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PubMed1976

Cyclic changes of cervical mucus enzymes related to the time of ovulation II. Amino peptidase and esterase.

The enzymes amino peptidase and esterase were identified in human cervical mucus. Their concentration was serially determined during a menstrual cycle in 5 normal ovulatory women and correlated with the time of ovulation as monitored by the basal body temperature and radioimmunoassay of serum luteinizing hormone (LH), progesterone, and estradiol (E2). The activity of both enzymes decreased at midcycle just before the LH surge and began to rise after ovulation. The preovulatory decline in enzyme activity was significant for esterase but not for amino peptidase. The site of production and functional significance of these enzymes are not at present identified.

Adult↗
PubMed1998

Endometrial morphology during hormone replacement therapy with estradiol gel combined to levonorgestrel-releasing intrauterine device or natural progesterone.

OBJECTIVES: To evaluate endometrial responses to three different forms of amenorrhea-inducing HRT in postmenopausal women. MATERIAL AND METHODS: Fifty-one postmenopausal women completing a one-year HRT trial with percutaneous estradiol gel containing 1.5 mg estradiol daily combined with a levonorgestrel-releasing intrauterine device (LNG-IUD) (n=18), or natural progesterone 100 mg daily orally (n= 19) or vaginally (n=15) during 1-25 calendar days of each month. Endometrial thickness and uterine size were measured by transvaginal ultrasound, and endometrial cytology/histology was assessed from specimens taken by needle aspiration before the study and at 12 months. RESULTS: Before medication, the median endometrial thickness was 2.0 mm in the LNG-IUD group, 2.4 mm in the oral P group and 2.5 mm in the vaginal P group. At 12 months of therapy the respective values, 3.0, 2.7 and 2.4 mm, did not differ significantly from the initial values. LNG-IUD induced epithelial atrophy in all women, which was accompanied by stromal decidualization in 12 women. On the contrary, only four women in the oral P group and five women in the vaginal P group had an inactive or atrophic endometrium. The remaining cases were dominated by proliferative features. No hyperplasia was seen in any of the groups. CONCLUSION: LNG-IUD appeared to be an effective method of counteracting the stimulatory effect of estrogen on the endometrium, whereas natural progesterone given orally or vaginally was not sufficiently effective in this function at the doses used. The vaginal and oral administrations of progesterone did not differ from each other in this respect.

Administration, Oral↗
PubMed1976

Pituitary responses to LRH in the postpartum periods.

Pituitary responses to luteinizing-hormone-releasing-hormone (LRH) in the postpartum periods were studied. Following a subcutaneous injection of 100 mug of synthetic LRH to postpartum subjects, no statistically significant changes in the levels of LH and FSH could be demonstrated in five subjects on postpartum day 1 or 3 and the three subjects on postpartum day 8. A normal elevation of LH and FSH following LRH was demonstrated in one subject 36 days post partum. The findings are in agreement with previous studies demonstrating a persistence of pituitary suppression during the early postpartum period. No correlation could be drawn between the pituitary responses to LRH and the plasma levels of estradiol-17 beta and progesterone.

Estradiol↗
PubMed1977

Prevention of the abortifacient action of antiprogesterone serum by progesterone.

Earlier studies1-4 showed that when rats of 10 days' gestation are passively immunized with antiprogesterone (A-P) globulins the biologically available progesterone (P) unbound by A-P (Pu) not only falls precipitously but also remains low for days, despite the rapid clearance of A-P. This finding suggested that the effective reduction of Pu affects P synthesis, probably through action on the fetoplacental unit. If so, pregnancy should be protected from the effect of A-P by P treatment to prevent the reduction of Pu. The present studies demonstrated that if P treatment was delayed for six hours after the administration of A-P, Pu did not return to physiologic levels, and pregnancy did not continue. However, if P was given three hours after A-P, at the same time, or three hours before A-P, the reduction of Pu was short-lived or prevented, and thus pregnancy was protected.

Abortifacient Agents↗
PubMed1981

Estradiol and progesterone receptors in estrogen-primed endometrium.

Estradiol and progesterone receptor levels were measured in endometrial samples obtained from patients who were on different dosages of estradiol therapy and from women in the late proliferative phase of a normal menstrual cycle. Samples of blood were collected at the time of biopsy, and the levels of estradiol, estrone, progesterone, follicle stimulating hormone, and luteinizing hormone were measured in the serum. The patients were divided into five groups. The first group (controls) consisted of patients in their late proliferative phase. The patients in groups two, three, and five were receiving estradiol in various doses by pellet therapy, along with a cyclic progestogen each month. The women in the fourth group also had implantation of estradiol pellets but failed to take the progestogen as advised. In our series, the levels of cytoplasmic estradiol and progesterone receptors were markedly elevated in the no progestogen group compared to the controls. There was no significant difference in the levels of the receptors in the groups which took the progestogen as advised.

Endometrium↗
PubMed1980

Levonorgestrel plasma concentrations and hormone profiles after insertion and after one year of treatment with a levonorgestrel-IUD.

Plasma concentrations of levonorgestrel, progesterone, estradiol, FSH and LH were measured in seven volunteers who had a levonorgestrel-releasing IUD inserted postmenstrually. Blood samples were collected twice weekly during a mean of 93 days immediately postmenstrually and during a mean of 41 days over the twelfth to fifteenth month of treatment. Patterns of bleeding were studied during the first year of treatment. The IUDs used were designed to release 25 micrograms/day of levonorgestrel. The mean +/- SD plasma concentration of levonorgestrel for all subjects during the first three months was 260 +/- 68 pg/ml, and 129 +/- 28 pg/ml after one year of treatment. During the initial period of blood sampling only two of the subjects ovulated, while only two did not ovulate after one year of treatment. Intermenstrual spotting occurred during the first sixty days of treatment. Three subjects developed amenorrhea at the end of the first year. All the subjects continued the use of the IUD and no pregnancies occurred.

Adult↗
PubMed1981

Studies on ovarian and adrenal steroids at different phases of the menstrual cycle: II. A comparative assessment of the circadian variation in steroid and lutropin levels during the follicular, periovulatory and luteal phases.

In six normally menstruating women, ovarian and adrenal steroids and biologically active lutropin (LH) were measured in peripheral plasma samples collected every 3 h. during a period of 39 h. in the early follicular phase, periovulatory period or luteal phase of three consecutive cycles. The purpose of the study was to assess the influence of the phases of the cycle on the diurnal variation in the levels of different steroids and lutropin following the elimination of the between subject variation. Cortisol, 17-hydroxypregnenolone, dehydroepiandrosterone and androstenedione showed a marked circadian rhythm in all three phases of the cycle. No changes in the levels of cortisol, 17-hydroxypregnenolone and dehydroepiandrosterone with the phase of the cycle were observed when the "morning" samples were considered; however, when the "evening" samples were analyzed, the levels of these steroids were higher in the luteal phase than in the follicular phase. As a result of this increase, the amplitude of the circadian rhythm of these steroids considerably decreased in the luteal phase. The "morning" as well as the "evening" increase observed in the levels of androstenedione during the periovulatory period was not able to mask the circadian rhythm. A circadian rhythm in pregnenolone, 17-hydroxyprogesterone, testosterone, and dihydrotestosterone levels was detected only in certain phases of the cycle. All these steroids showed a circadian rhythm in the early follicular phase. The rhythm of pregnenolone and 17-hydroxyprogesterone was still present in the periovulatory period but was no longer detectable in the luteal phase, meanwhile that of testosterone and dihydrotestosterone was not demonstrable neither in the periovulatory period nor in the luteal phase. Compared to the levels of the follicular phase, an increase in pregnenolone and 17-hydroxyprogesterone levels was observed in the periovulatory period which was followed by a further rise in the luteal phase. This increase completely masked the circadian rhythm in the luteal phase. An inverse circadian rhythm in lutropin levels was detected during the luteal phase. The "morning" values were lower than those found during the "evening" period. No such changes were observed in the other phases of the cycle. In none of the phases studied did the levels of progesterone or estradiol show any circadian variation. The data indicate that a circadian rhythm in the peripheral levels of a given steroid mainly depends on the relative contributions of the ovaries and adrenals and that these contributions exhibit major differences at the various phases of the cycles. It is concluded that - in contradistinction to the situation in the human male - in normally menstruating women, the peripheral levels of steroids of predominantly gonadal origin do not exhibit a circadian rhythmicity.

Adrenal Glands↗
PubMed1985

The interaction between sex hormone binding globulin and levonorgestrel released from vaginal rings in women.

The levels of levonorgestrel (L-NOG), progesterone and estradiol were measured in plasma samples of 17 normally menstruating women during a control cycle and during a subsequent period (90 days) with a L-NOG-releasing vaginal ring. During days 38-66 after the insertion of the vaginal ring the concentrations of sex hormone binding globulin binding sites (hereafter: SHBG levels) were also assayed. Significant correlations were found not only between the corresponding levels of SHBG and L-NOG during exposure to the latter compound (r = 0.44; P less than 0.05), but also between the levels of SHBG in the control cycle and the levels of L-NOG measured during exposure (r = 0.60; P less than 0.01). Furthermore, the decrease in SHBG levels during the vaginal administration of L-NOG was directly proportional to the levels of SHBG in the pretreatment cycle (r = 0.64; P less than 0.01). A significant relationship was found between the levels of L-NOG (and, hence - indirectly - the levels of SHBG) and the degree of suppression of ovarian function. Thus the levels of L-NOG were lower (P less than 0.01) in the subjects (n = 8) with an apparently normal or partially suppressed ovulatory-like pattern of progesterone than in those subjects (n = 9) in whom progesterone levels were completely suppressed.

Adult↗
PubMed1986

Abnormal endocrine profile among women with confirmed or presumed ovulation during long-term Norplant use.

FSH, LH, estradiol and progesterone were serially assayed during 8 cycles of six subjects using six subdermal implants releasing levonorgestrel (NORPLANT) for a period of 2 to 6 years. All 8 cycles studied had a very low LH peak and a low or nonexistent FSH peak as compared to 8 control cycles. The mean LH peak for NORPLANT users was 33.9 mIU/ml as compared to 142 mIU/ml in the control group; and FSH was 13.0 mIU/ml as compared to 31.3 mIU/ml in controls. A subsequent rise in progesterone was observed in the 8 cycles studied, but the mean mid-luteal levels were significantly lower than in controls (9.0 ng/ml vs. 15.6 ng/ml). No differences were observed in the estradiol curve. Two of the subjects using NORPLANT had a laparotomy performed on days 17 and 20 of the cycle, for surgical sterilization purposes. A distinctive corpus luteum with a stigma was observed. Our results indicate that women under prolonged use of NORPLANT do not have normal endocrine cycles, even though they may ovulate. It is doubtful however, that these ovulatory cycles can be fertile under the abnormal endocrine conditions found in our subjects. In addition to the possible effect of luteal insufficiency, the normal maturation of the oocyte may be impaired.

Adult↗
PubMed1987

Luteal contraception.

The impact of oral administration of RU 486 on the ongoing functional activity of the hypothalamic-gonadotropin-corpus luteum-endometrial (H-P-CL-E) axis was assessed during the mid-luteal (MLP) and the late-luteal phase (LLP) with and without hCG-induced pseudopregnancy. Longitudinal studies with daily dosing and frequent blood sampling were conducted during three consecutive cycles (control/treatment/recovery). During MLP, uterine bleeding occurred in all subjects within 36-72 h of the first dose of RU 486, but no histological changes were discernible on endometrial biopsy taken 12-24 h before bleeding. There was a significant decrease in LH secretion, pulse amplitude but not frequency. Response to GnRH on the last day of treatment was impaired. This was followed 3 days later by a rebound LH secretion lasting for 5 days. These events were accompanied by an initial decline of estradiol, but not progesterone, and a second peak of 5 days' duration for both estradiol and progesterone. Hence corpus luteum function was prolonged by 5 days, and second bleeding ensued following the spontaneous luteolysis. Recovery cycles were normal. During LLP, a single dose of RU 486 induced uterine bleeding in all cases. This was associated with a decreased LH pulse amplitude and frequency, and a faster decline of both estradiol and progesterone as compared to control cycles. Rescue of corpus luteum function by the administration of incremental doses of hCG failed to prevent the uterine bleeding after a single dose of RU 486. Recovery cycles were normal. While the antiprogesterone effect of RU 486 at the endometrial level was predictably expressed, its effects at the H-P-CL-E axis were also demonstrated. These findings provide important clues for the design of once-monthly contraceptive methods.

Abortifacient Agents, Steroidal↗
PubMed1989

Transdermal delivery of steroids.

The advantages of delivering drugs through the skin for systemic therapy have been widely recognized and represent a growing sector in drug development. Transdermal delivery of steroids is also a rapidly expanding field and in various clinical situations where hormonal replacement therapy is needed this route of administration is a real breakthrough, considering the relative toxicity of some steroids when given orally. Various transdermal systems have been designed, all of them aimed at achieving a constant release rate of the molecules contained in their reservoir through the intact skin. The skin itself, and especially the outermost layer, the stratum corneum, can play the roles of a reservoir and a rate-controlling membrane. So far, estradiol, progesterone and testosterone have been demonstrated to be good candidates for transdermal delivery. The effectiveness and the acceptability of transdermal delivery of estradiol in postmenopausal women have been demonstrated. The efficacy of topical administration of progesterone in patients with benign breast disease has also been proved. More recently, the high rate of acceptability and efficacy of transdermal testosterone in male hypogonadism has been demonstrated. The transdermal delivery of steroids is therefore expected to make a significant impact on the quality of patient care both in men and in women.

Administration, Cutaneous↗