Quingestanol Acetate Research Articles

Estudio clínico de un contraceptivo oral en dosis única mensual: quinestrol - quingestanol

El autor ha estudiado el efecto anticonceptivo de 2 mg. de quinestrol administrado el segundo día y el 22 día del ciclo más 2,5 mg. de acetato quingestanol en 22 días: se estudiaron 256 mujeres con un total de 2.610 ciclos; ninguna de las mujeres quedó embarazada durante el tratamiento. Los efectos secundarios registrados náuseas, vómitos, cefalea y mastalgia así como mucorrea; en la mayoría de los pacientes estos síntomas habían desaparecido del quinto ciclo de tratamiento manchado intermenstrual se observó en los primeros tres meses, con una incidencia de 25% y 24,6% luego disminuyó a 4,9 y el 3%. Los datos de laboratorio no mostraron modificaciones en estas mujeres.

In vitro effect of synthetic progestogens on estrone sulfatase activity in human breast carcinoma

The effect of progesterone and nine synthetic progestogens on the activity rate of microsome estrone sulfatase obtained from human breast carcinoma tissues was studied. The progestogens were classified into three groups: group I with a strict inhibitor effect: demegestone and chlormadinone acetate; group II with a strict activator effect: medroxyprogesterone acetate, quingestanol acetate, lynestrenol and progesterone and group III with a nonsignificant effect: dydrogesterone, promegestone, norgestrel and danazol. Demegestone was the most potent inhibitor and medroxyprogesterone acetate and quingestanol acetate had the highest activator effect. The effect of Triton X-100, a nonionic detergent, was also tested. This detergent consistently increased the microsome estrone sulfatase activity. A comparison was made between the effects of demegestone, medroxyprogesterone acetate and danazol on estrone sulfatase activity measured with or without Triton X-100 in the incubation medium. The presence of the detergent modified the progestogen action. Our results suggest that synthetic progestogens can influence the estrone sulfatase activity measured in human breast carcinoma tissues. However, the effect of progestogens was dependent on experimental conditions. Progestogens such as demegestone and chlormadinone acetate which inhibited estrone sulfatase activity in intact preparations, can reduce the intracellular production of biological active estrogen via the sulfatase pathway.

Regression of pathologic changes induced by the long-term administration of contraceptive steroids to rodents.

The induction of pathologic changes with hormone steroids has been studied in rodents, although comprehensive studies are lacking on the potential reversibility of these lesions. For these purposes, groups of rats were treated with quingestanol acetate and quinestrol, a progestogen-estrogen combination, for 50 weeks and observed for a subsequent 30-week period. Treatment resulted in a significant body weight gain suppression and reduction of food consumption which recovered after withdrawal. Other significant treatment-related effects were hair loss, ataxia due to pituitary enlargement, mammary chain masses with histologic adenocarcinoma, lens opacities, ovarian atrophy with follicular arrest, and uterine atrophic changes with suppurative inflammation throughout 50 weeks. Cessation of treatment did not effect hair loss or lens opacities, while mammary chain masses decreased in size and in incidence; mammary gland tumors showed regressive changes including the disappearance of adenocarcinoma, and the incidence of ataxia diminished together with reduced pituitary weights. Chromophobe cell hyperplasia with decreased eosinophils and acidophils and hemorrhage into the pituitary was observed up to 50 weeks and the tinctorial affinity of basophils and acidophils returned after withdrawal. Ovaries and uteri, which become atrophic and sustained chronic suppurative inflammation in the treatment phase, showed reduction of inflammatory reaction and disappearance of suppuration after withdrawal, and endometrial regeneration occurred with luteal cells seen in the ovaries. These results revealed the regressive characteristics of some of the mammary gland carcinomas as well as steroid-induced endocrine and pathologic lesions other than tegumentary and ocular changes in rats receiving high levels of steroids for prolonged periods of time.

Determination of Ethinyl Estradiol in Human Urine by Radiochemical GLC

A radiochemical GLC analysis was developed for 3H-labeled ethinyl estradiol in human urine. The technique was applied to the unconjugated and aglycone fractions of urine collected from women who were dosed orally with: (a) single capsules containing 2.0mg of 3H-quinestrol (900μCi) and 2.5mg of unlabeled quingestanol acetate dissolved in sesame oil and (6) single tablets containing 100μg of 3H-quinestrol (86μCi). Unconjugated ethinyl estradiol in Day 1 urine collections represented means of 0.02% of the high quinestrol dose and 0.12% of the low dose. Ethinyl estradiol glucuronide in the same collections represented means of 0.55% of the high drug dose and 1.35% of the low dose. The method could detect 1-ng quantities of 3H-ethinyl estradiol and 3H-quinestrol.

Some effects of progestogens, oestrogens and androgens on the ocular tension of rabbits and owl monkeys

Topically applied progestogens; progesterone, quingestanol acetate and norethisterone acetate, were shown to reduce the ocular tension of conscious rabbits. Quingestanol acetate and norethisterone acetate also reduced the ocular tension of conscious owl monkeys. It was found that quingestanol acetate did not increase outflow facility in anaesthetized rabbits, but it significantly reduced the clearance of [ 14C]inulin from the anterior chamber suggesting a reduction in aqueous flow. Androgens and oestrogens were not found to exert hypotensive effects in either species.

Influence of oral contraceptives on the acute effect of amphetamine on the hepatic endoplasmic reticulum of the rat

The interaction between amphetamine and synthetic oral contraceptive steroids have been studied in the female rat. A progestational agent, quingestanol acetate, and a standard combination contraceptive (quingestanol acetate/ethynyl estradiol) were given with and without the concurrent administration of amphetamine. Steroid treatments increased the activity of some drug-metabolizing enzymes (aminopyrine N-demethylase, coumarin3-hydroxylase, hexobarbital oxidase). Other parameters measured remained unaltered (glucose-6-phosphatase, aniline hydroxylase, cytochrome c reductase, cytochrome P 450, microsomal protein and phospholipid contents). Amphetamine treatment alone raised some drug-metabolizing enzymes (coumarin 3-hydroxylase, hexobarbital oxidase), increased microsomal phospholipid content and de novo synthesis, but elicited no effect on other enzymes measured. Amphetamine and quingestanol acetate given together significantly increased some drug metabolizing enzymes while the simultaneous treatment with combined steroids and amphetamine showed the most pronounced action. These experiments thus revealed that at least in the liver of the female rat, amphetamine elicited no overt hepatotoxicity, rather, brought about a weak inductive action of drug metabolizing enzymes. The application of steroid hormones also raised drug metabolism and the interaction between amphetamine and contraceptive steroids showed additive effects.

Effect of some progestational steroids on lactation in Egyptian women I. Milk yield during the first year of lactation

The effect of four progestational drugs on the amount of milk yield in a group of lactating Egyptian women was estimated during the first year of lactation. The milk yield was highest in the women given Depo-Provera, followed by those receiving Deladroxone and quingestanol acetate. Only in those women given chlormadinone acetate was the milk yield, on average, lower than in the control group of non-medicated women.

Effect of some progestational steroids on lactation in Egyptian women. II. Chemical composition of milk during the first year of lactation.

The effects of four progestational drugs on the composition of human milk during the first year of lactation were studied in Egyptian women. In comparison with a group of non-medicated women, chlormadinone acetate, Depo-Provera and Deladroxone all caused a marked increase in protein content in the early stages of lactation; quingestanol acetate had little overall effect. The lipid and lactose content showed irregular changes in the medicated groups as compared with the controls.

Studies on the Mechanism of Action of Continuous Microdose Quingestanol Acetate

The contraceptive mechanism of action of quingestanol acetate administered as a minipill was investigated in five healthy, ovulating women. Each woman served as her own control and was studied during a normal menstrual cycle followed by a cycle in which she received quingestanol acetate, 300 mug/day given orally beginning on cycle day 1, for 30 days. Urinary estrone, estradiol, estriol, total estrogens, pregnanediol; serum progesterone, follicle-stimulating hormone, and luteinizing hormone, together with cervical mucus properties (including viscosity, ferning, spinnbarkheit, cell content, pH, and proteins), sperm transport through mucus, vaginal cytology, and basal body temperature were studied serially during the control and study cycles. Endometrial biopsy specimens were obtained at the end of each cycle. The results indicated that all control cycles were ovulatory. In the treated cycles, endometrial morphology was slightly altered. There was also suppression of preovulatory follicle-stimulating hormone and luteinizing hormone peaks, alteration of urinary estrogens, and a decrease in serum progesterone during the luteal phase. Cervical mucus properties and sperm penetration were inhibited to varying degress during the treatment cycle. These findings suggested that at least three different factors, i.e., alteration of ovulation, disturbances of corpus luteum function, and cervical mucus changes causing inhibition of sperm penetration, were involved in the contraceptive mechanism of microdose quingestanol acetate.

CONTRACEPTIVE EFFECT OF GESTAGENS

Gestagens without additional estrogens have been used as contraceptives either as daily oral tablets or as im injections at 3-month intervals. The major side effects have been bleeding disturbances. Medroxyprogesterone acetate im has inhibited ovulation. The others have disturbed ovarian function but their efficacy depends on uterine factors such as changes in the cervical mucus and the endometrium. A table lists reported daily and im doses months of use and the Pearl index of each of the following compounds: chlormadinoe acetate .5 mg daily megestrol acetate .5 mg daily medroxyprogesterone acetate 150 mg im every 3rd month norethisterone .35 mg daily norethisterone .30 mg daily norethisterone enanthate 200 mg im every 12th week lynestrenol .5 mg daily dl-norgestrel .075 daily d-norgestrel .030 mg daily and quingestanol acetate .3 mg daily.

Effects of quingestanol acetate on the histology, histochemistry, and ultrastructure of the human endometrium

Quingestanol acetate is a potent progestogen which significantly alters the histology and histochemistry of the endometrium when studied by light and electron microscopy. The steroid did not alter transport mechanisms across the cell surfaces but, probably because of competition with estrogen for binding sites, altered sequences in carbohydrate and protein synthesis. It caused the development of platelet aggregates within the endometrial vessels and degeneration of endometrial cells through the entire menstrual cycle. The effectiveness of quingestanol acetate as a “mini-pill” is related to its alteration of the biology of the endometrial cells as well as its suppression of FSH and LH.

Clinical experience in India with a once-a-month oral contraceptive pill: Quingestanol and quinestrol

The results of several studies have shown favourable results with a once-a-month pill containing 2.5 mg quingestanol acetate and 2 mg quinestrol. In a multicentre study, 666 women were investigated for 3,130 woman months. Data analyzed using life-table method indicated a net cumulative continuation rate of only 15.0 per 100 users at the end of 12 months. Although the rate of discontinuing use of the pill for medical reasons was 42.2 per 100 users at 12 months, requests at the clinic for a “pill-a-month” method still continued. Further search for appropriate long-acting oral preparations is indicated for population groups included in this study.

Fertility following termination of the once-a-month oral contraceptive

Return to fertility was evaluated in women discontinuing the oncea-month oral contraceptive, quinestrol and quingestanol acetate. The time from the last drug-induced to the first post-treatment menstruation ranged from 25 to 45 days in 73% of the 290 women interviewed. Seventy-two percent of the endometrial biopsies, taken 14 days or less before this first menses, were found to be normal secretory. One-hundred-and-four women desiring to become pregnant after stopping therapy required an average of 7 months to conceive after their last treatment. The duration of contraceptive treatment did not influence the type of endometrial biopsy nor the time required to become pregnant. There was, however, a direct relationship between the duration of therapy and the length of time to the first post-treatment menses. The return to fertility in these women was found to be prompt with no evidence of significant delay.

Continuous microdose (0.3 mg) quingestanol acetate as an oral contraceptive agent

Quingestanol acetate, an oral progestin, was administered in a continuous daily dose of 0.3 mg to 382 healthy women for a total of 3,208 woman-months, for contraceptive purposes. There was a cumulative pregnancy rate of 2.9 percent and a cumulative continuation rate of only 50 percent at the end of 12 months. The predominant cause for discontinuation — 33 percent of all terminations — was menstrual cycle disruption, experienced by 86 percent of all users. The most frequent disturbance of this type was intermenstrual bleeding (63.6 percent of all users), although patients were more intolerant of amenorrhea and of menorrhagia, which occurred less frequently (19.8 percent and 2.9 percent, respectively). The incidence of systemic complaints was small, occurring in only 9.4 percent of the total acceptors for 15.7 percent of the terminations. The high incidence of menstrual cycle disturbances appears to be the major disadvantage of this oral contraceptive. The anticipated advantage of contraceptive protection without ovulation inhibition was not borne out by this study.

Further experience with quingestanol acetate as a postcoital oral contraceptive

A previous report based on investigations in Mexico suggested that quingestanol acetate might have potential as a postcoital oral contraceptive at a 800 mcg dose. This concept was based on some 1,000 cycles of therapy with no pregnancies in patients preselected to have 2 to 4 coital acts per week. Additional patients were then enrolled in this and two other centers. In the two new centers, patients were not preselected for frequency of intercourse. They accumulated some 3,400 cycles with a pregnancy rate of over 20 per 100 women years. The patients in the original center continued to take at least 2 to 4 doses the first two weeks regardless of coital frequency. They totaled some 5,500 cycles of experience with a 0.6 rate. The failure of the expanded studies in the general population was related to their coital frequency of only 8 per cycle. When doses of steroid were increased to 1.5 or 2.0 mg, the pregnancy rate declined considerably but the incidence of intermenstrual bleeding became unacceptable. These data indicated that the routine usage of the steroid as a postcoital contraceptive in the general patient population was probably not possible.

Quingestanol acetate metabolism in women.

The metabolism of quingestanol acetate (QA) was studied in 3 women, and an assessment of the bioavailability of the oral dosage form was made. QA was absorbed rapidly and showed a high order of bioavailability after oral administration. The composition of the radioactive steroids in the plasma suggests that the initial biotransformation of the drug involves 2 pathways, the deacylation to quingestanol and O-dealkylation to norethindrone acetate, and that both of these metabolites are subsequently converted to norethindrone.

Effect of Minipills on Physiologic Responses of Human Cervical Mucus, Endometrium, and Ovary

To evaluate the action of 4 different low-dose progestogen oral contraceptive preparations on in vitro sperm penetrability by their effect on the cervical mucus endometrial histology and ovarian function 42 normal healthy multiparous women 21-43 years old were divided into 4 random groups and administered daily either cingestol .25 mg quingestanol acetate .3 mg chlormadinone acetate .5 mg or megestrol acetate .5 mg for 6-18 months for a total of 370 studied cycles. 23 untreated women served as controls. Cervical mucus samples were obtained on Day 14 of the cycle and tested for receptivity with fresh semen samples. Endometrial biopsies were obtained on Day 20 of the cycle at 6-month intervals and 14 ovarian biopsies were performed during the course of tubal ligation in treated patients. Urinary pregnanediol levels were also tested in 20 patients on Cycle Day 22. Irregularities in the menstrual pattern occurred in 12%-19% of the minipill users during the first 6 months of contraceptive therapy but later disappeared. Cervical mucus samples revealed decreased spinnbarkheit and modified crystallization patterns. In vitro sperm penetration depths were remarkably lower in the treated groups than in the controls the means ranging from .6 cm (megestrol) to .8 cm (cingestol) compared with 3.4 cm in the control group. Spermatozoa were poorly motile or immotile. In the endometrial samples atypical rhythmic development of the glands and stroma were observed. Secretory changes occurred in 42% (megestrol) to 60% (cingestol) of the patients and proliferative pattern changes occurred in 31% (chlormadinone) to 44% (quingestanol). Normal corpora lutea were seen in 9 of the 14 ovarian biopsies but distended follicular cysts with or without luteinization were seen in half of these cases. Ovarian changes and 24-hour pregnanediol levels were in contradiction with endometrial patterns. No significant differences were noted between the different minipill compounds and their functional alterations. It is concluded that low-dose progestogens achieve their contraceptive effect through interference with sperm migration in the cervical mucus alteration of endometrial morphology and possible interference with hormonal equilibrium.

Life table analysis of a clinical study of a once-a-month oral steroid contraceptive: Quinestrol — Quingestanol

A clinical study of a long-acting oral steroid formulation, containing 2.0 mg quinestrol and 2.5 mg quingestanol acetate, was undertaken during a 31-month period. A total of 212 women were enrolled in the study and 2,781 women-months experience was accumulated. Life-table analysis of event rates at the end of 1 year revealed the event rates for discontinuation to be 7.3 for pregnancy, 11.2 for abnormal bleeding and 17.3 for other medical reasons. The cumulative continuation rate at the end of 1 year was only 46.9, indicating this method was not well accepted in this population group.

Effect of ovarian hormones and synthetic progestins on vaginal sialic acid in the rat.

SUMMARY Total amount and concentration of vaginal sialic acid were determined in rats after ovariectomy and treatment with oestradiol, progesterone, norethindrone acetate and quingestanol acetate. Sialic acid concentration increased after ovariectomy and decreased after subsequent treatment with oestradiol. Progesterone had no effect on sialic acid concentration in spayed rats. The synthetic progestins norethindrone acetate and quingestanol acetate, given orally, showed a diphasic effect, increasing vaginal sialic acid concentration at low doses and decreasing it at higher doses. These results are discussed in the light of the oestrogenic properties of progestins derived from 19-nortestosterone.

Ether derivatives of a progestin and estrogen in monthly dosage

The monthly ingestion of quingestanol acetate (2.5 mg) and quinestrol (2 mg) for 1 year by menopausal women was associated with increased numbers of superficial cells in Daginal smears and decreases in intermediate and parabasal cells. High serum FSH and LH levels were promptly returned to normal and remained normal. Serum triglyceride and T4 levels and plasma 11(OH) corticosteroids were consistently increased. Serum inorganic phosphorus and calcium levels decreased during the first month of treatment and remained decreased throughout the year. The calcium and phosphorus changes could reflect a protein‐anabolic effect with deposition of these ions in bone salts, but alternative explanations can be suggested. Serum solutes other than those already cited, serum enzymes, hematologic findings, electrocardiographic tracings, urinary steroids and creatinine, glucose tolerance and the associated serum insulin and growth hormone patterns, and a number of other routine laboratory procedures were not consistently affected by therapy with these dosages of quinestrol and quingestanol acetate. After 1 year of treatment urinary steroids and their responses to oral metyrapone were unchanged. Possible side etfects occurred in 3 of 18 patients: malaise, generalized pruritus, nausea, vomiting, and dizziness.