), and 3 proteins (ACIN1, ACSL4, PHGDH) were identified and constructed into independent prognostic models. Among patients receiving immunochemotherapy, those categorized as low-risk based on the model demonstrated significantly longer PFS compared with those in the high-risk group. These prognostic signatures also retained predictive value in patients who underwent second-line treatment with anlotinib plus immunochemotherapy. Integrated analysis revealed that glycine, serine, and threonine metabolism was the commonly enriched pathway across all three omics layers. Notably, PHGDH (protein), L-aspartate-semialdehyde and L-cysteine (metabolites), and PS (18:0_24:0) (lipid), key elements in this pathway, were all incorporated in the predictive model. In addition, models of the composition of these substances after one cycle of treatment can still predict the prognosis of patients. CONCLUSION: In this study, we constructed and validated a set of non-invasive, dynamically monitorable prognostic models (containing 5 metabolites, 6 lipids, and 3 proteins) using machine learning by integrating multiple time point data from the serum metabolome, lipid panel, and proteome to accurately distinguish the prognostic risk of patients with ES-SCLC receiving immunochemotherapy. PFS was significantly prolonged in patients in the low-risk group, and this model remains predictive in the subsequent second-line treatment with anlotinib in combination with immunochemotherapy. Glycine-serine-threonine metabolic pathway may be the key mechanism, of which PHGDH, L-aspartate semialdehyde, L-cysteine and PS (18:0_24:0) are the core predictors. This study provides the first multi-omics dynamic prognostic tool for ES-SCLC immunochemotherapy and reveals potential therapeutic targets.
The development of adenocarcinoma of the endometrium in young women receiving long-term sequential oral contraception.
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Occlusive retinal arteriolitis with neovascularization.
A 34-year-old white woman who had used oral contraceptives for six years showed an occlusive bilateral retinal arteriolitis that resulted in a branch arteriolar occlusion in the right eye and retinal neovascularization. Three years later, we observed active arteriolitis in the left eye with successive occlusion of several branch arterioles. The disease has shown spontaneous remissions and exacerbations. An extensive medical evaluation revealed only old pulmonary granulomatous disease and an elevated sedimentation rate in association with exacerbations of the arteriolitis.
Polarographic study of certain progestogens and their determination in oral contraceptive tablets by differential pulse polarography.
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The effect of kind of carbohydrate in the diet and use of oral contraceptives on metabolism of young women. I. Blood and urinary lactate, uric acid, and phosphorus.
Six oral contraceptive (OC) users and six control subjects consumed diets in which 43% of the calories came from either sucrose or starch for 4 weeks in a cross-over design. Kind of carbohydrate in the diet had no effect on blood lactate response to a sucrose load, but lactate response of OC users was greater than that of control subjects. Kind of carbohydrate in the diet did not affect urinary lactate excretion after a sucrose load; however, OC users excreted more lactate than did controls and there was a significant interaction between dietary carbohydrate and OC use. Serum uric acid levels were significantly higher when the sucrose diet was consumed, but levels were not affected by OC use. Serum phosphorus levels were not affected by kind of carbohydrate in the diet but were higher in control subjects than in OC users and there was a significant interaction between diet and OC use. There were no significant differences in urinary uric acid and phosphorus excretions after sucrose loads or in 24-hr urinary excretions of uric acid, phosphorus, or urea due to kind of carbohydrate in the diet or OC use.
Hormonal steroids: effects on the vascular system.
An increase in the incidence of thromboembolic disorders has been associated with oral contraceptive use, though the causative mechanisms remain unclear. Our studies indicate that the contraceptive steroids, irrespective of the intermediary metabolic processes involved, cause changes in the surface charge characteristics of the blood vessel wall and blood cells in the following cases: (i) in experiments using dogs, the hormonal steroids result in a greater reduction in the pore surface charge of veins than in arteries; (ii) in rats, the current induced mesenteric occlusion times are significantly lowered following administration of combined contraceptives steroids; (iii) in humans, the electrophoretic mobilities of erythrocytes and platelets from women taking Ovral and Demulen are lower than in controls, and (iv) there is no significant alteration of plasma coagulation times of women who are on injectable progestin therapy. Demulen and Ovral appear to result in a slight decrease in activated partial thromboplastin times compared to controls.
Bone mineral: effects of oral contraceptives, pregnancy, and lactation.
Estimating bone mineral by the photon absorption (125I) method applied to the distal part of the radius, it was found that young women using oral contraceptives containing a daily dose of 100 micrograms of mestranol had higher concentrations of bone mineral than non-users. Women twenty to fifty-nine years old who had lactated were among the poorly mineralized, while those who had lactated but were now using oral contraceptives in various combinations were among the highly mineralized.
Endometrial carcinoma in young women taking oral contraceptive agents.
The first 21 cases recorded in the Registry for Endometrial Carcinoma in Young Women Taking Oral Contraceptive Agents are reported. We have found no other such cases in the literature, and indeed several authors have stated that these agents, because of their predominantly progestional action, would be expected to be protective against this disease. In 8 of the 21 patients, factors were present which militated against a close relation between oral contraceptives and carcinoma, and 5 of these 8 patients had taken only or predominantly combined agents. On the other hand, 11 of the remaining 13 patients took sequential agents, a ratio directly opposite that of the usage of combined and sequential agents in the American population. The possible reasons for the excess of sequential agents, chiefly Oracon, are discussed, and directions for future study are suggested.
Hepatocellular adenoma and oral contraceptives.
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Endometrial carcinoma and oral contraceptive agents.
Six patients who took oral contraceptive agents for 5 to 18 years developed endometrial neoplasia. Endometrial adenocarcinoma occurred in 4 of these patients and severe adenomatous hyperplasia occured in 2. Five of the 6 patients took sequential agents; 1 patient used a combined agent. An additional patient who took Premarin and Provera sequentially developed adenocarcinoma of the endometrium. Eighteen cases of endometrial adenocarcinoma and 7 cases of adenomatous hyperplasia in patients with long-term sequential oral contraceptive use have previously been reported by others. Progestogens may not be completely protective against the endometrial cancer-causing potential of the estrogens, especially in the sequential regimens.
Progestational potency of oral contraceptives: a polemic.
Dickey and Stone have attempted an evaluation of progestational potencies of oral contraceptives based upon such uterine criteria as subnuclear vacuolization and delay of menses. Their review, unfortunately, is marred by numerous errors which vitiate the potency estimates. The actions of progestagens in target organs depend upon the specific binding of the compounds to a protein receptor that is produced by estrogen treatment. Potency of hormones depends ultimately upon this binding. Since it seems unlikely that specific binding occurs in such nontarget sites as the blood vessels, direct potency relationships are highly improbable between diverse phenomena. Possible relationships between oral contraceptives and specific side effects must be studied in relationship to individual side effects and particular contraceptive products. Possible coincidental activities, no matter how analyzed, are unlikely to contribute meaningfully to our understanding of these drugs.
Proper management of hepatic adenoma associated with oral contraceptives.
Four patients with oral contraceptive associated hepatic adenoma have been studied and the literature reviewed. Clinically, these patients can be divided into ruptured and nonruptured hepatoma groups. In instances of ruptured hepatomas, resection only sufficient to control hemorrhage definitely is recommended. In instances of nonruptured hepatomas, major resection should only be attempted by skilled surgeons, and small multiple lesions should be observed. These management principles will deserve re-evaluation as more experience with these tumors accumulates. Until then, a conservative approach is indicated. This includes the avoidance of oral contraception until the biochemistry of these tumors is better clarified.
[Contraception and endometrial carcinoma (author's transl)].
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