Pituitary and ovarian function during contraception with one subcutaneous implant releasing a progestin, ST-1435

Three women received one subcutaneous SilasticR capsule containing 40 mg of ST-1435 for contraception. Plasma levels of ST-1435, a 19-norprogesterone derivative, were measured during the treatment period of 13-15 months. The effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. The mean concentrations of ST-1435 during the treatment varied from 52 to 220 pg/ml in different subjects. These low concentrations of progestin were sufficient to suppress ovulation and make the implant effective for more than one year. No mid-cycle gonadotropin peaks were observed during the treatment. The subjects showed constantly low estradiol levels, thus also indicating a suppression of follicle development. Regular cyclic activity of the pituitary and ovaries, without the occurrence of ovulation, was observed in one subject. Increasing levels of estradiol parallelled a decrease of FSH and LH. It therefore seems that the negative feedback action of estradiol on gonadotropin release is unaffected but the positive feedback action of estradiol on LH appears to be blocked by the progestin ST-1435.     

Contraception with subdermal ST-1435 capsules: side-effects, endocrine profiles and liver function related to different lengths of capsules

One Silastic capsule of 15 mm, 20 mm or 30 mm length was inserted subcutaneously into the ventral aspect of the left forearm or upper arm of 28 healthy women during menstrual bleeding or not later than on the seventh day of the menstrual cycle. A new capsule of the same length was inserted after six months and both capsules were removed twelve months after the first insertion. Side-effects, including changes in body weight, blood pressure, menstrual bleeding and liver function test results, were registered. Blood samples were taken from selected subjects twice a week during the 1st, 2nd, 3rd, 6th, 7th and 12th month of use. Plasma concentrations of ST-1435 were measured by radioimmunoassay and the effects of treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. There were no differences in hormonal side-effects between subjects who had a 30 mm capsule or subjects who had 20 mm or 15 mm capsules, but subjects who had 20 or 15 mm capsules had significantly longer bleeding or spotting periods in comparison with subjects who had a 30 mm capsule. There were no changes in blood pressure, body weight or liver function test results in comparison with pre-insertion values. The plasma level of ST-1435 was not significantly higher during the use of 30 mm capsules than during the use of 20 or 15 mm capsules. During the use of the shorter ST-1435 capsules, plasma estradiol elevation and slightly suppressed FSH were seen, while the use of longer capsules resulted in a slight suppression of LH. Progesterone concentrations during monitored cycles indicated anovulation. No pregnancies occurred during the study period of one year. The continuation rate at one year was 71% in the 30 mm capsule group and 57% in the 20 and 15 mm capsule groups taken together.     

Milk and plasma concentrations of the progestin ST-1435 in women treated parenterally with ST-1435

A subcutaneous contraceptive capsule releasing progestin ST-1435 was used by 6 breast-feeding women. One to three paired milk and plasma samples were collected over a one-month period and the concentrations of ST-1435 were determined by radioimmunoassay. An improved and sensitive method for determination of ST-1435 in milk was developed. A column chromatographic purification of milk prior to radioimmunoassay decreased the blank and improved sensitivity. The average plasma concentration of ST-1435 was 62 +/- 20 pg/ml (mean +/- SD). The average milk concentration of ST-1435 was 38 pg/ml (ranging from 7 to 73 pg/ml), while the average milk to plasma ratio was 0.60 (ranging from 0.25 to 0.91). There was a significant correlation between ST-1435 concentrations in breast milk and plasma, indicating that the concentration in plasma is the major determinant for the amount of ST-1435 excreted into milk. Since studies with this drug have shown good contraceptive efficacy and low bioavailability after oral intake, ST-1435 is a good candidate for lactational contraception.     

Contraception with subdermal implants releasing the progestin ST-1435: a dose-finding study.

A new modified subdermal implant releasing the potent progestin ST-1435 was studied in eleven fertile-aged women. These implants have been developed for contraception and they have a life-time of two years. Three implant lengths of 4, 6 and 8 cm were tested to find the optimal steroid dose for inhibition of ovulation. Serum samples were collected twice per week during a six-week period every six months. The concentrations of serum ST-1435, estradiol and progesterone were determined by RIA. Ovulation was inhibited by all ST-1435 doses tested. The concentration of serum progesterone was below 6 nmol/l in all samples tested showing the absence of luteinization. The concentration of serum ST-1435 increased with increasing ST-1435 dose. Serum estradiol concentrations were quite variable, showing wide range and occasional high peak values typical of progestin treatment; the mean value of serum estradiol concentrations measured did not differ with different ST-1435 doses. The results of steroid determinations led to the conclusion that a single 4 cm subdermal implant is optimal for contraception. With this dosage level, ovulation is inhibited and side effects are minimized. Bleeding control was variable. No hormonal side effects due to the progestin ST-1435 were reported. This method, using a single 4 cm subcutaneous implant releasing the progestin ST-1435 with a life-time of two years, represents a promising alternative for inhibition of ovulation and contraception.     

Unaltered lipoprotein and carbohydrate metabolism during treatment with contraceptive subdermal implants containing ST-1435

Nine healthy, fertile women were treated for six months with subdermal contraceptive implants of two different sizes containing a potent progestogen, ST-1435. Lipoprotein cholesterol and triglyceride concentrations were not influenced by the treatment. Similarly, the main apolipoproteins in low- and high-density lipoproteins were not changed, which further supports the interpretation that the lipoprotein metabolism is not affected by this type of treatment. An oral glucose tolerance test (OGTT) including insulin determinations was performed in five of the volunteers with the largest implants. Blood glucose and insulin concentrations during the OGTT remained unchanged during treatment, indicating that the treatment with ST-1435 did not affect carbohydrate metabolism.     

Contraception with megestrol acetate implants. Megestrol acetate levels in plasma and the influence on the ovarian function

The ovarian steroid pattern and the levels of megestrol acetate in plasma were assessed in 4 women after the insertion of six silastic capsules filled with approximately 35 mg megestrol acetate. The implants were inserted subcutaneously in the ventral part of the left forearm and left in place for 121–226 days.

Judged by the plasma progesterone pattern, no ovulation occurred during treatment, but ovulatory patterns of estradiol and progesterone were restored within 30 days after removal of the capsules.

The estradiol levels in plasma varied. Development of follicles as judged from surges of estradiol was evident in two of the subjects throughout the study.

Frequent and prolonged episodes of spotting and bleeding were found in all subjects during treatment, especially when low plasma levels of estradiol were observed.

A release of approximately 300 μg MA gives a plasma level of around 0.6 ng MA/ml and is sufficient to inhibit ovulation, probably by inhibition of the positive feedback of estradiol on the release of LH.     

Contraception with d-norgestrei silastic rods. Plasma levels of d-norgestrel and influence on the ovarian function

Three silastic rods impregnated with d-norgestrel each containing 40 mg of the gestagen, were inserted subcutaneously in the left forearm of four women and left in place for 100–458 days. After about 300 days of treatment a daily oral dose of 50 Mg ethinylestradiol was given to three of the participants during 21 days, in order to increase the concentration of sex hormone binding globulin in plasma.The plasma levels of progesterone, estradiol and d-norgestrel were analysed by radioimmunoassay.The study demonstrated fairly constant plasma levels of d-norgestrel during treatment. The concentrations observed were in the range found 4–6 hours after intake of the mini-pill formulation of d-norgestrel (0.03 mg).When the sex hormone binding globulin levels were increased by oral ethinylestradiol treatment in the subjects with previous constant d-norgestrel levels in plasma, the d-norgestrel levels increased two- to sixfold indicating that sex hornome binding globulin is the main carrier protein for d-norgestrel.The concentrations of d-norgestrel in plasma did not inhibit the baseline levels of estradiol in plasma, but ovulation was inhibited during the first year of treatment. Ovulatory pattern of progesterone was restored within 20 days after removal of the rods.The amount of d-norgestrel lost from the rods during treatment suggest a contraceptive efficacy of at least 2 years.     

Contraception with a norethisterone-releasing IUD. Plasma levels of norethisterone and its influence on the ovarian function

Five healthy women had a norethindrone (NET)-releasing intrauterine device inserted postmenstrually. During a treatment time ranging between 80 and 114 days, plasma concentrations of NET, estradiol, and progesterone were determined by radioimmunoassay. Initial high plasma concentrations of NET were followed by fairly constant levels between 200 pg/ml and 400 pg/ml. Ovulation occurred regularly during nine out of sixteen studied treatment cycles, four cycles were anovulatory and three cycles showed a suppressed luteal phase. High estradiol peaks in plasma were seen at the time of disturbed ovulation. The bleeding pattern was regular and the menstrual bleeding was reduced in amount.     

Pituitary and ovarian function in women receiving hormonal contraception.

A study was performed to further evaluate pituitary-ovarian function in women receiving an oral contraceptive preparation. Basal hormone levels (follicle stimulating hormone, luteinizing hormone, estradiol and prolactin) and gonadotropic response to gonadotropic releasing hormone were studied in 12 healthy, regularly ovulating women in the early follicular and mid-luteal phases of their menstrual cycle (non-treatment control period). These same women were then given NORDETTE (ethinyl estradiol 30 microgram +d-Norgestrel 150 microgram) cyclically for 3 months. In the third month of treatment, the tests were repeated on day 21, i.e. after 21 active pills, and on day 28, i.e. after 21 active and 7 inactive tablets. On active preparation, basal luteinizing hormone, follicle stimulating hormone and estradiol and gonadotropin response to gonadotropin releasing hormone were significantly suppressed. However, by day 28 (after completion of the inactive tablets), basal gonadotropin and estradiol concentrations and the gonadotropic response to gonadotropic releasing hormone were not significantly different to their pretreatment levels. No consistent change in prolactin concentration occurred as a result of oral contraceptive therapy. These results indicate that the 'active' component of even a relatively low-dose pill causes considerable suppression of pituitary-ovarian function but that after 7 days of placebo, pituitary function and basal estradiol secretion have virtually returned to normal.     

Plasma levels of norethindrone and effect upon ovarian function during treatment with silastic implants containing norethindrone.

The study was made to evaluate the effect upon the ovarian steroid pattern during treatment with subcutaneously implanted silastic rods containing norethindrone. Four rods, each containing 37 mg norethindrone (NET), were implanted subcutaneously in five women and left in place for 135--200 days. Plasma levels of NET, estradiol and progesterone were determined by radioimmunoassays. After an initial peak found in all subjects, the plasma level of NET declined. Great day-to-day variations of NET were found. Ovulations were suppressed during treatment in three subjects. One subject had regular ovulations throughout treatment and in one subject a single ovulation was recorded. Peaks of estradiol without subsequent ovulation were found in two subjects. The bleeding pattern was irregular; three subjects had varying degrees of spotting and bleeding, two subjects were amenorrheic. The average daily release rate was 300/micrograms, calculated from the amount of steroids lost from the removed rods. This study indicates that the release of steroid from four NET rods is high enough only initially to completely inhibit ovulation.     

Transdermal absorption of the progestin ST-1435: therapeutic serum steroid concentrations and high excretion of the steroid in saliva.

The synthetic progestin ST-1435 was administered transdermally to six healthy women during the late luteal phase. The steroid was applied to the periumbilical area in a commercial gel ("Progestogel"), also containing progesterone. Single doses of 2.3, 4.5 and 9.0 mg of ST-1435 were given in three experiments and repeated doses of 2.3 mg of ST-1435 for five days were given in another three experiments. Samples of serum and saliva were collected and the concentrations of ST-1435 and progesterone were determined by radioimmunoassays. Transdermal absorption of the synthetic progestin ST-1435 was shown to result in serum steroid concentrations high enough for therapeutic purposes. The concentration of ST-1435 in serum was still high 24 hours after application, reflecting sustained release of the steroid from the skin. In the five-day experiments, relatively constant serum levels were achieved in different individuals, and a single dose per day seems sufficient. High excretion of ST-1435 in saliva was found two hours after gel application. However, the concentrations of serum and salivary ST-1435 were not directly correlated in different individuals. Transdermal application of ST-1435 might offer a good alternative for systemic progestin treatment.     

Pituitary and ovarian function and clinical performance during the use of a levonorgestrel-releasing intracervical contraceptive device

A levonorgestrel-releasing intracervical device (ICD) was inserted postmenstrually to twenty-one voluntary women. Eight subjects gave blood samples twice a week during the initial three months of use of the ICD and during the seventh and twelfth months of use. Clinical performance was studied; plasma concentrations of levonorgestrel were measured by radioimmunoassay and the effects of the treatment on pituitary and ovarian function were determined by assaying plasma concentrations of LH, FSH, estradiol and progesterone. The results of the first year are presented. Dysmenorrhea, menstrual flow and the number of days of bleeding decreased during the first treatment year. Three spontaneous expulsions occurred; two at the very beginning of the treatment and one after six months of use. Side-effects were few. The plasma level of levonorgestrel remained fairly constant during the observation time of 12 months. Thirty-one of the 36 cycles were ovulatory as judged by plasma progesterone elevations. No pregnancies occurred during the study period of one year.     

Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function

ObjectiveTo evaluate the effects of estetrol 15 mg/drospirenone 3 mg on ovarian function.Study designSingle-center, randomized, open-label, parallel study in healthy young women with proven ovulatory cycles. Participants received either estetrol 15 mg/drospirenone 3 mg (E4/DRSP) (n = 41) or ethinylestradiol 20 µg/drospirenone 3 mg (EE/DRSP) (n = 41) in a 24/4-day regimen for 3 consecutive cycles. Follicular size and endometrial thickness were measured by transvaginal ultrasound every 3 days in cycles 1 and 3. Blood was sampled for hormone analysis. Ovarian function expressed as Hoogland score was based on follicular size, serum estradiol (E2) and progesterone (P) concentrations. Ovulation was defined as a ruptured follicle-like structure >13 mm with serum E2 concentrations >100 pmol/L and serum P concentrations >5 nmol/L. We assessed return of ovulation after treatment cessation, and safety throughout the study.ResultsNone of the participants ovulated with E4/DRSP use, while one participant ovulated once and one participant ovulated twice during EE/DRSP treatment. Most participants had a Hoogland score of 1 (no ovarian activity) in cycle 1 (85.0% and 82.9% of participants on E4/DRSP and EE/DRSP, respectively) and in cycle 3 (65.8% and 83.8%, respectively). E4/DRSP suppressed follicle-stimulating hormone and luteinizing hormone to a lesser extent than EE/DRSP, whereas both treatments comparably suppressed E2 and P and endometrial thickness. Return of ovulation occurred, on average, 15.5 days after E4/DRSP treatment discontinuation. E4/DRSP was safe and well-tolerated.ConclusionsE4 15 mg/DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, comparable to a marketed combined oral contraceptive containing EE/DRSP.Implications statementTreatment with E4 15 mg/DRSP 3 mg showed complete ovulation inhibition, despite less suppression of follicle-stimulating hormone and luteinizing hormone compared to EE/DRSP. If it becomes commercially available, E4/DRSP, containing a naturally occurring estrogen, should be as effective as EE/DRSP.     

Use of a single implant of elcometrine (ST-1435), a nonorally active progestin, as a long acting contraceptive for postpartum nursing women.

Because of its unique features, the contraceptive effectiveness and tolerance during breast-feeding of 16-methylene-17 alpha-acetoxy-19-nor-4-pregnene-3,20-dione (elcometrine), delivered within a single subdermal capsule of medical grade polydimethylsiloxane, was investigated. Unlike other progestational steroids, elcometrine has no affinity for androgen and estrogen receptors and is inactive by the oral route. A total of 66 breast-feeding women receiving elcometrine by the subdermal route were enrolled in the study, and 69 women who elected to use Copper-T380 intrauterine devices (IUD) served as control subjects. The women and their infants were observed until the end of the first postpartum year. There were no significant differences in growth and development measurements among the infants in the elcometrine and control groups. The percentage of infants continuing to breast-feed at 3 and 6 months was significantly higher in the elcometrine group. There were no significant differences between the concentration of elcometrine in the mother's blood and milk. At 75 days, blood levels of elcometrine in the infants were near the undetectable and were significantly lower than the levels in maternal blood or milk (p < 0.01). In 15 of 25 infants, blood levels of elcometrine were at the limit of assay sensitivity or undetectable. Two pregnancies occurred in women using IUD, whereas none occurred in those using implants. There were menstrual bleeding irregularities in both groups. A single elcometrine capsule placed subcutaneously at 6-monthly intervals appears to be an effective method of contraception for lactating women and results in blood concentrations of nursing infants at or near undetectable levels.     

家兔卵巢组织异体皮下移植的形态与功能研究

目的:研究家兔卵巢组织玻璃化冷冻、异体皮下移植后激素水平和卵泡的生长发育情况。方法:将36只裸鼠随机分为4组,分别为正常对照组、新鲜移植组、冻存移植组、去势组。将新鲜和冻融卵巢组织分别异体异位移植到裸鼠颈部皮下,于移植术后第5天开始观察裸鼠的动情周期,术后35天左右动情期测鼠血清雌激素水平,并对各组子宫进行湿重及组织形态学观察比较。结果:新鲜及冻存卵巢组织移植后均可观察到存活组织块,移植卵巢内可见不同阶段的发育卵泡,并可见间质腺和黄体。两种移植组于动情期雌激素水平与正常对照组差异无统计学意义(P0.05),均明显高于去势组。结论:玻璃化法冷冻可以有效保存卵巢组织的结构和功能。冻存复苏后与新鲜卵巢皮质组织具有相同的生理活性。冻存卵巢皮质异体异位无血管皮下移植后能够存活、生长发育,并维持生殖内分泌功能。     

Contraception with long-acting subdermal implants. A five-year clinical trial with Silastic covered rod implants containing levonorgestrel. The International Committee for Contraception Research (ICCR) of the Population Council

A total of 189 women volunteered to accept subdermal implants for contraception. The implants were "covered rods", consisting of a core rod containing equal parts by weight of levonorgestrel and polydimethylsiloxane and sealed inside a thin-walled tube of Silastic tubing with medical adhesive. In one study 78 women used 4 3cm rods (study 07) and in the other 111 women used 6 3cm rods. In 5 years of use there were no pregnancies in either group. Terminations because of menstrual problems were twice as frequent among the 4-rod users than among users of the 6 rods. Menstrual pattern analysis is presented for the two rod regimens and compared with the previously reported patterns for the 6-capsule regimen (NORPLANT). Long--term in vivo release rates are also presented.     

Adult ovarian function can be affected by high levels of soy

Ovarian function in adults is controlled by hormones circulating in the body. The primary hormone responsible for cyclicity in animals and humans is estrogen. Estrogen is mostly produced in the ovary and enters the circulation where it then signals the brain for a response. The parts of the brain that controls reproductive hormones are the hypothalamus and anterior pituitary. Estrogen stimulates the hypothalamus to produce gonadotropin releasing hormone, which in turn signals the anterior pituitary to produce follicle stimulating hormone and luteinizing hormone. These hormones enter the circulation and signal the ovary to ovulate. Substances with estrogenic activity can potentially interfere with this signaling if levels of activity are sufficient to cause a response. Soy foods contain estrogenic substances called phytoestrogens. The predominant phytoestrogens found in soy are genistein and daidzein. The female reproductive system is dependent on hormones for proper function and phytoestrogens at very high levels can interfere with this process. This paper summarizes the literature on adult soy consumption and its effect on ovarian function.     

肝硬化患者血浆维生素C水平与血管内皮功能的关系

目的　探讨肝硬化患者血浆维生素C水平的变化及其与血管内皮释放的一氧化氮 (NO)和内皮素 - 1 (ET - 1 )之间的关系。方法　对 38例肝硬化患者和 30例健康人进行血清维生素C和血浆NO、ET - 1水平进行测定 ,测定血浆维生素C水平采用高效液相色谱分析法 ,测定NO采用化学比色法 ,测定ET - 1水平采用放射免疫法。结果　线性相关分析表明血浆患者血浆维生素C水平与NO水平、ET - 1水平呈显著负相关 (r =- 0 .5 8,- 0 .6 1 ,P <0 .0 1 )。结论　肝硬化患者存在血浆维生素C水平降低 ,NO、ET - 1水平升高 ,且随肝功能损伤加重血浆维生素C水平降低 ,血管内皮功能损伤加重