Pregnancy and reproductive function in a patient with non-mosaic Turner syndrome.

A patient with non-mosaic Turner syndrome and normal fertility had four documented pregnancies, two of which were carried to term. Although her fertility history can be considered normal, she did not have spontaneous sexual maturation or menarche, and bilateral streak gonads were identified on laparotomy for tubal ligation. A review of the literature on non-mosaic Turner syndrome and reproductive function indicates that there are several theories to account for the extreme variety of ovarian function in such patients, but not enough data are yet available to form a conclusion.

Inactivation of contraceptive steroid hormones by human intestinal clostridia.

Steroid hormones reduced in ring-A are devoid of hormonal activity. In metabolic experiments we found that human fecal flora reduced the delta 4-3-keto structure of natural progestins to 3 alpha-hydroxy, 5 beta-steroid metabolites (3 alpha,5 beta) and of synthetic progestins to a mixture of 3 alpha,5 beta and 3 beta,5 beta compounds. 3 alpha,5 beta-Reductase was synthesized by Clostridium paraputrificum and had a strong affinity for natural progestins such as progesterone. 3 beta,5 beta-Reductase was synthesized by Clostridium innoculin and had a stronger affinity for synthetic progestins. A third enzyme, 3 beta,5 alpha-reductase, was synthesized by St. Luke's strain 209 (Clostridium species "J-1") but was only observed when pure cultures were used. Ring-A reduction of synthetic progestins was 3 to 10 times slower than that of natural progestins, thus explaining the pharmacological superiority of synthetic progestins over naturally occurring analogs.

Incidence of endometrial cancer in relation to the use of oral contraceptives.

Female residents of King and Ierce Counties in the state of Washington in whom endometrial cancer was diagnosed during 1975--77 were interviewed concerning prior use of oral contraceptives. Their responses were compared with those of a random sample of women from the same population. Women who had taken Oracon (0.1 mg of ethinyl estradiol and 25 mg of dimethisterone) were estimated to have a risk of endometrial cancer 7.3 times that of other women (P = 0.007). This elevation in risk was not seen in users of other sequential preparations. Women who had used combined oral contraceptives had only 50 per cent of the incidence of endometrial cancer of nonusers (P = 0.05), although the protective effect was not evident among those who subsequently took menopausal estrogens for more than two years. These associations suggest that development of neoplasia in the endometrium can be extremely sensitive to hormonal factors: if an oral contraceptive, like Oracon, emphasizes the estrogenic component, promotion of cancer can result; if like combined preparations, the contraceptive emphasizes the progestational component, protection against cancer can result.

PIP: Interviews concerning prior use of oral contraceptives (OCs) were conducted among female residents of King and Pierce Counties in the state of Washington in whom endometrial cancer was diagnosed during 1975-1977. Their responses were compared with those of a random sample of women from the same population. Women who had taken Oracon (0.1 mg of ethinyl estradiol and 25 mg of dimethisterone) were estimated to have a risk of endometrial cancer of 7.3 times that of other women (P=0.007). This elevation in risk was not observed in users of other sequential preparations. Women who had used combined OCs had only 50% of the incidence of endometrial cancer of nonusers, although the protective effect was not evident among those who subsequently took menopausal estrogens for more than 2 years. It is likely that the use of Oracon predisposed women to the development of endometrial cancer. THese associations suggest that development of neoplasis in the endometrium can be very sensitive to hormonal factors. If an OC, like Oracon, emphasizes the estrogenic component, promotion of cancer can be the result. If, like combined preparations, the contraceptive emphasizes the progestational component, protection against cancer can be the result.

Oral contraceptives and endometrial cancer.

PIP: The exemplary study of Weiss and Sayvetz of the risk of endometrial cancer among oral contraceptive (OC) users is reported. The only study limitation is that the cases available were too few to provide highly precise estimates of all the associations seen. Yet the study did show that women who took the sequential drug Oracon have a risk of endometrial cancer that is appreciably higher than that of women who did not take OCs. The study also provides some evidence that the combined drugs do not increase the risk of endometrial cancer and that they might actually be protective. The study can only suggest that other sequential drugs are not as harmful as Oracon and that they may even be protective like the combined drugs. Oracon differed from all other OCs in 3 ways, and each contributed to making it the most estrogenic: 1) only Oracon used the weak progestogen dimethisterone; 2) only Oracon supplied 100 mg daily of the estrogen ethinyl estradiol; and 3) Oracon's monthly sequence included 16 days of estrogen alone while other sequential drugs included 14 or 15 days, and the combined OCs have no estrogen-only day. The finding of Weiss and Sayvets that, if accurate, will prove to be of greatest importance is the apparent anticarcinogenic effect of combined oral contraceptives.^ieng

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.

PIP: The long-term (7-year) effects of oral contraceptive steroids including a combination of norethindrone and ethinyl estradiol, a sequential regimen of dimethisterone and ethinyl estradiol, 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-ethinyl estradiol and dimethisterone-ethinyl estradiol treated dogs. These groups did not have accentuated mammary development or treatment related hyperplastic or neoplastic changes. For dogs given dimethisterone-ethinylestradiol, numerous acnelike 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 tumor, and adenocarcinoma appeared as distinct entitles although constant and intense mammary stimulation may be a common denominator. The relevance of the canine mammary changes to projecting potential tumorigenisis in women is questioned.

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.

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.

Spontaneous rupture of liver in patient on oral contraceptives.

Hemoperitoneum as a result of spontaneous rupture of the liver occurred in a 28-year-old woman who had been takingoral contraceptives for 7 years. The hemorrhage occurred between a benign tumour and the liver and was treated by left hepatic lobectomy. The pathologic aspects of this tumour are discussed and the current literature is reviewed. Conservative excision compatible with hemostasis is the recommended treatment.

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.

Endometrial abnormalities occurring in young women on long-term sequential oral contraception.

Recently the occurrence of adenocarcinoma of the endometrium has been reported in young women exposed to sequential oral contraceptive agents for long periods of time. Twelve young women who had been using Oracon for periods of from 13 to 93 months were subjected to office endometrial aspirations. Tissue specimens showed endometrium which varied in diagnosis from proliferative endometrium to severe atypical adenomatous endometrial hyperplasia bordering on endometrial carcinoma in situ. Adenomatous endometrial hyperplasia is though by many investigators to be a precancerous condition. The progression of endometrial changes from benign proliferation to cystic hyperplasia and adenomatous hyperplasia accompanied by varying degrees of anaplasia in young women exposed to Oracon for long periods of time is significant. It is not surprising, therefore, that adenocarcinoma of the endometrium has been reported in these women at an age where this condition had been relatively uncommon prior to the use of sequential oral contraceptives.

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.

The development of adenocarcinoma of the endometrium in young women receiving long-term sequential oral contraception.

PIP: 4 cases of adenocarcinoma of the endometrium were reported in young women. All were using and had used for periods of 4-12 years a sequential oral contraceptive, Oracon, manufactured by Mead Johnson Laboratories. Ethinyl estradiol and mestranol, the 3 methyl ether of ethinyl estradiol, are 25 times more potent than diethylstilbestrol, which has recently been implicated in the development of vaginal adenocarcinoma in female offspring of women treated during pregnancy with it. A study is now in progress to determine whether long-term use of Oracon produces premalignant changes in the endometrium. Doctors with patients on similar sequential contraceptives should watch for abnormal vaginal bleeding.^ieng

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.

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.

PIP: The effects of hormonal contraceptive agents on the vascular system were studied in rats, dogs, and 34 women taking oral or injectable steroid contraceptive agents. Changes in the surface charge characteristics of the blood vessel wall and blood cells were observed. In dogs, the reduction in pore surface charge was greater in veins than in arteries. In rats, the induced mesenteric occlusion times were significantly reduced (p less than .001). However, Provera did not significantly reduce induced occlusion time in these animals (p greater than .01). Ov ral and Demulen lowered the mobilities of erythrocytes and platelets in women. Plasma coagulation times were not markedly altered in women receiving injectable progestin. Acitivated partial thromboplastin times were slightly decreased by Ovral and Demulen. The results suggest an increased tendency toward thrombosis in women taking steroid hormone contraceptive agents.

Effects of exogenous estrogen and progestin on pituitary responsiveness to synthetic luteinizing hormone-releasing factor.

The effect of estrogen and progestin on pituitary responsiveness to 150 mug synthetic luteinizing hormone-releasing factor (LRF) was assessed in premenopausal women receiving sequential (n=12) and combination (n=7) contraceptive steroids. A marked contrast in the time-course and maximal response to LRF was found; a prompt but quantitatively smaller luteinizing hormone (LH) response was seen during cyclic combination therapy, while a delayed (five times) but enhanced (fivefold) LH response was observed during estrogen segments of cyclic sequential therapy. For follicle-stimulating hormone (FSH), the maximum rise was also higher, and the peak response was similarly delayed in the latter group. The quantitative secretion in response to LRF for LH (area under the curve), but not for FSH, was significantly greater (P < 0.01) in subjects receiving sequential, as compared to subjects receiving combination treatment. In both groups, characteristic gonadotropin responses to LRF were reproducible and were independent of the duration of treatment. Since LRF studies were performed during the estrogen segment of treatment cycle in subjects receiving sequential steroids, our data suggest that estrogen exerts a direct feedback action at the pituitary level and that pituitary responsiveness to LRF is augmented by estrogen.