The levonorgestrel intrauterine system: therapeutic aspects

Use of the levonorgestrel-releasing intrauterine system (LNG IUS) is associated with a strong reduction in the number of days of bleeding and menstrual blood loss. This effect is based on the marked local action of the intrauterine release of levonorgestrel (LNG) on the endometrium. In suppressed endometrium the production of many highly active compounds ceases. On the other hand, LNG stimulates the synthesis of some regulatory proteins in the endometrium. Reduction of menstrual blood loss results in improvement of the body iron balance and in an increase in hemoglobin concentration. The LNG IUS has been used in the prevention and treatment of iron deficiency anemia. Many studies have demonstrated that the LNG IUS is effective in the treatment of menorrhagia. Reduction of excessive blood loss is seen as soon as the first menstruation after insertion, and at 1 year the reduction is more than 90%. The therapeutic effect is maintained for more than 5 years after first placement of the LNG IUS in the uterine cavity. Correct insertion is essential, and complications and side effects are rare; fertility is preserved, and invasive procedures such as endometrial ablation or hysterectomy and hospitalization are avoided. The third major indication for therapeutic use is in protection of the endometrium in estrogen replacement therapy during peri- and postmenopausal years. A fundal position of the system in the uterine cavity results in reduction of bleeding, and an increasing number of women have no bleeding at all during use of the IUS. Acceptance and continuation of use of the LNG IUS in hormone replacement therapy (HRT) have been high.     

The use of progesterone antagonists and progesterone receptor modulators in contraception

Progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) have contraceptive potential by suppressing follicular development, delaying the surge of luteinizing hormone (LH), retarding endometrial maturation, and promoting endometrial bleeding. Mifepristone, in daily doses of 2-10 mg, blocks the LH surge and ovulation. Many of the studies were conducted in women not at risk of pregnancy, and thus the contraceptive efficacy is not yet known. Nevertheless, there is evidence that daily doses of 2 or 5 mg of mifepristone have contraceptive potential. Because of anovulation, there may be an unopposed estrogen effect on the endometrium, although this risk may be mitigated by the noncompetitive anti-estrogenic activity exhibited by both PAs and PRMs. Low doses of PAs and PRMs, which do not affect ovulation, retard endometrial maturation, indicating that the endometrium is exquisitely sensitive to these compounds. This raises the prospect of endometrial contraception, i.e. prevention of endometrial maturation without disturbing ovulation or producing alterations in bleeding patterns. This approach works well in monkeys but was not found to be very promising when given to women not using contraception. On the other hand, 200 mg mifepristone administered 48 h after the LH surge, which has minimal or no effect on ovulation and bleeding patterns, is an effective contraceptive; yet, it is not a practical approach to contraception. Late luteal phase administration of mifepristone produces menstrual bleeding. However, when mifepristone was administered every month at the end of the cycle either alone or together with prostaglandins, it was not very effective in preventing pregnancy. In contrast, a mifepristone-prostaglandin combination has been shown to be a very effective treatment for occasional menstrual regulation, with vaginal bleeding induced in 98% of pregnant women, with menses delay of 11 days or less. Mifepristone is an excellent agent for emergency contraception when used within 120 h of unprotected intercourse. It is also possible that PAs and PRMs may be used to reduce the occurrence of bleeding irregularities induced by progestin-only contraceptive methods. Both classes of progesterone receptor ligands may also have contraceptive efficacy by having a pharmacological effect on the embryo or altering tubal transport or other aspects of tubal physiology.     

Norethisterone contraceptive microspheres

Two formulations of polylactic and polyglycolic acid microcapsules containing 75 and 100 mg of NET respectively were studied for a 90-day period of anticipated contraceptive effect in two groups of five women. A 200 mg dose of NET preparation was also studied for a 180-day period of anticipated contraceptive effect in 19 women. Alteration in menstrual cycle, with tendency to short bleeding episodes, spotting days, and amenorrhea were the most important collateral effects. In the majority of cases, ovulation was inhibited. No cases of pregnancy were presented. The obtained NET circulating levels were very stable during the period of anticipated contraceptive effect.     

Subdermal contraceptive implants

Subdermal contraceptive implants involve the delivery of a steroid progestin from polymer capsules or rods placed under the skin. The hormone diffuses out slowly at a stable rate, providing contraceptive effectiveness for 1–5 years. The period of protection depends upon the specific progestin and the type of polymer. Advantages of progestin implants include long term contraceptive action without requiring the user's or provider's attention, low dose of highly effective contraception without the use of estrogen, and fertility is readily reversible after the removal of implants. The levonorgestrel implant Norplant R system is the only one that has been approved for distribution. The contraceptive efficacy of Norplant is the highest observed amongst the most effective methods with an annual pregnancy rate of 0.2 during the first and second year and 1.1 on the fifth year. Menstrual problems are the main reason for the discontinuation of Norplant and 9% of women stopped using it during the first year of treatment. Other implants are still under development trying to simplify the method by reducing the number of units and to introduce other progestins that may minimize side effects. Norplant-2 was designed to release the same dose of progestin from only two covered rods. Evaluation of 1400 women enrolled, indicates that over 2 years the cumulative pregnancy rate is below 0.5 per 100 women. There are three single implants under development: Nestorone, 3-Keto-desogestrel and Uniplant that are expected to be effective for 1–2 years. Phase II clinical trials with Nestorone have been completed and no pregnancies have been observed in 1570 woman-months of use. Bleeding irregularities occurred in 20–30% of the women but there were only four terminations because of bleeding problems. A multricentric study is ongoing with a newly designed 3-keto-desogestrel implant named Implanon, which releases approx. 60 μg/day of the hormone. The objectives of this study are to assess contraceptive efficacy, safety and acceptability of Implanon. Another multricentric study is ongoing with Uniplant, which releases nomegestrol acetate with a duration of action for only 1 year. The objectives of the trial are to study the endocrine profile of Uniplant users and to evaluate the efficacy and acceptability of the method.     

Efficacy of levonorgestrel when administered as an irradiated,slow‐release injectable matrix for feline contraception

Reliable and safe methods of reversible contraception are needed for use in zoo felids. The efficacy of levonorgestrel (LNG) as a contraceptive, when delivered as a cesium‐irradiated, slow‐release, injectable matrix, was tested in domestic cats as a model for exotic cats. An increase (P = 0.0017) in body weight was observed in treated but not control queens (P = 0.2146). All control queens (n = 6), which received injections of matrix only, but none of the LNG‐treated queens (n = 6) became pregnant during the trial. Levonorgestrel was effective in preventing pregnancy for at least 36 weeks after two injections of drug‐loaded formulations (40 mg/kg body weight), administered 68 days apart. Throughout the study, all control queens displayed luteal activity and fluctuating fecal estradiol concentrations, whereas the LNG‐treated queens displayed lower estradiol concentrations and no luteal activity after treatment. We conclude that LNG, when delivered as a cesium‐irradiated, slow‐release, injectable matrix, is an effective contraceptive in domestic cats, reducing follicular activity, and thus, preventing mating and luteal activity. Zoo Biol 20:407–421, 2001. © 2001 Wiley‐Liss, Inc.     

Vascular dysfunction as a cause of endometrial bleeding

Introduction.?Heavy menstrual bleeding (HMB) and the spotting and bleeding (S/B) associated with the use of hormonal contraceptives are distinct entities affecting endometrial vasculature and hemostasis. Materials and methods.?An overview of the major etiologies and potential treatments for each condition is provided. Results.?HMB is potentially caused by several different hemostatic dysfunctions. Combination oral contraceptives, levonorgestrel-releasing intrauterine system, non-steroidal anti-inflammatory drugs, and anti-fibrinolytics all have been shown to have some degree of efficacy in treating HMB. The basic cause of HMB is unknown in the majority of cases. Endometrial S/B related to hormonal contraceptives is a common occurrence and may well have a common etiology in altered angiogenesis resulting in abnormal blood vessels with fragile vessel walls. There is no effective treatment for this problem. Conclusions.?Medical therapy for HMB is limited and effective for reducing blood loss during menstruation. There is no effective treatment for the S/B associated with hormonal contraceptives.     

The use of long acting subcutaneous levonorgestrel (LNG) gel depot as an effective contraceptive option for cotton-top tamarins (Saguinus oedipus)

Cotton‐top tamarins (Saguinus oedipus) are a critically endangered species that have been bred successfully in captivity for many years. For two decades, the Cotton‐top Tamarin SSP^© has been challenged with a high rate of reproduction combined with a history of contraceptive failures and nonrecommended births using the current Depo Provera^® (medroxyprogesterone acetate) injection followed by MGA (melengestrol acetate) implant contraception combination. To address these issues we have developed and tested the use of levonorgestrel (LNG) as an effective contraception option for cotton‐top tamarins. LNG was delivered in an injectable, gel matrix consisting of polylactic‐co‐glycolic acid, triethyl citrate and N‐methylpyrrolidone. This gel matrix forms a biodegradable depot at the subcutaneous injection site providing slow release of the active ingredient. Gel matrix composition and LNG concentration were adjusted in four gel formulations to maximize the duration of contraceptive efficacy while minimizing immediate post‐injection increases in fecal LNG concentration. LNG treatment (68.44±8.61 mg/kg) successfully eliminated ovarian cycles (fecal pregnanediol‐3‐glucuronide (PdG) and estrone conjugates (E₁C)) for 198.8±70.3 days (formulation four; range 19–50 weeks). It was demonstrated that subcutaneous LNG depot injection was an effective, reversible contraceptive option for the management of cotton‐top tamarins in captivity. Zoo Biol 30:498–522, 2011. © 2010 Wiley Periodicals, Inc.     

Mifepristone for the prevention of breakthrough bleeding in new starters of depo-medroxyprogesterone acetate

Depo-medroxyprogesterone acetate (DMPA) is an effective injectable contraceptive with worldwide availability. However, it is associated with a high incidence of breakthrough bleeding (BTB) during the first 6 months of use which often leads to discontinuation. Mifepristone is a progesterone receptor antagonist that has been demonstrated to decrease BTB caused by the levonorgestrel subdermal implant (Norplant). The purpose of this study was to determine if mifepristone would decrease BTB in new starters of DMPA. Twenty regularly cycling women who were new starters of DMPA were randomized to receive 50 mg of mifepristone or placebo every 2 weeks for 24 weeks. Percent days of BTB and number of cycles with bleeding intervals > or =8 and > or =14 days were evaluated using daily bleeding diaries. Ovulation was determined by measuring thrice-weekly urinary metabolites of estrogen and progesterone. Endometrial concentrations of ER and PR were determined by immunohistochemistry. Mifepristone significantly decreased the percent days of BTB and the number of cycles with prolonged bleeding intervals when compared to placebo. No subject ovulated in either group. ER immunostaining increased and PR immunostaining decreased after mifepristone treatment. In conclusion, a 50 mg dose of mifepristone taken every 2 weeks decreases the incidence of BTB in new starters of DMPA. This effect may be due to modulation of endometrial estrogen and progesterone receptors.     

Pharmacokinetics of levonorgestrel in 18 women after 1 month of treatment with a triphasic oral contraceptive.

A triphasic levonorgestrel (LNG)- and ethinylestradiol-containing oral contraceptive was administered to 18 women. Plasma samples were obtained throughout a treatment cycle just before drug administration and on the last treatment day (day 21), several plasma samples were collected from each individual up to 48 h postadministration. LNG was determined by radioimmunoassay in all plasma samples. In addition, the concentration of sex-hormone-binding globulin (SHBG) was determined in plasma samples collected from the same subjects during treatment, as well as during a pre- and a posttreatment cycle. During the treatment cycle, plasma levels of LNG determined just before drug administration increased and reached steady state at about day 16. This increase was due to an increased dose of LNG according to the triphasic dose regimen, a concomitantly ethinylestradiol-induced increase in SHBG and due to pharmacokinetic accumulation, since LNG had a terminal half-life of approximately 28.5 h and the dosing interval was 24 h. Steady-state levels and pharmacokinetic parameters of LNG determined on the last day of treatment were in good accordance with previously published results.     

Inhibition of DNA synthesis in isolated human endometrial cells by a levonorgestrel-releasing intrauterine device

OBJECTIVE: To estimate the effect of an intrauterine device (IUD) releasing 20 micrograms levonorgestrel (LNG) per 24 hours on DNA synthesis in human endometrial cells before and after 12 months of use. STUDY DESIGN: Endometrial specimens were collected from the anterior or posterior wall of the miduterus from 6 females on cycle day 10-12 before insertion of the IUD and after 12 months of use. RESULTS: Previous results from our group did not reveal any influence on endometrial DNA cell content when a levonorgestrel IUD releasing 2 micrograms/24 h was used for 12 months in a group of fertile females. In this study, the IUD release rate, 20 micrograms LNG/24 h, was statistically significantly different from the results in the previous studies. The effect of the levonorgestrel IUD on endometrial proliferation was dose dependent, and a significant correlation could be found between continuous exposure to LNG and inhibition of DNA synthesis in endometrial cells. CONCLUSION: Inhibition of proliferative activity in endometrial cells seems to be reflected by a decrease in DNA synthesis per cell nucleus and contributes to the clinical performance of the LNG-releasing IUD.     

Biological characteristics of human menstrual blood‐derived endometrial stem cells

Successful isolation of human endometrial stem cells from menstrual blood, namely menstrual blood‐derived endometrial stem cells (MenSCs), has provided enticing alternative seed cells for stem cell‐based therapy. MenSCs are enriched in the self‐regenerative tissue, endometrium, which shed along the periodic menstrual blood and thus their acquisition involves no physical invasiveness. However, the impact of the storage duration of menstrual blood prior to stem cell isolation, the age of the donor, the number of passages on the self‐renewing of MenSCs, the paracrine production of biological factors in MenSCs and expression of adhesion molecules on MenSCs remain elusive. In this study, we confirmed that MenSCs reside in shedding endometrium, and documented that up to 3 days of storage at 4°C has little impact on MenSCs, while the age of the donor and the number of passages are negatively associated with proliferation capacity of MenSCs. Moreover, we found that MenSCs were actually immune‐privileged and projected no risk of tumour formation. Also, we documented a lung‐ and liver‐dominated, spleen‐ and kidney‐involved organic distribution profile of MenSC 3 days after intravenous transfer into mice. At last, we suggested that MenSCs may have potentially therapeutic effects on diseases through paracrine effect and immunomodulation.     

宫内节育器与宫腔支撑球囊联合应用治疗中重度宫腔粘连中的临床效果

摘要 目的：探讨宫内节育器与宫腔支撑球囊联合应用治疗中重度宫腔粘连的临床效果。方法：选择2016年12月至2019年8月于西安交通大学第一附属医院宫腔镜诊疗中心接受宫腔镜下中重度宫腔粘连分解术的患者共96例,采用随机对照表法将其分为两组。对照组48例,术后宫腔内放置宫内节育器(intrauterine contraceptive device,IUD);研究组48例,术后放置宫腔支撑球囊(intrauterine support balloon,ISB),3~5 d后更换为宫内节育器。两组术后均给予为期3月的人工周期治疗。术后1月,复查宫腔镜了解宫腔有无再粘连并取出宫内节育器,以此评估手术效果是否有效,术后3月时随访其月经来潮情况。统计比较两组术后5 d内阴道出血量、C反应蛋白水平、发热、下腹痛以及节育器或支持球囊有无脱落等情况,术后1月手术效果及术后3月月经恢复情况。结果：研究组的手术有效率及月经改善比例均显著高于对照组(P<0.05),术后5 d内阴道出血量显著少于对照组(P<0.05);下腹痛及球囊脱落事件发生率显著低于对照组(P<0.05)。两组在C反应蛋白水平、发热发生率对比无统计学差异(P>0.05)。结论：与单独使用宫内节育器相比,联合使用宫腔支撑球囊能提高中重度宫腔粘连分解手术有效率,改善月经,减少术后出血,不增加感染风险,但球囊易于脱落且会增加患者下腹疼痛。     

Endometrial vascular changes and bleeding disturbances with long-acting progestins

Unscheduled disturbances of bleeding with long-acting progestogen-only methods continue to be a major social inconvenience, and the most common reason for premature discontinuation of use. The patterns of bleeding with different methods are now well characterised, but in spite of a substantial amount of recent research we still do not clearly understand the actual mechanisms underlying these disturbances. The major changes occur locally within the endometrium, although these are influenced substantially by different dosages and regimens of contraceptive steroids. Hysteroscopic studies have demonstrated major changes in the extent of superficial endometrial vascularization, disturbances in superficial vascular morphology, and increased endometrial vascular and epithelial fragility in progestogen-only users. There may also be alterations in endometrial perfusion and vasomotion. Laboratory studies of cellular and molecular mechanisms have shown changes in vascular basement membranes, pericytes, migratory leukocytes, cellular architecture, cell adhesion molecules, and intercellular matrix breakdown systems, such as matrix metalloproteinases. It appears that continuous exposure to progestogen, in the presence of low to moderate levels of estrogen, results in an endometrium that histologically demonstrates 'suppressed secretory' changes, associated with disturbed angiogenesis, and a tendency to release molecules capable of causing focal endometrial epithelial and endothelial damage and bleeding.     

Progestin regulation of protein synthesis in endometrial cancer

Protein synthesis in cancerous and normal human endometrium was investigated by the incorporation of [35S]methionine and analysis of products by two-dimensional polyacrylamide gel electrophoresis. Comparison of the cellular products from organ cultures of endometrial carcinoma, obtained from each subject before and after in vivo administration of medroxyprogesterone acetate (MPA) for 10-14 days revealed: (i) a decrease in the synthesis of tubulin and of a protein of molecular weight (mol. wt) 68 kDa, isoelectric point (pI) 6.0, and (ii) an increase in the synthesis of creatine kinase (CK) and of protein of mol. wt 36 kDa, pI 4, following MPA therapy. The 68 kDa protein was expressed at relatively reduced levels in organ cultures of normal human endometrium throughout the menstrual cycle. In primary cultures of normal human endometrium throughout the menstrual cycle. In primary cultures from cancerous endometrium endometrium established for several weeks the 68 kDa protein was not expressed but could be induced by heatshock. Primary cultures were also used to investigate the early events following progesterone stimulation which revealed a decrease in synthesis of a protein mol. wt 36 kDa, pI 8 at 8 h following administration.     

左炔诺孕酮宫内节育系统联合桂枝茯苓胶囊对子宫腺肌症患者性激素、血脂及血清hs-CRP、VEGF水平的影响

摘要 目的：探讨左炔诺孕酮宫内节育系统联合桂枝茯苓胶囊对子宫腺肌症患者超敏C反应蛋白（hs-CRP）、性激素、血管内皮生长因子（VEGF）以及血脂的影响。方法：选取2016年4月~2019年8月期间我院接收的90例子宫腺肌症患者,按照随机数字表法分为对照组（45例,左炔诺孕酮宫内节育系统治疗）和研究组（45例,对照组的基础上联合桂枝茯苓胶囊治疗）,比较两组患者疗效、性激素、血脂、血清hs-CRP、VEGF水平、子宫内膜厚度、痛经视觉模拟评分法（VAS）评分以及不良反应。结果：治疗6个月后研究组临床总有效率较对照组高（P<0.05）。两组治疗6个月后卵泡刺激素（FSH）、hs-CRP、黄体生成素（LH）、VEGF水平以及子宫内膜厚度、痛经VAS评分均较治疗前下降,且研究组较对照组低（P<0.05）;雌二醇（E2）水平较治疗前升高,且研究组较对照组高（P<0.05）。两组治疗6个月后总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）水平对比未见统计学差异（P>0.05）。两组不良反应发生率对比无差异（P>0.05）。结论：左炔诺孕酮宫内节育系统联合桂枝茯苓胶囊治疗子宫腺肌症安全有效,可改善机体性激素、血清hs-CRP、VEGF水平及子宫内膜厚度,减轻痛经症状,且对机体血脂情况影响轻微。     

Life changes and menstrual discomfort.

The present study addressed the relationship between the accumulation of life changes and problems with menstruation. Female college students completed a Life Experiences Survey, which assesses desirable and undesirable life changes, and a menstruation questionnaire, which contains items relevant to menstrual discomfort and irregularity. Correlational analyses showed that undersirable life changes were correlated with reports of number of symptoms of menstrual discomfort, but not irregularity. Separate analyses among oral contraceptive users and nonusers showed that the relationship between life changes and menstrual discomfort occurred only among nonusers. A regression of contraceptive use, desirable life changes, and undersirable life changes on factors derived from the menstruation questionnaire indicated that undesirable life changes was the strongest predictor of menstrual problems.     

Wild fulvous fruit bats (Rousettus leschenaulti) exhibit human-like menstrual cycle

We investigated the menstrual cycle of wild fulvous fruit bats (Rousettus leschenaulti), focusing on changes in the endometrial and ovarian structure and pituitary and steroid hormones. The menstrual cycle lasts for 33 days in bats studied in their natural habitat and in captivity. Vaginal bleeding was restricted to a single day (Day 1). A preovulatory follicle was found in the ovary on Day 18 when the levels of LH and FSH reached their maxima, accompanied by a thickened endometrium. On Day 24, serum levels of progesterone and estradiol-17 were also maximal, and uterine glands increased in size. After that, the levels of progesterone dropped precipitously, leading to menstrual bleeding. Both the morphologic and hormonal changes observed in fulvous fruit bats during the menstrual cycle resemble similar changes in humans. Fulvous fruit bats may be useful nonprimate laboratory models to study menstruation and menstrual dysfunction.     

Evaluation of brain-derived neurotrophic factor in menstrual blood and its identification in human endometrium

The presence of high-affinity brain-derived neurotrophic factor receptor Trk B in mouse and in human fetal oocytes, together with the presence of neurotrophins in human follicular fluid suggests a paracrine role for brain-derived neurotrophic factor (BDNF) in female biology. This study aims to evaluate if BDNF is present and quantitatively determined in human menstrual blood and endometrium. Twenty-one women were studied and subdivided in two groups: A, 11 fertile women (27 ± 2 days cycle length) and B, 10 anovulatory women and/or women with inadequate luteal phase (36 ± 2 days cycle length). In fertile women menstrual BDNF levels was higher than plasma (679.3 ± 92.2 vs 301.9 ± 46.7 pg/ml p <0.001). Similarly, in Group B, BDNF in menstrual blood was higher than plasma (386.1 ± 85.2 vs 166.8 ± 24.1 pg/ml p < 0.001). Moreover, both menstrual and plasma BDNF concentrations in Group A were significantly higher respect to Group B (679.3 ± 92.2 vs 386.1 ± 85.2 pg/ml p < 0.001; 301.9 ± 46.7 vs 166.8 ± 24.1 pg/ml p < 0.001). Immunohistochemistry evidence of BDNF in endometrium, during follicular and luteal phase, was also shown. The detection of BDNF in the human menstrual blood and endometrium further supports the role of this neurotrophin in female reproductive function.     

Studying the Effects of Reproductive Hormones and Bacterial Vaginosis on the Glycome of Lavage Samples from the Cervicovaginal Cavity

The cervicovaginal fluid (CVF) coating the vaginal epithelium is an important immunological mediator, providing a barrier to infection. Glycosylation of CVF proteins, such as mucins, IgG and S-IgA, plays a critical role in their immunological functions. Although multiple factors, such as hormones and microflora, may influence glycosylation of the CVF, few studies have examined their impact on this important immunological fluid. Herein we analyzed the glycosylation of cervicovaginal lavage (CVL) samples collected from 165 women under different hormonal conditions including: (1) no contraceptive, post-menopausal, (2) no contraceptive, days 1-14 of the menstrual cycle, (3) no contraceptive, days 15-28 of the menstrual cycle, (4) combined-oral contraceptive pills for at least 6 months, (5) depo-medroxyprogesterone acetate (Depo-Provera) injections for at least 6 months, (6) levonorgestrel IUD for at least 1 month. Glycomic profiling was obtained using our lectin microarray system, a rapid method to analyze carbohydrate composition. Although some small effects were observed due to hormone levels, the major influence on the glycome was the presence of an altered bacterial cohort due to bacterial vaginosis (BV). Compared to normal women, samples from women with BV contained lower levels of sialic acid and high-mannose glycans in their CVL. The change in high mannose levels was unexpected and may be related to the increased risk of HIV-infection observed in women with BV, as high mannose receptors are a viral entry pathway. Changes in the glycome were also observed with hormonal contraceptive use, in a contraceptive-dependent manner. Overall, microflora had a greater impact on the glycome than hormonal levels, and both of these effects should be more closely examined in future studies given the importance of glycans in the innate immune system.     

Effects of menstrual cycle and oral contraceptive use on calf venous compliance

Numerous studies have shown that the female sex hormones estrogen and progesterone have multiple effects on the vasculature. Thus our goal was to investigate the effects of estrogen and progesterone on calf venous compliance by looking for cyclic changes during the early follicular, ovulatory, and midluteal phases of the menstrual cycle and during high and low hormone phases of oral contraceptive use. Additionally, we wanted to compare the venous compliance of normally menstruating women, oral contraceptive users, and men. We studied eight normally menstruating women (23 +/- 1 yr of age) during the early follicular, ovulatory, and midluteal phases of the menstrual cycle. Nine triphasic oral contraceptive users (21 +/- 1 yr of age) were studied during weeks of high and low hormone concentrations. Eight men (23 +/- 1 yr of age) were studied twice within 2-4 wk. With the use of venous occlusion plethysmography with mercury in-Silastic strain gauges, lower limb venous compliance was measured by inflating a venous collection cuff that was placed on the thigh to 60 mmHg for 8 min and then reducing the pressure to 0 mmHg at a rate of 1 mmHg/s. Venous compliance was calculated as the derivative of the pressure-volume curves. There were no differences between early follicular, ovulatory, and midluteal phases of the menstrual cycle or between high and low hormone phases of oral contraceptive use (P > 0.05). Male venous compliance was significantly greater than in normally menstruating women (P < 0.001) and oral contraceptive users (P < 0.002). These data support a sex difference but also suggest that venous compliance does not change with menstrual cycle phase or during the course of oral contraceptive use.