Inhibition of the positive feedback of oestradiol during treatment with subcutaneous implants of d-norgestrel.

The effects of d-norgestrel (40 mg), contained in a single dimethylp olysiloxane rod implanted subcutaneously in the gluteal region, were studied in 4 women. The rods were left in place for 93-128 days. Based on the pattern of plasma progesterone levels; all of the subjects appeared to ovulate. However, the inhibition of the positive feedback effects of natural estrogens indicated that ovulation was suppressed. There was no increase in plasma progesterone concentrations over the 3-4 month treatment period. Plasma estradiol concentrations fluctuated irregularly and showed surges characteristic of the midcycle peak. Plasma gonadotropin levels fluctuated periodically, though midcycle peaks of luteinizing hormone (LH) and follicle stimulating hormone (FSH) did not occur. FSH and LH concentrations were low when estradiol concentrations were high, and vice versa. Plasma concentrations of the hormone were similar to those found during the 1st 6-8 hours after ingestion of low-dose d-norgestrel. All the subjects had unpredictable bleeding patterns during treatment.     

Serum profile of gonadotropins and ovarian steroids in women during six months of treatment with ORG 485-50

The effect of Org 485-50¹ on endocrine parameters of the pituitary and ovarian function has been studied in seven healthy women. Daily serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol-17β and progesterone were measured by specific radioimmunoassay throughout the control and seventeen treatment cycles during a drug trial period of six months. The results show that Org 485-50 at this dose caused anovulation in seven medication cycles. All other treatment cycles had a significant, though variable, suppression of progesterone secretion. The biphasic pattern of estradiol secretion was similar in control and medication cycles, but the overall output of estradiol decreased during prolonged treatment. Midcycle LH surge was abolished in seven and impaired in ten of the treatment cycles. It is noteworthy that the alteration of the hormone profiles caused by Org 485-50 was markedly different between the individuals. The changes of the endocrine parameters indicative of anovulation or inadequate corpus luteum function were, in different individuals, constant or variable during treatment with Org 485-50.     

The endocrinological profile of normal menstrual cycles in a population of Chinese women

Endocrinological profiles of normal menstrual cycles were studied in 41 Chinese women. Daily serum concentration of luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2) and progesterone (P) were determined by RIA. Thirty-four cycles were of normal length (26-35 days) and 6 cycles were prolonged up to 40 days with a follicular phase of 22-26 days. One cycle was anovulatory. Cyclical changes of LH, FSH, E2 and P were typical of ovulatory cycles in other populations as reported in the literature. In the normal cycle group the geometric mean of the LH midcycle peak level was 46 IU/1, the FSH peak was 10 IU/1, the preovulatory estradiol peak was 1229 pmol/1 and the progesterone luteal maximum was 50 nmol/1. The pattern of cyclical changes in the prolonged ovulatory cycles was similar to the normal length cycles, except that there were significantly higher levels of LH in both follicular and luteal phases, lower FSH in luteal phase, and lower progesterone in luteal phase. A majority of cycles had a midcycle elevation of prolactin and mean PRL levels in the late luteal phase were higher than those in the follicular phase.     

Pituitary, ovarian and endometrial effects of 300 micrograms norethisterone and 30 micrograms levonorgestrel administered on cycle days 7 to 10

The ovarian, endometrial and pituitary effects of 300 micrograms norethisterone (NET) and 30 micrograms levonorgestrel (L-NOG) administered orally on cycle days 7-10 were investigated in two groups of 10 women each, by daily analysis of plasma estradiol (E2), progesterone (PROG), immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) in a pretreatment control cycle and during NET or L-NOG administration. Endometrial biopsies were obtained for morphometric analysis on cycle day 11 in the control and treatment cycles. Treatment with 300 micrograms NET resulted in an increase in the area under the E2 peak (p less than 0.05), reduction in the number of subjects with normal progesterone profile (p less than 0.05) and a decrease in the area under the progesterone curve (p less than 0.05). The treatment suppressed the LH peak in 4 subjects and progesterone in 4 subjects. The follicular phase was prolonged in one subject. Norethisterone induced marked subnuclear vacuolation in the endometrium, while the glandular mitoses were decreased during NET treatment. Treatment with 30 micrograms L-NOG resulted in a decrease in subjects with normal progesterone profiles (p less than 0.05) and in the area under the progesterone curve (p less than 0.05). The treatment suppressed the LH peak in 3 subjects and progesterone in 4 women. The follicular phase was prolonged in one subject. L-NOG did not significantly increase the diameter of glands or induce subnuclear vacuolation in the endometrial glands.     

Ovulation inhibition by a new low-dose progestagen.

A new synthetic progestagen, Org 2969 (13-ethyl-11-methylene-18,19-dinor-17alpha-pregn-4-en-20-yn-17-ol) was administered to 9 healthy normally menstruating women. 3 subjects (Group 1) ingested .030 mg, while 6 (Group 2) ingested .015 mg of the compound daily on Days 1-20 of 1 menstrual cycle. The previous menstrual cycle served as control. Serum follicle stimulating hormone, luteinizing hormone, progesterone, and estradiol analyzed on the Days 8-23 showed that all the treatment cycles of Group 1 were anovulatory and 2 subjects from Group 2 had ovulatory cycles. Serum activities of aspartase amino transferase, alanine amino transferase, alkaline phosphatase, gamma glutamyl transpeptidase, and bilirubin concentration determined on Days 8, 15, and 23 did not reveal any change in liver function. Serum cortisol measured on Days 8 and 23 remain unchanged. 1 subject from Group 1 and 3 from Group 2 experienced bleeding irregularities.     

Endocrine effects of chlorinated hydrocarbons in rhesus monkeys.

After the rhesus monkey was demonstrated to be a suitable model for man in both metabolic and endocrinological studies, effects of hexachlorobenzene (HCB) and polychlorinated biphenyls (PCB) on the pattern of sexual hormones in cycling female rhesus monkeys were investigated. After confirmed ovulation, four adult female rhesus monkeys were treated during the following cycle with 4 mg/kg/day of HCB, and four other monkeys were treated with the same dose of Clophen A 30. Ovulation was blocked in three PCB-treated and one HCB-treated monkeys. Whereas the levels of luteinizing hormone and follicle-stimulating hormone did not seem to be changed directly by the treatment, low estrogen levels were found during the anovulatory cycles. Studies with PCB- and HCB-treated superovulated rats indicated interaction of the chemicals with ovarian steroidogenesis. Altered hepatic steroid metabolism may also cause low estrogen levels in treated animals.     

The effects of chronic administration of LH-RH agonists and antagonists on the menstrual cycle and endometrium of the rhesus monkey

Regularly cycling rhesus monkeys (Macaca mulatta) were used to study the effects of prolonged administration of LH-RH analogs on the menstrual cycle and the endometrium. According to the treatment, animals were divided into: Group 1, vehicle; Group 2, LH-RH agonist (D-Trp6 LH-RH, 20 micrograms/day); and Group 3, LH-RH antagonist [( N-Ac-D-Trp1,3, D-p-Cl-Phe2,D-Arg6,D- Ala10 ]-LH-RH,200 micrograms/day) for 90 days. Follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and progesterone (P) were measured every second day until thirty days past the discontinuation of drug administration. Endometrial biopsies were obtained on days 10, 40, 90 and 120 and processed for histologic exam and determination of estrogen (E) and progesterone receptors. Animals of Group 1 presented regular cycles, while those in Groups 2 and 3 remained anovulatory throughout the treatment. Animals of Group 2 presented different degrees of endometrial hyperplasia during treatment and animals of Group 3 showed either resting or atrophic endometrium. Administration of LH-RH agonist produced a marked increase in E and P endometrial receptors and the antagonist produced a decrease in P receptors. In both instances, reversal of the effects on the menstrual cycle and in the endometrium was observed 30 days after discontinuation of drug administration.     

Studies on low dose oral contraceptives: plasma hormone changes in relation to deliberate pill ('Microgynon 30') omission.

The effects of deliberate omission of a Microgynon 30 (150 mcg of levonorgestrel and 30 mcg of ethinyl estradiol) tablet in the early and latter course of the pills were investigated by hormonal profiles (published figuratively) of luteinizing hormone, follicle stimulating hormone (FSH), estradiol 17-beta, and progesterone. 3 women deliberately missed Day 19, and blood samples were drawn from Day 17-24; 7 women deliberately omitted Day 4 treatment, and their blood was drawn from Day 1-7. Blood levels, contrary to previous findings which noted a sharp rise in FSH and near zero titers of steroids after omission of a Microgynon 30 tablet unintentionally, did not show any marked rise either early or late in the cycle omission. Cervical mucus examined in 6 of the subjects displayed physical characteristics associated with an uninterrupted ancillary contraceptive effect.     

Ovulatory potential of preovulatory sized follicles during oral contraceptive treatment

The ovulatory potential of preovulatory follicles was studied in five women taking monophasic gestodene pills containing 20 micrograms of ethinyl estradiol. After one normal pill cycle, follicles were allowed to grow to 16 mm in diameter by deliberate extension of the pill-free period. Once the size of the leading follicle reached 16 mm, the women resumed oral contraceptives for the following 21 days to investigate whether ovulation can be inhibited by late onset of the pill. In addition, 100 micrograms of gonadotropin releasing hormone analog was given intravenously on the third pill day to induce ovulation. Follicular growth and activity were monitored by ultrasonography and by serum concentrations of ethinyl estradiol, progesterone, luteinizing hormone, and follicle stimulating hormone from the last pill day of the first cycle until the end of the second pill intake of 21 days. An increase in luteinizing hormone secretion started before intravenous administration of a gonadotropin releasing hormone analog in all women, eventually leading to ovulation in four of five women. One woman developed an unruptured follicle. Thus, the ovulatory potential of a 16-mm functional follicle cannot be inhibited by reintroduction of pills containing 20 micrograms ethinyl estradiol and 75 micrograms of gestodene.     

Effect of norethindrone acetate released from a single silastic implant on serum FSH, LH, progesterone and estradiol-17beta of women during first eight months of treatment

4 healthy women of proven fertility and normal menstrual cycles were implanted with a single silastic implant D, filled with norethindrone acetate (ENTA) in order to study the effect of continuously released low levels of ENTA (150 mcg/day) on serum levels of follicle stimulating hormone, luteinizing hormone, estradiol-17beta, and progesterone and to assess the site of action. Steroids were measured by radioimmunoassay before the implant and 2-4 cycles during the first 8 months of treatment. Values of steroids prior to implant indicate that all subjects were ovulatory before treatment. During the 1st few months of use, values indicate that ovulation continued unsuppressed. Later cycles demonstrated hormonal disturbances with low serum progesterone during the luteal phase in most of the treatment cycles when compared with controls. Results indicate a gradually increasing suppression on the pituitary-gonadal function.     

Pituitary, ovarian and endometrial effects of 300 μg norethisterone and 30 μg levonorgestrel administered on cycle days 7 to 10

The ovarian, endometrial and pituitary effects of 300 μg norethisterone (NET) and 30 fig levonorgestrel (L-NOG) administered orally on cycle days 7–10 were investigated in two groups of 10 women each, by daily analysis of plasma estradiol (E₂), progesterone (PROG), immunoreactive luteinizing hormone (LH) and follicle stimulating hormone (FSH) in a pretreatment control cycle and during NET or L-NOG administration. Endometrial biopsies were obtained for morphometric analysis on cycle day 11 in the control and treatment cycles. Treatment with 300 μg NET resulted in an increase in the area under the E₂ peak (p<0.05), reduction in the number of subjects with normal progesterone profile (p<0.05) and a decrease in the area under the progesterone curve (p<0.05). The treatment suppressed the LH peak in 4 subjects and progesterone in 4 subjects. The follicular phase was prolonged in one subject, Norethisterone induced marked subnuclear vacuolation in the endometrium, while the glandular mitoses were decreased during NET treatment. Treatment with 30 μg L-NOG resulted in a decrease in subjects with normal progesterone profiles (p<0.05) and in the area under the progesterone curve (p<0.05). The treatment suppressed the LH peak in 3 subjects and progesterone in 4 women. The follicular phase was prolonged in one subject. L-NOG did not significantly increase the diameter of glands or induce subnuclear vacuolation in the endometrial glands.     

Effects of postovulatory norethindrone and estrogens on the plasma levels of estrogen and progesterone in rhesus monkeys

Norethindrone, ethinylestradiol and diethylstilbestrol were administered during the luteal phase in 31 menstrual cycles in rhesus monkeys. In eight of these cycles, chorionic gonadotrophin was administered when treatment with the compounds was discontinued. The effects of the compounds on the estrogen levels in plasma were insignificant.During treatment with norethindrone, progesterone levels decreased. A slight increase after treatment occurred in some cycles. Treatment with diethylstilbestrol resulted in an initial depression followed by an increase of plasma progesterone levels. The progesterone levels either increased or remained unchanged during and after ethinylestradiol treatment. Chorionic gonadotrophin administration after treatment with the compounds resulted in rapid surges of both progesterone and estrogen levels in the monkeys treated with the estrogens, but not in the monkeys treated with norethindrone.     

不孕症实施腹腔镜下输卵管、卵巢电凝电切手术对卵巢功能的近期影响

目的:研究不孕症腹腔镜下实施输卵管、卵巢电凝、电切手术对卵巢功能的近期影响。方法:不孕症行腹腔镜下输卵管、卵巢电凝、电切手术53例,分别于术前(月经第2～3天),术后第1天、第5天、1个月(月经第2～3天)、3个月(月经第2～3天)抽血测定卵泡刺激素(FSH)、黄体生成素(LH)、催乳素(PRL)、雌二醇(E2)、孕酮(P)、睾酮(T)水平,术后随访6个月了解其排卵及妊娠情况。结果:53例不孕症患者术后第1天LH、E2、P、T水平增高(P<0.05);术后1个月除E2增高、LH下降(P<0.05);3个月PRL下降(P<0.05)。术后半年排卵率为92.45%,妊娠率为39.62%。结论:不孕症行腹腔镜下输卵管、卵巢电凝、电切手术不加重卵巢近期功能的损害。不孕症输卵管、卵巢手术后可提高排卵率及妊娠率。     

Immunological reactivity of antibodies produced by Pr-beta-HCG-TT with different hormones.

Antisera produced by injection of Pr-β-HCG-TT in rhesus monkeys ($\text{Macaca mulatta}$) and goat have been analysed for reactivity with various hormones. All antisera bound ¹²⁵I-HCG. β-HCG competed with labelled HCG for binding to the sera in all cases. No cross-reactivity of human placental lactogen (HPL) and human growth hormone (HGH) was seen up to 1μg quantities per assay tube as gauged by competitive inhibition assays. Human follicle stimulating hormone (HFSH), human luteinizing hormone (HLH) and human thyroid stimulating hormone (HTSH) did not compete with ¹²⁵I-HCG at the normal maximum physiological concentration of these hormones. The concentrations in radioimmunoassay system at which the competition appears with other hormones have also been determined.     

Energy restriction does not alter bone mineral metabolism or reproductive cycling and hormones in female rhesus monkeys

Energy restriction (ER) extends the life span and slows aging and age-related diseases in short-lived mammalian species. Although a wide variety of physiological systems have been studied using this paradigm, little is known regarding the effects of ER on skeletal health and reproductive aging. Studies in rhesus monkeys have reported that ER delays sexual and skeletal maturation in young male monkeys and reduces bone mass in adult males. No studies have examined the chronic effects on bone health and reproductive aging in female rhesus monkeys. The present cross-sectional study examined the effects of chronic (6 y) ER on skeletal and reproductive indices in 40 premenopausal and perimenopausal (7-27 y old) female rhesus macaques (Macaca mulatta). Although ER monkeys weighed less and had lower fat mass, ER did not alter bone mineral density, bone mineral content, osteocalcin, 25-hydroxyvitamin D, 1,25-hydroxyvitamin D or parathyroid hormone concentrations, menstrual cycling or reproductive hormone concentrations. Body weight and lean mass were significantly related to bone mineral density and bone mineral content at all skeletal sites (total body, lumbar spine, mid and distal radius; P: < or = 0.04). The number of total menstrual cycles over 2 y, as well as the percentage of normal-length cycles (24-31 d), was lower in older than in younger monkeys (P: < or = 0.05). Older monkeys also had lower estradiol (P: = 0.02) and higher follicle-stimulating hormone (P: = 0.02) concentrations than did younger monkeys. We conclude that ER does not negatively affect these indices of skeletal or reproductive health and does not alter age-associated changes in the same variables.     

Effect of long-term centchroman treatment on some estrogen-sensitive biochemical constituents in the genital organs of female rhesus monkeys (Macaca mulatta)

Effect of long-term Centchroman (3,4,-trans-2,2-dimethyl-3-phenyl-4-p-(beta-pyrrolidinoethoxy)-phe nyl)-7-methoxy chroman) treatment on some estrogen-sensitive biochemical parameters in the genital organs of female rhesus monkey was studied. Centchroman treatment did not demonstrate any consistent pattern of stimulation or inhibition in any of the estrogen-sensitive biochemical parameters. However, glycogen recorded a gradual decline in uterus, cervix and vagina. The results thus indicate that Centchroman evoked a mixed response probably due to manifestations of both estrogenic and antiestrogenic properties.     

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.     

妇科止血灵片联合米非司酮治疗功能性子宫出血的Meta分析

目的 利用Meta分析方法对妇科止血灵片联合米非司酮治疗更年期功能性子宫出血的疗效和安全性进行评价分析。方法检索并选取1989—2020年国内、外公开发表的关于妇科止血灵片联合米非司酮治疗更年期功能性子宫出血的临床随机对照试验文献,筛选符合纳入标准的试验进行研究,采用Revman5.1软件统计并分析相关数据。结果 共有5项研究符合纳入标准。与对照组比较,妇科止血灵片联合米非司酮治疗更年期功能性子宫出血的神经功能缺损临床疗效比数比（OR）合并值为4.02(95%可信区间为2.09～7.73)。促黄体生成素水平的加权均数差（WMD）合并值为-1.90(95%可信区间为–2.35～-1.46)。卵泡刺激素水平的WMD合并值为-4.52(95%可信区间为-7.19～-1.85)。雌二醇水平的WMD合并值为–87.91(95%可信区间为-88.78～-87.03)。孕酮水平的WMD合并值为-3.97(95%可信区间为-5.71～-2.77)。用药安全风险OR合并值为0.89(95%可信区间为0.46～1.73)。结论 Meta分析结果显示,妇科止血灵片联合米非司酮治疗更年期功能性子宫出血安全、有...     

Dose-related actions of GnRH II analog in the cycling rhesus monkey

INTRODUCTION: Gonadotropin-releasing hormone (GnRH) II expression, specific high-affinity receptors for GnRH II and its potent bioactivity in human and baboon tissues led us to hypothesize that GnRH II is a bioactive peptide in primates. We recently demonstrated the contraceptive activity of GnRH II analog in rhesus monkeys. In the present experiment, we extended those studies to the dose-related action of this analog on parameters of luteal function and conception. METHODS: GnRH II analog (0-32 microg/day) or saline was administered via osmotic minipumps for 6 days (Days 1-6 postovulation) to regularly cycling rhesus monkeys mated with fertile males around the time of ovulation. Cycle dynamics was monitored through circulating luteinizing hormone, progesterone and estradiol. Pregnancy was determined by circulating chorionic gonadotropin concentrations. RESULTS: Progesterone production (Days 3-11) was significantly less (p<.05) for animals treated with 2, 4 or 8 microg/mL GnRH II analog than for controls, yet with higher doses of GnRH II analog (i.e., 16 or 32 microg/day), luteal progesterone was not different from that of saline-treated controls. The length of the luteal phase in all treated groups was similar to that of controls. In 18 animals mated at the time of ovulation and then treated with GnRH II analog (2-32 microg/day), no pregnancies resulted. In saline-treated controls, five of eight animals (62.5%) became pregnant. Thus, the contraceptive activity of this GnRH II analog did not correlate with luteal progesterone inhibition. CONCLUSIONS: These data demonstrate a dose-related action of GnRH II analog on luteal progesterone and establish the contraceptive activity of 2-32 microg/day GnRH II analog administered postovulation.     

Ovulation inhibition with nafarelin acetate nasal administration for six months

A group of 24 women with normal menstrual cycles were treated with nafarelin acetate administered in doses of either 125 ug or 250 ug daily intranasally for 6 months. Each subject was studied for one ovulatory control cycle, six treatment cycles, and post-treatment until the return of ovulation was documented. Once a week progesterone, estradiol, follicle stimulating hormone, and luteinizing hormone were measured in the serum. Acute hormone responses to nafarelin acetate were determined on-day 1, day 98 and day 186 of treatment.

Two subjects failed to complete the treatment phase. One subject using the 250 ug daily dose of nafarelin acetate discontinued treatment on the sixth day because of heavy uterine bleeding. One subject using the 125 ug daily dose of the study drug terminated treatment on day 126 because of a 21-pound weight gain.

There were significantly less presumed ovulatory cycles at the higher dose (2 out of 60 cycles) than at the lower dose (10 out of 54 cycles) (p<0.01). On the average menstrual cycles were reestablished 28.5 ± 8.3 (S.D.) days after discontinuing the 125 ug daily dose and 33.7 ± 17.9 (S.D.) days after terminating the 250 ug daily dose. With the higher dose of nafarelin acetate there were significantly fewer bleeding episodes, less number of days of bleeding, and longer cycles. During the treatment phase the area under the LH curve was significantly less and the acute response of LH in the last week of treatment was significantly less with the higher dose of drug. With both doses of nafarelin acotate the acute responses of LH, FSH and estradiol were significantly greater on day 1 than on either day 98 or day 186. Side effects observed during this study included galactorrhea (2 subjects) and vasomotor symptoms (7 subjects).