[Compared action of norethindrone and various steroids on Müller ducts of the female chick embryo]. / Action comparée de la noréthindrone et de divers stéroïdes sur les canaux de Müller de l'embryon femelle de Poulet.

Treatment of female chick embryo with norethindrone (NET), a potent progesterone-like steroid, caused caudal agenesia and cephalic regression of Mullerian ducts as the normal regression induced by anti-Mullerian-hormone in the male embryo. The comparative study of five other progesterone-like steroids shows that only lynestrenol which is metabolized into NET at least in man, possesses the same properties as NET. The four others, i.e. medroxyprogesterone, medrogestone, norgestrienone and 17 alpha hydroxyprogesterone are only able to induce agenesia, an unspecific property, which was observed with many steroidal hormones, as norethandrolone here studied.

Three-year experience with NORPLANT subdermal contraception.

NORPLANTTM (Laboratorios Gutfol, S.A., Mexico City, Mexico) subdermal implants containing levonorgestrel were accepted by 816 women in a two-phase study initiated in 1975 and augmented in 1978. Through 3 years of first-segment use, acceptors experienced five pregnancies, a cumulative net rate of 0.7 per 100, and a gross pregnancy rate of 1.1 per 100. First-segment continuation at 3 years was at the rate of 44.6 per 100, an annual average of 76 per 100. NORPLANT users experienced irregular menstruation, with high interindividual variation, but with normal average numbers of bleeding days and of bleeding episodes. Hemoglobin levels increased moderately during implant use. The incidence of systolic blood pressure readings above 145 mm Hg or diastolic readings above 95 mm Hg was similar to that observed among users of the TCu 200 intrauterine device enrolled under the same selection criteria in the same clinics between the two phases of the NORPLANT study. Comparative data on pregnancy and other rates are also given for these intrauterine device acceptors.

Experimental study of cervical blockage induced by continuous low-dose oral progestogens.

An investigation correlating scanning electron microscopic observations with sperm penetration tests carried out on cervical mucus under the influence of low-dose continuous progestogen (Norgestrienone) is presented. The results demonstrate that such type of contraceptive is involved in drastic alterations of mid-cycle cervical mucus at the macromolecular level. The meshwork which constitutes the infrastructure of the cervical secretion appears to be greatly tightened as a result of the treatment, thus giving the woof a general appearance typical of cervical mucus in the late luteal phase. The immobilizing effect of such modified mucus on spermatozoa is demonstrated and the duration of effectiveness after the administration of a last pill on the morning of day 13 is determined.

PIP: The antifertility and obstructive effects toward spermatozoa of a continuous low-dose progestogen contraceptive are examined in this study. Scanning electron microscopy (SEM) observations were correlated with sperm penetration tests carried out on cervical mucus. 11 healthy women aged 19 to 36 who were using no oral contraceptives were studied for 2 consecutive cycles. During the 2nd cycle, the women took a single, daily low-dose progestogen pill (350 ug of Norgestrienone) from the 1st till the 13th day. Blood samples were collected for determination of plasma estrogen levels, which were found to be normal during the control cycle. The progestogen was found to dramatically alter midcycle cervical mucus at the macromolecular level. The meshwork constituting the infrastructure of cervical secretion appeared to be greatly tightened by the treatment, giving the woof a general appearance typical of cervical mucus in the late luteal phase. The mucus framework revealed a tangle of micelles, and sperms leaving the seminal pool in the vagina were faced with such a succession of exhausting physical obstacles that they were unable to penetrate the uterine cavity. The SEM data shows that rendering the midcycle cervical mucus hostile interferes with sperm transport and this probably accounts for the effectiveness of the continuous low-dose progestogen therapy.

Clinical experience with implant contraception.

Subdermal implants of polysiloxane (Silastic) capsules containing a number of synthetic progestagens have been studied in clinical trials to determine their contraceptive effectiveness and acceptability. The steroids studied include norgestrienone (R2010), gestrigone (R2323), megestrol acetate, d-norgestrel, norethindrone, ST-1435, lynestrenol and R-1364. With some of these steroids, studies have been undertaken with a varying number of implanted capsules. The estimated duration of use varies from 6 months to 6 years depending on dose and release rate of the individual steroid. The results of these studies involving about 5000 women in 8 years, indicate in general a high rate of effectiveness, as well as acceptability. Continuation rates at one year were generally 80% or greater. Abnormal bleeding patterns are the major disadvantage. Studies with implatns containing a combination of estrogen and progestogen are being undertaken in an attempt to improve the bleeding pattern.

Clinical chemistry in women treated with progestogen implants.

Effects on metabolic parameters of six subdermal implants of d-norgestrel, norgestrienone (R2010) and methylnorgestrienone (R2323) were studied in women. In general, tests remained within the normal range. An exception was increases in serum transaminase levels in several subjects on R2323 implants. Average cortisol values showed a tendency to decrease on all three regimens, but remained within the significance only with R2323 at six months and R2010 at 12 months. Serum cholesterol levels showed significant decreases on R2010 implants.

Contraception with long acting subdermal implants: I. An effective and acceptable modality in international clinical trials.

This paper presents results of a double blind, multi-centered and multi-national study of two progestin only subdermal implants used for contraception. A regimen of six capsules of levonorgestrel (Ng) used by 492 women had a net cumulative 12-month pregnancy rate of 0.6 percent and a continuation rate of 74.6 percent. 498 women used six capsules of norgestrienone (R2010) and experienced a net cumulative 12-month pregnancy rate of 3.5 percent and a continuation rate of 79.4 percent. The difference in the pregnancy rate was significant at P less than 0.01, while there was no significant difference in the continuation rates. Menstrual problems were the principal reason for termination of the levonorgestrel regimen, accounting for approximately half of all terminations. There were significantly fewer menstrual problems among users of the norgestrienone (R2010) capsules; the net cumulative 12-month termination rate for this reason was 4.3 percent. Results are compared with continuation and termination rates for acceptors of the Copper T 200 at the same clinics. The low pregnancy rate and reasonably high continuation rate of the norgestrel implants coupled with the fact that the expected effective lifetime of a set of capsules is of the order of 3-5 years appears to warrant further development of this contraceptive regimen.

Long acting contraceptive implants. An analysis of menstrual bleeding patterns.

The menstrual patterns of women using subdermal implants of levonorgestrel and norgestrienone included in a double-blind clinical trial was evaluated by the method developed by the International Committee on Contraception Research. Women using Copper T200 randomly selected in the same clinics were used as controls. Both implant regimens were associated with a high frequency of reduced bleeding and norgestrel patients had also a high proportion of increased and irregular bleeding. Termination of use was associated to increased bleeding but not so much to reduced bleeding.

The effects of a once-a-week steroid contraceptive (R2323) on lipid and carbohydrate metabolism in women during three months of use.

Forty-four women were prospectively evaluated with a 3-hour oral glucose tolerance test while they used a new weekly oral contraceptive drug, R2323. The blood tests were carried out before the drug was administered and again 3 months after its use. Both blood glucose and plasma insulin levels were measured. In the 40 women with a "normal" control glucose tolerance test, it was found that only the 1-hour blood glucose value was significantly elevated after 3 months of drug use and the plasma insulin values were unchanged. The tests of three of the four women with borderline abnormal to abnormal control test curves converted to normal with 3 months of treatment and that of one remained unchanged. The fasting plasma cholesterol and triglyceride levels were unchanged over the 3 months' time. These results suggest that this steroid contraceptive has no effect on lipid metabolism. It also has minimal adverse effects on normal carbohydrate metabolism and may possibly improve abnormal metabolism.

The effect of a synthetic progestine on the fine structure of the epididymal head (stereological analysis).

The alterations induced in principal cells of the epididymal head tissue of the rat by administration of a synthetic progestine (R2323, ethinyl-norgestrienone) were studied by electron microscopy. A total of 3 male, sex mature rats was applicated ethinyl-norgestrienone during a 3 months period in low dosage (60 mug) per day and was studied with 5 control animals. Stereological methods devised by Weibel (1969) and Rohr et al. (1976) were applied to light and electron micrographs. The calculated values are related to 1 cm3 of epididymal tissue, 1 cm3 of epididymal cell and 1 cm3 of epididymal cell cytoplasm. The Golgi apparatus was further subdivided; the values for the Golgi compartments are therefore refered to 1 cm3 of Golgi apparatus was further subdivided; the values for the Golgi compartments are therefore refered to 1 cm3 of Golgi apparatus. In the treated animals there was, related to the unit of epididymal tissue, a significant decrease in the volume density of the interductular tissue, whereas that for the lumina was significantly higher. The volume density of the glandular epithelium remains unchanged. Refered to the unit volume of principal cell cytoplasm the rough endoplasmic reticulum shows a signficant decrease by 6.5%, whereas the smooth endoplasmic retiuclum is increased by 6.3%. The volume density of the lysosomes was calculated to be 4.3% (Control 2.5%). The stereological data of the Golgi apparatus indicate a vacuolar transformation: Increased volume of vacuoles, decreased volume fraction of saccules and vesicles. However, the volume density of the whole Golgi apparatus remains unchanged. An impaired secretory activity of the principal cells could be assumed.

PIP: The effect of a synthetic progestin (ethinyl-norgestrienone) on the epididymal head (stereological analysis) was studied in the rat by electron microscopy. 3 male mature rats were treated during a 3-month period in low dosage (60 mcg/day) and were studied with 5 control animals. The calculated values are related to 1 cc of each of the following: epididymal tissue, epididymal cell, and epididymal cell cytoplasm. In the treated animals there was a significant (p less than .05) decrease in volume density of the interductular tissue, whereas that for the lumina was significantly (p less than .05) higher. The volume density of the glandular epityhelium remained unchanged. The rough endoplasmic reticulum showed a significant (6.5%, p less than .05) decrease whereas the smooth endoplasmic reticulum increased (6.3%, p less than .05). The volume density of the lysosomes was 4.3% (control 2.5%). The stereological data of the Golgi apparatus indicate a vaculolar transormation due to increased volume of vacuoles, and decreased volume fraction of saccules and vasicles. However, the volume density of the whole Golgi apparatus remained unchanged, perhaps because of an impaired activity of the principal cell.

Ultrastructural stereology: a new approach to the study of prostatic function.

Stereology is a method used to obtain quantitative information of structural changes at the light and electron microscopic level. The basic principles of stereology are outlined below. This paper shows how stereologic techniques can be used to obtain structural data from histologic and electron micrographs of intact tissue and cells. A morphometric model, which provides information on the structure of the prostatic gland has been developed for the rat prostate. The model consists of morphologically defined space and membrane compartments of the prostatic gland and the glandular cells. The alterations, induced in the glandular cells of the ventral lobe of rat prostate by the administration of a synthetic progestin (ethinyl-norgestrienone), were studied by electron microscopy. The results presented are relative to a cubic centimeter of prostatic tissue, a cubic centimeter of acinar parenchyma, and glandular cell cytoplasm. An attempt to relate stereologic and biochemical data is shown.

Steroidal compounds (injectable and implants) affecting spermatogenesis in men.

The effect of androgen and different progestins on spermatogenesis was studied in young men with subfertility, prostatovesiculitis and haematospermia, and in older men with benign hypertrophy of the prostate. The compounds (testosterone, testosterone oenanthate, ethinyl oestradiol, megestrol acetate, ethinyl norgestrienone and Depo-Provera) were administered intramuscularly, orally or as subcutaneous silastic implants.

Action of midcycle contraceptive (R 2323) on the human endometrium.

Over 2,148 cycles of midcycle oral administration of R 2323 (50 mg. per day on Days 15,16, and 17), the authors recorded a drug-failure pregnancy rate of 5 per cent and an unusually regular cycle length of 28 +/- 2 days. During this trial, endometrial biopsies obtained in the luteal phase were examined by light and electron microscopy and compared to pretreatment biopsies. Light microscopy indicated a weakly secretory endometrium suggestive of some, albeit low, progesterone impregnation. Ultrastructural examination revealed deleterious changes in the development of the nucleolar channel system and giant mitochondria and a delay in the migration of glycogen granules. This low progesterone impregnation could be explained either by a direct effect of R 2323 on cell ultrastructure or by interference with progesterone availability. It would appear that R 2323 acts as a temporary substitute for progesterone at the receptor level but that it does not induce all the biological manifestations of this hormone, in particular, the endometrial changes required for implantation.

The effect of progestin R 2323 released from vaginal rings on ovarian function.

PIP: The effect of progestin R 2323 released from intravaginal rings (IVR) on ovarian function was studied in 20 young healthy volunteers. The silastic IVRs containing 10, 20, 50, or 200 mg of progestin R 2323 were inserted on the 1st day after menstrual bleeding and removed 21 days after insertion. The IVRs were tolerated well without irritation or alteration of the vaginal mucosa. Control plasma estradiol and progesterone levels revealed 18 of 20 cycles were ovulatory. No ovulation was observed during treatment, as revealed by consistently suppressed progesterone levels. Normal ovulation resumed after removal of the rings. 3 women experienced withdrawal bleeding; 9 had breakthrough bleeding and 13 had a normal postovulatory bleeding 15-33 days after ring removal. It was concluded that the bleeding control was unsatisfactory with every dosage of R 2323 used in this study.^ieng

[Hormone regulation of male fertility]. / Regulación hormonal de la fertilidad masculina

PIP: An innocuous, sure, reversible means of male fertility control which does not disturb the libido is being sought. 20 healthy volunteers from ages 20 to 36 participated, using a 2nd form of protection when necessary. 10 received implants of 60 mg testosterone equally divided into 3 tubes, and began oral ingestion of 100 mg weekly, divided into daily doses, of R2323 (13-ethyl-17-hydroxy-gonen 4,9,11, trien-3-one) until the sperm became ineffective. Then oral doses were given according to personal requirements from 50 to 25 mg. The 2nd series of 10 received no testosterone implants, but followed the same scheme for oral ingestion. All patients but 1 reduced their sperm count and 80% were low enough to consider the sperm inactive. For those who used the hormone treatment as the only protection against pregnancy, no pregnancy occurred. Of the 1st group, 2 had excessive weight gain, 3 felt their libido reduced, and 1 had pain in the nipples and 1 had pain in the hepatic region. Recuperation of normal sperm characteristics was slow, especially motility and vitality. The spermogram is so altered during treatment that any accidental pregnancy could result in a defective egg and serious complications. It should definitely be avoided.^ieng